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Multidisciplinary personalized approach in the management of vulvar cancer – the Vul.Can Team experience
  1. Luca Tagliaferri1,
  2. Giorgia Garganese2,
  3. Andrea D'Aviero3,
  4. Valentina Lancellotta1,
  5. Simona Maria Fragomeni2,
  6. Bruno Fionda1,
  7. Calogero Casà3,
  8. Benedetta Gui4,
  9. Germano Perotti5,
  10. Stefano Gentileschi6,
  11. Frediano Inzani7,
  12. Giacomo Corrado2,
  13. Milly Buwenge8,
  14. Alessio Giuseppe Morganti8,
  15. Vincenzo Valentini1,3,
  16. Giovanni Scambia2,3,
  17. Maria Antonietta Gambacorta1,3 and
  18. Gabriella Macchia9
  1. 1 Unità Operativa Complessa di Radioterapia Oncologica, Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Lazio, Italy
  2. 2 Dipartimento Scienze della Salute della Donna, del Bambino e di Sanità Pubblica, Unità di Ginecologia Oncologica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Lazio, Italy
  3. 3 Università Cattolica del Sacro Cuore, Roma, Lazio, Italy
  4. 4 Unità Operativa Complessa di Radiologia Diagnostica e Interventistica Generale, Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Roma, Lazio, Italy
  5. 5 Unità Operativa Complessa di Medicina Nucleare, Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Roma, Lazio, Italy
  6. 6 Unità Operativa Complessa di Chirurgia Plastica, Dipartimento per la Salute della Donna e del Bambino e della Salute Pubblica, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Roma, Lazio, Italy
  7. 7 Unità Operativa Semplice di Gineco-patologia e Patologia Mammaria, Dipartimento per la Salute della Donna e del Bambino e della Salute Pubblica, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Roma, Lazio, Italy
  8. 8 Department of Experimental, Diagnostic and Specialty Medicine – DIMES, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Emilia Romagna, Italy
  9. 9 Unità Operativa di Radioterapia, Gemelli Molise Hospital, Campobasso, Molise, Italy
  1. Correspondence to Dr Andrea D'Aviero, Università Cattolica del Sacro Cuore Sede di Roma, Roma 00168, Italy; andreadav89{at}gmail.com

Abstract

Introduction Multidisciplinary treatment strategy involving adjuvant radiotherapy for advanced vulvar cancer could be useful in offering the best personalized clinical approach. In 2013, the VULvar CANcer Multi-Disciplinary Team (Vul.Can MDT) was set up in our institution, in order to share knowledge and expertise, high-quality diagnosis, and evidence-based decision making in the context of personalized medicine. The aim of this observational study was to report on our series of vulvar cancer patients managed postoperatively with radiotherapy within the framework of a formal multidisciplinary tumor board.

Methods Coupling surgical and oncological international guidelines with “case-by-case” discussions, a multi-specialist consensus was progressively reached and internal recommendations were developed and introduced in the daily routine. Data from vulvar cancer patients who underwent primary surgery and adjuvant radiotherapy throughout a 5-year period were retrospectively collected. Actuarial local control was the primary endpoint, while secondary end-points were acute and late toxicities, disease-free survival, and overall survival. Toxicity was evaluated according to the Common Toxicity Criteria Adverse Event v 4.0 scale.

Results The analysis included 35 patients with squamous vulvar cancer treated with adjuvant radiotherapy±chemotherapy, from April 2013 to September 2017. Median age was 70 years (range 18–87), all patients underwent surgery followed by concomitant chemoradiation (45.7%) or radiotherapy alone (54.3%). The median prophylactic dose on lymphatic drainage was 45 Gy, while positive nodes and perineal area received 51.2 Gy and 52.6 Gy, respectively. Chemotherapy involved the cisplatin-based regimen (45.7%)±5-fluorouracil (37.1%). Median follow-up was 32 months (range 6–72): the 24-months local control, disease-free survival, and actuarial overall survival rates were 88.6%, 82.0%, and 91.0%, respectively. Low rates of severe acute (12%) and late (3%) toxicities occurred.

