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Reassessing chemotherapy in gastric and pancreatic cancer
GASTROENTEROLOGY
SELECTED
1985;89:917-21
SUMMARIES
ROBERTM. GLICKMAR
Selected Columbia College of New York,
Summaries Editor University Physicians & Surgeons New York 10032 STAFF
Thomas A. Brasitus, Chicago, Ill. Richard J, Deckelbaum, Jerusalem, Serge Erlinger, Paris, France W. G. M. Hardison,
San Diego,
Israel
Calif.
Lucien R. Jacobs, Davis, Calif. Khursheed Jeejeebhoy, Toronto, Canada Rayford S. Jones, Charlottesville, Va.
OF CONTRIBUTORS Seymour
M. Sabesin,
Memphis.
Term.
Martin F. Kagnoff, San Diego, Calif. Sumner C. Kraft, Chicago, Ill. Robert C. Kurtz, New York, N.Y. Richard P. MacDermott, Boston, Mass.
Melvin Schapiro, Los Angeles, Calif. Konrad Schulze-Delrieu, Iowa City, lowa Joseph Sweeting, New York, N.Y.
James McManus, Temple, Tex. Ann Ouyang, Philadelphia, Pa. David F. Ransohoff, Cleveland, Ohio
Martin H. Ulshen, Chapel Hill, N.C. Ernest Urban, San Antonio, Tex. Milton M. Weiser, Buffalo, N.Y.
REASSESSING CHEMOTHERAPY IN GASTRIC AND PANCREATIC CANCER Cullinan SA, Moertel CG, Fleming TR, et al. (North Central Cancer Treatment Group and Mayo Clinic, Rochester, Minnesota) A comparison of three chemotherapeutic regimens in the treatment of advanced pancreatic and gastric carcinoma. Fluorouracil vs fluorouracil and doxorubicin vs fluorouracil, doxorubicin, and mitomycin. JAMA 1985;253:2061-7. Three hundred five patients with histologic confirmation of unresectable or metastatic adenocarcinoma with a gastric or pancreatic primary were randomized to this study conducted by 11 member institutions of the North Central Cancer Treatment Group and the Mayo Clinic. Patients with both measurable and nonmeasurable disease who were ambulatory and capable of maintaining oral nutrition were stratified within each institution according to primary tumor, stage of disease, presence of measurable disease, and performance status. Patients were then randomized to fluorouracil alone (F), fluorouracil with adriamycin (FA), or FA with mitomycin (FAM). Treatment was continued until the patient showed progression of disease. Both progression of disease and objective response were defined according to already accepted criteria. Fluorouracil with adriamycin and FAM regimens were compared with F alone with respect to duration of survival, time to disease progression, objective regression probability among measurable patients, drug toxicity, and palliative effects. Very few patients (10, 3.3%) were found to be ineligible for analysis. Almost all (96.6%) of the 295 analyzable patients were dead at the time the manuscript was written. Sex, age, performance score, stage, and measurable disease were similar in all three treatment arms. These characteristics, except age, were significantly associated with survival time, which was the end point of the study. Elevation of serum bilirubin level in pancreatic cancer, site of cancer in the stomach, and prior resection of gastric cancer did not have any such association. The median survival for all patients with pancreatic cancer was 22 wk and for those with gastric cancer, 29 wk. There was no difference in survival among the three treatment arms for either pancreatic or gastric cancer. Similarly, the median interval to
progression was 9 wk for all patients with pancreatic cancer and 17 wk for all patients with gastric cancer and was not different within each tumor type. The objective response rates were also comparable between the three treatment arms and were 24% for F alone, 29% for FA, and 23% for FAM. The numbers were too small to make even tentative conclusions about comparative response rates within each tumor type. The FAM combination produced more frequent leukopenia, significantly more thrombocytopenia (p < O.OOl), and more cumulative myelosuppression (due to mitomycin) than treatment with either F alone or FA. Anorexia, nausea, and vomiting were significantly more common in doxorubicin (adriamycin)-containing regimens, whereas diarrhea and stomatitis were significantly more common with fluorouracil alone. Finally, the cost of treatment was $29 for F alone, $379 for FA, and $500 for FAM for an 8-wk cycle in a 2 sq m patient. The authors concluded that there is no good reason to use FA or FAM in place of 5-fluorouracil (5FU) alone in advanced gastric or pancreatic cancers. They believed that the high objective response rates and longer survival in responders than nonresponders with FAM are not valid. Objectivity in assessing response can often be subjective when dealing with poorly defined abdominal lumps. Additionally, responders will always be shown to live longer than nonresponders in any chemotherapy study with adequate numbers of patients. Responders have a better initial performance status and better nutritional status than nonresponders, and are going to live longer whether they are