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Chemotherapy as an Adjunct to Surgery in the Treatment of Cancer
Chemotherapy as an Adjunct to Surgery in the Treatment of Cancer From the Departments of Surgery, Veterans Administration Research Hospital and Northwestern University Medical School, Chicago, Illinois
PAUL F. NORA, M.D., F.A.C.S. Instructor in Surgery, Northwestern University Medical School; Attending Surgeon, Veterans Administration Research Hospital and Columbus Hospital
FREDERICK W. PRESTON, M.D., F.A.C.S. Professor of Surgery, Northwestern Uni1!ersity Medical School; Chief, Surgical Service, Veterans Administration Research Hospital
IN THIS ARTICLE we have attempted to appraise cancer chemotherapy as it is used at the operating table or in the immediate preoperative and postoperative periods. Surgeons have given potent drugs to curable patients noting that these drugs cause remission in some patients with advanced cancer and believing that even better response might follow if they were used in patients with less extensive disease. Cancer chemotherapy as an adjunct to surgery was originated in March 1956 when Warren Cole and his associates 7 used nitrogen mustard in patients undergoing surgery for cancer of the breast. Previously surgeons had irrigated wounds with solutions to eliminate cancer cells, but Cole's study was the first scientifically controlled attempt to test these agents. In 1957 a program designed to evaluate adjuvant cancer chemotherapy was organized under the direction of the National Cancer Institute, and studies were undertaken in university and Veterans Administration HospitalsY In addition, throughout the country surgeons have used chemotherapy as an adjunct to surgical resection, systemically, by intra-arterial infusion or perfusion, or locally into wounds. Sufficient time has elapsed so that some appraisal of progress can be made. Most of the drugs and the techniques for their administration are still of unproven value. Some drugs and techniques have been shown to be valueless. A few are ready for acceptance by surgeons. They have their limitations and should be used with caution.
39
40
PAUL F. NORA, FREDERICK
W.
PRESTON
Only about 35 per cent of patients with cancer are cured by conventional methods of treatment. Too often surgical resections are followed by recurrent or metastatic disease. Chemotherapy is looked upon as a source of hope for 65 per cent of the patients with cancer who cannot now be cured, and it is likely that it will occupy this position for some time to come. When a neoplasm is resected there may be implantation of cancer cells into the wound and dissemination of cells into vascular and lymphatic channels beyond the limits of surgical removal. Adjuvant cancer chemotherapy is directed at these methods of spread. The drugs may be given systemically, regionally or locally. SYSTEMIC ADJUVANT CHEMOTHERAPY
The basic hypothesis of Cole 6 is that tumor cells which are disseminated into the blood stream at operation are more sensitive to chemotherapeutic agents than those which have a firm vascular attachment. Cole and associates showed that a decrease in "takes" of Walker carcinosarcoma 256 occurred with adjuvant administration of nitrogen mustard. These investigators also studied 700 patients for the presence of cancer cells in the peripheral blood at the time of operation. 4 One hundred and eight of these patients were suitable for preoperative, operative and postoperative samplings. Approximately one-fifth of the 108 patients had cancer cells in their blood during the operation when none was demonstrated either before or after surgery. Equally significant were the findings of Moore I6 that cancer cells will disappear from the blood under the influence of systemic chemotherapy as evidenced by negative serial blood samples. As with any new procedure having clinical application, simulated experimental situations were evaluated. Overstreet and McDonald,20 studying the Walker carcinoma 256 in rats, showed that growth 0f the tumor depended upon the number of cells injected and the site of injection. Their data support the assumption that not all cells desquamating from human tumors survive and produce metastases. McDonald and associates showed that nitrogen mustard and thio-TEPA are effective in preventing "takes" of carcinoma 256 in rats. 13 This inhibition was most marked when the dose of tumor cells was small and when the drug was given immediately after the injection of tumor cells. 12 McCredie and dePeysterll correlated the effect of varying the route of administration of cancer cells (intraportal, intraperitoneal and subcutaneous) and of varying the route of administering the drugs (intraportal, intraperitoneal and peripheral vein). Results showed that tumor growth after intraportal injection of cancer cells is partially controlled by any method of administration of drug but growth following intraperitoneal injection of cancer cells was only controlled by intraperitoneal administration of
Chemotherapy as an Adjunct to Surgery in Cancer Treatment
41
drug. These are but a few of the experiments directed at the clinical problems of the correct method of administration, the ideal time and the amount of drug for the most effective adjuvant chemotherapy. Cole and associates 7 used adjuvant cancer chemotherapy in patients with cancer of the breast under 70 years of age who satisfied certain criteria. After undergoing radical mastectomy, one-half of the patients selected at random received nitrogen mustard. The dosage schedule consists of 0.2 mg./kg. intravenously at surgery with an additional 0.1 mg'; kg. intravenously on the first and second postoperative day with a maximum dosage not to exceed 30 mg. The patients also received 0.4 mg./kg. of nitrogen mustard intravenously every four months for the first year and thio-TEPA 15 mg. intravenously every month for the second year after operation. Results following this regimen have been encouraging. Only 16 out of 65 treated patients had recurrences compared to 23 out of 65 control patients. At the time of last report six of the 65 treated patients had died while 15 of 65 control patients were dead as a result of their disease. In order to evaluate a large number of cases under well controlled conditions, an adjuvant chemotherapy study was organized in 1957 under the direction of the Cancer Chemotherapy National Service Center (a division of the National Cancer Institute)Y The study was divided into two separate groups: the university group (59 participating hospitals) headed by Dr. George Moore and the Veterans Administration group (22 participating hospitals) under the direction of Dr. Lyndon Lee. The drugs were nitrogen mustard for bronchogenic carcinoma and triethylenethiophosphoramide (thio-TEPA) for breast and gastrointestinal carcinoma. Patients with carcinoma of the lung, breast, stomach, colon and rectum were evaluated. Adjuvant studies of patients with carcinoma of the ovary utilizing chlorambucil as the cancerocidal drug were added in 1959. Dosage schedules were approximately the same for both groups of investigators. Double blind studies were performed. Constant surveillance of patients caused the investigators in the university group to reduce the dosage of thio-TEPA from 0.8 mg./kg. to 0.6 mg./kg. as adjuvant treatment in cancer of the breast because of complications related to the drug. Further studies, however, showed that the higher dosage was more effective in preventing recurrences. Lee, reporting for the Veterans cooperative group,27 stated that there was an increase in the risk of surgery in the treated patients. Also, reduction of the dose of nitrogen mustard for lung cases and of the thioTEPA dose for the stomach cases produced a decrease in the incidence of complications. In the colon series, however, decrease in the dosage did not lower the incidence of complications. The overall evaluation of adjuvant cancer chemotherapy as cited above has resulted in at least two conclusions. There is agreement that well coordinated study groups under a central governing board can effectively
r 42
PAUL F. NORA, FREDERICK
W.
