Technology can be used to enhance communication, increase patient safety, and improve overall patient care. For example, many physicians have arranged for remote access to medical records and established a unique system of communication via a patient access support portal. A patient portal is a secure online website that provides patients 24-hour, on-demand access to their health information. Patient portals, while popular and oftentimes quite helpful, are not without drawbacks. Communication by electronic means with your patient can be viewed by some as impersonal and can make patients less tolerant to what they perceive to be a mistake, error, or unwanted outcome. A decrease in face-to-face contact and communication with your patient also gives you less time to resolve any conflict or disagreement. While communication via a patient access support portal has the potential to free up medical staff for direct patient care, such communication also carries liability risk.

Patient access support portal

A physician’s legal responsibility to communicate in a timely and accurate manner does not change, irrespective of the form of communication. However, communication via a patient access portal does have some unique features that must be considered by the practitioner. Practitioners must remember that any communication via the patient portal creates a permanent record, which can and will be used in the event of litigation. For example, when responding to a patient inquiry about a specific complaint, treatment provided, or test result, it will be presumed that the physician had access to the patient’s full medical record and that the full record will be utilized in making a response. Accessing the patient’s chart will leave an audit trail that will provide what is known as metadata, which in the context of electronic medical records, is what allows technicians to verify that the patient record was accessed, and it provides details as to when, and for how long it was accessed. These records are frequently pursued in litigation, so you must understand that parties can often re-create an intricate and accurate timeline of events. While state courts are divided on the issue of whether metadata contained within electronic medical records is discoverable, recent federal court decisions have held that such data is discoverable pursuant to the Federal Rules of Civil Procedure. Thus, once a patient has communicated with you via the portal, you will be responsible for responding in an appropriate and prompt fashion. For these reasons, it is imperative that you create an agreement with your patients as to how the portal will be used and clearly set forth the rules for such use.

Patient portal policies and procedures

In creating patient portal user agreements (See "Sample User Agreement," attached below), it is crucial that an agreement clearly identify the policies and procedures for use. A patient portal user agreement should:

• Set forth the rules and regulations for portal use.
• Include a verification procedure that requires the patients to confirm that they have the legal capacity to consent to the terms of use. This is especially important when treating patients with mental disability, elderly patients with dementia, minors, and any other individuals who may not legally consent.
• Include a verification procedure that requires the patients to confirm that they understand and agree to abide by the user agreement rules.
• Include a detailed list that informs users of the risks and benefits of communicating via the patient portal.
• Stress that communication through the patient portal is for nonemergent matters only.
• Set forth permissible topics for use, such as communicating with the physician or staff, obtaining test results or records, and setting, changing, or canceling appointments.
• Clearly indicate certain topics that should not be discussed via the patient portal, including mental health issues.
• Reiterate that communication via the patient portal is only one option, and that all other standard methods of communication remain available. In doing so, provide office telephone numbers, hotlines, and email addresses for convenience.
• Inform the patients that they should call the office with any questions or concerns regarding use of the patient portal.
• Include a statement that the patient should call 911 or proceed directly to the nearest hospital for any and all urgent or emergent medical matters.

Other considerations

There are, however, equally critical considerations to be made that go beyond the core details of the user agreement. For instance, use of the patient access portal should be limited to only current or active patients, and you should stress to patients the importance of keeping their contact information updated and accurate. This is especially vital in situations in which a patient is unresponsive to communication via the portal, as your staff will need to follow up via other means of communication. It is also imperative to ensure the patient portal is programmed to promptly alert you or your staff following an inquiry from the patient as the patient will likely expect an immediate response.

Notably, communication via the patient portal must still comply with the Health Insurance Portability and Accountability Act (HIPAA). This means that only authorized users are able to access records within the patient portal. To ensure compliance with HIPAA, all users should be instructed in the appropriate practices of maintaining patient privacy. This includes barring the use of shared passwords amongst multiple individuals, requiring that users enable an auto log-off setting, and programming work stations to turn off automatically after brief periods of nonuse. Further, all communications in the patient portal should be encrypted to prevent the patient’s sensitive information from being accessed in the event of an attempted security breach.

Finally, depending upon the practice, there may be instances in which someone other than the patient’s physician would be reading and responding to patient queries. In these situations, the patient should be informed of such potential. This way, if the communication is intended only for the physician, the patient will be afforded the opportunity to call the physician directly rather than communicate via the patient portal.

While the use of patient access portals is becoming far more prevalent, as they offer many practical benefits ranging from increased convenience and efficiency to enhanced patient care, they also carry the potential for increased liability exposure. As such, it is vital that physicians weigh all potential risks and benefits that are inherent in the use of patient access portals prior to making the decision to implement such technology.

Mr. Mills is an equity partner in Cunningham, Meyer & Vedrine, Chicago.

Technology can be used to enhance communication, increase patient safety, and improve overall patient care. For example, many physicians have arranged for remote access to medical records and established a unique system of communication via a patient access support portal. A patient portal is a secure online website that provides patients 24-hour, on-demand access to their health information. Patient portals, while popular and oftentimes quite helpful, are not without drawbacks. Communication by electronic means with your patient can be viewed by some as impersonal and can make patients less tolerant to what they perceive to be a mistake, error, or unwanted outcome. A decrease in face-to-face contact and communication with your patient also gives you less time to resolve any conflict or disagreement. While communication via a patient access support portal has the potential to free up medical staff for direct patient care, such communication also carries liability risk.

Patient access support portal

A physician’s legal responsibility to communicate in a timely and accurate manner does not change, irrespective of the form of communication. However, communication via a patient access portal does have some unique features that must be considered by the practitioner. Practitioners must remember that any communication via the patient portal creates a permanent record, which can and will be used in the event of litigation. For example, when responding to a patient inquiry about a specific complaint, treatment provided, or test result, it will be presumed that the physician had access to the patient’s full medical record and that the full record will be utilized in making a response. Accessing the patient’s chart will leave an audit trail that will provide what is known as metadata, which in the context of electronic medical records, is what allows technicians to verify that the patient record was accessed, and it provides details as to when, and for how long it was accessed. These records are frequently pursued in litigation, so you must understand that parties can often re-create an intricate and accurate timeline of events. While state courts are divided on the issue of whether metadata contained within electronic medical records is discoverable, recent federal court decisions have held that such data is discoverable pursuant to the Federal Rules of Civil Procedure. Thus, once a patient has communicated with you via the portal, you will be responsible for responding in an appropriate and prompt fashion. For these reasons, it is imperative that you create an agreement with your patients as to how the portal will be used and clearly set forth the rules for such use.

Patient portal policies and procedures

In creating patient portal user agreements (See "Sample User Agreement," attached below), it is crucial that an agreement clearly identify the policies and procedures for use. A patient portal user agreement should:

• Set forth the rules and regulations for portal use.
• Include a verification procedure that requires the patients to confirm that they have the legal capacity to consent to the terms of use. This is especially important when treating patients with mental disability, elderly patients with dementia, minors, and any other individuals who may not legally consent.
• Include a verification procedure that requires the patients to confirm that they understand and agree to abide by the user agreement rules.
• Include a detailed list that informs users of the risks and benefits of communicating via the patient portal.
• Stress that communication through the patient portal is for nonemergent matters only.
• Set forth permissible topics for use, such as communicating with the physician or staff, obtaining test results or records, and setting, changing, or canceling appointments.
• Clearly indicate certain topics that should not be discussed via the patient portal, including mental health issues.
• Reiterate that communication via the patient portal is only one option, and that all other standard methods of communication remain available. In doing so, provide office telephone numbers, hotlines, and email addresses for convenience.
• Inform the patients that they should call the office with any questions or concerns regarding use of the patient portal.
• Include a statement that the patient should call 911 or proceed directly to the nearest hospital for any and all urgent or emergent medical matters.

Other considerations

There are, however, equally critical considerations to be made that go beyond the core details of the user agreement. For instance, use of the patient access portal should be limited to only current or active patients, and you should stress to patients the importance of keeping their contact information updated and accurate. This is especially vital in situations in which a patient is unresponsive to communication via the portal, as your staff will need to follow up via other means of communication. It is also imperative to ensure the patient portal is programmed to promptly alert you or your staff following an inquiry from the patient as the patient will likely expect an immediate response.

Notably, communication via the patient portal must still comply with the Health Insurance Portability and Accountability Act (HIPAA). This means that only authorized users are able to access records within the patient portal. To ensure compliance with HIPAA, all users should be instructed in the appropriate practices of maintaining patient privacy. This includes barring the use of shared passwords amongst multiple individuals, requiring that users enable an auto log-off setting, and programming work stations to turn off automatically after brief periods of nonuse. Further, all communications in the patient portal should be encrypted to prevent the patient’s sensitive information from being accessed in the event of an attempted security breach.

Finally, depending upon the practice, there may be instances in which someone other than the patient’s physician would be reading and responding to patient queries. In these situations, the patient should be informed of such potential. This way, if the communication is intended only for the physician, the patient will be afforded the opportunity to call the physician directly rather than communicate via the patient portal.

While the use of patient access portals is becoming far more prevalent, as they offer many practical benefits ranging from increased convenience and efficiency to enhanced patient care, they also carry the potential for increased liability exposure. As such, it is vital that physicians weigh all potential risks and benefits that are inherent in the use of patient access portals prior to making the decision to implement such technology.

Mr. Mills is an equity partner in Cunningham, Meyer & Vedrine, Chicago.

Technology can be used to enhance communication, increase patient safety, and improve overall patient care. For example, many physicians have arranged for remote access to medical records and established a unique system of communication via a patient access support portal. A patient portal is a secure online website that provides patients 24-hour, on-demand access to their health information. Patient portals, while popular and oftentimes quite helpful, are not without drawbacks. Communication by electronic means with your patient can be viewed by some as impersonal and can make patients less tolerant to what they perceive to be a mistake, error, or unwanted outcome. A decrease in face-to-face contact and communication with your patient also gives you less time to resolve any conflict or disagreement. While communication via a patient access support portal has the potential to free up medical staff for direct patient care, such communication also carries liability risk.

Patient access support portal

A physician’s legal responsibility to communicate in a timely and accurate manner does not change, irrespective of the form of communication. However, communication via a patient access portal does have some unique features that must be considered by the practitioner. Practitioners must remember that any communication via the patient portal creates a permanent record, which can and will be used in the event of litigation. For example, when responding to a patient inquiry about a specific complaint, treatment provided, or test result, it will be presumed that the physician had access to the patient’s full medical record and that the full record will be utilized in making a response. Accessing the patient’s chart will leave an audit trail that will provide what is known as metadata, which in the context of electronic medical records, is what allows technicians to verify that the patient record was accessed, and it provides details as to when, and for how long it was accessed. These records are frequently pursued in litigation, so you must understand that parties can often re-create an intricate and accurate timeline of events. While state courts are divided on the issue of whether metadata contained within electronic medical records is discoverable, recent federal court decisions have held that such data is discoverable pursuant to the Federal Rules of Civil Procedure. Thus, once a patient has communicated with you via the portal, you will be responsible for responding in an appropriate and prompt fashion. For these reasons, it is imperative that you create an agreement with your patients as to how the portal will be used and clearly set forth the rules for such use.

Patient portal policies and procedures

In creating patient portal user agreements (See "Sample User Agreement," attached below), it is crucial that an agreement clearly identify the policies and procedures for use. A patient portal user agreement should:

• Set forth the rules and regulations for portal use.
• Include a verification procedure that requires the patients to confirm that they have the legal capacity to consent to the terms of use. This is especially important when treating patients with mental disability, elderly patients with dementia, minors, and any other individuals who may not legally consent.
• Include a verification procedure that requires the patients to confirm that they understand and agree to abide by the user agreement rules.
• Include a detailed list that informs users of the risks and benefits of communicating via the patient portal.
• Stress that communication through the patient portal is for nonemergent matters only.
• Set forth permissible topics for use, such as communicating with the physician or staff, obtaining test results or records, and setting, changing, or canceling appointments.
• Clearly indicate certain topics that should not be discussed via the patient portal, including mental health issues.
• Reiterate that communication via the patient portal is only one option, and that all other standard methods of communication remain available. In doing so, provide office telephone numbers, hotlines, and email addresses for convenience.
• Inform the patients that they should call the office with any questions or concerns regarding use of the patient portal.
• Include a statement that the patient should call 911 or proceed directly to the nearest hospital for any and all urgent or emergent medical matters.

Other considerations

There are, however, equally critical considerations to be made that go beyond the core details of the user agreement. For instance, use of the patient access portal should be limited to only current or active patients, and you should stress to patients the importance of keeping their contact information updated and accurate. This is especially vital in situations in which a patient is unresponsive to communication via the portal, as your staff will need to follow up via other means of communication. It is also imperative to ensure the patient portal is programmed to promptly alert you or your staff following an inquiry from the patient as the patient will likely expect an immediate response.

Notably, communication via the patient portal must still comply with the Health Insurance Portability and Accountability Act (HIPAA). This means that only authorized users are able to access records within the patient portal. To ensure compliance with HIPAA, all users should be instructed in the appropriate practices of maintaining patient privacy. This includes barring the use of shared passwords amongst multiple individuals, requiring that users enable an auto log-off setting, and programming work stations to turn off automatically after brief periods of nonuse. Further, all communications in the patient portal should be encrypted to prevent the patient’s sensitive information from being accessed in the event of an attempted security breach.

Finally, depending upon the practice, there may be instances in which someone other than the patient’s physician would be reading and responding to patient queries. In these situations, the patient should be informed of such potential. This way, if the communication is intended only for the physician, the patient will be afforded the opportunity to call the physician directly rather than communicate via the patient portal.

While the use of patient access portals is becoming far more prevalent, as they offer many practical benefits ranging from increased convenience and efficiency to enhanced patient care, they also carry the potential for increased liability exposure. As such, it is vital that physicians weigh all potential risks and benefits that are inherent in the use of patient access portals prior to making the decision to implement such technology.

Mr. Mills is an equity partner in Cunningham, Meyer & Vedrine, Chicago.

Vitamin D supplementation alone does not appear to reduce the risk of fracture, but a combination of vitamin D and calcium may, according to a systematic review and meta-analysis published in JAMA Network Open.

Pang Yao, PhD, from the Nuffield Department of Population Health at the University of Oxford (England) and coauthors wrote that, while randomized, controlled trials (RCTs) of vitamin D supplements – either alone or in combination with calcium supplementation – have found conflicting results, most only had limited power to detect differences in the risk of fracture.

Dr. Yao and associates performed a meta-analysis of 11 observational studies with 39,141 participants, 11 RCTs of vitamin D supplementation alone in 34,243 participants, and 6 RCTs of calcium plus vitamin D involving 49,282 participants.

The analysis of the observational studies revealed that each 10.0-ng/mL increase in blood 25-hydroxyvitamin D concentrations was associated with a 7% lower risk of any fracture. However the authors noted significant heterogeneity between individual studies.

The meta-analysis of the 11 trials of vitamin D alone found that supplementation was not associated with significant change in the risk for any fracture or for hip fracture. Even subgroup analyses looking at age, residential status, location, study design, daily supplementation, or duration of supplementation failed to find any effect. However, there was a median difference in blood 25-hydroxyvitamin D concentrations of 8.4 ng/mL with vitamin D supplementation.

In the meta-analysis of the six vitamin D plus calcium trials, there was a significant 6% reduction in the rate of any fracture and a 16% reduction in hip fracture rate with supplementation. Overall, there was a 1% reduction in the risk of any fracture for each 0.4-ng/mL difference in blood 25-hydroxyvitamin D concentration and 2% reduction in the risk of hip fracture.

However, the authors judged five of those six vitamin D plus calcium trials to be at high risk of bias, with two having open-label designs, although there was little heterogeneity among the studies. All the trials used either 800 or 400 IU/day of vitamin D and 1,200 or 800 mg/day of calcium, and the mean duration of treatment was 5.9 years.

Participants aged 80 years or older living in institutions showed greater reductions in the risk of any fracture with calcium plus vitamin D supplementation, compared with those younger than 80 years who were living in the community.

“In this systematic review and meta-analysis, the available evidence from completed RCTs provided no support for the effects of vitamin D alone on prevention of fracture, but most of these RCTs were constrained by methodological problems,” they wrote. “Meta-analyses of ongoing RCTs assessing the effects of higher daily doses of vitamin D on fracture risk are needed before making recommendations on the use of vitamin D for prevention of fracture.”

One author was supported by a Sino-British Fellowship Trust scholarship, and another received grants from the U.K. Medical Research Council. No conflicts of interest were declared.

SOURCE: Yao P et al. JAMA Netw Open. 2019. doi: 10.1001/jamanetworkopen.2019.17789.

Vitamin D supplementation alone does not appear to reduce the risk of fracture, but a combination of vitamin D and calcium may, according to a systematic review and meta-analysis published in JAMA Network Open.

Pang Yao, PhD, from the Nuffield Department of Population Health at the University of Oxford (England) and coauthors wrote that, while randomized, controlled trials (RCTs) of vitamin D supplements – either alone or in combination with calcium supplementation – have found conflicting results, most only had limited power to detect differences in the risk of fracture.

Dr. Yao and associates performed a meta-analysis of 11 observational studies with 39,141 participants, 11 RCTs of vitamin D supplementation alone in 34,243 participants, and 6 RCTs of calcium plus vitamin D involving 49,282 participants.

The analysis of the observational studies revealed that each 10.0-ng/mL increase in blood 25-hydroxyvitamin D concentrations was associated with a 7% lower risk of any fracture. However the authors noted significant heterogeneity between individual studies.

The meta-analysis of the 11 trials of vitamin D alone found that supplementation was not associated with significant change in the risk for any fracture or for hip fracture. Even subgroup analyses looking at age, residential status, location, study design, daily supplementation, or duration of supplementation failed to find any effect. However, there was a median difference in blood 25-hydroxyvitamin D concentrations of 8.4 ng/mL with vitamin D supplementation.

In the meta-analysis of the six vitamin D plus calcium trials, there was a significant 6% reduction in the rate of any fracture and a 16% reduction in hip fracture rate with supplementation. Overall, there was a 1% reduction in the risk of any fracture for each 0.4-ng/mL difference in blood 25-hydroxyvitamin D concentration and 2% reduction in the risk of hip fracture.

However, the authors judged five of those six vitamin D plus calcium trials to be at high risk of bias, with two having open-label designs, although there was little heterogeneity among the studies. All the trials used either 800 or 400 IU/day of vitamin D and 1,200 or 800 mg/day of calcium, and the mean duration of treatment was 5.9 years.

Participants aged 80 years or older living in institutions showed greater reductions in the risk of any fracture with calcium plus vitamin D supplementation, compared with those younger than 80 years who were living in the community.

“In this systematic review and meta-analysis, the available evidence from completed RCTs provided no support for the effects of vitamin D alone on prevention of fracture, but most of these RCTs were constrained by methodological problems,” they wrote. “Meta-analyses of ongoing RCTs assessing the effects of higher daily doses of vitamin D on fracture risk are needed before making recommendations on the use of vitamin D for prevention of fracture.”

One author was supported by a Sino-British Fellowship Trust scholarship, and another received grants from the U.K. Medical Research Council. No conflicts of interest were declared.

SOURCE: Yao P et al. JAMA Netw Open. 2019. doi: 10.1001/jamanetworkopen.2019.17789.

