We evaluated the prognostic factors and clinical outcomes of 56 patients with vulvar cancer treated with curative radiotherapy (RT) or concurrent chemoradiotherapy.
Overall survival (OS) and disease-free survival (DFS) were assessed retrospectively. Prognostic factors evaluated included age, International Federation of Gynecology and Obstetrics (FIGO) stage, TNM classification, tumor size, treatment modality, RT duration, and RT field. The association between the tumor human papillomavirus (HPV) status and survival was analyzed in 35 patients.
During the median follow-up of 2.8 years (range, 0.3 to 18.9 years), 21 patients (37.5%) experienced treatment failure. Fifteen patients (27%) had local failure: nine (16%) local failure only, three (5%) locoregional failure, two (4%) local and distant failure, and one (2%) locoregional and distant failure. Of 56 patients, seven (13%) had persistent disease at the first follow-up at 2 months and all but one died within a year after completing RT. The 5-year OS and DFS were 51.6% and 44.0%, respectively. In multivariate analysis, clinical size ≥3 cm predicted a poor prognostic factor for DFS (p = 0.040) and age (≥70 years) was poor prognostic for DFS (p = 0.032) and OS (p = 0.048). Patients with HPV-positive tumors tended to have better 5-year OS and DFS, but the differences were not significant statistically.
Clinical size ≥3 cm was a significant prognostic factor for DFS. However, age was the most important prognostic factor for DFS and OS in patients treated with curative RT. Further studies are needed to determine which treatment should be considered for old age ≥70 years.
Vulvar cancer is a relatively uncommon disease, accounting for about 5% of all gynecological malignancies [
The records of 118 patients with carcinoma of the vulva, who were treated at 7 institutions in Korea between 1998 and 2011, were retrospectively evaluated. Patients were included if they had biopsy-proven squamous cell carcinoma or adenocarcinoma of the vulva and had received RT or CCRT with curative intent. Patients were excluded from the analysis if they had as follows: 1) histological evidence of melanoma, basal cell carcinoma, or adenoid cystic carcinoma; 2) distant metastasis, other than pelvic LN metastasis; 3) had received neoadjuvant chemotherapy; or 4) had undergone radical vulvectomy. Ultimately, 56 patients were included in the analysis.
The patients' demographic data are shown in
All patients underwent physical and pelvic examinations, routine laboratory testing, chest radiography, colposcopy, cystoscopy, and sigmoidoscopy. When advanced-stage disease was diagnosed, further evaluation with magnetic resonance imaging (MRI) or positron emission tomography-computed tomography was performed.
Of all the patients, 23 (41%) received CCRT and 33 (59%) only RT (
Genomic deoxyribonucleic acid (DNA) was extracted from the paraffin-embedded tissue sections or frozen tissues using the QIAamp DNA mini kit (Digene Corp., Gaithersburg, MD, USA). When the cell samples were obtained by scraping the vulvar lesions, the brush containing the cellular material was placed directly in a vial containing PreservCyt solution (Digene Corp.) before testing. The HPV DNA titer was measured with a commercially available second-generation hybrid capture microplate-based HPV DNA test (HC2 test, Digene Corp.). The HC2 test uses an RNA probe mixture of 13 high-risk HPV types (HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68). The relative light unit (RLU)/cutoff ratios were calculated as the ratio of the specimen luminescence to the luminescence of the 1.0 pg/mL HPV 16 cutoff standard. RLU/cutoff ≥1.0 was considered positive, according to the manufacturer's recommendation (Digene reference no. 5199-1220).
Acute toxicity, measured from the initiation of treatment to three months after RT or CCRT, was assessed with the National Cancer Institute Common Terminology Criteria for Adverse Events (v4.0) [
The median follow-up period was 2.8 years (range, 0.3 to 18.9 years) for all patients. Of the 56 patients, 29 (51.8%) were alive at follow-up, 15 (26.8%) had died from vulvar cancer itself or treatment-related complications, and 11 (19.6%) had died from age-related or other causes. One patient was lost to follow-up after the first follow-up schedule.
