Radiotherapy May Offer Less Morbid Option for Vulvar Micrometastases

Lymph node irradiation may offer a safe alternative to inguinofemoral lymphadenectomy (IFL) for early vulvar cancer with small sentinel node (SN) metastases, a prospective multicenter study showed.

Nodal irradiation led to a 2-year groin recurrence rate of 1.6% for patients with SN micrometastases (≤2 mm). In contrast, the 2-year recurrence rate increased to 22% with SN macrometastases treated with inguinofemoral radiotherapy (IFRT), three times higher as compared with IFL.

The findings from the GROINSS-V-II trial extended results of a previously reported GROINSS-V-I study, which showed that IFL can be safely omitted for patients with vulvar cancer and negative SNs, reported Maaike H.M. Oonk, PhD, of University Medical Center Groningen in the Netherlands, and co-authors, in the Journal of Clinical Oncology.

“Inguinofemoral radiotherapy could spare vulvar cancer patients with SN micrometastases the morbidity of lymphadenectomy,” the authors stated. “This should be implemented in (inter)national treatment guidelines for vulvar cancer.”

“For patients with SN macrometastasis, radiotherapy with a total dose of 50 Gy showed more isolated groin recurrences than IFL,” the team added. “Radiotherapy dose escalation in combination with chemotherapy will be investigated for such patients in GROINSS-V-III.”

Over the past 10 years, SN biopsy has become standard of care for early vulvar tumors <4 cm associated with nonsuspicious groin nodes. GROINSS-V-I showed an isolated groin recurrence rate of 2.3% with observation for patients who had negative SN biopsy results. Omission of IFL was associated with a significant reduction in morbidity for patients who underwent SN. Subsequently, a U.S.-based trial showed a false-negative rate of 2.0% with SN biopsy in patients with tumors <4 cm.

For patients with early vulvar tumors and positive SNs, IFL remains the standard of care, followed by adjuvant radiation for patients with more than one involved lymph node or extracapsular spread. However, treatment-related morbidity is substantial, the authors noted.

Safely Reducing Morbidity

Data from GROINSS-V-I did not identify a threshold size of SN metastasis associated with sufficiently low risk to allow omission of IFL. GROINSS-V-II was designed to address the size issue by evaluating IFRT as a safe alternative to IFL.

The phase II trial involved investigators at 59 centers in 11 countries. Eligible patients had unifocal macroinvasive squamous cell carcinoma of the vulva <4 cm and preoperative imaging of the groins showing no suspicious lymph nodes.

SN biopsy was performed in all patients. Patients with negative results had no further treatment, and those with positive results received IFRT to a total dose of 50 Gy in 25-28 fractions. If a SN could not be identified, IFL was recommended. The primary endpoint was isolated groin recurrence at 24 months.

The investigators enrolled 1,535 patients from December 2005 to October 2016, and 322 (21.0%) had positive SNs. The trial had a safety stopping rule (groin recurrence rate of 8.1% from GROINSS-V-I), which was activated after accrual of 91 patients with positive SNs. At that point 10 patients had groin recurrences, all but one of which was >2 mm or exhibited extracapsular spread. The trial resumed with a protocol amendment that specified IFRT for patients with SNs ≤2 mm (micrometastases) and IFL for those with macrometastases (>2 mm).

Among all 322 patients with positive SNs, 160 (49.7%) had micrometastases, and 126 received IFRT. Overall, six patients (3.8%) had isolated groin recurrences at 2 years, including two recurrences in the 126 patients (1.6%) treated with radiotherapy.

Of 162 patients with macrometastases, 51 received IFRT (plus platinum-based chemotherapy in seven cases). Unilateral or bilateral IFL was performed in 105 patients, 59 of whom also received adjuvant radiotherapy. Six patients received no further treatment after IFL. The 2-year groin recurrence rate was 22.0% with IFRT versus 6.9% with IFL, with or without radiation therapy (P=0.011).

Despite the higher rate of groin recurrence for macrometastases treated with IFRT, the 2-year disease-specific survival was similar for patients treated with IFL or IFRT (24.2% vs 24.4%).

SN biopsy followed by IFRT was associated with grade 1-2 nausea, vomiting, mucositis, and incontinence (fecal and urinary), which decreased over time. The most commonly reported toxicity was skin irritation in the irradiated groin area. At 4 to 6 weeks after treatment, 21.3% of patients had grade 1 skin toxicity, 14.8% had grade 2, and 1.3% had grade 3. At 6 months, the rates had declined to 7.2%, 0.7% and 0.7%, respectively.

Potential Implications

The study reaffirmed the value of SN biopsy in vulvar cancer and added to previous findings by showing that IFRT provides adequate treatment for SN micrometastases, said Akila N. Viswanathan, MD, of Johns Hopkins Medicine in Baltimore, who was not involved with the study.

However, interpretation of the results should occur within the context of some of the trial’s limitations, particularly an inadequate radiation volume during much of the study period, she added. Because of that, the results will likely not change practice.

Nonetheless, the results are important, given the relative rarity of vulvar cancer, Viswanathan, a clinical/scientific expert for the American Society for Radiation Oncology, told MedPage Today via email. “Despite the limitations of the study, including the lack of pretreatment quality control and prospective quality assurance for the radiation arm, and the inadequate dose for control of macroscopic disease, this study is relevant to practice standards in the U.S.”

“In this study, patients with sentinel node micrometastases had a groin recurrence rate at 2 years of 1.6% and less morbidity than with inguinal femoral lymphadenectomy, suggesting this might be a reasonable treatment option,” she continued.

“There has been a persistent trend in all areas of oncology to seek and adopt treatment methods that are as effective but less morbid than traditional approaches,” she noted. “This study was conducted in that spirit and may change the approach to SN micrometastases and generate further studies to explore optimal nonmorbid treatment for SN macrometastases.”