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© 2002 American Society for Clinical Oncology Sphincter-Sparing Local Excision and Adjuvant Radiation for Anal-Rectal MelanomaByFrom the Departments of Radiation Oncology, Surgical Oncology, Melanoma Medical Oncology, and Pathology, University of Texas M.D. Anderson Cancer Center, Houston TX. Address reprint requests to Matthew T. Ballo, MD, Department of Radiation Oncology, Box 97, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; email: mballo{at}mdanderson.org
PURPOSE: To evaluate the outcome and toxicity of a sphincter-sparing treatment strategy in the management of patients with anal-rectal melanoma. PATIENTS AND METHODS: Between 1989 and 2000, 23 patients with invasive anal-rectal melanoma were managed with sphincter-sparing surgical resection and adjuvant radiation. Surgery consisted of primary local excision, as well as dissection for patients with documented regional nodal disease. Adjuvant radiation was delivered using a hypofractionated regimen of 30 Gy in five fractions over 2.5 weeks. Adjuvant systemic therapy was delivered to nine patients: cytotoxic chemotherapy in seven and immunotherapy in two. RESULTS: After a median follow-up of 32 months, 15 patients had relapsed and 15 patients had died. The actuarial 5-year overall, disease-specific, disease-free, and distant metastasis-free survival rates were 31%, 36%, 37%, and 35%, respectively. The actuarial 5-year local and regional nodal control rates were 74% and 84%, respectively. No patient had locoregional failure as the sole site of failure and no patient required salvage abdominoperineal resection (APR). By univariate analysis, patients with nodal disease at presentation had a decreased actuarial 5-year disease-specific (0% v 45%, P = .004), disease-free (0% v 45%, P < .001), and distant metastasis-free survival (0% v 42%, P < .001). The actuarial complication-free survival rate was 71%. Two patients developed mild scrotal edema (grade 1), and four patients developed moderate proctitis requiring prolonged medical management (grade 2). CONCLUSION: Sphincter-sparing local excision and adjuvant radiation is well tolerated and can effectively control local-regional disease while avoiding the functional morbidity of APR.
PRIMARY ANAL-RECTAL melanoma is an uncommon, aggressive malignancy characterized by early systemic spread and a generally poor prognosis. Typically presenting in the fifth or sixth decade of life, patients complain of rectal bleeding, pain, or a palpable anal mass.1 Traditionally, therapy has consisted of complete surgical resection, with systemic agents reserved for treatment of patients with documented distant metastatic disease. The surgical procedure of choice has ranged from radical abdominoperineal resection (APR) with elective lymph node dissection to conservative sphincter-sparing local excision alone. Although APR has been reported to result in improved local-regional control rates (70% local control after APR v 35% after local excision), no commensurate improvement in overall survival has ever been documented (< 25% 5-year survival).2-8 In light of the poor overall survival, it has been difficult to justify a functionally debilitating surgical procedure despite an anticipated higher rate of local control. Recognizing that the majority of patients ultimately succumb to metastatic disease, but in an attempt to avoid the untoward morbidity of local recurrence, physicians at the University of Texas M.D. Anderson Cancer Center (MDACC) have adopted an approach of combined sphincter-sparing local excision with adjuvant radiation. APR is reserved for patients with bulky disease where local excision would transect gross disease. In this study, we report the results of this approach in 23 patients with anal-rectal melanoma.
