Susan London

SEATTLE – Hydroxychloroquine is not efficacious for treating primary hand osteoarthritis, according to results from the first randomized trial to test the disease-modifying antirheumatic drug in this patient population.

Findings reported at the World Congress on Osteoarthritis showed that after 24 weeks of treatment, scores for pain and hand function budged little from baseline whether patients took hydroxychloroquine (Plaquenil) or a placebo. And although the drug was generally well tolerated, patients in that group more commonly had allergic reactions and developed rashes.

“The results of our study do not support the prescription of hydroxychloroquine in patients with hand osteoarthritis,” concluded lead investigator WeiChing Lee, Pharm.D., hospital pharmacist at the Maasstad Hospital Rotterdam in the Netherlands.

During a question and answer period, however, session attendees pointed out some study limitations that may still leave the door open for hydroxychloroquine in this setting.

“Thank you for doing this trial. I’ve always wanted to see a randomized, controlled trial looking at this. I’m a little depressed that it’s negative,” commented session attendee Dr. Grace Lo of the Baylor College of Medicine in Houston. An older case series did suggest a benefit of hydroxychloroquine in patients with more severe disease, “so I was wondering why you specifically excluded those people from this study.”

“We believed that patients with very severe disease are not likely to benefit from hydroxychloroquine because it is in the end stage,” Dr. Lee replied.

Dr. Lo further wondered if outcomes had been assessed separately among patients with different anatomic types of hand osteoarthritis, such as carpometacarpal osteoarthritis versus osteoarthritis of the proximal and distal interphalangeal joints. The investigators have not performed those analyses, according to Dr. Lee. “You just need to see if there is a difference,” Dr. Lo recommended.

Another attendee noted that pain scores at baseline suggested some patients had little to no pain. “Did you do a subgroup analysis looking at higher pain scores at baseline versus lower pain scores?” he asked.

“Yes, we did a subanalysis of patients with a pain score of 60 mm or more versus less [on a 100-mm scale], and we saw it improved with more severe pain symptoms; there was a decrease of 15 mm in the pain scores in both the placebo and hydroxychloroquine groups,” Dr. Lee replied, and still no difference between groups.

“Were you surprised there was no placebo response?” that attendee further asked.

“Yes, we were. That was the reason why we did the subanalysis,” Dr. Lee said; results showed a placebo effect in the group with more severe pain but not in the group with less severe pain.

A third attendee asked, “Do you have any data on how much inflammation these patients actually had at baseline? Could the lack of effect be due to low inflammation at baseline?”

The investigators have not looked at inflammatory markers, Dr. Lee replied.

In an interview, Dr. Xavier Chevalier, session comoderator and head of the department of rheumatology at the Henri Mondor Hospital, University Paris XII, in Créteil, France, agreed with the attendees’ points. “Unfortunately, this is a negative trial, but I’m afraid that the level of pain was not really well defined at the beginning of the study,” he said. “And it’s a little bit of a shame that they didn’t include patients with a very high level of pain.”

Introducing the study, Dr. Lee noted, “The cause and pathophysiology of hand osteoarthritis have not been clarified yet, but it is clear that inflammation plays an important tole. So it is believed that anti-inflammatory drugs might be effective in treating hand osteoarthritis.”

“Hydroxychloroquine is an anti-inflammatory drug that has been used successfully in other rheumatic diseases. It is prescribed commonly in hand osteoarthritis, but this indication is off label and not well investigated,” she said.

The investigators recruited to the trial 202 patients who met American College of Rheumatology criteria for primary hand osteoarthritis from outpatient rheumatology clinics in the Netherlands.

The patients had had pain from their arthritis for at least 1 year and had nodules or Kellgren-Lawrence grade 1, 2, or 3 changes in at least two symptomatic joints; those with grade 4 changes were excluded. They were randomized evenly to treatment with hydroxychloroquine (400 mg daily) or placebo.

Pain at baseline averaged about 44 mm on the 100-mm Visual Analog Scale (VAS) pain scale in each group, according to data reported at the meeting sponsored by the Osteoarthritis Research Society International.

Intention-to-treat analyses showed that at 24 weeks, the VAS score had increased by 0.10 mm in the placebo group and decreased by 1.3 mm in the hydroxychloroquine group, but the difference was not significant, reported Dr. Lee, who disclosed that she had no relevant conflicts of interest.

The groups were likewise statistically indistinguishable with respect to the change from baseline in the Australian/Canadian Osteoarthritis Hand Index (AUSCAN) scores and in total scores on the short form of the Arthritis Impact Measurement Scales 2 (AIMS2-SF).

About a fifth of patients in each group experienced adverse events. The hydroxychloroquine group had more allergic reactions (three vs. none) and cases of rash/pruritus (eight vs. three).

Dr. Lee disclosed that she had no relevant conflicts of interest.

SEATTLE – Hydroxychloroquine is not efficacious for treating primary hand osteoarthritis, according to results from the first randomized trial to test the disease-modifying antirheumatic drug in this patient population.

Findings reported at the World Congress on Osteoarthritis showed that after 24 weeks of treatment, scores for pain and hand function budged little from baseline whether patients took hydroxychloroquine (Plaquenil) or a placebo. And although the drug was generally well tolerated, patients in that group more commonly had allergic reactions and developed rashes.

“The results of our study do not support the prescription of hydroxychloroquine in patients with hand osteoarthritis,” concluded lead investigator WeiChing Lee, Pharm.D., hospital pharmacist at the Maasstad Hospital Rotterdam in the Netherlands.

During a question and answer period, however, session attendees pointed out some study limitations that may still leave the door open for hydroxychloroquine in this setting.

“Thank you for doing this trial. I’ve always wanted to see a randomized, controlled trial looking at this. I’m a little depressed that it’s negative,” commented session attendee Dr. Grace Lo of the Baylor College of Medicine in Houston. An older case series did suggest a benefit of hydroxychloroquine in patients with more severe disease, “so I was wondering why you specifically excluded those people from this study.”

“We believed that patients with very severe disease are not likely to benefit from hydroxychloroquine because it is in the end stage,” Dr. Lee replied.

Dr. Lo further wondered if outcomes had been assessed separately among patients with different anatomic types of hand osteoarthritis, such as carpometacarpal osteoarthritis versus osteoarthritis of the proximal and distal interphalangeal joints. The investigators have not performed those analyses, according to Dr. Lee. “You just need to see if there is a difference,” Dr. Lo recommended.

Another attendee noted that pain scores at baseline suggested some patients had little to no pain. “Did you do a subgroup analysis looking at higher pain scores at baseline versus lower pain scores?” he asked.

“Yes, we did a subanalysis of patients with a pain score of 60 mm or more versus less [on a 100-mm scale], and we saw it improved with more severe pain symptoms; there was a decrease of 15 mm in the pain scores in both the placebo and hydroxychloroquine groups,” Dr. Lee replied, and still no difference between groups.

“Were you surprised there was no placebo response?” that attendee further asked.

“Yes, we were. That was the reason why we did the subanalysis,” Dr. Lee said; results showed a placebo effect in the group with more severe pain but not in the group with less severe pain.

A third attendee asked, “Do you have any data on how much inflammation these patients actually had at baseline? Could the lack of effect be due to low inflammation at baseline?”

The investigators have not looked at inflammatory markers, Dr. Lee replied.

In an interview, Dr. Xavier Chevalier, session comoderator and head of the department of rheumatology at the Henri Mondor Hospital, University Paris XII, in Créteil, France, agreed with the attendees’ points. “Unfortunately, this is a negative trial, but I’m afraid that the level of pain was not really well defined at the beginning of the study,” he said. “And it’s a little bit of a shame that they didn’t include patients with a very high level of pain.”

Introducing the study, Dr. Lee noted, “The cause and pathophysiology of hand osteoarthritis have not been clarified yet, but it is clear that inflammation plays an important tole. So it is believed that anti-inflammatory drugs might be effective in treating hand osteoarthritis.”

“Hydroxychloroquine is an anti-inflammatory drug that has been used successfully in other rheumatic diseases. It is prescribed commonly in hand osteoarthritis, but this indication is off label and not well investigated,” she said.

The investigators recruited to the trial 202 patients who met American College of Rheumatology criteria for primary hand osteoarthritis from outpatient rheumatology clinics in the Netherlands.

The patients had had pain from their arthritis for at least 1 year and had nodules or Kellgren-Lawrence grade 1, 2, or 3 changes in at least two symptomatic joints; those with grade 4 changes were excluded. They were randomized evenly to treatment with hydroxychloroquine (400 mg daily) or placebo.

Pain at baseline averaged about 44 mm on the 100-mm Visual Analog Scale (VAS) pain scale in each group, according to data reported at the meeting sponsored by the Osteoarthritis Research Society International.

Intention-to-treat analyses showed that at 24 weeks, the VAS score had increased by 0.10 mm in the placebo group and decreased by 1.3 mm in the hydroxychloroquine group, but the difference was not significant, reported Dr. Lee, who disclosed that she had no relevant conflicts of interest.

The groups were likewise statistically indistinguishable with respect to the change from baseline in the Australian/Canadian Osteoarthritis Hand Index (AUSCAN) scores and in total scores on the short form of the Arthritis Impact Measurement Scales 2 (AIMS2-SF).

About a fifth of patients in each group experienced adverse events. The hydroxychloroquine group had more allergic reactions (three vs. none) and cases of rash/pruritus (eight vs. three).

Dr. Lee disclosed that she had no relevant conflicts of interest.

SEATTLE – Hydroxychloroquine is not efficacious for treating primary hand osteoarthritis, according to results from the first randomized trial to test the disease-modifying antirheumatic drug in this patient population.

Findings reported at the World Congress on Osteoarthritis showed that after 24 weeks of treatment, scores for pain and hand function budged little from baseline whether patients took hydroxychloroquine (Plaquenil) or a placebo. And although the drug was generally well tolerated, patients in that group more commonly had allergic reactions and developed rashes.

“The results of our study do not support the prescription of hydroxychloroquine in patients with hand osteoarthritis,” concluded lead investigator WeiChing Lee, Pharm.D., hospital pharmacist at the Maasstad Hospital Rotterdam in the Netherlands.

During a question and answer period, however, session attendees pointed out some study limitations that may still leave the door open for hydroxychloroquine in this setting.

“Thank you for doing this trial. I’ve always wanted to see a randomized, controlled trial looking at this. I’m a little depressed that it’s negative,” commented session attendee Dr. Grace Lo of the Baylor College of Medicine in Houston. An older case series did suggest a benefit of hydroxychloroquine in patients with more severe disease, “so I was wondering why you specifically excluded those people from this study.”

“We believed that patients with very severe disease are not likely to benefit from hydroxychloroquine because it is in the end stage,” Dr. Lee replied.

Dr. Lo further wondered if outcomes had been assessed separately among patients with different anatomic types of hand osteoarthritis, such as carpometacarpal osteoarthritis versus osteoarthritis of the proximal and distal interphalangeal joints. The investigators have not performed those analyses, according to Dr. Lee. “You just need to see if there is a difference,” Dr. Lo recommended.

Another attendee noted that pain scores at baseline suggested some patients had little to no pain. “Did you do a subgroup analysis looking at higher pain scores at baseline versus lower pain scores?” he asked.

“Yes, we did a subanalysis of patients with a pain score of 60 mm or more versus less [on a 100-mm scale], and we saw it improved with more severe pain symptoms; there was a decrease of 15 mm in the pain scores in both the placebo and hydroxychloroquine groups,” Dr. Lee replied, and still no difference between groups.

“Were you surprised there was no placebo response?” that attendee further asked.

“Yes, we were. That was the reason why we did the subanalysis,” Dr. Lee said; results showed a placebo effect in the group with more severe pain but not in the group with less severe pain.

A third attendee asked, “Do you have any data on how much inflammation these patients actually had at baseline? Could the lack of effect be due to low inflammation at baseline?”

The investigators have not looked at inflammatory markers, Dr. Lee replied.

In an interview, Dr. Xavier Chevalier, session comoderator and head of the department of rheumatology at the Henri Mondor Hospital, University Paris XII, in Créteil, France, agreed with the attendees’ points. “Unfortunately, this is a negative trial, but I’m afraid that the level of pain was not really well defined at the beginning of the study,” he said. “And it’s a little bit of a shame that they didn’t include patients with a very high level of pain.”

Introducing the study, Dr. Lee noted, “The cause and pathophysiology of hand osteoarthritis have not been clarified yet, but it is clear that inflammation plays an important tole. So it is believed that anti-inflammatory drugs might be effective in treating hand osteoarthritis.”

“Hydroxychloroquine is an anti-inflammatory drug that has been used successfully in other rheumatic diseases. It is prescribed commonly in hand osteoarthritis, but this indication is off label and not well investigated,” she said.

The investigators recruited to the trial 202 patients who met American College of Rheumatology criteria for primary hand osteoarthritis from outpatient rheumatology clinics in the Netherlands.

The patients had had pain from their arthritis for at least 1 year and had nodules or Kellgren-Lawrence grade 1, 2, or 3 changes in at least two symptomatic joints; those with grade 4 changes were excluded. They were randomized evenly to treatment with hydroxychloroquine (400 mg daily) or placebo.

Pain at baseline averaged about 44 mm on the 100-mm Visual Analog Scale (VAS) pain scale in each group, according to data reported at the meeting sponsored by the Osteoarthritis Research Society International.

