Radiation Therapy versus Pelvic Node Resection for Carcinoma of the Vulva with Positive Groin Nodes

Authors: Homesley HD, Bundy BN, Sedlis A, Adcock L.
Source:Obstet Gynecol. 1986 Dec; 68(6):733-40

Background

Vulvar cancers are usually squamous cell carcinomas and are more prevalent in elderly females.

• Treatment is primarily surgical with radical vulvectomy and bilateral inguinal lymphadenectomy.
• 20 years ago, vulvar cancer was rarely treated with external beam radiation therapy.
• Today radiation therapy is known to improve survival and regional metastasis and permit organ preservation in patients with locally advanced disease.
• Current recommendations for post-operative radiation therapy include:
• • Greater than one positive inguinal lymph node
  • One grossly positive inguinal lymph node
  • Extracapsular extension of lymph node disease
  • Small tumor in patients with medical issues preventing radical inguinofemoral lymph node dissection
  • Vulvar resection margin of less than 8-10 mm
• This study by Homesley et al. changed the standard of care of these patients; unfortunately, this preliminary report was never updated with longer follow-up information.
• This study compares inguinal and pelvic node irradiation to ~ 50 Gy after surgical resection vs. pelvic node dissection only in patients with positive inguinal nodes after surgical resection of the primary tumor.

Methods

• This was a randomized prospective study comparing radiation therapy vs. pelvic node dissection of groin node positive vulvar cancer patients.
• 118 patients analyzed in this study, 4 of these were ineligible. 59 assigned radiation therapy and 55 to pelvic node dissection. 4 patients randomized to radiation refused radiation therapy.
• Eligibility was patients with primary invasive squamous cell carcinoma of the vulva in which radical vulvectomy and bilateral inguinal lymphadenectomy sufficed to remove ALL of the primary lesion and groin nodes. If the positive groin nodes were not resected, the patient was deemed ineligible for this study.
• Ineligibility included patients with recurrence, prior malignancies, or those not candidates for radiation therapy.
• FIGO staging was not an entry or ineligibility criteria.
• All patients underwent radical vulvectomy and bilateral groin dissection.
• Inguinal lymphadenectomy included resection of groin nodes both superficial and deep to the inguinofemoral fascia with skeletonization of the femoral artery and vein.
• Patients were intraoperatively randomly assigned to either postoperative radiation therapy or ipsilateral pelvic node dissection.
• Radiation was started within 6 weeks postoperatively, encompassed both groins, obturator, external and internal iliac areas. Patients received 4500 to 5000 rads midplane of the pelvis halfway between the superior border of the obturator foramina and L5-S1 interspace at the rate of 180 to 200 rads per day. Patients were treated with AP/PA opposed fields.

Results

• The two arms of the study were similar with respect to FIGO staging with ~49% of patients having stage III disease.
• Surgical mortality in this study was 1.8% (2 of 114 patients) with no statistically significance between the two arms.
• Nearly half of the patients (49%) were clinically node negative despite being pathologically node positive.
• When clinically unilateral nodes were suspected, bilateral nodal involvement was found in ~12% to 27% of cases.
• Only clinical status of groin nodes and number of positive groin nodes were statistically prognostic variables. It should be noted that bilateral groin nodal involvement was statistically significant in relationship to survival but was not statistically significant in multivariate analysis due to bilateral groin involvement being encompassed, and overshadowed by the prognostic significance of the number of positive groin nodes.
• Radiation therapy survival was significantly better than survival for pelvic node dissection only group (68% vs. 54% at 2 yrs, p = 0.03).
• Clinical node status was a statistically significant prognostic variable, with 2 year survival estimates for N0, N1 being 78% vs. 52% for N2 disease and 33% for N3 node patients (p=0.01).
• Pathologic node status was a statistically significant prognostic variable, with 2 year survival estimates for patients with 4 or more LN was 27% vs. 66% for those patients with two or three nodes, and 80% for those with only one positive node (p < 0.0001)
• Adverse effects were under-reported and thus no conclusions could be drawn from these data.
• The radiation group was 68% progression-free and the pelvic nodes dissection group was 51% progression-free at two years.

Author's Conclusions

• The relative 2 year survival was superior for the group of patients receiving groin and pelvic radiation therapy (75%) after radical vulvectomy and groin node dissection compared with the 2 year survival of patients treated by surgery alone (56%). These data were statistically significant (p=0.03).
• The survival advantage was limited to those patients with clinical evident groin nodes or more than one positive groin node.
• There was not enough statistically power to prove benefit for those patients with occult metastases and only one positive groin node. This was in part due to the small sample size and the good survival of this subgroup of patients.
• Adjuvant radiation was more effective partially because groin node recurrences were reduced in the radiation therapy group.

Discussion

This paper is important in that it changed the standard of care for node positive vulvar cancer treatment. Furthermore, this study stands out with respect to a clear overall survival advantage for radiation over surgical resection alone.

Due to the premature halting of this study, there are a number of statistically weak points that the authors planned to resolve in an update to the paper, however, no update to this paper was ever published. Issues include:

• Due to statistically significant survival differences between the two treatment arms, the study was closed approximately 2 years short of the projected patient accrual goal.
• Periodic testing for treatment differences invalidates the meaning of the p-value associated with the classical hypothesis test.
• The median length of patient follow-up is not revealed. All 2 year data given as 2 year "estimates".
• Patients "were usually intraoperatively randomly assigned to either radiation therapy or ipsilateral pelvic node dissection". The definition of "usually" is never provided.
• The form of radiation is not discussed (i.e. Cobalt vs. linear accelerator).
• 75% of clinical N0, N1 patients were still being followed and without longer follow-up data conclusions are likely underpowered.

Despite these statistical question marks, external beam radiation therapy after surgical resection is accepted as the standard of care for this subgroup of patients due to the survival advantage demonstrated in this prospective randomized trial.