Biochemotherapy in patients with metastatic ... - Wiley Online Library

1478

Biochemotherapy in Patients with Metastatic Anorectal Mucosal Melanoma Kevin B. Kim, M.D.1 Angela M. Sanguino, M.D.1 Cynthia Hodges, A.P.N.1 Nicholas E. Papadopoulos, M.D.1 Omar Eton, M.D.1 Luis H. Camacho, M.D.1 Lyle D. Broemeling, Ph.D., M.S.2 Marcella M. Johnson, M.S.2 Matthew T. Ballo, M.D.3 Merrick I. Ross, M.D.4 Jeffrey E. Gershenwald, M.D.4 Jeffrey E. Lee, M.D.4 Paul F. Mansfield, M.D.4 Victor G. Prieto, M.D., Ph.D.5 Agop Y. Bedikian, M.D.1 1

Department of Melanoma Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston Texas.

2

Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston Texas.

3

Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston Texas.

4

Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston Texas.

BACKGROUND. Patients with metastatic anorectal melanoma generally have an unfavorable prognosis, but no effective systemic therapy has been reported. METHODS. The authors retrospectively evaluated the medical records of all patients with metastatic anorectal melanoma treated with biochemotherapy between January 1991 and December 2001 at the University of Texas M. D. Anderson Cancer Center (Houston, TX). RESULTS. The search yielded 18 patients. Of these patients, 14 had undergone treatment with cisplatin (CDDP), vinblastine (VB), dacarbazine (DTIC), interferon alpha-2b (IFN), and interleukin 2 (IL-2); 2 had undergone treatment with CDDP, VB, DTIC, and IFN; 1 had undergone treatment with CDDP, IFN, and IL-2; and 1 had undergone treatment with CDDP, VB, temozolomide, IFN, and IL-2. All IL-2 treatments were administered intravenously. The median follow-up time was 12.2 months (range, 3.5– 43.7 months). Eight patients (44%) had major responses, including two (11%) complete responses (CRs). Three patients were lost to followup evaluation after the completion of treatment. The median time to progression among the 15 remaining patients was 6.2 months. Four patients, including 1 with a CR, were alive at their last documented follow-up visits (survival: 14.0, 20.7, 31.3, and 43.7 months, respectively). The median overall survival was 12.2 months. Among 13 patients who received biochemotherapy as first-line systemic therapy, 6 patients (46%) had major responses, including two (15%) CRs. The median time to progression for this group was 6.2 months, and the median overall survival was 12.9 months. CONCLUSIONS. Biochemotherapy had substantial activity against metastatic anorectal melanoma and should be considered for use in the treatment of metastatic disease from primary anorectal melanoma. Cancer 2004;100:1478 – 83. © 2004 American Cancer Society. KEYWORDS: biochemotherapy, metastatic, anorectal, mucosal, melanoma.

5

Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston Texas.

The authors thank Ms. Lucy Gignac for her secretarial assistance. Address for reprints: Kevin B. Kim, M.D., Department of Melanoma Medical Oncology, Unit 430, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030; Fax: (713) 745-1046; E-mail: [email protected] Received August 4, 2003; revision received December 2, 2003; accepted January 7, 2004. © 2004 American Cancer Society DOI 10.1002/cncr.20113

A

lthough the anorectal region is the most common mucosal site for primary malignant melanoma, anorectal melanoma is a rare malignancy, accounting for approximately 0.5–1% of all anal canal tumors and approximately 0.2–1% of all melanomas.1– 4 Among all patients with melanoma, the proportion with anorectal melanoma may be relatively higher among darker-skinned populations.5 Anorectal melanoma tends to occur in the sixth decade of life and more commonly in women than in men. In many patients with anorectal melanoma, the correct diagnosis is delayed, as conservative treatment for what are presumed to be hemorrhoids is administered for many months before melanoma is considered as a possibility. As many as 80% of anorectal melanoma lesions lack obvious pigmentation, and approximately 20% are microscopically amelanotic, making their diagnosis even more difficult.6,7

Biochemotherapy for Anorectal Melanoma/Kim et al.

