Tailoring Adjuvant Radiotherapy For Stage I Endometrial Cancer: The Rationale For Less TherapyDaniel G. Petereit, MD Endometrial cancer is the most common gynecologic malignancy in the United States, with an annual incidence of approximately 36,000 new cases. Standard therapy consists of an extrafascial hysterectomy, bilateral salpingo-oophorectomy, peritoneal washings, and an assessment of the draining lymphatics. The Gynecologic Oncology Group (GOG) published a pathologic study (GOG study 33) that led to a new staging system and helped categorize stage I patients into prognostic groups based on tumor grade and depth of myometrial invasion.1 The indications for adjuvant radiotherapy in patients with stage I endometrial cancer continue to evolve. 2 Although pelvic irradiation has been shown to reduce local recurrences for patients with stage IC disease, the survival advantage is small and not statistically significant. 3 With adjuvant pelvic irradiation, the outcome for intermediate-risk patients (stage IC, grade 2/3) is similar to that of low-risk patients (stage IB, grade 1/2). 4,5 Although significant complications occur in less than 1% of patients who receive pelvic irradiation without surgical staging, they are as high as 7% to 11% in patients who have had even selective lymphadenectomies. 6-8 Therefore, the value of adjuvant pelvic radiotherapy has been questioned; a survival advantage has not been proven and a proportion of patients may experience significant complications, primarily enteric. Two randomized trials investigating the efficacy of pelvic irradiation have been published. 8,9 GOG study 99 randomized patients after complete surgical staging with lymphadenectomy either to observation or to 50.4 Gy in 28 fractions, without a brachytherapy boost. 8 The majority of patients in this phase III GOG study had low-risk endometrial cancer: stage IB = 60%, grades 1-2 = 80%. The 2-year progression-free rate was 96% in the radiation arm and 88% in the observation arm (P = 0.02). These results have been updated recently and the progression-free rate is now 94% versus 85%. Additional analysis of these results demonstrated that an unfavorable group that included one third of the patients accounted for two thirds of the recurrences. Higher-risk patients included women with outer-one-third myometrial invasion, grade 2-3 disease, and the presence of capillary-like space (CLS) involvement. Other characteristics of patients at higher risk for recurrence included age greater than 50 years with two of the above risk factors, or age greater than 70 years with one of the above risk factors. In this higher-risk group, the progression-free interval was 74% for those patients who were observed versus 88% for those patients who received whole pelvic radiotherapy. In these patients, pelvic radiation significantly reduced the incidence of local recurrence. Among recurrences in the group that did not receive pelvic irradiation, 19 of 39 were pelvic or vaginal recurrences. For patients who were observed after surgery, the vaginal recurrence rate was 6.9% (14/202) versus only 1.6% (3/190) for those treated. The isolated vaginal-cuff recurrence rate was 0.5% for those who actually were radiated, and 7.8% for those who were not (relative reduction risk of 93%). In these well-staged patients, a common site of preventable failure was the vaginal apex. Unfortunately, 8% of patients who received pelvic radiotherapy experienced a small bowel obstruction. Another randomized trial from Europe also compared pelvic irradiation to observation after surgery for a similar patient cohort. However, in this trial lymphadenectomy was not performed or permitted. Patients included had the following stages: stage IC, grade 1; stage IB or IC, grade 2; and stage IB, grade 3. 9 Randomized to observation or treatment to 46 Gy (without brachytherapy) were 715 patients. Local-regional recurrences were reduced from 14% to 4% with the addition of pelvic radiotherapy. Nearly 75% of the recurrences were at the vaginal cuff. However, with a minimum follow-up of 5 years, the 5-year actuarial survival was 81% in the radiotherapy group and 85% in the control group (P = .31). Patients who received adjuvant radiotherapy experienced a 2% significant complication rate (grade 3/4, primarily enteric) as opposed to 0.3% in the observation group. In one of the largest series to date, Elliott et al10 reported higher vaginal recurrence rates after surgery alone. Among patients with low-risk endometrial cancer (grade 1 or 2 with less than one-third myometrial invasion), vaginal cuff recurrences were observed in 5% of patients. This risk increased to 15% for grade 3 patients with inner-one-third myometrial invasion or grade 1 patients with middle-one-third myometrial invasion. Isolated vaginal cuff recurrences are morbid and frequently fatal. Salvage therapy includes external-beam irradiation, since the pelvic lymphatics are at high risk for harboring occult disease, and brachytherapy to enhance local control while adding little additional dose to the normal tissues. 