Nature Reviews Clinical Oncology | Perspectives | Opinion
Can advanced-stage ovarian cancer be cured?
Steven Narod Nature Reviews Clinical Oncology 13,255–261(2016)doi:10.1038/nrclinonc.2015.224
Abstract
Approximately 20% of women with advanced-stage ovarian cancer survive beyond 12 years after treatment and are effectively cured. Initial therapy for ovarian cancer comprises surgery and chemotherapy, and is given with the goal of eradicating as many cancer cells as possible.
Indeed, the three phases of therapy are as follows: debulking surgery to remove as much of the cancer as possible, preferably to a state of no visible residual disease; chemotherapy to eradicate any microscopic disease that remains present after surgery; and second-line or maintenance therapy, which is given to delay disease progression among patients with tumour recurrence.
If no cancer cells remain after initial therapy is completed, a cure is expected. By contrast, if residual cancer cells are present after initial treatment, then disease recurrence is likely.
Thus, the probability of cure is contingent on the combination of surgery and chemotherapy effectively eliminating all cancer cells. In this Perspectives article, I present the case that the probability of achieving a cancer-free state is maximized through a combination of maximal debulking surgery and intraperitoneal chemotherapy.
I discuss the evidence indicating that by taking this approach, cures could be achieved in up to 50% of women with advanced-stage ovarian cancer.
lunes, 28 de marzo de 2016
Gleason score at initial diagnosis and the efficacy of abiraterone acetate
Does Gleason score at initial diagnosis predict efficacy of abiraterone acetate therapy in patients with metastatic castration-resistant prostate cancer? An analysis of abiraterone acetate phase III trials
K. Fizazi1,*, T. W. Flaig2, M. Stöckle3, H. I. Scher4, J. S. de Bono5, D. E. Rathkopf4, C. J. Ryan6, T. Kheoh7, J. Li8, M. B. Todd9, T. W. Griffin10, A. Molina11 and C. H. Ohlmann3
↵*Correspondence to: Prof. Karim Fizazi, Department of Cancer Medicine, Institut Gustave Roussy, 114 Rue Edouard Vaillant, 94800 Villejuif, France. Tel: +33-1-42-11-43-17; E-mail: karim.fizazi@igr.fr
Abstract
Background The usefulness of Gleason score (<8 or ≥8) at initial diagnosis as a predictive marker of response to abiraterone acetate (AA) plus prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) was explored retrospectively.
Patients and Methods
Initial diagnosis Gleason score was obtained in 1048 of 1195 (COU-AA-301, post-docetaxel) and 996 of 1088 (COU-AA-302, chemotherapy-naïve) patients treated with AA 1 g plus prednisone 5 mg twice daily by mouth or placebo plus prednisone. Efficacy end points included radiographic progression-free survival (rPFS) and overall survival (OS). Distributions and medians were estimated by Kaplan–Meier method and hazard ratio (HR) and 95% confidence interval (CI) by Cox model.
Results
Baseline characteristics were similar across studies and treatment groups. Regardless of Gleason score, AA treatment significantly improved rPFS in post-docetaxel [Gleason score <8: median, 6.4 versus 5.5 months (HR = 0.70; 95% CI 0.56–0.86), P = 0.0009 and Gleason score ≥8: median, 5.6 versus 2.9 months (HR = 0.58; 95% CI 0.48–0.72), P < 0.0001] and chemotherapy-naïve patients [Gleason score <8: median, 16.5 versus 8.2 months (HR = 0.50; 95% CI 0.40–0.62), P < 0.0001 and Gleason score ≥8: median, 13.8 versus 8.2 months (HR = 0.61; 95% CI 0.49–0.76), P < 0.0001]. Clinical benefit of AA treatment was also observed for OS, prostate-specific antigen (PSA) response, objective response and time to PSA progression across studies and Gleason score subgroups. Conclusion
OS and rPFS trends demonstrate AA treatment benefit in patients with pre- or post-chemotherapy mCRPC regardless of Gleason score at initial diagnosis. The initial diagnostic Gleason score in patients with mCRPC should not be considered in the decision to treat with AA, as tumour metastases may no longer reflect the histology at the time of diagnosis.
Clinical trials number COU-AA-301 (NCT00638690); COU-AA-302 (NCT00887198).
K. Fizazi1,*, T. W. Flaig2, M. Stöckle3, H. I. Scher4, J. S. de Bono5, D. E. Rathkopf4, C. J. Ryan6, T. Kheoh7, J. Li8, M. B. Todd9, T. W. Griffin10, A. Molina11 and C. H. Ohlmann3
↵*Correspondence to: Prof. Karim Fizazi, Department of Cancer Medicine, Institut Gustave Roussy, 114 Rue Edouard Vaillant, 94800 Villejuif, France. Tel: +33-1-42-11-43-17; E-mail: karim.fizazi@igr.fr
Abstract
Background The usefulness of Gleason score (<8 or ≥8) at initial diagnosis as a predictive marker of response to abiraterone acetate (AA) plus prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) was explored retrospectively.
Patients and Methods
Initial diagnosis Gleason score was obtained in 1048 of 1195 (COU-AA-301, post-docetaxel) and 996 of 1088 (COU-AA-302, chemotherapy-naïve) patients treated with AA 1 g plus prednisone 5 mg twice daily by mouth or placebo plus prednisone. Efficacy end points included radiographic progression-free survival (rPFS) and overall survival (OS). Distributions and medians were estimated by Kaplan–Meier method and hazard ratio (HR) and 95% confidence interval (CI) by Cox model.