PRESTON
test and compare methods of treatment requiring large numbers of patients. Secondly, the drugs used in these cooperative studies have been of no benefit to patients undergoing resections for carcinoma of the lung, stomach, colon and rectum. The university study showed that adjuvant chemotherapy with thio-TEPA reduced the incidence of recurrent and metastatic cancer in patients with carcinoma of the breast. Not enough time has elapsed for evaluation of these patients in terms of long-term survival. Cole's study in which nitrogen mustard was used as adjuvant treatment for cancer of the breast is in agreement with these results and has shown in addition that survival of patients with carcinoma of the breast is prolonged. LOCAL ADJUVANT CHEMOTHERAPY
Regrowth of tumor in the suture line and at the operative site following resection is an important cause of failure of surgical procedures to cure cancer. More attention has been directed toward the incidence of this complication than toward its prevention or treatment. Bacon2 reported that local recurrences occurred in 17.9 per cent of his patients followed for five or more years after abdominoperineal resection for carcinoma and stated that the incidence in the literature for this operation varied from 6 to 39.5 per cent. Among Cole's patients having anterior resection for carcinoma of the rectosigmoid the incidence of local recurrence was 16 per cent, and the incidence of suture line recurrence was 10 per cent. 3 The local recurrence rate following radical mastectomy for carcinoma of the breast is usually reported between 10 and 30 per cent, and is even higher for radical neck dissection for head and neck cancer, affecting as many as 40 to 50 per cent of patients. Attempts to prevent local recurrences by irrigating wounds with various solutions antedate accurate knowledge concerning the incidence and significance of cancer cells which can be recovered from wounds and from body cavities. Smith25 at the National Cancer Institute found wound washings positive for cancer cells in 26 per cent of 120 patients having radical resection for cancer. Moore 15 found tumor cells in washings of the peritoneal cavity of 31 per cent of patients with carcinoma of the colon. When the lesion was noncurable the washings were positive in 47 per cent. The incidence was even higher for carcinoma of the ovary, and 67 per cent of these patients had positive wound washings when the tumor was confined to the ovary. Seventy-five per cent were positive when there was extension outside the ovary. The irrigation of wounds seeded with tumor cells is an effective method of inhibiting tumor growth and preventing the lethal effect of the tumor in the experimental animal. Figure 1 shows an experiment designed to simulate the seeding of cancer cells which might occur in the wounds of a patient having a resection for a malignant neoplasm. A 1.5 cm. incision
Chemotherapy as an Adjunct to Surgery in Cancer Treatment
k
43
C _ "K:~_ D
A Fig. 1. Experiment to simulate the seeding of cancer cells. For details, see text.
was made through the skin and superficial fascia of the flank of a rat (A). One million living Bagg lymphosarcoma cells were placed in the wound (B), and it was closed with a single suture (C, D). Thirty minutes later the suture was removed and a chemotherapeutic agent was placed in the wound. Results (Table 1) are expressed in terms of growth of the tumor and survival of the animal and are arranged in two groups depending upon whether the drugs were placed in the wounds undiluted or were dissolved in a large volume and used as an irrigation. Doses of drugs used were those suitable for local use in the human being. The most effective drug was nitrogen mustard, 1 mg./kg., dissolved in 2 ml. of 0.9 per cent saline instilled into the wound. In the animals treated in this manner there was a delay in appearance of the tumor, decrease in the number of takes and decrease in the mortality rate (to 42 per cent) as compared to the control animals (91 per cent). McDonald 4 has done similar experiments to evaluate various irrigating agents in pouches of rats inoculated with Walker carcinoma 256. Sodium hypo chloride 0.5 per cent buffered to pH 9, chlorpactin 2 per cent (too toxic for clinical use) and nitrogen mustard proved most effective. More recently Moore and associates 19 have used animal tumors and human tissue suspensions as a screening system for selecting drugs to eliminate tumor cells from surgical wounds. Nine dyes, two antimetabolites, ten alkylating agents, five oxidizing agents, seven miscellaneous drugs and three inorganic compounds were screened. The most promising of these were used in the wounds of 26 patients. These experiments raised the question of the effect on the local recurrence rate of irrigating a wound with saline solution. Can local recurrence be reduced by saline irrigation or does a saline irrigation drive tumor cells
44
PAUL F. NORA, FREDERICK
Table 1.
W.
