- Email: [email protected]
Maintenance therapy for non-small-cell lung cancer
Correspondence
1
2
3
4
5
Katsumata N, Yasuda M, Takahashi F, et al. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial. Lancet 2009; 374: 1331–38. Rustin GJ, Nelstrop AE, McClean P, et al. Defining response of ovarian carcinoma to initial chemotherapy according to serum CA 125. J Clin Oncol 1996; 14: 1545–51. Rustin GJ, Nelstrop AE, Tuxen MK, et al. Defining progression of ovarian carcinoma during follow-up according to CA 125: a North Thames Ovary Group Study. Ann Oncol 1996; 7: 361–64. Rustin GJ, Nelstrop AE, Crawford M. Phase II trial of oral altretamine for relapsed ovarian carcinoma: evaluation of defining response by serum CA125. J Clin Oncol 1997; 15: 172–76. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92: 205–16.
Authors’ reply Filippo Bellati and colleagues point out the low rate of optimum cytoreduction surgery and low compliance with chemotherapy in the control group in our trial. Neoadjuvant chemotherapy followed by surgery is another approach in advanced ovarian cancer.1 We have been doing a phase 3 study of treatment starting with neoadjuvant chemotherapy versus upfront debulking surgery for advanced ovarian cancer since November, 2006.2 The JGOG study allowed for the inclusion of patients who only underwent cytology instead of primary debulking surgery. Most of the patients who did not undergo primary surgery underwent interval debulking surgery after neoadjuvant chemotherapy. This is the reason why our study resulted in a low rate of optimum cytoreductive surgery. 87 patients (27%) in the control group discontinued the protocol therapy before six cycles of chemotherapy; however, 27 of these patients received platinum-based chemotherapy as a non-protocol therapy after stopping the protocol therapy. www.thelancet.com Vol 375 January 23, 2010
In the control group, median progression-free survival was 17·2 months (15·5 months in patients with stage III–IV disease, 12·0 months in patients with suboptimum residual disease). These results seem to be comparable with those of a recently published phase 3 study. The AGO trial3 used similar eligibility criteria to our study, and showed a median progression-free survival of 17·2 months in the paclitaxel and carboplatin group. In that trial, 62·6% of patients had optimum surgery. The GOG182 trial4 for stage III–IV disease showed 16·0 months of progressionfree survival in the paclitaxel and carboplatin group, with 70% having optimum residual disease.4 I disagree that an analysis of patients who received six or more cycles would allow more informative results because those who received more cycles of chemotherapy have many potential biases. I agree with Rong Wu and colleagues that it is reasonable to investigate whether CA-125 may be useful as a prognostic factor. However, at which time point CA-125 measurement gives the best prognostic factor is not yet known. We measured all the CA-125 concentrations before and after chemotherapy in each cycle, and will do exploratory analyses of CA-125 as a prognostic factor in an ancillary study. Wu and colleagues also question why we did not use RECIST for the assessment of response in our study. Because most Japanese investigators were not familiar with RECIST at the time the study began in 2003, we used the WHO criteria for the assessment of response. I declare that I have no conflicts of interest.
Noriyuki Katsumata [email protected] Department of Medical Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan 1
Vergote I, de Wever I, Tjalma W, Van Gramberen M, Decloedt J, Van Dam P. Interval debulking surgery: an alternative for primary surgical debulking? Semin Surg Oncol 2000; 19: 49–53.
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3
4
Onda T, Matsumoto K, Shibata T, et al. Phase III trial of upfront debulking surgery versus neoadjuvant chemotherapy for stage III/IV ovarian, tubal and peritoneal cancers: Japan Clinical Oncology Group Study JCOG0602. Jpn J Clin Oncol 2008; 38: 74–77. du Bois A, Luck HJ, Meier W, et al. A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst 2003; 95: 1320–29. Bookman MA, Brady MF, McGuire WP, et al. Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer: a phase III trial of the Gynecologic Cancer Intergroup. J Clin Oncol 2009; 27: 1419-25.
