- Email: [email protected]
Effect of docetaxel on safety and efficacy of radium-223
Comment
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Bajetta E, Floriani I, Di Bartolomeo M, et al. Randomized trial on adjuvant treatment with FOLFIRI followed by docetaxel and cisplatin versus 5-fluorouracil and folinic acid for radically resected gastric cancer. Ann Oncol 2014; 25: 1373–88. Tsuburaya A, Yoshida K, Kobayashi M, et al. Sequential paclitaxel followed by tegafur and uracil (UFT) or S-1 versus UFT or S-1 monotherapy as adjuvant chemotherapy for T4a/b gastric cancer (SAMIT): a phase 3 factorial randomised controlled trial. Lancet Oncol 2014; 15: 886–93. Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001; 345: 725–30.
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10
Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006; 355: 11–20. GASTRIC Group, Paoletti X, Oba K, Burzykowski T, et al. Benefit of adjuvant chemotherapy for resectable gastric cancer: a meta-analysis. JAMA 2010; 303: 1729–37.
Science Photo Library
Effect of docetaxel on safety and efficacy of radium-223
Published Online October 17, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)71026-5 See Articles page 1397
1292
The landscape of prostate cancer is shifting. Within the past 5 years, there have been major advances in the understanding of the biology of prostate cancer, which have translated into improved overall survival for men with metastatic castration-resistant prostate cancer. This wave of chemotherapeutics,1,2 immunotherapy,3 androgen-receptor-directed drugs,4–7 and a radioisotope8 have brought new hope for patients and new questions for clinicians. In The Lancet Oncology, Peter Hoskin and colleagues report the results of a prespecified subgroup analysis9 from the phase 3 ALSYMPCA trial, which provide insight into the tolerability and efficacy of radium-223 in the context of previous docetaxel treatment. Radium-223 was the first α-emitter to receive regulatory approval in the USA and Europe to treat patients with castration-resistant prostate cancer and symptomatic bone metastases but no known visceral metastases, and was approved for use in patients with or without previous treatment with docetaxel. In the ALSYMPCA trial,8 radium-223 provided an overall survival advantage, decreased symptomatic skeletal events, and improved total alkaline phosphatase concentrations and time to increase in prostate-specific antigen concentration. In this prespecified subgroup analysis,9 Hoskin and colleagues aimed to assess the effect of previous docetaxel use of the efficacy and safety of radium-223. The investigators report that radium-223 prolonged median overall survival irrespective of previous docetaxel use (previous docetaxel use, hazard ratios [HR] 0·70, 95% CI 0·56–0·88; p=0·002]; no previous docetaxel use, HR 0·69, 0·52–0·92; p=0·01).9 The benefit was maintained in most of the secondary efficacy endpoints. Within the armamentarium
of treatments for metastatic castration-resistant prostate cancer, abiraterone acetate and enzalutamide have been studied individually in the docetaxel-naive and post-docetaxel settings. Although median overall survival for patients treated with abiraterone acetate or enzalutamide in these two distinct clinical disease states are substantially different (about 32–35 months in docetaxel-naive patients vs about 15–18 months in post-docetaxel patients), the HRs for death comparing the active treatment against placebo are similar in both groups (0·63–0·75).4–7 Thus the clinical benefit is essentially agnostic to previous docetaxel exposure, as is also shown for radium-223 in Hoskin and colleagues’ analysis. The safety profile of radium-223 is quite favourable. Hoskin and colleagues’ safety analysis shows that patients who have previously received docetaxel treatment have an increased risk of haematological toxic effects of any grade compared with those with no previous docetaxel use; however, the frequency grade 3–4 thrombocytopenia was only increased compared with placebo in the subgroup of patients who had received previous docetaxel. The frequencies of grade 3–4 neutropenia and anaemia in the docetaxel subgroups were similar, although more patients who had received previous docetaxel than those who had not required a blood transfusion. The investigators did not report any differences in non-haematological adverse events between the subgroups. Unfortunately, data for the number of cycles of chemotherapy were not captured in the trial—these data would have allowed for a more comprehensive understanding of the increased haematological toxicity seen in patients who had received previous docetaxel treatment. Furthermore, www.thelancet.com/oncology Vol 15 November 2014
Comment
the absence of information about the reasons why patients did not receive docetaxel could confound the safety results in this subgroup analysis, since patients deemed not healthy enough to receive chemotherapy might have had more toxic effects. Hoskin and colleagues’ results9 show that men who have received previous docetaxel chemotherapy can be given radium-223 safely and its efficacy will be similar to that in patients who have not received previous docetaxel treatment. However, the oncology community needs to proceed cautiously, since the ALSYMPCA trial was not able to identify the optimum sequence of administration of docetaxel and radium-233. Additionally, the trial was designed before the approval of enzalutamide and abiraterone acetate, so the clinical benefit of concomitant or sequential use of radium-223 with these drugs is unknown. Perhaps most intriguing would be the opportunity to integrate immunotherapy (immune-checkpoint inhibitors, vaccines, etc) with radium-223 to generate necrosis, immunogenic cell death, and immune modulation. Radium, as an α-emitter, is an ideal agent to elicit an abscopal effect. Finally, the clinical efficacy of radium-223 noted in the setting of metastatic castration-resistant prostate cancer would suggest that early use in the hormone-sensitive period might provide some clinical benefit. However, well designed clinical trials will be needed to establish the safety and efficacy of these approaches. In the ALSYMPCA trial, all patients received a predetermined six doses of radium-223, irrespective of previous treatment or outcome. Although most had a clinical benefit, some subgroups had increased toxic effects and questionable clinical benefit. Identification of early and continuous markers of response will be crucial to allow optimisation of the duration of radium-223 treatment, especially now that patients with metastatic
