FDA Modifies Indication for Erlotinib in NSCLC
The use is limited to patients whose tumours have specific EGFR mutations
Date: 24 Oct 2016
Topic: Lung and other thoracic tumours / Anticancer agents & Biologic therapy
On 18 October, 2016, the US Food and Drug Administration (FDA) modified the indication for erlotinib (TARCEVA, Astellas Pharm Global Development Inc.) for treatment of non-small cell lung cancer (NSCLC) to limit use to patients whose tumours have specific epidermal growth factor receptor (EGFR) mutations.
The labelling change applies to patients with NSCLC receiving maintenance or second or greater line treatment. These indications will be limited to those patients whose tumours have EGFR exon 19 deletions or exon 21 L858R substitution mutations as detected by an FDA-approved test.
The first-line indication previously was limited to patients with EGFR exon 19 deletions or exon 21 substitution mutations.
This labelling supplement is based on the results of the IUNO trial, a randomised, double-blind, placebo-controlled, trial of erlotinib administered as maintenance therapy in 643 patients with advanced NSCLC who had not experienced disease progression or unacceptable toxicity during four cycles of platinum-based first-line chemotherapy. Patients whose tumours harboured activating EGFR mutations (exon 19 deletions or exon 21 L858R mutations) were excluded from this trial.
Patients were randomised 1:1 to receive erlotinib or placebo orally once daily (322 erlotinib, 321 placebo) until disease progression or unacceptable toxicity. Following progression on initial therapy, patients were eligible to enter an open-label phase. In total, 50% of patients randomised to erlotinib entered the open-label phase and received chemotherapy, while 77% of patients randomised to placebo entered the open-label phase and received erlotinib.
The trial’s primary endpoint was overall survival. Results demonstrated that survival following treatment with erlotinib was not better than placebo administered as maintenance in patients with metastatic NSCLC tumours not harbouring EGFR-activating mutations. No difference in progression-free survival between the erlotinib arm and the placebo arm was observed.
FDA will not require new post-marketing requirements or request post-marketing commitments based on the results of the IUNO trial.
miércoles, 26 de octubre de 2016
Chemoradiotherapy Alone in Inferior Rectal Cancer.
Inferior Rectal Cancer OS With Chemoradiotherapy Alone
Real-world data suggest that foregoing surgery after chemoradiotherapy may not be the best option for patients with stage II or III rectal adenocarcinoma
Date: 21 Oct 2016
Author: By Shreeya Nanda, Senior medwireNews Reporter
Topic: Anti-Cancer Agents & Biologic Therapy / Rectal Cancer / Surgery and/or Radiotherapy of Cancer
medwireNews: Treatment with chemoradiotherapy alone results in significantly reduced overall survival (OS) compared with when it is followed by surgery in patients with rectal adenocarcinoma, according to a research letter published in JAMA Oncology.
Using the National Cancer Database, the researchers identified 1655 patients who received chemoradiotherapy alone for stage II or III rectal cancer, while their 14,207 counterparts underwent “conventional treatment” comprising chemoradiotherapy and proctectomy.
OS was shorter for patients in the chemoradiotherapy alone group than for those who also received surgery, with 3- and 5-year survival rates of 71.34% versus 88.29% and 58.21% versus 77.12%, respectively. This equated to a significant 1.90-fold increased risk of death for patients given chemoradiotherapy alone.
The elevated risk with chemoradiotherapy alone persisted after adjustment for confounding factors, such as race, insurance status, comorbidity score and tumour grade, with an adjusted hazard ratio of 1.69, reports the team from the University of North Carolina at Chapel Hill in the USA.
Highlighting that their results are contrary to previous single-institution and clinical trial results, C Tyler Ellis and co-researchers say: “This finding is likely because chemoradiotherapy only can be viewed at once as both an innovative treatment paradigm in some settings and low-quality care in others.
“Although [nonoperative management] is an intentional approach for some patients, it is likely that many individuals forgoing surgery in the community are doing so as a result of systematic barriers. Our results point to disparities in the process of rectal cancer care where historically disadvantaged groups receive suboptimal care and experience worse outcomes.”
The authors point out that they could not determine whether patients responded completely to chemoradiotherapy or whether they failed to receive surgery for other reasons.
However, given that the use of chemoradiotherapy alone “has doubled among individuals with nonmetastatic rectal adenocarcinoma”, they find the results “concerning”.
The team concludes: “As [nonoperative management] becomes an increasingly accepted treatment approach, more comparative effectiveness studies evaluating outcomes in the real-world setting will be needed.”
Reference
Ellis CT, Dusetzina SB, Sanoff H, Stitzenberg KB. Long-term survival after chemoradiotherapy without surgery for rectal adenocarcinoma: a word of caution. JAMA Oncol; Advance online publication 20 October 2016. doi:10.1001/jamaoncol.2016.3424
lunes, 24 de octubre de 2016
Adjuvant Ipi Improves Survival in Melanoma
Medscape Oncology
Big News: Adjuvant Ipi Improves Survival in Melanoma
Caroline Robert, MD, PhD
Disclosures | October 17, 2016
Breakthrough in Adjuvant Therapy
Hello. I am Dr Caroline Robert, chief of dermatology at the Institut Gustave Roussy in France. Welcome to Medscape Oncology Insights. At the 2016 meeting of the European Society for Medical Oncology (ESMO), we heard exciting data in melanoma. I will share with you some of the highlights.
In melanoma, we have been living through a revolution for the past 6 years. We have two winning strategies: targeted agents for BRAF-mutant melanoma, which is about half of the patients that we take care of, and immunotherapy. Until this meeting, progress was mostly in the field of metastatic melanoma. We had not yet improved the management of patients with a high risk for relapse, and we had not really gone into the field of adjuvant therapy. Now, things have changed.
First, at this meeting, we heard the overall survival results of the EORTC trial,[1] which evaluated ipilimumab, an anti-CTLA-4 antibody, versus placebo. This trial was for patients with stage III melanoma, patients who have had a resection of their metastatic lymph nodes and who were at high risk for relapse. In this population of patients, we already knew that the duration before relapse had been significantly prolonged with ipilimumab. This actually gave rise to the authorization of ipilimumab in the United States. We have learned that we also have an overall survival benefit with ipilimumab. This is significant. The risk for death was decreased by 28%. At 5 years, there was a difference of 11% between the two arms: 65% in the patients who received ipilimumab versus 54%.
This is big news because, until now, we had only interferon for this population of patients, and the improvement in overall survival was not very consistent across all of the trials. We knew that we prolonged the duration before relapse, but we did not know that with interferon we could have an influence on overall survival. This [improvement in overall survival from ipilimumab] is a very important result. However, there were adverse events, with five deaths in the arm with patients treated with ipilimumab. This was due to immune-related adverse events. They occurred in close to 42% of the patients with a grade 3 or above. This is something that has to be prescribed by physicians who are used to treating patients with melanoma and who are used to managing these immune-related adverse events.
Metastatic Melanoma: Survival Still Climbing
Targeted Agents Yield 3-Year Survival of 45%
In the metastatic field, we have had two very important pieces of news—one in the field of targeted agents and one in the field of immunotherapy.
Targeted agents: Here, we talk about patients with BRAF-mutant melanoma. As I said before, it concerns about half of the population of patients with melanoma. We already knew that the combination of an anti-BRAF plus anti-MEK is much more effective than anti-BRAF monotherapy. We have the results of the 3-year overall survival of patients who were included in the phase 3 trial[2] evaluating the combination of dabrafenib plus trametinib, anti-BRAF plus anti-MEK, compared with vemurafenib, an anti-BRAF single agent.
We can now announce that after a median 28 months of follow-up of the patients in the combination arm, we have 45% of patients alive. This is a very significant improvement over vemurafenib, with only 32% of patients alive. This is the highest percentage of patients alive at 3 years in a randomized trial of patients with metastatic melanoma.
This is very important to note because, right now, a lot of physicians think that only immunotherapy is able to give rise to long-term responses, which we proved is not true. Combination targeted agents give the same ratio. For anti-PD-1 single agents, we will very soon have the 3-year overall survival results, and we think that it will also probably be around 40%-45%.
A lot of physicians think that only immunotherapy is able to give rise to long-term responses, which we proved is not true.
We also have patients with complete response, which was 19% in this trial of dabrafenib plus trametinib with a median duration of response of 39 months. We have long-term responses with the combination and the same percentage of patients alive at 3 years.
What is going to be extremely important is to follow these patients and to see if we arrive at a plateau. The follow-up of these patients in this arm is going to be very important. It is quite promising because we have 66 patients still on therapy who are censored in the arm of dabrafenib plus trametinib. It is always important in the Kaplan-Meier curve to look at the number of censored patients in each of the arms, especially the ones who are still on the active treatment. It is 66 patients in the dabrafenib-plus-trametinib arm and only 10 patients in the vemurafenib arm. Probably, the top curve will remain much flatter than the [vemurafenib arm].
Immunotherapy: Ipilimumab Dose Provides Unexpected Results
In the field of immunotherapy, the results that we are all looking forward to having are from the combination of anti-CTLA-4 plus anti-PD-1. We know that in terms of response and progression-free survival, it is better than an anti-PD-1 single agent,[3] but we still have to wait some months to have the overall survival results.
At this meeting, we learned some quite unexpected results. It was very interesting. Paolo Ascierto, our colleague from Italy, presented the results of ipilimumab 3 mg versus 10 mg.[4] I forgot to tell you that in the adjuvant trial, ipilimumab was given at 10 mg/kg, which is not the dose that is approved for metastatic melanoma. So it was very important to know the results of 3 mg versus 10 mg in the metastatic setting.
This trial with a long follow-up allowed us to get 3-year overall survival rates. In the 10-mg/kg arm, the benefit in terms of survival at 3 years was 31% of patients alive compared with 23% in the 3-mg/kg arm. There was significant improvement: The hazard ratio showed that the risk for death was decreased by 16%.
It actually came as a surprise to see the significant difference. We don't know today how it will impact the future, because now we all think that ipilimumab will probably more or less always be combined with an anti-PD-1 antibody. Nevertheless, this may be something that is important for other combinations. There is a dose effect of ipilimumab, with 10 mg being more effective than 3 mg in the metastatic setting.
It was quite rich in information for melanoma this year at ESMO. Thank you for joining me for this edition of Medscape Oncology Insights. This is Caroline Robert, reporting from ESMO 2016.
Big News: Adjuvant Ipi Improves Survival in Melanoma
Caroline Robert, MD, PhD
Disclosures | October 17, 2016
Breakthrough in Adjuvant Therapy
Hello. I am Dr Caroline Robert, chief of dermatology at the Institut Gustave Roussy in France. Welcome to Medscape Oncology Insights. At the 2016 meeting of the European Society for Medical Oncology (ESMO), we heard exciting data in melanoma. I will share with you some of the highlights.
In melanoma, we have been living through a revolution for the past 6 years. We have two winning strategies: targeted agents for BRAF-mutant melanoma, which is about half of the patients that we take care of, and immunotherapy. Until this meeting, progress was mostly in the field of metastatic melanoma. We had not yet improved the management of patients with a high risk for relapse, and we had not really gone into the field of adjuvant therapy. Now, things have changed.