PRESTON
Chemotherapy in Experimental Wounds TUMOR TAKES
(per cent) REAGENT
NO. OF RATS
None (controls) ....... ............ 132 Given by instillation* 14 2 ml. NaCI, 0.9% ..... 5-FU, 1 mg./kg ....... 26 5-FU, 0.5 mg./kg ..... 19 TSPA, 8 mg./kg ..... 31 Chlorpactin 1 % ... 15 Chlorpactin 0.5% .. ......... 29 HN2, 1 mg./kg ..... 24 Given by irrigationt 30 ml. saline 0.9% ...... 12 HN2,1 mg./kg ........... 26 TSPA, 8 mg./kg ........... 33 15 Chlorpactin 1 % .... Chlorpactin 0.5% .... 44 5-FU, 0.5 mg./kg ................ 33
MORTALITY 30 DAYS
2-14 Days
Total in 20 Days or Less
(per cent)
100
100
91
100 100 95 39 40 83 33
100 96 95 84 87 96 50
100 92 90 81 80 76 42
83 85 97 0 18 94
100 96 100 53 57 91
92 92 82 60 57 79
* Total volume placed in wound was 2 m!. Most reagents were dissolved in 0.9 per cent NaC!. t Total volume used as irrigation was 30 m!. Most reagents were dissolved in 0.9 per cent MaCe. 5-FU, 5-fluorouracil; TSPA, triethylenethiophosphoramide (thio-TEPA); HN2, nitrogen mURtard. into the tissues and promote local recurrence? To test the effectiveness of saline irrigation, the number of tumor cells injected into the wound depicted in the figure were adjusted so that tumor growth was fatal in 50 per cent of animals. Sixty animals were used in this experiment. Twenty received no irrigation. Twenty received 30 m!. of saline as an irrigant, and 20 received 150 m!. The irrigations were given so that the force and time of the irrigations were constant. Tumor growth and mortality of the animals were the same in the groups receiving no irrigation and in those receiving small and large amounts of saline (Table 2). This suggests that irrigation with saline, regardless of the amount or pressure used, is useless in the prevention of tumor growth secondary to tumor cells seeded into wounds. The theory that local recurrences are caused by seeding at operation dates back at least 80 years. Smith's recent data shows that in long-term follow-up of patients there was no correlation between positive wound washings and local recurrences, distant metastases or survival time.! Additional work by Smith24 with groups of operable cases of carcinoma of the cervix uteri and head and neck cancer treated by en bloc excision plus wound irrigation with 0.5 per cent formalin indicated no differences
Chemotherapy as an Adjunct Table 2.
to
Surgery in Cancer Treatment
45
Effect of Saline Irrigation AVERAGE TUMOR SIZE
3 X 10
5
TUMOR CELLS*
RATS
PLUS
None ................. 20 20 30 ml. saline. . 20 150 ml. saline. .
(em. 3 ) DIED - - - - - (per eent) Days
7
14
11
41
8 5
30
60
36
55
50
* Bagg lymphosarcoma. in local recurrence rate or survival time between control and treated groups. At the present time there is evidence that suture line recurrences following colon resection can be eliminated. Cole and his associates3 , 4 advocate avoidance of enemas, gentle handling of the tumor to avoid desquamation of cells, ligation of the bowel proximal and distal to the tumor and irrigation of the distal segment with distilled water. Attention to methods for preventing local recurrence including irrigation of the bowel with 1 :500 perchloride of mercury have been effective in Morgan's experience. 18 Reduction in local recurrence rates was achieved by Goligher and associates 8 by similar methods. More recently Rosi and associates23 reported no local recurrences in patients operated upon for carcinoma of the descending colon and sigmoid between 1950 and 1955 when irrigation of the rectum with water preceded the anastomosis. The incidence of mucosal and extraluminal recurrence during the five-year period before this (1945 to 1950), when no irrigations were used, was 18 per cent. None of these surgeons have evaluated wound irrigation alone to control local recurrences, and at the present time the usefulness of chemotherapy by itself to eliminate wound recurrences following any type of cancer operation has not been studied except by Smith and Moore and their associates.l 9, 24 The problem of local recurrence is so important and the application of cancer chemotherapeutic agents in this respect seems sufficiently promising to warrant more investigation of this problem. REGIONAL ADJUVANT CHEMOTHERAPY
The introduction of cancerocidal agents via the intra-arterial route in 1950 was the beginning of regional chemotherapy of cancer.9 This form of therapy has evolved into two main types, infusion and perfusion. Infusion is the introduction (intermittent or continuous) of a chemo-
:
46
PAUL F. NORA, FREDERICK
W.
PRESTON
therapeutic agent into the arterial blood flupply of a tumor without any attempt to isolate this area from other parts of the body. Systemic antagonists to the cancerocidal agent may be used in conjunction with an infusion. Perfusion also involves the introduction of these agents into the arterial blood supply but circulation to the areas containing the tumor is isolated from that of the rest of the body by ligation of collaterals, tourniquets, balloon catheters and vascular clamps. The venous return is attached to a pump oxygenator and is used for the recirculation of the cancerocidal agents through the perfused area. Both of these methods have been used for palliation in localized carcinoma, but only perfusion has been used as an adjuvant to surgery. Infusion has been used following surgery but not in the sense in which we have reference to adjuvant in this article. Stehlin and associates26 have reported the use of perfusion with phenylalanine mustard as an adjunct to surgery in the treatment of 18 patients with malignant melanoma of the extremities. Three patients experienced a temporary response and 15 are classified as having quiescent disease. The first perfusion was performed only 32 months prior to Stehlin's report which is too short a period for evaluation. Creech5 has divided his treated cases of melanomas of the extremity into two groups: perfusion only or excision plus perfusion. Of the 76 patients suitable for analysis, 39 fall into the latter category (adjuvant group). Twenty-one of the 39 had perfusion plus excision of a primary tumor, and 18 had perfusion combined with removal of a secondary tumor (either regional recurrence or metastasis). Eight of the 39 patients had a recurrence in a relatively short time and were considered to have received no benefit from perfusion plus excisional therapy. The most striking finding was that in the 18 cases in which the perfusion was combined with excision of a secondary tumor, nine were at least temporarily controlled. The natural history of melanoma is so variable that it is impossible to draw any significant conclusions. Creech21 also reported on the use of perfusion in 18 selected adenocarcinomas (breast, rectum, ovary, metastatic carcinoma to extremities, and endometrium). Nine of the 18 patients had carcinoma of the breast. A few of the breast cases could be classified in the adjuvant category because perfusion was combined with mastectomy. None of these cases have been followed for more than eight months, therefore no results are yet available for analysis. Adjuvant perfusion chemotherapy has been used in the treatment of sarcoma10 but the series is small. Nonetheless, it has helped in certain cases by reducing the size of the lesion and making a more conservative surgical procedure possible. Because of the short period of time and the limited number of cases, no conclusions can be reached as to the value of this therapy. rI
Chemotherapy as an Adjunct to Surgery in Cancer Treatment
47
SUMMARY
A review of published reports of cancer chemotherapy used as an adjunct to surgery is presented. Chemotherapy may be given systemically, regionally or locally. The incidence of recurrent and metastatic carcinoma can be reduced and the survival of patients increased following radical mastectomy for carcinoma of the breast by nitrogen mustard used as an adjunct to surgery. Adjuvant chemotherapy has been of no benefit to patients undergoing surgery for carcinomas of the lung, stomach, colon or rectum. Cancerocidal drugs used as irrigants for wounds seem logical as a method of reducing locally recurrent cancer after a resection for cancer. Published data on this subject is contradictory and at the present time these drugs cannot be recommended. Surgeons undertaking the use of drugs as an adjunct to surgery must be aware of the toxic effects of these agents and be prepared to deal with a variety of drug-induced complications, the most important of which is bone marrow depression.