Vitamin D supplementation alone does not appear to reduce the risk of fracture, but a combination of vitamin D and calcium may, according to a systematic review and meta-analysis published in JAMA Network Open.

Pang Yao, PhD, from the Nuffield Department of Population Health at the University of Oxford (England) and coauthors wrote that, while randomized, controlled trials (RCTs) of vitamin D supplements – either alone or in combination with calcium supplementation – have found conflicting results, most only had limited power to detect differences in the risk of fracture.

Dr. Yao and associates performed a meta-analysis of 11 observational studies with 39,141 participants, 11 RCTs of vitamin D supplementation alone in 34,243 participants, and 6 RCTs of calcium plus vitamin D involving 49,282 participants.

The analysis of the observational studies revealed that each 10.0-ng/mL increase in blood 25-hydroxyvitamin D concentrations was associated with a 7% lower risk of any fracture. However the authors noted significant heterogeneity between individual studies.

The meta-analysis of the 11 trials of vitamin D alone found that supplementation was not associated with significant change in the risk for any fracture or for hip fracture. Even subgroup analyses looking at age, residential status, location, study design, daily supplementation, or duration of supplementation failed to find any effect. However, there was a median difference in blood 25-hydroxyvitamin D concentrations of 8.4 ng/mL with vitamin D supplementation.

In the meta-analysis of the six vitamin D plus calcium trials, there was a significant 6% reduction in the rate of any fracture and a 16% reduction in hip fracture rate with supplementation. Overall, there was a 1% reduction in the risk of any fracture for each 0.4-ng/mL difference in blood 25-hydroxyvitamin D concentration and 2% reduction in the risk of hip fracture.

However, the authors judged five of those six vitamin D plus calcium trials to be at high risk of bias, with two having open-label designs, although there was little heterogeneity among the studies. All the trials used either 800 or 400 IU/day of vitamin D and 1,200 or 800 mg/day of calcium, and the mean duration of treatment was 5.9 years.

Participants aged 80 years or older living in institutions showed greater reductions in the risk of any fracture with calcium plus vitamin D supplementation, compared with those younger than 80 years who were living in the community.

“In this systematic review and meta-analysis, the available evidence from completed RCTs provided no support for the effects of vitamin D alone on prevention of fracture, but most of these RCTs were constrained by methodological problems,” they wrote. “Meta-analyses of ongoing RCTs assessing the effects of higher daily doses of vitamin D on fracture risk are needed before making recommendations on the use of vitamin D for prevention of fracture.”

One author was supported by a Sino-British Fellowship Trust scholarship, and another received grants from the U.K. Medical Research Council. No conflicts of interest were declared.

SOURCE: Yao P et al. JAMA Netw Open. 2019. doi: 10.1001/jamanetworkopen.2019.17789.

A new study has found that although dose escalation is common in RA patients being treated with infliximab, the low price of infliximab biosimilars that are currently commercially available in the United States often outweighs switching to a similarly administered tumor necrosis factor inhibitor with no biosimilar, such as intravenous golimumab (Simponi).

anttohoho/Thinkstock

“Given the 21% lower average sales price [ASP] of biosimilar infliximab-dyyb [Inflectra], as compared to the ASP of bio-originator infliximab, in Q3 2019, even infliximab dose[d] at 8 mg/kg [every] 6 weeks should be approximately neutral or cost saving, compared to golimumab IV,” wrote Jeffrey R. Curtis, MD, of the University of Alabama at Birmingham, and coauthors. The study was published in Arthritis Research & Therapy.

To determine if and when dose escalation of an infliximab biosimilar might offset the cost savings of its use, the researchers launched a cohort study of Medicare enrollees with RA who began treatment in 2013 (when intravenous golimumab first went on the market) through the end of 2016 (biosimilar infliximab-dyyb was first marketed in the United States in November 2016). They analyzed dose escalations and reimbursement amounts through 78 weeks for 5,174 patients who started infliximab and 2,843 patients who started golimumab. The golimumab patients were slightly older (70 years vs. 68.6 years) and more likely to receive monotherapy.

After 18 months, 5% of golimumab patients increased their dose, compared with 49% of infliximab patients (P less than .0001). Of patients who had no gap in infliximab treatment for greater than 10 weeks (n = 1,380), 72% had their dose escalated. Characteristics associated with dose escalation included being younger, being male, and not having chronic pulmonary disease. Physicians who owned their own infusion centers were 25% more likely to escalate doses of infliximab (adjusted odds ratio, 1.25; 95% confidence interval, 1.09-1.44).

Mean costs paid by Medicare for the first 18 months of treatment were significantly higher for golimumab ($28,146; 95% CI, $27,497-$28,810), compared with infliximab ($21,216; 95% CI, $20,737-$21,706). An analysis of patients who persisted on therapy for all 18 months with no treatment gap greater than 10 weeks revealed an even greater disparity in cost: $43,940 for golimumab (95% CI, $42,849-$45,058) versus $34,671 for infliximab (95% CI, $33,891-$35,470).

According to a sensitivity analysis, 34% of infliximab-treated patients increased their dose to 5 mg/kg, 5% increased their dose to 8 mg/kg, and 4% increased their dose to 10 mg/kg. In a modeling scenario that considered cost, dose, and frequency, infliximab at 8 mg/kg dosed every 6 weeks was cheaper than golimumab with a biosimilar discount of greater than 25%. At 10 mg/kg dosed every 6 weeks, infliximab was cheaper than golimumab with a biosimilar discount of 30% or more.

That said, given comparable clinical outcomes with other RA biologics plus the increased indirect costs and greater risk of serious infections associated with infliximab dose escalation, the researchers noted that “escalation beyond 5 mg/kg is probably not a prudent course of treatment for most RA patients, compared to switching to alternative treatment options.”

Though they emphasized their study’s strengths – including the impressive sample size of older Medicare patients – the authors also acknowledged its limitations, such as a lack of information on the clinical reasons for treatment discontinuation and dose escalation. They also were not able to examine whether safety or tolerability played a role in patients’ treatment decisions.

Two of the four authors reported receiving research grants and consulting fees from various medical and pharmaceutical companies, and one other author reported owning stock in Amgen.

SOURCE: Curtis JR et al. Arthritis Res Ther. 2019 Dec 12. doi: 10.1186/s13075-019-2022-8.

A new study has found that although dose escalation is common in RA patients being treated with infliximab, the low price of infliximab biosimilars that are currently commercially available in the United States often outweighs switching to a similarly administered tumor necrosis factor inhibitor with no biosimilar, such as intravenous golimumab (Simponi).

anttohoho/Thinkstock

“Given the 21% lower average sales price [ASP] of biosimilar infliximab-dyyb [Inflectra], as compared to the ASP of bio-originator infliximab, in Q3 2019, even infliximab dose[d] at 8 mg/kg [every] 6 weeks should be approximately neutral or cost saving, compared to golimumab IV,” wrote Jeffrey R. Curtis, MD, of the University of Alabama at Birmingham, and coauthors. The study was published in Arthritis Research & Therapy.

To determine if and when dose escalation of an infliximab biosimilar might offset the cost savings of its use, the researchers launched a cohort study of Medicare enrollees with RA who began treatment in 2013 (when intravenous golimumab first went on the market) through the end of 2016 (biosimilar infliximab-dyyb was first marketed in the United States in November 2016). They analyzed dose escalations and reimbursement amounts through 78 weeks for 5,174 patients who started infliximab and 2,843 patients who started golimumab. The golimumab patients were slightly older (70 years vs. 68.6 years) and more likely to receive monotherapy.

After 18 months, 5% of golimumab patients increased their dose, compared with 49% of infliximab patients (P less than .0001). Of patients who had no gap in infliximab treatment for greater than 10 weeks (n = 1,380), 72% had their dose escalated. Characteristics associated with dose escalation included being younger, being male, and not having chronic pulmonary disease. Physicians who owned their own infusion centers were 25% more likely to escalate doses of infliximab (adjusted odds ratio, 1.25; 95% confidence interval, 1.09-1.44).

Mean costs paid by Medicare for the first 18 months of treatment were significantly higher for golimumab ($28,146; 95% CI, $27,497-$28,810), compared with infliximab ($21,216; 95% CI, $20,737-$21,706). An analysis of patients who persisted on therapy for all 18 months with no treatment gap greater than 10 weeks revealed an even greater disparity in cost: $43,940 for golimumab (95% CI, $42,849-$45,058) versus $34,671 for infliximab (95% CI, $33,891-$35,470).

According to a sensitivity analysis, 34% of infliximab-treated patients increased their dose to 5 mg/kg, 5% increased their dose to 8 mg/kg, and 4% increased their dose to 10 mg/kg. In a modeling scenario that considered cost, dose, and frequency, infliximab at 8 mg/kg dosed every 6 weeks was cheaper than golimumab with a biosimilar discount of greater than 25%. At 10 mg/kg dosed every 6 weeks, infliximab was cheaper than golimumab with a biosimilar discount of 30% or more.

That said, given comparable clinical outcomes with other RA biologics plus the increased indirect costs and greater risk of serious infections associated with infliximab dose escalation, the researchers noted that “escalation beyond 5 mg/kg is probably not a prudent course of treatment for most RA patients, compared to switching to alternative treatment options.”

Though they emphasized their study’s strengths – including the impressive sample size of older Medicare patients – the authors also acknowledged its limitations, such as a lack of information on the clinical reasons for treatment discontinuation and dose escalation. They also were not able to examine whether safety or tolerability played a role in patients’ treatment decisions.

Two of the four authors reported receiving research grants and consulting fees from various medical and pharmaceutical companies, and one other author reported owning stock in Amgen.

SOURCE: Curtis JR et al. Arthritis Res Ther. 2019 Dec 12. doi: 10.1186/s13075-019-2022-8.

A new study has found that although dose escalation is common in RA patients being treated with infliximab, the low price of infliximab biosimilars that are currently commercially available in the United States often outweighs switching to a similarly administered tumor necrosis factor inhibitor with no biosimilar, such as intravenous golimumab (Simponi).

anttohoho/Thinkstock

“Given the 21% lower average sales price [ASP] of biosimilar infliximab-dyyb [Inflectra], as compared to the ASP of bio-originator infliximab, in Q3 2019, even infliximab dose[d] at 8 mg/kg [every] 6 weeks should be approximately neutral or cost saving, compared to golimumab IV,” wrote Jeffrey R. Curtis, MD, of the University of Alabama at Birmingham, and coauthors. The study was published in Arthritis Research & Therapy.

To determine if and when dose escalation of an infliximab biosimilar might offset the cost savings of its use, the researchers launched a cohort study of Medicare enrollees with RA who began treatment in 2013 (when intravenous golimumab first went on the market) through the end of 2016 (biosimilar infliximab-dyyb was first marketed in the United States in November 2016). They analyzed dose escalations and reimbursement amounts through 78 weeks for 5,174 patients who started infliximab and 2,843 patients who started golimumab. The golimumab patients were slightly older (70 years vs. 68.6 years) and more likely to receive monotherapy.

After 18 months, 5% of golimumab patients increased their dose, compared with 49% of infliximab patients (P less than .0001). Of patients who had no gap in infliximab treatment for greater than 10 weeks (n = 1,380), 72% had their dose escalated. Characteristics associated with dose escalation included being younger, being male, and not having chronic pulmonary disease. Physicians who owned their own infusion centers were 25% more likely to escalate doses of infliximab (adjusted odds ratio, 1.25; 95% confidence interval, 1.09-1.44).

Mean costs paid by Medicare for the first 18 months of treatment were significantly higher for golimumab ($28,146; 95% CI, $27,497-$28,810), compared with infliximab ($21,216; 95% CI, $20,737-$21,706). An analysis of patients who persisted on therapy for all 18 months with no treatment gap greater than 10 weeks revealed an even greater disparity in cost: $43,940 for golimumab (95% CI, $42,849-$45,058) versus $34,671 for infliximab (95% CI, $33,891-$35,470).

According to a sensitivity analysis, 34% of infliximab-treated patients increased their dose to 5 mg/kg, 5% increased their dose to 8 mg/kg, and 4% increased their dose to 10 mg/kg. In a modeling scenario that considered cost, dose, and frequency, infliximab at 8 mg/kg dosed every 6 weeks was cheaper than golimumab with a biosimilar discount of greater than 25%. At 10 mg/kg dosed every 6 weeks, infliximab was cheaper than golimumab with a biosimilar discount of 30% or more.

That said, given comparable clinical outcomes with other RA biologics plus the increased indirect costs and greater risk of serious infections associated with infliximab dose escalation, the researchers noted that “escalation beyond 5 mg/kg is probably not a prudent course of treatment for most RA patients, compared to switching to alternative treatment options.”

Though they emphasized their study’s strengths – including the impressive sample size of older Medicare patients – the authors also acknowledged its limitations, such as a lack of information on the clinical reasons for treatment discontinuation and dose escalation. They also were not able to examine whether safety or tolerability played a role in patients’ treatment decisions.

Two of the four authors reported receiving research grants and consulting fees from various medical and pharmaceutical companies, and one other author reported owning stock in Amgen.

SOURCE: Curtis JR et al. Arthritis Res Ther. 2019 Dec 12. doi: 10.1186/s13075-019-2022-8.

SAN ANTONIO – For detection of genomic aberrations in patients with advanced breast cancer, sensitivity of circulating tumor DNA (ctDNA) testing is effectively equivalent to that of tumor tissue sequencing, based on results of the plasmaMATCH trial.

Will Pass/MDedge News

When plasma and tumor tissue samples were collected within 60 days of one another, sensitivity of ctDNA testing was 98% for digital droplet PCR (ddPCR) and 100% for targeted sequencing with Guardant360, reported lead author Belinda Kingston, MB, ChB, of The Institute of Cancer Research, London.

In addition to analyzing ctDNA accuracy, Dr. Kingston and colleagues explored characteristics of genomic alterations in relation to one another and to disease subtypes.

“We have defined the genomic landscape of advanced breast cancer using ctDNA analysis,” Dr. Kingston said during a presentation at the San Antonio Breast Cancer Symposium.

The open-label plasmaMATCH trial, conducted at multiple centers in the United Kingdom, involved more than 1,000 patients with advanced breast cancer. The present analysis included 1,025 patients who underwent ctDNA testing via ddPCR, which screened for alterations in PIK3CA, ESR1, AKT1, and ERBB2. Eight hundred patients also underwent ctDNA testing with Guardant360 targeted sequencing (a 73-gene panel), while 77 patients additionally had tumor tissue sequencing performed on a fresh or frozen sample of metastatic tissue (a 16-gene panel).

Results showed that individual gene level agreement between the two ctDNA techniques ranged from 96% to 99% with kappa scores of at least 0.89. As described above, sensitivity of these tests, compared with tumor tissue sequencing, approached 100%.

Following this overview of diagnostic accuracy, Dr. Kingston described a series of genomic trends, focusing first on targetable alterations.

Both ctDNA techniques revealed that ESR1 mutations were common in cases of hormone receptor (HR)-positive disease, including approximately 40% of patients with HER2-negative breast cancer and approximately 20% of patients with HER2-positive breast cancer. In contrast, ESR1 mutations were found in less than 1% of patients with HR-negative disease. Although ERBB2 amplification was predominantly found in patients with HER2-positive breast cancer, this alteration was found in 1%-2% of patients with HER2-negative disease.

For the remainder of the presentation, Dr. Kingston focused on ctDNA targeted sequencing data.

Within this cohort of 800 participants, 92.9% of patients had a ctDNA alteration. The mean number of pathogenic alterations was 2.7; Dr. Kingston noted that, on average, patients with HR-positive, HER2-negative disease had significantly more alterations than did those with triple-negative breast cancer (3.0 vs 1.8; P less than .0001).

“We found that specific genes are enriched in certain breast cancer subtypes,” Dr. Kingston said, pointing out the “notable” rate of ERBB2 mutations (14%) in HER2-amplified disease.

Among patients with HR-positive disease, those who were HER2-negative often had ESR1 and KRAS mutations, whereas those with HER2-positive disease often had ESR1 mutations but not KRAS mutations.

Heterogeneity analysis showed that alterations in certain genes were clonally dominant, including AKT1, PIK3CA, GATA3, and TP53, while others were more often subclonal, including ESR1, RB1, SMAD4, and KRAS.

A closer look at frequency of alterations showed that AKT1, CDH1, and GATA3 were typically found as the only gene alteration present; in contrast, ESR1 alterations were often accompanied by multiple other gene hits.

Returning to targetable genes, the investigators found that there was significant variation in clonal dominance of pathogenic mutations in ESR1 and PIK3CA. A deeper analysis revealed that PIK3CA mutations were often double mutations in HR-positive disease, and that subclonal second mutations were found at APOBEC mutagenesis sites.

Carlos Arteaga, MD, of the University of Texas Southwestern Medical Center, Dallas, commented on the findings after the presentation and asked Dr. Kingston about a potential blind spot in the data.

Will Pass/MDedge News

SOURCE: Kingston et al. SABCS. 2019 Abstract GS3-07.

SAN ANTONIO – For detection of genomic aberrations in patients with advanced breast cancer, sensitivity of circulating tumor DNA (ctDNA) testing is effectively equivalent to that of tumor tissue sequencing, based on results of the plasmaMATCH trial.

Will Pass/MDedge News

When plasma and tumor tissue samples were collected within 60 days of one another, sensitivity of ctDNA testing was 98% for digital droplet PCR (ddPCR) and 100% for targeted sequencing with Guardant360, reported lead author Belinda Kingston, MB, ChB, of The Institute of Cancer Research, London.

In addition to analyzing ctDNA accuracy, Dr. Kingston and colleagues explored characteristics of genomic alterations in relation to one another and to disease subtypes.

“We have defined the genomic landscape of advanced breast cancer using ctDNA analysis,” Dr. Kingston said during a presentation at the San Antonio Breast Cancer Symposium.

The open-label plasmaMATCH trial, conducted at multiple centers in the United Kingdom, involved more than 1,000 patients with advanced breast cancer. The present analysis included 1,025 patients who underwent ctDNA testing via ddPCR, which screened for alterations in PIK3CA, ESR1, AKT1, and ERBB2. Eight hundred patients also underwent ctDNA testing with Guardant360 targeted sequencing (a 73-gene panel), while 77 patients additionally had tumor tissue sequencing performed on a fresh or frozen sample of metastatic tissue (a 16-gene panel).

Results showed that individual gene level agreement between the two ctDNA techniques ranged from 96% to 99% with kappa scores of at least 0.89. As described above, sensitivity of these tests, compared with tumor tissue sequencing, approached 100%.

Following this overview of diagnostic accuracy, Dr. Kingston described a series of genomic trends, focusing first on targetable alterations.

Both ctDNA techniques revealed that ESR1 mutations were common in cases of hormone receptor (HR)-positive disease, including approximately 40% of patients with HER2-negative breast cancer and approximately 20% of patients with HER2-positive breast cancer. In contrast, ESR1 mutations were found in less than 1% of patients with HR-negative disease. Although ERBB2 amplification was predominantly found in patients with HER2-positive breast cancer, this alteration was found in 1%-2% of patients with HER2-negative disease.

For the remainder of the presentation, Dr. Kingston focused on ctDNA targeted sequencing data.

Within this cohort of 800 participants, 92.9% of patients had a ctDNA alteration. The mean number of pathogenic alterations was 2.7; Dr. Kingston noted that, on average, patients with HR-positive, HER2-negative disease had significantly more alterations than did those with triple-negative breast cancer (3.0 vs 1.8; P less than .0001).