Maintenance therapy for non-small-cell lung cancer Thomas Stinchcombe and Howard West (Oct 24, p 1398)1 argue that our trial2 comparing maintenance pemetrexed with placebo fails to establish that the timing of the additional therapy is crucial. We disagree with this assertion. The current standard of care for patients with advanced non-smallcell lung cancer (NSCLC) is platinumbased combination therapy for four to six cycles, with no additional drug therapy before disease progression. About 30–50% of these patients do not received second-line therapy at progression either due to death, deteriorating health, or personal decision. Consistent with the current practice, 67% of patients in the placebo group of our trial received additional therapy with commonly used treatment options. The placebo group is therefore a good statistical representation of the established treatment standard. The important clinical question posed by our trial was whether immediate maintenance therapy with pemetrexed, after induction platinum therapy, is superior to the current standard of clinical practice. The trial documents that immediate administration of pemetrexed is superior (in terms of progression-free and overall survival) to the current 281
Correspondence
standard of delayed (or no) additional therapy. Delaying the additional therapy has also been shown to be a strategy that leads to a more rapid disease progression and shorter survival time than immediate additional therapy.3 We have no conclusive predictors of whether an individual patient will remain in good enough health to receive the additional treatment after disease progression. Why take the risk of the delayed strategy when the immediate strategy has now been shown to be both tolerable and effective? Maintenance pemetrexed is now the established paradigm for patients with advanced NSCLC. CPB is a consultant for Eli-Lilly. JL has no conflicts of interest.
*Chandra P Belani, Jason Liao [email protected] Penn State Hershey Cancer Institute, Hershey, PA 17033, USA 1
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3
Stinchcombe TE, West H. Maintenance therapy in non-small-cell lung cancer. Lancet 2009; 374: 1398–400. Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet 2009; 374: 1432–40. Soon YY, Stockler MR, Askie LM, Boyer MJ. Duration of chemotherapy for advanced non-small-cell lung cancer: a systematic review and meta-analysis of randomized trials. J Clin Oncol 2009; 27: 3277–83.
The undernutrition epidemic: an urgent health priority
4
5
Black RE, Allen LH, Bhutta ZA, et al. Maternal and child undernutrition: global and regional exposures and health consequences. Lancet 2008; 371: 243–60. Grantham-McGregor S, Cheung YB, Cueto S, Glewwe P, Richter L, Strupp B. Developmental potential in the first 5 years for children in developing countries. Lancet 2007; 369: 60–70. Bhutta ZA, Ahmed T, Black RE, et al. What works? Interventions for maternal and child undernutrition and survival. Lancet 2008; 371: 417–40.
*Christine P Stewart, Kathryn G Dewey, Per Ashorn [email protected]
We laud your Editorial (Oct 31, p 1473) for drawing renewed attention to the epidemic of undernutrition. However, we believe that it was misguided on two points of essential importance to addressing undernutrition in young children, the most vulnerable subgroup. First, the recommendation to use a body-mass index (BMI) of 16·0 or 18·5 kg/m² as a criterion to define
Photolibrary
3
We declare that we have no conflicts of interest.
1
282
undernutrition is inappropriate for young children and ignores stunting (low height for age) as a key indicator in this age group. According to WHO,2 the median BMI for a healthy 5-year-old child is roughly 15 kg/m². The proposed cutoff of 16 kg/m² has not been linked to added risk of mortality or morbidity in children and yet would classify more than half the world’s children as malnourished. In comparison, 14·5% of child deaths, 12·6% of disabilityadjusted life-years lost, and a large proportion of developmental losses have been attributed to stunting, which is estimated to affect 32% of children in low-income countries.3,4 Second, the assertion that malnutrition can simply be corrected with additional amounts of food is misleading, since it implies that insufficient energy intake is the main concern. In many areas of the world, poor dietary quality and inadequate intake of micronutrients are more widespread problems than low energy intake. Micronutrient fortification or supplementation, breastfeeding promotion, and improved complementary feeding interventions have great potential to reduce the burden of undernutrition,5 but these types of interventions with demonstrated efficacy must be delivered at scale to those in need.
Program in International and Community Nutrition, University of California, Davis, CA 95616, USA (CPS, KGD); and Department of International Health, University of Tampere Medical School, Tampere, Finland (PA) 1
2
The Lancet. The undernutrition epidemic: an urgent health priority. Lancet 2009; 374: 1473. WHO Multicentre Growth Reference Study Group. WHO Child Growth Standards for length/height-for-age, weight-for-age, weight-for-length, weight-for-height and body mass index-for-age: methods and development. Geneva: World Health Organization, 2006.