REFERENCES 1. Arons, M. S., Smith, R. R. and Myers, M. H.: Significance of cancer cells in operative wounds. Cancer 14: 1041, 1961. 2. Bacon, H. E.: Anus, Rectum, Sigmoid Colon. Philadelphia, J. B. Lippincott Co. 1949, Vol. 2, p. 762. 3. Cole, W. H.: Recurrence in carcinoma of the colon and proximal rectum following resection for carcinoma. Arch. Surg. 65: 264, 1952. 4. Cole, W. H., McDonald, G. 0., Roberts, S. S. and Southwich, H. W.: Dissemination of Cancer: Prevention and Therapy. Appleton-Century-Crofts, Inc., New York, 1961. 5. Creech, 0., Jr., Ryan, R. F. and Krementz, E. T.: Regional chemotherapy by isolated perfusion in the treatment of melanoma of the extremities. Plast. & Reconstruct. Surg. 28: 333, 1961. 6. Cruz, A., McDonald, P., Geraid, O. and Cole, W. H.: Prophylactic treatment of cancer and the use of chemotherapeutic agents to prevent tumor metastasis. Surgery 40: 291, 1956. 7. Economou, S., Mrazek, R., McDonald, G. 0., Slaughter, D. P. and Cole, W. H.: Adjuvant Therapy of Cancer Exhibit. Chicago Medical Society Annual Meeting, 1962. 8. Goligher, J. C., Dukes, C. E. and Bussey, H. J. R.: Local recurrence after sphincter-saving exciRions for carcinoma of the rectum and rectosigmoid. Brit. J. Surg. 39: 199, 1951. 9. Klopp, C. T., Alford, T. C., Bateman, J., Berry, G. N. and Winship, T.: Fractionated intra-arterial cancer chemotherapy with methyl bis amine hydrochloride: A preliminary report. Ann. Surg. 132: 811, 1950. 10. Krementz, E. T.: End results in the treatment of sarcoma by perfusion with chemotherapeutic agents. Cancer Chemother. Rep. 10: 83, 1960. 11. McCredie, J. A. and dePeyster, F. A.: Effects of giving nitrogen mustard by different routes to rats receiving Walker 256 cells intraportally, intraperitoneally and subcutaneously. Surgery 45: 709, 1959. 12. McDonald, C. T., Howie, J. S., Weeks, P. M. and Thomas, C. G.: Limiting
48 13. 14. 15. 16. 17. 18. 19.
20. 21. 22. 23. 24. 25. 26. 27.
PAUL F. NORA, FREDERICK
W.
PRESTON
factors in the prophylaxis of the spread of cancer at operation by chemotherapeutic methods. S. Forum 8: 164, 1958. McDonald, G. 0., Livingston, C., Boyles, C. F. and Cole, W. H.: The prophylactic treatment of malignant disease with nitrogen mustard and triethyelenethiophosphoramide (thioTEPA). Ann. Surg. 145: 624,1957. Moore, G. E., Katz, A. D., Sandberg, A. A. and Binks, E. M.: Incidence of tumor cells in blood and peritoneal fluid in patients with cancer. S. Forum 8: 152,1958. Moore, G. E., Sako, K., Kondo, T., Badillo, J. and Burke, E.: Assessment of the exfoliation of tumor cells into the body cavities. Surg. Gynec. & Obst. 112: 469, 1961. Moore, G. E., Sandberg, A. A. and Schubarg, J. R.: Clinical and experimental observations of the occurrence and fate of tumor cells in the blood stream. Am. Surgeon 146: 580, 1957. Moore, G. and Stiver, R.: Review of the University Surgical Adjuvant Chemotherapy Studies. Cancer Chemother. Rep. 7: 54, 1960. Morgan, C. N.: Trends in the treatment of tumours of the rectum, rectosigmoid and left colon. J. Roy. ColI. Surgeons Edinburgh 1: 112, 1955. Mukhtar, F. A., DiPaolo, J., Hoffmeister, F. S., Koike, A., Moore, G. E. and Wilkens, H.: Selection of compounds for topical chemotherapy of tumorcontaminated human surgical wounds. Proc. Am. A. Cancer Res. 3: 347, 1962. Overstreet, R. J. and McDonald, G. 0.: Role of cellular dosage on "takes" following inoculation of Walker 256 tumor cells in the rat. S. Forum 8: 161, 1958. Reemtsma, K., Ryan, R. F., Krementz, E. T. and Creech, 0., Jr.: Treatment of selected adenocarcinomas by perfusion technique. Arch. Surg. 78: 724, 1959. Review of the Cancer Chemotherapy National Service Center Program: Develop. ment and Organization. Cancer Chemother. Rep. 7: 41, 1960. Rosi, A., Cahill, W. J. and Carey, J.: A ten year study of hemicolectomy in the treatment of carcinoma of the left half of the colon. Surg. Gynec. & Obst. 114: 15, 1962. Smith, R. R. and Gehan, E. A.: Effect of formaldehyde wound wash on development of local wound recurrences. J. Nat. Cancer Inst. 23: 1339, 1959. Smith, R. R., Thomas, L. B. and Hilberg, A. W.: Cancer cell contamination of operative wounds. Cancer 11: 53, 1958. Stehlin, J. S., Jr., Smith, J. L., Jr. and Clark, R. L., Jr.: Results of perfusion for melanoma. Cancer Chemotherap. Rep. 10: 79, 1960. Veterans Administration Adjuvant Cancer Chemotherapy Cooperative Group: Status of adjuvant cancer chemotherapy. Arch. Surg. 82: 466, 1961.
