Editor(s): Jeffrey E. Gershenwald, M.D. Reviewers: Donald L. Morton, M.D., Douglas S. Reintgen, M.D., John F. Thompson, M.D.

General Reviews

Balch CM, Houghton AN, Sober AJ, Soong S. (eds.) Cutaneous Melanoma. Quality Medical Publishing, Inc., St. Louis, 1998.

Staging and Prognostic Factors

Balch CM, Soong, SJ, Gershenwald JE, et al: Prognostic factor analysis of 17,600 melanoma patients: validation of the new AJCC melanoma staging system. J Clin Oncol. 2001 Aug 15;19(16):3622-34

Balch CM, Buzaid AC, Soong, SJ, et al: Final version of the AJCC staging system for cutaneous melanoma. J Clin Oncol. 2001 Aug 15;19(16):3635-48.

The Melanoma Task Force of the AJCC has significantly revised the staging system for melanoma. Major revisions include 1) melanoma thickness and ulceration, but not level of invasion [except for melanomas up to 1 mm thick], to be used in the T classification; 2) the number of metastatic lymph nodes, rather than their gross dimensions, the delineation of microscopic versus macroscopic lymph node metastases, and presence of ulceration of the primary melanoma to be used in the N classification; 3) the site of distant metastases and the presence of elevated serum LDH, to be used in the M classification; 4) an upstaging of all patients with Stage I, II, and III disease when a primary melanoma is ulcerated; 5) a merging of satellite metastases around a primary melanoma and in-transit metastases into Stage III disease; and 6) a new convention for defining clinical and pathologic staging so as to take into account the new staging information gained from intraoperative lymphatic mapping and sentinel lymph node biopsy. These revisions will take effect in 2002.

Breslow A. Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma. Ann Surg 1970; 172(5):902-8.

This landmark paper proposed the significance of tumor thickness as a prognostic criterion.

Clark WH, Jr, From L, Bernardino EA, Mihm MC. The histogenesis and biologic behavior of primary human malignant melanomas of the skin. Cancer Res 1969; 29(3):705-27.

First journal reference description of present day Clark level of invasion.

Morton DL, Wanek L, Nizze JA, Elashoff RM, Wong JH. Improved long-term survival after lymphadenectomy of melanoma metastatic to regional nodes. Analysis of prognostic factors in 1134 patients from the John Wayne Cancer Clinic. Ann Surg 1991; 214(4):491-501.

A review of 1134 patients from the John Wayne Cancer Clinic with melanoma metastatic to regional lymph nodes was carried out to evaluate the importance of various prognostic features after lymphadenectomy. Multifactorial analysis showed that number of involved nodes, extremity location of primary, and Breslow thickness were significant predictors of survival.

Buzaid AC, Ross MI, Balch CM, et al. Critical analysis of the current American Joint Committee on Cancer staging system for cutaneous melanoma and proposal of a new staging system. J Clin Oncol 1997; 15(3):1039-51.

Excellent and comprehensive evaluation of the published data and reanalysis of the University of Alabama and Sydney Melanoma Unit databases (N=4,568). Examined the prognostic impact of several primary tumor factors as well as survival differences among patients with local, regional, and nodal metastases. Basis for the newly proposed AJCC staging system.

Manola J, Atkins M, Ibrahaim J, Kirkwood J. Prognostic factors in metastatic melanoma: A pooled analysis of Eastern Cooperative Oncology Group Trials. J Clin Oncol 18(22):3782-3793, 2000.

Multivariate analysis of 1,360 eligible patients with metastatic melanoma (8 ECOG trials conducted over the past 25 years). Factors conferring the greatest increased risk of death included the number of metastatic sites, ECOG performance status of 1 or more, or metastatic disease in the GI tract, liver, pleura, or lung. Prior immunotherapy and female sex were associated with prolonged survival. Abnormal LDH, abnormal alkaline phosphatase, or abnormal platelet counts were also associated with poor survival [in a model based on three recent studies in which these values were available].

