Cetuximab in Colon Cancer
http://www.100md.com
《新英格兰医药杂志》
To the Editor: In her Perspective article on chemotherapy for colorectal cancer, Schrag (July 22 issue)1 decries breakthrough cancer medicines as unaffordable. However, she fails to mention that the majority of spending on cancer care is for care other than drugs. Perhaps the right question is the following: What value is placed on cancer care as a whole, rather than on one type of therapy, singled out? Drugs provide a large proportion of all life-extending health care gains achieved during the past 30 years. The economist Frank Lichtenberg estimates that new medicines have provided 50 to 60 percent of the gains during this period.2 Furthermore, although federally supported cancer research is valuable, it is important to recognize that in 2003, pharmaceutical companies increased their investment in researching and developing new drugs and making them available to patients to more than $33 billion.
According to economists Kevin Murphy and Robert Topel, a reduction in deaths due to cancer by just 10 percent is worth $4.4 trillion to society.3 This is the kind of statistic that makes it clear why breakthrough cancer medicines are good for patients as well as essential to society's ability to meet critical health care needs efficiently.
Alan F. Holmer, J.D.
Pharmaceutical Research and Manufacturers of America
Washington, DC 20005
References
Schrag D. The price tag on progress -- chemotherapy for colorectal cancer. N Engl J Med 2004;351:317-319.
Lichtenberg FR. The expanding pharmaceutical arsenal in the war on cancer. NBER working paper no. 10328. Cambridge, Mass.: National Bureau of Economic Research, February 2004.
Murphy KM, Topel RH. The economic value of medical research. In: Murphy KM, Topel RH, eds. Measuring the gains from medical research: an economic approach. Chicago: University of Chicago Press, 2003:41-73.
To the Editor: Cunningham et al. (July 22 issue) conclude that cetuximab "has clinically significant activity when given alone or in combination with irinotecan in patients with irinotecan-refractory colorectal cancer."1 However, although a statistically significant difference between the combination-therapy and monotherapy groups was observed in terms of the rate of tumor response, the relatively small difference in median survival (1.7 months) did not reach statistical significance (P=0.48). Furthermore, no information was supplied to show whether a tumor response translated into an improvement in patients' well-being or performance status.
If we are going to recommend a regimen that does not affect survival and that costs more than $30,000 for an eight-week course (as Schrag notes in her Perspective article), surely information regarding possible improvements in the quality of life becomes an important factor for patients making decisions regarding their treatment options.
Michael J. Martin, Ph.D.
National Cancer Institute
Bethesda, MD 20892
martmich@mail.nih.gov
References
Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351:337-345.
To the Editor: What conclusions can be reached by comparing anything with itself? Cunningham and colleagues conducted a randomized, controlled trial comparing irinotecan plus cetuximab with cetuximab monotherapy. The purpose of the study was to evaluate the effect of cetuximab in patients with irinotecan-refractory colorectal cancer. However, since the only difference between the groups was the use or nonuse of irinotecan, the latter treatment is the only intervention actually studied. The authors come to the following conclusion: "Cetuximab has clinically significant activity when given alone or in combination with irinotecan in patients with irinotecan-refractory colorectal cancer." This is a conclusion one cannot reach on the basis of the presented data alone. In Cunningham and colleagues' study, cetuximab is a cointervention and not the studied drug. Analysis according to the treatment received would leave us with two case series. Moreover, findings derived from case series may be seen as data that generate no more than hypotheses in terms of treatment evaluation.
Andry F. Costa, M.D.
Guilherme B. Sander, M.D.
Paulo D. Picon, Ph.D.
Brazilian Ministry of Health
90470-420 Porto Alegre, Brazil
gbsander@yahoo.com.br
Dr. Schrag replies: It is indisputable that reducing the burden of death due to cancer is enormously valued and that the pharmaceutical industry has played a key role in developing better therapy. However, neither of these considerations justifies setting prices for cancer medicines in the stratosphere. There is no evidence that this practice is necessary to promote innovation. Mr. Holmer cites an estimate of $33 billion for the industry's investment in research and development — a figure that is not meaningful unless placed in context with estimates of the industry's profit margins, tax credits, and marketing budgets, as well as estimates of taxpayer-supported investment in medical research.
It is well known among economists, including the academics cited by Mr. Holmer, that people will express willingness to pay huge sums in order to avoid the threat of death. Yet that essential human vulnerability should not form the basis for establishing drug prices. Rather, what is needed is careful deliberation about our systems of drug development — constructive debate that avoids facile use of statistics and engages all key players: the pharmaceutical industry, the government, the medical profession, and especially the public.