treated or not. One has to be alive to show a response, and the nonresponders’ shorter survival could well be due to the deleterious effects of chemotherapy. Comment. Advanced gastric and pancreatic cancer rank as seventh and fifth as causes of cancer death in the United States. Carcinoma of the pancreas has had a steadily increasing incidence in this country over the past four decades (Cancer 1982;32:15-311, and ~15% of patients with cancer of the pancreas will be candidates for resection because of the advanced nature of the tumor at the time of diagnosis (Cancer 1979;42:2494-506). Unfortunately, 80%90% of patients with gastric c:ancer will present with or eventually develop metastatic disease. As a result of a number of trials reporting good response rates with FAM in advanced gastric and pancreatic cancers, the Food and Drug Administration has officially approved this regimen as effective
918
SELECTED SUMMARIES
GASTROENTEROLOGY
therapy for both tumors. The rationale behind using this regimen includes the more extensive experience with 5FU and mitomycin C as single agents in both diseases, with response rates being 20% and 15%-30%, respectively, in gastric cancer and ~8% and 27%, respectively, in pancreatic cancer, based on a substantial number of single-agent trials. On the other hand, although the efficacy of adriamycin as a single agent was impressive in gastric cancer, with response rates ranging from 22% to 36% (Front Gastrointest Cancer 1984;44), its role in pancreatic cancer as a single agent was questionable, with a response rate of only 13% (Cancer 1978;42:19-22). The poor response rates with single agents, which last only for a short duration, and the dramatic results of multidrug programs in the treatment of lymphomas and testicular cancers resulted in the evolution of multidrug regimens in the treatment of gastrointestinal cancers. The oncology literature is full of phase If trials that compare survival between responders and nonresponders rather than with the time-consuming controlled trials with different regimens, even if an untreated control group was not studied. Also, objective response rates must be correlated with improved survival and better quality of life. There are several controlled trials in advanced gastric cancer that show the benefit of adriamycin-containing regimens. The Gastrointestinal Tumor Study Group (Cancer Treat Rep 1979;63: 1863-9) reported a 47% response rate with FA methyl-CCNU (FAMe) versus a 17% response rate with 5FU, methyl-CCNU, and cytosine arabinoside, and a 24% response rate with adriamycin alone. Patients treated with FAMe had significantly improved survival compared with those in the other two groups. Another study demonstrated a 36% response rate with FAMe versus 9% with 5FU and methyl-CCNU (Proc Am Sot Clin Oncol 1979; 20:310). The Eastern Cooperative Oncology Group reported a randomized trial with 5FU and methyl-CCNU, FAMe, FAM, and AM. The highest response rates were seen with the FAM regimen (39%). In this study, the highest response rate was also associated with the longest median survival, and the toxicity was least with this regimen. Remarkably, the response to FAM was greatest (56%) among patients who were partially confined to bed. In an additional subset of patients who had received 5FU earlier with no response, the AM combination proved to be effective. On the other hand, the Southwest Oncology Group reported a 22% response rate and median survival of 22 wk with FAM. The survival was no different than in the other four arms in their trial (Proc Am Sot Clin Oncol 1983;2:122). The only study in pancreatic cancer that had an untreated control group reported highly significant survival for those treated with a combination of cyclophosphamide, vincristine, 5FU, mitomycin, and methotrexate (Br Med J 1980;281:1589-91). There are two trials comparing FAM with other regimens that reported response rates of 9.3% and 13%, respectively, and no significant benefit in response rate or survival over other arms (Proc Am Sot Clin Oncol 1982;1:90, Proc Am Sot Chn Oncol 1984;3:150). Every gastroenterologist, surgeon, and oncologist involved in the treatment of gastrointestinal cancers can recall several patients with advanced gastric cancer, and fewer patients with pancreatic cancer, where clinical improvement and longer than expected survival was seen with FAM. The question is whether this benefit was due to 5FU alone, an earlier stage of disease, or improved nutritional status of the patient. The present study has again pointed out the controversy that exists in the chemotherapy of gastrointestinal cancer. Clearly, new effective drugs and better tolerated treatment programs need to be developed. Until they arrive in clinical use, our present treatment programs should continue to be evaluated in a controlled setting wherever possible. V. SANTHI SWAROOP, M.D. ROBERT C. KURTZ, M.D.