“We found that specific genes are enriched in certain breast cancer subtypes,” Dr. Kingston said, pointing out the “notable” rate of ERBB2 mutations (14%) in HER2-amplified disease.

Among patients with HR-positive disease, those who were HER2-negative often had ESR1 and KRAS mutations, whereas those with HER2-positive disease often had ESR1 mutations but not KRAS mutations.

Heterogeneity analysis showed that alterations in certain genes were clonally dominant, including AKT1, PIK3CA, GATA3, and TP53, while others were more often subclonal, including ESR1, RB1, SMAD4, and KRAS.

A closer look at frequency of alterations showed that AKT1, CDH1, and GATA3 were typically found as the only gene alteration present; in contrast, ESR1 alterations were often accompanied by multiple other gene hits.

Returning to targetable genes, the investigators found that there was significant variation in clonal dominance of pathogenic mutations in ESR1 and PIK3CA. A deeper analysis revealed that PIK3CA mutations were often double mutations in HR-positive disease, and that subclonal second mutations were found at APOBEC mutagenesis sites.

Carlos Arteaga, MD, of the University of Texas Southwestern Medical Center, Dallas, commented on the findings after the presentation and asked Dr. Kingston about a potential blind spot in the data.

Will Pass/MDedge News

SOURCE: Kingston et al. SABCS. 2019 Abstract GS3-07.

SAN ANTONIO – For detection of genomic aberrations in patients with advanced breast cancer, sensitivity of circulating tumor DNA (ctDNA) testing is effectively equivalent to that of tumor tissue sequencing, based on results of the plasmaMATCH trial.

Will Pass/MDedge News

When plasma and tumor tissue samples were collected within 60 days of one another, sensitivity of ctDNA testing was 98% for digital droplet PCR (ddPCR) and 100% for targeted sequencing with Guardant360, reported lead author Belinda Kingston, MB, ChB, of The Institute of Cancer Research, London.

In addition to analyzing ctDNA accuracy, Dr. Kingston and colleagues explored characteristics of genomic alterations in relation to one another and to disease subtypes.

“We have defined the genomic landscape of advanced breast cancer using ctDNA analysis,” Dr. Kingston said during a presentation at the San Antonio Breast Cancer Symposium.

The open-label plasmaMATCH trial, conducted at multiple centers in the United Kingdom, involved more than 1,000 patients with advanced breast cancer. The present analysis included 1,025 patients who underwent ctDNA testing via ddPCR, which screened for alterations in PIK3CA, ESR1, AKT1, and ERBB2. Eight hundred patients also underwent ctDNA testing with Guardant360 targeted sequencing (a 73-gene panel), while 77 patients additionally had tumor tissue sequencing performed on a fresh or frozen sample of metastatic tissue (a 16-gene panel).

Results showed that individual gene level agreement between the two ctDNA techniques ranged from 96% to 99% with kappa scores of at least 0.89. As described above, sensitivity of these tests, compared with tumor tissue sequencing, approached 100%.

Following this overview of diagnostic accuracy, Dr. Kingston described a series of genomic trends, focusing first on targetable alterations.

Both ctDNA techniques revealed that ESR1 mutations were common in cases of hormone receptor (HR)-positive disease, including approximately 40% of patients with HER2-negative breast cancer and approximately 20% of patients with HER2-positive breast cancer. In contrast, ESR1 mutations were found in less than 1% of patients with HR-negative disease. Although ERBB2 amplification was predominantly found in patients with HER2-positive breast cancer, this alteration was found in 1%-2% of patients with HER2-negative disease.

For the remainder of the presentation, Dr. Kingston focused on ctDNA targeted sequencing data.

Within this cohort of 800 participants, 92.9% of patients had a ctDNA alteration. The mean number of pathogenic alterations was 2.7; Dr. Kingston noted that, on average, patients with HR-positive, HER2-negative disease had significantly more alterations than did those with triple-negative breast cancer (3.0 vs 1.8; P less than .0001).

“We found that specific genes are enriched in certain breast cancer subtypes,” Dr. Kingston said, pointing out the “notable” rate of ERBB2 mutations (14%) in HER2-amplified disease.

Among patients with HR-positive disease, those who were HER2-negative often had ESR1 and KRAS mutations, whereas those with HER2-positive disease often had ESR1 mutations but not KRAS mutations.

Heterogeneity analysis showed that alterations in certain genes were clonally dominant, including AKT1, PIK3CA, GATA3, and TP53, while others were more often subclonal, including ESR1, RB1, SMAD4, and KRAS.

A closer look at frequency of alterations showed that AKT1, CDH1, and GATA3 were typically found as the only gene alteration present; in contrast, ESR1 alterations were often accompanied by multiple other gene hits.

Returning to targetable genes, the investigators found that there was significant variation in clonal dominance of pathogenic mutations in ESR1 and PIK3CA. A deeper analysis revealed that PIK3CA mutations were often double mutations in HR-positive disease, and that subclonal second mutations were found at APOBEC mutagenesis sites.

Carlos Arteaga, MD, of the University of Texas Southwestern Medical Center, Dallas, commented on the findings after the presentation and asked Dr. Kingston about a potential blind spot in the data.

Will Pass/MDedge News

SOURCE: Kingston et al. SABCS. 2019 Abstract GS3-07.

Case

A 55-year-old male with a history of diabetes mellitus, lumbar degenerative disc disease, and chronic low back pain was admitted overnight with right lower extremity cellulitis. He reported taking oral hydromorphone for chronic pain, but review of the Prescription Drug Monitoring Program (PDMP) revealed multiple short-term prescriptions from various ED providers, as well as monthly prescriptions from a variety of primary care providers.

DMEPhotography/Getty Images

Throughout the EHR, he is described as manipulative and narcotic-seeking with notation of multiple ED visits for pain. Multiple discharges against medical advice were noted. He was given two doses of IV hydromorphone in the ED and requested that this be continued. He was admitted for IV antibiotics for severe leg pain that he rated 15/10.
 

Background

The Society of Hospital Medicine published a consensus statement in the Journal of Hospital Medicine in 2018 that included 16 clinical recommendations on the safe use of opioids for the treatment of acute pain in hospitalized adults.¹ In regard to communication about pain, clinicians are encouraged to set realistic goals and expectations of opioid therapy, closely monitor response to opioid therapy, and provide education about the side effects and potential risks of opioid therapy for patients and their families.

However, even when these strategies are employed, the social and behavioral complexities of individual patients can contribute to unsatisfactory interactions with health care staff. Because difficult encounters have been linked to provider burnout, enhanced communication strategies can benefit both the patient and physician.²

SHM’s Patient Experience Committee saw an opportunity to provide complementary evidence-based best-practice tips for communication about pain. Specifically, the committee worked collectively to develop a framework that can be applied to more challenging encounters.
 

The VIEW Framework

VISIT the patient’s chart and your own mental state.

First, visit the patient’s chart to review information relevant to the patient’s pain history. The EHR can be leveraged through filters and search functions to identify encounters, consultations, and notes relevant to pain management.

Look at the prior to admission medication list and active medication list and see if there are discrepancies. The medication administration record (MAR) can help identify adjunctive medications that the patient may be refusing. PDMP data should be screened for signs of aberrant use, including multiple pharmacies, multiple prescribers, short intervals between prescriptions, and serially prescribed, multiple, low-quantity prescriptions.

While documented pain scores can be a marker of patient distress, objective aspects of the patient’s functional status can shed light on how much his/her discomfort impairs day-to-day living. Examples of these measures include nutritional intake, sleep cycle, out of bed activity, and participation with therapy. Lastly, assess for opioid-related side-effects including constipation, decreased respiratory rate, and any notation of over sedation in narrative documentation from ancillary services.

Once this information has been accrued, it is important to take a moment of mindfulness before meeting with the patient. Take steps to minimize interruptions with electronic devices by silencing your pager/cell phone and disengaging from computers/tablets. Some examples of mindfulness-based practices include taking cycles of deep breathing, going for a short walk to appreciate hospital artwork or view points, or focusing on the sensory aspects of washing your hands prior to seeing the patient. Self-reflection on prior meaningful encounters can also help reset your state of mind. These activities can help clear prior subconscious thoughts and frustrations and prepare for the task ahead of you.³

Intense focus and awareness can enhance your recognition of patient distress, increase your ability to engage in active listening, and enable you to be more receptive to verbal and nonverbal cues.² Additionally, mindful behaviors have been shown to contribute to decreased burnout and improved empathy.^4,5
 

INTERVIEW the patient.

Once you enter the room, introduce yourself to the patient and others who are present. Interview the patient by eliciting subjective information. Use open-ended and nonjudgmental language, and take moments to summarize the patient’s perspective.

Inquire about the patient’s home baseline pain scores and past levels of acceptable function. Further explore the patient’s performance goals related to activities of daily living and quality of life. Ask about any prior history of addiction to any substance, and if needed, discuss your specific concerns related to substance misuse and abuse.
 

EMPATHIZE with the patient.

Integrate empathy into your interview by validating any frustrations and experience of pain. Identifying with loss of function and quality of life can help you connect with the patient and initiate a therapeutic relationship. Observe both verbal and nonverbal behaviors that reveal signs of emotional discomfort.⁶ Use open-ended questions to create space and trust for patients to share their feelings.

Pause to summarize the patient’s perspective while acknowledging and validating emotions that he or she may be experiencing such as anxiety, fear, frustration and anger.⁶ Statements such as “ I know it is frustrating to ... ” or “I can’t imagine what it must feel like to ... ” can help convey empathy. Multiple studies have suggested that enhanced provider empathy and positive messaging can also reduce patient pain and anxiety and increase quality of life.^7,8 Empathic responses to negative emotional expressions from patients have also been associated with higher ratings of communication.⁹
 

WRAP UP.

Finally, wrap up by aligning expectations with the patient for pain control and summarize your management recommendations. Educate the patient and his/her family on the risks and benefits of recommended therapy as well as the expected course of recovery. Setting shared goals for functionality relevant to the patient’s personal values and quality of life can build connection between you and your patient.

While handing over the patient to the next provider, refrain from using stereotypical language such as “narcotic-seeking patient.” Clearly communicate the management plan and milestones to other team members, such as nurses, physical therapists, and oncoming hospitalists, to maintain consistency. This will help align patients and their care team and may stave off maladaptive patient behaviors such as splitting.
 

Applying the VIEW framework to the case

Visit

Upon visiting the medical chart, the physician realized that the patient’s opioid use began in his 20s when he injured his back in a traumatic motor vehicle accident. His successful athletic career came to a halt after this injury and opioid dependence ensued.

While reviewing past notes and prescription data via the PDMP, the physician noted that the patient had been visiting many different providers in order to get more pain medications. The most recent prescription was for oral hydromorphone 4 mg every 4 hours as needed, filled 1 week prior to this presentation.

She reviewed his vital signs and found that he had been persistently hypertensive and tachycardic. His nurse mentioned that he appeared to be in severe pain because of facial grimacing with standing and walking.

Prior to entering the patient’s room, the physician took a moment of mindfulness to become aware of her emotional state because she recognized that she was worried this could be a difficult encounter. She considered how hard his life has been and how much emotional and physical pain he might be experiencing. She took a deep breath, silenced her phone, and entered the room.
 

Interview

The physician sat at the bedside and interviewed the patient using a calm and nonjudgmental tone. It was quickly obvious to her that he was experiencing real pain. His cellulitis appeared severe and was tender to even minimal palpation. She learned that the pain in his leg had been worsening over the past week to the point that it was becoming difficult to ambulate, sleep and perform his daily hygiene routine. He was taking 4 mg tablets of hydromorphone every 2 hours, and he had run out a few days ago. He added that his mood was increasingly depressed, and he had even admitted to occasional suicidal thoughts because the pain was so unbearable.

When asked directly, he admitted that he was worried he was addicted to hydromorphone. He had first received it for low back pain after the motor vehicle accident, and it been refilled multiple times for ongoing pain over the course of a year. Importantly, she also learned that he felt he was often treated as an addict by medical professionals and felt that doctors no longer listened to him or believed him.
 

Empathize

As the conversation went on, the physician offered empathetic statements, recognizing the way it might feel to have your pain ignored or minimized by doctors. She expressed how frustrating it is to not be able to perform basic functions and how difficult it must be to constantly live in pain.

She said, “I don’t want you to suffer in pain. I care about you and my goal is to treat your pain so that you can return to doing the things in life that you find meaningful.” She also recognized the severity of his depression and discussed with him the role and importance of psychiatric consultation.
 

Wrap Up

The physician wrapped up the encounter by summarizing her plan to treat the infection and work together with him to treat his pain with the goal that he could ambulate and perform activities of daily living.

She reviewed the side effects of both acute and long-term use of opioids and discussed the risks and benefits. Given the fact that patient was on chronic baseline opioids and also had objective signs of acute pain, she started an initial regimen of hydromorphone 6 mg tablets every 4 hours as needed (a 50% increase over his home dose) and added acetaminophen 1000 mg every 6 hours and ibuprofen 600 mg every 8 hours.

She informed him that she would check on him in the afternoon and that the ultimate plan would be to taper down on his hydromorphone dose each day as his cellulitis improved. She also communicated that bidirectional respect between the patient and care team members was critical to a successful pain management.

Finally, she explained that there was going to be a different doctor covering at night and major changes to the prescription regimen would be deferred to daytime hours.

When she left the room, she summarized the plan with the patient’s nurse and shared a few details about the patient’s difficult past. At the end of the shift, the physician signed out to the overnight team that the patient had objective signs of pain and recommended a visit to the bedside if the patient’s symptoms were reported as worsening.

During his hospital stay, she monitored the patient’s nonverbal responses to movement, participation in physical therapy, and ability to sleep. She tapered the hydromorphone down each day as the patient’s cellulitis improved. At discharge, he was prescribed a 3-day supply of his home dose of hydromorphone and the same acetaminophen and ibuprofen regimen he had been on in the hospital with instructions for tapering. Finally, after coming to an agreement with the patient, she arranged for follow-up in the opioid taper clinic and communicated the plan with the patient’s primary care provider.

Dr. Horman is a hospitalist and assistant professor of medicine at UC San Diego Health. Dr. Richards is a hospitalist and assistant professor of medicine at the University of Nebraska Medical Center in Omaha. Dr. Horman and Dr. Richards note that they wrote this article in collaboration with the Society of Hospital Medicine Patient Experience Committee.

Key points

• Spend adequate time to fully visit patients’ history as it relates to their current pain complaints.
• Review notes and prescription data to better understand past and current pain regimen.
• Be vigilant about taking a mindful moment to visit your thoughts and potential biases.
• Interview patients using a calm tone and nonjudgmental, reassuring words.
• Empathize with patients and validate any frustrations and experience of pain.
• Wrap-up by summarizing your recommendations with patients, their families, the care team, and subsequent providers.

References

1. Herzig SJ et al. Safe opioid prescribing for acute noncancer pain in hospitalized adults: A Systematic Review of Existing Guidelines. J Hosp Med. 2018;13(4):256-62.

2. An PG et al. (MEM Investigators). Burden of difficult encounters in primary care: data from the minimizing error, maximizing outcomes study. Arch Intern Med. 2009;169(4):410-4.

3. Sanyer O, Fortenberry K. Using Mindfulness Techniques to improve difficult clinical encounters. Am Fam Physician. 2013;87(6):402.

4. Beckman HB et al. The impact of a program in mindful communication on primary care physicians. Acad Med. 2012;87(6):815-8.

5. Krasner MS et al. Association of an educational program in mindful communication with burnout, empathy, and attitudes among primary care physicians. JAMA. 2009;302(12):1284-93.

6. Dean M, Street R. A 3-Stage model of patient centered communication for addressing cancer patients’ emotional distress. Patient Educ Couns. 2014;94(2):143-8.

7. Howick J et al. Effects of empathic and positive communication in healthcare consultations: A systematic review and meta-analysis. J R Soc Med. 2018;111(7):240-52.

8. Mistiaen P et al. The effect of patient-practitioner communication on pain: A systematic review. Eur J Pain. 2016;20:675-88.

9. Weiss R et al. Associations of physician empathy with patient anxiety and ratings of communication in hospital admission encounters. J Hosp Med. 2017;12(10):805-10.

Case

A 55-year-old male with a history of diabetes mellitus, lumbar degenerative disc disease, and chronic low back pain was admitted overnight with right lower extremity cellulitis. He reported taking oral hydromorphone for chronic pain, but review of the Prescription Drug Monitoring Program (PDMP) revealed multiple short-term prescriptions from various ED providers, as well as monthly prescriptions from a variety of primary care providers.

DMEPhotography/Getty Images

Throughout the EHR, he is described as manipulative and narcotic-seeking with notation of multiple ED visits for pain. Multiple discharges against medical advice were noted. He was given two doses of IV hydromorphone in the ED and requested that this be continued. He was admitted for IV antibiotics for severe leg pain that he rated 15/10.
 

Background

The Society of Hospital Medicine published a consensus statement in the Journal of Hospital Medicine in 2018 that included 16 clinical recommendations on the safe use of opioids for the treatment of acute pain in hospitalized adults.¹ In regard to communication about pain, clinicians are encouraged to set realistic goals and expectations of opioid therapy, closely monitor response to opioid therapy, and provide education about the side effects and potential risks of opioid therapy for patients and their families.

However, even when these strategies are employed, the social and behavioral complexities of individual patients can contribute to unsatisfactory interactions with health care staff. Because difficult encounters have been linked to provider burnout, enhanced communication strategies can benefit both the patient and physician.²

SHM’s Patient Experience Committee saw an opportunity to provide complementary evidence-based best-practice tips for communication about pain. Specifically, the committee worked collectively to develop a framework that can be applied to more challenging encounters.
 

The VIEW Framework

VISIT the patient’s chart and your own mental state.

First, visit the patient’s chart to review information relevant to the patient’s pain history. The EHR can be leveraged through filters and search functions to identify encounters, consultations, and notes relevant to pain management.

Look at the prior to admission medication list and active medication list and see if there are discrepancies. The medication administration record (MAR) can help identify adjunctive medications that the patient may be refusing. PDMP data should be screened for signs of aberrant use, including multiple pharmacies, multiple prescribers, short intervals between prescriptions, and serially prescribed, multiple, low-quantity prescriptions.

While documented pain scores can be a marker of patient distress, objective aspects of the patient’s functional status can shed light on how much his/her discomfort impairs day-to-day living. Examples of these measures include nutritional intake, sleep cycle, out of bed activity, and participation with therapy. Lastly, assess for opioid-related side-effects including constipation, decreased respiratory rate, and any notation of over sedation in narrative documentation from ancillary services.

Once this information has been accrued, it is important to take a moment of mindfulness before meeting with the patient. Take steps to minimize interruptions with electronic devices by silencing your pager/cell phone and disengaging from computers/tablets. Some examples of mindfulness-based practices include taking cycles of deep breathing, going for a short walk to appreciate hospital artwork or view points, or focusing on the sensory aspects of washing your hands prior to seeing the patient. Self-reflection on prior meaningful encounters can also help reset your state of mind. These activities can help clear prior subconscious thoughts and frustrations and prepare for the task ahead of you.³

Intense focus and awareness can enhance your recognition of patient distress, increase your ability to engage in active listening, and enable you to be more receptive to verbal and nonverbal cues.² Additionally, mindful behaviors have been shown to contribute to decreased burnout and improved empathy.^4,5
 

INTERVIEW the patient.