333 East Huron Street Chicago 11, Illinois
PAUL F. NORA, M.D., F.A.C.S. Instructor in Surgery, Northwestern University Medical School; Attending Surgeon, Veterans Administration Research Hospital and Columbus Hospital
FREDERICK W. PRESTON, M.D., F.A.C.S. Professor of Surgery, Northwestern Uni1!ersity Medical School; Chief, Surgical Service, Veterans Administration Research Hospital
IN THIS ARTICLE we have attempted to appraise cancer chemotherapy as it is used at the operating table or in the immediate preoperative and postoperative periods. Surgeons have given potent drugs to curable patients noting that these drugs cause remission in some patients with advanced cancer and believing that even better response might follow if they were used in patients with less extensive disease. Cancer chemotherapy as an adjunct to surgery was originated in March 1956 when Warren Cole and his associates 7 used nitrogen mustard in patients undergoing surgery for cancer of the breast. Previously surgeons had irrigated wounds with solutions to eliminate cancer cells, but Cole's study was the first scientifically controlled attempt to test these agents. In 1957 a program designed to evaluate adjuvant cancer chemotherapy was organized under the direction of the National Cancer Institute, and studies were undertaken in university and Veterans Administration HospitalsY In addition, throughout the country surgeons have used chemotherapy as an adjunct to surgical resection, systemically, by intra-arterial infusion or perfusion, or locally into wounds. Sufficient time has elapsed so that some appraisal of progress can be made. Most of the drugs and the techniques for their administration are still of unproven value. Some drugs and techniques have been shown to be valueless. A few are ready for acceptance by surgeons. They have their limitations and should be used with caution.
39
40
PAUL F. NORA, FREDERICK
W.
PRESTON
Only about 35 per cent of patients with cancer are cured by conventional methods of treatment. Too often surgical resections are followed by recurrent or metastatic disease. Chemotherapy is looked upon as a source of hope for 65 per cent of the patients with cancer who cannot now be cured, and it is likely that it will occupy this position for some time to come. When a neoplasm is resected there may be implantation of cancer cells into the wound and dissemination of cells into vascular and lymphatic channels beyond the limits of surgical removal. Adjuvant cancer chemotherapy is directed at these methods of spread. The drugs may be given systemically, regionally or locally. SYSTEMIC ADJUVANT CHEMOTHERAPY
The basic hypothesis of Cole 6 is that tumor cells which are disseminated into the blood stream at operation are more sensitive to chemotherapeutic agents than those which have a firm vascular attachment. Cole and associates showed that a decrease in "takes" of Walker carcinosarcoma 256 occurred with adjuvant administration of nitrogen mustard. These investigators also studied 700 patients for the presence of cancer cells in the peripheral blood at the time of operation. 4 One hundred and eight of these patients were suitable for preoperative, operative and postoperative samplings. Approximately one-fifth of the 108 patients had cancer cells in their blood during the operation when none was demonstrated either before or after surgery. Equally significant were the findings of Moore I6 that cancer cells will disappear from the blood under the influence of systemic chemotherapy as evidenced by negative serial blood samples. As with any new procedure having clinical application, simulated experimental situations were evaluated. Overstreet and McDonald,20 studying the Walker carcinoma 256 in rats, showed that growth 0f the tumor depended upon the number of cells injected and the site of injection. Their data support the assumption that not all cells desquamating from human tumors survive and produce metastases. McDonald and associates showed that nitrogen mustard and thio-TEPA are effective in preventing "takes" of carcinoma 256 in rats. 13 This inhibition was most marked when the dose of tumor cells was small and when the drug was given immediately after the injection of tumor cells. 12 McCredie and dePeysterll correlated the effect of varying the route of administration of cancer cells (intraportal, intraperitoneal and subcutaneous) and of varying the route of administering the drugs (intraportal, intraperitoneal and peripheral vein). Results showed that tumor growth after intraportal injection of cancer cells is partially controlled by any method of administration of drug but growth following intraperitoneal injection of cancer cells was only controlled by intraperitoneal administration of
Chemotherapy as an Adjunct to Surgery in Cancer Treatment
41
drug. These are but a few of the experiments directed at the clinical problems of the correct method of administration, the ideal time and the amount of drug for the most effective adjuvant chemotherapy. Cole and associates 7 used adjuvant cancer chemotherapy in patients with cancer of the breast under 70 years of age who satisfied certain criteria. After undergoing radical mastectomy, one-half of the patients selected at random received nitrogen mustard. The dosage schedule consists of 0.2 mg./kg. intravenously at surgery with an additional 0.1 mg'; kg. intravenously on the first and second postoperative day with a maximum dosage not to exceed 30 mg. The patients also received 0.4 mg./kg. of nitrogen mustard intravenously every four months for the first year and thio-TEPA 15 mg. intravenously every month for the second year after operation. Results following this regimen have been encouraging. Only 16 out of 65 treated patients had recurrences compared to 23 out of 65 control patients. At the time of last report six of the 65 treated patients had died while 15 of 65 control patients were dead as a result of their disease. In order to evaluate a large number of cases under well controlled conditions, an adjuvant chemotherapy study was organized in 1957 under the direction of the Cancer Chemotherapy National Service Center (a division of the National Cancer Institute)Y The study was divided into two separate groups: the university group (59 participating hospitals) headed by Dr. George Moore and the Veterans Administration group (22 participating hospitals) under the direction of Dr. Lyndon Lee. The drugs were nitrogen mustard for bronchogenic carcinoma and triethylenethiophosphoramide (thio-TEPA) for breast and gastrointestinal carcinoma. Patients with carcinoma of the lung, breast, stomach, colon and rectum were evaluated. Adjuvant studies of patients with carcinoma of the ovary utilizing chlorambucil as the cancerocidal drug were added in 1959. Dosage schedules were approximately the same for both groups of investigators. Double blind studies were performed. Constant surveillance of patients caused the investigators in the university group to reduce the dosage of thio-TEPA from 0.8 mg./kg. to 0.6 mg./kg. as adjuvant treatment in cancer of the breast because of complications related to the drug. Further studies, however, showed that the higher dosage was more effective in preventing recurrences. Lee, reporting for the Veterans cooperative group,27 stated that there was an increase in the risk of surgery in the treated patients. Also, reduction of the dose of nitrogen mustard for lung cases and of the thioTEPA dose for the stomach cases produced a decrease in the incidence of complications. In the colon series, however, decrease in the dosage did not lower the incidence of complications. The overall evaluation of adjuvant cancer chemotherapy as cited above has resulted in at least two conclusions. There is agreement that well coordinated study groups under a central governing board can effectively
r 42
PAUL F. NORA, FREDERICK
W.