Vol. 89, No. 4
MICROSCOPIC COLITIS AND CHRONIC DIARRHEA Bo-Linn G, Vendrell D, Lee E, et al. (Departments of Internal Medicine and Pathology, Baylor University Medical Center; Department of Pathology, Dallas Veterans Administration Medical Center, Dallas, Texas] An evaluation of the significance of microscopic colitis in patients with chronic diarrhea. J Clin Invest 1985;75:1559-69. The number of patients with diarrhea of unknown cause remains discouragingly high. Fortunately, most of the problems are not clinically serious and are usually ascribed to the irritable bowel syndrome. Occasionally, however, the amount of diarrhea in these undiagnosed cases is significant. Read et al. (Gastroenterology 1980; 78264-71) previously reported a major effort to find an etiology in 27 patients who were referred for evaluation of large volume, undiagnosed diarrhea1 disease. Despite investigative studies far beyond the resources of most physicians, only 13 of the patients had a definite cause found for the diarrhea. In one subset of this group (8 of 27), biopsy specimens of the colon or rectum showed a nonspecific, mild to moderate, generalized inflammation, in spite of normal findings on barium enema and colonoscopy. The present paper from the same center reports further studies on 6 patients, 5 of which are newly described patients. They all had significant, nonbloody watery diarrhea that ranged from 400 to 1200 ml/day when the patients were eating normally. When they fasted, 5 of 6 patients demonstrated a decrease in stool volume to near normal levels. A major part of the present study consisted of establishing the validity of the histologic distinction between controls and patients. Two control groups were used. One was a normal group without diarrhea (n = 9) and the other (n = 9) had chronic diarrhea but no microscopic colitis at biopsy. Two pathologists blindly reviewed all the biopsy specimens on two occasions. The overall concordance was >99%. The inflammation was found on biopsy specimens taken throughout the entire colon and the pathologists were unable to tell the sites from which the biopsy specimens had been obtained. Intestinal absorption in these 6 patients was studied using triple-lumen tubes for perfusion of the jejunum, ileum, and colon. Absorption of water, electrolytes, and xylose was studied in these areas and the potential difference across the mucosa was determined using the perfused electrolyte solution as a flowing intraluminal electrode. Unidirectional fluxes were determined [in some patients) by using labeled sodium and chloride. The most consistent finding was a significant reduction in water absorption in the colon of the patients with microscopic colitis. Mean normal water absorption in the colon in previously studied normals was 159 ml/h compared with 26 ml/h in the patients with microscopic colitis. It is of note that 3 of 5 patients with idiopathic diarrhea and normal biopsy specimens (part of the chronic diarrhea control group) also had decreased water absorption in the colon, indicating that microscopic colitis is not a requisite finding in patients with impaired colonic water absorption. Net sodium and chloride absorption in the colon also tended to be reduced
SELECTED
1985;89:917-21
SUMMARIES
ROBERTM. GLICKMAR
Selected Columbia College of New York,
Summaries Editor University Physicians & Surgeons New York 10032 STAFF
Thomas A. Brasitus, Chicago, Ill. Richard J, Deckelbaum, Jerusalem, Serge Erlinger, Paris, France W. G. M. Hardison,
San Diego,
Israel
Calif.
