- Email: [email protected]
Squamous cell carcinoma of the anal canal
Squamous
Cell Carcinoma of the Anal Canal
J. MD, FACS, FRCSC, Robert J. Myerson, Pho, MD, Susan J. Shapiro, MD, James W. Fleshman, Jr., MD, FAG, Robert D. Fry, MD, FACS, John D. Halverson, MD, FACS, Ira J. Kodner, MD, FACS, William W. Monafo, MD, FACS, SI. Louis, Missouri
Between 1979 and 1988,33 patients with squamous cell carcinoma of the anal canal were treated with chemoradiation. There were 24 women and 9 men, fawn 37 to 90 years of age (median: 63 years). Complete tumor regre&on occurred in 29 of the 33 patients (88%), only one of whom later developed recurrence. In the other four patients, there was persistent tumor after 3 months; three of these patients died within 2 years; and one is alive with distant metastases 2 years later. During the first 5 years of the study, seven patients with complete tumor regression underwent planned abdominoperineal resection following chemoradiation. Four of the abdominoperineal resection specimens were free of tumor, but three were not. These three patients, who had abdominoperineal resection within 3 months of chemoradiation, are disease-free. Ten of the 29 patients who had complete tumor regression had biopsies of the primary site 3 months after treatment. All biopsies were negative for rcsidual carcinoma. At present, 26 patients (79%) arc alive and disease-free from 2 to 10 years posttreatment (median: 4 years). Two patients died of unrelated causes, four of cancer, and one is alive with cancer. Complications of the chemoradiation required surgical intervention in two patients, and two others developed severe hematologic toxicity, for a complication rate of 12% (4 of 33 patients). There was no treatment-related mortality. These results support the efficacy of chemoradiation treatment for carcinoma of the anal canal. They suggest that abdominoperineal mtion no longer need be part of the planned initial management, and that posttreatment biopsy of the primary site is unnecessary, unless palpable or visible abnormalities are present 3 months after treatment.
From the Department of Surgery, Washington University School of Medicine, Bamcs (MJL, JDH, WWM) and Jewish (JWF, RDF, IJK) Hospitals, and theMallinckrodt Institute of Radiol%y (RJM, SJS), St. Louis, Missouri. Requests for reprints should be addressed to Marvin J. Lopez, MD, 5 102 Quceny Tower, Barnes Hospital Plaza,St. Louis,Mkscuri 63 1IO. Presentai at the 43rd Annual Meeting of the Southwestern Surgical Congrss. Las Vegas. Nevada, April 2 l-24,1991.
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quamous cell carcinoma of the anal canal is uncomS mon, accounting for less than 0.2% of all cancers and 2% to 5% of all anorectal malignancies [1,2]. Approximately 45,500 new cases of rectal cancer will be diagnosed this year in the United States. The expected annual number of new anal cancers in this country is, therefore, between !I00 and 2,000 [3]. In the past, this disease pre dominated in the elderly, many of whom had long-standing, benign anorectal disease. At present, carcinoma of the anal canal is diagnosed more frequently in younger patients, especially in men. For many years, standard therapy for this lesion was abdominoperineal resection, which was advocated based on retrospective studies. Fiveyear survival rates averaged 50% [3]. These results re mained virtually unchanged for several decades [3]. Moreover, when tumor resection was incomplete, postoperative irradiation was shown to be of limited value [4]. Historically, radiofherapy alone was utilized only for locally advanced and unresectable tumors or for patients too ill to withstand operation. More recent data, however, suggest that treatment with external beam radiotherapy may be equal to or superior to resection alone 141. Evidence has existed for nearly 20 years that anal carcinoma responds to combined chemotherapy and radiation [5], so called “chemoradiation.” During the last decade, several investigators reported promising results using chemoradiation [6-I]]. More recent studies confirm that the 5-year survival rates are not only superior to those obtained with abdominoperineal resection alone, but anal sphincter preservation is achieved in up to 80% of patients [22-151. The interest generated by these new therapeutic successes resulted in the reappraisal of virtually every aspect of this neoplasm. Fortunately, this has led to the unification of the assessment of anatomical boundaries, histopathologic nomenclature, staging classification, biologic behavior, and treatment approaches. While these concepts are still in evolution and many questions remain unanswered [ 14, remarkable progress has occurred. Controversies now focus on issues of lesser magnitude. As with any emerging therapy, further experience is necessary to assess its validity. The purpose of this study is to report our experience with chemoradiation for the treatment of patients with squamous cell carcinoma of the anal canal. PATIENTS AND METHODS In 1979, chemoradiation became the standard of care for patients with squamous cell carcinomas of the anal canal at Washington University Medical Center in St. Louis, Missouri. All patients were evaluated in a multidisciplinary manner. All tumors were biopsied and clinically staged. Computerized tomography (CT) of the abdomen and pelvis was performed in all patients.
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The study group comprised thirty-three patients who received chemoradiation during the period 1979 to 1988. There were 24 women and 9 men. The youngest patient was 37 years of age, and the oldest 90; the median age was 63 years. The 1988 International Union Against Cancer and the American Joint Committee for Cancer Staging (UICC/AJC) classification was used (Table I) [I 71.This classification defines the anal canal as the area extending from just above the dentate line to the anal verge. Twenty-four of 33 tumors were classified T2NO (73%), and five were TlNO (15%). Of the remaining four patients, two had T3NO tumors, one had TlNl tumor, and one had T2N2 tumor. Thus, 88% (29 of 33 patients) of patients had early disease (Tl,T2, or NO), and 12% (4 of 33 patients) presented with locally advanced disease. Only two of 33 patients had lymph node metastases upon initial evaluation. On CT and clinical evaluation, one patient had perirectal positive lymph nodes (Nl), and the other had both perirectal and inguinal lymph node metastases (N2). Histologic confiiation of squamous cell carcinoma was made in all cases. Follow-up was complete, with a median observation time of 4 years. Treatment consisted of combined external beam radiotherapy and chemotherapy. Twenty-five patients (76%) received 3,000 cGy in 25 fractions. Four patients received 5,000 cGy, two patients 4,600 cGy, and the two remaining patients received 5,600 cGy and 2,600 cGy, respectively. Chemotherapy consisted of mitomycin-C 10 mg/m*, given as a bolus intravenous injection on day 2 of the radiotherapy, and Muorouracil 1,000 mg/m* by continuous intravenous infusion, daily for 5 consecutive days, also starting on day 2 of the protocol. Ten patients received one chemotherapy course, and 13 patients re ceived a second course of chemotherapy on day 28 of radiotherapy. Ten patients were given 5-fluorouracil but not mitomycin-C. Patients selected to receive a second course of chemotherapy were those with protracted tumor regression. Radiotherapeutic doses over 3,000 cGy were given during the early years of the study. RESULTS Treatment outcome is presented in TabIe II. Complete clinical tumor regression was obtained in 29 of the 33 patients (88%), all but one of whom remained free of disease. That patient developed recurrence 5 months after treatment and underwent abdominoperineal resection but died of metastases 7 months later. Tumor regression was incomplete in the remaining four patients. Two had abdominoperineal resection but died with local recurrence and metastases within 2 years. A third patient had both locoregional and distant metastases and died. The fourth patient with incomplete tumor regression underwent abdominoperineal resection and is alive with distant metastases. Thus, none of the patients with either persistent or recurrent tumor following the chemoradiition were salvaged by abdominoperineal resection. In contrast, of seven planned abdominoperineal resections performed during the early part of the study, four had tumor-free specimens. These four patients are alive and diseasefree. THE AMERICAN
TABLE I UICC/AJC Staging Classlflcation for Squamous Cell Carcinoma of the Anal Canal Primary tumors Tl Tumor 2 cm or less in greatest dimension T2 Tumor more than 2 cm but not more than 5 cm in greatest dimension T3 Tumor more than 5 cm in greatest dimension T4 Tumor of any size invades adjacent organ(s), invofvement of sphincter muscle(s) alone not classifted as T4 Lymph NO Ni N2 N3
node No regional lymph node metastasis Metastasis in perirectal lymph node(s) Metastasis in unilateral internal iliac and/or inguinal lymph node(s) Metastasis in perirectal and inguinal lymph nodes, and/or bilateral internal iliac, and/or inguinal lymph nodes
Distant metastasis (M) MO No distant metastasis Ml Distant metastasis Staging grouping 0 Tis I Tl II T2 T3 IIIA T4 Tl T2 T3 IIIB T4 Any T Any T IV AnyT
NO NO NO NO NO Nl Nl Nl Nl N2 N3 Any N
MO MO MO MO MO MO MO MO MO MO MO Ml
UICC = Iniernaticjnal Union Against Cancer; AIC = American Joint Committee on Cancer
Classification;
T = primary
tumors;
N = lymph
node;
M = distant
metastasis.
