Vaginal brachytherapy versus external beam pelvic radiotherapy for high-intermediate risk endometrial cancer: Results of the randomized PORTEC-2 trial

Presenter: R.A. Nout
Presenter's Affiliation: Leiden University Medical Center, Leiden, Netherlands
Type of Session: Scientific

Background

• Endometrial carcinoma represents the most common gynecologic malignancy in the United States, and the second most common cause of gynecologic cancer death.
• Tumor grade (1 -3), histology, and depth of invasion are important prognostic factors for patients with endometrial carcinoma, and depth of invasion is incorporated into the staging system as follows:
  • Stage I disease: Tumor confined to corpus uteri
    • IA: Tumor limited to endometrium
    • IB: Tumor invading less than 50% of myometrium
    • IC: Tumor invading greater than 50% of myometrium
  • Stage II: Tumor invades cervix, but does not extend beyond uterus
  • Stage III: Tumor with local/ regional spread
  • Stage IV: Tumor invasion to bowel/ bladder and/ or metastatic disease.
• In the absence of co-morbidities that prevent surgery, patients with endometrial carcinoma confined to the uterus and cervix are generally treated surgically, with or without adjuvant treatment.
• Multiple groups have studied the role of adjuvant radiotherapy for patients with localized, resectable disease (Stage I and II):
  • The Gynecologic Oncology Group (GOG) randomized patients with stages IB, IC, and occult II (intermediate-risk) endometiral cancer to observation versus post-operative whole pelvis radiotherapy (RT) to a dose of 50.4 Gray (Gy) following total abdominal hysterectomy, bilateral salpingo-oophorectomy (TAH/ BSO), and lymph node dissection in the GOG 99 trial. Radiotherapy was found to decrease risk of local recurrence, but had no effect on overall survival (Keys, 2004).
  • A similar trial, the Post-Operative Radiotherapy in Endometrial Cancer (PORTEC) trial,  randomized patients with stage IB grade 2-3 and stage IC grade 1-2 disease to observation versus whole pelvis RT to 46 Gy following TAH/ BSO. Lymph node dissection was not performed. Radiotherapy decreased local recurrence rates from 14% to 4% (p < 0.001), with no difference in overall survival or development of distant metastatic disease.  The majority of failures (75%) were in the vaginal vault (Creutzberg, 2000). 
    • In the PORTEC trial, several high-risk features were identified, including grade 3 disease, involvement of the outer 50% of the myometrium, and age greater than 60 years.
    • Patients with at least two of these factors were classified as having "high-intermediate-risk" disease.
    • When a separate analysis of high-intermediate patients was performed, local recurrence risk was decreased from 19% to 5% with use of radiotherapy, without significant impact on overall survival.  
    • The incidence of GI toxicity was significantly increased in the group of patients receiving radiotherapy, from <1% to 17% (p < 0.0001).
• Phase II trials have suggested that vaginal brachytherapy (VBT) may be as effective as external beam radiotherapy (EBRT), although much of this work has been done in patients with low-risk disease.
• The results of the second PORTEC trial, PORTEC-2, are presented here; this trial was designed to compare the efficacy of VBT versus EBRT in patients with high-intermediate risk localized endometrial cancer following TAH/BSO in a randomized, controlled, fashion.
  • This trial was designed to assess not only overall survival and local recurrence, but quality of life with regards to treatment modality.

Materials and Methods

• The PORTEC-2 trial was designed as a multi-center, phase III, randomized controlled trial.
• The trial was designed to assess patients with high-intermediate risk disease based on the findings of the PORTEC-1 trial. Eligible patients were as follows:
  • Age greater than 60 years, with stage IC, grade 1-2, or stage IB, grade 3 disease.
  • Any age and stage 2A, grade 1-2.
• All patients underwent TAH/ BSO without lymph node dissection.
• Patients were subsequently randomized to EBRT (46 Gy delivered in 23 fractions), or VBT (21 Gy delivered via 3 high-dose rate fractions, or 30 Gy delivered via low-dose rate brachytherapy).
• The primary endpoint assessed was vaginal recurrence rate (VRR), which was expected to be 2% at 3-years in the EBRT group based on data from PORTEC-1. In order to estimate differences in the VBT group with adequate precision (standard error 2%), an accrual of 400 patients over 4 years was planned to provide power of 80%.
• Secondary endpoints included quality of life (QOL), overall survival (OS), and local-regional recurrence (LRR)
• Analysis was done by intention-to-treat, using the competing risk method to assess VRR, LRR, and distant relapse, and the Kaplan-Meier method to assess OS and relapse-free survival (RFS).

