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Chemotherapy for Colorectal Cancer
Chemotherapy for Colorectal Cancer DONALD R. COLE, M.D., F.A.C.S.* LOUIS M. ROUSSELOT, M.D., MED. Se. D. (SURG.), F.A.C.S.** CARLO GROSSI, M.D., F.A.C.S.***
A recent contribution to the treatment of resectable and unresectable colorectal cancer has evolved with the development and use of new and more effective chemical agents. These agents or combination of agents may be administered by a variety of methods. 29 , 33 These include: (1) local administration (intraluminal; by perfusion and infusion; intracavitary; and by implantation) and (2) systemic administration. Drugs available for cancer of the colorectum are classified in two categories-alkylating agents 6 , 67 and antimetabolites. 28 . 66 The alkylating agents include the nitrogen mustards (HN2), ethyleneimines, sulfonic acid esters and epoxides. 12 Besides being cytotoxic, these agents are mutogenic and randomly attack the DNA molecule. 34 Since the damage produced is similar to that from roentgen rays they have been referred to as "radiomimetic substances."21 It should be noted that none of the alkylating agents is selective in its action although HN2 and Thio-TEPA (TSPA) have proved to be most useful clinically.ll The antimetabolites constitute the largest group of chemotherapeutic agents. Folic acid antagonists, purine analogues and fluorinated pyrimidines have shown antineoplastic activity in a wide range of solid tumors. The results to date definitely indicate that From the Department of Surgery, St. Vincent's Hospital and Medical Center of the City of New York and New York University School of Medicine * Assistant Professor of Clinical Surgery, New York University School of Medicine; Associate Attending Surgeon St. Vincent's Hospital and Medical Center; Attending Surgeon, Kingsbridge Veterans Administration Hospital, Bronx, New York; Consultant in Surgery and Chemotherapy, St. Vincent's Hospital of the Borough of Richmond ** Professor of Clinical Surgery, New York University School of Medicine; Director of Surgery, St. Vincent's Hospital and Medical Center of the City of New York *** Assistant Professor of Clinical Surgery, New York University School of Medicine; Associate Attending Surgeon, St. Vincent's Hospital and Medical Center of the City of New York
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5-fluorouracil (5-FU) and 5-fluoro-2'deoxyuridine (5-FUDR) are able to suppress the growth of certain adenocarcinomas of the colon and rectum. 5-FU and 5-FUDR are believed to affect cell metabolism by interfering with DNA synthesis and inhibiting RNA synthesis. 30 Inherent in the use of almost all chemotherapeutic agents is the threat of toxicity to the patient which may be manifest by effects on the gastrointestinal, hemopoietic and lymphatic systems, reproductive organs, kidneys, liver, central nervous system and skin.48 Both 5-FU and 5-FUDR have a rather low therapeutic index since they are frequently toxic at effective doses. 23 Many experimental attempts are under way to effect a reduction in toxicity of the chemical agents. These strategems include the use of chemotherapeutic antidotes/3. 43 bone marrow protection by means of extremity tourniquets, 59 mid-torso occlusion,42 and bone marrow replacement. 41 The remainder of this presentation will be divided into two sections. The first will be concerned with the use of chemotherapy as an adjunct in resectable cancer, and the second with its use, mainly palliative, in unresect able cancer. Resectable cancer will include those cases in which surgery is performed for cure.
RESECTABLE CANCER Local Chemotherapy A repeated observation in cancer surgery is the unexpected and often rapid recurrence of cancer following what seems to be a successful operation. This may be related to the fact that surgical manipulation opens new pathways and enhances the passage of viable cancer cells into the circulation5 (Fig. 1). The problem of cancer emboli and their treatment at operation has been demonstrated by an experiment in which Walker-256 carcinosarcoma cells were injected into the portal vein of rats. One minute later 0.5 mg.jkg. of HN2 was injected into the portal vein and the percentage of "takes" (liver metastases) was reduced from 91.7 per cent in the controls to 17.8 per cent in the treated. When HN2 was injected into the peritoneal cavity one hour after the inoculation of the cells, the percentage of "takes" in the controls was 86.7 per cent and the treated 41.3 per cent. TSPA gave similar results. 16 . 18 To help combat cancer cell spillage at operation, Warren Cole initiated the practice of isolating the tumor-bearing area of the intestine between single umbilical tapes as the abdominal cavity is entered and irrigating the bowel or instilling with hypochloride solution just before making the anastomosis. 60 In addition he advocated the use of HN2, 0.1 mg.jkg. injected into the portal vein at the end of the resection, leaving a similar amount in the peritoneal cavity before closing the abdomen. On the first and second postoperative days, 0.1 mg.jkg. of HN2 is inj ected intravenously. 21
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Fisher and Turnbu1l24 have emphasized ligations of mesenteric vessels draining the tumor segment early in the operation. McCreadie and Inch39 have introduced HN2 intraluminally proximal and distal to the ligated tumor-bearing segment after interruption of its circulation. Rousselot and Cole50 , 51, 53 introduced an adjuvant procedure for the treatment of circulating cancer cells present intraluminally in the area of the tumor site and in the collateral mesenteric venous and lymphatic vessels. On entering the abdominal cavity the tumor-bearing area is isolated between two pairs of snugly tied umbilical tapes, one proximal and the other distal to the tumor. Paired tapes are used since leakage of drug and presumably cancer cells through the tape was noted with single tapes. The drug HN2 or 5-FU is introduced into the isolated segment by direct needle puncture within a purse-string suture which is tied immediately after withdrawal of the needle (Fig. 2). The circulation to the area is maintained for 30 minutes before the pedicle vessels are ligated. Good local absorption has been demonstrated for HN2 and 5-FU and systemic absorption for HN214 , 15, 52 Fig. 3,4). The rationale is that maximal drug concentration in the desired area could result in injury to or destruction of free-floating viable cells present within the gastrointestinal segment, the intramural mesenteric veins and lymphatics and the systemic circulation. C. Grossi27 in our laboratory produced simulated colon carcinoma in rats using Walker-256 carcinosarcoma implanted in the cecal pouch. When
Figure 1
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Figure 2
HN2 was used there was a reduction in the rate of local recurrences from 42 per cent in the control to 20 per cent in the treated animals. This local recurrence rate of 20 per cent with intraluminal HN2 appears lower than when systemic HN2 is used adjuvant to surgery. Similar improved results were obtained in rats who received intraluminal 5-FU plus systemic 5-FU on the first and second postoperative days.26 Clinically 163 patients have been treated. The HN2 group receive 0.4 mg./kg. by the intraluminal route while those receiving 5-FU are given 30 mg./kg. intraluminally at the time of operation and 10 mg./kg. systemically on the first and second postoperative days. Since 5-FU is a larger molecule, absorption is slower, thereby necessitating postoperative adniinistration. Our three-year experience using adjuvant intraluminal chemotherapy has been compared with results in comparable cases treated by conventional excision alone. The results appear to indicate increased survival rate in the treated group versus the control.
