Adjuvant therapy of mucosal melanoma

Introduction

As compared to cutaneous melanomas, mucosal melanomas (MM) are extremely rare in Caucasians (1.3% of all melanomas) and relatively rare in Asians based on lower incidence of melanoma, though MM are the secondary predominant subtypes of melanomas in Asians (1-3). MM are generally classified according to primary sites (4). MM have a very poor prognosis and significantly worse outcomes than cutaneous melanomas (4-7). Early diagnosis combined with appropriate surgical therapy is currently the only curative treatment for melanoma (8,9). Despite that systemic adjuvant therapy has been investigated for cutaneous melanoma, it remains expected for MM. Either strategies for early diagnosis of MM or effective adjuvant therapies for MM are urgently needed to be established. Systemic adjuvant treatment for melanoma should be considered when a patient is clinically free of disease following surgical excision of the primary high-risk tumor and is at high risk for recurrence, especially for patients with AJCC stage of IIB, IIC and III (8,10,11). Currently, some approaches have been studied to reduce the risk of recurrence in MM patients. These include adjuvant immunotherapy, chemotherapy, targeted therapy and radiotherapy (RT). In this review we aim to summarize and evaluate these therapies in development.

Adjuvant treatment

Adjuvant treatment with immunotherapy

Interferon

At present the most common adjuvant treatment in high risk cutaneous melanomas is high-dose IFN-α2b (HDI). The randomized trials with HDI suggest that HDI can significantly improve relapse-free survival (RFS) and/or overall survival (OS) of high-risk cutaneous melanoma patients (12-14). In clinical trials of HDI as adjuvant therapy (E1684, E1690 and E1694), only a few mucosal melanoma patients were enrolled, but the efficacy in this subset was not specified (12-14). Trials of adjuvant treatment with HDI are seldom performed for MM. Our randomized study comparing HDI with chemotherapy for resected mucosal melanoma presented an interesting result, the median RFS of HDI group in the trial was only 9 months (15), which was much less than the previously reported RFS in cutaneous melanoma and less than our another trial of HDI in acral melanoma (median RFS: about 22.5 months) (12-14,16). Considering that all the enrolled patients in current trial were in stage II/III (localized and regional), this difference in RFS may be due to the different subtypes of enrolled melanoma patients, with our trial focusing on MM patients who usually had very poor prognosis. However, HDI could also improve the RFS and OS of stage II/III MM patients as compared to observation, suggesting that HDI may be a choice of adjuvant therapy for MM patients.

Adjuvant pegylated interferon alfa-2b (PEG-IFN-2b) was approved for treatment of resected stage III melanoma in 2011. Some follow-up data has been published recently from the EORTC 18991 study, showing that PEG-IFN increases the RFS, but no significant differences were observed in OS between the two groups (17). Similarly there was no mucosal melanoma patients be enrolled in this randomized trial.

Checkpoint inhibitors

Nowadays, only IFN has shown to be beneficial in RFS and in less degree in OS in high risk cutaneous patients, therefore it is necessary to continue to study on novel therapies. Some new agents against metastatic melanoma may be used as adjuvant therapy in the future, the representative agents are checkpoint inhibitors, including CTLA-4 and PD-1/PD-L1 inhibitor.

Ipilimumab, an anti-cytotoxic T-lymphocyte antigen 4 antibody, was the first compound demonstrated to improve OS in melanoma and was approved as a new therapy for melanoma by U.S. Food and Drug Administration in 2011, as phase III studies shows an OS benefit for patients with advanced melanoma (18,19). However, the efficacy of ipilimumab in mucosal melanoma is still largely unclear. In 2014, a study reported efficacy and safety of ipilimumab 3 mg/kg in 71 patients with pretreated, metastatic, mucosal melanoma. With a median follow-up of 21.8 months, the response rate was 12%. Median progression-free survival (PFS) and OS were 4.3 and 6.4 months, respectively (20). Another multicenter, retrospective analysis of 33 patients with unresectable or metastatic mucosal melanoma treated with ipilimumab reported that the median OS from the time of the first dose of ipilimumab was 6.4 months (range, 1.8-26.7 months). Long-lasting response to ipilimumab were observed, but the overall response rate was low (21). All results above suggested that ipilimumab may be a feasible treatment option in pretreated patients with metastatic mucosal melanoma. So far the benefit of ipilimumab for earlier-stage disease has not been established yet. Ipilimumab in the adjuvant setting has been being evaluated in two ongoing phase III trials (NCT00636168 and NCT01274338). In NCT00636168, ipilimumab is being compared with placebo after resection of high-risk stage III melanoma, with recurrence-free survival as the primary endpoint. Accrual has been completed and results are anticipated. Ipilimumab is also being compared with high-dose recombinant interferon-α-2b in another trial (NCT01274338) (22).

