Anal carcinoma: Current therapeutic concepts

Anal Carcinoma: Current Therapeutic Concepts Jerold P. Green, MD, San Francisco, California Wlllls C. Schaupp, MD, San Francisco, California Slmeon T. Cantril, MD, San Francisco, California Gerald Schall, MD, San Francisco, California

The surgical approach to anal and perianal carcinoma, either anteroposterior resection or wide local excision, continues to be recommended by most investigators in the field. Adjuvant radiation therapy, with or without chemotherapy, is gaining popularity. The use of definitive radiation therapy has never been well supported in the surgical literature, with concern expressed about radionecrosis and incurability. There have been only sporadic reports of radiation-treated anal carcinoma. Because of our relatively large experience with the radiotherapeutic management of anal carcinoma, it was thought worthwhile to review this material. Material

and Methods

From 1966 to 1979, thirty-eight patients with a diagnosis of anal carcinoma were seen, 33 of whom were treated in the Radiation Therapy Departments of St. Francis Memorial Hospital and Children’s Hospital of San Francisco. There were 16 male and 22 female patients, ranging in age between 38 and 84 years (average 64.9). For purposes of review, the patients were subdivided by clinical presentation into six groups: group IA, localized favorable disease (21 patients); group IB, localized unfavorable disease (3 patients); group II, primary lesion and inguinal metastases (3 patients); group III, inguinal metastases only (3 patients); group IV, metastatic disease (2 patients); group V, miscellaneous (6 patients). All patients received external supervoltage radiation therapy using cobalt-60,25 meV betatron x-rays or high energy electrons, or both. One patient also had an iridium-192 interstitial implant. The histopathologic features of all cases have been confirmed by one of us (GS) (Table I). Whole-body gallium scans were performed in nine patients as part of the clinical evaluation and staging. The studies were begun 48 hours From St. Francis Memorial Hospital and Children’s Hospital, San Francisco, California. F&pint requests should be addressed to Jerold P. Green, MD. Department of Radiation Therapy, St. Francis Memorial Hospital, 900 Hyde Street, San Francisco. California 94109. Presented at the 51st Annual Meeting of the Pacific Coast Surgical Association, Kauai, Hawaii, February 17-20. 1980.

Volume 140, July 1980

after the intravenous administration of 3 to 6 mCi of gallium-67 citrate along with routine bowel preparation. Group IA: Twenty-one patients with lesions 5 cm or less in diameter, 19 of the anal canal and 2 external to the sphincter, were categorized as having localiied disease with a favorable prognosis. Except for the latter two patients who were radiated with perineal portals only, the remainder were treated with pelvic and perineal portals. Four patients were treated with preoperative intent and received 4,500 rads in 5 weeks. Seventeen patients were treated definitively, 12 after biopsy only and 5 after local excision. In the former group, the tumor doses ranged from 6,075 in 44 days to 7,425 rads in 52 days and in the latter group, from 6,000 rads in 53 days to 6,750 rads in 51 days. No patient received prophylactic inguinal irradiation. Group IB: Three patients presented with localized massive disease, one with multiple vaginal and cutaneous fistulas, one with an 8 cm neoplasm invading the rectovaginal septum and one with a 6 cm circumferential lesion. The first patient received 5,300 rads in 43 days with preoperative intent; the second received 7,000 rads in 81 days. Both underwent anteroposterior resection for persistent disease. The third patient received 5,760 rads in 65 days followed by an iridium-192 implant, delivering an additional 2,000 rads to the lesion. Group II: Of the three patients who presented with inguinal metastases, two had synchronous metastases (one with a 4 cm primary lesion and bilateral 5 cm fixed inguinal nodes, the other with a 7 cm primary lesion and a unilateral 3 cm mobile node). The former received a tumor dose of 6,500 rads in 61 days to the primary site and groin, and the latter received 6,075 rads in 49 days to the primary lesion and excision of the palpable node. The third patient was treated for local recurrence (1 cm) and metastases to both inguinal areas (two 1 cm nodes bilaterally) 1 year after local excision of what clinically was thought to be a “hemorrhoidal tag.” She received a tumor dose to all three involved areas of 5,900 rads in 58 days. Group III: Three patients presented with unilateral metachronous metastasis, one 8 months after local excision of an anal lesion and one 3 years and one 5 years after anteroposterior resection. All three presented with large, fixed masses and one patient had massive leg edema. Tumor dose ranged from 5,000 rads in 37 days to 6,150 rads in 46 days. 151

Green et al

TABLE I

Tumor Histopathology No.