First, at this meeting, we heard the overall survival results of the EORTC trial,[1] which evaluated ipilimumab, an anti-CTLA-4 antibody, versus placebo. This trial was for patients with stage III melanoma, patients who have had a resection of their metastatic lymph nodes and who were at high risk for relapse. In this population of patients, we already knew that the duration before relapse had been significantly prolonged with ipilimumab. This actually gave rise to the authorization of ipilimumab in the United States. We have learned that we also have an overall survival benefit with ipilimumab. This is significant. The risk for death was decreased by 28%. At 5 years, there was a difference of 11% between the two arms: 65% in the patients who received ipilimumab versus 54%.
This is big news because, until now, we had only interferon for this population of patients, and the improvement in overall survival was not very consistent across all of the trials. We knew that we prolonged the duration before relapse, but we did not know that with interferon we could have an influence on overall survival. This [improvement in overall survival from ipilimumab] is a very important result. However, there were adverse events, with five deaths in the arm with patients treated with ipilimumab. This was due to immune-related adverse events. They occurred in close to 42% of the patients with a grade 3 or above. This is something that has to be prescribed by physicians who are used to treating patients with melanoma and who are used to managing these immune-related adverse events.
Metastatic Melanoma: Survival Still Climbing
Targeted Agents Yield 3-Year Survival of 45%
In the metastatic field, we have had two very important pieces of news—one in the field of targeted agents and one in the field of immunotherapy.
Targeted agents: Here, we talk about patients with BRAF-mutant melanoma. As I said before, it concerns about half of the population of patients with melanoma. We already knew that the combination of an anti-BRAF plus anti-MEK is much more effective than anti-BRAF monotherapy. We have the results of the 3-year overall survival of patients who were included in the phase 3 trial[2] evaluating the combination of dabrafenib plus trametinib, anti-BRAF plus anti-MEK, compared with vemurafenib, an anti-BRAF single agent.
We can now announce that after a median 28 months of follow-up of the patients in the combination arm, we have 45% of patients alive. This is a very significant improvement over vemurafenib, with only 32% of patients alive. This is the highest percentage of patients alive at 3 years in a randomized trial of patients with metastatic melanoma.
This is very important to note because, right now, a lot of physicians think that only immunotherapy is able to give rise to long-term responses, which we proved is not true. Combination targeted agents give the same ratio. For anti-PD-1 single agents, we will very soon have the 3-year overall survival results, and we think that it will also probably be around 40%-45%.
A lot of physicians think that only immunotherapy is able to give rise to long-term responses, which we proved is not true.
We also have patients with complete response, which was 19% in this trial of dabrafenib plus trametinib with a median duration of response of 39 months. We have long-term responses with the combination and the same percentage of patients alive at 3 years.
What is going to be extremely important is to follow these patients and to see if we arrive at a plateau. The follow-up of these patients in this arm is going to be very important. It is quite promising because we have 66 patients still on therapy who are censored in the arm of dabrafenib plus trametinib. It is always important in the Kaplan-Meier curve to look at the number of censored patients in each of the arms, especially the ones who are still on the active treatment. It is 66 patients in the dabrafenib-plus-trametinib arm and only 10 patients in the vemurafenib arm. Probably, the top curve will remain much flatter than the [vemurafenib arm].
Immunotherapy: Ipilimumab Dose Provides Unexpected Results
In the field of immunotherapy, the results that we are all looking forward to having are from the combination of anti-CTLA-4 plus anti-PD-1. We know that in terms of response and progression-free survival, it is better than an anti-PD-1 single agent,[3] but we still have to wait some months to have the overall survival results.
At this meeting, we learned some quite unexpected results. It was very interesting. Paolo Ascierto, our colleague from Italy, presented the results of ipilimumab 3 mg versus 10 mg.[4] I forgot to tell you that in the adjuvant trial, ipilimumab was given at 10 mg/kg, which is not the dose that is approved for metastatic melanoma. So it was very important to know the results of 3 mg versus 10 mg in the metastatic setting.
This trial with a long follow-up allowed us to get 3-year overall survival rates. In the 10-mg/kg arm, the benefit in terms of survival at 3 years was 31% of patients alive compared with 23% in the 3-mg/kg arm. There was significant improvement: The hazard ratio showed that the risk for death was decreased by 16%.
It actually came as a surprise to see the significant difference. We don't know today how it will impact the future, because now we all think that ipilimumab will probably more or less always be combined with an anti-PD-1 antibody. Nevertheless, this may be something that is important for other combinations. There is a dose effect of ipilimumab, with 10 mg being more effective than 3 mg in the metastatic setting.
It was quite rich in information for melanoma this year at ESMO. Thank you for joining me for this edition of Medscape Oncology Insights. This is Caroline Robert, reporting from ESMO 2016.
Active Surveillance and Prostate Cancer in Sweden
Medscape Medical News > Oncology
Sweden Hits Record Highs for Watching Prostate Cancer
Can US Measure Up?
Nick Mulcahy
October 20, 2016
The use of active surveillance for the management of nonaggressive prostate cancer has soared to record highs in Sweden in recent years, providing a "benchmark" for the rest of the world, according to the authors of a new study.
From 2009 to 2014, the proportion of Swedish men with very-low-risk cancer choosing active surveillance increased from 57% to 91% and, among those with low-risk cancer, it rose from 40% to 74%, report the investigators, led by Stacy Loeb, MD, MSc, from New York University in New York City. The authors used data from a nationwide prostate cancer registry.
Low-risk prostate cancer and its prolonged natural history can be safely managed with active surveillance and the deferred, as-needed use of curative treatment, such as prostatectomy and radiation therapy, explain Dr Loeb and her coauthors, who include academics from three different Swedish universities.
Notably, in Sweden, medical records distinguish between active surveillance, which includes blood testing, biopsy, and imaging, and watchful waiting, which is a passive approach that waits to see whether clinical symptoms develop before medical intervention.
The new Swedish active surveillance data, which are an update from an earlier report that extended only to 2011, are the "highest rates yet reported" and "should serve as a benchmark to compare the use of active surveillance for favorable-risk disease around the world," write the authors.
Currently, the United States does not measure up very well, suggest the authors. Most low-risk disease is treated immediately, they observe.
"We hope that our data from Sweden will showcase that…the use of this management option is growing around the world and will encourage US men who are diagnosed with low-risk prostate cancer to ask their doctor about it," Dr Loeb told Medscape Medical News.
Dr Loeb has been an ongoing supporter of the use of active surveillance. At a press conference at the 2014 annual meeting of the American Urological Association (AUA), she declared the "era of active surveillance" had arrived. This meeting featured multiple studies indicating large upticks in its use.
The new study from Dr Loeb and colleagues is published online today in JAMA Oncology.
The high rate of active surveillance in Sweden "is likely a goal to which we should aspire on both sides of the Atlantic," says Matthew R. Cooperberg, MD, MPH, from University of California San Francisco in an accompanying editorial.
Dr Cooperberg also says that active surveillance rates "are still too low" in the United States.
Still, progress is being made, he suggests.
Dr Cooperberg says that data from some prospective, community-based registries have shown use of active surveillance "skyrocketing" to 40% to 50% for low-risk disease in the current decade, up from historical rates of about 10% (JAMA. 2015;314:80-82).
He also highlights guidance newly endorsed by the American Society of Clinical Oncology that surveillance is "not merely an option" for men with low-risk disease but rather is the "preferred alternative" for any clinically localized, Gleason 3 + 3 cancer.
But Dr Cooperberg makes no mention of guidance from the most influential organization in the United States with regard to prostate cancer: the AUA.
The AUA has not updated its guidelines for the management of localized prostate cancer, which include active surveillance recommendations, since 2007.
With regard to Sweden, the study authors describe some "potential facilitating factors" for the "rapid uptake" of active surveillance.
For example, in 2007 national guidelines were issued that recommended active surveillance for men with low-risk prostate cancer and a life expectancy of 10 to 20 years. Then, in 2014, the life expectancy limit was abandoned, and active surveillance was recommended for all men with very-low-risk prostate cancer.
The study authors also believe it is important that Sweden's National Prostate Cancer Register provides "real-time feedback" to practices on their adherence to these national guidelines and also in annual reports publicly available online.
Furthermore, the Swedish healthcare system "is dominated by equal access, tax-funded care without financial incentives for clinicians to recommend curative treatment," the authors observe.
Overall, 32,518 men with a median age of 67 years were diagnosed with favorable-risk prostate cancer during the study period.
These included 4693 men with very-low-risk disease (clinical stage, T1c; Gleason score 6 or less; prostate-specific antigen [PSA], <10 ng/mL; PSA density <0.15 ng/mL/cm3; and <8-mm total cancer length in 4 positive biopsy cores).
A total of 15,403 men with low-risk disease (including all men in the very-low-risk group) (T1 to T2; Gleason score, 6 or less; and PSA <10 ng/mL), and 17,115 men had intermediate-risk disease (T1 to T2; Gleason score, 7; and/or PSA, 10 to 20 ng/mL).
Use of active surveillance for intermediate-risk disease was much lower — only 19% of cases in 2014.
In a press statement, Dr Loeb said that more US men opting for active surveillance "could go a long way toward reducing the harms of screening by minimizing overtreatment of non-aggressive prostate cancer."
Dr Cooperberg agrees.
In his editorial, he writes: "A default assumption that most low-risk prostate cancers do not need immediate treatment would completely shift the balance of benefits and harms for prostate cancer early detection efforts, and it will prove invaluable in reframing the ongoing national debate regarding optimal screening policy."
Funding support for the study was provided by the Swedish Cancer Society, the Laura and Isaac Perlmutter Cancer Center, and the Louis Feil Charitable Lead Trust. The study authors and Dr Cooperberg have disclosed no relevant financial relationships.
JAMA Oncol. Published online October 20, 2016. Abstract, Editorial
Follow Medscape senior journalist Nick Mulcahy on Twitter: @MulcahyNick
Follow Medscape Oncology on Twitter: @MedscapeOnc
Sweden Hits Record Highs for Watching Prostate Cancer
Can US Measure Up?
Nick Mulcahy
October 20, 2016
The use of active surveillance for the management of nonaggressive prostate cancer has soared to record highs in Sweden in recent years, providing a "benchmark" for the rest of the world, according to the authors of a new study.
From 2009 to 2014, the proportion of Swedish men with very-low-risk cancer choosing active surveillance increased from 57% to 91% and, among those with low-risk cancer, it rose from 40% to 74%, report the investigators, led by Stacy Loeb, MD, MSc, from New York University in New York City. The authors used data from a nationwide prostate cancer registry.
Low-risk prostate cancer and its prolonged natural history can be safely managed with active surveillance and the deferred, as-needed use of curative treatment, such as prostatectomy and radiation therapy, explain Dr Loeb and her coauthors, who include academics from three different Swedish universities.
Notably, in Sweden, medical records distinguish between active surveillance, which includes blood testing, biopsy, and imaging, and watchful waiting, which is a passive approach that waits to see whether clinical symptoms develop before medical intervention.
The new Swedish active surveillance data, which are an update from an earlier report that extended only to 2011, are the "highest rates yet reported" and "should serve as a benchmark to compare the use of active surveillance for favorable-risk disease around the world," write the authors.
Currently, the United States does not measure up very well, suggest the authors. Most low-risk disease is treated immediately, they observe.
"We hope that our data from Sweden will showcase that…the use of this management option is growing around the world and will encourage US men who are diagnosed with low-risk prostate cancer to ask their doctor about it," Dr Loeb told Medscape Medical News.
Dr Loeb has been an ongoing supporter of the use of active surveillance. At a press conference at the 2014 annual meeting of the American Urological Association (AUA), she declared the "era of active surveillance" had arrived. This meeting featured multiple studies indicating large upticks in its use.
