Interpretation on Expert Consensus for Diagnosis and Treatment of Melanoma in China
DU Fu-rong, WU Yin-ping, YANG Xue, YU Li-fang, YE Zhen-hua*
Editorial Board of Journal of International Translational Medicine
*Corresponding Author: YE Zhen-hua , E-mail: jitm2012@jitm.hk
Abstract

In recent years, melanoma has become a tumor with the fastest increase of morbidity in all malignant tumors, and its annual increase is 3%-5%. Both morbidity and mortality of melanoma are low in China, but they are showing an increasing tendency in recent years. However, the morbidity of melanoma is increasing in most European and American countries, but the mortality keeps stable and is not in an increasing tendency along with the increasing morbidity, demonstrating that there are great differences between China and Western countries in the diagnosis and treatment of melanoma. At present, melanoma has become one of the diseases that severely threaten human health. Compared with other common malignant tumors, there are significant differences in the clinical diagnosis and specific treatment of melanoma. To better adapt the rapid development of treatment for melanoma, and to make the clinical practice of melanoma more specific and internationalized in China, Expert Committee on Melanoma, Chinese Society of Clinical Oncology, has updated the Guidelines for Diagnosis and Treatment of Melanoma in China. Therefore, the editorial board of this journal interpreted this guideline in details, aiming to provide the lastest and most practical evidence-based evidence for clinical oncologists in China.

Key words: Melanoma; Adjuvant radiotherapy Epidemiology; Recombinant human endostatin; Consensus
Epidemiology

In recent years, melanoma has become a tumor with the fastest increase of morbidity in all malignant tumors, and its annual increase is 3%-5%. In 2012, the global new cases of melanin were 232 000, with 55 000 dead [1]. According to the statistics, the morbidity of melanoma in males and females is 8.6/100 000 and 8.9/100 000, while the mortality being 2.0/100 000 and 1.3/100 000 respectively in European countries. However, in Asian countries, the morbidity in males and females is 0.5/100 000 and 0.4/100 000, while the mortality being 0.4/100 000 and 0.3/100 000, respectively. Compared with European and American countries, the morbidity of melanoma is lower in Asian countries, but it increases faster. According to the statistics of Chinese Registered Annual Report of Tumors[2], in 2011, the new Chinese cases of melanoma were 6 505, with morbidity being 0.48/100 000, while 2 660 cases died, with mortality being 0.20/100 000. Both morbidity and mortality of melanoma are low in China, but they are showing an increasing tendency in recent years. However, the morbidity of melanoma is increasing in most European and American countries, but the mortality keeps stable and is not in an increasing tendency along with the increasing morbidity, demonstrating that there are great differences between China and Western countries in the diagnosis and treatment of melanoma.

The ratio of males and females with melanoma in China is 1.12:1, and the median diagnostic age is 50-55 years. Of these patients, elderly patients ≥ 65 years old account for 17.8%, and most of them are complicated with thick primary nidus ulcer (44.8%). Patients with thickness of primary nidi ≥ 4 mm account for 40.8%, while those with thickness being 1-4 mm for 44.4%. In initial diagnosis, the number of patients in stage II is the largest, followed by those in stage III (25.1%) and IV (12.8%). Survival analysis found that the staging was in close association with the survival in that the 5-year survival rates of patients in stage I, II, III and IV were 94%, 44%, 38% and 4.6%, and the median survival time was 5.00, 4.25, 2.83 and 1.42 years respectively, the primary nidus thickness was closely connected with the survival because the 5-year survival rates of patients with thickness ≤ 1 mm and > 4 mm were 92% and 43%, respectively, and the ulcer of primary nidi had a certain correlation with the survival, but there was no significant difference, and the 5-year survival rates of patients with and without ulcer were 42% and 69%, respectively [3]. Multivariate analysis of genetic mutation and survival prognosis showed that the mutation of BRAF and KIT genes were the independent prognostic factors for melanoma [4, 5].