TABLE II Results of Chemoradlatlon In 33 Patients With Squamous Cell Carcinoma of the Anal Canal Treatment Outcome
No. of Patlents (%)
Complete tumor regression (n = 33) Recurred and died (n = 29) Partial tumor regression (n = 33) Persisted and died (n = 4) Alive with disease (n = 4) Alive and disease-free (n = 33) Dead from other causes (n = 33) Salvaged by APR (n = 4)
29 1 4 3 f 26
(66) (3) (12) (75) (25) (79)
2 (6) 0 (0)
APR = abdominoparineal resection.
The remaining three patients with microscopic tumor in the surgical specimen are also free of disease. Of five patients whose cancer persisted or recurred, two patients had locally advanced (T3NO) tumors at the time of diagnosis, two had T2NO tumors, and one had T2N2 disease. After a median follow-up of 4 years, 26 patients (7996) are alive and free of disease. Four died of cancer, two died of unrelated causes, and one patient is alive with distant metastases. Short-term treatment toxicity was universal.
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However, perineal skin reactions, nausea, vomiting, and diarrhea were self-limiting and did not require surgical intervention or hospitalization. Major morbidity occurred in only four patients (12%). One patient developed severe lower abdominal pain, paralytic ileus, and abdominal wall rigidity during the course of treatment. During exploratory laparotomy, acute radiation enteritis involving the terminal ileum was found. This patient recovered uneventfully. A second patient developed a perirectal ab scess that was incised and drained without further complications. Two patients experienced severe neutropenia (less than l,000/mm3), thrombocytopenia (less than 50,000/mm3), and diarrhea. Their treatment consisted of intravenous hydration, nutritional support, and prophylactic antibiotic therapy, resulting in complete recovery. There was no mortality attributable to chemoradiation. The preservation of anorectal function was possible in all patients with complete regression.
COMMENTS In 1988, the UICC and the AJC agreed on a unified staging classification for carcinomas of the anal canal. The UICC/AJC staging method provides an opportunity for uniform reporting of treatment results (Table I) [Z7]. In this classification, the anal canal includes only the transitional zone and the pecten. Squamous ccl1 carcinomas arising from the perianal skin are classified as skin cancers. Therefore, the anal margin no longer exists for staging purposes. While certain tumors may possess a more aggressive biologic behavior [Z8] (small cell, undifferentiated, mucoepidermoid, and pseudoadenoid cystic carcinomas), all tumors arising in the anal canal are classified according to their degree of differentiation but are grouped under the broad category of squamous cell carcinomas. Furthermore, it has been proposed that the terms cloacogenic, basaloid, and transitional cell be eliminated to avoid further confusion [19]. Abdominoperineal resection is no longer the primary treatment for anal carcinoma. However, radical pelvic surgery, including even pelvic exenteration, remains a viable option for patients with locally advanced (T4) tumors or in patients whose tumors remain localized after incomplete tumor regression [20]. Local resection alone is reasonable for small tumors that can be excised with adequate margins without compromising anorectal function. Patients with superficial tumors of 1 cm or less, located in the distal anal canal without sphincteric muscle involvement, can be treated by local excision with a 100% survival rate, according to Beahrs and Wilson [22]. The Memorial Hospital experience, as reported by Stearns et al [2], also suggests that local excision of noninfiltrating small lesions is reasonable, provided there is frequent follow-up observation. Parks [22] described his techniques of local excision, which vary according to the depth of tumor penetration. If the carcinoma is small and extends only superficially into the internal sphincter, the lesion is excised with the underlying internal sphincter muscle. At present, there is consensus that chemoradiation is preferred for tumors invading the sphincters. The development of multimodal therapy for anal car582
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cinema was influenced by the recognition that certain antineoplastic chemotherapeutic drugs are radiosensitizing agents. The pioneering studies of Heidelberger et al [23] demonstrated the additive effect of 5-fluorouracil and irradiation, and Bagshaw [24] showed greater in uitrokilling of a squamous cell carcinoma cell line when 5-fluorouracil and irradiation were combined. The contributions of Vietti et al [25] and Bylield et al [26l led to the concept of radiosensitization of human tumors. It is not entirely clear whether chemotherapy sensitizes tumor cells to the effects of radiation or if ionizing radiation sensitizes the tumor to the lethal effects of chemotherapy. The landmark paper by Nigro et al [.5] brought this concept of cancer therapy into the clinical arena in 1974. Chemoradiation has now come of age in the management of anal carcinomas. The initial efforts at establishing chemoradiation therapy for anal carcinoma were conducted within the context of planned preoperative (neoadjuvant) therapy [5,9]. It soon became doubtful whether routine abdominoperineal resection following chemoradiation was necessary, as a substantial number of specimens were free of tumor [2,5,7,9]. Furthermore, as in three of seven patients in our study, when abdominoperineal resection is performed within 3 months after the completion of chemoradiation, residual disease may still be demonstrable histologically, but its significance is questionable as clinical recurrence in this setting is rare [2,3,5,7,9]. This appreciation of the slow rate of tumor regression in response to chemoradiation has led to the practice of deferring biopsy of the cancer site until 3 months have elapsed after chemoradiation. If residual disease is demonstrated after 3 months, retreatment with chemoradiation may be performed in selected patients [IO]. Abdominoperineal resection or exenterative pelvic surgery may play a salvage role at this stage. Several trials have reported results of chemoradiation without surgery in the treatment of anal carcinoma [7-251. These treatment protocols have some differences regarding total radiotherapeutic dose and the number of chemotherapeutic cycles, but all have adhered to the principle that both modalities must be given concurrently. However minor these differences in protocol design may be, it makes interpretation of treatment results difficult. Thus, the next logical step in the study of this disease was to institute a cooperative clinical trial. The first multicenter prospective trial of chemoradiation was conducted by the Radiation Therapy Oncology Group and reported in 1989 [13]. Sischy et al [13] treated 75 patients with squamous cell carcinoma of the anal canal between 1983 and 1987. The study design, the most commonly utilized in the past, consisted of external beam pelvic and perineal radiotherapy to a total dose of 4,080 cGy with mitomycin-C 10 mg/m2, given as one bolus intravenous injection on day 2 of the radiation treatment, and a continuous infusion of 5-fluorouracil1,OOO mg/m*/24 hours for 96 hours on days 2 and 28. The inguinal nodal areas also received 4,000 cGy. At a median follow-up of 3 years, these authors reported a 73% survival rate [13]. Similar results were obtained in our series: 79% of our
