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ORIGINAL REPORTS
Gynecologic Cancer
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Quality of Life After Pelvic Radiotherapy or Vaginal Brachytherapy for Endometrial Cancer: First Results of the Randomized PORTEC-2 Trial
Abstract
Studies on quality of life (QOL) among women with endometrial cancer have shown that patients who undergo pelvic radiotherapy report lower role functioning and more diarrhea and fatigue. In the Post Operative Radiation Therapy in Endometrial Cancer (PORTEC) trial, patients with endometrial carcinoma were randomly assigned to receive external-beam radiotherapy (EBRT) or vaginal brachytherapy (VBT). QOL was evaluated by using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and subscales from the prostate cancer module, PR-25, and the ovarian cancer module, OV-28.
PORTEC-2 accrued 427 patients between 2002 and 2006, of whom 214 were randomly assigned to EBRT, and 213 were randomly assigned to VBT. Three-hundred forty-eight patients (81%) were evaluable for QOL. QOL outcomes were analyzed at a median follow-up of 2 years.
At baseline after surgery, patient functioning was at the lowest level, and it increased during and after radiotherapy to reach a plateau after 12 months. Patients in the VBT group reported better social functioning (P < .002) and lower symptom scores for diarrhea, fecal leakage, the need to stay close to the toilet, and limitation in daily activities because of bowel symptoms (P < .001). At baseline, 15% of patients were sexually active; this increased significantly to 39% during the first year (P < .001). Sexual functioning and symptoms did not differ between the treatment groups.
Patients who received EBRT reported significantly higher levels of diarrhea and bowel symptoms. This resulted in a higher need to remain close to a toilet and, as a consequence, more limitation of daily activities because of bowel symptoms and decreased social functioning. Vaginal brachytherapy provides a better QOL, and should be the preferred treatment from a QOL perspective.
Endometrial carcinoma is the most common gynecologic malignancy among postmenopausal women in western countries.1 Most patients are diagnosed at an early stage, and surgery, which consists of total abdominal hysterectomy and bilateral salpingo-oophorectomy, is the cornerstone of treatment.
Randomized trials on postoperative radiotherapy in endometrial carcinoma have shown that pelvic external-beam radiotherapy (EBRT) significantly reduced the rate of locoregional relapse. However, reduction of relapse did not translate into a survival benefit, and was achieved at the cost of more (predominantly mild) gastrointestinal toxicity.2–7
As a result of the first Post Operative Radiation Therapy in Endometrial Cancer (PORTEC) trial, the indication for radiotherapy was abandoned in the Netherlands for patients with a low risk of locoregional recurrence.3 For the remaining, so-called high-intermediate risk patients (ie, age 60 years or older and stage IC grades 1 or 2 or stage IB grade 3), the benefit in terms of locoregional control (ie, 19% locoregional relapse without radiotherapy v 5% with EBRT) and disease-free survival were considered to outweigh the risks in terms of treatment-related toxicity. As most (75%) locoregional relapses were located in the vagina, the multicenter, randomized, PORTEC-2 trial was initiated to investigate if vaginal brachytherapy (VBT) would be equally effective in reducing the risk of locoregional recurrence while at the same time reducing treatment-related toxicity and improving health-related quality of life (HRQOL).
Little is known about HRQOL and the impact of adjuvant radiotherapy on HRQOL in survivors of endometrial cancer. All studies are retrospective, most are quite small, and most have low questionnaire-return rates (< 40%).8–12 One retrospective study with an adequate return rate (75%) found that EBRT was negatively associated with vitality and physical and social well-being, but scores of patients treated both with or without radiotherapy were similar to those of an age-matched population.13 Although patient-perceived HRQOL is an important factor to be used in the decision-making process, whether or not postoperative radiotherapy should be recommended, there is a clear lack of data on HRQOL among patients with endometrial cancer.
The aim of this analysis was to investigate short-term HRQOL of patients with high-intermediate risk endometrial carcinoma treated in the PORTEC-2 trial and to evaluate the impact of EBRT compared with VBT on patient-perceived HRQOL.
The PORTEC-2 trial was a multicenter, randomized trial that was conducted throughout the Netherlands to compare EBRT and VBT. Surgery consisted of total abdominal hysterectomy and bilateral salpingo-oophorectomy; clinically suspicious pelvic and/or periaortic lymph nodes were removed, but no routine lymphadenectomy was performed. The diagnosis of endometrial carcinoma, grade, histologic subtype, and depth of myometrial invasion were made by the regional pathologist. International Federation of Gynecology and Obstetrics 1988 staging was assigned on the basis of surgical and pathologic findings.14
Patients were eligible for the study if they had one of the following combinations of age and postoperative International Federation of Gynecology and Obstetrics stage: age ≥ 60 years and stage IC, grade 1 or 2, or stage IB, grade 3 disease; or any age and stage 2A disease (except grade 3 disease with > 50% myometrial invasion). All patients had a WHO performance score of ≤ 2. Written informed consent was obtained from all patients. The protocol was approved by the Dutch Cancer Society and the medical ethics committees of all participating centers.
EBRT was given to a total dose of 46 Gy in 2-Gy daily fractions, and five fractions were given per week. VBT was delivered to the upper half of the by vagina using a vaginal cylinder. High–dose-rate (HDR; 90% of patients) and low–dose-rate (LDR; 10% of patients) schedules were used, which aimed at an equivalent of 45 to 50 Gy to the vaginal mucosa with HDR schedules of 21 Gy at 5-mm depth, given in three fractions of 7 Gy, each 1 week apart; and LDR schedules of 30 Gy at 5-mm depth, given in one session at 0.50 Gy/h.
