Groningen International Study on Sentinel nodes in Vulvar cancer - III, a prospective phase II treatment trial

GROINSS-V I showed that omission of inguinofemoral lymphadenectomy is safe in
patients with a negative SN. In an in-depth analysis of GROINSS-V-I data, for
which we reviewed 723 SNs, it was shown that in patients with SN metastases <=
2mm additional metastases were observed in 3/43 patients (7%) and in patients
with SN metastases > 2mm in 12/36 (33%). In GROINSS-V II, patients with a
positive SN were treated with radiotherapy instead of inguinofemoral
lymphadenectomy in order to reduce morbidity. While the final results are
pending, in GROINSS-V II, interim analysis of patients with a positive SN that
were treated with radiotherapy (50 Gy) so far showed 3% groin recurrence rate
in patients with SN metastases <= 2mm and 18% in patients with SN metastases >
2mm. These preliminary data show that there is effect of radiotherapy (50 Gy,
given at the right depth and localization), but that the dose is not enough to
eradicate macrometastatic disease in the absence of a full lymph node
dissection.
The efficacy of radiotherapy can be increased by either increasing the dose and
/ or adding concurrent chemotherapy. It is well known from other (HPV-related)
squamous cell carcinomas that adding chemotherapy as a radiosensitizer during
radiotherapy improves both local control and survival. In cervical cancer,
several studies and meta-analyses demonstrated the beneficial effect of adding
chemotherapy, both in the primary and adjuvant setting. A Cochrane
meta-analysis and several small studies of neoadjuvant or primary
chemoradiation for vulvar cancer showed high response rates and up to 64%
clinical complete remission rates [15-18]. In general the addition of
chemotherapy to radiotherapy will increase the effectiveness of treatment with
20-25% (relative increase in complete remission/local control), which
translates in general in 10% absolute benefit of the addition of chemotherapy.
In studies on chemoradiation in cervical cancer there is remarkable symmetry in
the reduction of relative risk of relapse or death by 30-50%. In a large
population-based analysis, addition of chemotherapy resulted in a significant
38% reduction in mortality risk for node-positive vulvar cancer patients who
received adjuvant radiotherapy.

This study has been transitioned to CTIS with ID 2023-508722-99-00 check the CTIS register for the current data.

Primary objective:
- Investigate the safety of replacing inguinofemoral lymphadenectomy by
chemoradiation in early stage vulvar cancer patients with a macrometastasis
(>2mm) and/or extracapsular extension in the sentinel lymph node

Secondary objectives:
- Evaluate the short and long-term morbidity associated with the sentinel node
procedure and chemoradiation

A prospective phase II treatment trial of chemoradiation will be performed in
patients with early stage SCC of the vulva and a macrometastasis in their SN.
Eligible for SN detection are patients with a T1 SCC of the vulva, < 4cm in
diameter, depth of invasion > 1mm, and no suspicious lymph node at imaging of
the groins (ultrasound, CT or MRI). Patients with SN metastases > 2mm and / or
with extracapsular spread will be eligible for this study. Patients with > 1
micrometastasis can also be included.
Dose schedule:
Cisplatin 40 mg/m2 intravenously on days 1, 8, 15, 22 and 29 of RT
- In case of renal impairment (creatinine clearance between 40-60 mmol/ml)
cisplatin 20mg/m2 or carboplatin AUC2 can be given.
- In case of significant other comorbidities an alternative schedule of weekly
carboplatin AUC2 can be used on days 1, 8, 15, 22 and 29 .
Radiotherapy: 56 Gy to the involved inguinal site. A dose of 48-50 Gy in 1.8 Gy
daily fractions will be given to the inguinofemoral and external iliac nodal
regions, with a boost dose to the involved site for a total dose of 56 Gy over
5-6 weeks, preferably with simultaneous integrated boost technique.

When definitive histopathological examination shows a SN metastasis > 2mm
and/or extracapsular extension, chemoradiation will be given: in principle only
the side with the metastatic involved side of SN is treated in case of
bilateral SN with only one side with metastases. Depending on the pathologic
evaluation of the primary vulvar cancer (radicality, size, presence of
extensive LVSI) the vulva may be included in the target volume on an individual
basis.

Radiotherapy and chemotherapy are associated with other side effects than
standard treatment (lymphadenectomy). During treatment there might be
complaints of nausea, vomiting, diarrhea or obsitpation.

The treatment is a combination of radiotherapy and chemotherapy, possibly
results in less longterm morbidity (less lymphedema, less infections) compared
to the standard treatment (full lymphadenectomy).
After treatment there is always a risk of disease recurrence in the groin.
After standard treatment this risk is approximately 10%. The risk might be
higher after chemoradiation.