www.thelancet.com/oncology Vol 15 November 2014
castration-resistant prostate cancer have several treatment options. The ALSYMPCA investigators should be commended for having the foresight to address docetaxel status prospectively and for examining the response and safety of radium-223 within the context of docetaxel use. Although these results provide clarity, many questions remain, resulting in new opportunities for exploration. Robert B Den, *W Kevin Kelly Departments of Radiation Oncology (RBD), Cancer Biology (RBD), Urology (WKK), and Medical Oncology (WKK), Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA william.kelly@jefferson.edu We declare no competing interests. 1
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de Bono JS, Oudard S, Ozguroglu M, et al, for the TROPIC Investigators. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 2010; 376: 1147–54. Tannock IF, de Wit R, Berry WR, et al, for the TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351: 1502–12. Kantoff PW, Higano CS, Shore ND, et al, for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363: 411–22. Beer TM, Armstrong AJ, Rathkopf DE, et al, for the PREVAIL Investigators. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014; 371: 424–33. de Bono JS, Logothetis CJ, Molina A, et al, for the COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011; 364: 1995–2005. Ryan CJ, Smith MR, de Bono JS, et al, for the COU-AA-302 Investigators. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013; 368: 138–48. Scher HI, Fizazi K, Saad F, et al, for the AFFIRM Investigators. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367: 1187–97. Parker C, Nilsson S, Heinrich D, et al, for the ALSYMPCA Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013; 369: 213–23. Hoskin P, Sartor O, O’Sullivan JM, et al. Efficacy and safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases, with or without previous docetaxel use: a prespecified subgroup analysis from the randomised, double-blind, phase 3 ALSYMPCA trial. Lancet Oncol 2014; published online Oct 17. http://dx.doi.org/10.1016/ S1470-2045(14)70474-7
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Bajetta E, Floriani I, Di Bartolomeo M, et al. Randomized trial on adjuvant treatment with FOLFIRI followed by docetaxel and cisplatin versus 5-fluorouracil and folinic acid for radically resected gastric cancer. Ann Oncol 2014; 25: 1373–88. Tsuburaya A, Yoshida K, Kobayashi M, et al. Sequential paclitaxel followed by tegafur and uracil (UFT) or S-1 versus UFT or S-1 monotherapy as adjuvant chemotherapy for T4a/b gastric cancer (SAMIT): a phase 3 factorial randomised controlled trial. Lancet Oncol 2014; 15: 886–93. Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001; 345: 725–30.
9
10
Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006; 355: 11–20. GASTRIC Group, Paoletti X, Oba K, Burzykowski T, et al. Benefit of adjuvant chemotherapy for resectable gastric cancer: a meta-analysis. JAMA 2010; 303: 1729–37.
Science Photo Library
Effect of docetaxel on safety and efficacy of radium-223
Published Online October 17, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)71026-5 See Articles page 1397
1292
The landscape of prostate cancer is shifting. Within the past 5 years, there have been major advances in the understanding of the biology of prostate cancer, which have translated into improved overall survival for men with metastatic castration-resistant prostate cancer. This wave of chemotherapeutics,1,2 immunotherapy,3 androgen-receptor-directed drugs,4–7 and a radioisotope8 have brought new hope for patients and new questions for clinicians. In The Lancet Oncology, Peter Hoskin and colleagues report the results of a prespecified subgroup analysis9 from the phase 3 ALSYMPCA trial, which provide insight into the tolerability and efficacy of radium-223 in the context of previous docetaxel treatment. Radium-223 was the first α-emitter to receive regulatory approval in the USA and Europe to treat patients with castration-resistant prostate cancer and symptomatic bone metastases but no known visceral metastases, and was approved for use in patients with or without previous treatment with docetaxel. In the ALSYMPCA trial,8 radium-223 provided an overall survival advantage, decreased symptomatic skeletal events, and improved total alkaline phosphatase concentrations and time to increase in prostate-specific antigen concentration. In this prespecified subgroup analysis,9 Hoskin and colleagues aimed to assess the effect of previous docetaxel use of the efficacy and safety of radium-223. The investigators report that radium-223 prolonged median overall survival irrespective of previous docetaxel use (previous docetaxel use, hazard ratios [HR] 0·70, 95% CI 0·56–0·88; p=0·002]; no previous docetaxel use, HR 0·69, 0·52–0·92; p=0·01).9 The benefit was maintained in most of the secondary efficacy endpoints. Within the armamentarium