PRESTON
test and compare methods of treatment requiring large numbers of patients. Secondly, the drugs used in these cooperative studies have been of no benefit to patients undergoing resections for carcinoma of the lung, stomach, colon and rectum. The university study showed that adjuvant chemotherapy with thio-TEPA reduced the incidence of recurrent and metastatic cancer in patients with carcinoma of the breast. Not enough time has elapsed for evaluation of these patients in terms of long-term survival. Cole's study in which nitrogen mustard was used as adjuvant treatment for cancer of the breast is in agreement with these results and has shown in addition that survival of patients with carcinoma of the breast is prolonged. LOCAL ADJUVANT CHEMOTHERAPY
Regrowth of tumor in the suture line and at the operative site following resection is an important cause of failure of surgical procedures to cure cancer. More attention has been directed toward the incidence of this complication than toward its prevention or treatment. Bacon2 reported that local recurrences occurred in 17.9 per cent of his patients followed for five or more years after abdominoperineal resection for carcinoma and stated that the incidence in the literature for this operation varied from 6 to 39.5 per cent. Among Cole's patients having anterior resection for carcinoma of the rectosigmoid the incidence of local recurrence was 16 per cent, and the incidence of suture line recurrence was 10 per cent. 3 The local recurrence rate following radical mastectomy for carcinoma of the breast is usually reported between 10 and 30 per cent, and is even higher for radical neck dissection for head and neck cancer, affecting as many as 40 to 50 per cent of patients. Attempts to prevent local recurrences by irrigating wounds with various solutions antedate accurate knowledge concerning the incidence and significance of cancer cells which can be recovered from wounds and from body cavities. Smith25 at the National Cancer Institute found wound washings positive for cancer cells in 26 per cent of 120 patients having radical resection for cancer. Moore 15 found tumor cells in washings of the peritoneal cavity of 31 per cent of patients with carcinoma of the colon. When the lesion was noncurable the washings were positive in 47 per cent. The incidence was even higher for carcinoma of the ovary, and 67 per cent of these patients had positive wound washings when the tumor was confined to the ovary. Seventy-five per cent were positive when there was extension outside the ovary. The irrigation of wounds seeded with tumor cells is an effective method of inhibiting tumor growth and preventing the lethal effect of the tumor in the experimental animal. Figure 1 shows an experiment designed to simulate the seeding of cancer cells which might occur in the wounds of a patient having a resection for a malignant neoplasm. A 1.5 cm. incision
Chemotherapy as an Adjunct to Surgery in Cancer Treatment
k
43
C _ "K:~_ D
A Fig. 1. Experiment to simulate the seeding of cancer cells. For details, see text.
was made through the skin and superficial fascia of the flank of a rat (A). One million living Bagg lymphosarcoma cells were placed in the wound (B), and it was closed with a single suture (C, D). Thirty minutes later the suture was removed and a chemotherapeutic agent was placed in the wound. Results (Table 1) are expressed in terms of growth of the tumor and survival of the animal and are arranged in two groups depending upon whether the drugs were placed in the wounds undiluted or were dissolved in a large volume and used as an irrigation. Doses of drugs used were those suitable for local use in the human being. The most effective drug was nitrogen mustard, 1 mg./kg., dissolved in 2 ml. of 0.9 per cent saline instilled into the wound. In the animals treated in this manner there was a delay in appearance of the tumor, decrease in the number of takes and decrease in the mortality rate (to 42 per cent) as compared to the control animals (91 per cent). McDonald 4 has done similar experiments to evaluate various irrigating agents in pouches of rats inoculated with Walker carcinoma 256. Sodium hypo chloride 0.5 per cent buffered to pH 9, chlorpactin 2 per cent (too toxic for clinical use) and nitrogen mustard proved most effective. More recently Moore and associates 19 have used animal tumors and human tissue suspensions as a screening system for selecting drugs to eliminate tumor cells from surgical wounds. Nine dyes, two antimetabolites, ten alkylating agents, five oxidizing agents, seven miscellaneous drugs and three inorganic compounds were screened. The most promising of these were used in the wounds of 26 patients. These experiments raised the question of the effect on the local recurrence rate of irrigating a wound with saline solution. Can local recurrence be reduced by saline irrigation or does a saline irrigation drive tumor cells
44
PAUL F. NORA, FREDERICK
Table 1.
W.
