Therapy for Colorectal Cancer
http://www.100md.com
《新英格兰医药杂志》
To the Editor: We believe Meyerhardt and Mayer's discussion of regional, targeted therapies for colorectal cancer (Feb. 3 issue)1 is incomplete. Regional infusion of interleukin-2 or interferon alfa through the hepatic artery, combined with chemotherapy, yields better results than chemotherapy alone in patients with metastatic colorectal disease.2,3,4 Moreover, modulation of fluorouracil-metabolizing enzymes by interleukin-2 appears to enhance the effectiveness of this chemotherapeutic agent. In addition, major surgery for liver metastases induces stimulation of angiogenesis and immunosuppression consisting of lymphocytopenia, reductions in the blood levels of antitumor interleukin-2 and interleukin-12, and increases in the level of immunosuppressive interleukin-6.5 On the other hand, according to clinical trials, preoperative subcutaneous administration of interleukin-2 may prevent surgery-induced immunosuppression, and may counteract surgery-induced stimulation of angiogenesis either by reducing the increased levels of angiogenic vascular endothelial growth factor observed during surgery or by opposing the decline in the blood levels of antiangiogenic and antitumor interleukin-12. Interleukin-2 administration appears to be well tolerated and without cardiovascular complications during the perioperative period.5 Therefore, surgeons might consider introducing this preoperative immunotherapeutic approach.5
Jannis Kountouras, M.D., Ph.D.
Christos Zavos, M.D.
Dimitrios Chatzopoulos, M.D.
Aristotle University of Thessaloniki
546 42 Thessaloniki, Greece
jannis@med.auth.gr
References
Meyerhardt JA, Mayer RJ. Systemic therapy for colorectal cancer. N Engl J Med 2005;352:476-487.
Kountouras J, Zavos C, Chatzopoulos D, Zavos N, Boura P, Safioleas M. Locoregional immunochemotherapy in primary and metastatic liver disease: meta-analysis and review of literature. Hepatogastroenterology 2003;50:1506-1510.
Lygidakis NJ, Sgourakis G, Vlachos L, et al. Metastatic liver disease of colorectal origin: the value of locoregional immunochemotherapy combined with systemic chemotherapy following liver resection: results of a prospective randomized study. Hepatogastroenterology 2001;48:1685-1691.
Sato T. Locoregional immuno(bio)therapy for liver metastases. Semin Oncol 2002;29:160-167.
Kountouras J, Zavos C, Chatzopoulos D. Immunotherapy in metastatic liver disease. In: Lee F, ed. Liver cancer: new research. New York: Nova Science (in press).
To the Editor: Many patients with a diagnosis of colorectal cancer are young and may be cured. Fertility and reproductive issues among patients who have received fluorouracil as adjuvant therapy have rarely been addressed.
A 31-year-old woman was examined because of hematochezia. A colonoscopy showed a tumor in the sigmoid colon. A left hemicolectomy was performed. Pathological examination showed a 3-cm adenocarcinoma and metastatic disease in two lymph nodes examined. The patient received six cycles of fluorouracil plus leucovorin for 5 days every 28 days. At 30 months of follow-up, she had no evidence of relapse. She later became pregnant. Her pregnancy was uneventful, and a normal child was delivered.
The limited value of this report should be complemented by data gathered after long-term follow-up from randomized trials. In the meantime, this case points to the real benefits that adjuvant chemotherapy may offer to some young patients.
Gustavo Jankilevich, M.D.
Hospital Durand
1426 Buenos Aires, Argentina
gustavojank@hotmail.com
To the Editor: In reading the review article by Meyerhardt and Mayer, I was unable to find any indication of quality of life in association with the extension of survival (from 6 to more than 20 months) documented in Figure 1. The question really is this: What was the quality of life during the months gained as a result of the blast of toxic chemicals? My observation is that patients who have received such treatment are in fact quite miserable. It is not uncommon to hear patients say, "I wish I had never had it." I strongly recommend that investigators embarking on these highly toxic endeavors include quality-of-life measurements.
William S. Masland, M.D.
2475 Ave. A
Yuma, AZ 85364
To the Editor: Meyerhardt and Mayer cite several articles in support of their statement that "the use of chemotherapy in patients with metastatic disease prolongs survival and enhances quality of life in comparison to palliative care alone." The World Health Organization describes palliative care as an "impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual."1 The articles cited by Meyerhardt and Mayer do not mention a treatment group receiving palliative care defined in this way. One report describes supportive care as "symptomatic therapy and/or assistance of a psychotherapist,"2 which hardly constitutes palliative care. Given Mayer's endorsement of palliative care,3 we are surprised at the noncritical acceptance of the studies cited. We are not arguing that chemotherapy may not offer an advantage in terms of quality of life over palliative care; rather, studies either have not yet tested this hypothesis or have not described their methods of supportive care sufficiently. Palliative interventions have been well described, so studies in which the "best supportive care" is used should include standardized protocols for palliation. Otherwise, quality-of-life claims, such as those made by the authors of this review, are likely to be subject to ongoing criticism.