The new study from Dr Loeb and colleagues is published online today in JAMA Oncology.
The high rate of active surveillance in Sweden "is likely a goal to which we should aspire on both sides of the Atlantic," says Matthew R. Cooperberg, MD, MPH, from University of California San Francisco in an accompanying editorial.
Dr Cooperberg also says that active surveillance rates "are still too low" in the United States.
Still, progress is being made, he suggests.
Dr Cooperberg says that data from some prospective, community-based registries have shown use of active surveillance "skyrocketing" to 40% to 50% for low-risk disease in the current decade, up from historical rates of about 10% (JAMA. 2015;314:80-82).
He also highlights guidance newly endorsed by the American Society of Clinical Oncology that surveillance is "not merely an option" for men with low-risk disease but rather is the "preferred alternative" for any clinically localized, Gleason 3 + 3 cancer.
But Dr Cooperberg makes no mention of guidance from the most influential organization in the United States with regard to prostate cancer: the AUA.
The AUA has not updated its guidelines for the management of localized prostate cancer, which include active surveillance recommendations, since 2007.
With regard to Sweden, the study authors describe some "potential facilitating factors" for the "rapid uptake" of active surveillance.
For example, in 2007 national guidelines were issued that recommended active surveillance for men with low-risk prostate cancer and a life expectancy of 10 to 20 years. Then, in 2014, the life expectancy limit was abandoned, and active surveillance was recommended for all men with very-low-risk prostate cancer.
The study authors also believe it is important that Sweden's National Prostate Cancer Register provides "real-time feedback" to practices on their adherence to these national guidelines and also in annual reports publicly available online.
Furthermore, the Swedish healthcare system "is dominated by equal access, tax-funded care without financial incentives for clinicians to recommend curative treatment," the authors observe.
Overall, 32,518 men with a median age of 67 years were diagnosed with favorable-risk prostate cancer during the study period.
These included 4693 men with very-low-risk disease (clinical stage, T1c; Gleason score 6 or less; prostate-specific antigen [PSA], <10 ng/mL; PSA density <0.15 ng/mL/cm3; and <8-mm total cancer length in 4 positive biopsy cores).
A total of 15,403 men with low-risk disease (including all men in the very-low-risk group) (T1 to T2; Gleason score, 6 or less; and PSA <10 ng/mL), and 17,115 men had intermediate-risk disease (T1 to T2; Gleason score, 7; and/or PSA, 10 to 20 ng/mL).
Use of active surveillance for intermediate-risk disease was much lower — only 19% of cases in 2014.
In a press statement, Dr Loeb said that more US men opting for active surveillance "could go a long way toward reducing the harms of screening by minimizing overtreatment of non-aggressive prostate cancer."
Dr Cooperberg agrees.
In his editorial, he writes: "A default assumption that most low-risk prostate cancers do not need immediate treatment would completely shift the balance of benefits and harms for prostate cancer early detection efforts, and it will prove invaluable in reframing the ongoing national debate regarding optimal screening policy."
Funding support for the study was provided by the Swedish Cancer Society, the Laura and Isaac Perlmutter Cancer Center, and the Louis Feil Charitable Lead Trust. The study authors and Dr Cooperberg have disclosed no relevant financial relationships.
JAMA Oncol. Published online October 20, 2016. Abstract, Editorial
Follow Medscape senior journalist Nick Mulcahy on Twitter: @MulcahyNick
Follow Medscape Oncology on Twitter: @MedscapeOnc
viernes, 21 de octubre de 2016
ESMO Presidential Symposia Medscape Oncology
Coverage from the European Society for Medical Oncology (ESMO) Congress
Medscape Oncology
COMMENTARY
Clinical Takeaways From the ESMO Presidential Symposia
Stefan Zimmermann, MD
Disclosures | October 10, 2016
Pembrolizumab First-Line Beats Chemo: 'It's a New Day for Lung Cancer'
Prolonged Survival With Adjuvant Ipilimumab in Stage 3 Melanoma
Ribociclib Offers 'Paradigm Shift' in Advanced Breast Cancer
Editor's Note:
ESMO promised practice-changing clinical trials at their annual congress this year, and the final program delivered, particularly in lung cancer.
Throughout ESMO 2016, Stefan Zimmermann, MD, has been contributing his perspectives on the most important trials at ESMO to Medscape's ESMO 2016 Live Blog,
Below are Dr Zimmermann's clinical takeaways on three of these trials, presented during the first two Presidential Symposia at ESMO 2016. They are preceded in each case by a brief introduction to the study data.
Lung Cancer
The Presidential Symposia featured two important trials on immunotherapy in lung cancer, including a landmark trial of pembrolizumab alone as first-line therapy and new data on pembrolizumab plus chemotherapy, also in the first-line setting.
The data on first-line pembrolizumab in non–small-cell lung cancer (NSCLC) come from the first 305 patients enrolled in the phase 3 KEYNOTE-024 study,[1] presented by Martin Reck, MD, PhD, and published simultaneously in the New England Journal of Medicine.
This study was conducted in patients whose lung cancer biopsies showed no EGFR or ALK mutations and showed high expression of programmed death-ligand 1 (PD-L1) (defined as expression in 50% of tumor cells).
In this patient population, pembrolizumab alone gave superior results to platinum-containing doublet chemotherapy—median progression-free survival (PFS) was 10.3 vs 6 months (hazard ratio [HR], 0.50). The secondary endpoint of overall survival (OS) was also significantly improved: The OS rate at 6 months was 80% vs 72% (HR, 0.60) and the 1-year OS rates were 70% vs 54%. Toxicity was lower with immunotherapy compared with chemotherapy as well (grade 3/4 adverse events, 27% vs 53%).
The other data on pembrolizumab plus chemotherapy in the first-line setting come from a small phase 2 trial of 123 patients in the KEYNOTE-021 study,[2] presented by Corey Langer, MD, from the University of Pennsylvania.
This study was conducted in patients with squamous NSCLC who were not selected on the basis of PD-L1 expression, so it is a bigger patient population than the pembrolizumab-alone study—but again, patients with EGFR and ALK mutations were excluded. Pembrolizumab was added onto the chemotherapy doublet of carboplatin plus pemetrexed, and compared with chemotherapy.
The addition of pembrolizumab improved PFS to 13.0 vs 8.9 months (HR, 0.53; P = .0102), but it also added to toxicity (grade 3 or higher, 39% vs 26%).
In KEYNOTE-024, a randomized trial of pembrolizumab vs platinum-based chemotherapy in patients with previously untreated advanced NSCLC with high PD-L1 expression (> 50%), pembrolizumab produced a higher response rate, longer median PFS, and longer median OS despite a 50% crossover rate.
The HR for PFS was 0.5, with a median PFS of 10.3 months in the pembrolizumab arm vs 6.0 months in the chemotherapy arm. The HR for death was 0.6, and median OS has not been not reached. It is a understatement to say that thoracic oncologists are not used to HRs in this range. To complete the fairy tale, tolerability was in favor of pembrolizumab, with only 26% grade 3/4 adverse events.
We do indeed have a new standard of care for this subgroup of patients with high expression of PD-L1. Yet the discussant, Jean-Charles Soria, MD, PhD, raised a very valid point: The portion of patients who can benefit from upfront immunotherapy desperately needs to be enlarged. If 1934 patients are screened but only 500 patients are randomized, it means we treat about 1 out of 4 of our everyday patients. On a positive note, he highlighted the response rate of 44%—a record in the first-line setting—and the HR was a record low of 0.35 in the squamous subgroup.
The future might well belong to combinations, with early-phase trial results—KEYNOTE-021, for instance—hinting at combinations massively outperforming monotherapy.
Corey Langer, MD, presented the results of cohort G from KEYNOTE-021, a randomized phase 2 trial. The response rate reached 55% in the combination arm vs 29% for chemotherapy alone. Median time to response was 1.5 months—much faster than with chemotherapy alone. The response rate reached a whopping 80% in PD-L1 high expressors. PFS was massively increased, with an HR of 0.53 and a median PFS of 13.0 vs 8.9 months. Of note, response rates were similar for PD-L1–positive and PD-L1–negative patients. These phase 2 findings must be confirmed by the sister phase 3 trials KEYNOTE-189 (platinum/pemetrexed with or without pembrolizumab in nonsquamous tumors) and KEYNOTE-407 (carboplatin/paclitaxel with or without pembrolizumab in squamous tumors).
The landscape is changing faster than we can fathom.
The landscape is changing faster than we can fathom. We barely got used to the idea of pembrolizumab as first-line therapy in high expressors. Phase 3 trials will also provide insight into subgroups.
The million-dollar question now is whether chemotherapy is necessary at all in PD-L1–low subgroups, and whether pembrolizumab monotherapy can be beaten. Can we move to a chemotherapy-free regimen for most patients?
The answer may reside in the combination of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and PD-1/PD-L1 checkpoint blockade. This is currently being pursued in at least three trials: CheckMate 227, NEPTUNE, and MYSTIC. CheckMate 227 is two studies, actually; PD-L1–positive patients are randomly assigned to receive ipilimumab plus nivolumab vs nivolumab alone vs chemotherapy, whereas PD-L1–negative patients are randomly assigned to two different schedules/doses of nivolumab plus ipilimumab, or to chemotherapy.
NEPTUNE is testing durvalumab plus tremilimumab vs chemotherapy, and MYSTIC is testing durvalumab alone, vs durvalumab plus tremelimumab, vs chemotherapy. Missing in these trials is a chemotherapy plus chemotherapy arm, which might now well be the adequate comparator arm
Breast Cancer
Ribociclib is a new cyclin-dependent kinase 4/6 (CDK4/6) inhibitor for use in combination with letrozole in patients with metastatic hormone-dependent breast cancer that is HER2-negative. It is a similar drug to the recently approved palbociclib (Ibrance®; Pfizer).
Interim results from the MONALEESA-2 study[3] presented at ESMO 2016 indicate that adding ribociclib to letrozole improves PFS by 44% and significantly improves overall response to therapy. After a median follow-up of 15.3 months, ribociclib was associated with a significant improvement in PFS, with an HR of 0.556 (P = 3.29 × 106). This corresponded with a median PFS of 14.7 months in the placebo arm, whereas median PFS was not reached in the ribociclib arm.
Among patients with measurable disease at baseline, the overall response rate was 52.7% with ribociclib vs 37.1% with placebo (P < .001). The clinical benefit rate was 80% and 72%, respectively (P = .02). The most common grade 3/4 adverse events reported in at least 5% of ribociclib and placebo recipients, respectively, were neutropenia (59% vs 1%), leukopenia (21% vs 1%), hypertension (10% vs 11%), and elevated alanine aminotransferase levels (9% vs 1%). Discontinuation rates because of adverse events were 7.5% and 2.1%, respectively. We have all been waiting for a serious strategy to delay acquired resistance to frontline antihormone therapy. And yet we know all too well that not just any combination with aromatase inhibitors is a step in the right direction: Despite a massive improvement in PFS, the combination of exemestane and everolimus is poorly tolerated, and enthusiastic oncologists are few. Enter ribociclib. The HR for PFS was 0.556, median PFS not reached (14 months in the letrozole alone arm). Neutropenia was very frequent, but febrile neutropenia rare. High-grade nonhematologic toxicity was rare. It looks like we have a serious contender after all. Good points from the invited discussant, Stephen Johnston, MD, PhD, from the Royal Marsden Hospital in London: The FALCON study presented this morning during the breast cancer session demonstrated superior PFS with fulvestrant over the aromatase inhibitor anastrozole. Fortunately, MONALEESA-3 (ribociclib plus fulvestrant first-line/second-line) is fully accrued. Stay tuned. Also, the curves separated early: A large portion of patients derived a benefit, in contrast with the aromatase inhibitor-alone arm, where we witnessed a rapid fall at the beginning of the PFS curve. Ribociclib results are in line with those for albociclib in the same setting, studied in the PALOMA-2 trial. It seems we actually have two good drugs to combine with first-line letrozole. Dr Johnston's conclusion: It is a game changer.
