The Radiotherapy Role in the Multidisciplinary Management of Locally Advanced Vulvar Cancer: A Multidisciplinary VulCan Team Review

Simple Summary Locally advanced vulvar cancer (LAVC) requires a multidisciplinary management. The aim of this paper is to conduct a review of all relevant studies regarding the role of radiotherapy in LAVC. Based on the available evidence, radiotherapy, with or without concurrent chemotherapy, has a relevant role in neoadjuvant, adjuvant or exclusive treatments. A multidisciplinary and multidimensional assessment can also be useful to identify the most suitable approach, in view of a better treatment personalization. Abstract Locally advanced vulvar cancer (LAVC) is a challenging disease, requiring multidisciplinary management. The aim of this review is to propose an integrated clinical approach including radiotherapy (RT) in the multidisciplinary management of LAVC to customize the treatment. A review of the literature was conducted on PubMed, Scopus, and Cochrane library to acquire all relevant studies on RT in LAVC. Based on the available evidence, RT, with or without concurrent chemotherapy, has a relevant role as adjuvant and exclusive treatment or in the neoadjuvant setting. However, multicentric prospective trials are needed to define the best treatment options based on tumor and patient characteristics. A multidisciplinary and multidimensional assessment can also be useful to identify the most suitable approach, considering patients’ age and comorbidities, in view of a better treatment personalization.

VC patients require a multidisciplinary evaluation for primary surgery and inguinal lymph node assessment, and potentially adjuvant radiation and/or chemotherapy [4][5][6][7][8]. Radiotherapy (RT) and/or chemotherapy may be considered for primary treatment instead of surgery in cases that would otherwise require radical surgery such as abdominal-perineal resection or exenterative procedures.
As there is no standard treatment algorithm that fits all patients, multimodal clinical approaches, especially in VC involving perineal tissues, have been proposed [8][9][10].
Groin and pelvic adjuvant RT should be administered for any nodal metastasis and/or close/involved margins unfit for further surgery. Large tumors, or those at high risk of surgical morbidity, are candidates for primary (chemo) radiation treatment, and multidisciplinary teams play an important role in the evaluation phase [11][12][13][14][15].
In recent decades, RT has benefited from major technological improvements, with image-guided and intensity-modulated treatments. The use of computed tomography (CT) and magnetic resonance imaging (MRI) for treatment planning allows for the precise delineation of the tumor and surrounding organs (OARs), improving target dose coverage. Modern techniques allow the delivery of comparatively higher doses to the tumor, while minimizing doses to healthy tissue. In several cancers, these improvements lead to a better outcome, in terms of both local control and toxicity rates [16][17][18].
The aim of this review is to summarise the main evidence published in the last 30 years on the role of RT in the multidisciplinary management of locally advanced VC.

Data Sources and Searches
A systematic search was carried out using PubMed (https://pubmed.ncbi.nlm.nih. gov/, first accessed on 15 June 2021), Scopus (https://www.scopus.com/, first accessed on 15 June 2021), and Cochrane library (https://www.cochranelibrary.com/, first accessed on 15 June 2021) to identify full papers reporting on RT in patients with locally advanced VC. We selected the studies including the terms "vulvar neoplasms" and "radiotherapy" as medical subject headings (MeSH) and/or keywords. The Medline search strategy was: ["Radiotherapy" (MeSH) OR "Radiation therapy" (All fields)] AND ["Vulvar Neoplasms" (MeSH) OR "Vulvar Cancer" (All fields)]. To avoid missing relevant studies, we chose this strategy, which is burdened by a high sensitivity and low specificity. All full-text papers published in English and reporting on patients with locally advanced VC treated with RT were identified and reviewed.

Study Selection
The articles that met the following inclusion criteria were retained in the final analysis: (a) clinical prospective or retrospective studies on patients with histological confirmation of primary VC; (b) sample size ≥ 10 patients; (c) RT delivered with or without concurrent chemotherapy in adjuvant, neoadjuvant, or definitive setting; (d) studies published in English between 1997 and 2021; (e) studies reporting oncological outcomes and/or toxicity. Planning studies, case reports, surveys, letters, editorials, book chapters, review articles, and conference abstracts were excluded.

