Sphincter-Sparing Local Excision and Hypofractionated Radiation Therapy for Anorectal Melanoma

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1 Sphincter-Sparing Local Excision and Hypofractionated Radiation Therapy for Anorectal Melanoma A 20-Year Experience Patrick Kelly, MD, PhD 1 ; Gunar K. Zagars, MD 1 ; Jancie N. Cormier, MD, MPH 2 ; Merrick I. Ross, MD 2 ; and B. Ashleigh Guadagnolo, MD, MPH 1 BACKGROUND: Anorectal melanoma is a rare disease with a poor prognosis. Because survival is determined by distant failure, many centers have adopted sphincter-sparing excision for primary tumor control. However, this approach is associated with high rates of local failure (50%). In this study, the authors report their 20-year experience with sphincter-sparing excision combined with radiation therapy (RT) for the treatment of localized anorectal melanoma. METHODS: The authors reviewed the records of 54 patients with localized anorectal melanoma who were treated at the University of Texas MD Anderson Cancer Center from 1989 to All patients underwent definitive local excision with or without sentinel lymph node biopsy or lymph node dissection. RT (25-36 grays in 5-6 fractions) was delivered to extended fields that targeted the primary site and draining pelvic/inguinal lymphatics in 39 patients and to limited fields that targeted only the primary site in 15 patients. RESULTS: The 5-year rates of local control (LC), lymph node control (NC), and sphincter preservation were 82%, 88%, and 96%, respectively. However, because of the high rate of distant metastasis, the overall survival (OS) rate at 5 years was only 30%. Although there were no significant differences in LC, NC, or OS based on RT field extent, patients who received extended-field RT had higher rates of lymphedema than patients who received limited-field RT. CONCLUSIONS: The current results indicated that combined sphincter-sparing local excision and RT is a well tolerated approach that provides effective LC for patients with anorectal melanoma. Inclusion of the inguinal lymph node basins in the RT fields did not improve outcomes and was associated with an increased risk of lymphedema. Cancer 2011;117: VC 2011 American Cancer Society. KEYWORDS: anorectal melanoma, radiation therapy, sphincter preservation, radiation complications. Anorectal melanoma is a rare malignancy comprising <1% of all anal and rectal cancers. 1 Although approximately 70% of patients with anorectal melanoma present with no detectable disease outside of the pelvis, the vast majority of patients die of distant metastasis within 2 to 3 years of diagnosis This predominant pattern of distant failure has lead to controversy about the therapeutic approach for the primary anorectal lesion. Early studies argued for abdominoperineal resection (APR), suggesting that this radical procedure was associated with improved outcomes. 4,7,18 More recent studies argue for sphincter-sparing wide local excision (WLE), because this approach appears to provide survival outcomes equivalent to those achieved by APR with reduced surgical morbidity and the potential for improved quality of life without a colostomy. 6,8,11-13,16,17,19 Nevertheless, the rates of local recurrence after WLE reported in these studies approach 50%. 6,8,11-13,16,17,19 Because local recurrence of anorectal melanoma can be morbid and generally requires repeat surgery (often APR), this high rate of local recurrence has the potential to compromise the goals of doing limited surgery. In 1990, The University of Texas MD Anderson Cancer Center (MDACC) adopted a sphincter-sparing WLE approach for patients with localized anorectal melanoma. With the goal of reducing the risk of local recurrence, adjuvant hypofractionated radiation therapy (RT) was added. We previously reported our initial experience with this combination Corresponding author: B. Ashleigh Guadagnolo, MD, MPH, Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030; Fax: (713) ; aguadagn@mdanderson.org 1 Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; 2 Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas DOI: /cncr.26088, Received: October 27, 2010; Revised: January 3, 2011; Accepted: February 2, 2011, Published online March 28, 2011 in Wiley Online Library (wileyonlinelibrary.com) Cancer October 15,

