External Radiation Therapy without Chemotherapy in the Management of Anal Cancer

Transcription

1 1736 External Radiation Therapy without Chemotherapy in the Management of Anal Cancer James A. Martenson, ]r., M.D., and Leonard 1. Gunderson, M.S., M.D, Background. Most therapeutic regimens currently in use for sphincter preservation in anal cancer utilize combined radiation therapy and chemotherapy. To provide a basis for comparison with combined therapy results, an analysis was made of patients treated with external radiation therapy without chemotherapy. Methods. Eighteen patients with squamous cell, basaloid, or cloacogenic carcinoma of the anal canal were treated with external radiation therapy between January 1,1980, and December 31,1989, with the goal of sphincter preservation and cure. Before radiation therapy, five patients had incisional biopsies, two underwent piecemeal removal of the tumor, three had excisional biopsies with positive margins, five had excisional biopsies with negative margins, and three had excisional biopsies with unknown margins. All patients received 45 to Gy in 25 to 28 fractions to the pelvis and perineum, and 16 of the 18 received an additional boost to the primary site to bring the total dose to 55 to 67 Gy in 30 to 38 fractions. Results. With follow-up of 2.5 to 11.2 years in surviving patients, 5-year projected survival and freedom from local recurrence were 94% and looo%, respectively. Two patients required a temporary colostomy because of treatment complications. No patient required a permanent colostomy or had permanent loss of anal sphincter function as a result of local recurrence or complications. Conclusions. These results, combined with others, suggest that external radiation therapy without chemotherapy is an acceptable alternative to combined radiation therapy and chemotherapy in the management of anal cancer. Cancer 1993; 71: Key words: anal cancer, radiation therapy, sphincter preservation, combined therapy. Until approximately 10 years ago, the standard of care for cancer of the anus was abdominal-perineal resec- From the Division of Radiation Oncology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota. Address for reprints: James A. Martenson, Jr., M.D., Mayo Clinic, 200 First Street SW, Rochester, MN Accepted for publication September 11, tion. Five-year survival rates of 60% to 70% andlocalregional recurrence rates of 25% are associated with this approach.'i2 Within the last decade, there have been reports of sphincter-sparing approaches with either radiation therapy a10ne~-~ or radiation therapy in combination with ~hemotherapy.~-'~ The most common sphincter-sparing regimens used today are based on the combined modality regimen first described by Nigro et al.13 from Wayne State University. It consists of radiation therapy (30 Gy in 15 fractions), 5-fluorouracil(l g/m2 per day by continuous intravenous infusion on days 1 through 4 and 28 through 31), and mitomycin C (15 mg/m2 on day 1). Some have suggested that this regimen, or minor variations of it, should represent the sole standard of care in the sphincter-sparing management of anal cancer.'^'^ To provide a basis for comparison with results obtained by combined chemotherapy and radiation therapy, a review was made of the Mayo Clinic (Rochester, MN) experience in patients with anal cancer treated by external radiation therapy without chemotherapy. The results and those of others suggest that external beam radiation therapy alone should be considered an acceptable alternative to combined modality therapy for anal cancer. Materials and Methods The medical records of all patients with a diagnosis of cancer of the anal canal who were treated with external radiation therapy between January 1, 1980, and December 31, 1989, were reviewed. Seven patients treated by combined radiation therapy and chemotherapy were excluded. Eighteen patients treated by external radiation therapy without chemotherapy with the goal of sphincter preservation form the basis of this retrospective study. Two were male patients and 16 were female. Staging in all patients was according to the American Joint Committee system.15 Nine patients presented with primary lesions < 2 cm (Tl), eight with lesions 2 to 5 cm (T2), and one with a lesion > 5 cm (T3).

