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Randomized Trials in Melanoma: An Update
Surg Oncol Clin N Am 15 (2006) 439–451
Randomized Trials in Melanoma: An Update Alexander M.M. Eggermont, MD, PhD Professor of Surgical Oncology, Erasmus Medical Center, Daniel den Hoed Cancer Center, 301 Groene Hilledijk, EA 3075, Rotterdam, the Netherlands
After Breslow showed that the thickness of the primary lesion determined the prognosis of melanoma, experts began to challenge the concept of a 5-cm margin of excision. Several randomized trials, summarized in Table 1, examined width of margins. Three trials involving patients who had thin melanomas smaller than 2 mm were the WHO-10 trial, which randomized patients to undergo surgery with excision margins of 1 cm or 3 cm (N Cascinelli, personal communication, 1995) [1], and separate French [2] and Scandinavian trials [3] that compared margins of 2 cm with those of 5 cm. The Intergroup Trial in the United States [4,5] randomized patients who had 1-mm to 4-mm melanomas to undergo a 2-cm or 4-cm excision. The narrow and wide excision arms of these studies showed virtually identical local recurrence rates, disease-free survival (DFS), and overall survival (OS). A large nonrandomized study suggested the same was true for patients who had melanomas thicker than 4 mm and therefore a 2-cm excision margin was safe [6]. Thus, a 1-cm margin is adequate for melanomas smaller than 2 mm, and a 2-cm margin for melanomas larger than 2 mm, which means that split skin grafts are rarely necessary.
Surgical management Adjuvant surgical procedures for primary melanoma Margins The United Kingdom Melanoma Study Group [7] compared 1-cm and 3-cm excision margins for melanomas larger than 2 mm in 900 randomized patients, with controversial results. The outcome of this trial was different
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Table 1 Margins and primary melanoma Trial
No. of patients
NE LR
WE LR
NE DFS
WE DFS
NE OS
WE OS
At years
1 vs 3 2 vs 5 2 vs 5
623 319 769
2.5% d 0.8%
1.0% d 1.0%
81% 91% 76%
81% 87% 80%
87% 93% 90%
87% 90% 93%
10 y 4y 5y
2 vs 4 2 vs 4
486 470
0.8% 2.1%
1.7% 2.6%
NS NS
NS NS
80% NS
82% NS
6y 8y
! 2 vs 3–5 1 vs 3
278 900
8%
16%
30%
28%
58% 64% HR 1.07 P ¼ .6
50% 66%
5y
NS
NS
NS
5y
HR 1.26 P ¼ .05 Scandinavian Trial [8]
2 vs 4
936
NS
HR 1.21 P ¼ .06 NS
NS
Abbreviations: DFS, disease-free survival; LR, local recurrence; NE, narrow excision; NS, not significant; OS, overall survival; WE, wide excision.
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Melanoma ! 2 mm WHO-10 [1] French trial [2] Scandinavian [3] Melanoma 1–4 mm Intergroup Trial [4] Update [5] Melanoma O 2 mm Nonrandomized study [6] UK-MsG trial [7]
Margin
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from expected (that again the narrow and wide margins would have equal results). The narrow excision arm showed significantly more locoregional metastases, including local recurrences, in-transit metastases, and regional lymph node metastases (hazard ratio [HR], 1.26; P ¼ .05), and the two arms showed a borderline difference in DFS (HR, 1.21; P ¼ .06). However, an HR of 1.07 showed no difference in survival (P ¼ .6). These results are poorly understood and contradict those of all other trials, although they briefly revived the discussion of whether the recommended 3-cm margins for melanomas thicker than 2 mm should be used. However, the results of a Scandinavian trial, which randomized 936 patients who had melanomas thicker than 2 mm to undergo excisions of 2 cm versus 4 cm, seem to have appeased this concern [8]. This report was presented at the 6th World Congress on Melanoma in Vancouver in September 2005. Trial results were virtually identical in aspects such as locoregional recurrences, distant recurrences, and OS. These results indicate that 2-cm margins are safe and adequate for treating primary melanomas thicker than 2 mm. Regional lymph nodes Failure of elective lymph node dissections to improve survival Experts acknowledge that lymphatic spread usually occurs concurrently with hematogenous metastasis in most solid tumors, including melanoma, and that lymph node metastases are ‘‘indicators rather than governors of survival’’ [9]. Four randomized trials evaluated whether elective (immediate) regional lymph node dissection (ELND) improved survival [10–13]. None of the trials showed a survival benefit for ELND, and therefore the procedure was largely abandoned in Europe. The WHO-14 trial suggested that patients who had micrometastases in lymph nodes after ELND experienced improved survival compared with who underwent a delayed lymph node dissection (DLND) for clinically positive nodes [13]. These data seemed to support the implementation of sentinel node (SN) biopsy [14] as an ideal staging procedure. Sentinel node biopsy SN staging is based on the now well-supported hypothesis that melanoma lymphatic metastases follow an orderly progression through afferent lymphatic channels to SNs before spreading into other regional nonsentinel nodes. Sentinel node status is strongest prognostic factor SN status is the strongest prognostic factor in patients who have melanoma. Literature studies show 5-year OS rates of 93% and 89% for patients who are SN-negative, and OS rates of between 67% and 64% for those who are SN-positive [15–17].
