Symposium on Surgical Practice at the University of Chicago Clinics
The Gastrointestinal Oncology Clinic A Multidisciplinary Approach to Cancer Diagnosis and Management at a University Medical Center
Bernard Levin, M.D.,* David A. Karlin, M.D.,t Susan Schulman, A.B.,! Gloria W. Thorp,! Joseph B. Kirsner, M.D., Ph.D.,§ and 1. H. Rosenberg, M.D.**
The diagnosis and therapy of gastrointestinal neoplasms present multiple, challenging problems. Early detection remains the best hope for cure, yet too many physicians neglect to perform proctoscopic or even rectal examinations as part of a general evaluation of the patient. Individuals with certain diseases, such as ulcerative colitis or adenomatous polyps, have an increased risk for developing colorectal carcinoma, yet few intensive testing programs for these groups have been carried out in the past. The patient with metastatic disease may be in need of one or more modalities of therapy; yet communication among physicians in the different disciplines may be sporadic, superficial, and uninformative. To try to resolve these difficulties, a gastrointestinal oncology program was organized and started at this institution in early 1973. From the Department of Medicine, University of Chicago Pritzker School of Medicine, Chicago, Illinois "Assistant Professor of Medicine t Fellow in Medicine :::Staff §Louis Block Distinguished Service Professor of Medicine and Chief, Clinical Staff; Deputy Dean for Medical Affairs, Division of Biological Science and the Pritzker School of Medicine ""Associate Professor of Medicine Supported by USPHS Clinical Cancer Training Grant CA 08077; Dr. Levin's research supported by U.C. Cancer Research Center Grant #CA 14599 and National Large Bowel Contract #CA 16918.
Surgical Clinics of North America- Vol. 56, No.1, February 1976
233
234
BERNARD LEVIN ET AL.
The purpose of this program has been to provide an interdisciplinary approach to the detection, treatment, and follow-up of patients with gastrointestinal, particularly colorectal carcinoma.
ORGANIZATION OF THE GASTROINTESTINAL ONCOLOGY CLINIC The Gastrointestinal Oncology Clinic was organized in order to provide optimal patient care, teaching, and clinical research (Table 1). The clinic meets and has treatment and office facilities in the Gastroenterology outpatient clinic; but it has its own staff and is a distinctly separate administrative unit. The staff is committed to providing the patient with a wide variety of services from both a medical and an emotionally supportive standpoint. All of the clinic's staff physicians are general gastroenterologists with a research interest in gastrointestinal oncology. A full-time clinical coordinator and nurse-oncologist contribute valuable administrative and nursing expertise, and assist in the conduct and evaluation of the chemotherapy protocols used in the clinic. Both the nurse and the coordinator are responsible for record keeping systems designed especially for the clinic's use. Chemotherapy cards provide sequential, day-to-day information on patients currently receiving treatment, and a "Termatrex" punch-card system permits long-term data collection and retrieval. A part-time social worker is also available to provide both concrete and psychologic assistance to patients and their families. The clinic's activities center around a weekly Gastrointestinal Oncology Conference, an interdisciplinary forum for both the evaluation of specific clinical problems and a general discussion of new developments in diagnosis and therapy. A surgeon, radiotherapist, and general oncologist attend each conference; and each patient's diagnosis is discussed in detail by a pathologist. Nursing, social service, and administrative aspects of patient management also are explained at the conference so as to provide comprehensive approach to patient care. Students and housestaff members play an integral role both at conference presentations and in patient evaluation and management. Patients are initially evaluated by the gastroenterologist together with the trainees, residents, or students. A course of management is Table 1. Gastrointestinal Oncology Clinic - Personnel Core Gastroenterologist Gastroenterology trainee Medical resident Medical student
Coordinator Nurse oncologist Social worker
Consultative Hematologist-oncologist Pathologist
Surgeon Radiotherapist
THE GASTROINTESTINAL ONCOLOGY CLINIC
235
formulated which is later presented at the weekly conference for discussion by the consultative members of the clinic. Thereafter a consensus is usually reached which is communicated to the patient, relatives, and referring physician. The patient may be followed in the clinic or may occasionally be referred back with specific recommendations to the local physician. As a result of this conference, vital consultations with physicians in many disciplines can take place. An educational experience for all participants is achieved. The organization of the clinic has been well received at this institution; others have expressed interest in patterning new programs after this model.