2 External Radiation for Anal CancerlMartenson and Gunderson 1737 Unilateral inguinal lymph node involvement was present in three patients, and one patient had bilateral lymph node involvement. All patients had biopsy proof of invasive malignant disease. In all instances, the histologic description was squamous cell carcinoma, basaloid carcinoma, clodcogenic carcinoma, or a composite of these. In 16 patients, radiation therapy was initiated after biopsy confirmation of disease, and in the other 2, radiation therapy was initiated at the time of local progression 6 to 8 months after management by local excision alone. Five patients had incisional biopsies, two underwent piecemeal removal of the tumor, three had excisional biopsies with positive margins, five had excisional biopsies with negative margins, and three had excisional biopsies with unknown margins. Three patients with metastatically involved inguinal lymph nodes underwent superficial unilateral inguinal lymph node dissection before initiation of radiation therapy. A variety of irradiation techniques were used. All patients received 45 to Gy with 4 to 10 megavoltage photons to the pelvis, anal canal, and perineum in 25 to 28 fractions with use of either anteroposterior-posteroanterior (AP-PA) parallel opposed fields or a four-field box technique. Dose was specified on the central axis at midplane for AP-PA parallel opposed fields and at the isocenter for multiple-field techniques. Sixteen of the 18 patients received a boost to the tumor or tumor bed to total cumulative doses of 55 to 67 Gy in 30 to 38 fractions. Boost field treatment was delivered by photons with multiple fields and the dose specified at isocenter or by a single perineal port with photons or 0-MeV to 18-MeV electrons (or both), the patient in the lithotomy position, and the dose specified at the central axis at the depth of the tumor. Inguinal nodes lateral to the medial 1.5 cm of the femoral head were treated in 11 patients, with total I I I I I I I Years Figure 2. Freedom from local recurrence. Numbers in parentheses indicate evaluable patients followed-up to a given interval. doses ranging from 36 to 45 Gy in 20 to 25 fractions for patients without clinical evidence of inguinal adenopathy (7 patients) and 47 to 66 Gy in 25 to 36 fractions in patients with metastatically involved inguinal lymph nodes (4 patients). In two patients, inguinal node irradiation was given by separate anterior fields, with the dose specified on the central axis at the depth of the inguinal nodes. In the remaining nine patients, inguinal nodes were treated by expansion of the AP-PA photon field laterally. After 45 to 49 Gy, electrons were used to deliver a final inguinal boost of 60 to 66 Gy in three of these nine patients. Follow-up in surviving patients ranged from 27 to 105 months (median, 72 months). The Kaplan-Meier method" was used in analysis of survival and freedom from local recurrence, with survival and time to local recurrence measured from the first day of radiation therapy, For determination of freedom from local recurrence, patients dying without evidence of local recurrence were censored at the time of death. Results Years Figure 1, Overall survival. Numbers in parentheses indicate patients followed-up to a given interval. Survival rates at 5 and 7 years were 94% and 86%, respectively (Fig. 1). Two patients died: one of unknown causes and one as a result of peritoneal metastatic disease. Rates of freedom from local recurrence at 5 and 7 years were 100% and go%, respectively (Fig. 2). In one patient, locally recurrent carcinoma in situ devel- oped 5.5 years after treatment. This was treated b>; local excision with sphincter preservation, and the patient has remained free of disease for 6 years after salvage therapy. Acute toxicity during radiation therapy generally was acceptable. Perineal moist desquamation that de- veloped in ll patients resolved within several weeks after completion of treatment. Severe diarrhea-up to

3 1738 CANCER March 2, 2993, Volume 71, No bowel movements a day-in one patient resolved after a break in radiation therapy. One patient required hospitalization after 21.6 Gy because of nausea, vomiting, anorexia, and dysuria; after a 2-week break, radiation therapy resumed, and these symptoms were medically controlled for the remainder of the course of radiation. Two patients experienced serious gastrointestinal complications subsequent to radiation therapy. In one patient, a nonhealing anal ulcer persisted at the completion of radiation therapy. An end-sigmoid temporary colostomy was performed, and the ulcer subsequently healed. The colostomy was taken down, and the patient had normal sphincter function at latest follow-up, 2.2 years after takedown. In the other patient, a rectovaginal fistula developed 5.5 years after the completion of radiation therapy and was corrected surgically. At 6.5 years after radiation therapy, surgery was required for repair of a cecal-sigmoid fistula. A temporary diverting colostomy was necessary, but this was later taken down with restoration of sphincter function. At latest follow-up, 1 month after restoration of sphincter function, the patient had intermittent