Systeni.c Chemotherapy In a recent study by the National Adjuvant Cancer Chemotherapy
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TIME IN MINUTES Figure 4.
Typical systemic absorption curve for 5-fluorouracil.
Studies,46. 49 in which 693 patients with colon cancer were given TSPA systemically following surgery, a significant increase in survival for females, from 15 months through 72 months, was noted. UNRESECTABLE CANCER Local Chemotherapy (Liver Metastases)
The problem of delivering adequate drug to the tumor site has prompted the development of techniques designed for administering a high dose directly into the cancer.
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INFUSION, PERFUSION. It is not uncommon for a patient with colorectal cancer to have hepatic metastases as the sole demonstrable disease site. These techniques find their major clinical usefulness in this setting provided the patient is not in liver failure and has a life expectancy of at least 90 days. Regional perfusion is designed to achieve isolation or semi-isolation of the area to be treated by mechanically controlling both arterial inflow and venous outflow of the anatomic region. Hypothetically, the ideal agent for intra-arterial chemotherapy would be completely removed in the first passage through the regional capillary bed. The technique of regional perfusion with the pump oxygenator has not yielded encouraging results. 31 . 37 Intra-arterial infusion consists of continuous 24-hour drug infusion with a polyethlene catheter inserted into the artery or arteries supplying the tumor area. The rationale for this type of therapy is high regional concentration and constant action of the drug (to contact the cells in all phases of mitoses). A differential increase in concentration of therapeutic agent is achieved in the tumor area compared to general circulation because of removal of significant drug in circulation through the first capillary bed. Since no attempt is made to prevent the agent from entering the general circulation, the proportion reaching the venous drainage governs the maximum tolerable dosage. 35 . 36, 61. 64 The hepatic artery is used instead of the portal vein for delivery of a cancer chemotherapeutic drug to liver metastases since their blood supply is solely arterial. 8 If the patient is in poor condition and a positive tissue diagnosis is available, the use of percutaneous antegrade arterial catheters with infusion of the celiac axis may be employed. In general, this method allows one to infuse an agent from 2 to 21 days employing Cournand catheters.9 Significant palliation has been obtained by Bierman,7 Golomb25 and Brennan, 9 employing this technique. Others have felt that the percutaneous route of arterial catheters has not allowed selective delivery of drugs via the hepatic artery and have developed the technique of operative local hepatic artery catherization. Sullivan and Watkins 61 , 64 have been the foremost proponents of this form of therapy and have reported the longest periods of palliation employing the antimetabolites. A new technique has been developed by our group of temporary hepatic outflow block with hepatic artery infusion. 55 This was developed in an attempt to concentrate drugs selectively in the liver during infusion. By introduction of a caval balloon catheter it is possible to occlude the hepatic veins for ten minutes in dogs with survival and to produce selectively a greater organ concentration of either HN2 or 5-FU during the period of the hepatic outflow block. 54 This technique is now cautiously being applied to human cases of metastatic liver carcinoma. At laparotomy a No.4 Teflon catheter is introduced into the gastroduodenal artery and threaded into the hepatic artery. A double balloon vascular catheter is introduced
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Figure 5. Temporary hepatic outflow block with hepatic artery infusion. Teflon~
catheter in gastroduodenal artery
via the saphenous vein into the vena cava and the balloons positioned at the liver level. With the balloons inflated at the diaphragm and above the renal vein the hepatic outflow is blocked (Fig. 5). In one instance in which the outflow block was produced for six minutes there were no severe cardiovascular alterations. Intrahepatic artery infusion of 5-FU resulted in this instance in a much greater concentration in hepatic vein blood than in the systemic circulation for the period of the block. 66 It has been shown that relatively large doses of 5-FU can be administered via the hepatic artery without any systemic toxicity. If these doses were given intravenously, systemic toxicity would ensue. Alkylating agents, antibiotics and other antimetabolites have also been used. In general, the alkylating agents have been abandoned because of their rapid passage through the liver with systemic leak and systemic toxicity.
Systemic Chemotherapy Intermittent systemic administration of a chemotherapeutic agent is the most common method used in treating unresectable malignancies of the colorectum. HN2 was early used in four daily doses of 0.1 mg./kg. Hurley et al. have reported 34 patients with an objective response in four for three months or longer. 32 TSPA and cyclophosphamide (Cytoxan) have also been administered systemically with no benefit reported. 32 Antimetabolites have more recently received increasing attention. Curreri et aU 9 , 20 have shown that the administration of 5-FU produced significant objective improvement in many patients with far advanced colorectal cancer. Besides the constant action of an antimetabolite when it is continuously infused, there is the possibility that its metabolic fate may be altered, thus affecting its biological activity. This was observed in studies of the continuous intravenous infusion of 5-FU and 5-FUDR,44, 62
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Whereas single daily injections of 15 mg./kg. of 5-FU may produce moderate toxicity in four or five days, continuous 24-hour intravenous administration at the same dose may be tolerated for as long as 36 days without signs of toxicity.2, 3, 40 Although clinical studies indicate that continuous infusion with 5-FUDR has increased the therapeutic effect, its toxicity is greatly increased. 40 The most frequent 5-FU dose schedule employed for the "averagerisk" patient is 15 mg./kg. daily for five days followed by 7.5 mg./kg. every other day until toxicity is observed. 4, 20 The "poorer-risk" patients are maintained on a modified dose regimen. The daily dose of 15 mg./kg. is given for three successive days followed by a single dose of 7.5 mg./kg. on the fifth day. In both types of patients a course of therapy may be' repeated 30 days after the last course. 22 , 65, 66 The reported response rate of carcinoma of the colorectum to 5-FU ranges from 8 per cent to 41 per cent. 32 , 58 The evaluation of the effects of treatment may be extremely difficult, but this probably plays only a small role in explaining the difference. All of the groups cited defined improvement as the objective regression of the disease accompanied by subjective benefit and increase in the performance status. In all instances this improvement persisted from one to three months, that is, at least until another course of the drug could be given. The program of therapy with 5-FUDR has been found to be effective in a routine similar to that outlined for 5-FU except that the daily dose is doubled. 23
Combination Therapy Numerous reports have indicated the capacity of the fluorinated pyrimidines to increase radiosensit.ivity. 5-FU is given in subtoxic doses concomitantly with deep x-ray therapy. Toxicity of both agents is increased and the ultimate beneficial effect is not yet entirely clear. Observations on patients treated suggest either an additive effect when the two treatments are used simultaneously or one may potentiate the antitumor effect of the other.l, 10, 17, 28, 38, 63 In a recent study involving 61 patients with adenocarcinoma of the colon and rectum, no increase in survival was noted among those patients who received supervoltage radiation therapy combined with 5-FU.45 Because of the formidable side effects, this form of therapy must be considered experimental. However, with some adaptation it may be beneficial in selected cases. 47
CONCLUSION
Chemotherapy of colorectal cancer has become of major importance because of the development of new drugs as well as techniques. These have
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contributed substantially to the care of the cancer patient. Various dose schedules have been initiated to enhance selective action on cancer cells. 5-FU is a valuable drug in the treatment of patients with advanced malignant colorectal disease. Regional perfusion, arterial infusion and combination therapy should still be considered experimental. Because of anatomical differences these methods may be applied more easily to some organs than to others. This does not mean that these procedures are without merit but that a useful role has not as yet been established. Studies are in progress to determine whether various alkylating agents or antimetabolites given adjuvant to or following a theoretically curative resection will delay the recurrence of the disease or increase the cure rate. There is hope that this added treatment may give better results than surgery alone by destruction of malignant cells released from the primary zone as a result of the manipulation inherent in the surgical procedure.