Patients were identified through a search of the MDACC Department of Radiation Oncology and institutional patient databases. A waiver of informed consent was obtained before analysis from our institutional review board. Between the years 1989 and 2000, 23 patients with primary invasive anal-rectal melanoma managed with sphincter-sparing local excision and adjuvant radiation were identified. During this time, three additional patients required APR with adjuvant irradiation and were excluded from the present analysis, as were four patients treated with visceral metastases. Patients’ ages at the time of presentation ranged from 33 to 89 years (median age, 55 years). There were 17 female and six male patients. All patients underwent complete history and physical examination, routine blood tests, chest radiography, and other appropriate radiologic imaging studies. Of the 23 patients, 20 had undergone an incisional biopsy at an outside institution while three patients presented after excisional biopsy for suspected malignancy. After the initial evaluation was complete, two patients were believed to have had an adequate surgical procedure and were referred for immediate adjuvant irradiation. In the remaining 21 patients, the recommendation was for additional local excision alone in 13 patients and local excision with directed inguinal lymph node surgery in eight patients. Pathologic examination of the eight nodal specimens revealed disease in four patients. Three of the eight patients presented with clinically suspicious inguinal adenopathy and underwent superficial and deep inguinal node dissection. All three surgical specimens revealed metastatic melanoma. The remaining five patients presented without clinically suspicious adenopathy and underwent sentinel lymph node biopsy. The sentinel lymph node was identified in four of these patients and histologic review revealed nodal metastases in one. The number of involved nodes ranged from one to 11 (median, four), and the nodes ranged in size from 0.8 to 4 cm (median, 2.8 cm). The median primary tumor thickness or size was 5 mm (range, 0.3 to 35 mm). For the purposes of analysis, 4 mm was used to separate patients into two primary tumor size groups. This cut point creates a distinction between tumors measured with a micrometer (thickness) and those measured grossly with a ruler (size). The primary tumor margins were microscopically negative in 22 patients and microscopically positive in one patient. Additional tumor characteristics are listed in Table 1.
After adequate sphincter-sparing local excision of the primary tumor, with or without nodal surgery, all patients were referred for adjuvant irradiation. The dose and fractionation schedule was 30 Gy in five fractions (6 Gy per fraction) delivered over 2.5 weeks, on Monday and Thursday or Tuesday and Friday. Customized portal shaping was used to limit the dose to the small bowel, with the upper border set at the bottom of the sacral-iliac joint. Also, wide anterior and narrow posterior photon fields were used to treat the pelvis with matched anterior electron beams to supplement the dose to the lateral inguinal nodal basins. This technique creates a homogeneous dose to the primary tumor site and regional lymphatics while sparing the femoral heads. Four patients received a 6-Gy boost to the primary tumor site. Two of these patients had large primary tumors, which measured 2 cm in one patient and 3.5 cm in the other. Overall comprehensive irradiation to the draining lymphatics using the fields described above was delivered to 21 patients. The remaining two patients were treated using small pelvic fields encompassing the primary tumor site only. In one patient, this was because of previous pelvic irradiation for endometrial cancer. Adjuvant systemic therapy was delivered to nine patients. Therapy consisted of cisplatin, vinblastine, and dacarbazine in four patients, interleukin 2, interferon, cisplatin, vinblastine, and dacarbazine in three patients, and interferon alone in two patients.
The median follow-up of the eight patients alive at last contact was 32 months (range, 12 to 102 months). Disease relapse was defined as any clinical or radiographic evidence of tumor regrowth. Failures were considered nodal only if they occurred within the expected draining lymphatics of the primary tumor site; otherwise, they were considered distant. Actuarial plots for local control, nodal control, and disease-free, distant metastasis-free, disease-specific, and overall survivals were calculated using the Kaplan-Meier method,9 and tests of significance were based on the log-rank statistic. An analysis of factors correlating with all outcomes was performed and included age, sex, primary tumor size, presence of primary tumor ulceration, nodal status, radiotherapy field size, dose, and use of adjuvant chemotherapy. The significance of differences between proportions was tested with the
At the time of analysis, 15 of the 23 patients had developed disease relapse and 15 had died. Two patients died of a non–cancer-related illness and three patients are alive with distant metastases. The median time to disease relapse was 14 months (range, 2.5 to 102 months). The actuarial 5-year overall, disease-specific, disease-free, and distant metastasis-free survival rates were 31%, 36%, 37%, and 35%, respectively (Fig 1). Univariate analysis of factors correlating with outcome revealed that nodal disease was associated with significantly inferior disease-specific, disease-free, and distant metastasis-free survival. Specifically, the actuarial 5-year disease-specific survival rate was 45% when nodes were uninvolved compared with 0% when they were involved (P = .004). Corresponding rates for disease-free survival were 45% compared with 0% (P < .001), and for distant metastasis-free survival they were 42% compared with 0% (P < .001). For disease-free survival, univariate analysis also revealed an inferior outcome when the primary tumor was more than 4 mm in size (19% v 66%, P = .04). Radiotherapy dose  30 Gy seemed to predict for inferior disease-specific, disease-free, and distant metastasis-free survival on univariate analysis, but only the association between nodal disease and inferior disease-specific (P = .02), disease-free (P = .004), and distant metastasis-free survival (P = .004) remained significant on multivariate analysis. The median time to death after relapse was 11 months (range, 2 to 42 months).