Results

• This study enrolled 427 patients during the period from 2002 to 2006. Patients were randomized to EBRT (n = 214) versus VBT (n = 213).
  • A total of 12 patients from the EBRT group and 10 from the VBT group were ineligible or withdrew from the study. 
  • No patient was lost to follow-up, and all patients were included in the intent-to-treat analysis.
  • No difference in baseline patient characteristics was observed.
  • Median follow-up for the entire population was 36 months.
• Three-year actuarial vaginal recurrence rates were 1.9% in both arms (p = 0.97).
• Three-year local recurrence rates were 2.5% in the EBRT arm, and 4.0% in the VBT arm (p = 0.15).
• Three-year pelvic nodal recurrence rates were 0.6% in the EBRT arm, and 3.5% in the VBT arm (p = 0.03).
• Three-year rates of distant metastasis were 5.7% in the EBRT arm, and 6.3% in the VBT arm (p = 0.37).
• Death rates were 9.7% in the EBRT arm and 9.2% in the VBT arm (p = 0.96). There were no significant differences in 3-year OS (90.4% versus 90.8%, respectively, p = 0.55) or RFS (89.5% versus 89.1%, p = 0.38).
• Type of first failure was assessed between the two arms:
  • Type of first failure was VRR in 1.4% of patients receiving EBRT, and 0% of patients receiving VBT.
  • First failure was pelvic nodal recurrence in 0.7% of EBRT patients, and 1.3% of VBT patients.
  • First failure was distant metastatic disease in 6.0% of EBRT patients, and 6.4% of VBT patients.
• On assessment of QOL, the incidence of diarrhea limiting daily activity was significantly increased in the EBRT group (p < 0.001), and this difference persisted for at least 24 months.
  • This correlated with increased level of social functioning in the VBT group.
• Although grade 1-2 skin toxicity increased within the EBRT group, no differences in genitourinary toxicity, sexual function, or sexual activity were observed between the two groups.

Author's Conclusions

• The authors conclude that results with regards to VRR, LRR, and OS in both arms of PORTEC-2 are comparable to those observed in PORTEC-1 and GOG 99, as expected.
• Results with VBT versus EBRT are in keeping with these prior results, with no difference in VRR, RFS, or OS observed between the two groups.
• They note that although risk of pelvic nodal recurrence was greater in the VBT group when compared to EBRT, this difference did not translate to a survival decrease, since the rates of distant disease were similar between the two groups.
• The authors describe VBT as a safe alternative to EBRT that offers significant improvement in QOL; they conclude that VBT should thus be the treatment of choice for high-intermediate risk endometrial carcinoma after TAH/BSO.

Clinical/Scientific Implications

• This trial represents an important comparison of two techniques for delivery of adjuvant radiotherapy to patients with high-intermediate risk endometrial cancer after TAH/BSO. It examines an important clinical question, with regards to both clinical outcomes and QOL, and  has been performed in a well-designed and well-executed manner.
• The value of EBRT after TAH/BSO was largely in reduction of VRR in the PORTEC-1 trial. Recognizing this, the investigators designing PORTEC-2 sought to determine whether VBT could adequately replace EBRT, potentially improving QOL.
• In the PORTEC-1 trial, the risk of vaginal vault recurrence in patients randomized to observation alone was approximately 10%. The majority of these patients were subsequently salvaged, and no difference in overall survival existed between the EBRT and observation alone arms.
  • PORTEC-1 considered a group of patients that included intermediate risk disease as well as high-intermediate; however, in a subsequent analysis that did not consider stage IB patients, EBRT continued to reduce LRR without altering OS significantly (Scholten, 2005).
• Based on this data, the risk of VRR following TAH/BSO appears to be relatively low, and radiotherapy is given with the intention of reducing it further, not improving survival.
• In this situation, QOL issues are particularly important, as a significant portion of patients may be undergoing radiotherapy “unnecessarily.”
  • Although most patients experiencing VRR in the setting of observation will likely be salvaged based on PORTEC-1, the psychological ramifications of such a recurrence are difficult to assess.
  • Still, the goal of maintaining excellent QOL during and after treatment is extremely important in the setting of giving radiotherapy that is expected to reduce risk of VRR, but not expected to affect OS.
• Based on the data from PORTEC-2 presented here, VBT appears to be a safe and reasonable alternative to EBRT, and appears to affect QOL significantly less than EBRT. The authors’ conclusions that VBT should replace EBRT in this setting seem reasonable.
• Further consideration of risk-based management could potentially be considered in the future, as radiotherapy could possibly be avoided in certain patients with a minimally increased risk to survival. In the future, patient autonomy and choice, as well as other objective factors, could also potentially and safely contribute to decisions regarding adjuvant radiotherapy.