A STUDY IN CANCER DETECTION: THE ASSESSMENT OF CLINICAL AND LABORATORY PARAMETERS IN IDENTIFYING PREMALIGNANT CHANGES IN PATIENTS HAVING ULCERATIVE COLITIS Cancer of the colon arid of the rectum is among the most common neoplasms detected in this country. It is estimated that 100,000 cases of this disease will be diagnosed this year, with a mortality rate of 50 per cent. We are searching for new and improved methods of early detection of colorectal carcinomas, with the aim of accurate detection at the "premalignant" stage, when proctocolectomy is likely to effect a cure. Colonic neoplasm is a well recognized complication of chronic, nonspecific, ulcerative colitis ,and patients with Crohn's colitis are also at increased risk. 5. 13 The risk of developing colonic cancer increases with duration of ulcerative colitis beyond 10 years and rises exponentially thereafter. Associated factors are onset of ulcerative colitis in childhood or youth, total colon involvement, and lengthy periods of quiescent disease. The patient population for inclusion in this study thus far has been obtained by using a computer data file which identifies over 1600 patients with inflammatory bowel disease who have been seen in the Gastroenterology Clinic at the University of Chicago within the past 10 years. Physicians in this clinic also refer new patients who meet the criteria. The criteria for patient selection currently include a radiologic diagnosis of pancolitis at some stage of the patient's disease, duration of at least 7 years, inactivity 6f the disease, and current maintenance on no greater than 10 mg per day of prednisone. Of the 78 patients invited to participate in the study thus far, 29 have accepted, with 21 completing the study once and two twice to date. Fourteen patients have rMused to participate, citing reasons such as fear of reactivating their long-quiescent colitis, fear of participation in research, and the self-conviction that they would never develop cancer. Four former patients informed us that they had undergone colectomy elsewhere, and 14 patients were impossible to locate. Ideally, 50 new patients will be entered into the study each year. As an outpatient, the study patient receives a complete physical examination, colon and chest x-rays, electrocardiogram, and complete
236
BERNARD LEVIN ET AL.
blood count and screening biochemistry profile. After these test results are obtained, the patient enters the hospital for 2 days, during which time he has a pancolonoscopy, with lavage to provide material for cytologic studies,6 and with biopsies from the cecum and ascending, transverse, and descending colon. These biopsies are studied histologically according to the criteria of Morson9 (Riddell, R.: personal communication) to identify premalignant changes. A proctoscopic examination with rectal biopsies is also performed to obtain mucosa for histologic and immunohistochemical studies, for culture with colcemid for cytogenetics, and for study by scanning and transmission electron microscopy. PPD, trichophyton, candida and mumps skin tests are performed; and blood is drawn for CEA (Hoffman-LaRoche assay), lymphocyte response (quantitation of Band T-cell lymphocytes), immunoglobulin quantitation (IgM, IgA, IgG, IgD, and IgE) and immunologic studies (collagen battery, rheumatoid factor, complement profile, and a variety of bacterial and viral antibodies). To present any conclusive results from the study at this time would be premature. A larger patient population must be studied and followed, probably for 3 to 5 years, to assess accurately the efficacy of each individual test or procedure in predicting the future development of carcinoma of the colon or rectum. Biopsies of colon and rectal tissue undergo histopathologic examination to determine the occurrence and extent of dysplastic changes, so that proctocolectomy may be considered when these changes predict development of carcinoma. Dysplastic changes have occurred in one research patient to date, and proctocolectomy is scheduled. Cytologic studies performed on material washed and brushed from the colon and rectum have been negative for malignant cells on all patients studied thus far. In the search for a method 6f using cytogenetics as a diagnostic procedure for premalignancy, tissue obtained at rectal biopsy is processed and screened using chromosome banding procedures to determine karyotypes and diagnosis of any abnormalities. Problems have been encountered in culturing biopsy material and an investigation of mitogenic agents is under way in an effort to increase the yield of mitotic figures from this tissue. In attempting to assess the distribution of carcinoembryonic antigen (CEA) in the ulcerative colitis patients at high risk for developing malignancy, and to evaluate its potential as a diagnostic tool, both Todd and Hansen assay methods are being employed. Thus far, there is no correlation between elevated CEA and evidence of dysplastic change on biopsy. This finding is consistent with that of other investigators. 4 Patients with CEA levels above 5.0 ng per ml are being reevaluated. The discovery of methods which are usable as tools for early detection of colonic neoplasms requires painstaking labor and a major cooperative effort by researchers, clinicians, and technicians alike. The necessity of long-term follow-up of the patients participating in this study is clearly evident, as the ultimate outcome of these patients will determine the importance of each test or procedure as an indicator of early carcinoma.