Etiology, Pathology and Diagnosis
Etiology

Excessive exposure to ultraviolet, photosensitive skin, large amount of common moles or moles with alloplasia, and family history of skin cancer are in close association with the development of melanoma [6, 7, 8]. The primary nidi of patients in Asian and African countries are located mainly in the parts with less exposure to ultraviolet, such as palms, fingers, heels and toes, but its pathogenesis is still unclear. Meanwhile, improper treatment (local stimulation by lancination, laser and freezing, etc.) may also induce the malignant transformation and rapid growth of melanoma. The common pathological types of melanoma include superficial diffuse type, modular type, malignant freckle type and acral freckle type, and the rare types contain epithelial, desmoplastic, malignant amelanotic nevus, balloon-like-cell, shuttle-cell, and giant pigmented nevus melanoma, etc. Acral freckle melanoma is most commonly seen in yellow and black people, while superficial diffuse melanoma in white people [9, 10].

Pathology

In recent years, with continuous deepening of studies on the relationships between molecular biological characteristics, clinical histological characteristics of melanoma and genovariation, it has found that certain types of melanoma are in close association with specific genovariation. The detection results of KIT genes in 502 primary melanoma samples in China revealed that the total mutation and gene amplification rates were 10.8% and 7.4%, in which those in acral melanoma, mucosal melanoma, chronic sunlight-damaged melanoma, non-chronic sunlight-damaged melanoma and melanoma with unknown primary nidus were 11.9% and 7.3%, 9.6% and 10.2%, 20.7% and 3.4%, 8.1% and 3.2, and 7.8% and 5.9%, respectively. These results provide a theoretical basis for application of KIT inhibitors in Chinese patients. The BRAF mutation rate was 25.9% in 468 primary melanoma samples in China, and was 17.9% and 12.5% in acral and mucosal melanoma respectively, in which V600E was the most common mutation site (87.3%). This study provides a theoretical basis for application of BRAFV600inhibitors in Chinese patients [4, 5].

In 2013, microsatellite nidi were defined by College of American Pathologists as the tiny meyastatic nidi > 0.05 mm in diameter in reticular dermis, panniculus adiposus and vessels > 0.3 mm away from primary nidi, which predicted a extremely high risk of local or general metastasis [11, 12]. Patients with microsatellite nidi should be classified into stage N2c, and they have a similar prognosis with those in stage IIIB. According to American Joint Committee On Cancer (AJCC) staging, melanoma can be classified into locally non-metastatic melanoma (stage I-II), regional metastatic melanoma (stage III) and distant metastatic melanoma (stage IV) [13, 14]. As to the patients in local stage, thickness, ulcer and mitosis rate are all the most important characteristics for the diagnosis of prognosis [13].

Diagnosis

Typical clinical manifestations and examinations of physical signs are common methods for the diagnosis of melanoma. Pathological examinations are the terminal criteria for the confirmation of melanoma (even staging), so it is of great importance in the diagnosis, staging, treatment and prognostic diagnosis of melanoma. Immunohistochemical staining is an important adjuvant method for the differentiation of melanoma. S-100, HMB-45 and vimentin are specific indexes for the diagnosis of melanoma, in which HMB-45 is more specific than S-100.

Treatment
Surgical treatment

Previous guidelines recommended that patients with positive sentinel lymph node biopsy (SLNB) should receive regional lymph node dissection. A recent study in Rotterdam [15]has showed that the 5-year survival rate of patients with tumor diameter < 0.1 mm in sentinel lymph nodes reaches to 91%, thus further regional lymph node dissection is unnecessary to these people. Ultrasound or computed tomography (CT) can be used to judge whether there is regional lymph node metastasis, also known as the advice for ultrasound diagnosis of lymph node metastasis: peripheral blood supply, disappearance of central echo (disappearance of target cyclic structure) and balloon-like changes. The sensitivity and positive coincidence rates of the above 3 indexes are 77% and 52%, 60% and 65%, and 30% and 96%, respectively. If the 3 indexes appear simultaneously, the sensitivity will be 82%. The margin of carcinoma in situ is changed from 0.5 cm to 0.5-1.0 cm [16]. As to the primary nidi on the skin of head and neck, parotidectomy and cervical lymph node dissection in drainage region are recommended due to the discovery of periparotid lymph node metastasis in clinic or under microscope.