SUMMARY Chemotherapy for patients with colorectal cancer is undergoing extensive study and development. Three areas under investigation are systemic administration as a primary treatment for unresectable cancer, local administration of drugs to an isolated area by means of perfusion and infusion, and administration of drugs adjuvant to surgery and radiotherapy;
REFERENCES 1. Allaire, E. J., Thieme, E. T. and Korst, D. R.: Cancer chemotherapy with 5-fluorouracil alone and in combination with x-ray therapy. Cancer Chemotherapy Rep. 14: 59, 1961. 2. Ansfield, F. J.: Further clinical comparison between 5-fluoro-2'deoxyuridine (5-FUDR) and 5-fluorouracil (5-FU): A comparison of the clinical effectiveness of 5-FUDR administered by the continuous intravenous infusion and the single daily injection. Proc. Am. A. Cancer Res. 3: 205 (March) 1961. 3. Ansfield, F. J.: Further clinical studies with 5-fluoro-2'-deoxyuridine (5-FUDR): Preliminary comparison with 5-fluorouracil (5-FU). Proc. Am. A. Cancer Res. 3: 92 (March) 1960. 4. Ansfield, F. J. and Curreri, A. R.: Clinical studies with 5-fluorouracil. Proc. Am. A. Cancer Res. 2: 276 (March) 1958. 5. Battista, O. A.: Toward the Conquest of Cancer. Philadelphia, Chilton Press, 1961. 6. Bergel, F.: Development, possibilities and prospects of alkylating agents. Chester Beatly Research Institute, Institute of Cancer Research, Royal Cancer Hospital, London. 7. Bierman, H. R., Byron, R. L., Kelly, K. H. and Grady, A.: Studies in blood supply of tumors in man: III. Vascular patterns of liver by hepatic arteriography in vivo. J. Nat. Cancer Inst. 12: 107, 1951. 8. Breedis, C. and Young, G.: Blood supply of neoplasms in liver. Am. J. Path. 30: 969-985, 1954. 9. Brennan, M. J. et al.: 5-Fluorouracil treatment of liver metastases by continuous hepatic artery infusion via Cournand catheters. Ann. Surg. 158: 405-419 (Sept.) 1963.
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10. Brule, G.: Combination Treatment. Chemotherapy of Cancer, World Health Organization, 1964, pp. 246-247. 11. Chemotherapy of Cancer. World Health Organization, 1962. 12. Clark, R. L.: Cancer Chemotherapy. Springfield, Ill., C. C Thomas, 1961, p. 13. 13. Clarkson, B. and Lawrence, W., Jr.: Perfusion and infusion techniques in cancer chemotherapy. M. Clin. North America 45: 689-710,1961. 14. Cole, D., Tan, Y. and Rousselot, L. M.: Peripheral detection of alkylating agents during intraluminal perfusion. Clin. Research 12: 283 (April) 1964. 15. Cole, D., Rousselot, L. M., Slattery, J. and Conte, A. J.: Absorption patterns of intraluminal 5-fluorouracil in the isolated right colon of the dog. Surgery 55: 252257 (Feb.) 1964. 16. Cole, W. H., Packard, D. and Southwick, H. W.: Carcinoma of the colon with special reference to prevention of recurrence. J.A.M.A. 155: 1549, 1954. 17. Crews, Q. E., Jr.: Observations on the combined use of 5-fluorouracil and 2 mev radiation in advanced solid tumors in man. Cancer Chemotherapy Rep. 14: 45, 1961. 18. Cruz, E. P., McDonald, G. O. and Cole, W. H.: Prophylactic treatment of cancer: Use of chemotherapeutic agents to prevent tumor metastases. Surgery 40: 291, 1956. 19. Curreri, A. R.: Further clinical studies with 5-fluorouracil. Proc. Am. A. Cancer Research 3: 14, 1959. 20. Curreri, A. R., Ansfield, F. J., McIver, F. A., Shaisman, H. A. and Heidelberger, C.: Clinical studies with 5-fluorouracil. Cancer Research 18: 478, 1958. 21. Economou, S. G. and Cole, W. H.: Chemotherapy of cancer of the alimentary tract. S. CLIN. NORTH AMERICA 42: 1147 (Oct.) 1962. 22. Ellison, R. R.: Clinical applications of the fluorinated pyrimidines. M. Clin. North America 45: 677 (May) 1961. 23. Ellison, R. R.: Experience with fluorinated pyrimidines in adenocarcinoma of the lower intestinal tract. New York J. Med. 62: 2364 (July 15) 1962. 24. Fischer, E. R. and Turnbull, R. B., Jr.: Cytologic demonstration and significance of tumor cells in the mesenteric venous blood in patients with colorectal carcinoma. Surg. Gynec. & Obst. 100: 102 (Jan.) 1955. 25. Golomb, F. M. et al: Chemotherapy of human cancer by regional perfusion. Report of 52 perfusions. Cancer 15: 828 (July-Aug.) 1962. 26. Grossi, C., Cole, D. and Rousselot, L. M.: Intraluminal chemotherapy with 5-fluorouracil of simulated colon cancer in the rat. To be published. 27. Grossi, C., Cole, D. and Rousselot, L. M.: Intraluminal chemotherapy with nitrogen mustard in simulated cancer of the colon in the rat. J. S. Research 4: 334-336 (July) 1964. 28. Hall, B. E. et al: Treatment of inoperable cancer with 5-fluorouracil and irradiation. Lancet 7115: 115, 1960. 29. Harrison: Principles of Internal Medicine. New York, Blakiston-McGraw, 1963. 30. Heidelberger, Charles: Biochemistry of 5-fluorouracil. Chemotherapy of Cancer, World Health Organization, 1964, pp. 88-98. 31. Herbst, A. L. et al: Factors influencing the disappearance of nitrogen mustard from blood. Ann. Surgery 156: 307 (Aug.) 1962. 32. Hurley, J. D. and Ellison, E. H.: Chemotherapy of solid cancer arising from gastrointestinal tract. Ann. Surgery 152: 568 (Oct.) 1960. 33. Karnofsky, David: Chemotherapy of malignant diseases. 2nd Internat. Symposium on Chemotherapy, Naples, 1961, pp. 1-44; 1963, pp. 1-44. 34. Karnofsky, D. A. and Clarkson, B. D.: Cellular effects of anti-cancer drugs. Annual Rev. Pharmacol. Vol. 3, 1963. 35. Khazei, A. M., Watkins, E. and Sullivan, R.: Hepatic artery catheterization for prolonged infusion chemotherapy of liver cancer. S. CLIN. NORTH AMERICA 44: 763 (June) 1964. 36. Klopp, C. T., Alford, T. C., Bateman,J., Berry, G. N. and Winship, T.:Fractionated intra-arterial cancer chemotherapy with methyl-bis-amine hydrochloride: Preliminary report. Ann. Surg. 132: 811, 1950. 37. Krementz, E. T. and Knudson, L.: Effects of increased oxygen tension on the tumoricidal effect of nitrogen mustard. Surgery 50: 26 (July) 1961.