Intention-to-treat analyses showed that at 24 weeks, the VAS score had increased by 0.10 mm in the placebo group and decreased by 1.3 mm in the hydroxychloroquine group, but the difference was not significant, reported Dr. Lee, who disclosed that she had no relevant conflicts of interest.

The groups were likewise statistically indistinguishable with respect to the change from baseline in the Australian/Canadian Osteoarthritis Hand Index (AUSCAN) scores and in total scores on the short form of the Arthritis Impact Measurement Scales 2 (AIMS2-SF).

About a fifth of patients in each group experienced adverse events. The hydroxychloroquine group had more allergic reactions (three vs. none) and cases of rash/pruritus (eight vs. three).

Dr. Lee disclosed that she had no relevant conflicts of interest.

SEATTLE – Smoking is related to prevalent and incident joint pain in patients who have knee osteoarthritis or are at high risk for it, but the mechanism of this association is unclear, in a study of 3,026 patients.

“Previous studies have shown that compared to nonsmokers, smokers have more musculoskeletal pain and report more severe pain,” Jingbo Niu, D.Sc. of the Clinical Epidemiology Research & Training Unit at Boston University reported at the World Congress on Osteoarthritis.

Possible mechanisms include down-regulation of the hypothalamic-pituitary-adrenal axis or triggering of nicotine-sensitive acetylcholine receptors in the dorsal root ganglion. “These factors may translate to a change in pain perception among smokers,” she said.

Dr. Niu and her colleagues analyzed data from the Multicenter Osteoarthritis Study (MOST), a prospective cohort study of risk factors for the development and progression of knee osteoarthritis and knee pain in patients initially aged 50-79 years. They performed cross-sectional analyses at baseline and at the 7-year follow-up visit, and longitudinal analyses for the interim period.

At baseline, 56% of the cohort were never-smokers, 38% were former smokers, and 6% were current smokers, reported Dr. Niu, who disclosed that she had no relevant conflicts of interest. Smoking intensity averaged 22 pack-years.

Study results showed that at baseline, current smokers had significantly more severe knee pain than did never-smokers, with an adjusted difference of 0.83 points on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) knee pain scale.

Also at baseline, former smokers were more likely than were never-smokers to have widespread joint pain, defined as pain in all five regions of a joint pain homunculus (adjusted odds ratio, 1.3). And there was a dose-response relationship, whereby the greater the number of pack-years at baseline, the higher the risk of developing widespread joint pain during follow-up (P = .02).

However, neither smoking status nor smoking intensity was significantly associated with pain sensitization, assessed from the pressure pain threshold at the right wrist, according to the data reported at the meeting, which was sponsored by the Osteoarthritis Research Society International.

“We found smoking was related to knee pain severity and widespread pain, but not with pain sensitization,” Dr. Niu concluded.

“The number of current smokers in our analysis was limited,” she said. In addition, “subjects with knee pain were more likely to be recruited into the MOST study because they have a high risk of developing knee osteoarthritis. This inclusion criterion may lead to selection bias when we study knee pain and other pain-related outcomes.”

One session attendee noted that the confounders in the analyses did not include socioeconomic factors and recommended they be added. “Of course, smoking status could be confounded by socioeconomic factors, and couldn’t it just be that smoking is a surrogate measure?” he asked.

“It’s a good suggestion,” Dr. Niu agreed, noting that the data set has some socioeconomic measures, such as education, that could be incorporated into analyses.

In an interview, Dr. Timothy McAlindon, one of the session’s comoderators and a professor of medicine at Tufts University, Boston, said, “I think this is a very nicely done study looking at the association of smoking with pain in osteoarthritis.

“What they found is there is clearly a significant association of smoking with pain and incident widespread pain. What was less clear was the mechanistic relationship. Maybe they didn’t test the right mechanistic measures,” he proposed.

“If there is a causal relationship, it could perhaps suggest intervention. But I think that is very conjectural based on what they have done so far,” Dr. McAlindon concluded.

SEATTLE – Smoking is related to prevalent and incident joint pain in patients who have knee osteoarthritis or are at high risk for it, but the mechanism of this association is unclear, in a study of 3,026 patients.

“Previous studies have shown that compared to nonsmokers, smokers have more musculoskeletal pain and report more severe pain,” Jingbo Niu, D.Sc. of the Clinical Epidemiology Research & Training Unit at Boston University reported at the World Congress on Osteoarthritis.

Possible mechanisms include down-regulation of the hypothalamic-pituitary-adrenal axis or triggering of nicotine-sensitive acetylcholine receptors in the dorsal root ganglion. “These factors may translate to a change in pain perception among smokers,” she said.

Dr. Niu and her colleagues analyzed data from the Multicenter Osteoarthritis Study (MOST), a prospective cohort study of risk factors for the development and progression of knee osteoarthritis and knee pain in patients initially aged 50-79 years. They performed cross-sectional analyses at baseline and at the 7-year follow-up visit, and longitudinal analyses for the interim period.

At baseline, 56% of the cohort were never-smokers, 38% were former smokers, and 6% were current smokers, reported Dr. Niu, who disclosed that she had no relevant conflicts of interest. Smoking intensity averaged 22 pack-years.

Study results showed that at baseline, current smokers had significantly more severe knee pain than did never-smokers, with an adjusted difference of 0.83 points on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) knee pain scale.

Also at baseline, former smokers were more likely than were never-smokers to have widespread joint pain, defined as pain in all five regions of a joint pain homunculus (adjusted odds ratio, 1.3). And there was a dose-response relationship, whereby the greater the number of pack-years at baseline, the higher the risk of developing widespread joint pain during follow-up (P = .02).

However, neither smoking status nor smoking intensity was significantly associated with pain sensitization, assessed from the pressure pain threshold at the right wrist, according to the data reported at the meeting, which was sponsored by the Osteoarthritis Research Society International.

“We found smoking was related to knee pain severity and widespread pain, but not with pain sensitization,” Dr. Niu concluded.

“The number of current smokers in our analysis was limited,” she said. In addition, “subjects with knee pain were more likely to be recruited into the MOST study because they have a high risk of developing knee osteoarthritis. This inclusion criterion may lead to selection bias when we study knee pain and other pain-related outcomes.”

One session attendee noted that the confounders in the analyses did not include socioeconomic factors and recommended they be added. “Of course, smoking status could be confounded by socioeconomic factors, and couldn’t it just be that smoking is a surrogate measure?” he asked.

“It’s a good suggestion,” Dr. Niu agreed, noting that the data set has some socioeconomic measures, such as education, that could be incorporated into analyses.

In an interview, Dr. Timothy McAlindon, one of the session’s comoderators and a professor of medicine at Tufts University, Boston, said, “I think this is a very nicely done study looking at the association of smoking with pain in osteoarthritis.

“What they found is there is clearly a significant association of smoking with pain and incident widespread pain. What was less clear was the mechanistic relationship. Maybe they didn’t test the right mechanistic measures,” he proposed.

“If there is a causal relationship, it could perhaps suggest intervention. But I think that is very conjectural based on what they have done so far,” Dr. McAlindon concluded.

SEATTLE – Smoking is related to prevalent and incident joint pain in patients who have knee osteoarthritis or are at high risk for it, but the mechanism of this association is unclear, in a study of 3,026 patients.

“Previous studies have shown that compared to nonsmokers, smokers have more musculoskeletal pain and report more severe pain,” Jingbo Niu, D.Sc. of the Clinical Epidemiology Research & Training Unit at Boston University reported at the World Congress on Osteoarthritis.

Possible mechanisms include down-regulation of the hypothalamic-pituitary-adrenal axis or triggering of nicotine-sensitive acetylcholine receptors in the dorsal root ganglion. “These factors may translate to a change in pain perception among smokers,” she said.

Dr. Niu and her colleagues analyzed data from the Multicenter Osteoarthritis Study (MOST), a prospective cohort study of risk factors for the development and progression of knee osteoarthritis and knee pain in patients initially aged 50-79 years. They performed cross-sectional analyses at baseline and at the 7-year follow-up visit, and longitudinal analyses for the interim period.

At baseline, 56% of the cohort were never-smokers, 38% were former smokers, and 6% were current smokers, reported Dr. Niu, who disclosed that she had no relevant conflicts of interest. Smoking intensity averaged 22 pack-years.

Study results showed that at baseline, current smokers had significantly more severe knee pain than did never-smokers, with an adjusted difference of 0.83 points on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) knee pain scale.

Also at baseline, former smokers were more likely than were never-smokers to have widespread joint pain, defined as pain in all five regions of a joint pain homunculus (adjusted odds ratio, 1.3). And there was a dose-response relationship, whereby the greater the number of pack-years at baseline, the higher the risk of developing widespread joint pain during follow-up (P = .02).

However, neither smoking status nor smoking intensity was significantly associated with pain sensitization, assessed from the pressure pain threshold at the right wrist, according to the data reported at the meeting, which was sponsored by the Osteoarthritis Research Society International.

“We found smoking was related to knee pain severity and widespread pain, but not with pain sensitization,” Dr. Niu concluded.

“The number of current smokers in our analysis was limited,” she said. In addition, “subjects with knee pain were more likely to be recruited into the MOST study because they have a high risk of developing knee osteoarthritis. This inclusion criterion may lead to selection bias when we study knee pain and other pain-related outcomes.”

One session attendee noted that the confounders in the analyses did not include socioeconomic factors and recommended they be added. “Of course, smoking status could be confounded by socioeconomic factors, and couldn’t it just be that smoking is a surrogate measure?” he asked.

“It’s a good suggestion,” Dr. Niu agreed, noting that the data set has some socioeconomic measures, such as education, that could be incorporated into analyses.

In an interview, Dr. Timothy McAlindon, one of the session’s comoderators and a professor of medicine at Tufts University, Boston, said, “I think this is a very nicely done study looking at the association of smoking with pain in osteoarthritis.

“What they found is there is clearly a significant association of smoking with pain and incident widespread pain. What was less clear was the mechanistic relationship. Maybe they didn’t test the right mechanistic measures,” he proposed.

“If there is a causal relationship, it could perhaps suggest intervention. But I think that is very conjectural based on what they have done so far,” Dr. McAlindon concluded.

Nicotinamide, an inexpensive, over-the-counter form of vitamin B₃, is safe and efficacious for the chemoprevention of nonmelanoma skin cancer in patients at high risk, according to data from the Australian Oral Nicotinamide to Reduce Actinic Cancer (ONTRAC) Study.

Results reported in a press briefing held before the annual meeting of the American Society of Clinical Oncology showed that patients taking nicotinamide were about one-fourth less likely than peers taking a placebo to develop new basal cell and squamous cell skin cancers. They also had a smaller reduction in new actinic keratoses.

“Nicotinamide, vitamin B₃, significantly reduced nonmelanoma skin cancers and keratoses in just 12 months in a group of pretty high-risk patients. It’s safe, it’s almost obscenely inexpensive, and it’s already widely commercially available, so this one’s ready to go straight into the clinic,” commented senior investigator Dr. Diona Damian, professor of dermatology at the University of Sydney.

She cautioned that the results apply only to the population studied: adults who had experienced two or more nonmelanoma skin cancers in the past 5 years.

“These are the people we’d be recommending it for – people who have already got a skin cancer track record. It’s not something that we’d recommend at this stage for the general population,” she said. Likewise, the findings do not speak to patients at the other end of the spectrum who are in treatment for advanced or metastatic skin cancer, as they also were excluded.

That said, the researchers are planning additional studies in other populations, such patients who are at high risk because they have immunosuppression, according to Dr. Damian.

“We still need the overall skin cancer prevention strategies of sun-safe behavior, sunscreen, and regular skin surveillance,” she stressed, “but we now have an additional exciting opportunity for affordable skin cancer chemoprevention which we can instantly translate into clinical practice.”

Dr. Peter Paul Yu, ASCO President and a medical oncologist and hematologist who is director of cancer research at the Palo Alto Medical Foundation, Sunnyvale, Calif., commented, “This is a very exciting prevention trial. We all know that we clamor for preventing rather than treating diseases, and this is a major advance for us.”

Exposure to ultraviolet light packs a one-two punch to the skin, both damaging cellular DNA and suppressing the skin’s immune response, according to Dr. Damian. The investigators opted to test nicotinamide as it counters both of these events.

The 386 patients in ONTRAC had heavily sun damaged skin, with a mean of 8 nonmelanoma skin cancers in the past 5 years and 50 keratoses at baseline. They were randomized evenly to receive nicotinamide (500 mg twice daily) or placebo for 12 months.

Results showed that the average number of new nonmelanoma skin cancers per patient during the treatment period was 1.77 in the nicotinamide group and 2.42 in the placebo group. The difference translated to a 23% lower rate of new cancers with the vitamin.

“There were comparable reductions seen for both basal and squamous cell carcinomas,” Dr. Damian noted. “Interestingly, this reduction in skin cancers seemed to start as early as the first 3-month visit. And then when people stopped taking their tablets after 12 months, the benefit was no longer seen. In other words, you need to continue taking the tablets in order for them to be effective.”

The nicotinamide group also had a roughly 15% lower rate of new actinic keratoses, compared with the placebo group.

“Nicotinamide was very well tolerated. There was no difference in adverse events, blood parameters, or blood pressure in the two arms” of the study, reported Dr. Damian. She stressed that it is critically important to distinguish nicotinamide from niacin (nicotinic acid), another form of vitamin B₃ that has a host of side effects such as headache and flushing.