Percent

Squamous carcinwna Well differentiated Moderately well differentiated Poorly differentiated Basaloid squamous carcinoma Well differentiated Anaplastic

18 6 6 6 20 15 5

47.5

Total

38

Tumor

.. . . G.;

. ...

Group IV: Two patients were treated palliatively for pain relief, one for local recurrence (3,100 rads in 18 days) and one to the bony pelvis (4,000 rads in 20 days). Miscellaneous: Of the six patients in this category, one patient was treated after anteroposterior resection because of inadequate surgical margins. She received only 2,500 rads in 18 days, as therapy was discontinued when acute cholecystitis with septicemia developed. A second patient was treated 4 years after local excision for a massive local recurrence (8 cm) with 6,500 rads in 66 days after preradiation chemotherapy (bleomycin, methotrexate and cisplatinum). Two patients were treated surgically for small (I cm) lesions, one by local excision and the other by anteroposterior resection. One patient presented with widespread metastases to the lung, liver and brain and received no local treatment. A final patient refused conventional therapy and was treated with Laetrile’.

Results Group IA: Localized

favorable

disease (21 patients):

Preoperative

radiation: Of the 21 patients treated with localized favorable lesions, four were treated with preop-

erative intent to 4,500 rads in 5.5 weeks. One patient refused surgery or further irradiation and is without evidence of disease at 13 months. A second patient also refused further treatment or surgery and had local recurrence treated by local excision at 7 months. At 11 months, anteroposterior resection was performed for a nonhealing ulcer at the excision site but cancer was not found in the specimen. He remains free of disease at 26 months. The other two preoperatively treated patients underwent anteroposterior resection within 6 weeks of radiation therapy. Both had persistent carcinoma in the specimen, and in both liver metastasis had developed. One died at 2 months and one is living with metastasis at 16 months on chemotherapy. None of the four patients has evidence of local disease at last follow-up examination. Definitive irradiation: The remaining 1’7patients were treated for definitive local control with radiation therapy. Of these, 5 of 17 were treated after excisional biopsy and 12 of 17 were treated for palpable and/or visible disease. Of those treated after excision, four of five are living without disease 8 to 48 months after treatment. One died at 6 months after therapy with pelvic and distant recurrence. She had received a maximal tumor dose of 6,000 rads in 53 days. 152