Department of Error Campbell J, Oulton JA, McPake B, Buchan J. Removing user fees? Engage the health workforce. Lancet 2009; 374: 1966—In this Correspondence letter (Dec 12), the last sentence of the penultimate paragraph should have read: “Finally, health systems and workforce surveillance must be enhanced to actively assess emerging trends”.
www.thelancet.com Vol 375 January 23, 2010
1
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3
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5
Katsumata N, Yasuda M, Takahashi F, et al. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial. Lancet 2009; 374: 1331–38. Rustin GJ, Nelstrop AE, McClean P, et al. Defining response of ovarian carcinoma to initial chemotherapy according to serum CA 125. J Clin Oncol 1996; 14: 1545–51. Rustin GJ, Nelstrop AE, Tuxen MK, et al. Defining progression of ovarian carcinoma during follow-up according to CA 125: a North Thames Ovary Group Study. Ann Oncol 1996; 7: 361–64. Rustin GJ, Nelstrop AE, Crawford M. Phase II trial of oral altretamine for relapsed ovarian carcinoma: evaluation of defining response by serum CA125. J Clin Oncol 1997; 15: 172–76. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92: 205–16.
Authors’ reply Filippo Bellati and colleagues point out the low rate of optimum cytoreduction surgery and low compliance with chemotherapy in the control group in our trial. Neoadjuvant chemotherapy followed by surgery is another approach in advanced ovarian cancer.1 We have been doing a phase 3 study of treatment starting with neoadjuvant chemotherapy versus upfront debulking surgery for advanced ovarian cancer since November, 2006.2 The JGOG study allowed for the inclusion of patients who only underwent cytology instead of primary debulking surgery. Most of the patients who did not undergo primary surgery underwent interval debulking surgery after neoadjuvant chemotherapy. This is the reason why our study resulted in a low rate of optimum cytoreductive surgery. 87 patients (27%) in the control group discontinued the protocol therapy before six cycles of chemotherapy; however, 27 of these patients received platinum-based chemotherapy as a non-protocol therapy after stopping the protocol therapy. www.thelancet.com Vol 375 January 23, 2010
In the control group, median progression-free survival was 17·2 months (15·5 months in patients with stage III–IV disease, 12·0 months in patients with suboptimum residual disease). These results seem to be comparable with those of a recently published phase 3 study. The AGO trial3 used similar eligibility criteria to our study, and showed a median progression-free survival of 17·2 months in the paclitaxel and carboplatin group. In that trial, 62·6% of patients had optimum surgery. The GOG182 trial4 for stage III–IV disease showed 16·0 months of progressionfree survival in the paclitaxel and carboplatin group, with 70% having optimum residual disease.4 I disagree that an analysis of patients who received six or more cycles would allow more informative results because those who received more cycles of chemotherapy have many potential biases. I agree with Rong Wu and colleagues that it is reasonable to investigate whether CA-125 may be useful as a prognostic factor. However, at which time point CA-125 measurement gives the best prognostic factor is not yet known. We measured all the CA-125 concentrations before and after chemotherapy in each cycle, and will do exploratory analyses of CA-125 as a prognostic factor in an ancillary study. Wu and colleagues also question why we did not use RECIST for the assessment of response in our study. Because most Japanese investigators were not familiar with RECIST at the time the study began in 2003, we used the WHO criteria for the assessment of response. I declare that I have no conflicts of interest.
Noriyuki Katsumata [email protected] Department of Medical Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan 1
Vergote I, de Wever I, Tjalma W, Van Gramberen M, Decloedt J, Van Dam P. Interval debulking surgery: an alternative for primary surgical debulking? Semin Surg Oncol 2000; 19: 49–53.
2
3
4
Onda T, Matsumoto K, Shibata T, et al. Phase III trial of upfront debulking surgery versus neoadjuvant chemotherapy for stage III/IV ovarian, tubal and peritoneal cancers: Japan Clinical Oncology Group Study JCOG0602. Jpn J Clin Oncol 2008; 38: 74–77. du Bois A, Luck HJ, Meier W, et al. A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst 2003; 95: 1320–29. Bookman MA, Brady MF, McGuire WP, et al. Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer: a phase III trial of the Gynecologic Cancer Intergroup. J Clin Oncol 2009; 27: 1419-25.
