Objective Since vulvar cancer is such a rare disease, the international experience with electrochemotherapy has been derived from only a few centers. The aim of this study was to evaluate clinical outcome and side effects profile with the use of electrochemotherapy in patients with primary or recurrent vulvar cancer.
Methods Data were retrospectively collected from November 2017 to November 2019 in two major Italian oncologic institutes: Regina Elena Institute and Fondazione Policlinico Universitario Agostino Gemelli IRCCS. Electrochemotherapy was offered in a palliative setting to patients with a primary or recurrent vulvar cancer who were not candidates for surgery or any other treatment, because of poor performance status or previous delivered treatments. All patients underwent general anesthesia. Electrical pulses were delivered using a pulse generator. Intravenous bleomycin was administered in conjunction with electrochemotherapy. Follow-up examinations were performed at 1, 3, and 6 months. Primary endpoint was to assess the response rate of electrochemotherapy as palliative treatment in patients with vulvar cancer.
Results A total of 15 patients were included in the study. Fourteen patients (93.3%) had a squamous cell carcinoma and one patient had vulvar carcinosarcoma. Ten patients (66.7 %) had a single lesion and 5 patients (33.3%) had multiple lesions. Median number of electrical pulses was 22 (range 3–42) and median operative time was 13 (range 7–20) min. No intra-procedure complications occurred. One patient had pneumonia during their post-operative stay. Overall response rate after 1 month was 80%. At the 3-month follow-up, 3 patients (20%) had disease progression, 3 patients (20%) had died from ongoing disease, 1 patient (6.7%) died for other reasons, whereas the other patients maintained their 1-month clinical response. A total of 8/13 patients (61.5%) were alive at 6-month follow-up, whereas 6/12 patients (50%) were alive at 1-year follow-up.
Conclusions Electrochemotherapy is a feasible, easy to perform, and reproducible procedure in patients with primary or recurrent vulvar cancer who are unable to undergo surgery. Survival after 1 year in this population was 50%. Electrochemotherapy may have a role in the management of vulvar cancer, especially as palliative treatment when other therapies are no longer applicable.
- palliative care
- vulvar neoplasms
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Electrochemotherapy is a feasible, easy to perform, and reproducible procedure in patients with vulvar cancer who are not surgical candidates.
Electrochemotherapy administration is associated with a 1-year overall response rate of 50%.
The median operative time was 13 min and there were no intra-operative complications.
Vulvar cancer accounts for 5% of all gynaecologic malignancies,1 and since it is a rare disease the optimal treatment is routinely being redefined. Surgery currently represents one of the key treatments in the management of early and advanced disease. Unfortunately, although the vulvo-perineal region is an area characterized by poor wound healing due to urinary and fecal pathogen contamination, a fast post-operative recovery is often necessary to allow commencement of adjuvant therapies.2 3 For this reason, radical surgery is often followed by extensive reconstructive techniques,2 3 which may provide favorable long-term results despite a high post-operative burden.4 However, since vulvar cancer predominantly affects elderly patients, the presence of multiple co-morbidities often makes surgery unfeasible. Furthermore, even when surgery, radiotherapy, and/or chemotherapy are feasible, the high recurrence rates increase the need for new therapeutic strategies.5–8
Electrochemotherapy is a novel treatment that combines electroporation and chemotherapeutic drugs in order to destroy or reduce the size of lesions. Drug delivery is improved by an increase in cell membrane permeability induced by electroporation, and therefore the efficacy of chemotherapy is intensified.8 Electrochemotherapy has already shown favorable results and its role is widespread in the treatment of different metastatic tumors such as breast cancer,9 melanoma,10 and head and neck tumors.11 Since vulvar cancer is such a rare disease, the international experience with electrochemotherapy has been derived from only a few centers.12 The aim of this study was to evaluate our experience in two of reference centers for vulvar cancer treatment over a 2-year period, by evaluating the electrochemotherapy procedure in terms of clinical outcome and side effects profile.