Once you enter the room, introduce yourself to the patient and others who are present. Interview the patient by eliciting subjective information. Use open-ended and nonjudgmental language, and take moments to summarize the patient’s perspective.

Inquire about the patient’s home baseline pain scores and past levels of acceptable function. Further explore the patient’s performance goals related to activities of daily living and quality of life. Ask about any prior history of addiction to any substance, and if needed, discuss your specific concerns related to substance misuse and abuse.
 

EMPATHIZE with the patient.

Integrate empathy into your interview by validating any frustrations and experience of pain. Identifying with loss of function and quality of life can help you connect with the patient and initiate a therapeutic relationship. Observe both verbal and nonverbal behaviors that reveal signs of emotional discomfort.⁶ Use open-ended questions to create space and trust for patients to share their feelings.

Pause to summarize the patient’s perspective while acknowledging and validating emotions that he or she may be experiencing such as anxiety, fear, frustration and anger.⁶ Statements such as “ I know it is frustrating to ... ” or “I can’t imagine what it must feel like to ... ” can help convey empathy. Multiple studies have suggested that enhanced provider empathy and positive messaging can also reduce patient pain and anxiety and increase quality of life.^7,8 Empathic responses to negative emotional expressions from patients have also been associated with higher ratings of communication.⁹
 

WRAP UP.

Finally, wrap up by aligning expectations with the patient for pain control and summarize your management recommendations. Educate the patient and his/her family on the risks and benefits of recommended therapy as well as the expected course of recovery. Setting shared goals for functionality relevant to the patient’s personal values and quality of life can build connection between you and your patient.

While handing over the patient to the next provider, refrain from using stereotypical language such as “narcotic-seeking patient.” Clearly communicate the management plan and milestones to other team members, such as nurses, physical therapists, and oncoming hospitalists, to maintain consistency. This will help align patients and their care team and may stave off maladaptive patient behaviors such as splitting.
 

Applying the VIEW framework to the case

Visit

Upon visiting the medical chart, the physician realized that the patient’s opioid use began in his 20s when he injured his back in a traumatic motor vehicle accident. His successful athletic career came to a halt after this injury and opioid dependence ensued.

While reviewing past notes and prescription data via the PDMP, the physician noted that the patient had been visiting many different providers in order to get more pain medications. The most recent prescription was for oral hydromorphone 4 mg every 4 hours as needed, filled 1 week prior to this presentation.

She reviewed his vital signs and found that he had been persistently hypertensive and tachycardic. His nurse mentioned that he appeared to be in severe pain because of facial grimacing with standing and walking.

Prior to entering the patient’s room, the physician took a moment of mindfulness to become aware of her emotional state because she recognized that she was worried this could be a difficult encounter. She considered how hard his life has been and how much emotional and physical pain he might be experiencing. She took a deep breath, silenced her phone, and entered the room.
 

Interview

The physician sat at the bedside and interviewed the patient using a calm and nonjudgmental tone. It was quickly obvious to her that he was experiencing real pain. His cellulitis appeared severe and was tender to even minimal palpation. She learned that the pain in his leg had been worsening over the past week to the point that it was becoming difficult to ambulate, sleep and perform his daily hygiene routine. He was taking 4 mg tablets of hydromorphone every 2 hours, and he had run out a few days ago. He added that his mood was increasingly depressed, and he had even admitted to occasional suicidal thoughts because the pain was so unbearable.

When asked directly, he admitted that he was worried he was addicted to hydromorphone. He had first received it for low back pain after the motor vehicle accident, and it been refilled multiple times for ongoing pain over the course of a year. Importantly, she also learned that he felt he was often treated as an addict by medical professionals and felt that doctors no longer listened to him or believed him.
 

Empathize

As the conversation went on, the physician offered empathetic statements, recognizing the way it might feel to have your pain ignored or minimized by doctors. She expressed how frustrating it is to not be able to perform basic functions and how difficult it must be to constantly live in pain.

She said, “I don’t want you to suffer in pain. I care about you and my goal is to treat your pain so that you can return to doing the things in life that you find meaningful.” She also recognized the severity of his depression and discussed with him the role and importance of psychiatric consultation.
 

Wrap Up

The physician wrapped up the encounter by summarizing her plan to treat the infection and work together with him to treat his pain with the goal that he could ambulate and perform activities of daily living.

She reviewed the side effects of both acute and long-term use of opioids and discussed the risks and benefits. Given the fact that patient was on chronic baseline opioids and also had objective signs of acute pain, she started an initial regimen of hydromorphone 6 mg tablets every 4 hours as needed (a 50% increase over his home dose) and added acetaminophen 1000 mg every 6 hours and ibuprofen 600 mg every 8 hours.

She informed him that she would check on him in the afternoon and that the ultimate plan would be to taper down on his hydromorphone dose each day as his cellulitis improved. She also communicated that bidirectional respect between the patient and care team members was critical to a successful pain management.

Finally, she explained that there was going to be a different doctor covering at night and major changes to the prescription regimen would be deferred to daytime hours.

When she left the room, she summarized the plan with the patient’s nurse and shared a few details about the patient’s difficult past. At the end of the shift, the physician signed out to the overnight team that the patient had objective signs of pain and recommended a visit to the bedside if the patient’s symptoms were reported as worsening.

During his hospital stay, she monitored the patient’s nonverbal responses to movement, participation in physical therapy, and ability to sleep. She tapered the hydromorphone down each day as the patient’s cellulitis improved. At discharge, he was prescribed a 3-day supply of his home dose of hydromorphone and the same acetaminophen and ibuprofen regimen he had been on in the hospital with instructions for tapering. Finally, after coming to an agreement with the patient, she arranged for follow-up in the opioid taper clinic and communicated the plan with the patient’s primary care provider.

Dr. Horman is a hospitalist and assistant professor of medicine at UC San Diego Health. Dr. Richards is a hospitalist and assistant professor of medicine at the University of Nebraska Medical Center in Omaha. Dr. Horman and Dr. Richards note that they wrote this article in collaboration with the Society of Hospital Medicine Patient Experience Committee.

Key points

• Spend adequate time to fully visit patients’ history as it relates to their current pain complaints.
• Review notes and prescription data to better understand past and current pain regimen.
• Be vigilant about taking a mindful moment to visit your thoughts and potential biases.
• Interview patients using a calm tone and nonjudgmental, reassuring words.
• Empathize with patients and validate any frustrations and experience of pain.
• Wrap-up by summarizing your recommendations with patients, their families, the care team, and subsequent providers.

References

1. Herzig SJ et al. Safe opioid prescribing for acute noncancer pain in hospitalized adults: A Systematic Review of Existing Guidelines. J Hosp Med. 2018;13(4):256-62.

2. An PG et al. (MEM Investigators). Burden of difficult encounters in primary care: data from the minimizing error, maximizing outcomes study. Arch Intern Med. 2009;169(4):410-4.

3. Sanyer O, Fortenberry K. Using Mindfulness Techniques to improve difficult clinical encounters. Am Fam Physician. 2013;87(6):402.

4. Beckman HB et al. The impact of a program in mindful communication on primary care physicians. Acad Med. 2012;87(6):815-8.

5. Krasner MS et al. Association of an educational program in mindful communication with burnout, empathy, and attitudes among primary care physicians. JAMA. 2009;302(12):1284-93.

6. Dean M, Street R. A 3-Stage model of patient centered communication for addressing cancer patients’ emotional distress. Patient Educ Couns. 2014;94(2):143-8.

7. Howick J et al. Effects of empathic and positive communication in healthcare consultations: A systematic review and meta-analysis. J R Soc Med. 2018;111(7):240-52.

8. Mistiaen P et al. The effect of patient-practitioner communication on pain: A systematic review. Eur J Pain. 2016;20:675-88.

9. Weiss R et al. Associations of physician empathy with patient anxiety and ratings of communication in hospital admission encounters. J Hosp Med. 2017;12(10):805-10.

Case

A 55-year-old male with a history of diabetes mellitus, lumbar degenerative disc disease, and chronic low back pain was admitted overnight with right lower extremity cellulitis. He reported taking oral hydromorphone for chronic pain, but review of the Prescription Drug Monitoring Program (PDMP) revealed multiple short-term prescriptions from various ED providers, as well as monthly prescriptions from a variety of primary care providers.

DMEPhotography/Getty Images

Throughout the EHR, he is described as manipulative and narcotic-seeking with notation of multiple ED visits for pain. Multiple discharges against medical advice were noted. He was given two doses of IV hydromorphone in the ED and requested that this be continued. He was admitted for IV antibiotics for severe leg pain that he rated 15/10.
 

Background

The Society of Hospital Medicine published a consensus statement in the Journal of Hospital Medicine in 2018 that included 16 clinical recommendations on the safe use of opioids for the treatment of acute pain in hospitalized adults.¹ In regard to communication about pain, clinicians are encouraged to set realistic goals and expectations of opioid therapy, closely monitor response to opioid therapy, and provide education about the side effects and potential risks of opioid therapy for patients and their families.

However, even when these strategies are employed, the social and behavioral complexities of individual patients can contribute to unsatisfactory interactions with health care staff. Because difficult encounters have been linked to provider burnout, enhanced communication strategies can benefit both the patient and physician.²

SHM’s Patient Experience Committee saw an opportunity to provide complementary evidence-based best-practice tips for communication about pain. Specifically, the committee worked collectively to develop a framework that can be applied to more challenging encounters.
 

The VIEW Framework

VISIT the patient’s chart and your own mental state.

First, visit the patient’s chart to review information relevant to the patient’s pain history. The EHR can be leveraged through filters and search functions to identify encounters, consultations, and notes relevant to pain management.

Look at the prior to admission medication list and active medication list and see if there are discrepancies. The medication administration record (MAR) can help identify adjunctive medications that the patient may be refusing. PDMP data should be screened for signs of aberrant use, including multiple pharmacies, multiple prescribers, short intervals between prescriptions, and serially prescribed, multiple, low-quantity prescriptions.

While documented pain scores can be a marker of patient distress, objective aspects of the patient’s functional status can shed light on how much his/her discomfort impairs day-to-day living. Examples of these measures include nutritional intake, sleep cycle, out of bed activity, and participation with therapy. Lastly, assess for opioid-related side-effects including constipation, decreased respiratory rate, and any notation of over sedation in narrative documentation from ancillary services.

Once this information has been accrued, it is important to take a moment of mindfulness before meeting with the patient. Take steps to minimize interruptions with electronic devices by silencing your pager/cell phone and disengaging from computers/tablets. Some examples of mindfulness-based practices include taking cycles of deep breathing, going for a short walk to appreciate hospital artwork or view points, or focusing on the sensory aspects of washing your hands prior to seeing the patient. Self-reflection on prior meaningful encounters can also help reset your state of mind. These activities can help clear prior subconscious thoughts and frustrations and prepare for the task ahead of you.³

Intense focus and awareness can enhance your recognition of patient distress, increase your ability to engage in active listening, and enable you to be more receptive to verbal and nonverbal cues.² Additionally, mindful behaviors have been shown to contribute to decreased burnout and improved empathy.^4,5
 

INTERVIEW the patient.

Once you enter the room, introduce yourself to the patient and others who are present. Interview the patient by eliciting subjective information. Use open-ended and nonjudgmental language, and take moments to summarize the patient’s perspective.

Inquire about the patient’s home baseline pain scores and past levels of acceptable function. Further explore the patient’s performance goals related to activities of daily living and quality of life. Ask about any prior history of addiction to any substance, and if needed, discuss your specific concerns related to substance misuse and abuse.
 

EMPATHIZE with the patient.

Integrate empathy into your interview by validating any frustrations and experience of pain. Identifying with loss of function and quality of life can help you connect with the patient and initiate a therapeutic relationship. Observe both verbal and nonverbal behaviors that reveal signs of emotional discomfort.⁶ Use open-ended questions to create space and trust for patients to share their feelings.

Pause to summarize the patient’s perspective while acknowledging and validating emotions that he or she may be experiencing such as anxiety, fear, frustration and anger.⁶ Statements such as “ I know it is frustrating to ... ” or “I can’t imagine what it must feel like to ... ” can help convey empathy. Multiple studies have suggested that enhanced provider empathy and positive messaging can also reduce patient pain and anxiety and increase quality of life.^7,8 Empathic responses to negative emotional expressions from patients have also been associated with higher ratings of communication.⁹
 

WRAP UP.

Finally, wrap up by aligning expectations with the patient for pain control and summarize your management recommendations. Educate the patient and his/her family on the risks and benefits of recommended therapy as well as the expected course of recovery. Setting shared goals for functionality relevant to the patient’s personal values and quality of life can build connection between you and your patient.

While handing over the patient to the next provider, refrain from using stereotypical language such as “narcotic-seeking patient.” Clearly communicate the management plan and milestones to other team members, such as nurses, physical therapists, and oncoming hospitalists, to maintain consistency. This will help align patients and their care team and may stave off maladaptive patient behaviors such as splitting.
 

Applying the VIEW framework to the case

Visit

Upon visiting the medical chart, the physician realized that the patient’s opioid use began in his 20s when he injured his back in a traumatic motor vehicle accident. His successful athletic career came to a halt after this injury and opioid dependence ensued.

While reviewing past notes and prescription data via the PDMP, the physician noted that the patient had been visiting many different providers in order to get more pain medications. The most recent prescription was for oral hydromorphone 4 mg every 4 hours as needed, filled 1 week prior to this presentation.

She reviewed his vital signs and found that he had been persistently hypertensive and tachycardic. His nurse mentioned that he appeared to be in severe pain because of facial grimacing with standing and walking.

Prior to entering the patient’s room, the physician took a moment of mindfulness to become aware of her emotional state because she recognized that she was worried this could be a difficult encounter. She considered how hard his life has been and how much emotional and physical pain he might be experiencing. She took a deep breath, silenced her phone, and entered the room.
 

Interview

The physician sat at the bedside and interviewed the patient using a calm and nonjudgmental tone. It was quickly obvious to her that he was experiencing real pain. His cellulitis appeared severe and was tender to even minimal palpation. She learned that the pain in his leg had been worsening over the past week to the point that it was becoming difficult to ambulate, sleep and perform his daily hygiene routine. He was taking 4 mg tablets of hydromorphone every 2 hours, and he had run out a few days ago. He added that his mood was increasingly depressed, and he had even admitted to occasional suicidal thoughts because the pain was so unbearable.

When asked directly, he admitted that he was worried he was addicted to hydromorphone. He had first received it for low back pain after the motor vehicle accident, and it been refilled multiple times for ongoing pain over the course of a year. Importantly, she also learned that he felt he was often treated as an addict by medical professionals and felt that doctors no longer listened to him or believed him.
 

Empathize

As the conversation went on, the physician offered empathetic statements, recognizing the way it might feel to have your pain ignored or minimized by doctors. She expressed how frustrating it is to not be able to perform basic functions and how difficult it must be to constantly live in pain.

She said, “I don’t want you to suffer in pain. I care about you and my goal is to treat your pain so that you can return to doing the things in life that you find meaningful.” She also recognized the severity of his depression and discussed with him the role and importance of psychiatric consultation.
 

Wrap Up

The physician wrapped up the encounter by summarizing her plan to treat the infection and work together with him to treat his pain with the goal that he could ambulate and perform activities of daily living.

She reviewed the side effects of both acute and long-term use of opioids and discussed the risks and benefits. Given the fact that patient was on chronic baseline opioids and also had objective signs of acute pain, she started an initial regimen of hydromorphone 6 mg tablets every 4 hours as needed (a 50% increase over his home dose) and added acetaminophen 1000 mg every 6 hours and ibuprofen 600 mg every 8 hours.

She informed him that she would check on him in the afternoon and that the ultimate plan would be to taper down on his hydromorphone dose each day as his cellulitis improved. She also communicated that bidirectional respect between the patient and care team members was critical to a successful pain management.

Finally, she explained that there was going to be a different doctor covering at night and major changes to the prescription regimen would be deferred to daytime hours.

When she left the room, she summarized the plan with the patient’s nurse and shared a few details about the patient’s difficult past. At the end of the shift, the physician signed out to the overnight team that the patient had objective signs of pain and recommended a visit to the bedside if the patient’s symptoms were reported as worsening.

During his hospital stay, she monitored the patient’s nonverbal responses to movement, participation in physical therapy, and ability to sleep. She tapered the hydromorphone down each day as the patient’s cellulitis improved. At discharge, he was prescribed a 3-day supply of his home dose of hydromorphone and the same acetaminophen and ibuprofen regimen he had been on in the hospital with instructions for tapering. Finally, after coming to an agreement with the patient, she arranged for follow-up in the opioid taper clinic and communicated the plan with the patient’s primary care provider.

Dr. Horman is a hospitalist and assistant professor of medicine at UC San Diego Health. Dr. Richards is a hospitalist and assistant professor of medicine at the University of Nebraska Medical Center in Omaha. Dr. Horman and Dr. Richards note that they wrote this article in collaboration with the Society of Hospital Medicine Patient Experience Committee.

Key points

• Spend adequate time to fully visit patients’ history as it relates to their current pain complaints.
• Review notes and prescription data to better understand past and current pain regimen.
• Be vigilant about taking a mindful moment to visit your thoughts and potential biases.
• Interview patients using a calm tone and nonjudgmental, reassuring words.
• Empathize with patients and validate any frustrations and experience of pain.
• Wrap-up by summarizing your recommendations with patients, their families, the care team, and subsequent providers.

References

1. Herzig SJ et al. Safe opioid prescribing for acute noncancer pain in hospitalized adults: A Systematic Review of Existing Guidelines. J Hosp Med. 2018;13(4):256-62.

2. An PG et al. (MEM Investigators). Burden of difficult encounters in primary care: data from the minimizing error, maximizing outcomes study. Arch Intern Med. 2009;169(4):410-4.

3. Sanyer O, Fortenberry K. Using Mindfulness Techniques to improve difficult clinical encounters. Am Fam Physician. 2013;87(6):402.

4. Beckman HB et al. The impact of a program in mindful communication on primary care physicians. Acad Med. 2012;87(6):815-8.

5. Krasner MS et al. Association of an educational program in mindful communication with burnout, empathy, and attitudes among primary care physicians. JAMA. 2009;302(12):1284-93.

6. Dean M, Street R. A 3-Stage model of patient centered communication for addressing cancer patients’ emotional distress. Patient Educ Couns. 2014;94(2):143-8.

7. Howick J et al. Effects of empathic and positive communication in healthcare consultations: A systematic review and meta-analysis. J R Soc Med. 2018;111(7):240-52.

8. Mistiaen P et al. The effect of patient-practitioner communication on pain: A systematic review. Eur J Pain. 2016;20:675-88.

9. Weiss R et al. Associations of physician empathy with patient anxiety and ratings of communication in hospital admission encounters. J Hosp Med. 2017;12(10):805-10.

SAN ANTONIO – For patients with newly diagnosed HER2-negative breast cancer who are BRCA carriers, neoadjuvant cisplatin does not offer a higher pathologic complete response (pCR) rate than standard doxorubicin/cyclophosphamide (AC), based on results from the phase 2 INFORM trial.

