By Robert L. Coleman, MD
Professor, University of Texas; M.D. Anderson Cancer Center, Houston
Dr. Coleman reports no financial relationships relevant to this field of study.
This article originally appeared in the January 2014 issue of OB/GYN Clinical Alert.
Synopsis: Long-term complications, particularly secondary cancers, were significantly more common in patients receiving whole pelvic radiation (vs brachytherapy alone) for early-stage endometrial cancer. No difference in overall survival was found in women receiving additional radiation therapy.
Source: Onsrud M, et al. Long-term outcomes after pelvic radiation for early-stage endometrial cancer. J Clin Oncol 2013;31:3951-3956.
Between 1968 and 1974, 568 patients with stage 1 endometrial cancer were treated adjuvantly with vaginal brachytherapy and then randomized to either external beam whole pelvic radiation (n = 288) or no further therapy (n = 280). A trial reported in 1980 demonstrated no improvement in overall survival for the addition of pelvic radiation.1 This current trial was conducted to examine the long-term effects of external beam radiation therapy (EBRT) in this population. Stratification was made for age given the high degree of noncancer mortality. After median 20.5 years (range, 0-43.4 years) of follow-up, no statistically significant difference was revealed in overall survival (P = 0.19) between treatment groups. However, women younger than age 60 years had significantly higher mortality rates after EBRT (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.06-1.76) than the control group. The risk of secondary cancer increased after EBRT, especially in women younger than age 60 years (HR, 2.02; 95% CI, 1.30-3.15). The HR for secondary cancer in women older than age 60 years was 0.81 (95% CI, 0.45-1.43). The median time to a secondary cancer was 15 years. The authors conclude no survival benefit of external pelvic radiation in early-stage endometrial carcinoma. In women younger than age 60 years, pelvic radiation decreased survival and increased the risk of secondary cancer. Adjuvant EBRT should be used with caution, especially in women with a long life expectancy.
It's actually quite remarkable that in the 33 years since this landmark paper was published, the role of adjuvant radiation is still not defined in women with early-stage endometrial cancer.1 While, in some regard, the good overall prognosis of this cohort does not lend itself to be "modality evaluable," the topic of external beam pelvic radiation therapy is hotly debated, and routinely used as standard of care in many parts of the world. However, in locations where surgical staging (pelvic and para-aortic lymphadenectomy) is universally applied or patient-individualized, adjuvant treatment plans are primarily based on findings in uterine and extrauterine tissue samples. In this context, patients without metastatic disease but deemed at high risk for recurrence are increasingly being treated with systemic chemotherapy. This pattern of care has largely eliminated pelvic radiotherapy from many treatment algorithms. Thus, three principle issues can frame the debate of which adjuvant therapy is most appropriate in early-stage endometrial cancer: assessment of risk, role of lymphatic dissection (surgical staging), and the ultimate impact of therapy (survival).
Endometrial cancer is largely considered among the most "survivable" of the gynecological tumors given its predominately early stage at diagnosis and curative impact of simple organ removal. Overall, the 5-year survival for women with early stage endometrial cancer exceeds 85%. However, a small proportion of these patients will experience recurrence, despite a negative evaluation of extra-uterine disease. Patterns of recurrence are roughly one-third local, one-third distant, and one-third both local and distant in nature. Recognizing these issues and the difficulty in curing all but the most focal of recurrences, researchers have devised a series of clinical trials to evaluate adjuvant therapy in the hopes of mitigating this risk. As mentioned, the first randomized trial to do so was that of Aalders and colleagues. In this trial, women with stage I endometrial cancer were given adjuvant vaginal brachytherapy to address recurrence at the vaginal cuff and then were randomized to either whole pelvic radiation or no further therapy. The trial's accrual window was opened 45 years ago, used clinical staging (based on preoperative findings), and delivered radiation with fairly low-energy cobalt machines in a two-field (AP-PA) exposure. The results demonstrated a decrease in local recurrence with pelvic radiation therapy, but no difference in overall survival (see Table). Despite this remarkable trial's conclusions, each of the variables mentioned (old staging criteria, lack of lymphadenectomy, and radiation technique) were criticisms to widespread adoption of the practice. Also, since vaginal brachytherapy was given to all patients, its contribution to the findings was questioned.
In 1987, the Gynecologic Oncology Group (GOG) launched a trial to evaluate pelvic radiation vs no further therapy in women undergoing formal surgical staging with stage IB, grade 2-3, or IC grade 1-2 uterine cancer. Like the previous trial, local recurrence was increased in the no further therapy arm but overall survival was similar.2 Also similar to the previous trial, long-term toxicity was increased in women receiving adjuvant pelvic radiotherapy. Review of the risk stratification from the GOG trial identified a cohort of women in which additional therapy appeared to improve long-term outcomes over no further therapy. In light of these findings, subsequent trials conceded that there were a group of low-risk patients for whom adjuvant therapy was of no benefit and could be safely eliminated. However, the argument as to whether surgical staging was necessary to identify these patients continued, and unfortunately, is still unresolved.
Since the risk of nodal metastases is not much different than the risk of recurrence (about 10%), the merit of unselected adjuvant therapy is still questioned. This contention was bolstered by the PORTEC trial, which randomized 714 women with "intermediate risk" for recurrence to the same treatment arms outlined in GOG 99, but in this case, did not require lymphatic evaluation.3 As can be seen in the Table, the recurrence risk, survival, and toxicity observations are nearly matched to GOG 99. Subsequently, several trials have been conducted to try to clarify the first two tenets of the debate: risk assessment and the need for lymphadenectomy, using variously defined factors.4,5 These generally consider age, grade of the tumor, myometrial invasion, involvement of the lymph-vascular spaces, and tumor size/location. The bottom line is that while routine lymphadenectomy as a staging procedure accurately identifies those patients with metastatic disease, the impact on long-term outcome is limited. One response to the lack of this evaluation is increased use of pelvic radiation to "cover" the regional lymphatics for potential early metastatic (but undiagnosed) disease. As has been well covered in several meta-analyses, the practice leads to equivalent outcomes, but as was identified in the Aalders and PORTEC-1 trials, comes with a cost — the risk for secondary malignancy.6,7
Long-term risk from therapy is an uncommon topic in most gynecological malignancies. This is because outside of non-epithelial ovarian and early-stage cervix and endometrial cancer, expected survival is far shorter than the time frame for a second cancer to develop. However, the current trial emphasizes the importance of evaluating the cost of therapy both short- and long-term. Since many of the patients apparently cured of their primary disease received DNA damaging therapy unnecessarily (i.e., not risk stratified), the issue is of great relevance. One effort to mitigate both recurrence and toxicity risk is the use of short-term adjuvant chemotherapy added to vaginal brachytherapy. Since nearly two-thirds of recurrences will include an element of distant disease, it is hypothesized that systemic chemotherapy may be better situated to address this risk. Since vaginal brachytherapy appears to be as good as pelvic radiation in patients undergoing accurate staging, the combination of two would appear an ideal combination. However, the proof of chemotherapy efficacy is lacking despite one randomized trial that suggests its equivalence to pelvic radiation.8 It is hoped that the strategy, currently being evaluated in a Phase 3 trial, can provide long-term benefit while lowering long-term adverse events. These will be welcomed additions if proven, because more than ever, patients are experiencing long post-diagnosis survivorships.