2 Table 1. Patient and Tumor Characteristics Characteristic No. of Patients (%) Median [Range] Sex Men 19 Women 35 Age, y 61 [33-89] Follow-up, mo 36 [11-192] Location of primary melanoma Anus 41 (76) Rectum 13 (24) Melanoma thickness, mm 5 [0.3-35] Patients with LN involvement 11 (20) Type of surgery Sphincter-sparing excision alone 28 (52) Sphincter-sparing excision and SLNB 16 (27) Sphincter-sparing excision and inguinal LND 6 (11) Sphincter-sparing excision and inguinal/pelvic LND 3 (6) Sphincter-sparing excision, SLNB, and inguinal LND 1 (2) Timing of radiation Postoperative 52 (96) Preoperative 2 (4) Radiation extent Primary only 39 (72) Primary and LN 15 (28) Chemotherapy/biochemotherapy Adjuvant 23 (43) Neoadjuvant 5 (9) LN indicates lymph node; SLNB, sentinel lymph node biopsy; LND, lymph node dissection. approach of WLE and hypofractioned RT in 23 patients with anorectal melanoma. 6 That analysis demonstrated a 5 year local/regional control rate of 74% with acceptable toxicity, suggesting that this sphincter-sparing approach was an appropriate therapeutic option. In the current study, we update our 20-year experience with sphinctersparing surgery and hypofractioned RT for anorectal melanoma. The primary objective of the study was to evaluate the effectiveness of this approach as local therapy. In addition, we reviewed the outcomes and complications associated with this approach in an effort to refine our technique and improve our care for patients with anorectal melanoma. MATERIALS AND METHODS Patients were identified through a search of the MDACC Department of Radiation Oncology databases. A detailed review of medical records commenced after approval from our institution s internal review board. Between 1989 and 2008, 56 patients with primary, invasive anorectal melanoma who were managed with sphincter-sparing local excision and adjuvant RT were identified (Table 1). Two patients were excluded from the analysis, including 1 patient who had metastasis to the liver and lungs at the time of presentation and 1 patient who had lymph node disease and was treated with systemic therapy only. The remaining 54 patients who underwent sphincter-sparing surgery and received adjuvant RT with curative intent comprised the cohort for this analysis. Twenty-three of those patients were included in the previous analysis. 6 Patient, Tumor, and Treatment Characteristics The patients ranged in age from 33 years to 89 years (median, 61 years), and there were 19 men and 35 women. All patients underwent a complete history, physical examination, and appropriate radiologic examination to assess for the presence of distant metastases at the time of presentation. The location of the primary tumor was determined by the treating surgeon at the time of presentation. Lesions originating above the dentate line were considered rectal melanomas. Lesions between the dentate line and the anal verge and lesions in the perianal skin within 3 cm of the anal verge were considered anal melanomas. The majority of patients (n ¼ 41; 76%) had 4748 Cancer October 15, 2011

3 Role of Radiation in Anorectal Melanoma/Kelly et al melanomas located in the anus, and the remaining patients had melanomas located in the rectum (n ¼ 13). Of the 54 patients, 44 (81%) had undergone an incisional biopsy at an outside institution, and 10 patients presented after excisional biopsy. Twenty-nine patients had no gross residual disease at the primary site upon presentation to MDACC, whereas 25 patients had gross residual disease. Five patients who had undergone a prereferral excisional biopsy with no gross residual disease at presentation to MDACC were evaluated by a surgical oncologist, who assessed their previous surgical procedure as adequate and referred them for immediate postoperative RT. Of the remaining 49 patients, 47 underwent an additional sphincter-sparing excision followed by RT, and 2 were referred for preoperative RT followed by excision. Thus, in total, 52 patients