Lucien R. Jacobs, Davis, Calif. Khursheed Jeejeebhoy, Toronto, Canada Rayford S. Jones, Charlottesville, Va.
OF CONTRIBUTORS Seymour
M. Sabesin,
Memphis.
Term.
Martin F. Kagnoff, San Diego, Calif. Sumner C. Kraft, Chicago, Ill. Robert C. Kurtz, New York, N.Y. Richard P. MacDermott, Boston, Mass.
Melvin Schapiro, Los Angeles, Calif. Konrad Schulze-Delrieu, Iowa City, lowa Joseph Sweeting, New York, N.Y.
James McManus, Temple, Tex. Ann Ouyang, Philadelphia, Pa. David F. Ransohoff, Cleveland, Ohio
Martin H. Ulshen, Chapel Hill, N.C. Ernest Urban, San Antonio, Tex. Milton M. Weiser, Buffalo, N.Y.
REASSESSING CHEMOTHERAPY IN GASTRIC AND PANCREATIC CANCER Cullinan SA, Moertel CG, Fleming TR, et al. (North Central Cancer Treatment Group and Mayo Clinic, Rochester, Minnesota) A comparison of three chemotherapeutic regimens in the treatment of advanced pancreatic and gastric carcinoma. Fluorouracil vs fluorouracil and doxorubicin vs fluorouracil, doxorubicin, and mitomycin. JAMA 1985;253:2061-7. Three hundred five patients with histologic confirmation of unresectable or metastatic adenocarcinoma with a gastric or pancreatic primary were randomized to this study conducted by 11 member institutions of the North Central Cancer Treatment Group and the Mayo Clinic. Patients with both measurable and nonmeasurable disease who were ambulatory and capable of maintaining oral nutrition were stratified within each institution according to primary tumor, stage of disease, presence of measurable disease, and performance status. Patients were then randomized to fluorouracil alone (F), fluorouracil with adriamycin (FA), or FA with mitomycin (FAM). Treatment was continued until the patient showed progression of disease. Both progression of disease and objective response were defined according to already accepted criteria. Fluorouracil with adriamycin and FAM regimens were compared with F alone with respect to duration of survival, time to disease progression, objective regression probability among measurable patients, drug toxicity, and palliative effects. Very few patients (10, 3.3%) were found to be ineligible for analysis. Almost all (96.6%) of the 295 analyzable patients were dead at the time the manuscript was written. Sex, age, performance score, stage, and measurable disease were similar in all three treatment arms. These characteristics, except age, were significantly associated with survival time, which was the end point of the study. Elevation of serum bilirubin level in pancreatic cancer, site of cancer in the stomach, and prior resection of gastric cancer did not have any such association. The median survival for all patients with pancreatic cancer was 22 wk and for those with gastric cancer, 29 wk. There was no difference in survival among the three treatment arms for either pancreatic or gastric cancer. Similarly, the median interval to
progression was 9 wk for all patients with pancreatic cancer and 17 wk for all patients with gastric cancer and was not different within each tumor type. The objective response rates were also comparable between the three treatment arms and were 24% for F alone, 29% for FA, and 23% for FAM. The numbers were too small to make even tentative conclusions about comparative response rates within each tumor type. The FAM combination produced more frequent leukopenia, significantly more thrombocytopenia (p < O.OOl), and more cumulative myelosuppression (due to mitomycin) than treatment with either F alone or FA. Anorexia, nausea, and vomiting were significantly more common in doxorubicin (adriamycin)-containing regimens, whereas diarrhea and stomatitis were significantly more common with fluorouracil alone. Finally, the cost of treatment was $29 for F alone, $379 for FA, and $500 for FAM for an 8-wk cycle in a 2 sq m patient. The authors concluded that there is no good reason to use FA or FAM in place of 5-fluorouracil (5FU) alone in advanced gastric or pancreatic cancers. They believed that the high objective response rates and longer survival in responders than nonresponders with FAM are not valid. Objectivity in assessing response can often be subjective when dealing with poorly defined abdominal lumps. Additionally, responders will always be shown to live longer than nonresponders in any chemotherapy study with adequate numbers of patients. Responders have a better initial performance status and better nutritional status than nonresponders, and are going to live longer whether they are treated or not. One has to be alive to show a response, and the nonresponders’ shorter survival could well be due to the deleterious effects of chemotherapy. Comment. Advanced gastric and pancreatic cancer rank as seventh and fifth as causes of cancer death in the United States. Carcinoma of the pancreas has had a steadily increasing incidence in this country over the past four decades (Cancer 1982;32:15-311, and ~15% of patients with cancer of the pancreas will be candidates for resection because of the advanced nature of the tumor at the time of diagnosis (Cancer 1979;42:2494-506). Unfortunately, 80%90% of patients with gastric c:ancer will present with or eventually develop metastatic disease. As a result of a number of trials reporting good response rates with FAM in advanced gastric and pancreatic cancers, the Food and Drug Administration has officially approved this regimen as effective