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patients are alive and disease-free at a median follow-up time of 4 years. Our results are also in concert with those of Nigro et al [12] who reported an actuarial 5-year survival rate of 7%. Locoregional treatment failures occur predominantly in patients with locally advanced disease at presentation. Papillon and associates [27,28] and Sischy and associates [13] found that tumor size greater than 3 to 4 cm had a major influence on the recurrence rates. Other morphologic tumor factors, such as differentiation, vascular or lymphatic permeation, and growth patterns (endophytic versus exophytic), have not been carefully studied. Nigro et al [ 121 have made the interesting observation that the salvage rate of abdominoperineal resection for locoregional failures is poor. Nine of their 44 patients had tumors measuring 6 cm or larger. In four patients, gross residual tumor remained after chemoradiation, and all died of metastatic disease, despite abdominoperineal resection. Whether patients with large (T4) tumors should be managed with planned preoperative chemoradiation followed by radical surgery, avoiding a 3-month waiting period, remains speculative. Nigro et al [6’J have proposed that patients with lesions 6 cm or larger be treated by chemoradiation followed by abdominoperineal resection. It is clear that complete tumor disappearance after chemoradiation is associated with excellent long-term survival and local control. However, a minority (1% to 6%) of patients will experience recurrence 1 to 5 years after treatment [IZ,I3]. Therefore, it is imperative that intensive follow-up be provided. Our recurrence rate following complete response to chemoradiation was 3% (1 of 29 patients). Three patients whose tumors persisted underwent abdominoperineal resection with curative intent but died of disease, as already noted. The role of abdominoperineal resection as a salvage procedure remains incompletely documented. While chemoradiation is now widely accepted as the primary treatment modality for anal carcinoma, many questions remain unanswered [ 14. One trial is investigating whether mitomycin-C can be eliminated from the treatment protocol without affecting outcome. Deletion of mitomycin-C led to a fall in local control rates at one institution [16]. The ultimate role of this drug will be defined in an ongoing randomized prospective multicenter study. The overwhelming success of chemoradiation for carcinoma of the anal canal is a tribute to multidisciplinary cancer care and the application of new concepts in radiobiology, chemotherapy, and basic research. This is clearly a disease where traditional surgical concepts have been successfully superseded. Nonetheless, the role of the surgeon in the treatment of this disease remains important in the initial evaluation, diagnosis, and staging, as well as in the timely management of persistent disease.
REFERENCES 1.de1 Regato JA, Spjut
HJ, Cox JD. Anus. In: Ackerman LV, de1 Regato JA, editors. Cancer. St. Louis: C.V. Mosby CO., 1985: 567-15. 2. Stearns MW, Urmacher C, Sternberg SS, et al. Cancer of the THE AMERICAN
CANAL
anal canal. Curr Prob Surg 1980: 4: l-44. 3. Lopez MJ, Bliss DP Jr, Kraybill WG, Soybel Dl. Carcinoma of the anal region. Curr Probl Surg 1989; 26: 527-600. 4. Dobrowsky W. Radiotherapy of epidermoid anal canal cancer. Br J Radio1 1989; 62: 53-8. 5. Nigro ND, Vaitkevicius VK, Considine B. Combined therapy for cancer of the anal canal: a preliminary report. Dis Colon Rectum 1974; 17: 354-6. 6. Nigro ND, Seydel HG, Considine B, et al. Combined preoperative radiation and chemotherapy for squamous cell carcinoma of the anal canal. Cancer 1983; 51: 1826-9. 7. Sischy B. The use of radiation therapy combmed with chemotherapy in the management of squamous cell carcinoma of the anus and marginally resectable adenocarcinoma of the rectum. lnt J Radiat Qncol Biol Phys 1985; 11: 1587-93. 8. Cummings BJ, Rider WD, Harwood AR, et al. Combined radical radiation therapy and chemotherapy for primary squamous cell carcinoma of the anal canal. Cancer Treat Rev 1982; 66: 489-92. 9. Michaelson RA, Magill GB, Quan SH, et al. Preoperative chemotherapy and radiation therapy in the management of anal epidermoid carcinoma. Cancer 1983; 51: 390-5. 10. Flam MS, John MJ, Mowry PA, et al. Definitive combined modality therapy of carcinoma of the anus. Dis Colon Rectum 1987; 30: 495-502. I I. Wanebo HJ, Futrell W, Constable W. Multimodality approach to surgical management of locally advanced epidermoid carcinoma of the anorectum. Cancer 1981; 47: 2817-26. 12. Nigro ND, Vaitkevicius VK, Considine B Jr. Dynamic management of squamous cell cancer of the anal canal. Invest New Drugs 1989; 7: 83-9. 13. Sischy B, Scotte Doggett RL, Krall JM, et al. Definitive irradiation and chemotherapy for radiosensitization in management of anal carcinoma: interim report on Radiation Therapy Oncology Group Study No. 8314. J Nat1 Cancer lnst 1989; 81: 850-6. 14. Habr-Gama A, Da Silva AH, Sousa SF Jr, et al. Epidermoid carcinoma of the anal canal: results of treatment by combined chemotherapy and radiation therapy. Dis Colon Rectum 1989; 32: 773-7. 15. Knecht BH. Combined chemotherapy and radiotherapy for carcinoma of the anus. Am J Surg 1990; 159: 518-21. 16. Cummings BJ. The treatment of anal cancer. lnt J Radiat Oncol Biol Phys 1989; 17: 1359-61. 17. American Joint Committee on Cancer. In: Beahrs OH, Henson DE, Hutter RV, et nl, editors. Manual for staging of cancer. 3rd e-d. Philadelphia: J.B. Lippincott Co., 1988: 81-5, 133-8. 18. Morson BC. The pathology and results of treatment of squamous cell carcinoma of the anal canal and anal margin. Proc R Sot Med 1960; 53: 416-20. 19. Dougherty BG, Evans HL. Carcinoma of the anal canal: a study of 79 cases. Am J Clin Path01 1985; 83: 159-64. 20. Lopez MJ, Kraybill WG, Downey Rs, ef al. Exenterative surgery for locally advanced rectosigmoid cancers. Is it worthwhile? Surgery 1987; 102: 644-51. 21. Beahrs OH, Wilson SM. Carcinoma of the anus. Ann Surg 1976; 184: 422-8. 22. Parks A. Squamous carcinoma of the anal canal. Ann Gastroenterol Hepatol 1981; 17: 103-7. 23. Heidelberger C, Griesbach L, Montag BJ, et al. Studies on fluorinated pyrimidines. Il. Effects on transplanted tumors. Cancer Res 1958; 18: 305-17. 24. Bagshaw MA. Possible role of potentiators in radiation therapy. AJR Am J Roentgen01 1961; 85: 822-33. 25. Vietti T, Eggerding F, Valeriote F. Combined effect of x radiation and 5-fluorouracil on survival of transplanted leukemic cells. J Nat1 Cancer lnst 1971; 47: 865-70.
