Quality of life of women with recurrent vulvar cancer treated with electrochemotherapy

Vulvar cancer is a rare malignant disease that accounts for 4–5% of all gynecologic cancers and 0.3% of all cancers.^1,2 Risk factors for vulvar cancer include increasing age, infection with human papillomavirus, inflammatory diseases of the vulva, immunodeficiency and cigarette smoking.³ In the last decade, a significant increase in the incidence of vulvar cancer has been observed in younger women worldwide, which can be attributed to infection with the human papillomavirus.^2,4,5 More than 90% of cases of vulvar cancer are squamous cell carcinomas. Other pathological subtypes include vulvar melanoma (5–7%), vulvar basal cell carcinoma (2–4%), and vulvar extramammary Paget’s disease (1–3%).^2,6

The decision on the treatment of vulvar cancer depends on the stage, the age of the patient, the performance status, and the presence of concomitant diseases.⁷ The main treatment modalities for vulvar cancer are surgery and radiotherapy.⁸ Local recurrences of vulvar cancer are reported in 40% of patients with early-stage disease in the first 10 years of follow-up, and a second recurrence is reported in approximately 20% of these patients.^9,10 In patients with a first local recurrence of vulvar cancer, the disease-specific survival rate decreases by 20% and even further decreases after additional recurrences.^10,11 The treatment of local recurrences is usually challenging. The aim of surgery is to achieve a free tumor surgical margin status, which often leads to radical procedures with partial resection of the urethra, anus, clitoris and vagina. Radical surgery in the vulvar area can therefore lead to scarring and mutilation of the external genitalia.^12,13 Owing to the potential for mutilation and morbidity following surgery for local recurrence of vulvar cancer, the approach to treating vulvar cancer has evolved from invasive surgery to more conservative approaches that are as individualized as possible and incorporate new surgical techniques.^14,15 In addition to the new surgical techniques, non-thermal ablative therapies, i.e. electrochemotherapy, have also proven effective in the treatment of such recurrences.¹⁶

In electrochemotherapy, short electric high-voltage pulses are used to improve the local administration of chemotherapeutic agents.¹⁷ The procedure, which is easy to use and relatively inexpensive compared with other alternatives, involves an intravenous bolus infusion of bleomycin or an intratumoral injection of bleomycin or cisplatin.^18,19 Electrochemotherapy is already used for the treatment of superficial tumors such as melanoma, squamous cell carcinoma, basal cell carcinoma and sarcoma.^20–23 It is also used to treat deep-seated tumors such as colorectal cancer, colorectal liver metastases and primary hepatocellular carcinoma.^24–28 The unique advantage of electrochemotherapy over surgery is its selectivity for cancer cells while sparing surrounding healthy tissue.²⁹ The use of electrochemotherapy in patients with vulvar cancer has been described in only a few studies or clinical cases and only for palliative purposes.^30–34 Recently, our group used electrochemotherapy for the first time to treat the recurrence of vulvar cancer for nonpalliative purposes. The data from our studies have shown that electrochemotherapy is a feasible, safe and effective technique for the treatment of vulvar cancer recurrence.^13,16

To the best of our knowledge, few studies address the impact of vulvar cancer treatment on patients’ quality of life.¹² Vulvar cancer can cause severe pain and bleeding and lead to limitations in daily activities. After radical surgery in the vulvar area, women can develop urinary and fecal incontinence, which can cause severe discomfort and lead to a deterioration in quality of life and psychosocial well-being as well as social isolation.^35,36 Potential problems related to sexuality are rarely addressed preoperatively, as disease prognosis is of paramount importance.^12,37 In recent years, the quality of life of patients undergoing surgical or other oncological treatments for various types of cancer has become a central topic of cancer care.^14,38,39

Data from previous studies have shown that electrochemotherapy can be used as a modern therapeutic tool for patients who would otherwise have to undergo surgery involving mutilation of the external genitalia.¹³ Electrochemotherapy also appears to be less mutilating and could be a promising alternative treatment for vulvar cancer recurrence, especially in cases where the clitoris, vagina, urethra and anus are in close proximity.¹⁶ The aim of the present study was to determine the quality of life of women with vulvar cancer recurrence treated with electrochemotherapy for nonpalliative purposes and to compare the quality of life of women treated with electrochemotherapy for nonpalliative purposes with the quality of life of women treated surgically.

All 11 patients treated with electrochemotherapy completed the EQ-5D questionnaire, the EORTC QLQ-C30 questionnaire, the EORTC QLQ-VU34 questionnaire and the VAS questionnaire before electrochemotherapy and one, three and six months after electrochemotherapy. All 15 patients with vulvar cancer recurrence treated with wide local excision completed the EORTC QLQ-C30 questionnaire and the VAS questionnaire before surgery and three and six months after surgery.