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No proof sentinel node staging provides survival benefit The impact of SN staging on survival is unknown. A recent study by Doubrovsky and colleagues [17] shows that sentinel lymph node biopsy (SLNB) is superior to ELND because of differences in histopathologic protocols for examining the lymph nodes. However, patients who underwent SLNB had no survival advantage compared with patients who underwent ELND in this matched control study. More importantly, the interim analysis of the Multicenter Selective Lymphadenectomy Trial does not suggest any survival benefit for SN staging in the overall population that has high-risk primary melanomas. Survival rates at 5 years are 87% and 86%, respectively, regardless of whether a SN procedure is performed [18]. Whether performing a complete lymph node dissection at identification of a positive SN improves survival is also unclear at the moment. The survival rates at 5 years in patients who are SN-positive are reportedly higher than in patients who did not undergo SN staging and who later underwent a DLND because they developed clinically positive nodes. However, this comparison is not strictly randomized; patients who develop clinically positive disease may represent a biologically unfavorable selection compared with the complete set of patients who are SN-positive. No proof sentinel node staging enhances locoregional recurrence rates Some reports assume an SN procedure increases the rate of in-transit metastasis [19]. However, important unbalances in primary tumor characteristics, such as Breslow thickness and ulceration, occurred in these studies. Studies involving more cases show that the increased rate of in-transit metastasis is not real, but occurs because of a prolonged recurrence-free interval. Because SN procedure avoids nodal recurrences, it increases the chance of in-transit metastases to manifest as a first recurrence site. The overall intransit probability, however, remains unchanged, despite whether early or delayed excision of nodal metastases is performed [20–23]. SN staging can be used in randomized systemic adjuvant therapy trials to stratify patients into more homogeneous populations to determine if the therapies are beneficial [24]. SN staging may improve long-term locoregional control in the lymph node basin compared with patients who undergo DLND [18]. However, ultrasound of the regional lymph nodes may also provide this control by detecting very small nonpalpable lymph node metastases, thus offering an alternative to an SN procedure [25]. In-transit metastasis Failure of prophylactic isolated limb perfusion to improve survival Prophylactic isolated limb perfusion (ILP) as an adjunct to the surgical management of patients who are at high risk for relapse was popular in Europe because retrospective studies suggested improved outcomes. A large
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intergroup trial, which randomized 832 patients to undergo either wide excision alone or wide excision with ILP, showed that prophylactic ILP had a regional effect, with a reduction in the incidence of in-transit metastasis from 6.6% to 3.3% and a reduction in regional lymph node metastases from 16.7% to 12.6%, but no effect on distant relapse-free or OS [26]. Therefore, prophylactic ILP is no longer performed or reimbursed in Europe. In contrast, ILP, especially when melphalan is combined with TNF, is highly effective in treating symptomatic multiple or bulky in-transit metastases, showing complete response (CR) rates of 70%, and in treating melphalan ILP failures with similarly high CR rates [27,28]. Conclusions Phase III randomized trials have shown that wide margins, ELNDs, SLNB, and prophylactic ILPs have not improved survival and therefore cannot be considered standard of care in the routine management of primary melanoma.
Systemic adjuvant therapies Failure of chemotherapy, aspecific immunostimulants, and vaccines Approximately 25 trials have evaluated chemotherapy or aspecific immunostimulants, such as bacille Calmette-Guerin, Corynebacterium parvum, levamisole, or combinations of these agents with dacarbazine, as adjuvant therapies for treating stage II and III melanoma. The trials were largely underpowered and yielded negative results, with the exception of some incidental, nonrepeatable, small trials [9]. Of five randomized trials with allogeneic melanoma cell-based vaccines, none has shown a significant impact on survival, although the results in the Australian trial came very close to showing a significant benefit for an allogeneic tumor cell–based oncolysate vaccine [29]. The Melacine vaccine (Corixa Corporation, Seattle, Washington) trial in patients who had stage II melanoma showed negative results overall [30], but encouraging results in patients who had particular HLA types [31]. A small trial of the ganglioside GM2 showed a benefit, but only in a subset of patients who had stage III melanoma who were seronegative for ganglioside antibodies before trial entry [32]. This study led to the currently ongoing EORTC-18961 trial in patients who have stage II melanoma [9]. The large adjuvant trials with the allogenic cell-based vaccine Canvaxin (CancerVax, Carlsbad, California) in stage III and in resected stage IV melanoma have demonstrated no impact of the vaccine on survival and were recently stopped for further follow up (stage III) or accrual (stage IV) on the basis of interim analyses, in spite of promising outcome suggested by matched control studies [33].
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Adjuvant therapy with interferon alpha an ongoing controversy The use of high-dose interferon (HDI) therapy is approved by the U.S. Food and Drug Administration and European Medicine Evaluation Agency (EMEA) for high-risk melanoma (stage IIB and III). Although often used in the United States and despite its impact on DFS, HDI is used rarely in Europe because of its unproven effect on OS, a different appreciation of the toxicity associated with HDI, and the high costs of the treatment [9,34]. A systematic review of all trials [35], a meta-analysis of all phase III trials [36], and a pooled data analysis of all HDI trials [37] showed consistent improvement in DFS but none in OS. Low-dose interferon (LDI) therapy has shown less impact on DFS in stage III and consistent improvement of DFS in stage II, but never improvement of OS [34]. Regardless, the EMEA approved LDI for stage II although the FDA did not. Therefore, because LDI has not shown worthwhile activity, its use cannot be justified [36]. The largest phase III trial to date (EORTC18952) tested intermediate doses of IFN (IMI), showing some statistically insignificant activity in stage IIB and III disease (7.2% increase of distant metastases-free interval; 5.4% increase of OS at 4.65 years follow-up) for 25 months of therapy using 5 million units, and no effect for 13 months of therapy using 10 million units [38]. The better outcome for the lower dose at longer duration in the EORTC-18952 trial suggests that duration is more important than dose. The EORTC-18991 trial, which will be analyzed in 2006, tests this theory by comparing 5 years of PEGINTRON therapy (Schering-Plough Corporation, Kenilworth, New Jersey) with observation in 1256 patients who have stage III melanoma. Overall, IFN fails to show significant impact on OS in stage IV and in the adjuvant setting. The subpopulation of patients who have melanoma and will benefit of IFN therapy must be identified and the role of IFN determined [34]. Conclusions The lack of effective adjuvant therapies in stage II and III melanoma reflects the lack of effective drugs in stage IV disease. Chemotherapeutic drugs, immunostimulants, and various vaccines have all failed. Although IFN has some effect, many experts believe it too slight to consider this therapy standard of care. Ongoing genomics and proteomics studies must identify the population of patients that can benefit from IFN. The potential value of long-term maintenance therapy using pegylated IFN (EORTC18991) or vaccine therapy using Canvaxin will be analyzed in 2006. Systemic therapies for stage IV disease No effective systemic therapy exists for metastatic melanoma Little progress has been made over the past 3 decades in the systemic treatment of metastatic melanoma. The response rate to the standard