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38. Langdon, E. A., Ottoman, R. E., Rochlin, D. B. and Smart, C. R.: Early results of combined radiation and chemotherapy in treatment of malignant disease. Radiology 81: 1008-1013 (Dec.) 1963. 39. McCredie, J. A. and Inch, W. R.: Nitrogen mustard toxicity, Arch. Surg. 83: 597, 1961. 40. Miller, E.: Arterial infusion in cancer chemotherapy. Chemotherapy of Cancer, World Health Organization, 1964. 41. Miller, D. G. and Diamond, H. D.: Biological basis and clinical application of bone marrow transplantation. M. Clin. North America 45: 711-731, 1961. 42. Miller, D. G. and Lawrence, W., Jr.: Mid-torso occlusion for regional cancer. Chemotherapy 18: 43-47, 1962. 43. Miller, Edward: Arterial infusion in cancer chemotherapy. Biological Research Department of Hoffmann-La Roche, Inc., 1964. 44. Miller, E., Sullivan, R. D., Young, C. W. and Burchenal, J. H.: Clinical effects of continuous infusion of anti-metabolites-prevention of toxicity of 5-fluoro-2'deoxyuridine by thymidine. Proc. Am. A. Cancer Res. 3: 251, 1961. 45. Moertel, C. G., Reitemeier, R. J., Childs, D. S., Jr., Colby, M. Y. and Holbrook, M. A.: Combined 5-fluorouracil and supervoltage radiation therapy in the palliative management of advanced gastrointestinal cancer: A pilot study. Mayo Clinic Proc. 39: 767-777 (Oct.) 1964. 46. Myhre, Kare, and Fjaerli, J.: Treatment of malignant tumours with 5-fluorouracil in 80 patients. Acta radiol. 2: 129-138 (April) 1964. 47. Ottoman, R. E., Langdon, E. A., Rochlin, D. B. and Smart, C. R.: Side effects of combined radiation and chemotherapy in the treatment of malignant tumors. Radiological Society of North America, November 25-30,1962. 48. Plattner, P.L.A.: Chemotherapy of Cancer, World Health Organization, 1964, pp. 293-295, 300. 49. Report on Colo-Rectal Clinical Trials. Adjuvant Cancer Chemotherapy Studies. Department of Preventive Medicine, University of California, Oct. 15, 1964. 50. Rousselot, L. M. and Cole, D.: Intraluminal perfusion of 5-fluorouracil adjuvant to surgery for gastro-intestinal cancer. Am. J. Digest. Dis. 9: 501-505 (July) 1964. 51. Rousselot, L. M. and Cole, D.: Intravisceral use of chemotherapeutic agents. Surgery 50: 639-643, (Oct.) 1961. 52. Rousselot, L. M., Cole, D., Slattery, J. and Conte, A. J.: Absorption patterns of intraluminal injected nitrogen mustard in the isolated right colon of the dog. J. Surg. Research 2: 201-204 (May) 1962. 53. Rousselot, L. M., Cole, D., Slattery, J. and Conte, A. J.: Intraluminal visceral perfusion as adjuvant chemotherapy to surgery for gastrointestinal cancer. Surgery 52: 232-237 (July) 1962. 54. Rousselot, L. M. Grossi, C., Slattery, J., Rossi, P., Conte, A. J. and Ruzicka, F. F.: Hepatic outflow occlusion during hepatic artery infusion with chemotherapeutic agents. Cancer 17: 1579-1585, 1964. 55. Rousselot, L. M., Grossi, C., Slattery, J., Rossi, P., Conte, A. J. and Ruzicka, F. F.: Temporary hepatic outflow block with hepatic artery perfusion by anti-cancer agents. Surg. Gynec. & Obst. 18: 1295-1304, 1964. 56. Rousselot, L. M., Grossi, C., Slattery, J., Rossi, P., Ruzicka, F. F. and Prytz, B. Selective concentration of anti-cancer drugs in the liver in hepatic artery infusion by induced hepatic outflow block. J.A.M.A. 191: 707-710 (March 1) 1965. 57. Ryan, R. F., Winbald, J. N., Krementz, E. T. and Creech, 0., Jr.: Treatment of malignant neoplasms with chemotherapeutic agents utilizing a pump oxygenator: Techniques and early results. Bull. Tulane M. Proc. 17: 133, 1958. 58. Schell, H. W.: Current status of 5-fluorouracil therapy in far advanced neoplastic disease, 265-270 (April) 1964. 59. Schilling, A. and Goodman, L. E.: Repetitive massive chemotherapy with sulfur mustard analogues and bone marrow protection by vascular occlusion. Cancer Chemotherapy Rep. 16: 527-530, 1962. 60. Southwick, H. W., Harridge, W. H. and Cole, W. H.: Recurrence at the suture line following resection for carcinoma of the colon. Am. J. Surg. 103: 86-89 (Jan.) 1962. 61. Sullivan, R. D., Norcross, J. W. and Watkins, E. J. R.: Chemotherapy of metastatic
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liver cancer by prolonged hepatic artery infusion. New England J. Med. 270: 321 (Feb. 13) 1964. Sullivan, R. D., Young, C. W., Miller, E., Glatstein, N., Clarkson, B. and Burchenal, J. H.: Clinical effects of the continuous administration of fluorinated pyrimidines (5-fluorouracil and 5-fluoro-2'-deoxyuridine) Cancer Chemotherapy Rep. No.8, 1960, pp. 77-83. Von Essen, C. F., Kligerman, M. M. and Calabresi, P.: Radiation and 5-fluorouracil: A controlled clinical study. Radiology 81: 1018 (Dec.) 1963. Watkins, E. and Sullivan, R.: Cancer chemotherapy by prolonged arterial infusion. Surg. Gynec. & Obst. 118: 3 (Jan.) 1964. Young, C. W. et al.: Evaluation of therapeutic response of large bowel cancer to the fluorinated pyrimidines in relation to clinical patterns. Cancer Chemotherapy Rep. 3: 164 (March) 1960. Young, C. W., Ellison, R. R. and Sullivan, R. D.: Clinical evaluation of 5-fluorouracil and 5-fluoro-2-deoxyuridine in solid tumors in adults. Cancer Chemotherapy Reports, No.6, U.S. Dept. of Health, Education and Welfare, 1960.
