M.L.M. Lybeert

Radiotherapy for locoregional relapses of rectal carcinoma after initial radical surgery: definite but limited influence on relapse-free survival and survival

A group of 95 patients, treated with irradiation for relapse after radical surgery as only initial treatment modality for a rectal carcinoma was studied. The term locoregional relapse relates to evidence of tumor recurrent in the pelvis or the perineal area. Seventy-six patients presented with locoregional relapse only, and 19 patients presented with locoregional relapse and concomitant distant metastases. All patients were irradiated at the site of locoregional relapse. Total dose of irradiation was resp. 44 Gy median (range 6-66 Gy) and 40 Gy median (range 6-50 Gy). In the group of patients with locoregional relapse only, recurrence-free survival and survival after radiotherapy were, respectively, 23% and 61% at 1 year, and 6% and 13% at 3 years. In the group of patients with concomitant distant metastases, survival after radiotherapy was even worse, 33% at one year, and nihil at 3 years. Recurrences after radiotherapy occurred early during follow-up with 75% of the recurrences being recorded during the first year of follow-up. Recurrent or persistent disease inside the irradiation volume was the most important clinical problem in both groups, being documented in, respectively, 43/76 and 7/19 (7/13 if six patients were excluded with a survival of less than 3 months from onset of therapy). In the group of patients with locoregional relapse only, using recurrence-free survival as the endpoint, dose of irradiation (p = 0.01) was a significant multivariate prognostic factor and using survival as the endpoint, dose of irradiation (p = 0.005) and grade of tumor differentiation (p = 0.002) were significant. Potentials of current radiotherapy regimes are limited. Therefore, maximal initial treatment is warranted. In the event of a relapse after initial radical surgery, one should opt for either more aggressive standard therapy, or either new combined modalities approaches should be studied.

Endometrial carcinoma: high dose-rate brachytherapy in combination with external irradiation; a multivariate analysis of relapses

From June 1974 to June 1984, 347 women with endometrial carcinoma were referred to the radiotherapy department of the Catharina Hospital, Eindhoven, The Netherlands. Of this total number, 327 patients were considered eligible for analysis; 36 being referred for recurrences of previous surgically treated endometrial carcinoma, and 291 being referred for radiotherapy as part of the initial treatment. The 28% 5-year relapse-free survival (RFS) of the group of 36 patients demonstrated that endometrial carcinoma may behave as a radiosensitive tumour. The remaining 291 had all undergone surgery, except 10. Radiotherapy consisted of high dose-rate brachytherapy applied to the vaginal vault for pathological stage I tumours, well differentiated, and with superficial myometrial invasion. All other patients received external beam irradiation to a pelvic dose of 40 Gy in 4 weeks, followed by brachytherapy (4 fractions of 5 Gy each). The 5-year RFS for pathologically staged patients was: stage I (232 patients) 88%, stage II (27 patients) 68%, stage III and IV (22 patients) 50%. Treatment-related complications were minimal. In-field recurrences were rare: 5% locoregional, 2.2% both loco-regional and distant, versus 9.3% distant failures. Multivariate RFS analysis demonstrated age, stage and tumour differentiation as independent prognostic factors, tumour differentiation being the most important factor.

Postoperative radiotherapy for endometrial carcinoma stage I. Wide variation in referral patterns but no effect on long-term survival in a retrospective study in the southeast Netherlands

The aim of this study was to assess the referral pattern and the impact on long-term survival of postoperative radiotherapy in patients with adenocarcinoma of the endometrium stage I. This was a retrospective study performed in a regional cancer registry which covers a population of approximately 1,000,000 persons. All 724 patients registered between 1975 and 1992 in the Comprehensive Cancer Centre South, Eastern Section, The Netherlands, were analysed. All patients had received surgery as primary treatment which was performed in one of the seven community hospitals of the region. Radiotherapy was given in one regional department. All pathology reports were checked for data on tumour differentiation and myometrial invasion. Almost half the patients (45%) were referred for postoperative radiotherapy. The depth of myometrial invasion and the degree of tumour differentiation were the main factors (P < 0.0001) influencing referral for postoperative radiotherapy. The referral pattern varied between the different hospitals, but became more similar during 1985-1988, to diverge again in recent years. In patients younger than 60 years, the depth of myometrial invasion was significantly (P = 0.01) correlated with survival. In patients older than 60 years, tumour differentiation (P = 0.05) and age (P < 0.001) were correlated with survival, but not the depth of myometrial invasion. After adjustment for known prognostic factors, a survival benefit of postoperative radiotherapy could not be established. The studied group had an excess death rate over the normal Dutch female population. This excess death rate did not decrease during follow-up, as even after 10 years an excess death rate was found. A prospective randomised trial is ongoing in The Netherlands.

Brachytherapy after external beam radiotherapy and limited surgery preserves bladders for patients with solitary pT1-pT3 bladder tumors.