Wagner JD, Schauwecker D, Davidson D, et al. Prospective study of fluorodeoxyglucose-positron emission tomography imaging of lymph node basins in melanoma patients undergoing sentinel node biopsy. J Clin Oncol 1999; 17(5):1508-15.

Authors conclude that FDG-PET is at present an insensitive indicator of occult regional lymph node metastasis in patients with primary melanoma and clinically negative regional nodal basins.

Tyler DS, Onaitis M. Kherani A, et al: Positron emission tomography scanning in malignant melanoma - Clinical utility in patients with Stage III disease. Cancer. 89(5):1019-1025, 2000.

Contemporary prospective evaluation of 106 whole body PET scans obtained after injection of FDG was performed in 95 patients with clinically evident stage III lymph node and/or in-transit melanoma. A change in the patient's clinical management was noted after 16 of the 106 PET scans (15.1%). Authors conclude PET scanning may be helpful in managing patients with stage III melanoma and for whom further surgery is contemplated, although PET's inability to identify microscopic disease suggests that it is of limited use in evaluating patients with stages I-II disease.

Lymphoscintigraphy

Uren RF, Howman-Giles R, et al: Interval nodes - The forgotten sentinel nodes in patients with melanoma. Archives of Surgery. 135(10):1168-1172, 2000.

Excellent and comprehensive evaluation of preoperative lymphoscintigraphic drainage patterns in 2,045 patients with cutaneous melanoma studied over a 13-year period demonstrates that interval nodes (nodes that are situated along the course of a lymphatic vessel between a primary melanoma site and a recognized nodal field) were found in 148 patients (7.2%). Among patients who underwent sentinel node biopsy which included such sites, micrometastatic disease was found in 14% of these interval nodes, and is similar to the incidence of metastatic disease in sentinel nodes located in recognized fields. Interval nodes should therefore be removed surgically along with any additional sentinel nodes in standard nodal basins if the sentinel node biopsy procedure is to be complete. In some patients, an interval node will be the only lymph node that contains metastatic disease.

Thompson JF, Uren RF, Shaw HM, et al. Location of sentinel lymph nodes in patients with cutaneous melanoma: New insights into lymphatic anatomy. J Am Coll Surg 1999; 189(2):195-204.

An outstanding analysis of lymphatic drainage patterns in 1,759 melanoma patients.

Norman J, Cruse CW, Espinosa C, et al. Redefinition of cutaneous lymphatic drainage with the use of lymphoscintigraphy for malignant melanoma. Am J Surg 1991;162(5):432-7.

Early analysis of lymphoscintigraphy in patients with melanoma of the head, neck, shoulder, and trunk. Drainage patterns differed significantly from classic anatomic studies, and demonstrated much larger areas of ambiguous drainage in these patients than previously reported. Data supports that patients with melanomas arising in these locations should undergo lymphoscintigraphy to define relevant drainage basins at risk for metastatic disease.

Treatment of Primary Melanoma - Margins of Excision

Heaton KM, Sussman JJ, Gershenwald JE, et al. Surgical margins and prognostic factors in patients with thick (>4 mm) primary melanoma. Ann Surg Oncol 1998; 5(4):322-8.

Multi-institutional retrospective review demonstrates that margins of excisions greater than 2 cm do not improve local recurrence rates, disease-free survival, or overall survival compared to a margin of 2 cm or less in patients with thick primary melanomas.

Veronesi U, Cascinelli N, Adamus J, et al. Thin stage I primary cutaneous malignant melanoma. Comparison of excision with margins of 1 or 3 cm. N Engl J Med 1988; 318(18):1159-62.

Landmark randomized, prospective study assessing efficacy of narrow excision for primary melanomas up to 2 mm in thickness. Disease-free and overall survival rates were similar between patients who underwent 1 cm vs. 3 cm or more margin of excision. Only 3 patients had a local recurrence as a first relapse, all of whom had undergone narrow excision, and each had a primary melanoma with a thickness of at least 1 mm. However, no statistically significant difference in local recurrence rates among the two treatment groups.

Balch CM, Urist MM, Karakousis CP, et al. Efficacy of 2-cm surgical margins for intermediate-thickness melanomas (1 to 4 mm). Results of a multi-institutional randomized surgical trial. Ann Surg 1993; 218(3):262?9.