Shiri Etzioni, M.D.
Ken Rosenfeld, M.D.
Greater Los Angeles Veterans Hospital
Los Angeles, CA 90073
shiri.etzioni@med.va.gov
References
World Health Organization. Palliative care. 2005. (Accessed April 8, 2005, at http://www.who.int/cancer/palliative.)
Cunningham D, Pyrhonen S, James RD, et al. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 1998;352:1413-1418.
Cancer care during the last phase of life. J Clin Oncol 1998;16:1986-1996.
The authors reply: Drs. Etzioni and Rosenfeld address the need for clearly defined definitions to help distinguish "palliative care" from the "best supportive care." In the area of advanced colorectal cancer, multiple randomized trials conducted more than 15 years ago showed that the use of chemotherapy prolongs survival when compared with the "best supportive care,"1 and some of these trials also indicated that anticancer treatment improves the "quality of life." Although one may question the precise definition of "palliative care," the fact that the cohorts of patients assigned to systemic treatment survived two to three times as long as those not assigned to chemotherapy and appeared, according to "quality of life" measurements, to have had a reduction in symptoms during that time appears to us to represent a positive step forward. Dr. Masland's reference to systemic treatment for colorectal cancer as a "blast of toxic chemicals" should be balanced by the reality that such treatment is routinely given on an outpatient basis, that it usually allows patients to continue the majority of their normal professional and social activities, and as illustrated by Dr. Jankilevich, that it often does not interfere with subsequent fertility.
Dr. Kountouras and colleagues focus on the regional and systemic use of interleukin-2 or interferon alfa in the treatment of patients with advanced colorectal cancer. Meta-analyses, however, have not shown a survival advantage with hepatic arterial infusion among patients with unresectable liver metastases2 or among those who have undergone a hepatic metastasectomy.3 Furthermore, randomized trials have failed to demonstrate any benefit of the addition of interleukin-2 or interferon alfa to fluorouracil for advanced disease.4,5
Jeffrey A. Meyerhardt, M.D., M.P.H.
Robert J. Mayer, M.D.
Dana–Farber Cancer Institute
Boston, MA 02115
References
Simmonds PC. Palliative chemotherapy for advanced colorectal cancer: systematic review and meta-analysis. BMJ 2000;321:531-535.
Meta-Analysis Group in Cancer. Reappraisal of hepatic arterial infusion in the treatment of nonresectable liver metastases from colorectal cancer. J Natl Cancer Inst 1996;88:252-258.
Clancy TE, Dixon E, Perlis R, Sutherland FR, Zinner MJ. Hepatic arterial infusion after curative resection of colorectal cancer metastases: a meta-analysis of prospective clinical trials. J Gastrointest Surg 2005;9:198-206.
Heys SD, Eremin O, Ruggeri EM, et al. A phase III study of recombinant interleukin-2, 5-fluorouracil and leucovorin versus 5-fluorouracil and leucovorin in patients with unresectable or metastatic colorectal carcinoma. Eur J Cancer 1995;31:19-25.
Thirion P, Piedbois P, Buyse M, et al. Alpha-interferon does not increase the efficacy of 5-fluorouracil in advanced colorectal cancer. Br J Cancer 2001;84:611-620.
Jannis Kountouras, M.D., Ph.D.
Christos Zavos, M.D.
Dimitrios Chatzopoulos, M.D.
Aristotle University of Thessaloniki
546 42 Thessaloniki, Greece
jannis@med.auth.gr
References
Meyerhardt JA, Mayer RJ. Systemic therapy for colorectal cancer. N Engl J Med 2005;352:476-487.
Kountouras J, Zavos C, Chatzopoulos D, Zavos N, Boura P, Safioleas M. Locoregional immunochemotherapy in primary and metastatic liver disease: meta-analysis and review of literature. Hepatogastroenterology 2003;50:1506-1510.
Lygidakis NJ, Sgourakis G, Vlachos L, et al. Metastatic liver disease of colorectal origin: the value of locoregional immunochemotherapy combined with systemic chemotherapy following liver resection: results of a prospective randomized study. Hepatogastroenterology 2001;48:1685-1691.
Sato T. Locoregional immuno(bio)therapy for liver metastases. Semin Oncol 2002;29:160-167.
Kountouras J, Zavos C, Chatzopoulos D. Immunotherapy in metastatic liver disease. In: Lee F, ed. Liver cancer: new research. New York: Nova Science (in press).
To the Editor: Many patients with a diagnosis of colorectal cancer are young and may be cured. Fertility and reproductive issues among patients who have received fluorouracil as adjuvant therapy have rarely been addressed.
A 31-year-old woman was examined because of hematochezia. A colonoscopy showed a tumor in the sigmoid colon. A left hemicolectomy was performed. Pathological examination showed a 3-cm adenocarcinoma and metastatic disease in two lymph nodes examined. The patient received six cycles of fluorouracil plus leucovorin for 5 days every 28 days. At 30 months of follow-up, she had no evidence of relapse. She later became pregnant. Her pregnancy was uneventful, and a normal child was delivered.