The actuarial 5-year local control rate was 74%, while the 5-year actuarial nodal control rate was 84% (Fig 2). There were a total of five local failures and three nodal failures. One of each was a marginal failure just superior to the upper border of the radiation field. No patient had locoregional failure as the sole site of failure, and no patient required salvage APR for palliation of local-regional disease recurrence. Univariate analysis revealed a superior actuarial 5-year local control rate for female patients (83% v 50%, P = .05) and patients treated with comprehensive fields of irradiation encompassing both the primary tumor site and draining lymphatics (81% v 0%, P < .001). The nodal control rate was unaffected by patient- or treatment-related factors on univariate analysis. The small number of local and/or nodal failures precluded meaningful multivariate analysis.
Treatment was well tolerated. Acute radiation-related dermatitis, particularly in the inguinal folds, was noted by most patients and was usually a self-limited toxicity. Six patients developed a chronic radiation-related toxicity: mild scrotal edema (grade 1) occurred in two patients and moderate proctitis requiring prolonged medical management (grade 2) occurred in four patients. The actuarial 5-year complication-free survival rate was 71%. The median time to development of these complications was 8 months (range, 1 to 12 months). No patient- or treatment-related factor was associated with the development of a complication.
The results of the present series confirm the previously reported poor prognosis of patients with anal-rectal melanoma.2-8 As detailed in Tables 2 and 3, the 5-year overall survival rate seems to be unrelated to the extent of surgical resection. This consistently reported finding has resulted in a lack of uniform treatment recommendations. Some investigators have consistently advocated APR with pelvic lymphadenectomy in the management of anal-rectal melanoma.5,11,12 This recommendation has been based on the hypothesis that "lesser surgical procedures are unlikely to provide negative margins in a disease that spreads proximally via the submucosa."5 In addition, the propensity for mesenteric node involvement is emphasized, and therefore complete surgical removal of the primary tumor with all draining lymphatics is advocated. Furthermore, retrospective analysis has revealed a statistically significant improvement in local-regional control when patients are managed with APR compared with local excision alone (without radiation). Other investigators, however, have taken a more nihilistic approach to this disease and have recommended sphincter-sparing local excision only. Proponents of this approach are willing to accept the higher local-regional failure rates, conceding that treatment is often palliative.13,14
At the University of Texas MDACC, an alternative to these two treatment strategies has been adopted. The significant improvement in local-regional control utilizing APR was recognized in the early 1990s.4 The fact that many patients were succumbing to metastatic disease shortly after diagnosis, however, raised doubts as to the appropriateness of this procedure for the majority of patients with anal-rectal melanoma. Rather than continue to recommend a functionally debilitating treatment with less than satisfactory local-regional control rates, a sphincter-sparing approach capitalizing on the strengths of other disciplines was adopted. With use of local excision and adjuvant irradiation, APR is reserved for patients in whom local excision would transect gross disease.