Medscape Oncology
COMMENTARY
Clinical Takeaways From the ESMO Presidential Symposia
Stefan Zimmermann, MD
Disclosures | October 10, 2016
Pembrolizumab First-Line Beats Chemo: 'It's a New Day for Lung Cancer'
Prolonged Survival With Adjuvant Ipilimumab in Stage 3 Melanoma
Ribociclib Offers 'Paradigm Shift' in Advanced Breast Cancer
Editor's Note:
ESMO promised practice-changing clinical trials at their annual congress this year, and the final program delivered, particularly in lung cancer.
Throughout ESMO 2016, Stefan Zimmermann, MD, has been contributing his perspectives on the most important trials at ESMO to Medscape's ESMO 2016 Live Blog,
Below are Dr Zimmermann's clinical takeaways on three of these trials, presented during the first two Presidential Symposia at ESMO 2016. They are preceded in each case by a brief introduction to the study data.
Lung Cancer
The Presidential Symposia featured two important trials on immunotherapy in lung cancer, including a landmark trial of pembrolizumab alone as first-line therapy and new data on pembrolizumab plus chemotherapy, also in the first-line setting.
The data on first-line pembrolizumab in non–small-cell lung cancer (NSCLC) come from the first 305 patients enrolled in the phase 3 KEYNOTE-024 study,[1] presented by Martin Reck, MD, PhD, and published simultaneously in the New England Journal of Medicine.
This study was conducted in patients whose lung cancer biopsies showed no EGFR or ALK mutations and showed high expression of programmed death-ligand 1 (PD-L1) (defined as expression in 50% of tumor cells).
In this patient population, pembrolizumab alone gave superior results to platinum-containing doublet chemotherapy—median progression-free survival (PFS) was 10.3 vs 6 months (hazard ratio [HR], 0.50). The secondary endpoint of overall survival (OS) was also significantly improved: The OS rate at 6 months was 80% vs 72% (HR, 0.60) and the 1-year OS rates were 70% vs 54%. Toxicity was lower with immunotherapy compared with chemotherapy as well (grade 3/4 adverse events, 27% vs 53%).
The other data on pembrolizumab plus chemotherapy in the first-line setting come from a small phase 2 trial of 123 patients in the KEYNOTE-021 study,[2] presented by Corey Langer, MD, from the University of Pennsylvania.
This study was conducted in patients with squamous NSCLC who were not selected on the basis of PD-L1 expression, so it is a bigger patient population than the pembrolizumab-alone study—but again, patients with EGFR and ALK mutations were excluded. Pembrolizumab was added onto the chemotherapy doublet of carboplatin plus pemetrexed, and compared with chemotherapy.
The addition of pembrolizumab improved PFS to 13.0 vs 8.9 months (HR, 0.53; P = .0102), but it also added to toxicity (grade 3 or higher, 39% vs 26%).
In KEYNOTE-024, a randomized trial of pembrolizumab vs platinum-based chemotherapy in patients with previously untreated advanced NSCLC with high PD-L1 expression (> 50%), pembrolizumab produced a higher response rate, longer median PFS, and longer median OS despite a 50% crossover rate.
The HR for PFS was 0.5, with a median PFS of 10.3 months in the pembrolizumab arm vs 6.0 months in the chemotherapy arm. The HR for death was 0.6, and median OS has not been not reached. It is a understatement to say that thoracic oncologists are not used to HRs in this range. To complete the fairy tale, tolerability was in favor of pembrolizumab, with only 26% grade 3/4 adverse events.
We do indeed have a new standard of care for this subgroup of patients with high expression of PD-L1. Yet the discussant, Jean-Charles Soria, MD, PhD, raised a very valid point: The portion of patients who can benefit from upfront immunotherapy desperately needs to be enlarged. If 1934 patients are screened but only 500 patients are randomized, it means we treat about 1 out of 4 of our everyday patients. On a positive note, he highlighted the response rate of 44%—a record in the first-line setting—and the HR was a record low of 0.35 in the squamous subgroup.
The future might well belong to combinations, with early-phase trial results—KEYNOTE-021, for instance—hinting at combinations massively outperforming monotherapy.
Corey Langer, MD, presented the results of cohort G from KEYNOTE-021, a randomized phase 2 trial. The response rate reached 55% in the combination arm vs 29% for chemotherapy alone. Median time to response was 1.5 months—much faster than with chemotherapy alone. The response rate reached a whopping 80% in PD-L1 high expressors. PFS was massively increased, with an HR of 0.53 and a median PFS of 13.0 vs 8.9 months. Of note, response rates were similar for PD-L1–positive and PD-L1–negative patients. These phase 2 findings must be confirmed by the sister phase 3 trials KEYNOTE-189 (platinum/pemetrexed with or without pembrolizumab in nonsquamous tumors) and KEYNOTE-407 (carboplatin/paclitaxel with or without pembrolizumab in squamous tumors).
The landscape is changing faster than we can fathom.
The landscape is changing faster than we can fathom. We barely got used to the idea of pembrolizumab as first-line therapy in high expressors. Phase 3 trials will also provide insight into subgroups.
The million-dollar question now is whether chemotherapy is necessary at all in PD-L1–low subgroups, and whether pembrolizumab monotherapy can be beaten. Can we move to a chemotherapy-free regimen for most patients?
The answer may reside in the combination of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and PD-1/PD-L1 checkpoint blockade. This is currently being pursued in at least three trials: CheckMate 227, NEPTUNE, and MYSTIC. CheckMate 227 is two studies, actually; PD-L1–positive patients are randomly assigned to receive ipilimumab plus nivolumab vs nivolumab alone vs chemotherapy, whereas PD-L1–negative patients are randomly assigned to two different schedules/doses of nivolumab plus ipilimumab, or to chemotherapy.
NEPTUNE is testing durvalumab plus tremilimumab vs chemotherapy, and MYSTIC is testing durvalumab alone, vs durvalumab plus tremelimumab, vs chemotherapy. Missing in these trials is a chemotherapy plus chemotherapy arm, which might now well be the adequate comparator arm
Breast Cancer
Ribociclib is a new cyclin-dependent kinase 4/6 (CDK4/6) inhibitor for use in combination with letrozole in patients with metastatic hormone-dependent breast cancer that is HER2-negative. It is a similar drug to the recently approved palbociclib (Ibrance®; Pfizer).
Interim results from the MONALEESA-2 study[3] presented at ESMO 2016 indicate that adding ribociclib to letrozole improves PFS by 44% and significantly improves overall response to therapy. After a median follow-up of 15.3 months, ribociclib was associated with a significant improvement in PFS, with an HR of 0.556 (P = 3.29 × 106). This corresponded with a median PFS of 14.7 months in the placebo arm, whereas median PFS was not reached in the ribociclib arm.
Among patients with measurable disease at baseline, the overall response rate was 52.7% with ribociclib vs 37.1% with placebo (P < .001). The clinical benefit rate was 80% and 72%, respectively (P = .02). The most common grade 3/4 adverse events reported in at least 5% of ribociclib and placebo recipients, respectively, were neutropenia (59% vs 1%), leukopenia (21% vs 1%), hypertension (10% vs 11%), and elevated alanine aminotransferase levels (9% vs 1%). Discontinuation rates because of adverse events were 7.5% and 2.1%, respectively. We have all been waiting for a serious strategy to delay acquired resistance to frontline antihormone therapy. And yet we know all too well that not just any combination with aromatase inhibitors is a step in the right direction: Despite a massive improvement in PFS, the combination of exemestane and everolimus is poorly tolerated, and enthusiastic oncologists are few. Enter ribociclib. The HR for PFS was 0.556, median PFS not reached (14 months in the letrozole alone arm). Neutropenia was very frequent, but febrile neutropenia rare. High-grade nonhematologic toxicity was rare. It looks like we have a serious contender after all. Good points from the invited discussant, Stephen Johnston, MD, PhD, from the Royal Marsden Hospital in London: The FALCON study presented this morning during the breast cancer session demonstrated superior PFS with fulvestrant over the aromatase inhibitor anastrozole. Fortunately, MONALEESA-3 (ribociclib plus fulvestrant first-line/second-line) is fully accrued. Stay tuned. Also, the curves separated early: A large portion of patients derived a benefit, in contrast with the aromatase inhibitor-alone arm, where we witnessed a rapid fall at the beginning of the PFS curve. Ribociclib results are in line with those for albociclib in the same setting, studied in the PALOMA-2 trial. It seems we actually have two good drugs to combine with first-line letrozole. Dr Johnston's conclusion: It is a game changer.
domingo, 16 de octubre de 2016
Liquid Biopsy Testing in NSCLC
Liquid Biopsy Testing in NSCLC: How, Why, and When
Thomas Stinchcombe, MD - 8/3/2016 More from this author
As of July 2016, there are 2 indications for molecular profiling in the treatment of non-small-cell lung cancer (NSCLC). Patients with nonsquamous NSCLC should be assessed for EGFR, ALK, and ROS1 rearrangements at the time of diagnosis, and patients with an EGFR mutation who are treated with an EGFR tyrosine kinase inhibitor (TKI) should have molecular profiling at the time of disease progression to test for the EGFR T790M resistance mutation or other mechanisms of resistance.
However, approximately one quarter of our patients are not tested or do not have molecular profiling available when initiating first-line therapy. Various factors such as insufficient tissue and the need to start therapy before the test results are available contribute to this situation. Liquid biopsies, which analyze cell-free DNA, may address this deficiency in the current treatment paradigm.
Recently, Sacher and colleagues conducted a prospective study in NSCLC looking at the time required for a plasma biopsy vs a tissue biopsy in 120 newly diagnosed patients and 60 patients with acquired resistance to an EGFR TKI. For a newly diagnosed patient, the median turnaround time for a plasma PCR test was 3 days (range: 1-7) vs 12 days (range: 1-54) using a standard tumor biopsy. For patients tested at the time of resistance, median turnaround times were 2 days (range: 1-4) for plasma genotyping vs 27 days (range: 1-146) for tissue genotyping. In practice, liquid biopsy tests require 2 tubes of approximately 5-10 mL of blood, and the turnaround time for commercially available tests is in the range of 3-14 days. The time to perform and obtain tissue biopsy results can take up to 3-4 weeks. This can cause a delay in starting therapy and anxiety in patients with a diagnosis of lung cancer who are eager to begin treatment.
Liquid Biopsy Testing
There are currently multiple commercially available, CLIA-certified liquid biopsy tests that use different platforms and technologies although only one of these tests is currently FDA approved. The advantage of liquid biopsy testing is, of course, that you omit the delay related to obtaining the tumor biopsy, and this can sometimes expedite care. However, it is clearly important that these assays must be sensitive and specific enough to detect small quantities of tumor DNA in a background of normal DNA. In general, liquid biopsy tests have a sensitivity of approximately 80% to 85% when compared with tumor biopsies and have a specificity of approximately 99%. A positive result indicates a mutation is likely present, whereas a negative result could be a false negative, and a tumor biopsy might be pursued.