Data Extraction
The citation list of all the included articles was screened independently and in duplicate by two authors (MF, CC) at the title and abstract level to identify other potentially relevant studies without any duplication. Eligible citations were retrieved for full-text review. Uncertainties about inclusion in the review were resolved by an expert radiation oncologist involved in the VUL.CAN board (VULvar CANcer tumor board) (VL). For each study, the following data were extracted: first author's last name, enrollment period, study design, oncological outcomes and toxicity. All relevant papers were analysed and organised according to the RT setting (adjuvant, neoadjuvant, and definitive RT) and discussed by the VUL.CAN board of our institution, including radiation oncologists, gynaecologists, medical oncologists, plastic surgeons, radiologists, and onco-geriatricians. The preliminary results were finally discussed and validated by two radiation oncologists (LT and MAG) of the first author's institution and by two radiation oncologists (AGM and GM) and one gynaecologist (GG) from other institutions. The primary outcome was clinical/pathological complete response. Secondary outcomes included local control (LC), disease-free survival (DFS), overall survival (OS), clinical/pathological response and rate of adverse events. A descriptive statistical analysis was conducted of the data available from the published papers.

Neoadjuvant Radio-Chemotherapy
From the 310 retrieved papers, five studies reporting data on 782 patients (median age, 68 years; range 88-73.5 years) met our inclusion criteria and included patients who underwent preoperative (chemo) radiation [19][20][21][22][23], as shown in Figure 1. The 3-year OS for women treated with primary RT/RCT was 41.7% compared with 57.1% for women treated with RT/RCT + S (p < 0.001). Older age (p < 0.001), higher Charlson-Deyo score (p < 0.001), and AJCC stage N3 versus N0 (p < 0.001) were associated with compromised OS Exclusive RCT with doses less than or equal to 55 Gy had a 3-year OS of 33.0% compared with 50.3% for those who received doses of more than 55 Gy (p < 0.001).
Richman [ Older age, poor tumor differentiation, positive surgical margin, and lymphovascular space invasion were found to be important prognostic factors for disease-related outcomes Abbreviation. CT: chemotherapy; RCT: radio-chemotherapy; cCR: clininical complete response; cPR: clininical partial response; DFS: disease free survival; FU: follow-up; Gy: gray; LC: local control; Mo.: monocentric; N: nodes; NA: not available; Na: not available; pCR: patological complete response; OS: overall survival; y: years; RT: radiotherapy; Rec: recurrence.  More nodes examined, higher T stage, older age, and more co-morbidities were also associated with worse OS. OS was highest for the RCT group for both patients with one N+ and those with two or more N+. Significantly decreased mortality for patients with 1 N+ who received EBRT (p = 0.001), patients with 2 or more N+ receiving EBRT (p < 0.001), patients with 1 N+ receiving RCT (p = 0.004), and patients with 2 or more N+ receiving RCT (p < 0.001).
Patients were treated with exclusive radio-chemotherapy for primary carcinoma of the vulva due to severe associated medical problems or extensive local disease that precluded curative surgical resection.
Close margin was generally defined as a distance of less than 8 mm between cut tissue edge and invasive tumor.
Recommendations for adjuvant radiotherapy were margins status (close or positive), tumor depth of invasion >5 mm; nodal status (single positive lymph node if metastasis diameter is <2 mm). Recommendations for adjuvant radio-chemotherapy were positive margin, presence of a single positive lymph node if metastases diameter is >2 mm; presence of two or more positive lymph nodes; presence of node with extracapsular extension (ECE).
Five-year overall survival (OS) was highest among patients with one positive node who received radio-chemotherapy (68.1%), compared to 55.9% for adjuvant EBRT and 46.1% for no adjuvant treatment. Survival was likewise highest among the patients with two or more positive nodes who received RCT (49.1%), compared to 29.4% for adjuvant EBRT and 21.2% for no adjuvant treatment [15].