This seminal multi-institutional randomized prospective surgical trial demonstrated that a 2 cm margin of excision is adequate for primary intermediate thickness melanoma.

Treatment of Primary Melanoma - Elective Lymph Node Dissection

Balch CM, Soong S, Ross MI, et al. Long-term results of a multi-institutional randomized trial comparing prognostic factors and surgical results for intermediate thickness melanomas (1.0 to 4.0 mm) Intergroup melanoma surgical trial. Ann Surg Oncol 2000; 7(2):87-97.

Overall 10-year survival was not significantly different for patients who received ELND or nodal observation (77% versus 73%; p = .12). Among the prospectively stratified subgroups of patients, 10-year survival rates favored those patients with ELND, with a 30% reduction and mortality rate for the 543 patients with non-ulcerated melanomas (84% versus 77%; p = .03), a 30% reduction in mortality rate for the 446 patients with tumor thickness of 1.0 mm to 2.0 mm (86% versus 80%; p = .03), and a 27% reduction in mortality rate for 385 patients with limb melanomas (84% versus 78%; p =.05). The authors also conclude that presence or absence of ulceration should be the key factor for making treatment recommendations with regard to ELND for patients with intermediate thickness melanomas.

Cascinelli N, Morabito A, Santinami M, MacKie RM, Belli F. Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: a randomised trial. Lancet 1998; 351(9105):793-6.

Multicenter randomised prospective trial sponsored by the WHO Melanoma Programme which evaluated the efficacy of immediate regional node dissection in patients with melanomas of the trunk at least 1.5 mm thick demonstrated that routine use of immediate node dissection had no impact on survival. Interestingly, compared with patients who had an immediate lymph node dissection and microscopic regional node metastasis identified only after pathologic analysis of the surgical specimen, patients in whom the node dissection was delayed until regional nodes became clinically and histologically positive during follow-up had the poorest prognosis, suggesting that the dissection of clinically undetectable regional node metastasis leads to higher long?term survival.

Reintgen D. The role of elective lymph node dissection in malignant melanoma: who should undergo this nodal staging procedure? J Am Coll Surg 1999; 189(2):224-32.

Current review article

Slingluff CL Jr, Stidham KR, Ricci WM, Stanley WE, Seigler HF. Surgical management of regional lymph nodes in patients with melanoma. Experience with 4682 patients. Ann Surg 219(2):120-30, 1994.

Treatment of Primary Melanoma - Sentinel Lymphadenectomy

Morton DL, Wen DR, Wong JH, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992; 127(4):392-9.

Landmark paper demonstrating that lymphatic drainage of a primary melanoma could be predicted intraoperatively and that sentinel lymph node biopsy reliably predicts the histologic status of the regional nodal basin.

Gershenwald JE, Thompson W, Mansfield PF, et al. Multi-institutional melanoma lymphatic mapping experience. The prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol 17(3): 976-983, 1999

Pathologic status of the sentinel node in primary melanoma patients with clinically negative nodes is the most important prognostic factor for both disease-free and disease-specific survival.

Morton DL, Thompson JF, Essner R, et al. Validation of the accuracy of intraoperative lymphatic mapping and sentinel lymphadenectomy for early-stage melanoma - A multicenter trial. Multicenter Selective Lymphadenectomy Trial Group. Ann Surg 1999; 230(4):453-63.

This study examined the accuracy of lymphatic mapping, sentinel lymphadenectomy, and selective complete lymph node dissection in the ongoing multicenter Selective Lymphadenectomy Trial by comparing trial data to that of the organizing center (John Wayne Cancer Institute). The authors concluded that lymphatic mapping and sentinel lymphadenectomy can be successfully learned and applied in a standardized fashion by multiple centers. A multidisciplinary approach, a learning phase of at least 30 consecutive cases, and use of blue dye plus radiocolloid are important components of a successful approach.

Reintgen D, Cruse CW, Wells K, et al. The orderly progression of melanoma nodal metastases. Ann Surg 1994; 220(6):759-67.