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drug dacarbazine is probably less than 10% and no treatment is good enough to be considered standard of care [39]. Polychemotherapy and addition of tamoxifen, interferon, and interleukin-2 have failed to improve survival in more than 27 phase III trials [40–67], which are summarized in Tables 2 through 4. Patients who have stage IV melanoma should be offered new agents as first-line treatments to identify those that are active. Moreover, vaccine therapy trials have yielded very low response rates and no indication of any impact on survival [68]. Dendritic cells [69] and peptides in combination with IL-2 failed to show response in randomized trials [70]. The anti–cytotoxic Tlymphocyte–associated protein-4 (CTLA-4) antibody may be important alone or in combination with cytokines and vaccines because it fundamentally changes the balance between T-helper and T-supressor cells and can change the immune response and status of patients who have melanoma and cause (lasting) tumor regressions [71]. Phase III trials are currently testing the anti–CTLA-4 antibody alone and in combination with IL-2 and vaccines. The proapoptotic agent oblimersen was administered in a large phase III trial involving 777 patients. When given in combination with dacarbazine, it improved response rates and progression-free survival significantly, although OS did not significantly improve. Only the patients who had normal lactate dehydrogenase levels seemed to experience all benefits and a significant impact on survival (two thirds of the total population) [72]. Another important development is Sorafenib (Bayer Pharmaceuticals Corporation, Hartford, Connecticut), a tyrosine kinase (B-RAF) inhibitor with important antivascular endothelial growth factor receptor 2–mediated antiangiogenic properties that is currently being evaluated in combination with chemotherapy Table 2 Chemotherapy versus polychemotherapy G tamoxifen Study Chemotherapies Jungnelius, 1998 [40] Je´lic, 2002 [41]
Regimen
DV vs DVC 326 D1CaV vs D2CaV 219 vs VBIC vs CaP TMZ vs TMZþC 132
Bafaloukos, 2005 [42] Chemotherapies involving tamoxifen Cocconi, 1992 [43] D vs DT Rusthoven, 1996 [44] BCB vs DCBT Falkson, 1998 [45] DGTGIFN Agarwala, 1999 [46] Creagan, 1999 [47] Chapman, 1999 [48]
No. of Median patients survival (y)
DþCarboGT DCaCGT D vs DCBT
117 204 248 56 184 240
5.9 vs 7.2 4 vs 5 vs 6 vs 4 11.5 vs 12
Significance NS NS NS
6.5 vs 11 P ¼ .02 7 vs 7 NS 10 vs 9 vs 8 NS vs 9.5 7 vs 4.6 NS 6.8 vs 6.9 NS 6.4 vs 7.7 NS
Abbreviations: B, BCNU; BI, bleomycin; C, cisplatin; Ca, carmustine; Carbo, carboplatin; D, dacarbazine; IFN, interferonalpha; NS, not significant; P, procarbazine; T, tamoxifen; TMZ, temozolomide; V, vinblastine.
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Table 3 Chemotherapy G IFN Study
Regimen
No. of Median patients survival
Chemotherapy þ/ interferon-a Falkson, 1991 [49] D vs DþIFN 64 Thomson, 1993 [50] D vs DþIFN 170 Bajetta, 1994 [51] D vs DþIFN (3MU) 242 vs DþIFN (9MU) Falkson, 1998 [45] DGTGIFN 248 Dorval, 1999 [52] Middleton, 2000 [53] Young, 2001 [54] Vuoristo, 2005 [55]
C/IL-2GIFN DþIFN vs DCBT D vs DþIFN DþnIFN vs DCBTþrIFN vs DþrIFN vs DCBTþrIFN
117 105 61 108
Significance
9.6 vs 17.6 P ! .01 8.8 vs 7.6 NS 11 vs 11 vs 13 NS 10 vs 9 vs 8 vs 9.5 10.4 vs 10.9 6.5 vs 6.5 7.2 vs 4.3 11 vs 10 vs 9 vs 7.5NS
NS NS NS NS NS
Abbreviations: B, BCNU; C, cisplatin; D, dacarbazine; IFN, interferon alpha; IL-2, interleukin2; NS, not significant; T, tamoxifen; V, vinblastine.
in phase III trials as first- and second-line treatment [74]. More complex, but of fundamental importance, is the ongoing research on the use of dendritic cells. Rosenberg’s group has reported remarkable results with chemotherapy lymphodepletion followed by adoptive transfer of autologous tumor– reactive lymphocytes in patients who have refractory melanoma who have undergone extensive pretreatment [74]. With this therapy, they reported Table 4 Phase III trials with IL-2 (and IFN)-containing regimens Study
Regimen
No. of patients
Median survival
Significance
IFN- and IL-2–containing regimens Sparano, 1993 [56] Keilholz, 1997 [57] Johnston, 1998 [58] Dorval, 1999 [52] Rosenberg, 1999 [59] Hauschild, 2001 [60] Eton, 2002 [61] Atzpodien, 2002 [62] Agarwalla, 2002 [63] Ridolfi, 2002 [64] Del Vecchio, 2003 [65] Atkins, 2003 [66] Keilholz, 2005 [67]
IL-2 G IFN IL-2/IFN G C CDBT G IFN/IL-2 C/IL-2 G/ IFN CDT G IFN/IL-2 D/IFN G IL-2 CVD G IFN/IL-2 D/B/C/T G IFN/IL-2 IL-2 vs HistamineþIL-2 CVD G IFN/IL-2 CVD G IFN/IL-2 CVD G IFN/IL-2 CD/IFN G IL-2
85 133 65 117 105 290 183 124 305 176 139 416 363
10.2 vs 9.7 9 vs 9 5.5 vs 5.0 10.4 vs 10.9 15.8 vs 10.7 11 vs 11 9.5 vs 11.8 13 vs 12 8.2 vs 9.1 9.5 vs 11 12 vs 11 8.7 vs 8.4 9 vs 9
NS NS NS NS P ! .06 NS P ! .06 NS NS NS NS NS NS
Abbreviations: B, BCNU; C, cisplatin; D, dacarbazine; IFN, interferon alpha; IL-2, interleukin2; NS, not significant.
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a response rate of 51% in 35 patients, providing insight into what patients who have melanoma require to experience tumor regression. Summary No effective therapy for metastatic melanoma exists. Polychemotherapy or chemoimmunotherapy have not shown survival benefits. Vaccines have shown little activity in stage IV disease. To advance the identification of effective agents, new drugs can and should be offered as first-line treatment. Efforts must be made to improve understanding of the biology of malignant melanoma. Too many phase III trials have been conducted with a poor understanding of the mechanism of action of the involved drugs. References [1] 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: 1159–62. [2] Banzet P, Thomas A, Vuillemin E, et al. Wide versus narrow surgical excision in thin (! 2 mm) stage I primary cutaneous malignant melanoma: long term results of a French multicentric prospective randomized trial on 319 patients. Proc Am Assoc Clin Oncol 1993;12:387. [3] Cohn-Cedermark G, Rutqvist LE, Andersson R, et al. Long term results of a randomized study by the Swedish Melanoma Study Group on 2-cm versus 5-cm resection margins for patients with cutaneous melanoma with a tumor thickness of 0.8–2.0 mm. Cancer 2000; 89:1495–501. [4] 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;218:262–7 [discussion: 267–9]. [5] Balch CM, Soong SJ, Smith T, et al. Long-term results of a prospective surgical trial comparing 2 cm vs. 4 cm excision margins for 740 patients with 1–4 mm melanomas. Ann Surg Oncol 2001;8:101–8. [6] Heaton KM, Sussman JJ, Gershenwald JE, et al. Surgical margins and prognostic factors in patients with thick (O 4mm) primary melanoma. Ann Surg Oncol 1998;5: 322–8. [7] Thomas JM, Newton-Bishop J, A’Hern R, et al. Excision margins in high-risk malignant melanoma. N Engl J Med 2004;350(8):757–66. [8] Ringborg U, Mansson Brahme E, Drzewiecki K, et al. Randomized trial of a resection margin of 2 cm versus 4 cm for cutaneous malignant melanoma with a tumor thickness of more than 2 mm. Abstract 28; Proceedings of the 6th World Congress on Melanoma. Vancouver, September 6–10, 2005. [9] Eggermont AMM, Gore M. European approach to adjuvant treatments of intermediateand high-risk malignant melanoma. Semin Oncol 2002;29(4):382–8. [10] Veronesi U, Adamus J, Bandiera DC, et al. Inefficacy of immediate node dissection in stage 1 melanoma of the limbs. N Engl J Med 1977;297:627–30. [11] Sim FH, Taylor WF, Ivins JC, et al. A prospective randomized study of the efficacy of routine elective lymphadenectomy in management of malignant melanoma. Preliminary results. Cancer 1978;41:948–56. [12] 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;7:87–97.
