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Sentinel node mapping adequately detects nodal spread of endometrial cancer
CHICAGO – Sentinel lymph node mapping is a safe, less extensive alternative to lymph node dissection in women with endometrial cancer regardless of the clinically suspected risk of metastases, suggest a pair of retrospective cohort studies reported at the annual meeting of the Society of Gynecologic Oncology.
“The role and extent of surgical staging in endometrial carcinoma is controversial. The various strategies range from no lymphadenectomy to a full lymphadenectomy dissection up to the renal vessels,” said Dr. Ane Gerda Zahl Eriksson, a surgical fellow in gynecologic oncology at the Memorial Sloan Kettering Cancer Center, New York.
“The use of SLN [sentinel lymph node] mapping is emerging as an acceptable approach for nodal assessment in endometrial carcinoma. However, as always when introducing a novel management strategy, we must be mindful not to compromise oncologic outcome or otherwise inflict harm on our patients by our approach,” she added.
Dr. Eriksson and colleagues assessed clinicopathologic outcomes according to nodal assessment approach among women with low-risk endometrial cancer, defined as that with endometrioid histology of any grade with myometrial invasion of less than 50%.
They compared 493 women who had selective lymph node dissection (LND) at the Mayo Clinic between 2004 and 2008 according to an institutional algorithm (complete pelvic and para-aortic lymphadenectomy to the renal veins in cases deemed at risk for nodal metastasis) with 642 women who had SLN mapping at the Memorial Sloan Kettering Cancer Center between 2006 and 2013 according to an institutional algorithm. The SLNs were evaluated by pathologic ultrastaging and were considered positive whether they had macrometastases, micrometastases, or isolated tumor cells.
Results showed that patients in the SLN cohort were more likely to have pelvic nodes excised (93% vs. 58%) and less likely to have para-aortic nodes excised (14% vs. 50%), Dr. Eriksson reported.
Markedly fewer lymph nodes were removed per patient with the SLN algorithm, yet it yielded a higher detection rate of stage IIIC1 disease (4.8% vs. 1.8%) and similar detection rates of stage IIIA/B and stage IIIC2 disease.
Patients in the SLN cohort were more than twice as likely to receive adjuvant therapy (27% vs. 12%). (Dr. Eriksson noted that patients in the SLN cohort who had positive nodes were offered the same adjuvant therapy options regardless of the amount of metastases found in the nodes.)
With a median follow-up of 2.1 years in the SLN cohort and 3.5 years in the LND cohort, the cohorts had statistically indistinguishable 3-year rates of freedom from isolated nodal recurrence (99.6% in each) and disease-free survival (94.9% and 96.8%).
“The application of the SLN algorithm does not appear to compromise oncologic outcome in this short follow-up. The value of SLN dissection or selective lymphadenectomy in patients with tumors equal to or less than 2 cm remains controversial,” Dr. Eriksson commented. “The clinical significance of disease detected on ultrastaging and the role of adjuvant therapy in these patients remains to be determined.”
“Prospective assessment of the SLN algorithm is needed and underway,” she concluded. “Our findings support the use of either strategy for endometrial cancer staging with no apparent detriment to the SLN algorithm.”
In the second study, investigators led by Dr. Jennifer A. Ducie, also a surgical fellow in gynecologic oncology at the Memorial Sloan Kettering Cancer Center, performed a similar analysis among women with intermediate-risk endometrial cancer, defined as that having endometrioid histology with any grade and at least 50% myometrial invasion, and high-risk endometrial cancer, defined as serous or clear cell carcinoma.
In the intermediate-risk group, there were 82 patients in the SLN cohort and 107 patients in the LND cohort. The groups had a similar detection rate of stage IIIC disease overall (35% and 28%), but the SLN cohort had a higher rate of detection of stage IIIC1 disease (32% vs. 11%) and the LND cohort had a higher rate of detection of stage IIIC2 disease (17% vs. 4%), Dr. Ducie reported.
In the high-risk group, there were 120 patients in the SLN cohort and 103 patients in the LND cohort. Patients in the SLN cohort were more likely to have pelvic nodes removed (98% vs. 85%) but had fewer nodes removed (11 vs. 30). Among patients who had para-aortic nodes removed, the SLN cohort was similarly as likely as the LND cohort to have positive nodes, but had a smaller median number positive (two vs. five). The rate of detection of stage IIIC disease overall (23% vs. 19%) and of the substages was statistically indistinguishable.
“Though both strategies yield similar detection rates of stage IIIC disease, it remains to be determined if removal of more normal-appearing lymph nodes will improve survival,” Dr. Ducie concluded. “A limitation of this portion of our collaborative study is that we don’t address adjuvant therapy or outcomes, but these will be addressed in future analyses.”
CHICAGO – Sentinel lymph node mapping is a safe, less extensive alternative to lymph node dissection in women with endometrial cancer regardless of the clinically suspected risk of metastases, suggest a pair of retrospective cohort studies reported at the annual meeting of the Society of Gynecologic Oncology.
“The role and extent of surgical staging in endometrial carcinoma is controversial. The various strategies range from no lymphadenectomy to a full lymphadenectomy dissection up to the renal vessels,” said Dr. Ane Gerda Zahl Eriksson, a surgical fellow in gynecologic oncology at the Memorial Sloan Kettering Cancer Center, New York.
“The use of SLN [sentinel lymph node] mapping is emerging as an acceptable approach for nodal assessment in endometrial carcinoma. However, as always when introducing a novel management strategy, we must be mindful not to compromise oncologic outcome or otherwise inflict harm on our patients by our approach,” she added.
Dr. Eriksson and colleagues assessed clinicopathologic outcomes according to nodal assessment approach among women with low-risk endometrial cancer, defined as that with endometrioid histology of any grade with myometrial invasion of less than 50%.
They compared 493 women who had selective lymph node dissection (LND) at the Mayo Clinic between 2004 and 2008 according to an institutional algorithm (complete pelvic and para-aortic lymphadenectomy to the renal veins in cases deemed at risk for nodal metastasis) with 642 women who had SLN mapping at the Memorial Sloan Kettering Cancer Center between 2006 and 2013 according to an institutional algorithm. The SLNs were evaluated by pathologic ultrastaging and were considered positive whether they had macrometastases, micrometastases, or isolated tumor cells.
Results showed that patients in the SLN cohort were more likely to have pelvic nodes excised (93% vs. 58%) and less likely to have para-aortic nodes excised (14% vs. 50%), Dr. Eriksson reported.
Markedly fewer lymph nodes were removed per patient with the SLN algorithm, yet it yielded a higher detection rate of stage IIIC1 disease (4.8% vs. 1.8%) and similar detection rates of stage IIIA/B and stage IIIC2 disease.
Patients in the SLN cohort were more than twice as likely to receive adjuvant therapy (27% vs. 12%). (Dr. Eriksson noted that patients in the SLN cohort who had positive nodes were offered the same adjuvant therapy options regardless of the amount of metastases found in the nodes.)
With a median follow-up of 2.1 years in the SLN cohort and 3.5 years in the LND cohort, the cohorts had statistically indistinguishable 3-year rates of freedom from isolated nodal recurrence (99.6% in each) and disease-free survival (94.9% and 96.8%).
“The application of the SLN algorithm does not appear to compromise oncologic outcome in this short follow-up. The value of SLN dissection or selective lymphadenectomy in patients with tumors equal to or less than 2 cm remains controversial,” Dr. Eriksson commented. “The clinical significance of disease detected on ultrastaging and the role of adjuvant therapy in these patients remains to be determined.”
“Prospective assessment of the SLN algorithm is needed and underway,” she concluded. “Our findings support the use of either strategy for endometrial cancer staging with no apparent detriment to the SLN algorithm.”
In the second study, investigators led by Dr. Jennifer A. Ducie, also a surgical fellow in gynecologic oncology at the Memorial Sloan Kettering Cancer Center, performed a similar analysis among women with intermediate-risk endometrial cancer, defined as that having endometrioid histology with any grade and at least 50% myometrial invasion, and high-risk endometrial cancer, defined as serous or clear cell carcinoma.
In the intermediate-risk group, there were 82 patients in the SLN cohort and 107 patients in the LND cohort. The groups had a similar detection rate of stage IIIC disease overall (35% and 28%), but the SLN cohort had a higher rate of detection of stage IIIC1 disease (32% vs. 11%) and the LND cohort had a higher rate of detection of stage IIIC2 disease (17% vs. 4%), Dr. Ducie reported.
In the high-risk group, there were 120 patients in the SLN cohort and 103 patients in the LND cohort. Patients in the SLN cohort were more likely to have pelvic nodes removed (98% vs. 85%) but had fewer nodes removed (11 vs. 30). Among patients who had para-aortic nodes removed, the SLN cohort was similarly as likely as the LND cohort to have positive nodes, but had a smaller median number positive (two vs. five). The rate of detection of stage IIIC disease overall (23% vs. 19%) and of the substages was statistically indistinguishable.
“Though both strategies yield similar detection rates of stage IIIC disease, it remains to be determined if removal of more normal-appearing lymph nodes will improve survival,” Dr. Ducie concluded. “A limitation of this portion of our collaborative study is that we don’t address adjuvant therapy or outcomes, but these will be addressed in future analyses.”
CHICAGO – Sentinel lymph node mapping is a safe, less extensive alternative to lymph node dissection in women with endometrial cancer regardless of the clinically suspected risk of metastases, suggest a pair of retrospective cohort studies reported at the annual meeting of the Society of Gynecologic Oncology.
“The role and extent of surgical staging in endometrial carcinoma is controversial. The various strategies range from no lymphadenectomy to a full lymphadenectomy dissection up to the renal vessels,” said Dr. Ane Gerda Zahl Eriksson, a surgical fellow in gynecologic oncology at the Memorial Sloan Kettering Cancer Center, New York.
“The use of SLN [sentinel lymph node] mapping is emerging as an acceptable approach for nodal assessment in endometrial carcinoma. However, as always when introducing a novel management strategy, we must be mindful not to compromise oncologic outcome or otherwise inflict harm on our patients by our approach,” she added.
Dr. Eriksson and colleagues assessed clinicopathologic outcomes according to nodal assessment approach among women with low-risk endometrial cancer, defined as that with endometrioid histology of any grade with myometrial invasion of less than 50%.
They compared 493 women who had selective lymph node dissection (LND) at the Mayo Clinic between 2004 and 2008 according to an institutional algorithm (complete pelvic and para-aortic lymphadenectomy to the renal veins in cases deemed at risk for nodal metastasis) with 642 women who had SLN mapping at the Memorial Sloan Kettering Cancer Center between 2006 and 2013 according to an institutional algorithm. The SLNs were evaluated by pathologic ultrastaging and were considered positive whether they had macrometastases, micrometastases, or isolated tumor cells.
Results showed that patients in the SLN cohort were more likely to have pelvic nodes excised (93% vs. 58%) and less likely to have para-aortic nodes excised (14% vs. 50%), Dr. Eriksson reported.
Markedly fewer lymph nodes were removed per patient with the SLN algorithm, yet it yielded a higher detection rate of stage IIIC1 disease (4.8% vs. 1.8%) and similar detection rates of stage IIIA/B and stage IIIC2 disease.
Patients in the SLN cohort were more than twice as likely to receive adjuvant therapy (27% vs. 12%). (Dr. Eriksson noted that patients in the SLN cohort who had positive nodes were offered the same adjuvant therapy options regardless of the amount of metastases found in the nodes.)
With a median follow-up of 2.1 years in the SLN cohort and 3.5 years in the LND cohort, the cohorts had statistically indistinguishable 3-year rates of freedom from isolated nodal recurrence (99.6% in each) and disease-free survival (94.9% and 96.8%).
“The application of the SLN algorithm does not appear to compromise oncologic outcome in this short follow-up. The value of SLN dissection or selective lymphadenectomy in patients with tumors equal to or less than 2 cm remains controversial,” Dr. Eriksson commented. “The clinical significance of disease detected on ultrastaging and the role of adjuvant therapy in these patients remains to be determined.”
“Prospective assessment of the SLN algorithm is needed and underway,” she concluded. “Our findings support the use of either strategy for endometrial cancer staging with no apparent detriment to the SLN algorithm.”
In the second study, investigators led by Dr. Jennifer A. Ducie, also a surgical fellow in gynecologic oncology at the Memorial Sloan Kettering Cancer Center, performed a similar analysis among women with intermediate-risk endometrial cancer, defined as that having endometrioid histology with any grade and at least 50% myometrial invasion, and high-risk endometrial cancer, defined as serous or clear cell carcinoma.
In the intermediate-risk group, there were 82 patients in the SLN cohort and 107 patients in the LND cohort. The groups had a similar detection rate of stage IIIC disease overall (35% and 28%), but the SLN cohort had a higher rate of detection of stage IIIC1 disease (32% vs. 11%) and the LND cohort had a higher rate of detection of stage IIIC2 disease (17% vs. 4%), Dr. Ducie reported.
In the high-risk group, there were 120 patients in the SLN cohort and 103 patients in the LND cohort. Patients in the SLN cohort were more likely to have pelvic nodes removed (98% vs. 85%) but had fewer nodes removed (11 vs. 30). Among patients who had para-aortic nodes removed, the SLN cohort was similarly as likely as the LND cohort to have positive nodes, but had a smaller median number positive (two vs. five). The rate of detection of stage IIIC disease overall (23% vs. 19%) and of the substages was statistically indistinguishable.
“Though both strategies yield similar detection rates of stage IIIC disease, it remains to be determined if removal of more normal-appearing lymph nodes will improve survival,” Dr. Ducie concluded. “A limitation of this portion of our collaborative study is that we don’t address adjuvant therapy or outcomes, but these will be addressed in future analyses.”
AT THE ANNUAL MEETING ON WOMEN’S CANCER
Key clinical point: SLN mapping performs similarly to LND for detecting stage IIIC disease in women with endometrial cancer.
Major finding: SLN mapping had a higher detection rate of stage IIIC1 disease in low-risk disease (4.8% vs. 1.8%) and a similar detection rate of stage IIIC disease overall in intermediate- and high-risk disease.
Data source: Two retrospective cohort studies of 1,135 women with low-risk endometrial cancer and 412 women with intermediate- or high-risk endometrial cancer.
Disclosures: Dr. Eriksson disclosed that she had no relevant conflicts of interest. Dr. Ducie disclosed that she had no relevant conflicts of interest.
New 9-valent HPV vaccine is efficacious, well tolerated
CHICAGO – The 9-valent human papillomavirus (HPV) vaccine recently approved by the Food and Drug Administration has high efficacy for preventing disease caused by the vaccine-covered viral types and is well tolerated, according to end-of study data from a randomized trial.
The vaccine was on par with the quadrivalent vaccine when it came to protection against infection with the four original viral types covered by both vaccines. Additionally, for the five new viral types, it was associated with a 97% reduction in all cervical, vaginal, and vulvar intraepithelial neoplasia, a 100% reduction in cervical intraepithelial neoplasia 3, and a more than 90% reduction in related procedures and treatments, investigators reported at the Annual meeting of Society of Gynecologic Oncology. Meanwhile, it had a good safety profile.
“The consistency of the data is very reassuring,” said Dr. Elmar A. Joura of the Medical University of Vienna, General Hospital, and Comprehensive Cancer Center, also in Vienna.
Dr. Marcela delCarmen, session comoderator and a gynecologic oncologist at the Massachusetts General Hospital in Boston, asked, “You’ve presented data on the efficacy of the vaccine in the study population, but do you have any data on the effectiveness or the impact that the vaccine will have on the public health atmosphere of the general population?”
“First of all, we saw that the vaccine was doing exactly what was expected. These vaccines don’t have any therapeutic effect, so those women who have been infected at the time of vaccination, we did not observe a benefit during the course of the study. But from the previous study of the quadrivalent vaccine, we know [that] over the course of time, they also will get some benefit,” Dr. Joura replied.
“The second thing is, the vaccine really has the potential with this high effectiveness to change the screening practice in the long term. But what’s definitely needed is good coverage. And in many countries and also in this country, the coverage rates are far from optimal. Once you achieve a rate like in Australia or the United Kingdom, then the next step definitely is a change of screening algorithm,” such as a switch to primary HPV screening, he added.
There is a persistent medical need to develop new HPV vaccines, even though two highly effective vaccines have been on the market for some time, Dr. Joura maintained. “With HPV 16 and 18, you cover about 70% of invasive cervical cancer and about 50% of cervical precancer. Adding the next five most common most oncogenic HPV strains would give a coverage of 90% for both invasive and precancer, giving an additional benefit of 20% for invasive cancer and 35% for cervical precancer,” he elaborated.
In the Merck-sponsored phase IIb/III trial, the investigators randomized 14,215 women aged 16-26 to double-blind receipt of the quadrivalent vaccine (Gardasil, which covers viral types 6, 11, 16, and 18) or the 9-valent vaccine (Gardasil 9, which additionally covers viral types 31, 33, 45, 52, and 58). “It was not possible to have this trial placebo-controlled since two effective vaccines were available, so the controls were vaccinated with the quadrivalent HPV vaccine,” Dr. Joura explained. The women had follow-up with sample collection for up to 54 months.
Initial results showed that antibody titers for the original four viral types in the group given the 9-valent vaccine were noninferior to those in the group given the quadrivalent vaccine, and when compared against the historical placebo arm of the quadrivalent vaccine trial, there was dramatic and near full protection against type 16- and 18-related cervical, vaginal, and vulvar neoplasia. These findings led to approval of the vaccine late last year and a recent publication (N. Engl. J. Med. 2015;372:711-23).
The new, end-of-study data, capturing roughly an additional year of observation, showed that relative to the quadrivalent vaccine, the 9-valent vaccine provided good protection for the five new viral types among women negative for these types at baseline: Efficacy was 97.7% for protection against any neoplasia of the cervix, vagina, or vulva; 97.4% for protection against high-grade neoplasia; and 96.0% for protection against 6-month persistent infection.