The primary end point was 5-year vaginal relapse rate (VRR) as cumulative incidence, with death as a competing risk.15 Secondary end points were HRQOL, treatment-related toxicity, pelvic lymph node and distant relapse rates, and overall survival. To detect a clinical relevant difference in VRR with sufficient precision, a total of 400 patients were required during an accrual period of 4 years. For evaluation of HRQOL this sample size would be more than sufficient to obtain significant and clinically relevant results, even when taking dropout into account.
Cancer-specific HRQOL was measured with the European Organization for Research and Treatment of Cancer C30 questionnaire (EORTC QLQ-C30, version 3.0).16 The EORTC QLQ-C30 is a multidimensional, cancer-specific QOL questionnaire developed for repeated assessments in clinical trials, and it has been found valid and reliable in various cancer populations. The QLQ-C30 questionnaire contains five functional scales (physical, cognitive, emotional, social, and role functioning), a global health status/QOL scale, three symptom scales (pain, fatigue, and nausea/vomiting), and six single items to assess additional symptoms (dyspnea, insomnia, loss of appetite, constipation, diarrhea) and perceived financial impact.
Although an endometrial cancer module is currently being developed by the EORTC Quality of Life Group, no endometrial cancer–specific symptom questionnaire was available when PORTEC-2 was active. With approval of the EORTC Quality of Life Group, relevant subscales from existing published EORTC modules, which had previously undergone psychometric evaluation and validation, were combined into a symptom module for this study. The subscales for bowel and bladder symptoms from the prostate cancer module (PR-25) and the subscale for sexual functioning and symptoms from the ovarian cancer module (OV-28) were used.17,18
For all items, Likert-type response scales were used, and the response scale ranged from 4 to 7 points. All subscales and individual-item responses were linearly converted to 0 to 100 scales. A higher score for a functional and global QOL scale represented a better level of functioning. For the symptom scales and items, a higher score reflected a higher level of symptoms and decreased QOL.
Baseline QOL questionnaires were handed out at the first consultation with the radiation oncologist, usually 3 to 4 weeks after surgery, and had to be returned before the start of radiotherapy. The end-of-treatment QOL questionnaire was handed out 2 to 4 weeks after the completion of radiotherapy. After that time, the questionnaires were sent directly to each patient's home address at 6, 12, 18, 24, 36, 48, and 60 months from the date of random assignment. Patients were considered evaluable for the QOL assessment if they had returned the baseline questionnaire and at least one of the follow-up questionnaires (ie, responders).
All statistical analyses were performed with SPSS, version 14.0 (SPSS, Chicago, IL). Data on patient and tumor characteristics from the trial register enabled us to compare responders with nonresponders by using χ2 statistics or Fisher's exact test for categoric variables and t test for continuous variables (P = .05 was considered significant). These tests were also used to compare the VBT group with the EBRT group.
QOL analysis was done according to the guidelines provided by the EORTC Quality of Life Group.19 Descriptive median scores are listed in the tables. Baseline scores of both treatment groups were compared with a t test or the Armitage trend test for single items. To exclude a treatment effect on baseline scores, baseline forms completed later than the first day of radiotherapy were excluded for this comparison. To obtain estimates of the EORTC QLQ-C30 and the PR-25 and OV-28 subscales at each of the fixed time points, a linear mixed model was used with the patient as random effect and time (categoric), random assignment, and their interaction as fixed effects. Single items were analyzed by using (ordinal) logistic regression with random effects. The difference in QOL between the two treatment groups was tested by Wald's test in the linear or ordinal logistic mixed model (P random assignment), which excluded the baseline value. The same test was applied to look for significant changes of QOL scores over time (P time), and score changes over time were compared between both treatment groups (P time by random assignment), which included the baseline value. To guard against false-positive results because of multiple testing, a two-sided P value of .01 was considered statistically significant.
The PORTEC-2 trial accrued 427 patients between 2002 and 2006; 214 patients were allocated to EBRT, and 213 were allocated to VBT. The median follow-up at the time of analysis (January 2008) for all randomly assigned patients was 2.7 years (range, 0.9 to 5.3 years). Baseline questionnaires and at least one follow-up questionnaire were received from 348 patients (81%), who were considered responders. The median follow-up of responders was 2.7 years; because of ongoing follow-up at the time of analysis, the rate of responders at the 2-year time point was 53% (Data Supplement, online only).
All returned questionnaires were complete for all items of the QLQ-C30 in 83% of the responders and for items on bladder and bowel symptom subscales (PR-25) in 92%. When up to two missing items were allowed, these rates were 96% and 97%, respectively. In contrast, patients were more reluctant about responding to questions about their sexual functioning and symptoms. The sexual functioning subscale (OV-28) was complete for all items in 66%; the sexual symptom subscale was complete for all items in 80% among responders who were sexually active. Overall, the treatment groups did not differ significantly with regard to questionnaire response rates and missing items. Although there were more patients who received EBRT among the nonresponders (48 patients in EBRT v 31 patients in VBT; P = .04), patient characteristics were equally balanced between the EBRT and VBT groups and between responders and nonresponders (Table 1).