“One of the great things about [nicotinamide] is that it really has hardly any drug interactions, which means that elderly patients who may be taking a whole cocktail of medications for their heart disease and their hypertension, and whatever else, the nicotinamide won’t interact with those,” she added.

Some evidence also has shown nonsteroidal anti-inflammatory drugs to reduce the risk of skin cancer. “The advantage of nicotinamide is that it doesn’t have the potential gastrointestinal bleeding or renal side effects of nonsteroidals, so it may be suitable for a group of people who aren’t suitable for taking nonsteroidals,” she said. “In our ONTRAC study, we didn’t find synergy or additional benefit in people who were coincidentally taking nonsteroidals for other indications.”

The trial’s results should be generalizable to similar high-risk patients in less sunny parts of the world, Dr. Damian said. “If their skin has shown that degree of damage to get skin cancer, then we suspect nicotinamide would offer benefits to them as well.”

Dr. Damian disclosed no relevant conflicts of interest. The study was funded by the National Health & Medical Research Council.

Nicotinamide, an inexpensive, over-the-counter form of vitamin B₃, is safe and efficacious for the chemoprevention of nonmelanoma skin cancer in patients at high risk, according to data from the Australian Oral Nicotinamide to Reduce Actinic Cancer (ONTRAC) Study.

Results reported in a press briefing held before the annual meeting of the American Society of Clinical Oncology showed that patients taking nicotinamide were about one-fourth less likely than peers taking a placebo to develop new basal cell and squamous cell skin cancers. They also had a smaller reduction in new actinic keratoses.

“Nicotinamide, vitamin B₃, significantly reduced nonmelanoma skin cancers and keratoses in just 12 months in a group of pretty high-risk patients. It’s safe, it’s almost obscenely inexpensive, and it’s already widely commercially available, so this one’s ready to go straight into the clinic,” commented senior investigator Dr. Diona Damian, professor of dermatology at the University of Sydney.

She cautioned that the results apply only to the population studied: adults who had experienced two or more nonmelanoma skin cancers in the past 5 years.

“These are the people we’d be recommending it for – people who have already got a skin cancer track record. It’s not something that we’d recommend at this stage for the general population,” she said. Likewise, the findings do not speak to patients at the other end of the spectrum who are in treatment for advanced or metastatic skin cancer, as they also were excluded.

That said, the researchers are planning additional studies in other populations, such patients who are at high risk because they have immunosuppression, according to Dr. Damian.

“We still need the overall skin cancer prevention strategies of sun-safe behavior, sunscreen, and regular skin surveillance,” she stressed, “but we now have an additional exciting opportunity for affordable skin cancer chemoprevention which we can instantly translate into clinical practice.”

Dr. Peter Paul Yu, ASCO President and a medical oncologist and hematologist who is director of cancer research at the Palo Alto Medical Foundation, Sunnyvale, Calif., commented, “This is a very exciting prevention trial. We all know that we clamor for preventing rather than treating diseases, and this is a major advance for us.”

Exposure to ultraviolet light packs a one-two punch to the skin, both damaging cellular DNA and suppressing the skin’s immune response, according to Dr. Damian. The investigators opted to test nicotinamide as it counters both of these events.

The 386 patients in ONTRAC had heavily sun damaged skin, with a mean of 8 nonmelanoma skin cancers in the past 5 years and 50 keratoses at baseline. They were randomized evenly to receive nicotinamide (500 mg twice daily) or placebo for 12 months.

Results showed that the average number of new nonmelanoma skin cancers per patient during the treatment period was 1.77 in the nicotinamide group and 2.42 in the placebo group. The difference translated to a 23% lower rate of new cancers with the vitamin.

“There were comparable reductions seen for both basal and squamous cell carcinomas,” Dr. Damian noted. “Interestingly, this reduction in skin cancers seemed to start as early as the first 3-month visit. And then when people stopped taking their tablets after 12 months, the benefit was no longer seen. In other words, you need to continue taking the tablets in order for them to be effective.”

The nicotinamide group also had a roughly 15% lower rate of new actinic keratoses, compared with the placebo group.

“Nicotinamide was very well tolerated. There was no difference in adverse events, blood parameters, or blood pressure in the two arms” of the study, reported Dr. Damian. She stressed that it is critically important to distinguish nicotinamide from niacin (nicotinic acid), another form of vitamin B₃ that has a host of side effects such as headache and flushing.

“One of the great things about [nicotinamide] is that it really has hardly any drug interactions, which means that elderly patients who may be taking a whole cocktail of medications for their heart disease and their hypertension, and whatever else, the nicotinamide won’t interact with those,” she added.

Some evidence also has shown nonsteroidal anti-inflammatory drugs to reduce the risk of skin cancer. “The advantage of nicotinamide is that it doesn’t have the potential gastrointestinal bleeding or renal side effects of nonsteroidals, so it may be suitable for a group of people who aren’t suitable for taking nonsteroidals,” she said. “In our ONTRAC study, we didn’t find synergy or additional benefit in people who were coincidentally taking nonsteroidals for other indications.”

The trial’s results should be generalizable to similar high-risk patients in less sunny parts of the world, Dr. Damian said. “If their skin has shown that degree of damage to get skin cancer, then we suspect nicotinamide would offer benefits to them as well.”

Dr. Damian disclosed no relevant conflicts of interest. The study was funded by the National Health & Medical Research Council.

Nicotinamide, an inexpensive, over-the-counter form of vitamin B₃, is safe and efficacious for the chemoprevention of nonmelanoma skin cancer in patients at high risk, according to data from the Australian Oral Nicotinamide to Reduce Actinic Cancer (ONTRAC) Study.

Results reported in a press briefing held before the annual meeting of the American Society of Clinical Oncology showed that patients taking nicotinamide were about one-fourth less likely than peers taking a placebo to develop new basal cell and squamous cell skin cancers. They also had a smaller reduction in new actinic keratoses.

“Nicotinamide, vitamin B₃, significantly reduced nonmelanoma skin cancers and keratoses in just 12 months in a group of pretty high-risk patients. It’s safe, it’s almost obscenely inexpensive, and it’s already widely commercially available, so this one’s ready to go straight into the clinic,” commented senior investigator Dr. Diona Damian, professor of dermatology at the University of Sydney.

She cautioned that the results apply only to the population studied: adults who had experienced two or more nonmelanoma skin cancers in the past 5 years.

“These are the people we’d be recommending it for – people who have already got a skin cancer track record. It’s not something that we’d recommend at this stage for the general population,” she said. Likewise, the findings do not speak to patients at the other end of the spectrum who are in treatment for advanced or metastatic skin cancer, as they also were excluded.

That said, the researchers are planning additional studies in other populations, such patients who are at high risk because they have immunosuppression, according to Dr. Damian.

“We still need the overall skin cancer prevention strategies of sun-safe behavior, sunscreen, and regular skin surveillance,” she stressed, “but we now have an additional exciting opportunity for affordable skin cancer chemoprevention which we can instantly translate into clinical practice.”

Dr. Peter Paul Yu, ASCO President and a medical oncologist and hematologist who is director of cancer research at the Palo Alto Medical Foundation, Sunnyvale, Calif., commented, “This is a very exciting prevention trial. We all know that we clamor for preventing rather than treating diseases, and this is a major advance for us.”

Exposure to ultraviolet light packs a one-two punch to the skin, both damaging cellular DNA and suppressing the skin’s immune response, according to Dr. Damian. The investigators opted to test nicotinamide as it counters both of these events.

The 386 patients in ONTRAC had heavily sun damaged skin, with a mean of 8 nonmelanoma skin cancers in the past 5 years and 50 keratoses at baseline. They were randomized evenly to receive nicotinamide (500 mg twice daily) or placebo for 12 months.

Results showed that the average number of new nonmelanoma skin cancers per patient during the treatment period was 1.77 in the nicotinamide group and 2.42 in the placebo group. The difference translated to a 23% lower rate of new cancers with the vitamin.

“There were comparable reductions seen for both basal and squamous cell carcinomas,” Dr. Damian noted. “Interestingly, this reduction in skin cancers seemed to start as early as the first 3-month visit. And then when people stopped taking their tablets after 12 months, the benefit was no longer seen. In other words, you need to continue taking the tablets in order for them to be effective.”

The nicotinamide group also had a roughly 15% lower rate of new actinic keratoses, compared with the placebo group.

“Nicotinamide was very well tolerated. There was no difference in adverse events, blood parameters, or blood pressure in the two arms” of the study, reported Dr. Damian. She stressed that it is critically important to distinguish nicotinamide from niacin (nicotinic acid), another form of vitamin B₃ that has a host of side effects such as headache and flushing.

“One of the great things about [nicotinamide] is that it really has hardly any drug interactions, which means that elderly patients who may be taking a whole cocktail of medications for their heart disease and their hypertension, and whatever else, the nicotinamide won’t interact with those,” she added.

Some evidence also has shown nonsteroidal anti-inflammatory drugs to reduce the risk of skin cancer. “The advantage of nicotinamide is that it doesn’t have the potential gastrointestinal bleeding or renal side effects of nonsteroidals, so it may be suitable for a group of people who aren’t suitable for taking nonsteroidals,” she said. “In our ONTRAC study, we didn’t find synergy or additional benefit in people who were coincidentally taking nonsteroidals for other indications.”

The trial’s results should be generalizable to similar high-risk patients in less sunny parts of the world, Dr. Damian said. “If their skin has shown that degree of damage to get skin cancer, then we suspect nicotinamide would offer benefits to them as well.”

Dr. Damian disclosed no relevant conflicts of interest. The study was funded by the National Health & Medical Research Council.

Using chemotherapy earlier in the course of advanced prostate cancer improves outcomes, according to first survival results of the STAMPEDE trial (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy).

Results showed that adding docetaxel to the standard of hormone therapy at the time of diagnosis reduced the risk of treatment failure or death by 38% and the risk of death by 24%, researchers reported in a press briefing held in advance of the annual meeting of the American Society of Clinical Oncology. The benefit was clear among men with metastatic disease but less so among those with nonmetastatic disease.

roobcio/Thinkstock.com

“Docetaxel improves survival in men with hormone-naive prostate cancer starting hormone therapy for the first time,” concluded lead researcher Dr. Nicholas David James, director of the cancer research unit at the University of Warwick and consultant in clinical oncology at Queen Elizabeth Hospital Birmingham (England).

“Docetaxel should be considered as routine practice in men with newly diagnosed metastatic disease,” he asserted. “For nonmetastatic disease, there remains uncertainty as to whether there is a survival benefit or not, but it certainly improves failure-free survival by a substantial amount, so we would argue that it should be considered for selected men with high-risk nonmetastatic disease.”

Clinicians should use an individualized approach to adding docetaxel in the subgroup with nonmetastatic disease. “What I am doing in my own clinic, for example, is having a discussion with the patients about the pros and cons. … I think it will be something we discuss on a case-by-case basis,” he said, adding that a planned meta-analysis should better clarify the survival benefit in this subgroup.

Dr. Peter Paul Yu, ASCO president and a medical oncologist and hematologist, who is director of cancer research at the Palo Alto Medical Foundation, Sunnyvale, Calif., said that the STAMPEDE data contribute to an ongoing paradigm shift in treating advanced prostate cancer.

“The paradigm for years or even decades has been to treat this with hormone therapy because [it] is relatively less toxic. … The advice has been to use hormone therapy until it’s exhausted, until there is no response left, and then at the last moment use chemotherapy, which often is a potentially self-defeating strategy because you are using chemotherapy when the disease has evolved to a point where it’s much more aggressive,” he said.

Accumulating data, however, suggest that a strategy of combining chemotherapy with hormonal therapy upfront yields better outcomes than their sequential use. “This paradigm shift is continuing and should be highlighted,” he maintained.

“The really interesting thing is the hint … and I would say a very strong hint as an editorial comment, that this strategy of bringing chemotherapy early on can have a benefit even in men who do not have evidence of metastases at the time they are starting hormone therapy … what we would traditionally call the adjuvant use of chemotherapy,” Dr. Yu added.

Men were eligible for STAMPEDE if they were starting long-term hormone therapy for the first time and had high-risk locally advanced disease, lymph node–positive disease, metastatic disease, or disease that had relapsed aggressively after surgery or radiation therapy. STAMPEDE has an innovative, adaptive design whereby novel agents can be incrementally added to those found to be efficacious in earlier arms, generating a new standard of care. The trial receives funding and support in part from Sanofi-Aventis, Novartis, Pfizer, Janssen, and Astellas.

Dr. James presented findings for four of the trial’s nine arms, in which 2,962 patients were randomized to standard of care (androgen deprivation therapy with or without radiation therapy) alone, or with the addition of six cycles of docetaxel (Taxotere), 2 years of the bisphosphonate zoledronic acid (Zometa), or both.

Docetaxel is approved by the U.S. Food and Drug Administration for treatment of metastatic hormone-refractory prostate cancer, and zoledronic acid is approved for the treatment of hypercalcemia due to cancer.

With a median follow-up of 42 months, compared with standard care alone, adding docetaxel significantly reduced the risks of failure-free survival events (hazard ratio, 0.62) and death (HR, 0.76). Median overall survival was 77 months with the drug and 67 months without it, and the difference was largely driven by prostate cancer deaths, according to Dr. James.