“What is important for public health decisions is what is the effect on procedures and treatments,” Dr. Joura said. In fact, the 9-valent vaccine was highly efficacious for reducing external genital biopsies (92.3% risk reduction), cervical biopsy (97.7%), and loop electrosurgical excision procedure/conization (90.2%) related to the five new viral types covered.
The rate of vaccine-related adverse events was 92.2% with the 9-valent vaccine and 87.6% with the quadrivalent vaccine, with the difference mainly due to more injection site reactions with the former. There was two vaccine-related serious adverse events in the 9-valent group and one in the quadrivalent group.
Prevalence data will help assess trends, tailor screening
In a related study, investigators led by Dr. Warner K. Huh, a professor in the department of obstetrics and gynecology at the University of Alabama at Birmingham, determined the relative prevalence of HPV genotypes in the U.S. population.
“We are going to see a transition from the quadrivalent vaccine to the 9-valent vaccine, so information regarding genotypes in this country becomes extremely important,” he said. “There is very limited information in terms of the HPV prevalence for genotypes across the U.S. and more importantly, we almost have zero information on what that prevalence is in a low-risk population. To understand changes in the prevalence in this country, particularly with vaccination and then ultimately as it relates to screening, you are going to need to understand what that baseline data is.”
The investigators analyzed data from 46,751 women aged 21 years or older in the ATHENA study (Evaluation of the Cobas 4800 HPV Test for the Detection of High-Grade Cervical Disease), the largest HPV screening cohort nationally. The Roche-funded study was used to gain Food and Drug Administration approval for primary HPV screening in the United States. Less than 3% of enrolled women had received an HPV vaccine.
The women had HPV testing, in addition to liquid-based Pap testing and colposcopy, with follow-up out to 3 years in a subset. Genotyping was used to detect 16 high-risk types of HPV (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 73, and 82), and the prevalence of each was benchmarked to that of HPV 16.
“We benchmarked to HPV 16 for a couple of reasons,” Dr. Huh explained. “One of which is that we now have two vaccines – the quadrivalent and the 9-valent vaccines – and we thought it would be interesting to see what happens to that ratio as we have had one for essentially 10 years and the other one transitions in. The other reason, of course, is that it’s a highly prevalent type and a type that’s seen in both vaccines.”
Results showed that the absolute prevalence of all 16 types combined was 11.5% in the entire cohort and 10.0% in the low-risk subset with normal Pap results. In age-stratified analyses, it was higher among women aged 21-24 years than among older women.
The prevalence ratio relative to HPV 16 for the most common viral types among those assessed ranged from 0.12 for HPV 33 to 0.57 for HPV 52.
“The ratios may not be relevant to you today, but they may become highly relevant 10, 20, or 30 years from now,” Dr. Huh commented, discussing HPV type 31, which had a ratio of 0.43, as an example. As coverage by the quadrivalent vaccine and hence protection against type 16 rises, “what we would expect over the next 10 years is that ratio to increase substantially, some theorize as much as fourfold. Then as you roll out the 9-valent vaccine, theoretically, that ratio should normalize back to 0.43, assuming again that the efficacy is equivalent for [type 31] and for type 16,” he explained. “So this is where it becomes very interesting, because if it doesn’t, there is something else going on in the population.”
The new data additionally allow good ability to track the phenomenon of viral type replacement, Dr. Huh said.
“But most importantly, what it allows us to do is to look at screening and the impact of the nonavalent vaccine on screening in the United States. If you all buy into primary HPV screening, the current algorithm uses type 16 and type 18. Well, if type 16 and type 18 go away and these ratios change, then we need to seriously revisit how we do primary HPV screening because the current algorithm is probably not the right algorithm to use,” he maintained.
CHICAGO – The 9-valent human papillomavirus (HPV) vaccine recently approved by the Food and Drug Administration has high efficacy for preventing disease caused by the vaccine-covered viral types and is well tolerated, according to end-of study data from a randomized trial.
The vaccine was on par with the quadrivalent vaccine when it came to protection against infection with the four original viral types covered by both vaccines. Additionally, for the five new viral types, it was associated with a 97% reduction in all cervical, vaginal, and vulvar intraepithelial neoplasia, a 100% reduction in cervical intraepithelial neoplasia 3, and a more than 90% reduction in related procedures and treatments, investigators reported at the Annual meeting of Society of Gynecologic Oncology. Meanwhile, it had a good safety profile.
“The consistency of the data is very reassuring,” said Dr. Elmar A. Joura of the Medical University of Vienna, General Hospital, and Comprehensive Cancer Center, also in Vienna.
Dr. Marcela delCarmen, session comoderator and a gynecologic oncologist at the Massachusetts General Hospital in Boston, asked, “You’ve presented data on the efficacy of the vaccine in the study population, but do you have any data on the effectiveness or the impact that the vaccine will have on the public health atmosphere of the general population?”
“First of all, we saw that the vaccine was doing exactly what was expected. These vaccines don’t have any therapeutic effect, so those women who have been infected at the time of vaccination, we did not observe a benefit during the course of the study. But from the previous study of the quadrivalent vaccine, we know [that] over the course of time, they also will get some benefit,” Dr. Joura replied.
“The second thing is, the vaccine really has the potential with this high effectiveness to change the screening practice in the long term. But what’s definitely needed is good coverage. And in many countries and also in this country, the coverage rates are far from optimal. Once you achieve a rate like in Australia or the United Kingdom, then the next step definitely is a change of screening algorithm,” such as a switch to primary HPV screening, he added.
There is a persistent medical need to develop new HPV vaccines, even though two highly effective vaccines have been on the market for some time, Dr. Joura maintained. “With HPV 16 and 18, you cover about 70% of invasive cervical cancer and about 50% of cervical precancer. Adding the next five most common most oncogenic HPV strains would give a coverage of 90% for both invasive and precancer, giving an additional benefit of 20% for invasive cancer and 35% for cervical precancer,” he elaborated.
In the Merck-sponsored phase IIb/III trial, the investigators randomized 14,215 women aged 16-26 to double-blind receipt of the quadrivalent vaccine (Gardasil, which covers viral types 6, 11, 16, and 18) or the 9-valent vaccine (Gardasil 9, which additionally covers viral types 31, 33, 45, 52, and 58). “It was not possible to have this trial placebo-controlled since two effective vaccines were available, so the controls were vaccinated with the quadrivalent HPV vaccine,” Dr. Joura explained. The women had follow-up with sample collection for up to 54 months.
Initial results showed that antibody titers for the original four viral types in the group given the 9-valent vaccine were noninferior to those in the group given the quadrivalent vaccine, and when compared against the historical placebo arm of the quadrivalent vaccine trial, there was dramatic and near full protection against type 16- and 18-related cervical, vaginal, and vulvar neoplasia. These findings led to approval of the vaccine late last year and a recent publication (N. Engl. J. Med. 2015;372:711-23).
The new, end-of-study data, capturing roughly an additional year of observation, showed that relative to the quadrivalent vaccine, the 9-valent vaccine provided good protection for the five new viral types among women negative for these types at baseline: Efficacy was 97.7% for protection against any neoplasia of the cervix, vagina, or vulva; 97.4% for protection against high-grade neoplasia; and 96.0% for protection against 6-month persistent infection.
“What is important for public health decisions is what is the effect on procedures and treatments,” Dr. Joura said. In fact, the 9-valent vaccine was highly efficacious for reducing external genital biopsies (92.3% risk reduction), cervical biopsy (97.7%), and loop electrosurgical excision procedure/conization (90.2%) related to the five new viral types covered.
The rate of vaccine-related adverse events was 92.2% with the 9-valent vaccine and 87.6% with the quadrivalent vaccine, with the difference mainly due to more injection site reactions with the former. There was two vaccine-related serious adverse events in the 9-valent group and one in the quadrivalent group.
Prevalence data will help assess trends, tailor screening
In a related study, investigators led by Dr. Warner K. Huh, a professor in the department of obstetrics and gynecology at the University of Alabama at Birmingham, determined the relative prevalence of HPV genotypes in the U.S. population.
“We are going to see a transition from the quadrivalent vaccine to the 9-valent vaccine, so information regarding genotypes in this country becomes extremely important,” he said. “There is very limited information in terms of the HPV prevalence for genotypes across the U.S. and more importantly, we almost have zero information on what that prevalence is in a low-risk population. To understand changes in the prevalence in this country, particularly with vaccination and then ultimately as it relates to screening, you are going to need to understand what that baseline data is.”
The investigators analyzed data from 46,751 women aged 21 years or older in the ATHENA study (Evaluation of the Cobas 4800 HPV Test for the Detection of High-Grade Cervical Disease), the largest HPV screening cohort nationally. The Roche-funded study was used to gain Food and Drug Administration approval for primary HPV screening in the United States. Less than 3% of enrolled women had received an HPV vaccine.
The women had HPV testing, in addition to liquid-based Pap testing and colposcopy, with follow-up out to 3 years in a subset. Genotyping was used to detect 16 high-risk types of HPV (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 73, and 82), and the prevalence of each was benchmarked to that of HPV 16.
“We benchmarked to HPV 16 for a couple of reasons,” Dr. Huh explained. “One of which is that we now have two vaccines – the quadrivalent and the 9-valent vaccines – and we thought it would be interesting to see what happens to that ratio as we have had one for essentially 10 years and the other one transitions in. The other reason, of course, is that it’s a highly prevalent type and a type that’s seen in both vaccines.”
Results showed that the absolute prevalence of all 16 types combined was 11.5% in the entire cohort and 10.0% in the low-risk subset with normal Pap results. In age-stratified analyses, it was higher among women aged 21-24 years than among older women.
The prevalence ratio relative to HPV 16 for the most common viral types among those assessed ranged from 0.12 for HPV 33 to 0.57 for HPV 52.
“The ratios may not be relevant to you today, but they may become highly relevant 10, 20, or 30 years from now,” Dr. Huh commented, discussing HPV type 31, which had a ratio of 0.43, as an example. As coverage by the quadrivalent vaccine and hence protection against type 16 rises, “what we would expect over the next 10 years is that ratio to increase substantially, some theorize as much as fourfold. Then as you roll out the 9-valent vaccine, theoretically, that ratio should normalize back to 0.43, assuming again that the efficacy is equivalent for [type 31] and for type 16,” he explained. “So this is where it becomes very interesting, because if it doesn’t, there is something else going on in the population.”
The new data additionally allow good ability to track the phenomenon of viral type replacement, Dr. Huh said.
“But most importantly, what it allows us to do is to look at screening and the impact of the nonavalent vaccine on screening in the United States. If you all buy into primary HPV screening, the current algorithm uses type 16 and type 18. Well, if type 16 and type 18 go away and these ratios change, then we need to seriously revisit how we do primary HPV screening because the current algorithm is probably not the right algorithm to use,” he maintained.
CHICAGO – The 9-valent human papillomavirus (HPV) vaccine recently approved by the Food and Drug Administration has high efficacy for preventing disease caused by the vaccine-covered viral types and is well tolerated, according to end-of study data from a randomized trial.
The vaccine was on par with the quadrivalent vaccine when it came to protection against infection with the four original viral types covered by both vaccines. Additionally, for the five new viral types, it was associated with a 97% reduction in all cervical, vaginal, and vulvar intraepithelial neoplasia, a 100% reduction in cervical intraepithelial neoplasia 3, and a more than 90% reduction in related procedures and treatments, investigators reported at the Annual meeting of Society of Gynecologic Oncology. Meanwhile, it had a good safety profile.
“The consistency of the data is very reassuring,” said Dr. Elmar A. Joura of the Medical University of Vienna, General Hospital, and Comprehensive Cancer Center, also in Vienna.
Dr. Marcela delCarmen, session comoderator and a gynecologic oncologist at the Massachusetts General Hospital in Boston, asked, “You’ve presented data on the efficacy of the vaccine in the study population, but do you have any data on the effectiveness or the impact that the vaccine will have on the public health atmosphere of the general population?”
“First of all, we saw that the vaccine was doing exactly what was expected. These vaccines don’t have any therapeutic effect, so those women who have been infected at the time of vaccination, we did not observe a benefit during the course of the study. But from the previous study of the quadrivalent vaccine, we know [that] over the course of time, they also will get some benefit,” Dr. Joura replied.
“The second thing is, the vaccine really has the potential with this high effectiveness to change the screening practice in the long term. But what’s definitely needed is good coverage. And in many countries and also in this country, the coverage rates are far from optimal. Once you achieve a rate like in Australia or the United Kingdom, then the next step definitely is a change of screening algorithm,” such as a switch to primary HPV screening, he added.
There is a persistent medical need to develop new HPV vaccines, even though two highly effective vaccines have been on the market for some time, Dr. Joura maintained. “With HPV 16 and 18, you cover about 70% of invasive cervical cancer and about 50% of cervical precancer. Adding the next five most common most oncogenic HPV strains would give a coverage of 90% for both invasive and precancer, giving an additional benefit of 20% for invasive cancer and 35% for cervical precancer,” he elaborated.
In the Merck-sponsored phase IIb/III trial, the investigators randomized 14,215 women aged 16-26 to double-blind receipt of the quadrivalent vaccine (Gardasil, which covers viral types 6, 11, 16, and 18) or the 9-valent vaccine (Gardasil 9, which additionally covers viral types 31, 33, 45, 52, and 58). “It was not possible to have this trial placebo-controlled since two effective vaccines were available, so the controls were vaccinated with the quadrivalent HPV vaccine,” Dr. Joura explained. The women had follow-up with sample collection for up to 54 months.
Initial results showed that antibody titers for the original four viral types in the group given the 9-valent vaccine were noninferior to those in the group given the quadrivalent vaccine, and when compared against the historical placebo arm of the quadrivalent vaccine trial, there was dramatic and near full protection against type 16- and 18-related cervical, vaginal, and vulvar neoplasia. These findings led to approval of the vaccine late last year and a recent publication (N. Engl. J. Med. 2015;372:711-23).
The new, end-of-study data, capturing roughly an additional year of observation, showed that relative to the quadrivalent vaccine, the 9-valent vaccine provided good protection for the five new viral types among women negative for these types at baseline: Efficacy was 97.7% for protection against any neoplasia of the cervix, vagina, or vulva; 97.4% for protection against high-grade neoplasia; and 96.0% for protection against 6-month persistent infection.
“What is important for public health decisions is what is the effect on procedures and treatments,” Dr. Joura said. In fact, the 9-valent vaccine was highly efficacious for reducing external genital biopsies (92.3% risk reduction), cervical biopsy (97.7%), and loop electrosurgical excision procedure/conization (90.2%) related to the five new viral types covered.
The rate of vaccine-related adverse events was 92.2% with the 9-valent vaccine and 87.6% with the quadrivalent vaccine, with the difference mainly due to more injection site reactions with the former. There was two vaccine-related serious adverse events in the 9-valent group and one in the quadrivalent group.
Prevalence data will help assess trends, tailor screening
In a related study, investigators led by Dr. Warner K. Huh, a professor in the department of obstetrics and gynecology at the University of Alabama at Birmingham, determined the relative prevalence of HPV genotypes in the U.S. population.
“We are going to see a transition from the quadrivalent vaccine to the 9-valent vaccine, so information regarding genotypes in this country becomes extremely important,” he said. “There is very limited information in terms of the HPV prevalence for genotypes across the U.S. and more importantly, we almost have zero information on what that prevalence is in a low-risk population. To understand changes in the prevalence in this country, particularly with vaccination and then ultimately as it relates to screening, you are going to need to understand what that baseline data is.”
The investigators analyzed data from 46,751 women aged 21 years or older in the ATHENA study (Evaluation of the Cobas 4800 HPV Test for the Detection of High-Grade Cervical Disease), the largest HPV screening cohort nationally. The Roche-funded study was used to gain Food and Drug Administration approval for primary HPV screening in the United States. Less than 3% of enrolled women had received an HPV vaccine.
The women had HPV testing, in addition to liquid-based Pap testing and colposcopy, with follow-up out to 3 years in a subset. Genotyping was used to detect 16 high-risk types of HPV (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 73, and 82), and the prevalence of each was benchmarked to that of HPV 16.
“We benchmarked to HPV 16 for a couple of reasons,” Dr. Huh explained. “One of which is that we now have two vaccines – the quadrivalent and the 9-valent vaccines – and we thought it would be interesting to see what happens to that ratio as we have had one for essentially 10 years and the other one transitions in. The other reason, of course, is that it’s a highly prevalent type and a type that’s seen in both vaccines.”
Results showed that the absolute prevalence of all 16 types combined was 11.5% in the entire cohort and 10.0% in the low-risk subset with normal Pap results. In age-stratified analyses, it was higher among women aged 21-24 years than among older women.
The prevalence ratio relative to HPV 16 for the most common viral types among those assessed ranged from 0.12 for HPV 33 to 0.57 for HPV 52.
“The ratios may not be relevant to you today, but they may become highly relevant 10, 20, or 30 years from now,” Dr. Huh commented, discussing HPV type 31, which had a ratio of 0.43, as an example. As coverage by the quadrivalent vaccine and hence protection against type 16 rises, “what we would expect over the next 10 years is that ratio to increase substantially, some theorize as much as fourfold. Then as you roll out the 9-valent vaccine, theoretically, that ratio should normalize back to 0.43, assuming again that the efficacy is equivalent for [type 31] and for type 16,” he explained. “So this is where it becomes very interesting, because if it doesn’t, there is something else going on in the population.”
The new data additionally allow good ability to track the phenomenon of viral type replacement, Dr. Huh said.
“But most importantly, what it allows us to do is to look at screening and the impact of the nonavalent vaccine on screening in the United States. If you all buy into primary HPV screening, the current algorithm uses type 16 and type 18. Well, if type 16 and type 18 go away and these ratios change, then we need to seriously revisit how we do primary HPV screening because the current algorithm is probably not the right algorithm to use,” he maintained.
AT THE ANNUAL MEETING ON WOMEN’S CANCER
Key clinical point: The 9-valent vaccine has broader coverage than does the quadrivalent vaccine and is similarly safe.