Anorectal melanoma is considered to be an aggressive malignancy, and patients with anorectal melanoma generally have an unfavorable prognosis. The median survival of all patients with anorectal melanoma ranges from 8 months to 23 months from initial diagnosis, and the 5-year overall survival rate ranges from 3% to 22%.3,7–16 Most patients with localized or locoregional disease are surgically treated with either abdominoperineal resection (APR) or local excision (LE) with or without radiation. However, regardless of the type of surgical treatment, most of these patients die of distant metastatic disease within 5 years. The overall survival duration for patients with recurrent disease or distant metastases is quite short. Most series report an overall survival of ⬍ 10 months.3,7,9,10,13,14 To our knowledge, no patient with distant metastatic anorectal melanoma has been reported to have survived for ⬎ 5 years. Despite the high mortality rate associated with anorectal melanoma, no consensus exists regarding the optimal systemic therapy regimen. Reports on the efficacy of systemic therapy are scarce, due to the rarity of the disease. Most are case reports that describe a limited number of patients who underwent systemic therapy, often with missing details regarding treatment regimens and responses to therapy. As a result, the response rates to certain systemic therapy regimens in patients with advanced disease remain unknown. The benefits of systemic therapy are also uncertain. Biochemotherapy has been used to treat advanced metastatic melanoma, mostly in cases of cutaneous origin, and it is associated with the highest response rates among systemic therapy regimens.17–19 The overall response rates range from 40% to 60%, the complete response (CR) rates range from 5% to 20% in most studies, and approximately 10% of patients who undergo interleukin 2 (IL-2)-based therapy survive for ⬎ 5 years.18 Furthermore, biochemotherapy appeared to improve overall and disease-free survival rates compared with chemotherapy alone in a recent Phase III trial.20 Because of the aggressiveness of anorectal melanoma, its early systemic spread, and its poor prognosis, we set out to determine whether biochemotherapy is an effective treatment for patients with advanced anorectal melanoma. Therefore, we performed the current retrospective analysis to evaluate the effectiveness of biochemotherapy in patients with metastatic anorectal melanoma.

MATERIALS AND METHODS Patients with a diagnosis of anorectal melanoma who had been evaluated at The University of Texas M. D.

1479

Anderson Cancer Center (MDACC; Houston, TX) between January 1991 and December 2001 were identified through a search of the institutional patient database. The informed consent requirement was waived by our institutional review board before the analysis was undertaken. Biochemotherapy was defined as systemic therapy that included at least one chemotherapeutic agent and at least one biologic agent (either interferon alpha-2b [IFN] or IL-2) administered during the same cycle. Partial responses (PRs) and CRs were considered major responses. A PR was defined as a reduction of ⱖ 50% in the sum of the products of bidimensional measurements of lesions, and a CR was defined as the disappearance of all clinical evidence of visible tumors. Disease progression was defined as an increase of ⱖ 25% in the sum of the products of bidimensional measurements or the appearance of a new lesion. The time to progression (TTP) and the length of overall survival were measured from the start of biochemotherapy. Actuarial plots for the TTP and overall survival were calculated using the Kaplan–Meier method.21

RESULTS Patients Our database search identified 69 patients treated for anorectal melanoma, 39 of whom had undergone at least 1 systemic treatment at MDACC. Of these 39 patients, 18 had been treated with biochemotherapy for advanced disease. Their medical charts were retrospectively reviewed for data on response to therapy and length of survival. Table 1 summarizes patient characteristics. Two patients who received adjuvant biochemotherapy (cisplatin [CDDP]/vinblastine [VB]/dacarbazine [DTIC]/IL-2/IFN) after inguinal lymph node dissection and 19 patients who received either chemotherapy or cytokine therapy alone were not included in the analysis. Of the 19 patients who received systemic therapy other than biochemotherapy, 2 did not have adequate follow-up visits for the assessment of response. An additional six patients already had received DTIC-based chemotherapy before being evaluated at MDACC and therefore received secondline therapy at MDACC. These six patients did not have any clinical responses to the second-line treatment. Table 2 summarizes the treatment regimens of 11 patients who received first-line therapy other than biochemotherapy at MDACC. Among the 18 patients treated with biochemotherapy, the median serum lactate dehydrogenase (LDH) level was 544 international units (IU) per liter (range, 375–3705 IU/L; the institutional upper limit for serum LDH is 650 IU/L). Eight patients (44%) had