|
| Characteristic | Responders (n = 348) | Nonresponders (n = 79) | ||||||
|---|---|---|---|---|---|---|---|---|
| EBRT (n = 166) | VBT (n = 182) | P * | ||||||
| No. of Patients | % | No. of Patients | % | No. of Patients | % | P † | ||
| Age, years | ||||||||
| Mean | 69.5 | 70.1 | .45 | 71.3 | .16 | |||
| Range | 52-88 | 46-86 | 52-89 | |||||
| < 60 | 7 | 4.2 | 6 | 3.3 | .29 | 3 | 3.8 | .33 |
| ≥ 60 | 159 | 95.8 | 176 | 96.7 | 75 | 96.2 | ||
| FIGO stage | .73 | .99 | ||||||
| 1B | 11 | 6.1 | 13 | 7.2 | 8 | 9.2 | ||
| 1C | 137 | 82.9 | 147 | 80.7 | 58 | 75 | ||
| 2A | 18 | 11 | 22 | 12.2 | 9 | 11.8 | ||
| Histologic grade | .83 | .42 | ||||||
| 1 | 77 | 46.4 | 89 | 48.9 | 36 | 46.1 | ||
| 2 | 78 | 47 | 79 | 43.4 | 34 | 43.4 | ||
| 3 | 11 | 6.6 | 14 | 7.7 | 9 | 10.5 | ||
| KPS | .18 | .10 | ||||||
| 0 | 118 | 71.1 | 119 | 65.4 | 61 | 78.2 | ||
| 1 | 47 | 28.3 | 59 | 32.4 | 16 | 20.5 | ||
| 2 | 1 | 0.6 | 4 | 2.2 | 1 | 1.3 | ||
| Comorbidity | ||||||||
| IBD | 2 | 1.2 | 2 | 1.1 | .93 | 2 | 2.6 | .34 |
| Diabetes | 19 | 11.4 | 31 | 17 | .14 | 12 | 15.4 | .82 |
| Hypertension | 61 | 37 | 63 | 34.8 | .68 | 26 | 33.3 | .68 |
| Cardiovascular | 38 | 23 | 42 | 23.1 | .99 | 18 | 23.4 | .95 |
| Other | 24 | 14.5 | 28 | 15.5 | .79 | 14 | 17.9 | .51 |
Abbreviations: EBRT, external beam radiotherapy; VBT, vaginal brachytherapy; FIGO, International Federation of Gynaecology and Obstetrics; KPS, Karnofsky performance score; IBD, inflammatory bowel disease.
*P for comparison of EBRT v VBT.
†P for comparison of responders v nonresponders.
Mean scores of the EORTC QLQ-C30 functioning subscales and global health status and for the OV-28 subscales on sexual functioning and symptoms are summarized in Table 2. Development of the functioning scores over time is displayed in Figure 1. Baseline functioning scores did not differ significantly between the treatment groups. For both treatment groups, global heath status and functioning scales were low at baseline, showed a significant improvement in the first 6 months, and reached a plateau at 12 months (Fig 1).
|
| Evaluation by Type of Therapy | Scores and Analyses | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Questionnaire Time Points | P | |||||||||
| Baseline | P * | After RT | Month | Time | Random Assignment | Time by Random Assignment | ||||
| 6 | 12 | 18 | 24 | |||||||
| EORTC QLQ-C30 | ||||||||||
| Global health status | ||||||||||
| EBRT | 69.1 | .97 | 73.2 | 76.8 | 75.7 | 77.0 | 75.7 | < .001 | .35 | .82 |
| VBT | 70.3 | 76.2 | 79.2 | 77.7 | 78.9 | 80.3 | ||||
| Functional scales | ||||||||||
| Physical | ||||||||||
| EBRT | 72.0 | .47 | 76.3 | 80.7 | 79.0 | 80.4 | 77.3 | < .001 | .24 | .98 |
| VBT | 73.6 | 79.4 | 82.3 | 81.7 | 81.8 | 81.1 | ||||
| Role | ||||||||||
| EBRT | 61.0 | .18 | 71.5 | 80.5 | 81.0 | 82.9 | 80.7 | < .001 | .29 | .66 |
| VBT | 59.1 | 77.5 | 83.6 | 82.9 | 84.4 | 82.9 | ||||
| Emotional | ||||||||||
| EBRT | 75.6 | .54 | 82.4 | 84.0 | 83.4 | 85.4 | 86.1 | < .001 | .73 | .81 |
| VBT | 76.2 | 83.2 | 85.0 | 85.0 | 87.9 | 87.1 | ||||
| Cognitive | ||||||||||
| EBRT | 84.3 | .46 | 86.6 | 86.3 | 86.9 | 87.3 | 85.9 | .22 | .21 | .76 |
| VBT | 86.6 | 87.9 | 89.3 | 89.3 | 89.8 | 88.6 | ||||
| Social | ||||||||||
| EBRT | 77.7 | .72 | 82.5 | 87.0 | 87.1 | 90.4 | 89.9 | < .001 | .002 | .42 |
| VBT | 78.0 | 89.3 | 92.7 | 93.4 | 93.8 | 92.1 | ||||
| EORTC OV-28 | ||||||||||
| Sexual functioning | ||||||||||
| Sexual interest | ||||||||||
| EBRT | 9.6 | .14 | 12.0 | 15.5 | 16.3 | 16.7 | 16.4 | < .001 | .63 | .50 |
| VBT | 6.2 | 11.7 | 16.2 | 15.5 | 15.0 | 13.0 | ||||
| Sexual activity | ||||||||||
| EBRT | 6.8 | .34 | 11.2 | 14.1 | 14.9 | 13.0 | 13.5 | < .001 | .35 | .42 |
| VBT | 3.9 | 8.8 | 13.9 | 12.2 | 13.0 | 10.6 | ||||
| Sexual symptoms | ||||||||||
| To what extent was sex enjoyable | ||||||||||
| EBRT | 52.9 | .05 | 46.4 | 48.5 | 51.0 | 53.1 | 53.7 | .053 | .05 | .54 |
| VBT | 23.3 | 50.0 | 47.2 | 42.5 | 50.0 | 42.6 | ||||
| Vaginal dryness | ||||||||||
| EBRT | 26.7 | .20 | 30.3 | 31.2 | 35.5 | 40.5 | 37.0 | .725 | .13 | .02 |
| VBT | 44.4 | 31.6 | 38.9 | 35.6 | 24.4 | 29.6 | ||||
NOTE. For functioning scales, a higher score indicates higher functioning; for symptom scales, a higher score indicates more symptoms.