The limited value of this report should be complemented by data gathered after long-term follow-up from randomized trials. In the meantime, this case points to the real benefits that adjuvant chemotherapy may offer to some young patients.
Gustavo Jankilevich, M.D.
Hospital Durand
1426 Buenos Aires, Argentina
gustavojank@hotmail.com
To the Editor: In reading the review article by Meyerhardt and Mayer, I was unable to find any indication of quality of life in association with the extension of survival (from 6 to more than 20 months) documented in Figure 1. The question really is this: What was the quality of life during the months gained as a result of the blast of toxic chemicals? My observation is that patients who have received such treatment are in fact quite miserable. It is not uncommon to hear patients say, "I wish I had never had it." I strongly recommend that investigators embarking on these highly toxic endeavors include quality-of-life measurements.
William S. Masland, M.D.
2475 Ave. A
Yuma, AZ 85364
To the Editor: Meyerhardt and Mayer cite several articles in support of their statement that "the use of chemotherapy in patients with metastatic disease prolongs survival and enhances quality of life in comparison to palliative care alone." The World Health Organization describes palliative care as an "impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual."1 The articles cited by Meyerhardt and Mayer do not mention a treatment group receiving palliative care defined in this way. One report describes supportive care as "symptomatic therapy and/or assistance of a psychotherapist,"2 which hardly constitutes palliative care. Given Mayer's endorsement of palliative care,3 we are surprised at the noncritical acceptance of the studies cited. We are not arguing that chemotherapy may not offer an advantage in terms of quality of life over palliative care; rather, studies either have not yet tested this hypothesis or have not described their methods of supportive care sufficiently. Palliative interventions have been well described, so studies in which the "best supportive care" is used should include standardized protocols for palliation. Otherwise, quality-of-life claims, such as those made by the authors of this review, are likely to be subject to ongoing criticism.
Shiri Etzioni, M.D.
Ken Rosenfeld, M.D.
Greater Los Angeles Veterans Hospital
Los Angeles, CA 90073
shiri.etzioni@med.va.gov
References
World Health Organization. Palliative care. 2005. (Accessed April 8, 2005, at http://www.who.int/cancer/palliative.)
Cunningham D, Pyrhonen S, James RD, et al. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 1998;352:1413-1418.
Cancer care during the last phase of life. J Clin Oncol 1998;16:1986-1996.
The authors reply: Drs. Etzioni and Rosenfeld address the need for clearly defined definitions to help distinguish "palliative care" from the "best supportive care." In the area of advanced colorectal cancer, multiple randomized trials conducted more than 15 years ago showed that the use of chemotherapy prolongs survival when compared with the "best supportive care,"1 and some of these trials also indicated that anticancer treatment improves the "quality of life." Although one may question the precise definition of "palliative care," the fact that the cohorts of patients assigned to systemic treatment survived two to three times as long as those not assigned to chemotherapy and appeared, according to "quality of life" measurements, to have had a reduction in symptoms during that time appears to us to represent a positive step forward. Dr. Masland's reference to systemic treatment for colorectal cancer as a "blast of toxic chemicals" should be balanced by the reality that such treatment is routinely given on an outpatient basis, that it usually allows patients to continue the majority of their normal professional and social activities, and as illustrated by Dr. Jankilevich, that it often does not interfere with subsequent fertility.
Dr. Kountouras and colleagues focus on the regional and systemic use of interleukin-2 or interferon alfa in the treatment of patients with advanced colorectal cancer. Meta-analyses, however, have not shown a survival advantage with hepatic arterial infusion among patients with unresectable liver metastases2 or among those who have undergone a hepatic metastasectomy.3 Furthermore, randomized trials have failed to demonstrate any benefit of the addition of interleukin-2 or interferon alfa to fluorouracil for advanced disease.4,5
Jeffrey A. Meyerhardt, M.D., M.P.H.
Robert J. Mayer, M.D.
Dana–Farber Cancer Institute
Boston, MA 02115
References
Simmonds PC. Palliative chemotherapy for advanced colorectal cancer: systematic review and meta-analysis. BMJ 2000;321:531-535.
Meta-Analysis Group in Cancer. Reappraisal of hepatic arterial infusion in the treatment of nonresectable liver metastases from colorectal cancer. J Natl Cancer Inst 1996;88:252-258.
Clancy TE, Dixon E, Perlis R, Sutherland FR, Zinner MJ. Hepatic arterial infusion after curative resection of colorectal cancer metastases: a meta-analysis of prospective clinical trials. J Gastrointest Surg 2005;9:198-206.
Heys SD, Eremin O, Ruggeri EM, et al. A phase III study of recombinant interleukin-2, 5-fluorouracil and leucovorin versus 5-fluorouracil and leucovorin in patients with unresectable or metastatic colorectal carcinoma. Eur J Cancer 1995;31:19-25.
Thirion P, Piedbois P, Buyse M, et al. Alpha-interferon does not increase the efficacy of 5-fluorouracil in advanced colorectal cancer. Br J Cancer 2001;84:611-620.