Data were retrospectively collected from November 2017 to November 2019 in two Italian tertiary cancer centers: Regina Elena National Cancer Institute and Fondazione Policlinico Universitario Agostino Gemelli. The study was approved by the Internal Review Board (N° PROT. APROV. IST CICOG-31-10-18\105). Informed consent for electrochemotherapy was obtained in accordance with local and international legislation (Declaration of Helsinki).13 The technical features followed the European Standard Operating Procedures on Electrochemotherapy (ESOPE) and its update.14 15 All the patients with vulvar cancer, for which no further therapies were applicable or patients unfit for extensive surgery, were included.
Study Design and Endpoints
Electrochemotherapy was offered in a palliative setting to patients with a primary or recurrent vulvar cancer diagnosis that was unsuitable for surgery or any other treatment because of poor performance status or previous delivered treatments (ie, previous surgery, radiotherapy, and/or chemotherapy). The primary endpoint was to assess the response rate to electrochemotherapy in the palliative treatment of vulvar cancer. For each case, the indication for electrochemotherapy was given after a discussion within a dedicated multidisciplinary board. A personalized treatment plan was provided for each patient after assessment of distribution, size, and number of the skin or mucosal lesions. Based on this information, tailored choices were made to modulate the extension of the treatment and to select the most suitable technique and instrumentation.
All patients underwent general anesthesia. Intravenous bleomycin was administered (IV bolus 5 min) at a dose of 15 000 IU/m2. Electrical pulses were started 8 min afterwards and were delivered using a pulse generator (Cliniporator, IGEA S.p.A Carpi, Italy) with a frequency of 5 kHz and each pulse lasted 100 microseconds. The type of manipulator was chosen according to the morphology of the lesion. Electrodes were gently inserted into the affected skin area, which was previously delimited using a dermographic pen (Figure 1A–1B), at a depth of at least 1 cm. Repeated adjacent insertions were performed to cover the entire area of single or multiple lesions, as appropriate. The procedure required a 1-day hospital stay.
Assessment of Clinical Response
Response evaluation according to the Response Evaluation Criteria In Solid Tumours (RECIST) were followed: complete response in case of no evidence of residual lesion; partial response with at least a 30% reduction in the sum of the longest diameter of the target lesion; stable disease when neither partial response or progressive disease criteria were met; and progressive disease with at least a 20% increase in the sum of the longest diameter of the target lesion.16 Follow-up examinations were performed at 1, 3, and 6 months.
Data on patient characteristics, previous treatments (surgery, radiotherapy, and/or chemotherapy administration), clinical characteristics (number, site, diameter) and histopathologic features of the treated lesions, intra-procedure and post-procedure complications, and subsequent additional treatments after electrochemotherapy administration were stored and managed by the RedCapTM database system (www.redcap.org) with sensitive data tied to the patient’s unique ID at the two institutions. Furthermore, photographic images were collected if available. All data were collected in a dedicated electronic database, managed according to international privacy regulations.
Fifteen patients were included in the study: one with primary advanced disease and 14 with recurrent disease. The median age was 83 (range 45–89) years. Patient and tumor characteristics are given in Table 1. A total of 14 (93.3%) patients had previous treatments before electrochemotherapy: 11 patients (73.3%) underwent surgery, six patients (40%) underwent radiotherapy, and three patients (20%) underwent chemotherapy and radiotherapy. Further details are given in Table 1. Fourteen patients (93.3%) had a squamous cell carcinoma and one patient had vulvar carcinosarcoma. Ten patients (66.7 %) had a single lesion and five patients (33.3%) had multiple lesions. The most common site of the lesions was the vaginal introitus (four cases) and the paraurethral region (four cases) followed by the left hemi-vulva (three cases). The median area of the lesions before electrochemotherapy was 100 (range 30–250) mm2, with a median maximum diameter of 45 (range 10–100) mm, and 10 patients had lesions with a maximum diameter ≥3 cm. The median dose of bleomycin was 25.2 (range 21–28.2) mg. Median number of electrical pulses was 22 (range 3–42) and median operative time was 13 (range 7–20) min. The most commonly used manipulators were the linear (L-30ST) or the hexagonal (H-30ST).