Abbreviations: EORTC QLQ-C30, European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire C30; OV-28, ovarian cancer module; RT, radiotherapy; EBRT, external-beam radiotherapy; VBT, vaginal brachytherapy.
*P for baseline comparison; t test to compare means; Armitage trend test for single items.
Fig 1. Patient functioning on subscales from European Organization for Research and Treatment of Cancer C30 questionnaire (EORTCQLQ-C30) and ovarian cancer questionnaire module (OV-28). A higher score indicates a higher level of functioning. Bars represent 99% CIs. The vertical axis is in the (A-C) upper-50% range; and (D) lower-50% range. VBT, vaginal brachytherapy; EBRT, external-beam radiotherapy; RT, radiation therapy.
Patients treated with VBT reported significantly higher social functioning scores after radiotherapy and with additional follow-up than patients treated with EBRT. The maximum difference between both treatment groups was 6% after radiotherapy (EBRT, 83% v VBT, 89%; P random assignment = .002); this difference remained at approximately the same level during the first year of follow-up. Mean scores for global health status and for the remaining functioning scores were somewhat higher for patients treated with VBT, but these differences were not statistically significant.
Sexual activity and interest were lowest at baseline (ie, after surgery), when 15% of the patients indicated that they were sexually active. Both interest and activity increased significantly during the first 6 months to reach a plateau (39% active) without significant differences between the treatment groups. Of the patients who indicated they were active, 80% reported on their sexual symptoms; in these patients, there were no significant differences in sexual symptoms.
Mean scores on the symptom scales of EORTC QLQ-C30, PR-25, and OV-28 are summarized in Table 3. Development of the mean symptom scores over time is displayed in Figure 2, and development of patient responses is in Figure 3. Baseline symptom scores did not differ significantly between the treatment groups.
|
| Evaluation by Type of Therapy | Scores and Analyses | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Questionnaire Time Points | P | |||||||||
| Baseline | P * | After RT | Month | Time | Random Assignment | Time by Random Assignment | ||||
| 6 | 12 | 18 | 24 | |||||||
| EORTC QLQ-C30 | ||||||||||
| Symptom scales | ||||||||||
| Fatigue | ||||||||||
| EBRT | 34.8 | .83 | 32.3 | 24.6 | 25.5 | 23.9 | 24.7 | < .001 | .06 | .84 |
| VBT | 34.1 | 26.3 | 21.1 | 20.1 | 19.9 | 18.9 | ||||
| Nausea and vomiting | ||||||||||
| EBRT | 4.6 | .60 | 6.4 | 2.9 | 4.5 | 2.5 | 3.4 | .001 | .013 | .54 |
| VBT | 5.1 | 3.8 | 2.3 | 1.4 | 2.3 | 1.8 | ||||
| Pain | ||||||||||
| EBRT | 18.4 | .25 | 15.7 | 12.9 | 14.4 | 13.2 | 12.6 | < .001 | .23 | .74 |
| VBT | 19.5 | 13.6 | 10.5 | 11.7 | 8.9 | 10.6 | ||||
| Dyspnea | ||||||||||
| EBRT | 13.1 | .54 | 14.9 | 11.9 | 20.9 | 13.1 | 11.8 | .13 | .35 | .008 |
| VBT | 11.7 | 10.1 | 12.4 | 22.2 | 15.2 | 18.1 | ||||
| Insomnia | ||||||||||
| EBRT | 27.5 | .59 | 22.9 | 21.4 | 26.4 | 22.3 | 21.4 | .006 | .77 | .94 |
| VBT | 25.7 | 21.0 | 19.3 | 23.6 | 20.4 | 20.7 | ||||
| Appetite loss | ||||||||||
| EBRT | 13.7 | .24 | 15.7 | 8.7 | 20.5 | 5.1 | 6.9 | < .001 | .10 | .02 |
| VBT | 10.7 | 7.2 | 3.2 | 11.0 | 4.6 | 5.5 | ||||
| Constipation | ||||||||||
| EBRT | 13.7 | .74 | 8.2 | 6.5 | 15.1 | 6.6 | 9.0 | < .001 | .92 | .76 |
| VBT | 12.8 | 6.5 | 5.4 | 18.0 | 7.1 | 7.5 | ||||
| Diarrhea | ||||||||||
| EBRT | 7.9 | .10 | 30.6 | 17.4 | 25.9 | 13.1 | 12.8 | < .001 | < .001 | .08 |
| VBT | 5.0 | 9.1 | 5.4 | 17.5 | 5.2 | 5.6 | ||||
| Financial difficulties | ||||||||||
| EBRT | 2.2 | .02 | 5.1 | 3.5 | 9.2 | 3.0 | 2.2 | .025 | .70 | .82 |
| VBT | 5.5 | 4.9 | 3.7 | 9.8 | 3.0 | 2.5 | ||||
| EORTC PR-25 | ||||||||||
| Urinary symptoms | ||||||||||
| Frequency in daytime | ||||||||||
| EBRT | 32.9 | .11 | 40.0 | 29.4 | 32.6 | 30.6 | 30.2 | < .001 | .09 | .32 |
| VBT | 36.6 | 36.9 | 29.6 | 24.0 | 26.7 | 29.4 | ||||
| Frequency at night | ||||||||||
| EBRT | 31.2 | .11 | 38.3 | 28.7 | 29.5 | 29.8 | 29.5 | < .001 | .19 | .17 |
| VBT | 34.3 | 34.3 | 27.0 | 25.2 | 30.6 | 31.6 | ||||
| Urinary urgency | ||||||||||
| EBRT | 22.4 | .33 | 39.4 | 26.3 | 31.9 | 32.3 | 34.3 | .005 | .015 | .02 |
| VBT | 23.3 | 24.6 | 28.0 | 27.3 | 30.2 | 28.3 | ||||