About 60% of the men had metastases. In stratified analyses, adding docetaxel improved failure-free survival whether men had metastatic disease or not, but it improved overall survival only in those with metastatic disease (43 vs. 65 months). However, the standard-care arm in the nonmetastatic subgroup performed better than expected, and there have been too few deaths in that subgroup overall to fully power the analysis, Dr. James said.

Toxicity with the addition of docetaxel was manageable. Zoledronic acid did not improve either outcome relative to hormone therapy alone, and adding both zoledronic acid and docetaxel netted similar results to those seen with docetaxel alone.

Several other therapies, including next-generation hormone therapies and chemotherapy agents, also are showing promise in prostate cancer, and the optimal timing and sequencing of agents is unknown. STAMPEDE is the first to look at docetaxel and these hormone therapies at the time of diagnosis of advanced disease, he noted.

At present, the data support giving docetaxel before either abiraterone or enzalutamide in this treatment setting, as the drug’s survival advantage persisted even though patients often went on to receive those hormone therapies; however, that strategy might change with future results from this and other trials. “To be honest, it would be a nice position to be in if we had two treatments that improved overall survival upfront. That just gives us a choice. It would be good news obviously,” he concluded.

Dr. James disclosed that he has a consulting, advisory, or speakers’ bureau role with or receives honoraria or research funding (institutional) from Sanofi, Bayer, Merck, Astellas, Janssen, Pierre Fabre, Ferring, OncoGenex, and Pfizer.

Using chemotherapy earlier in the course of advanced prostate cancer improves outcomes, according to first survival results of the STAMPEDE trial (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy).

Results showed that adding docetaxel to the standard of hormone therapy at the time of diagnosis reduced the risk of treatment failure or death by 38% and the risk of death by 24%, researchers reported in a press briefing held in advance of the annual meeting of the American Society of Clinical Oncology. The benefit was clear among men with metastatic disease but less so among those with nonmetastatic disease.

roobcio/Thinkstock.com

“Docetaxel improves survival in men with hormone-naive prostate cancer starting hormone therapy for the first time,” concluded lead researcher Dr. Nicholas David James, director of the cancer research unit at the University of Warwick and consultant in clinical oncology at Queen Elizabeth Hospital Birmingham (England).

“Docetaxel should be considered as routine practice in men with newly diagnosed metastatic disease,” he asserted. “For nonmetastatic disease, there remains uncertainty as to whether there is a survival benefit or not, but it certainly improves failure-free survival by a substantial amount, so we would argue that it should be considered for selected men with high-risk nonmetastatic disease.”

Clinicians should use an individualized approach to adding docetaxel in the subgroup with nonmetastatic disease. “What I am doing in my own clinic, for example, is having a discussion with the patients about the pros and cons. … I think it will be something we discuss on a case-by-case basis,” he said, adding that a planned meta-analysis should better clarify the survival benefit in this subgroup.

Dr. Peter Paul Yu, ASCO president and a medical oncologist and hematologist, who is director of cancer research at the Palo Alto Medical Foundation, Sunnyvale, Calif., said that the STAMPEDE data contribute to an ongoing paradigm shift in treating advanced prostate cancer.

“The paradigm for years or even decades has been to treat this with hormone therapy because [it] is relatively less toxic. … The advice has been to use hormone therapy until it’s exhausted, until there is no response left, and then at the last moment use chemotherapy, which often is a potentially self-defeating strategy because you are using chemotherapy when the disease has evolved to a point where it’s much more aggressive,” he said.

Accumulating data, however, suggest that a strategy of combining chemotherapy with hormonal therapy upfront yields better outcomes than their sequential use. “This paradigm shift is continuing and should be highlighted,” he maintained.

“The really interesting thing is the hint … and I would say a very strong hint as an editorial comment, that this strategy of bringing chemotherapy early on can have a benefit even in men who do not have evidence of metastases at the time they are starting hormone therapy … what we would traditionally call the adjuvant use of chemotherapy,” Dr. Yu added.

Men were eligible for STAMPEDE if they were starting long-term hormone therapy for the first time and had high-risk locally advanced disease, lymph node–positive disease, metastatic disease, or disease that had relapsed aggressively after surgery or radiation therapy. STAMPEDE has an innovative, adaptive design whereby novel agents can be incrementally added to those found to be efficacious in earlier arms, generating a new standard of care. The trial receives funding and support in part from Sanofi-Aventis, Novartis, Pfizer, Janssen, and Astellas.

Dr. James presented findings for four of the trial’s nine arms, in which 2,962 patients were randomized to standard of care (androgen deprivation therapy with or without radiation therapy) alone, or with the addition of six cycles of docetaxel (Taxotere), 2 years of the bisphosphonate zoledronic acid (Zometa), or both.

Docetaxel is approved by the U.S. Food and Drug Administration for treatment of metastatic hormone-refractory prostate cancer, and zoledronic acid is approved for the treatment of hypercalcemia due to cancer.

With a median follow-up of 42 months, compared with standard care alone, adding docetaxel significantly reduced the risks of failure-free survival events (hazard ratio, 0.62) and death (HR, 0.76). Median overall survival was 77 months with the drug and 67 months without it, and the difference was largely driven by prostate cancer deaths, according to Dr. James.

About 60% of the men had metastases. In stratified analyses, adding docetaxel improved failure-free survival whether men had metastatic disease or not, but it improved overall survival only in those with metastatic disease (43 vs. 65 months). However, the standard-care arm in the nonmetastatic subgroup performed better than expected, and there have been too few deaths in that subgroup overall to fully power the analysis, Dr. James said.

Toxicity with the addition of docetaxel was manageable. Zoledronic acid did not improve either outcome relative to hormone therapy alone, and adding both zoledronic acid and docetaxel netted similar results to those seen with docetaxel alone.

Several other therapies, including next-generation hormone therapies and chemotherapy agents, also are showing promise in prostate cancer, and the optimal timing and sequencing of agents is unknown. STAMPEDE is the first to look at docetaxel and these hormone therapies at the time of diagnosis of advanced disease, he noted.

At present, the data support giving docetaxel before either abiraterone or enzalutamide in this treatment setting, as the drug’s survival advantage persisted even though patients often went on to receive those hormone therapies; however, that strategy might change with future results from this and other trials. “To be honest, it would be a nice position to be in if we had two treatments that improved overall survival upfront. That just gives us a choice. It would be good news obviously,” he concluded.

Dr. James disclosed that he has a consulting, advisory, or speakers’ bureau role with or receives honoraria or research funding (institutional) from Sanofi, Bayer, Merck, Astellas, Janssen, Pierre Fabre, Ferring, OncoGenex, and Pfizer.

Using chemotherapy earlier in the course of advanced prostate cancer improves outcomes, according to first survival results of the STAMPEDE trial (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy).

Results showed that adding docetaxel to the standard of hormone therapy at the time of diagnosis reduced the risk of treatment failure or death by 38% and the risk of death by 24%, researchers reported in a press briefing held in advance of the annual meeting of the American Society of Clinical Oncology. The benefit was clear among men with metastatic disease but less so among those with nonmetastatic disease.

roobcio/Thinkstock.com

“Docetaxel improves survival in men with hormone-naive prostate cancer starting hormone therapy for the first time,” concluded lead researcher Dr. Nicholas David James, director of the cancer research unit at the University of Warwick and consultant in clinical oncology at Queen Elizabeth Hospital Birmingham (England).

“Docetaxel should be considered as routine practice in men with newly diagnosed metastatic disease,” he asserted. “For nonmetastatic disease, there remains uncertainty as to whether there is a survival benefit or not, but it certainly improves failure-free survival by a substantial amount, so we would argue that it should be considered for selected men with high-risk nonmetastatic disease.”

Clinicians should use an individualized approach to adding docetaxel in the subgroup with nonmetastatic disease. “What I am doing in my own clinic, for example, is having a discussion with the patients about the pros and cons. … I think it will be something we discuss on a case-by-case basis,” he said, adding that a planned meta-analysis should better clarify the survival benefit in this subgroup.

Dr. Peter Paul Yu, ASCO president and a medical oncologist and hematologist, who is director of cancer research at the Palo Alto Medical Foundation, Sunnyvale, Calif., said that the STAMPEDE data contribute to an ongoing paradigm shift in treating advanced prostate cancer.

“The paradigm for years or even decades has been to treat this with hormone therapy because [it] is relatively less toxic. … The advice has been to use hormone therapy until it’s exhausted, until there is no response left, and then at the last moment use chemotherapy, which often is a potentially self-defeating strategy because you are using chemotherapy when the disease has evolved to a point where it’s much more aggressive,” he said.

Accumulating data, however, suggest that a strategy of combining chemotherapy with hormonal therapy upfront yields better outcomes than their sequential use. “This paradigm shift is continuing and should be highlighted,” he maintained.

“The really interesting thing is the hint … and I would say a very strong hint as an editorial comment, that this strategy of bringing chemotherapy early on can have a benefit even in men who do not have evidence of metastases at the time they are starting hormone therapy … what we would traditionally call the adjuvant use of chemotherapy,” Dr. Yu added.

Men were eligible for STAMPEDE if they were starting long-term hormone therapy for the first time and had high-risk locally advanced disease, lymph node–positive disease, metastatic disease, or disease that had relapsed aggressively after surgery or radiation therapy. STAMPEDE has an innovative, adaptive design whereby novel agents can be incrementally added to those found to be efficacious in earlier arms, generating a new standard of care. The trial receives funding and support in part from Sanofi-Aventis, Novartis, Pfizer, Janssen, and Astellas.

Dr. James presented findings for four of the trial’s nine arms, in which 2,962 patients were randomized to standard of care (androgen deprivation therapy with or without radiation therapy) alone, or with the addition of six cycles of docetaxel (Taxotere), 2 years of the bisphosphonate zoledronic acid (Zometa), or both.

Docetaxel is approved by the U.S. Food and Drug Administration for treatment of metastatic hormone-refractory prostate cancer, and zoledronic acid is approved for the treatment of hypercalcemia due to cancer.

With a median follow-up of 42 months, compared with standard care alone, adding docetaxel significantly reduced the risks of failure-free survival events (hazard ratio, 0.62) and death (HR, 0.76). Median overall survival was 77 months with the drug and 67 months without it, and the difference was largely driven by prostate cancer deaths, according to Dr. James.

About 60% of the men had metastases. In stratified analyses, adding docetaxel improved failure-free survival whether men had metastatic disease or not, but it improved overall survival only in those with metastatic disease (43 vs. 65 months). However, the standard-care arm in the nonmetastatic subgroup performed better than expected, and there have been too few deaths in that subgroup overall to fully power the analysis, Dr. James said.

Toxicity with the addition of docetaxel was manageable. Zoledronic acid did not improve either outcome relative to hormone therapy alone, and adding both zoledronic acid and docetaxel netted similar results to those seen with docetaxel alone.

Several other therapies, including next-generation hormone therapies and chemotherapy agents, also are showing promise in prostate cancer, and the optimal timing and sequencing of agents is unknown. STAMPEDE is the first to look at docetaxel and these hormone therapies at the time of diagnosis of advanced disease, he noted.

At present, the data support giving docetaxel before either abiraterone or enzalutamide in this treatment setting, as the drug’s survival advantage persisted even though patients often went on to receive those hormone therapies; however, that strategy might change with future results from this and other trials. “To be honest, it would be a nice position to be in if we had two treatments that improved overall survival upfront. That just gives us a choice. It would be good news obviously,” he concluded.

Dr. James disclosed that he has a consulting, advisory, or speakers’ bureau role with or receives honoraria or research funding (institutional) from Sanofi, Bayer, Merck, Astellas, Janssen, Pierre Fabre, Ferring, OncoGenex, and Pfizer.

SEATTLE – Certain clinical factors help predict which patients with knee meniscal tears and osteoarthritis will abandon physical therapy (PT) for surgery, according to a study reported at the World Congress on Osteoarthritis.

Investigators led by Dr. Jeffrey N. Katz performed a secondary analysis of the randomized, controlled MeTeOR (Meniscal Tear in Osteoarthritis Research) trial, which compared PT with arthroscopic partial meniscectomy among 351 patients.

Results showed that patients assigned to PT had a 6%-8% higher risk of crossing over to surgery if they had greater pain, a shorter symptom duration, or weaker hamstrings. But four-fifths of patients obtained pain relief from surgery, regardless of whether they were initially assigned to it or crossed over to it.

“Patients with the most painful and acute presentations and those with hamstring weakness were most likely to cross over from PT to arthroscopic partial meniscectomy in this trial,” commented Dr. Katz, who is a professor of rheumatology at Harvard Medical School and codirector of the Brigham Spine Center at Brigham and Women’s Hospital, Boston. However, “the risk ratios were very modest, suggesting we have limited capacity to predict crossovers.”

“From a research standpoint, crossovers compromise trial interpretation, so targeting patients most likely to cross over with efforts to try to retain them in their original treatment arm would enhance the value of trials,” he added. “From a clinical standpoint, there appears to be no disadvantage in delaying surgery until a trial of physical therapy has been undertaken, and that conclusion underscores the advice from many of these trials suggesting that PT be offered as first-line therapy for patients with degenerative meniscal tears.”

In an interview, Dr. Rolando Espinosa Morales, session comoderator and chief of the rheumatology service at the National Institute of Rehabilitation, Mexico City, said, “The study shows us there are no perfect predictors [of crossover] in these patients,” and careful evaluation is needed to discern which patients really need surgery and which will fare well with PT alone.