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[13] Cascinelli N, Morabito A, Santinami M, et al. Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: a randomised trial. WHO Melanoma Programme. Lancet 1998;351:793–6. [14] Morton DL, Wen DR, Wong JH, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992;127:392–9. [15] 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 1999;17:976–83. [16] Vuylsteke RJ, van Leeuwen PA, Statius Muller MG, et al. Clinical outcome of stage I/II melanoma patients after selective sentinel lymph node dissection: long-term follow-up results. J Clin Oncol 2003;21:1057–65. [17] Doubrovsky A, De Wilt JH, Scolyer RA, et al. Sentinel node biopsy provides more accurate staging than elective lymph node dissection in patients with cutaneous melanoma. Ann Surg Oncol 2004;11:829–36. [18] Morton DL, Thompson JF, Cochran AJ, et al. Interim results of the Multicenter Selective Lymphadenectomy Trial (MSLT-I) in clinical stage I melanoma. Abstract 7500. Available at: http://www.asco.org/ac/1,1003,_12–002511–00_18–0034–00_19–003013,00.asp. 2005. Accessed May 25, 2005. [19] Thomas JM, Clark MA. Selective lymphadenectomy in sentinel node-positive patients may increase the risk of local/in-transit recurrence in malignant melanoma. Eur J Surg Oncol 2004;30(6):686–91. [20] Kretschmer L, Beckmann I, Thoms KM, et al. Sentinel lymphonodectomy does not increase the risk of loco-regional cutaneous metastases of malignant melanomas. Eur J Cancer 2005; 41:531–8. [21] van Poll D, Thompson JF, Colman MH, et al. A sentinel node biopsy does not increase the incidence of in-transit metastasis in patients with primary cutaneous melanoma. Ann Surg Oncol 2005;12(8):597–608. [22] Kang JC, Wanek LA, Essner R, et al. Sentinel lymphadenectomy does not increase the incidence of in-transit metastases in primary melanoma. J Clin Oncol 2005;23(21):4764–70. [23] Pawlik TM, Ross MI, Thompson JF, et al. The risk of in-transit metastasis depends on tumor biology and not the surgical approach to regional lymph nodes. J Clin Oncol 2005;23: 4588–90. [24] Eggermont AMM. Adjuvant therapy of malignant melanoma and the role of sentinel node mapping. Recent Results Cancer Res 2000;157:178–89. [25] Eggermont AMM. Reducing the need for sentinel node procedures by ultrasound examination of regional lymph nodes. Ann Surg Oncol 2005;12(1):3–5. [26] Koops HS, Vaglini M, Suciu S, et al. Prophylactic isolated limb perfusion for localized, highrisk limb melanoma: results of a multicenter randomized phase III trial. European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593. J Clin Oncol 1998;16(9): 2906–12. [27] Gru¨nhagen DJ, Brunstein F, Graveland WJ, et al. One hundred consecutive isolated limb perfusions with TNF-alpha and melphalan in melanoma patients with multiple in-transit metastases. Ann Surg 2004;240:939–47. [28] Gru¨nhagen DJ, van Etten B, Brunstein F, et al. Efficacy of repeat isolated limb perfusions with tumor necrosis factor alpha and melphalan for multiple in-transit metastases in patients with prior isolated limb perfusion failure. Ann Surg Oncol 2005;12(8):597–608. [29] Hersey P, Coates AS, McCarthy WH, et al. Adjuvant immunotherapy of patients with highrisk melanoma using vaccinia viral lysates of melanoma: results of a randomized trial. J Clin Oncol 2002;20(20):4181–90. [30] Sondak VK, Liu PY, Tuthill RJ, et al. Adjuvant immunotherapy of resected, intermediate-thickness, node-negative melanoma with an allogeneic tumor vaccine: overall results
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[31]
[32]
[33]
[34] [35] [36] [37]
[38]
[39] [40]
[41]
[42]
[43] [44]
[45]
[46]
[47]
[48]
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[49] Falkson CI, Falkson G, Falkson HC. Improved results with the addition of interferon alfa2b to dacarbazine in the treatment of patients with metastatic malignant melanoma. J Clin Oncol 1991;9:1403–8. [50] Thomson DB, Adena M, McLeod GRC, et al. Interferon-alpha 2a does not improve response or survival when combined with dacarbazine in metastatic malignant melanoma: results of a multi-institutional Australian randomized trial. Melanoma Res 1993;3:133–8. [51] Bajetta E, Di Leo A, Zampino MG, et al. Multicenter randomized trial of dacarbazine alone or in combination with two different doses and schedules of interferon alfa-2a in the treatment of advanced melanoma. J Clin Oncol 1994;12(4):806–11. [52] Dorval T, Negrier S, Chevreau C, et al. Randomized trial of treatment with cisplatin and interleukin-2 either alone or in combination with interferon-alpha-2a in patients with metastatic melanoma: a Federation Nationale des Centres de Lutte Contre le Cancer Multicenter, parallel study. Cancer 1999;85:1060–6. [53] Middleton MR, Lorigan P, Owen J, et al. A randomized phase III study comparing dacarbazine, BCNU, cisplatin and tamoxifen with dacarbazine and interferon in advanced melanoma. Br J Cancer 2000;82:1158–62. [54] Young AM, Marsden J, Goodman A, et al. Prospective randomized comparison of dacarbazine (DTIC) versus DTIC plus interferon-alpha (IFN-alpha) in metastatic melanoma. Clin Oncol 2001;13:458–65. [55] Vuoristo MS, Hahka-Kemppinen M, Parvinen LM, et al. Randomized trial of dacarbazine versus bleomycin, vincristine, lomustine and dacarbazine (BOLD) chemotherapy combined with natural or recombinant interferon-alpha in patients with advanced melanoma. Melanoma Res 2005;15(4):291–6. [56] Sparano JA, Fisher RI, Sunderland M, et al. Randomized phase III trial of treatment with high-dose interleukin-2 either alone or in combination with interferon alfa-2a in patients with advanced