BACKGROUND Several French, Belgian and Dutch radiation oncologists have reported good results with the combination of limited surgery after external beam radiotherapy (EBRT) followed by brachytherapy in early-stage muscle-invasive bladder cancer. PATIENTS AND METHODS Data from 12 of 13 departments which are using this approach have been collected retrospectively, in a multicenter database, resulting in 1040 patients: 811 males and 229 females with a median age of 66 years, range 28-92 years. Results were analyzed according to tumor stage and diameter, histology grade, age and brachytherapy technique, continuous low-dose rate (CLDR) and pulsed dose rate (PDR). RESULTS At 1, 3 and 5 years, the local recurrence-free probability was 91%, 80% and 75%, metastasis-free probability was 91%, 80% and 74%, disease-free probability was 85%, 68% and 61% and overall survival probability was 91%, 74% and 62%, respectively. The differences in the outcome between the contributing departments were small. After multivariate analysis, the only factor influencing the local control rate was the brachytherapy technique. Toxicity consisted mainly of 24 fistula, 144 ulcers/necroses and 93 other types. CONCLUSIONS EBRT followed by brachytherapy, combined with limited surgery, offers excellent results in terms of bladder sparing for selected groups of patients suffering from bladder cancer.BACKGROUND Several French, Belgian and Dutch radiation oncologists have reported good results with the combination of limited surgery after external beam radiotherapy (EBRT) followed by brachytherapy in early-stage muscle-invasive bladder cancer. PATIENTS AND METHODS Data from 12 of 13 departments which are using this approach have been collected retrospectively, in a multicenter database, resulting in 1040 patients: 811 males and 229 females with a median age of 66 years, range 28-92 years. Results were analyzed according to tumor stage and diameter, histology grade, age and brachytherapy technique, continuous low-dose rate (CLDR) and pulsed dose rate (PDR). RESULTS At 1, 3 and 5 years, the local recurrence-free probability was 91%, 80% and 75%, metastasis-free probability was 91%, 80% and 74%, disease-free probability was 85%, 68% and 61% and overall survival probability was 91%, 74% and 62%, respectively. The differences in the outcome between the contributing departments were small. After multivariate analysis, the only factor influencing the local control rate was the brachytherapy technique. Toxicity consisted mainly of 24 fistula, 144 ulcers/necroses and 93 other types. CONCLUSIONS EBRT followed by brachytherapy, combined with limited surgery, offers excellent results in terms of bladder sparing for selected groups of patients suffering from bladder cancer.

Adjuvant postoperative radiotherapy for adenocarcinoma of the rectum and rectosigmoid. A retrospective analysis of locoregional control, survival, and prognostic factors on 178 patients.

Results arc presented of a retrospective study on 178 patients receiving adjuvant postoperative radiotherapy after curative surgery for adenocarcinoma of the rectum and rectosigmoid. Tumorstages according to Gunderson-Sosin were B2: 67, B3: 5, C1: 9, C2: 94, and C3: 3. Median total dosage was 50 Gy (range: 10–66 Gy), with a median dose per fraction of 2.0 Gy, 5 fractions per week. The censored overall 5-year survival rate was 42%, and 5-year disease-free survival rate was 37%. The respective rates for stage B2 patients (n = 67) were 59% and 53%, and for stage C2 patients (n = 94), 25% and 25%. Recurrences occurred in 89% within 3 years, 8% in the fourth, and 1% in the fifth year of follow-up. Five-year local relapse rates were 27% for the stage B2 tumors and 40% for the stage C2 tumors. For survival, stage (P = .006), grade (P = .02), fixation at surgery (P = .03), and gender (P = .03) were independent prognostic factors. With local relapse-free probability (LRFP) as endpoint, grade (P < .02) was an independent prognostic factor. Dose of radiation was not of prognostic significance, neither for survival (P = .63) nor for LRFP (P = .61). Since improvement should be made in locoregional control, initiatives are taken to start preoperative radiotherapy; furthermore, the key role of surgery is emphasized.