Will Pass/MDedge News

Findings from this trial and others suggest that BRCA deficiency may be a marker of sensitivity to DNA-damaging chemotherapy generally, instead of platinum agents specifically, reported lead author Nadine Tung, MD, of Beth Israel Deaconess Medical Center in Boston.

While single-agent platinum chemotherapy has shown significant clinical activity in the neoadjuvant and metastatic settings for BRCA-mutated triple-negative breast cancer (TNBC), prospective trials comparing platinum-based therapy with non–platinum-based therapy have been lacking, Dr. Tung said during a presentation at the San Antonio Breast Cancer Symposium.

“Almost no data exist for the response to platinum agents among BRCA carriers with hormone receptor–positive breast cancer,” Dr. Tung said.

The investigators aimed to address both of these knowledge gaps with a head-to-head trial. Although the investigators aimed for an accrual of 170 participants, all newly diagnosed patients, only 118 were enrolled, of whom 117 were included in the final analysis. All patients had HER2-negative breast cancer with at least one germline BRCA mutation. About two-thirds of patients (69%) were BRCA1 positive, about one-third (30%) were BRCA2 positive, and the small remainder (2%) had both mutations. Clinical stage proportions were as follows: I (19%), II (63%), and III (18%). Almost three-fourths of patients (70%) had TNBC, and 45% had nodal involvement upon enrollment.

Patients were randomized at a 1:1 ratio to receive either cisplatin (75 mg/m² every 3 weeks for four cycles) or standard AC (doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² every 2-3 weeks for four cycles). These treatments were followed by surgery. The primary endpoint was pCR . Secondary endpoints included residual cancer burden of 0-1 (RCB 0/1), 3-year disease-free survival, and toxicities.

Most patients completed the regimens as planned; however, seven patients received more than four cycles of chemotherapy while four patients completed fewer than four cycles. These 11 patients were categorized as not having a pathologic complete response.

Among the remaining patients, platinum-based chemotherapy was associated with an 18% pCR rate, compared with 26% for standard AC, which translated to a risk ratio of 0.70 that was not significant. Among patients with TNBC (n = 82), pCR rates followed a similar trend (22% vs. 28%), again without statistical significance. For patients with estrogen receptor–positive disease, the numerical disparity in pCR rate was greater (cisplatin at 6% vs. AC at 21%); however, once more, this difference was not statistically significant. Because of the small number of patients in this subgroup (n = 35), Dr. Tung advised that results be interpreted with caution.

Results for RCB 0/1 were similar to pCR. AC was associated with a higher rate of RCB 0-1 for all patients (46% vs. 33%), patients with TNBC (47% vs. 36%), and patients with hormone receptor–positive disease (42% vs. 25%). Across all patients and subtypes, these differences were not statistically significant.

Safety profiles were similar to previously published data for both regimens.

“In conclusion, contrary to our initial expectations, the pCR rate and RCB 0/1 rate is not significantly higher after cisplatin than after AC in BRCA carriers with early-stage breast cancer, whether triple-negative or estrogen receptor–positive HER2-negative disease,” Dr. Tung said. “Our statistician has concluded that there is no realistic scenario by which the pCR with cisplatin would have been significantly higher than with AC had this study met its accrual.”

“We believe the results of the INFORM trial are consistent with those of the GeparSixto and BrightTNess neoadjuvant trials,” Dr. Tung said. “One interpretation of the INFORM trial results, as well as these two trials, is that breast cancer in BRCA carriers is more sensitive than in noncarriers to DNA-damaging agents. … BRCA deficiency or homologous combination deficiency may simply be a marker of sensitivity to DNA-damaging chemotherapy rather than platinum agents specifically.”

The investigators disclosed relationships with Merck, AstraZeneca, Genentech, and others.

SOURCE: Tung N et al. SABCS 2019, Abstract GS6-03.

SAN ANTONIO – For patients with newly diagnosed HER2-negative breast cancer who are BRCA carriers, neoadjuvant cisplatin does not offer a higher pathologic complete response (pCR) rate than standard doxorubicin/cyclophosphamide (AC), based on results from the phase 2 INFORM trial.

Will Pass/MDedge News

Findings from this trial and others suggest that BRCA deficiency may be a marker of sensitivity to DNA-damaging chemotherapy generally, instead of platinum agents specifically, reported lead author Nadine Tung, MD, of Beth Israel Deaconess Medical Center in Boston.

While single-agent platinum chemotherapy has shown significant clinical activity in the neoadjuvant and metastatic settings for BRCA-mutated triple-negative breast cancer (TNBC), prospective trials comparing platinum-based therapy with non–platinum-based therapy have been lacking, Dr. Tung said during a presentation at the San Antonio Breast Cancer Symposium.

“Almost no data exist for the response to platinum agents among BRCA carriers with hormone receptor–positive breast cancer,” Dr. Tung said.

The investigators aimed to address both of these knowledge gaps with a head-to-head trial. Although the investigators aimed for an accrual of 170 participants, all newly diagnosed patients, only 118 were enrolled, of whom 117 were included in the final analysis. All patients had HER2-negative breast cancer with at least one germline BRCA mutation. About two-thirds of patients (69%) were BRCA1 positive, about one-third (30%) were BRCA2 positive, and the small remainder (2%) had both mutations. Clinical stage proportions were as follows: I (19%), II (63%), and III (18%). Almost three-fourths of patients (70%) had TNBC, and 45% had nodal involvement upon enrollment.

Patients were randomized at a 1:1 ratio to receive either cisplatin (75 mg/m² every 3 weeks for four cycles) or standard AC (doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² every 2-3 weeks for four cycles). These treatments were followed by surgery. The primary endpoint was pCR . Secondary endpoints included residual cancer burden of 0-1 (RCB 0/1), 3-year disease-free survival, and toxicities.

Most patients completed the regimens as planned; however, seven patients received more than four cycles of chemotherapy while four patients completed fewer than four cycles. These 11 patients were categorized as not having a pathologic complete response.

Among the remaining patients, platinum-based chemotherapy was associated with an 18% pCR rate, compared with 26% for standard AC, which translated to a risk ratio of 0.70 that was not significant. Among patients with TNBC (n = 82), pCR rates followed a similar trend (22% vs. 28%), again without statistical significance. For patients with estrogen receptor–positive disease, the numerical disparity in pCR rate was greater (cisplatin at 6% vs. AC at 21%); however, once more, this difference was not statistically significant. Because of the small number of patients in this subgroup (n = 35), Dr. Tung advised that results be interpreted with caution.

Results for RCB 0/1 were similar to pCR. AC was associated with a higher rate of RCB 0-1 for all patients (46% vs. 33%), patients with TNBC (47% vs. 36%), and patients with hormone receptor–positive disease (42% vs. 25%). Across all patients and subtypes, these differences were not statistically significant.

Safety profiles were similar to previously published data for both regimens.

“In conclusion, contrary to our initial expectations, the pCR rate and RCB 0/1 rate is not significantly higher after cisplatin than after AC in BRCA carriers with early-stage breast cancer, whether triple-negative or estrogen receptor–positive HER2-negative disease,” Dr. Tung said. “Our statistician has concluded that there is no realistic scenario by which the pCR with cisplatin would have been significantly higher than with AC had this study met its accrual.”

“We believe the results of the INFORM trial are consistent with those of the GeparSixto and BrightTNess neoadjuvant trials,” Dr. Tung said. “One interpretation of the INFORM trial results, as well as these two trials, is that breast cancer in BRCA carriers is more sensitive than in noncarriers to DNA-damaging agents. … BRCA deficiency or homologous combination deficiency may simply be a marker of sensitivity to DNA-damaging chemotherapy rather than platinum agents specifically.”

The investigators disclosed relationships with Merck, AstraZeneca, Genentech, and others.

SOURCE: Tung N et al. SABCS 2019, Abstract GS6-03.

SAN ANTONIO – For patients with newly diagnosed HER2-negative breast cancer who are BRCA carriers, neoadjuvant cisplatin does not offer a higher pathologic complete response (pCR) rate than standard doxorubicin/cyclophosphamide (AC), based on results from the phase 2 INFORM trial.

Will Pass/MDedge News

Findings from this trial and others suggest that BRCA deficiency may be a marker of sensitivity to DNA-damaging chemotherapy generally, instead of platinum agents specifically, reported lead author Nadine Tung, MD, of Beth Israel Deaconess Medical Center in Boston.

While single-agent platinum chemotherapy has shown significant clinical activity in the neoadjuvant and metastatic settings for BRCA-mutated triple-negative breast cancer (TNBC), prospective trials comparing platinum-based therapy with non–platinum-based therapy have been lacking, Dr. Tung said during a presentation at the San Antonio Breast Cancer Symposium.

“Almost no data exist for the response to platinum agents among BRCA carriers with hormone receptor–positive breast cancer,” Dr. Tung said.

The investigators aimed to address both of these knowledge gaps with a head-to-head trial. Although the investigators aimed for an accrual of 170 participants, all newly diagnosed patients, only 118 were enrolled, of whom 117 were included in the final analysis. All patients had HER2-negative breast cancer with at least one germline BRCA mutation. About two-thirds of patients (69%) were BRCA1 positive, about one-third (30%) were BRCA2 positive, and the small remainder (2%) had both mutations. Clinical stage proportions were as follows: I (19%), II (63%), and III (18%). Almost three-fourths of patients (70%) had TNBC, and 45% had nodal involvement upon enrollment.

Patients were randomized at a 1:1 ratio to receive either cisplatin (75 mg/m² every 3 weeks for four cycles) or standard AC (doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² every 2-3 weeks for four cycles). These treatments were followed by surgery. The primary endpoint was pCR . Secondary endpoints included residual cancer burden of 0-1 (RCB 0/1), 3-year disease-free survival, and toxicities.

Most patients completed the regimens as planned; however, seven patients received more than four cycles of chemotherapy while four patients completed fewer than four cycles. These 11 patients were categorized as not having a pathologic complete response.

Among the remaining patients, platinum-based chemotherapy was associated with an 18% pCR rate, compared with 26% for standard AC, which translated to a risk ratio of 0.70 that was not significant. Among patients with TNBC (n = 82), pCR rates followed a similar trend (22% vs. 28%), again without statistical significance. For patients with estrogen receptor–positive disease, the numerical disparity in pCR rate was greater (cisplatin at 6% vs. AC at 21%); however, once more, this difference was not statistically significant. Because of the small number of patients in this subgroup (n = 35), Dr. Tung advised that results be interpreted with caution.

Results for RCB 0/1 were similar to pCR. AC was associated with a higher rate of RCB 0-1 for all patients (46% vs. 33%), patients with TNBC (47% vs. 36%), and patients with hormone receptor–positive disease (42% vs. 25%). Across all patients and subtypes, these differences were not statistically significant.

Safety profiles were similar to previously published data for both regimens.

“In conclusion, contrary to our initial expectations, the pCR rate and RCB 0/1 rate is not significantly higher after cisplatin than after AC in BRCA carriers with early-stage breast cancer, whether triple-negative or estrogen receptor–positive HER2-negative disease,” Dr. Tung said. “Our statistician has concluded that there is no realistic scenario by which the pCR with cisplatin would have been significantly higher than with AC had this study met its accrual.”

“We believe the results of the INFORM trial are consistent with those of the GeparSixto and BrightTNess neoadjuvant trials,” Dr. Tung said. “One interpretation of the INFORM trial results, as well as these two trials, is that breast cancer in BRCA carriers is more sensitive than in noncarriers to DNA-damaging agents. … BRCA deficiency or homologous combination deficiency may simply be a marker of sensitivity to DNA-damaging chemotherapy rather than platinum agents specifically.”

The investigators disclosed relationships with Merck, AstraZeneca, Genentech, and others.

SOURCE: Tung N et al. SABCS 2019, Abstract GS6-03.

NEW ORLEANS – It wasn’t until her teenage daughter wanted to get her belly button pierced that Cora Breuner, MD, became interested in the safety of tattoos and piercings for adolescents.

“You’re a pediatrician,” her daughter said. “Where should I go? Should I get this done?” Although Dr. Breuner didn’t want her daughter to get the piercing, she knew saying “no” wasn’t likely to stop her teenager any more than it would another adolescent, so she looked to the medical literature … and didn’t find much.

“I couldn’t find an article summarizing complication rates or just about the legality of it or other issues around tattooing and piercing,” said Dr. Breuner a professor of pediatrics at Seattle Children’s Hospital and the University of Washington, also in Seattle. So she and the American Academy of Pediatrics’ Committee on Adolescent Health did the work themselves and wrote one.

Now she recommends that all health care workers treating children ask their adolescent patients about tattoos and piercings at every health care visit. “I want to make sure that you are talking to your teenagers about this,” she told attendees at the annual meeting of the American Academy of Pediatrics. In her presentation, she focused on knowing the legal age of consent for body modifications and what to watch for in terms of complications.
 

Tattoos growing in popularity

More than a third (38%) of people aged 18-29 years have at least one tattoo, according to a Pew Research Center report Dr. Breuner cited, and 23% had piercings somewhere on their body besides their ears. In fact, Americans spend about $1.65 billion on tattoos each year.

Most of the people with tattoos (72%), however, had them in places that were covered and not visible, reinforcing the need to ask about them. The popularity of tattoos has been increasing in general, Dr. Breuner noted. In just the 4 years from 2012 to 2016, the prevalence of U.S. adults with at least one tattoo increased 20%.

And people don’t appear to be sorry to have them. According to a Harris Poll that Dr. Breuner cited, 86% of respondents in 2012 did not regret getting their tattoo, and respondents listed a number of feelings they associated with their tattoos: feeling sexy, rebellious, attractive, strong, spiritual, healthier, intelligent, and athletic.

Although the techniques for tattooing have changed over the years since the first documented ones in 4,000 B.C., the basic concept of injecting ink into the dermis hasn’t changed much. By injecting the ink below the epidermis, the ink remains visible for the rest of a person’s life.

Courtesy Annie Fulton

The laws for tattoos vary by state, so you need to check the laws where they live. Not much data exist on infections and complaints, but data from the Michigan Department of Health & Human Services suggests the infection rate – at least those infections reported – is low while the rate of illegally operating facilities is a bigger risk. Local health districts in Michigan have received reports of only 18 infections since 2010, but they’ve received 85 reports of illegal operations and 69 reports of social media parties centered on all attendees getting a tattoo.
 

Risks of tattoos

The biggest concern for adolescents is ensuring they understand the risks of tattoos and piercings and what to look for. One risk for tattoos is hepatitis C. However, the studies on the risk of contracting hepatitis C from tattooing are confounded by the fact that many people getting tattoos also may be engaging in other risky behaviors, such as intravenous drug use or risky sexual behaviors. Still, some research suggests that “commercially acquired tattoos accounted for more than twice as many infections as injection-drug use,” Dr. Breuner said.

Another risk is tattoo-associated bacterial skin infections (Clin Infect Dis. 2019 Aug 30;69[6]:949-55; MMWR Morb Mortal Wkly Rep. 2012 Aug 24;61[33]:653-6).
 

Risks of body piercing

Although body piercing doesn’t date back quite as far as tattoos – about 700 A.D. – its history remains long. Research suggests the top reason people get body piercings is simply liking the way it looks, as 77% of respondents reported in one study (J Am Osteopath Assoc. 2007 Oct;107[10]:432-8). Other reasons including looking fashionable, catching attention, feeling different, making a personal statement, being daring, fitting in, pressuring from peers, and defying parents.

The most serious potential complication from piercings is gangrene, but the most common is infection. Other possible complications include an allergic reaction to the metal used, a bleeding complication (estimated in 1 of 10), a scar or site reaction (estimated in 1 of 15), or, much less commonly, toxic shock syndrome. In some areas, there’s a risk of nerve damage if the nerve is pierced, such as in the eyebrow or in the bridge of the nose.

Teens particularly should be aware of the average time it takes for a piercing to heal, depending on where they get it. A navel piercing, for example, can take up to 9 months to heal. Others with long healing times include the penis (3-9 months), labia majora (2-4 months), nipple (2-4 months), and scrotum (2-3 months). Other non-ear regions range from 2 to 8 weeks.

Bleeding definitely is a risk for piercings, Dr. Breuner said, especially now that so many teens are piercing body parts besides their ears. “The one I found most disturbing was that of the uvula,” she said. Bleeding risks tend to be low with ear and nose piercings, but the risk increases with the tongue, uvula, navel, nipples, and genitalia.

Another risk of mouth piercings, particularly tongue piercing, is damage to the teeth and gums, Dr. Breuner said. Barbells, the most popular type of mouth piercing, can lead to receding gums and chipped teeth with extended wear, especially because people wearing them have a tendency to frequently bite down on them.

One study found that half the participants who wore a long barbell piercing (1.59 cm or longer) for at least 2 years had lingual recession on their mandibular central incisors (J Periodontol. 2002 Mar;73[3]:289-97). Among those with a tongue piercing of at least 4 years, 47% had tooth chipping on their molars and premolars.

Another study found gingival recession was 11 times more likely among people with tongue piercings than without (J Clin Periodontol. 2010 Aug 1;37(8):712-8). Gingival recession also is a risk with lip piercings, but the risk is greater with tongue piercing, and only tongue piercings have been associated with tooth injuries (Aust Dent J. 2012 Mar;57[1]:71-8; Int J Dent Hyg. 2016 Feb;14[1]:62-73).

Hepatitis C also is a concern with body piercing. According to a systematic review of 12 studies, body piercing was a risk factor for hepatitis C infection in the majority of them (Am J Infect Control. 2001 Aug;29[4]:271-4).
 

Counseling adolescents on body modifications

You should ask teens about any tattoos or piercings they have at each visit and ask whether they have any plans to get any. Then you can answer questions about them and ensure the teens are aware of risks, particularly viral and bacterial infections and, with piercing, bleeding.

Beyond the medical risks, it’s important for teens to understand that tattoos have the potential to limit their employment in the future, depending on the job and how visible their tattoo is.

Social acceptance of tattoos and piercings have been increasing, but a survey of nearly 2,700 people conducted by Salary.com in 2013 found that 76% of respondents believed tattoos and piercings could reduce a job applicant’s chances of being hired.

If you want to learn more specifically about the safest places in your community for tattoos and piercings, Dr. Breuner recommended going out and visiting the shops. Tattoo artists generally are the most knowledgeable people in the community about the risks of their industry and often welcome local physicians who want to learn and see their equipment, she said.

NEW ORLEANS – It wasn’t until her teenage daughter wanted to get her belly button pierced that Cora Breuner, MD, became interested in the safety of tattoos and piercings for adolescents.

“You’re a pediatrician,” her daughter said. “Where should I go? Should I get this done?” Although Dr. Breuner didn’t want her daughter to get the piercing, she knew saying “no” wasn’t likely to stop her teenager any more than it would another adolescent, so she looked to the medical literature … and didn’t find much.

“I couldn’t find an article summarizing complication rates or just about the legality of it or other issues around tattooing and piercing,” said Dr. Breuner a professor of pediatrics at Seattle Children’s Hospital and the University of Washington, also in Seattle. So she and the American Academy of Pediatrics’ Committee on Adolescent Health did the work themselves and wrote one.

Now she recommends that all health care workers treating children ask their adolescent patients about tattoos and piercings at every health care visit. “I want to make sure that you are talking to your teenagers about this,” she told attendees at the annual meeting of the American Academy of Pediatrics. In her presentation, she focused on knowing the legal age of consent for body modifications and what to watch for in terms of complications.
 