Deborah Schrag, M.D., M.P.H.
Memorial Sloan-Kettering Cancer Center
New York, NY 10021
Drs. Chau and Cunningham reply: The purpose of our randomized study was to evaluate the relative importance of irinotecan-based chemotherapy when added to cetuximab in patients with epidermal growth factor receptor (EGFR)–expressing, irinotecan-refractory colorectal cancer. Our results support the concept that resistance to chemotherapy can be circumvented in a proportion of patients by means of EGFR blockade and confirm the observations made in two previously reported nonrandomized, phase 2 studies.1,2
In our study, the rate of radiologic response was used as the primary end point. This was considered a useful surrogate marker for clinical benefit in a group of heavily pretreated patients in whom radiologic responses would be uncommon. A radiologic response was observed in 22.9 percent of the patients receiving cetuximab plus irinotecan. Oxaliplatin, in conjunction with infused fluorouracil and leucovorin, was also first granted approval by the Food and Drug Administration on the basis of a randomized study in which the radiologic response was used as the primary end point.3 In that study, a response rate of 9.9 percent was obtained in irinotecan-resistant patients with the oxaliplatin-based combination. This chemotherapy regimen was subsequently found to offer a survival advantage as compared with a regimen of irinotecan plus bolus fluorouracil and leucovorin when used as a first-line treatment for metastatic colorectal cancer,4 and it is now considered a standard treatment in that setting.
The combination of irinotecan and cetuximab is being tested in an ongoing randomized trial involving patients who have not previously received irinotecan; it is hoped that this trial will provide further data on survival as well as symptoms, performance status, and the quality of life. The cost of delivering effective care for cancer is substantial; the societal and medical decisions surrounding the evaluation of such treatment are complex and were considered beyond the scope of our clinical report.
Ian Chau, M.B., B.S.
David Cunningham, M.D.
Royal Marsden Hospital
London SW3 6JJ, United Kingdom
david.cunningham@icr.ac.uk
References
Saltz L, Rubin MS, Hochster HS, et al. Cetuximab (IMC-C225) plus irinotecan (CPT-11) is active in CPT-11 refractory colorectal cancer that expresses epidermal growth factor receptor. Proc Am Soc Clin Oncol 2001;20:3a. abstract.
Saltz LB, Meropol NJ, Loehrer PJ Sr, Needle MN, Kopit J, Mayer RJ. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 2004;22:1201-1208.
Rothenberg ML, Oza AM, Bigelow RH, et al. Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a Phase III trial. J Clin Oncol 2003;21:2059-2069.
Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004;22:23-30.
According to economists Kevin Murphy and Robert Topel, a reduction in deaths due to cancer by just 10 percent is worth $4.4 trillion to society.3 This is the kind of statistic that makes it clear why breakthrough cancer medicines are good for patients as well as essential to society's ability to meet critical health care needs efficiently.
Alan F. Holmer, J.D.
Pharmaceutical Research and Manufacturers of America
Washington, DC 20005
References
Schrag D. The price tag on progress -- chemotherapy for colorectal cancer. N Engl J Med 2004;351:317-319.
Lichtenberg FR. The expanding pharmaceutical arsenal in the war on cancer. NBER working paper no. 10328. Cambridge, Mass.: National Bureau of Economic Research, February 2004.
Murphy KM, Topel RH. The economic value of medical research. In: Murphy KM, Topel RH, eds. Measuring the gains from medical research: an economic approach. Chicago: University of Chicago Press, 2003:41-73.
To the Editor: Cunningham et al. (July 22 issue) conclude that cetuximab "has clinically significant activity when given alone or in combination with irinotecan in patients with irinotecan-refractory colorectal cancer."1 However, although a statistically significant difference between the combination-therapy and monotherapy groups was observed in terms of the rate of tumor response, the relatively small difference in median survival (1.7 months) did not reach statistical significance (P=0.48). Furthermore, no information was supplied to show whether a tumor response translated into an improvement in patients' well-being or performance status.
If we are going to recommend a regimen that does not affect survival and that costs more than $30,000 for an eight-week course (as Schrag notes in her Perspective article), surely information regarding possible improvements in the quality of life becomes an important factor for patients making decisions regarding their treatment options.
Michael J. Martin, Ph.D.
National Cancer Institute
Bethesda, MD 20892
martmich@mail.nih.gov
References
Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351:337-345.