Regarding the EGFR T790M mutation, patients who have a positive plasma test but a negative tumor biopsy test may be considered false positives in some of the analyses. This could be due to intratumor heterogeneity or the biopsy of a metastatic lesion that does not have the resistance mutation (intertumor heterogeneity). To date, patients with a positive plasma test for the EGFR T790M mutation have similar response rates and PFS as those with a positive tumor test, suggesting a similar benefit from third-generation EGFR TKI therapy regardless of how this mutation is detected. However, it should be noted that the data for this to date are based on retrospective analyses.
The sole FDA-approved liquid biopsy test at this time is the Cobas EGFR mutation test (v2) that is approved as a companion diagnostic to detect EGFR exon 19 deletions or the exon 21 L858R mutation in lung cancer. This test also detects another 42 mutations within EGFR exons 18-21, including the T790M-acquired resistance mutation. However, it is limited to EGFR mutations. Liquid biopsy tests that could detect additional abnormalities (eg, ALK and ROS1 rearrangements) at the time of diagnosis are certainly of clinical interest.
Applying Liquid Biopsy Tests in Clinical Practice
I think that liquid biopsies are most likely to be used for patients with nonsquamous NSCLC with insufficient tumor tissue for molecular testing or if molecular testing is incomplete at the time of diagnosis. This may avoid a repeat a tumor biopsy, and if an oncogenic driver mutation is identified, the appropriate treatment can be initiated.
Liquid biopsies could also be used to detect the EGFR T790M mutation after progression on an EGFR TKI. In this situation, if a patient had a liquid biopsy that was negative, I would pursue a tumor biopsy (if feasible and safe) to ensure that I identify any detectable T790M mutation. This is important because patients with T790M mutation have an effective approved therapy, osimertinib, and investigational treatment options.
Unfortunately, patients without the T790M mutation have fewer options, so you want to be certain the patient is T790M-mutation negative.
Liquid Biopsy Tests: Looking Forward
One of the most promising potential uses of liquid biopsy tests is to conduct serial measurements during treatment. Preliminary data have suggested that a decreasing frequency of the mutation in serial liquid biopsies is associated with an increased likelihood of a response and remaining on therapy. Conversely, patients with liquid biopsies that demonstrate the persistence of the mutations on treatment are more likely to experience disease progression. Of importance, the use of serial liquid biopsy assays for guiding clinical decisions is currently investigational.
Also, some of these tests can detect resistance mechanisms for third-generation EGFR TKIs. Collecting samples at the time of progression may improve understanding of resistance and thereby facilitate new drug development.
Finally, at ASCO 2016, Wakelee and colleagues presented an analysis of EGFR mutation detection between blood, urine, and tissue samples from patients with EGFR mutation–positive NSCLC treated with rociletinib, a third-generation EGFR inhibitor. Of note, the urine liquid biopsy assay uses 100 mL of fluid and is stable at room temperature for 2 weeks. This assay had a very similar sensitivity compared with the plasma assay for detecting the T790M mutation, and patient outcomes were similar between urine, plasma, and tissue testing. Thus, in the future, it is possible that we may be able to effectively apply liquid biopsy testing with either plasma or urine samples.
Share your thoughts on liquid biopsies for EGFR and other mutations in the space below.
Thomas Stinchcombe, MD - 8/3/2016 More from this author
As of July 2016, there are 2 indications for molecular profiling in the treatment of non-small-cell lung cancer (NSCLC). Patients with nonsquamous NSCLC should be assessed for EGFR, ALK, and ROS1 rearrangements at the time of diagnosis, and patients with an EGFR mutation who are treated with an EGFR tyrosine kinase inhibitor (TKI) should have molecular profiling at the time of disease progression to test for the EGFR T790M resistance mutation or other mechanisms of resistance.
However, approximately one quarter of our patients are not tested or do not have molecular profiling available when initiating first-line therapy. Various factors such as insufficient tissue and the need to start therapy before the test results are available contribute to this situation. Liquid biopsies, which analyze cell-free DNA, may address this deficiency in the current treatment paradigm.
Recently, Sacher and colleagues conducted a prospective study in NSCLC looking at the time required for a plasma biopsy vs a tissue biopsy in 120 newly diagnosed patients and 60 patients with acquired resistance to an EGFR TKI. For a newly diagnosed patient, the median turnaround time for a plasma PCR test was 3 days (range: 1-7) vs 12 days (range: 1-54) using a standard tumor biopsy. For patients tested at the time of resistance, median turnaround times were 2 days (range: 1-4) for plasma genotyping vs 27 days (range: 1-146) for tissue genotyping. In practice, liquid biopsy tests require 2 tubes of approximately 5-10 mL of blood, and the turnaround time for commercially available tests is in the range of 3-14 days. The time to perform and obtain tissue biopsy results can take up to 3-4 weeks. This can cause a delay in starting therapy and anxiety in patients with a diagnosis of lung cancer who are eager to begin treatment.
Liquid Biopsy Testing
There are currently multiple commercially available, CLIA-certified liquid biopsy tests that use different platforms and technologies although only one of these tests is currently FDA approved. The advantage of liquid biopsy testing is, of course, that you omit the delay related to obtaining the tumor biopsy, and this can sometimes expedite care. However, it is clearly important that these assays must be sensitive and specific enough to detect small quantities of tumor DNA in a background of normal DNA. In general, liquid biopsy tests have a sensitivity of approximately 80% to 85% when compared with tumor biopsies and have a specificity of approximately 99%. A positive result indicates a mutation is likely present, whereas a negative result could be a false negative, and a tumor biopsy might be pursued.
Regarding the EGFR T790M mutation, patients who have a positive plasma test but a negative tumor biopsy test may be considered false positives in some of the analyses. This could be due to intratumor heterogeneity or the biopsy of a metastatic lesion that does not have the resistance mutation (intertumor heterogeneity). To date, patients with a positive plasma test for the EGFR T790M mutation have similar response rates and PFS as those with a positive tumor test, suggesting a similar benefit from third-generation EGFR TKI therapy regardless of how this mutation is detected. However, it should be noted that the data for this to date are based on retrospective analyses.
The sole FDA-approved liquid biopsy test at this time is the Cobas EGFR mutation test (v2) that is approved as a companion diagnostic to detect EGFR exon 19 deletions or the exon 21 L858R mutation in lung cancer. This test also detects another 42 mutations within EGFR exons 18-21, including the T790M-acquired resistance mutation. However, it is limited to EGFR mutations. Liquid biopsy tests that could detect additional abnormalities (eg, ALK and ROS1 rearrangements) at the time of diagnosis are certainly of clinical interest.
Applying Liquid Biopsy Tests in Clinical Practice
I think that liquid biopsies are most likely to be used for patients with nonsquamous NSCLC with insufficient tumor tissue for molecular testing or if molecular testing is incomplete at the time of diagnosis. This may avoid a repeat a tumor biopsy, and if an oncogenic driver mutation is identified, the appropriate treatment can be initiated.
Liquid biopsies could also be used to detect the EGFR T790M mutation after progression on an EGFR TKI. In this situation, if a patient had a liquid biopsy that was negative, I would pursue a tumor biopsy (if feasible and safe) to ensure that I identify any detectable T790M mutation. This is important because patients with T790M mutation have an effective approved therapy, osimertinib, and investigational treatment options.
Unfortunately, patients without the T790M mutation have fewer options, so you want to be certain the patient is T790M-mutation negative.
Liquid Biopsy Tests: Looking Forward
One of the most promising potential uses of liquid biopsy tests is to conduct serial measurements during treatment. Preliminary data have suggested that a decreasing frequency of the mutation in serial liquid biopsies is associated with an increased likelihood of a response and remaining on therapy. Conversely, patients with liquid biopsies that demonstrate the persistence of the mutations on treatment are more likely to experience disease progression. Of importance, the use of serial liquid biopsy assays for guiding clinical decisions is currently investigational.
Also, some of these tests can detect resistance mechanisms for third-generation EGFR TKIs. Collecting samples at the time of progression may improve understanding of resistance and thereby facilitate new drug development.
Finally, at ASCO 2016, Wakelee and colleagues presented an analysis of EGFR mutation detection between blood, urine, and tissue samples from patients with EGFR mutation–positive NSCLC treated with rociletinib, a third-generation EGFR inhibitor. Of note, the urine liquid biopsy assay uses 100 mL of fluid and is stable at room temperature for 2 weeks. This assay had a very similar sensitivity compared with the plasma assay for detecting the T790M mutation, and patient outcomes were similar between urine, plasma, and tissue testing. Thus, in the future, it is possible that we may be able to effectively apply liquid biopsy testing with either plasma or urine samples.
Share your thoughts on liquid biopsies for EGFR and other mutations in the space below.
Pembrolizumab in NSCLC. NEJM
ORIGINAL ARTICLE
Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small-Cell Lung Cancer
Martin Reck, M.D., Ph.D., Delvys Rodríguez-Abreu, M.D., Andrew G. Robinson, M.D., Rina Hui, M.B., B.S., Ph.D., Tibor Csőszi, M.D., Andrea Fülöp, M.D., Maya Gottfried, M.D., Nir Peled, M.D., Ph.D., Ali Tafreshi, M.D., Sinead Cuffe, M.D., Mary O’Brien, M.D., Suman Rao, M.D., Katsuyuki Hotta, M.D., Ph.D., Melanie A. Leiby, Ph.D., Gregory M. Lubiniecki, M.D., Yue Shentu, Ph.D., Reshma Rangwala, M.D., Ph.D., and Julie R. Brahmer, M.D., for the KEYNOTE-024 Investigators*
October 9, 2016DOI: 10.1056/NEJMoa1606774
Comments open through October 16, 2016
BACKGROUND
Pembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non–small-cell lung cancer (NSCLC), with increased activity in tumors that express programmed death ligand 1 (PD-L1).
METHODS
In this open-label, phase 3 trial, we randomly assigned 305 patients who had previously untreated advanced NSCLC with PD-L1 expression on at least 50% of tumor cells and no sensitizing mutation of the epidermal growth factor receptor gene or translocation of the anaplastic lymphoma kinase gene to receive either pembrolizumab (at a fixed dose of 200 mg every 3 weeks) or the investigator’s choice of platinum-based chemotherapy. Crossover from the chemotherapy group to the pembrolizumab group was permitted in the event of disease progression. The primary end point, progression-free survival, was assessed by means of blinded, independent, central radiologic review. Secondary end points were overall survival, objective response rate, and safety.
RESULTS
Median progression-free survival was 10.3 months (95% confidence interval [CI], 6.7 to not reached) in the pembrolizumab group versus 6.0 months (95% CI, 4.2 to 6.2) in the chemotherapy group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.37 to 0.68; P<0.001). The estimated rate of overall survival at 6 months was 80.2% in the pembrolizumab group versus 72.4% in the chemotherapy group (hazard ratio for death, 0.60; 95% CI, 0.41 to 0.89; P=0.005). The response rate was higher in the pembrolizumab group than in the chemotherapy group (44.8% vs. 27.8%), the median duration of response was longer (not reached [range, 1.9+ to 14.5+ months] vs. 6.3 months [range, 2.1+ to 12.6+]), and treatment-related adverse events of any grade were less frequent (occurring in 73.4% vs. 90.0% of patients), as were grade 3, 4, or 5 treatment-related adverse events (26.6% vs. 53.3%).
