Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial.

BACKGROUND: After surgery for intermediate-risk endometrial carcinoma, the vagina is the most frequent site of recurrence. This study established whether vaginal brachytherapy (VBT) is as effective as pelvic external beam radiotherapy (EBRT) in prevention of vaginal recurrence, with fewer adverse effects and improved quality of life. METHODS: In this open-label, non-inferiority, randomised trial undertaken in 19 Dutch radiation oncology centres, 427 patients with stage I or IIA endometrial carcinoma with features of high-intermediate risk were randomly assigned by a computer-generated, biased coin minimisation procedure to pelvic EBRT (46 Gy in 23 fractions; n=214) or VBT (21 Gy high-dose rate in three fractions, or 30 Gy low-dose rate; n=213). All investigators were masked to the assignment of treatment group. The primary endpoint was vaginal recurrence. The predefined non-inferiority margin was an absolute difference of 6% in vaginal recurrence. Analysis was by intention to treat, with competing risk methods. The study is registered, number ISRCTN16228756. FINDINGS: At median follow-up of 45 months (range 18-78), three vaginal recurrences had been diagnosed after VBT and four after EBRT. Estimated 5-year rates of vaginal recurrence were 1.8% (95% CI 0.6-5.9) for VBT and 1.6% (0.5-4.9) for EBRT (hazard ratio [HR] 0.78, 95% CI 0.17-3.49; p=0.74). 5-year rates of locoregional relapse (vaginal or pelvic recurrence, or both) were 5.1% (2.8-9.6) for VBT and 2.1% (0.8-5.8) for EBRT (HR 2.08, 0.71-6.09; p=0.17). 1.5% (0.5-4.5) versus 0.5% (0.1-3.4) of patients presented with isolated pelvic recurrence (HR 3.10, 0.32-29.9; p=0.30), and rates of distant metastases were similar (8.3% [5.1-13.4] vs 5.7% [3.3-9.9]; HR 1.32, 0.63-2.74; p=0.46). We recorded no differences in overall (84.8% [95% CI 79.3-90.3] vs 79.6% [71.2-88.0]; HR 1.17, 0.69-1.98; p=0.57) or disease-free survival (82.7% [76.9-88.6] vs 78.1% [69.7-86.5]; HR 1.09, 0.66-1.78; p=0.74). Rates of acute grade 1-2 gastrointestinal toxicity were significantly lower in the VBT group than in the EBRT group at completion of radiotherapy (12.6% [27/215] vs 53.8% [112/208]). INTERPRETATION: VBT is effective in ensuring vaginal control, with fewer gastrointestinal toxic effects than with EBRT. VBT should be the adjuvant treatment of choice for patients with endometrial carcinoma of high-intermediate risk. FUNDING: Dutch Cancer Society.

Comparison of dose-volume histograms and dose-wall histograms of the rectum of patients treated with intracavitary brachytherapy.

The correlation between dose values from dose-volume histograms (DVHs) and dose values from dose-wall histograms (DWHs) of the rectum tissue of patient with uterine cervix cancer was determined. The minimum dose in 2 cm3 in the high-dose region of the DVH is a good estimate of the dose in the rectum wall.

Inter-observer variation in delineation of bladder and rectum contours for brachytherapy of cervical cancer.

BACKGROUND AND PURPOSE: In 3D treatment planning of low dose rate brachytherapy of cervical carcinoma the dose in bladder and rectum can be estimated from dose-volume histograms (DVHs). In this study, the influence of inter-observer variation in delineation of bladder and rectum on DVHs and dose at specific bladder and rectum points was investigated. MATERIALS AND METHODS: Three observers delineated bladder and rectum on axial CT images of ten patients. The highest minimum dose in bladder and rectum was determined for, respectively, 2 cm(3) (D(2)) and 5 cm(3) (D(5)), as well as the dose at specific points placed on the bladder and rectum wall. RESULTS: The inter-observer variation in D(2) was 10% (1 average relative SD) in bladder and 11% (1 SD) in rectum. In D(5) the variation was 8% (1 SD) in bladder and 11% in rectum. The variation in the bladder point was 13% (1 SD) and in the rectum point 11% (1 SD). Differences in delineation among the observers were caused by unclear organ boundaries on the CT images. CONCLUSIONS: Taking the inter-observer variation caused by delineation differences into account, dose in bladder and rectum can be determined within an accuracy of about 10% (1 SD).