Discussion The outcomes of this series support the benefit of a multidisciplinary personalized approach in the management of vulvar cancer.

  • vulvar and vaginal cancer
  • radiation oncology
  • radiotherapy
  • surgical oncology
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HIGHLIGHTS

  • Multidisciplinary approach is essential for personalized medicine in cancer patients.

  • With a median follow-up time of 32 months, the 24- and 36-months local control rates were 88.6% and 79.3 %, respectively

  • The 24- and 36-month actuarial disease-free survival rates were 82.0% and 72.4%, respectively for the entire population, while 24- and 36-months disease-free survival rates in node positive patients were 77.8%, and 65.2%, respectively

Introduction

Vulvar cancer is a rare disease, accounting for an estimated 5.6% of overall gynecologic malignancies and 3.7% of gynecologic cancer deaths.1 Ninety percent of primary vulvar cancer are squamous cell carcinoma, while the other rare histologies include Bartholin gland adenocarcinoma, melanoma, extra-mammary Paget’s disease, verrucous carcinoma, basal cell carcinoma, and sarcoma. Risk factors for the development of vulvar neoplasia include advanced age, human papillomavirus infection, cigarette smoking, inflammatory conditions, and immunodeficiency.2 Treatment of regionally advanced vulvar cancer has evolved from 'en-bloc' surgery with high morbidity to more conservative approaches without compromising oncologic safety. In the 1980s and the 1990s, the neoadjuvant chemoradiotherapy approach was introduced among the therapeutic options, however, large treatment volumes, high doses required, and frailty of patients complicated the completion of this treatment. Even adjuvant radiotherapy approaches have been extensively investigated in vulvar cancer with controversial results.3–10

Recently, intensity-modulated radiation therapy (IMRT) or other inverse-planned computerized techniques have become standard options in vulvar cancer treatment, improving the avoidance of critical structures and offering the opportunity to safely escalate the dose.11 Therefore, in order to improve the benefits of technical radiotherapy advances and maximize optimal care delivery, multidisciplinary care has emerged as an ideal therapeutic platform for patients with vulvar neoplasm. The Gynecologic Oncology Group (GOG) 37 and GOG 101 prospective clinical trials set the paradigm for changes in the management of vulvar cancer, highlighting how a multidisciplinary treatment strategy could be potentially useful in offering the best personalized clinical approach.4 12

In our hospital, in 2013, the VULvar CANcer Multi-Disciplinary Team (Vul.Can) was set up in order to share knowledge and expertise, high-quality diagnosis, and evidence-based decision-making in the context of personalized medicine discussing different treatment approaches. Starting from surgical and oncologic international guidelines, Vul.Can MDT progressively reached a multi-specialist consensus and developed internal guidelines that were introduced and followed in daily routines. For instance, whereas one or more positive nodes are present, patients’ selection criteria and adjuvant regimen choice represent controversial topics and the clinical decision is generally based on several risk factors13 14 and concomitant conditions.15 There is a growing interest in this issue, resulting in an increasing number of publications, but robust evidence on the role of adjuvant radiotherapy is still lacking.2–10 16

In this context, the aim of this observational study was to report our series of vulvar cancer patients managed postoperatively with radiotherapy within the framework of a formal multidisciplinary tumor board.

Methods

Study design and end-points

This is an observational study aimed at investigating the impact of the multidisciplinary team in daily clinical practice and at assessing the efficacy/safety of adjuvant radiotherapy in vulvar cancer patients treated at Policlinico Universitario A. Gemelli IRCCS. The core team of the Vul.Can working group includes dedicated gynecologic oncologists, plastic surgeons, radiation oncologists, medical oncologists, radiologists, nuclear medicine physicians, and pathologists. Moreover, among the radiation oncologists, the experts of the Interventional Oncology Center17 take part in the multidisciplinary meetings to provide the additional options of interventional procedures with the most innovative technologies, such as electrochemotherapy or interstitial interventional radiotherapy (brachytherapy), according to the individual patient.