In total, 21 patients (37.5%) experienced treatment failure (
The 5-year OS and DFS rates were 51.6% and 44.0%, respectively (
The most common acute toxicity affected the skin (
HPV-positive vulvar cancer was more common in younger patients (median age was 64.5 years in HPV-positive patients and 75 years in HPV-negative patients). Nine (60%) of the 15 HPV-positive patients were <70 years old (Pearson χ2, p = 0.036). The HPV-positive patients tended to have better 5-year OS and DFS, but these trends were not significant in the univariate analysis (all p > 0.05) (
Because the disease is rare and surgery is the mainstay treatment for early vulvar cancer, limited data are available on the outcomes of primary RT for vulvar cancer. Many published studies have included the results for heterogeneous groups of patients, with disease severity extending from FIGO stage I to stage IV, so the treatment outcomes reported tend to vary. Tans et al. [
Our study shows that the general treatment outcomes of vulvar cancer are poor, with 5-year OS, and DFS rates of 51.6% and 44.0%, respectively. The main cause of treatment failure was local failure, and a substantial amount of persistent local disease was noted at the end of RT in 13% (7/56) of patients. One reason for the considerably higher local failure rate was the RT technique used. These patients were treated with an RT technique that evolved from 2D-RT to intensity-modulated RT (IMRT) between 1989 and 2012. It is difficult to deliver a homogeneous radiation dose to the target area, which includes the vulvar, the inguinofemoral LNs, and even the pelvic LNs, with 2D-RT or 3D-CRT. Therefore, techniques such as IMRT, which can deliver different doses to the primary site and the regional LNs, are required. According to the report of Beriwal et al. [
It has been observed that there are two different etiologic pathogenesis in vulvar carcinogenesis [
Compared with the acute skin grade 3 toxicity rate of 21% observed in the current study, IMRT seems to entail a lower risk of skin toxicity, with a good clinical response. In our study, IMRT was used in only five patients (8.9%), two of whom treated with IMRT alone suffered local recurrence, leading to their deaths whereas the remaining 3 patients were treated with CCRT (concomitant platinum-based chemotherapy with IMRT). A previous study showed that chemoradiation achieved a better local control rate and survival rate than RT alone when used as the primary treatment for vulvar cancer [
One of the limitations of our study was that we could not collect accurate data for the tumor response during or at the end of RT. In many cases, the medical records did not determine whether the tumor had responded completely on image/physical examination. A higher radiation dose is associated with a better tumor control, however a radiation dose of ≥65 Gy to the gross tumor volume appeared to be associated with a higher failure rate in this study. We interpret this finding as resulting from the use of a higher radiation dose in patients whose interim response was poor. However, we have to admit that the limitation of this study made it conjecture. In the future, further prospective study would be necessary to investigate the correlation between radiation dose and tumor response. Secondly, we are unable to report any late toxicity in this study because the medical records for many of these patients were unfaithful. Two patients who received over 100 Gy radiation to the primary site could not be assessed for late toxicity because they were lost to follow-up. Considering that insufficient fracture was reported from up to 45% of the patients after pelvic RT in cervical cancer [
Our data do not show that the survival rates differed according to the clinical stage of the disease, but only age and tumor size most effectively predicted the survival outcomes. We retrospectively investigated the clinical outcomes and prognostic factors of patients with vulvar cancer treated primarily with RT. The median age was 71 years (range, 28 to 90 years). Of sixteen patients with stage I and II disease, 9 (56%) were older than 70 years. In general, medically inoperable patients with early stage disease might be referred to receive RT, consequently, which had resulted in poor outcome in those patients. A substantial amount of persistent local disease was also noted at the end of RT in 13% (7/56) of patients, who were all older than 70 years. It could explain why surgical consolidation therapy was not considered in those patients. In the future, further investigation would be necessary to determine which could be the treatment of choice for old age group.
In conclusion, this study suggests that a tumor size ≥3 cm is associated with a negative clinical outcome in DFS in patients with treated with curative RT. However, age ≥70 years indicates the most significant poor prognosis for OS and DFS. In the future, further study would be necessary to determine which treatment should be considered for old age group and more investigations are needed to define the prognoses of old age group with different etiologies according to HPV-related or chronic-inflammation-related carcinogenesis.
This study was supported by a grant from the National Cancer Center, Korea (No. 1310070 and 1310300).
Values are presented as median (range) or number (%).
FIGO, International Federation of Gynecology and Obstetrics; HPV, human papillomavirus.
Values are presented as number (%) or median (range).
RT, radiotherapy; CCRT, concurrent chemoradiotherapy; 2D-RT, two-dimensional radiotherapy; 3D-CRT, three-dimensional conformal radiotherapy; IMRT, intensity-modulated radiotherapy.
OS, overall survival; DFS, disease-free survival; FIGO, International Federation of Gynecology and Obstetrics; LN, lymph node; RT, radiotherapy; CCRT, concurrent chemoradiotherapy; 2D-RT, two-dimensional radiotherapy; 3D-CRT, three-dimensional conformal radiotherapy; IMRT, intensity-modulated radiotherapy; HPV, human papillomavirus.
a)+ WP = vulva + inguinal + whole pelvis.
*Statistically significant at p < 0.05.
OS, overall survival; DFS, disease-free survival; HR, hazard ratio; LN, lymph node; RT, radiotherapy; CCRT, concurrent chemoradio-therapy.
*Statistically significant at p < 0.05.
CTCAE, Common Terminology Criteria for Adverse Events v4.0; GI, gastrointestinal; GU, genitourinary; NA, not assessed.