According to the results of the Journal of Clinical Oncology.1
Of a total of 1535 patients enrolled in the study, 21.0% (n = 322) had sentinel node metastases. The stop rule was activated in June 2010 because the isolated groin recurrence rate in 91 patients with sentinel node positivity exceeded the predefined threshold for the study.
Of 10 patients with isolated groin recurrence, 9 had sentinel node metastases larger than 2 mm and / or had extracapsular spread. The study protocol was changed so that those with macrometastasis in the sentinel node, which was defined as larger than 2 mm, received a standard inguinofemoral lymphadenectomy (IFL). Those with sentinel node micrometastases, defined as smaller than 2 mm, continued to receive inguinofemoral radiation therapy.
Of the 160 patients with sentinel node micrometastases, 126 received inguinofemoral radiation therapy and had a 2-year ipsilateral isolated groin recurrence rate of 1.6%. In the 162 patients with macrometastases in the sentinel nodes, the ipsilateral isolated groin recurrence rate after 2 years was 22% in the patients who received radiation therapy and 6.9% in the patients with standard care (P. = 0.011).
“GROINSS-V-II has shown that inguinofemoral radiation therapy in patients with sentinel node micrometastases leads to a very low isolated inguinal recurrence rate with acceptable treatment-related morbidity,” Maaike HM Oonk, PhD, from the Department of Obstetrics and Gynecology at the Medical University Center Groningen, Netherlands, and colleagues wrote. “For patients with sentinel node macrometastases, inguinofemoral radiation therapy with a total dose of 50 Gy is not a safe alternative to IFL in view of the higher risk of isolated groin recurrence.”
Several advances have been made in the treatment of patients with early-stage vulvar cancer over the past decade. In patients with unifocal tumors smaller than 4 cm and not suspicious inguinal nodules, a sentinel node biopsy has become the standard of treatment instead of elective IFL. For patients with sentinel node metastases, however, further treatment with IFL remains standard.
The GROINSS VI study has shown that inguinofemoral lymphadenectomy can be safely omitted in patients with negative sentinel nodes, which leads to a significant reduction in morbidity. Patients with metastases to the sentinel must continue to undergo IFL to prevent inguinal recurrences, which are often fatal.
Investigators introduced GROINSS-V-II to identify an equally effective but less morbid approach for patients with a metastatic sentinel node. To do this, they wanted to determine whether inguinofemoral radiation therapy could be a safe alternative to IFL in this population. They also wanted to examine the short- and long-term treatment-related morbidity for this strategy.
The prospective, multicenter, single-arm study enrolled patients with early-stage vulvar cancer who were scheduled to undergo surgery. To be included in the study, patients had to have unifocal microinvasive squamous cell carcinoma of the vulva less than 4 cm in size, and preoperative imaging of their groin did not reveal any suspicious lumps.
The primary endpoint of the study was the isolated groin recurrence rate for 24 months.
The researchers used a radioactive tracer with a lymphoscintigram and blue dye to perform sentinel node biopsies on study participants. When metastases were identified, the size and presence of extracapsular spread was established. If the Sentinel Node could not be identified, an IFL was recommended. If the sentinel node was negative after ultrastaging, no further treatment was performed. If tumor cells were detected, the patients were considered metastatic.
If metastasis was found in the sentinel node, inguinofemoral radiation therapy was indicated. The decision as to whether treatment was administered in patients with unilateral sentinel node involvement on one or both sides was dependent on the participating center. The radiation therapy had to be carried out within 6 weeks after the operation and was administered in a total dose of 50 Gy in 25 to 28 fractions of 1.8 Gy to 2.0 Gy, 5 fractions per week. The target dose of 50 Gy was chosen because it was an effective dose for subclinical diseases.
Between December 2005 and October 2016, a total of 1708 patients were registered for the study. Of 1535 patients who met the eligibility criteria for the study, 79.0% (n = 1213) had a negative sentinel node and 21.0% (n = 322) had a metastatic sentinel node. Of the 322 patients with metastatic sentinel nodes, 160 had micrometastases and 162 macrometastases.
Among those with micrometastases, 78.8% (n = 126) received inguinofemoral radiation therapy. 14 of these patients received radiation therapy plus chemotherapy; 9 received cisplatin and 5 had cisplatin and fluorouracil. Ten percent of the 126 patients received IFL instead of radiation therapy, and 11.3% received no further treatment due to patient refusal, severe comorbidity, or old age.