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26. Byfield JE, Calabro-Jones P, Klisak I, et al. Pharmacologic
requirementsfor obtaining sensitization of human tumor cells in vitro to combined 5fluorouracil or ftorafur and x-rays. Int J Radiat
Oncol Biol Phys 1982; 8: 1923-33. 27. Papillon J, Montbarbon JF. Epidermoid carcinoma of the anal canal: a series of 276 cases. Dis Colon Rectum 1987; 30: 324-33. 28. Papillon J, Montbarbon JF, Gerard JP, et al. Interstitial curietherapy in the conservative treatment of anal and rectal cancers. Int J Radiat Oncol Biol Phys 1989; 17: 1161-9.
DISCUSSION Robert W. Beart (Scottsdale, AZ): Dr. Lopez, is survival with chemoradiation really better than with surgery alone? Most of the patients in this study had early stage tumors (Tl, T2), unlike patients in the usual distribution of this disease. While their 79% survival rate is certainly admirable, it is not substantially different than in the reported series by Boman et al (Cancer 1984; 54: 114-25) of a large number of patients treated by abdominoperineal resection with a 5-year survival rate of 71%. It is evident that tumor size and histologic differentiation are important prognostic indicators in anal carcinoma. These data from France clearly show that failure rates relate to tumor size and histology. Indeed, well-differentiated squamous cell carcinomas have a different biologic behavior than poorly differentiated or basal carcinomas. Smaller tumors have significantly lower incidences of lymph node metastases than larger tumors. Recognizing these prognostic elements, do the authors feel that all patients should be treated with chemoradiation, or is there a role for abdominoperineal resection as a planned procedure in the management of anal cancer? Finally, since this group of patients was treated with significant variations in therapy, what is the combination of radiation and chemotherapy that they recommend at this time? Kent C. Westbrook (Little Rock, AK): My question to Dr. Lopez is in regard to the management of regional lymph node metastasis. Are patients presenting with clinically positive inguinal nodes managed any differently than those without palpable nodes? Michael L. Hawkins (Augusta, GA): Since the patients who developed recurrence presumably died from systemic disease, what, if any, pretreatment work-up is undertaken to search for metastatic disease? Also, what is the quality of anal function after 3,000 or more rads are administered to the perineal region? Frank E. Johnson (St. Louis, MO): Interstitial radiotherapy has been advocated by some authors for treatment of squamous cell carcinoma of the anal canal. Would Dr. Lopez comment on the current role of brachytherapy for these tumors? Nicholas P. Lang (Little Rock, AK): My question is in regard to variations in radiation dosimetry. Were these variations in terms of total rads administered or in the number of fractions given? Marvin J. Lopez (closing): Dr. Beart correctly points out that the results of abdominoperineal resection for
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early stage anal carcinoma are comparable to chemoradiation. However, the fact that similar results may be obtained without abdominoperineal resection makes chemoradiation a logical first choice since preservation of anorectal function is an extremely important goal, provided it does not compromise local-regional control of cancer or survival. It has been my experience that bulky endophytic tumors do not respond well to chemoradiation. I am in complete agreement with Dr. Beart that there is a definite role for a planned abdominoperineal resection in conjunction with chemoradiation for highly selected, locally advanced tumors. Dr. Nigro and other students of this disease have expressed similar opinions. We were unable to find any significant survival differences between well or moderately differentiated carcinomas, and none had anaplastic tumors. There is a group of very aggressive carcinomas including small cell and the adenocystic types that tend to recur and disseminate very early. At present, our standard therapy for squamous cell carcinoma in the anal canal consists of 3,000 rads in 25 fractions in combination with both 5-fluorouracil and mitomycin-C. Patients who have a brisk perineal reaction to chemoradiation may need a rest period after the first half of therapy. We prefer to administer a second course of chemotherapy 1 month later for those patients whose tumors respond very slowly. Doses higher than 3,000 rads are administered to patients with large T2 or T3 lesions. Dr. Westbrook, squamous cell carcinoma metastatic to the inguinal regions has been traditionally treated by a radical groin dissection. However, since the entire pelvis including both groins are treated with chemoradiation, we find it appropriate to await the response to nonsurgical treatment and perform a groin dissection should palpable adenopathy remain 6 to 12 weeks after therapy. Dr. Hawkins, all patients receive a CT scan of the abdomen and pelvis to rule out nodal or visceral metastasis, but just as important is a good examination of the patient under anesthesia, precise clinical staging, and careful posttreatment monitoring. After the acute radiation changes to the perineum and anal canal have subsided, virtually all patients have recovered absolutely normal anorectal function. As Dr. Johnson pointed out, some authors, most notably Papillon and associates from France, have extensive experience with brachytherapy for these tumors. However, these techniques are very elaborate, require substantial expertise, and have not been adopted widely in this country. I would speculate that the best role for brachytherapy would be as an addition to chemoradiation for locally advanced carcinomas in patients who are not candidates for a planned abdominoperineal resection. Dr. Lang, a total dose of 3,000 rads was given in 25 fractions over a 5-week period. Variations in treatment duration were dictated by the total dose divided by 200 rad fractions. As mentioned, rest periods from radiation became necessary in some patients experiencing severe perineal reactions during the course of treatment.