200 Park Avenue New York, N. Y. 10017 (Dr. Cole)
A recent contribution to the treatment of resectable and unresectable colorectal cancer has evolved with the development and use of new and more effective chemical agents. These agents or combination of agents may be administered by a variety of methods. 29 , 33 These include: (1) local administration (intraluminal; by perfusion and infusion; intracavitary; and by implantation) and (2) systemic administration. Drugs available for cancer of the colorectum are classified in two categories-alkylating agents 6 , 67 and antimetabolites. 28 . 66 The alkylating agents include the nitrogen mustards (HN2), ethyleneimines, sulfonic acid esters and epoxides. 12 Besides being cytotoxic, these agents are mutogenic and randomly attack the DNA molecule. 34 Since the damage produced is similar to that from roentgen rays they have been referred to as "radiomimetic substances."21 It should be noted that none of the alkylating agents is selective in its action although HN2 and Thio-TEPA (TSPA) have proved to be most useful clinically.ll The antimetabolites constitute the largest group of chemotherapeutic agents. Folic acid antagonists, purine analogues and fluorinated pyrimidines have shown antineoplastic activity in a wide range of solid tumors. The results to date definitely indicate that From the Department of Surgery, St. Vincent's Hospital and Medical Center of the City of New York and New York University School of Medicine * Assistant Professor of Clinical Surgery, New York University School of Medicine; Associate Attending Surgeon St. Vincent's Hospital and Medical Center; Attending Surgeon, Kingsbridge Veterans Administration Hospital, Bronx, New York; Consultant in Surgery and Chemotherapy, St. Vincent's Hospital of the Borough of Richmond ** Professor of Clinical Surgery, New York University School of Medicine; Director of Surgery, St. Vincent's Hospital and Medical Center of the City of New York *** Assistant Professor of Clinical Surgery, New York University School of Medicine; Associate Attending Surgeon, St. Vincent's Hospital and Medical Center of the City of New York
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5-fluorouracil (5-FU) and 5-fluoro-2'deoxyuridine (5-FUDR) are able to suppress the growth of certain adenocarcinomas of the colon and rectum. 5-FU and 5-FUDR are believed to affect cell metabolism by interfering with DNA synthesis and inhibiting RNA synthesis. 30 Inherent in the use of almost all chemotherapeutic agents is the threat of toxicity to the patient which may be manifest by effects on the gastrointestinal, hemopoietic and lymphatic systems, reproductive organs, kidneys, liver, central nervous system and skin.48 Both 5-FU and 5-FUDR have a rather low therapeutic index since they are frequently toxic at effective doses. 23 Many experimental attempts are under way to effect a reduction in toxicity of the chemical agents. These strategems include the use of chemotherapeutic antidotes/3. 43 bone marrow protection by means of extremity tourniquets, 59 mid-torso occlusion,42 and bone marrow replacement. 41 The remainder of this presentation will be divided into two sections. The first will be concerned with the use of chemotherapy as an adjunct in resectable cancer, and the second with its use, mainly palliative, in unresect able cancer. Resectable cancer will include those cases in which surgery is performed for cure.
RESECTABLE CANCER Local Chemotherapy A repeated observation in cancer surgery is the unexpected and often rapid recurrence of cancer following what seems to be a successful operation. This may be related to the fact that surgical manipulation opens new pathways and enhances the passage of viable cancer cells into the circulation5 (Fig. 1). The problem of cancer emboli and their treatment at operation has been demonstrated by an experiment in which Walker-256 carcinosarcoma cells were injected into the portal vein of rats. One minute later 0.5 mg.jkg. of HN2 was injected into the portal vein and the percentage of "takes" (liver metastases) was reduced from 91.7 per cent in the controls to 17.8 per cent in the treated. When HN2 was injected into the peritoneal cavity one hour after the inoculation of the cells, the percentage of "takes" in the controls was 86.7 per cent and the treated 41.3 per cent. TSPA gave similar results. 16 . 18 To help combat cancer cell spillage at operation, Warren Cole initiated the practice of isolating the tumor-bearing area of the intestine between single umbilical tapes as the abdominal cavity is entered and irrigating the bowel or instilling with hypochloride solution just before making the anastomosis. 60 In addition he advocated the use of HN2, 0.1 mg.jkg. injected into the portal vein at the end of the resection, leaving a similar amount in the peritoneal cavity before closing the abdomen. On the first and second postoperative days, 0.1 mg.jkg. of HN2 is inj ected intravenously. 21
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Fisher and Turnbu1l24 have emphasized ligations of mesenteric vessels draining the tumor segment early in the operation. McCreadie and Inch39 have introduced HN2 intraluminally proximal and distal to the ligated tumor-bearing segment after interruption of its circulation. Rousselot and Cole50 , 51, 53 introduced an adjuvant procedure for the treatment of circulating cancer cells present intraluminally in the area of the tumor site and in the collateral mesenteric venous and lymphatic vessels. On entering the abdominal cavity the tumor-bearing area is isolated between two pairs of snugly tied umbilical tapes, one proximal and the other distal to the tumor. Paired tapes are used since leakage of drug and presumably cancer cells through the tape was noted with single tapes. The drug HN2 or 5-FU is introduced into the isolated segment by direct needle puncture within a purse-string suture which is tied immediately after withdrawal of the needle (Fig. 2). The circulation to the area is maintained for 30 minutes before the pedicle vessels are ligated. Good local absorption has been demonstrated for HN2 and 5-FU and systemic absorption for HN214 , 15, 52 Fig. 3,4). The rationale is that maximal drug concentration in the desired area could result in injury to or destruction of free-floating viable cells present within the gastrointestinal segment, the intramural mesenteric veins and lymphatics and the systemic circulation. C. Grossi27 in our laboratory produced simulated colon carcinoma in rats using Walker-256 carcinosarcoma implanted in the cecal pouch. When
Figure 1
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Figure 2
HN2 was used there was a reduction in the rate of local recurrences from 42 per cent in the control to 20 per cent in the treated animals. This local recurrence rate of 20 per cent with intraluminal HN2 appears lower than when systemic HN2 is used adjuvant to surgery. Similar improved results were obtained in rats who received intraluminal 5-FU plus systemic 5-FU on the first and second postoperative days.26 Clinically 163 patients have been treated. The HN2 group receive 0.4 mg./kg. by the intraluminal route while those receiving 5-FU are given 30 mg./kg. intraluminally at the time of operation and 10 mg./kg. systemically on the first and second postoperative days. Since 5-FU is a larger molecule, absorption is slower, thereby necessitating postoperative adniinistration. Our three-year experience using adjuvant intraluminal chemotherapy has been compared with results in comparable cases treated by conventional excision alone. The results appear to indicate increased survival rate in the treated group versus the control.