Major finding: The 9-valent vaccine had 97% efficacy against disease related to the five newly covered viral types.
Data source: A randomized, double-blind, phase IIb/III trial among 14,215 women aged 16 to 26.
Disclosures: Dr. Joura disclosed that he is an investigator for Merck HPV vaccines and with GlaxoSmithKline epidemiologic trials, and lectures for Merck, Sanofi Pasteur MSD, GlaxoSmithKline, and Roche; the trial was sponsored by Merck. Dr. Huh disclosed that he is a nonpaid consultant for Roche Molecular Systems and a Scientific Advisory Board member for Merck’s Gardasil 9 program; the study was funded by Roche.
Bevacizumab confers survival benefit in platinum-sensitive ovarian cancer
CHICAGO – Adding the anti-angiogenic agent bevacizumab to chemotherapy improves outcomes in women with platinum-sensitive recurrent epithelial ovarian cancer, the randomized Gynecologic Oncology Group 213 trial has shown.
Results reported at the annual meeting of the Society of Gynecologic Oncology showed that addition of bevacizumab reduced the risk of death (one of the trial’s co-primary endpoints) by a near-significant 17%, which amounted to 4.9 more months of life.
“Paclitaxel, carboplatin, and bevacizumab extended overall survival in patients with platinum-sensitive recurrent ovarian cancer, but narrowly missed that statistical upper limit of significance. The combination was associated with a significant improvement in progression-free survival as well as objective response,” commented lead investigator Dr. Robert L. Coleman, professor and vice chair of clinical research in the department of gynecologic oncology and reproductive medicine, University of Texas MD Anderson Cancer Center in Houston.
“Although toxicity was more commonly observed on the concomitant bevacizumab arm, no new safety signals were detected, and no negative impact on a patient-reported global functioning scale was observed,” he added.
Session attendee Dr. Brad Monk of the University of Arizona Cancer Center in Phoenix wondered if the overall survival results could be interpreted as positive in light of information gleaned since the trial’s inception.
“I think we all accept that 5 months is 5 months of overall survival. I accepted 8 years ago, when the study was developed, that [the statistical test used] was a two-sided test, looking for both superiority and inferiority,” he said. “But today we would never expect that bevacizumab would make survival worse. So if you were to apply a one-tailed test, the P value would go from .056 to .028, and then you would say it’s positive. I know that we can’t change the statistical design, but is this study really negative statistically? Is this a practice-changing study?”
“You are right, we have learned a lot,” Dr. Coleman agreed. “I think one of the most striking differences in this trial versus what our expectations were was the performance of the control arm,” wherein survival far exceeded the 22 months assumed in the trial’s planning; meanwhile, a progression-free survival benefit of bevacizumab was preserved. “I think that this is the strongest signal for that, and the fact that we were able to achieve that knowing that the environment has changed so much, to me, does feel like it is practice changing,” he said.
Two previous trials — CALYPSO (Caelyx Plus Carboplatin Versus Paclitaxel Plus Carboplatin in Patients With Epithelial Ovarian Cancer in Late Relapse) and OCEANS (Ovarian Cancer Study Comparing Efficacy and Safety of Chemotherapy and Anti-Angiogenic Therapy in Platinum-Sensitive Recurrent Disease) — tested variations on a chemotherapy backbone exclusively among platinum-sensitive patients, he noted, giving some background to the research. Neither found a significant survival benefit (Br J Cancer. 2012;107:588-91 and J Clin Oncol. 2012;30:2039-45).
Participants in the current trial were 674 women with ovarian cancer from the United States, Japan, and South Korea who had a complete response to primary therapy but experienced a recurrence at least 6 months later. They were randomized twice: first to receive secondary cytoreductive surgery or not, and then to receive carboplatin plus paclitaxel, with versus without concurrent and maintenance bevacizumab (Avastin). Genentech provided the agent and supported the National Cancer Institute/Cancer Therapy Evaluation Program for the trial.
In terms of adverse events of special interest, the bevacizumab group had significantly higher rates of grade 3 or worse thromboembolism (4% vs. 1%), infection (13% vs. 6%), hypertension (12% vs. less than 1%), proteinuria (8% vs. 0%), and joint pain (15% vs. 5%), reported Dr. Coleman, who disclosed that he had no conflicts of interest.
“However, arterial thrombosis, neutropenia, and febrile neutropenia were not different between the two arms. And in addition, while gastrointestinal events were more common in the experimental arm, the grade 3/4 events were no different, and no patient died as a result of this adverse event, “ he noted. Furthermore, the allergy (mainly carboplatin hypersensitivity) and grade 3 or worse neuropathy were essentially equally common across groups.
Median overall survival was 42.2 months with bevacizumab and 37.3 months without it (hazard ratio 0.83; P = .056). In subgroup analyses, benefit was similar of whether patients had undergone randomization for cytoreductive surgery, had a progression-free interval of more than 12 months, and had received bevacizumab before.
Progression-free survival was 13.8 months with bevacizumab and 10.4 months without it, a significant difference (hazard ratio 0.61; P less than .0001). The overall response rate was also better with the anti-angiogenic agent (79% vs. 59%, P less than .0001).
Patient-reported quality of life did not differ significantly between the two treatment groups, according to Dr. Coleman. Not surprisingly, those given bevacizumab were less likely to receive more of that agent or another anti-angiogenic agent as the next line of therapy after progression.
Data for the second co-primary endpoint, the overall survival impact of secondary cytoreductive surgery, are currently pending, he said.
CHICAGO – Adding the anti-angiogenic agent bevacizumab to chemotherapy improves outcomes in women with platinum-sensitive recurrent epithelial ovarian cancer, the randomized Gynecologic Oncology Group 213 trial has shown.
Results reported at the annual meeting of the Society of Gynecologic Oncology showed that addition of bevacizumab reduced the risk of death (one of the trial’s co-primary endpoints) by a near-significant 17%, which amounted to 4.9 more months of life.
“Paclitaxel, carboplatin, and bevacizumab extended overall survival in patients with platinum-sensitive recurrent ovarian cancer, but narrowly missed that statistical upper limit of significance. The combination was associated with a significant improvement in progression-free survival as well as objective response,” commented lead investigator Dr. Robert L. Coleman, professor and vice chair of clinical research in the department of gynecologic oncology and reproductive medicine, University of Texas MD Anderson Cancer Center in Houston.
“Although toxicity was more commonly observed on the concomitant bevacizumab arm, no new safety signals were detected, and no negative impact on a patient-reported global functioning scale was observed,” he added.
Session attendee Dr. Brad Monk of the University of Arizona Cancer Center in Phoenix wondered if the overall survival results could be interpreted as positive in light of information gleaned since the trial’s inception.
“I think we all accept that 5 months is 5 months of overall survival. I accepted 8 years ago, when the study was developed, that [the statistical test used] was a two-sided test, looking for both superiority and inferiority,” he said. “But today we would never expect that bevacizumab would make survival worse. So if you were to apply a one-tailed test, the P value would go from .056 to .028, and then you would say it’s positive. I know that we can’t change the statistical design, but is this study really negative statistically? Is this a practice-changing study?”
“You are right, we have learned a lot,” Dr. Coleman agreed. “I think one of the most striking differences in this trial versus what our expectations were was the performance of the control arm,” wherein survival far exceeded the 22 months assumed in the trial’s planning; meanwhile, a progression-free survival benefit of bevacizumab was preserved. “I think that this is the strongest signal for that, and the fact that we were able to achieve that knowing that the environment has changed so much, to me, does feel like it is practice changing,” he said.
Two previous trials — CALYPSO (Caelyx Plus Carboplatin Versus Paclitaxel Plus Carboplatin in Patients With Epithelial Ovarian Cancer in Late Relapse) and OCEANS (Ovarian Cancer Study Comparing Efficacy and Safety of Chemotherapy and Anti-Angiogenic Therapy in Platinum-Sensitive Recurrent Disease) — tested variations on a chemotherapy backbone exclusively among platinum-sensitive patients, he noted, giving some background to the research. Neither found a significant survival benefit (Br J Cancer. 2012;107:588-91 and J Clin Oncol. 2012;30:2039-45).
Participants in the current trial were 674 women with ovarian cancer from the United States, Japan, and South Korea who had a complete response to primary therapy but experienced a recurrence at least 6 months later. They were randomized twice: first to receive secondary cytoreductive surgery or not, and then to receive carboplatin plus paclitaxel, with versus without concurrent and maintenance bevacizumab (Avastin). Genentech provided the agent and supported the National Cancer Institute/Cancer Therapy Evaluation Program for the trial.
In terms of adverse events of special interest, the bevacizumab group had significantly higher rates of grade 3 or worse thromboembolism (4% vs. 1%), infection (13% vs. 6%), hypertension (12% vs. less than 1%), proteinuria (8% vs. 0%), and joint pain (15% vs. 5%), reported Dr. Coleman, who disclosed that he had no conflicts of interest.
“However, arterial thrombosis, neutropenia, and febrile neutropenia were not different between the two arms. And in addition, while gastrointestinal events were more common in the experimental arm, the grade 3/4 events were no different, and no patient died as a result of this adverse event, “ he noted. Furthermore, the allergy (mainly carboplatin hypersensitivity) and grade 3 or worse neuropathy were essentially equally common across groups.
Median overall survival was 42.2 months with bevacizumab and 37.3 months without it (hazard ratio 0.83; P = .056). In subgroup analyses, benefit was similar of whether patients had undergone randomization for cytoreductive surgery, had a progression-free interval of more than 12 months, and had received bevacizumab before.
Progression-free survival was 13.8 months with bevacizumab and 10.4 months without it, a significant difference (hazard ratio 0.61; P less than .0001). The overall response rate was also better with the anti-angiogenic agent (79% vs. 59%, P less than .0001).
Patient-reported quality of life did not differ significantly between the two treatment groups, according to Dr. Coleman. Not surprisingly, those given bevacizumab were less likely to receive more of that agent or another anti-angiogenic agent as the next line of therapy after progression.
Data for the second co-primary endpoint, the overall survival impact of secondary cytoreductive surgery, are currently pending, he said.
CHICAGO – Adding the anti-angiogenic agent bevacizumab to chemotherapy improves outcomes in women with platinum-sensitive recurrent epithelial ovarian cancer, the randomized Gynecologic Oncology Group 213 trial has shown.
Results reported at the annual meeting of the Society of Gynecologic Oncology showed that addition of bevacizumab reduced the risk of death (one of the trial’s co-primary endpoints) by a near-significant 17%, which amounted to 4.9 more months of life.
“Paclitaxel, carboplatin, and bevacizumab extended overall survival in patients with platinum-sensitive recurrent ovarian cancer, but narrowly missed that statistical upper limit of significance. The combination was associated with a significant improvement in progression-free survival as well as objective response,” commented lead investigator Dr. Robert L. Coleman, professor and vice chair of clinical research in the department of gynecologic oncology and reproductive medicine, University of Texas MD Anderson Cancer Center in Houston.
“Although toxicity was more commonly observed on the concomitant bevacizumab arm, no new safety signals were detected, and no negative impact on a patient-reported global functioning scale was observed,” he added.
Session attendee Dr. Brad Monk of the University of Arizona Cancer Center in Phoenix wondered if the overall survival results could be interpreted as positive in light of information gleaned since the trial’s inception.
“I think we all accept that 5 months is 5 months of overall survival. I accepted 8 years ago, when the study was developed, that [the statistical test used] was a two-sided test, looking for both superiority and inferiority,” he said. “But today we would never expect that bevacizumab would make survival worse. So if you were to apply a one-tailed test, the P value would go from .056 to .028, and then you would say it’s positive. I know that we can’t change the statistical design, but is this study really negative statistically? Is this a practice-changing study?”
“You are right, we have learned a lot,” Dr. Coleman agreed. “I think one of the most striking differences in this trial versus what our expectations were was the performance of the control arm,” wherein survival far exceeded the 22 months assumed in the trial’s planning; meanwhile, a progression-free survival benefit of bevacizumab was preserved. “I think that this is the strongest signal for that, and the fact that we were able to achieve that knowing that the environment has changed so much, to me, does feel like it is practice changing,” he said.
Two previous trials — CALYPSO (Caelyx Plus Carboplatin Versus Paclitaxel Plus Carboplatin in Patients With Epithelial Ovarian Cancer in Late Relapse) and OCEANS (Ovarian Cancer Study Comparing Efficacy and Safety of Chemotherapy and Anti-Angiogenic Therapy in Platinum-Sensitive Recurrent Disease) — tested variations on a chemotherapy backbone exclusively among platinum-sensitive patients, he noted, giving some background to the research. Neither found a significant survival benefit (Br J Cancer. 2012;107:588-91 and J Clin Oncol. 2012;30:2039-45).
Participants in the current trial were 674 women with ovarian cancer from the United States, Japan, and South Korea who had a complete response to primary therapy but experienced a recurrence at least 6 months later. They were randomized twice: first to receive secondary cytoreductive surgery or not, and then to receive carboplatin plus paclitaxel, with versus without concurrent and maintenance bevacizumab (Avastin). Genentech provided the agent and supported the National Cancer Institute/Cancer Therapy Evaluation Program for the trial.
In terms of adverse events of special interest, the bevacizumab group had significantly higher rates of grade 3 or worse thromboembolism (4% vs. 1%), infection (13% vs. 6%), hypertension (12% vs. less than 1%), proteinuria (8% vs. 0%), and joint pain (15% vs. 5%), reported Dr. Coleman, who disclosed that he had no conflicts of interest.
“However, arterial thrombosis, neutropenia, and febrile neutropenia were not different between the two arms. And in addition, while gastrointestinal events were more common in the experimental arm, the grade 3/4 events were no different, and no patient died as a result of this adverse event, “ he noted. Furthermore, the allergy (mainly carboplatin hypersensitivity) and grade 3 or worse neuropathy were essentially equally common across groups.
Median overall survival was 42.2 months with bevacizumab and 37.3 months without it (hazard ratio 0.83; P = .056). In subgroup analyses, benefit was similar of whether patients had undergone randomization for cytoreductive surgery, had a progression-free interval of more than 12 months, and had received bevacizumab before.
Progression-free survival was 13.8 months with bevacizumab and 10.4 months without it, a significant difference (hazard ratio 0.61; P less than .0001). The overall response rate was also better with the anti-angiogenic agent (79% vs. 59%, P less than .0001).
Patient-reported quality of life did not differ significantly between the two treatment groups, according to Dr. Coleman. Not surprisingly, those given bevacizumab were less likely to receive more of that agent or another anti-angiogenic agent as the next line of therapy after progression.
Data for the second co-primary endpoint, the overall survival impact of secondary cytoreductive surgery, are currently pending, he said.
AT THE ANNUAL MEETING ON WOMEN’S CANCER
Key clinical point: Addition of bevacizumab to chemotherapy yielded a near-significant 4.9-month gain in overall survival.
Major finding: Patients given bevacizumab had a reduced risk of death relative to peers given chemotherapy alone (hazard ratio 0.83; P = .056).
Data source: A randomized phase 3 trial in 674 women with platinum-sensitive recurrent ovarian cancer.
Disclosures: Dr. Coleman disclosed that he had no conflicts of interest. Genentech provided the bevacizumab and supported the National Cancer Institute/Cancer Therapy Evaluation Program for the trial.
SCORPION: Interval debulking is safer in advanced ovarian cancer
CHICAGO – Delaying debulking until patients have had some chemotherapy is a safer strategy for women with advanced ovarian cancer, according to interim results of the randomized phase III SCORPION trial (Surgical Complications Related to Primary or Interval Debulking in Ovarian Neoplasm).
The odds of complications such as sepsis, organ failure, and death in the perioperative period were 19.3 times higher among women who underwent primary debulking than among counterparts who underwent neoadjuvant chemotherapy followed by interval debulking, Dr. Anna Fagotti reported at the annual meeting of the Society of Gynecologic Oncology.
“Primary debulking surgery is associated with a statistically significantly higher risk of major perioperative morbidity with respect to interval debulking surgery in high–tumor load advanced epithelial ovarian cancer patients,” she said.
“Most of these complications, however, are grade 3, with a higher incidence than reported from retrospective analyses in the literature. The reported mortality rate [with primary debulking] … is in line with the literature data,” added Dr. Fagotti of the University of Perugia, Terni, Italy. “Our survival data will definitely clarify whether such a severe complication rate is acceptable in terms of cost-effectiveness.”
The trial also offers a cautionary note about study methodology in this setting, she said. Specifically, “any neoadjuvant chemotherapy clinical study that is based on instrumental or clinical evaluation only, excluding staging laparoscopy, might include very heterogeneous populations, thus leading to substantial biases.”
Giving some background to the research, Dr. Fagotti noted that case series have shown a survival advantage for women with advanced ovarian cancer who undergo primary debulking with optimal or no residual tumor, albeit at the cost of more extensive surgery. But randomized trials have shown similar survival and fewer complications with the interval debulking approach.
“We know also that many limits can be ascribed to these studies, so, as a consequence, there are gray-zone patients in whom the best primary treatment option is not clear yet,” she commented.
The 110 patients studied in SCORPION had suspected advanced ovarian cancer with a FIGO (International Federation of Gynecology and Obstetrics) stage of IIIc or IV, and had an intraoperative staging laparoscopy score of 8-12. They were randomized evenly to primary debulking followed by adjuvant chemotherapy or to neoadjuvant chemotherapy followed by interval debulking.
Three patients in the latter arm had progression during their chemotherapy and were therefore unable to proceed to their planned surgery, Dr. Fagotti reported.
On average, women in the interval debulking group had less extensive surgery than peers in the primary debulking group. In particular, they were significantly less likely to undergo pelvic and/or abdominal peritonectomy (58% vs. 100%), bowel resection (19% vs. 100%), diaphragmatic peritonectomy or resection (38% vs. 100%), partial hepatectomy (0% vs. 18%), and splenectomy (4% vs. 53%). Overall, they were nearly half as likely to have any upper abdominal procedure (58% vs. 100%).