1480

CANCER April 1, 2004 / Volume 100 / Number 7

TABLE 1 Summary of Characteristics of 18 Patients Included in the Current Retrospective Analysis Characteristic Median no. of treatment courses (range) Gender Male Female Median age in yrs (range) Extent of disease Regional metastasis Distant metastasis Lactate dehydrogenase level Normal Greater than upper limit of normal Previous chemotherapy No Yes Metastatic site Lymph nodes and soft tissues Lung Liver Bone Brain Median no. of sites with metastatic lesions (range) Posttherapy surgical resection of residual disease Biochemotherapy regimen CDDP, VB, DTIC, IL-2, IFN CDDP, VB, temozolomide, IL-2, IFN CDDP, VB, DTIC, IFN CDDP, IL-2, IFN

No. of patients (%) 4 (1–6) 5 (28) 13 (72) 49 (33–70) 4 (22) 14 (78) 10 (56) 8 (44) 13 (72) 5 (28) 14 (78) 6 (33) 7 (39) 2 (11) 2 (11) 2 (1–4) 5 (28) 14 (78) 1 (6) 2 (11) 1 (6)

CDDP: cisplatin; VB: vinblastine; DTIC: dacarbazine; IL-2: interleukin 2; IFN: interferon alpha-2b.

elevated serum LDH levels at the beginning of biochemotherapy treatment. All patients had distant metastatic melanoma, except for four patients who had unresectable regional metastatic disease with bulky primary tumors and lymph node involvement. Five patients, including three with regional metastatic melanoma, underwent a complete surgical resection of the residual disease after two to six cycles of biochemotherapy. Thirteen of the 18 patients received biochemotherapy as a first-line treatment (excluding previous adjuvant IFN therapy). Among the other five patients, three had received one previous chemotherapy regimen, one had received two previous regimens, and one had received three previous regimens.

Biochemotherapy Regimens For 14 patients, the biochemotherapy regimen included the 5-drug combination of CDDP, VB, DTIC, IFN, and IL-2, with all administered either concurrently or sequentially. Two patients received the same combination without IL-2. One patient received the

combination of CDDP, IFN, and IL-2, and another received the combination of CDDP, VB, temozolomide, IFN, and IL-2. All IL-2 treatments were administered intravenously.

Responses Of the 18 patients, 8 (44%) had major responses to biochemotherapy, including 2 patients (11%) who had CRs. One of these patients was a 70-year-old woman who initially had been diagnosed with anorectal melanoma with a rectal mass and multiple liver metastases. She was treated with two courses of a combination of CDDP/VB/DTIC/IFN, after which significant tumor shrinkage was observed in both regions. Subsequently, she underwent a local resection of the residual primary lesion of the rectum. Histopathologic examination revealed a pathologic CR. She received postoperative radiotherapy at a dose of 30 Gy in 5 fractions administered to the primary tumor site and the bilateral inguinal lymph nodes. The residual liver lesions were observed without further treatment. Three months after the completion of biochemotherapy, a computed tomographic (CT) scan revealed resolution of the liver lesions. She had undergone follow-up with serial CT scans of the body and had not experienced any tumor recurrence 43.7 months after the start of biochemotherapy. The second patient who experienced a CR, a 41year-old man, was treated with 6 cycles of a combination of CDDP/VB/DTIC/IFN/IL-2 for rapid local disease recurrence (a 2 cm mass) and inguinal lymph node metastases that had developed within 6 weeks after APR for primary anorectal melanoma. He received adjuvant radiotherapy administered to the perineum and bilateral inguinal lymph nodes after having a complete response with the biochemotherapy. The patient remained free of disease until he developed a brain metastasis (TTP, 11.3 months). He died of disease progression in the brain within 6 months of the diagnosis of brain metastasis, with no evidence of any other systemic disease. In the current series, the median follow-up time was 12.2 months (range, 3.5– 43.7 months). Three of the 18 patients had not returned for follow-up evaluation after the completion of treatment. The median TTP among the remaining 15 patients was 6.2 months (95% confidence limits [CL]: [4.4 months, 11.3 months]; Fig 1), and the median overall survival for the entire group was 12.2 months (95% CL: [11.3 months, upper limit not reached]; Fig. 2). Four patients, including one with a CR, were alive at their last documented follow-up visits. Their individual survival durations were 14.0, 20.7, 31.3, and 43.7 months, respectively. Of the 13 patients who underwent biochemo-

Biochemotherapy for Anorectal Melanoma/Kim et al.