Although the present study is retrospective in design, the actuarial 5-year local and nodal control rates of 74% and 84%, respectively, compare favorably to those obtained with surgery alone. In seven recent series (Table 2), involving 68 patients managed with local excision alone, the crude local control rate was 35%.2-8 Although APR can significantly improve on the results of surgery alone (Table 3), the combined outcome of 98 patients treated by APR still has a local-regional control rate of only 70% (P < .0001, To address the propensity for submucosal spread and frequent lymphatic involvement, comprehensive adjuvant local irradiation is utilized as it is in many other disease sites. Fields of irradiation in the present series were designed to encompass these two patterns of spread. Thus, the primary tumor site and the regional pericolic and inguinal lymphatics were generally treated.1,3-6 In fact, evidence for the effectiveness of adjuvant irradiation can be appreciated in the patterns of local failure seen in the present series. Two of the five local failures were noted in the only two patients treated with fields of irradiation encompassing the primary tumor site only, with no additional coverage for potential mucosal or lymphatic spread. In addition, the current nodal control rate compares favorably with historical experiences.1,4,6 Previously reported crude inguinal nodal failure rates have ranged from 27% to 47%.4,6 In the present series, there were only two inguinal node failures. Similarly, the previously reported crude perirectal lymph node involvement rate in those patients undergoing APR has been as high as 70%.1,6 In the present series, there was only one pelvic lymph node failure. Adjuvant irradiation, therefore, seems to be a means for obtaining local-regional disease control, but comprehensive treatment fields covering the primary lesion and inguinal/low pericolic lymph nodes are required. The radiation dose and fractionation schedule of 30 Gy in five fractions (6 Gy per fraction) was well tolerated and resulted in satisfactory local and regional control. This fractionation has traditionally been used at MDACC for patients with melanoma, because melanoma cells tend to be more sensitive to large-dose-per-fraction radiation.15 In addition, the regimen can be delivered quickly to a group of patients with a median overall survival time of only 23 months. In conclusion, this multimodality treatment strategy has several potential benefits for patients with anal-rectal malignant melanoma. First and foremost, this strategy preserves anal sphincter function by avoiding a functionally debilitating APR. Second, potentially morbid local or regional failures, which commonly occur after local excision alone, are infrequent. Third, the radiation fractionation schedule is quickly delivered with minimal acute and/or chronic toxicity. Despite these successes, there does not seem to be any obvious im-pact on overall survival. Continued investigation of adju-vant systemic therapies with novel agents is warranted in these patients. Until improvements in prognosis are documented from such therapies, sphincter-preserving local excision with adjuvant local-regional radiation seems to be an acceptable treatment option for the majority of patients with anal-rectal melanoma.
Supported in part by grant no. CA 06294 awarded by the National Cancer Institute, United States Department of Health and Human Services, Bethesda, MD.
1. Cooper PH, Mills SE, Allen MS: Malignant melanoma of the anus: Report of 12 patients and analysis of 255 additional cases. Dis Colon Rectum 25: 693-703, 1982[Medline] 2. Goldman S, Glimelius B, Påhlman L: Anorectal malignant melanoma in Sweden: Report of 49 patients. Dis Colon Rectum 33: 874-877, 1990[CrossRef][Medline] 3. Slingluff CL, Vollmer RT, Seigler HF: Anorectal melanoma: Clinical characteristics and results of surgical management in twenty-four patients. Surgery 107: 1-9, 1990[Medline]
4. Ross M, Pezzi C, Pezzi T, et al: Patterns of failure in anorectal melanoma. Arch Surg 125: 313-316, 1990 5. Brady MS, Kavolius JP, Quan SHQ: Anorectal melanoma: A 64-year experience at Memorial Sloan-Kettering Cancer Center. Dis Colon Rectum 38: 146-151, 1995[CrossRef][Medline] 6. Konstadoulakis MM, Ricaniadis N, Walsh D, et al: Malignant melanoma of the anorectal region. J Surg Oncol 58: 118-120, 1995[Medline] 7. Luna-Perez P, Rodriguez DF, Macouzet JG, et al: Anorectal malignant melanoma. Surg Oncol 5: 165-168, 1996[Medline] 8. Roumen RMH: Anorectal melanoma in the Netherlands: A report of 63 patients. Eur J Surg Cancer 22: 598-601, 1996 9. Harris EK, Albert A: Survivorship Analysis for Clinical Studies. New York, NY, Marcel Dekker, 1991, pp 5-125 10. Altman DG: Practical Statistics for Medical Research. London, United Kingdom, Chapman and Hall, 1991
11. Quan SHQ, Deddish MR: Noncutaneous melanoma: Malignant melanoma of the anorectum. CA Cancer J Clin 16: 111-114, 1966 12. Wanebo HJ, Woodruff JM, Farr GH, et al: Anorectal melanoma. Cancer 47: 1891-1900, 1981[CrossRef][Medline] 13. Thibault C, Sagar P, Nivatvongs S, et al: Anorectal melanoma: An incurable disease? Dis Colon Rectum 40: 661-668, 1997[CrossRef][Medline] 14. Siegel B, Cohen D, Jacob ET: Surgical treatment of anorectal melanomas. Am J Surg 146: 336-338, 1983[CrossRef][Medline] 15. Bentzen SM, Overgaard J, Thames HD, et al: Clinical radiobiology of malignant melanoma. Radiother Oncol 16: 169-182, 1989[CrossRef][Medline] Submitted March 1, 2002; accepted July 31, 2002.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 statistic or with Fisher’s exact test, as appropriate.