Authors performed sentinel node biopsy on 42 patients followed by a synchronous complete node dissection. Eight of the 42 patients had positive sentinel nodes, with seven of the eight having the sentinel node as the only site of disease. Thirty-four additional patients had histologically negative sentinel nodes, with the rest of the nodes in the basin also being negative. Since no skip metastasis were documented, the authors concluded that nodal metastasis from cutaneous melanoma are not random events and the sentinel node histology accurately reflects the histology of the remainder of lymphatic basin, and can therefore be used as a prognostic factor for patients with melanoma.

Albertini JJ, Cruse CW, Rapaport D, et al: Intraoperative radiolymphoscintigraphy improves sentinel lymph node identification for patients with melanoma. Ann Surg 223(2):217-24, 1996.

This study demonstrates that use of intraoperative radiolymphoscintigraphy can improve the identification of all sentinel nodes during selective lymphadenectomy

Gershenwald J, Mansfield PF, Lee JE, Ross MI: The role for lymphatic mapping and sentinel lymph node biopsy in patients with thick (>4 mm) primary melanoma. Ann Surg Oncol 7(2):160-5, 2000.

Sentinel node pathologic status was the most important independent clinicopathologic factor for disease-specific survival in patients with thick primary melanoma.

Clary BM, Brady MS, Lewis JJ, Coit DG: Sentinel lymph node biopsy in the management of patients with primary cutaneous melanoma: review of a large single-institutional experience with an emphasis on recurrence. Ann Surg 233(2):250-8, 2001.

Recent single institution experience.

McMasters KM, Reintgen DS, Ross MI, et al: Sentinel lymph node biopsy for melanoma: how many radioactive nodes should be removed? Ann Surg Oncol 8(3):192-7, 2001.

Analysis of 1184 patients enrolled in Sunbelt Melanoma Trial. Authors recommend that all blue nodes and all nodes that measure 10% or higher of the ex vivo radioactive counts of the hottest sentinel node should be harvested for optimal detection of nodal metastases.

Porter GA, Ross MI, Berman RS, et al: How many lymph nodes are enough during sentinel lymphadenectomy for primary melanoma? Surgery 128(2):306-11, 2000

Gershenwald JE, Tseng CH, Thompson W, et al: Improved sentinel lymph node localization in patients with primary melanoma with the use of radiolabeled colloid. Surgery 124(2):203-10, 1998.

SLN identification is enhanced (from 87% [dye alone] to 99% [dye and colloid]) by the addition of radiolabeled sulfur colloid and intraoperative use of the hand-held gamma probe and may identify SLNs missed by the blue dye alone.

Pathologic and Molecular Staging

Gershenwald JE, Colome MI, Lee JE, et al. Patterns of recurrence following a negative sentinel lymph node biopsy in 243 patients with stage I or II melanoma. J Clin Oncol 1998; 16(6):2253-60.

Retrospective reanalysis of sentinel lymph nodes in patients who had a negative SLN biopsy by routine histologic techniques and subsequently failed in the mapped regional nodal basin most commonly occurred because conventional histologic evaluation was unable to identify occult metastatic disease in the SLN. Emphasizes that specialized pathologic techniques are necessary to further reduce already low false?negative rates and improve disease staging.

Shivers SC, Wang X, Li W, et al. Molecular staging of malignant melanoma: correlation with clinical outcome. JAMA 1998; 280(16):1410-5.

Early outcome analysis on 114 melanoma patients with clinical stage I and II disease whose lymph nodes were submitted for both routine histologic analysis as well as RT-PCR for tyrosinase messenger RNA. Demonstrates that molecular staging of sentinel lymph nodes may result in improved prediction of melanoma recurrence.

Bostick PJ, Morton DL, Turner RR, et al. Prognostic significance of occult metastases detected by sentinel lymphadenectomy and reverse transcriptase-polymerase chain reaction in early-stage melanoma patients. J Clin Oncol 1999; 17(10):3238-44.