1481

TABLE 2 Summary of 11 Patients Who Received Systemic Therapy Other than Biochemotherapy as First-Line Treatment at The University of Texas M. D. Anderson Cancer Center (Houston, TX) Patient

Gender

Age (yrs)

Disease site(s)

Serum LDH (IU/L)a

Regimen

Response

L.D. S.K. R.B. P.S. E.P. B.C. E.S. J.S. J.D. J.B. R.S.

F F M F F F M F M M M

40 55 59 65 70 61 45 62 34 40 54

LN/lung/liver/brain/LMD LN LN LN/ST ST/liver/lungs Lung Liver Lung/ST ST/LN ST/LN ST/LN

1577 NA 562 581 NA 458 458 351 509 471 432

CDDP/PT/TZ/TH CDDP/VB/DTIC DTIC/CDDP/PT CDDP/VB/DTIC CCNU CDDP/VB/DTIC IL-2/IFN CDDP/VB/DTIC CDDP/VB/DTIC CDDP/VB/DTIC IFN

PD SD SD SD PD SD PD SD PR SD SD

LDH: lactate dehydrogenase; IU: international units; F: female; M: male; LN: lymph node; ST: soft tissue; LMD: leptomeningeal disease; NA: not available; CDDP: cisplatin; PT: paclitaxel; TZ: temozolomide; TH: thalidomide; VB: vinblastine; DTIC: dacarbazine; CCNU: lomustine; IL-2: interleukin 2; IFN: interferon alpha-2b; PD: progressive disease; SD: stable disease; PR: partial response. a Institutional upper limit for serum lactate dehydrogenase levels is 650 international units per liter.

FIGURE 1.

Kaplan–Meier time-to-progression curve. The median time to progression was 6.2 months.

FIGURE 2. Kaplan–Meier overall survival curve. The median overall survival was 12.2 months.

therapy as first-line systemic therapy, 6 (46%) had major responses, which included 2 CRs (15%). The TTP for this group was 6.2 months (95% CL: [5.8 months, upper limit not reached]), and the median overall survival was 12.9 months (95% CL: [11.7 months, upper limit not reached]).

therapy for distant metastatic melanoma of cutaneous origin survive for 5 years.18,19,22–24 Several possible explanations for the poor prognosis associated with anorectal melanoma exist. Many cases are difficult to diagnose correctly at an early stage because of vague symptoms that suggest a diagnosis of hemorrhoids. As a result, many patients are conservatively treated for hemorrhoids for many months before surgical intervention or biopsy is performed. Accordingly, at the time of diagnosis, many anorectal melanoma lesions have large or thick melanoma involvement. Ulceration, which is associated with a poor prognosis in patients with cutaneous melanoma, frequently is observed in tumor specimens.25 The anatomy of the anorectal region may also contribute to the poor survival of patients. Because this region has a rich lymphovascular network, which allows

DISCUSSION Anorectal melanoma is a rare malignancy, and the current understanding of its biology is limited. In previous reports, it has been suggested that anorectal melanoma is associated with a poorer prognosis compared with cutaneous melanoma, and reports of clinical responses to systemic therapy have been anecdotal. No patient with distant metastatic anorectal melanoma has been reported to have survived ⬎ 5 years, whereas 2–10% of patients treated with systemic

1482

CANCER April 1, 2004 / Volume 100 / Number 7

for early metastasis, most patients ultimately develop distant metastases, even when radical APR is performed with curative intention. Finally, it is also possible that anorectal melanoma intrinsically possesses more aggressive biologic behavior and a tendency to be resistant to chemotherapy. For many years, APR has been performed to reduce the risk of locoregional recurrence of primary anorectal melanoma. However, APR is functionally debilitating and yields no clear improvement in overall survival compared with LE. The majority of patients ultimately develop distant metastases regardless of the type of surgical procedure performed.7,9 –11,14 Recently, Ballo et al.26 reported that sphinctersparing LE of the primary lesion followed by adjuvant radiotherapy to both the primary tumor site and the bilateral inguinal lymph node basins leads to a high locoregional tumor control rate at least as effectively as APR does. With 5-year local and lymph node control rates of 74% and 84%, respectively, sphinctersparing LE undoubtedly results in better quality of life for patients. Nonetheless, because of the high metastatic potential of the disease, a substantial proportion of patients are likely to develop distant melanoma lesions even after undergoing postoperative radiotherapy. Currently, no standard systemic therapeutic regimen exists for metastatic anorectal melanoma. The rarity of the disease makes it difficult to assess the clinical efficacy of systemic therapy. Only a small number of publications can be found in the medical literature concerning systemic therapy for anorectal melanoma and most of them are case reports on a limited number of patients. In addition, because chemotherapy regimens vary widely in these reports, it is not possible to reach a conclusion about the response rate to certain regimens in patients with advanced anorectal melanoma. Many years of patient accrual would be necessary to conduct a prospective clinical trial of any specific regimen. Furthermore, systemic therapy regimens may continually evolve over the years of such a study, possibly making the study regimens obsolete by the time the study was completed. Therefore, because of the lack of reports on systemic therapy for this grave disease, recommending treatment options for patients with advanced or recurrent anorectal melanoma presents a dilemma for oncologists. In the current retrospective study, biochemotherapy was associated with a 44% overall response rate and an 11% CR rate, which are similar to the rates reported for biochemotherapy in the treatment of advanced cutaneous melanoma. It is noteworthy that the median TTP was 6.2 months among the 15 patients