Adjuvant treatment

Patients’ postoperative prognosis varies with their risk factors. Patients can be classified into stage IA (low risk), stage IB-IIA (intermediate risk), stage IIB-IIIA (high risk) and stage IIIB-IV (extremely high risk) according to the risk factors, such as infiltration depth of nidi, presence or absence of ulcer and lymph node metastasis. Low-risk patients can survive for a long time, with 5-year survival rate up to 95%. However, the 5-year survival rate is 80% in intermediate-risk patients, and is only 10%-50% in those with high- or extremely high risks. Different adjuvant therapies can be selected according to different stages. Low- and middle-dose interferon, as the adjuvant treatment after the resection of high-risk melanoma, does not obtain survival benefit, only a few studies have indicated that it may benefit patients without recurrence in survival time [17, 18, 19, 20, 21]. At present, low- and middle-dose interferon is not recommended as the adjuvant treatment for patients with melanoma. A study [22] on adjuvant treatment with CTLA-4 monoclonal antibody in 2014 suggested that compared with observation group, treatment group was markedly lower in the recurrent and metastatic risks (25%), but the results showed no improvement when compared with the history data of high-dose interferon. CTLA-4 monoclonal antibody has not been included in adjuvant treatment because it is expensive and cannot be compared with standard interferon, and high-risk interferon is still recommended as the adjuvant therapeutic protocol for high-risk melanoma.

According to a study [23] in Australia, the adjuvant radiotherapy has been revised. Indications of radiotherapy for patients with regional metastasis include: (1) the lactate dehydrogenase (LDH) < 1.5 folds of normal upper limit; (2) meeting any one of the following conditions: metastatic lymph node in parotid gland ≥ 1, or ≥ 2 in neck or armpit, or ≥ 3 in groin, and the maximum diameter of metastatic lymph node ≥ 3 cm in neck or armpit, or ≥ 4 cm in groin, or extranodal invasion of lymph nodes. The significance of adjuvant radiotherapy in increasing local control rate has been generally recognized by expert group, but its adverse reactions and potential tendency in reducing patients’ total survival time recorded in partial clinical trials have indicated that application of adjuvant radiotherapy is still controversial in clinic.

Systemic treatment

Patients with inoperable melanoma in stage III or metastatic melanoma are recommended to receive systemic treatment focusing on internal medicine, or to participate in clinical trials. Systemic treatment includes CTLA-4 monoclonal antibody, PD-1 monoclonal antibody, BRAFV600inhibitor, CKIT inhibitor, MEK inhibitor, large amount of interleukin (IL)-2, and chemotherapy, etc. In recent years, treatment for advanced melanoma has made breakthrough achievements, and individual target therapy, immunological target therapy, and anti-angiogenic target therapy have become hot topics for current studies.

Individualized target therapy

Imatinib (KIT inhibitor): A phase II multicenter study [24] on Imatinib in the treatment of 43 patients with KIT gene mutation or amplification in China showed that the 6-month progression-free survival rate (PFS) was 36.6%, with median PFS being 3.5 months; the median PFS was markedly longer in patients with mutation of No. 11 or No. 13 exons than those with mutation of other exons, and was longer in patients with multiple CKIT mutation than those with single CKIT mutation (no difference was observed); 1-year survival rate was up to 50% and median overall survival (OS) was 14 months, and there was significant difference between patients with partial remission (PR) or stable disease (SD) and those with progressive disease (PD) in OS (15 months) (P=0.036), thus Imatinib was recommended as the type II evidence for advanced melanoma patients with CKIT mutation or amplification.