melanoma. J Clin Oncol 1993;11:1969–77. [57] Keilholz U, Goey SH, Punt CJ, et al. Interferon alfa-2a and interleukin-2 with or without cisplatin in metastatic melanoma: a randomized trial of the European Organization for Research and Treatment of Cancer Melanoma Cooperative Group. J Clin Oncol 1997;7: 2579–88. [58] Johnston SR, Constenla DO, Moore J, et al. Randomized phase II trial of BCDT [carmustine (BCNU), cisplatin, dacarbazine (DTIC) and tamoxifen] with or without interferon alpha (IFN-alpha) and interleukin (IL-2) in patients with metastatic melanoma. Br J Cancer 1998;77:1280–6. [59] Rosenberg SA, Yang JC, Schwartzentruber DJ, et al. Prospective randomized trial of the treatment of patients with metastatic melanoma using chemotherapy with cisplatin, dacarbazine, and tamoxifen alone or in combination with interleukin-2 and interferon alfa-2b. J Clin Oncol 1999;17:968–75. [60] Hauschild A, Garbe C, Stolz W, et al. Dacarbazine and interferon alpha with or without interleukin 2 in metastatic melanoma: a randomized phase III multicentre trial of the Dermatologic Cooperative Oncology Group (DeCOG). Br J Cancer 2001;84: 1036–42. [61] 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: 2045–52. [62] Atzpodien J, Neuber K, Kamanabrou D, et al. Combination chemotherapy with or without s.c. IL-2 and IFN-alpha: results of a prospectively randomized trial of the Cooperative Advanced Malignant Melanoma Chemoimmunotherapy group (ACIMM). Br J Cancer 2002; 86:179–84. [63] Agarwala SS, Glaspy J, O’Day SJ, et al. Results from a randomized phase III study comparing combined treatment with histamine dihydrochloride plus interleukin-2 versus interleukin-2 alone in patients with metastatic melanoma. J Clin Oncol 2002;20:125–33.
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[64] Ridolfi R, Chiarion-Sileni V, Guida M, et al. Cisplatin, Dacarbazine with or without subcutaneous interleukin-2 and interferon alfa-2b in advanced melanoma outpatients: results from an Italian multicenter phase III randomized clinical trial. J Clin Oncol 2002;20:1600–7. [65] 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). Proc Am Soc Clin Oncol 2003;22:709. Abstract 2849. [66] Atkins MB, Lee S, Flaherty LE, et al. 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 ECOGcoordinated intergroup trial. Proc Am Soc Clin Oncol 2003;22:708. Abstract 2847. [67] Keilholz U, Punt CJ, Gore M, et al. Dacarbazine, Cisplatin, and interferon-alfa-2b with or without interleukin-2 in metastatic melanoma: a randomized phase iii trial (18951) of the European Organisation for Research and Treatment of Cancer Melanoma Group. J Clin Oncol 2005;23(27):6747–55. [68] Rosenberg SA, Yang JC, Restifo NP. Cancer-immunotherapy: moving beyond current vaccines. Nat Med 2004;10:909–15. [69] Schadendorf D, Nestle FO, Broecker EB, et al, DeCOG-DC Study Group. Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) as first-line treatment of patients with metastatic melanoma: results of a prospective-randomized phase III study. J Clin Oncol 2004;22(14 Suppl):7508. [70] Ernstoff M, Carrillo C, Urba W, et al. A Cytokine Working Group (CWG) 3-arm phase II trial of gp100 (209–2M) peptide þ high dose (HD) Interleukin-2 (IL-2) in HLA-A2þ (A2þ) advanced melanoma patients (pts). Proceedings of the 41st Annual Meeting of the American Society of Clinical Oncology; May 13–17, 2005; Orlando, Fla. Abstract 7504. [71] Korman A, Yellin M, Keler T. Tumor immunotherapy: preclinical and clinical activity of anti-CTLA4 antibodies. Curr Opin Invest Drugs 2005;6:582–91. [72] Flaherty KT. New molecular targets in melanoma. Curr Opin Oncol 2004;16:150–4 [Review]. [73] Kirkwood JM, Bedikian AY, Millward MJ, et al. Long-term survival results of a randomized multinational phase 3 trial of dacarbazine (DTIC) with or without Bcl-2 antisense (oblimersen sodium) in patients (pts) with advanced malignant melanoma (MM). Proceedings of the 41st Annual Meeting of the American Society of Clinical Oncology; May 13–17, 2005; Orlando, Fla. Abstract 7506. [74] Dudley ME, Wunderlich JR, Yang JC, et al. Adoptive cell transfer therapy following nonmyeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol 2005;23:2346–57.
Randomized Trials in Melanoma: An Update Alexander M.M. Eggermont, MD, PhD Professor of Surgical Oncology, Erasmus Medical Center, Daniel den Hoed Cancer Center, 301 Groene Hilledijk, EA 3075, Rotterdam, the Netherlands
After Breslow showed that the thickness of the primary lesion determined the prognosis of melanoma, experts began to challenge the concept of a 5-cm margin of excision. Several randomized trials, summarized in Table 1, examined width of margins. Three trials involving patients who had thin melanomas smaller than 2 mm were the WHO-10 trial, which randomized patients to undergo surgery with excision margins of 1 cm or 3 cm (N Cascinelli, personal communication, 1995) [1], and separate French [2] and Scandinavian trials [3] that compared margins of 2 cm with those of 5 cm. The Intergroup Trial in the United States [4,5] randomized patients who had 1-mm to 4-mm melanomas to undergo a 2-cm or 4-cm excision. The narrow and wide excision arms of these studies showed virtually identical local recurrence rates, disease-free survival (DFS), and overall survival (OS). A large nonrandomized study suggested the same was true for patients who had melanomas thicker than 4 mm and therefore a 2-cm excision margin was safe [6]. Thus, a 1-cm margin is adequate for melanomas smaller than 2 mm, and a 2-cm margin for melanomas larger than 2 mm, which means that split skin grafts are rarely necessary.