Authors conclude that multi-marker expression by RT-PCR in the sentinel node more accurately reflects melanoma micro?metastasis and is a more powerful predictor of disease relapse than routine histologic techniques alone.

Therapeutic Lymph Node Dissection

Strobbe LJ, Jonk A, Hart AA, Nieweg OE, Kroon BB. Positive iliac and obturator nodes in melanoma: survival and prognostic factors. Ann Surg Oncol 1999; 6(3):255-62.

Review of 362 therapeutic groin dissections performed at a tertiary referral center revealed 71 patients (20%) with positive iliac and/or obturator nodes. Patients with involved deep nodes exhibited overall 5-year and 10-year survival rates of 24% and 20%, respectively. Independent prognostic factors for survival were the number of positive iliac nodes, the Breslow thickness, and the site of primary tumor. The short- and long-term morbidity rates were also evaluated.

Mann GB, Coit DG. Does the extent of operation influence the prognosis in patients with melanoma metastatic to inguinal nodes? Ann Surg Oncol 1999; 6(3):263-71.

Retrospective review of 227 consecutive patients having superficial or combined inguinal lymphadenectomy for cutaneous melanoma. Overall 5-year survival for node-positive patients was 39%. Survival for patients with positive superficial nodes was 40%; for those with positive deep nodes it was 35% (p = ns). In node-positive patients, number and size of involved lymph nodes and the presence of extranodal spread, failure to receive adjuvant therapy, and tumor ulceration were associated with poorer prognosis. The authors concluded that some patients with deep nodal involvement apparently are cured by combined inguinal lymphadenectomy, although the biology of the disease and not the extent of surgery primarily governs outcome. The authors also concluded that patients with clinical or radiological evidence of pelvic nodal disease without evidence of systemic disease should have a CLND, but found no evidence to support CLND if the pelvic nodes were clinically and radiologically negative.

Chan AD, Essner R, Wanek LA, Morton DL: Judging the therapeutic value of lymph node dissections for melanoma. J Am Coll Surg 191(1):16-23, 2000.

Comprehensive analysis of 548 patients with stage III melanoma who underwent regional lymph node dissection. The number of pathologically involved lymph nodes as well as the extent of lymph node dissection were independent factors for overall survival.

Adjuvant Therapy

Kirkwood JM, Ibrahim JG, Sosman JA, et al: High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIb-III melanoma: results of intergroup trial E1694/S9512/C509801. J Clin Oncol 19(9):2370-80, 2001.

Interim analysis of prospective, randomized Intergroup trial to evaluate efficacy of high-dose interferon (HOI) for 1 year versus vaccination with GM2-KLH/QS-21. Overall, 880 patients randomized; 774 eligible for efficacy analysis. Eligible patients had resected stage IIB/III melanoma. Interim analysis indicated that RFS and OS were lower for patients receiving the vaccine compared with HDI. Trial closed by ECOG following interim analysis.

Kirkwood JM, Ibrahim JC, Sondak VK, et al. High- and low-dose interferon alfa-2b in high-risk melanoma: first Analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol 2000; 18(12):2444-2458.

Prospective, randomized, three-arm, Intergroup trial evaluated the efficacy of high-dose IFN alpha-2b (HDI) for 1 year and low-dose IFN alpha-2b (LDI) for 2 years versus observation in high-risk (stage IIB and III) melanoma with relapse-free survival (RFS) and overall survival (OS) end points (N=642). Most patients (75%) had nodal metastases (50% had nodal recurrence). Unlike E1684, E1690 allowed entry of patients with T4 primary tumors whether or not node dissection was performed, and 25% of the patients entered onto this trial had deep primary tumors (compared with 11% in E1684). At 52 months' median follow-up, HDI demonstrated an RFS benefit exceeding that of LDI compared with observation. The 5-year estimated RFS rates for the HDI, LDI, and observation arms were 44%, 40%, and 35%, respectively (P =.03). The RFS benefit was equivalent for node-negative and node-positive patients. Neither HDI nor LDI has demonstrated an OS benefit compared with observation at this time. An analysis of salvage therapy for patients who relapsed on E1690 demonstrated that a significantly larger proportion of patients in the observation arm received IFN alpha-containing salvage therapy compared with the HDI arm; this therapy was unavailable to patients during E1684, and patients with undissected regional nodes were not included in E1684. Analysis of treatments received at recurrence demonstrated significantly more frequent use of IFN alpha-2b at relapse from observation than from HDI, which may have confounded interpretation of the survival benefit of assigned treatments in E1690.

