Introduction Electrochemotherapy involves the use of transient tumor permeabilization via electric pulses in combination with low-dose chemotherapeutic agents. It has recently emerged as an alternative treatment modality in vulvar cancer. The aim of this meta-analysis was to ascertain the effectiveness of electrochemotherapy in the context of palliative care.
Methods The following databases were searched: MEDLINE, Scopus, and Cochrane Database, to identify all registered articles pertaining to palliative vulvar cancer treatment with electrochemotherapy from inception until August 2019, in line with PRISMA guidelines. A single-proportion meta-analysis was performed for the outcomes of overall response, complete response, partial response, stable disease, and progressive disease raterespectively, using the random-effect model. Sensitivity analysis was performed to address heterogeneity.
Results Four studies were included totaling 104 women. The studies were of moderate quality. Pooled results from four studies rendered a summary proportion of 78.8% (95% CI 70.4% to 86.1%) for the outcome of overall response. The median age ranged between 68 and 85 years. The sample size per study ranged between eight and 61 women. The tumors’ histological types included: squamous-cell carcinoma (96.2%), Paget’s disease (2.9%), and malignant melanoma (0.9%). A total of 65 patients (62.5%) presented with a single nodule, whilst 39 patients (37.5%) presented with multiple nodules. Eighty-nine women (85.6%) were previously submitted to other treatment modalities. The overall response rate ranged from 73.2% to 80.9%. The pooled proportion for the outcomes of complete and partial response rate was 48.7% (95% CI 30.74% to 61.5%) and 30.2% (95% CI 21.7% to 39.4%), respectively. The follow-up ranged from 1 to 51 months. No severe adverse effects were reported. The safety profile of electrochemotherapy was favorable.
Conclusions Electrochemotherapy is an effective and minimally invasive treatment modality in the palliative care management of patients with vulvar cancer. The effective control of vulvar tumors by electrochemotherapy may contribute to improvement of quality-of-life. In light of the moderate quality of evidence, a multi-center cooperation is warranted to confirm its palliative benefit.
- quality-of-life (PRO)/palliative care
- vulvar neoplasms
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Overall response rate for women with vulvar cancer after undergoing palliative electrochemotherapy was 78.8%
A complete response was noted in 48.7% of patients and a partial response in 30.2% of patients
No severe adverse effects reported.
Vulvar cancer is a rare disease, accounting for 2% to 5% of all gynecological malignancies.1 It has been regarded as a disease of advanced age with a 10-fold higher incidence among elderly women.2 Treatment should be individualized and tailored to the histological subtype and the extent of the disease. Other factors including age, performance status, and comorbidities could also influence the management options.
The mainstay of treatment for recurrent vulvar cancer is surgery;however, for some cases, adequate excision of the tumor with clear margins can solely be achieved by exenteration and the formation of bowel and/or urinary stoma.3 Furthermore, surgical management is often precluded amongst compromised and elderly women.4 5 Chemoradiation is a well-described alternative treatment modality for repeated loco-regional recurrences.6 Nonetheless, its use is often burdened with significant toxicity amongst women previously treated with radiotherapy.7 Chemotherapy can also be used in recurrent cases; notwithstanding, its role remains limited.3 8
Electrochemotherapy is an alternative loco-regional anti-tumor treatment modality, which involves the use of transient tumor permeabilization via electric pulses in combination with low-dose intra-tumor or intravenous chemotherapeutic agents, namely bleomycin or cisplatin.9 10 The use of electric pulses results in transient pores on the cell membrane, facilitating drug delivery into the tumor cell cytosol and enhancing cytotoxicity.11 12 Its efficacy amongst cutaneous and subcutaneous tumors is well established.13 14 Electrochemotherapy has recently emerged as an alternative treatment modality among women with vulvar cancer. This systematic review aims to synthesize all available evidence that stems exclusively from vulvar cancer case series to ascertain the efficacy and safety of electrochemotherapy among vulvar cancer patients treated with palliative intent.
We systematically searched MEDLINE, Scopus, and Cochrane Database to identify all registered articles pertaining to palliative vulvar cancer treatment with electrochemotherapy from inception until August 2019, in line with PRISMA guidelines.15 Eligible studies were identified based on the Boolean search strategy (PICO) to describe the patient population (P: women with vulvar cancer), the intervention (I: electrochemotherapy), the outcome (O: clinical response OR post-treatment pain intensity OR quality-of-life), without defining any comparison (C:/) or study design (S:/). For MEDLINE search the following MeSH terms and keywords were combined: vulvar cancer*; carcinoma*; malignant*; neoplasm*; electrochemotherapy*. References of selected studies were searched to retrieve articles not identified by the electronic search.