In 2012, preliminary investigations of PD-1 inhibitors came to fruition, demonstrating a strong sign of efficacy and safety. PD-L1 antibodies are being developed in tandem with PD-1 (23). Many tumor responses achieved with PD-1 and PD-L1 inhibition were durable in the phase I trials and were observed in a larger proportion of patients with melanoma than typically observed with ipilimumab antibodies, with an acceptable toxicity profile (24). Whether PD-1/PD-L1 inhibitors can be used for adjuvant therapy for melanoma, especially mucosal melanoma, will need to be confirmed.

Adjuvant treatment with chemotherapy

In previous randomized studies, adjuvant chemotherapy has not shown any significant benefit in cutaneous melanoma, even at high doses with the support of autologous bone marrow (25). Retrospective studies on adjuvant chemotherapy for patients with mucosal melanoma have been reported (26,27). However, interpretable data derived from randomized clinical trials on adjuvant chemotherapy in patients with mucosal melanoma are lacking. In vitro studies suggest that cisplatin may enhance the antitumor activity of temozolomide by its ability to downregulate alkylgua-nine alkyltransferase (28). Most recently, Flaherty and colleagues reported that biochemotherapy consisting of dacarbazine, cisplatin, vinblastine, interleukin-2 (IL-2), IFN-a, and G-CSF showed significant improvements in RFS (median, 4.0 vs. 1.9 years; P=0.034) in high-risk stage III melanoma, but not in OS, which was a co-primary endpoint, as compared with HDI (29). This study indicated that dacarbazine in combination with cisplatin can be used in adjuvant chemotherapy for melanoma. But most of these studies were retrospective, either with small sample sizes or nonrandomized studies. Therefore there is no convincing evidence for adjuvant chemotherapy for patients with mucosal melanoma.

Most recently, we reported a randomized phase II study comparing the activity and safety of temozolomide plus cisplatin with that of HDI in patients with resected mucosal melanoma. In this trial, MM patients in stage II/III after surgery were randomized into three groups: observation group (group A, surgery alone), HDI group (group B, treated with 15×10⁶ Unit/m²/day IFN-α2b, followed by 9×10⁶ Unit IFN-α2b), and temozolomide (200 mg/m²/day) plus cisplatin (75 mg/m²) group (group C). The endpoints were RFS OS and toxicity. One hundred and eighty-nine patients were enrolled and finally analyzed. With a median follow-up of 26.8 months, the median RFS were 5.4, 9.4 and 20.8 months in group A, B and C, respectively. Estimated median OS in group A, B and C were 21.2, 40.4 and 48.7 months, respectively. Patients treated with temozolomide plus cisplatin demonstrated significant improvement in RFS (P<0.001) and OS (P<0.01) than those treated with either HDI or surgery alone. Toxicity was generally mild to moderate (15). Our trial is the first to suggest that temozolomide based chemotherapy may be better than HDI in terms of both RFS and OS in this speific subtype of patients with mucosal melanoma. However, as a single-center trial, adjuvant therapy using chemotherapy or HDI in patients with mucosal melanoma may require more randomly controlled trials in the future.

Adjuvant treatment with targeted therapy

The finding that melanomas frequently contain driver oncogenes such as BRAF, NRAS, and KIT has revolutionized treatment for advanced melanoma during the past decades. Approximately 40-50% of patients harbor activating mutations of BRAF in Caucasians melanoma patients (30). The frequency of c-kit mutations is 10.8% in Chinese melanoma patients and 9.6% in mucosal melanoma patients (2). Targeted therapies are evolving rapidly in the treatment of melanoma. The c-kit inhibitor imatinib (enrolled 13/28 mucosal melanoma patients) (31), the BRAF inhibitors vemurafenib (32) and dabrafenib (33), and the MEK inhibitor trametinib (34) significantly improve survival in patients with advanced disease. However, these targeted therapies have not been clinically evaluated for melanoma as adjuvant therapy. BRAF inhibitor vemurafenib and the combination of dabarafenib and trametinib are currently being evaluated in the adjuvant setting in patients with stage III and high risk stage II disease. Given results that adjuvant imatinib improves survival in GI stromal tumors (35,36), we conducted a randomized phase II clinical trial in resected melanoma (include MM) patients to compare the efficacy and safety of HDI with imatinib as adjuvant therapy. All the results of these studies are eagerly awaited.