Systeni.c Chemotherapy In a recent study by the National Adjuvant Cancer Chemotherapy
1079
CHEMOTHERAPY FOR COLORECTAL CANCER
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Figure 3. Typical local absorption curve for nitrogen mustards.
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TIME IN MINUTES Figure 4.
Typical systemic absorption curve for 5-fluorouracil.
Studies,46. 49 in which 693 patients with colon cancer were given TSPA systemically following surgery, a significant increase in survival for females, from 15 months through 72 months, was noted. UNRESECTABLE CANCER Local Chemotherapy (Liver Metastases)
The problem of delivering adequate drug to the tumor site has prompted the development of techniques designed for administering a high dose directly into the cancer.
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INFUSION, PERFUSION. It is not uncommon for a patient with colorectal cancer to have hepatic metastases as the sole demonstrable disease site. These techniques find their major clinical usefulness in this setting provided the patient is not in liver failure and has a life expectancy of at least 90 days. Regional perfusion is designed to achieve isolation or semi-isolation of the area to be treated by mechanically controlling both arterial inflow and venous outflow of the anatomic region. Hypothetically, the ideal agent for intra-arterial chemotherapy would be completely removed in the first passage through the regional capillary bed. The technique of regional perfusion with the pump oxygenator has not yielded encouraging results. 31 . 37 Intra-arterial infusion consists of continuous 24-hour drug infusion with a polyethlene catheter inserted into the artery or arteries supplying the tumor area. The rationale for this type of therapy is high regional concentration and constant action of the drug (to contact the cells in all phases of mitoses). A differential increase in concentration of therapeutic agent is achieved in the tumor area compared to general circulation because of removal of significant drug in circulation through the first capillary bed. Since no attempt is made to prevent the agent from entering the general circulation, the proportion reaching the venous drainage governs the maximum tolerable dosage. 35 . 36, 61. 64 The hepatic artery is used instead of the portal vein for delivery of a cancer chemotherapeutic drug to liver metastases since their blood supply is solely arterial. 8 If the patient is in poor condition and a positive tissue diagnosis is available, the use of percutaneous antegrade arterial catheters with infusion of the celiac axis may be employed. In general, this method allows one to infuse an agent from 2 to 21 days employing Cournand catheters.9 Significant palliation has been obtained by Bierman,7 Golomb25 and Brennan, 9 employing this technique. Others have felt that the percutaneous route of arterial catheters has not allowed selective delivery of drugs via the hepatic artery and have developed the technique of operative local hepatic artery catherization. Sullivan and Watkins 61 , 64 have been the foremost proponents of this form of therapy and have reported the longest periods of palliation employing the antimetabolites. A new technique has been developed by our group of temporary hepatic outflow block with hepatic artery infusion. 55 This was developed in an attempt to concentrate drugs selectively in the liver during infusion. By introduction of a caval balloon catheter it is possible to occlude the hepatic veins for ten minutes in dogs with survival and to produce selectively a greater organ concentration of either HN2 or 5-FU during the period of the hepatic outflow block. 54 This technique is now cautiously being applied to human cases of metastatic liver carcinoma. At laparotomy a No.4 Teflon catheter is introduced into the gastroduodenal artery and threaded into the hepatic artery. A double balloon vascular catheter is introduced
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Figure 5. Temporary hepatic outflow block with hepatic artery infusion. Teflon~
catheter in gastroduodenal artery
via the saphenous vein into the vena cava and the balloons positioned at the liver level. With the balloons inflated at the diaphragm and above the renal vein the hepatic outflow is blocked (Fig. 5). In one instance in which the outflow block was produced for six minutes there were no severe cardiovascular alterations. Intrahepatic artery infusion of 5-FU resulted in this instance in a much greater concentration in hepatic vein blood than in the systemic circulation for the period of the block. 66 It has been shown that relatively large doses of 5-FU can be administered via the hepatic artery without any systemic toxicity. If these doses were given intravenously, systemic toxicity would ensue. Alkylating agents, antibiotics and other antimetabolites have also been used. In general, the alkylating agents have been abandoned because of their rapid passage through the liver with systemic leak and systemic toxicity.
