- Email: [email protected]
Improving prognosis after surgery for gastric cancer
Comment
kinase inhibitors are definitively characterised by limited activity for patients with EGFR wild-type non-smallcell lung cancer. Findings from TAILOR,9 a debated trial comparing second-line docetaxel with erlotinib in patients with EGFR wild type, showed an increase in progression-free and overall survival in the docetaxel group. Findings from a recent meta-analysis10 suggested an improvement in progression-free survival with chemotherapy compared with EGFR tyrosine kinase inhibition in EGFR wild-type patients. Rationally, in EGFR wild-type non-small-cell lung cancer, at least two lines of chemotherapy should be considered before treatment with an EGFR tyrosine kinase inhibitor. Irreversible covalent binding to EGFR did not improve dacomitinib activity in the EGFR wild-type setting in Archer 1009. More disappointing is that dacomitinib was not shown to be beneficial compared with firstgeneration EGFR tyrosine kinase inhibition in oncogeneaddicted previously untreated or resistant non-small-cell lung cancer, but was associated with more toxic effects. Only customised, prospective, randomised studies will accurately compare the activity of EGFR tyrosine kinase inhibitors in EGFR-mutated non-small-cell lung cancer, such as the ongoing ARCHER 1050 study comparing dacomitinib with gefitinib as first-line therapy, or upcoming randomised trials of third-generation EGFR tyrosine kinase inhibitors (which show promising activity in overcoming Thr790Met resistance) versus first-generation EGFR tyrosine kinase inhibitors. In this era of new treatment strategies, including immunotherapy, use of EGFR tyrosine kinase inhibitors in EGFR wild-type advanced non-small-cell lung cancer should be restricted to erlotinib in its indication defined 10 years ago in the BR.21 trial, where only a
small improvement over best supportive care in clinical outcome should be expected. *Solange Peters, Egbert Smit Oncology Department, Av Bugnon 46, CHUV, 1011 Lausanne, Switzerland (SP); and VU University Medical Center, Amsterdam, Netherlands (ES) [email protected] We declare no competing interests. 1 2
3
4
5
7
8
9
10
Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005; 353: 123–32. Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005; 366: 1527–37. Miller VA, Hirsh V, Cadranel J, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol 2012; 13: 528–38. Ellis PM, Shepherd FA, Millwaråd M, et al. Dacomitinib compared with placebo in pretreated patients with advanced or metastatic non-small-cell lung cancer (NCIC CTG BR.26): a double-blind, randomised, phase 3 trial. Lancet Oncol 2014; published online Oct 15. http://dx.doi.org/10.1016/ S1470-2045(14)70472-3. Nishino K, Imamura F, Morita S, et al. A retrospective analysis of 335 Japanese lung cancer patients who responded to initial gefitinib treatment. Lung Cancer 2013; 82: 299–304. 6 Ramalingam SS, Jänne PA, Mok T, et al. Dacomitnib versus erlotinib in patients with advanced-stage, previously treated non-small-cell lung cancer (ARCHER 1009): a randomised, doubleblind, phase 3 trial. Lancet Oncol 2014; published online Oct 15. http://dx. doi.org/10.1016/S1470-2045(14)70452-8. Fiala O, Pesek M, Finek J, Benesova L, Belsanova B, Minarik M. The dominant role of G12C over other KRAS mutation types in the negative prediction of efficacy of epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Cancer genetics 2013; 206: 26–31. Metro G, Chiari R, Duranti S, et al. Impact of specific mutant KRAS on clinical outcome of EGFR-TKI-treated advanced non-small cell lung cancer patients with an EGFR wild type genotype. Lung Cancer 2012; 78: 81–86. Garassino MC, Martelli O, Broggini M, et al. Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial. Lancet Oncol 2013; 14: 981–88. Lee JK, Hahn S, Kim DW, et al. Epidermal growth factor receptor tyrosine kinase inhibitors vs conventional chemotherapy in non-small cell lung cancer harboring wild-type epidermal growth factor receptor: a meta-analysis. JAMA 2014; 311: 1430–37.