THE GASTROINTESTINAL ONCOLOGY CLINIC
237
A CANCER THERAPY PROTOCOL: COMBINED CYCLOPHOSPHAMIDE, CCNU, AND 5-FU CHEMOTHERAPY FOR METASTATIC COLORECTAL ADENOCARCINOMA Therapy of metastatic gastrointestinal adenocarcinoma has made few significant advances since the introduction of 5-fluorouracil (5-FU) in 1957. The overall reported response rate to this drug as a single agent in colorectal cancer is 24 per cent (of 1255 cases).7 Responses in most cases are of 2 to 6 months' duration, although some in excess of a year have been seen.lO The classic mode of administering 5-FU is in 5 to 7day "loading" schedules given at monthly intervals, and is accompanied by significant toxicity, with drug-related mortality ranging from 0.5 to 2.9 per cent,!· 3 In April of 1973, Baker2 reported on the results of 5-FU given at 30 mg per kg per day as a continuous, 120-hour infusion to patients with metastatic colorectal carcinoma; 15 out of 34 patients (44 per cent) responded to this regimen, while 8 out of 36 (22 per cent) of those treated with an intravenous "bolus" of 5-FU had> 50 per cent objective tumor regression. Although the study was prospective and randomized, to some extent this difference in response rate may have been accounted for by the fact that lung and liver metastases were more common in the "bolus" group. However, most striking was the absence of significant myelosuppression in the group receiving the 5-day continuous infusion: 4 out of 34 (12 per cent) had < 4000 WBC per mm 3 and none had WBC < 2000 per mm 3 or significant thrombocytopenia. The group receiving "bolus" treatment developed myelosuppression in 26 out of 36 (72 per cent), 11 of whom (30 per cent) had WBC < 2000, with two drug-related deaths. The selection of 5-fluorouracil, cyclophosphamide, and CCNU for combined chemotherapy in patients with metastatic gastrointestinal adenocarcinoma is based upon a protocol provided by the Section of Developmental Therapeutics, M.D. Anderson Hospital and Tumor Institute, Houston, Texas. We have elected to modify their original protocol by using these agents in a sequential manner. Based on solid tumor kinetic studies in animals by Schabel,!" 12 use of cyclophosphamide and CCNU (two cell-cycle-nonspecific agents) followed sequentially by 5-fluorouracil (a cell-cycle-specific agent) would appear to be possibly more effective than the simultaneous use of all three agents as they have been used by the group at M.D. Anderson. This protocol has been available for patients without prior progression of disease on Cytoxan and/or CCNU; a limited number of patients who received previous 5-FU therapy have also been accepted. Only patients with a measurable malignant lesion, usually hepatic or pulmonary, have been eligible for the study. Although all patients have had an estimated life expectancy of greater than 6 weeks, the performance status of these patients has been quite variable. Poor risk patients, as well as those who are good risks, have been accepted for therapy so as to provide as wide a patient population range as possible. Age levels also have varied, with the youngest patient being 34 years old, the oldest 82, and the mean 59.3.
238
BERNARD LEVIN ET AL.