“It’s a hot topic right now in the world,” he commented. “We really don’t want to use surgery in all patients; we need to use it in a [restricted] number of patients.”

During a question and answer period, session attendee Ewa M. Roos, Ph.D., University of Southern Denmark in Odense, said, “You showed a lot of patient-related factors that could potentially explain crossover, but what is the role of the surgeon? … Is there a fact that if you can, you will cross over?”

“I agree with what I think is your implicit suggestion that there probably is a large role for the surgeon. We looked at heterogeneity in crossovers among surgeons in the trial, and there is some variability. There are probably cultural differences as well,” Dr. Katz replied. “I think … the question is, how fully are patients consented to not receiving surgery?”

Participants in MeTeOR were aged 45 years or older and had a meniscal tear on magnetic resonance imaging with degenerative cartilage changes and at least one meniscal symptom. They were randomized evenly to a standardized PT regimen emphasizing strength and range of motion, or to arthroscopic partial meniscectomy accompanied by standardized PT.

Overall, 27% of patients in the PT arm crossed over to surgery within about 5 months, Dr. Katz reported at the meeting sponsored by the Osteoarthritis Research Society International.

Multivariate analyses showed that patients initially assigned to PT were more likely to cross over to surgery if they had greater pain, scoring 40 or higher on the 100-point Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scale (relative risk, 1.08); had experienced symptoms for less than a year (1.07); or had hamstring strength of less than 30 pounds (1.06).

However, the rate of treatment success, defined as an improvement of at least 10 points on the 100-point Knee Injury and Osteoarthritis Outcome Score (KOOS) at 6 months, was similarly high for the patients who were randomized to and received surgery (80%) and the patients who were randomized to PT but crossed over to surgery (81%).

The trial had several limitations, according to Dr. Katz. “From the standpoint of external validity, trial samples are not necessarily generalizable as we know. And with respect to internal validity, our comparison of immediate and delayed arthroscopic partial meniscectomy was post randomization, and the groups are not necessarily balanced,” he said.

Dr. Katz disclosed no relevant conflicts of interest.

SEATTLE – Certain clinical factors help predict which patients with knee meniscal tears and osteoarthritis will abandon physical therapy (PT) for surgery, according to a study reported at the World Congress on Osteoarthritis.

Investigators led by Dr. Jeffrey N. Katz performed a secondary analysis of the randomized, controlled MeTeOR (Meniscal Tear in Osteoarthritis Research) trial, which compared PT with arthroscopic partial meniscectomy among 351 patients.

Results showed that patients assigned to PT had a 6%-8% higher risk of crossing over to surgery if they had greater pain, a shorter symptom duration, or weaker hamstrings. But four-fifths of patients obtained pain relief from surgery, regardless of whether they were initially assigned to it or crossed over to it.

“Patients with the most painful and acute presentations and those with hamstring weakness were most likely to cross over from PT to arthroscopic partial meniscectomy in this trial,” commented Dr. Katz, who is a professor of rheumatology at Harvard Medical School and codirector of the Brigham Spine Center at Brigham and Women’s Hospital, Boston. However, “the risk ratios were very modest, suggesting we have limited capacity to predict crossovers.”

“From a research standpoint, crossovers compromise trial interpretation, so targeting patients most likely to cross over with efforts to try to retain them in their original treatment arm would enhance the value of trials,” he added. “From a clinical standpoint, there appears to be no disadvantage in delaying surgery until a trial of physical therapy has been undertaken, and that conclusion underscores the advice from many of these trials suggesting that PT be offered as first-line therapy for patients with degenerative meniscal tears.”

In an interview, Dr. Rolando Espinosa Morales, session comoderator and chief of the rheumatology service at the National Institute of Rehabilitation, Mexico City, said, “The study shows us there are no perfect predictors [of crossover] in these patients,” and careful evaluation is needed to discern which patients really need surgery and which will fare well with PT alone.

“It’s a hot topic right now in the world,” he commented. “We really don’t want to use surgery in all patients; we need to use it in a [restricted] number of patients.”

During a question and answer period, session attendee Ewa M. Roos, Ph.D., University of Southern Denmark in Odense, said, “You showed a lot of patient-related factors that could potentially explain crossover, but what is the role of the surgeon? … Is there a fact that if you can, you will cross over?”

“I agree with what I think is your implicit suggestion that there probably is a large role for the surgeon. We looked at heterogeneity in crossovers among surgeons in the trial, and there is some variability. There are probably cultural differences as well,” Dr. Katz replied. “I think … the question is, how fully are patients consented to not receiving surgery?”

Participants in MeTeOR were aged 45 years or older and had a meniscal tear on magnetic resonance imaging with degenerative cartilage changes and at least one meniscal symptom. They were randomized evenly to a standardized PT regimen emphasizing strength and range of motion, or to arthroscopic partial meniscectomy accompanied by standardized PT.

Overall, 27% of patients in the PT arm crossed over to surgery within about 5 months, Dr. Katz reported at the meeting sponsored by the Osteoarthritis Research Society International.

Multivariate analyses showed that patients initially assigned to PT were more likely to cross over to surgery if they had greater pain, scoring 40 or higher on the 100-point Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scale (relative risk, 1.08); had experienced symptoms for less than a year (1.07); or had hamstring strength of less than 30 pounds (1.06).

However, the rate of treatment success, defined as an improvement of at least 10 points on the 100-point Knee Injury and Osteoarthritis Outcome Score (KOOS) at 6 months, was similarly high for the patients who were randomized to and received surgery (80%) and the patients who were randomized to PT but crossed over to surgery (81%).

The trial had several limitations, according to Dr. Katz. “From the standpoint of external validity, trial samples are not necessarily generalizable as we know. And with respect to internal validity, our comparison of immediate and delayed arthroscopic partial meniscectomy was post randomization, and the groups are not necessarily balanced,” he said.

Dr. Katz disclosed no relevant conflicts of interest.

SEATTLE – Certain clinical factors help predict which patients with knee meniscal tears and osteoarthritis will abandon physical therapy (PT) for surgery, according to a study reported at the World Congress on Osteoarthritis.

Investigators led by Dr. Jeffrey N. Katz performed a secondary analysis of the randomized, controlled MeTeOR (Meniscal Tear in Osteoarthritis Research) trial, which compared PT with arthroscopic partial meniscectomy among 351 patients.

Results showed that patients assigned to PT had a 6%-8% higher risk of crossing over to surgery if they had greater pain, a shorter symptom duration, or weaker hamstrings. But four-fifths of patients obtained pain relief from surgery, regardless of whether they were initially assigned to it or crossed over to it.

“Patients with the most painful and acute presentations and those with hamstring weakness were most likely to cross over from PT to arthroscopic partial meniscectomy in this trial,” commented Dr. Katz, who is a professor of rheumatology at Harvard Medical School and codirector of the Brigham Spine Center at Brigham and Women’s Hospital, Boston. However, “the risk ratios were very modest, suggesting we have limited capacity to predict crossovers.”

“From a research standpoint, crossovers compromise trial interpretation, so targeting patients most likely to cross over with efforts to try to retain them in their original treatment arm would enhance the value of trials,” he added. “From a clinical standpoint, there appears to be no disadvantage in delaying surgery until a trial of physical therapy has been undertaken, and that conclusion underscores the advice from many of these trials suggesting that PT be offered as first-line therapy for patients with degenerative meniscal tears.”

In an interview, Dr. Rolando Espinosa Morales, session comoderator and chief of the rheumatology service at the National Institute of Rehabilitation, Mexico City, said, “The study shows us there are no perfect predictors [of crossover] in these patients,” and careful evaluation is needed to discern which patients really need surgery and which will fare well with PT alone.

“It’s a hot topic right now in the world,” he commented. “We really don’t want to use surgery in all patients; we need to use it in a [restricted] number of patients.”

During a question and answer period, session attendee Ewa M. Roos, Ph.D., University of Southern Denmark in Odense, said, “You showed a lot of patient-related factors that could potentially explain crossover, but what is the role of the surgeon? … Is there a fact that if you can, you will cross over?”

“I agree with what I think is your implicit suggestion that there probably is a large role for the surgeon. We looked at heterogeneity in crossovers among surgeons in the trial, and there is some variability. There are probably cultural differences as well,” Dr. Katz replied. “I think … the question is, how fully are patients consented to not receiving surgery?”

Participants in MeTeOR were aged 45 years or older and had a meniscal tear on magnetic resonance imaging with degenerative cartilage changes and at least one meniscal symptom. They were randomized evenly to a standardized PT regimen emphasizing strength and range of motion, or to arthroscopic partial meniscectomy accompanied by standardized PT.

Overall, 27% of patients in the PT arm crossed over to surgery within about 5 months, Dr. Katz reported at the meeting sponsored by the Osteoarthritis Research Society International.

Multivariate analyses showed that patients initially assigned to PT were more likely to cross over to surgery if they had greater pain, scoring 40 or higher on the 100-point Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scale (relative risk, 1.08); had experienced symptoms for less than a year (1.07); or had hamstring strength of less than 30 pounds (1.06).

However, the rate of treatment success, defined as an improvement of at least 10 points on the 100-point Knee Injury and Osteoarthritis Outcome Score (KOOS) at 6 months, was similarly high for the patients who were randomized to and received surgery (80%) and the patients who were randomized to PT but crossed over to surgery (81%).

The trial had several limitations, according to Dr. Katz. “From the standpoint of external validity, trial samples are not necessarily generalizable as we know. And with respect to internal validity, our comparison of immediate and delayed arthroscopic partial meniscectomy was post randomization, and the groups are not necessarily balanced,” he said.

Dr. Katz disclosed no relevant conflicts of interest.

SEATTLE – Adding clinical factors to a commonly used risk model improves by about 20% the prediction of which patients will be readmitted after undergoing total joint replacement surgery, new data show.

The new, combined model employs diagnostic codes and a variety of clinical factors, such as preoperative patient-reported measures – emotional status assessed with the mental component score of the 12-item Short Form Health Survey, moderate to severe pain in other weight-bearing joints (the contralateral joint, the hips or knees, and low back), and history of smoking – and the Charlson comorbidity index.

Investigators led by Dr. Patricia D. Franklin, a professor in the department of orthopedics and physical rehabilitation, University of Massachusetts, Worcester, set out to improve on the Centers for Medicare & Medicaid (CMS) risk prediction model for 30-day readmission. Rates of readmission using the model are publicly reported as an indicator of the quality of care at hospitals.

“Analyses are described as risk adjusted, implying that the remaining outcome variation is due to variation in quality of care,” she told attendees of the World Congress on Osteoarthritis. “The CMS risk adjustment model, while expertly developed, was limited to the billing and diagnosis data that were available to them and for patients over 65 years of age.”

The researchers tested the model using data from FORCE-TJR (Function and Outcomes Research for Comparative Effectiveness in Total Joint Replacement and Quality Improvement), the first national total joint replacement registry. Analyses were based on 2,560 patients aged 65 years or older who underwent total knee or hip replacement during 2011 and 2012.

Overall, 4.7% of the patients were readmitted within 30 days. About one-third of the readmissions were for implant-related issues, while the rest were due to complications of a major surgery in older patients with comorbidities, according to Dr. Franklin, who disclosed that she has received investigator-initiated research awards from Zimmer and Biomet.

In multivariate analysis, discrimination of patients having a readmission with the combined model was superior to that with the model based on diagnostic codes alone (c-statistic, 0.75 vs. 0.64), she reported at the meeting sponsored by the Osteoarthritis Research Society International.

“We believe that in the combined risk-adjustment model … the key predictors were indeed older age and gender and that list of ICD codes. However, the addition of medical and musculoskeletal comorbidities – in particular, moderate and severe pain in other weight-bearing joints – was important to the success,” Dr. Franklin commented, noting that the findings will be validated using 2013 registry data.

“We have been advising total joint replacement surgeons to collect these musculoskeletal factors in a systematic way so that they can be included in these future analyses. We believe it would be wise to integrate clinician-defined and -reported risk factors before public reporting,” she concluded.

Session attendee Dr. Jeffrey N. Katz, a professor at Harvard Medical School and codirector of the Brigham Spine Center at Brigham and Women’s Hospital, Boston, wondered whether pain in the other knee is a proxy for the severity and systemic nature of the osteoarthritis in these patients.

Identifying the real risk factors at play will be important, Dr. Katz said, adding, “I think we see this a lot in risk models. ... and addressing the proxy may not address the underlying issue.”

“I’m just very afraid of the law of unintended consequences” of risk models potentially being used to deny some patients surgery, commented session comoderator Dr. Nigel Arden, professor of rheumatology at the University of Oxford, England.

“A lot of the risk factors you identified were not obviously reversible,” Dr. Arden commented. “So are these people going to get prehab, or would you operate but do lots of extensive postoperative rehab? Or is this going to be a patient decision aid?”

The main aims of the research were to better ensure that the model was truly reflecting surgical care and to provide surgeons with information for planning and counseling patients, according to Dr. Franklin.

“I think patients should be informed what their risk is. … Average readmission rates or mortality rates don’t inform individuals,” she added. “So our goal actually is to begin to have some strategies to parse out subgroups of patients at greater or lesser risk for complications, and for benefits from the surgery.”

