Demographics, Pattern of Care, and Outcome Analysis of Malignant Melanomas - Experience From a Tertiary Cancer Centre in India

Background Treatment of malignant melanoma has undergone a paradigm shift with the advent of immune checkpoint inhibitors (ICI) and targeted therapies. However, access to ICI is limited in low-middle income countries (LMICs). Patients and Methods Histologically confirmed malignant melanoma cases registered from 2013 to 2019 were analysed for pattern of care, safety, and efficacy of systemic therapies (ST). Results There were 659 patients with a median age of 53 (range 44–63) years; 58.9% were males; 55.2% were mucosal melanomas. Most common primary sites were extremities (36.6%) and anorectum (31.4%). Nearly 10.8% of the metastatic cohort were BRAF mutated. Among 368 non-metastatic patients (172 prior treated, 185 de novo, and 11 unresectable), with a median follow-up of 26 months (0–83 months), median EFS and OS were 29.5 (95% CI: 22–40) and 33.3 (95% CI: 29.5–41.2) months, respectively. In the metastatic cohort, with a median follow up of 24 (0–85) months, the median EFS for BSC was 3.1 (95% CI 1.9–4.8) months versus 3.98 (95% CI 3.2–4.7) months with any ST (HR: 0.69, 95% CI: 0.52–0.92; P = 0.011). The median OS was 3.9 (95% CI 3.3–6.4) months for BSC alone versus 12.0 (95% CI 10.5–15.1) months in any ST (HR: 0.38, 95% CI: 0.28–0.50; P < 0.001). The disease control rate was 51.55%. Commonest grade 3–4 toxicity was anemia with chemotherapy (9.5%) and ICI (8.8%). In multivariate analysis, any ST received had a better prognostic impact in the metastatic cohort. Conclusions Large real-world data reflects the treatment patterns adopted in LMIC for melanomas and poor access to expensive, standard of care therapies. Other systemic therapies provide meaningful clinical benefit and are worth exploring especially when the standard therapies are challenging to administer.


INTRODUCTION
Melanoma is relatively rare in India, compared to other tropical countries. However, its incidence is rising globally (1). The incidence of melanoma depends on multiple factors such as age (more with advanced age), melanin content (inversely proportional) of the skin, latitude (more in tropical regions with increased UV exposure), altitude (more in higher altitude), and ethnicity (2).There are ethnic variations in the clinical and histopathological subtypes depending on the geography with superficial spreading and nodular subtypes common in Caucasians, while acral and mucosal predominantly are seen in Asians (3)(4)(5)(6).
Melanoma cells are sensitive to T-cell mediated immune response mediated by tumor-infiltrated lymphocytes (TIL) due to the high tumor mutational burden caused by ultraviolet light exposure, cancer testis antigen expression, and mimicry of melanocyte lineage proteins (7), and these factors make melanoma a substrate for widespread utility of immune check point inhibitors and targeted therapy. The clinical feature of melanoma is a change in the size, color, and shape of the lesion making it distinct and different from the surrounding skin lesions (ugly duckling sign) (8). Although there is a marked increase in the diagnosis of localised melanoma due to overdiagnosis of stage 1 and 2 melanoma with the advances in screening and health care systems, there seems to be an increase in the incidence and diagnosis of metastatic melanoma also contributing to nearly 5% of the total melanoma cases (9). However, in the real-world scenario, there is under-documentation of the localised melanoma as treatment is sought at primary health care level and most patients present to tertiary care academic institutes with locally advanced or metastatic disease.
The 5 year survival for localised melanoma is nearly 99% but drops to 20% in the presence of upfront metastasis and highlights the importance of early diagnosis and treatment initiation (10). Historically, metastatic melanoma has a dismal prognosis with 5 year OS of approximately 10% (11). However, the advent of immune checkpoint inhibitors (ICI), including drugs that target programmed cell death 1 (PD-1) with or without inhibitors of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), BRAF, and MEK-targeted therapies, has improved the prognosis (1, 3-6, 12, 13) of metastatic melanoma with nearly half of patients on combination immunotherapy and one in three patients with targeted therapy surviving for 5 years (14).
The annual cost of melanoma treatment has increased exponentially by 288% in less than a decade, and it is expected to rise further with the advent of immune check point inhibitors and targeted therapies (2). The health care scenario in lowmiddle income countries (LMIC) has higher out-of-pocket expenditure (OOPE) from patients with low insurance coverage in the midst of low per capita income (15). Access to standard therapies is challenging in LMICs, and this has propelled research into other systemic therapies (ST) including chemotherapy, oral metronomic chemotherapy (OMCT), and low-dose subcutaneous interferons (LD-SC-IFN) with immunomodulatory properties. There is sparse data from realworld settings in India and merits exploration.