Ninety percent of all patients had optimal cytoreduction to residual disease of 1 cm or less, with no significant difference between groups, Dr. Fagotti said.
In terms of surgical measures, the interval debulking group had a median operative time that was about a third shorter and median blood loss and hospital stays about half those with primary debulking.
The interval debulking group was significantly less likely to experience any major postoperative complication (6% vs. 53%, P = .001). Notably, they had lower rates of pleural effusion (2% vs. 31%), sepsis (0% vs. 7%), pulmonary thromboembolism (0% vs. 6%), reoperation with organ resection (0% vs. 4%), multiorgan failure (0% vs. 2%), and surgery-related death (0% vs. 4%).
CHICAGO – Delaying debulking until patients have had some chemotherapy is a safer strategy for women with advanced ovarian cancer, according to interim results of the randomized phase III SCORPION trial (Surgical Complications Related to Primary or Interval Debulking in Ovarian Neoplasm).
The odds of complications such as sepsis, organ failure, and death in the perioperative period were 19.3 times higher among women who underwent primary debulking than among counterparts who underwent neoadjuvant chemotherapy followed by interval debulking, Dr. Anna Fagotti reported at the annual meeting of the Society of Gynecologic Oncology.
“Primary debulking surgery is associated with a statistically significantly higher risk of major perioperative morbidity with respect to interval debulking surgery in high–tumor load advanced epithelial ovarian cancer patients,” she said.
“Most of these complications, however, are grade 3, with a higher incidence than reported from retrospective analyses in the literature. The reported mortality rate [with primary debulking] … is in line with the literature data,” added Dr. Fagotti of the University of Perugia, Terni, Italy. “Our survival data will definitely clarify whether such a severe complication rate is acceptable in terms of cost-effectiveness.”
The trial also offers a cautionary note about study methodology in this setting, she said. Specifically, “any neoadjuvant chemotherapy clinical study that is based on instrumental or clinical evaluation only, excluding staging laparoscopy, might include very heterogeneous populations, thus leading to substantial biases.”
Giving some background to the research, Dr. Fagotti noted that case series have shown a survival advantage for women with advanced ovarian cancer who undergo primary debulking with optimal or no residual tumor, albeit at the cost of more extensive surgery. But randomized trials have shown similar survival and fewer complications with the interval debulking approach.
“We know also that many limits can be ascribed to these studies, so, as a consequence, there are gray-zone patients in whom the best primary treatment option is not clear yet,” she commented.
The 110 patients studied in SCORPION had suspected advanced ovarian cancer with a FIGO (International Federation of Gynecology and Obstetrics) stage of IIIc or IV, and had an intraoperative staging laparoscopy score of 8-12. They were randomized evenly to primary debulking followed by adjuvant chemotherapy or to neoadjuvant chemotherapy followed by interval debulking.
Three patients in the latter arm had progression during their chemotherapy and were therefore unable to proceed to their planned surgery, Dr. Fagotti reported.
On average, women in the interval debulking group had less extensive surgery than peers in the primary debulking group. In particular, they were significantly less likely to undergo pelvic and/or abdominal peritonectomy (58% vs. 100%), bowel resection (19% vs. 100%), diaphragmatic peritonectomy or resection (38% vs. 100%), partial hepatectomy (0% vs. 18%), and splenectomy (4% vs. 53%). Overall, they were nearly half as likely to have any upper abdominal procedure (58% vs. 100%).
Ninety percent of all patients had optimal cytoreduction to residual disease of 1 cm or less, with no significant difference between groups, Dr. Fagotti said.
In terms of surgical measures, the interval debulking group had a median operative time that was about a third shorter and median blood loss and hospital stays about half those with primary debulking.
The interval debulking group was significantly less likely to experience any major postoperative complication (6% vs. 53%, P = .001). Notably, they had lower rates of pleural effusion (2% vs. 31%), sepsis (0% vs. 7%), pulmonary thromboembolism (0% vs. 6%), reoperation with organ resection (0% vs. 4%), multiorgan failure (0% vs. 2%), and surgery-related death (0% vs. 4%).
CHICAGO – Delaying debulking until patients have had some chemotherapy is a safer strategy for women with advanced ovarian cancer, according to interim results of the randomized phase III SCORPION trial (Surgical Complications Related to Primary or Interval Debulking in Ovarian Neoplasm).
The odds of complications such as sepsis, organ failure, and death in the perioperative period were 19.3 times higher among women who underwent primary debulking than among counterparts who underwent neoadjuvant chemotherapy followed by interval debulking, Dr. Anna Fagotti reported at the annual meeting of the Society of Gynecologic Oncology.
“Primary debulking surgery is associated with a statistically significantly higher risk of major perioperative morbidity with respect to interval debulking surgery in high–tumor load advanced epithelial ovarian cancer patients,” she said.
“Most of these complications, however, are grade 3, with a higher incidence than reported from retrospective analyses in the literature. The reported mortality rate [with primary debulking] … is in line with the literature data,” added Dr. Fagotti of the University of Perugia, Terni, Italy. “Our survival data will definitely clarify whether such a severe complication rate is acceptable in terms of cost-effectiveness.”
The trial also offers a cautionary note about study methodology in this setting, she said. Specifically, “any neoadjuvant chemotherapy clinical study that is based on instrumental or clinical evaluation only, excluding staging laparoscopy, might include very heterogeneous populations, thus leading to substantial biases.”
Giving some background to the research, Dr. Fagotti noted that case series have shown a survival advantage for women with advanced ovarian cancer who undergo primary debulking with optimal or no residual tumor, albeit at the cost of more extensive surgery. But randomized trials have shown similar survival and fewer complications with the interval debulking approach.
“We know also that many limits can be ascribed to these studies, so, as a consequence, there are gray-zone patients in whom the best primary treatment option is not clear yet,” she commented.
The 110 patients studied in SCORPION had suspected advanced ovarian cancer with a FIGO (International Federation of Gynecology and Obstetrics) stage of IIIc or IV, and had an intraoperative staging laparoscopy score of 8-12. They were randomized evenly to primary debulking followed by adjuvant chemotherapy or to neoadjuvant chemotherapy followed by interval debulking.
Three patients in the latter arm had progression during their chemotherapy and were therefore unable to proceed to their planned surgery, Dr. Fagotti reported.
On average, women in the interval debulking group had less extensive surgery than peers in the primary debulking group. In particular, they were significantly less likely to undergo pelvic and/or abdominal peritonectomy (58% vs. 100%), bowel resection (19% vs. 100%), diaphragmatic peritonectomy or resection (38% vs. 100%), partial hepatectomy (0% vs. 18%), and splenectomy (4% vs. 53%). Overall, they were nearly half as likely to have any upper abdominal procedure (58% vs. 100%).
Ninety percent of all patients had optimal cytoreduction to residual disease of 1 cm or less, with no significant difference between groups, Dr. Fagotti said.
In terms of surgical measures, the interval debulking group had a median operative time that was about a third shorter and median blood loss and hospital stays about half those with primary debulking.
The interval debulking group was significantly less likely to experience any major postoperative complication (6% vs. 53%, P = .001). Notably, they had lower rates of pleural effusion (2% vs. 31%), sepsis (0% vs. 7%), pulmonary thromboembolism (0% vs. 6%), reoperation with organ resection (0% vs. 4%), multiorgan failure (0% vs. 2%), and surgery-related death (0% vs. 4%).
AT THE ANNUAL MEETING ON WOMEN’S CANCER
Key clinical point: Complications were much less common with interval debulking than with primary debulking.
Major finding: The odds of major perioperative morbidity were 19.3 times higher with primary debulking than with neoadjuvant chemotherapy followed by interval debulking.
Data source: Interim results of a randomized phase III trial among 110 patients with ovarian cancer and a high tumor load.
Disclosures: Dr. Fagotti disclosed that she had no relevant conflicts of interest.
QOL independently predicts outcomes in ovarian cancer
CHICAGO– Quality of life at baseline and during treatment is an important prognostic factor in women with ovarian cancer, confirms an analysis reported at the annual meeting of the Society of Gynecologic Oncology.
Patients’ baseline quality of life score was independently associated with both progression-free and overall survival among 1,152 women participating in the Gynecologic Oncology Group (GOG) 218 trial, a randomized phase III trial comparing chemotherapy with versus without bevacizumab (Avastin), reported Dr. Neil T. Phippen of Walter Reed National Military Medical Center, Bethesda, Md.
Quality of life was assessed at six time points with FACT-O TOI (the Functional Assessment of Cancer Therapy–Ovarian Trial Outcome Index), on which possible scores range from 0-104 and higher scores indicate better quality of life. Women were included in analyses if they had completed the questionnaire at two or more time points.
Patients whose FACT-O TOI scores improved during treatment had a 4- to 5-month longer progression-free survival and a 20- to 25-month longer overall survival than counterparts whose scores worsened.
“Coupled with previously published data establishing quality of life as an independent predictor of survival across cancer sites, our results underscore the importance of quality of life surveillance in phase III clinical trials and support the inclusion of quality of life as an important component of composite clinical trial endpoints currently under development,” Dr. Phippen commented.
“Considering the independent prognostic value of the baseline FACT-O TOI score and the trend in the FACT-O TOI, methods to improve compliance with this evaluation metric are needed,” he maintained.
Patient-reported quality of life has been shown to be independently prognostic in at least five other cancers, according to Dr. Phippen. In advanced ovarian cancer, baseline FACT-O score (J. Clin. Oncol. 2005;23:5605-12) and the physical well-being scale of this score (Gynecol. Oncol. 2012;124:379-82) have previously been linked to overall survival.
In the new study, multivariate analysis that included potential confounders (age, performance status, stage, suboptimal debulking, and history of stroke or MI) showed that each 1-point decrease in baseline FACT-O TOI score was associated with significantly worse progression-free survival (hazard ratio, 1.005) and overall survival (HR, 1.0008), reported Dr. Phippen, who disclosed that he had no relevant conflicts of interest.
Additionally, within the group with lowest-quartile FACT-O TOI scores (indicating poorest quality of life), relative to peers who had a worsening of scores during treatment, women who had an improvement had significantly better progression-free survival (12.7 vs. 8.6 months) and overall survival (40.8 vs. 16 months).
Similarly, within the group having scores in higher quartiles, women who had an improvement in score during treatment again had significantly better progression-free survival (16.7 vs. 11.1 months) and overall survival (54.4 vs. 33.6 months).
CHICAGO– Quality of life at baseline and during treatment is an important prognostic factor in women with ovarian cancer, confirms an analysis reported at the annual meeting of the Society of Gynecologic Oncology.
Patients’ baseline quality of life score was independently associated with both progression-free and overall survival among 1,152 women participating in the Gynecologic Oncology Group (GOG) 218 trial, a randomized phase III trial comparing chemotherapy with versus without bevacizumab (Avastin), reported Dr. Neil T. Phippen of Walter Reed National Military Medical Center, Bethesda, Md.
Quality of life was assessed at six time points with FACT-O TOI (the Functional Assessment of Cancer Therapy–Ovarian Trial Outcome Index), on which possible scores range from 0-104 and higher scores indicate better quality of life. Women were included in analyses if they had completed the questionnaire at two or more time points.
Patients whose FACT-O TOI scores improved during treatment had a 4- to 5-month longer progression-free survival and a 20- to 25-month longer overall survival than counterparts whose scores worsened.
“Coupled with previously published data establishing quality of life as an independent predictor of survival across cancer sites, our results underscore the importance of quality of life surveillance in phase III clinical trials and support the inclusion of quality of life as an important component of composite clinical trial endpoints currently under development,” Dr. Phippen commented.
“Considering the independent prognostic value of the baseline FACT-O TOI score and the trend in the FACT-O TOI, methods to improve compliance with this evaluation metric are needed,” he maintained.
Patient-reported quality of life has been shown to be independently prognostic in at least five other cancers, according to Dr. Phippen. In advanced ovarian cancer, baseline FACT-O score (J. Clin. Oncol. 2005;23:5605-12) and the physical well-being scale of this score (Gynecol. Oncol. 2012;124:379-82) have previously been linked to overall survival.
In the new study, multivariate analysis that included potential confounders (age, performance status, stage, suboptimal debulking, and history of stroke or MI) showed that each 1-point decrease in baseline FACT-O TOI score was associated with significantly worse progression-free survival (hazard ratio, 1.005) and overall survival (HR, 1.0008), reported Dr. Phippen, who disclosed that he had no relevant conflicts of interest.
Additionally, within the group with lowest-quartile FACT-O TOI scores (indicating poorest quality of life), relative to peers who had a worsening of scores during treatment, women who had an improvement had significantly better progression-free survival (12.7 vs. 8.6 months) and overall survival (40.8 vs. 16 months).
Similarly, within the group having scores in higher quartiles, women who had an improvement in score during treatment again had significantly better progression-free survival (16.7 vs. 11.1 months) and overall survival (54.4 vs. 33.6 months).
CHICAGO– Quality of life at baseline and during treatment is an important prognostic factor in women with ovarian cancer, confirms an analysis reported at the annual meeting of the Society of Gynecologic Oncology.
Patients’ baseline quality of life score was independently associated with both progression-free and overall survival among 1,152 women participating in the Gynecologic Oncology Group (GOG) 218 trial, a randomized phase III trial comparing chemotherapy with versus without bevacizumab (Avastin), reported Dr. Neil T. Phippen of Walter Reed National Military Medical Center, Bethesda, Md.
Quality of life was assessed at six time points with FACT-O TOI (the Functional Assessment of Cancer Therapy–Ovarian Trial Outcome Index), on which possible scores range from 0-104 and higher scores indicate better quality of life. Women were included in analyses if they had completed the questionnaire at two or more time points.
Patients whose FACT-O TOI scores improved during treatment had a 4- to 5-month longer progression-free survival and a 20- to 25-month longer overall survival than counterparts whose scores worsened.
“Coupled with previously published data establishing quality of life as an independent predictor of survival across cancer sites, our results underscore the importance of quality of life surveillance in phase III clinical trials and support the inclusion of quality of life as an important component of composite clinical trial endpoints currently under development,” Dr. Phippen commented.
“Considering the independent prognostic value of the baseline FACT-O TOI score and the trend in the FACT-O TOI, methods to improve compliance with this evaluation metric are needed,” he maintained.
Patient-reported quality of life has been shown to be independently prognostic in at least five other cancers, according to Dr. Phippen. In advanced ovarian cancer, baseline FACT-O score (J. Clin. Oncol. 2005;23:5605-12) and the physical well-being scale of this score (Gynecol. Oncol. 2012;124:379-82) have previously been linked to overall survival.
In the new study, multivariate analysis that included potential confounders (age, performance status, stage, suboptimal debulking, and history of stroke or MI) showed that each 1-point decrease in baseline FACT-O TOI score was associated with significantly worse progression-free survival (hazard ratio, 1.005) and overall survival (HR, 1.0008), reported Dr. Phippen, who disclosed that he had no relevant conflicts of interest.
Additionally, within the group with lowest-quartile FACT-O TOI scores (indicating poorest quality of life), relative to peers who had a worsening of scores during treatment, women who had an improvement had significantly better progression-free survival (12.7 vs. 8.6 months) and overall survival (40.8 vs. 16 months).
Similarly, within the group having scores in higher quartiles, women who had an improvement in score during treatment again had significantly better progression-free survival (16.7 vs. 11.1 months) and overall survival (54.4 vs. 33.6 months).
AT THE ANNUAL MEETING ON WOMEN’S CANCER
Key clinical point: Baseline QOL and changes in QOL during treatment are prognostic in women with ovarian cancer.
Major finding: Patients whose FACT-O TOI scores improved vs. worsened during treatment had a 4- to 5-month longer progression-free survival and a 20- to 25-month longer overall survival.
Data source: An analysis of data from 1,152 women with ovarian cancer in a randomized phase III trial.
Disclosures: Dr. Phippen disclosed that he had no relevant conflicts of interest.
Biomarker is linked to rucaparib benefit in ovarian cancer
CHICAGO – Women whose ovarian cancers harbor a BRCA mutation or have a similar genomic signature are most likely to benefit from the investigational agent rucaparib, suggest interim results of a phase II trial reported at the annual meeting of the Society of Gynecologic Oncology.
Investigators assessed activity of this novel oral PARP (poly-ADP-ribose) inhibitor in ARIEL2, A Study of Rucaparib in Patients With Platinum-Sensitive, Relapsed, High-Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer. The study was sponsored by Clovis Oncology, manufacturer of rucaparib.
They also tested a biomarker of homologous recombination deficiency (HRD), which confers susceptibility to PARP inhibitors and is commonly seen in BRCA-mutated tumors, said Dr. Elizabeth Swisher, medical director of the breast and ovarian cancer prevention program at the Seattle Cancer Care Alliance and a professor at the University of Washington, Seattle.
Tumors were genomically profiled with next-generation sequencing, which picks up the loss of heterozygosity caused by HRD, whether specifically due to a BRCA mutation or to other molecular aberrations that give tumors a similar genomic signature.
Results in the first 121 evaluable patients showed that 25% had tumors with a BRCA mutation (a percentage capped in the study) and 42% had tumors that lacked such mutation but nonetheless had a BRCA-like signature, while 33% had tumors negative for the biomarker, Dr. Swisher reported.
The response rate to rucaparib according to RECIST (Response Evaluation Criteria In Solid Tumors) was 43% among 61 evaluable patients overall. But it varied significantly by HRD biomarker status: It was 65% in those with BRCA-mutated tumors and 40% in those with a BRCA-like signature, but only 8% in those with tumors negative for the biomarker (P less than .001).
The most common treatment-related adverse events were nausea, fatigue, and transient elevation of liver function tests. None of the patients stopped treatment because of toxicity.
“Rucaparib is active and well tolerated in high-grade ovarian cancer,” summarized Dr. Swisher.
“Comprehensive genomic analysis of the tumor based on a next-generation sequencing platform can prospectively identify ovarian cancer patients who respond to rucaparib, and it identifies both relevant BRCA mutations and a BRCA-like signature in one test,” she said. “The BRCA-like signature could have utility in other cancer types beyond ovarian cancer, potentially.”