PRESTON
Chemotherapy in Experimental Wounds TUMOR TAKES
(per cent) REAGENT
NO. OF RATS
None (controls) ....... ............ 132 Given by instillation* 14 2 ml. NaCI, 0.9% ..... 5-FU, 1 mg./kg ....... 26 5-FU, 0.5 mg./kg ..... 19 TSPA, 8 mg./kg ..... 31 Chlorpactin 1 % ... 15 Chlorpactin 0.5% .. ......... 29 HN2, 1 mg./kg ..... 24 Given by irrigationt 30 ml. saline 0.9% ...... 12 HN2,1 mg./kg ........... 26 TSPA, 8 mg./kg ........... 33 15 Chlorpactin 1 % .... Chlorpactin 0.5% .... 44 5-FU, 0.5 mg./kg ................ 33
MORTALITY 30 DAYS
2-14 Days
Total in 20 Days or Less
(per cent)
100
100
91
100 100 95 39 40 83 33
100 96 95 84 87 96 50
100 92 90 81 80 76 42
83 85 97 0 18 94
100 96 100 53 57 91
92 92 82 60 57 79
* Total volume placed in wound was 2 m!. Most reagents were dissolved in 0.9 per cent NaC!. t Total volume used as irrigation was 30 m!. Most reagents were dissolved in 0.9 per cent MaCe. 5-FU, 5-fluorouracil; TSPA, triethylenethiophosphoramide (thio-TEPA); HN2, nitrogen mURtard. into the tissues and promote local recurrence? To test the effectiveness of saline irrigation, the number of tumor cells injected into the wound depicted in the figure were adjusted so that tumor growth was fatal in 50 per cent of animals. Sixty animals were used in this experiment. Twenty received no irrigation. Twenty received 30 m!. of saline as an irrigant, and 20 received 150 m!. The irrigations were given so that the force and time of the irrigations were constant. Tumor growth and mortality of the animals were the same in the groups receiving no irrigation and in those receiving small and large amounts of saline (Table 2). This suggests that irrigation with saline, regardless of the amount or pressure used, is useless in the prevention of tumor growth secondary to tumor cells seeded into wounds. The theory that local recurrences are caused by seeding at operation dates back at least 80 years. Smith's recent data shows that in long-term follow-up of patients there was no correlation between positive wound washings and local recurrences, distant metastases or survival time.! Additional work by Smith24 with groups of operable cases of carcinoma of the cervix uteri and head and neck cancer treated by en bloc excision plus wound irrigation with 0.5 per cent formalin indicated no differences
Chemotherapy as an Adjunct Table 2.
to
Surgery in Cancer Treatment
45
Effect of Saline Irrigation AVERAGE TUMOR SIZE
3 X 10
5
TUMOR CELLS*
RATS
PLUS
None ................. 20 20 30 ml. saline. . 20 150 ml. saline. .
(em. 3 ) DIED - - - - - (per eent) Days
7
14
11
41
8 5
30
60
36
55
50
* Bagg lymphosarcoma. in local recurrence rate or survival time between control and treated groups. At the present time there is evidence that suture line recurrences following colon resection can be eliminated. Cole and his associates3 , 4 advocate avoidance of enemas, gentle handling of the tumor to avoid desquamation of cells, ligation of the bowel proximal and distal to the tumor and irrigation of the distal segment with distilled water. Attention to methods for preventing local recurrence including irrigation of the bowel with 1 :500 perchloride of mercury have been effective in Morgan's experience. 18 Reduction in local recurrence rates was achieved by Goligher and associates 8 by similar methods. More recently Rosi and associates23 reported no local recurrences in patients operated upon for carcinoma of the descending colon and sigmoid between 1950 and 1955 when irrigation of the rectum with water preceded the anastomosis. The incidence of mucosal and extraluminal recurrence during the five-year period before this (1945 to 1950), when no irrigations were used, was 18 per cent. None of these surgeons have evaluated wound irrigation alone to control local recurrences, and at the present time the usefulness of chemotherapy by itself to eliminate wound recurrences following any type of cancer operation has not been studied except by Smith and Moore and their associates.l 9, 24 The problem of local recurrence is so important and the application of cancer chemotherapeutic agents in this respect seems sufficiently promising to warrant more investigation of this problem. REGIONAL ADJUVANT CHEMOTHERAPY
The introduction of cancerocidal agents via the intra-arterial route in 1950 was the beginning of regional chemotherapy of cancer.9 This form of therapy has evolved into two main types, infusion and perfusion. Infusion is the introduction (intermittent or continuous) of a chemo-
:
46
PAUL F. NORA, FREDERICK
W.
PRESTON
therapeutic agent into the arterial blood flupply of a tumor without any attempt to isolate this area from other parts of the body. Systemic antagonists to the cancerocidal agent may be used in conjunction with an infusion. Perfusion also involves the introduction of these agents into the arterial blood supply but circulation to the areas containing the tumor is isolated from that of the rest of the body by ligation of collaterals, tourniquets, balloon catheters and vascular clamps. The venous return is attached to a pump oxygenator and is used for the recirculation of the cancerocidal agents through the perfused area. Both of these methods have been used for palliation in localized carcinoma, but only perfusion has been used as an adjuvant to surgery. Infusion has been used following surgery but not in the sense in which we have reference to adjuvant in this article. Stehlin and associates26 have reported the use of perfusion with phenylalanine mustard as an adjunct to surgery in the treatment of 18 patients with malignant melanoma of the extremities. Three patients experienced a temporary response and 15 are classified as having quiescent disease. The first perfusion was performed only 32 months prior to Stehlin's report which is too short a period for evaluation. Creech5 has divided his treated cases of melanomas of the extremity into two groups: perfusion only or excision plus perfusion. Of the 76 patients suitable for analysis, 39 fall into the latter category (adjuvant group). Twenty-one of the 39 had perfusion plus excision of a primary tumor, and 18 had perfusion combined with removal of a secondary tumor (either regional recurrence or metastasis). Eight of the 39 patients had a recurrence in a relatively short time and were considered to have received no benefit from perfusion plus excisional therapy. The most striking finding was that in the 18 cases in which the perfusion was combined with excision of a secondary tumor, nine were at least temporarily controlled. The natural history of melanoma is so variable that it is impossible to draw any significant conclusions. Creech21 also reported on the use of perfusion in 18 selected adenocarcinomas (breast, rectum, ovary, metastatic carcinoma to extremities, and endometrium). Nine of the 18 patients had carcinoma of the breast. A few of the breast cases could be classified in the adjuvant category because perfusion was combined with mastectomy. None of these cases have been followed for more than eight months, therefore no results are yet available for analysis. Adjuvant perfusion chemotherapy has been used in the treatment of sarcoma10 but the series is small. Nonetheless, it has helped in certain cases by reducing the size of the lesion and making a more conservative surgical procedure possible. Because of the short period of time and the limited number of cases, no conclusions can be reached as to the value of this therapy. rI
Chemotherapy as an Adjunct to Surgery in Cancer Treatment
47
SUMMARY
A review of published reports of cancer chemotherapy used as an adjunct to surgery is presented. Chemotherapy may be given systemically, regionally or locally. The incidence of recurrent and metastatic carcinoma can be reduced and the survival of patients increased following radical mastectomy for carcinoma of the breast by nitrogen mustard used as an adjunct to surgery. Adjuvant chemotherapy has been of no benefit to patients undergoing surgery for carcinomas of the lung, stomach, colon or rectum. Cancerocidal drugs used as irrigants for wounds seem logical as a method of reducing locally recurrent cancer after a resection for cancer. Published data on this subject is contradictory and at the present time these drugs cannot be recommended. Surgeons undertaking the use of drugs as an adjunct to surgery must be aware of the toxic effects of these agents and be prepared to deal with a variety of drug-induced complications, the most important of which is bone marrow depression.
