Long term results of radiotherapy in vulvar cancer patients in Slovenia between 1997–2004

Classical surgical approach is radical vulvectomy. More conservative surgery which reduced morbidity without compromising prognosis is used in early stage vulvar SCC. Wide local excision of the tumour with sentinel lymph node biopsy (SNB) with or without inguinofemoral lymphadenectomy is an attractive alternative.^8-12 The most suitable candidates for SNB are patients with tumour diameter < 4 cm and with no palpable groin nodes.^9,13,14Patients with positive sentinel-node metastases are candidates for additional treatment.^8,9 The lymph node status and particularly inguinofemoral lymph node status is the most important prognostic factor for survival, while the tumour free margin is the most important prognostic factor for local recurrence.³, ^15-17

Radiotherapy in postoperative adjuvant treatment is used to additionally treat the primary site, groins and/or pelvis. Radiotherapy to the primary site is indicated in case of positive or close margin (≤ 8 mm) and large primary tumour (>4 cm).^2,3,18 OS of patients with close/positive margins who received adjuvant radiotherapy was similar to those with negative margins.¹⁸ Radiotherapy to the groins is indicated in case of two or more microscopically positive groin nodes, in case of one or more macroscopically positive node, or in case of extracapsular extension (ECE). When only one microscopically positive groin node is identified, adjuvant radiotherapy can be omitted, although recent recommendations show improvement in disease free survival (DFS) when adding radiotherapy also in a single microscopic node positive disease.⁵, ^19-22 Lymph node involvement is the strongest negative predictive factor for survival. The 3-years PFS and OS for node positive disease was 35.2% and 56.2% compared to 75.2% and 90.2% for node negative disease.^5,11,23 Despite adjuvant radiotherapy in node positive disease and clinical benefit in PFS, OS remains poor (57.7% with adjuvant radiotherapy vs 51.4% without radiotherapy at 3-years, p = 0.17).⁵

Radiotherapy is the treatment option for bulky primary site and/or extensive groin disease. The addition of chemotherapy to radiotherapy improves survival in several SCC.^6,7,24,25 As high as 60% of patients with locally advanced disease can present with nodal metastases, the reason that urge for more aggressive treatment which combines chemotherapy and radiotherapy in locally advanced disease. After primary chemoradiotherapy surgery can be performed in selected cases. There are only a few studies, mainly single institution or phase II studies that report results of such approach.^4,6,25-28

In this retrospective single institution study the long term results of vulvar cancer treatment in Slovenia between 1997 and 2004 with radiotherapy alone or combined with surgery or chemotherapy were analysed.

69 patients with vulvar cancer treated with radiotherapy from January 1997 till December 2004 were retrospectively analysed. Thirteen patients were excluded from the study, because the palliative dose was used to treat the cancer. At the end 56 patients with histologically confirmed vulvar cancer treated with curative intent with radiotherapy, +/- surgery, +/- chemotherapy were enrolled and retrospectively analysed.

Mean patient age was 74.4 +/- 9.7 years. All patients were staged according to the FIGO 1988 staging system (13). FIGO stage distribution, available in 94.6% of the patients, was as follows: stage I 5 (8.9%), stage II 4 (7.1%), stage III 33 (58.9%) and stage IV 11 (19.6%) and not specified in 3 patients.

Histological type of the tumour was SCC in all patients included in the study. Other histological types ranging from malignant melanoma (2 patients), adenocarcinoma of the Bartholin’s gland (1 patient) and Paget’s disease (1 patient) were rare and were excluded from further analysis. The diagnostic work-up before the treatment consisted of clinical examination with biopsy and chest radiography in operated patients, while imaging studies such as abdominal and groin ultrasound or chest/ abdominal computer tomography (CT) were only rarely performed.

Patients, tumour and treatment characteristics are listed in Table 1.

The study was approved by the Protocol Review Board at the Institute of Oncology Ljubljana (ERID-KESOPKR-14). The investigation followed recommendations of the Helsinki Declaration (1964, with later amendments) and of the European Council Convention on Protection of Human Rights in Bio-Medicine (Oviedo 1997).

In this retrospective study radiotherapy was used as the part of the treatment in all patients and it was most frequently combined with surgery in 31 patients (55.4%). Chemoradiotherapy was used in 11 patients (17.9%). At that time the most commonly used cytotoxic agent in adjuvant setting was bleomycin or cisplatin. Radiotherapy was also used at the time of relapse in 14 patients (25%): local relapse at the site of primary tumour was detected in 6 patients, and nodal relapse in 10 patients. The majority of relapses developed within two years after the primary treatment.