with substantial follow-up times. This figure also was similar to the TTP reported for biochemotherapy in the treatment of metastatic cutaneous melanoma. In addition, the overall median survival length of 12.2 months is longer than the previously reported3,7,10,13–15,27 expected survival of 4 –9 months for patients with metastatic anorectal melanoma. Therefore, metastatic anorectal melanoma may not be as resistant to systemic therapy as was previously believed, and patients with this disease may benefit from biochemotherapy. For comparison, there was only 1 PR (9%) observed among 11 patients who received systemic therapy other than biochemotherapy. However, it is difficult to draw any conclusions regarding the clinical benefit of the treatment received by these patients, due to the limited number of patients assessed and the variety of regimens used. Recent Phase III trials comparing combination chemotherapy with biochemotherapy28 –30 indicated a lack of survival benefit associated with biochemotherapy in patients with advanced melanoma, despite the finding of increased time to disease progression in most studies. These trials primarily involved patients with advanced melanoma of a cutaneous origin. Without further understanding of the biology of mucosal melanoma cells, it is difficult to apply the results of these Phase III studies to patients with anorectal mucosal melanoma. It is therefore very important to study the molecular biology and the behavior of mucosal melanoma cells and to develop effective treatments for patients with such malignancies. Furthermore, these patients should be encouraged to participate in clinical trials. Nonetheless, based on the current analysis, which suggests that in comparison with other types of systemic therapy, biochemotherapy yields superior response rates, it is reasonable to use biochemotherapy to treat patients with advanced anorectal melanoma, and especially patients with large, unresectable tumors that cause symptoms such as severe pain. Although the current study was a retrospective evaluation involving a limited number of patients, it is the largest series to date to evaluate the clinical efficacy of systemic therapy for anorectal mucosal melanoma. Its results may provide some guidance regarding the treatment of this disease and a direction for a multicenter trial. Biochemotherapy appears to have considerable activity against metastatic anorectal melanoma and should be considered for use in the treatment of this malignancy.

REFERENCES 1.

Pack GT, Lenson N, Gerber DM. Regional distribution of moles and melanomas. Arch Surg. 1952;65:862– 870.

Biochemotherapy for Anorectal Melanoma/Kim et al. 2.

3. 4. 5.

6. 7.

8.

9.

10.

11.

12.

13.

14. 15. 16. 17.

18.

