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Carcinoma of the anal canal—radiation or radiation plus chemotherapy?
03s3016/83/091417~2503.00/0 Copyright 6 1983 Pergamon Press Ltd.
Inr J Radiation Oncology Biol. Phys, Vol 9. pp. 1411-1418 Printed in the U.S A. All rights reserved.
??Editorial CARCINOMA OF THE ANAL CANAL-RADIATION RADIATION PLUS CHEMOTHERAPY? B.J. CUMMINGS, Department Anal carcinoma,
Radiation
M.B.,
of Radiation
CH.B.,
F.R.C.P.(C),
Oncology,
The Princess
Reprint requests to: B.J. Cummings, Margaret Hospital, M4X 1K9, Canada.
Hospital,
M.R.A.C.R. Toronto
conservatively. Minor telangiectasia or fibrosis of the perianal area is common after radiation treatment and usually requires no specific treatment. However, serious necrosis or strictures requiring surgical intervention have occurred in from 5 to 10% of patients in many series.3q9 Although Cantril et ~1.~ and others3,5 have successfully used uninterrupted courses of external beam megavoltage therapy for the treatment of anal carcinoma, Papillon’ suggests that a combination of external beam therapy and interstitial therapy by split course technique may reduce the incidence of late major toxicity. During the past 10 years there has been increasing use in North America of protocols combining chemotherapy and radiation for anal carcinoma. The most commonly used protocol has included external beam radiation and 5-Fluorouracil and Mitomycin C, although other cytotoxic agents have also been used.2.3 The delivery into a peripheral vein of a four or five day continuous infusion of 5-Fluorouracil, and a single bolus injection of Mitomycin C, starting on the first day of pelvic radiation has been reported to produce complete clinical regression of the primary anal carcinoma, and absence of histologically identifiable tumor in subsequent surgical resection or biopsy specimens, in about 85% of patients.4,7.” The external beam radiation doses used in the various series have ranged from 3000 cGy/3 weeks in patients treated preoperatively to 5000 cGy/4 weeks or higher in patients treated definitively.4.6.7.”The use of uninterrrupted external beam irradiation to 5000 &y/4 weeks combined with 5-Fluorouracil and Mitomycin C has been discontinued at the Princess Margaret Hospital because of severe acute hematological and gastrointestinal toxicity. Although split course therapy (2500 cGy/2 weeks, one month rest period, 2500 cGy/2 weeks; chemotherapy with each course) produces fewer acute complications, the risk of late necrosis appears to be similar to that for external beam radiation alone, and to be between 5 and 10%. Current protocols have been designed to study whether this necrosis rate can be reduced by decreasing the size of
therapy, Chemotherapy.
Although carcinoma of the anal canal has long been recognized by radiation therapists as being potentially curable by radiation, the most common method of management of such tumors in North American patients was, until recently, surgical resection by abdominoperineal resection. However, following the initial report of the successful preoperative use of combined chemotherapy and radiation by Nigro et al. in 1974,8 several centers have confirmed the effectiveness of such combinations either as preoperative or as definitive treatment of anal carcinomas, and marty patients are now being referred for radiation therapy. The article by Cantril et al.’ in this issue describes the successful treatment of anal carcinomas by radiation alone, and raises the important issue of whether radiation plus chemotherapy is more effective treatment than radiation alone for squamous or cloacogenic carcinomas arising in the anal canal or perianal area. Several centers, e$pecially those in France, have a long tradition of treating anal carcinomas by radical radiation therapy alone.3.5s9They have shown that the primary tumor can be controlled by radiation in from 40 to 80% of patients, with the average control rate being about 70%. Five year survival rates have been numerically similar to those described by centers which favor radical surgical resection and range from 35 to 60%~~However, the lack of a generally accepted clinical staging system prevents any more than a superficial comparison of results between different centers or between different treatment regimens. The highest control rates with radiation have been achieved for primary tumors less than 4 to 5 cm in diameter, and where the function of the anal sphincters has not been irretrievably lost. Surgical resection and colostomy have been reserved in these series from radiation centers for those patients who have residual or recurrent primary cancer, or for those patients in whom radiation induced necrosis or stricture cannot be managed