Patients and Methods
Patients with histologically proven malignant melanomas, who presented to our tertiary care centre (blinded for peer review) between January 2013 and December 2019, were studied, including those with de novo or recurrent and/or metastatic disease.
Staging workup included MRI/contrast-enhanced (CE) CT scan of the affected primary site, whole-body F18 fluorodeoxyglucose positron emission tomography CECT (FDG PET-CECT), or X-ray and ultrasonography. Baseline demographic features, primary site, stage, histological details, mutation status, and treatment details were obtained from the electronic medical records. All patients were discussed in the multidisciplinary tumor board (MDT) after the staging and histopathology confirmation of melanoma. Localised melanoma was treated with surgery and adjuvant radiation for margin positivity or definitive radiotherapy with radical intent if deemed unresectable in the MDT. Locally advanced stage III cancers were given the option of adjuvant immunotherapy postsurgery. Locally advanced unresectable and metastatic melanoma patients were given the option of systemic therapy with immune check point inhibitors or targeted therapy (in BRAF positive patients). In patients who were not feasible for ICI or targeted therapies, palliative systemic therapy with chemotherapeutic agents were initiated based on the performance status and tolerance and clinical/radiological response was assessed every 2-3 month intervals.

Ethics Statement
The study was conducted after approval from the Institutional Ethics Committee (IEC). Waiver of consent was obtained for retrospective study. All data were anonymized before the start of analysis. failures or progression or death). Overall survival (OS) was defined as the time from the date of diagnosis to death from any cause or last documented follow-up. Patients who were lost to follow-up were censored on the date of their last follow-up. Any radiological response was taken as response, and it was not strictly RECIST-based. Baseline host and tumor characteristics were correlated with survival outcomes. The data were analyzed using IBM SPSS Statistics for Windows, Version 24.0. Descriptive statistics were represented as median or percentage, and group comparisons were made using the c2 test or Mann-Whitney U test, as appropriate. Survival was estimated using the Kaplan-Meier method and compared using the log-rank test.
At a median follow-up of 23.5 months (0-86 months), the median EFS and OS are highlighted in Table 2 Figure 2B). For uveal group, median OS and 2-year OS were 12 (95% CI 13.7-NA) months and 60.5% (95% CI 43.7-83.8%), respectively. Pair-wise log rank p value was significant between mucosal and cutaneous (P < 0.001) with better EFS and OS for cutaneous group, mucosal and uveal (P = 0.044) with better EFS and OS for the uveal group, and insignificant between cutaneous and uveal (P = 0.431).
Among patients who did not undergo surgery or receive ST (due to comorbidities or poor ECOG-performance status (PS)) (n = 57), there were 34 events. The median EFS was 4.3 (95% CI 3.3-9.3) months, and 2-year EFS was 9.3% (95% CI 2.8-30.3%) ( Figure 3A). The median OS was 4.8 (95% CI 3.6-9.3) months with 34 deaths and 2-year OS of 9% (95% CI 2.8-29.7%) ( Figure 3B).  Figure 1 shows the distribution of patients with melanoma into the metastatic and nonmetastatic cohort which was used for subgroup analysis in the study. The green schematic boxes show the different modalities of treatment adopted in metastatic and non-metastatic setting with their median PFS. P+C, paclitaxel and carboplatin; Interferon, subcutaneous, low dose interferon; OMCT, oral metronomic chemotherapy; TMZ, temozolamide; BSC, best supportive care; PR, partial response; SD, stable disease; PD, progressive disease; CR, complete response; LFU, lost to follow up.  Figure 4B).

Prognostic Markers
The factors that were found to be significant for prognosis in the univariate analysis for EFS and OS are shown in Table 3.  Table 3).