She noted that ARIEL2 has recently been expanded to be a registration study for the treatment of patients with ovarian cancer who have had failure of three prior therapies, regardless of BRCA mutational status, and remains open for enrollment.
Investigators with the ARIEL program are refining the HRD biomarker, according to Dr. Swisher. “We will look at different cutoffs to see if we can get an even better cutoff for defining the BRCA-like cases. That biomarker will be locked down and tested prospectively in ARIEL3, which is the pivotal phase III, randomized, placebo-controlled study – recurrent, maintenance, platinum sensitive – that hopefully will be a registration study,” she elaborated.
Dr. Swisher disclosed that she had no relevant conflicts of interest. The trial was sponsored by Clovis Oncology.
CHICAGO – Women whose ovarian cancers harbor a BRCA mutation or have a similar genomic signature are most likely to benefit from the investigational agent rucaparib, suggest interim results of a phase II trial reported at the annual meeting of the Society of Gynecologic Oncology.
Investigators assessed activity of this novel oral PARP (poly-ADP-ribose) inhibitor in ARIEL2, A Study of Rucaparib in Patients With Platinum-Sensitive, Relapsed, High-Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer. The study was sponsored by Clovis Oncology, manufacturer of rucaparib.
They also tested a biomarker of homologous recombination deficiency (HRD), which confers susceptibility to PARP inhibitors and is commonly seen in BRCA-mutated tumors, said Dr. Elizabeth Swisher, medical director of the breast and ovarian cancer prevention program at the Seattle Cancer Care Alliance and a professor at the University of Washington, Seattle.
Tumors were genomically profiled with next-generation sequencing, which picks up the loss of heterozygosity caused by HRD, whether specifically due to a BRCA mutation or to other molecular aberrations that give tumors a similar genomic signature.
Results in the first 121 evaluable patients showed that 25% had tumors with a BRCA mutation (a percentage capped in the study) and 42% had tumors that lacked such mutation but nonetheless had a BRCA-like signature, while 33% had tumors negative for the biomarker, Dr. Swisher reported.
The response rate to rucaparib according to RECIST (Response Evaluation Criteria In Solid Tumors) was 43% among 61 evaluable patients overall. But it varied significantly by HRD biomarker status: It was 65% in those with BRCA-mutated tumors and 40% in those with a BRCA-like signature, but only 8% in those with tumors negative for the biomarker (P less than .001).
The most common treatment-related adverse events were nausea, fatigue, and transient elevation of liver function tests. None of the patients stopped treatment because of toxicity.
“Rucaparib is active and well tolerated in high-grade ovarian cancer,” summarized Dr. Swisher.
“Comprehensive genomic analysis of the tumor based on a next-generation sequencing platform can prospectively identify ovarian cancer patients who respond to rucaparib, and it identifies both relevant BRCA mutations and a BRCA-like signature in one test,” she said. “The BRCA-like signature could have utility in other cancer types beyond ovarian cancer, potentially.”
She noted that ARIEL2 has recently been expanded to be a registration study for the treatment of patients with ovarian cancer who have had failure of three prior therapies, regardless of BRCA mutational status, and remains open for enrollment.
Investigators with the ARIEL program are refining the HRD biomarker, according to Dr. Swisher. “We will look at different cutoffs to see if we can get an even better cutoff for defining the BRCA-like cases. That biomarker will be locked down and tested prospectively in ARIEL3, which is the pivotal phase III, randomized, placebo-controlled study – recurrent, maintenance, platinum sensitive – that hopefully will be a registration study,” she elaborated.
Dr. Swisher disclosed that she had no relevant conflicts of interest. The trial was sponsored by Clovis Oncology.
CHICAGO – Women whose ovarian cancers harbor a BRCA mutation or have a similar genomic signature are most likely to benefit from the investigational agent rucaparib, suggest interim results of a phase II trial reported at the annual meeting of the Society of Gynecologic Oncology.
Investigators assessed activity of this novel oral PARP (poly-ADP-ribose) inhibitor in ARIEL2, A Study of Rucaparib in Patients With Platinum-Sensitive, Relapsed, High-Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer. The study was sponsored by Clovis Oncology, manufacturer of rucaparib.
They also tested a biomarker of homologous recombination deficiency (HRD), which confers susceptibility to PARP inhibitors and is commonly seen in BRCA-mutated tumors, said Dr. Elizabeth Swisher, medical director of the breast and ovarian cancer prevention program at the Seattle Cancer Care Alliance and a professor at the University of Washington, Seattle.
Tumors were genomically profiled with next-generation sequencing, which picks up the loss of heterozygosity caused by HRD, whether specifically due to a BRCA mutation or to other molecular aberrations that give tumors a similar genomic signature.
Results in the first 121 evaluable patients showed that 25% had tumors with a BRCA mutation (a percentage capped in the study) and 42% had tumors that lacked such mutation but nonetheless had a BRCA-like signature, while 33% had tumors negative for the biomarker, Dr. Swisher reported.
The response rate to rucaparib according to RECIST (Response Evaluation Criteria In Solid Tumors) was 43% among 61 evaluable patients overall. But it varied significantly by HRD biomarker status: It was 65% in those with BRCA-mutated tumors and 40% in those with a BRCA-like signature, but only 8% in those with tumors negative for the biomarker (P less than .001).
The most common treatment-related adverse events were nausea, fatigue, and transient elevation of liver function tests. None of the patients stopped treatment because of toxicity.
“Rucaparib is active and well tolerated in high-grade ovarian cancer,” summarized Dr. Swisher.
“Comprehensive genomic analysis of the tumor based on a next-generation sequencing platform can prospectively identify ovarian cancer patients who respond to rucaparib, and it identifies both relevant BRCA mutations and a BRCA-like signature in one test,” she said. “The BRCA-like signature could have utility in other cancer types beyond ovarian cancer, potentially.”
She noted that ARIEL2 has recently been expanded to be a registration study for the treatment of patients with ovarian cancer who have had failure of three prior therapies, regardless of BRCA mutational status, and remains open for enrollment.
Investigators with the ARIEL program are refining the HRD biomarker, according to Dr. Swisher. “We will look at different cutoffs to see if we can get an even better cutoff for defining the BRCA-like cases. That biomarker will be locked down and tested prospectively in ARIEL3, which is the pivotal phase III, randomized, placebo-controlled study – recurrent, maintenance, platinum sensitive – that hopefully will be a registration study,” she elaborated.
Dr. Swisher disclosed that she had no relevant conflicts of interest. The trial was sponsored by Clovis Oncology.
AT THE ANNUAL MEETING ON WOMEN’S CANCER
Key clinical point: A biomarker identified women with ovarian cancer most likely to have a response to rucaparib.
Major finding: The response rate was 65% in women whose tumors had a BRCA mutation and 40% in women whose tumors had a BRCA-like genomic signature.
Data source: An interim analysis of a phase II trial with data from 121 women with high-grade platinum-sensitive ovarian cancer.
Disclosures: Dr. Swisher disclosed that she had no relevant conflicts of interest. The trial was sponsored by Clovis Oncology.
Model accurately spots low-risk endometrial cancer
CHICAGO – A preoperative risk model accurately identifies women with endometrial cancer who are unlikely to have lymph node metastases, finds a prospective cohort study reported at the annual Meeting of the Society of Gynecologic Oncology.
The model – which uses favorable MRI features, endometrioid histology on biopsy, and a cancer antigen 125 (CA125) level of 35 U/mL or lower to define a low-risk group – had a negative predictive value of 97% when tested in 529 Asian women.
“Using [our model], we can reliably identify patients with a low risk for lymph node metastasis before surgery,” said Dr. Sokbom Kang, director of the division of gynecologic oncology at the National Cancer Center, Goyang, Korea.
“In the clinic, our preoperative risk assessment may be useful in patient counseling. By sharing this risk information with our patients, we may improve their decision-making process about their surgery,” he added. “Not only does it help patient counseling and surgical planning, but it also may be useful in patient selection for future surgical trials.”
Some guidelines have stopped recommending routine lymphadenectomy in patients with endometrial cancer, according to Dr. Kang. “However, some experts still endorse this procedure, even in low-risk patients. Their argument is, low-risk patients cannot be accurately identified because preoperative tests are inaccurate.”
The risk model was developed by the Korean Gynecologic Oncology group (J. Clin. Oncol. 2012;30:1329-34) and has since been validated in smaller single-nationality cohorts.
In the new study, known as PALME (Preoperative Risk Assessment for Lymph Node Metastasis in Endometrial Cancer), it was tested among consecutive women from 25 hospitals in Korea, Japan, and China who had a histologic diagnosis of endometrial cancer. Those with squamous cell carcinoma or sarcoma histologies were excluded.
The women underwent MRI and CA125 testing in the 4 weeks before surgery. They had surgical staging with pelvic lymphadenectomy, and para-aortic lymphadenectomy was recommended. The median number of nodes removed was 23.
Results showed that the model classified 51% of the patients as having a low risk of lymph node metastases, reported Dr. Kang, who disclosed that he had no relevant conflicts of interest.
On the basis of surgical findings, the model had a negative predictive value of 97%, corresponding to a false-negative predictive rate of just 3%, which was in line with earlier results seen in the smaller validation studies.
In a receiver operating characteristic curve analysis, the model had a summarized sensitivity of 91% and a summarized specificity of 54%.
The performance was similar when tumor grade was substituted for CA125 level, except that specificity decreased significantly. “The lower specificity means fewer patients will benefit from our selective lymphadenectomy strategy, so it impairs the cost-effectiveness of our strategy,” Dr. Kang said.
The model performed similarly as well as a model using features of the primary tumor drawn from the final pathology report. “This proves our preoperative risk assessment has similar accuracy to the postoperative risk assessment for identifying a low risk of lymph node metastasis,” he concluded.
CHICAGO – A preoperative risk model accurately identifies women with endometrial cancer who are unlikely to have lymph node metastases, finds a prospective cohort study reported at the annual Meeting of the Society of Gynecologic Oncology.
The model – which uses favorable MRI features, endometrioid histology on biopsy, and a cancer antigen 125 (CA125) level of 35 U/mL or lower to define a low-risk group – had a negative predictive value of 97% when tested in 529 Asian women.
“Using [our model], we can reliably identify patients with a low risk for lymph node metastasis before surgery,” said Dr. Sokbom Kang, director of the division of gynecologic oncology at the National Cancer Center, Goyang, Korea.
“In the clinic, our preoperative risk assessment may be useful in patient counseling. By sharing this risk information with our patients, we may improve their decision-making process about their surgery,” he added. “Not only does it help patient counseling and surgical planning, but it also may be useful in patient selection for future surgical trials.”
Some guidelines have stopped recommending routine lymphadenectomy in patients with endometrial cancer, according to Dr. Kang. “However, some experts still endorse this procedure, even in low-risk patients. Their argument is, low-risk patients cannot be accurately identified because preoperative tests are inaccurate.”
The risk model was developed by the Korean Gynecologic Oncology group (J. Clin. Oncol. 2012;30:1329-34) and has since been validated in smaller single-nationality cohorts.
In the new study, known as PALME (Preoperative Risk Assessment for Lymph Node Metastasis in Endometrial Cancer), it was tested among consecutive women from 25 hospitals in Korea, Japan, and China who had a histologic diagnosis of endometrial cancer. Those with squamous cell carcinoma or sarcoma histologies were excluded.
The women underwent MRI and CA125 testing in the 4 weeks before surgery. They had surgical staging with pelvic lymphadenectomy, and para-aortic lymphadenectomy was recommended. The median number of nodes removed was 23.
Results showed that the model classified 51% of the patients as having a low risk of lymph node metastases, reported Dr. Kang, who disclosed that he had no relevant conflicts of interest.
On the basis of surgical findings, the model had a negative predictive value of 97%, corresponding to a false-negative predictive rate of just 3%, which was in line with earlier results seen in the smaller validation studies.
In a receiver operating characteristic curve analysis, the model had a summarized sensitivity of 91% and a summarized specificity of 54%.
The performance was similar when tumor grade was substituted for CA125 level, except that specificity decreased significantly. “The lower specificity means fewer patients will benefit from our selective lymphadenectomy strategy, so it impairs the cost-effectiveness of our strategy,” Dr. Kang said.
The model performed similarly as well as a model using features of the primary tumor drawn from the final pathology report. “This proves our preoperative risk assessment has similar accuracy to the postoperative risk assessment for identifying a low risk of lymph node metastasis,” he concluded.
CHICAGO – A preoperative risk model accurately identifies women with endometrial cancer who are unlikely to have lymph node metastases, finds a prospective cohort study reported at the annual Meeting of the Society of Gynecologic Oncology.
The model – which uses favorable MRI features, endometrioid histology on biopsy, and a cancer antigen 125 (CA125) level of 35 U/mL or lower to define a low-risk group – had a negative predictive value of 97% when tested in 529 Asian women.
“Using [our model], we can reliably identify patients with a low risk for lymph node metastasis before surgery,” said Dr. Sokbom Kang, director of the division of gynecologic oncology at the National Cancer Center, Goyang, Korea.
“In the clinic, our preoperative risk assessment may be useful in patient counseling. By sharing this risk information with our patients, we may improve their decision-making process about their surgery,” he added. “Not only does it help patient counseling and surgical planning, but it also may be useful in patient selection for future surgical trials.”
Some guidelines have stopped recommending routine lymphadenectomy in patients with endometrial cancer, according to Dr. Kang. “However, some experts still endorse this procedure, even in low-risk patients. Their argument is, low-risk patients cannot be accurately identified because preoperative tests are inaccurate.”
The risk model was developed by the Korean Gynecologic Oncology group (J. Clin. Oncol. 2012;30:1329-34) and has since been validated in smaller single-nationality cohorts.
In the new study, known as PALME (Preoperative Risk Assessment for Lymph Node Metastasis in Endometrial Cancer), it was tested among consecutive women from 25 hospitals in Korea, Japan, and China who had a histologic diagnosis of endometrial cancer. Those with squamous cell carcinoma or sarcoma histologies were excluded.
The women underwent MRI and CA125 testing in the 4 weeks before surgery. They had surgical staging with pelvic lymphadenectomy, and para-aortic lymphadenectomy was recommended. The median number of nodes removed was 23.
Results showed that the model classified 51% of the patients as having a low risk of lymph node metastases, reported Dr. Kang, who disclosed that he had no relevant conflicts of interest.
On the basis of surgical findings, the model had a negative predictive value of 97%, corresponding to a false-negative predictive rate of just 3%, which was in line with earlier results seen in the smaller validation studies.
In a receiver operating characteristic curve analysis, the model had a summarized sensitivity of 91% and a summarized specificity of 54%.
The performance was similar when tumor grade was substituted for CA125 level, except that specificity decreased significantly. “The lower specificity means fewer patients will benefit from our selective lymphadenectomy strategy, so it impairs the cost-effectiveness of our strategy,” Dr. Kang said.
The model performed similarly as well as a model using features of the primary tumor drawn from the final pathology report. “This proves our preoperative risk assessment has similar accuracy to the postoperative risk assessment for identifying a low risk of lymph node metastasis,” he concluded.
AT THE ANNUAL MEETING ON WOMEN’S CANCER
Key clinical point: A preoperative risk model may help identify women with endometrial cancer who can skip lymphadenectomy.
Major finding: The model had a negative predictive value of 97%.
Data source: A prospective cohort study of 529 Asian women with endometrial cancer.
Disclosures: Dr. Kang disclosed that he had no relevant conflicts of interest.
SLN mapping found accurate in endometrial cancer
CHICAGO – Sentinel lymph node mapping alone may suffice for initial staging in women with clinical high-risk endometrial cancer, according to a prospective cohort study reported at the annual meeting of the Society of Gynecologic Oncology.
“While the majority of women with endometrial cancer do not have nodal involvement, positive nodes are an important prognostic factor and often guide postoperative adjuvant therapy. The use of SLN [sentinel lymph node] mapping could potentially maximize the identification of positive nodes while minimizing the risk of full lymphadenectomy,” noted Dr. Pamela T. Soliman, Center Medical Director of the Gynecologic Medical Center at The University of Texas MD Anderson Cancer Center, Houston.
 |
| Susan London/Frontline Medical News |
Dr. Pamela Soliman |
She and her colleagues studied 60 women who had clinical stage II disease with high-risk features on preoperative biopsy. All women underwent preoperative PET-CT, then SLN mapping, and finally a full surgical staging with pelvic and para-aortic lymphadenectomy to the renal vessels.
Results showed that 92% of women had at least one SLN detected and 61% had SLNs detected bilaterally. “These findings are consistent with others reported in the literature suggesting that this technique is reproducible,” Dr. Soliman maintained.
Importantly, she said, all of the patients ultimately found to have stage IIIc disease had at least one positive SLN identified, translating to a sensitivity of SLN mapping of 100% and a false-negative rate of zero.
“While we do not expect that the true false-negative rate is zero in this patient population, our results are very promising, and we are hopeful that with our study and other studies presented here, we can potentially change the way we manage patients with high-risk endometrial cancer,” she said.
“If we continue to successfully identify the women with positive lymph nodes using the mapping technique, potentially an SLN biopsy alone could be considered for women with high-risk endometrial cancer. It’s unclear, however, how this change in practice will affect our postoperative management as well as our long-term survival,” Dr. Soliman added.
The SLN mapping in the study was done with a cervical injection of dye, both superficial and deep, at the 3 and 9 o’clock positions, with the surgical approach (laparotomy, laparoscopy, robot-assisted, or a combination) and type of dye used for mapping left up to the surgeon. Indocyanine green was used in about two-thirds of cases.
The high SLN detection rate was consistent across different surgical approaches and types of dye used, reported Dr. Soliman, who disclosed that she had no relevant conflicts of interest.
A total of 146 SLNs were identified in 56 women. Seventeen of these SLNs – all external iliac or obturator nodes – in 10 patients were positive; in half of these patients, the SLNs were the only histologically positive nodes found.