We collected clinic-pathologic and outcome data from vulvar cancer patients who had undergone primary surgery and adjuvant radiotherapy throughout a 5- year period from the start of the working group until 2017. Inclusion criteria were age ≥ 18 years, Karnofsky Performance Status>60, vulvar cancer histology, close (distance from the margin <8 mm at the definitive histology) margin or positive surgical margins, presence of depth tumor invasion (the measurement from the epithelial junction of the most superficial adjacent dermal papillae to the deepest point of invasion) and/or lympho-vascular involvement, and clinical and/or nodal involvement. Exclusion criteria were: pregnancy and breastfeeding, previous radiotherapy treatments, and synchronous or metachronous cancer. Patients signed an informed consent for treatment and use of their clinical data for research or educational purposes. The primary study end-point was the actuarial local control, while the secondary end-points were the rate and severity of acute and late toxicities, the disease-free survival, and the overall survival.

Procedures

Starting from indications reported in the international surgical and oncological guidelines coupled with a “case by case” discussion, the multidisciplinary team progressively reached a multi-specialist consensus and developed internal recommendations, that were introduced and followed in daily routine. The Vul.Can multidisciplinary team internal recommendations for adjuvant radiotherapy in vulvar cancer are summarized in Box 1, while RT details as well as the dose/fractionation schedules are reported in Table 1. After 2015, the IMRT technique with a simultaneous integrated boost (SIB) was systematically used as standard radiotherapy treatment for vulvar cancer.

Box 1

Vul.Can MDT internal recommendation for adjuvant radiotherapy in vulvar cancer

Prescription of adjuvant exclusive radiotherapy

Major criteria (at least one for indication)

  • Margins status:

    • Close: distance from the margin <8 mm at the definitive histology (if a second surgery is not planned/possible)

    • Positive (R1): presence of focal microscopic disease (if a second surgery is not planned/possible)

  • Tumor depth of invasion >5 mm

  • Nodal status: single positive lymph node if metastasis diameter is <2 mm

Minor criteria (not sufficient, a priori, to prescribe adjuvant radiotherapy, but useful elements for discussion in the MDTB. The final decision in some cases could be made considering also these minor criteria and the patient's general condition)

  • Presence of lymphovascular invasion

  • Tumor size >4 cm

  • Multifocal tumor

  • Grading Grade-3

  • Anterior tumor site

  • Loco-regional recurrence after previous surgery

Prescription of adjuvant radio-chemotherapy

  • Margins status:

    • Positive (R2) due macroscopic disease (if a second surgery is not planned/possible)

  • 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 ECE

  • ECE: extracapsular extension; MDTB: multidisciplinary tumor board.

Table 1

Treatment protocol

In the presence of macroscopic positive margins and evidence of bulky lesion at imaging post-surgery (MRI), the opportunity to deliver the radiotherapy boost using external beam radiation therapy or the interventional radio therapy (IRT – brachytherapy) technique was discussed in MDT. The final decision was based on the tumor volume, and the patients’ comorbidity and compliance. In order to offer a personalized and precision IRT treatment, a MRI-guided interstitial procedure was performed.18

A specific data set for standardized data collection was developed by the principal investigators (LT and GG). Technical/dosimetric details of radiotherapy, and data about outcome measures of disease, acute and late toxicities, and follow-up were also collected. A major break was defined as a RT stop longer than 7 days. Clinical target volumes (CTVs) were defined according to pathological and clinical evaluations. In all patients CTV1 included perineum and vulva, while CTV2 included bilateral inguino-femoral and internal, external, and obturator nodes. The definition of CTVs and dose protocol are reported in Table 1. Planning target volumes were obtained by adding a 0.8 cm isotropic margin to both CTVs including perineal volumes and 0.7–1 cm for nodal CTVs.