Surgical management Adjuvant surgical procedures for primary melanoma Margins The United Kingdom Melanoma Study Group [7] compared 1-cm and 3-cm excision margins for melanomas larger than 2 mm in 900 randomized patients, with controversial results. The outcome of this trial was different
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Table 1 Margins and primary melanoma Trial
No. of patients
NE LR
WE LR
NE DFS
WE DFS
NE OS
WE OS
At years
1 vs 3 2 vs 5 2 vs 5
623 319 769
2.5% d 0.8%
1.0% d 1.0%
81% 91% 76%
81% 87% 80%
87% 93% 90%
87% 90% 93%
10 y 4y 5y
2 vs 4 2 vs 4
486 470
0.8% 2.1%
1.7% 2.6%
NS NS
NS NS
80% NS
82% NS
6y 8y
! 2 vs 3–5 1 vs 3
278 900
8%
16%
30%
28%
58% 64% HR 1.07 P ¼ .6
50% 66%
5y
NS
NS
NS
5y
HR 1.26 P ¼ .05 Scandinavian Trial [8]
2 vs 4
936
NS
HR 1.21 P ¼ .06 NS
NS
Abbreviations: DFS, disease-free survival; LR, local recurrence; NE, narrow excision; NS, not significant; OS, overall survival; WE, wide excision.
EGGERMONT
Melanoma ! 2 mm WHO-10 [1] French trial [2] Scandinavian [3] Melanoma 1–4 mm Intergroup Trial [4] Update [5] Melanoma O 2 mm Nonrandomized study [6] UK-MsG trial [7]
Margin
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from expected (that again the narrow and wide margins would have equal results). The narrow excision arm showed significantly more locoregional metastases, including local recurrences, in-transit metastases, and regional lymph node metastases (hazard ratio [HR], 1.26; P ¼ .05), and the two arms showed a borderline difference in DFS (HR, 1.21; P ¼ .06). However, an HR of 1.07 showed no difference in survival (P ¼ .6). These results are poorly understood and contradict those of all other trials, although they briefly revived the discussion of whether the recommended 3-cm margins for melanomas thicker than 2 mm should be used. However, the results of a Scandinavian trial, which randomized 936 patients who had melanomas thicker than 2 mm to undergo excisions of 2 cm versus 4 cm, seem to have appeased this concern [8]. This report was presented at the 6th World Congress on Melanoma in Vancouver in September 2005. Trial results were virtually identical in aspects such as locoregional recurrences, distant recurrences, and OS. These results indicate that 2-cm margins are safe and adequate for treating primary melanomas thicker than 2 mm. Regional lymph nodes Failure of elective lymph node dissections to improve survival Experts acknowledge that lymphatic spread usually occurs concurrently with hematogenous metastasis in most solid tumors, including melanoma, and that lymph node metastases are ‘‘indicators rather than governors of survival’’ [9]. Four randomized trials evaluated whether elective (immediate) regional lymph node dissection (ELND) improved survival [10–13]. None of the trials showed a survival benefit for ELND, and therefore the procedure was largely abandoned in Europe. The WHO-14 trial suggested that patients who had micrometastases in lymph nodes after ELND experienced improved survival compared with who underwent a delayed lymph node dissection (DLND) for clinically positive nodes [13]. These data seemed to support the implementation of sentinel node (SN) biopsy [14] as an ideal staging procedure. Sentinel node biopsy SN staging is based on the now well-supported hypothesis that melanoma lymphatic metastases follow an orderly progression through afferent lymphatic channels to SNs before spreading into other regional nonsentinel nodes. Sentinel node status is strongest prognostic factor SN status is the strongest prognostic factor in patients who have melanoma. Literature studies show 5-year OS rates of 93% and 89% for patients who are SN-negative, and OS rates of between 67% and 64% for those who are SN-positive [15–17].
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No proof sentinel node staging provides survival benefit The impact of SN staging on survival is unknown. A recent study by Doubrovsky and colleagues [17] shows that sentinel lymph node biopsy (SLNB) is superior to ELND because of differences in histopathologic protocols for examining the lymph nodes. However, patients who underwent SLNB had no survival advantage compared with patients who underwent ELND in this matched control study. More importantly, the interim analysis of the Multicenter Selective Lymphadenectomy Trial does not suggest any survival benefit for SN staging in the overall population that has high-risk primary melanomas. Survival rates at 5 years are 87% and 86%, respectively, regardless of whether a SN procedure is performed [18]. Whether performing a complete lymph node dissection at identification of a positive SN improves survival is also unclear at the moment. The survival rates at 5 years in patients who are SN-positive are reportedly higher than in patients who did not undergo SN staging and who later underwent a DLND because they developed clinically positive nodes. However, this comparison is not strictly randomized; patients who develop clinically positive disease may represent a biologically unfavorable selection compared with the complete set of patients who are SN-positive. No proof sentinel node staging enhances locoregional recurrence rates Some reports assume an SN procedure increases the rate of in-transit metastasis [19]. However, important unbalances in primary tumor characteristics, such as Breslow thickness and ulceration, occurred in these studies. Studies involving more cases show that the increased rate of in-transit metastasis is not real, but occurs because of a prolonged recurrence-free interval. Because SN procedure avoids nodal recurrences, it increases the chance of in-transit metastases to manifest as a first recurrence site. The overall intransit probability, however, remains unchanged, despite whether early or delayed excision of nodal metastases is performed [20–23]. SN staging can be used in randomized systemic adjuvant therapy trials to stratify patients into more homogeneous populations to determine if the therapies are beneficial [24]. SN staging may improve long-term locoregional control in the lymph node basin compared with patients who undergo DLND [18]. However, ultrasound of the regional lymph nodes may also provide this control by detecting very small nonpalpable lymph node metastases, thus offering an alternative to an SN procedure [25]. In-transit metastasis Failure of prophylactic isolated limb perfusion to improve survival Prophylactic isolated limb perfusion (ILP) as an adjunct to the surgical management of patients who are at high risk for relapse was popular in Europe because retrospective studies suggested improved outcomes. A large
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intergroup trial, which randomized 832 patients to undergo either wide excision alone or wide excision with ILP, showed that prophylactic ILP had a regional effect, with a reduction in the incidence of in-transit metastasis from 6.6% to 3.3% and a reduction in regional lymph node metastases from 16.7% to 12.6%, but no effect on distant relapse-free or OS [26]. Therefore, prophylactic ILP is no longer performed or reimbursed in Europe. In contrast, ILP, especially when melphalan is combined with TNF, is highly effective in treating symptomatic multiple or bulky in-transit metastases, showing complete response (CR) rates of 70%, and in treating melphalan ILP failures with similarly high CR rates [27,28]. Conclusions Phase III randomized trials have shown that wide margins, ELNDs, SLNB, and prophylactic ILPs have not improved survival and therefore cannot be considered standard of care in the routine management of primary melanoma.