Five patients (33%) underwent an additional surgical procedure during the same electrochemotherapy session: three patients underwent an inguinofemoral lymphadenectomy and two patients a protective colostomy. Surgical procedures performed during the electrochemotherapy session had a palliative purpose. In fact, the colostomy was performed because, in both cases, the neoplasm reached the anal orifice whereas the lymphadenectomies were performed in patients with bulky lymph nodes with a high risk of skin ulceration, and advanced disease, in which radical surgery was unfeasible because of co-morbidities and lack of availability of additional treatments. No intra-operative complications occurred. One patient had pneumonia during the post-operative stay.
Response rates are shown in Table 2. The 1-month overall response rate (two complete response and 10 partial response) was 80% (Figure 1C). At the 3-month follow-up, three patients (20%) showed progressive disease, three patients (20%) had died from the disease, one patient (6.7%) died for other reasons, whereas the other patients maintained their 1-month clinical response. A total of 8/13 patients (61.5%) were alive at 6-month follow-up, whereas 6/12 patients (50%) were alive at 1-year follow-up. The total median follow-up interval was 240 (range 35–635) days: eight patients (53.3%) died of disease and one patient (6.7%) died from other causes. After the electrochemotherapy, three patients (20%) were considered fit for surgery and further treatments (surgery with or without adjuvant radiotherapy): one patient was a case of recurrence after complete response and two were patients with partial response. One patient refused further treatment and follow-up examinations after the last cycle of electrochemotherapy. In four patients (26.7%) more than one cycle of electrochemotherapy was administered: a second electrochemotherapy treatment was performed in three patients, whereas in one patient a total of four cycles were administered. All patients had a single lesion with the exception of one patient with multiple lesions (10) and the median maximum diameter was 45 (range 13–50) mm. No intra- or post-operative complications occurred. The 1-month partial response rate was 66.7% and there were no complete responses at this time point when extra cycles of electrochemotherapy were administered.
Our study showed that electrochemotherapy had an overall response rate of 80%, in the absence of adverse events. In four studies previously published in the literature,17–20 electrochemotherapy was employed as palliative treatment in patients with vulvar cancer (Table 3) and in one study it was administered as a neoadjuvant treatment.21 In our study, most of the patients were elderly (median age 83 years) and our data are similar to those from other studies, in which the median age was in the range 68−85 years (Table 3). The most frequent histotype was squamous cell vulvar carcinoma, in accordance with the previous series reported in the literature (Table 3). However, other histotypes have been treated by electrochemotherapy and described, namely vulvar carcinosarcoma (in our study), Paget disease, and vulvar melanoma (Table 3).
With the publication of the ESOPE guidelines in 200613 and the update in 2018,14 the technical features of electrochemotherapy administration have been standardized and all the studies on electrochemotherapy are quite homogeneous. In our study and in others in the literature, bleomycin was chosen as the ideal chemotherapy because its uptake is enhanced by electroporation pulses compared with drugs such as cisplatin.22 The ESOPE guidelines recommend intravenous administration for tumors >3 cm. In our study, bleomycin was always administered intravenously, as in all the other studies, and most of the lesions were >3 cm. According to the ESOPE guidelines, either local or general anesthesia could be administered.