Tattoos growing in popularity

More than a third (38%) of people aged 18-29 years have at least one tattoo, according to a Pew Research Center report Dr. Breuner cited, and 23% had piercings somewhere on their body besides their ears. In fact, Americans spend about $1.65 billion on tattoos each year.

Most of the people with tattoos (72%), however, had them in places that were covered and not visible, reinforcing the need to ask about them. The popularity of tattoos has been increasing in general, Dr. Breuner noted. In just the 4 years from 2012 to 2016, the prevalence of U.S. adults with at least one tattoo increased 20%.

And people don’t appear to be sorry to have them. According to a Harris Poll that Dr. Breuner cited, 86% of respondents in 2012 did not regret getting their tattoo, and respondents listed a number of feelings they associated with their tattoos: feeling sexy, rebellious, attractive, strong, spiritual, healthier, intelligent, and athletic.

Although the techniques for tattooing have changed over the years since the first documented ones in 4,000 B.C., the basic concept of injecting ink into the dermis hasn’t changed much. By injecting the ink below the epidermis, the ink remains visible for the rest of a person’s life.

Courtesy Annie Fulton

The laws for tattoos vary by state, so you need to check the laws where they live. Not much data exist on infections and complaints, but data from the Michigan Department of Health & Human Services suggests the infection rate – at least those infections reported – is low while the rate of illegally operating facilities is a bigger risk. Local health districts in Michigan have received reports of only 18 infections since 2010, but they’ve received 85 reports of illegal operations and 69 reports of social media parties centered on all attendees getting a tattoo.
 

Risks of tattoos

The biggest concern for adolescents is ensuring they understand the risks of tattoos and piercings and what to look for. One risk for tattoos is hepatitis C. However, the studies on the risk of contracting hepatitis C from tattooing are confounded by the fact that many people getting tattoos also may be engaging in other risky behaviors, such as intravenous drug use or risky sexual behaviors. Still, some research suggests that “commercially acquired tattoos accounted for more than twice as many infections as injection-drug use,” Dr. Breuner said.

Another risk is tattoo-associated bacterial skin infections (Clin Infect Dis. 2019 Aug 30;69[6]:949-55; MMWR Morb Mortal Wkly Rep. 2012 Aug 24;61[33]:653-6).
 

Risks of body piercing

Although body piercing doesn’t date back quite as far as tattoos – about 700 A.D. – its history remains long. Research suggests the top reason people get body piercings is simply liking the way it looks, as 77% of respondents reported in one study (J Am Osteopath Assoc. 2007 Oct;107[10]:432-8). Other reasons including looking fashionable, catching attention, feeling different, making a personal statement, being daring, fitting in, pressuring from peers, and defying parents.

The most serious potential complication from piercings is gangrene, but the most common is infection. Other possible complications include an allergic reaction to the metal used, a bleeding complication (estimated in 1 of 10), a scar or site reaction (estimated in 1 of 15), or, much less commonly, toxic shock syndrome. In some areas, there’s a risk of nerve damage if the nerve is pierced, such as in the eyebrow or in the bridge of the nose.

Teens particularly should be aware of the average time it takes for a piercing to heal, depending on where they get it. A navel piercing, for example, can take up to 9 months to heal. Others with long healing times include the penis (3-9 months), labia majora (2-4 months), nipple (2-4 months), and scrotum (2-3 months). Other non-ear regions range from 2 to 8 weeks.

Bleeding definitely is a risk for piercings, Dr. Breuner said, especially now that so many teens are piercing body parts besides their ears. “The one I found most disturbing was that of the uvula,” she said. Bleeding risks tend to be low with ear and nose piercings, but the risk increases with the tongue, uvula, navel, nipples, and genitalia.

Another risk of mouth piercings, particularly tongue piercing, is damage to the teeth and gums, Dr. Breuner said. Barbells, the most popular type of mouth piercing, can lead to receding gums and chipped teeth with extended wear, especially because people wearing them have a tendency to frequently bite down on them.

One study found that half the participants who wore a long barbell piercing (1.59 cm or longer) for at least 2 years had lingual recession on their mandibular central incisors (J Periodontol. 2002 Mar;73[3]:289-97). Among those with a tongue piercing of at least 4 years, 47% had tooth chipping on their molars and premolars.

Another study found gingival recession was 11 times more likely among people with tongue piercings than without (J Clin Periodontol. 2010 Aug 1;37(8):712-8). Gingival recession also is a risk with lip piercings, but the risk is greater with tongue piercing, and only tongue piercings have been associated with tooth injuries (Aust Dent J. 2012 Mar;57[1]:71-8; Int J Dent Hyg. 2016 Feb;14[1]:62-73).

Hepatitis C also is a concern with body piercing. According to a systematic review of 12 studies, body piercing was a risk factor for hepatitis C infection in the majority of them (Am J Infect Control. 2001 Aug;29[4]:271-4).
 

Counseling adolescents on body modifications

You should ask teens about any tattoos or piercings they have at each visit and ask whether they have any plans to get any. Then you can answer questions about them and ensure the teens are aware of risks, particularly viral and bacterial infections and, with piercing, bleeding.

Beyond the medical risks, it’s important for teens to understand that tattoos have the potential to limit their employment in the future, depending on the job and how visible their tattoo is.

Social acceptance of tattoos and piercings have been increasing, but a survey of nearly 2,700 people conducted by Salary.com in 2013 found that 76% of respondents believed tattoos and piercings could reduce a job applicant’s chances of being hired.

If you want to learn more specifically about the safest places in your community for tattoos and piercings, Dr. Breuner recommended going out and visiting the shops. Tattoo artists generally are the most knowledgeable people in the community about the risks of their industry and often welcome local physicians who want to learn and see their equipment, she said.

NEW ORLEANS – It wasn’t until her teenage daughter wanted to get her belly button pierced that Cora Breuner, MD, became interested in the safety of tattoos and piercings for adolescents.

“You’re a pediatrician,” her daughter said. “Where should I go? Should I get this done?” Although Dr. Breuner didn’t want her daughter to get the piercing, she knew saying “no” wasn’t likely to stop her teenager any more than it would another adolescent, so she looked to the medical literature … and didn’t find much.

“I couldn’t find an article summarizing complication rates or just about the legality of it or other issues around tattooing and piercing,” said Dr. Breuner a professor of pediatrics at Seattle Children’s Hospital and the University of Washington, also in Seattle. So she and the American Academy of Pediatrics’ Committee on Adolescent Health did the work themselves and wrote one.

Now she recommends that all health care workers treating children ask their adolescent patients about tattoos and piercings at every health care visit. “I want to make sure that you are talking to your teenagers about this,” she told attendees at the annual meeting of the American Academy of Pediatrics. In her presentation, she focused on knowing the legal age of consent for body modifications and what to watch for in terms of complications.
 

Tattoos growing in popularity

More than a third (38%) of people aged 18-29 years have at least one tattoo, according to a Pew Research Center report Dr. Breuner cited, and 23% had piercings somewhere on their body besides their ears. In fact, Americans spend about $1.65 billion on tattoos each year.

Most of the people with tattoos (72%), however, had them in places that were covered and not visible, reinforcing the need to ask about them. The popularity of tattoos has been increasing in general, Dr. Breuner noted. In just the 4 years from 2012 to 2016, the prevalence of U.S. adults with at least one tattoo increased 20%.

And people don’t appear to be sorry to have them. According to a Harris Poll that Dr. Breuner cited, 86% of respondents in 2012 did not regret getting their tattoo, and respondents listed a number of feelings they associated with their tattoos: feeling sexy, rebellious, attractive, strong, spiritual, healthier, intelligent, and athletic.

Although the techniques for tattooing have changed over the years since the first documented ones in 4,000 B.C., the basic concept of injecting ink into the dermis hasn’t changed much. By injecting the ink below the epidermis, the ink remains visible for the rest of a person’s life.

Courtesy Annie Fulton

The laws for tattoos vary by state, so you need to check the laws where they live. Not much data exist on infections and complaints, but data from the Michigan Department of Health & Human Services suggests the infection rate – at least those infections reported – is low while the rate of illegally operating facilities is a bigger risk. Local health districts in Michigan have received reports of only 18 infections since 2010, but they’ve received 85 reports of illegal operations and 69 reports of social media parties centered on all attendees getting a tattoo.
 

Risks of tattoos

The biggest concern for adolescents is ensuring they understand the risks of tattoos and piercings and what to look for. One risk for tattoos is hepatitis C. However, the studies on the risk of contracting hepatitis C from tattooing are confounded by the fact that many people getting tattoos also may be engaging in other risky behaviors, such as intravenous drug use or risky sexual behaviors. Still, some research suggests that “commercially acquired tattoos accounted for more than twice as many infections as injection-drug use,” Dr. Breuner said.

Another risk is tattoo-associated bacterial skin infections (Clin Infect Dis. 2019 Aug 30;69[6]:949-55; MMWR Morb Mortal Wkly Rep. 2012 Aug 24;61[33]:653-6).
 

Risks of body piercing

Although body piercing doesn’t date back quite as far as tattoos – about 700 A.D. – its history remains long. Research suggests the top reason people get body piercings is simply liking the way it looks, as 77% of respondents reported in one study (J Am Osteopath Assoc. 2007 Oct;107[10]:432-8). Other reasons including looking fashionable, catching attention, feeling different, making a personal statement, being daring, fitting in, pressuring from peers, and defying parents.

The most serious potential complication from piercings is gangrene, but the most common is infection. Other possible complications include an allergic reaction to the metal used, a bleeding complication (estimated in 1 of 10), a scar or site reaction (estimated in 1 of 15), or, much less commonly, toxic shock syndrome. In some areas, there’s a risk of nerve damage if the nerve is pierced, such as in the eyebrow or in the bridge of the nose.

Teens particularly should be aware of the average time it takes for a piercing to heal, depending on where they get it. A navel piercing, for example, can take up to 9 months to heal. Others with long healing times include the penis (3-9 months), labia majora (2-4 months), nipple (2-4 months), and scrotum (2-3 months). Other non-ear regions range from 2 to 8 weeks.

Bleeding definitely is a risk for piercings, Dr. Breuner said, especially now that so many teens are piercing body parts besides their ears. “The one I found most disturbing was that of the uvula,” she said. Bleeding risks tend to be low with ear and nose piercings, but the risk increases with the tongue, uvula, navel, nipples, and genitalia.

Another risk of mouth piercings, particularly tongue piercing, is damage to the teeth and gums, Dr. Breuner said. Barbells, the most popular type of mouth piercing, can lead to receding gums and chipped teeth with extended wear, especially because people wearing them have a tendency to frequently bite down on them.

One study found that half the participants who wore a long barbell piercing (1.59 cm or longer) for at least 2 years had lingual recession on their mandibular central incisors (J Periodontol. 2002 Mar;73[3]:289-97). Among those with a tongue piercing of at least 4 years, 47% had tooth chipping on their molars and premolars.

Another study found gingival recession was 11 times more likely among people with tongue piercings than without (J Clin Periodontol. 2010 Aug 1;37(8):712-8). Gingival recession also is a risk with lip piercings, but the risk is greater with tongue piercing, and only tongue piercings have been associated with tooth injuries (Aust Dent J. 2012 Mar;57[1]:71-8; Int J Dent Hyg. 2016 Feb;14[1]:62-73).

Hepatitis C also is a concern with body piercing. According to a systematic review of 12 studies, body piercing was a risk factor for hepatitis C infection in the majority of them (Am J Infect Control. 2001 Aug;29[4]:271-4).
 

Counseling adolescents on body modifications

You should ask teens about any tattoos or piercings they have at each visit and ask whether they have any plans to get any. Then you can answer questions about them and ensure the teens are aware of risks, particularly viral and bacterial infections and, with piercing, bleeding.

Beyond the medical risks, it’s important for teens to understand that tattoos have the potential to limit their employment in the future, depending on the job and how visible their tattoo is.

Social acceptance of tattoos and piercings have been increasing, but a survey of nearly 2,700 people conducted by Salary.com in 2013 found that 76% of respondents believed tattoos and piercings could reduce a job applicant’s chances of being hired.

If you want to learn more specifically about the safest places in your community for tattoos and piercings, Dr. Breuner recommended going out and visiting the shops. Tattoo artists generally are the most knowledgeable people in the community about the risks of their industry and often welcome local physicians who want to learn and see their equipment, she said.

SAN ANTONIO – Oral supplementation with a proprietary blend of human milk oligosaccharides improved all of the core symptoms of irritable bowel syndrome in a large open-label study, Magnus Simren, MD, PhD, reported at the annual meeting of the American College of Gastroenterology.

Bruce Jancin/MDedge News

The human milk oligosaccharides (HMOs) were well tolerated, too. Only 2.5% of 317 study participants at 17 U.S. sites discontinued the 12-week study because of side effects, which consisted of flatulence and other mild gastrointestinal symptoms, noted Dr. Simren, a gastroenterologist and professor of medicine at the University of Gothenburg (Sweden).

These positive study results are consistent with the notion that an altered gut microbiota plays a pathophysiological role in irritable bowel syndrome (IBS).

“The challenge is to identify suitable interventions that restore intestinal microbiota composition and functioning,” Dr. Simren observed.

Oral HMOs show promise as one such intervention. In prior small proof-of-concept studies, Dr. Simren and his coworkers demonstrated that HMOs increased gut levels of Bifidobacteria, which are microorganisms important to a healthy gut and are depleted in IBS. The investigators also established that HMOs increased levels of metabolites essential for the gut’s barrier and immune functions.

HMOs are the third-largest constituent in human breast milk. Interest in their potential therapeutic application in IBS grew out of earlier pediatric work demonstrating that HMOs are of great importance in infant health: They bind pathogens and promote gut barrier maturation and immune function.

Dr. Simren reported on 317 patients who met Rome IV criteria for IBS. Nearly two-thirds of them had severe IBS based upon an IBS–Symptom Severity Score above 300. Another third had moderate IBS. Subjects were instructed to take 5 g/day of a 4:1 mix of the HMOs 2’-fucosyllactose and lacto-N-neotetraose, a proprietary nutritional support product available over the counter as Holigos. Participants remained on stable background medications throughout the 12-week study, during which they were evaluated every 4 weeks.

The primary outcome was the effect of daily oral consumption of HMOs on stool consistency as assessed using the Bristol Stool Form Scale. At baseline, 50.3% of subjects had IBS constipation as defined by Bristol type 1-2 stools. By week 4, the proportion of patients with constipation dropped to 32.9%, and at weeks 8 and 12, just under 31%. Similarly, the proportion of patients with diarrhea as reflected in Bristol type 6-7 stools quickly improved from 40.4% at baseline to 27.5% at week 4 and 26% thereafter. Meanwhile, the proportion of patients with normal stools on the Bristol scale jumped from 9.3% at baseline to 39.6% at week 4 and nearly 43% thereafter.

About 77% of patients reported a significant reduction in symptom severity within 4 weeks, and 87% did so by 12 weeks. Bloating decreased by 59%, as did abdominal pain severity. In addition, scores on the IBS Quality of Life Scale improved by 48%.

The observed improvements in symptoms and quality of life were consistent across all IBS subtypes.

“Of course, the next step now is to perform a randomized, placebo-controlled, double-blind study to see if these encouraging results can be confirmed in that setting,” Dr. Simren commented.

Session comoderator Brooks D. Cash, MD, of the University of Texas, Houston, called the HMO study “very provocative” and declared he is looking forward to the randomized, controlled trial, which he hopes will assess the long-term durability of the treatment benefits. That trial is still in the planning stages.

Dr. Simren reported serving on an advisory board for Glycom, the Danish company which markets Holigos and sponsored the open-label U.S. study.

bjancin@mdedge.com

SAN ANTONIO – Oral supplementation with a proprietary blend of human milk oligosaccharides improved all of the core symptoms of irritable bowel syndrome in a large open-label study, Magnus Simren, MD, PhD, reported at the annual meeting of the American College of Gastroenterology.

Bruce Jancin/MDedge News

The human milk oligosaccharides (HMOs) were well tolerated, too. Only 2.5% of 317 study participants at 17 U.S. sites discontinued the 12-week study because of side effects, which consisted of flatulence and other mild gastrointestinal symptoms, noted Dr. Simren, a gastroenterologist and professor of medicine at the University of Gothenburg (Sweden).

These positive study results are consistent with the notion that an altered gut microbiota plays a pathophysiological role in irritable bowel syndrome (IBS).

“The challenge is to identify suitable interventions that restore intestinal microbiota composition and functioning,” Dr. Simren observed.

Oral HMOs show promise as one such intervention. In prior small proof-of-concept studies, Dr. Simren and his coworkers demonstrated that HMOs increased gut levels of Bifidobacteria, which are microorganisms important to a healthy gut and are depleted in IBS. The investigators also established that HMOs increased levels of metabolites essential for the gut’s barrier and immune functions.

HMOs are the third-largest constituent in human breast milk. Interest in their potential therapeutic application in IBS grew out of earlier pediatric work demonstrating that HMOs are of great importance in infant health: They bind pathogens and promote gut barrier maturation and immune function.

Dr. Simren reported on 317 patients who met Rome IV criteria for IBS. Nearly two-thirds of them had severe IBS based upon an IBS–Symptom Severity Score above 300. Another third had moderate IBS. Subjects were instructed to take 5 g/day of a 4:1 mix of the HMOs 2’-fucosyllactose and lacto-N-neotetraose, a proprietary nutritional support product available over the counter as Holigos. Participants remained on stable background medications throughout the 12-week study, during which they were evaluated every 4 weeks.

The primary outcome was the effect of daily oral consumption of HMOs on stool consistency as assessed using the Bristol Stool Form Scale. At baseline, 50.3% of subjects had IBS constipation as defined by Bristol type 1-2 stools. By week 4, the proportion of patients with constipation dropped to 32.9%, and at weeks 8 and 12, just under 31%. Similarly, the proportion of patients with diarrhea as reflected in Bristol type 6-7 stools quickly improved from 40.4% at baseline to 27.5% at week 4 and 26% thereafter. Meanwhile, the proportion of patients with normal stools on the Bristol scale jumped from 9.3% at baseline to 39.6% at week 4 and nearly 43% thereafter.

About 77% of patients reported a significant reduction in symptom severity within 4 weeks, and 87% did so by 12 weeks. Bloating decreased by 59%, as did abdominal pain severity. In addition, scores on the IBS Quality of Life Scale improved by 48%.

The observed improvements in symptoms and quality of life were consistent across all IBS subtypes.

“Of course, the next step now is to perform a randomized, placebo-controlled, double-blind study to see if these encouraging results can be confirmed in that setting,” Dr. Simren commented.

Session comoderator Brooks D. Cash, MD, of the University of Texas, Houston, called the HMO study “very provocative” and declared he is looking forward to the randomized, controlled trial, which he hopes will assess the long-term durability of the treatment benefits. That trial is still in the planning stages.

Dr. Simren reported serving on an advisory board for Glycom, the Danish company which markets Holigos and sponsored the open-label U.S. study.

bjancin@mdedge.com

SAN ANTONIO – Oral supplementation with a proprietary blend of human milk oligosaccharides improved all of the core symptoms of irritable bowel syndrome in a large open-label study, Magnus Simren, MD, PhD, reported at the annual meeting of the American College of Gastroenterology.