VOLUME 162 DECEMBER 1991
Cell Carcinoma of the Anal Canal
J. MD, FACS, FRCSC, Robert J. Myerson, Pho, MD, Susan J. Shapiro, MD, James W. Fleshman, Jr., MD, FAG, Robert D. Fry, MD, FACS, John D. Halverson, MD, FACS, Ira J. Kodner, MD, FACS, William W. Monafo, MD, FACS, SI. Louis, Missouri
Between 1979 and 1988,33 patients with squamous cell carcinoma of the anal canal were treated with chemoradiation. There were 24 women and 9 men, fawn 37 to 90 years of age (median: 63 years). Complete tumor regre&on occurred in 29 of the 33 patients (88%), only one of whom later developed recurrence. In the other four patients, there was persistent tumor after 3 months; three of these patients died within 2 years; and one is alive with distant metastases 2 years later. During the first 5 years of the study, seven patients with complete tumor regression underwent planned abdominoperineal resection following chemoradiation. Four of the abdominoperineal resection specimens were free of tumor, but three were not. These three patients, who had abdominoperineal resection within 3 months of chemoradiation, are disease-free. Ten of the 29 patients who had complete tumor regression had biopsies of the primary site 3 months after treatment. All biopsies were negative for rcsidual carcinoma. At present, 26 patients (79%) arc alive and disease-free from 2 to 10 years posttreatment (median: 4 years). Two patients died of unrelated causes, four of cancer, and one is alive with cancer. Complications of the chemoradiation required surgical intervention in two patients, and two others developed severe hematologic toxicity, for a complication rate of 12% (4 of 33 patients). There was no treatment-related mortality. These results support the efficacy of chemoradiation treatment for carcinoma of the anal canal. They suggest that abdominoperineal mtion no longer need be part of the planned initial management, and that posttreatment biopsy of the primary site is unnecessary, unless palpable or visible abnormalities are present 3 months after treatment.
From the Department of Surgery, Washington University School of Medicine, Bamcs (MJL, JDH, WWM) and Jewish (JWF, RDF, IJK) Hospitals, and theMallinckrodt Institute of Radiol%y (RJM, SJS), St. Louis, Missouri. Requests for reprints should be addressed to Marvin J. Lopez, MD, 5 102 Quceny Tower, Barnes Hospital Plaza,St. Louis,Mkscuri 63 1IO. Presentai at the 43rd Annual Meeting of the Southwestern Surgical Congrss. Las Vegas. Nevada, April 2 l-24,1991.
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quamous cell carcinoma of the anal canal is uncomS mon, accounting for less than 0.2% of all cancers and 2% to 5% of all anorectal malignancies [1,2]. Approximately 45,500 new cases of rectal cancer will be diagnosed this year in the United States. The expected annual number of new anal cancers in this country is, therefore, between !I00 and 2,000 [3]. In the past, this disease pre dominated in the elderly, many of whom had long-standing, benign anorectal disease. At present, carcinoma of the anal canal is diagnosed more frequently in younger patients, especially in men. For many years, standard therapy for this lesion was abdominoperineal resection, which was advocated based on retrospective studies. Fiveyear survival rates averaged 50% [3]. These results re mained virtually unchanged for several decades [3]. Moreover, when tumor resection was incomplete, postoperative irradiation was shown to be of limited value [4]. Historically, radiofherapy alone was utilized only for locally advanced and unresectable tumors or for patients too ill to withstand operation. More recent data, however, suggest that treatment with external beam radiotherapy may be equal to or superior to resection alone 141. Evidence has existed for nearly 20 years that anal carcinoma responds to combined chemotherapy and radiation [5], so called “chemoradiation.” During the last decade, several investigators reported promising results using chemoradiation [6-I]]. More recent studies confirm that the 5-year survival rates are not only superior to those obtained with abdominoperineal resection alone, but anal sphincter preservation is achieved in up to 80% of patients [22-151. The interest generated by these new therapeutic successes resulted in the reappraisal of virtually every aspect of this neoplasm. Fortunately, this has led to the unification of the assessment of anatomical boundaries, histopathologic nomenclature, staging classification, biologic behavior, and treatment approaches. While these concepts are still in evolution and many questions remain unanswered [ 14, remarkable progress has occurred. Controversies now focus on issues of lesser magnitude. As with any emerging therapy, further experience is necessary to assess its validity. The purpose of this study is to report our experience with chemoradiation for the treatment of patients with squamous cell carcinoma of the anal canal. PATIENTS AND METHODS In 1979, chemoradiation became the standard of care for patients with squamous cell carcinomas of the anal canal at Washington University Medical Center in St. Louis, Missouri. All patients were evaluated in a multidisciplinary manner. All tumors were biopsied and clinically staged. Computerized tomography (CT) of the abdomen and pelvis was performed in all patients.
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The study group comprised thirty-three patients who received chemoradiation during the period 1979 to 1988. There were 24 women and 9 men. The youngest patient was 37 years of age, and the oldest 90; the median age was 63 years. The 1988 International Union Against Cancer and the American Joint Committee for Cancer Staging (UICC/AJC) classification was used (Table I) [I 71.This classification defines the anal canal as the area extending from just above the dentate line to the anal verge. Twenty-four of 33 tumors were classified T2NO (73%), and five were TlNO (15%). Of the remaining four patients, two had T3NO tumors, one had TlNl tumor, and one had T2N2 tumor. Thus, 88% (29 of 33 patients) of patients had early disease (Tl,T2, or NO), and 12% (4 of 33 patients) presented with locally advanced disease. Only two of 33 patients had lymph node metastases upon initial evaluation. On CT and clinical evaluation, one patient had perirectal positive lymph nodes (Nl), and the other had both perirectal and inguinal lymph node metastases (N2). Histologic confiiation of squamous cell carcinoma was made in all cases. Follow-up was complete, with a median observation time of 4 years. Treatment consisted of combined external beam radiotherapy and chemotherapy. Twenty-five patients (76%) received 3,000 cGy in 25 fractions. Four patients received 5,000 cGy, two patients 4,600 cGy, and the two remaining patients received 5,600 cGy and 2,600 cGy, respectively. Chemotherapy consisted of mitomycin-C 10 mg/m*, given as a bolus intravenous injection on day 2 of the radiotherapy, and Muorouracil 1,000 mg/m* by continuous intravenous infusion, daily for 5 consecutive days, also starting on day 2 of the protocol. Ten patients received one chemotherapy course, and 13 patients re ceived a second course of chemotherapy on day 28 of radiotherapy. Ten patients were given 5-fluorouracil but not mitomycin-C. Patients selected to receive a second course of chemotherapy were those with protracted tumor regression. Radiotherapeutic doses over 3,000 cGy were given during the early years of the study. RESULTS Treatment outcome is presented in TabIe II. Complete clinical tumor regression was obtained in 29 of the 33 patients (88%), all but one of whom remained free of disease. That patient developed recurrence 5 months after treatment and underwent abdominoperineal resection but died of metastases 7 months later. Tumor regression was incomplete in the remaining four patients. Two had abdominoperineal resection but died with local recurrence and metastases within 2 years. A third patient had both locoregional and distant metastases and died. The fourth patient with incomplete tumor regression underwent abdominoperineal resection and is alive with distant metastases. Thus, none of the patients with either persistent or recurrent tumor following the chemoradiition were salvaged by abdominoperineal resection. In contrast, of seven planned abdominoperineal resections performed during the early part of the study, four had tumor-free specimens. These four patients are alive and diseasefree. THE AMERICAN
TABLE I UICC/AJC Staging Classlflcation for Squamous Cell Carcinoma of the Anal Canal Primary tumors Tl Tumor 2 cm or less in greatest dimension T2 Tumor more than 2 cm but not more than 5 cm in greatest dimension T3 Tumor more than 5 cm in greatest dimension T4 Tumor of any size invades adjacent organ(s), invofvement of sphincter muscle(s) alone not classifted as T4 Lymph NO Ni N2 N3
node No regional lymph node metastasis Metastasis in perirectal lymph node(s) Metastasis in unilateral internal iliac and/or inguinal lymph node(s) Metastasis in perirectal and inguinal lymph nodes, and/or bilateral internal iliac, and/or inguinal lymph nodes
Distant metastasis (M) MO No distant metastasis Ml Distant metastasis Staging grouping 0 Tis I Tl II T2 T3 IIIA T4 Tl T2 T3 IIIB T4 Any T Any T IV AnyT
NO NO NO NO NO Nl Nl Nl Nl N2 N3 Any N
MO MO MO MO MO MO MO MO MO MO MO Ml
UICC = Iniernaticjnal Union Against Cancer; AIC = American Joint Committee on Cancer
Classification;
T = primary
tumors;
N = lymph
node;
M = distant
metastasis.