One woman had a negative SLN on the right, although the non-SLNs on that side were positive. “She was not considered a false-negative because her SLN biopsy on the other side was positive,” Dr. Soliman explained.
CHICAGO – Sentinel lymph node mapping alone may suffice for initial staging in women with clinical high-risk endometrial cancer, according to a prospective cohort study reported at the annual meeting of the Society of Gynecologic Oncology.
“While the majority of women with endometrial cancer do not have nodal involvement, positive nodes are an important prognostic factor and often guide postoperative adjuvant therapy. The use of SLN [sentinel lymph node] mapping could potentially maximize the identification of positive nodes while minimizing the risk of full lymphadenectomy,” noted Dr. Pamela T. Soliman, Center Medical Director of the Gynecologic Medical Center at The University of Texas MD Anderson Cancer Center, Houston.
|
| Susan London/Frontline Medical News |
Dr. Pamela Soliman |
She and her colleagues studied 60 women who had clinical stage II disease with high-risk features on preoperative biopsy. All women underwent preoperative PET-CT, then SLN mapping, and finally a full surgical staging with pelvic and para-aortic lymphadenectomy to the renal vessels.
Results showed that 92% of women had at least one SLN detected and 61% had SLNs detected bilaterally. “These findings are consistent with others reported in the literature suggesting that this technique is reproducible,” Dr. Soliman maintained.
Importantly, she said, all of the patients ultimately found to have stage IIIc disease had at least one positive SLN identified, translating to a sensitivity of SLN mapping of 100% and a false-negative rate of zero.
“While we do not expect that the true false-negative rate is zero in this patient population, our results are very promising, and we are hopeful that with our study and other studies presented here, we can potentially change the way we manage patients with high-risk endometrial cancer,” she said.
“If we continue to successfully identify the women with positive lymph nodes using the mapping technique, potentially an SLN biopsy alone could be considered for women with high-risk endometrial cancer. It’s unclear, however, how this change in practice will affect our postoperative management as well as our long-term survival,” Dr. Soliman added.
The SLN mapping in the study was done with a cervical injection of dye, both superficial and deep, at the 3 and 9 o’clock positions, with the surgical approach (laparotomy, laparoscopy, robot-assisted, or a combination) and type of dye used for mapping left up to the surgeon. Indocyanine green was used in about two-thirds of cases.
The high SLN detection rate was consistent across different surgical approaches and types of dye used, reported Dr. Soliman, who disclosed that she had no relevant conflicts of interest.
A total of 146 SLNs were identified in 56 women. Seventeen of these SLNs – all external iliac or obturator nodes – in 10 patients were positive; in half of these patients, the SLNs were the only histologically positive nodes found.
One woman had a negative SLN on the right, although the non-SLNs on that side were positive. “She was not considered a false-negative because her SLN biopsy on the other side was positive,” Dr. Soliman explained.
CHICAGO – Sentinel lymph node mapping alone may suffice for initial staging in women with clinical high-risk endometrial cancer, according to a prospective cohort study reported at the annual meeting of the Society of Gynecologic Oncology.
“While the majority of women with endometrial cancer do not have nodal involvement, positive nodes are an important prognostic factor and often guide postoperative adjuvant therapy. The use of SLN [sentinel lymph node] mapping could potentially maximize the identification of positive nodes while minimizing the risk of full lymphadenectomy,” noted Dr. Pamela T. Soliman, Center Medical Director of the Gynecologic Medical Center at The University of Texas MD Anderson Cancer Center, Houston.
|
| Susan London/Frontline Medical News |
Dr. Pamela Soliman |
She and her colleagues studied 60 women who had clinical stage II disease with high-risk features on preoperative biopsy. All women underwent preoperative PET-CT, then SLN mapping, and finally a full surgical staging with pelvic and para-aortic lymphadenectomy to the renal vessels.
Results showed that 92% of women had at least one SLN detected and 61% had SLNs detected bilaterally. “These findings are consistent with others reported in the literature suggesting that this technique is reproducible,” Dr. Soliman maintained.
Importantly, she said, all of the patients ultimately found to have stage IIIc disease had at least one positive SLN identified, translating to a sensitivity of SLN mapping of 100% and a false-negative rate of zero.
“While we do not expect that the true false-negative rate is zero in this patient population, our results are very promising, and we are hopeful that with our study and other studies presented here, we can potentially change the way we manage patients with high-risk endometrial cancer,” she said.
“If we continue to successfully identify the women with positive lymph nodes using the mapping technique, potentially an SLN biopsy alone could be considered for women with high-risk endometrial cancer. It’s unclear, however, how this change in practice will affect our postoperative management as well as our long-term survival,” Dr. Soliman added.
The SLN mapping in the study was done with a cervical injection of dye, both superficial and deep, at the 3 and 9 o’clock positions, with the surgical approach (laparotomy, laparoscopy, robot-assisted, or a combination) and type of dye used for mapping left up to the surgeon. Indocyanine green was used in about two-thirds of cases.
The high SLN detection rate was consistent across different surgical approaches and types of dye used, reported Dr. Soliman, who disclosed that she had no relevant conflicts of interest.
A total of 146 SLNs were identified in 56 women. Seventeen of these SLNs – all external iliac or obturator nodes – in 10 patients were positive; in half of these patients, the SLNs were the only histologically positive nodes found.
One woman had a negative SLN on the right, although the non-SLNs on that side were positive. “She was not considered a false-negative because her SLN biopsy on the other side was positive,” Dr. Soliman explained.
AT THE ANNUAL MEETING ON WOMEN’S CANCER
Key clinical point: SLN mapping had a false-negative rate of zero.
Major finding: The SLN mapping procedure identified all cases of pathologic stage IIIc disease.
Data source: A prospective cohort study of 60 women with clinical stage II high-risk endometrial cancer.
Disclosures: Dr. Soliman disclosed that she had no conflicts of interest.
Cannabinoid therapy shows benefit in pediatric epilepsy
SEATTLE – Cannabinoid therapy holds promise for the treatment of pediatric epilepsy, but more research is needed to rigorously assess its safety and efficacy, according to experts in the field.
Cannabis contains numerous cannabinoids, including the nonpsychoactive cannabidiol (CBD) and the psychoactive tetrahydrocannabinol (THC).
Two CBD products – an oil-based extract (Epidiolex) and an oral solution (Insys Therapeutics) – have been granted orphan drug status by the Food and Drug Administration for treatment of some forms of epilepsy. In addition, families can obtain artisanal preparations, which may contain a variety of cannabinoids as well as other chemical compounds.
However, use and study of cannabinoids in the United States has been complicated by the federal classification of marijuana as a schedule I controlled substance and the patchwork legal status of medical and recreational use across states.
Investigators reported findings of several clinical studies of cannabinoid therapy in pediatric epilepsy at the annual meeting of the American Epilepsy Society and discussed implications for clinical practice and future research, as well as legal and regulatory status of this therapy.
Benefit may be greatest in Dravet syndrome
Dr. Orrin Devinsky, director of the Comprehensive Epilepsy Center at the NYU Langone Medical Center, and his colleagues undertook a prospective, open-label, multicenter, observational study among pediatric patients with treatment-resistant epilepsy.
In the study, supported in part by GW Pharmaceuticals, 151 patients were treated with Epidiolex, added to their baseline regimen of up to three antiepileptic drugs (AEDs).
Main efficacy analyses based on the 58 patients treated for at least 3 months showed that the median reduction in seizure frequency was about 35% overall and 55% for patients with Dravet syndrome.
The 3-month rate of seizure freedom was 10% overall and 22% in the subset with Dravet syndrome. “These were much higher rates than we would expect, for example, from a placebo response alone,” Dr. Devinsky said in a press briefing.
Data from the 40 patients having longer follow-up, at least 16 weeks, showed that benefit was sustained, indicating that patients did not develop tolerance.
Safety results for all 151 patients showed the most common adverse events were somnolence, seen in 19% of patients, and fatigue, seen in 11%. A single serious adverse event, status epilepticus, was considered possibly related to the CBD. Laboratory measures did not show any noteworthy changes.
“Based on the experience at these five sites, in an open-label, nonrandomized controlled trial ... there is good evidence that the Epidiolex 98% product of CBD is an effective drug for many children with treatment-resistant epilepsy, that the patients with Dravet syndrome appear to be the most responsive ones (but again, this is a relatively small population right now), that the drug overall is quite well tolerated, and most of the side effects when they occur are relatively mild and oftentimes limited,” Dr. Devinsky said.
“The critical take-home message is that these are promising early results, but we need controlled trials to know how to move forward, he said, noting that randomized phase III trials are planned in both patients with Dravet syndrome and patients with Lennox-Gastaut syndrome.
Classifying CBD as schedule I – reserved for drugs having a high danger of abuse, lack of acceptable safety data, and no potential therapeutic benefit – presents hurdles for researchers and doesn’t make sense, according to Dr. Devinsky, who disclosed no relevant conflicts of interest.
“Cannabidiol is approved as part of Sativex, for example, in more than 25 European countries and Canada [for treatment of spasticity due to multiple sclerosis]. So we know it’s got benefit in double-blind studies, so that part ... is wrong. And cannabidiol has been tested extensively in humans. We have adult safety data; this drug’s been on the market,” he explained. So we know it’s wrong to schedule it as schedule I. And it’s not at all clear to many of us why the [Drug Enforcement Agency] is persisting in this scheduling classification.”
Impact on levels of AEDs is unpredictable
Investigators led by Dr. Daniel Friedman, director of both the ICU Epilepsy Monitoring Service and the Epilepsy Consult Service at NYU Langone Medical Center, assessed levels of coadministered AEDs in 57 patients from the above study. He noted that such research is important as preclinical data suggest that CBD inhibits enzymes that metabolize commonly used AEDs.
Results showed that over the first 2 months of CBD therapy, 33% of patients on valproate and 24% of patients on clobazam (Onfi) had their doses reduced because they experienced elevated drug levels or sedation attributed to the drugs, Dr. Friedman reported.
But none of the AEDs showed a consistent pattern of change in levels with the addition of CBD. “Many patients experienced decreases; some experienced increases. But especially for the most common drugs, we found that the ranges were pretty wide,” he said.
Data from five patients showed an average threefold increase in the level of the active metabolite of clobazam, N-desmethylclobazam, without any change in levels of the drug itself, suggesting that the CBD was interfering with clearance of the metabolite.
The findings are not definitive, given that the patients were on multiple medications that can influence levels of each other, stressed Dr. Friedman, who disclosed no relevant conflicts of interest.
“Until formal drug-drug interaction studies are done, we refrain from any specific advice, except for, make sure if your patients are on CBD, whether they are getting it through artisanal preparations or as part of a compassionate use study, that background AEDs are monitored, and if they are on clobazam, make sure to check the N-desmethyl metabolite level as well,” he recommended.
Expectations may influence perceived benefit
Dr. Kevin E. Chapman, associate professor at Children’s Hospital Colorado, Aurora, and his colleagues retrospectively reviewed data of 75 patients who reported using oral cannabis extract.
In Colorado, cannabis is legal for both medical and recreational use. However, patients must become residents, obtain a prescription from two specialized physicians, get a medical marijuana ID card (“red card”), and purchase the product from a dispensary, paying out of pocket, as it is not yet covered by insurance.
“We have had a fairly large influx of patients from out of state ever since medical marijuana became legal in our state,” Dr. Chapman noted in a press briefing. However, neurologists are often reluctant to raise the topic with patients “because of the concerns about the fact that it’s still illegal at the federal level. We worry about our own personal DEA licenses if we were to prescribe the medication.”
But when they learn patients are starting CBD therapy, “our practice is to encourage families not to make dramatic changes to seizure medications because for us, then it becomes hard to know how many of the problems that they have are from the CBD or how much of the benefit is from the CBD.”
On average, patients used their extract for 5.6 months. Overall, 33% had a response, defined as a decrease of more than half in seizure frequency as reported by parents (a rate similar to that seen with placebo). The rate was 0% among those with Doose syndrome, 25% among those with Dravet syndrome, and 89% among those with Lennox-Gastaut syndrome.
But analyses identified only a single predictor of response: moving to the state to obtain the extract. “I think it’s understandable that families have high hopes when they move to Colorado that it’s going to be effective … I don’t know if there is a bit of bias by families really wanting for it to work and that’s part of the reason we saw that,” said Dr. Chapman, who disclosed no relevant conflicts of interest.
A total of 10% of patients who had electroencephalograms (EEGs) both before and after starting extract had improvements in their interictal EEGs. However, none of them were among the group who had a response.
Use of extract was associated with some other benefits: Thirty-three percent of patients reported better alertness and/or behavior, 11% reported better language and motor skills, and 7% reported better sleep.
The most common adverse event was a worsening of seizures, seen in 13% of children, followed by somnolence, seen in 12%, and gastrointestinal symptoms, seen in 11%.
“What our study really sort of shows for us was that we really need a better study, something a little bit more controlled, because there are a lot of different strains that are being used out there, and we were not able to tease out what strain of cannabis worked best in our patient population. People are using CBD strains, THC strains, a combination of things, whereas I think we really need more of a uniform strain or preparation, and then more of a placebo-controlled trial,” Dr. Chapman said.
“At this point I think it’s a bit early to be selling the farm, so to speak, and moving to Colorado,” he concluded. “Right now there’s quite a bit of uncertainty about how effective the medication is. Also, we still have a lot of unknowns about drug interactions, adverse effects of the medication. We have no long-term data because ours is just short-term follow-up data.”
Open communication is critical
Dr. Jeffrey Gold, a pediatric neurologist at Rady Children’s Hospital in San Diego, and his colleagues reported the case of a boy with Doose syndrome whose seizures resolved after initiation of cannabinoid therapy.
“We face somewhat different challenges in California, where recreational marijuana is not legal. Medical marijuana has some acceptance, but it exists in a nebulous legal area,” he noted in the press briefing.
The boy’s seizures were refractory to medical therapy and video EEG features suggested a high risk of progression. His parents opted to try CBD instead of the ketogenic diet, the standard of care in such cases.
“They obtained the product from the local family group, which is challenging for us because we don’t really know what’s in it. We don’t know what the composition is. The family doesn’t know what the composition of the product is,” Dr. Gold said. However, the boy’s mother obtained independent testing, which showed that it was sometimes high in CBD, other times high in THC.
After starting therapy, the boy had apparent worsening of seizures. Testing revealed that his valproic acid level had risen from 115 to 178 mcg/mL, suggesting the CBD was interfering with the drug’s clearance.
The valproic acid dose was lowered, and over a 4-month period, the patient became seizure free. “We obtained another EEG which was completely normal, honestly to our surprise,” reported Dr. Gold, who disclosed no relevant conflicts of interest. “And I don’t know why that was, if that was because he got some extra valproic acid and that tripped a mechanism that set off improvement, or if that’s because of the CBD. Resolution of seizures and normalization of the EEG has been reported before in Doose syndrome and can happen spontaneously or as a result of medication.
“We wanted to get this report out to the community so that they would know, if families choose to start CBD therapy, we strongly advocate that they share that information with their physicians and that physicians manage the other antiseizure treatments the child is receiving,” Dr. Gold said. “We have heard from parents and from other providers that once they told their provider that they were doing CBD, they were told to not come back to the office because they were doing a nonapproved therapy, and we don’t support that. We want families to feel like they can share their treatments with their physicians and receive the help they need because we don’t know what these medications do to other treatments that the patient might be receiving, and it’s imperative that families stay in contact with their physicians.”
Families often tinker with artisanal cannabis products themselves, hoping to find just the right combination, Dr. Gold noted. “It emphasizes both the difficulties of doing the artisanal preparations but more specifically, the difficulties of not doing it scientifically. Science is hard, it’s very difficult, it’s expensive, and it’s time consuming. But it’s the right way to do it. And studies ... that are coming up are the right way to do it,” he maintained.
“So we encourage families to pursue conventional treatment, enroll in clinical trials when they are offered, to get involved with the scientific community as you can, and we will get an answer to these questions. But it is going to take time. We need to do it the right way,” he concluded.
SEATTLE – Cannabinoid therapy holds promise for the treatment of pediatric epilepsy, but more research is needed to rigorously assess its safety and efficacy, according to experts in the field.
Cannabis contains numerous cannabinoids, including the nonpsychoactive cannabidiol (CBD) and the psychoactive tetrahydrocannabinol (THC).
Two CBD products – an oil-based extract (Epidiolex) and an oral solution (Insys Therapeutics) – have been granted orphan drug status by the Food and Drug Administration for treatment of some forms of epilepsy. In addition, families can obtain artisanal preparations, which may contain a variety of cannabinoids as well as other chemical compounds.
However, use and study of cannabinoids in the United States has been complicated by the federal classification of marijuana as a schedule I controlled substance and the patchwork legal status of medical and recreational use across states.
Investigators reported findings of several clinical studies of cannabinoid therapy in pediatric epilepsy at the annual meeting of the American Epilepsy Society and discussed implications for clinical practice and future research, as well as legal and regulatory status of this therapy.
Benefit may be greatest in Dravet syndrome
Dr. Orrin Devinsky, director of the Comprehensive Epilepsy Center at the NYU Langone Medical Center, and his colleagues undertook a prospective, open-label, multicenter, observational study among pediatric patients with treatment-resistant epilepsy.
In the study, supported in part by GW Pharmaceuticals, 151 patients were treated with Epidiolex, added to their baseline regimen of up to three antiepileptic drugs (AEDs).
Main efficacy analyses based on the 58 patients treated for at least 3 months showed that the median reduction in seizure frequency was about 35% overall and 55% for patients with Dravet syndrome.
The 3-month rate of seizure freedom was 10% overall and 22% in the subset with Dravet syndrome. “These were much higher rates than we would expect, for example, from a placebo response alone,” Dr. Devinsky said in a press briefing.
Data from the 40 patients having longer follow-up, at least 16 weeks, showed that benefit was sustained, indicating that patients did not develop tolerance.