Bruce Jancin/MDedge News

The human milk oligosaccharides (HMOs) were well tolerated, too. Only 2.5% of 317 study participants at 17 U.S. sites discontinued the 12-week study because of side effects, which consisted of flatulence and other mild gastrointestinal symptoms, noted Dr. Simren, a gastroenterologist and professor of medicine at the University of Gothenburg (Sweden).

These positive study results are consistent with the notion that an altered gut microbiota plays a pathophysiological role in irritable bowel syndrome (IBS).

“The challenge is to identify suitable interventions that restore intestinal microbiota composition and functioning,” Dr. Simren observed.

Oral HMOs show promise as one such intervention. In prior small proof-of-concept studies, Dr. Simren and his coworkers demonstrated that HMOs increased gut levels of Bifidobacteria, which are microorganisms important to a healthy gut and are depleted in IBS. The investigators also established that HMOs increased levels of metabolites essential for the gut’s barrier and immune functions.

HMOs are the third-largest constituent in human breast milk. Interest in their potential therapeutic application in IBS grew out of earlier pediatric work demonstrating that HMOs are of great importance in infant health: They bind pathogens and promote gut barrier maturation and immune function.

Dr. Simren reported on 317 patients who met Rome IV criteria for IBS. Nearly two-thirds of them had severe IBS based upon an IBS–Symptom Severity Score above 300. Another third had moderate IBS. Subjects were instructed to take 5 g/day of a 4:1 mix of the HMOs 2’-fucosyllactose and lacto-N-neotetraose, a proprietary nutritional support product available over the counter as Holigos. Participants remained on stable background medications throughout the 12-week study, during which they were evaluated every 4 weeks.

The primary outcome was the effect of daily oral consumption of HMOs on stool consistency as assessed using the Bristol Stool Form Scale. At baseline, 50.3% of subjects had IBS constipation as defined by Bristol type 1-2 stools. By week 4, the proportion of patients with constipation dropped to 32.9%, and at weeks 8 and 12, just under 31%. Similarly, the proportion of patients with diarrhea as reflected in Bristol type 6-7 stools quickly improved from 40.4% at baseline to 27.5% at week 4 and 26% thereafter. Meanwhile, the proportion of patients with normal stools on the Bristol scale jumped from 9.3% at baseline to 39.6% at week 4 and nearly 43% thereafter.

About 77% of patients reported a significant reduction in symptom severity within 4 weeks, and 87% did so by 12 weeks. Bloating decreased by 59%, as did abdominal pain severity. In addition, scores on the IBS Quality of Life Scale improved by 48%.

The observed improvements in symptoms and quality of life were consistent across all IBS subtypes.

“Of course, the next step now is to perform a randomized, placebo-controlled, double-blind study to see if these encouraging results can be confirmed in that setting,” Dr. Simren commented.

Session comoderator Brooks D. Cash, MD, of the University of Texas, Houston, called the HMO study “very provocative” and declared he is looking forward to the randomized, controlled trial, which he hopes will assess the long-term durability of the treatment benefits. That trial is still in the planning stages.

Dr. Simren reported serving on an advisory board for Glycom, the Danish company which markets Holigos and sponsored the open-label U.S. study.

bjancin@mdedge.com

SAN ANTONIO – Maintenance therapy with the immune checkpoint inhibitor durvalumab (Imfinzi) did not improve outcomes compared with chemotherapy for patients with metastatic breast cancer, although there was a trend toward benefit for patients with triple-negative breast cancer and those whose tumors were positive for programmed death ligand 1 (PD-L1), a substudy of SAFIR-02 Breast.

Neil Osterweil/MDedge News

Median progression-free survival for 131 patients with metastatic or locally advanced, HER2-negative, hormone receptor–negative or endocrine-resistant breast cancer who received durvalumab maintenance following chemotherapy in the study was 2.7 months, compared with 4.4 months for 68 patients who received maintenance chemotherapy, reported Florence Dalenc, MD, of Institut Claudius Regaud, Toulouse, France.

“For hormone receptor–positive metastatic breast cancer, exploratory analyses suggest that anti-PD-L1 as a single agent is less effective than chemotherapy as maintenance,” she said at the San Antonio Breast Cancer Symposium.

The rationale for investigating an anti-PD-L1 agent for maintenance in patients with metastatic breast cancer is that the tumor is (presumably) not growing when immunotherapy is introduced and disease burden, a mechanism of immune suppression, has been reduced by chemotherapy. In addition, chemotherapy attracts tumor infiltrating lymphocytes (TILs) to the tumor bed, and response to chemotherapy may be a marker for immunogenic tumors, she said.

Durvalumab is a human immunoglobulin G1 kappa monoclonal antibody that blocks the interaction of the programmed death protein 1 with PD-L1. In the GeparNuevo trial, the addition of durvalumab to anthracycline-/taxane-based neoadjuvant chemotherapy increased the pathologic complete response (pCR) rate particularly in patients treated with durvalumab alone before the start of chemotherapy.

To see whether durvalumab could offer a benefit over chemotherapy in the maintenance setting, Dr. Dalenc and colleagues studied patients who were enrolled in SAFIR-02 Breast, which was designed to assess the efficacy of genomic analysis as a therapeutic decision tool in patients with metastatic breast cancer.

In the trial, patients with HER2-negative metastatic breast cancer who have a complete or partial response or stable disease following six to eight chemotherapy cycles (or 4 cycles if chemotherapy was stopped for toxicities) are randomized based on the presence or absence of targetable molecular alterations. Patients with identified alteration are then randomized to either targeted therapy matched to genomics, or to maintenance chemotherapy.

Patients without molecular alterations – the population included in the SAFIR02-IMMUNO substudy reported by Dr. Dalenc and colleagues – are stratified by one or two prior lines of chemotherapy and by response type, and then stratified on a 2:1 basis to maintenance with either durvalumab 10 mg/kg every 14 days or standard maintenance chemotherapy for up to 2 years.

In each arm, the median patient age was 56, and approximately 58% of patients had Eastern Cooperative Oncology Group (ECOG) performance status of 0. Approximately 43% of patients in each arm had three or more metastatic sites, and roughly half had liver metastases, while slightly more than one-fourth had metastases to lung.

As noted before, median PFS in the overall substudy population, the primary endpoint, was 4.6 months for patients on maintenance chemotherapy, compared with 2.7 months with durvalumab. This difference translated into an adjusted hazard ratio for progression with durvalumab of 1.40 (P = .047).

Also as noted, there were nonsignificant trends toward benefit with durvalumab among patients with triple-negative breast cancer or PD-L1-positive tumors. For all other subgroups, however, maintenance chemotherapy was favored, with significant benefit seen among patients with disease that progressed after second-line chemotherapy, patients with a clinical response at the time of re-randomization, those 50 years and older, patients with non-triple-negative disease, patients with liver metastases, and those whose tumors were negative for PD-L1.

Median overall survival (OS) was numerically longer with durvalumab (21.7 vs. 17.9 months), but this difference was not statistically significant.

In exploratory analyses, median OS for patients with triple-negative disease was 21 vs. 14 months, respectively, with an unadjusted hazard ratio favoring durvalumab of 0.54 (P = .0377). Among patients with PD-L1 positive tumors, the median OS was 26 months with durvalumab vs. 12 months with chemotherapy, with an unadjusted hazard ratio of 0.42, which just missed statistical significance (P = .0552).

Dr. Dalenc said that the study generates the hypothesis that single-agent durvalumab could improve outcomes in metastatic triple-negative breast cancer, but also raises questions about which disease parameters limit the response to anti-PD-L1 therapy.

The study was sponsored by UNICANCER with support from Fondation ARC and AstraZeneca. Dr. Dalenc reported research grants, travel, and/or advisory board activity for AstraZeneca and others.

SOURCE: Dalenc F et al. SABCS 2019. Abstract GS3-02.

SAN ANTONIO – Maintenance therapy with the immune checkpoint inhibitor durvalumab (Imfinzi) did not improve outcomes compared with chemotherapy for patients with metastatic breast cancer, although there was a trend toward benefit for patients with triple-negative breast cancer and those whose tumors were positive for programmed death ligand 1 (PD-L1), a substudy of SAFIR-02 Breast.

Neil Osterweil/MDedge News

Median progression-free survival for 131 patients with metastatic or locally advanced, HER2-negative, hormone receptor–negative or endocrine-resistant breast cancer who received durvalumab maintenance following chemotherapy in the study was 2.7 months, compared with 4.4 months for 68 patients who received maintenance chemotherapy, reported Florence Dalenc, MD, of Institut Claudius Regaud, Toulouse, France.

“For hormone receptor–positive metastatic breast cancer, exploratory analyses suggest that anti-PD-L1 as a single agent is less effective than chemotherapy as maintenance,” she said at the San Antonio Breast Cancer Symposium.

The rationale for investigating an anti-PD-L1 agent for maintenance in patients with metastatic breast cancer is that the tumor is (presumably) not growing when immunotherapy is introduced and disease burden, a mechanism of immune suppression, has been reduced by chemotherapy. In addition, chemotherapy attracts tumor infiltrating lymphocytes (TILs) to the tumor bed, and response to chemotherapy may be a marker for immunogenic tumors, she said.

Durvalumab is a human immunoglobulin G1 kappa monoclonal antibody that blocks the interaction of the programmed death protein 1 with PD-L1. In the GeparNuevo trial, the addition of durvalumab to anthracycline-/taxane-based neoadjuvant chemotherapy increased the pathologic complete response (pCR) rate particularly in patients treated with durvalumab alone before the start of chemotherapy.

To see whether durvalumab could offer a benefit over chemotherapy in the maintenance setting, Dr. Dalenc and colleagues studied patients who were enrolled in SAFIR-02 Breast, which was designed to assess the efficacy of genomic analysis as a therapeutic decision tool in patients with metastatic breast cancer.

In the trial, patients with HER2-negative metastatic breast cancer who have a complete or partial response or stable disease following six to eight chemotherapy cycles (or 4 cycles if chemotherapy was stopped for toxicities) are randomized based on the presence or absence of targetable molecular alterations. Patients with identified alteration are then randomized to either targeted therapy matched to genomics, or to maintenance chemotherapy.

Patients without molecular alterations – the population included in the SAFIR02-IMMUNO substudy reported by Dr. Dalenc and colleagues – are stratified by one or two prior lines of chemotherapy and by response type, and then stratified on a 2:1 basis to maintenance with either durvalumab 10 mg/kg every 14 days or standard maintenance chemotherapy for up to 2 years.

In each arm, the median patient age was 56, and approximately 58% of patients had Eastern Cooperative Oncology Group (ECOG) performance status of 0. Approximately 43% of patients in each arm had three or more metastatic sites, and roughly half had liver metastases, while slightly more than one-fourth had metastases to lung.

As noted before, median PFS in the overall substudy population, the primary endpoint, was 4.6 months for patients on maintenance chemotherapy, compared with 2.7 months with durvalumab. This difference translated into an adjusted hazard ratio for progression with durvalumab of 1.40 (P = .047).

Also as noted, there were nonsignificant trends toward benefit with durvalumab among patients with triple-negative breast cancer or PD-L1-positive tumors. For all other subgroups, however, maintenance chemotherapy was favored, with significant benefit seen among patients with disease that progressed after second-line chemotherapy, patients with a clinical response at the time of re-randomization, those 50 years and older, patients with non-triple-negative disease, patients with liver metastases, and those whose tumors were negative for PD-L1.

Median overall survival (OS) was numerically longer with durvalumab (21.7 vs. 17.9 months), but this difference was not statistically significant.

In exploratory analyses, median OS for patients with triple-negative disease was 21 vs. 14 months, respectively, with an unadjusted hazard ratio favoring durvalumab of 0.54 (P = .0377). Among patients with PD-L1 positive tumors, the median OS was 26 months with durvalumab vs. 12 months with chemotherapy, with an unadjusted hazard ratio of 0.42, which just missed statistical significance (P = .0552).

Dr. Dalenc said that the study generates the hypothesis that single-agent durvalumab could improve outcomes in metastatic triple-negative breast cancer, but also raises questions about which disease parameters limit the response to anti-PD-L1 therapy.

The study was sponsored by UNICANCER with support from Fondation ARC and AstraZeneca. Dr. Dalenc reported research grants, travel, and/or advisory board activity for AstraZeneca and others.

SOURCE: Dalenc F et al. SABCS 2019. Abstract GS3-02.

SAN ANTONIO – Maintenance therapy with the immune checkpoint inhibitor durvalumab (Imfinzi) did not improve outcomes compared with chemotherapy for patients with metastatic breast cancer, although there was a trend toward benefit for patients with triple-negative breast cancer and those whose tumors were positive for programmed death ligand 1 (PD-L1), a substudy of SAFIR-02 Breast.

Neil Osterweil/MDedge News

Median progression-free survival for 131 patients with metastatic or locally advanced, HER2-negative, hormone receptor–negative or endocrine-resistant breast cancer who received durvalumab maintenance following chemotherapy in the study was 2.7 months, compared with 4.4 months for 68 patients who received maintenance chemotherapy, reported Florence Dalenc, MD, of Institut Claudius Regaud, Toulouse, France.

“For hormone receptor–positive metastatic breast cancer, exploratory analyses suggest that anti-PD-L1 as a single agent is less effective than chemotherapy as maintenance,” she said at the San Antonio Breast Cancer Symposium.

The rationale for investigating an anti-PD-L1 agent for maintenance in patients with metastatic breast cancer is that the tumor is (presumably) not growing when immunotherapy is introduced and disease burden, a mechanism of immune suppression, has been reduced by chemotherapy. In addition, chemotherapy attracts tumor infiltrating lymphocytes (TILs) to the tumor bed, and response to chemotherapy may be a marker for immunogenic tumors, she said.

Durvalumab is a human immunoglobulin G1 kappa monoclonal antibody that blocks the interaction of the programmed death protein 1 with PD-L1. In the GeparNuevo trial, the addition of durvalumab to anthracycline-/taxane-based neoadjuvant chemotherapy increased the pathologic complete response (pCR) rate particularly in patients treated with durvalumab alone before the start of chemotherapy.

To see whether durvalumab could offer a benefit over chemotherapy in the maintenance setting, Dr. Dalenc and colleagues studied patients who were enrolled in SAFIR-02 Breast, which was designed to assess the efficacy of genomic analysis as a therapeutic decision tool in patients with metastatic breast cancer.

In the trial, patients with HER2-negative metastatic breast cancer who have a complete or partial response or stable disease following six to eight chemotherapy cycles (or 4 cycles if chemotherapy was stopped for toxicities) are randomized based on the presence or absence of targetable molecular alterations. Patients with identified alteration are then randomized to either targeted therapy matched to genomics, or to maintenance chemotherapy.

Patients without molecular alterations – the population included in the SAFIR02-IMMUNO substudy reported by Dr. Dalenc and colleagues – are stratified by one or two prior lines of chemotherapy and by response type, and then stratified on a 2:1 basis to maintenance with either durvalumab 10 mg/kg every 14 days or standard maintenance chemotherapy for up to 2 years.

In each arm, the median patient age was 56, and approximately 58% of patients had Eastern Cooperative Oncology Group (ECOG) performance status of 0. Approximately 43% of patients in each arm had three or more metastatic sites, and roughly half had liver metastases, while slightly more than one-fourth had metastases to lung.

As noted before, median PFS in the overall substudy population, the primary endpoint, was 4.6 months for patients on maintenance chemotherapy, compared with 2.7 months with durvalumab. This difference translated into an adjusted hazard ratio for progression with durvalumab of 1.40 (P = .047).

Also as noted, there were nonsignificant trends toward benefit with durvalumab among patients with triple-negative breast cancer or PD-L1-positive tumors. For all other subgroups, however, maintenance chemotherapy was favored, with significant benefit seen among patients with disease that progressed after second-line chemotherapy, patients with a clinical response at the time of re-randomization, those 50 years and older, patients with non-triple-negative disease, patients with liver metastases, and those whose tumors were negative for PD-L1.

Median overall survival (OS) was numerically longer with durvalumab (21.7 vs. 17.9 months), but this difference was not statistically significant.

In exploratory analyses, median OS for patients with triple-negative disease was 21 vs. 14 months, respectively, with an unadjusted hazard ratio favoring durvalumab of 0.54 (P = .0377). Among patients with PD-L1 positive tumors, the median OS was 26 months with durvalumab vs. 12 months with chemotherapy, with an unadjusted hazard ratio of 0.42, which just missed statistical significance (P = .0552).

Dr. Dalenc said that the study generates the hypothesis that single-agent durvalumab could improve outcomes in metastatic triple-negative breast cancer, but also raises questions about which disease parameters limit the response to anti-PD-L1 therapy.

The study was sponsored by UNICANCER with support from Fondation ARC and AstraZeneca. Dr. Dalenc reported research grants, travel, and/or advisory board activity for AstraZeneca and others.

SOURCE: Dalenc F et al. SABCS 2019. Abstract GS3-02.

In this edition of “How I Will Treat My Next Patient,” I highlight two recent studies that reinforce prior diagnostic and treatment preferences among many oncologists and will certainly influence the discussions we all will have with our patients in the coming weeks and months.

Rituximab maintenance in follicular lymphoma

The largest trial addressing the role of maintenance CD20-targeted antibody therapy was the Primary Rituximab and Maintenance (PRIMA) phase 3, intergroup study in 1,018 advanced follicular lymphoma patients with an initial response to induction chemoimmunotherapy. The induction regimen could be either of three commonly used regimens plus rituximab. Importantly, none of the induction regimens included bendamustine.

Patients were randomized to 2 years of rituximab maintenance or observation. Prior interim analyses at 3 and 6 years showed improvements for the rituximab maintenance patients in progression-free survival and other secondary endpoints, but no improvement in overall survival. Emmanuel Bachy, MD, PhD, and colleagues published the final survival data after 9 years of follow-up, including a final safety analysis (J Clin Oncol. 2019 Nov 1;37[31]:2815-24).

Among the 607 patients consenting to extended follow-up, median progression-free survival was 10.5 years with rituximab maintenance, compared with 4.1 years for observation (hazard ratio, 0.61; P less than .001). There were more patients with progression-free survival at 3 years, complete response or unconfirmed complete response at 2 years, longer time to next antilymphoma treatment, and later time to next chemotherapy. But the 10-year overall survival was similar in the two groups, as were the quality of life ratings.

In all, 503 patients experienced disease progression. Overall survival after progression was shorter in the rituximab maintenance arm versus the observation arm. Among the approximately 4% of patients experiencing transformation from follicular lymphoma to a more aggressive histology, there was no difference observed in time to transformation. Results were independent of the induction regimen received, response to induction, Follicular Lymphoma International Prognostic Index score, and other clinical factors.

In the safety analysis, there were more grade 3-4 adverse events among the rituximab maintenance patients – primarily cytopenia and infections – more serious adverse events, and more adverse events overall. Fatal adverse events were low in both groups (1.6 vs. 0.6%).
 

How these results influence practice

Many years ago, a senior mentor of mine taught that “progression-free survival is an important endpoint since the quality of life for patients is generally superior before relapse than afterwards.”

With that mantra playing in my mind and with the reality that discussions about relapse and subsequent treatment are never easy, the results of PRIMA seem straightforward: Rituximab maintenance is beneficial, despite the absence of an overall survival benefit, in a disease with multiple options for subsequent therapy and a long natural history. In this 9-year, final analysis of PRIMA, rituximab maintenance seems to have achieved its goals of deepening responses with low (but not inconsequential) toxicity and delaying substantially those difficult conversations with patients about how to proceed after relapse.