Systemic adjuvant therapies Failure of chemotherapy, aspecific immunostimulants, and vaccines Approximately 25 trials have evaluated chemotherapy or aspecific immunostimulants, such as bacille Calmette-Guerin, Corynebacterium parvum, levamisole, or combinations of these agents with dacarbazine, as adjuvant therapies for treating stage II and III melanoma. The trials were largely underpowered and yielded negative results, with the exception of some incidental, nonrepeatable, small trials [9]. Of five randomized trials with allogeneic melanoma cell-based vaccines, none has shown a significant impact on survival, although the results in the Australian trial came very close to showing a significant benefit for an allogeneic tumor cell–based oncolysate vaccine [29]. The Melacine vaccine (Corixa Corporation, Seattle, Washington) trial in patients who had stage II melanoma showed negative results overall [30], but encouraging results in patients who had particular HLA types [31]. A small trial of the ganglioside GM2 showed a benefit, but only in a subset of patients who had stage III melanoma who were seronegative for ganglioside antibodies before trial entry [32]. This study led to the currently ongoing EORTC-18961 trial in patients who have stage II melanoma [9]. The large adjuvant trials with the allogenic cell-based vaccine Canvaxin (CancerVax, Carlsbad, California) in stage III and in resected stage IV melanoma have demonstrated no impact of the vaccine on survival and were recently stopped for further follow up (stage III) or accrual (stage IV) on the basis of interim analyses, in spite of promising outcome suggested by matched control studies [33].
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Adjuvant therapy with interferon alpha an ongoing controversy The use of high-dose interferon (HDI) therapy is approved by the U.S. Food and Drug Administration and European Medicine Evaluation Agency (EMEA) for high-risk melanoma (stage IIB and III). Although often used in the United States and despite its impact on DFS, HDI is used rarely in Europe because of its unproven effect on OS, a different appreciation of the toxicity associated with HDI, and the high costs of the treatment [9,34]. A systematic review of all trials [35], a meta-analysis of all phase III trials [36], and a pooled data analysis of all HDI trials [37] showed consistent improvement in DFS but none in OS. Low-dose interferon (LDI) therapy has shown less impact on DFS in stage III and consistent improvement of DFS in stage II, but never improvement of OS [34]. Regardless, the EMEA approved LDI for stage II although the FDA did not. Therefore, because LDI has not shown worthwhile activity, its use cannot be justified [36]. The largest phase III trial to date (EORTC18952) tested intermediate doses of IFN (IMI), showing some statistically insignificant activity in stage IIB and III disease (7.2% increase of distant metastases-free interval; 5.4% increase of OS at 4.65 years follow-up) for 25 months of therapy using 5 million units, and no effect for 13 months of therapy using 10 million units [38]. The better outcome for the lower dose at longer duration in the EORTC-18952 trial suggests that duration is more important than dose. The EORTC-18991 trial, which will be analyzed in 2006, tests this theory by comparing 5 years of PEGINTRON therapy (Schering-Plough Corporation, Kenilworth, New Jersey) with observation in 1256 patients who have stage III melanoma. Overall, IFN fails to show significant impact on OS in stage IV and in the adjuvant setting. The subpopulation of patients who have melanoma and will benefit of IFN therapy must be identified and the role of IFN determined [34]. Conclusions The lack of effective adjuvant therapies in stage II and III melanoma reflects the lack of effective drugs in stage IV disease. Chemotherapeutic drugs, immunostimulants, and various vaccines have all failed. Although IFN has some effect, many experts believe it too slight to consider this therapy standard of care. Ongoing genomics and proteomics studies must identify the population of patients that can benefit from IFN. The potential value of long-term maintenance therapy using pegylated IFN (EORTC18991) or vaccine therapy using Canvaxin will be analyzed in 2006. Systemic therapies for stage IV disease No effective systemic therapy exists for metastatic melanoma Little progress has been made over the past 3 decades in the systemic treatment of metastatic melanoma. The response rate to the standard
445
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drug dacarbazine is probably less than 10% and no treatment is good enough to be considered standard of care [39]. Polychemotherapy and addition of tamoxifen, interferon, and interleukin-2 have failed to improve survival in more than 27 phase III trials [40–67], which are summarized in Tables 2 through 4. Patients who have stage IV melanoma should be offered new agents as first-line treatments to identify those that are active. Moreover, vaccine therapy trials have yielded very low response rates and no indication of any impact on survival [68]. Dendritic cells [69] and peptides in combination with IL-2 failed to show response in randomized trials [70]. The anti–cytotoxic Tlymphocyte–associated protein-4 (CTLA-4) antibody may be important alone or in combination with cytokines and vaccines because it fundamentally changes the balance between T-helper and T-supressor cells and can change the immune response and status of patients who have melanoma and cause (lasting) tumor regressions [71]. Phase III trials are currently testing the anti–CTLA-4 antibody alone and in combination with IL-2 and vaccines. The proapoptotic agent oblimersen was administered in a large phase III trial involving 777 patients. When given in combination with dacarbazine, it improved response rates and progression-free survival significantly, although OS did not significantly improve. Only the patients who had normal lactate dehydrogenase levels seemed to experience all benefits and a significant impact on survival (two thirds of the total population) [72]. Another important development is Sorafenib (Bayer Pharmaceuticals Corporation, Hartford, Connecticut), a tyrosine kinase (B-RAF) inhibitor with important antivascular endothelial growth factor receptor 2–mediated antiangiogenic properties that is currently being evaluated in combination with chemotherapy Table 2 Chemotherapy versus polychemotherapy G tamoxifen Study Chemotherapies Jungnelius, 1998 [40] Je´lic, 2002 [41]
Regimen
DV vs DVC 326 D1CaV vs D2CaV 219 vs VBIC vs CaP TMZ vs TMZþC 132
Bafaloukos, 2005 [42] Chemotherapies involving tamoxifen Cocconi, 1992 [43] D vs DT Rusthoven, 1996 [44] BCB vs DCBT Falkson, 1998 [45] DGTGIFN Agarwala, 1999 [46] Creagan, 1999 [47] Chapman, 1999 [48]
No. of Median patients survival (y)
DþCarboGT DCaCGT D vs DCBT
117 204 248 56 184 240
5.9 vs 7.2 4 vs 5 vs 6 vs 4 11.5 vs 12
Significance NS NS NS
6.5 vs 11 P ¼ .02 7 vs 7 NS 10 vs 9 vs 8 NS vs 9.5 7 vs 4.6 NS 6.8 vs 6.9 NS 6.4 vs 7.7 NS
Abbreviations: B, BCNU; BI, bleomycin; C, cisplatin; Ca, carmustine; Carbo, carboplatin; D, dacarbazine; IFN, interferonalpha; NS, not significant; P, procarbazine; T, tamoxifen; TMZ, temozolomide; V, vinblastine.