Improving prognosis after surgery for gastric cancer Published Online October 15, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)71019-8 See Articles page 1389
1290
5-year overall survival is the gold standard measure to compare treatments for gastric cancer. However, it requires long follow-up, and might be affected by subsequent treatments or by death caused by unrelated diseases, especially in elderly people. Some studies have used other surrogates, such as progression-free survival, disease-free survival, or shorter endpoints, including two randomised trials from Asia of adjuvant treatment for gastric cancer.1,2 Yung-Jae Bang and colleagues2
reported that capecitabine plus oxaliplatin improved the primary endpoint of 3-year disease-free survival for patients with operable gastric cancer and D2 dissection (hazard ratio [HR] 0·56, 95% CI 0·44–0·72; p<0·0001), whereas its effect on overall survival was less definitive (0·72, 0·52–1·00; p=0·0493). Although a meta-analysis3 has suggested that disease-free survival is a faithful surrogate for overall survival in clinical trials, real 5-year overall survival data are still superior to any surrogates. www.thelancet.com/oncology Vol 15 November 2014
Comment
www.thelancet.com/oncology Vol 15 November 2014
and Brazil, Europe, and New Zealand9 have shown clinical benefit for patients with adenocarcinoma of the stomach or gastro-oesophageal junction, although other postoperative chemotherapy has failed to show benefit for such patients. Results of a meta-analysis of individual patient data show that postoperative chemotherapy based on fluorouracil regimens has a small but significant benefit.10 As a result, administration of chemotherapy before or after surgery (or both) has increased in clinical practice outside of Asia, although strong evidence for its effect in nonAsian patients is still lacking. The first stage of adjuvant treatment for curative gastric cancer in Asia has been established by the two fluoropyrimidine-based studies.4,5 Clinical trials should now move to the next stages of comparative testing with one of the two established regimens as a control. In these studies, individual optimisation with predictive biomarkers should be explored, or the efficacy of preoperative and postoperative chemotherapy might be compared, as has been done for oesophageal cancer. Other approaches to improve prognosis of patients with gastric cancer include the introduction of targeted drugs—eg, anti-HER2 antibodies—into adjuvant treatment, and immunotherapeutic treatments. Finally, the cost-effectiveness and cost utility of adjuvant treatment should be assessed.
GJLP/Science Photo Library
In The Lancet Oncology, Sung Hoon Noh and colleagues4 report the final results of CLASSIC with median follow-up of 5 years. They show that adjuvant capecitabine plus oxaliplatin improved both diseasefree survival (HR 0·58, 95% CI 0·47–0·72; p<0·0001) and overall survival (0·66, 0·51–0·85; p=0·0015) by a similar degree after a median follow-up of 62·4 months (IQR 54–70). These results, combined with those of ACTS-GC,5 which are much the same, strongly advocate adjuvant treatment for Asian patients with stage II and III gastric cancer after D2 surgery. In ACTS-GC, the oral fluoropyrimidine S-1 was administered for 12 months whereas the treatment was for 6 months in CLASSIC. Two drugs seems to be more intensive than one. A more intensive regimen with FOLFIRI (leucovorin, fluorouracil, and irinotecan) followed by docetaxel plus cisplatin did not show any benefit compared with fluorouracil and leucovorin in ITACA-S,6 and, for Asian patients, sequential polychemotherapy did not significantly improve disease-free survival in SAMIT,7 suggesting that intensified and prolonged adjuvant chemotherapy might not always benefit patients with gastric cancer. Both capecitabine plus oxaliplatin and S-1 regimens were efficacious for stage II disease, but less so for stage III disease, suggesting that new treatment strategies might be needed for advanced stage disease. Moreover, decreased physical strength after gastric surgery might limit the intensity and continuity of adjuvant treatment that patients can tolerate, and adherence to chemotherapy might depend on the perioperative condition of patients, therefore individual optimisation of regimens might be needed in clinical practice. The