Morton DL, Ollila DW, Hsueh EC, Essner R, Gupta RK. Cytoreductive surgery and adjuvant immunotherapy: A new management paradigm for metastatic melanoma. CA A Cancer J Clin 1999; 49(2):101-16.

A comprehensive review.

Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Interferon-alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 1996; 14(1):7-17.

Pivotal study used by the FDA for approval of interferon alfa-2b as the first adjuvant therapy for melanoma to be effective following resection of disease in patients with deep primary or regional lymph node metastases.

Grob JJ, Dreno B, de la Salmoniere P, Delaunay M, Cupissol D., Guillot B, et al. Randomised trial of interferon alpha-2a as adjuvant therapy in resected primary melanoma thicker than 1.5 mm without clinically detectable node metastases. French Cooperative Group on Melanoma. Lancet 1998; 351(9120):1905-10.

After a median follow-up of 5 years, the French cooperative group on melanoma showed a benefit with respect to disease-free survival but without an overall survival advantage to patients who received 18 months of 3M units sc tiw of interferon alfa-2a vs. observation. Of note, the regional nodal basins in these patients were not pathologically staged by either ELND or sentinel node biopsy.

Pehamberger H, Soyer HP, Steiner A, et al. Adjuvant interferon alfa-2a treatment in resected primary stage II cutaneous melanoma. Austrian Melanoma Cooperative Group. J Clin Oncol 1998; 16(4):1425-29.

Prospective randomized study in patients with primary melanoma at least 1.5 mm thick. Patients received either adjuvant interferon alpha 2a (low-dose for 12 months) or observation after wide excision of the primary tumor. After median follow-up of approximately 3 years, prolonged disease-free survival was observed in patients treated with interferon. Of note, however, is the absence of pathologic staging of the regional nodal basins.

Hyperthermic isolated limb perfusion

Vrouenraets BC, Nieweg OE, Kroon BB. Thirty-five years of isolated limb perfusion for melanoma: indications and results. Br J Surg 1996; 83(10):1319-28.

A comprehensive review.

Thompson JF, Hunt JA, Shannon KF, Kam PC. Frequency and duration of remission after isolated limb perfusion for melanoma. Arch Surg 1997; 132(8):903-7.

Of 111 assessable isolated limb perfusions with cytotoxic agents, 81 (73%) resulted in complete limb tumor remission and 14 (13%) resulted in partial remission (> 50% reduction in size of tumor deposits). Complete remission was maintained in 37 (46%) of the 81 cases without any further treatment at a median follow-up of 33 months. Of the other 44 cases, disease subsequently recurred in the perfused limb with a median time to recurrence of 9.5 months (range, 2-65 months). In 19 of these 44 cases, the limb was again rendered disease-free at last follow-up after either local surgery or repeat isolated limb perfusion, demonstrating that complete locoregional control was achieved after 50% of assessable isolated limb profusions, and a long-term disease-free state in the limb was achieved overall in 56 (69%) of the 81 cases in which an initial complete remission occurred. Also provides review of previously published studies.

Koops HS, Vaglini M, Suciu S, et al. Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. J Clin Oncol 1998; 16(9):2906-12.

This international prospective, randomized trial found no benefit to patients with primary cutaneous melanoma at least 1.5mm in thickness who underwent prophylactic isolated limb perfusion compared to patients randomized to wide excision alone.

Isolated Limb Infusion

Thompson JF, Kam PC, Waugh RC, Harman CR: Isolated limb infusion with cytotoxic agents: a simple alternative to isolated limb perfusion. Semin Surg Oncol 14(3):238-47, 1998.

Comprehensive review and early experience by developers of this alternative approach to isolated limb perfusion for patients with recurrent extremity melanoma.