CONCLUSIONS
In patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells, pembrolizumab was associated with significantly longer progression-free and overall survival and with fewer adverse events than was platinum-based chemotherapy. (Funded by Merck; KEYNOTE-024 ClinicalTrials.gov number, NCT02142738.)
Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small-Cell Lung Cancer
Martin Reck, M.D., Ph.D., Delvys Rodríguez-Abreu, M.D., Andrew G. Robinson, M.D., Rina Hui, M.B., B.S., Ph.D., Tibor Csőszi, M.D., Andrea Fülöp, M.D., Maya Gottfried, M.D., Nir Peled, M.D., Ph.D., Ali Tafreshi, M.D., Sinead Cuffe, M.D., Mary O’Brien, M.D., Suman Rao, M.D., Katsuyuki Hotta, M.D., Ph.D., Melanie A. Leiby, Ph.D., Gregory M. Lubiniecki, M.D., Yue Shentu, Ph.D., Reshma Rangwala, M.D., Ph.D., and Julie R. Brahmer, M.D., for the KEYNOTE-024 Investigators*
October 9, 2016DOI: 10.1056/NEJMoa1606774
Comments open through October 16, 2016
BACKGROUND
Pembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non–small-cell lung cancer (NSCLC), with increased activity in tumors that express programmed death ligand 1 (PD-L1).
METHODS
In this open-label, phase 3 trial, we randomly assigned 305 patients who had previously untreated advanced NSCLC with PD-L1 expression on at least 50% of tumor cells and no sensitizing mutation of the epidermal growth factor receptor gene or translocation of the anaplastic lymphoma kinase gene to receive either pembrolizumab (at a fixed dose of 200 mg every 3 weeks) or the investigator’s choice of platinum-based chemotherapy. Crossover from the chemotherapy group to the pembrolizumab group was permitted in the event of disease progression. The primary end point, progression-free survival, was assessed by means of blinded, independent, central radiologic review. Secondary end points were overall survival, objective response rate, and safety.
RESULTS
Median progression-free survival was 10.3 months (95% confidence interval [CI], 6.7 to not reached) in the pembrolizumab group versus 6.0 months (95% CI, 4.2 to 6.2) in the chemotherapy group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.37 to 0.68; P<0.001). The estimated rate of overall survival at 6 months was 80.2% in the pembrolizumab group versus 72.4% in the chemotherapy group (hazard ratio for death, 0.60; 95% CI, 0.41 to 0.89; P=0.005). The response rate was higher in the pembrolizumab group than in the chemotherapy group (44.8% vs. 27.8%), the median duration of response was longer (not reached [range, 1.9+ to 14.5+ months] vs. 6.3 months [range, 2.1+ to 12.6+]), and treatment-related adverse events of any grade were less frequent (occurring in 73.4% vs. 90.0% of patients), as were grade 3, 4, or 5 treatment-related adverse events (26.6% vs. 53.3%).
CONCLUSIONS
In patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells, pembrolizumab was associated with significantly longer progression-free and overall survival and with fewer adverse events than was platinum-based chemotherapy. (Funded by Merck; KEYNOTE-024 ClinicalTrials.gov number, NCT02142738.)
miércoles, 5 de octubre de 2016
Genomic Data Commons (GDC): Toward a Shared Vision for Cancer Genomic Data
Perspective
Toward a Shared Vision for Cancer Genomic Data
Robert L. Grossman, Ph.D., Allison P. Heath, Ph.D., Vincent Ferretti, Ph.D., Harold E. Varmus, M.D., Douglas R. Lowy, M.D., Warren A. Kibbe, Ph.D., and Louis M. Staudt, M.D., Ph.D.
N Engl J Med 2016; 375:1109-1112September 22, 2016DOI: 10.1056/NEJMp1607591
For the past 2 years, the National Cancer Institute (NCI), the University of Chicago, the Ontario Institute for Cancer Research, and Leidos Biomedical Research have been developing an information system called the NCI Genomic Data Commons (GDC) (see figureFigure 1Functionality and Utility of the National Cancer Institute Genomic Data Commons (GDC).). The GDC will initially contain raw genomic data as well as diagnostic, histologic, and clinical outcome data from NCI-funded projects such as the Cancer Genome Atlas (TCGA) and the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) program. Unlike previous versions of these data sets, the genomic data will be “harmonized” using uniform analytic pipelines to align the raw sequencing data to the genome and identify mutations, copy-number alterations, and gene-expression changes. The research community can access the GDC through an interactive portal (https://gdc-portal.nci.nih.gov), computer systems can interact through the GDC Application Programming Interface, and developers can suggest new features based on GDC open-source code.
An unusual and powerful feature of the GDC is that all researchers will be welcome to submit their cancer genomics data and use the system’s computational pipelines, as long as they agree to share their data broadly. The GDC will add value to the researcher’s own project by providing access to state-of-the-art bioinformatics tools, and the researcher’s data will incrementally increase the interpretive power of the GDC. The system enables researchers to meet the data-access standards for publication in scientific journals and the requirements of the National Institutes of Health (NIH) Genomic Data Sharing policy, and it uses the database of Genotypes and Phenotypes (dbGaP) system to ensure proper data use as specified in informed-consent documents.
Clearly, data sharing will have a pivotal role in precision oncology. A worthy goal set forth by the Institute of Medicine is to develop a new taxonomy of disease based on molecular pathogenesis. By facilitating the sharing of cancer genomic and clinical data, the GDC will gather the information needed by the research and medical community to build a new molecular taxonomy of cancer that has clinical utility. Analysis of current cancer genomic data sets suggests that we are still far from uncovering all the genetic alterations that promote malignant phenotypes, which are known as cancer “drivers.” These calculations suggest that in order to discover genes that acquire driver mutations in 2% or more of patients with cancer, more than 100,000 cancers need to be analyzed.1 The prevalence of cancer drivers follows a long-tail distribution, meaning that the driver events causing disease in many patients with cancer are not prevalent alleles, such as BRAF V600E in melanoma, but are, rather, rare alleles, many of which have not yet been described.
The need to identify such rare drivers of cancer is clear: for any given patient with cancer, detection of a rare genetic driver may be the key to successful therapy. For example, translocation and overexpression of the ROS1 gene occurs in roughly 1% of lung adenocarcinomas, and small-molecule ROS1 inhibitors can induce complete or partial responses in many affected patients.2 The co-occurrence of mutations in rare subgroups of cancers can limit the effectiveness of single targeted drugs such as vemurafenib, but in some cases the problem may be overcome by combinations of drugs.3 The clinical heterogeneity of human cancers is also driven by epigenetic diversity. For example, the response of diffuse large B-cell lymphomas to targeted agents can be predicted by gene-expression profiles.4 Hence, multiple genomic methods are required to provide a molecular description of cancer that has maximum clinical import.
From the inception of cancer genomics, the value of data sharing has been evident. First, the complexity of genomic data inevitably means that only a fraction of the insights inherent in the data can be reported in any one publication. Second, researchers cannot realistically generate within any one project all the genomic data necessary to draw important conclusions, but they can enrich their study by reusing genomic data from other projects.
However, a major challenge for researchers working with cancer genomic data sets is their sheer size. The TCGA data set alone is over a petabyte in size and consists of more than 575,000 files. Just to download the data using a 10-Gbit-per-second connection would take over 3 weeks. Setting up a secure, compliant infrastructure of sufficient scale to store and analyze the data is not only technically challenging, but also expensive. In 2016, the computing equipment required to analyze the raw TCGA sequencing data costs over $1 million, not including the cost of systems maintenance, security, and compliance that are necessary when working with human genomic and clinical data. The GDC addresses these logistic and economic barriers by democratizing access to cancer genomics data, enabling researchers to bring their hypotheses to the data.
The recent explosion of cancer genome analysis has left in its wake a trail of data ambiguity that must be addressed and rectified. Often, genomic studies are published without the authors’ providing raw sequencing data in a public repository, making it impossible to judge the validity of the reported genetic aberrations. Identifying somatic genetic alterations in cancer samples is challenging because of variable contributions of nonmalignant cells, changes in gene copy number, and the presence of tumor subclones. Similarly, the description of copy-number alterations and the quantification of gene expression have not been standardized, posing a problem for researchers trying to compare data from different studies. The GDC addresses these issues by using a harmonization process in which raw sequencing reads are processed through uniform analytic pipelines, and it provides results from multiple analytic methods when there is no single standard. As the human genome sequence is further refined and annotated, and as better analytic pipelines are developed, the GDC will reharmonize its entire genomic content.
The GDC is the foundation of a multiyear NCI effort to foster a new molecular taxonomy of cancer that provides prognostic information and predicts response or resistance to particular therapies. This project will require the curation of data from clinical trials with embedded genomics and from laboratory experiments that assign biologic phenotypes to particular cancer variants, as well as the development of new methods for integrating multiple clinical and molecular data types. Achievement of this goal will be greatly facilitated by genomic data sharing through the GDC, which will be required for all researchers supported by the NCI and should prove attractive to any investigator whose research would benefit from GDC tools. The genomic and clinical data from NCI-sponsored precision-medicine trials such as the NCI Molecular Analysis for Therapy Choice (MATCH) study will be shared through the GDC, allowing researchers to discern the molecular basis of response and resistance to the many targeted agents being investigated.
The NCI expects investigators to share clinical trial data as outlined in a recent editorial5 and believes that the GDC will be an appropriate venue for sharing data from NCI-supported clinical trials. As the number of cases in the GDC grows, GDC data could provide evidence of drugs working in cancer subtypes that are too rare to be discerned in smaller clinical trial cohorts.
The GDC could expand rapidly as the acquisition of genomic data becomes routine in the course of cancer care. In time, it may be possible for individual patients to become “cancer information donors” and allow their genomic data to be shared through the GDC. Mechanisms for enabling such donation are being developed under the NIH Precision Medicine Initiative Cohort program. Given appropriate informed-consent systems, the GDC could identify patients with rare molecular subtypes of cancer who could be contacted for potential participation in clinical trials appropriate for their particular cancer.
Clearly, the principles and practice of precision oncology will be accelerated by sharing data from thousands of patients with cancer. We hope that the GDC will be embraced by researchers, clinicians, regulatory agencies, patients, and other interested parties as a means to achieve this goal.
Disclosure forms provided by the authors are available at NEJM.org.
Source Information
From the Center for Data Intensive Science, University of Chicago, Chicago (R.L.G., A.P.H.); the Ontario Institute for Cancer Research, Toronto (V.F.); Weill Cornell Medicine, Cornell University, New York (H.E.V.); and the National Cancer Institute, Bethesda, MD (D.R.L., W.A.K., L.M.S.).
Toward a Shared Vision for Cancer Genomic Data
Robert L. Grossman, Ph.D., Allison P. Heath, Ph.D., Vincent Ferretti, Ph.D., Harold E. Varmus, M.D., Douglas R. Lowy, M.D., Warren A. Kibbe, Ph.D., and Louis M. Staudt, M.D., Ph.D.
