Encyclopedia
Please note this is a comparison between Version 1 by Salvatore D'Alessandro and Version 2 by Wendy Huang.
Among the mucosal melanomas, vaginal melanomas are very rare tumors, accounting for less than 20% of melanomas arising from the female genital tract. They occur most frequently in women in post-menopausal age, but younger patients may also experience this neoplasm, mainly located in the lower third of the vagina or the anterior wall. The optimal management of this tumor remains controversial, with surgery reported as the most frequently adopted approach. However, a clear benefit of surgical treatment in terms of survival has not yet been demonstrated. Conversely, radiotherapy may represent an attractive non-invasive alternative, and there are several favorable reports of the role of radiation therapy, either delivered with photons, brachytherapy, or hadrontherapy.
- vaginal melanoma
- radiotherapy
- immunotherapy
- surgery
- EBRT
- SBRT
1. Introduction
Vaginal melanomas (VM) are a rare entity among the mucosal melanomas, accounting for less than 20% of melanomas located in the female genital tract. Clinical staging of VM is derived from cutaneous disease, and tumor size and lymph-nodal metastases are related to a poorer prognosis, with an overall survival rate of 5 years ranging between 5% and 25% [1].
It more commonly affects women in the post-menopausal period between 60 and 70 years of age, but sometimes it might also be observed in younger patients. The preferred site of presentation is usually the lower third of the vagina or the anterior vaginal wall. Melanocytic presentation is the most common occurrence, although very rare cases of non-melanocytic diseases are reported in the literature. Disease staging is based on the International Federation of Gynecology and Obstetrics(FIGO) classification for vaginal cancer, although TNM classification is also widely adopted, and the depth of invasion is considered an important risk factor, such as for cutaneous melanomas.
Due to the rarity of the disease, optimal management remains a matter of debate. Unlike non-melanoma vaginal cancer, where surgery has a limited role in very early stages or advanced stage IV disease with healthy structures invasion, for vaginal melanomas, surgical resection is the preferred approach, although with a debated survival benefit and a wide spectrum of complications, such as infection, bladder or urethral damage, fistulas, or hemorrhages [2].
Furthermore, diagnosis occurs more frequently in the advanced stages of the disease, with a reduced probability of surgical radicality and a higher risk of severe sequelae. However, combined approaches with adjuvant radiotherapy have resulted in very poor outcomes due to the high rates of local and distant recurrences [3].
Systemic therapy options for mucosal melanoma are limited, given the reduced response to conventional cytotoxic drugs. Also, BRAF mutations are rarely present in mucosal melanomas, compared to cutaneous disease, while, KIT mutations are more frequently reported [4].
In this scenario, immunotherapy has recently been introduced with a sensitive improvement in clinical outcomes, reporting objective response rates ranging between 20% and 75%, with durable responses reported in the literature [5].
Although response rates to immunotherapy are lower for mucosal melanomas compared to cutaneous melanomas, the possibility of combining radiotherapy with immunotherapy is an attractive treatment option in this setting [6][7][6,7].
Melanoma is traditionally considered a radio-resistant tumor with a natural capacity to repair damages caused by low-dose radiotherapy. These features of the disease have led clinicians to explore alternatives to conventional external beam radiotherapy (EBRT), such as brachytherapy or hadrontherapy, both of which can deliver higher doses to the target with limited exposure to organs at risk.
In recent years, based on the radiobiological characteristics of VM, the use of stereotactic body radiotherapy (SBRT) has also been increasingly reported, not only as a therapeutic option able to overcome the intrinsic radio-resistance of melanoma but also for its potential effect on enhanced immunogenicity [8].
SBRT allows clinicians to deliver very high doses to small volumes, with a steep dose gradient and a reduced low-dose bath of healthy nearby structures [9].
Some studies have favorably reported the combination of high-dose radiotherapy with immunotherapy, with improved clinical outcomes in comparison with patients treated with immunotherapy alone [10][11][12][13][10,11,12,13].
As surgery remains the preferred treatment option for the management of VM, radiotherapy may represent an effective alternative for patients unfit for surgical excision, with a further potential benefit provided by immunotherapy.
2. Treatment
The optimal management of VM remains a matter of investigation due to the rarity of the disease. The literature reports surgery as the most frequently adopted approach. However, the extent of surgical resection may vary from wide excision to pelvic exenteration, including a more aggressive approach to the lymph nodes when compared to vulvar disease. Moreover, a clear benefit in terms of survival has not yet been demonstrated [14][24].
In this scenario, modern radiotherapy techniques have emerged as a potential non-invasive alternative.
Initial experiences of brachytherapy alone or in combination with EBRT are reported in the literature, suggesting the feasibility of delivering high doses to the tumor using BRT, especially as a boost after conventional EBRT [15][16].
Hadrontherapy has recently been reported as a potential therapeutic option for mucosal melanomas due to its higher radiobiological effect, useful in the case of radio-resistant tumor histologies, and for the peculiar dose distribution to optimally spare nearby healthy structures [16][25].
In addition to the major sparing of the proximal organs at risk, the higher release of energy in a single point, compared to photons, is supposed to result in a higher probability of double-strand DNA breaks, with a consequent enhanced effect of tumor cell killing [17][26].
All these features justify the potential of hadrontherapy for radio-resistant tumors, although the global availability of this technology is quite limited to date.
Murata et al. [18] reported the outcomes of one of the largest series of female genital tract melanomas, including 22 patients with VM, treated with CIRT. Despite referring to a series of patients with mixed primary sites, the researcheuthors reported excellent rates of complete response (about 81%) with 2-year LC, OS, and DPFS rates of 71%, 53%, and 29%, respectively. Interestingly, only three acute grade 3 skin adverse events were recorded.