Among the 160 patients, 6 isolated groin recurrences occurred 2 years after the primary operation; the 2-year rate in this population was 3.8% (95% CI, 0.8% -6.8%). Only 2 isolated ipsilateral groin recurrences were observed in the 126 patients who received radiation therapy, in addition to 1 in a contralateral sentinel-node-negative groin area. Another 2 out of 6 groin recurrences were reported in patients who received no further treatment with IFL or radiation therapy. In addition, a groin recurrence was observed in the contralateral sentinel-node-negative groin after unilateral IFL for a metastatic lump.
Among the 18 patients who received no additional treatment, the ipsilateral isolated groin recurrence rate was found to be higher than those who received radiation therapy; the 2-year rates were 11.8% (95% CI, 0.0% – 27.2%) and 1.6% (95% CI, 0.0% – 3.9%) (P. = 0.006).
Of the 162 patients with macrometastases, 31.5% received only radiation therapy of the groin and 13.7% received radiation therapy plus chemotherapy in the form of cisplatin. In addition, 64.8% of these patients (n = 105) had unilateral or bilateral IFL; 56.2% of these patients also received adjuvant radiation therapy. Six patients received no further treatment after removal of the sentinel nodes.
Among those with macrometastases, 19 groin recurrences were reported. The 2-year groin recurrence rates in those who received radiation therapy compared to those who received IFL were 22.0% (95% CI, 10.5% -33.5%) and 6.9%, respectively (95% CI, 2.0% -11.8%). Relapse was observed in a patient with 2 sentinel node macrometastases who was not receiving adjuvant treatment. No recurrences were reported in the contralateral unirradiated groin.
Among those who received IFL, the rate of groin recurrence in those who received adjuvant radiation therapy was no different from those who did not receive adjuvant radiation therapy (P. = .43). No recurrences were reported in the 7 patients who received radiation plus chemotherapy. A trend towards better disease control was seen in those who received this combination (P. = .091).
Of the 1213 patients with sentinel node negativity, 31 had isolated groin recurrences. Metastases were found retrospectively in 2 patients. In 4 patients, not all of the nodes visible on the lymphoscintigram were removed. No concrete explanations were found for the other cases.
In patients with negative sentinel nodes, the estimated risk of disease-specific death after 2 years was 2.1% (95% CI, 1.3-2.9%). In those with micrometastases, this rate was 6.5% (95% CI, 2.6% -10.4%). this rate was 25.5% (95% CI, 18.6% -32.5%). P. P.
Of the 56 patients who relapsed, 31 died of their disease during the study follow-up. The estimated risk of disease-specific death at 2 years in those with macrometastasis was found to be 24.2% (95% CI, 15.7%) in those who received IFL with or without radiation therapy and those who received radiation therapy only. -32.6%) as comparable and 24.4% (95% CI, 12.4% -36.4%) or (P. = .88). In addition, 25.5% of patients who received radiation therapy died from vulvar cancer only, versus 22.9% of patients who underwent IFL.
It is noteworthy that a sentinel node biopsy and subsequent radiotherapy of the groin were associated with low-grade toxicity. Cases of nausea, vomiting, mucositis, or anal and urinary incontinence were only affected at severity grade 1 or 2. Diarrhea occurred most frequently 4 to 6 weeks (grade 1, 12.3%; grade 2, 2.3%; grade 3, 0.6%) or 6 months after radiation therapy (7.9%, 0.0% and 6 months, respectively) 0.7%).
In addition, 21.3% of patients reported Grade 1 toxicity related to the skin in the irradiated groin; in 14.8% and 1.3% of patients, this effect was affected by severity grade 2 and 3, respectively. However, it was found that after 6 months the incidence of this toxicity decreased significantly. Notably, no grade 4 or 5 effects were observed.
In patients who developed lymphedema more than once 6 months or 12 months after treatment, this effect was less common after a biopsy alone (5.1% and 4.1%, respectively) than after a biopsy and subsequent radiation therapy (16), 4% and 10.7%%, or (P. P. <.001>
“Inguinofemoral radiation therapy for vulvar cancer patients with sentinel node micrometastases appears to be a safe alternative to IFL. The toxicity of radiation therapy is acceptable and treatment-related morbidity is less common compared to IFL, ”the study authors concluded. “In patients with sentinel node macrometastases, radiation therapy with a total dose of 50 Gy showed more isolated groin recurrences than IFL.”
The GROINSS V III study (NTR7677 / NL7435) examines the dose escalation of radiation therapy in combination with chemotherapy in patients with sentinel node macrometastases.
- Oonk MHM, Slomovitz B, Baldwin PJW et al. Radiation therapy versus inguinofemoral lymphadenectomy for the treatment of vulvar cancer patients with micrometastases in the sentinel node: results from GROINSS-V II. J Clin Oncol. Published online on August 25, 2021. doi: 10.1200 / JCO.21.00006