In order to evaluate LC and survival among different treatment modalities, three treatment groups were formed (Table 1). 31 patients were included in the primary operated group (group A), where the primary treatment modality was surgery with radiotherapy +/- chemotherapy as an adjuvant treatment. This was the largest group, reflecting that operation therapy +/- radiotherapy is the most important treatment modality in the management of advanced vulvar cancer. Chemoradiotherapy was used only in 2/31 patients, respectively. In the primary irradiated group (group B) 11 patients were included. Radiotherapy was used as the only treatment in 4/11 patients, combined with chemotherapy in 7/11 patients, used preoperatively in 1 or pre- and postoperatively in 1 patient, respectively. In the relapse group (group C) radiotherapy alone or combined with surgery was used at the time of relapse in 9/14 patients and 5/14 patients, respectively. Chemoradiotherapy was used in 2/14 patients.

Surgery is the cornerstone in the treatment of vulvar cancer. The most frequently used type of operation was radical vulvectomy in 29 and wide local excision in 16 patients. SNB was performed only in 6 patients. Vulvar cancer patients were diagnosed in different gynaecological centres in Slovenia and were mainly operated in the three main centres: University Medical Centre Ljubljana (33.9%), Institute of Oncology Ljubljana (37.5%) and University Medical Centre Maribor (5.4%). Unilateral and bilateral inguinofemoral lymph node dissection was performed in 26.8% and 33.9%, respectively. The mean number of removed lymph nodes was 7 (range 1–19). Among all operated patients adjuvant radiotherapy was used in 65.1%, radiochemotherapy in 6.9% and radiotherapy at the time of relapse in 27.9%.

Radiotherapy is an important modality of the treatment in adjuvant setting, as a radical treatment in locally advanced cancer or as a treatment of choice at the time of relapse. External beam radiotherapy was delivered with 5–15 MV linear accelerator or Cobalt-60 machine. In addition, electrons were sometimes applied to boost inguinal areas or primary tumour. Mostly supine position has been used, but “frogleg” position has been used as well, particularly in fat patients. Various two-dimensional (2D) techniques were used to radiate primary tumour and/or inguinal nodes at that time.

First technique used wide anteroposterior (AP) field that included the pelvic and inguinal area, with a narrow posteroanterior (PA) field covering pelvis only. The fields were weighted equally 1:1. The inguinal nodes were boosted to a certain depth determined by a clinician, with a separate anterior field. Bolus material on the primary tumour or inguinal areas was used according to the physician’s decision. The physician’s determined depth of the inguinal nodes was usually 3 to 4 cm. The second technique used AP/PA field of the same dimension. An alternative technique consisted of a wide AP field and narrow PA field with a partial transmission block at the central portion of the AP field. The dose at a specified depth to the inguinal areas was delivered through the AP field.

The two opposite fields technique was applied in majority of the patients. Other techniques, such as four field (box)technique was used as well (16.2%). There were many variations in the prescribed dose to the inguinal nodes among patients due to different inguinal depth chosen by a physician and different radiation techniques that were used. The daily dose was usually 1.8–2.0 Gy per fraction, a daily dose of 2.5 –3.0 Gy per fraction was seldom used as well, with a total dose mainly in the range between 45–60 Gy. In order to enable comparison of the dose to the inguinal area, the depth dose was calculated for all patients at the same depth. The so called “inguinal depth” was determined on CT scans of the fifty women treated with pelvic radiotherapy at the time of collecting data for this study. The mean depth of the inguinal nodes was 5.5 cm (range 2–18 cm), which was more than arbitrary by a physician determined depth.

Today chemotherapy combined with radiotherapy is the fundamental strategy in the treatment of advanced vulvar cancer. At the time of this study it was not so widely used, altogether 11 patients (19.6%) got some kind of chemotherapy. Platinum-based chemotherapy is the treatment of choice in squamous cell carcinomas. In our study cisplatin was used alone or in combination with other cytotoxic drugs such as bleomycin or 5-fluorouracil. Rarely, in case of renal dysfunction, carboplatin was used instead of cisplatin.

First follow-up was usually performed 3 months after the treatment. Consecutive follow-ups were usually performed alternately by gynaecologist or radiation oncologist at 3 to 6 month intervals for the first 5 years and once per year later on.

The data were analysed using IBM SPSS statistical software package version 23.0 (SPSS Inc., Chicago, IL, USA), p values of < 0.05 were considered statistically significant.

Kaplan-Meier method was applied to calculate actuarial survival and loco-regional control rates. The endpoint for OS was death from any cause, for DSS the disease related death and for LC any evidence of loco-regional recurrent disease. Patients without relapse were censored at the time of the last follow-up, visit or death. Surviving patients were censored at the time of the last follow-up. No effort was made to compare results between different treatment groups due to small number of patients in each group and consequently a low power of the test.

The influence of positive lymph nodes, ECE, size of primary tumour and completeness of surgical resection on survival and LC were analysed. Arbitrary cut off points for positive lymph nodes and ECE (negative versus positive), size of primary tumour (up to 4 cm versus ≥ 4 cm) and completeness of surgical resection (complete R0 versus incomplete R1/R2) were used.

The data regarding the side effects of the radiotherapy treatment or surgery were not systematically recorded and were in general missing in the patient’s record, therefore the analysis of side effects of the treatment was omitted in this study.