Results
Baseline characteristics were similar across studies and treatment groups. Regardless of Gleason score, AA treatment significantly improved rPFS in post-docetaxel [Gleason score <8: median, 6.4 versus 5.5 months (HR = 0.70; 95% CI 0.56–0.86), P = 0.0009 and Gleason score ≥8: median, 5.6 versus 2.9 months (HR = 0.58; 95% CI 0.48–0.72), P < 0.0001] and chemotherapy-naïve patients [Gleason score <8: median, 16.5 versus 8.2 months (HR = 0.50; 95% CI 0.40–0.62), P < 0.0001 and Gleason score ≥8: median, 13.8 versus 8.2 months (HR = 0.61; 95% CI 0.49–0.76), P < 0.0001]. Clinical benefit of AA treatment was also observed for OS, prostate-specific antigen (PSA) response, objective response and time to PSA progression across studies and Gleason score subgroups. Conclusion
OS and rPFS trends demonstrate AA treatment benefit in patients with pre- or post-chemotherapy mCRPC regardless of Gleason score at initial diagnosis. The initial diagnostic Gleason score in patients with mCRPC should not be considered in the decision to treat with AA, as tumour metastases may no longer reflect the histology at the time of diagnosis.
Clinical trials number COU-AA-301 (NCT00638690); COU-AA-302 (NCT00887198).
domingo, 27 de marzo de 2016
Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cance
Volume 387, No. 10024, p1163–1177, 19 March 2016
Articles
Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial
Prof Nicholas D James, PhD, Matthew R Sydes, MSccorrespondenceemail, Prof Noel W Clarke, ChM, Prof Malcolm D Mason, MD, Prof David P Dearnaley, MD, Melissa R Spears, MSc, Alastair W S Ritchie, MD, Christopher C Parker, MD, J Martin Russell, FRCR, Gerhardt Attard, MD PhD, Prof Johann de Bono, PhD, William Cross, PhD, Prof Rob J Jones, PhD, Prof George Thalmann, MD, Claire Amos, PhD, David Matheson, PhD, Robin Millman, Mymoona Alzouebi, FRCR, Sharon Beesley, FRCR, Alison J Birtle, MD, Susannah Brock, FRCR, Richard Cathomas, MD, Prabir Chakraborti, FRCR, Simon Chowdhury, MD, Audrey Cook, FRCR, Tony Elliott, PhD, Joanna Gale, DM, Stephanie Gibbs, FRCR, John D Graham, FRCP, John Hetherington, FRCS[Eng], Robert Hughes, FRCR, Robert Laing, FRCR, Fiona McKinna, FRCR, Duncan B McLaren, FRCR, FRCP[Ed], Prof Joe M O'Sullivan, MD, Omi Parikh, FRCR, Clive Peedell, FRCR, Andrew Protheroe, PhD, Angus J Robinson, FRCR, Narayanan Srihari, MD, Rajaguru Srinivasan, FRCR, John Staffurth, MD, Santhanam Sundar, FRCR, Shaun Tolan, MD, David Tsang, MCRP, Prof John Wagstaff, MD, Prof Mahesh K B Parmar, DPhil for the STAMPEDE investigators†
†Members listed at end of paper
Show all authors
Published Online: 21 December 2015
Summary
Background
Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone.
Methods
Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m2) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544).
Findings
2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60–71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23–184). Median follow-up was 43 months (IQR 30–60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79–1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66–0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69–0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3–5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc.
Interpretation
Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy.
Articles
Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial
Prof Nicholas D James, PhD, Matthew R Sydes, MSccorrespondenceemail, Prof Noel W Clarke, ChM, Prof Malcolm D Mason, MD, Prof David P Dearnaley, MD, Melissa R Spears, MSc, Alastair W S Ritchie, MD, Christopher C Parker, MD, J Martin Russell, FRCR, Gerhardt Attard, MD PhD, Prof Johann de Bono, PhD, William Cross, PhD, Prof Rob J Jones, PhD, Prof George Thalmann, MD, Claire Amos, PhD, David Matheson, PhD, Robin Millman, Mymoona Alzouebi, FRCR, Sharon Beesley, FRCR, Alison J Birtle, MD, Susannah Brock, FRCR, Richard Cathomas, MD, Prabir Chakraborti, FRCR, Simon Chowdhury, MD, Audrey Cook, FRCR, Tony Elliott, PhD, Joanna Gale, DM, Stephanie Gibbs, FRCR, John D Graham, FRCP, John Hetherington, FRCS[Eng], Robert Hughes, FRCR, Robert Laing, FRCR, Fiona McKinna, FRCR, Duncan B McLaren, FRCR, FRCP[Ed], Prof Joe M O'Sullivan, MD, Omi Parikh, FRCR, Clive Peedell, FRCR, Andrew Protheroe, PhD, Angus J Robinson, FRCR, Narayanan Srihari, MD, Rajaguru Srinivasan, FRCR, John Staffurth, MD, Santhanam Sundar, FRCR, Shaun Tolan, MD, David Tsang, MCRP, Prof John Wagstaff, MD, Prof Mahesh K B Parmar, DPhil for the STAMPEDE investigators†
†Members listed at end of paper
Show all authors
Published Online: 21 December 2015
Summary
Background
Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone.
Methods
Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m2) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544).
Findings
2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60–71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23–184). Median follow-up was 43 months (IQR 30–60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79–1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66–0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69–0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3–5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc.
Interpretation
Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy.
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