Actuarial local control was defined as the time interval between the date of adjuvant radiotherapy and the date of inside radiotherapy field relapse/progression of disease or the last follow-up visit. Actuarial disease-free survival was defined as the time interval between the date of adjuvant radiotherapy and the date of local or distant progression, or the last follow-up visit: overall survival was defined as the time interval between the date of adjuvant radiotherapy and the date of death of disease or the last follow-up visit. Toxicity was evaluated by the Common Toxicity Criteria Adverse Event v 4.0 scale.19

Analysis of data and statistical methods

All clinical data were progressively collected in a database obtained by the “SPEED” technology (connected with COBRA/BOA informatic architecture20), an electronic institutional platform, that is an evolution of the “SPIDER’S NET” system.21 The data processing was carried out by A. D’A. Patient characteristics were represented as frequencies and percentages. The Kaplan–Meier method was used to analyze actuarial outcomes: differences between subgroups were evaluated by log-rank tests. Statistical analysis was performed using Prism version 8.31 for macOS software (1994–2019 GraphPad Software, La Jolla California USA, www.graphpad.com).

Results

This analysis included 35 patients with squamous vulvar cancer treated with adjuvant radiotherapy±chemotherapy, from April 2013 to September 2017. The therapeutic choice was performed within the Vul.Can multidisciplinary team according to the internal recommendation and treatment protocol as per Box 1, Table 1.

Median age was 70 years (range; 18–87), and the large majority of patients presented with stage III (68.6%) disease. All patients underwent partial (13, 37.1%) or radical (22, 62.9%) vulvectomy with bilateral inguinal lymphadenectomy in 30 (85.7%) patients, followed by concomitant chemoradiation (16, 45.7%) or radiotherapy alone (19, 54.3%) on the basis of pathologic risk factors (Table 2). As for the risk factors that guided the choice of treatment, the most important were advanced stage with nodal involvement (68.5%), close or positive surgical margins (48.5%), deep stromal invasion (85.7%), and large tumor volume (54.2%).

Table 2

Patients characteristics

All patients completed adjuvant treatment, without any major break (radiotherapy breaks longer than 7 days). The median prophylactic dose on lymph-nodes was 45 Gy, while positive nodes and perineal area received 51.2 Gy (range: 45–60 Gy) and 52.6 Gy (range: 50–65 Gy), respectively. Chemotherapy was cisplatin-based regimen (16, 45.7%) or cisplatin plus 5-fluorouracil (13, 37.1%). With a median follow-up time of 32 months (range; 6–72), the 24- and 36-months local control rate were 88.6% and 79.3%, respectively. In the subgroup of patients (24) with nodal involvement, the local control was 83.3% and 73.7% at 24- and 36 months, respectively (Figure 1B). As far as recurrence rate outside the field is concerned, the 24- and 36-month actuarial disease-free survival rates were 82.0% and 72.4%, respectively for the entire population, while 24- and 36-months disease-free survival rate in node positive patients were 77.8 %, and 65.2%, respectively (Figure 1C). The 24- and 36-month actuarial overall survival rate were both 91.0%, with no difference according to nodal status (Figure 1A).

Figure 1

Kaplan–Meier plot: overall survival (A), local control (B) and disease-free survival (C) for whole population (black line) and for N0 (blue line) patients and N+ (red line) patients.

As per severe toxicity, defined as grade ≥3 (according to the Common Toxicity Criteria Adverse Event v 4.0 scale toxicity) the incidence was low with no grade 4 toxicity, nor severe lymphedema or vaginal stenosis. Overall, four patients (12%) experienced a grade-3 acute skin toxicity and one patient (3%) had a grade-3 late skin toxicity with no correlation with dose (acute, P=0.33 and late, P=0.11) and concurrent chemotherapy (acute, P=0.86 and late, P=0.28).

Discussion

Our series of vulvar cancer patients managed postoperatively within the framework of a formal multidisciplinary tumor board confirm the safety and the efficacy of modern radiotherapy techniques. Outcomes data are encouraging also in node positive patients, supporting the role of the multidisciplinary approach in the management of vulvar cancer.

The role of adjuvant treatments in locally advanced vulvar cancer is controversial. Due to the rarity of the disease and the advanced median age of onset, randomized prospective trials are lacking. Most of the indications for adjuvant treatments after surgery are taken from retrospective studies with low series, heterogeneous stage of disease, and type of approach.3–10 Furthermore, treatments are often adapted to the elderly patients, who have often undergone various re-excisions, or are extrapolated from effective adjuvant treatments for anal or cervical neoplasm.