Princess Ontario,
F.R.C.R., Margaret
OR
M.B., F.R.C.P.(C), The 500 Sherbourne Street, Toronto,
Accepted
1417
for publication
24 June 1983.
1418
Radiation Oncology 0 Biology 0 Physics
each radiation fraction or the total radiation dose. The most effective scheduling of radiation and 5Fluorouracil and Mitomycin C is still undetermined. Many centers have copied the initial schedule of Nigro et a/.,* and have given the radiation and chemotherapy synchronously. At Memorial Hospital,6 where chemotherapy was given first and followed one to three days later by pelvic irradiation (3000 cGy/3 weeks), only 13/27 tumors regressed completely by clinical assessment prior to surgery compared to 15/ 19 treated synchronously by Nigro et al.’ It is impossible to determine whether this was due to differences in tumor size, to differences in drug and radiation scheduling, or to the shorter interval between irradiation and surgery (one week in New York compared to four to six weeks in Detroit). The interactions of radiation and 5-Fluorouracil or Mitomycin C have been studied in laboratory models. Rockwell” found additive cytotoxicity only between Mitomycin C and radiation. Byfield et al.’ described some evidence for a superadditive effect when cells were exposed to 5-Fluorouracil after prior irradiation, although their data do not exclude simple additivity. It is of course possible that neither of these models is relevant to the clinical treatment of anal carcinoma. Laboratory studies incorporating all three agents have not yet been reported. Although the short-term complete regression rates of anal carcinomas treated by combined radiation, 5-
September 1983, Volume 9, Number 9
Fluorouracil and Mitomycin C appear better than those achieved in many series where treatment has been by radiation alone, none of the combined chemotherapyradiation protocols has been tested over sufficient time to establish long term control rates or complication rates with any certainty. The current enthusiasm for such protocols should not obscure the fact that radiation alone may be just as effective as radiation plus chemotherapy. The suggestion by Cantril et al.’ that radiation alone to radical doses is sufficient treatment for tumors less than 5 cm in diameter may be correct, although it was small tumors of similar size which regressed completely with only 3000 cGy/l3 weeks and Mitomycin C and 5Fluorouracil and encouraged surgeons to defer abdominoperineal resection.6.7 The relative toxicity produced by these two treatment regimens will clearly be of great importance. Tumors larger than about 5 cm diameter do appear to respond better to combined radiation and chemotherapy than to radiation alone, but the possibility of late relapses cannot yet be excluded.4*9The infrequency with which anal carcinoma occurs suggests that only a carefully designed multicenter study will resolve the choice of radiation alone or radiation plus chemotherapy. In the absence of such a trial our preference is to continue to study combined modality treatment with careful attention to toxicity and to establishing whether the therapeutic ratio is improved compared to radiation alone.
REFERENCES 1. Byfield, J.E., Calabro-Jones, P., Klisak, I., Kulhanian, F.: Pharmacologic requirements for obtaining sensitization of human tumor cells in vitro to combined S-Fluorouracil or Ftorafur and X-Rays. Int. J. Radiat. Oncol. Biol. Phys. 8: 1923-l 933, 1982. W.C.: 2. Cantril, S.T., Green, J.P., Schall, G., Schaupp, Primary radiation therapy in the treatment of anal carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 9: 127 l-1218, 1983. B.J.: The place of radiation therapy in the 3. Cummings, treatment of carcinoma of the anal canal. Cancer Treat. Rev. 9: 125-147,1982. 4. Cummings, B.J., Rider, W.D., Harwood, A.R., Keane, T.J., Thomas, G.M., Erlichman, C., Fine, S.: Combined radical radiation therapy and chemotherapy for primary squamous cell carcinoma of the anal canal. Cancer Treat. Rep. 66: 489-492, 1982. B.J., Thomas, G.M., Keane, T.J., Harwood, 5. Cummings, A.R., Rider, W.D.: Primary radiation therapy in the treatment of anal canal carcinoma. Dis. Colon Rectum 25: 778-782,1982.
6. Michaelson, R.A., Magill, G.B., Quart, S.H.Q., Learning, R.H., Nikrui, M., Stearns, M.W.: Preoperative chemotherapy and radiation therapy in the management of anal epidermoid carcinoma. Cancer 51: 39&395, 1982. 7. Nigro, N.D., Vaitkevicius, V.K., Buroker, T., Bradley, G.T., Considine, B.: Combined therapy for cancer of the anal canal. Dis. Colon Rectum 24: 73-75, 1981. 8. Nigro, N.D., Vaitkevicius, V.K., Considine, B., Jr.: Combined therapy for cancer of the anal canal: a preliminary report. Dis. Colon Rectum 17: 354-356, 1974. 9. Papillon, J.: Conservative treatment by irradiation-an alternative to radical surgery. Rectal and Anal Cancers. New York, Springer-Verlag, 1982. 10. Rockwell, S.: Cytotoxicities of Mitomycin C and X-rays to aerobic and hypoxic in vitro. tnt. J. Radiat. Oncol. Biol. Phys. 8: 1035-1039,1982. 11. Sischy, B., Remington, J.H., Hinson, E.J., Sobel, S.H., Wall, J.E.: Definitive treatment of anal canal carcinoma by means of radiation therapy and chemotherapy. Dis. Colon Rectum 25: 685-688,1982.