TABLE II Results of Chemoradlatlon In 33 Patients With Squamous Cell Carcinoma of the Anal Canal Treatment Outcome
No. of Patlents (%)
Complete tumor regression (n = 33) Recurred and died (n = 29) Partial tumor regression (n = 33) Persisted and died (n = 4) Alive with disease (n = 4) Alive and disease-free (n = 33) Dead from other causes (n = 33) Salvaged by APR (n = 4)
29 1 4 3 f 26
(66) (3) (12) (75) (25) (79)
2 (6) 0 (0)
APR = abdominoparineal resection.
The remaining three patients with microscopic tumor in the surgical specimen are also free of disease. Of five patients whose cancer persisted or recurred, two patients had locally advanced (T3NO) tumors at the time of diagnosis, two had T2NO tumors, and one had T2N2 disease. After a median follow-up of 4 years, 26 patients (7996) are alive and free of disease. Four died of cancer, two died of unrelated causes, and one patient is alive with distant metastases. Short-term treatment toxicity was universal.
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However, perineal skin reactions, nausea, vomiting, and diarrhea were self-limiting and did not require surgical intervention or hospitalization. Major morbidity occurred in only four patients (12%). One patient developed severe lower abdominal pain, paralytic ileus, and abdominal wall rigidity during the course of treatment. During exploratory laparotomy, acute radiation enteritis involving the terminal ileum was found. This patient recovered uneventfully. A second patient developed a perirectal ab scess that was incised and drained without further complications. Two patients experienced severe neutropenia (less than l,000/mm3), thrombocytopenia (less than 50,000/mm3), and diarrhea. Their treatment consisted of intravenous hydration, nutritional support, and prophylactic antibiotic therapy, resulting in complete recovery. There was no mortality attributable to chemoradiation. The preservation of anorectal function was possible in all patients with complete regression.
COMMENTS In 1988, the UICC and the AJC agreed on a unified staging classification for carcinomas of the anal canal. The UICC/AJC staging method provides an opportunity for uniform reporting of treatment results (Table I) [Z7]. In this classification, the anal canal includes only the transitional zone and the pecten. Squamous ccl1 carcinomas arising from the perianal skin are classified as skin cancers. Therefore, the anal margin no longer exists for staging purposes. While certain tumors may possess a more aggressive biologic behavior [Z8] (small cell, undifferentiated, mucoepidermoid, and pseudoadenoid cystic carcinomas), all tumors arising in the anal canal are classified according to their degree of differentiation but are grouped under the broad category of squamous cell carcinomas. Furthermore, it has been proposed that the terms cloacogenic, basaloid, and transitional cell be eliminated to avoid further confusion [19]. Abdominoperineal resection is no longer the primary treatment for anal carcinoma. However, radical pelvic surgery, including even pelvic exenteration, remains a viable option for patients with locally advanced (T4) tumors or in patients whose tumors remain localized after incomplete tumor regression [20]. Local resection alone is reasonable for small tumors that can be excised with adequate margins without compromising anorectal function. Patients with superficial tumors of 1 cm or less, located in the distal anal canal without sphincteric muscle involvement, can be treated by local excision with a 100% survival rate, according to Beahrs and Wilson [22]. The Memorial Hospital experience, as reported by Stearns et al [2], also suggests that local excision of noninfiltrating small lesions is reasonable, provided there is frequent follow-up observation. Parks [22] described his techniques of local excision, which vary according to the depth of tumor penetration. If the carcinoma is small and extends only superficially into the internal sphincter, the lesion is excised with the underlying internal sphincter muscle. At present, there is consensus that chemoradiation is preferred for tumors invading the sphincters. The development of multimodal therapy for anal car582
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cinema was influenced by the recognition that certain antineoplastic chemotherapeutic drugs are radiosensitizing agents. The pioneering studies of Heidelberger et al [23] demonstrated the additive effect of 5-fluorouracil and irradiation, and Bagshaw [24] showed greater in uitrokilling of a squamous cell carcinoma cell line when 5-fluorouracil and irradiation were combined. The contributions of Vietti et al [25] and Bylield et al [26l led to the concept of radiosensitization of human tumors. It is not entirely clear whether chemotherapy sensitizes tumor cells to the effects of radiation or if ionizing radiation sensitizes the tumor to the lethal effects of chemotherapy. The landmark paper by Nigro et al [.5] brought this concept of cancer therapy into the clinical arena in 1974. Chemoradiation has now come of age in the management of anal carcinomas. The initial efforts at establishing chemoradiation therapy for anal carcinoma were conducted within the context of planned preoperative (neoadjuvant) therapy [5,9]. It soon became doubtful whether routine abdominoperineal resection following chemoradiation was necessary, as a substantial number of specimens were free of tumor [2,5,7,9]. Furthermore, as in three of seven patients in our study, when abdominoperineal resection is performed within 3 months after the completion of chemoradiation, residual disease may still be demonstrable histologically, but its significance is questionable as clinical recurrence in this setting is rare [2,3,5,7,9]. This appreciation of the slow rate of tumor regression in response to chemoradiation has led to the practice of deferring biopsy of the cancer site until 3 months have elapsed after chemoradiation. If residual disease is demonstrated after 3 months, retreatment with chemoradiation may be performed in selected patients [IO]. Abdominoperineal resection or exenterative pelvic surgery may play a salvage role at this stage. Several trials have reported results of chemoradiation without surgery in the treatment of anal carcinoma [7-251. These treatment protocols have some differences regarding total radiotherapeutic dose and the number of chemotherapeutic cycles, but all have adhered to the principle that both modalities must be given concurrently. However minor these differences in protocol design may be, it makes interpretation of treatment results difficult. Thus, the next logical step in the study of this disease was to institute a cooperative clinical trial. The first multicenter prospective trial of chemoradiation was conducted by the Radiation Therapy Oncology Group and reported in 1989 [13]. Sischy et al [13] treated 75 patients with squamous cell carcinoma of the anal canal between 1983 and 1987. The study design, the most commonly utilized in the past, consisted of external beam pelvic and perineal radiotherapy to a total dose of 4,080 cGy with mitomycin-C 10 mg/m2, given as one bolus intravenous injection on day 2 of the radiation treatment, and a continuous infusion of 5-fluorouracil1,OOO mg/m*/24 hours for 96 hours on days 2 and 28. The inguinal nodal areas also received 4,000 cGy. At a median follow-up of 3 years, these authors reported a 73% survival rate [13]. Similar results were obtained in our series: 79% of our