N Engl J Med 2016; 375:1109-1112September 22, 2016DOI: 10.1056/NEJMp1607591
For the past 2 years, the National Cancer Institute (NCI), the University of Chicago, the Ontario Institute for Cancer Research, and Leidos Biomedical Research have been developing an information system called the NCI Genomic Data Commons (GDC) (see figureFigure 1Functionality and Utility of the National Cancer Institute Genomic Data Commons (GDC).). The GDC will initially contain raw genomic data as well as diagnostic, histologic, and clinical outcome data from NCI-funded projects such as the Cancer Genome Atlas (TCGA) and the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) program. Unlike previous versions of these data sets, the genomic data will be “harmonized” using uniform analytic pipelines to align the raw sequencing data to the genome and identify mutations, copy-number alterations, and gene-expression changes. The research community can access the GDC through an interactive portal (https://gdc-portal.nci.nih.gov), computer systems can interact through the GDC Application Programming Interface, and developers can suggest new features based on GDC open-source code.
An unusual and powerful feature of the GDC is that all researchers will be welcome to submit their cancer genomics data and use the system’s computational pipelines, as long as they agree to share their data broadly. The GDC will add value to the researcher’s own project by providing access to state-of-the-art bioinformatics tools, and the researcher’s data will incrementally increase the interpretive power of the GDC. The system enables researchers to meet the data-access standards for publication in scientific journals and the requirements of the National Institutes of Health (NIH) Genomic Data Sharing policy, and it uses the database of Genotypes and Phenotypes (dbGaP) system to ensure proper data use as specified in informed-consent documents.
Clearly, data sharing will have a pivotal role in precision oncology. A worthy goal set forth by the Institute of Medicine is to develop a new taxonomy of disease based on molecular pathogenesis. By facilitating the sharing of cancer genomic and clinical data, the GDC will gather the information needed by the research and medical community to build a new molecular taxonomy of cancer that has clinical utility. Analysis of current cancer genomic data sets suggests that we are still far from uncovering all the genetic alterations that promote malignant phenotypes, which are known as cancer “drivers.” These calculations suggest that in order to discover genes that acquire driver mutations in 2% or more of patients with cancer, more than 100,000 cancers need to be analyzed.1 The prevalence of cancer drivers follows a long-tail distribution, meaning that the driver events causing disease in many patients with cancer are not prevalent alleles, such as BRAF V600E in melanoma, but are, rather, rare alleles, many of which have not yet been described.
The need to identify such rare drivers of cancer is clear: for any given patient with cancer, detection of a rare genetic driver may be the key to successful therapy. For example, translocation and overexpression of the ROS1 gene occurs in roughly 1% of lung adenocarcinomas, and small-molecule ROS1 inhibitors can induce complete or partial responses in many affected patients.2 The co-occurrence of mutations in rare subgroups of cancers can limit the effectiveness of single targeted drugs such as vemurafenib, but in some cases the problem may be overcome by combinations of drugs.3 The clinical heterogeneity of human cancers is also driven by epigenetic diversity. For example, the response of diffuse large B-cell lymphomas to targeted agents can be predicted by gene-expression profiles.4 Hence, multiple genomic methods are required to provide a molecular description of cancer that has maximum clinical import.
From the inception of cancer genomics, the value of data sharing has been evident. First, the complexity of genomic data inevitably means that only a fraction of the insights inherent in the data can be reported in any one publication. Second, researchers cannot realistically generate within any one project all the genomic data necessary to draw important conclusions, but they can enrich their study by reusing genomic data from other projects.
However, a major challenge for researchers working with cancer genomic data sets is their sheer size. The TCGA data set alone is over a petabyte in size and consists of more than 575,000 files. Just to download the data using a 10-Gbit-per-second connection would take over 3 weeks. Setting up a secure, compliant infrastructure of sufficient scale to store and analyze the data is not only technically challenging, but also expensive. In 2016, the computing equipment required to analyze the raw TCGA sequencing data costs over $1 million, not including the cost of systems maintenance, security, and compliance that are necessary when working with human genomic and clinical data. The GDC addresses these logistic and economic barriers by democratizing access to cancer genomics data, enabling researchers to bring their hypotheses to the data.
The recent explosion of cancer genome analysis has left in its wake a trail of data ambiguity that must be addressed and rectified. Often, genomic studies are published without the authors’ providing raw sequencing data in a public repository, making it impossible to judge the validity of the reported genetic aberrations. Identifying somatic genetic alterations in cancer samples is challenging because of variable contributions of nonmalignant cells, changes in gene copy number, and the presence of tumor subclones. Similarly, the description of copy-number alterations and the quantification of gene expression have not been standardized, posing a problem for researchers trying to compare data from different studies. The GDC addresses these issues by using a harmonization process in which raw sequencing reads are processed through uniform analytic pipelines, and it provides results from multiple analytic methods when there is no single standard. As the human genome sequence is further refined and annotated, and as better analytic pipelines are developed, the GDC will reharmonize its entire genomic content.
The GDC is the foundation of a multiyear NCI effort to foster a new molecular taxonomy of cancer that provides prognostic information and predicts response or resistance to particular therapies. This project will require the curation of data from clinical trials with embedded genomics and from laboratory experiments that assign biologic phenotypes to particular cancer variants, as well as the development of new methods for integrating multiple clinical and molecular data types. Achievement of this goal will be greatly facilitated by genomic data sharing through the GDC, which will be required for all researchers supported by the NCI and should prove attractive to any investigator whose research would benefit from GDC tools. The genomic and clinical data from NCI-sponsored precision-medicine trials such as the NCI Molecular Analysis for Therapy Choice (MATCH) study will be shared through the GDC, allowing researchers to discern the molecular basis of response and resistance to the many targeted agents being investigated.
The NCI expects investigators to share clinical trial data as outlined in a recent editorial5 and believes that the GDC will be an appropriate venue for sharing data from NCI-supported clinical trials. As the number of cases in the GDC grows, GDC data could provide evidence of drugs working in cancer subtypes that are too rare to be discerned in smaller clinical trial cohorts.
The GDC could expand rapidly as the acquisition of genomic data becomes routine in the course of cancer care. In time, it may be possible for individual patients to become “cancer information donors” and allow their genomic data to be shared through the GDC. Mechanisms for enabling such donation are being developed under the NIH Precision Medicine Initiative Cohort program. Given appropriate informed-consent systems, the GDC could identify patients with rare molecular subtypes of cancer who could be contacted for potential participation in clinical trials appropriate for their particular cancer.
Clearly, the principles and practice of precision oncology will be accelerated by sharing data from thousands of patients with cancer. We hope that the GDC will be embraced by researchers, clinicians, regulatory agencies, patients, and other interested parties as a means to achieve this goal.
Disclosure forms provided by the authors are available at NEJM.org.
Source Information
From the Center for Data Intensive Science, University of Chicago, Chicago (R.L.G., A.P.H.); the Ontario Institute for Cancer Research, Toronto (V.F.); Weill Cornell Medicine, Cornell University, New York (H.E.V.); and the National Cancer Institute, Bethesda, MD (D.R.L., W.A.K., L.M.S.).
Prostate Cancer: Patient-Reported Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer
Original Article
Patient-Reported Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer
Jenny L. Donovan, Ph.D., F.Med.Sci., Freddie C. Hamdy, F.R.C.S.(Urol.), F.Med.Sci., J. Athene Lane, Ph.D., Malcolm Mason, M.D., Chris Metcalfe, Ph.D., Eleanor Walsh, M.Sc., Jane M. Blazeby, Ph.D., F.R.C.S., Tim J. Peters, Ph.D., F.Med.Sci., Peter Holding, R.G.N., Susan Bonnington, R.G.N., Teresa Lennon, R.G.N., Lynne Bradshaw, R.G.N., Deborah Cooper, R.G.N., Phillipa Herbert, R.G.N., Joanne Howson, R.G.N., Amanda Jones, R.G.N., Norma Lyons, R.G.N., Elizabeth Salter, R.G.N., Pauline Thompson, R.G.N., Sarah Tidball, R.G.N., Jan Blaikie, R.G.N., Catherine Gray, R.G.N., Prasad Bollina, M.B., B.S., F.R.C.S.(Urol.), James Catto, Ph.D., F.R.C.S.(Urol.), Andrew Doble, M.S., F.R.C.S.(Urol.), Alan Doherty, F.R.C.S.(Urol.), David Gillatt, M.S., F.R.C.S.(Urol.), Roger Kockelbergh, D.M., F.R.C.S.(Urol.), Howard Kynaston, M.D., F.R.C.S.(Urol.), Alan Paul, M.D., F.R.C.S.(Urol.), Philip Powell, M.D., F.R.C.S.(Urol.), Stephen Prescott, M.D., F.R.C.S.(Urol.), Derek J. Rosario, M.D., F.R.C.S.(Urol.), Edward Rowe, M.D., F.R.C.S.(Urol.), Michael Davis, M.Sc., Emma L. Turner, Ph.D., Richard M. Martin, Ph.D., and David E. Neal, F.R.C.S., F.Med.Sci., for the ProtecT Study Group*
September 14, 2016DOI: 10.1056/NEJMoa1606221
Background
Robust data on patient-reported outcome measures comparing treatments for clinically localized prostate cancer are lacking. We investigated the effects of active monitoring, radical prostatectomy, and radical radiotherapy with hormones on patient-reported outcomes.
Methods
We compared patient-reported outcomes among 1643 men in the Prostate Testing for Cancer and Treatment (ProtecT) trial who completed questionnaires before diagnosis, at 6 and 12 months after randomization, and annually thereafter. Patients completed validated measures that assessed urinary, bowel, and sexual function and specific effects on quality of life, anxiety and depression, and general health. Cancer-related quality of life was assessed at 5 years. Complete 6-year data were analyzed according to the intention-to-treat principle.
Results
The rate of questionnaire completion during follow-up was higher than 85% for most measures. Of the three treatments, prostatectomy had the greatest negative effect on sexual function and urinary continence, and although there was some recovery, these outcomes remained worse in the prostatectomy group than in the other groups throughout the trial. The negative effect of radiotherapy on sexual function was greatest at 6 months, but sexual function then recovered somewhat and was stable thereafter; radiotherapy had little effect on urinary continence. Sexual and urinary function declined gradually in the active-monitoring group. Bowel function was worse in the radiotherapy group at 6 months than in the other groups but then recovered somewhat, except for the increasing frequency of bloody stools; bowel function was unchanged in the other groups. Urinary voiding and nocturia were worse in the radiotherapy group at 6 months but then mostly recovered and were similar to the other groups after 12 months. Effects on quality of life mirrored the reported changes in function. No significant differences were observed among the groups in measures of anxiety, depression, or general health-related or cancer-related quality of life.
Conclusions
In this analysis of patient-reported outcomes after treatment for localized prostate cancer, patterns of severity, recovery, and decline in urinary, bowel, and sexual function and associated quality of life differed among the three groups. (Funded by the U.K. National Institute for Health Research Health Technology Assessment Program; ProtecT Current Controlled Trials number, ISRCTN20141297; ClinicalTrials.gov number, NCT02044172.)