According to the protocol, each patient would receive three complete courses of chemotherapy: 40 mg per m 2 per day of oral CCNU on days 1 and 2 of each course, 200 mg per m 2 of oral cyclophosphamide on days 1 through 5. and 800 mg per m 2 per day of 5-FU by continuous. 120hour intravenous infusion on days 12 through 17. Whenever possible, the oral chemotherapeutic agents have been administered on an outpatient basis to try to reduce unnecessary hospitalization. The availability of an expert nurse oncologist has facilitated this. Reduced doses have been given to patients who received radiation therapy prior to the chemotherapy, and to some patients who experienced severe leukopenia at the higher dose levels. Leukopenia (WBC < 3000 per mm 3 ) has been experienced by most patients, and has often necessitated a delay in beginning one or both of the two treatment periods in each course. Other signs of toxicity including thrombocytopenia (platelets < 100,000 per mm 3 ) nausea, vomiting, diarrhea, and alopecia, have not been severe enough to cause major delays in treatment. After three courses have been completed, each patient has been comprehensively reevaluated. Both subjective status and objective data, such as measurements of the size of metastatic lesions by the investigators, liver scan, CEA and liver function studies, have been taken into account. If a patient has objective progression of disease as demonstrated by increase in indicator lesion size, liver function abnormalities, or deterioration in performance status, he or she is dropped from the study and given alternate therapy, either at this institution or elsewhere. Patients who have responded to the therapy, or patients whose disease has remained stable, continue to receive treatment until progression is observed. For patients who cannot be cured of their disease by surgical resection, chemotherapy remains an important means of attempting palliation and prolongation of survival. At this time, this particular study does not appear to be a significant improvement over standard 5-FU chemotherapy, nor is it likely to be better than the results obtained by Moertel with 5-FU in combination with methyl CCNU.8 However, studies such as this one will continue to utilize basic research data for clinical purposes in hopes of finding useful drug combinations.
CONCLUSION The Gastrointestinal Oncology Clinic looks forward to expansion of its present programs, as well as to the initiation of other programs for cancer therapy. A new development will be the introduction of surgical adjuvant programs for patients with colorectal cancer involving immunotherapy, chemotherapy, and radiotherapy in the early postoperative period. The emphasis on interdisciplinary cooperation, and on a comprehensive approach to patient care, will continue to be stressed.
THE GASTROINTESTINAL ONCOLOGY CLINIC
239
ACKNOWLEDGMENTS
The following colleagues have collaborated with us on projects in progress at the Gastrointestinal Oncology Clinic: Phyllis A. Cullen, R.N., B.S.N. Michael Blackstone, M.D. Leroy Cockerham, C.T. Larry Eisenstat Carolyn Elliot, R.N. Warren, E. Enker, M.D. William G. Fischer, Jr., M.D. Harold Ford, B.S. Harvey Golomb, M.D. Melvin Griem, M.D. Robert Kippen, M.D.
Sumner Kraft, M.D. Paulette Martin, B.S. Willa Murdock, M.S.W. Charles Platz, M.D. Richard Reilly, M.D. Robert Riddell, M.B. Julian Rimpila, M.D. Hyman Rochman, M.D. B. H. Gerald Rogers, M.D. Slavko Stanis, M.S.
REFERENCES 1. Ansfield, F. J.: A less toxic fluorouracil dosage schedule. J.A.M.A., 190:686-688, 1964. 2. Baker, L.: Prolonged infusion of 5-fluorouracil versus bolus 5-fluorouracilin the treatment of advanced colorectal carcinoma. (Abstracts). Am. Soc. Clin. Oncology (#86), 1973. 3. Curreri, A. R. Anfield, F. J., McIver. F. A., et al.: Clinical studies with 5-fluorouracil. Cancer Res., 18:478-484, 1958. 4. Dilawari, J. B., et al.: Estimation of carcinoembryonic antigen in ulcerative colitis with special reference to malignant change. Gut, 16:255-260, 1975. 5. Goldgraber, M. B., and Kirsner, J. B.: Carcinoma of the colon in ulcerative colitis. Cancer, 17:657-665, 1964. 6. Katz, S., et al.: Rectocolonic exfoliative cytology: A new approach. Am. J. Digest. Dis., 17:1109-1116, '1972. 7. Livingston, R., and Carter, S.: Single Agents in Cancer Chemotherapy. New York, Plenum Press, 1970, pp. 195-226. 8. Moertel, C. G., et al: Therapy of advanced colorectal cancer with a combination of 5fluorouracil, methyl1,3-cis (2-chloroethyl)-I-nitrosourea, and vincristine J. Nat. Cancer Inst., 54:69-71, 1975. 9. Morson, B. C., and Pang, L. S.: Rectal biopsy as an aid to cancer control in ulcerative colitis. Gut, 8:423-434, 1967. 10. Ramirez, G., Korbitz, B. C., Davis, H. L., Jr., et al.: Comparative study of monthly courses versus weekly doses of 5-fluorouracil. Cancer Chemother. Rep., 53:243-247, 1969. 11. Schabel, F. M., Jr.: The use of tumor growth kinetics in planning "curative" chemotherapy of advanced solid tumors. Cancer Res., 29:2384-2389, 1969. 12. Schabel, F. M., Jr.: Drug treatment of malignant tumors of man and animals. A rational approach to cancer chemotherapy. South. Med. Bull., 57:40-46, 1969. 13. Weedon, D. D., et al.: Crohn's disease and cancer. N. Eng. J. Med., 289:1099-1103,1973.