Inr J Radiation Oncology Biol. Phys, Vol 9. pp. 1411-1418 Printed in the U.S A. All rights reserved.
??Editorial CARCINOMA OF THE ANAL CANAL-RADIATION RADIATION PLUS CHEMOTHERAPY? B.J. CUMMINGS, Department Anal carcinoma,
Radiation
M.B.,
of Radiation
CH.B.,
F.R.C.P.(C),
Oncology,
The Princess
Reprint requests to: B.J. Cummings, Margaret Hospital, M4X 1K9, Canada.
Hospital,
M.R.A.C.R. Toronto
conservatively. Minor telangiectasia or fibrosis of the perianal area is common after radiation treatment and usually requires no specific treatment. However, serious necrosis or strictures requiring surgical intervention have occurred in from 5 to 10% of patients in many series.3q9 Although Cantril et ~1.~ and others3,5 have successfully used uninterrupted courses of external beam megavoltage therapy for the treatment of anal carcinoma, Papillon’ suggests that a combination of external beam therapy and interstitial therapy by split course technique may reduce the incidence of late major toxicity. During the past 10 years there has been increasing use in North America of protocols combining chemotherapy and radiation for anal carcinoma. The most commonly used protocol has included external beam radiation and 5-Fluorouracil and Mitomycin C, although other cytotoxic agents have also been used.2.3 The delivery into a peripheral vein of a four or five day continuous infusion of 5-Fluorouracil, and a single bolus injection of Mitomycin C, starting on the first day of pelvic radiation has been reported to produce complete clinical regression of the primary anal carcinoma, and absence of histologically identifiable tumor in subsequent surgical resection or biopsy specimens, in about 85% of patients.4,7.” The external beam radiation doses used in the various series have ranged from 3000 cGy/3 weeks in patients treated preoperatively to 5000 cGy/4 weeks or higher in patients treated definitively.4.6.7.”The use of uninterrrupted external beam irradiation to 5000 &y/4 weeks combined with 5-Fluorouracil and Mitomycin C has been discontinued at the Princess Margaret Hospital because of severe acute hematological and gastrointestinal toxicity. Although split course therapy (2500 cGy/2 weeks, one month rest period, 2500 cGy/2 weeks; chemotherapy with each course) produces fewer acute complications, the risk of late necrosis appears to be similar to that for external beam radiation alone, and to be between 5 and 10%. Current protocols have been designed to study whether this necrosis rate can be reduced by decreasing the size of
therapy, Chemotherapy.
Although carcinoma of the anal canal has long been recognized by radiation therapists as being potentially curable by radiation, the most common method of management of such tumors in North American patients was, until recently, surgical resection by abdominoperineal resection. However, following the initial report of the successful preoperative use of combined chemotherapy and radiation by Nigro et al. in 1974,8 several centers have confirmed the effectiveness of such combinations either as preoperative or as definitive treatment of anal carcinomas, and marty patients are now being referred for radiation therapy. The article by Cantril et al.’ in this issue describes the successful treatment of anal carcinomas by radiation alone, and raises the important issue of whether radiation plus chemotherapy is more effective treatment than radiation alone for squamous or cloacogenic carcinomas arising in the anal canal or perianal area. Several centers, e$pecially those in France, have a long tradition of treating anal carcinomas by radical radiation therapy alone.3.5s9They have shown that the primary tumor can be controlled by radiation in from 40 to 80% of patients, with the average control rate being about 70%. Five year survival rates have been numerically similar to those described by centers which favor radical surgical resection and range from 35 to 60%~~However, the lack of a generally accepted clinical staging system prevents any more than a superficial comparison of results between different centers or between different treatment regimens. The highest control rates with radiation have been achieved for primary tumors less than 4 to 5 cm in diameter, and where the function of the anal sphincters has not been irretrievably lost. Surgical resection and colostomy have been reserved in these series from radiation centers for those patients who have residual or recurrent primary cancer, or for those patients in whom radiation induced necrosis or stricture cannot be managed