Of those treated with palpable disease, 12 of 12 are without evidence of disease 10 months to 9 years after therapy, as follows: 9 years, 1 patient; 7 years, 1; 6 years, 1; 4 years 5 months, 2; 4 years, 1; 3 years 3 months, 1; 2 years 7 months, 1; 2 years 2 months, 1; 1 year 7 months, 1; 1 year, 1; and 10 months, 1. Three of 12 had small persistent nodules after radiation therapy. One patient who received 6,000 rads in 79 days had anteroposterior resection and tumor was found with extension into perianal fat. She survived 4 years 5 months and died without evidence of tumor. The other two patients received 7,000 rads in 54 days and 7,425 rads in.52 days. The former was found to have a 3 mm focus of tumor in scar tissue and the other was found to have carcinoma in situ in association with a preexisting condyloma acuminatum. These two patients are alive and well at 3 years 3 months and 12 months, respectively. Of the total group treated definitively with radiation therapy, 13 of 17 have required no further treatment and are free of disease 7 months to 9 years after therapy. Morbidity: All 17 patients have tolerated the therapy remarkably well. There have been no cases of favorable lesions with persistent mucosal or skin ulcerations. Colostomy has not been required except in the two patients in whom anteroposterior resection was performed for persistent disease. Only one patient has required anal dilatation for partial stenosis of the anal canal. In all other patients bowel habits have returned to normal. Sexual potency, where applicable, has been preserved. Metastasis: Only one of 17 patients has shown evidence of inguinal or distant metastatic disease. Group IB: Localized unfavorable disease (3 patients): One patient with an 8 cm mass involving the rectovaginal septum and one with a huge neoplasm fistulizing into the vagina and skin died 36 and 14 months later. Local control was maintained, but there was dissemination including inguinal nodes. A third patient who presented with a 6 cm circumferential lesion now has persistent disease 5 months after treatment that will require anteroposterior resection. Group II: Primary and inguinal nodes (three patients): One patient is asymptomatic and free of disease at 39 months and one is alive at 26 months with recurrence in the groin and primary site. Although the third patient (84 years old) is only 2 months after radiation, he is worthy of mention in view of how easily he tolerated 6,100 rads in 49 days; he presently has no clinically apparent neoplasm. Group III: Inguinal metastasis only (three patients): One patient died free of disease at 4 years 9 months and one is living free of disease at 4 years 10 months. The third patient has had local control for 3 years but recently had a recurrence within the untreated pelvis. There have been no untoward reactions to groin irradiation in these patients. Group IV: Primary and disseminated disease (two patients): Both patients achieved excellent pain relief with relatively low doses. Group V: Miscellaneous (six patients): One patient, who received 2,500 rads after anteroposterior resection, had The American Journalof Surgery

Anal Carcinoma

metastasis to the sacrum at 3 years. The patient treated for massive local recurrence 4 years after local excision is alive and has no evidence of disease, but it has been only 2 months since the completion of her course of treatment. Four patients in the series were treated surgically without radiation therapy. The first was a 47 year old woman who had curative anteroposterior resection as initial therapy. Comparison of this patient with a similar patient with irradiation, who retained good rectal function, was the stimulus to begin the series. From this patient we concluded that surgery alone is often curative but rectal function is lost. The second patient was a 47 year old woman with a tiny infiltrating squamous carcinoma treated by wide local excision and periodic follow-up study. She is free of disease 6 years 3 months later. We concluded from this patient that local excision is occasionally sufficient therapy. The third patient was a 73 year old man with a 1 cm highly malignant basaloid carcinoma who was initially treated by total local excision. While the patient was under consideration for radiation, liver, lung and brain metastases developed and he died within 9 months. From this patient we concluded that there is nothing to be gained by using radical local therapy in the presence of disseminated disease. The fourth patient, a 38 year old woman who initially had excisional biopsy of a moderately differentiated squamous cell carcinoma, refused irradiation or radical surgery but instead chose to go on “full Laetrile therapy” (diet, vitamins, minerals and weekly injections of Laetrile). A left inguinal node was positive on biopsy 5 months later; a local recurrence developed after 4 years 2 months and was reexcised. The patient again declined irradiation and redoubled her efforts with Laetrile. Five months later the patient had a biopsy-positive left supraclavicular node. She is living with disease 5 years 4 months after diagnosis. This case probably represents the natural history of the disease. Gallium-67 scanning: Gallium scans were positive in six of nine patients (67 percent). The primary tumor only was delineated in two cases, metastases only in three cases and both primary tumor and multiple metastases in one case. Sites of metastases included inguinal nodes, liver and brain. The histologic features of the tumor or the degree of differentiation did not seem to influence detectability on the gallium scan.

Comments There are some interesting points to be made about the makeup of our population. The average age was 64.6 years, somewhat higher than the 55 to 61 year average reported in larger series [I-4]. There were essentially equal numbers of squamous and basaloid squamous carcinomas, different for no apparent reason from Beahrs’s series [5] of 55 percent squamous, 31 percent basaloid and 14 percent. miscellaneous tumors. The incidence of anal carcinoma at St. Francis was Volume 140,July 1990