of treatments for metastatic castration-resistant prostate cancer, abiraterone acetate and enzalutamide have been studied individually in the docetaxel-naive and post-docetaxel settings. Although median overall survival for patients treated with abiraterone acetate or enzalutamide in these two distinct clinical disease states are substantially different (about 32–35 months in docetaxel-naive patients vs about 15–18 months in post-docetaxel patients), the HRs for death comparing the active treatment against placebo are similar in both groups (0·63–0·75).4–7 Thus the clinical benefit is essentially agnostic to previous docetaxel exposure, as is also shown for radium-223 in Hoskin and colleagues’ analysis. The safety profile of radium-223 is quite favourable. Hoskin and colleagues’ safety analysis shows that patients who have previously received docetaxel treatment have an increased risk of haematological toxic effects of any grade compared with those with no previous docetaxel use; however, the frequency grade 3–4 thrombocytopenia was only increased compared with placebo in the subgroup of patients who had received previous docetaxel. The frequencies of grade 3–4 neutropenia and anaemia in the docetaxel subgroups were similar, although more patients who had received previous docetaxel than those who had not required a blood transfusion. The investigators did not report any differences in non-haematological adverse events between the subgroups. Unfortunately, data for the number of cycles of chemotherapy were not captured in the trial—these data would have allowed for a more comprehensive understanding of the increased haematological toxicity seen in patients who had received previous docetaxel treatment. Furthermore, www.thelancet.com/oncology Vol 15 November 2014
Comment
the absence of information about the reasons why patients did not receive docetaxel could confound the safety results in this subgroup analysis, since patients deemed not healthy enough to receive chemotherapy might have had more toxic effects. Hoskin and colleagues’ results9 show that men who have received previous docetaxel chemotherapy can be given radium-223 safely and its efficacy will be similar to that in patients who have not received previous docetaxel treatment. However, the oncology community needs to proceed cautiously, since the ALSYMPCA trial was not able to identify the optimum sequence of administration of docetaxel and radium-233. Additionally, the trial was designed before the approval of enzalutamide and abiraterone acetate, so the clinical benefit of concomitant or sequential use of radium-223 with these drugs is unknown. Perhaps most intriguing would be the opportunity to integrate immunotherapy (immune-checkpoint inhibitors, vaccines, etc) with radium-223 to generate necrosis, immunogenic cell death, and immune modulation. Radium, as an α-emitter, is an ideal agent to elicit an abscopal effect. Finally, the clinical efficacy of radium-223 noted in the setting of metastatic castration-resistant prostate cancer would suggest that early use in the hormone-sensitive period might provide some clinical benefit. However, well designed clinical trials will be needed to establish the safety and efficacy of these approaches. In the ALSYMPCA trial, all patients received a predetermined six doses of radium-223, irrespective of previous treatment or outcome. Although most had a clinical benefit, some subgroups had increased toxic effects and questionable clinical benefit. Identification of early and continuous markers of response will be crucial to allow optimisation of the duration of radium-223 treatment, especially now that patients with metastatic
www.thelancet.com/oncology Vol 15 November 2014
castration-resistant prostate cancer have several treatment options. The ALSYMPCA investigators should be commended for having the foresight to address docetaxel status prospectively and for examining the response and safety of radium-223 within the context of docetaxel use. Although these results provide clarity, many questions remain, resulting in new opportunities for exploration. Robert B Den, *W Kevin Kelly Departments of Radiation Oncology (RBD), Cancer Biology (RBD), Urology (WKK), and Medical Oncology (WKK), Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA william.kelly@jefferson.edu We declare no competing interests. 1
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3
4
5
6
7
8
9
de Bono JS, Oudard S, Ozguroglu M, et al, for the TROPIC Investigators. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 2010; 376: 1147–54. Tannock IF, de Wit R, Berry WR, et al, for the TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351: 1502–12. Kantoff PW, Higano CS, Shore ND, et al, for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363: 411–22. Beer TM, Armstrong AJ, Rathkopf DE, et al, for the PREVAIL Investigators. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014; 371: 424–33. de Bono JS, Logothetis CJ, Molina A, et al, for the COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011; 364: 1995–2005. Ryan CJ, Smith MR, de Bono JS, et al, for the COU-AA-302 Investigators. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013; 368: 138–48. Scher HI, Fizazi K, Saad F, et al, for the AFFIRM Investigators. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367: 1187–97. Parker C, Nilsson S, Heinrich D, et al, for the ALSYMPCA Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013; 369: 213–23. Hoskin P, Sartor O, O’Sullivan JM, et al. Efficacy and safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases, with or without previous docetaxel use: a prespecified subgroup analysis from the randomised, double-blind, phase 3 ALSYMPCA trial. Lancet Oncol 2014; published online Oct 17. http://dx.doi.org/10.1016/ S1470-2045(14)70474-7
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