Miller BJ, Rutherford LF, McLeod GR, Cohen JR. Where the sun never shines: anorectal melanoma. Aust N Z J Surg. 1997;67:846 – 848. Weinstock MA. Epidemiology and prognosis of anorectal melanoma. Gastroenterology. 1993;104:174 –178. Husa A, Hockerstedt K. Anorectal malignant melanoma. A report of fourteen cases. Acta Chir Scand. 1974;140:68 –72. Pandey M, Mathew A, Abraham EK, Ahamed IM, Nair KM. Primary malignant melanoma of the mucous membranes. Eur J Surg Oncol. 1998;24:303–307. Morson BC, Volkstadt H. Malignant melanoma of the anal canal. J Clin Pathol. 1963;16:126 –132. Slingluff CL Jr., Vollmer RT, Seigler HF. Anorectal melanoma: clinical characteristics and results of surgical management in twenty-four patients. Surgery. 1990;107:1–9. Rossetti C, Koukouras D, Eboli M, Andreola S, Bertario L. Primary anorectal melanomas: an istitutional [sic] experience. J Exp Clin Cancer Res. 1997;16:81– 85. Brady MS, Kavolius JP, Quan SH. Anorectal melanoma. A 64-year experience at Memorial Sloan-Kettering Cancer Center. Dis Colon Rectum. 1995;38:146 –151. Goldman S, Glimelius B, Pahlman L. Anorectal malignant melanoma in Sweden. Report of 49 patients. Dis Colon Rectum. 1990;33:874 – 877. 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;125:313–316. Konstadoulakis MM, Ricaniadis N, Walsh D, Karakousis CP. Malignant melanoma of the anorectal region. J Surg Oncol. 1995;58:118 –120. Thibault C, Sagar P, Nivatvongs S, Ilstrup DM, Wolff BG. Anorectal melanoma—an incurable disease? Dis Colon Rectum. 1997;40:661– 668. Roumen RM. Anorectal melanoma in The Netherlands: a report of 63 patients. Eur J Surg Oncol. 1996;22:598 – 601. Siegal B, Cohen D, Jacob ET. Surgical treatment of anorectal melanomas. Am J Surg. 1983;146:336 –338. Wanebo HJ, Woodruff JM, Farr GH, Quan SH. Anorectal melanoma. Cancer. 1981;47:1891–1900. Legha SS, Ring S, Bedikian A, et al. Treatment of metastatic melanoma with combined chemotherapy containing cisplatin, vinblastine and dacarbazine (CVD) and biotherapy using interleukin-2 and interferon-alpha. Ann Oncol. 1996;7: 827– 835. Keilholz U, Conradt C, Legha SS, et al. Results of interleukin2-based treatment in advanced melanoma: a case recordbased analysis of 631 patients. J Clin Oncol. 1998;16:2921– 2929.

1483

19. Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999;17:2105–2116. 20. Eton O, Legha SS, Bedikian AY, et al. Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a Phase III randomized trial. J Clin Oncol. 2002; 20:2045–2052. 21. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;55:457– 481. 22. Creagan ET, Schaid DJ, Ahmann DL, Frytak S. Disseminated malignant melanoma and recombinant interferon: analysis of seven consecutive Phase II investigations. J Invest Dermatol. 1990;95:188S–192S. 23. Ahmann DL, Creagan ET, Hahn RG, Edmonson JH, Bisel HF, Schaid DJ. Complete responses and long-term survivals after systemic chemotherapy for patients with advanced malignant melanoma. Cancer. 1989;63:224 –227. 24. Barth A, Wanek LA, Morton DL. Prognostic factors in 1,521 melanoma patients with distant metastases. J Am Coll Surg. 1995;181:193–201. 25. Balch CM, Soong SJ, Gershenwald JE, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol. 2001;19:3622–3634. 26. Ballo MT, Gershenwald JE, Zagars GK, et al. Sphincter-sparing local excision and adjuvant radiation for anal-rectal melanoma. J Clin Oncol. 2002;20:4555– 4558. 27. Antoniuk PM, Tjandra JJ, Webb BW, Petras RE, Milsom JW, Fazio VW. Anorectal malignant melanoma has a poor prognosis. Int J Colorectal Dis. 1993;8:81– 86. 28. Atkins MB, Lee S, Flaherty LE, Sosman JA, Sondak VK, Kirkwood JM. A prospective randomized Phase III trial of concurrent biochemotherapy (BCT) with cisplatin, vinblastine, dacarbazine (CVD), IL-2 and interferon alpha-2b (IFN) versus CVD alone in patients with metastatic melanoma (E3695): an ECOG-coordinated intergroup trial [abstract]. Proc Am Soc Clin Oncol. 2003;22:708. 29. Keilholz U, Punt CJ, Gore M, et al. Dacarbazine, cisplatin and IFN-␣2b with or without IL-2 in advanced melanoma: final analysis of EORTC randomized Phase III trial 18951 [abstract]. Proc Am Soc Clin Oncol. 2003;22:708. 30. Del Vecchio M, Bajetta E, Vitali M, et al. Multicenter Phase III randomized trial of cisplatin, vindesine and dacarbazine (CVD) versus CVD plus subcutaneous (sc) interleukin-2 (IL-2) and interferon-alpha-2b (IFN) in metastatic melanoma patients (pts) [abstract]. Proc Am Soc Clin Oncol. 2003;22:709.