918
SELECTED SUMMARIES
GASTROENTEROLOGY
therapy for both tumors. The rationale behind using this regimen includes the more extensive experience with 5FU and mitomycin C as single agents in both diseases, with response rates being 20% and 15%-30%, respectively, in gastric cancer and ~8% and 27%, respectively, in pancreatic cancer, based on a substantial number of single-agent trials. On the other hand, although the efficacy of adriamycin as a single agent was impressive in gastric cancer, with response rates ranging from 22% to 36% (Front Gastrointest Cancer 1984;44), its role in pancreatic cancer as a single agent was questionable, with a response rate of only 13% (Cancer 1978;42:19-22). The poor response rates with single agents, which last only for a short duration, and the dramatic results of multidrug programs in the treatment of lymphomas and testicular cancers resulted in the evolution of multidrug regimens in the treatment of gastrointestinal cancers. The oncology literature is full of phase If trials that compare survival between responders and nonresponders rather than with the time-consuming controlled trials with different regimens, even if an untreated control group was not studied. Also, objective response rates must be correlated with improved survival and better quality of life. There are several controlled trials in advanced gastric cancer that show the benefit of adriamycin-containing regimens. The Gastrointestinal Tumor Study Group (Cancer Treat Rep 1979;63: 1863-9) reported a 47% response rate with FA methyl-CCNU (FAMe) versus a 17% response rate with 5FU, methyl-CCNU, and cytosine arabinoside, and a 24% response rate with adriamycin alone. Patients treated with FAMe had significantly improved survival compared with those in the other two groups. Another study demonstrated a 36% response rate with FAMe versus 9% with 5FU and methyl-CCNU (Proc Am Sot Clin Oncol 1979; 20:310). The Eastern Cooperative Oncology Group reported a randomized trial with 5FU and methyl-CCNU, FAMe, FAM, and AM. The highest response rates were seen with the FAM regimen (39%). In this study, the highest response rate was also associated with the longest median survival, and the toxicity was least with this regimen. Remarkably, the response to FAM was greatest (56%) among patients who were partially confined to bed. In an additional subset of patients who had received 5FU earlier with no response, the AM combination proved to be effective. On the other hand, the Southwest Oncology Group reported a 22% response rate and median survival of 22 wk with FAM. The survival was no different than in the other four arms in their trial (Proc Am Sot Clin Oncol 1983;2:122). The only study in pancreatic cancer that had an untreated control group reported highly significant survival for those treated with a combination of cyclophosphamide, vincristine, 5FU, mitomycin, and methotrexate (Br Med J 1980;281:1589-91). There are two trials comparing FAM with other regimens that reported response rates of 9.3% and 13%, respectively, and no significant benefit in response rate or survival over other arms (Proc Am Sot Clin Oncol 1982;1:90, Proc Am Sot Chn Oncol 1984;3:150). Every gastroenterologist, surgeon, and oncologist involved in the treatment of gastrointestinal cancers can recall several patients with advanced gastric cancer, and fewer patients with pancreatic cancer, where clinical improvement and longer than expected survival was seen with FAM. The question is whether this benefit was due to 5FU alone, an earlier stage of disease, or improved nutritional status of the patient. The present study has again pointed out the controversy that exists in the chemotherapy of gastrointestinal cancer. Clearly, new effective drugs and better tolerated treatment programs need to be developed. Until they arrive in clinical use, our present treatment programs should continue to be evaluated in a controlled setting wherever possible. V. SANTHI SWAROOP, M.D. ROBERT C. KURTZ, M.D.