The detailed data of the patients and the tumor characteristics are shown in Table 1 and were analyzed and described in our previous work.¹⁶ The electrochemotherapy group and the surgery group were homogeneous. There were no statistically significant differences between the electrochemotherapy group and the surgical group in terms of the mean body mass index, associated diseases, previous treatments, presence of lichen sclerosus or p16 status.

No significant differences in EQ-5D scores were found between quality of life before electrochemotherapy and at each follow-up visit (Table 2).

Table 3 summarizes the functional and symptom scales and global health status from the EORTC QLQ-C30 questionnaire for the electrochemotherapy group and the surgery group. Most patients in both groups had no problems with nausea, vomiting, constipation, diarrhea and financial difficulties, and these data were not analyzed further. In the electrochemotherapy group, there were significant improvement in the functional scales (with the exception of physical functioning), symptom scales (with the exception of dyspnea) and global health status after electrochemotherapy. A significant improvement was observed 3 months after electrochemotherapy. There was no significant difference between 3 and 6 months after electrochemotherapy. There was no significant difference in the functional and symptom scales and global health status before and after the surgical procedure.

According to the analyses of the EORTC QLQ-C30 questionnaire, the comparison between the electrochemotherapy group and the surgery group showed a significant difference in emotional functioning before the procedure in favor of surgery. Three and six months after the procedure, there was a significant difference in physical functioning, fatigue, insomnia and global health status in favor of the electrochemotherapy group. In addition, six months after the procedure, there was a significant difference in role functioning, cognitive functioning, social functioning and appetite loss in favor of the electrochemotherapy group. A detailed comparison of the groups is shown in Table 4.

According to the EORTC QLQ-VU34 questionnaire, patients treated with electrochemotherapy had no changes in defecation or problems with leakage of stool or felt the urge to hurry to get to the toilet. In addition, there was no change or deterioration in feelings and physical attractiveness in patients treated with electrochemotherapy. There was an improvement in urinary symptoms: less pain or burning when urinating, less urine leakage and less urge to urinate. The significant difference in improvement in urination was between 1 month and 3 months after electrochemotherapy. There was also an improvement in symptoms related to scarring and mutilation of the external genitalia, with less difficulty sitting and less narrowing or tightness of the vaginal entrance. The significant difference in improvement in scarring and mutilation of the external genitalia was between 1 month and 3 months after electrochemotherapy (Table 5).

The case of vulvar cancer recurrence at the vaginal entrance near the urethra is shown in Figure 1A. One month after electrochemotherapy, the necrosis can be seen in Figure 1B. Three months after treatment with electrochemotherapy, the wound was completely healed (Figure 1C). Six months after treatment with electrochemotherapy, the woman had no problems with urination, defecation and sitting and there were no signs of vulvar cancer (Figure 1D).

FIGURE 1.

Vulvar cancer recurrence at the vaginal entrance near the urethra (A). Presence of necrosis one month after treatment with electrochemotherapy (B). The wound completely healed three months after treatment with electrochemotherapy (C). The woman had no problems with urination, defecation and sitting six months after treatment with electrochemotherapy (D).

The VAS score did not differ significantly between the electrochemotherapy group and the surgical group before and 3 months and 6 months after the procedure (Table 6). Before electrochemotherapy, the mean VAS score was 2.36 ± 1.12, and before surgery, the mean VAS score was 2.21 ± 1.48. One month after electrochemotherapy, the mean VAS score was 3.64 ± 2.19. Three months after electrochemotherapy, the mean VAS score was 1.64 ± 1.57, and three months after surgery, the mean VAS score was 2.07 ± 1.07. Six months after electrochemotherapy, the mean VAS score was 1.82 ± 1.83, and six months after surgery, the mean VAS score was 2.14 ± 1.23.

To our knowledge, this is the first study to report the quality of life of women with recurrent vulvar cancer treated with electrochemotherapy for nonpalliative purposes. This study has shown that the quality of life after treatment with electrochemotherapy is comparable and in some segments better than after surgical treatment.

In the electrochemotherapy group, the EQ-5D questionnaires and the EORTC QLQ-VU34 questionnaires were associated with the lowest quality of life one month after the procedure. The main reason for this is that in most of our patients, necrosis developed at the site of the tumor two weeks after electrochemotherapy. In the case of necrosis after electrochemotherapy, tissue healing occurs secondarily over 4–10 weeks, depending on the tumor size and tumor response.⁴⁷ In our study, the main symptom one month after electrochemotherapy, apart from necrosis, was pain, with a mean VAS score of 3.64 ± 2.19. When treating ulcerated neoplastic wounds, it is advisable to involve a specialized care team, together with a cancer pain service.¹⁸ In our cases, pain was treated with nonopioid and opioid peroral analgesics, and cancer pain services were not needed. In general, the treated skin can be covered with nonadherent, comfortable dressings during the inflammatory phase, whereas ulcerated lesions are best treated with advanced dressings such as alginates, charcoal and silver. Tissue necrosis can be treated by enzymatic and/or surgical debridement to prevent superinfection and promote healing, according to standard operating procedures for electrochemo-therapy.⁴⁵ In all patients in the electrochemotherapy group, the wounds were completely healed three months after treatment. Three months after electrochemotherapy, the mean VAS score was 1.64 ± 1.57, which was lower than that in the surgical group, where it was 2.07 ± 1.07.