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patients are alive and disease-free at a median follow-up time of 4 years. Our results are also in concert with those of Nigro et al [12] who reported an actuarial 5-year survival rate of 7%. Locoregional treatment failures occur predominantly in patients with locally advanced disease at presentation. Papillon and associates [27,28] and Sischy and associates [13] found that tumor size greater than 3 to 4 cm had a major influence on the recurrence rates. Other morphologic tumor factors, such as differentiation, vascular or lymphatic permeation, and growth patterns (endophytic versus exophytic), have not been carefully studied. Nigro et al [ 121 have made the interesting observation that the salvage rate of abdominoperineal resection for locoregional failures is poor. Nine of their 44 patients had tumors measuring 6 cm or larger. In four patients, gross residual tumor remained after chemoradiation, and all died of metastatic disease, despite abdominoperineal resection. Whether patients with large (T4) tumors should be managed with planned preoperative chemoradiation followed by radical surgery, avoiding a 3-month waiting period, remains speculative. Nigro et al [6’J have proposed that patients with lesions 6 cm or larger be treated by chemoradiation followed by abdominoperineal resection. It is clear that complete tumor disappearance after chemoradiation is associated with excellent long-term survival and local control. However, a minority (1% to 6%) of patients will experience recurrence 1 to 5 years after treatment [IZ,I3]. Therefore, it is imperative that intensive follow-up be provided. Our recurrence rate following complete response to chemoradiation was 3% (1 of 29 patients). Three patients whose tumors persisted underwent abdominoperineal resection with curative intent but died of disease, as already noted. The role of abdominoperineal resection as a salvage procedure remains incompletely documented. While chemoradiation is now widely accepted as the primary treatment modality for anal carcinoma, many questions remain unanswered [ 14. One trial is investigating whether mitomycin-C can be eliminated from the treatment protocol without affecting outcome. Deletion of mitomycin-C led to a fall in local control rates at one institution [16]. The ultimate role of this drug will be defined in an ongoing randomized prospective multicenter study. The overwhelming success of chemoradiation for carcinoma of the anal canal is a tribute to multidisciplinary cancer care and the application of new concepts in radiobiology, chemotherapy, and basic research. This is clearly a disease where traditional surgical concepts have been successfully superseded. Nonetheless, the role of the surgeon in the treatment of this disease remains important in the initial evaluation, diagnosis, and staging, as well as in the timely management of persistent disease.
REFERENCES 1.de1 Regato JA, Spjut
HJ, Cox JD. Anus. In: Ackerman LV, de1 Regato JA, editors. Cancer. St. Louis: C.V. Mosby CO., 1985: 567-15. 2. Stearns MW, Urmacher C, Sternberg SS, et al. Cancer of the THE AMERICAN
CANAL
anal canal. Curr Prob Surg 1980: 4: l-44. 3. Lopez MJ, Bliss DP Jr, Kraybill WG, Soybel Dl. Carcinoma of the anal region. Curr Probl Surg 1989; 26: 527-600. 4. Dobrowsky W. Radiotherapy of epidermoid anal canal cancer. Br J Radio1 1989; 62: 53-8. 5. Nigro ND, Vaitkevicius VK, Considine B. Combined therapy for cancer of the anal canal: a preliminary report. Dis Colon Rectum 1974; 17: 354-6. 6. Nigro ND, Seydel HG, Considine B, et al. Combined preoperative radiation and chemotherapy for squamous cell carcinoma of the anal canal. Cancer 1983; 51: 1826-9. 7. Sischy B. The use of radiation therapy combmed with chemotherapy in the management of squamous cell carcinoma of the anus and marginally resectable adenocarcinoma of the rectum. lnt J Radiat Qncol Biol Phys 1985; 11: 1587-93. 8. Cummings BJ, Rider WD, Harwood AR, et al. Combined radical radiation therapy and chemotherapy for primary squamous cell carcinoma of the anal canal. Cancer Treat Rev 1982; 66: 489-92. 9. Michaelson RA, Magill GB, Quan SH, et al. Preoperative chemotherapy and radiation therapy in the management of anal epidermoid carcinoma. Cancer 1983; 51: 390-5. 10. Flam MS, John MJ, Mowry PA, et al. Definitive combined modality therapy of carcinoma of the anus. Dis Colon Rectum 1987; 30: 495-502. I I. Wanebo HJ, Futrell W, Constable W. Multimodality approach to surgical management of locally advanced epidermoid carcinoma of the anorectum. Cancer 1981; 47: 2817-26. 12. Nigro ND, Vaitkevicius VK, Considine B Jr. Dynamic management of squamous cell cancer of the anal canal. Invest New Drugs 1989; 7: 83-9. 13. Sischy B, Scotte Doggett RL, Krall JM, et al. Definitive irradiation and chemotherapy for radiosensitization in management of anal carcinoma: interim report on Radiation Therapy Oncology Group Study No. 8314. J Nat1 Cancer lnst 1989; 81: 850-6. 14. Habr-Gama A, Da Silva AH, Sousa SF Jr, et al. Epidermoid carcinoma of the anal canal: results of treatment by combined chemotherapy and radiation therapy. Dis Colon Rectum 1989; 32: 773-7. 15. Knecht BH. Combined chemotherapy and radiotherapy for carcinoma of the anus. Am J Surg 1990; 159: 518-21. 16. Cummings BJ. The treatment of anal cancer. lnt J Radiat Oncol Biol Phys 1989; 17: 1359-61. 17. American Joint Committee on Cancer. In: Beahrs OH, Henson DE, Hutter RV, et nl, editors. Manual for staging of cancer. 3rd e-d. Philadelphia: J.B. Lippincott Co., 1988: 81-5, 133-8. 18. Morson BC. The pathology and results of treatment of squamous cell carcinoma of the anal canal and anal margin. Proc R Sot Med 1960; 53: 416-20. 19. Dougherty BG, Evans HL. Carcinoma of the anal canal: a study of 79 cases. Am J Clin Path01 1985; 83: 159-64. 20. Lopez MJ, Kraybill WG, Downey Rs, ef al. Exenterative surgery for locally advanced rectosigmoid cancers. Is it worthwhile? Surgery 1987; 102: 644-51. 21. Beahrs OH, Wilson SM. Carcinoma of the anus. Ann Surg 1976; 184: 422-8. 22. Parks A. Squamous carcinoma of the anal canal. Ann Gastroenterol Hepatol 1981; 17: 103-7. 23. Heidelberger C, Griesbach L, Montag BJ, et al. Studies on fluorinated pyrimidines. Il. Effects on transplanted tumors. Cancer Res 1958; 18: 305-17. 24. Bagshaw MA. Possible role of potentiators in radiation therapy. AJR Am J Roentgen01 1961; 85: 822-33. 25. Vietti T, Eggerding F, Valeriote F. Combined effect of x radiation and 5-fluorouracil on survival of transplanted leukemic cells. J Nat1 Cancer lnst 1971; 47: 865-70.