| Sleep deprivation because of US | ||||||||||
| EBRT | 14.4 | .07 | 20.0 | 13.1 | 16.7 | 13.4 | 13.2 | .009 | .05 | .10 |
| VBT | 16.3 | 13.8 | 10.9 | 13.9 | 13.2 | 15.4 | ||||
| Need to remain close to toilet | ||||||||||
| EBRT | 7.3 | .39 | 21.4 | 14.2 | 15.0 | 13.3 | 12.9 | .02 | < .001 | .42 |
| VBT | 7.1 | 8.7 | 7.0 | 7.3 | 8.4 | 7.9 | ||||
| Incontinence for urine | ||||||||||
| EBRT | 11.0 | .95 | 18.1 | 12.3 | 16.8 | 15.7 | 16.2 | .016 | .40 | .35 |
| VBT | 10.6 | 13.0 | 14.0 | 15.4 | 14.8 | 16.0 | ||||
| Dysuria | ||||||||||
| EBRT | 5.3 | .37 | 8.6 | 3.2 | 2.9 | 1.4 | 2.5 | < .0001 | .61 | .80 |
| VBT | 8.0 | 9.4 | 3.6 | 3.3 | 1.2 | 1.1 | ||||
| Limitation of daily activities because of US | ||||||||||
| EBRT | 3.4 | .54 | 8.6 | 5.2 | 7.0 | 5.1 | 8.3 | .005 | .85 | .88 |
| VBT | 3.1 | 5.4 | 4.4 | 3.8 | 4.9 | 6.2 | ||||
| Bowel symptoms | ||||||||||
| Limitation of daily activities because of BS | ||||||||||
| EBRT | 8.9 | .08 | 21.8 | 15.2 | 14.5 | 13.8 | 13.7 | < .001 | < .001 | .48 |
| VBT | 5.2 | 6.3 | 5.0 | 3.6 | 4.6 | 2.8 | ||||
| Fecal leakage | ||||||||||
| EBRT | 4.0 | .26 | 9.3 | 10.5 | 7.8 | 8.4 | 8.7 | .002 | < .001 | .12 |
| VBT | 1.5 | 3.8 | 2.3 | 2.2 | 3.6 | 1.7 | ||||
| Rectal blood loss | ||||||||||
| EBRT | 0.4 | .95 | 2.2 | 2.1 | 1.0 | 2.5 | 1.6 | .162 | .04 | .57 |
| VBT | 0.2 | 1.2 | 0.8 | 0.9 | 0.2 | 0.8 | ||||
| Bloated feeling | ||||||||||
| EBRT | 16.1 | .61 | 16.8 | 15.4 | 14.4 | 12.6 | 10.8 | .006 | .15 | .96 |
| VBT | 15.5 | 14.2 | 12.4 | 9.6 | 9.6 | 8.8 | ||||
NOTE. For functioning scales, a higher score indicates higher functioning; for symptom scales, a higher score indicates more symptoms.
Abbreviations: EORTC QLQ-C30, European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire C30; PR-25, prostate cancer module; RT, radiotherapy; EBRT, external-beam radiotherapy; VBT, vaginal brachytherapy; US, urinary symptoms; BS, bowel symptoms.
*P for baseline comparison; t test to compare means; Armitage trend test for single items.
Fig 2. Summary scores for symptom scales of European Organization for Research and Treatment of Cancer C30 questionnaire (EORTCQLQ-C30) and prostate cancer questionnaire module (PR-25). A higher score indicates more symptoms. Bars represent 99% CIs. For all figures, the vertical axis is in the lower-50% range. Scores correspond to summary scores listed in Table 3. BS, bowel symptoms; VBT, vaginal brachytherapy; EBRT, external-beam radiotherapy; RT, radiation therapy.
Fig 3. Patient responses on single-item symptom scales of diarrhea, fecal leakage, need to remain close to the toilet, and limitation in daily activities as a result of bowel symptoms. EBRT, external-beam radiotherapy; VBT, vaginal brachytherapy.
Patients treated with EBRT reported a 21% increase in mean diarrhea scores after radiotherapy compared with patients treated with VBT (30%, EBRT v 9%, VBT; P random assignment < .001). After EBRT, 15.4% and 7.3% of the patients reported quite a bit or very much diarrhea, respectively, whereas these rates were 2.8% and 2.8%, respectively, after VBT (Fig 3). Although diarrhea scores of patients in the EBRT group decreased, they remained at significantly higher levels with additional follow-up. Conversely, diarrhea scores in the VBT group remained low, at baseline level (P time < .001).
In addition, patients treated with EBRT reported an 8% increase in mean scores of fecal leakage 6 months after radiotherapy (10%, EBRT v 2%, VBT; P random assignment < .001), and scores remained stable with additional follow-up. Within the bowel symptom subscale, the item on limitations of daily activities because of bowel problems showed the largest difference (15%) between the treatment groups in favor of VBT (22%, EBRT v 6%, VBT; P random assignment < .001). Although there was a trend toward a higher level of urinary urgency after EBRT (P random assignment = .015), the same question on limitation of daily activities because of bladder problems did not show a significant difference. In fact, the only urinary symptom item that showed a significant difference between treatment groups, both after radiotherapy and with additional follow-up, was the question, “Have you had difficulty going out of the house because you needed to be close to a toilet?” This question, however, is not specific for urinary symptoms and could also be related to bowel symptoms.