In patients treated with electrochemotherapy, the EORTC QLQ-VU34 questionnaire showed that electrochemotherapy did not cause problems with defecation, even when the tumor was located in close proximity to the anal sphincter and anal canal. This is the unique advantage of electrochemotherapy because of its selectivity for cancer cells while sparing the surrounding healthy tissue.²⁹ Surgical removal of the tumor, which is located in the immediate vicinity of the anal sphincter muscle and the anal canal, can lead to impaired defecation with leakage of stool and, in the worst case, to the formation of an intestinal stoma.⁴⁸ The EORTC QLQ-VU34 questionnaire showed that electrochemotherapy did not worsen feelings and physical attractiveness. All women in the electrochemotherapy group were not sexually active in the six months following the procedure. According to the literature, vulvar cancer has a role in worsening sexual functioning with a disruption and reduction in sexual activity, a lower quality of partner relationships and maritial satisfaction. Sexual dysfunction is closely related to anxiety and depressive symptoms.¹² Owing to the consequences of surgery, psychological stress may be related to altered body image. Women may experience shame and embarrassment associated with severe social stigmatization, which can lead to feelings of isolation and loss of self-esteem.¹² The EORTC QLQ-VU34 questionnaire showed that women treated with electrochemotherapy had improved urinary symptoms. Six months after electrochemotherapy treatment, none of the patients showed signs of urinary incontinence. The EORTC QLQ-VU34 questionnaire also showed an improvement in symptoms related to scarring and mutilation of the external genitalia after electrochemotherapy. Since the surrounding healthy tissue is spared during electrochemotherapy and no sutures are used as in surgery, the mutilation of the external genitalia is less pronounced after electrochemotherapy, and the narrowing and scarring of the vaginal entrance is also less pronounced. Significant improvement was observed between one and three months after electrochemotherapy, which was due to the presence of necrosis one month after electrochemotherapy. Three months after electrochemotherapy, the women no longer had difficulty sitting, which is very important for daily life.

The EORTC QLQ-C30 questionnaire showed a significant improvement in quality of life three months after electrochemotherapy. There was no significant improvement in quality of life between three and six months after electrochemotherapy. The EQ-5D and EORTC QLQ-VU34 questionnaires also showed no significant improvement in quality of life between three and six months after electrochemotherapy. These results indicate that an improvement in quality of life can be expected three months after electrochemotherapy and that no improvement or deterioration in quality of life can be expected later.

The comparison of the EORTC QLQ-C30 questionnaires between the electrochemotherapy group and the surgery group showed that three months after the procedure, the women treated with electrochemotherapy were able to take a longer walk, needed to stay in bed or in a chair less during the day and required less help with eating, dressing and washing. These women also slept better and were less tired. In addition, six months after the procedure, the women treated with electrochemotherapy were able to perform normal daily activities and hobbies, had less difficulty concentrating on things, had better family life and a better appetite. There is a lack of scientific evidence on the quality of life of patients with vulvar cancer. It is therefore very difficult to compare our results with those of electrochemotherapy treatment with those that can be achieved with other therapies in this situation.^44,49

The main limitation of the study is the small number of patients included. However, vulvar cancer recurrences are rare and difficult to treat. Therefore, even small prospective studies are important to verify the value of new treatment methods. Another limitation of the study is the short-term follow-up, but our study suggests an improvement in quality of life three months after electrochemotherapy and that no improvement or worsening of quality of life is expected later. Our study showed that six months after treatment, the quality of life of patients treated with electrochemotherapy was no worse than the quality of life of patients treated with surgery. Despite some limitations of this study, this is the first study to provide information on the quality of life of women treated with electrochemotherapy for nonpalliative purposes in vulvar cancer recurrence. Furthermore, the patients in the electrochemotherapy group and the surgical group were homogeneous and had similar clinical characteristics, histologic types, previous treatments, and anatomic sites.

In conclusion, our study showed that the quality of life after treatment with electrochemotherapy is comparable and in some segments even better than after surgical treatment. Electrochemotherapy is suggested in cases where the recurrence of vulvar cancer occurs in close proximity to the urethra, anus or vaginal entrance to improve quality of life and avoid mutilating surgery on the external genitalia. However, further studies are needed to analyze and identify the best candidates for this promising treatment. Owing to the rarity of vulvar cancer, centralization of the treatment of this disease is necessary.