11 Ackerman et al12 reported high salvage rates for isolated vaginal failures (67%) and suggested that radiation could be withheld until relapse. However, many other studies have reported much lower salvage rates (0% to 64%).13,14 Since the vaginal apex is a common site of failure and isolated recurrences are difficult to salvage, there is a strong rationale to substitute vaginal brachytherapy for pelvic radiotherapy in these patients. In addition, the therapeutic ratio is better for brachytherapy than for pelvic irradiation in this setting. The target volume for vaginal brachytherapy varies from the entire vagina to simply the vaginal apex. The rationale for treating the entire vagina is to include the suburethral area, which can be a site for recurrences. Elliott et al10 observed a relative relapse risk for vaginal apex versus lower vagina of 4:1 in low-risk patients followed closely after surgery. The disadvantage of treating the entire vaginal mucosa is the higher agglutination rates, especially for high-dose-rate (HDR) brachytherapy, where large fraction sizes are used. Pearcey and Petereit have published an analysis of fractionation schedules for patients undergoing HDR brachytherapy alone after surgery. 15 It appears that a wide range of schedules are effective in reducing the risk for an isolated vaginal-cuff recurrence with minimal complication rates. In a study at the University of Wisconsin, among 191 patients who underwent HDR brachytherapy using vaginal ovoids, with a dose of 16.2 Gy X 2 given to the vaginal apex, the vaginal control rate was 100% with but a single complication. 16 The most common fractionation schedule using vaginal cylinders to treat the upper one third to one half of the vagina is 7 Gy X 3 at 5 mm. The use of brachytherapy alone for patients with completely staged, high-risk stage I endometrial cancer has been reported by Anderson et al17 and Chadha et al. 18 The group from the University of Arizona reported a 94% local-regional control rate in 31 patients who had negative lymphadenectomies and who were treated with HDR brachytherapy alone (5 Gy X 3 at 5 mm), despite having high-risk stage I disease (lymphovascular space invasion, lower-uterine-segment involvement, grade 3 and/or outer-one-third myometrial invasion). 17 No significant radiation-related late complications were reported. Chadha et al18 investigated the use of brachytherapy alone in 38 high-risk surgically staged patients (stage IB, grade 3 = 12, stage IC, grade 1 = 14; stage IC, grade 2 = 9; and stage IB, grade 3 = 3). These patients received 7 Gy X 3 at 5 mm via HDR brachytherapy. The 5-year actuarial survival and disease-free survival were 93% and 87%, respectively, with no grade 3 or 4 complications. Although three patients had recurrences in the upper abdomen, no vaginal or pelvic recurrences were seen. In summary, the vagina represents the most common and preventable site of recurrence after surgery for stage I endometrial cancer. Salvage of vaginal recurrences remains challenging and morbid. The therapeutic value of pelvic irradiation for low-risk and intermediate-risk patients continues to be defined, particularly for the latter group of patients who are incompletely staged. The excellent therapeutic ratio described by many groups supports the use of brachytherapy, particulary HDR, in preventing vaginal recurrences for low-risk patients, and possibly for thoroughly staged intermediate-risk patients as well. The table lists the author’s recommendations for adjuvant radiotherapy for stage I endometrial cancer; these are guidelines only.
Other treatment considerations include the extent of surgical staging, risk factors
that would preclude pelvic radiation, presence of lymphvascular space invasion and patient
preference. For example, the data from Elliot et al10 would suggest that
recurrence patterns are primarily in the vaginal cuff in patients with grade 3 tumors that
invade the inner one third of the myometrium, and with grade 1 lesions with
middle-one-third invasion. Vaginal-cuff brachytherapy is an acceptable alternative to
pelvic radiotherapy, especially if these patients are well staged. In addition,
vaginal-cuff brachytherapy might yield a better therapeutic ratio in patients with grade 2
or 3 deeply invasive tumors if a complete lymphadenectomy has been performed. The data
from Chadha et al18 and Anderson et al17 would support this
treatment strategy. On the other hand, vaginal-cuff brachytherapy alone is probably
insufficient for incompletely staged patients with grade 2 or grade 3 tumors that invade
more than one third of the myometrium. The clinical trial that desperately needs to be
investigated is pelvic radiotherapy versus vaginal cuff brachytherapy in stage I disease,
with a stratification based on whether patients have been thoroughly staged. This protocol
has been proposed to the GOG Corpus Committee numerous times. However, due to strong
institutional bias, this study will probably never be completed in the United States in a
cooperative group setting. Published November 2000 |