other question related to these studies is how well the regimen applies to non-Asian patients. NonAsian practice has some significant differences from Asian practice in terms of surgery for gastric cancer: D2 dissection is used in Asia whereas less extensive surgery is preferred elsewhere; distal cancer is the main form of the disease in Asia whereas elsewhere it is gastrooesophageal cancer; histologically differentiated gastric cancer is predominant in Asia and undifferentiated elsewhere. Furthermore, toxic effects and tolerance to chemotherapeutic drugs can differ between patients of different ethnic origins, so different strategies might be needed. Two studies of perioperative chemotherapy and chemoradiation done in the USA,8
*Toshirou Nishida, Toshihiko Doi National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan [email protected] TN has received funding for basic research from Novartis, and honoraria for speeches from Bayer, Pfizer, and Novartis. TD has received funding for clinical research from Taiho, Bayer, Eisai, Eli Lilly, Pfizer, NanoCarrier, Zenyakukogyo, Bristol-Myers Squibb, Sanofi-Aventis, Novartis, Parexel International, Takeda, and Merck Serono, and honoraria for speeches from Chugai and Takeda. 1
2
3
4
5
Sakuramoto S, Sasako M, Yamaguchi T, et al. ACTS-GC Group. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 2007; 357: 1810–20. Bang YJ, Kim YW, Yang HK, et al. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet 2012; 379: 315–21. Oba K, Paoletti X, Alberts S, et al. Disease-free survival as a surrogate for overall survival in adjuvant trials of gastric cancer: a meta-analysis. J Natl Cancer Inst 2013; 105: 1600–07. Noh SH, Park SR, Yang H-K, et al, on behalf of the CLASSIC trial investigators. Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial. Lancet Oncol 2014; published online Oct 15. http://dx.doi. org/10.1016/S1470-2045(14)70473-5. Sasako M, Sakuramoto S, Katai H, et al. Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. J Clin Oncol 2011; 29: 4387–93.
1291
Comment
6
7
8
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
kinase inhibitors are definitively characterised by limited activity for patients with EGFR wild-type non-smallcell lung cancer. Findings from TAILOR,9 a debated trial comparing second-line docetaxel with erlotinib in patients with EGFR wild type, showed an increase in progression-free and overall survival in the docetaxel group. Findings from a recent meta-analysis10 suggested an improvement in progression-free survival with chemotherapy compared with EGFR tyrosine kinase inhibition in EGFR wild-type patients. Rationally, in EGFR wild-type non-small-cell lung cancer, at least two lines of chemotherapy should be considered before treatment with an EGFR tyrosine kinase inhibitor. Irreversible covalent binding to EGFR did not improve dacomitinib activity in the EGFR wild-type setting in Archer 1009. More disappointing is that dacomitinib was not shown to be beneficial compared with firstgeneration EGFR tyrosine kinase inhibition in oncogeneaddicted previously untreated or resistant non-small-cell lung cancer, but was associated with more toxic effects. Only customised, prospective, randomised studies will accurately compare the activity of EGFR tyrosine kinase inhibitors in EGFR-mutated non-small-cell lung cancer, such as the ongoing ARCHER 1050 study comparing dacomitinib with gefitinib as first-line therapy, or upcoming randomised trials of third-generation EGFR tyrosine kinase inhibitors (which show promising activity in overcoming Thr790Met resistance) versus first-generation EGFR tyrosine kinase inhibitors. In this era of new treatment strategies, including immunotherapy, use of EGFR tyrosine kinase inhibitors in EGFR wild-type advanced non-small-cell lung cancer should be restricted to erlotinib in its indication defined 10 years ago in the BR.21 trial, where only a
small improvement over best supportive care in clinical outcome should be expected. *Solange Peters, Egbert Smit Oncology Department, Av Bugnon 46, CHUV, 1011 Lausanne, Switzerland (SP); and VU University Medical Center, Amsterdam, Netherlands (ES) [email protected] We declare no competing interests. 1 2
3
4
5
7
8
9
10
Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005; 353: 123–32. Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005; 366: 1527–37. Miller VA, Hirsh V, Cadranel J, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol 2012; 13: 528–38. Ellis PM, Shepherd FA, Millwaråd M, et al. Dacomitinib compared with placebo in pretreated patients with advanced or metastatic non-small-cell lung cancer (NCIC CTG BR.26): a double-blind, randomised, phase 3 trial. Lancet Oncol 2014; published online Oct 15. http://dx.doi.org/10.1016/ S1470-2045(14)70472-3. Nishino K, Imamura F, Morita S, et al. A retrospective analysis of 335 Japanese lung cancer patients who responded to initial gefitinib treatment. Lung Cancer 2013; 82: 299–304. 6 Ramalingam SS, Jänne PA, Mok T, et al. Dacomitnib versus erlotinib in patients with advanced-stage, previously treated non-small-cell lung cancer (ARCHER 1009): a randomised, doubleblind, phase 3 trial. Lancet Oncol 2014; published online Oct 15. http://dx. doi.org/10.1016/S1470-2045(14)70452-8. Fiala O, Pesek M, Finek J, Benesova L, Belsanova B, Minarik M. The dominant role of G12C over other KRAS mutation types in the negative prediction of efficacy of epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Cancer genetics 2013; 206: 26–31. Metro G, Chiari R, Duranti S, et al. Impact of specific mutant KRAS on clinical outcome of EGFR-TKI-treated advanced non-small cell lung cancer patients with an EGFR wild type genotype. Lung Cancer 2012; 78: 81–86. Garassino MC, Martelli O, Broggini M, et al. Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial. Lancet Oncol 2013; 14: 981–88. Lee JK, Hahn S, Kim DW, et al. Epidermal growth factor receptor tyrosine kinase inhibitors vs conventional chemotherapy in non-small cell lung cancer harboring wild-type epidermal growth factor receptor: a meta-analysis. JAMA 2014; 311: 1430–37.
Improving prognosis after surgery for gastric cancer Published Online October 15, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)71019-8 See Articles page 1389
1290
5-year overall survival is the gold standard measure to compare treatments for gastric cancer. However, it requires long follow-up, and might be affected by subsequent treatments or by death caused by unrelated diseases, especially in elderly people. Some studies have used other surrogates, such as progression-free survival, disease-free survival, or shorter endpoints, including two randomised trials from Asia of adjuvant treatment for gastric cancer.1,2 Yung-Jae Bang and colleagues2
reported that capecitabine plus oxaliplatin improved the primary endpoint of 3-year disease-free survival for patients with operable gastric cancer and D2 dissection (hazard ratio [HR] 0·56, 95% CI 0·44–0·72; p<0·0001), whereas its effect on overall survival was less definitive (0·72, 0·52–1·00; p=0·0493). Although a meta-analysis3 has suggested that disease-free survival is a faithful surrogate for overall survival in clinical trials, real 5-year overall survival data are still superior to any surrogates. www.thelancet.com/oncology Vol 15 November 2014
Comment
www.thelancet.com/oncology Vol 15 November 2014
and Brazil, Europe, and New Zealand9 have shown clinical benefit for patients with adenocarcinoma of the stomach or gastro-oesophageal junction, although other postoperative chemotherapy has failed to show benefit for such patients. Results of a meta-analysis of individual patient data show that postoperative chemotherapy based on fluorouracil regimens has a small but significant benefit.10 As a result, administration of chemotherapy before or after surgery (or both) has increased in clinical practice outside of Asia, although strong evidence for its effect in nonAsian patients is still lacking. The first stage of adjuvant treatment for curative gastric cancer in Asia has been established by the two fluoropyrimidine-based studies.4,5 Clinical trials should now move to the next stages of comparative testing with one of the two established regimens as a control. In these studies, individual optimisation with predictive biomarkers should be explored, or the efficacy of preoperative and postoperative chemotherapy might be compared, as has been done for oesophageal cancer. Other approaches to improve prognosis of patients with gastric cancer include the introduction of targeted drugs—eg, anti-HER2 antibodies—into adjuvant treatment, and immunotherapeutic treatments. Finally, the cost-effectiveness and cost utility of adjuvant treatment should be assessed.