Department of Medicine University of Chicago Pritzker School of Medicine 950 East 59th Street Chicago, Illinois 60637
The Gastrointestinal Oncology Clinic A Multidisciplinary Approach to Cancer Diagnosis and Management at a University Medical Center
Bernard Levin, M.D.,* David A. Karlin, M.D.,t Susan Schulman, A.B.,! Gloria W. Thorp,! Joseph B. Kirsner, M.D., Ph.D.,§ and 1. H. Rosenberg, M.D.**
The diagnosis and therapy of gastrointestinal neoplasms present multiple, challenging problems. Early detection remains the best hope for cure, yet too many physicians neglect to perform proctoscopic or even rectal examinations as part of a general evaluation of the patient. Individuals with certain diseases, such as ulcerative colitis or adenomatous polyps, have an increased risk for developing colorectal carcinoma, yet few intensive testing programs for these groups have been carried out in the past. The patient with metastatic disease may be in need of one or more modalities of therapy; yet communication among physicians in the different disciplines may be sporadic, superficial, and uninformative. To try to resolve these difficulties, a gastrointestinal oncology program was organized and started at this institution in early 1973. From the Department of Medicine, University of Chicago Pritzker School of Medicine, Chicago, Illinois "Assistant Professor of Medicine t Fellow in Medicine :::Staff §Louis Block Distinguished Service Professor of Medicine and Chief, Clinical Staff; Deputy Dean for Medical Affairs, Division of Biological Science and the Pritzker School of Medicine ""Associate Professor of Medicine Supported by USPHS Clinical Cancer Training Grant CA 08077; Dr. Levin's research supported by U.C. Cancer Research Center Grant #CA 14599 and National Large Bowel Contract #CA 16918.
Surgical Clinics of North America- Vol. 56, No.1, February 1976
233
234
BERNARD LEVIN ET AL.
The purpose of this program has been to provide an interdisciplinary approach to the detection, treatment, and follow-up of patients with gastrointestinal, particularly colorectal carcinoma.