The study selection was processed in two stages. Full titles and abstracts were examined, and relevant articles were obtained. All the articles that met the inclusion criteria were retrieved as full texts. The methodological index for non-randomized studies (0–16 scale) was used to evaluate the quality of the included studies.16 Study selection, data extraction, and quality assessment performed in parallel by two co-authors and any discrepancies were resolved by consensus. Ethical approval was not required, as this is a meta-analysis.
The primary endpoint was to evaluate the response to electrochemotherapy. Tumor response was clinically assessed using the Response Evaluation Criteria in Solid Tumors: complete response when the tumor nodule disappeared or not palpable; partial response when the tumor size decreased by more than 50% in the products of the largest perpendicular diameters of the measurable lesions; no change when the lesion had a reduction of less than 50% and an increase of up to 25%; and progressive disease when the lesion had an increase of more than 25%.17 The secondary endpoints consisted of the short- and long-term side effects, and symptomatic response. The impact of electrochemotherapy on the quality-of-life was assessed using the Visual Analog Scale as well as the Vulvar Cancer Sub-scale part of functional assessment of vulvar cancer therapy (FACT-V).18
The inclusion criteria consisted of the following: confirmed diagnosis of vulvar cancer; palliative treatment with electrochemotherapy; accurate digital mapping and measurement of all lesions; exclusion of distant metastases; adherence to the European Standard Operating Procedures of electrochemotherapy study guidelines;19 reported data concerning the clinical response, post-treatment side effects and quality-of-life; assessment of response according to Response Evaluation Criteria in Solid Tumors; appropriate follow-up; randomized controlled trials; and observational studies. Exclusion criteria consisted of the following: studies irrelevant to palliative treatment of vulvar cancer with electrochemotherapy; insufficient data for response and post-treatment complications; case reports, reviews, and small case series of five or fewer patients; and repeated or overlapped data.
We pooled proportions to calculate the following parameters: overall response; complete response; partial response; stable disease; and progression of disease. The Freeman–Tukey transformation was used to calculate the weighted summary proportions.20 A random-effects model was selected to summarize the response rate, using proportions and 95% CIs. We assessed the percentage of total variation across studies due to heterogeneity by the I 2 index, and the Cochran’s Q test was used to establish the significance of heterogeneity.21 P was set at 0.10. Statistical analysis was performed using MedCalc (MedCalc software, Ostend, Belgium). Leave-one-out analyses were performed to explore the influence of individual studies.
Four studies encompassing 104 women with vulvar cancer were included in the review22–25 (Figure 1). The studies were published between 2013 and 2019. Three studies were prospective,23–25 while one study was partly prospective and retrospective.22 The methodological index for non-randomized studies was nine for all studies; hence, the included studies were of moderate quality (online supplementary table 1). The median age ranged between 68 and 85 years. The sample size per study ranged between eight and 61 women. The tumors’ histological types included: squamous-cell carcinoma (100 women, 96.2%), Paget’s disease (three women, 2.9%), and malignant melanoma (one woman, 0.9%). A total of 65 patients (62.5%) presented a single nodule, while 39 patients (37.5%) presented with multiple nodules. A total of 89 women (85.6%) were previously submitted to other treatment modalities. The same electrochemotherapy protocol was used for all the included patients according to European Standard Operating Procedures of electrochemotherapy study guidelines.19 Intravenous bolus bleomycin was injected at a dose of 15 000 UI/m2. Electric pulses started 8 min after bolus and completed within 28 min. Pulse delivery frequency was 5 kHz at a duration of 100 μs. Type II needle electrodes were used for small nodules, whilst type III needle electrodes were used in a hexagonal-centered configuration for larger lesions. The procedure was performed under general or local anesthesia. The length of stay in the hospital ranged from 1 to 8 days. No severe adverse effects were reported. The follow-up ranged from 1 to 51 months. Detailed characteristics of the relevant literature are presented in Table 1.
Pooling of results from four studies22–25 encompassing 98 women rendered a summary proportion of 78.8% (95% CI 70.4% to 86.2%; Figure 2A) for overall response with no significant inter-study heterogeneity (I2 =0%, P=0.40; Figure 3). Pooling of results from four studies22–25 rendered a summary proportion of 48.7% (95% CI 30.7% to 61.50%; Figure 2B) for complete response with moderate inter-study heterogeneity (I2 =31.3%, P=0.22; Figure 3). Pooling of results from four studies22–25 rendered a summary proportion of 30.2% (95% CI 21.7% to 39.4%; Figure 2C) for partial response with no significant inter-study heterogeneity (I2 =0%, P=0.66; Figure 3). Pooling of results from four studies22–25 rendered a summary proportion of 13.5% (95% CI 7.6% to 20.8%; Figure 2D) for stable disease with no significant inter-study heterogeneity (I2 =0%, P=0.83). Pooling of results from four studies22–25 rendered a summary proportion of 8.9% (95% CI 2.3% to 19.2%; Figure 2E) for progressive disease with high inter-study heterogeneity (I2 =47.8%, P=0.12).