To evaluate the clinical response, the RECIST criteria were used in two of the previously published studies, whereas the WHO criteria were used in the remaining two studies (Table 3). As is well known, the definition of complete response is the same in both evaluation systems. Compared with the other studies, in our series the complete response rate was lower (13.3% vs 46.7%, respectively, in our study and the other studies we reviewed, Table 3). Conversely, other response results (partial response, stable disease, or progressive disease) are defined differently in the two evaluation systems, therefore we chose to compare our results only to the studies with a RECIST evaluation. In our study we found a partial response rate higher than in the other studiess (66.6% vs 26.3%, respectively, in our study and the other studies we reviewed in which RECIST criteria were used, Table 3). As a possible explanation for these differences in response rates we can hypothesize that despite a higher number of treated lesions (39.9% vs 33.3%), the median diameter was on average minor compared with that of treated lesions in our study (median maximum diameter 20 mm vs 40 mm, respectively, in our study and Perrone et al.).20 However, our overall response rate (complete plus partial response: 80%) was similar to the rate reported both by Perrone et al. in vulvar cancer18 20 and Morley at al. in a meta-analysis on electrochemotherapy in different kinds of tumors.22 Another crucial aspect to be considered is that not all the patients in our study had a squamous cell carcinoma and one patient with stable disease had carcinosarcoma, which is a more aggressive type of tumor.
Some studies reported a different clinical response according to the size of the lesion and to previous treatments. Although a recent meta-analysis on electrochemotherapy in tumors other than vulvar cancer reported a reduction in electrochemotherapy efficacy when the tumor was >3 cm and when previous treatments were administered,22 none of the studies in our review noted differences in response rates.18 20 Furthermore, although we did not perform this evaluation, due to the small number of patients, we obtained a favorable clinical response, despite the high rate of both previous treatments and lesions >3 cm. Few data exist on additional cycles of electrochemotherapy,22 and only two studies in our review reported more than one cycle of electrochemotherapy: Perrone et al. reported an overall response rate of 40% when a second cycle of electrochemotherapy was administered18 and Pellegrino et al. performed more than two cycles of electrochemotherapy and no complications occurred.19 In our study, only three patients underwent a second cycle of electrochemotherapy, and in one patient the procedure was performed for four cycles without any complications. The overall response rate was evaluated for each extra cycle and it was adequate (66.6%). Moreover, only one of the studies on electrochemotherapy in vulvar cancer has evaluated the role of this procedure as a neoadjuvant treatment. Perrone et al. reported a tumor downsizing in 6/9 patients and suggested a role for electrochemotherapy in allowing a less invasive, extensive, and disabling surgery.21 None of the studies reviewed reported serious adverse events. The most common adverse events reported were local: minimal blood loss, edema, erythema, hyperpigmentation, skin ulceration, and mild pain (Table 3). We reported a case of post-procedure pneumonia, whereas no intra-procedure complications occurred.
Regarding the survival outcomes, it is difficult to derive conclusions because of the different therapies administered before electrochemotherapy that may have affected the results. However, with a median follow-up of 6–12 months, the overall survival reported by the studies reviewed exceeded 50%. In our study, 61.5% of patients were alive at 6-month follow-up, whereas 36.4% of patients were alive at 1-year follow-up. Considering that electrochemotherapy is a local treatment and, in our case, it was administered as a palliative treatment when no more therapies were applicable, this result may be considered promising.
A recent meta-analysis on electrochemotherapy in vulvar cancer showed a high overall response rate and favorable safety profile, thus concluding that it may be considered an additional treatment modality in vulvar cancer, leading to a less aggressive and morbid intervention in women who are not suitable for conventional treatments.23 In conclusion, electrochemotherapy has been demonstrated to be feasible, easy to perform, and reproducible. For these reasons, it may have a role in the management of vulvar cancer, especially as a palliative treatment when other therapies are no longer an option. Although electrochemotherapy gave promising results even as neoadjuvant treatment, further studies are needed to draw more concrete conclusions, and a national database is required given that a randomized controlled trial might not be feasible due to the rarity of the disease.
Contributors Authors' contributions are described in the article. Conceptualization: GC; methodology: VB; software: LT; validation: LT; formal analysis: EM; investigation: IP; resources: GS; data curation: IP; writing – original draft: GC; writing – review and editing: GC and SF; visualization: EV; supervision: GG; project administration: SF.
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 Data are available upon reasonable request.