rectal bleeding and pain with defecation. Complications potentially related to treatment of inguinal nodes developed in five patients. In three pa- tients, femoral head or neck fractures developed after radiation therapy. In each case, the area of the fracture had received at least 45 Gy through AP-PA ports or a four-field box technique. The precise contribution of radiation therapy to these complications is uncertain. One patient, for example, had a stress fracture in one hip before radiation therapy began. The other patients were elderly women, 77 and 87 years of age, respectively, and it is possible that underlying osteoporosis contributed to the problem. In two patients with metastatically involved inguinal nodes, lower extremity edema developed 6 and 7.5 years, respectively, after, inguinal node dissection and postoperative inguinal radiation therapy to total doses of 65 to 66 Gy. Discussion Although radiation therapy has gained widespread acceptance as a sphincter-sparing alternative to abdominal-perineal resection in patients with anal cancer, what should constitute optimal management of this problem is controversial. Some have argued that combined modality therapy with radiation, 5-fluorouracil, and mitomycin C, either as described by Nigro et al.i3 or as altered in a minor way, should constitute the sole standard of care for patients with this malignant condi- Table 1. Local Control and Survival After Sphincter-Preserving Therapy in Anal Cancer: Selected Series Total radiation Duration dose of RT No. of Primary tumor Local control S u r v i v a I Authors (Gv) (wk)* Chemotherapy patients size Percent Follow-up Percent Folloriwp Sischy et al." Leichman et al." Flam et al9 Tveit et al " Cummings et al.* FU. mito-c 79 5-FU, mito-c 45 5-FU, mito-c 30 5-FU, mito-c 5-FU 24$ 66 5-FU, mito-c 69 hone 57 < 3 cm z 3 cm 2-8 cm Y' 3 YT mo (median) 6-90 mo mo Y' 3 yr SO mo (median) 6-90 mo nio 5 Yr 61 5 YT T yr 72 5 yr Eschwege et al.' None 1: T yr 35 5 Y' Dobrowsky' None mo 65 5 YT Doggett et al.' None cm mo 92 5 Y' T1-28 (17 patients) Current study None 18 7 yr# 86 7 I Y' T3n (1 patient) I 90 5-FU: 5-fluorouracil; mito-c: mitomycin C; RT: radiation therapy. Duration is given exclusive of treatment breaks. t Some information on tumor extent provided, but results not presented according to tumor size. $ Includes three patients with distant metastasis before treatment began. 5 The most common regimen was Gy; 28% of patients were treated with interstitial therapy, either in combination with external radiation therapy (seven patients) or alone (nine patients). I( International Union Against Cancer staging system." ll American Joint Committee staging system. t Carcinoma in situ developed in one patient after treatment; salvage was successful with local excision and preservation of sphincter function (see text) 5 Y'

4 ~ ~ External Radiation for Anal CancerlMartenson and Gunderson 1739 Table 2. Complications Resulting in Colostomy After External Radiation Therapy With or Without Chemotherapy Authors. - Total tumor dose (Gy) Cummings et a!.' Flam et al Doggett et al Current stiidv FU: 5-fluorouracil; mito-c: mitomycin C; RT: radiation therapy. Duration I!; given ecclusive of treatment breaks. Daily fraction Duration of who could be size (Gy) RT (wk)* Chemotherapy examined Usually None FU, mito-c FU, rnito-c 30 Usually None 34t None 18 t One patient treated with interstitial implantation is excluded. $ In both patients, restoration of gastrointestinal continuity and sphincter function was possible. -- colostomy from complications No. Percent f 11 ti~n.~,'* In contrast, others have suggested that radiation therapy without chemotherapy can provide excellent local control and functional result^.^,^ Although randomized prospective trials are being conducted in Europe to compare the value of radiation therapy with that of combined modality therapy, results will not be available for some time. In the meantime, results of different treatment policies can be compared to see if one treatment policy is obviously more advantageous than another. Table 1 shows results from major series that used either combined modality therapy or radiation therapy alone in the treatment of anal cancer. No obvious advantage of one treatment approach over the other is apparent. Table 2 compares complications resulting in colostomy in reports of external radiation therapy with or without chemotherapy. Again, no obvious advantage of one approach over another is apparent. Two reports in the literature are of particular interest because they provide the only comparisons within a single institution between results achieved with combined modality therapy and those with radiation therapy alone. In a retrospective analysis from Princess Margaret Hospital,' combined modality therapy with radiation, 5-fluorouracil, and mitomycin C was associated with a 5-year primary tumor control rate of 86%, which compared favorably with primary control rates of 62% for radiation therapy and 5-fluorouracil and % for radiation therapy alone. This report must be interpreted with caution, because patients receiving radiation therapy alone generally were treated with relatively low doses (usually