underwent surgical excision followed by postoperative RT, and 2 patients received preoperative RT followed by surgical excision. The median tumor thickness was 5 mm (range, mm). For the purposes of the current analysis, 4 mm was used to separate the patients into 2 groups, because this cutoff point reflects the distinction between tumors measured with a micrometer (4 mm) and those measured grossly with a ruler. Upon histopathologic review, ulceration was present in 34 patients (64%). The primary tumor margins after sphincter-sparing surgery were microscopically negative in 45 patients (83%) and positive in 9 patients (17%). Seventeen patients underwent sentinel lymph node biopsy for pathologic assessment of their regional lymph node basins, and 9 patients underwent lymph node dissection. Of the 17 patients who underwent sentinel lymph node biopsy, 3 patients had lymph node involvement. One of these 3 patients went on to undergo completion inguinal lymph node dissection. Of the 10 patients who underwent lymph node dissection (including the 1 patient who underwent lymph node dissection after sentinel lymph node biopsy), 7 underwent inguinal lymph node dissection alone, and 3 underwent pelvic and inguinal lymph node dissections. Of these 10 patients, 9 had confirmed metastatic lymph node disease. Thus, 11 patients (21%) had regional lymph node involvement identified, and 43 patients (79%) had no lymph node disease identified. Five patients had only 1 lymph node involved, and 6 patients had more than 1 tumor-involved lymph node. Location of the involved lymph nodes differed by primary tumor location. Of the 8 patients who had primary anal melanoma, 5 had involvement of the inguinal lymph nodes, and 3 had involvement of the inguinal and pelvic lymph nodes. Of the 3 patients who had primary rectal melanoma, 2 had involvement of the pelvic lymph nodes, and 1 had involvement of the inguinal and pelvic lymph nodes. The median size of the tumor deposit within the lymph nodes was 2.0 cm (range, cm) for the entire cohort. For patients who had undergone sentinel lymph node biopsy, the median tumor deposit size was 1.7 cm (range, cm). For patients who had undergone lymph node dissection, the median tumor deposit size was 3 cm (range, cm). Three patients had evidence of extranodal extension. After sphincter-sparing excision of the primary tumor with or without lymph node surgery (or before in 2 patients), RT was administered to the primary site only in 15 patients and to the primary site and regional lymph node basins (either unilateral or bilateral groins, as deemed appropriate at the time of treatment) in 39 patients. The RT dose administered was 30 grays (Gy) given in 5 fractions (600 centigrays [cgy] per fraction) and delivered twice weekly (Monday/Thursday or Tuesday/Friday) to 48 patients. Another 4 patients received the same RT dose and fractionation schedule along with a 6-Gy boost in 1 fraction to the primary tumor site. Two patients received preoperative RT with a dose and fractionation regimen of 25 Gy in 5 fractions (500 cgy per fraction) delivered daily over 1 week. Five patients received preoperative systemic chemotherapy, and 23 patients received postoperative systemic chemotherapy. Eighteen patients received biochemotherapy, which consisted of combined cisplatin, vinblastine, dacarbazine, interferon alpha-2b, and interleukin-2. Three patients received cisplatin-based chemotherapy without interferon alpha-2b or interleukin-2, and the 5 remaining patients received nonstandard investigational systemic therapy. Follow-Up and Statistical Analysis The median follow-up of the patients who remained alive at last contact was 36 months (range, months). Disease relapse was defined as any clinical or radiographic evidence of tumor recurrence. Regional relapse was scored if there was any evidence of lymph node, dermal, subcutaneous, or soft tissue tumor recurrence within or around the dissected lymph node basin. Local control, lymph node control, disease-free survival, distant metastasis-free survival (DMFS), disease-specific survival (DSS), complication-free survival, and overall survival (OS) curves were calculated using the Kaplan-Meier method, and tests of significance were based on the log-rank statistic. Differences between proportions for categorical variables were Cancer October 15,