5.8 percent of all colorectal cancer seen during the period of study, higher than the 2.0 percent at Children’s and the 2.4 to 4.0 percent range generally reported elsewhere [3,6-81. Three of our patients (two men and one woman) with well differentiated squamous carcinoma had associated condyloma acuminatum, one a classic giant condyloma acuminatum of Buschke and Lowenstein. Welch and Malt [9] noted carcinoma in association with condyloma in 3 of 53 patients; Sawyers [ 71, in 4 of 26 patients; and Hickey et al [3], in 1 of 156 patients. Although the sex ratio (22 to 16, or 57.9 percent female) is fairly typical of that reported [I-4,6,9,10], the patients at one of our hospitals (St. Francis) were predominantly male (11 to 9, or 55 percent). Nine of the 11, all unmarried, had canal lesions, whereas the other 2 had external cancer. Sexual histories were not elicited and a survey of the literature was generally unrewarding except for the recent report by Cooper et al [II] of four male anoreceptive homosexuals with cloacogenic carcinoma. These limited data seem at least to suggest a sexually related neoplasm, laying down the mandate for more careful sexual histories and epidemiologic studies of future similar patients. Local control and survival: Most surgical reports advocate anteroposterior resection unless the lesion is less than 2 cm in size or smaller than half the anal circumference [7,10]. With local excision for such favorable lesions, excellent 5 year disease-free survivals of 70 percent [IO] and 83.3 percent [2] for 10 and 21 patients, respectively, have been reported, although local excision in conjunction with a grift has been associated with imperfect continence [IO]. Five year survival after anteroposterior resection varies from 33 to 60.7 percent [5-91. Local recurrence rates are less easily discerned from the literature but appear to be about 25 percent [5,9,10], and although Welch and Malt [9] noted that almost all lesions recur in the first 2 years, Al-Jurf et al [IO] observed recurrences up to 14 years later. The literature on radiation therapy has sparse reports and few patients, many treated with outdated techniques and for disease beyond the scope of curative surgery. Dalby and Pointon [12] reviewed the largest series (106 patients). Treating all patients with radium needles, they had an overall 5 year survival of 43.5 percent; however, subdivided into early, moderately advanced and late stages, the results were 72.2, 64.8 and 24.3 percent, respectively. Twentythree patients experienced necrosis (24 percent), 10 of whom required surgery [12]. Williams [13], treating 37 patients with 1 meV external irradiation (4,500 rads in 4 weeks) had a 5 153

Green el al

year disease-free survival rate of 37.5 percent, rather remarkable considering that 55 percent of the patients in his series had fixed or bilateral inguinal nodes. Six patients (37 percent) had necrosis, three requiring surgery. Papillon (141 of Lyons, using a fractionated radium implant scheme or cobalt-60 teletherapy and a radium implant for larger lesions, had a 68 percent 5 year disease-free survival rate in 64 patients, 4 requiring surgery for residual disease. He noted four cases of severe radionecrosis and 20 mild ulcers that healed with conservative management. All ulcerations occurred within the 1st year and there were no sphincter problems. The Mayo Clinic experience of 101 patients, as reported by Beahrs [5], includes 13 patients treated by radiation alone, with a 5 year survival of 18.2 percent. However, there is no mention of patient selection or the factors of radiation therapy. Ager et al [15] recently reported on four patients treated by external beam and interstitial implant (iridium-192 or cesium-137) after biopsy, excision or both. Three are free of disease 15 to 28 months after therapy. One required colostomy for complications. Buroker et al [16] describe 10 patients treated preoperatively with fluorouracil, mitomycin C and 3,000 rads in 3 weeks. Nine patients had anteroposterior resection, with no cancer in six of the specimens. Memorial Sloan-Kettering Cancer Center, according to Quan [6], has embarked on a similar program with seven anteroposterior resections and nine local excisions, but has not yet reported the results. In our series of 17 patients treated definitively, 3 patients had subsequent surgery for residual minimal disease. To date, there has been only one local recurrence in a patient who died in 6 months with a fulminant course, Two of the three patients with massive primary lesions had preoperative irradiation and anteroposterior resection. Although they died with dissemination, local control was achieved. The third patient is alive and well at only 2 months. This report includes 27 patients who received cancericidal doses of radiation to the pelvis-perineum, all through supervoltage external beam. Four patients had subsequent anteroposterior resections as part of their cancer therapy. No colostomies have been required except for those subjected to anteroposterior resection for residual or recurrent cancer. There have been neither persistent rectal ulcers nor sphincter problems. One patient with condyloma, who had anteroposterior resection for a residual mass, had inexplicable fecal incontinence not thought to be a sphincter-related phenomenon. 154