The results of the leave‐one‐out analysis did not significantly alter the statistical significance of the primary outcomes of the meta‐analysis. The overall response rate ranged from 73.2% to 80.9%. The complete and partial response rates ranged from 45.2% to 53.3%, and from 28.9% to 31.6%, respectively. Finally, the stable disease and progression of disease rate ranged from 12.54% to 15.99% and from 6.17% to 13.55%, respectively.
Recently, surgical procedures and systemic treatments have been supplemented with electrochemotherapy, which is a welcome development for women with recurrent or advanced loco-regional vulvar cancer, who are unsuitable for conventional treatments. Our study demonstrated that palliative electrochemotherapy is seemingly associated with good local disease control, improved quality-of-life, and limited side effects. To the best of our knowledge, this is the first meta-analysis on the topic.
There is a growing body of evidence to suggest that electrochemotherapy is an efficacious treatment modality in the local control of unresectable cutaneous and subcutaneous malignancies, especially in melanoma and squamous skin cancer.13 14 Following the release of European Standard Operating Procedures of electrochemotherapy study guidelines in 2006, it has been routinely used as a loco-regional alternative treatment for disseminated malignancies or as palliative treatment to improve quality-of-life.19 A recent meta-analysis reported an 82.2% overall response rate among cutaneous and subcutaneous tumors treated with electrochemotherapy.13 Conversely, the reported overall response rate was 19.9% for the tumors treated with cisplatin or bleomycin alone.13 In light of the aforementioned promising evidence, a fair number of studies aimed to ascertain its efficacy in new settings including vulvar cancer.22–25
The present meta-analysis determined that the first cycle of electrochemotherapy afforded complete response in nearly half of women, while the overall response rate accounted for approximately 80%. Only two studies evaluated the efficacy of a second electrochemotherapy cycle amongst women with partial response or recurrence after initial complete response.22 24 The reported complete response rate was 40%.22 24 It is worth noting that the re-treatment is seemingly beneficial in partial responders in addition to out-of-field recurrences.26 27 From a theoretical standpoint, an additional electrochemotherapy cycle could exert a negative impact on malignant cells surviving after the first application, at the expense though of higher post-treatment skin toxicity and pain.28 Furthermore, the follow-up in all included studies was limited. A longer follow-up could theoretically demonstrate a higher complete response rate as a result of the immune inflammatory reactions triggered by electrochemotherapy, leading thus to prolonged anticancer action.22
There is divergent evidence as to the correlation between the tumor size and the overall response post-electrochemotherapy administration. Some studies highlighted that electrochemotherapy applied to tumors larger than 3 cm is less likely to achieve complete response.13 28 29 To add to the controversy, the ELECHTRA trial demonstrated no significant difference in overall response for vulvar lesions greater than 3 cm.22 Namely, the overall response was 90.1% and 87% for vulvar nodules less than 3 cm and more than 3 cm, respectively. Similarly, Perrone et al, found no significant difference in overall response rate amongst vulvar lesions with size greater than 4.5 cm2.24 It remains therefore unclear whether larger tumors may require tailored management including larger electrodes and repeated sessions to achieve complete response. It is possible that large tumors may lack in sufficient concentration of the chemotherapeutic agent as a result of the insufficient or delayed distribution at the time of the electroporation.30
The number of the treated nodules could also adversely affect the efficacy of the electrochemotherapy. Some early studies highlighted that treatment of more than 20 nodules is associated with the lower possibility of response to electrochemotherapy.26 29 It has been hypothesized that the non-responsive lesions had late electroporation extending beyond the 28 min interval suggested by the European Standard Operating Procedures of electrochemotherapy guidelines.19 There is evidence, however, suggesting that bleomycin can maintain its effect up to 40 min.31 Perrone et al, demonstrated no significant difference as to response to electrochemotherapy between the single and multiple nodules group.22 In this trial, however, the maximum number of treated lesions was seven. Considering the moderate number of lesions, it can be postulated that the electroporation was performed within the recommended time frame. Intravenous bleomycin was used in all studies. The European Standard Operating Procedures of electrochemotherapy study demonstrated no significant difference in effectiveness of electrochemotherapy between intravenous and intratumor administration of bleomycin.19 On the other hand, a recent meta-analysis highlighted a significantly higher complete response rate with intra-tumor administration of bleomycin compared with the intravenous route.13 The latter may be explained by the insufficient agent concentration in the tumor as a result of the heterogeneous blood flow or the low agent concentration at the time of electroporation.13 The impact of the number of nodules and route of agent administration on the electrochemotherapy efficacy remains questionable and would need to be debated in future research.