Princess Ontario,
F.R.C.R., Margaret
OR
M.B., F.R.C.P.(C), The 500 Sherbourne Street, Toronto,
Accepted
1417
for publication
24 June 1983.
1418
Radiation Oncology 0 Biology 0 Physics
each radiation fraction or the total radiation dose. The most effective scheduling of radiation and 5Fluorouracil and Mitomycin C is still undetermined. Many centers have copied the initial schedule of Nigro et a/.,* and have given the radiation and chemotherapy synchronously. At Memorial Hospital,6 where chemotherapy was given first and followed one to three days later by pelvic irradiation (3000 cGy/3 weeks), only 13/27 tumors regressed completely by clinical assessment prior to surgery compared to 15/ 19 treated synchronously by Nigro et al.’ It is impossible to determine whether this was due to differences in tumor size, to differences in drug and radiation scheduling, or to the shorter interval between irradiation and surgery (one week in New York compared to four to six weeks in Detroit). The interactions of radiation and 5-Fluorouracil or Mitomycin C have been studied in laboratory models. Rockwell” found additive cytotoxicity only between Mitomycin C and radiation. Byfield et al.’ described some evidence for a superadditive effect when cells were exposed to 5-Fluorouracil after prior irradiation, although their data do not exclude simple additivity. It is of course possible that neither of these models is relevant to the clinical treatment of anal carcinoma. Laboratory studies incorporating all three agents have not yet been reported. Although the short-term complete regression rates of anal carcinomas treated by combined radiation, 5-
September 1983, Volume 9, Number 9
Fluorouracil and Mitomycin C appear better than those achieved in many series where treatment has been by radiation alone, none of the combined chemotherapyradiation protocols has been tested over sufficient time to establish long term control rates or complication rates with any certainty. The current enthusiasm for such protocols should not obscure the fact that radiation alone may be just as effective as radiation plus chemotherapy. The suggestion by Cantril et al.’ that radiation alone to radical doses is sufficient treatment for tumors less than 5 cm in diameter may be correct, although it was small tumors of similar size which regressed completely with only 3000 cGy/l3 weeks and Mitomycin C and 5Fluorouracil and encouraged surgeons to defer abdominoperineal resection.6.7 The relative toxicity produced by these two treatment regimens will clearly be of great importance. Tumors larger than about 5 cm diameter do appear to respond better to combined radiation and chemotherapy than to radiation alone, but the possibility of late relapses cannot yet be excluded.4*9The infrequency with which anal carcinoma occurs suggests that only a carefully designed multicenter study will resolve the choice of radiation alone or radiation plus chemotherapy. In the absence of such a trial our preference is to continue to study combined modality treatment with careful attention to toxicity and to establishing whether the therapeutic ratio is improved compared to radiation alone.
REFERENCES 1. Byfield, J.E., Calabro-Jones, P., Klisak, I., Kulhanian, F.: Pharmacologic requirements for obtaining sensitization of human tumor cells in vitro to combined S-Fluorouracil or Ftorafur and X-Rays. Int. J. Radiat. Oncol. Biol. Phys. 8: 1923-l 933, 1982. W.C.: 2. Cantril, S.T., Green, J.P., Schall, G., Schaupp, Primary radiation therapy in the treatment of anal carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 9: 127 l-1218, 1983. B.J.: The place of radiation therapy in the 3. Cummings, treatment of carcinoma of the anal canal. Cancer Treat. Rev. 9: 125-147,1982. 4. Cummings, B.J., Rider, W.D., Harwood, A.R., Keane, T.J., Thomas, G.M., Erlichman, C., Fine, S.: Combined radical radiation therapy and chemotherapy for primary squamous cell carcinoma of the anal canal. Cancer Treat. Rep. 66: 489-492, 1982. B.J., Thomas, G.M., Keane, T.J., Harwood, 5. Cummings, A.R., Rider, W.D.: Primary radiation therapy in the treatment of anal canal carcinoma. Dis. Colon Rectum 25: 778-782,1982.
6. Michaelson, R.A., Magill, G.B., Quart, S.H.Q., Learning, R.H., Nikrui, M., Stearns, M.W.: Preoperative chemotherapy and radiation therapy in the management of anal epidermoid carcinoma. Cancer 51: 39&395, 1982. 7. Nigro, N.D., Vaitkevicius, V.K., Buroker, T., Bradley, G.T., Considine, B.: Combined therapy for cancer of the anal canal. Dis. Colon Rectum 24: 73-75, 1981. 8. Nigro, N.D., Vaitkevicius, V.K., Considine, B., Jr.: Combined therapy for cancer of the anal canal: a preliminary report. Dis. Colon Rectum 17: 354-356, 1974. 9. Papillon, J.: Conservative treatment by irradiation-an alternative to radical surgery. Rectal and Anal Cancers. New York, Springer-Verlag, 1982. 10. Rockwell, S.: Cytotoxicities of Mitomycin C and X-rays to aerobic and hypoxic in vitro. tnt. J. Radiat. Oncol. Biol. Phys. 8: 1035-1039,1982. 11. Sischy, B., Remington, J.H., Hinson, E.J., Sobel, S.H., Wall, J.E.: Definitive treatment of anal canal carcinoma by means of radiation therapy and chemotherapy. Dis. Colon Rectum 25: 685-688,1982.