Systemic Chemotherapy Intermittent systemic administration of a chemotherapeutic agent is the most common method used in treating unresectable malignancies of the colorectum. HN2 was early used in four daily doses of 0.1 mg./kg. Hurley et al. have reported 34 patients with an objective response in four for three months or longer. 32 TSPA and cyclophosphamide (Cytoxan) have also been administered systemically with no benefit reported. 32 Antimetabolites have more recently received increasing attention. Curreri et aU 9 , 20 have shown that the administration of 5-FU produced significant objective improvement in many patients with far advanced colorectal cancer. Besides the constant action of an antimetabolite when it is continuously infused, there is the possibility that its metabolic fate may be altered, thus affecting its biological activity. This was observed in studies of the continuous intravenous infusion of 5-FU and 5-FUDR,44, 62
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Whereas single daily injections of 15 mg./kg. of 5-FU may produce moderate toxicity in four or five days, continuous 24-hour intravenous administration at the same dose may be tolerated for as long as 36 days without signs of toxicity.2, 3, 40 Although clinical studies indicate that continuous infusion with 5-FUDR has increased the therapeutic effect, its toxicity is greatly increased. 40 The most frequent 5-FU dose schedule employed for the "averagerisk" patient is 15 mg./kg. daily for five days followed by 7.5 mg./kg. every other day until toxicity is observed. 4, 20 The "poorer-risk" patients are maintained on a modified dose regimen. The daily dose of 15 mg./kg. is given for three successive days followed by a single dose of 7.5 mg./kg. on the fifth day. In both types of patients a course of therapy may be' repeated 30 days after the last course. 22 , 65, 66 The reported response rate of carcinoma of the colorectum to 5-FU ranges from 8 per cent to 41 per cent. 32 , 58 The evaluation of the effects of treatment may be extremely difficult, but this probably plays only a small role in explaining the difference. All of the groups cited defined improvement as the objective regression of the disease accompanied by subjective benefit and increase in the performance status. In all instances this improvement persisted from one to three months, that is, at least until another course of the drug could be given. The program of therapy with 5-FUDR has been found to be effective in a routine similar to that outlined for 5-FU except that the daily dose is doubled. 23
Combination Therapy Numerous reports have indicated the capacity of the fluorinated pyrimidines to increase radiosensit.ivity. 5-FU is given in subtoxic doses concomitantly with deep x-ray therapy. Toxicity of both agents is increased and the ultimate beneficial effect is not yet entirely clear. Observations on patients treated suggest either an additive effect when the two treatments are used simultaneously or one may potentiate the antitumor effect of the other.l, 10, 17, 28, 38, 63 In a recent study involving 61 patients with adenocarcinoma of the colon and rectum, no increase in survival was noted among those patients who received supervoltage radiation therapy combined with 5-FU.45 Because of the formidable side effects, this form of therapy must be considered experimental. However, with some adaptation it may be beneficial in selected cases. 47
CONCLUSION
Chemotherapy of colorectal cancer has become of major importance because of the development of new drugs as well as techniques. These have
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contributed substantially to the care of the cancer patient. Various dose schedules have been initiated to enhance selective action on cancer cells. 5-FU is a valuable drug in the treatment of patients with advanced malignant colorectal disease. Regional perfusion, arterial infusion and combination therapy should still be considered experimental. Because of anatomical differences these methods may be applied more easily to some organs than to others. This does not mean that these procedures are without merit but that a useful role has not as yet been established. Studies are in progress to determine whether various alkylating agents or antimetabolites given adjuvant to or following a theoretically curative resection will delay the recurrence of the disease or increase the cure rate. There is hope that this added treatment may give better results than surgery alone by destruction of malignant cells released from the primary zone as a result of the manipulation inherent in the surgical procedure.
SUMMARY Chemotherapy for patients with colorectal cancer is undergoing extensive study and development. Three areas under investigation are systemic administration as a primary treatment for unresectable cancer, local administration of drugs to an isolated area by means of perfusion and infusion, and administration of drugs adjuvant to surgery and radiotherapy;
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10. Brule, G.: Combination Treatment. Chemotherapy of Cancer, World Health Organization, 1964, pp. 246-247. 11. Chemotherapy of Cancer. World Health Organization, 1962. 12. Clark, R. L.: Cancer Chemotherapy. Springfield, Ill., C. C Thomas, 1961, p. 13. 13. Clarkson, B. and Lawrence, W., Jr.: Perfusion and infusion techniques in cancer chemotherapy. M. Clin. North America 45: 689-710,1961. 14. Cole, D., Tan, Y. and Rousselot, L. M.: Peripheral detection of alkylating agents during intraluminal perfusion. Clin. Research 12: 283 (April) 1964. 15. Cole, D., Rousselot, L. M., Slattery, J. and Conte, A. J.: Absorption patterns of intraluminal 5-fluorouracil in the isolated right colon of the dog. Surgery 55: 252257 (Feb.) 1964. 16. Cole, W. H., Packard, D. and Southwick, H. W.: Carcinoma of the colon with special reference to prevention of recurrence. J.A.M.A. 155: 1549, 1954. 17. Crews, Q. E., Jr.: Observations on the combined use of 5-fluorouracil and 2 mev radiation in advanced solid tumors in man. Cancer Chemotherapy Rep. 14: 45, 1961. 18. Cruz, E. P., McDonald, G. O. and Cole, W. H.: Prophylactic treatment of cancer: Use of chemotherapeutic agents to prevent tumor metastases. Surgery 40: 291, 1956. 19. Curreri, A. R.: Further clinical studies with 5-fluorouracil. Proc. Am. A. Cancer Research 3: 14, 1959. 20. Curreri, A. R., Ansfield, F. J., McIver, F. A., Shaisman, H. A. and Heidelberger, C.: Clinical studies with 5-fluorouracil. Cancer Research 18: 478, 1958. 21. Economou, S. G. and Cole, W. H.: Chemotherapy of cancer of the alimentary tract. S. CLIN. NORTH AMERICA 42: 1147 (Oct.) 1962. 22. Ellison, R. R.: Clinical applications of the fluorinated pyrimidines. M. Clin. North America 45: 677 (May) 1961. 23. Ellison, R. R.: Experience with fluorinated pyrimidines in adenocarcinoma of the lower intestinal tract. New York J. Med. 62: 2364 (July 15) 1962. 24. Fischer, E. R. and Turnbull, R. B., Jr.: Cytologic demonstration and significance of tumor cells in the mesenteric venous blood in patients with colorectal carcinoma. Surg. Gynec. & Obst. 100: 102 (Jan.) 1955. 25. Golomb, F. M. et al: Chemotherapy of human cancer by regional perfusion. Report of 52 perfusions. Cancer 15: 828 (July-Aug.) 1962. 26. Grossi, C., Cole, D. and Rousselot, L. M.: Intraluminal chemotherapy with 5-fluorouracil of simulated colon cancer in the rat. To be published. 27. Grossi, C., Cole, D. and Rousselot, L. M.: Intraluminal chemotherapy with nitrogen mustard in simulated cancer of the colon in the rat. J. S. Research 4: 334-336 (July) 1964. 28. Hall, B. E. et al: Treatment of inoperable cancer with 5-fluorouracil and irradiation. Lancet 7115: 115, 1960. 29. Harrison: Principles of Internal Medicine. New York, Blakiston-McGraw, 1963. 30. Heidelberger, Charles: Biochemistry of 5-fluorouracil. Chemotherapy of Cancer, World Health Organization, 1964, pp. 88-98. 31. Herbst, A. L. et al: Factors influencing the disappearance of nitrogen mustard from blood. Ann. Surgery 156: 307 (Aug.) 1962. 32. Hurley, J. D. and Ellison, E. H.: Chemotherapy of solid cancer arising from gastrointestinal tract. Ann. Surgery 152: 568 (Oct.) 1960. 33. Karnofsky, David: Chemotherapy of malignant diseases. 2nd Internat. Symposium on Chemotherapy, Naples, 1961, pp. 1-44; 1963, pp. 1-44. 34. Karnofsky, D. A. and Clarkson, B. D.: Cellular effects of anti-cancer drugs. Annual Rev. Pharmacol. Vol. 3, 1963. 35. Khazei, A. M., Watkins, E. and Sullivan, R.: Hepatic artery catheterization for prolonged infusion chemotherapy of liver cancer. S. CLIN. NORTH AMERICA 44: 763 (June) 1964. 36. Klopp, C. T., Alford, T. C., Bateman,J., Berry, G. N. and Winship, T.:Fractionated intra-arterial cancer chemotherapy with methyl-bis-amine hydrochloride: Preliminary report. Ann. Surg. 132: 811, 1950. 37. Krementz, E. T. and Knudson, L.: Effects of increased oxygen tension on the tumoricidal effect of nitrogen mustard. Surgery 50: 26 (July) 1961.