The safety profile of electrochemotherapy was favorable. The treatment was acceptable and well-tolerated, even in elderly women. No severe systemic adverse sequelae were reported. Electrochemotherapy side effects were mainly confined to the skin including edema, blood oozing, erythema, and hyperpigmentation, which resolved within 24–72 hours. The mild pain in the application site was easily controlled with analgesics. The vast majority of the included patients had previous treatment with radiotherapy, which could increase the risk of tissue fibrosis and necrosis.31 Furthermore, the treatment of large and/or widespread tumors could cause skin ulceration, owing to skin ischemia triggered by the anti-vascular effects of electrochemotherapy.32 The skin ulceration rate in the ELECHTRA trial was 1%.22 The local control of the recurrent disease resulted in significant improvement in quality-of-life and reduction in pain burden.23–25 This symptom alleviation is extremely important for women treated with palliative intent. Electrochemotherapy also appears to have an advantageous cost/benefit ratio, as the technology and the agents used do not require large investments.23 In view of the high overall response, the minimal side effects and the short length-of-stay in the hospital, its wide use might also be cost-saving for health systems. Logistic and cost-effectiveness analyses are needed.
The evidence of the current meta-analysis is promising yet it is should be considered preliminary. A randomized controlled trial might not be feasible due to the rarity of the disease and ethical concerns linked with palliative patients;notwithstanding, a national debate is required. This strategy will need multi-center cooperation to confirm efficacy and safety. Robust multi-center studies that collate different cytostatic agents and route of administration are warranted to ascertain a dose-response relationship and adherence. The limited follow-up in the published studies makes it difficult to assess its true long-term outcome. Future research has yet to explore the impact of histology, tumor size, number of nodules, and repeated sessions on the electrochemotherapy efficacy. The administration of electrochemotherapy in the neoadjuvant setting could also be evaluated in the context of clinical trials.33 Another implication for future treatment is the combined use of electrochemotherapy and ipilimumab in skin melanoma patients.34 35 In this regard, the role of a combination of electrochemotherapy and immunothepapy in vulvar melanoma would also need to be explored.
The findings of this systematic review are based on a thorough literature search. No date or language restriction was applied. We included all studies meeting the inclusion criteria regardless of their design hence, partly reducing the selection bias risk. We assessed the quality of the yielded studies using a widely known and used tool. We thoroughly assessed the short- and long-term electrochemotherapy impact on local tumor control and patients’ quality-of-life. Sensitivity analysis was performed to address heterogeneity.
Nonetheless, some limitations should be acknowledged. Only four observational studies were identified. Therefore, our review contributes moderate-quality evidence. There were no available randomized controlled trials. The vast majority of the patients were diagnosed with squamous cell vulvar carcinomas. Tumor response might have been biased, as it was solely clinically assessed and possibly overestimated. Our findings are limited by the small study sizes, lack of control group, and limited follow-up. Subgroup analysis to assess the impact of histology, tumor size, number of lesions, and repeated treatment on the overall response was not feasible. The survival analysis was poorly reported. Solely, three studies reported on quality-of-life outcomes. Furthermore, some clinical heterogeneity was observed amongst these studies, which partly limits the comparability. Therefore, the findings of this meta-analysis are constrained by the data available and should be interpreted with caution.
In light of the high overall response rate and the favorable safety profile, electrochemotherapy may be considered as an additional treatment modality in vulvar cancer, leading to less aggressive and morbid intervention amongst women, who are unsuitable for conventional treatments. In the absence of standard guidelines, this meta-analysis provides the evidence to support the efficacy of electrochemotherapy. As this evidence is preliminary, cross-institutional collaboration is warranted.
The authors would like to thank Mr Rahul Nath for his invaluable support and professional expertise.
AT and DG contributed equally.
Contributors Study conception and design belongs to AT and DG. AT and DG carried out acquisition, analysis, and interpretation of data as well as manuscript editing. AT and AS carried out the statistical analysis. RN, GM, and CF critically revised and appraised the manuscript.
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 may be obtained from a third party and are not publicly available.