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26. Byfield JE, Calabro-Jones P, Klisak I, et al. Pharmacologic
requirementsfor obtaining sensitization of human tumor cells in vitro to combined 5fluorouracil or ftorafur and x-rays. Int J Radiat
Oncol Biol Phys 1982; 8: 1923-33. 27. Papillon J, Montbarbon JF. Epidermoid carcinoma of the anal canal: a series of 276 cases. Dis Colon Rectum 1987; 30: 324-33. 28. Papillon J, Montbarbon JF, Gerard JP, et al. Interstitial curietherapy in the conservative treatment of anal and rectal cancers. Int J Radiat Oncol Biol Phys 1989; 17: 1161-9.
DISCUSSION Robert W. Beart (Scottsdale, AZ): Dr. Lopez, is survival with chemoradiation really better than with surgery alone? Most of the patients in this study had early stage tumors (Tl, T2), unlike patients in the usual distribution of this disease. While their 79% survival rate is certainly admirable, it is not substantially different than in the reported series by Boman et al (Cancer 1984; 54: 114-25) of a large number of patients treated by abdominoperineal resection with a 5-year survival rate of 71%. It is evident that tumor size and histologic differentiation are important prognostic indicators in anal carcinoma. These data from France clearly show that failure rates relate to tumor size and histology. Indeed, well-differentiated squamous cell carcinomas have a different biologic behavior than poorly differentiated or basal carcinomas. Smaller tumors have significantly lower incidences of lymph node metastases than larger tumors. Recognizing these prognostic elements, do the authors feel that all patients should be treated with chemoradiation, or is there a role for abdominoperineal resection as a planned procedure in the management of anal cancer? Finally, since this group of patients was treated with significant variations in therapy, what is the combination of radiation and chemotherapy that they recommend at this time? Kent C. Westbrook (Little Rock, AK): My question to Dr. Lopez is in regard to the management of regional lymph node metastasis. Are patients presenting with clinically positive inguinal nodes managed any differently than those without palpable nodes? Michael L. Hawkins (Augusta, GA): Since the patients who developed recurrence presumably died from systemic disease, what, if any, pretreatment work-up is undertaken to search for metastatic disease? Also, what is the quality of anal function after 3,000 or more rads are administered to the perineal region? Frank E. Johnson (St. Louis, MO): Interstitial radiotherapy has been advocated by some authors for treatment of squamous cell carcinoma of the anal canal. Would Dr. Lopez comment on the current role of brachytherapy for these tumors? Nicholas P. Lang (Little Rock, AK): My question is in regard to variations in radiation dosimetry. Were these variations in terms of total rads administered or in the number of fractions given? Marvin J. Lopez (closing): Dr. Beart correctly points out that the results of abdominoperineal resection for
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early stage anal carcinoma are comparable to chemoradiation. However, the fact that similar results may be obtained without abdominoperineal resection makes chemoradiation a logical first choice since preservation of anorectal function is an extremely important goal, provided it does not compromise local-regional control of cancer or survival. It has been my experience that bulky endophytic tumors do not respond well to chemoradiation. I am in complete agreement with Dr. Beart that there is a definite role for a planned abdominoperineal resection in conjunction with chemoradiation for highly selected, locally advanced tumors. Dr. Nigro and other students of this disease have expressed similar opinions. We were unable to find any significant survival differences between well or moderately differentiated carcinomas, and none had anaplastic tumors. There is a group of very aggressive carcinomas including small cell and the adenocystic types that tend to recur and disseminate very early. At present, our standard therapy for squamous cell carcinoma in the anal canal consists of 3,000 rads in 25 fractions in combination with both 5-fluorouracil and mitomycin-C. Patients who have a brisk perineal reaction to chemoradiation may need a rest period after the first half of therapy. We prefer to administer a second course of chemotherapy 1 month later for those patients whose tumors respond very slowly. Doses higher than 3,000 rads are administered to patients with large T2 or T3 lesions. Dr. Westbrook, squamous cell carcinoma metastatic to the inguinal regions has been traditionally treated by a radical groin dissection. However, since the entire pelvis including both groins are treated with chemoradiation, we find it appropriate to await the response to nonsurgical treatment and perform a groin dissection should palpable adenopathy remain 6 to 12 weeks after therapy. Dr. Hawkins, all patients receive a CT scan of the abdomen and pelvis to rule out nodal or visceral metastasis, but just as important is a good examination of the patient under anesthesia, precise clinical staging, and careful posttreatment monitoring. After the acute radiation changes to the perineum and anal canal have subsided, virtually all patients have recovered absolutely normal anorectal function. As Dr. Johnson pointed out, some authors, most notably Papillon and associates from France, have extensive experience with brachytherapy for these tumors. However, these techniques are very elaborate, require substantial expertise, and have not been adopted widely in this country. I would speculate that the best role for brachytherapy would be as an addition to chemoradiation for locally advanced carcinomas in patients who are not candidates for a planned abdominoperineal resection. Dr. Lang, a total dose of 3,000 rads was given in 25 fractions over a 5-week period. Variations in treatment duration were dictated by the total dose divided by 200 rad fractions. As mentioned, rest periods from radiation became necessary in some patients experiencing severe perineal reactions during the course of treatment.
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