GJLP/Science Photo Library
In The Lancet Oncology, Sung Hoon Noh and colleagues4 report the final results of CLASSIC with median follow-up of 5 years. They show that adjuvant capecitabine plus oxaliplatin improved both diseasefree survival (HR 0·58, 95% CI 0·47–0·72; p<0·0001) and overall survival (0·66, 0·51–0·85; p=0·0015) by a similar degree after a median follow-up of 62·4 months (IQR 54–70). These results, combined with those of ACTS-GC,5 which are much the same, strongly advocate adjuvant treatment for Asian patients with stage II and III gastric cancer after D2 surgery. In ACTS-GC, the oral fluoropyrimidine S-1 was administered for 12 months whereas the treatment was for 6 months in CLASSIC. Two drugs seems to be more intensive than one. A more intensive regimen with FOLFIRI (leucovorin, fluorouracil, and irinotecan) followed by docetaxel plus cisplatin did not show any benefit compared with fluorouracil and leucovorin in ITACA-S,6 and, for Asian patients, sequential polychemotherapy did not significantly improve disease-free survival in SAMIT,7 suggesting that intensified and prolonged adjuvant chemotherapy might not always benefit patients with gastric cancer. Both capecitabine plus oxaliplatin and S-1 regimens were efficacious for stage II disease, but less so for stage III disease, suggesting that new treatment strategies might be needed for advanced stage disease. Moreover, decreased physical strength after gastric surgery might limit the intensity and continuity of adjuvant treatment that patients can tolerate, and adherence to chemotherapy might depend on the perioperative condition of patients, therefore individual optimisation of regimens might be needed in clinical practice. The other question related to these studies is how well the regimen applies to non-Asian patients. NonAsian practice has some significant differences from Asian practice in terms of surgery for gastric cancer: D2 dissection is used in Asia whereas less extensive surgery is preferred elsewhere; distal cancer is the main form of the disease in Asia whereas elsewhere it is gastrooesophageal cancer; histologically differentiated gastric cancer is predominant in Asia and undifferentiated elsewhere. Furthermore, toxic effects and tolerance to chemotherapeutic drugs can differ between patients of different ethnic origins, so different strategies might be needed. Two studies of perioperative chemotherapy and chemoradiation done in the USA,8
*Toshirou Nishida, Toshihiko Doi National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan [email protected] TN has received funding for basic research from Novartis, and honoraria for speeches from Bayer, Pfizer, and Novartis. TD has received funding for clinical research from Taiho, Bayer, Eisai, Eli Lilly, Pfizer, NanoCarrier, Zenyakukogyo, Bristol-Myers Squibb, Sanofi-Aventis, Novartis, Parexel International, Takeda, and Merck Serono, and honoraria for speeches from Chugai and Takeda. 1
2
3
4
5
Sakuramoto S, Sasako M, Yamaguchi T, et al. ACTS-GC Group. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 2007; 357: 1810–20. Bang YJ, Kim YW, Yang HK, et al. Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial. Lancet 2012; 379: 315–21. Oba K, Paoletti X, Alberts S, et al. Disease-free survival as a surrogate for overall survival in adjuvant trials of gastric cancer: a meta-analysis. J Natl Cancer Inst 2013; 105: 1600–07. Noh SH, Park SR, Yang H-K, et al, on behalf of the CLASSIC trial investigators. Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial. Lancet Oncol 2014; published online Oct 15. http://dx.doi. org/10.1016/S1470-2045(14)70473-5. Sasako M, Sakuramoto S, Katai H, et al. Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. J Clin Oncol 2011; 29: 4387–93.
1291
Comment
6
7
8
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