SEATTLE – Adding clinical factors to a commonly used risk model improves by about 20% the prediction of which patients will be readmitted after undergoing total joint replacement surgery, new data show.

The new, combined model employs diagnostic codes and a variety of clinical factors, such as preoperative patient-reported measures – emotional status assessed with the mental component score of the 12-item Short Form Health Survey, moderate to severe pain in other weight-bearing joints (the contralateral joint, the hips or knees, and low back), and history of smoking – and the Charlson comorbidity index.

Investigators led by Dr. Patricia D. Franklin, a professor in the department of orthopedics and physical rehabilitation, University of Massachusetts, Worcester, set out to improve on the Centers for Medicare & Medicaid (CMS) risk prediction model for 30-day readmission. Rates of readmission using the model are publicly reported as an indicator of the quality of care at hospitals.

“Analyses are described as risk adjusted, implying that the remaining outcome variation is due to variation in quality of care,” she told attendees of the World Congress on Osteoarthritis. “The CMS risk adjustment model, while expertly developed, was limited to the billing and diagnosis data that were available to them and for patients over 65 years of age.”

The researchers tested the model using data from FORCE-TJR (Function and Outcomes Research for Comparative Effectiveness in Total Joint Replacement and Quality Improvement), the first national total joint replacement registry. Analyses were based on 2,560 patients aged 65 years or older who underwent total knee or hip replacement during 2011 and 2012.

Overall, 4.7% of the patients were readmitted within 30 days. About one-third of the readmissions were for implant-related issues, while the rest were due to complications of a major surgery in older patients with comorbidities, according to Dr. Franklin, who disclosed that she has received investigator-initiated research awards from Zimmer and Biomet.

In multivariate analysis, discrimination of patients having a readmission with the combined model was superior to that with the model based on diagnostic codes alone (c-statistic, 0.75 vs. 0.64), she reported at the meeting sponsored by the Osteoarthritis Research Society International.

“We believe that in the combined risk-adjustment model … the key predictors were indeed older age and gender and that list of ICD codes. However, the addition of medical and musculoskeletal comorbidities – in particular, moderate and severe pain in other weight-bearing joints – was important to the success,” Dr. Franklin commented, noting that the findings will be validated using 2013 registry data.

“We have been advising total joint replacement surgeons to collect these musculoskeletal factors in a systematic way so that they can be included in these future analyses. We believe it would be wise to integrate clinician-defined and -reported risk factors before public reporting,” she concluded.

Session attendee Dr. Jeffrey N. Katz, a professor at Harvard Medical School and codirector of the Brigham Spine Center at Brigham and Women’s Hospital, Boston, wondered whether pain in the other knee is a proxy for the severity and systemic nature of the osteoarthritis in these patients.

Identifying the real risk factors at play will be important, Dr. Katz said, adding, “I think we see this a lot in risk models. ... and addressing the proxy may not address the underlying issue.”

“I’m just very afraid of the law of unintended consequences” of risk models potentially being used to deny some patients surgery, commented session comoderator Dr. Nigel Arden, professor of rheumatology at the University of Oxford, England.

“A lot of the risk factors you identified were not obviously reversible,” Dr. Arden commented. “So are these people going to get prehab, or would you operate but do lots of extensive postoperative rehab? Or is this going to be a patient decision aid?”

The main aims of the research were to better ensure that the model was truly reflecting surgical care and to provide surgeons with information for planning and counseling patients, according to Dr. Franklin.

“I think patients should be informed what their risk is. … Average readmission rates or mortality rates don’t inform individuals,” she added. “So our goal actually is to begin to have some strategies to parse out subgroups of patients at greater or lesser risk for complications, and for benefits from the surgery.”

SEATTLE – Adding clinical factors to a commonly used risk model improves by about 20% the prediction of which patients will be readmitted after undergoing total joint replacement surgery, new data show.

The new, combined model employs diagnostic codes and a variety of clinical factors, such as preoperative patient-reported measures – emotional status assessed with the mental component score of the 12-item Short Form Health Survey, moderate to severe pain in other weight-bearing joints (the contralateral joint, the hips or knees, and low back), and history of smoking – and the Charlson comorbidity index.

Investigators led by Dr. Patricia D. Franklin, a professor in the department of orthopedics and physical rehabilitation, University of Massachusetts, Worcester, set out to improve on the Centers for Medicare & Medicaid (CMS) risk prediction model for 30-day readmission. Rates of readmission using the model are publicly reported as an indicator of the quality of care at hospitals.

“Analyses are described as risk adjusted, implying that the remaining outcome variation is due to variation in quality of care,” she told attendees of the World Congress on Osteoarthritis. “The CMS risk adjustment model, while expertly developed, was limited to the billing and diagnosis data that were available to them and for patients over 65 years of age.”

The researchers tested the model using data from FORCE-TJR (Function and Outcomes Research for Comparative Effectiveness in Total Joint Replacement and Quality Improvement), the first national total joint replacement registry. Analyses were based on 2,560 patients aged 65 years or older who underwent total knee or hip replacement during 2011 and 2012.

Overall, 4.7% of the patients were readmitted within 30 days. About one-third of the readmissions were for implant-related issues, while the rest were due to complications of a major surgery in older patients with comorbidities, according to Dr. Franklin, who disclosed that she has received investigator-initiated research awards from Zimmer and Biomet.

In multivariate analysis, discrimination of patients having a readmission with the combined model was superior to that with the model based on diagnostic codes alone (c-statistic, 0.75 vs. 0.64), she reported at the meeting sponsored by the Osteoarthritis Research Society International.

“We believe that in the combined risk-adjustment model … the key predictors were indeed older age and gender and that list of ICD codes. However, the addition of medical and musculoskeletal comorbidities – in particular, moderate and severe pain in other weight-bearing joints – was important to the success,” Dr. Franklin commented, noting that the findings will be validated using 2013 registry data.

“We have been advising total joint replacement surgeons to collect these musculoskeletal factors in a systematic way so that they can be included in these future analyses. We believe it would be wise to integrate clinician-defined and -reported risk factors before public reporting,” she concluded.

Session attendee Dr. Jeffrey N. Katz, a professor at Harvard Medical School and codirector of the Brigham Spine Center at Brigham and Women’s Hospital, Boston, wondered whether pain in the other knee is a proxy for the severity and systemic nature of the osteoarthritis in these patients.

Identifying the real risk factors at play will be important, Dr. Katz said, adding, “I think we see this a lot in risk models. ... and addressing the proxy may not address the underlying issue.”

“I’m just very afraid of the law of unintended consequences” of risk models potentially being used to deny some patients surgery, commented session comoderator Dr. Nigel Arden, professor of rheumatology at the University of Oxford, England.

“A lot of the risk factors you identified were not obviously reversible,” Dr. Arden commented. “So are these people going to get prehab, or would you operate but do lots of extensive postoperative rehab? Or is this going to be a patient decision aid?”

The main aims of the research were to better ensure that the model was truly reflecting surgical care and to provide surgeons with information for planning and counseling patients, according to Dr. Franklin.

“I think patients should be informed what their risk is. … Average readmission rates or mortality rates don’t inform individuals,” she added. “So our goal actually is to begin to have some strategies to parse out subgroups of patients at greater or lesser risk for complications, and for benefits from the surgery.”

CHICAGO – Olaparib improves outcomes in women with ovarian cancer who have a germline BRCA mutation, but its use at least as maintenance therapy is not cost-effective, according to research reported at the annual meeting of the Society of Gynecologic Oncology.

The Food and Drug Administration approved olaparib, an oral inhibitor of poly-ADP-ribose polymerase (PARP), in December 2014 for the treatment of patients who have recurrent ovarian cancer with a germline BRCA mutation and have received at least three prior lines of therapy. It is currently not approved for maintenance therapy in the United States.

Subsequent therapy may mask a survival benefit

In the first of three studies, investigators led by Dr. Ursula A. Matulonis performed a post hoc, exploratory analysis of data from a pivotal randomized phase II trial in platinum-sensitive relapsed ovarian cancer (Study 19). The trial, sponsored by AstraZeneca, compared olaparib (Lynparza) with placebo as maintenance therapy.

Susan London/Frontline Medical News

A previous stratified analysis among 265 patients revealed that those with a BRCA mutation had a marked progression-free survival benefit with olaparib versus placebo (11.2 vs. 4.3 months; hazard ratio, 0.18) but no significant gain in overall survival (34.9 vs. 31.9 months; hazard ratio, 0.73) (Lancet Oncol. 2014;15:852-61), according to Dr. Matulonis, medical director and program leader of the medical gynecologic oncology program at the Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School, both in Boston.

Crossover to olaparib was not permitted in the trial, but patients may have accessed PARP inhibitors outside of the study, she noted. “It was hypothesized that patients switching treatments may have reduced the beneficial impact of olaparib on the overall survival results. We know that switching is common in randomized trials in oncology but difficult to prevent practically and ethically, and it certainly may make an impact on overall survival.”

In the new, exploratory analysis, she and her colleagues reassessed outcomes after excluding all trial sites at which at least one patient received a PARP inhibitor after progression, which left 198 patients.

Results still showed a dramatic progression-free survival benefit for olaparib over placebo for those with a BRCA mutation (12.4 vs. 4.4 months; hazard ratio, 0.14). But now, olaparib also conferred a significant overall survival benefit, halving the risk of death (34.9 vs. 26.6 months; hazard ratio, 0.52), reported Dr. Matulonis, who disclosed that she has received research funding and speakers bureau remuneration from AstraZeneca.

“This change in overall survival hazard ratio may suggest a confounding influence that reduced the beneficial impact of olaparib,” she said. “There remains a degree of uncertainty owing to small sample sizes and lack of data maturity, so further analysis on more mature data is required to confirm these findings.”

Analysis confirms efficacy, safety in heavily pretreated patients

In the second study, Dr. Matulonis and colleagues performed a pooled analysis to assess the impact of olaparib in patients with advanced relapsed ovarian cancer having a germline BRCA mutation. Results were based on 273 patients given olaparib monotherapy in six AstraZeneca-sponsored phase I and II trials.

In the entire cohort, the overall response rate was 36% and the median duration of response was 7.4 months. The corresponding values were 31% and 7.8 months in the three-fourths of patients who had received at least three prior lines of chemotherapy.

Benefit was seen whether patients’ disease was platinum sensitive, resistant, or unknown, Dr. Matulonis reported. However, the response rate fell as the number of previous lines of therapy increased.

The rate of grade 3 or worse adverse events was 50% in the total population and 54% in the subset who received three or more previous therapies, and the rate of serious adverse events was 30% and 34%, respectively. Eight patients (all in the heavily pretreated group) had a serious adverse event leading to death, but none were considered causally related to olaparib.

“Olaparib treatment benefits were observed in all the patient subgroups,” Dr. Matulonis said. “The safety profile of olaparib was acceptable in patients who had received three or more prior lines of therapy.”

She noted that an ongoing series of phase III trials of monotherapy in patients with germline BRCA mutations – the Studies of Olaparib in Ovarian Cancer (SOLO) 1, 2, and 3 trials – should provide more information on use of the drug in various settings.

Susan London/Frontline Medical News

Invited discussant Dr. Elizabeth Swisher, medical director of the breast and ovarian cancer prevention program at the Seattle Cancer Care Alliance and professor in the gynecologic oncology division at the University of Washington, noted the uncertainty surrounding the optimal use of PARP inhibitors in ovarian cancer and mentioned that olaparib is approved as maintenance therapy in Europe.

“Many of you have probably been in the same situation that I have, where I have a patient in front of me and have to say, ‘Yes, this would be a good drug for you, but you need to fail a couple more lines of chemotherapy first,’ ” she said. “And we all know that later in the disease course, GI symptoms become more prominent and an oral drug may not be tolerated, so we might lose the opportunity to treat these patients with these drugs.”

Therefore, the field should address some key unanswered questions about PARP inhibitor therapy, according to Dr. Swisher: “Really, what is the best time point for using it – is it at maintenance, or is it at the time of relapse? And if we use it as maintenance, is it in the primary setting or the recurrent setting?” she elaborated.

She noted that women with somatic BRCA mutations as opposed to germline ones seem to benefit similarly from olaparib, but as insurance companies in the United States often resist covering tumor testing, this subset of women is often missed. “Predictors of response and resistance other than BRCA mutations are needed,” she added.

Models suggest maintenance therapy is not cost-effective

In the third study, investigators led by Dr. Haller J. Smith, a resident in obstetrics and gynecology at the University of Alabama, Birmingham, constructed models to assess the cost-effectiveness of olaparib maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer.

Susan London/Frontline Medical News

They used as a target population 5,549 women who had a complete response to primary therapy, experienced a recurrence, and then had at least a partial response to second-line chemotherapy. Analyses assumed a germline BRCA mutation prevalence of 20%.

In the model, patients received six cycles of chemotherapy, followed by either observation or olaparib maintenance therapy. The cost of olaparib was set at $7,000 per month, while the cost of observation was based on national guidelines and Medicare reimbursement rates. “The cost of adverse events was not included in the model as the majority of these in the phase II trial were grade 1 or 2,” Dr. Smith noted.

Results of the base case analysis showed that among patients with a BRCA mutation, the incremental cost-effectiveness ratio (ICER) for olaparib relative to observation was $135,672 per progression-free life-year saved – more than double the $50,000 threshold the investigators considered to be cost-effective, Dr. Smith reported. Among patients with wild type for BRCA, the ICER was sharply higher, at $315,840.