The influence of the final analysis of PRIMA, however, may be more complicated that it would initially seem. Bendamustine-containing regimens were not employed, are commonly used now, and some studies with bendamustine have suggested higher nonrelapse mortality with rituximab maintenance.

Low-grade adverse events take on greater importance for patients on long-term therapy than they do for patients receiving abbreviated treatment, and with noncurative treatment, the higher adverse event profile with 2 years of rituximab maintenance needs to be taken seriously. Induction and maintenance regimens involving rituximab alone, lenalidomide, or obinutuzumab may be preferred for some patients. For all of those reasons, the discussion about rituximab with advanced follicular lymphoma patients remains a long one, demanding detailed descriptions of risks, benefits, limitations of the data, and multiple modern day alternatives to the treatments employed in PRIMA.
 

Supplemental MRI for dense breast tissue

In the DENSE trial, investigators assigned 40,373 women with extremely dense breast tissue and negative results on screening mammography to be offered either supplemental MRI or mammography screening every other year only. The women were 50-75 years old and were enrolled in the Dutch population-based digital mammography screening program. The primary outcome was the difference in the number of cancers that developed in the 2-year interval between mammograms (N Engl J Med 2019;381:2091-102).

The interval cancer rate was 2.5 per 1,000 screenings among 4,783 women in the “MRI-invitation” group (41% of whom did not actually agree to have an MRI), and 5 per 1,000 in the 32,312 women in the “mammography-only” group, a difference of 2.5 per 1,000 screenings (P less than .001).

Of the 20 interval cancers diagnosed in the MRI-invitation group, 4 were diagnosed in the 59% of women who had undergone MRI (0.8 per 1,000 screenings). The remaining 16 were diagnosed in those who had declined an MRI (4.9 per 1,000 screenings) – virtually identical to the rate of interval cancers in the group that was not invited to have an MRI. This speaks against nonrandom allocation of patients between the mammography-only and the supplemental MRI groups.

Although supplemental MRI was associated with a cancer-detection rate of 16.5 per 1,000 screenings, there was a false positive rate of 8.0% (79.8 per 1,000 screenings). Of the women who underwent a breast biopsy after MRI, 73.7% did not have cancer. Among the women who had MRI-detected cancers, in general, the malignancies diagnosed were smaller, more likely node negative, better differentiated, and more often hormone receptor–positive, compared with those in the mammography-only group.

At the next screening mammogram, the cancer detection rate was lower in the MRI-screened group (2 per 1,000 screenings) than in the MRI–“offered but declined” (7.1 per 1,000 screenings) or mammogram-only groups (6 per 1,000 screenings).
 

How these results influence practice

American physicians are obligated to inform women with dense breast tissue about the limitations (for them) of conventional mammography, an unquantified, but elevated, risk of breast cancer in women with dense breast tissue, and the fact that there are no universally accepted recommended subsequent steps those women should take.

One side benefit of the requirement to disclose information about breast density, however, is that disclosure can prompt discussions about breast cancer risk reduction – an important discussion with multiple possible health-maintaining interventions.

The DENSE trial is very important news, with potential for even more value in future years. It is finite (2 years of study, with only one MRI scan mandated), narrow (Vopara or BI-RADs breast density grade 4 only), and oligo-institutional (eight participating centers in the Netherlands). Still, it provides randomized, rigorously gathered and analyzed data where there were previously none. Importantly, it answers the question, “So what can I do now, doctor?”

I have some concerns about whether we, as a medical community, have the discipline to restrict application of supplemental MRI screening beyond the population that was studied in the Netherlands. Will we be able to restrain ourselves from ordering MRI scans in women with heterogeneously dense – but not extremely dense – breasts? Will we truly manage patients whose MRI scans had BI-RADs readings of less than 4 in the rigorous, but conservative, fashion employed in the trial? Would we miss fewer significant cancers and subject fewer patients to potential expense and harm with annual mammography, instead of the biennial screening performed in the Netherlands? Does tomo-synthesis improve the interpretation of screening mammograms so much that the interval cancer rate is a lot closer to the rate obtained with supplemental MRI scans? Is the expense of MRI scanning, with the resultant subsequent tests and procedures, justified by the reduction in detecting relatively favorable breast cancers that may not materially impact overall survival?

The DENSE study promises to be a “gift that keeps on giving” as the investigators continue to assess a number of factors including: the value of ongoing supplemental MRI scans (compared with the one-time-only screening reported here); whether there will be a reduction in the advanced cancers and subsequent mortality benefit; the extent of over diagnosis, costs, and impact on quality-of-life; and the applicability of artificial intelligence techniques to reduce false positive MRI results.

While the study may not be practice changing in the United States at the present time, it may be just that as subsequent analyses emerge.
 

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

In this edition of “How I Will Treat My Next Patient,” I highlight two recent studies that reinforce prior diagnostic and treatment preferences among many oncologists and will certainly influence the discussions we all will have with our patients in the coming weeks and months.

Rituximab maintenance in follicular lymphoma

The largest trial addressing the role of maintenance CD20-targeted antibody therapy was the Primary Rituximab and Maintenance (PRIMA) phase 3, intergroup study in 1,018 advanced follicular lymphoma patients with an initial response to induction chemoimmunotherapy. The induction regimen could be either of three commonly used regimens plus rituximab. Importantly, none of the induction regimens included bendamustine.

Patients were randomized to 2 years of rituximab maintenance or observation. Prior interim analyses at 3 and 6 years showed improvements for the rituximab maintenance patients in progression-free survival and other secondary endpoints, but no improvement in overall survival. Emmanuel Bachy, MD, PhD, and colleagues published the final survival data after 9 years of follow-up, including a final safety analysis (J Clin Oncol. 2019 Nov 1;37[31]:2815-24).

Among the 607 patients consenting to extended follow-up, median progression-free survival was 10.5 years with rituximab maintenance, compared with 4.1 years for observation (hazard ratio, 0.61; P less than .001). There were more patients with progression-free survival at 3 years, complete response or unconfirmed complete response at 2 years, longer time to next antilymphoma treatment, and later time to next chemotherapy. But the 10-year overall survival was similar in the two groups, as were the quality of life ratings.

In all, 503 patients experienced disease progression. Overall survival after progression was shorter in the rituximab maintenance arm versus the observation arm. Among the approximately 4% of patients experiencing transformation from follicular lymphoma to a more aggressive histology, there was no difference observed in time to transformation. Results were independent of the induction regimen received, response to induction, Follicular Lymphoma International Prognostic Index score, and other clinical factors.

In the safety analysis, there were more grade 3-4 adverse events among the rituximab maintenance patients – primarily cytopenia and infections – more serious adverse events, and more adverse events overall. Fatal adverse events were low in both groups (1.6 vs. 0.6%).
 

How these results influence practice

Many years ago, a senior mentor of mine taught that “progression-free survival is an important endpoint since the quality of life for patients is generally superior before relapse than afterwards.”

With that mantra playing in my mind and with the reality that discussions about relapse and subsequent treatment are never easy, the results of PRIMA seem straightforward: Rituximab maintenance is beneficial, despite the absence of an overall survival benefit, in a disease with multiple options for subsequent therapy and a long natural history. In this 9-year, final analysis of PRIMA, rituximab maintenance seems to have achieved its goals of deepening responses with low (but not inconsequential) toxicity and delaying substantially those difficult conversations with patients about how to proceed after relapse.

The influence of the final analysis of PRIMA, however, may be more complicated that it would initially seem. Bendamustine-containing regimens were not employed, are commonly used now, and some studies with bendamustine have suggested higher nonrelapse mortality with rituximab maintenance.

Low-grade adverse events take on greater importance for patients on long-term therapy than they do for patients receiving abbreviated treatment, and with noncurative treatment, the higher adverse event profile with 2 years of rituximab maintenance needs to be taken seriously. Induction and maintenance regimens involving rituximab alone, lenalidomide, or obinutuzumab may be preferred for some patients. For all of those reasons, the discussion about rituximab with advanced follicular lymphoma patients remains a long one, demanding detailed descriptions of risks, benefits, limitations of the data, and multiple modern day alternatives to the treatments employed in PRIMA.
 

Supplemental MRI for dense breast tissue

In the DENSE trial, investigators assigned 40,373 women with extremely dense breast tissue and negative results on screening mammography to be offered either supplemental MRI or mammography screening every other year only. The women were 50-75 years old and were enrolled in the Dutch population-based digital mammography screening program. The primary outcome was the difference in the number of cancers that developed in the 2-year interval between mammograms (N Engl J Med 2019;381:2091-102).

The interval cancer rate was 2.5 per 1,000 screenings among 4,783 women in the “MRI-invitation” group (41% of whom did not actually agree to have an MRI), and 5 per 1,000 in the 32,312 women in the “mammography-only” group, a difference of 2.5 per 1,000 screenings (P less than .001).

Of the 20 interval cancers diagnosed in the MRI-invitation group, 4 were diagnosed in the 59% of women who had undergone MRI (0.8 per 1,000 screenings). The remaining 16 were diagnosed in those who had declined an MRI (4.9 per 1,000 screenings) – virtually identical to the rate of interval cancers in the group that was not invited to have an MRI. This speaks against nonrandom allocation of patients between the mammography-only and the supplemental MRI groups.

Although supplemental MRI was associated with a cancer-detection rate of 16.5 per 1,000 screenings, there was a false positive rate of 8.0% (79.8 per 1,000 screenings). Of the women who underwent a breast biopsy after MRI, 73.7% did not have cancer. Among the women who had MRI-detected cancers, in general, the malignancies diagnosed were smaller, more likely node negative, better differentiated, and more often hormone receptor–positive, compared with those in the mammography-only group.

At the next screening mammogram, the cancer detection rate was lower in the MRI-screened group (2 per 1,000 screenings) than in the MRI–“offered but declined” (7.1 per 1,000 screenings) or mammogram-only groups (6 per 1,000 screenings).
 

How these results influence practice

American physicians are obligated to inform women with dense breast tissue about the limitations (for them) of conventional mammography, an unquantified, but elevated, risk of breast cancer in women with dense breast tissue, and the fact that there are no universally accepted recommended subsequent steps those women should take.

One side benefit of the requirement to disclose information about breast density, however, is that disclosure can prompt discussions about breast cancer risk reduction – an important discussion with multiple possible health-maintaining interventions.

The DENSE trial is very important news, with potential for even more value in future years. It is finite (2 years of study, with only one MRI scan mandated), narrow (Vopara or BI-RADs breast density grade 4 only), and oligo-institutional (eight participating centers in the Netherlands). Still, it provides randomized, rigorously gathered and analyzed data where there were previously none. Importantly, it answers the question, “So what can I do now, doctor?”

I have some concerns about whether we, as a medical community, have the discipline to restrict application of supplemental MRI screening beyond the population that was studied in the Netherlands. Will we be able to restrain ourselves from ordering MRI scans in women with heterogeneously dense – but not extremely dense – breasts? Will we truly manage patients whose MRI scans had BI-RADs readings of less than 4 in the rigorous, but conservative, fashion employed in the trial? Would we miss fewer significant cancers and subject fewer patients to potential expense and harm with annual mammography, instead of the biennial screening performed in the Netherlands? Does tomo-synthesis improve the interpretation of screening mammograms so much that the interval cancer rate is a lot closer to the rate obtained with supplemental MRI scans? Is the expense of MRI scanning, with the resultant subsequent tests and procedures, justified by the reduction in detecting relatively favorable breast cancers that may not materially impact overall survival?

The DENSE study promises to be a “gift that keeps on giving” as the investigators continue to assess a number of factors including: the value of ongoing supplemental MRI scans (compared with the one-time-only screening reported here); whether there will be a reduction in the advanced cancers and subsequent mortality benefit; the extent of over diagnosis, costs, and impact on quality-of-life; and the applicability of artificial intelligence techniques to reduce false positive MRI results.

While the study may not be practice changing in the United States at the present time, it may be just that as subsequent analyses emerge.
 

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

In this edition of “How I Will Treat My Next Patient,” I highlight two recent studies that reinforce prior diagnostic and treatment preferences among many oncologists and will certainly influence the discussions we all will have with our patients in the coming weeks and months.

Rituximab maintenance in follicular lymphoma

The largest trial addressing the role of maintenance CD20-targeted antibody therapy was the Primary Rituximab and Maintenance (PRIMA) phase 3, intergroup study in 1,018 advanced follicular lymphoma patients with an initial response to induction chemoimmunotherapy. The induction regimen could be either of three commonly used regimens plus rituximab. Importantly, none of the induction regimens included bendamustine.

Patients were randomized to 2 years of rituximab maintenance or observation. Prior interim analyses at 3 and 6 years showed improvements for the rituximab maintenance patients in progression-free survival and other secondary endpoints, but no improvement in overall survival. Emmanuel Bachy, MD, PhD, and colleagues published the final survival data after 9 years of follow-up, including a final safety analysis (J Clin Oncol. 2019 Nov 1;37[31]:2815-24).

Among the 607 patients consenting to extended follow-up, median progression-free survival was 10.5 years with rituximab maintenance, compared with 4.1 years for observation (hazard ratio, 0.61; P less than .001). There were more patients with progression-free survival at 3 years, complete response or unconfirmed complete response at 2 years, longer time to next antilymphoma treatment, and later time to next chemotherapy. But the 10-year overall survival was similar in the two groups, as were the quality of life ratings.

In all, 503 patients experienced disease progression. Overall survival after progression was shorter in the rituximab maintenance arm versus the observation arm. Among the approximately 4% of patients experiencing transformation from follicular lymphoma to a more aggressive histology, there was no difference observed in time to transformation. Results were independent of the induction regimen received, response to induction, Follicular Lymphoma International Prognostic Index score, and other clinical factors.

In the safety analysis, there were more grade 3-4 adverse events among the rituximab maintenance patients – primarily cytopenia and infections – more serious adverse events, and more adverse events overall. Fatal adverse events were low in both groups (1.6 vs. 0.6%).
 

How these results influence practice

Many years ago, a senior mentor of mine taught that “progression-free survival is an important endpoint since the quality of life for patients is generally superior before relapse than afterwards.”

With that mantra playing in my mind and with the reality that discussions about relapse and subsequent treatment are never easy, the results of PRIMA seem straightforward: Rituximab maintenance is beneficial, despite the absence of an overall survival benefit, in a disease with multiple options for subsequent therapy and a long natural history. In this 9-year, final analysis of PRIMA, rituximab maintenance seems to have achieved its goals of deepening responses with low (but not inconsequential) toxicity and delaying substantially those difficult conversations with patients about how to proceed after relapse.

The influence of the final analysis of PRIMA, however, may be more complicated that it would initially seem. Bendamustine-containing regimens were not employed, are commonly used now, and some studies with bendamustine have suggested higher nonrelapse mortality with rituximab maintenance.

Low-grade adverse events take on greater importance for patients on long-term therapy than they do for patients receiving abbreviated treatment, and with noncurative treatment, the higher adverse event profile with 2 years of rituximab maintenance needs to be taken seriously. Induction and maintenance regimens involving rituximab alone, lenalidomide, or obinutuzumab may be preferred for some patients. For all of those reasons, the discussion about rituximab with advanced follicular lymphoma patients remains a long one, demanding detailed descriptions of risks, benefits, limitations of the data, and multiple modern day alternatives to the treatments employed in PRIMA.
 

Supplemental MRI for dense breast tissue

In the DENSE trial, investigators assigned 40,373 women with extremely dense breast tissue and negative results on screening mammography to be offered either supplemental MRI or mammography screening every other year only. The women were 50-75 years old and were enrolled in the Dutch population-based digital mammography screening program. The primary outcome was the difference in the number of cancers that developed in the 2-year interval between mammograms (N Engl J Med 2019;381:2091-102).

The interval cancer rate was 2.5 per 1,000 screenings among 4,783 women in the “MRI-invitation” group (41% of whom did not actually agree to have an MRI), and 5 per 1,000 in the 32,312 women in the “mammography-only” group, a difference of 2.5 per 1,000 screenings (P less than .001).

Of the 20 interval cancers diagnosed in the MRI-invitation group, 4 were diagnosed in the 59% of women who had undergone MRI (0.8 per 1,000 screenings). The remaining 16 were diagnosed in those who had declined an MRI (4.9 per 1,000 screenings) – virtually identical to the rate of interval cancers in the group that was not invited to have an MRI. This speaks against nonrandom allocation of patients between the mammography-only and the supplemental MRI groups.

Although supplemental MRI was associated with a cancer-detection rate of 16.5 per 1,000 screenings, there was a false positive rate of 8.0% (79.8 per 1,000 screenings). Of the women who underwent a breast biopsy after MRI, 73.7% did not have cancer. Among the women who had MRI-detected cancers, in general, the malignancies diagnosed were smaller, more likely node negative, better differentiated, and more often hormone receptor–positive, compared with those in the mammography-only group.

At the next screening mammogram, the cancer detection rate was lower in the MRI-screened group (2 per 1,000 screenings) than in the MRI–“offered but declined” (7.1 per 1,000 screenings) or mammogram-only groups (6 per 1,000 screenings).
 

How these results influence practice

American physicians are obligated to inform women with dense breast tissue about the limitations (for them) of conventional mammography, an unquantified, but elevated, risk of breast cancer in women with dense breast tissue, and the fact that there are no universally accepted recommended subsequent steps those women should take.

One side benefit of the requirement to disclose information about breast density, however, is that disclosure can prompt discussions about breast cancer risk reduction – an important discussion with multiple possible health-maintaining interventions.

The DENSE trial is very important news, with potential for even more value in future years. It is finite (2 years of study, with only one MRI scan mandated), narrow (Vopara or BI-RADs breast density grade 4 only), and oligo-institutional (eight participating centers in the Netherlands). Still, it provides randomized, rigorously gathered and analyzed data where there were previously none. Importantly, it answers the question, “So what can I do now, doctor?”

I have some concerns about whether we, as a medical community, have the discipline to restrict application of supplemental MRI screening beyond the population that was studied in the Netherlands. Will we be able to restrain ourselves from ordering MRI scans in women with heterogeneously dense – but not extremely dense – breasts? Will we truly manage patients whose MRI scans had BI-RADs readings of less than 4 in the rigorous, but conservative, fashion employed in the trial? Would we miss fewer significant cancers and subject fewer patients to potential expense and harm with annual mammography, instead of the biennial screening performed in the Netherlands? Does tomo-synthesis improve the interpretation of screening mammograms so much that the interval cancer rate is a lot closer to the rate obtained with supplemental MRI scans? Is the expense of MRI scanning, with the resultant subsequent tests and procedures, justified by the reduction in detecting relatively favorable breast cancers that may not materially impact overall survival?

The DENSE study promises to be a “gift that keeps on giving” as the investigators continue to assess a number of factors including: the value of ongoing supplemental MRI scans (compared with the one-time-only screening reported here); whether there will be a reduction in the advanced cancers and subsequent mortality benefit; the extent of over diagnosis, costs, and impact on quality-of-life; and the applicability of artificial intelligence techniques to reduce false positive MRI results.

While the study may not be practice changing in the United States at the present time, it may be just that as subsequent analyses emerge.
 

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.