Patient-Reported Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer
Jenny L. Donovan, Ph.D., F.Med.Sci., Freddie C. Hamdy, F.R.C.S.(Urol.), F.Med.Sci., J. Athene Lane, Ph.D., Malcolm Mason, M.D., Chris Metcalfe, Ph.D., Eleanor Walsh, M.Sc., Jane M. Blazeby, Ph.D., F.R.C.S., Tim J. Peters, Ph.D., F.Med.Sci., Peter Holding, R.G.N., Susan Bonnington, R.G.N., Teresa Lennon, R.G.N., Lynne Bradshaw, R.G.N., Deborah Cooper, R.G.N., Phillipa Herbert, R.G.N., Joanne Howson, R.G.N., Amanda Jones, R.G.N., Norma Lyons, R.G.N., Elizabeth Salter, R.G.N., Pauline Thompson, R.G.N., Sarah Tidball, R.G.N., Jan Blaikie, R.G.N., Catherine Gray, R.G.N., Prasad Bollina, M.B., B.S., F.R.C.S.(Urol.), James Catto, Ph.D., F.R.C.S.(Urol.), Andrew Doble, M.S., F.R.C.S.(Urol.), Alan Doherty, F.R.C.S.(Urol.), David Gillatt, M.S., F.R.C.S.(Urol.), Roger Kockelbergh, D.M., F.R.C.S.(Urol.), Howard Kynaston, M.D., F.R.C.S.(Urol.), Alan Paul, M.D., F.R.C.S.(Urol.), Philip Powell, M.D., F.R.C.S.(Urol.), Stephen Prescott, M.D., F.R.C.S.(Urol.), Derek J. Rosario, M.D., F.R.C.S.(Urol.), Edward Rowe, M.D., F.R.C.S.(Urol.), Michael Davis, M.Sc., Emma L. Turner, Ph.D., Richard M. Martin, Ph.D., and David E. Neal, F.R.C.S., F.Med.Sci., for the ProtecT Study Group*
September 14, 2016DOI: 10.1056/NEJMoa1606221
Background
Robust data on patient-reported outcome measures comparing treatments for clinically localized prostate cancer are lacking. We investigated the effects of active monitoring, radical prostatectomy, and radical radiotherapy with hormones on patient-reported outcomes.
Methods
We compared patient-reported outcomes among 1643 men in the Prostate Testing for Cancer and Treatment (ProtecT) trial who completed questionnaires before diagnosis, at 6 and 12 months after randomization, and annually thereafter. Patients completed validated measures that assessed urinary, bowel, and sexual function and specific effects on quality of life, anxiety and depression, and general health. Cancer-related quality of life was assessed at 5 years. Complete 6-year data were analyzed according to the intention-to-treat principle.
Results
The rate of questionnaire completion during follow-up was higher than 85% for most measures. Of the three treatments, prostatectomy had the greatest negative effect on sexual function and urinary continence, and although there was some recovery, these outcomes remained worse in the prostatectomy group than in the other groups throughout the trial. The negative effect of radiotherapy on sexual function was greatest at 6 months, but sexual function then recovered somewhat and was stable thereafter; radiotherapy had little effect on urinary continence. Sexual and urinary function declined gradually in the active-monitoring group. Bowel function was worse in the radiotherapy group at 6 months than in the other groups but then recovered somewhat, except for the increasing frequency of bloody stools; bowel function was unchanged in the other groups. Urinary voiding and nocturia were worse in the radiotherapy group at 6 months but then mostly recovered and were similar to the other groups after 12 months. Effects on quality of life mirrored the reported changes in function. No significant differences were observed among the groups in measures of anxiety, depression, or general health-related or cancer-related quality of life.
Conclusions
In this analysis of patient-reported outcomes after treatment for localized prostate cancer, patterns of severity, recovery, and decline in urinary, bowel, and sexual function and associated quality of life differed among the three groups. (Funded by the U.K. National Institute for Health Research Health Technology Assessment Program; ProtecT Current Controlled Trials number, ISRCTN20141297; ClinicalTrials.gov number, NCT02044172.)
Localized Prostate Cancer: 10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer. NEJM
Original Article
10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer
Freddie C. Hamdy, F.R.C.S.(Urol.), F.Med.Sci., Jenny L. Donovan, Ph.D., F.Med.Sci., J. Athene Lane, Ph.D., Malcolm Mason, M.D., F.R.C.R., Chris Metcalfe, Ph.D., Peter Holding, R.G.N., M.Sc., Michael Davis, M.Sc., Tim J. Peters, Ph.D., F.Med.Sci., Emma L. Turner, Ph.D., Richard M. Martin, Ph.D., Jon Oxley, M.D., F.R.C.Path., Mary Robinson, M.B., B.S., F.R.C.Path., John Staffurth, M.B., B.S., M.D., Eleanor Walsh, M.Sc., Prasad Bollina, M.B., B.S., F.R.C.S.(Urol.), James Catto, Ph.D., F.R.C.S.(Urol.), Andrew Doble, M.S., F.R.C.S.(Urol.), Alan Doherty, F.R.C.S.(Urol.), David Gillatt, M.S., F.R.C.S.(Urol.), Roger Kockelbergh, D.M., F.R.C.S.(Urol.), Howard Kynaston, M.D., F.R.C.S.(Urol.), Alan Paul, M.D., F.R.C.S.(Urol.), Philip Powell, M.D., F.R.C.S., Stephen Prescott, M.D., F.R.C.S.(Urol.), Derek J. Rosario, M.D., F.R.C.S.(Urol.), Edward Rowe, M.D., F.R.C.S.(Urol.), and David E. Neal, F.R.C.S., F.Med.Sci., for the ProtecT Study Group*
September 14, 2016DOI: 10.1056/NEJMoa1606220
Background
The comparative effectiveness of treatments for prostate cancer that is detected by prostate-specific antigen (PSA) testing remains uncertain.
Methods
We compared active monitoring, radical prostatectomy, and external-beam radiotherapy for the treatment of clinically localized prostate cancer. Between 1999 and 2009, a total of 82,429 men 50 to 69 years of age received a PSA test; 2664 received a diagnosis of localized prostate cancer, and 1643 agreed to undergo randomization to active monitoring (545 men), surgery (553), or radiotherapy (545). The primary outcome was prostate-cancer mortality at a median of 10 years of follow-up. Secondary outcomes included the rates of disease progression, metastases, and all-cause deaths.
Results
There were 17 prostate-cancer–specific deaths overall: 8 in the active-monitoring group (1.5 deaths per 1000 person-years; 95% confidence interval [CI], 0.7 to 3.0), 5 in the surgery group (0.9 per 1000 person-years; 95% CI, 0.4 to 2.2), and 4 in the radiotherapy group (0.7 per 1000 person-years; 95% CI, 0.3 to 2.0); the difference among the groups was not significant (P=0.48 for the overall comparison). In addition, no significant difference was seen among the groups in the number of deaths from any cause (169 deaths overall; P=0.87 for the comparison among the three groups). Metastases developed in more men in the active-monitoring group (33 men; 6.3 events per 1000 person-years; 95% CI, 4.5 to 8.8) than in the surgery group (13 men; 2.4 per 1000 person-years; 95% CI, 1.4 to 4.2) or the radiotherapy group (16 men; 3.0 per 1000 person-years; 95% CI, 1.9 to 4.9) (P=0.004 for the overall comparison). Higher rates of disease progression were seen in the active-monitoring group (112 men; 22.9 events per 1000 person-years; 95% CI, 19.0 to 27.5) than in the surgery group (46 men; 8.9 events per 1000 person-years; 95% CI, 6.7 to 11.9) or the radiotherapy group (46 men; 9.0 events per 1000 person-years; 95% CI, 6.7 to 12.0) (P<0.001 for the overall comparison). Conclusions
At a median of 10 years, prostate-cancer–specific mortality was low irrespective of the treatment assigned, with no significant difference among treatments. Surgery and radiotherapy were associated with lower incidences of disease progression and metastases than was active monitoring. (Funded by the National Institute for Health Research; Current Controlled Trials number, ISRCTN20141297; ClinicalTrials.gov number, NCT02044172.)
10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer
Freddie C. Hamdy, F.R.C.S.(Urol.), F.Med.Sci., Jenny L. Donovan, Ph.D., F.Med.Sci., J. Athene Lane, Ph.D., Malcolm Mason, M.D., F.R.C.R., Chris Metcalfe, Ph.D., Peter Holding, R.G.N., M.Sc., Michael Davis, M.Sc., Tim J. Peters, Ph.D., F.Med.Sci., Emma L. Turner, Ph.D., Richard M. Martin, Ph.D., Jon Oxley, M.D., F.R.C.Path., Mary Robinson, M.B., B.S., F.R.C.Path., John Staffurth, M.B., B.S., M.D., Eleanor Walsh, M.Sc., Prasad Bollina, M.B., B.S., F.R.C.S.(Urol.), James Catto, Ph.D., F.R.C.S.(Urol.), Andrew Doble, M.S., F.R.C.S.(Urol.), Alan Doherty, F.R.C.S.(Urol.), David Gillatt, M.S., F.R.C.S.(Urol.), Roger Kockelbergh, D.M., F.R.C.S.(Urol.), Howard Kynaston, M.D., F.R.C.S.(Urol.), Alan Paul, M.D., F.R.C.S.(Urol.), Philip Powell, M.D., F.R.C.S., Stephen Prescott, M.D., F.R.C.S.(Urol.), Derek J. Rosario, M.D., F.R.C.S.(Urol.), Edward Rowe, M.D., F.R.C.S.(Urol.), and David E. Neal, F.R.C.S., F.Med.Sci., for the ProtecT Study Group*
September 14, 2016DOI: 10.1056/NEJMoa1606220
Background
The comparative effectiveness of treatments for prostate cancer that is detected by prostate-specific antigen (PSA) testing remains uncertain.
Methods
We compared active monitoring, radical prostatectomy, and external-beam radiotherapy for the treatment of clinically localized prostate cancer. Between 1999 and 2009, a total of 82,429 men 50 to 69 years of age received a PSA test; 2664 received a diagnosis of localized prostate cancer, and 1643 agreed to undergo randomization to active monitoring (545 men), surgery (553), or radiotherapy (545). The primary outcome was prostate-cancer mortality at a median of 10 years of follow-up. Secondary outcomes included the rates of disease progression, metastases, and all-cause deaths.
Results
There were 17 prostate-cancer–specific deaths overall: 8 in the active-monitoring group (1.5 deaths per 1000 person-years; 95% confidence interval [CI], 0.7 to 3.0), 5 in the surgery group (0.9 per 1000 person-years; 95% CI, 0.4 to 2.2), and 4 in the radiotherapy group (0.7 per 1000 person-years; 95% CI, 0.3 to 2.0); the difference among the groups was not significant (P=0.48 for the overall comparison). In addition, no significant difference was seen among the groups in the number of deaths from any cause (169 deaths overall; P=0.87 for the comparison among the three groups). Metastases developed in more men in the active-monitoring group (33 men; 6.3 events per 1000 person-years; 95% CI, 4.5 to 8.8) than in the surgery group (13 men; 2.4 per 1000 person-years; 95% CI, 1.4 to 4.2) or the radiotherapy group (16 men; 3.0 per 1000 person-years; 95% CI, 1.9 to 4.9) (P=0.004 for the overall comparison). Higher rates of disease progression were seen in the active-monitoring group (112 men; 22.9 events per 1000 person-years; 95% CI, 19.0 to 27.5) than in the surgery group (46 men; 8.9 events per 1000 person-years; 95% CI, 6.7 to 11.9) or the radiotherapy group (46 men; 9.0 events per 1000 person-years; 95% CI, 6.7 to 12.0) (P<0.001 for the overall comparison). Conclusions
At a median of 10 years, prostate-cancer–specific mortality was low irrespective of the treatment assigned, with no significant difference among treatments. Surgery and radiotherapy were associated with lower incidences of disease progression and metastases than was active monitoring. (Funded by the National Institute for Health Research; Current Controlled Trials number, ISRCTN20141297; ClinicalTrials.gov number, NCT02044172.)
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