Systemic Therapy

Haigh PI, Difronzo LA, Gammon G, Morton DL. Vaccine therapy for patients with melanoma. Oncology 1999; 13(11):1561-74.

A recent review article.

Nathan FE, Mastrangelo MJ. Systemic therapy in melanoma. Semin Surg Oncol 1998; 14(4):319-27.

A recent review article.

Radiation Therapy

Stevens G, Thompson JF, Firth I, et al: Locally advanced melanoma: results of postoperative hypofractionated radiation therapy. Cancer 88(1):88-94, 2000.

Postoperative adjuvant radiation therapy given according to a hypofractionated schedule was effective in reducing local recurrence in patients at high risk of local regional failure among 174 patients with 1 to 3 melanoma who received postoperative radiation either as a component of their initial management or following surgery for recurrence.

Recent ASCO & SSO Abstracts

Gershenwald JE, Schacherer C, Emerson M, et al: Patterns of failure and survival analysis in sentinel lymph node positive melanoma patients. Proc Amer Soc Clin Oncol 20(1396):350a, 2001.

Kirkwood JM, Manola J, Ibrahim J, Sondak VK, Ernstoff MS: Pooled-analysis of four ECOG/Intergroup trials of high-dose interferon alfa-2b (HDI) in 1916 patients with high-risk resected cutaneous melanoma. Proc Amer Soc Clin Oncol 20(1395):350a, 2001.

Wheatley K, Hancock B, Gore M, Suciu S, Eggermont A: Interferon-a as adjuvant therapy for melanoma: A meta-analysis of the randomized trials. Proc Amer Soc Clin Oncol 20(1394):349a, 2001.

Sosman JA, Unger JM, Liu P, et al: Significant impact of HLA class I alleles on outcome in T3NO melanoma patients treated with Melacine™ (MEL): an allogeneic melanoma cell lysate vaccine: prospective analysis of Southwest Oncology Group (SWOG)-9035. Proc Amer Soc Clin Oncol 20(1402):351a, 2001.

Splichal JE, Ornstein DL, Hong-Dice YG, Downs JR, Fischer JR: Lovastatin for the prevention of melanoma: analysis of AFCAPS/TexCAPS. Proc Amer Soc Clin Oncol 20(1399):351a, 2001.

Dessureault S, Soong S, Ross M, et al: Improved survival for node-negative patients with intermediate-to-thick melanomas (>1 mm) staged with sentinel lymph node (SLN) biopsy. Proc Soc Surg Oncol, abstr 53, 2001.

Gershenwald JE, Sumner W, Porter G, et al: Role of sentinel lymph node biopsy in patients with thin (< 1 mm) cutaneous melanoma. Proc Soc Surg Oncol 27, 2000.

Eton A, Legha S, Bedikian A, et al: Phase III randomized trial of cisplatin, vinblastine and dacarbazine (CVD) plus interleukin-2 (IL2) and interferon-alpha-2b (INF) versus CVD in patients with metastatic melanoma. Proc Amer Soc Clin Oncol 19(2174):552a, 2000.

Gershenwald JE, Prieto V, Colome-Grimmer MI, et al: The prognostic significance of microscopic tumor burden in 945 melanoma patients undergoing sentinel lymph node biopsy. Proc Amer Soc Clin Oncol 19(2169):551a, 2000.

Selected Major Clinical Trials

Multicenter Selective Lymphadenectomy Trial (MSLT) - A clinical study of wide excision alone versus wide excision with intraoperative lymphatic mapping and selective lymph node dissection in the treatment of patients with cutaneous invasive melanoma.

MSLT is a randomized two-arm clinical trial designed to compare wide local excision alone vs. wide excision in addition to intraoperative lymphatic mapping and sentinel lymphadenectomy in patients with primary melanomas at least 1 mm thick or at least Clark level IV or V with any Breslow thickness. Pre-randomization stratification factors will be utilized: (1) Breslow thickness (1.20-1.79 mm, 1.80-3.50 mm) and (2) Primary site (extremity vs. non-extremity). The primary objective of the study will be to evaluate the effect upon overall and disease-free survival by identifying patients who may benefit by more aggressive surgical intervention at the time they are diagnosed using the sentinel node technique. Accrual of an estimated 1,200 patients is expected to be complete in 2000.