Two general patterns of change in symptom scores over time could be distinguished (Fig 2.). In the first pattern, baseline symptom scores were high and decreased in the subsequent time points to reach a plateau around 12 months. Fatigue, nausea and vomiting, pain, appetite loss, and constipation are examples of this first pattern and are considered symptoms related to recovery from surgery. The second pattern is associated with radiotherapy, as baseline scores are low but increase significantly during and after radiotherapy before declining again (eg, bowel and urinary symptoms).
To our knowledge, PORTEC-2 is the first phase III, randomized, multicenter trial to compare the efficacy of VBT and EBRT to determine which treatment provides optimal local control with the least morbidity and best QOL for patients with high-intermediate risk endometrial cancer. In this first analysis of patient-reported QOL during the first 2 years after treatment, marked differences between the treatment groups were found.
Bowel symptoms, such as diarrhea and fecal leakage, were significantly increased after EBRT compared with VBT. Furthermore, patients treated with EBRT reported a significantly higher need to remain close to a toilet, which resulted in a higher level of limitation of daily activities because of bowel problems. Finally, social functioning after EBRT was at a significantly lower level than after VBT. These differences remained stable with additional follow-up.
Although higher fatigue rates among the patients who underwent EBRT were expected,13 a sharp decrease of fatigue rates during radiotherapy and during the first year after treatment in both groups was observed. The trend was toward less fatigue after VBT compared with EBRT (P = .06).
Reported late adverse effects of VBT include vaginal dryness with painful intercourse and tightening and/or shortening of the vagina.20–23 Little is known about the influence of these adverse effects on sexual functioning. Patients generally were more reluctant to respond to questions on this subject; 66% completed the questions on sexual activity. Nonetheless, 39% of these elderly women indicated they were sexually active at 6 months after surgery, which is in the range of results reported in elderly women.24 Other than to the significant increase in sexual activity in both treatment groups, there were no significant differences in sexual functioning or symptoms between the groups.
The observed increases in diarrhea scores (on QLQ-C30) and bowel symptoms (on PR-25) show the internal consistency of these main findings. The same is true for the lower levels of social functioning and increased limitation of daily activities reported by patients treated with EBRT. Increased bowel symptoms and diarrhea scores after EBRT are consistent with both clinical experience and the higher rates of gastrointestinal toxicity reported in the randomized trials.4,6 In the PORTEC-1 trial, the rate of grades 1 to 4 late toxicity for EBRT patients was 26%, of which 20% was gastrointestinal toxicity (grades 1 to 2, 17%; grades 3 to 4, 3%).4 Phase II studies of VBT reported low rates of gastrointestinal toxicity, which is consistent with the finding that symptom scores among the patients in the PORTEC-2 VBT arm remained at baseline level.20–23
Reference values of the Swedish and Danish norm-population for the EORTC QLQ-C30 show higher functioning scores and lower symptom rates as compared to the baseline scores for both EBRT and VBT groups.25,26 However, the plateau that occurred in most scores at 6 to 12 months after treatment is in the range of these reference values, which indicates that, for most women, the stressful period of diagnosis and treatment for endometrial cancer has a clear but transient influence on functioning. This observation is in concordance with the largest retrospective HRQOL study among patients with endometrial cancer at 5 to 10 years after treatment; in this study, scores of patients treated with and without EBRT were similar to those of an age-matched population, although scores on vitality and physical and social well-being were significantly lower when patients who received EBRT were compared with patients who had received no radiotherapy.13
When changes in QOL scores are interpreted, definition of a clinically relevant change in a score is important. Earlier studies on the magnitude of clinically relevant differences agree on a difference of 5% to 10% of the instrument range as clinically relevant.27–29 For the EORTC QLQ-C30, Osoba et al28 found that patients valued a change of 5% to 10% as little, 10% to 20% as moderate, and more than 20% as very much difference.28 For these results, this would mean that there was very much improvement in functioning scales in the first 6 months after surgery for both groups. Furthermore, patients treated with EBRT reported very much diarrhea and little symptoms of fecal leakage, whereas patients treated with VBT did not report an increase in these symptoms. In addition, patients treated with EBRT reported a moderate increase in the need to remain close the toilet because of bowel symptoms and limitation of daily activities. This resulted in little reduction of social functioning for patients who received EBRT.
In conclusion, patients who received EBRT reported significant and clinically relevant higher levels of diarrhea and fecal leakage. This resulted in a higher need to remain close to a toilet, more limitation of daily activities because of bowel symptoms, and decreased social functioning. VBT did not have this negative effect on HRQOL and can be regarded as the preferred treatment from an HRQOL perspective. This QOL benefit will have to be balanced against the outcome of the efficacy analysis. First results suggest that VBT is effective and should be regarded as the treatment of choice for patients with high- to intermediate-risk endometrial carcinoma.30
Written on behalf of the PORTEC-2 Study Group.
Supported by research Grant No. CKTO 2001-04 of the Dutch Cancer Society.
Presented in part at the 14th Biennial European Cancer Conference, September 23-27, 2007, Barcelona, Spain.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
Clinical Trials repository link available on JCO.org.
Clinical trial information can be found for the following: ISRCTN16228756.
The author(s) indicated no potential conflicts of interest.