The use of a transverse CT image for the estimation of the dose given to the rectum in intracavitary brachytherapy for carcinoma of the cervix.

BACKGROUND AND PURPOSE: The three-dimensional (3D) dose distribution in combination with 3D anatomy of 13 patients treated for cervical carcinoma with intracavitary brachytherapy was analyzed. The aim of this study was to determine the correlation between a dose value obtained from the integral dose volume histogram (DVH) of the rectum and (a) the Nederlands Kanker Instituut (NKI) point of reference for the rectum dose (R) and (b) the highest dose to the frontal rectum wall in the transverse CT slice near the top of the vagina through point R. RESULTS: The correlation between the DVH rectum dose value for 2 cm3 in the highest dose region and the rectum dose at point R was poor (regression coefficient 0.50). On the contrary, however, the correlation between the DVH rectum dose value for 2 cm3 in the highest dose region and the maximum rectum dose value in a transverse CT slice through point R was good (regression coefficient 0.90). CONCLUSIONS: The maximal rectum dose value obtained from a transverse CT slice near the top of the vagina through point R was found to be a more representative point for the rectal dose burden and might therefore show a good correlation with complications. The point of reference for the rectal dose (R) was found not to be a reliable estimation of the maximal dose in the rectum.

Cyfra 21-1 in monitoring cervical cancer: a comparison with tissue polypeptide antigen and squamous cell carcinoma antigen.

Cyfra 21-1, measuring serum fragments of cytokeratin 19, has been found to be related to tumor stage and tumour size in patients with cervical cancer and suggested to be a promising marker in squamous lung cancer. We compared the value of this new marker with tissue polypeptide antigen (TPA) and squamous cell carcinoma antigen (SCC-Ag) in monitoring 30 patients with squamous cell cervical cancer. Serum levels of each marker were studied in relation to tumour stage and clinical status of patient. The clinical performance of the various assays to separate those patients with complete remission from those patients with the presence of tumour (i.e., partial remission, stable disease, or progressive disease) was assessed by their receiver operating characteristic (ROC) curves. We found that tumour stage was a prognostic factor for survival (p = 0.02). Pretreatment serum Cyfra 21-1, TPA, and SCC-Ag levels were not related to stage of disease and were not found to be predictive of survival. In contrast, an elevated post-treatment serum SCC-Ag level was associated with a poor survival rate (p = 0.03). Such a relation was not found for Cyfra 21-1 or TPA. The clinical performance of post-treatment serum SCC-Ag levels in predicting the presence of tumour was better than the Cyfra 21-1 or TPA assays. This is shown by the left uppermost position of the ROC curve for SCC-Ag. We concluded that SCC-Ag appeared to be a better parameter than Cyfra 21-1 and TPA in predicting the presence of tumour during follow-up and survival of patients with cervical cancer.

Ewing's sarcoma of the pelvis: changes over 25 years in treatment and results.

The pelvic localisations of Ewing's sarcoma have the worst prognosis due to large size at diagnosis, frequent distant metastases, radiosensitive organs next to the tumour and difficult surgery. The purpose of the present study was to analyse treatment results over a period of 25 years and to investigate the impact of newer chemotherapy schedules, improved radiotherapy techniques and newer surgical methods on the prognosis. 35 children and young adults were identified from 1967 to 1994 for whom diagnosis, presentation, performed treatment and outcome were available. Tumour size, as measured from CT scans, response to chemotherapy and radiotherapy target volume, could be reviewed in the later years. Actuarial 5-year survival for the whole group was 31% and for the 24 non-metastatic patients 40%, with a disease-free interval of 19%. Tumour size could be measured in 27 patients and ranged from 36 to 1540 cm3. There were 12 local recurrences, 1 in the 4 patients treated with surgery. After 1983, 9 out of 17 irradiated patients developed local failure. 3 patients had adequate fields and one a close field which did not cover completely the prechemotherapy extent and 3 of these recurred. All 4 patients with stable disease after neoadjuvant CT failed locally, not withstanding high-dose radiotherapy. The mean length of neoadjuvant CT tended to be shorter in patients without local relapse. There was no significant difference in survival before and after 1983.