ORGANIZATION OF THE GASTROINTESTINAL ONCOLOGY CLINIC The Gastrointestinal Oncology Clinic was organized in order to provide optimal patient care, teaching, and clinical research (Table 1). The clinic meets and has treatment and office facilities in the Gastroenterology outpatient clinic; but it has its own staff and is a distinctly separate administrative unit. The staff is committed to providing the patient with a wide variety of services from both a medical and an emotionally supportive standpoint. All of the clinic's staff physicians are general gastroenterologists with a research interest in gastrointestinal oncology. A full-time clinical coordinator and nurse-oncologist contribute valuable administrative and nursing expertise, and assist in the conduct and evaluation of the chemotherapy protocols used in the clinic. Both the nurse and the coordinator are responsible for record keeping systems designed especially for the clinic's use. Chemotherapy cards provide sequential, day-to-day information on patients currently receiving treatment, and a "Termatrex" punch-card system permits long-term data collection and retrieval. A part-time social worker is also available to provide both concrete and psychologic assistance to patients and their families. The clinic's activities center around a weekly Gastrointestinal Oncology Conference, an interdisciplinary forum for both the evaluation of specific clinical problems and a general discussion of new developments in diagnosis and therapy. A surgeon, radiotherapist, and general oncologist attend each conference; and each patient's diagnosis is discussed in detail by a pathologist. Nursing, social service, and administrative aspects of patient management also are explained at the conference so as to provide comprehensive approach to patient care. Students and housestaff members play an integral role both at conference presentations and in patient evaluation and management. Patients are initially evaluated by the gastroenterologist together with the trainees, residents, or students. A course of management is Table 1. Gastrointestinal Oncology Clinic - Personnel Core Gastroenterologist Gastroenterology trainee Medical resident Medical student
Coordinator Nurse oncologist Social worker
Consultative Hematologist-oncologist Pathologist
Surgeon Radiotherapist
THE GASTROINTESTINAL ONCOLOGY CLINIC
235
formulated which is later presented at the weekly conference for discussion by the consultative members of the clinic. Thereafter a consensus is usually reached which is communicated to the patient, relatives, and referring physician. The patient may be followed in the clinic or may occasionally be referred back with specific recommendations to the local physician. As a result of this conference, vital consultations with physicians in many disciplines can take place. An educational experience for all participants is achieved. The organization of the clinic has been well received at this institution; others have expressed interest in patterning new programs after this model.
A STUDY IN CANCER DETECTION: THE ASSESSMENT OF CLINICAL AND LABORATORY PARAMETERS IN IDENTIFYING PREMALIGNANT CHANGES IN PATIENTS HAVING ULCERATIVE COLITIS Cancer of the colon arid of the rectum is among the most common neoplasms detected in this country. It is estimated that 100,000 cases of this disease will be diagnosed this year, with a mortality rate of 50 per cent. We are searching for new and improved methods of early detection of colorectal carcinomas, with the aim of accurate detection at the "premalignant" stage, when proctocolectomy is likely to effect a cure. Colonic neoplasm is a well recognized complication of chronic, nonspecific, ulcerative colitis ,and patients with Crohn's colitis are also at increased risk. 5. 13 The risk of developing colonic cancer increases with duration of ulcerative colitis beyond 10 years and rises exponentially thereafter. Associated factors are onset of ulcerative colitis in childhood or youth, total colon involvement, and lengthy periods of quiescent disease. The patient population for inclusion in this study thus far has been obtained by using a computer data file which identifies over 1600 patients with inflammatory bowel disease who have been seen in the Gastroenterology Clinic at the University of Chicago within the past 10 years. Physicians in this clinic also refer new patients who meet the criteria. The criteria for patient selection currently include a radiologic diagnosis of pancolitis at some stage of the patient's disease, duration of at least 7 years, inactivity 6f the disease, and current maintenance on no greater than 10 mg per day of prednisone. Of the 78 patients invited to participate in the study thus far, 29 have accepted, with 21 completing the study once and two twice to date. Fourteen patients have rMused to participate, citing reasons such as fear of reactivating their long-quiescent colitis, fear of participation in research, and the self-conviction that they would never develop cancer. Four former patients informed us that they had undergone colectomy elsewhere, and 14 patients were impossible to locate. Ideally, 50 new patients will be entered into the study each year. As an outpatient, the study patient receives a complete physical examination, colon and chest x-rays, electrocardiogram, and complete
236
BERNARD LEVIN ET AL.