Conception and design: Ina M. Jürgenliemk-Schulz, Jan J. Jobsen, Ludy C.H.W. Lutgens, Elzbieta M. van der Steen-Banasik, Annerie Slot, Marika C. Stenfert Kroese, Carien L. Creutzberg
Administrative support: Philine P. van den Tol
Provision of study materials or patients: Ina M. Jürgenliemk-Schulz, Jan J. Jobsen, Ludy C.H.W. Lutgens, Elzbieta M. van der Steen-Banasik, Jan Willem M. Mens, Annerie Slot, Marika C. Stenfert Kroese, Bart N.F.M. van Bunningen, Carien L. Creutzberg
Collection and assembly of data: Remi A. Nout, Ina M. Jürgenliemk-Schulz, Jan J. Jobsen, Ludy C.H.W. Lutgens, Elzbieta M. van der Steen-Banasik, Jan Willem M. Mens, Annerie Slot, Marika C. Stenfert Kroese, Bart N.F.M. van Bunningen, Vincent T.H.B.M. Smit, Philine P. van den Tol, Carien L. Creutzberg
Data analysis and interpretation: Remi A. Nout, Hein Putter
Manuscript writing: Remi A. Nout, Hein Putter, Carien L. Creutzberg
Final approval of manuscript: Remi A. Nout, Hein Putter, Ina M. Jürgenliemk-Schulz, Jan J. Jobsen, Ludy C.H.W. Lutgens, Elzbieta M. van der Steen-Banasik, Jan Willem M. Mens, Annerie Slot, Marika C. Stenfert Kroese, Bart N.F.M. van Bunningen, Vincent T.H.B.M. Smit, Hans W. Nijman, Philine P. van den Tol, Carien L. Creutzberg
| 1. | F Bray, AH Loos, M Oostindier , etal: Geographic and temporal variations in cancer of the corpus uteri: Incidence and mortality in pre- and postmenopausal women in Europe Int J Cancer 117: 123– 131,2005 Crossref, Medline, Google Scholar |
| 2. | J Aalders, V Abeler, P Kolstad , etal: Postoperative external irradiation and prognostic parameters in stage I endometrial carcinoma: Clinical and histopathologic study of 540 patients Obstet Gynecol 56: 419– 427,1980 Medline, Google Scholar |
| 3. | CL Creutzberg, WL van Putten, PC Koper , etal: Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: Multicentre randomised trial—PORTEC Study Group: Post Operative Radiation Therapy in Endometrial Carcinoma Lancet 355: 1404– 1411,2000 Crossref, Medline, Google Scholar |
| 4. | CL Creutzberg, WL van Putten, PC Koper , etal: The morbidity of treatment for patients with stage I endometrial cancer: Results from a randomized trial Int J Radiat Oncol Biol Phys 51: 1246– 1255,2001 Crossref, Medline, Google Scholar |
| 5. | J Orton, P Blake , etal: Adjuvant external-beam radiotherapy (EBRT) in the treatment of endometrial cancer: Results of the randomised MRC ASTEC and NCIC CTG EN 5 trial J Clin Oncol 25: 275s,2007 suppl abstr 5504 Google Scholar |
| 6. | HM Keys, JA Roberts, VL Brunetto , etal: A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: A Gynecologic Oncology Group study Gynecol Oncol 92: 744– 751,2004 Crossref, Medline, Google Scholar |
| 7. | AN Scholten, WL van Putten, H Beerman , etal: Postoperative radiotherapy for stage 1 endometrial carcinoma: Long-term outcome of the randomized PORTEC trial with central pathology review Int J Radiat Oncol Biol Phys 63: 834– 838,2005 Crossref, Medline, Google Scholar |
| 8. | S Bradley, S Rose, S Lutgendorf , etal: Quality of life and mental health in cervical and endometrial cancer survivors Gynecol Oncol 100: 479– 486,2006 Crossref, Medline, Google Scholar |
| 9. | A Bye, C Trope, JH Loge , etal: Health-related quality of life and occurrence of intestinal side effects after pelvic radiotherapy: Evaluation of long-term effects of diagnosis and treatment Acta Oncol 39: 173– 180,2000 Crossref, Medline, Google Scholar |
| 10. | M Klee, D Machin: Health-related quality of life of patients with endometrial cancer who are disease-free following external irradiation Acta Oncol 40: 816– 824,2001 Crossref, Medline, Google Scholar |
| 11. | C Li, G Samsioe, C Iosif: Quality of life in endometrial cancer survivors Maturitas 31: 227– 236,1999 Crossref, Medline, Google Scholar |
| 12. | L Zhu, T Le, D Popkin, O Olatunbosun: Quality-of-life analysis in the management of endometrial cancer Am J Obstet Gynecol 192: 1388– 1390,2005 Crossref, Medline, Google Scholar |
| 13. | LV van de Poll-Franse, F Mols, ML Essink-Bot , etal: Impact of external-beam adjuvant radiotherapy on health-related quality of life for long-term survivors of endometrial adenocarcinoma: A population-based study Int J Radiat Oncol Biol Phys 69: 125– 132,2007 Crossref, Medline, Google Scholar |
| 14. | JH Shepherd: Revised FIGO staging for gynaecological cancer Br J Obstet Gynaecol 96: 889– 892,1989 Crossref, Medline, Google Scholar |
| 15. | H Putter, M Fiocco, RB Geskus: Tutorial in biostatistics: Competing risks and multi-state models Stat Med 26: 2389– 2430,2007 Crossref, Medline, Google Scholar |
| 16. | NK Aaronson, S Ahmedzai, B Bergman , etal: The European Organization for Research and Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in oncology J Natl Cancer Inst 85: 365– 376,1993 Crossref, Medline, Google Scholar |