Carcinoma of the uterine cervix stage IB and IIA: results of postoperative irradiation in patients with microscopic infiltration in the parametrium and/or lymph node metastasis.

One hundred and thirty-two patients received postoperative radiation therapy following radical hysterectomy and pelvic lymphadenectomy for carcinoma of the uterine cervix Stage IB and IIA. In 43 patients with negative lymph node the 5- and 10-year survival rate was 85%. The other 89 patients with positive lymph node had 5- and 10-year survival rates of 60% and 51%, respectively. Multifactorial analysis of prognostic factors in the group of patients with lymph node metastasis disclosed pathology, microscopic infiltration in the parametrium and vascular space invasion as independent prognostic factors, that is, the 5-year survival rates were: 66% for squamous cell carcinomas versus, 25% for adenocarcinomas (p value: 0.001), 76% negative parametrium versus 39% positive parametrium (p value: 0.008), 68% no vascular space invasion versus 43% if invasion was observed (p value: 0.04). Sites of failure in 37 recurrences out of 89 patients with lymph node metastasis were pelvic alone 9, distant metastases alone 15, and combined pelvic plus distant metastasis in 12 patients. In one patient the site of failure was unknown. These data warrant more intensive local and systemic treatment, particularly in patients with poor prognostic factors. In the whole group, severe complications were observed in 11 patients.

Surgical repair of radiation damage of the rectum: a systematic approach to a difficult problem.

Twenty-three patients with serious irradiation damage of the rectum underwent surgical treatment. Patients were classified according to the level of the lesion and the presence of stenosis. Patients with high lesions (Type I) (n = 5), were treated by resection with end to end anastomosis. Patients with low lesions, with stenosis (Type II) (n = 6), were treated by resection with descending colon flap repair. Patients with low lesions, without stenosis (Type III) (n = 7) were treated by gracilis muscle repair. The remaining patients (n = 5) with miscellaneous, often complex problems (Type IV) were treated by a variety of techniques. Results in Type I, II, and III patients were encouraging with 80% of the reconstructed patients obtaining normal faecal continence.

Total abdominal irradiation in stage I and II carcinoma of the ovary.

In the period from 1981 to 1986, 85 patients with ovarian carcinoma stage I and II were treated in a prospective study. All patients underwent primary surgery: bilateral salpingo-oophorectomy, hysterectomy and omentectomy followed by a staging procedure. In 46 patients, the staging was completed by a retroperitoneal lymph-node dissection, whereas in 39 patients, this procedure was omitted. Total abdominal irradiation (25 Gy/1.50 Gy per fraction) was followed by a pelvic boost dose (25 Gy/1.75 Gy per fraction). Patients with stage I and IIa well differentiated tumours received no adjuvant radiotherapy and are not reported here. The 5-year actuarial recurrence-free survival rate for the irradiated group was 75%. Stage according to FIGO appeared to be of significant prognostic influence. There was no difference in survival between completely and incompletely staged patients. Serious (small) bowel complications occurred however in 6 out of 45 patients who had undergone complete staging.

Treatment of Hodgkin's disease in children with or without radiotherapy.

From 1975 until 1984 37 children with newly diagnosed Hodgkin's disease were treated with six mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) courses with or without involved field radiotherapy (25 Gy) independent of the stage of their disease. Patients with small lymph node tumors (less than 4 cm) received only six MOPP-courses. Patients with large lymph node tumors (greater than 4 cm) received involved field radiotherapy, 25 Gy to the large tumor masses, between the third and fourth MOPP-course. For the 21 patients with "small" tumors, the disease-free survival (DFS) rate is 90%. In this group two patients with clinical stage (CS) III disease have relapsed but both are alive after successful salvage treatment. The median follow-up time is 69.7+ months. For the 16 patients with larger tumor masses (greater than 4 cm) the DFS rate is 87.5%. In this group one patient with CS II relapsed and died of Hodgkin's disease, and one with CS III relapsed after 37 months, but is now without evidence of disease, 61 months from diagnosis. The median follow-up time is 62+ months. Most of the children with Hodgkin's disease diagnosed before or during puberty can be cured with chemotherapy alone, and thus will not suffer from the damaging late effects of radiotherapy.