4 Figure 1. These Kaplan-Meier curves illustrate overall survival (solid black line) and disease-specific survival (black dashed line) for patients with anorectal melanoma. Vertical tick marks indicate censored observations. analyzed using the chi-square statistic or the Fisher exact test, as appropriate. Correlations between variables were assessed using the Spearman correlation coefficient. Surgical and RT-related surgical complications were scored as follows: mild (self-limited and requiring no treatment), moderate (requiring conservative medical management), or severe (requiring surgical intervention or hospitalization). Sphincter function was graded as good, fair (occasional leakage), or poor (incontinence requiring daily pad use or surgical correction). RESULTS Survival Outcomes and Predictors At the time of final analysis, 39 patients (72%) had experienced disease relapse, and 42 patients (78%) had died. The median OS was 29 months. Melanoma was most common cause of death, accounting for 88% of the deaths in this population. Consequently, DSS closely approximated OS (Fig. 1), and the actuarial DSS and OS rates were 60% and 59%, respectively, at 2 years and 32% and 30%, respectively, at 5 years. Univariate analysis of the clinicopathologic factors associated with disease outcomes revealed that the presence of lymph node disease was predictive of inferior DSS (P ¼.004) (Fig. 2) and OS (P ¼.008) (Table 2). In addition, the presence of multiple involved lymph nodes predicted worse outcomes compared with having a single involved lymph node (Table 2). On multivariate analysis, the only factor that was significantly predictive for DSS and OS was lymph node involvement (P ¼.03 and P ¼.04, respectively). Other factors, such as age, sex, primary Figure 2. These Kaplan-Meier curves illustrate disease-specific survival for patients with (black dashed line) and without (solid black line) lymph node metastasis at the time of presentation. Disease-specific survival was significantly better among patients without lymph node metastasis (P ¼.004; log-rank test).vertical tick marks indicate censored observations. tumor site, lesion thickness, the presence of ulceration, date of treatment ( vs ), and radiation of the draining lymphatics, were not associated with disease outcome (Table 2.) Patterns of Failure The predominant pattern of failure was distant metastases in 70% of patients. The median time to the development of distant metastasis was 10 months (range, 1-87 months), with 59% of patients reporting distant disease at 2 years and 72% reporting distant disease at 5 years (Fig. 3). The most common site of initial distant metastasis was lung (n ¼ 19), followed by liver (n ¼ 7), bone (n ¼ 3), brain (n ¼ 2), and bowel (n ¼ 1). In addition, 5 patients developed distant metastases in multiple organs simultaneously. Although age, RT dose, lymph node involvement, and the number of involved lymph nodes all were associated with DMFS on univariate analysis (Table 3), on multivariate analysis, only lymph node involvement was associated significantly with an increased risk of distant metastasis (P ¼.02). Nine patients (17%) experienced recurrence at the site of the primary tumor. Overall, the local disease control rate was 85% at 2 years and 82% at 5 years (Fig. 3). No adverse prognostic factors were identified for local control on univariate or multivariate analysis. Treatment included local salvage with a repeat wide local excision in 4 patients, abdominoperineal resection in 2 patients, chemotherapy alone in 2 patients, and proctectomy with coloanal anastomosis in 1 patient. Thus, only 2 patients 4750 Cancer October 15, 2011