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Table 3 Chemotherapy G IFN Study
Regimen
No. of Median patients survival
Chemotherapy þ/ interferon-a Falkson, 1991 [49] D vs DþIFN 64 Thomson, 1993 [50] D vs DþIFN 170 Bajetta, 1994 [51] D vs DþIFN (3MU) 242 vs DþIFN (9MU) Falkson, 1998 [45] DGTGIFN 248 Dorval, 1999 [52] Middleton, 2000 [53] Young, 2001 [54] Vuoristo, 2005 [55]
C/IL-2GIFN DþIFN vs DCBT D vs DþIFN DþnIFN vs DCBTþrIFN vs DþrIFN vs DCBTþrIFN
117 105 61 108
Significance
9.6 vs 17.6 P ! .01 8.8 vs 7.6 NS 11 vs 11 vs 13 NS 10 vs 9 vs 8 vs 9.5 10.4 vs 10.9 6.5 vs 6.5 7.2 vs 4.3 11 vs 10 vs 9 vs 7.5NS
NS NS NS NS NS
Abbreviations: B, BCNU; C, cisplatin; D, dacarbazine; IFN, interferon alpha; IL-2, interleukin2; NS, not significant; T, tamoxifen; V, vinblastine.
in phase III trials as first- and second-line treatment [74]. More complex, but of fundamental importance, is the ongoing research on the use of dendritic cells. Rosenberg’s group has reported remarkable results with chemotherapy lymphodepletion followed by adoptive transfer of autologous tumor– reactive lymphocytes in patients who have refractory melanoma who have undergone extensive pretreatment [74]. With this therapy, they reported Table 4 Phase III trials with IL-2 (and IFN)-containing regimens Study
Regimen
No. of patients
Median survival
Significance
IFN- and IL-2–containing regimens Sparano, 1993 [56] Keilholz, 1997 [57] Johnston, 1998 [58] Dorval, 1999 [52] Rosenberg, 1999 [59] Hauschild, 2001 [60] Eton, 2002 [61] Atzpodien, 2002 [62] Agarwalla, 2002 [63] Ridolfi, 2002 [64] Del Vecchio, 2003 [65] Atkins, 2003 [66] Keilholz, 2005 [67]
IL-2 G IFN IL-2/IFN G C CDBT G IFN/IL-2 C/IL-2 G/ IFN CDT G IFN/IL-2 D/IFN G IL-2 CVD G IFN/IL-2 D/B/C/T G IFN/IL-2 IL-2 vs HistamineþIL-2 CVD G IFN/IL-2 CVD G IFN/IL-2 CVD G IFN/IL-2 CD/IFN G IL-2
85 133 65 117 105 290 183 124 305 176 139 416 363
10.2 vs 9.7 9 vs 9 5.5 vs 5.0 10.4 vs 10.9 15.8 vs 10.7 11 vs 11 9.5 vs 11.8 13 vs 12 8.2 vs 9.1 9.5 vs 11 12 vs 11 8.7 vs 8.4 9 vs 9
NS NS NS NS P ! .06 NS P ! .06 NS NS NS NS NS NS
Abbreviations: B, BCNU; C, cisplatin; D, dacarbazine; IFN, interferon alpha; IL-2, interleukin2; NS, not significant.
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a response rate of 51% in 35 patients, providing insight into what patients who have melanoma require to experience tumor regression. Summary No effective therapy for metastatic melanoma exists. Polychemotherapy or chemoimmunotherapy have not shown survival benefits. Vaccines have shown little activity in stage IV disease. To advance the identification of effective agents, new drugs can and should be offered as first-line treatment. Efforts must be made to improve understanding of the biology of malignant melanoma. Too many phase III trials have been conducted with a poor understanding of the mechanism of action of the involved drugs. References [1] 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: 1159–62. [2] Banzet P, Thomas A, Vuillemin E, et al. Wide versus narrow surgical excision in thin (! 2 mm) stage I primary cutaneous malignant melanoma: long term results of a French multicentric prospective randomized trial on 319 patients. Proc Am Assoc Clin Oncol 1993;12:387. [3] Cohn-Cedermark G, Rutqvist LE, Andersson R, et al. Long term results of a randomized study by the Swedish Melanoma Study Group on 2-cm versus 5-cm resection margins for patients with cutaneous melanoma with a tumor thickness of 0.8–2.0 mm. Cancer 2000; 89:1495–501. [4] 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;218:262–7 [discussion: 267–9]. [5] Balch CM, Soong SJ, Smith T, et al. Long-term results of a prospective surgical trial comparing 2 cm vs. 4 cm excision margins for 740 patients with 1–4 mm melanomas. Ann Surg Oncol 2001;8:101–8. [6] Heaton KM, Sussman JJ, Gershenwald JE, et al. Surgical margins and prognostic factors in patients with thick (O 4mm) primary melanoma. Ann Surg Oncol 1998;5: 322–8. [7] Thomas JM, Newton-Bishop J, A’Hern R, et al. Excision margins in high-risk malignant melanoma. N Engl J Med 2004;350(8):757–66. [8] Ringborg U, Mansson Brahme E, Drzewiecki K, et al. Randomized trial of a resection margin of 2 cm versus 4 cm for cutaneous malignant melanoma with a tumor thickness of more than 2 mm. Abstract 28; Proceedings of the 6th World Congress on Melanoma. Vancouver, September 6–10, 2005. [9] Eggermont AMM, Gore M. European approach to adjuvant treatments of intermediateand high-risk malignant melanoma. Semin Oncol 2002;29(4):382–8. [10] Veronesi U, Adamus J, Bandiera DC, et al. Inefficacy of immediate node dissection in stage 1 melanoma of the limbs. N Engl J Med 1977;297:627–30. [11] Sim FH, Taylor WF, Ivins JC, et al. A prospective randomized study of the efficacy of routine elective lymphadenectomy in management of malignant melanoma. Preliminary results. Cancer 1978;41:948–56. [12] 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;7:87–97.
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