Management of inguinal node involvement: In the current series, 29 patients were seen at the time of initial diagnosis, 3 (10 percent) with synchronous adenopathy. In two others metachronous groin metastases developed. Most other reports indicate an overall incidence of inguinal metastasis of around 50 percent, with about one third presenting with adenopathy [1,8,9,12,13,17]. It is too early to make a definitive statement regarding our actual incidence, but it may well be lower than that reported elsewhere. Our experience indicates that inguinal metastasis can be treated by radiation, with four of five patients achieving complete response in the absence of any ill effects.

Conclusions Despite frequent comment to the contrary [1,3,7,18], we believe that anal carcinoma can no longer be considered solely a surgical problem. Although individualization of cases remains a cornerstone in management, in selected patients carefully executed radiation therapy is a viable alternative from the points of both local control and preservation of function. Summary The generally preferred method of treatment of epidermoid carcinoma of the anus and anorectum has basically been surgical, although there have been instances of cure by radiation therapy alone. Techniques of radiotherapy have greatly improved, permitting high level irradiation to the anorectum while preserving good rectal function. Recent reports of the use of combined surgery and irradiation have shown dramatic results and have begun to change the concept of a strictly surgical approach to this disease. Thirty-eight patients treated by a combined approach in a community hospital setting from 1966 to 1979 were studied. The entire spectrum of epidermoid carcinoma, from highly malignant cloacogenic carcinoma to well differentiated squamous cell carcinoma, is included. Initially all patients had an accurate histologic diagnosis from adequate biopsy material followed by radiation therapy. Adjuvant chemotherapy was not used in this series. Determination of necessary surgical therapy, ranging from local excision to radical abdominoperineal resection, was delayed until maximal effects of irradiation were realized. Gallium scanning proved useful because many of the lesions and their metastases were gallium positive. Results have been excellent, with a high overall cure rate. Many patients subsequently needed little or no further surgery. The American Journal ol Surgwy

Anal Carcinoma

References 1. Sink JD, Kramer SA, Copeland DD, Seigler HF. Cloacogenic carcinoma. Ann Surg 1978;188:53. 2. Paradis P, Douglass Jr Ho, Holyoke ED. The clinical implications of staging system for carcinoma of the anus. Surgery 1975;141:411. 3. Hickey RC, Martin RG, Kheir S, MacKay B, Gallager HS. Anal cancer-with special reference to the cloacogenic variety. Surg Clin North Am 1972;52:943. 4. Kuehn PG, Eisenberg H, Reed JF. Epidermoid carcinoma of the perianal skin and anal canal. Cancer 1988;22:932. 5. Beahrs 0. Management of cancer of the anus. Am J Roentgenol 1979;133:791. 8. Quan SHQ. Anal and para-anal tumors. Surg Clin North Am 1978;58:591. 7. Sawyers JL. Squamous cell cancer of the perianus and anus. Surg Clin North Am 1972;52:935. 8. Klotz Jr RG, Pamukcoglu T, Souilliard DH. Transitional cloacogenic carcinoma of the anal canal. Cancer 1967;20: 1727. 9. Welch JP, Malt RA. Appraisal of the treatment of carcinoma of the anus and anal canal. Surg Gynecol Obstet 1977; 145~837. 10. Al-Jurf AS, Turnbull RB, Fazio VW. Local treatment of squamous cell carcinoma of the anus. Surg Gynecol Obstet 1979:148:576. 11. Cooper HS, Patchefsky AS, Marks G. Cloacogenic carcinoma of the ancrectum in homosexual men: an observation of four cases. Dis Colon Rectum 1979;12:557. 12. Dalby JE, Pointon RS. The treatment of anal carcinoma by interstitial irradiation. Am J Roentgen01 1961;85:515. 13. Williams IG. Carcinoma of the anus and anal canal. Clin Radio1 1962;13:30. 14. Papillon J. Radiation therapy in the management of epidermoid carcinoma of the anal region. Dis Colon Rectum 1974; 17: 181. 15. Ager P, Samala E, Bosworth J, Rubin M, Ghossein NA. The conservative management of anorectal cancer by radiotherapy. Am J Surg 1979;137:226. 16. Buroker TR, Nigro N, Bradley G et al. Combined therapy for cancer of the anal canal: a follow-up report. Dis Colon Rectum 1977;20:677. 17. Levin SE, Cooperman H, Freilich M, Lomas M, Kaplan L. Transitional cloacogenic carcinoma of the anus. Dis Colon Rectum 1977;20:17. 18. Grodsky L. Current concepts on cloacogenic transitional cell anorectal cancers. JAMA 1969;207:2057.