Discussion
This review provides, in our opinion, consistent evidence of RT's efficacy in terms of clinical outcomes across different clinical settings, with acceptable toxicity rates.
The 30% of VC patients presenting with locally advanced disease (T3/T4) may represent a problem regarding the treatment. Ultraradical surgery alone (radical vulvar operation combined with a partial or total pelvic exenterative-type procedure) is associated with a 4.3% mortality rate and 46% disease-free survival [43]. However, although this is not well reported in the literature, there is significant physical and psychological morbidity resulting from these procedures due to a permanent colostomy, urostomy or both [43,44]. In comparison with radical surgery, chemotherapy has been shown to be associated with poor survival and significant treatment-related toxicity [45,46]. RT combined with chemotherapy, followed by organ-sparing surgery has shown efficacy in preventing stoma formation, but is also associated with significant wound-healing problems and treatment-related mortality [24,26,27]. High-quality evidence on neoadjuvant RT was difficult to collect for several reasons, such as a small sample size, the heterogeneity of studies, and the use of different radio-chemotherapy schedules, RT dose fractionation techniques and target definitions. There was no evidence of a survival advantage or reduction in toxicity when neoadjuvant radio-chemotherapy was compared to primary surgery for women with locally advanced VC [47]. In patients with large tumours that can only be treated with anterior and/or posterior exenteration, the complications of neo-adjuvant therapy might outweigh the complications of exenterative surgery. Neoadjuvant therapy is not justified in patients with tumours that can be adequately treated with radical vulvectomy and bilateral groin node dissection alone [48].
Exclusive radio-chemotherapy of locally advanced VC was tested by several studies, based on the results reported in patients treated with neoadjuvant radio-chemotherapy. Compared with an upfront radical surgical approach, definitive radio-chemotherapy allows for organ preservation with good clinical outcomes. Landrum et al. demonstrated that at a median follow-up of 31 months (range from 3-161 months), there were no significant differences in OS and DFS according to treatment group (radio-chemotherapy versus surgery) (p = 0.83, p = 0.81, respectively) [30]. There was no evidence of a survival advantage when primary surgery was compared to radio-chemotherapy for women with locally advanced VC [48]. There were no studies showing a statistically significant difference in treatment-related adverse effects with the above-mentioned methods of treatment. Due to the sparse data and the relatively high risk of bias in the literature data, no definite conclusions can be drawn [48].
The results of the present study suggest that dose escalation, utilizing modern RT techniques with concurrent chemotherapy in the definitive setting, may lead to an improved response and similar or improved tolerance. In the present systematic review, the median delivered total dose was 61 Gy, as compared to 57.6 Gy in GOG 205 [49] and 47.6 Gy in GOG 101 [23]. The rates of cCR were 48% in GOG 101, 64% in GOG 205, and 58.1% (range 27.8-88%) in the present study. A comparison between these response rates and historic controls from GOG 101 and GOG 205 suggests that a dose-response relationship may exist [25]. The importance of the clinical/pathological response was underlined in one study, showing it to be significantly correlated with improved OS [32]. The high rate of CR achieved by exclusive radio-chemotherapy and the low rate of relapse suggest that the combination of RT and chemotherapy could be synergistic [15]. Furthermore, the combination of RT plus concurrent chemotherapy resulted in significantly improved relapse-free survival [20], disease-specific survival [20] and OS [20,27] compared to RT alone.
Age was a significant predictor of OS [25,26,30,33,36]. When survival in patients younger than the median age of 64 was compared to those aged 65 and older, significant improvements were noted in OS [25,26,30,33,36] as well as PFS [30]. Furthermore, age above 60-68 years also had a detrimental effect on complete response rate [26].