Maintenance therapy for non-small-cell lung cancer Thomas Stinchcombe and Howard West (Oct 24, p 1398)1 argue that our trial2 comparing maintenance pemetrexed with placebo fails to establish that the timing of the additional therapy is crucial. We disagree with this assertion. The current standard of care for patients with advanced non-smallcell lung cancer (NSCLC) is platinumbased combination therapy for four to six cycles, with no additional drug therapy before disease progression. About 30–50% of these patients do not received second-line therapy at progression either due to death, deteriorating health, or personal decision. Consistent with the current practice, 67% of patients in the placebo group of our trial received additional therapy with commonly used treatment options. The placebo group is therefore a good statistical representation of the established treatment standard. The important clinical question posed by our trial was whether immediate maintenance therapy with pemetrexed, after induction platinum therapy, is superior to the current standard of clinical practice. The trial documents that immediate administration of pemetrexed is superior (in terms of progression-free and overall survival) to the current 281
Correspondence
standard of delayed (or no) additional therapy. Delaying the additional therapy has also been shown to be a strategy that leads to a more rapid disease progression and shorter survival time than immediate additional therapy.3 We have no conclusive predictors of whether an individual patient will remain in good enough health to receive the additional treatment after disease progression. Why take the risk of the delayed strategy when the immediate strategy has now been shown to be both tolerable and effective? Maintenance pemetrexed is now the established paradigm for patients with advanced NSCLC. CPB is a consultant for Eli-Lilly. JL has no conflicts of interest.
*Chandra P Belani, Jason Liao [email protected] Penn State Hershey Cancer Institute, Hershey, PA 17033, USA 1
2
3
Stinchcombe TE, West H. Maintenance therapy in non-small-cell lung cancer. Lancet 2009; 374: 1398–400. Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet 2009; 374: 1432–40. Soon YY, Stockler MR, Askie LM, Boyer MJ. Duration of chemotherapy for advanced non-small-cell lung cancer: a systematic review and meta-analysis of randomized trials. J Clin Oncol 2009; 27: 3277–83.
The undernutrition epidemic: an urgent health priority
4
5
Black RE, Allen LH, Bhutta ZA, et al. Maternal and child undernutrition: global and regional exposures and health consequences. Lancet 2008; 371: 243–60. Grantham-McGregor S, Cheung YB, Cueto S, Glewwe P, Richter L, Strupp B. Developmental potential in the first 5 years for children in developing countries. Lancet 2007; 369: 60–70. Bhutta ZA, Ahmed T, Black RE, et al. What works? Interventions for maternal and child undernutrition and survival. Lancet 2008; 371: 417–40.
*Christine P Stewart, Kathryn G Dewey, Per Ashorn [email protected]
We laud your Editorial (Oct 31, p 1473) for drawing renewed attention to the epidemic of undernutrition. However, we believe that it was misguided on two points of essential importance to addressing undernutrition in young children, the most vulnerable subgroup. First, the recommendation to use a body-mass index (BMI) of 16·0 or 18·5 kg/m² as a criterion to define
Photolibrary
3
We declare that we have no conflicts of interest.
1
282
undernutrition is inappropriate for young children and ignores stunting (low height for age) as a key indicator in this age group. According to WHO,2 the median BMI for a healthy 5-year-old child is roughly 15 kg/m². The proposed cutoff of 16 kg/m² has not been linked to added risk of mortality or morbidity in children and yet would classify more than half the world’s children as malnourished. In comparison, 14·5% of child deaths, 12·6% of disabilityadjusted life-years lost, and a large proportion of developmental losses have been attributed to stunting, which is estimated to affect 32% of children in low-income countries.3,4 Second, the assertion that malnutrition can simply be corrected with additional amounts of food is misleading, since it implies that insufficient energy intake is the main concern. In many areas of the world, poor dietary quality and inadequate intake of micronutrients are more widespread problems than low energy intake. Micronutrient fortification or supplementation, breastfeeding promotion, and improved complementary feeding interventions have great potential to reduce the burden of undernutrition,5 but these types of interventions with demonstrated efficacy must be delivered at scale to those in need.
Program in International and Community Nutrition, University of California, Davis, CA 95616, USA (CPS, KGD); and Department of International Health, University of Tampere Medical School, Tampere, Finland (PA) 1
2
The Lancet. The undernutrition epidemic: an urgent health priority. Lancet 2009; 374: 1473. WHO Multicentre Growth Reference Study Group. WHO Child Growth Standards for length/height-for-age, weight-for-age, weight-for-length, weight-for-height and body mass index-for-age: methods and development. Geneva: World Health Organization, 2006.
Department of Error Campbell J, Oulton JA, McPake B, Buchan J. Removing user fees? Engage the health workforce. Lancet 2009; 374: 1966—In this Correspondence letter (Dec 12), the last sentence of the penultimate paragraph should have read: “Finally, health systems and workforce surveillance must be enhanced to actively assess emerging trends”.
www.thelancet.com Vol 375 January 23, 2010