| 17. | NK Aaronson, G van Andel: An international field of the reliability and validity of the QLQ-C30 and a disease-specific questionnaire module (QLQ-PR25) for assessing quality of life of patients with prostate cancer: European Organization for Research and Treatment of Cancer study protocol (15011) 2002 EORTC Genitourinary Tract Cancer Group Brussels, Belgium European Organisation for Research and Treatment of Cancer Google Scholar |
| 18. | E Greimel, A Bottomley, A Cull , etal: An international field study of the reliability and validity of a disease-specific questionnaire module (the QLQ-OV28) in assessing the quality of life of patients with ovarian cancer Eur J Cancer 39: 1402– 1408,2003 Crossref, Medline, Google Scholar |
| 19. | PM Fayers, NK Aaronson, K Bjordal , etal: EORTC QLQ-C30 Scoring Manual 1999 ed 2 Brussels, Belgium European Organisation for Research and Treatment of Cancer Google Scholar |
| 20. | M Chadha, PJ Nanavati, P Liu , etal: Patterns of failure in endometrial carcinoma stage IB grade 3 and IC patients treated with postoperative vaginal vault brachytherapy Gynecol Oncol 75: 103– 107,1999 Crossref, Medline, Google Scholar |
| 21. | GH Eltabbakh, MS Piver, RE Hempling , etal: Excellent long-term survival and absence of vaginal recurrences in 332 patients with low-risk stage I endometrial adenocarcinoma treated with hysterectomy and vaginal brachytherapy without formal staging lymph node sampling: Report of a prospective trial Int J Radiat Oncol Biol Phys 38: 373– 380,1997 Crossref, Medline, Google Scholar |
| 22. | RG Pearcey, DG Petereit: Post-operative high dose rate brachytherapy in patients with low to intermediate risk endometrial cancer Radiother Oncol 56: 17– 22,2000 Crossref, Medline, Google Scholar |
| 23. | E Weiss, P Hirnle, H Arnold-Bofinger , etal: Adjuvant vaginal high-dose-rate afterloading alone in endometrial carcinoma: Patterns of relapse and side effects following low-dose therapy Gynecol Oncol 71: 72– 76,1998 Crossref, Medline, Google Scholar |
| 24. | ST Lindau, LP Schumm, EO Laumann , etal: A study of sexuality and health among older adults in the United States N Engl J Med 357: 762– 774,2007 Crossref, Medline, Google Scholar |
| 25. | M Klee, M Groenvold, D Machin: Quality of life of Danish women: Population-based norms of the EORTC QLQ-C30 Qual Life Res 6: 27– 34,1997 Crossref, Medline, Google Scholar |
| 26. | H Michelson, C Bolund, B Nilsson , etal: Health-related quality of life measured by the EORTC QLQ-C30: Reference values from a large sample of Swedish population Acta Oncol 39: 477– 484,2000 Crossref, Medline, Google Scholar |
| 27. | B Barrett, D Brown, M Mundt , etal: Sufficiently important difference: Expanding the framework of clinical significance Med Decis Making 25: 250– 261,2005 Crossref, Medline, Google Scholar |
| 28. | D Osoba, G Rodrigues, J Myles , etal: Interpreting the significance of changes in health-related quality-of-life scores J Clin Oncol 16: 139– 144,1998 Link, Google Scholar |
| 29. | J Ringash, B O'Sullivan, A Bezjak, DA Redelmeier: Interpreting clinically significant changes in patient-reported outcomes Cancer 110: 196– 202,2007 Crossref, Medline, Google Scholar |
| 30. | RA Nout, H Putter, IM Jürgenliemk-Schulz , etal: Vaginal brachytherapy versus external-beam pelvic radiotherapy for high-intermediate risk endometrial cancer: Results of the randomized PORTEC-2 trial J Clin Oncol 26: 293s,2008 suppl abstr LBA5503 Link, Google Scholar |
Acknowledgment
We thank the radiation oncologists, gynecologists, and data managers at the participating centers, and we thank the patients who greatly contributed by repeatedly filling in the questionnaires throughout the study years.
The following Radiation Oncology institutions participated in the Post Operative Radiation Therapy in Endometrial Cancer trial: University Medical Center Utrecht (I.M. Jürgenliemk-Schulz); Medisch Spectrum Twente, Enschede (J.J. Jobsen); MAASTricht Radiation Oncology Clinic, Maastricht (L.C.H.W. Lutgens); Arnhem Radiotherapy Institute, Arnhem (E.M. v.d. Steen–Banasik); Erasmus MC Rotterdam/Daniel den Hoed Cancer Center, Rotterdam (J.W.M. Mens); Leiden University Medical Center, Leiden (C.L. Creutzberg, R.A. Nout); Radiotherapy Institute Friesland, Leeuwarden (A. Slot); Radiotherapy Institute Stedendriehoek en Omstreken, Deventer (M.C. Stenfert Kroese); Netherlands Cancer Institute, Amsterdam (B.N.F.M. van Bunningen); Catharina Hospital, Eindhoven (M.L.M. Lybeert); University Medical Center Radboud, Nijmegen (J.W. Leer); Sophia Hospital, Zwolle (P.R. Timmer); VU Medical Center, Amsterdam (O.W.M. Meijer, B. van Triest); University Medical Center Groningen (B. Pras); Medical Centre Haaglanden, The Hague (R. Wiggenraad); Academic Medical Center, Amsterdam (L. Uitterhoeve); Haga Hospital, The Hague (P.C.M. Koper); R. de Graaf Hospital, Delft (J. Pomp); Zeeuwsch Radiotherapy Institute, Vlissingen (V.L.M. Coen).