Adjuvant RT is indicated in patients with high risk factors, such as close/involved margins or inguinal lymph node involvement, to decrease the rate of recurrence, and thus improve OS, as shown in our results. Statistically significant improvements in OS and DFS according to low-stage and negative nodal status [31] were found, together with an improved LC in patients with close/involved surgical margins after adjuvant RT [33]. Even in the adjuvant setting, we recorded high clinical outcome rates [32][33][34]. These results, particularly in terms of LC, favorably compare with surgery alone. In fact, even in patients with early VC, surgical resection is associated with local recurrence rates of up to 40%. [50]. Moreover, after surgery that affect tissues worsening tolerance, severe acute/late toxicity was reported in about one third of patients, mainly in terms of skin side effects.
The treatment with IRT that allows for the delivery of a high radiation dose to the tumor, while sparing the surrounding, at-risk organs, with a very sharp dose fall-off, deserves special attention. It is well known that IRT is an effective treatment option for primary and recurrent VC, especially in patients with severe comorbidities and contraindications for surgery [1]. Our analysis confirmed previous findings, which reported encouraging 5-year clinical outcomes, especially considering the preferential selection of most frail patients for IRT [23,45,46,48,51]. Despite these positive data, IRT is rarely considered among the therapeutic options for locally advanced VC patients. It is likely that the rarity of this tumor, lack of widespread experience and expertise, and complexities in performing this treatment technique limit the use of IRT in the majority of RT centers [52,53]. IRT could theoretically also be used as a boost after concurrent radio-chemotherapy to improve LC rates, especially in larger VCs. However, the role and real efficacy of IRT-based boost is largely unproven, with no prospective or randomized controlled trials available in this setting [54].
The small sample size and retrospective design of most studies, along with the wide enrollment interval (1991-2021) and consequent inclusion of patients treated with obsolete RT techniques, represent the limits of our analysis. These issues resulted in a high risk of bias and poor generalizability of the results. However, given the complex target shape, it is challenging to deliver high doses and achieve a uniform target irradiation with the optimal sparing of healthy tissues with this technique. In centers equipped with intensitymodulated treatments, both IMRT and volumetric-modulated arc therapy are increasingly used. However, only a few studies have tested IMRT in patients with locally advanced VC [19,26,55]. For instance, Beriwal et al. reported a reduced irradiation in small-bowel, bladder, rectum, and femoral heads, with 71.0% and 42.8% complete clinical and pathological response rates, respectively and good local control [19]. Delivering a total dose of 70 Gy, Rao et al. achieved a cCR of 61% and a pCR of 44%. Another recognized limitation is the lack of human papilloma virus (HPV) status in the analyzed papers. Several reports investigating the relationship between HPV infection and vulvar carcinoma prognosis reported conflicting results. Nevertheless, the evidence provided by these studies is mainly indirect, as most of them did not provide data on HPV detection [56,57]. Therefore, the design of large databases that can assist in defining patients' and tumors' characteristics and allow for greater personalization of treatment strategies appears useful. In this framework, two national data collection projects (OLDLADY-1 and OLDLADY-2) are currently underway in our centers to generate two large databases on exclusive and adjuvant radio-chemotherapy in patients with VC, respectively [58,59]. Despite the difficulties in deriving conclusions as to which clinical or pathological factors are predictors of recurrence and survival in the dose-escalated modern RT technique era, the data on CR and low toxicity are promising.

Conclusions
Most of the evidence on RT of VCs is low-level, based on retrospective studies. However, in different treatment settings, RT results are quite homogeneously encouraging even if there is clearly room for further improvements, in terms of both treatment outcomes and late sequelae and patient selection. These improvements may derive from prospective and possibly randomized studies, even if the rarity of VCs severely limits their feasibility. In parallel, or alternatively, the design of large databases could allow for the development of predictive models, which are particularly useful for defining individualized treatments based on tumors and patients' characteristics. To date, the multidisciplinary management of these patients, based on tumor board discussion, represents the broader and more fruitful cooperation possible when choosing the best treatment for each patient.