5 Role of Radiation in Anorectal Melanoma/Kelly et al Table 2. Univariate Analysis of Factors Potentially Affecting Actuarial Rates of Local Control and Distant Metastasis-Free Survival at 5 Years Characteristic No. of Patients (%) LC, % P DMFS, % P Entire cohort 55 (100) Age, y (52) >64 26 (48) Sex Men 19 (35) Women 35 (65) Site of primary Anus 41 (76) Rectum 13 (24) Thickness of primary, mm 4 18 (38) >4 29 (62) Ulceration No 20 (36) Yes 34 (64) LN disease No 43 (79) Yes 11 (21) 91 0 No. of LNs 1 20 (78) 94 a <.0001 >1 6 (22) 83 0 RT dose, Gy (93) >30 4 (7) RT field extent Primary only 15 (28) Primary and LN 39 (72) Adjuvant chemotherapy No 31 (57) Yes 23 (43) Date of treatment (39) (61) LC indicates local control; DMFS, distant metastasis-free survival; LN, lymph node; RT, radiation therapy; Gy, grays. a At 2 years. in the entire cohort of 54 patients ultimately required a permanent colostomy. Of the 52 patients who had intact sphincters, sphincter function was good in 50 patients and fair in 2 patients. No patient in this cohort required daily pad use or surgical intervention for fecal incontinence. Six patients experienced lymph node relapse, and the actuarial rate of lymph node relapse was 12% at 2 years and beyond. It is noteworthy that no patient experienced an isolated lymph node relapse, because 4 patients had a lymph node relapse coincident with or after they developed a distant relapse, and 2 patients had a lymph node relapse with a coincident local recurrence. Of the 6 patients who relapsed, 1 patient had undergone inguinal lymph node dissection, which revealed the presence of melanoma in 5 of 19 lymph nodes, and then received adjuvant inguinal RT; 1 patient had undergone a negative sentinel lymph node biopsy and then received adjuvant inguinal RT; 3 patients had undergone no inguinal surgery but received adjuvant inguinal RT; and 1 patient had neither undergone inguinal surgery nor received adjuvant inguinal RT. Cancer October 15,

6 (either scrotal or lower extremity edema) after RT, including 6 patients who had mild edema and 3 patients who had moderate edema. Edema was observed only in patients who had received extended-field RT. All patients who had moderate edema had undergone inguinal lymph node dissection in addition to receiving RT. Figure 3. These Kaplan-Meier curves illustrate local control (solid black line), lymph node control (gray dashed line), and distant metastasis-free survival (black dashed line) for patients with anorectal melanoma. Vertical tick marks indicate censored observations. Survival After Relapse Two (4%) of the patients who developed recurrent disease were eligible to undergo additional surgical treatment or salvage treatment, whereas 37 patients (69%) were not. The median survival after relapse was 11 months. Complications Treatment generally was well tolerated. In the 49 patients who underwent surgery at MDACC, surgical complications were uncommon. Three patients (6%) had nonlifethreatening infections that required antibiotics, and 1 patient had postoperative bleeding that required surgical intervention. Acute RT-related dermatitis was documented in most patients, particularly in the perianal area and the inguinal folds. This reaction generally was selflimited; however, 1 patient did require admission for pain control. Late RT-associated complications were documented in 26 patients (48%), including 16 mild complications, 9 moderate complications, and 1 severe complication. The most common complication was proctitis (n ¼ 17), followed by scrotal edema (n ¼ 7), combined proctitis and edema (n ¼ 2), unilateral lymphedema (n ¼ 1), and dyspareunia (n ¼ 1). Of the patients who experienced proctitis, 11 patients had asymptomatic, self-limited rectal bleeding; 5 patients had rectal bleeding that resolved with medical management; and 1 patient experienced rectal bleeding that required hospitalization and surgical intervention. The incidence of proctitis was no different between those who received limited RT versus extended (inguinal) RT. Nine patients experienced lymphedema DISCUSSION In the late 1980s, recognition of the universally poor outcomes of patients with anal and rectal melanoma challenged physicians at MDACC to reconsider their radical approach to local therapy for this disease. 