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38. Langdon, E. A., Ottoman, R. E., Rochlin, D. B. and Smart, C. R.: Early results of combined radiation and chemotherapy in treatment of malignant disease. Radiology 81: 1008-1013 (Dec.) 1963. 39. McCredie, J. A. and Inch, W. R.: Nitrogen mustard toxicity, Arch. Surg. 83: 597, 1961. 40. Miller, E.: Arterial infusion in cancer chemotherapy. Chemotherapy of Cancer, World Health Organization, 1964. 41. Miller, D. G. and Diamond, H. D.: Biological basis and clinical application of bone marrow transplantation. M. Clin. North America 45: 711-731, 1961. 42. Miller, D. G. and Lawrence, W., Jr.: Mid-torso occlusion for regional cancer. Chemotherapy 18: 43-47, 1962. 43. Miller, Edward: Arterial infusion in cancer chemotherapy. Biological Research Department of Hoffmann-La Roche, Inc., 1964. 44. Miller, E., Sullivan, R. D., Young, C. W. and Burchenal, J. H.: Clinical effects of continuous infusion of anti-metabolites-prevention of toxicity of 5-fluoro-2'deoxyuridine by thymidine. Proc. Am. A. Cancer Res. 3: 251, 1961. 45. Moertel, C. G., Reitemeier, R. J., Childs, D. S., Jr., Colby, M. Y. and Holbrook, M. A.: Combined 5-fluorouracil and supervoltage radiation therapy in the palliative management of advanced gastrointestinal cancer: A pilot study. Mayo Clinic Proc. 39: 767-777 (Oct.) 1964. 46. Myhre, Kare, and Fjaerli, J.: Treatment of malignant tumours with 5-fluorouracil in 80 patients. Acta radiol. 2: 129-138 (April) 1964. 47. Ottoman, R. E., Langdon, E. A., Rochlin, D. B. and Smart, C. R.: Side effects of combined radiation and chemotherapy in the treatment of malignant tumors. Radiological Society of North America, November 25-30,1962. 48. Plattner, P.L.A.: Chemotherapy of Cancer, World Health Organization, 1964, pp. 293-295, 300. 49. Report on Colo-Rectal Clinical Trials. Adjuvant Cancer Chemotherapy Studies. Department of Preventive Medicine, University of California, Oct. 15, 1964. 50. Rousselot, L. M. and Cole, D.: Intraluminal perfusion of 5-fluorouracil adjuvant to surgery for gastro-intestinal cancer. Am. J. Digest. Dis. 9: 501-505 (July) 1964. 51. Rousselot, L. M. and Cole, D.: Intravisceral use of chemotherapeutic agents. Surgery 50: 639-643, (Oct.) 1961. 52. Rousselot, L. M., Cole, D., Slattery, J. and Conte, A. J.: Absorption patterns of intraluminal injected nitrogen mustard in the isolated right colon of the dog. J. Surg. Research 2: 201-204 (May) 1962. 53. Rousselot, L. M., Cole, D., Slattery, J. and Conte, A. J.: Intraluminal visceral perfusion as adjuvant chemotherapy to surgery for gastrointestinal cancer. Surgery 52: 232-237 (July) 1962. 54. Rousselot, L. M. Grossi, C., Slattery, J., Rossi, P., Conte, A. J. and Ruzicka, F. F.: Hepatic outflow occlusion during hepatic artery infusion with chemotherapeutic agents. Cancer 17: 1579-1585, 1964. 55. Rousselot, L. M., Grossi, C., Slattery, J., Rossi, P., Conte, A. J. and Ruzicka, F. F.: Temporary hepatic outflow block with hepatic artery perfusion by anti-cancer agents. Surg. Gynec. & Obst. 18: 1295-1304, 1964. 56. Rousselot, L. M., Grossi, C., Slattery, J., Rossi, P., Ruzicka, F. F. and Prytz, B. Selective concentration of anti-cancer drugs in the liver in hepatic artery infusion by induced hepatic outflow block. J.A.M.A. 191: 707-710 (March 1) 1965. 57. Ryan, R. F., Winbald, J. N., Krementz, E. T. and Creech, 0., Jr.: Treatment of malignant neoplasms with chemotherapeutic agents utilizing a pump oxygenator: Techniques and early results. Bull. Tulane M. Proc. 17: 133, 1958. 58. Schell, H. W.: Current status of 5-fluorouracil therapy in far advanced neoplastic disease, 265-270 (April) 1964. 59. Schilling, A. and Goodman, L. E.: Repetitive massive chemotherapy with sulfur mustard analogues and bone marrow protection by vascular occlusion. Cancer Chemotherapy Rep. 16: 527-530, 1962. 60. Southwick, H. W., Harridge, W. H. and Cole, W. H.: Recurrence at the suture line following resection for carcinoma of the colon. Am. J. Surg. 103: 86-89 (Jan.) 1962. 61. Sullivan, R. D., Norcross, J. W. and Watkins, E. J. R.: Chemotherapy of metastatic
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liver cancer by prolonged hepatic artery infusion. New England J. Med. 270: 321 (Feb. 13) 1964. Sullivan, R. D., Young, C. W., Miller, E., Glatstein, N., Clarkson, B. and Burchenal, J. H.: Clinical effects of the continuous administration of fluorinated pyrimidines (5-fluorouracil and 5-fluoro-2'-deoxyuridine) Cancer Chemotherapy Rep. No.8, 1960, pp. 77-83. Von Essen, C. F., Kligerman, M. M. and Calabresi, P.: Radiation and 5-fluorouracil: A controlled clinical study. Radiology 81: 1018 (Dec.) 1963. Watkins, E. and Sullivan, R.: Cancer chemotherapy by prolonged arterial infusion. Surg. Gynec. & Obst. 118: 3 (Jan.) 1964. Young, C. W. et al.: Evaluation of therapeutic response of large bowel cancer to the fluorinated pyrimidines in relation to clinical patterns. Cancer Chemotherapy Rep. 3: 164 (March) 1960. Young, C. W., Ellison, R. R. and Sullivan, R. D.: Clinical evaluation of 5-fluorouracil and 5-fluoro-2-deoxyuridine in solid tumors in adults. Cancer Chemotherapy Reports, No.6, U.S. Dept. of Health, Education and Welfare, 1960.
200 Park Avenue New York, N. Y. 10017 (Dr. Cole)