Starting from this rationale, our multidisciplinary tumor board was prompted to define an internal guideline within the boundaries reported by international guidelines,14 22–24 attempting to develop criteria used in daily clinical practice. Furthermore, we analyzed and reported our clinical series of locally advanced vulvar cancer patients treated according to team-shared homogeneous criteria for personalized therapy in terms of radiotherapy prescription and delivery. Concerning the internal guideline in term of recommendations of adjuvant chemoradiotherapy, we considered as major criteria the nodal and margin status, nodal extracapsular spread, and depth of invasion, establishing that at least one has to be present for radiotherapy indication.11 14 22–24 Moreover, we considered as minor criteria the lymphovascular invasion, tumor size >4 cm, multifocal tumor, grade 3, anterior tumor site, and local recurrence after previous surgery. A consensus was collectively agreed to consider that minor criteria not sufficient, a priori, to prescribe adjuvant radiotherapy, but useful elements for case discussion in the team.

The evaluation of the risk factors is a challenging task, given the type and the quality of surgery. In the era of conservative and reconstructive surgery, the extent of surgical margins becomes an important prognostic factor for local recurrence, but the confidence in resection status may depend on the tissue reconstructive techniques.25 26 In particular, close or positive margins call for re-excision to obtain negative surgical margins. However, when re-excision leads to excessive morbidity, then adjuvant radiation is considered, despite there being no consensus on the threshold of margin distance below which adjuvant radiotherapy is advisable. In our experience, less than a 8 mm-free margin has been considered a reasonable cut-off to define a “close-margin” according to the literature.10 22 27

As far as the radiotherapy schedule is concerned, our prescription doses are in line with the literature, moreover, modern techniques such as IMRT and the possibility of using IRT give us the possibility of increasing the total dose where a macroscopic tumor burden is present. Indeed due to the rapid dose fall-off, IRT results in an optimal technique to deliver a high conformal dose to the target (dose-escalation) avoiding organs at risk, in order to improve local control and reduce the risk of toxicity.10 28–30 Recently data from Moffitt Cancer Center, USA reported clinical outcomes, pattern of failure, and toxicity after high-dose IMRT for advanced vulvar cancer in the exclusive setting. Authors concluded that high-dose IMRT for vulvar cancer achieves high rates of local control through the delivery of high doses with a complete response rate of 80.7%. Authors also reported an improved organ-at-risk sparing resulting in acceptable dose dependent long-term toxicity.31

In the context of adjuvant treatment, the reduced doses, as well as the use of modern radiotherapy techniques could make the difference in terms of toxicity: in particular, our experience seems to confirm safety data showing a low incidence and low grade of toxicity coupled with encouraging outcomes data compared with the literature. Chapman et al in a large cohort study of 3075 patients with positive margins after surgery for primary vulvar cancer showed a 3-year overall survival improvement with the addition of adjuvant radiotherapy.3 Three-year overall survival improved from 34.7% to 52.0% (P<0.001) in patients with node-positive disease and from 66.6% to 72.6% (P=0.005) in patients with node-negative disease.3 Mahner et al also showed an improvement in 3-year progression-free survival from 26% to 40% with the addition of adjuvant radiotherapy in node-positive patients (P<0.005).7 In our experience loco-regional and systemic disease control are favorable, not only in node-negative patients, but also in node-positive patients, commonly burdened by an unfavorable prognosis. Although our data should be confirmed in patients with longer follow-up, these results could be considered a result of the combination of patient-weighted surgery and radiation treatment, in conjunction with the input from a multidisciplinary team.

References

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Footnotes

  • Contributors Conception and design: LT, GG, GM. Data collection: AD’A, CC, SMF. Analysis and interpretation of data: VL, MB, BF. Manuscript writing: LT, GM, AD’A. Final manuscript approval: LT, GG, BG, GP, SG, FI, GC, AGM, VV, GS, MAG, GM.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

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