Similar outcomes are reported in a smaller series by Barcellini et al. [19] including two patients with VM treated with CIRT and by Ohno et al. in a single case report [20][15].
Beyond the role of hadrontherapy, another topic of potential interest for the treatment of VM relies on the combination of radiotherapy with novel systemic agents.
For this purpose, an interesting case is reported by Yin et al. [21][23] of a 55-year-old patient with metastatic VM, who received conventional EBRT in combination with temozolomide + tyrosine kinase inhibitors, with good results in terms of local control but short-term distant progression.
In recent years, the combination of radiotherapy with immunotherapy has attracted increasing interest, as reported in other clinical settings, especially for non-small cell lung cancer, kidney cancer, cutaneous melanomas, and cutaneous squamous cell carcinoma [22][23][27,28].
Starting from pre-clinical studies that suggest a major immunogenic effect from radiotherapy when delivered using higher doses per fraction (i.e., 8 to 10 Gy for 1–3 fractions) [24][29], several studies highlight SBRT as a means of releasing neo-antigens capable of activating and proliferating T-cells against tumor cells. This effect favorably combines with the intrinsic activity of recruiting T-cells mediated by immunotherapy [23][28]. Moreover, SBRT, compared to conventionally fractionated radiotherapy, generates higher endothelial vascular damage, which facilitates the delivery of targeted therapies to the tumor [25][30].
Several reports in the literature, specifically for cutaneous melanoma, support the combination of immunotherapy with high-dose SBRT, particularly for brain metastases [26][27][31,32].
On the contrary, the combination of SBRT with immunotherapy for extracranial melanoma is currently a matter of debate, with some studies reporting a detrimental impact of radiotherapy when combined with immunotherapy [28][29][33,34].
In contrast, Youland et al. [30][35] reported improved outcomes for extracranial melanomas when SBRT is chosen as the preferred approach, with a statistically significant impact on local control, distant progression, and overall survival in a cohort of 75 patients.
This conflicting evidence highlights the need to further investigate the optimal combination of radiotherapy with immunotherapy, not only in terms of dose and fractionation but also (and probably with more interest) for the sequencing of these two therapeutic tools [31][36].
A majority of the literature supports the beneficial effect of upfront SBRT followed by immunotherapy in order to enhance the response of the immune system, and other combinations are also reported in the scientific community. Fenioux et al. recently reported favorable outcomes in a cohort of 62 patients with brain metastases from melanoma when immunotherapy was delivered for a long interval (12 weeks) prior to stereotactic radiosurgery [31][36].
A recent literature review published by Tian et al. reported improved outcomes for brain metastases when concurrent radiotherapy and immunotherapy were delivered in terms of clinical outcomes, but at the same time, the researcheuthors focused on the need for a precise definition of “concurrent administration” in terms of time intervals. Starting from an analysis of the biological mechanisms of both SBRT and immunotherapy, the researcheauthors hypothesized a peak in the immunogenic effect of high-dose radiotherapy within 24–72 h from the end of treatment, suggesting that right after this interval, immunotherapy has a higher benefit due to the radiotherapy boost effect [32][37].
Of note, a major incidence of adverse events is reported in the case of concurrent SBRT with immunocheckpoint inhibitors.
Despite being referred to as cutaneous melanoma, all these data suggest the need for better design prospective studies with precise time intervals between SBRT and immunotherapy since this feature might be crucial for an optimal combinatorial response.
Nonetheless, another caveat in the combination of radiotherapy (either with conventional fractionation or SBRT) with immunotherapy is represented by the potential increased risk of severe adverse events [33][38].
Mesko et al. [34][17] reported a case of a 70-year-old patient who received conventional EBRT (45 Gy + electron boost up to 63 Gy) for a VM with concurrent ipilimumab. Despite reporting severe acute skin toxicity, the patient remained free of disease after 15 months, with a complete response on PET-FDG scan. Data on skin toxicity with concurrent radiotherapy and ipilimumab are limited, but the researcheuthors addressed this phenomenon to the high dose of the target and the size of the planning target volume (PTV).
Schiavone et al. [7] reported the outcomes of a case series including three patients with VM treated with concurrent radiotherapy and immunotherapy, with two patients treated with 30 Gy/5 fx with good tolerance. Notably, two patients in this series also received surgery after the radiotherapy treatment in order to maximize local control.
In light of the higher risk of toxicity when administered concurrently with immunocheckpoint inhibitors, SBRT appears to be a more attractive alternative, as it is usually delivered in smaller volumes compared to the larger volumes of conventional EBRT, and SBRT also offers the abovementioned potential to enhance the response to immunotherapy.
In this scenario, favorable responses are reported. Parisi et al. [35][20] reported a case of complete remission of VM treated with volumetric modulated arc technique (VMAT)-based SBRT (24 Gy/3 fx once a week) plus pembrolizumab in an 80-year-old patient unfit for surgical approaches. This report highlights the feasibility of stereotactic approaches in older cancer patients, suggesting the potential synergistic role of radiation therapy and immunotherapy, especially when radiotherapy is delivered at higher doses per fraction [22][27].
Sezen et al. [36][21] reported the outcomes of a 73-year-old patient with upfront metastatic VM who received concurrent nivolumab and ipilimumab with palliative 30 Gy/5 fx to the primary tumor site for vaginal bleeding. The subsequent PET-FDG scan detected a complete response to the site of SBRT, and the onset of three liver metastases and one to the right groin. All these sites received SBRT treatment in combination with double immunotherapy followed by nivolumab monotherapy maintenance, with the patient reaching a complete metabolic response 32 months after the diagnosis. This study reinforces the hypothesis of high-dose radiotherapy as a sort of in-situ vaccine, able to facilitate the release of antigens enhancing the immune response to tumor cells [23][37][28,39].