Sensitivity analyses showed that olaparib therapy was still not cost-effective when the prevalence of BRCA mutations and progression-free survival were varied. But the ICER fell to $97,404 when the cost of the drug was reduced to $5,000 and fell to $49,584 when it was reduced to $2,500.

“In order to achieve an ICER of less than $50,000, the cost of olaparib would have to be $2,500 or less per month,” Dr. Smith said. However, “in the era of molecular targeted therapies, an ICER of less than $100,000 would be considered by many to be cost-effective,” she acknowledged.

“While PARP inhibitors and other molecular targeted therapies represent exciting new therapeutic options for our patients, the costs associated with these drugs remain a significant concern. As health care costs continue to increase, cost-effectiveness studies are likely to become a more important part of the drug development and approval process,” she concluded.

CHICAGO – Olaparib improves outcomes in women with ovarian cancer who have a germline BRCA mutation, but its use at least as maintenance therapy is not cost-effective, according to research reported at the annual meeting of the Society of Gynecologic Oncology.

The Food and Drug Administration approved olaparib, an oral inhibitor of poly-ADP-ribose polymerase (PARP), in December 2014 for the treatment of patients who have recurrent ovarian cancer with a germline BRCA mutation and have received at least three prior lines of therapy. It is currently not approved for maintenance therapy in the United States.

Subsequent therapy may mask a survival benefit

In the first of three studies, investigators led by Dr. Ursula A. Matulonis performed a post hoc, exploratory analysis of data from a pivotal randomized phase II trial in platinum-sensitive relapsed ovarian cancer (Study 19). The trial, sponsored by AstraZeneca, compared olaparib (Lynparza) with placebo as maintenance therapy.

Susan London/Frontline Medical News

A previous stratified analysis among 265 patients revealed that those with a BRCA mutation had a marked progression-free survival benefit with olaparib versus placebo (11.2 vs. 4.3 months; hazard ratio, 0.18) but no significant gain in overall survival (34.9 vs. 31.9 months; hazard ratio, 0.73) (Lancet Oncol. 2014;15:852-61), according to Dr. Matulonis, medical director and program leader of the medical gynecologic oncology program at the Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School, both in Boston.

Crossover to olaparib was not permitted in the trial, but patients may have accessed PARP inhibitors outside of the study, she noted. “It was hypothesized that patients switching treatments may have reduced the beneficial impact of olaparib on the overall survival results. We know that switching is common in randomized trials in oncology but difficult to prevent practically and ethically, and it certainly may make an impact on overall survival.”

In the new, exploratory analysis, she and her colleagues reassessed outcomes after excluding all trial sites at which at least one patient received a PARP inhibitor after progression, which left 198 patients.

Results still showed a dramatic progression-free survival benefit for olaparib over placebo for those with a BRCA mutation (12.4 vs. 4.4 months; hazard ratio, 0.14). But now, olaparib also conferred a significant overall survival benefit, halving the risk of death (34.9 vs. 26.6 months; hazard ratio, 0.52), reported Dr. Matulonis, who disclosed that she has received research funding and speakers bureau remuneration from AstraZeneca.

“This change in overall survival hazard ratio may suggest a confounding influence that reduced the beneficial impact of olaparib,” she said. “There remains a degree of uncertainty owing to small sample sizes and lack of data maturity, so further analysis on more mature data is required to confirm these findings.”

Analysis confirms efficacy, safety in heavily pretreated patients

In the second study, Dr. Matulonis and colleagues performed a pooled analysis to assess the impact of olaparib in patients with advanced relapsed ovarian cancer having a germline BRCA mutation. Results were based on 273 patients given olaparib monotherapy in six AstraZeneca-sponsored phase I and II trials.

In the entire cohort, the overall response rate was 36% and the median duration of response was 7.4 months. The corresponding values were 31% and 7.8 months in the three-fourths of patients who had received at least three prior lines of chemotherapy.

Benefit was seen whether patients’ disease was platinum sensitive, resistant, or unknown, Dr. Matulonis reported. However, the response rate fell as the number of previous lines of therapy increased.

The rate of grade 3 or worse adverse events was 50% in the total population and 54% in the subset who received three or more previous therapies, and the rate of serious adverse events was 30% and 34%, respectively. Eight patients (all in the heavily pretreated group) had a serious adverse event leading to death, but none were considered causally related to olaparib.

“Olaparib treatment benefits were observed in all the patient subgroups,” Dr. Matulonis said. “The safety profile of olaparib was acceptable in patients who had received three or more prior lines of therapy.”

She noted that an ongoing series of phase III trials of monotherapy in patients with germline BRCA mutations – the Studies of Olaparib in Ovarian Cancer (SOLO) 1, 2, and 3 trials – should provide more information on use of the drug in various settings.

Susan London/Frontline Medical News

Invited discussant Dr. Elizabeth Swisher, medical director of the breast and ovarian cancer prevention program at the Seattle Cancer Care Alliance and professor in the gynecologic oncology division at the University of Washington, noted the uncertainty surrounding the optimal use of PARP inhibitors in ovarian cancer and mentioned that olaparib is approved as maintenance therapy in Europe.

“Many of you have probably been in the same situation that I have, where I have a patient in front of me and have to say, ‘Yes, this would be a good drug for you, but you need to fail a couple more lines of chemotherapy first,’ ” she said. “And we all know that later in the disease course, GI symptoms become more prominent and an oral drug may not be tolerated, so we might lose the opportunity to treat these patients with these drugs.”

Therefore, the field should address some key unanswered questions about PARP inhibitor therapy, according to Dr. Swisher: “Really, what is the best time point for using it – is it at maintenance, or is it at the time of relapse? And if we use it as maintenance, is it in the primary setting or the recurrent setting?” she elaborated.

She noted that women with somatic BRCA mutations as opposed to germline ones seem to benefit similarly from olaparib, but as insurance companies in the United States often resist covering tumor testing, this subset of women is often missed. “Predictors of response and resistance other than BRCA mutations are needed,” she added.

Models suggest maintenance therapy is not cost-effective

In the third study, investigators led by Dr. Haller J. Smith, a resident in obstetrics and gynecology at the University of Alabama, Birmingham, constructed models to assess the cost-effectiveness of olaparib maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer.

Susan London/Frontline Medical News

They used as a target population 5,549 women who had a complete response to primary therapy, experienced a recurrence, and then had at least a partial response to second-line chemotherapy. Analyses assumed a germline BRCA mutation prevalence of 20%.

In the model, patients received six cycles of chemotherapy, followed by either observation or olaparib maintenance therapy. The cost of olaparib was set at $7,000 per month, while the cost of observation was based on national guidelines and Medicare reimbursement rates. “The cost of adverse events was not included in the model as the majority of these in the phase II trial were grade 1 or 2,” Dr. Smith noted.

Results of the base case analysis showed that among patients with a BRCA mutation, the incremental cost-effectiveness ratio (ICER) for olaparib relative to observation was $135,672 per progression-free life-year saved – more than double the $50,000 threshold the investigators considered to be cost-effective, Dr. Smith reported. Among patients with wild type for BRCA, the ICER was sharply higher, at $315,840.

Sensitivity analyses showed that olaparib therapy was still not cost-effective when the prevalence of BRCA mutations and progression-free survival were varied. But the ICER fell to $97,404 when the cost of the drug was reduced to $5,000 and fell to $49,584 when it was reduced to $2,500.

“In order to achieve an ICER of less than $50,000, the cost of olaparib would have to be $2,500 or less per month,” Dr. Smith said. However, “in the era of molecular targeted therapies, an ICER of less than $100,000 would be considered by many to be cost-effective,” she acknowledged.

“While PARP inhibitors and other molecular targeted therapies represent exciting new therapeutic options for our patients, the costs associated with these drugs remain a significant concern. As health care costs continue to increase, cost-effectiveness studies are likely to become a more important part of the drug development and approval process,” she concluded.

CHICAGO – Olaparib improves outcomes in women with ovarian cancer who have a germline BRCA mutation, but its use at least as maintenance therapy is not cost-effective, according to research reported at the annual meeting of the Society of Gynecologic Oncology.

The Food and Drug Administration approved olaparib, an oral inhibitor of poly-ADP-ribose polymerase (PARP), in December 2014 for the treatment of patients who have recurrent ovarian cancer with a germline BRCA mutation and have received at least three prior lines of therapy. It is currently not approved for maintenance therapy in the United States.

Subsequent therapy may mask a survival benefit

In the first of three studies, investigators led by Dr. Ursula A. Matulonis performed a post hoc, exploratory analysis of data from a pivotal randomized phase II trial in platinum-sensitive relapsed ovarian cancer (Study 19). The trial, sponsored by AstraZeneca, compared olaparib (Lynparza) with placebo as maintenance therapy.

Susan London/Frontline Medical News

A previous stratified analysis among 265 patients revealed that those with a BRCA mutation had a marked progression-free survival benefit with olaparib versus placebo (11.2 vs. 4.3 months; hazard ratio, 0.18) but no significant gain in overall survival (34.9 vs. 31.9 months; hazard ratio, 0.73) (Lancet Oncol. 2014;15:852-61), according to Dr. Matulonis, medical director and program leader of the medical gynecologic oncology program at the Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School, both in Boston.

Crossover to olaparib was not permitted in the trial, but patients may have accessed PARP inhibitors outside of the study, she noted. “It was hypothesized that patients switching treatments may have reduced the beneficial impact of olaparib on the overall survival results. We know that switching is common in randomized trials in oncology but difficult to prevent practically and ethically, and it certainly may make an impact on overall survival.”

In the new, exploratory analysis, she and her colleagues reassessed outcomes after excluding all trial sites at which at least one patient received a PARP inhibitor after progression, which left 198 patients.

Results still showed a dramatic progression-free survival benefit for olaparib over placebo for those with a BRCA mutation (12.4 vs. 4.4 months; hazard ratio, 0.14). But now, olaparib also conferred a significant overall survival benefit, halving the risk of death (34.9 vs. 26.6 months; hazard ratio, 0.52), reported Dr. Matulonis, who disclosed that she has received research funding and speakers bureau remuneration from AstraZeneca.

“This change in overall survival hazard ratio may suggest a confounding influence that reduced the beneficial impact of olaparib,” she said. “There remains a degree of uncertainty owing to small sample sizes and lack of data maturity, so further analysis on more mature data is required to confirm these findings.”

Analysis confirms efficacy, safety in heavily pretreated patients

In the second study, Dr. Matulonis and colleagues performed a pooled analysis to assess the impact of olaparib in patients with advanced relapsed ovarian cancer having a germline BRCA mutation. Results were based on 273 patients given olaparib monotherapy in six AstraZeneca-sponsored phase I and II trials.

In the entire cohort, the overall response rate was 36% and the median duration of response was 7.4 months. The corresponding values were 31% and 7.8 months in the three-fourths of patients who had received at least three prior lines of chemotherapy.

Benefit was seen whether patients’ disease was platinum sensitive, resistant, or unknown, Dr. Matulonis reported. However, the response rate fell as the number of previous lines of therapy increased.

The rate of grade 3 or worse adverse events was 50% in the total population and 54% in the subset who received three or more previous therapies, and the rate of serious adverse events was 30% and 34%, respectively. Eight patients (all in the heavily pretreated group) had a serious adverse event leading to death, but none were considered causally related to olaparib.

“Olaparib treatment benefits were observed in all the patient subgroups,” Dr. Matulonis said. “The safety profile of olaparib was acceptable in patients who had received three or more prior lines of therapy.”

She noted that an ongoing series of phase III trials of monotherapy in patients with germline BRCA mutations – the Studies of Olaparib in Ovarian Cancer (SOLO) 1, 2, and 3 trials – should provide more information on use of the drug in various settings.

Susan London/Frontline Medical News

Invited discussant Dr. Elizabeth Swisher, medical director of the breast and ovarian cancer prevention program at the Seattle Cancer Care Alliance and professor in the gynecologic oncology division at the University of Washington, noted the uncertainty surrounding the optimal use of PARP inhibitors in ovarian cancer and mentioned that olaparib is approved as maintenance therapy in Europe.

“Many of you have probably been in the same situation that I have, where I have a patient in front of me and have to say, ‘Yes, this would be a good drug for you, but you need to fail a couple more lines of chemotherapy first,’ ” she said. “And we all know that later in the disease course, GI symptoms become more prominent and an oral drug may not be tolerated, so we might lose the opportunity to treat these patients with these drugs.”

Therefore, the field should address some key unanswered questions about PARP inhibitor therapy, according to Dr. Swisher: “Really, what is the best time point for using it – is it at maintenance, or is it at the time of relapse? And if we use it as maintenance, is it in the primary setting or the recurrent setting?” she elaborated.

She noted that women with somatic BRCA mutations as opposed to germline ones seem to benefit similarly from olaparib, but as insurance companies in the United States often resist covering tumor testing, this subset of women is often missed. “Predictors of response and resistance other than BRCA mutations are needed,” she added.

Models suggest maintenance therapy is not cost-effective

In the third study, investigators led by Dr. Haller J. Smith, a resident in obstetrics and gynecology at the University of Alabama, Birmingham, constructed models to assess the cost-effectiveness of olaparib maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer.

Susan London/Frontline Medical News

They used as a target population 5,549 women who had a complete response to primary therapy, experienced a recurrence, and then had at least a partial response to second-line chemotherapy. Analyses assumed a germline BRCA mutation prevalence of 20%.