Safety results for all 151 patients showed the most common adverse events were somnolence, seen in 19% of patients, and fatigue, seen in 11%. A single serious adverse event, status epilepticus, was considered possibly related to the CBD. Laboratory measures did not show any noteworthy changes.
“Based on the experience at these five sites, in an open-label, nonrandomized controlled trial ... there is good evidence that the Epidiolex 98% product of CBD is an effective drug for many children with treatment-resistant epilepsy, that the patients with Dravet syndrome appear to be the most responsive ones (but again, this is a relatively small population right now), that the drug overall is quite well tolerated, and most of the side effects when they occur are relatively mild and oftentimes limited,” Dr. Devinsky said.
“The critical take-home message is that these are promising early results, but we need controlled trials to know how to move forward, he said, noting that randomized phase III trials are planned in both patients with Dravet syndrome and patients with Lennox-Gastaut syndrome.
Classifying CBD as schedule I – reserved for drugs having a high danger of abuse, lack of acceptable safety data, and no potential therapeutic benefit – presents hurdles for researchers and doesn’t make sense, according to Dr. Devinsky, who disclosed no relevant conflicts of interest.
“Cannabidiol is approved as part of Sativex, for example, in more than 25 European countries and Canada [for treatment of spasticity due to multiple sclerosis]. So we know it’s got benefit in double-blind studies, so that part ... is wrong. And cannabidiol has been tested extensively in humans. We have adult safety data; this drug’s been on the market,” he explained. So we know it’s wrong to schedule it as schedule I. And it’s not at all clear to many of us why the [Drug Enforcement Agency] is persisting in this scheduling classification.”
Impact on levels of AEDs is unpredictable
Investigators led by Dr. Daniel Friedman, director of both the ICU Epilepsy Monitoring Service and the Epilepsy Consult Service at NYU Langone Medical Center, assessed levels of coadministered AEDs in 57 patients from the above study. He noted that such research is important as preclinical data suggest that CBD inhibits enzymes that metabolize commonly used AEDs.
Results showed that over the first 2 months of CBD therapy, 33% of patients on valproate and 24% of patients on clobazam (Onfi) had their doses reduced because they experienced elevated drug levels or sedation attributed to the drugs, Dr. Friedman reported.
But none of the AEDs showed a consistent pattern of change in levels with the addition of CBD. “Many patients experienced decreases; some experienced increases. But especially for the most common drugs, we found that the ranges were pretty wide,” he said.
Data from five patients showed an average threefold increase in the level of the active metabolite of clobazam, N-desmethylclobazam, without any change in levels of the drug itself, suggesting that the CBD was interfering with clearance of the metabolite.
The findings are not definitive, given that the patients were on multiple medications that can influence levels of each other, stressed Dr. Friedman, who disclosed no relevant conflicts of interest.
“Until formal drug-drug interaction studies are done, we refrain from any specific advice, except for, make sure if your patients are on CBD, whether they are getting it through artisanal preparations or as part of a compassionate use study, that background AEDs are monitored, and if they are on clobazam, make sure to check the N-desmethyl metabolite level as well,” he recommended.
Expectations may influence perceived benefit
Dr. Kevin E. Chapman, associate professor at Children’s Hospital Colorado, Aurora, and his colleagues retrospectively reviewed data of 75 patients who reported using oral cannabis extract.
In Colorado, cannabis is legal for both medical and recreational use. However, patients must become residents, obtain a prescription from two specialized physicians, get a medical marijuana ID card (“red card”), and purchase the product from a dispensary, paying out of pocket, as it is not yet covered by insurance.
“We have had a fairly large influx of patients from out of state ever since medical marijuana became legal in our state,” Dr. Chapman noted in a press briefing. However, neurologists are often reluctant to raise the topic with patients “because of the concerns about the fact that it’s still illegal at the federal level. We worry about our own personal DEA licenses if we were to prescribe the medication.”
But when they learn patients are starting CBD therapy, “our practice is to encourage families not to make dramatic changes to seizure medications because for us, then it becomes hard to know how many of the problems that they have are from the CBD or how much of the benefit is from the CBD.”
On average, patients used their extract for 5.6 months. Overall, 33% had a response, defined as a decrease of more than half in seizure frequency as reported by parents (a rate similar to that seen with placebo). The rate was 0% among those with Doose syndrome, 25% among those with Dravet syndrome, and 89% among those with Lennox-Gastaut syndrome.
But analyses identified only a single predictor of response: moving to the state to obtain the extract. “I think it’s understandable that families have high hopes when they move to Colorado that it’s going to be effective … I don’t know if there is a bit of bias by families really wanting for it to work and that’s part of the reason we saw that,” said Dr. Chapman, who disclosed no relevant conflicts of interest.
A total of 10% of patients who had electroencephalograms (EEGs) both before and after starting extract had improvements in their interictal EEGs. However, none of them were among the group who had a response.
Use of extract was associated with some other benefits: Thirty-three percent of patients reported better alertness and/or behavior, 11% reported better language and motor skills, and 7% reported better sleep.
The most common adverse event was a worsening of seizures, seen in 13% of children, followed by somnolence, seen in 12%, and gastrointestinal symptoms, seen in 11%.
“What our study really sort of shows for us was that we really need a better study, something a little bit more controlled, because there are a lot of different strains that are being used out there, and we were not able to tease out what strain of cannabis worked best in our patient population. People are using CBD strains, THC strains, a combination of things, whereas I think we really need more of a uniform strain or preparation, and then more of a placebo-controlled trial,” Dr. Chapman said.
“At this point I think it’s a bit early to be selling the farm, so to speak, and moving to Colorado,” he concluded. “Right now there’s quite a bit of uncertainty about how effective the medication is. Also, we still have a lot of unknowns about drug interactions, adverse effects of the medication. We have no long-term data because ours is just short-term follow-up data.”
Open communication is critical
Dr. Jeffrey Gold, a pediatric neurologist at Rady Children’s Hospital in San Diego, and his colleagues reported the case of a boy with Doose syndrome whose seizures resolved after initiation of cannabinoid therapy.
“We face somewhat different challenges in California, where recreational marijuana is not legal. Medical marijuana has some acceptance, but it exists in a nebulous legal area,” he noted in the press briefing.
The boy’s seizures were refractory to medical therapy and video EEG features suggested a high risk of progression. His parents opted to try CBD instead of the ketogenic diet, the standard of care in such cases.
“They obtained the product from the local family group, which is challenging for us because we don’t really know what’s in it. We don’t know what the composition is. The family doesn’t know what the composition of the product is,” Dr. Gold said. However, the boy’s mother obtained independent testing, which showed that it was sometimes high in CBD, other times high in THC.
After starting therapy, the boy had apparent worsening of seizures. Testing revealed that his valproic acid level had risen from 115 to 178 mcg/mL, suggesting the CBD was interfering with the drug’s clearance.
The valproic acid dose was lowered, and over a 4-month period, the patient became seizure free. “We obtained another EEG which was completely normal, honestly to our surprise,” reported Dr. Gold, who disclosed no relevant conflicts of interest. “And I don’t know why that was, if that was because he got some extra valproic acid and that tripped a mechanism that set off improvement, or if that’s because of the CBD. Resolution of seizures and normalization of the EEG has been reported before in Doose syndrome and can happen spontaneously or as a result of medication.
“We wanted to get this report out to the community so that they would know, if families choose to start CBD therapy, we strongly advocate that they share that information with their physicians and that physicians manage the other antiseizure treatments the child is receiving,” Dr. Gold said. “We have heard from parents and from other providers that once they told their provider that they were doing CBD, they were told to not come back to the office because they were doing a nonapproved therapy, and we don’t support that. We want families to feel like they can share their treatments with their physicians and receive the help they need because we don’t know what these medications do to other treatments that the patient might be receiving, and it’s imperative that families stay in contact with their physicians.”
Families often tinker with artisanal cannabis products themselves, hoping to find just the right combination, Dr. Gold noted. “It emphasizes both the difficulties of doing the artisanal preparations but more specifically, the difficulties of not doing it scientifically. Science is hard, it’s very difficult, it’s expensive, and it’s time consuming. But it’s the right way to do it. And studies ... that are coming up are the right way to do it,” he maintained.
“So we encourage families to pursue conventional treatment, enroll in clinical trials when they are offered, to get involved with the scientific community as you can, and we will get an answer to these questions. But it is going to take time. We need to do it the right way,” he concluded.
SEATTLE – Cannabinoid therapy holds promise for the treatment of pediatric epilepsy, but more research is needed to rigorously assess its safety and efficacy, according to experts in the field.
Cannabis contains numerous cannabinoids, including the nonpsychoactive cannabidiol (CBD) and the psychoactive tetrahydrocannabinol (THC).
Two CBD products – an oil-based extract (Epidiolex) and an oral solution (Insys Therapeutics) – have been granted orphan drug status by the Food and Drug Administration for treatment of some forms of epilepsy. In addition, families can obtain artisanal preparations, which may contain a variety of cannabinoids as well as other chemical compounds.
However, use and study of cannabinoids in the United States has been complicated by the federal classification of marijuana as a schedule I controlled substance and the patchwork legal status of medical and recreational use across states.
Investigators reported findings of several clinical studies of cannabinoid therapy in pediatric epilepsy at the annual meeting of the American Epilepsy Society and discussed implications for clinical practice and future research, as well as legal and regulatory status of this therapy.
Benefit may be greatest in Dravet syndrome
Dr. Orrin Devinsky, director of the Comprehensive Epilepsy Center at the NYU Langone Medical Center, and his colleagues undertook a prospective, open-label, multicenter, observational study among pediatric patients with treatment-resistant epilepsy.
In the study, supported in part by GW Pharmaceuticals, 151 patients were treated with Epidiolex, added to their baseline regimen of up to three antiepileptic drugs (AEDs).
Main efficacy analyses based on the 58 patients treated for at least 3 months showed that the median reduction in seizure frequency was about 35% overall and 55% for patients with Dravet syndrome.
The 3-month rate of seizure freedom was 10% overall and 22% in the subset with Dravet syndrome. “These were much higher rates than we would expect, for example, from a placebo response alone,” Dr. Devinsky said in a press briefing.
Data from the 40 patients having longer follow-up, at least 16 weeks, showed that benefit was sustained, indicating that patients did not develop tolerance.
Safety results for all 151 patients showed the most common adverse events were somnolence, seen in 19% of patients, and fatigue, seen in 11%. A single serious adverse event, status epilepticus, was considered possibly related to the CBD. Laboratory measures did not show any noteworthy changes.
“Based on the experience at these five sites, in an open-label, nonrandomized controlled trial ... there is good evidence that the Epidiolex 98% product of CBD is an effective drug for many children with treatment-resistant epilepsy, that the patients with Dravet syndrome appear to be the most responsive ones (but again, this is a relatively small population right now), that the drug overall is quite well tolerated, and most of the side effects when they occur are relatively mild and oftentimes limited,” Dr. Devinsky said.
“The critical take-home message is that these are promising early results, but we need controlled trials to know how to move forward, he said, noting that randomized phase III trials are planned in both patients with Dravet syndrome and patients with Lennox-Gastaut syndrome.
Classifying CBD as schedule I – reserved for drugs having a high danger of abuse, lack of acceptable safety data, and no potential therapeutic benefit – presents hurdles for researchers and doesn’t make sense, according to Dr. Devinsky, who disclosed no relevant conflicts of interest.
“Cannabidiol is approved as part of Sativex, for example, in more than 25 European countries and Canada [for treatment of spasticity due to multiple sclerosis]. So we know it’s got benefit in double-blind studies, so that part ... is wrong. And cannabidiol has been tested extensively in humans. We have adult safety data; this drug’s been on the market,” he explained. So we know it’s wrong to schedule it as schedule I. And it’s not at all clear to many of us why the [Drug Enforcement Agency] is persisting in this scheduling classification.”
Impact on levels of AEDs is unpredictable
Investigators led by Dr. Daniel Friedman, director of both the ICU Epilepsy Monitoring Service and the Epilepsy Consult Service at NYU Langone Medical Center, assessed levels of coadministered AEDs in 57 patients from the above study. He noted that such research is important as preclinical data suggest that CBD inhibits enzymes that metabolize commonly used AEDs.
Results showed that over the first 2 months of CBD therapy, 33% of patients on valproate and 24% of patients on clobazam (Onfi) had their doses reduced because they experienced elevated drug levels or sedation attributed to the drugs, Dr. Friedman reported.
But none of the AEDs showed a consistent pattern of change in levels with the addition of CBD. “Many patients experienced decreases; some experienced increases. But especially for the most common drugs, we found that the ranges were pretty wide,” he said.
Data from five patients showed an average threefold increase in the level of the active metabolite of clobazam, N-desmethylclobazam, without any change in levels of the drug itself, suggesting that the CBD was interfering with clearance of the metabolite.
The findings are not definitive, given that the patients were on multiple medications that can influence levels of each other, stressed Dr. Friedman, who disclosed no relevant conflicts of interest.
“Until formal drug-drug interaction studies are done, we refrain from any specific advice, except for, make sure if your patients are on CBD, whether they are getting it through artisanal preparations or as part of a compassionate use study, that background AEDs are monitored, and if they are on clobazam, make sure to check the N-desmethyl metabolite level as well,” he recommended.
Expectations may influence perceived benefit
Dr. Kevin E. Chapman, associate professor at Children’s Hospital Colorado, Aurora, and his colleagues retrospectively reviewed data of 75 patients who reported using oral cannabis extract.
In Colorado, cannabis is legal for both medical and recreational use. However, patients must become residents, obtain a prescription from two specialized physicians, get a medical marijuana ID card (“red card”), and purchase the product from a dispensary, paying out of pocket, as it is not yet covered by insurance.
“We have had a fairly large influx of patients from out of state ever since medical marijuana became legal in our state,” Dr. Chapman noted in a press briefing. However, neurologists are often reluctant to raise the topic with patients “because of the concerns about the fact that it’s still illegal at the federal level. We worry about our own personal DEA licenses if we were to prescribe the medication.”
But when they learn patients are starting CBD therapy, “our practice is to encourage families not to make dramatic changes to seizure medications because for us, then it becomes hard to know how many of the problems that they have are from the CBD or how much of the benefit is from the CBD.”
On average, patients used their extract for 5.6 months. Overall, 33% had a response, defined as a decrease of more than half in seizure frequency as reported by parents (a rate similar to that seen with placebo). The rate was 0% among those with Doose syndrome, 25% among those with Dravet syndrome, and 89% among those with Lennox-Gastaut syndrome.
But analyses identified only a single predictor of response: moving to the state to obtain the extract. “I think it’s understandable that families have high hopes when they move to Colorado that it’s going to be effective … I don’t know if there is a bit of bias by families really wanting for it to work and that’s part of the reason we saw that,” said Dr. Chapman, who disclosed no relevant conflicts of interest.
A total of 10% of patients who had electroencephalograms (EEGs) both before and after starting extract had improvements in their interictal EEGs. However, none of them were among the group who had a response.
Use of extract was associated with some other benefits: Thirty-three percent of patients reported better alertness and/or behavior, 11% reported better language and motor skills, and 7% reported better sleep.
The most common adverse event was a worsening of seizures, seen in 13% of children, followed by somnolence, seen in 12%, and gastrointestinal symptoms, seen in 11%.
“What our study really sort of shows for us was that we really need a better study, something a little bit more controlled, because there are a lot of different strains that are being used out there, and we were not able to tease out what strain of cannabis worked best in our patient population. People are using CBD strains, THC strains, a combination of things, whereas I think we really need more of a uniform strain or preparation, and then more of a placebo-controlled trial,” Dr. Chapman said.
“At this point I think it’s a bit early to be selling the farm, so to speak, and moving to Colorado,” he concluded. “Right now there’s quite a bit of uncertainty about how effective the medication is. Also, we still have a lot of unknowns about drug interactions, adverse effects of the medication. We have no long-term data because ours is just short-term follow-up data.”
Open communication is critical
Dr. Jeffrey Gold, a pediatric neurologist at Rady Children’s Hospital in San Diego, and his colleagues reported the case of a boy with Doose syndrome whose seizures resolved after initiation of cannabinoid therapy.
“We face somewhat different challenges in California, where recreational marijuana is not legal. Medical marijuana has some acceptance, but it exists in a nebulous legal area,” he noted in the press briefing.
The boy’s seizures were refractory to medical therapy and video EEG features suggested a high risk of progression. His parents opted to try CBD instead of the ketogenic diet, the standard of care in such cases.
“They obtained the product from the local family group, which is challenging for us because we don’t really know what’s in it. We don’t know what the composition is. The family doesn’t know what the composition of the product is,” Dr. Gold said. However, the boy’s mother obtained independent testing, which showed that it was sometimes high in CBD, other times high in THC.
After starting therapy, the boy had apparent worsening of seizures. Testing revealed that his valproic acid level had risen from 115 to 178 mcg/mL, suggesting the CBD was interfering with the drug’s clearance.
The valproic acid dose was lowered, and over a 4-month period, the patient became seizure free. “We obtained another EEG which was completely normal, honestly to our surprise,” reported Dr. Gold, who disclosed no relevant conflicts of interest. “And I don’t know why that was, if that was because he got some extra valproic acid and that tripped a mechanism that set off improvement, or if that’s because of the CBD. Resolution of seizures and normalization of the EEG has been reported before in Doose syndrome and can happen spontaneously or as a result of medication.
“We wanted to get this report out to the community so that they would know, if families choose to start CBD therapy, we strongly advocate that they share that information with their physicians and that physicians manage the other antiseizure treatments the child is receiving,” Dr. Gold said. “We have heard from parents and from other providers that once they told their provider that they were doing CBD, they were told to not come back to the office because they were doing a nonapproved therapy, and we don’t support that. We want families to feel like they can share their treatments with their physicians and receive the help they need because we don’t know what these medications do to other treatments that the patient might be receiving, and it’s imperative that families stay in contact with their physicians.”