2 The traditional APR was abandoned in favor of a sphincter-sparing approach of WLE followed by hypofractionated RT. In the current report, we present our 20-year experience with this treatment approach, demonstrating that combined surgical WLE and adjuvant RT provides good local disease control with acceptable side effects. Several single-institution experiences 6,8,11-13,16,17,19 and 2 larger, population-based studies 14,15 have reported equivalent survival outcomes for patients with anorectal melanoma who underwent WLE or APR. Thus, many have argued that WLE should be the standard local therapy for these patients, because it provides a sphincter-sparing approach and reduced surgical morbidity. 9,10,14,15 However, the rates of local recurrence after WLE in those studies approached 50%. This high rate of recurrence has led some to question whether WLE alone is adequate local therapy for patients with anorectal melanoma, because it exposes many patients to the morbidity of local recurrence and salvage surgery as well as the risks of persistent local disease. 6,7,16 The combination of WLE and hypofractionated RT used in the current study resulted in a crude local recurrence rate of only 17% and was associated with a high rate of sphincter preservation and generally good sphincter function. Take together, these findings suggest that adjuvant RT may improve upon WLE for local therapy. Despite the favorable local control rates, the overall prognosis for patients with anorectal melanoma remains extremely poor. Distant relapse remains the predominant pattern of failure and the primary determinant of patient survival in all studies. The 5-year OS rate of 30% and the DSS rate of 32% observed in our study were similar to the survival rates reported in recent analyses and remain largely unchanged compared with historic series (Table 4). 2,3,9,10,18,20-22 In addition, despite advances in imaging and systemic therapy, there was no detectable 4752 Cancer October 15, 2011

7 Role of Radiation in Anorectal Melanoma/Kelly et al Table 3. Univariate Analysis of Factors Potentially Affecting Actuarial Rates of Overall Survival and Disease-Specific Survival at 5 Years Characteristic No. of Patients (%) OS, % P DSS, % P Entire cohort 55 (100) Age, y (52) >64 26 (48) Sex Men 19 (35) Women 35 (65) Site of primary Anus 41 (76) Rectum 13 (24) Thickness of primary, mm 4 18 (38) >4 29 (62) Ulceration No 20 (36) Yes 34 (64) LN disease No 43 (79) Yes 11 (21) 0 0 No. of LNs 1 20 (78) >1 6 (22) 0 0 RT dose, Gy (93) >30 4 (7) 0 0 RT field Primary only 15 (28) Primary and LN 39 (72) Adjuvant chemotherapy No 31 (57) Yes 23 (43) Date of treatment (39) (61) OS indicates overall survival; DSS, disease-specific survival; LN, lymph node; RT, radiation therapy; Gy, grays. difference in outcomes between patients who were treated before or after 2001 in this study. When analyzed specifically, we observed no association between the receipt of systemic therapy and outcome. However, because the decision to offer adjuvant therapy was made based on the patient s risk of distant recurrence, the benefits of therapy probably were offset by patient selection. Nevertheless, these data suggest that further improvement is needed. In 1 of the largest series published to date on melanoma of the anus and rectum, we sought to determine which clinicopathologic characteristics were associated with various outcomes. The presence of lymph node metastasis at the time of diagnosis was associated with poor DMFS, DSS, and OS. Greater than 90% of patients who had lymph node metastasis at presentation went on to develop distant metastasis; the median OS for this subgroup was only 20 months, and there were no survivors at 5 years. This finding is consistent with previous reports, 3,8,13,15-17 including a recent analysis of the National Cancer Institute s Surveillance, Epidemiology, and End Results Program, in which 143 patients with anorectal melanoma had lymph node metastasis Cancer October 15,