blood count and screening biochemistry profile. After these test results are obtained, the patient enters the hospital for 2 days, during which time he has a pancolonoscopy, with lavage to provide material for cytologic studies,6 and with biopsies from the cecum and ascending, transverse, and descending colon. These biopsies are studied histologically according to the criteria of Morson9 (Riddell, R.: personal communication) to identify premalignant changes. A proctoscopic examination with rectal biopsies is also performed to obtain mucosa for histologic and immunohistochemical studies, for culture with colcemid for cytogenetics, and for study by scanning and transmission electron microscopy. PPD, trichophyton, candida and mumps skin tests are performed; and blood is drawn for CEA (Hoffman-LaRoche assay), lymphocyte response (quantitation of Band T-cell lymphocytes), immunoglobulin quantitation (IgM, IgA, IgG, IgD, and IgE) and immunologic studies (collagen battery, rheumatoid factor, complement profile, and a variety of bacterial and viral antibodies). To present any conclusive results from the study at this time would be premature. A larger patient population must be studied and followed, probably for 3 to 5 years, to assess accurately the efficacy of each individual test or procedure in predicting the future development of carcinoma of the colon or rectum. Biopsies of colon and rectal tissue undergo histopathologic examination to determine the occurrence and extent of dysplastic changes, so that proctocolectomy may be considered when these changes predict development of carcinoma. Dysplastic changes have occurred in one research patient to date, and proctocolectomy is scheduled. Cytologic studies performed on material washed and brushed from the colon and rectum have been negative for malignant cells on all patients studied thus far. In the search for a method 6f using cytogenetics as a diagnostic procedure for premalignancy, tissue obtained at rectal biopsy is processed and screened using chromosome banding procedures to determine karyotypes and diagnosis of any abnormalities. Problems have been encountered in culturing biopsy material and an investigation of mitogenic agents is under way in an effort to increase the yield of mitotic figures from this tissue. In attempting to assess the distribution of carcinoembryonic antigen (CEA) in the ulcerative colitis patients at high risk for developing malignancy, and to evaluate its potential as a diagnostic tool, both Todd and Hansen assay methods are being employed. Thus far, there is no correlation between elevated CEA and evidence of dysplastic change on biopsy. This finding is consistent with that of other investigators. 4 Patients with CEA levels above 5.0 ng per ml are being reevaluated. The discovery of methods which are usable as tools for early detection of colonic neoplasms requires painstaking labor and a major cooperative effort by researchers, clinicians, and technicians alike. The necessity of long-term follow-up of the patients participating in this study is clearly evident, as the ultimate outcome of these patients will determine the importance of each test or procedure as an indicator of early carcinoma.
THE GASTROINTESTINAL ONCOLOGY CLINIC
237
A CANCER THERAPY PROTOCOL: COMBINED CYCLOPHOSPHAMIDE, CCNU, AND 5-FU CHEMOTHERAPY FOR METASTATIC COLORECTAL ADENOCARCINOMA Therapy of metastatic gastrointestinal adenocarcinoma has made few significant advances since the introduction of 5-fluorouracil (5-FU) in 1957. The overall reported response rate to this drug as a single agent in colorectal cancer is 24 per cent (of 1255 cases).7 Responses in most cases are of 2 to 6 months' duration, although some in excess of a year have been seen.lO The classic mode of administering 5-FU is in 5 to 7day "loading" schedules given at monthly intervals, and is accompanied by significant toxicity, with drug-related mortality ranging from 0.5 to 2.9 per cent,!· 3 In April of 1973, Baker2 reported on the results of 5-FU given at 30 mg per kg per day as a continuous, 120-hour infusion to patients with metastatic colorectal carcinoma; 15 out of 34 patients (44 per cent) responded to this regimen, while 8 out of 36 (22 per cent) of those treated with an intravenous "bolus" of 5-FU had> 50 per cent objective tumor regression. Although the study was prospective and randomized, to some extent this difference in response rate may have been accounted for by the fact that lung and liver metastases were more common in the "bolus" group. However, most striking was the absence of significant myelosuppression in the group receiving the 5-day continuous infusion: 4 out of 34 (12 per cent) had < 4000 WBC per mm 3 and none had WBC < 2000 per mm 3 or significant thrombocytopenia. The group receiving "bolus" treatment developed myelosuppression in 26 out of 36 (72 per cent), 11 of whom (30 per cent) had WBC < 2000, with two drug-related deaths. The selection of 5-fluorouracil, cyclophosphamide, and CCNU for combined chemotherapy in patients with metastatic gastrointestinal adenocarcinoma is based upon a protocol provided by the Section of Developmental Therapeutics, M.D. Anderson Hospital and Tumor Institute, Houston, Texas. We have elected to modify their original protocol by using these agents in a sequential manner. Based on solid tumor kinetic studies in animals by Schabel,!" 12 use of cyclophosphamide and CCNU (two cell-cycle-nonspecific agents) followed sequentially by 5-fluorouracil (a cell-cycle-specific agent) would appear to be possibly more effective than the simultaneous use of all three agents as they have been used by the group at M.D. Anderson. This protocol has been available for patients without prior progression of disease on Cytoxan and/or CCNU; a limited number of patients who received previous 5-FU therapy have also been accepted. Only patients with a measurable malignant lesion, usually hepatic or pulmonary, have been eligible for the study. Although all patients have had an estimated life expectancy of greater than 6 weeks, the performance status of these patients has been quite variable. Poor risk patients, as well as those who are good risks, have been accepted for therapy so as to provide as wide a patient population range as possible. Age levels also have varied, with the youngest patient being 34 years old, the oldest 82, and the mean 59.3.