Sunbelt Melanoma Trial (SMT)- A multicenter trial of adjuvant interferon alfa-2b for melanoma patients with early lymph node metastasis.

The objectives of the SMT are: (1) to determine whether regional lymphadenectomy plus high?dose interferon alfa-2b therapy improves disease?free and overall survival for melanoma patients with sub?microscopic sentinel node metastasis compared to lymphadenectomy alone; (2) to determine whether lymphadenectomy alone improves disease-free and overall survival for patients with sub-microscopic sentinel node metastasis compared to observation; (3) to determine the natural history of patients with sub-microscopic sentinel lymph node metastasis detected by RT-PCR, and; (4) to determine the positive and negative predictive value of RT-PCR analysis of sentinel lymph nodes and peripheral blood to identify patients at risk for recurrence and death. Patients must have invasive cutaneous melanoma with a Breslow thickness of at least 1 mm and clinically negative nodal basins. Target accrual is 3,000 patients.

A phase III randomized double-blind pivotal trial of immunotherapy with BCG plus a polyvalent melanoma vaccine, CancerVax (C-VAX), versus BCG plus a placebo as a post-surgical treatment for stage III melanoma.

The objectives of this multicenter randomized double?blind trial are to determine whether adjuvant BCG plus C-VAX will effectively prolong overall and disease-free survival compared to BCG plus placebo in stage III melanoma patients rendered NED after surgical resection of tumor-containing lymph nodes. Patients must be within 4 months of diagnosis of AJCC stage III melanoma with nodal metastases arising from a primary cutaneous site or metastatic site from unknown primary and must have no physical, clinical, radiographic, or pathological evidence of residual metastatic melanoma. This protocol remains open to patient accrual.

A phase III randomized double-blind trial of immunotherapy with a polyvalent melanoma vaccine (CancerVax©) plus BCG versus placebo plus BCG as a post-surgical treatment for stage IV melanoma.

The objectives of this multicenter randomized double?blind trial are to determine whether adjuvant CancerVax plus BCG will effectively prolong disease?free and overall survival compared to placebo plus BCG in stage IV melanoma patients who have been rendered NED after surgical resection. Patients must be within 6 months of diagnosis of AJCC stage IV melanoma arising from a primary cutaneous site or metastatic site from unknown primary and must have no physical, clinical, radiographic, or pathological evidence of residual metastatic melanoma. In addition, eligible patients must have no more than two involved organ sites and no more than 5 individual metastases. Approximately 420 patients with AJCC stage IV disease will be randomized to receive either CancerVax or placebo. This protocol remains open to patient accrual.

American College of Surgeons Oncology Group (ACOSOG) - A randomized phase III trial of hyperthermic isolated limb perfusion and Melphalan with and without tumor necrosis factor in patients with localized advanced extremity melanoma.

Patients with extremity melanoma will be randomized to receive a standard ILP with hyperthermia and melphalan or ILP with hyperthermia, melphalan, and tumor necrosis factor. Patients will be stratified into high tumor burden, low tumor burden, and reperfusion field. The primary objective is to compare response of lesions in the perfusion field. Secondary objectives are to compare treatment toxicity, time to progression in the treated limb, improvement in regional symptoms related to the tumor, progression?free survival, and overall survival among the treatments groups. Patients must have biopsy-proven melanoma of an extremity with one or more evaluable intransit metastasis indicating advanced local diseaseand have all disease within the perfusion field of the extremity; patients may have disease outside the perfusion field if additional criterion are met (the tumor burden in the extremity is considered high, the patient has significant morbidity associated with the extremity, or at least 80% of the known tumor is within the extremity perfusion field). The patient must also have an estimated life expectancy of at least 6 months, and no evidence of brain metastasis. The trial is planned to randomize 216 patients evenly between the arms and patients will be stratified according to tumor burden and previous perfusion status.