8 Table 4. Local Recurrence and Overall Survival Rates for Anorectal Melanoma After Abdominoperineal Resection or Wide Local Excision Without Adjuvant Radiation Therapy WLE Local Recurrence a APR Local Recurrence a Reference Location/ Center No. of Patients/ Total No. % 5-Year OS, % No. of Patients/ Total No. % 5-Year OS, % Ross MDACC 7/ / Goldman Stockholm 9/ /15 27 Slingluff Duke University 7/ / Konstadoulakis Roswell Park 3/ /9 22 Luna-Perez Mexico City 1/ / Roumen Netherlands 12/ / Weyandt Wurtzberg 5/8 62 1/5 20 Pessaux Gustave Roussy 10/ / Yeh MSKCC 7/ b 5/ b Belli Milan 8/ / Zhang Beijing 11/ / Zhou Guangxi 6/15 c / Total 91/ / Current study MDACC 45/ WLE indicates wide local excision; APR, abdominoperineal resection; OS, overall survival; MDACC, The University of Texas MD Anderson Cancer Center; MSKCC, Memorial Sloan-Kettering Cancer Center. a Crude rate of local recurrence. b Disease-specific survival. c One patient received adjuvant radiation therapy. associated with a median OS of only 17 months and an OS rate of 9.8% at 5 years. 14 Those findings contrast with a report from the Memorial Sloan-Kettering Cancer Center in which the presence of lymph node metastasis was not associated with poor survival. 11 In that series, patients with lymph node disease (n ¼ 9) reportedly had a 28% DSS rate at 5 years, which was significantly higher than other reports. The finding that lymph node metastasis is associated with poor survival is consistent with what is known about prognostic factors for patients with cutaneous melanoma However, in patients with cutaneous melanoma who have metastatic disease to regional lymph nodes, the overall incidence of metastatic progression is approximately 50%, and the 5-year OS rate is approximately 30% Therefore, it appears that the presence of lymph node metastasis in patients with anorectal melanoma may be an even stronger predictor of a poor outcome than that observed in cutaneous melanomas. Other factors, such as tumor size, primary tumor thickness, the presence of ulceration, radiation dose, and the receipt of chemotherapy, were not associated with survival in our analysis. However, the cohorts may have been too small to detect such differences. In addition, comprehensive RT of the regional lymphatics, including the inguinal lymph node basins, was not associated with an improvement in DMFS or patient survival. Moreover, the rates of local recurrence and lymph node recurrence were not significantly different with respect to RT field extent. Although the low rates of local and regional failure preclude a conclusive analysis of these outcomes with respect field size, taken together, these results call into question the therapeutic benefit of comprehensive lymph node RT for patients with anorectal melanoma. Although it was not possible to detect a difference in local control, regional control, or survival between comprehensive RT and limited-field RT, a significant difference in toxicity was observed between the 2 approaches. The most common toxicity, radiation proctitis, generally was self-limited. The incidence of radiation proctitis was not significantly different in patients who received comprehensive RT and those who received limited-field RT. However, 23% of patients who received comprehensive RT developed symptomatic scrotal/lower extremity lymphedema, which was not observed in patients who received limited-field RT. This finding is consistent with previously reported series of cutaneous melanoma in which patients received inguinal RT Because comprehensive RT appears to be associated with additional side effects in the absence of detectable clinical benefit, our group no longer recommends adjuvant RT to the inguinal region for all patients. Instead, inguinal RT is reserved only for the purpose of involved lymph node basin control in patients who are at very high risk for 4754 Cancer October 15, 2011