In the model, patients received six cycles of chemotherapy, followed by either observation or olaparib maintenance therapy. The cost of olaparib was set at $7,000 per month, while the cost of observation was based on national guidelines and Medicare reimbursement rates. “The cost of adverse events was not included in the model as the majority of these in the phase II trial were grade 1 or 2,” Dr. Smith noted.

Results of the base case analysis showed that among patients with a BRCA mutation, the incremental cost-effectiveness ratio (ICER) for olaparib relative to observation was $135,672 per progression-free life-year saved – more than double the $50,000 threshold the investigators considered to be cost-effective, Dr. Smith reported. Among patients with wild type for BRCA, the ICER was sharply higher, at $315,840.

Sensitivity analyses showed that olaparib therapy was still not cost-effective when the prevalence of BRCA mutations and progression-free survival were varied. But the ICER fell to $97,404 when the cost of the drug was reduced to $5,000 and fell to $49,584 when it was reduced to $2,500.

“In order to achieve an ICER of less than $50,000, the cost of olaparib would have to be $2,500 or less per month,” Dr. Smith said. However, “in the era of molecular targeted therapies, an ICER of less than $100,000 would be considered by many to be cost-effective,” she acknowledged.

“While PARP inhibitors and other molecular targeted therapies represent exciting new therapeutic options for our patients, the costs associated with these drugs remain a significant concern. As health care costs continue to increase, cost-effectiveness studies are likely to become a more important part of the drug development and approval process,” she concluded.

CHICAGO – Circulating tumor cells are a prognostic biomarker for overall survival in women with advanced cervical cancer who are receiving chemotherapy with or without bevacizumab, according to an analysis of the Gynecologic Oncology Group’s 240 trial.

The risk of death among patients given cisplatin-paclitaxel plus bevacizumab was reduced by 10% for those who had a higher pretreatment level of circulating tumor cells (CTCs) and by 13% for those who had a greater treatment-related decline in CTCs, Dr. Krishnansu S. Tewari reported at the annual meeting of the Society of Gynecologic Oncology.

Susan London/ Frontline Medical News

“We can predict that leaky vasculature resulting from tumor angiogenesis may permit systemic distribution of CTCs through intratumoral vascular shunting, and the vulnerability to anti-angiogenesis therapies may be due to this increased vascularization,” said Dr. Tewari of UC Irvine Health in Orange, Calif.

In comments provided by e-mail, session comoderator Dr. Charles N. Landen Jr. of the University of Virginia, Charlottesville, said that the study is important in that it demonstrates the feasibility of using CTCs as a biomarker in this setting, but its results are not practice changing.

“If you had a decrease in CTCs, you were more likely to have a good response to therapy. However, this was not any better at detecting response than conventional methods such as a CT scan,” he explained.

Giving some background to the research, Dr. Tewari said that “it’s difficult to monitor response in patients with advanced cervical cancer. Doing imaging studies after every two cycles is expensive, and there are no validated serum tumor markers in this disease. In addition, tumor is not often accessible for interrogation to help guide subsequent therapy when patients ultimately progress on anti-VEGF [vascular endothelial growth factor] therapy. Finally, predictive biomarkers are lacking in advanced cervical cancer.”

“CTCs can be seen as minimally invasive liquid biopsies, and their presence in breast cancer, prostate cancer, and non–small cell lung cancer has been correlated with survival,” he noted. “However, all three of those solid tumors are known to spread hematogenously. While hematogenous spread can occur in cervical cancer, it is felt to be rare.”

The phase III trial enrolled women with recurrent, persistent, or metastatic cervical cancer and tested the addition of bevacizumab (Avastin, manufactured by Genentech/Roche) to doublet chemotherapy (cisplatin-paclitaxel or topotecan-paclitaxel) given on 21-day cycles. Main results showed a significant gain in overall survival from the addition of bevacizumab (N. Engl. J. Med. 2014;370:734-43), leading to regulatory approval of combination therapy in the United States and elsewhere.

The new analysis focused on the 174 women (39%) in the trial who had 8.5 mL of whole blood collected for CTC measurement before starting the first cycle of therapy and, in most cases, again 36 days after the first cycle.

The investigators were able to identify CTCs for 97% of patients in the pretreatment sample and for 81% in the post-treatment sample, Dr. Tewari noted.

Results showed that the median CTC count in the sample fell from seven cells pretreatment to four cells post-treatment (P < .0001). Of note, there was no correlation with the response to treatment according to RECIST (Response Evaluation Criteria in Solid Tumors).

Patients with high (above-median) pretreatment levels of CTCs had significantly better median progression-free survival with bevacizumab than without it (10.8 vs. 6.9 months; hazard ratio [HR], 0.59). In contrast, there was no significant benefit for patients with low (below-median) pretreatment levels of CTCs (7.3 and 6.2 months).

Among patients given cisplatin-paclitaxel plus bevacizumab, the higher the pretreatment CTC level, the lower the risk of death (HR, 0.90). Among patients given cisplatin-paclitaxel overall, the higher the post-treatment CTC level, the greater the risk of death (HR, 1.12), Dr. Tewari reported.

Finally, the greater the decline in CTCs from before to after treatment in patients given cisplatin-paclitaxel plus bevacizumab, the lower the risk of death (HR, 0.87), he said.

Dr. Tewari disclosed that he is a consultant to Genentech/Roche, Advaxis, and Caris Life Sciences; receives honoraria/reimbursement or grants from Genentech/Roche; and performs research for Caris Life Sciences.

CHICAGO – Circulating tumor cells are a prognostic biomarker for overall survival in women with advanced cervical cancer who are receiving chemotherapy with or without bevacizumab, according to an analysis of the Gynecologic Oncology Group’s 240 trial.

The risk of death among patients given cisplatin-paclitaxel plus bevacizumab was reduced by 10% for those who had a higher pretreatment level of circulating tumor cells (CTCs) and by 13% for those who had a greater treatment-related decline in CTCs, Dr. Krishnansu S. Tewari reported at the annual meeting of the Society of Gynecologic Oncology.

Susan London/ Frontline Medical News

“We can predict that leaky vasculature resulting from tumor angiogenesis may permit systemic distribution of CTCs through intratumoral vascular shunting, and the vulnerability to anti-angiogenesis therapies may be due to this increased vascularization,” said Dr. Tewari of UC Irvine Health in Orange, Calif.

In comments provided by e-mail, session comoderator Dr. Charles N. Landen Jr. of the University of Virginia, Charlottesville, said that the study is important in that it demonstrates the feasibility of using CTCs as a biomarker in this setting, but its results are not practice changing.

“If you had a decrease in CTCs, you were more likely to have a good response to therapy. However, this was not any better at detecting response than conventional methods such as a CT scan,” he explained.

Giving some background to the research, Dr. Tewari said that “it’s difficult to monitor response in patients with advanced cervical cancer. Doing imaging studies after every two cycles is expensive, and there are no validated serum tumor markers in this disease. In addition, tumor is not often accessible for interrogation to help guide subsequent therapy when patients ultimately progress on anti-VEGF [vascular endothelial growth factor] therapy. Finally, predictive biomarkers are lacking in advanced cervical cancer.”

“CTCs can be seen as minimally invasive liquid biopsies, and their presence in breast cancer, prostate cancer, and non–small cell lung cancer has been correlated with survival,” he noted. “However, all three of those solid tumors are known to spread hematogenously. While hematogenous spread can occur in cervical cancer, it is felt to be rare.”

The phase III trial enrolled women with recurrent, persistent, or metastatic cervical cancer and tested the addition of bevacizumab (Avastin, manufactured by Genentech/Roche) to doublet chemotherapy (cisplatin-paclitaxel or topotecan-paclitaxel) given on 21-day cycles. Main results showed a significant gain in overall survival from the addition of bevacizumab (N. Engl. J. Med. 2014;370:734-43), leading to regulatory approval of combination therapy in the United States and elsewhere.

The new analysis focused on the 174 women (39%) in the trial who had 8.5 mL of whole blood collected for CTC measurement before starting the first cycle of therapy and, in most cases, again 36 days after the first cycle.

The investigators were able to identify CTCs for 97% of patients in the pretreatment sample and for 81% in the post-treatment sample, Dr. Tewari noted.

Results showed that the median CTC count in the sample fell from seven cells pretreatment to four cells post-treatment (P < .0001). Of note, there was no correlation with the response to treatment according to RECIST (Response Evaluation Criteria in Solid Tumors).

Patients with high (above-median) pretreatment levels of CTCs had significantly better median progression-free survival with bevacizumab than without it (10.8 vs. 6.9 months; hazard ratio [HR], 0.59). In contrast, there was no significant benefit for patients with low (below-median) pretreatment levels of CTCs (7.3 and 6.2 months).

Among patients given cisplatin-paclitaxel plus bevacizumab, the higher the pretreatment CTC level, the lower the risk of death (HR, 0.90). Among patients given cisplatin-paclitaxel overall, the higher the post-treatment CTC level, the greater the risk of death (HR, 1.12), Dr. Tewari reported.

Finally, the greater the decline in CTCs from before to after treatment in patients given cisplatin-paclitaxel plus bevacizumab, the lower the risk of death (HR, 0.87), he said.

Dr. Tewari disclosed that he is a consultant to Genentech/Roche, Advaxis, and Caris Life Sciences; receives honoraria/reimbursement or grants from Genentech/Roche; and performs research for Caris Life Sciences.

CHICAGO – Circulating tumor cells are a prognostic biomarker for overall survival in women with advanced cervical cancer who are receiving chemotherapy with or without bevacizumab, according to an analysis of the Gynecologic Oncology Group’s 240 trial.

The risk of death among patients given cisplatin-paclitaxel plus bevacizumab was reduced by 10% for those who had a higher pretreatment level of circulating tumor cells (CTCs) and by 13% for those who had a greater treatment-related decline in CTCs, Dr. Krishnansu S. Tewari reported at the annual meeting of the Society of Gynecologic Oncology.

Susan London/ Frontline Medical News

“We can predict that leaky vasculature resulting from tumor angiogenesis may permit systemic distribution of CTCs through intratumoral vascular shunting, and the vulnerability to anti-angiogenesis therapies may be due to this increased vascularization,” said Dr. Tewari of UC Irvine Health in Orange, Calif.

In comments provided by e-mail, session comoderator Dr. Charles N. Landen Jr. of the University of Virginia, Charlottesville, said that the study is important in that it demonstrates the feasibility of using CTCs as a biomarker in this setting, but its results are not practice changing.

“If you had a decrease in CTCs, you were more likely to have a good response to therapy. However, this was not any better at detecting response than conventional methods such as a CT scan,” he explained.

Giving some background to the research, Dr. Tewari said that “it’s difficult to monitor response in patients with advanced cervical cancer. Doing imaging studies after every two cycles is expensive, and there are no validated serum tumor markers in this disease. In addition, tumor is not often accessible for interrogation to help guide subsequent therapy when patients ultimately progress on anti-VEGF [vascular endothelial growth factor] therapy. Finally, predictive biomarkers are lacking in advanced cervical cancer.”

“CTCs can be seen as minimally invasive liquid biopsies, and their presence in breast cancer, prostate cancer, and non–small cell lung cancer has been correlated with survival,” he noted. “However, all three of those solid tumors are known to spread hematogenously. While hematogenous spread can occur in cervical cancer, it is felt to be rare.”

The phase III trial enrolled women with recurrent, persistent, or metastatic cervical cancer and tested the addition of bevacizumab (Avastin, manufactured by Genentech/Roche) to doublet chemotherapy (cisplatin-paclitaxel or topotecan-paclitaxel) given on 21-day cycles. Main results showed a significant gain in overall survival from the addition of bevacizumab (N. Engl. J. Med. 2014;370:734-43), leading to regulatory approval of combination therapy in the United States and elsewhere.

The new analysis focused on the 174 women (39%) in the trial who had 8.5 mL of whole blood collected for CTC measurement before starting the first cycle of therapy and, in most cases, again 36 days after the first cycle.

The investigators were able to identify CTCs for 97% of patients in the pretreatment sample and for 81% in the post-treatment sample, Dr. Tewari noted.

Results showed that the median CTC count in the sample fell from seven cells pretreatment to four cells post-treatment (P < .0001). Of note, there was no correlation with the response to treatment according to RECIST (Response Evaluation Criteria in Solid Tumors).

Patients with high (above-median) pretreatment levels of CTCs had significantly better median progression-free survival with bevacizumab than without it (10.8 vs. 6.9 months; hazard ratio [HR], 0.59). In contrast, there was no significant benefit for patients with low (below-median) pretreatment levels of CTCs (7.3 and 6.2 months).

Among patients given cisplatin-paclitaxel plus bevacizumab, the higher the pretreatment CTC level, the lower the risk of death (HR, 0.90). Among patients given cisplatin-paclitaxel overall, the higher the post-treatment CTC level, the greater the risk of death (HR, 1.12), Dr. Tewari reported.

Finally, the greater the decline in CTCs from before to after treatment in patients given cisplatin-paclitaxel plus bevacizumab, the lower the risk of death (HR, 0.87), he said.

Dr. Tewari disclosed that he is a consultant to Genentech/Roche, Advaxis, and Caris Life Sciences; receives honoraria/reimbursement or grants from Genentech/Roche; and performs research for Caris Life Sciences.