Mar 28, 2011 - Texas MD Anderson Cancer Center, Houston, Texas. Cancer. October 15, 2011 ..... these results call into q
Original Article
Sphincter-Sparing Local Excision and Hypofractionated Radiation Therapy for Anorectal Melanoma A 20-Year Experience Patrick Kelly, MD, PhD1; Gunar K. Zagars, MD1; Jancie N. Cormier, MD, MPH2; Merrick I. Ross, MD2; and B. Ashleigh Guadagnolo, MD, MPH1
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 2008. 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 C 2011 American Cancer Society. associated with an increased risk of lymphedema. Cancer 2011;117:4747–55. V KEYWORDS: anorectal melanoma, radiation therapy, sphincter preservation, radiation complications.
Anorectal melanoma is a rare malignancy comprising 4
Ulceration No Yes
LN disease No Yes
No. of LNs 1 >1
RT dose, Gy £30 >30
RT field extent Primary only Primary and LN
Adjuvant chemotherapy No Yes
Date of treatment 1989-2000 2001-2009
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
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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.
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Original Article
(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
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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 experiences6,8,11-13,16,17,19 and 2 larger, population-based studies14,15 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 Cancer
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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
P
DSS, %
P
Characteristic
No. of Patients (%)
OS, %
Entire cohort
55 (100)
30
28 (52) 26 (48)
19 41
.63
19 46
.17
19 (35) 35 (65)
30 29
.90
30 29
.98
41 (76) 13 (24)
32 16
.70
34 16
.53
18 (38) 29 (62)
32 27
.28
37 27
.15
20 (36) 34 (64)
39 22
.15
43 23
.13
43 (79) 11 (21)
37 0
.008
40 0
.004
20 (78) 6 (22)
18 0
.009
18 0
.009
50 (93) 4 (7)
32 0
.03
34 0
.02
15 (28) 39 (72)
46 27
.66
46 29
.79
31 (57) 23 (43)
34 24
.75
37 24
.39
21 (39) 33 (61)
35 24
.55
35 27
.65
32
Age, y £64 >64
Sex Men Women
Site of primary Anus Rectum
Thickness of primary, mm £4 >4
Ulceration No Yes
LN disease No Yes
No. of LNs 1 >1
RT dose, Gy £30 >30
RT field Primary only Primary and LN
Adjuvant chemotherapy No Yes
Date of treatment 1989-2000 2001-2009
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
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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
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Original Article 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
APR
a
Local Recurrencea
Reference
Location/ Center
No. of Patients/ Total No.
%
5-Year OS, %
No. of Patients/ Total No.
%
5-Year OS, %
Ross 19902 Goldman 199020 Slingluff 19903 Konstadoulakis 199521 Luna-Perez 19965 Roumen 199622 Weyandt 20037 Pessaux 20048 Yeh 200611 Belli 200913 Zhang 201016 Zhou 201017 Total Current study
MDACC Stockholm Duke University Roswell Park Mexico City Netherlands Wurtzberg Gustave Roussy MSKCC Milan Beijing Guangxi
7/12 9/18 7/7 3/6 1/1 12/16 5/8 10/21 7/27 8/18 11/17 6/15c 91/164 45/54
58 50 100 50 100 75 62 47 26 46 65 40 52 17
3 — — 0 0 35 — 19 35b 19 23 16
4/14 4/15 3/6 2/9 5/6 1/18 1/5 2/9 5/19 0/13 5/32 4/39 36/185
29 27 50 22 83 6 20 22 26 0 16 10 19
0 — 25 — 0 25 — 33 34b 19 24 30
MDACC
30
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.23-25 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%.23-25 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
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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.24-26 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
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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.24-26 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.
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