Vol. 89, No. 4
MICROSCOPIC COLITIS AND CHRONIC DIARRHEA Bo-Linn G, Vendrell D, Lee E, et al. (Departments of Internal Medicine and Pathology, Baylor University Medical Center; Department of Pathology, Dallas Veterans Administration Medical Center, Dallas, Texas] An evaluation of the significance of microscopic colitis in patients with chronic diarrhea. J Clin Invest 1985;75:1559-69. The number of patients with diarrhea of unknown cause remains discouragingly high. Fortunately, most of the problems are not clinically serious and are usually ascribed to the irritable bowel syndrome. Occasionally, however, the amount of diarrhea in these undiagnosed cases is significant. Read et al. (Gastroenterology 1980; 78264-71) previously reported a major effort to find an etiology in 27 patients who were referred for evaluation of large volume, undiagnosed diarrhea1 disease. Despite investigative studies far beyond the resources of most physicians, only 13 of the patients had a definite cause found for the diarrhea. In one subset of this group (8 of 27), biopsy specimens of the colon or rectum showed a nonspecific, mild to moderate, generalized inflammation, in spite of normal findings on barium enema and colonoscopy. The present paper from the same center reports further studies on 6 patients, 5 of which are newly described patients. They all had significant, nonbloody watery diarrhea that ranged from 400 to 1200 ml/day when the patients were eating normally. When they fasted, 5 of 6 patients demonstrated a decrease in stool volume to near normal levels. A major part of the present study consisted of establishing the validity of the histologic distinction between controls and patients. Two control groups were used. One was a normal group without diarrhea (n = 9) and the other (n = 9) had chronic diarrhea but no microscopic colitis at biopsy. Two pathologists blindly reviewed all the biopsy specimens on two occasions. The overall concordance was >99%. The inflammation was found on biopsy specimens taken throughout the entire colon and the pathologists were unable to tell the sites from which the biopsy specimens had been obtained. Intestinal absorption in these 6 patients was studied using triple-lumen tubes for perfusion of the jejunum, ileum, and colon. Absorption of water, electrolytes, and xylose was studied in these areas and the potential difference across the mucosa was determined using the perfused electrolyte solution as a flowing intraluminal electrode. Unidirectional fluxes were determined [in some patients) by using labeled sodium and chloride. The most consistent finding was a significant reduction in water absorption in the colon of the patients with microscopic colitis. Mean normal water absorption in the colon in previously studied normals was 159 ml/h compared with 26 ml/h in the patients with microscopic colitis. It is of note that 3 of 5 patients with idiopathic diarrhea and normal biopsy specimens (part of the chronic diarrhea control group) also had decreased water absorption in the colon, indicating that microscopic colitis is not a requisite finding in patients with impaired colonic water absorption. Net sodium and chloride absorption in the colon also tended to be reduced