9 Role of Radiation in Anorectal Melanoma/Kelly et al morbid lymph node relapse, such as those with a combination of large lymph node burden and extranodal extension of disease into the soft tissues In conclusion, anorectal melanoma is a rare disease with a poor prognosis. Local, sphincter-sparing excision of the primary tumor followed by hypofractionated RT offers effective local therapy that is well tolerated. Therefore, it is our clinical practice to recommend adjuvant RT after patients undergo negative-margin surgical resection of a primary anorectal melanoma. Because the outcome for patients with anorectal melanoma is determined by distant disease recurrence, further progress in the care of these patients likely will come from improved systemic therapies that address the risk of distant disease. FUNDING SOURCES No specific funding was disclosed. CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures. REFERENCES 1. Chang AE, Karnell LH, Menck HR. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer. 1998;83: Ross M, Pezzi C, Pezzi T, Meurer D, Hickey R, Balch C. Patterns of failure in anorectal melanoma. A guide to surgical therapy. Arch Surg. 1990;125: Slingluff CL Jr, Vollmer RT, Seigler HF. Anorectal melanoma: clinical characteristics and results of surgical management in 24 patients. Surgery. 1990;107: Brady MS, Kavolius JP, Quan SH. Anorectal melanoma. A 64-year experience at Memorial Sloan-Kettering Cancer Center. Dis Colon Rectum. 1995;38: Luna-Perez P, Rodriguez DF, Macouzet JG, Labastida S. Anorectal malignant melanoma. Surg Oncol. 1996;5: Ballo MT, Gershenwald JE, Zagars GK, et al. Sphinctersparing local excision and adjuvant radiation for anal-rectal melanoma. J Clin Oncol. 2002;20: Weyandt GH, Eggert AO, Houf M, Raulf F, Brocker EB, Becker JC. Anorectal melanoma: surgical management guidelines according to tumour thickness. Br J Cancer. 2003; 89: Pessaux P, Pocard M, Elias D, et al. Surgical management of primary anorectal melanoma. Br J Surg. 2004;91: Yap LB, Neary P. A comparison of wide local excision with abdominoperineal resection in anorectal melanoma. Melanoma Res. 2004;14: Droesch JT, Flum DR, Mann GN. Wide local excision or abdominoperineal resection as the initial treatment for anorectal melanoma? Am J Surg. 2005;189: Yeh JJ, Shia J, Hwu WJ, et al. The role of abdominoperineal resection as surgical therapy for anorectal melanoma. Ann Surg. 2006;244: Ramakrishnan AS, Mahajan V, Kannan R. Optimizing local control in anorectal melanoma. Indian J Cancer. 2008;45: Belli F, Gallino GF, Lo Vullo S, Mariani L, Poiasina E, Leo E. Melanoma of the anorectal region: the experience of the National Cancer Institute of Milano. Eur J Surg Oncol. 2009; 35: Iddings DM, Fleisig AJ, Chen SL, Faries MB, Morton DL. Practice patterns and outcomes for anorectal melanoma in the USA, reviewing 3 decades of treatment: is more extensive surgical resection beneficial in all patients? Ann Surg Oncol. 2009;17: Nilsson PJ, Ragnarsson-Olding BK. Importance of clear resection margins in anorectal malignant melanoma. BrJSurg. 2010;97: Zhang S, Gao F, Wan D. Abdominoperineal resection or local excision? a survival analysis of anorectal malignant melanoma with surgical management. Melanoma Res. 2010;20: Zhou HT, Zhou ZX, Zhang HZ, Bi JJ, Zhao P. Wide local excision could be considered as the initial treatment of primary anorectal malignant melanoma. Chin Med J (Engl). 2010;123: Wanebo HJ, Woodruff JM, Farr GH, Quan SH. Anorectal melanoma. Cancer. 1981;47: Bullard KM, Tuttle TM, Rothenberger DA, et al. Surgical therapy for anorectal melanoma. J Am Coll Surg. 2003;196: Goldman S, Glimelius B, Pahlman L. Anorectal malignant melanoma in Sweden. Report of 49 patients. Dis Colon Rectum. 1990;33: Konstadoulakis MM, Ricaniadis N, Walsh D, Karakousis CP. Malignant melanoma of the anorectal region. J Surg Oncol. 1995;58: Roumen RM. Anorectal melanoma in the Netherlands: a report of 63 patients. Eur J Surg Oncol. 1996;22: Chang DT, Amdur RJ, Morris CG, Mendenhall WM. Adjuvant radiotherapy for cutaneous melanoma: comparing hypofractionation to conventional fractionation. Int J Radiat Oncol Biol Phys. 2006;66: Ballo MT, Ross MI, Cormier JN, et al. Combined-modality therapy for patients with regional nodal metastases from melanoma. Int J Radiat Oncol Biol Phys. 2006;64: Burmeister BH, Mark Smithers B, Burmeister E, et al. A prospective phase II study of adjuvant postoperative radiation therapy after nodal surgery in malignant melanoma Trans-Tasman Radiation Oncology Group (TROG) Study Radiother Oncol. 2006;81: Ballo MT, Bonnen MD, Garden AS, et al. Adjuvant irradiation for cervical lymph node metastases from melanoma. Cancer. 2003;97: Cancer October 15,