Discussion J. Engelbert Dunphy (San Francisco, CA): This excellent report is one of the largest series on anal carcinoma yet reported by a single surgeon, and the primary emphasis on the use of radiation rather than abdominoperineal resection represents a major contribution. For many years I have felt that local, limited lesions could be excised locally and that abdominoperineal dissection was required for larger lesions, especially for the more deep-seated cloacogenie cancerous lesions. Dr. Schaupp ‘did not refer specifically to cloacogenic lesions, and I wonder if he would clarify this. In comparison to Dr. Schaupp’s experience, in a 10 year period at the University of California, San Francisco (1967 to 1977), there were 14 cases of anal carcinoma: 11 were squamous, 1 cloacogenic and 2 mucoid. Surgery without radiation was used in 10 cases, radiation in 1 and surgery plus radiation Volume 140, July ISSO

in 1. One lesion was so advanced and widely disseminated that no treatment was given. The overall survival rate was 50 percent in those patients treated before 1972. I congratulate Dr. Schaupp on a significant contribution to our understanding of the nature and treatment of carcinoma arising in the anal canal. Richard E. Robins (Vancouver, BC): I take a modified course on what Dr. Schaupp has suggested. In Vancouver we have come to the conclusion that surgery alone is not the best treatment for squamous cell cancer of the anus, and we too are very interested in the use of radiation therapy. This is a modality that the surgeon should be aware of, and the surgeon should determine the patients who are treated by radiation and should be in control of the individual case. It is the surgeon’s duty, with the patient under anesthesia, to biopsy and stage the disease. I agree with Dr. Dunphy that it is most important to separate superficial lesions in the anal canal from so-called anorectal squamous lesions that extend up into the rectum. Our policy now is to treat lesions of the anal canal with radiation only and then follow up patients and treat them surgically if there is recurrence. Careful search for inguinal node involvement should be made in these patients. We believe that the anorectal lesions that are clearly resectable should be treated primarily with surgery. For more advanced and yet potentially curable lesions we give preoperative irradiation and then follow with abdominoperineal resection even though there may have been good response to radiation. Our experience has been that if you wait until there is recurrence, the chance of curing these lesions is far less. Lastly, we recently had experience with two huge inoperable lesions, both of which were treated for palliation. For one of these the surgeon performed a debulking procedure, which I would caution against, leaving a raw bleeding surface, and a very intense radiation reaction developed. However, in the patient who simply underwent biopsy and irradiation, early control of the tumor was achieved. Willis C. Schaupp (closing): I have no real disagreement with Dr. Robins in that the surgeon should be in control of treatment in each case. I certainly have been in control in all of my cases in which radiation was used. I do not let my patients receive radiation treatment without seeing me regularly in addition to the radiation therapist. I think in time Dr. Robins will change his treatment of patients with large lesions by surgery primarily because he is going to find that in some of the lesions radiated preoperatively, no tumor is left in the specimen at the time of surgery. This has been reported in a number of series including a large one from the Mayo Clinic. Dr. Dunphy, the lesions were equally divided between cloacogenic and squamous, and in the text of the report they are broken down very carefully into superficial and deep ones. However, it is surprising how what appears to be a very hopeless, largely bulky lesion will melt away sometimes altogether with radiation and operation will not be necessary. 155