To the Editor: What conclusions can be reached by comparing anything with itself? Cunningham and colleagues conducted a randomized, controlled trial comparing irinotecan plus cetuximab with cetuximab monotherapy. The purpose of the study was to evaluate the effect of cetuximab in patients with irinotecan-refractory colorectal cancer. However, since the only difference between the groups was the use or nonuse of irinotecan, the latter treatment is the only intervention actually studied. The authors come to the following conclusion: "Cetuximab has clinically significant activity when given alone or in combination with irinotecan in patients with irinotecan-refractory colorectal cancer." This is a conclusion one cannot reach on the basis of the presented data alone. In Cunningham and colleagues' study, cetuximab is a cointervention and not the studied drug. Analysis according to the treatment received would leave us with two case series. Moreover, findings derived from case series may be seen as data that generate no more than hypotheses in terms of treatment evaluation.
Andry F. Costa, M.D.
Guilherme B. Sander, M.D.
Paulo D. Picon, Ph.D.
Brazilian Ministry of Health
90470-420 Porto Alegre, Brazil
gbsander@yahoo.com.br
Dr. Schrag replies: It is indisputable that reducing the burden of death due to cancer is enormously valued and that the pharmaceutical industry has played a key role in developing better therapy. However, neither of these considerations justifies setting prices for cancer medicines in the stratosphere. There is no evidence that this practice is necessary to promote innovation. Mr. Holmer cites an estimate of $33 billion for the industry's investment in research and development — a figure that is not meaningful unless placed in context with estimates of the industry's profit margins, tax credits, and marketing budgets, as well as estimates of taxpayer-supported investment in medical research.
It is well known among economists, including the academics cited by Mr. Holmer, that people will express willingness to pay huge sums in order to avoid the threat of death. Yet that essential human vulnerability should not form the basis for establishing drug prices. Rather, what is needed is careful deliberation about our systems of drug development — constructive debate that avoids facile use of statistics and engages all key players: the pharmaceutical industry, the government, the medical profession, and especially the public.
Deborah Schrag, M.D., M.P.H.
Memorial Sloan-Kettering Cancer Center
New York, NY 10021
Drs. Chau and Cunningham reply: The purpose of our randomized study was to evaluate the relative importance of irinotecan-based chemotherapy when added to cetuximab in patients with epidermal growth factor receptor (EGFR)–expressing, irinotecan-refractory colorectal cancer. Our results support the concept that resistance to chemotherapy can be circumvented in a proportion of patients by means of EGFR blockade and confirm the observations made in two previously reported nonrandomized, phase 2 studies.1,2
In our study, the rate of radiologic response was used as the primary end point. This was considered a useful surrogate marker for clinical benefit in a group of heavily pretreated patients in whom radiologic responses would be uncommon. A radiologic response was observed in 22.9 percent of the patients receiving cetuximab plus irinotecan. Oxaliplatin, in conjunction with infused fluorouracil and leucovorin, was also first granted approval by the Food and Drug Administration on the basis of a randomized study in which the radiologic response was used as the primary end point.3 In that study, a response rate of 9.9 percent was obtained in irinotecan-resistant patients with the oxaliplatin-based combination. This chemotherapy regimen was subsequently found to offer a survival advantage as compared with a regimen of irinotecan plus bolus fluorouracil and leucovorin when used as a first-line treatment for metastatic colorectal cancer,4 and it is now considered a standard treatment in that setting.
The combination of irinotecan and cetuximab is being tested in an ongoing randomized trial involving patients who have not previously received irinotecan; it is hoped that this trial will provide further data on survival as well as symptoms, performance status, and the quality of life. The cost of delivering effective care for cancer is substantial; the societal and medical decisions surrounding the evaluation of such treatment are complex and were considered beyond the scope of our clinical report.
Ian Chau, M.B., B.S.
David Cunningham, M.D.
Royal Marsden Hospital
London SW3 6JJ, United Kingdom
david.cunningham@icr.ac.uk
References
Saltz L, Rubin MS, Hochster HS, et al. Cetuximab (IMC-C225) plus irinotecan (CPT-11) is active in CPT-11 refractory colorectal cancer that expresses epidermal growth factor receptor. Proc Am Soc Clin Oncol 2001;20:3a. abstract.
Saltz LB, Meropol NJ, Loehrer PJ Sr, Needle MN, Kopit J, Mayer RJ. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 2004;22:1201-1208.
Rothenberg ML, Oza AM, Bigelow RH, et al. Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a Phase III trial. J Clin Oncol 2003;21:2059-2069.
Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004;22:23-30.