BRAFV600inhibitor and MEK inhibitor: BRAF gene mutation is present in half of the white people with metastatic melanoma [25]. Vemurafenib is a specific BRAF gene mutation inhibitor [26]. In a phase III clinical trial, 675 untreated patients with metastatic melanoma complicated by BRAF gene mutation were randomly divided into two groups, and the efficacy of Vemurafenib and Dacarbazine was compared. The results displayed that compared with Dacarbazine, Vemurafenib could prolong OS and PFS; at 6 months, OS was 84% (95%CI, 78 to 89) in the Vemurafenib group and 64% (95%CI, 56 to 73) in the Dacarbazine group; skin complications were common adverse events associated with Vemurafenib [27]. Based on this study, Vemurafenib was approved by Food and Drug Administration (FDA) for melanoma with BRAFV600E gene mutation or unresectable melanoma in August 2011. After then, two kinds of BRAF inhibitors were also approved by FDA. A phase III study [28] on Dabrafenib and Dacarbazine in the treatment of patients with BRAFV600Egene mutation totally enrolled 250 patients in stage IV or unresectable stage III, and the results suggested that the PFS was 5.1 months and 2.7 months in Dabrafenib group and Dacarbazine group, respectively; the rate of adverse reactions ≥ grading 2 was 53.0% in Dabrafenib group, and adverse reactions in grading 3-4 were rarely seen; compared with Dacarbazine, Dabrafenib-associated squamous cell carcinoma of skin or keratoacanthoma was rarely seen, while fever was more common. In MAP signal transduction pathway, MEK1 and MEK2 are located in the downstream of BRAF gene. Trametinib is an oral agent of MEK1 and MEK2 inhibitors. Totally 322 patients with BRAFV600E gene mutation metastatic melanoma were divided into two groups in a phase III clinical trial [29] and the clinical efficacy of Trametinib and chemotherapy was compared. The results illustrated that the PFS and 6-month survival rate (4.8 months vs.1.5 months; 81.0% vs. 67.0%) increased in Trametinib group. Different to BRAF inhibitors, less patients in Trametinib group had secondary skin damage, but the response rate was also low (22.0% vs. 48.0%-50.0%) in patients with initial treatment.

At present, Vemurafenib, Dabrafenib and Trametinib have not been marketed at home but the rate of BRAFV600E gene mutation is up to 26.0% in Chinese patients with melanoma. Though the rate is evidently lower than the 50.0% in white people, treatment for Chinese patients with melanoma is still of great importance. Therefore, these drugs are recommended as the type I evidence for patients with BRAFV600E gene mutation.

Immunological target therapy

CTLA-4 monoclonal antibody, PD-1 monoclonal antibody, and their combination: In a clinical phase III study, the OS of patients with initial treatment in single Ipilimumab (Ipi) group and combination group (Ipi combined with Dacarbazine) was evidently longer than that in control group, but Ipi should be highly concerned because it could cause severe immune-mediated adverse reactions. At present, Ipi has not been marketed in China. American FDA has approved PD-1 monoclonal antibody (Pembrolizymab and Nivolumab) for the second-line treatment of patients with resistance to Ipi and BRAF inhibitors. Expert group believed that compared with Ipi, Pembrolizymab and Nivolumab could be used as first-line treatment because they were higher in response rate and less in adverse reactions. As to patients with hypophysitis induced by previous application of Ipi, Pembrolizymab can be administered following initial treatment with hormone replacement therapy (HRT). A clinical study on Nivolumab combined with Ipi totally enrolled 142 patients with advanced or unresectable melanoma, and the results demonstrated that the response rate was 60% and 11% in combination group and single group, while PFS was 8.9 months and 4.7 months (P=0.0012), whereas the subgroup analysis pointed out that patients with poorer prognosis benefited more, but their adverse reactions in grading 3-4 also increased more significantly in combination group; patients with endocrine diseases were improved by additional replacement therapy, while the rest 83% by immunosuppressors like prednisone, etc.

IL-2: The biological effect of IL-2 is extremely complicated, in which oncotherapy-associated mechanism is to enhance cytotoxic lymphocyte (CTL) and natural killer (NK) cell division. Its toxicity is marked by flu-like symptoms, while specific toxicity is capillary leak syndrome. At present, phase II trial [30] on recombinant humanized IL-2 in the treatment of advanced melanoma has been developed at home, and the results discovered that the overall response rate was only 8.3% and PFS was less than 2 months in Chinese patients with advanced melanoma after administration of high-dose IL-2, evidently lower than the results reported in foreign literatures. Though FDA has approved IL-2 for metastatic melanoma, more multicenter randomized controlled trails are still required to explore its optimal dose and predictive factors for efficacy.

Anti-angiogenic target therapy

Recombinant human endostatin (Endostar): Endostatin can specifically inhibit endothelial proliferation, and effectively suppress tumor growth and metastasis. It is the most effective angiogenesis inhibitor up to now. However, endostatin, as a kind of protein agent, is expensive and unstable in clinical efficacy. According to the Folkman concept and prophase basic research results, Endostar, synthesized by professor Yongzhang Luo, has successfully resolve the technical issues like protein refolding, thus it can be commercially produced and applied in clinic. As a new type of antitumor drug, endostatin not only has antitumor activity, but also has obvious synergistic effect with conventional chemotherapy and radiotherapy.