Adjuvant treatment with radiotherapy (RT)

It is an option in melanomas with a high risk of regional recurrence after lymphatic clearance. In a randomized study with 227 patients, considered as having a high risk of recurrence, 109 were included in the adjuvant RT group and 108 were in control group. After a mean follow up of 27 months, 20 patients had recurrences in the RT group and 34 did in the control group (P=0.0410), suggesting a better improvement in the local recurrences with RT but not in the survival rate (37).

As with mucosal melanoma, any clinical benefit derived from adjuvant RT appears to be limited to the primary site. RT is commonly used in the adjuvant treatment of surgically resected head and neck MM, one retrospective analysis of 69 patients with head and neck MM suggested improved local control for patients treated with adjuvant RT (38). With regard to anorectal mucosal melanoma, due to the risk of local recurrence and its associated morbidity, adjuvant RT may be considered after definitive surgical resection. RT delivered in this setting does not appear to alter long-term survival, though some series have suggested it may improve local control following sphincter sparing surgery (39,40). However, most of these studies were retrospective, small sample-sized or non-randomized studies, more randomized studies need to be performed in the future.

Conclusions

MM has a very poor prognosis and significantly worse outcomes than cutaneous melanoma. Surgical resection remains the most important treatment and can result in cure of tumor. Systemic adjuvant treatment of MM may be considered specially for high-risk patients. Temozolomide based chemotherapy may be better than HDI as adjuvant therapy of MM. Targeted therapy and checkpoint inhibitors could be novel strategies of adjuvant therapy for MM. Adjuvant RT may improve local control but not OS. It is expected to analyze these adjuvant therapies in randomized clinical trials in order to improve prognosis of MM patients.

Acknowledgements

Disclosure: The authors declare no conflict of interest.