238
BERNARD LEVIN ET AL.
According to the protocol, each patient would receive three complete courses of chemotherapy: 40 mg per m 2 per day of oral CCNU on days 1 and 2 of each course, 200 mg per m 2 of oral cyclophosphamide on days 1 through 5. and 800 mg per m 2 per day of 5-FU by continuous. 120hour intravenous infusion on days 12 through 17. Whenever possible, the oral chemotherapeutic agents have been administered on an outpatient basis to try to reduce unnecessary hospitalization. The availability of an expert nurse oncologist has facilitated this. Reduced doses have been given to patients who received radiation therapy prior to the chemotherapy, and to some patients who experienced severe leukopenia at the higher dose levels. Leukopenia (WBC < 3000 per mm 3 ) has been experienced by most patients, and has often necessitated a delay in beginning one or both of the two treatment periods in each course. Other signs of toxicity including thrombocytopenia (platelets < 100,000 per mm 3 ) nausea, vomiting, diarrhea, and alopecia, have not been severe enough to cause major delays in treatment. After three courses have been completed, each patient has been comprehensively reevaluated. Both subjective status and objective data, such as measurements of the size of metastatic lesions by the investigators, liver scan, CEA and liver function studies, have been taken into account. If a patient has objective progression of disease as demonstrated by increase in indicator lesion size, liver function abnormalities, or deterioration in performance status, he or she is dropped from the study and given alternate therapy, either at this institution or elsewhere. Patients who have responded to the therapy, or patients whose disease has remained stable, continue to receive treatment until progression is observed. For patients who cannot be cured of their disease by surgical resection, chemotherapy remains an important means of attempting palliation and prolongation of survival. At this time, this particular study does not appear to be a significant improvement over standard 5-FU chemotherapy, nor is it likely to be better than the results obtained by Moertel with 5-FU in combination with methyl CCNU.8 However, studies such as this one will continue to utilize basic research data for clinical purposes in hopes of finding useful drug combinations.
CONCLUSION The Gastrointestinal Oncology Clinic looks forward to expansion of its present programs, as well as to the initiation of other programs for cancer therapy. A new development will be the introduction of surgical adjuvant programs for patients with colorectal cancer involving immunotherapy, chemotherapy, and radiotherapy in the early postoperative period. The emphasis on interdisciplinary cooperation, and on a comprehensive approach to patient care, will continue to be stressed.
THE GASTROINTESTINAL ONCOLOGY CLINIC
239
ACKNOWLEDGMENTS
The following colleagues have collaborated with us on projects in progress at the Gastrointestinal Oncology Clinic: Phyllis A. Cullen, R.N., B.S.N. Michael Blackstone, M.D. Leroy Cockerham, C.T. Larry Eisenstat Carolyn Elliot, R.N. Warren, E. Enker, M.D. William G. Fischer, Jr., M.D. Harold Ford, B.S. Harvey Golomb, M.D. Melvin Griem, M.D. Robert Kippen, M.D.
Sumner Kraft, M.D. Paulette Martin, B.S. Willa Murdock, M.S.W. Charles Platz, M.D. Richard Reilly, M.D. Robert Riddell, M.B. Julian Rimpila, M.D. Hyman Rochman, M.D. B. H. Gerald Rogers, M.D. Slavko Stanis, M.S.
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Department of Medicine University of Chicago Pritzker School of Medicine 950 East 59th Street Chicago, Illinois 60637