A phase II multicenter, double-blinded, randomized controlled study [31]on Endostar or placebo combined with Dacarbazine as first-line treatment for patients with unresectable melanoma in stage IIIc or IV were launched at home. A total of 110 patients were enrolled and divided into group A (Dacarbazine 250 mg/m2, d1-5 + placebo, d1-14) and group B (Dacarbazine 250 mg/m2, d1-5 + Endostar 7.5 mg/m2, d1-14) by ratio of 1:1, and 21 days were as a cycle. The results demonstrated that of the 110 enrolled patients, there were 0.9% of patients in stage IIIc, 32.1% in stage M1a, 44.6% in stage M1b and 23.2% in stage M1c. In group A and group B, the objective response rate was 3.7% vs. 8.9%; disease control rate (DCR) was 33.3% vs. 53.6% (P=0.051); median PFS was 1.5 months vs. 4.5 months (HR: 0.58; 95%CI: 0.38-0.89; P=0.013); media OS was 8.0 months vs.12.0 months (HR: 0.52; 95%CI: 0.33-0.82; P=0.005); 1-year survival rate was 22.5% vs. 49.7%, and 2-year survival rate was 14.3% vs. 22.2%, respectively. The adverse reactions were similar in two groups, and the total therapeutic tolerance was favorable. These results indicated that Endostar combined with Dacarbazine could be recommended as the first-line treatment for progressive melanoma because it had longer PFS and OS than single Dacarbazine, and was excellent in drug tolerance.

Bevacizumab: Bevacizumab, as a recombinant humanized monoclonal IgG1 antibody, can selectively combine with human vascular endothelial growth factor (VEGF) and reduce the biological activity of VEGF, so as to inhibit tumor angiogenesis. In addition, it can also increase VEGF-dependent vascular permeability, induce the closing of endothelial window and cellular gap, and reduce vascular permeability, so as to reduce the pressure in tumor tissues, and improve the transmission of chemotherapeutic agents to tumor tissues. The later the stage of melanoma is, the more the angiogenic factors are, and the richer the tumor blood supply is, which provides a theoretical basis for Bevacizumab in the treatment of melanoma. Multiple phase II studies [31, 32, 33, 34] have reported the clinical efficacy of Bevacizumab combined with chemotherapy. In BEAM trial, a total of 214 patients with initial treatment were randomly enrolled by the ratio of 2:1 and received Paclitaxel + Carboplatin combined with Bevacizumab or placebo, and the results showed that Bevacizumab group was longer in PFS (5.6 months vs. 4.2 months; HR: 0.78; P=0.16) and survival time (12.3 months vs. 9.2 months; HR: 0.79; P=0.19), but there was no significant difference. Another phase II study applied a 2-week protocol of Bevacizumab combined with protocol of Carboplatin + weekly Paclitaxel in the retreatment of 53 patients, and the results suggested that the median PFS and OS were 6 months and 12 months, respectively, but the rate of hematological toxicity in grading 3 increased evidently, in which neutropenia, leucopenia and thrombocytopenia accounted for 53%, 38% and 11%, respectively. And 31 patients had more than 40 times of hemorrhagic events, including 2 cases of grading 2 bronchial pulmonary hemorrhagic diseases and fatal hemorrhage of central nervous system.

Conclusion

This consensus has greatly changed the treatment for advanced melanoma. According to gene mutation and disease progression, cytotoxic agents combined with antiangiogenic agents can be used in the first-line treatment. As to the patients with gene mutation and fast progression, individual target agents are recommended initially to quickly shrink the tumor, after which immunological target agents can be applied, whereas to patients with slow progression, immunological target agents are primarily recommended. For the patients with wild-type genes and fast progression, cytotoxic agents combined with antiangiogenic agents are optimally considered to quickly diminish the tumor, after which immunological target agents can be applied, whereas for the patients with slow progression, immunological target agents are primarily recommended, after which cytotoxic agents combined with antiangiogenic agents can be regarded.

This Consensus strives to be comprehensive, specific and internationalized. However, the protocols should be established according to local medical level and patients’ constitution, complicated diseases and economic conditions in clinical practice.

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