Gy) and in some cases with interstitial radiation therapy alone. A retrospective study of 57 patients from the University of Kansas stands in contrast to the Princess Margaret experience because combined modality treatment was not associated with improvement in primary tumor control over that with radiation therapy alone. Local control was 83% for radiation therapy alone (13 patients) and 82% for combined modality therapy (44 patients). Like the Princess Margaret study, the University of Kansas experience did not document a difference in survival with either treatment The current experience is in agreement with studies suggesting excellent rates of local control and survival with radiation therapy alone. The possibility that local excision before radiation therapy in 13 of 18 patients contributed to the high rate of local control must be considered. Table 3 summarizes the two series that have provided explicit information on the use of local excision before radiation therapy. Although the small number of patients and the nonrandomized nature of Table 3. Local Recurrence of Anal Cancer After Either Local Excision and Radiation Therapy or Radiation Therapy Alone LE and RT RT alone local recurrence local recurrence Authors at risk No. Percent at risk No. Percent Dobrowsky' Current study Total LE: local excision; RT: radiation therauv

5 1740 CANCER March I, 2993, Volume 71, No. 5 the comparison preclude a definitive conclusion, local excision has no obvious advantage. Moreover, others have reported excellent results using radiation therapy alone without local ex~ision.~,~ In the current study, only one patient had a T3 primary tumor and no patients had T4 primary tumors, and this lack of advanced stages also may have contributed to the high rate of local control. Results from Princess Margaret Hospital' suggest that any beneficial effect of adding chemotherapy to radiation therapy may be confined to patients with more advanced lesions. Although two patients required temporary diverting colostomy due to radiation-related gastrointestinal toxicity, both had subsequent takedown of the colostomy and restoration of sphincter function. This rate of serious gastrointestinal toxicity lies within the range described for combined modality therapy (Table 2). Complications with inguinal treatment possibly were related to radiation technique. Lower-extremity edema in two patients occurred after a combination of inguinal node dissection and high-dose irradiation, and femoral neck or head fractures occurred in three patients after use of techniques that delivered 2 45 Gy to the region of the subsequent fracture. Radiation therapy techniques directed toward inguinal lymph nodes have now been modified. Inguinal irradiation is given through anterior fields with a combination of photons and electrons, which minimizes dose to the femoral head and neck. The posterior radiation therapy field includes the primary lesion and the pelvic lymph nodes, but only the medial inguinal nodes, so that most of the femoral head and neck is excluded. Retrospective uncontrolled comparisons of results achieved with radiation therapy alone and results from combined modality therapy must be interpreted with extreme caution. Although such comparisons suggest that these methods of treating anal cancer may be about equal in effectiveness, a definitive answer can result only from a randomized prospective clinical trial. Randomized trials comparing radiation therapy alone with combined modality therapy are currently under way in both the United Kingdom and the European Organization for the Research and Treatment of Cancer. Until results from these trials are available, our work, as well as that of others, indicates that external radiation therapy without chemotherapy should be considered an acceptable option in the treatment of anal cancer. References 1. Frost DB, Richards PC, Montague ED, Giacco GG, Martin RG. Epidermoid cancer of the anorectum. Cancer 1984; 53: Boman BM, Moertel CG, O'Connell MJ, Scott M, Weiland LH, Beart RW, et al. Carcinoma of the anal canal: a clinical and pathologic study of 188 cases. Cancer 1984; 54: Doggett SW, Green JP, Cantril ST. Efficacy of radiation therapy alone for limited squamous cell carcinoma of the anal canal. Int ] Radiat Oncol Biol Phys 1988; 15: Eschwege F, Lasser P, Chavy A, Wibault P, Kac J, Rougier P, et al. Squamous cell carcinoma of the anal canal: treatment by external beam irradiation. Radiother Oncol 1985; 3:145-. Schlienger M, Krzisch C, Pene F, Marin J-L, Gindrey-Vie B, Mauban S, et al. Epidermoid carcinoma of the anal canal: treatment results and prognostic variables in a series of 242 cases. Int ] Radiat Oncol Biol Phys 1989; 17: Dobrowsky W. Radiotherapy of epidermoid anal canal cancer. Br ] Radio/ 1989; 62: Cummings B, Keane T, Thomas G, Harwood A, Rider W. Results and toxicity of the treatment of anal canal carcinoma by radiation therapy or radiation therapy and chemotherapy. Cancer 1984; 54: Cummings BJ, Keane TJ, O'Sullivan 8, Wong CS, Catton CN. Epidermoid anal cancer: treatment by radiation alone or by radiation and 5-fluorouracil with and without mitomycin C. 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