DISCUSSION
In India, cancer registries report that the age-specific incidence rate for cutaneous malignant melanoma is less than 0.5 per 100,000 (16). The highest age-standardized incidence rates (ASIR) per 100,000 general population were reported in Australia (54.1) and United States (21.0), while the lowest ones include Asia Pacific (0.7) and South Asia (1.1) (17).
In our study, 44.2% of patients were metastatic at presentation. Contrastingly, in a West-Asian study, around 12% patients were metastatic at the baseline, and according to the western literature, 4% patients presented with metastasis (18,19). The higher number of metastatic patients at presentation in our settings is attributed to the paucity of a proper melanoma registry and lack of awareness in patients and community practitioners about melanoma diagnosis. Moreover, logistic constraints in LMIC leading to delayed referral and upstaging also contributes for the same (15,20,21). In the present study, the most common metastatic site was non-regional nodes (61.1%), in contrast to a western study, wherein lung constituted the predominant metastatic site, in 85% cases (22). This is partially explained by the differential distribution of primary sites and types. However, there might be pharmacogenomic variations as well, which are largely unexplored. The median age was 54 years, with 58.9% of males. This correlates with the European, Australian, and other Asian countries where men are more susceptible to melanoma than females, and the median age is in the 5 th decade (2,23). It is important to note that taking age into consideration, adolescents and young adult women are more susceptible to melanoma than men are, but after the age of 40 years, the pattern reverses with a relatively higher prevalence in men (2).
In the current study, the most common site was extremity (36.6%), followed by anorectal region (31.4%). Overall, 55.2% of patients had mucosal melanoma, while 44.8% had cutaneous primary. This contrasts with the data from tropical countries and other parts of the world (22,24). In a Eurocare-5 study report, 15% of the patients had cutaneous melanoma of the head and neck region (24). In other Indian studies also, mucosal melanomas were more common. However, there is a variable pattern that is partly explained by referral pattern and draining area (24). Notably, ophthalmic melanoma was reported as the most common in a study from a leading ophthalmology referral center. In other study, albeit with small numbers, anorectal and extremity were the predominant sites (43% for both) (25). Among various histopathological subtypes, nodular melanoma was the most common in our study. However, in other Asian and western studies, the superficial spreading type was more common. Considering ours as a cancer referral centre, we receive tumours and lesions of larger sizes (18,24).
Among the limited patients who were tested, the incidence of BRAF mutation was 10.8%, which is comparable to other Asian data (15-25%). However, this is lower than the western literature (45%) (26,27). In another Indian study, the incidence of BRAF mutations was around 30% (28). BRAF is less common in mucosal melanomas than cutaneous melanomas, and this analysis cohort had a higher proportion of mucosal melanoma and this could partly explain the low prevalence of BRAF mutations. Notably none of the tested mucosal or uveal melanoma were BRAF mutation positive. This small sample artifact partly explains this, and the entire cohort needs testing to know the actual incidence of BRAF mutations in India.
In spite of the lack of standard of care options, such as ICI and/ or targeted therapy, there was a statistically significant improvement in EFS and OS in the metastatic cohort with any ST in comparison to the BSC alone. In real world practice, other therapies such as LD-SCIFN and OMCT were used in some patients, which has immunomodulatory properties. One can argue that there might be higher poor ECOG PS patients in BSC rather than in ST arm; however, a significant number of patients with advanced disease in real world scenario of LMIC present with high tumour burden, brain metastasis, nutritional deficiencies, extremes of ages, and poor ECOG PS. Although we do not have exact numbers of patients who presented with poor PS in each group owing to inadequate documentation of this factor in all patients, this could be a potential confounder owing to inherent limitation of retrospective analysis. Among various treatment options other than immunotherapy and targeted therapy, the disease control rates and median PFS were better with paclitaxel and carboplatin with or without low dose subcutaneous interferon compared to temozolamide based regimens as shown in Figure 1. The survival statistics seem comparable with these regimens, in comparison to other regimens used in literature, and are worth exploring systematically (29) ( Table 4).
A large majority of patients from this part of the world is selfpaying. A monthly therapy with either pembrolizumab, 200 mg 3 weekly schedule or for nivolumab 3 mg/kg, two weekly schedules for an average-weight person costs nearly 5000 USD, which is beyond reach to a vast majority of patients in LMIC (35,36). India's existing data suggest that only 1.6% of the eligible patients could afford ICI, which reflects the gross discrepancies between higher-income countries versus LMIC. Studies from even developed countries, such as Australia and developing countries, have concluded that rapidly rising treatment costs of melanoma warrant an urgent need for a comprehensive melanoma control strategy (30,31). The survival in patients harbouring cutaneous melanoma was superior compared to mucosal melanoma, which is similar to published literature (32)(33)(34). Site-wise, cases with extremity tumors fared much better than others, and anorectal melanomas had the worst outcomes, as similarly reported by others (32)(33)(34)37). Anorectal melanoma is known to have a very aggressive behaviour (38,39). Table 4 highlights various studies of ST for the management of MM.
Despite being one of the few studies from our subcontinent, this study has several limitations, including nonrandomized character with inherent biases; our institute being the tertiary care referral centre, there is a chance of referral bias, and this may not represent the true population, including the primary site and subtypes. However, this is the most extensive data from India, where melanoma is a rare diagnosis and can provide meaningful inferences.
Only 10% of patients received the standard of care options, including ICI and targeted therapies due to financial constraints. However, this is the real-world data and mirrors the actual practice.
Malignant melanoma is a rare disease in this part of the world and has a dismal prognosis without ICI or targeted therapy. However, meaningful responses can be achieved with other systemic therapies, if these standard options are not feasible (40)(41)(42). There is an urgent need to have a national registry, national and international collaborations for clinical trials, and patients support programs to increase access to the standard therapy. However, till then, other STs including those with immunomodulatory potential, such as chemo with LD-IFN and OMCTs, are worth exploring as an option. The efficacy of these systemic therapy options needs further validation in prospective studies and caution should be exercised in correct interpretation of the results as these are certainly not the substitute for standard of care therapies.
Large real-world data reflects the treatment patterns adopted in a LMIC for melanomas and the hard reality of poor access to expensive standard of care therapies. In such real-world situations, when standard options are beyond reach, other systemic therapies may provide meaningful clinical benefit and are worth considering.

DATA AVAILABILITY STATEMENT
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

ETHICS STATEMENT
The study was conducted after approval from the Institutional Ethics Committee (IEC). Waiver of consent was obtained for retrospective study. All data were anonymized before the start of analysis. With surgery and without systemic therapy as NACT (n = 6), the median OS was 13.7 months (95% CI 13.7-NA) with 1 death. Without surgery and with ST as NACT (n = 3), the median OS was 13.7 months (95% CI 7.8-NA) with 2 deaths. Without surgery and without systemic therapy as NACT (n = 2), the median OS was 2.6 months (95% CI 0.7-NA) with 2 deaths.