References

1. Gutman M, Inbar M, Chaitchik S, et al. Malignant melanoma of the mucous membranes. Eur J Surg Oncol 1992;18:307-12. [PubMed]
2. Chi Z, Li S, Sheng X, et al. Clinical presentation, histology, and prognoses of malignant melanoma in ethnic Chinese: a study of 522 consecutive cases. BMC Cancer 2011;11:85. [PubMed]
3. Shoo BA, Kashani-Sabet M. Melanoma arising in African-, Asian-, Latino- and Native-American populations. Semin Cutan Med Surg 2009;28:96-102. [PubMed]
4. Chang AE, Karnell LH, Menck HR. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer 1998;83:1664-78. [PubMed]
5. Thompson LD, Wieneke JA, Miettinen M. Sinonasal tract and nasopharyngeal melanomas: a clinicopathologic study of 115 cases with a proposed staging system. Am J Surg Pathol 2003;27:594-611. [PubMed]
6. Patel SG, Prasad ML, Escrig M, et al. Primary mucosal malignant melanoma of the head and neck. Head Neck 2002;24:247-57. [PubMed]
7. Owens JM, Roberts DB, Myers JN. The role of postoperative adjuvant radiation therapy in the treatment of mucosal melanomas of the head and neck region. Arch Otolaryngol Head Neck Surg 2003;129:864-8. [PubMed]
8. Garbe C, Eigentler TK, Keilholz U, et al. Systematic review of medical treatment in melanoma: current status and future prospects. Oncologist 2011;16:5-24. [PubMed]
9. Eggermont AM, Gore M. Randomized adjuvant therapy trials in melanoma: surgical and systemic. Semin Oncol 2007;34:509-15. [PubMed]
10. 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;15:1039-51. [PubMed]
11. Agarwala SS, Kirkwood JM. Adjuvant therapy of melanoma. Semin Surg Oncol 1998;14:302-10. [PubMed]
12. 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;14:7-17. [PubMed]
13. Kirkwood JM, Ibrahim JG, 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;18:2444-58. [PubMed]
14. 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 2001;19:2370-80. [PubMed]
15. Lian B, Si L, Cui C, et al. Phase II randomized trial comparing high-dose IFN-α2b with temozolomide plus cisplatin as systemic adjuvant therapy for resected mucosal melanoma. Clin Cancer Res 2013;19:4488-98. [PubMed]
16. Mao L, Si L, Chi Z, et al. A randomised phase II trial of 1 month versus 1 year of adjuvant high-dose interferon α-2b in high-risk acral melanoma patients. Eur J Cancer 2011;47:1498-503. [PubMed]
17. Eggermont AM, Suciu S, Testori A, et al. Long-term results of the randomized phase III trial EORTC 18991 of adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma. J Clin Oncol 2012;30:3810-8. [PubMed]
18. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711-23. [PubMed]
19. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011;364:2517-26. [PubMed]
20. Del Vecchio M, Di Guardo L, Ascierto PA, et al. Efficacy and safety of ipilimumab 3mg/kg in patients with pretreated, metastatic, mucosal melanoma. Eur J Cancer 2014;50:121-7. [PubMed]
21. Postow MA, Luke JJ, Bluth MJ, et al. Ipilimumab for patients with advanced mucosal melanoma. Oncologist 2013;18:726-32. [PubMed]
22. Callahan MK, Postow MA, Wolchok JD. Immunomodulatory therapy for melanoma: ipilimumab and beyond. Clin Dermatol 2013;31:191-9. [PubMed]
23. Page DB, Postow MA, Callahan MK, et al. Checkpoint modulation in melanoma: an update on ipilimumab and future directions. Curr Oncol Rep 2013;15:500-8. [PubMed]
24. Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res 2013;19:5300-9. [PubMed]
25. Moschos SJ, Kirkwood JM. Adjuvant therapy for cutaneous melanoma. In: Rigel DS, Friedman RJ, Dzubow LM, et al. eds. Cancer of the Skin, Chapter 52. Philadelphia, PA, USA: Elsevier Saunders, 2005:641-54.
26. Yang X, Ren GX, Zhang CP, et al. Neck dissection and post-operative chemotherapy with dimethyl triazeno imidazole carboxamide and cisplatin protocol are useful for oral mucosal melanoma. BMC Cancer 2010;10:623. [PubMed]
27. Yi JH, Yi SY, Lee HR, et al. Dacarbazine-based chemotherapy as first-line treatment in noncutaneous metastatic melanoma: multicenter, retrospective analysis in Asia. Melanoma Res 2011;21:223-7. [PubMed]
28. Piccioni D, D’Atri S, Papa G, et al. Cisplatin increases sensitivity of human leukemic blasts to triazene compounds. J Chemother 1995;7:224-9. [PubMed]
29. Flaherty LE, Moon J, Atkins MB, et al. Phase III trial of high-dose interferon alpha-2b versus cisplatin, vinblastine, DTIC plus IL-2 and interferon in patients with high-risk melanoma (SWOG S0008): an intergroup study of CALGB, COG,ECOG, and SWOG. J Clin Oncol 2014;30:abstr 8504.
30. Tsao H, Chin L, Garraway LA, et al. Melanoma: from mutations to medicine. Genes Dev 2012;26:1131-55. [PubMed]
31. Guo J, Si L, Kong Y, et al. Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol 2011;29:2904-9. [PubMed]
32. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507-16. [PubMed]
33. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2012;380:358-65. [PubMed]
34. Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 2012;367:107-14. [PubMed]
35. Dematteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet 2009;373:1097-104. [PubMed]
36. Joensuu H, Eriksson M, Sundby Hall K, et al. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA 2012;307:1265-72. [PubMed]
37. Burmeister B, Henderson M, Thompson J, et al. Adjuvant Radiotherapy Improves Regional (Lymph Node Field) Control in Melanoma Patients after Lymphadenectomy: Results of an Intergroup Randomized Trial (TROG 02.01/ANZMTG 01.02). Int J Radiat Oncol Biol Phys 2009;3:2.
38. Temam S, Mamelle G, Marandas P, et al. Postoperative radiotherapy for primary mucosal melanoma of the head and neck. Cancer 2005;103:313-9. [PubMed]
39. Ballo MT, Gershenwald JE, Zagars GK, et al. Sphincter-sparing local excision and adjuvant radiation for anal-rectal melanoma. J Clin Oncol 2002;20:4555-8. [PubMed]
40. Kelly P, Zagars GK, Cormier JN, et al. Sphincter-sparing local excision and hypofractionated radiation therapy for anorectal melanoma: a 20-year experience. Cancer 2011;117:4747-55. [PubMed]