Families often tinker with artisanal cannabis products themselves, hoping to find just the right combination, Dr. Gold noted. “It emphasizes both the difficulties of doing the artisanal preparations but more specifically, the difficulties of not doing it scientifically. Science is hard, it’s very difficult, it’s expensive, and it’s time consuming. But it’s the right way to do it. And studies ... that are coming up are the right way to do it,” he maintained.
“So we encourage families to pursue conventional treatment, enroll in clinical trials when they are offered, to get involved with the scientific community as you can, and we will get an answer to these questions. But it is going to take time. We need to do it the right way,” he concluded.
AT AES 2014
Jury still out on survival benefit of resecting primary in mCRC
SAN FRANCISCO – Resecting the primary tumor in patients with metastatic colon or colorectal cancer may prolong survival. But then again, it may not.
This was the overarching take-home message from a trio of cohort studies presented at the Gastrointestinal Cancers Symposium cosponsored by the AGA Institute, the American Society of Clinical Oncology, ASTRO, and the Society of Surgical Oncology. Results were reported in a poster session.
“Whereas surgery is the primary treatment of localized colorectal cancer, resection of the primary tumor in patients with incurable metastatic disease is usually recommended for palliative purposes to manage obstruction, perforation, or bleeding,” Dr. Shahid Ahmed, lead investigator of one of the studies, noted in comments provided by e-mail. “The role of surgical resection of the primary tumor in patients with newly diagnosed incurable stage IV colorectal cancer remains controversial.”
In earlier research, he and colleagues found a survival benefit of primary resection among Canadian patients whose cancer was diagnosed between 1992 and 2005 (Cancer 2014;120:683-91). But the majority did not receive systemic therapy, and those who did were often given older regimens.
In a new study aimed at testing the association in the contemporary treatment era, the researchers analyzed data from 569 patients with stage IV colorectal cancer diagnosed between 2006 and 2010 who had a median follow-up of 11 months. Overall, 55% had resection of the primary tumor.
Among the 57% of patients who received systemic therapy, 91% received FOLFIRI or FOLFOX, 65% received bevacizumab (Avastin), and 10% received cetuximab (Erbitux) or panitumumab (Vectibix), according to Dr. Ahmed, professor of medicine, University of Saskatchewan, Canada.
Results for the entire cohort showed that median overall survival was 18 months in patients who had resection of their primary versus 4 months in those who did not (multivariate hazard ratio, 0.44; P less than .001).
Among the subgroup of patients who received chemotherapy, median survival was 27 months with primary resection versus 14 months without it (P less than .0001). And among the subgroup that specifically received FOLFIRI or FOLFOX and a biologic agent, it was 35 months with primary resection and 23 months without it (P less than .001).
“Surgical resection of primary tumor improves survival of patients with stage IV colorectal cancer, independent of other prognostic variables including age, performance status, comorbid illness, and chemotherapy,” maintained Dr. Ahmed. “The current study validates our findings and supports surgical resection of primary tumor in patients with stage IV colorectal cancer who are treated with modern chemotherapy and biologics.
“A well-designed prospective randomized trial is warranted to confirm the survival benefit conferred by the primary tumor resection,” he added, noting that two such trials in Europe – SYNCHRONOUS and CAIRO4 – are underway.
“If the magnitude of survival benefit is confirmed in these future randomized studies, surgical resection of the primary tumor could potentially be a more cost-effective intervention compared with novel systemic therapy in the management of metastatic colorectal cancer,” he concluded.
In a second study, Dr. Aaron Lewis, a surgical oncology fellow at the City of Hope, Duarte, Calif., and colleagues analyzed data from patients with stage IV colon cancer in the Surveillance, Epidemiology, and End Results (SEER) database for the years 1998 through 2011. They excluded those who died within 30 days of diagnosis or had resection of metastases. Overall, 70% of the 28,068 included patients had resection of their primary.
In multivariate analyses, patients who underwent resection had half the risk of death when compared with peers who did not have this surgery (hazard ratio, 0.49), reported Dr. Lewis.
Findings were essentially the same when the analysis was repeated in a subset of matched patients: Median survival was 17 months with resection versus 9 months without it (hazard ratio, 0.48; P less than .0001). Estimated 3-year survival was 23% and 6%, respectively.
“There are limitations, factors that we couldn’t completely control for. For example, there is no chemotherapy data in the SEER database. We didn’t know the timing of surgery in relation to chemotherapy. And we didn’t know whether these patients were asymptomatic or symptomatic,” Dr. Lewis noted in an interview. “But analysis of this huge group of patients in the United States that are getting treated shows that there is a survival benefit.”
Possible reasons why surgery might prolong life in this setting are unknown but may include the effects of tumor debulking or some enhancement of the immune response, he proposed.
To definitively confirm a survival benefit, a randomized controlled trial is needed, he agreed. “This seems to be a popular question in the literature in the last couple of years, so maybe somebody will be willing to take it on.”
In a third study, a team led by Dr. Zeinab Alawadi, a surgeon and postdoctoral fellow at the University of Texas MD Anderson Cancer Center, Houston, analyzed data from 14,399 patients in the National Cancer Data Base. They had been diagnosed with stage IV colon cancer between 2003 and 2005. The researchers excluded patients who had nonelective resection or surgery at other sites, such as metastasectomy.
The primary tumor was resected in 55% of all patients studied and in 74% of patients included in a 1-year landmark analysis done to account for early deaths related to comorbidity or disease burden, reported Dr. Alawadi.
In the entire cohort, primary resection conferred a significant survival benefit after standard multivariate adjustment (hazard ratio, 0.39) that persisted after propensity score weighting to account for treatment selection bias (hazard ratio, 0.41). The benefit was also significant, but much attenuated, in an instrumental variable analysis, another method for accounting for treatment selection bias (relative mortality rate, 0.88).
In the 1-year landmark population, primary resection conferred a smaller significant survival benefit after standard multivariate adjustment (hazard ratio, 0.60) that persisted after propensity score weighting (hazard ratio, 0.59). But there was no longer a significant benefit in the instrumental variable analysis here.
“Among the entire cohort of patients with stage 4 colon cancer, primary tumor resection offered no survival benefit over systemic chemotherapy alone when the [instrumental variable] method was applied at the 1 year landmark,” the investigators write.
“Subject to selection and survivor treatment bias, standard regression analysis may overestimate the benefit of [primary tumor resection],” they concluded.
SAN FRANCISCO – Resecting the primary tumor in patients with metastatic colon or colorectal cancer may prolong survival. But then again, it may not.
This was the overarching take-home message from a trio of cohort studies presented at the Gastrointestinal Cancers Symposium cosponsored by the AGA Institute, the American Society of Clinical Oncology, ASTRO, and the Society of Surgical Oncology. Results were reported in a poster session.
“Whereas surgery is the primary treatment of localized colorectal cancer, resection of the primary tumor in patients with incurable metastatic disease is usually recommended for palliative purposes to manage obstruction, perforation, or bleeding,” Dr. Shahid Ahmed, lead investigator of one of the studies, noted in comments provided by e-mail. “The role of surgical resection of the primary tumor in patients with newly diagnosed incurable stage IV colorectal cancer remains controversial.”
In earlier research, he and colleagues found a survival benefit of primary resection among Canadian patients whose cancer was diagnosed between 1992 and 2005 (Cancer 2014;120:683-91). But the majority did not receive systemic therapy, and those who did were often given older regimens.
In a new study aimed at testing the association in the contemporary treatment era, the researchers analyzed data from 569 patients with stage IV colorectal cancer diagnosed between 2006 and 2010 who had a median follow-up of 11 months. Overall, 55% had resection of the primary tumor.
Among the 57% of patients who received systemic therapy, 91% received FOLFIRI or FOLFOX, 65% received bevacizumab (Avastin), and 10% received cetuximab (Erbitux) or panitumumab (Vectibix), according to Dr. Ahmed, professor of medicine, University of Saskatchewan, Canada.
Results for the entire cohort showed that median overall survival was 18 months in patients who had resection of their primary versus 4 months in those who did not (multivariate hazard ratio, 0.44; P less than .001).
Among the subgroup of patients who received chemotherapy, median survival was 27 months with primary resection versus 14 months without it (P less than .0001). And among the subgroup that specifically received FOLFIRI or FOLFOX and a biologic agent, it was 35 months with primary resection and 23 months without it (P less than .001).
“Surgical resection of primary tumor improves survival of patients with stage IV colorectal cancer, independent of other prognostic variables including age, performance status, comorbid illness, and chemotherapy,” maintained Dr. Ahmed. “The current study validates our findings and supports surgical resection of primary tumor in patients with stage IV colorectal cancer who are treated with modern chemotherapy and biologics.
“A well-designed prospective randomized trial is warranted to confirm the survival benefit conferred by the primary tumor resection,” he added, noting that two such trials in Europe – SYNCHRONOUS and CAIRO4 – are underway.
“If the magnitude of survival benefit is confirmed in these future randomized studies, surgical resection of the primary tumor could potentially be a more cost-effective intervention compared with novel systemic therapy in the management of metastatic colorectal cancer,” he concluded.
In a second study, Dr. Aaron Lewis, a surgical oncology fellow at the City of Hope, Duarte, Calif., and colleagues analyzed data from patients with stage IV colon cancer in the Surveillance, Epidemiology, and End Results (SEER) database for the years 1998 through 2011. They excluded those who died within 30 days of diagnosis or had resection of metastases. Overall, 70% of the 28,068 included patients had resection of their primary.
In multivariate analyses, patients who underwent resection had half the risk of death when compared with peers who did not have this surgery (hazard ratio, 0.49), reported Dr. Lewis.
Findings were essentially the same when the analysis was repeated in a subset of matched patients: Median survival was 17 months with resection versus 9 months without it (hazard ratio, 0.48; P less than .0001). Estimated 3-year survival was 23% and 6%, respectively.
“There are limitations, factors that we couldn’t completely control for. For example, there is no chemotherapy data in the SEER database. We didn’t know the timing of surgery in relation to chemotherapy. And we didn’t know whether these patients were asymptomatic or symptomatic,” Dr. Lewis noted in an interview. “But analysis of this huge group of patients in the United States that are getting treated shows that there is a survival benefit.”
Possible reasons why surgery might prolong life in this setting are unknown but may include the effects of tumor debulking or some enhancement of the immune response, he proposed.
To definitively confirm a survival benefit, a randomized controlled trial is needed, he agreed. “This seems to be a popular question in the literature in the last couple of years, so maybe somebody will be willing to take it on.”
In a third study, a team led by Dr. Zeinab Alawadi, a surgeon and postdoctoral fellow at the University of Texas MD Anderson Cancer Center, Houston, analyzed data from 14,399 patients in the National Cancer Data Base. They had been diagnosed with stage IV colon cancer between 2003 and 2005. The researchers excluded patients who had nonelective resection or surgery at other sites, such as metastasectomy.
The primary tumor was resected in 55% of all patients studied and in 74% of patients included in a 1-year landmark analysis done to account for early deaths related to comorbidity or disease burden, reported Dr. Alawadi.
In the entire cohort, primary resection conferred a significant survival benefit after standard multivariate adjustment (hazard ratio, 0.39) that persisted after propensity score weighting to account for treatment selection bias (hazard ratio, 0.41). The benefit was also significant, but much attenuated, in an instrumental variable analysis, another method for accounting for treatment selection bias (relative mortality rate, 0.88).
In the 1-year landmark population, primary resection conferred a smaller significant survival benefit after standard multivariate adjustment (hazard ratio, 0.60) that persisted after propensity score weighting (hazard ratio, 0.59). But there was no longer a significant benefit in the instrumental variable analysis here.
“Among the entire cohort of patients with stage 4 colon cancer, primary tumor resection offered no survival benefit over systemic chemotherapy alone when the [instrumental variable] method was applied at the 1 year landmark,” the investigators write.
“Subject to selection and survivor treatment bias, standard regression analysis may overestimate the benefit of [primary tumor resection],” they concluded.
SAN FRANCISCO – Resecting the primary tumor in patients with metastatic colon or colorectal cancer may prolong survival. But then again, it may not.
This was the overarching take-home message from a trio of cohort studies presented at the Gastrointestinal Cancers Symposium cosponsored by the AGA Institute, the American Society of Clinical Oncology, ASTRO, and the Society of Surgical Oncology. Results were reported in a poster session.
“Whereas surgery is the primary treatment of localized colorectal cancer, resection of the primary tumor in patients with incurable metastatic disease is usually recommended for palliative purposes to manage obstruction, perforation, or bleeding,” Dr. Shahid Ahmed, lead investigator of one of the studies, noted in comments provided by e-mail. “The role of surgical resection of the primary tumor in patients with newly diagnosed incurable stage IV colorectal cancer remains controversial.”
In earlier research, he and colleagues found a survival benefit of primary resection among Canadian patients whose cancer was diagnosed between 1992 and 2005 (Cancer 2014;120:683-91). But the majority did not receive systemic therapy, and those who did were often given older regimens.
In a new study aimed at testing the association in the contemporary treatment era, the researchers analyzed data from 569 patients with stage IV colorectal cancer diagnosed between 2006 and 2010 who had a median follow-up of 11 months. Overall, 55% had resection of the primary tumor.
Among the 57% of patients who received systemic therapy, 91% received FOLFIRI or FOLFOX, 65% received bevacizumab (Avastin), and 10% received cetuximab (Erbitux) or panitumumab (Vectibix), according to Dr. Ahmed, professor of medicine, University of Saskatchewan, Canada.
Results for the entire cohort showed that median overall survival was 18 months in patients who had resection of their primary versus 4 months in those who did not (multivariate hazard ratio, 0.44; P less than .001).
Among the subgroup of patients who received chemotherapy, median survival was 27 months with primary resection versus 14 months without it (P less than .0001). And among the subgroup that specifically received FOLFIRI or FOLFOX and a biologic agent, it was 35 months with primary resection and 23 months without it (P less than .001).
“Surgical resection of primary tumor improves survival of patients with stage IV colorectal cancer, independent of other prognostic variables including age, performance status, comorbid illness, and chemotherapy,” maintained Dr. Ahmed. “The current study validates our findings and supports surgical resection of primary tumor in patients with stage IV colorectal cancer who are treated with modern chemotherapy and biologics.
“A well-designed prospective randomized trial is warranted to confirm the survival benefit conferred by the primary tumor resection,” he added, noting that two such trials in Europe – SYNCHRONOUS and CAIRO4 – are underway.
“If the magnitude of survival benefit is confirmed in these future randomized studies, surgical resection of the primary tumor could potentially be a more cost-effective intervention compared with novel systemic therapy in the management of metastatic colorectal cancer,” he concluded.
In a second study, Dr. Aaron Lewis, a surgical oncology fellow at the City of Hope, Duarte, Calif., and colleagues analyzed data from patients with stage IV colon cancer in the Surveillance, Epidemiology, and End Results (SEER) database for the years 1998 through 2011. They excluded those who died within 30 days of diagnosis or had resection of metastases. Overall, 70% of the 28,068 included patients had resection of their primary.
In multivariate analyses, patients who underwent resection had half the risk of death when compared with peers who did not have this surgery (hazard ratio, 0.49), reported Dr. Lewis.
Findings were essentially the same when the analysis was repeated in a subset of matched patients: Median survival was 17 months with resection versus 9 months without it (hazard ratio, 0.48; P less than .0001). Estimated 3-year survival was 23% and 6%, respectively.
“There are limitations, factors that we couldn’t completely control for. For example, there is no chemotherapy data in the SEER database. We didn’t know the timing of surgery in relation to chemotherapy. And we didn’t know whether these patients were asymptomatic or symptomatic,” Dr. Lewis noted in an interview. “But analysis of this huge group of patients in the United States that are getting treated shows that there is a survival benefit.”
Possible reasons why surgery might prolong life in this setting are unknown but may include the effects of tumor debulking or some enhancement of the immune response, he proposed.
To definitively confirm a survival benefit, a randomized controlled trial is needed, he agreed. “This seems to be a popular question in the literature in the last couple of years, so maybe somebody will be willing to take it on.”
In a third study, a team led by Dr. Zeinab Alawadi, a surgeon and postdoctoral fellow at the University of Texas MD Anderson Cancer Center, Houston, analyzed data from 14,399 patients in the National Cancer Data Base. They had been diagnosed with stage IV colon cancer between 2003 and 2005. The researchers excluded patients who had nonelective resection or surgery at other sites, such as metastasectomy.
The primary tumor was resected in 55% of all patients studied and in 74% of patients included in a 1-year landmark analysis done to account for early deaths related to comorbidity or disease burden, reported Dr. Alawadi.
In the entire cohort, primary resection conferred a significant survival benefit after standard multivariate adjustment (hazard ratio, 0.39) that persisted after propensity score weighting to account for treatment selection bias (hazard ratio, 0.41). The benefit was also significant, but much attenuated, in an instrumental variable analysis, another method for accounting for treatment selection bias (relative mortality rate, 0.88).
In the 1-year landmark population, primary resection conferred a smaller significant survival benefit after standard multivariate adjustment (hazard ratio, 0.60) that persisted after propensity score weighting (hazard ratio, 0.59). But there was no longer a significant benefit in the instrumental variable analysis here.
“Among the entire cohort of patients with stage 4 colon cancer, primary tumor resection offered no survival benefit over systemic chemotherapy alone when the [instrumental variable] method was applied at the 1 year landmark,” the investigators write.
“Subject to selection and survivor treatment bias, standard regression analysis may overestimate the benefit of [primary tumor resection],” they concluded.
AT THE GASTROINTESTINAL CANCERS SYMPOSIUM
Key clinical point: Data are mixed regarding an overall survival benefit of resecting the primary tumor.
Major finding: Two studies found a halving of the risk of death, whereas one study found lesser or even no benefit.
Data source: A trio of cohort studies in 569 patients, 28,068 patients, and 14,399 patients with metastatic colon or colorectal cancer.
Disclosures: Dr. Ahmed, Dr. Lewis, and Dr. Alawadi disclosed that they had no conflicts of interest.