REFERENCES 1. Arons, M. S., Smith, R. R. and Myers, M. H.: Significance of cancer cells in operative wounds. Cancer 14: 1041, 1961. 2. Bacon, H. E.: Anus, Rectum, Sigmoid Colon. Philadelphia, J. B. Lippincott Co. 1949, Vol. 2, p. 762. 3. Cole, W. H.: Recurrence in carcinoma of the colon and proximal rectum following resection for carcinoma. Arch. Surg. 65: 264, 1952. 4. Cole, W. H., McDonald, G. 0., Roberts, S. S. and Southwich, H. W.: Dissemination of Cancer: Prevention and Therapy. Appleton-Century-Crofts, Inc., New York, 1961. 5. Creech, 0., Jr., Ryan, R. F. and Krementz, E. T.: Regional chemotherapy by isolated perfusion in the treatment of melanoma of the extremities. Plast. & Reconstruct. Surg. 28: 333, 1961. 6. Cruz, A., McDonald, P., Geraid, O. and Cole, W. H.: Prophylactic treatment of cancer and the use of chemotherapeutic agents to prevent tumor metastasis. Surgery 40: 291, 1956. 7. Economou, S., Mrazek, R., McDonald, G. 0., Slaughter, D. P. and Cole, W. H.: Adjuvant Therapy of Cancer Exhibit. Chicago Medical Society Annual Meeting, 1962. 8. Goligher, J. C., Dukes, C. E. and Bussey, H. J. R.: Local recurrence after sphincter-saving exciRions for carcinoma of the rectum and rectosigmoid. Brit. J. Surg. 39: 199, 1951. 9. Klopp, C. T., Alford, T. C., Bateman, J., Berry, G. N. and Winship, T.: Fractionated intra-arterial cancer chemotherapy with methyl bis amine hydrochloride: A preliminary report. Ann. Surg. 132: 811, 1950. 10. Krementz, E. T.: End results in the treatment of sarcoma by perfusion with chemotherapeutic agents. Cancer Chemother. Rep. 10: 83, 1960. 11. McCredie, J. A. and dePeyster, F. A.: Effects of giving nitrogen mustard by different routes to rats receiving Walker 256 cells intraportally, intraperitoneally and subcutaneously. Surgery 45: 709, 1959. 12. McDonald, C. T., Howie, J. S., Weeks, P. M. and Thomas, C. G.: Limiting
48 13. 14. 15. 16. 17. 18. 19.
20. 21. 22. 23. 24. 25. 26. 27.
PAUL F. NORA, FREDERICK
W.
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factors in the prophylaxis of the spread of cancer at operation by chemotherapeutic methods. S. Forum 8: 164, 1958. McDonald, G. 0., Livingston, C., Boyles, C. F. and Cole, W. H.: The prophylactic treatment of malignant disease with nitrogen mustard and triethyelenethiophosphoramide (thioTEPA). Ann. Surg. 145: 624,1957. Moore, G. E., Katz, A. D., Sandberg, A. A. and Binks, E. M.: Incidence of tumor cells in blood and peritoneal fluid in patients with cancer. S. Forum 8: 152,1958. Moore, G. E., Sako, K., Kondo, T., Badillo, J. and Burke, E.: Assessment of the exfoliation of tumor cells into the body cavities. Surg. Gynec. & Obst. 112: 469, 1961. Moore, G. E., Sandberg, A. A. and Schubarg, J. R.: Clinical and experimental observations of the occurrence and fate of tumor cells in the blood stream. Am. Surgeon 146: 580, 1957. Moore, G. and Stiver, R.: Review of the University Surgical Adjuvant Chemotherapy Studies. Cancer Chemother. Rep. 7: 54, 1960. Morgan, C. N.: Trends in the treatment of tumours of the rectum, rectosigmoid and left colon. J. Roy. ColI. Surgeons Edinburgh 1: 112, 1955. Mukhtar, F. A., DiPaolo, J., Hoffmeister, F. S., Koike, A., Moore, G. E. and Wilkens, H.: Selection of compounds for topical chemotherapy of tumorcontaminated human surgical wounds. Proc. Am. A. Cancer Res. 3: 347, 1962. Overstreet, R. J. and McDonald, G. 0.: Role of cellular dosage on "takes" following inoculation of Walker 256 tumor cells in the rat. S. Forum 8: 161, 1958. Reemtsma, K., Ryan, R. F., Krementz, E. T. and Creech, 0., Jr.: Treatment of selected adenocarcinomas by perfusion technique. Arch. Surg. 78: 724, 1959. Review of the Cancer Chemotherapy National Service Center Program: Develop. ment and Organization. Cancer Chemother. Rep. 7: 41, 1960. Rosi, A., Cahill, W. J. and Carey, J.: A ten year study of hemicolectomy in the treatment of carcinoma of the left half of the colon. Surg. Gynec. & Obst. 114: 15, 1962. Smith, R. R. and Gehan, E. A.: Effect of formaldehyde wound wash on development of local wound recurrences. J. Nat. Cancer Inst. 23: 1339, 1959. Smith, R. R., Thomas, L. B. and Hilberg, A. W.: Cancer cell contamination of operative wounds. Cancer 11: 53, 1958. Stehlin, J. S., Jr., Smith, J. L., Jr. and Clark, R. L., Jr.: Results of perfusion for melanoma. Cancer Chemotherap. Rep. 10: 79, 1960. Veterans Administration Adjuvant Cancer Chemotherapy Cooperative Group: Status of adjuvant cancer chemotherapy. Arch. Surg. 82: 466, 1961.
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