Primary gastric non-Hodgkin's lymphoma stage IE and IIE

The aim of this study was to evaluate retrospectively the different treatment approaches and outcome of patients with stage IE and IIE gastric non-Hodgkins lymphoma in a cancer registry. Between 1982 and 1992, the Comprehensive Cancer Centre South (CCCS), Eastern Section, The Netherlands, registered, in a population of 1 million people, a total of 81 cases of gastric lymphoma stage IE and IIE (43 men and 38 women). Median age was 69.7 years (range 30.4-88.1). According to the Working Formulation, the malignancy grade was: 9 low, 55 intermediate and 14 high. According to the MALT classification, the malignancy grade was: 38 low and 40 high. Grade was unknown in 3 patients. Patients received the following treatment modalities: surgery alone (n = 22), locoregional radiotherapy without (n = 12) or with (n = 13) surgery; or systemic chemotherapy alone (n = 10) or with radiotherapy and/or surgery (n = 18). No treatment was given or recorded in 6 patients. For stage IE, 5-year actuarial survival and relapse-free survival rates were, respectively, 76 and 64% in 18 patients who received only surgery; 70 and 67% in 17 patients given locoregional treatment (radiotherapy with or without surgery), and 76 and 62% in 13 patients given systemic treatment (chemotherapy alone or with radiotherapy and/or surgery). Radiotherapy as sole treatment seemed to be as effective as other treatment modalities in achieving local and abdominal control. For stage IIE, none of the 4 patients who were treated with surgery alone survived 5 years. The 5-year actuarial survival and relapse-free survival rates of 8 patients who received radiotherapy with or without surgery were, respectively, 25 and 17% and 49 and 33%, for 14 patients given systemic therapy (chemotherapy alone and/or radiotherapy/surgery). In stage IIE, local, abdominal as well as distant relapse were more common, irrespective of treatment modality. In the multivariate analyses, stage (P = 0.002), grade (P = 0.02), age (P = 0.04) and gender (P = 0.04) were significant prognostic factors. This report on a limited number of patients shows that the outcome of patients with stage IIE gastric lymphoma is much worse than for patients with stage IE. Grade, age, gender and particularly stage are much stronger indicators for survival than different modes of treatment. Systemic therapy might improve outcome for stage IIE, but not for stage IE, for which radiotherapy alone seems a good option.

Low-dose total body irradiation in non-Hodgkin lymphoma: short- and long-term toxicity and prognostic factor.

The toxicity of low-dose total body irradiation (LTBI), the prognostic factors related to survival and relapse-free survival, and the efficacy of treatment given for relapse after LTBI were analyzed in 68 patients with non-Hodgkin lymphoma (NHL) treated at the Rotterdamsch Radiotherapeutisch Institute. All patients received LTBI between 1973 and 1979. The patient material was heterogeneous with respect to malignancy grade, stage, age, and therapy given before or after LTBI; the unifying principle was that all patients received LTBI and had symptomatic NHL. Analysis of prognostic variables with Coxs model revealed grade (p < 0.001) and age (p = 0.004) as predictors for survival and grade (p < 0.001) and dose of LTBI (p = 0.056) as predictors for relapse-free survival after LTBI. No subjective toxicity was observed during or after LTBI treatment. Hematologic toxicity was dose-limiting and was increased if patients had received cytotoxic treatment before LTBI. LTBI-related hematologic toxicity was lower in patients with low-grade NHL than in those with intermediate or high-grade NHL, was limited in time, and recovered in all patients. Patients relapsing after LTBI received a variety of therapies. Response rates were high, but of short duration, especially in intermediate or high-grade NHL. Duration of response was progressively shorter after multiple relapses.

Age as a prognostic factor in carcinoma of the cervix

To investigate whether age is a prognostic factor in patients with carcinoma of the cervix, a retrospective study was undertaken of 261 patients, aged 45 years or less, who were referred to the Rotterdamsch Radio-Therapeutisch Instituut (RRTI) between 1973 and 1982. Patients were referred for either primary treatment--surgery or radiotherapy--or for adjuvant radiotherapy. Overall 5-year survival figures were rather low, which may be explained by negative patient selection as the RRTI is a referral hospital: stage IB, 72%; stage IIA; 61%; stage IIB; 52%; stage III; 29%. A particular poor survival was noted for patients (n = 22) aged 28 or less. Overall 5-year survival of these patients was only 39% in contrast to 67% 5-year survival of older patients. This difference was highly significant (p less than 0.002). Even if corrected for stage, very young patients had a poorer prognosis (stage IB: 45% versus 75% 5-year survival of older patients). Within the older age group, no trend towards a better prognosis with increasing age could be identified. As a treatment was similar for all patients, no explanation is available for this observation.

Multicenter cohort study on treatment results and risk factors in stage II endometrial carcinoma.

The aim of this study was to report outcome data and prognostic factors from a large cohort of pathologic stage II endometrioid type endometrial carcinoma. One hundred forty-two stage IIA–B patients were included. A central histopathologic review was performed. Follow-up ranged from 2 to 217 months with a median of 61 months. End points of the study were local and locoregional recurrence rates, distant metastasis–free survival (DMFS), disease-free survival (DFS), and disease-specific survival (DSS). The local failure rate was 5.1% for stage IIA patients and 10.8% for stage IIB patients. Grade was the only significant prognostic factor for local failure. With respect to DMFS, DFS, and DSS, grade 3 showed to be the most prominent prognostic factor in multivariate analyses. Lymphvascular space involvement combined with grades 3 and 2 and myometrial invasion greater than 0.5 also showed to be significant for DMFS and DFS. Our study showed grade 3 to be the most important single independent predictive factor for locoregional and distant recurrences in endometrial carcinoma stage II

The morbidity of treatment for patients with stage I endometrial cancer: results from a randomized trial

Purpose: To compare the treatment complications for patients with Stage I endometrial cancer treated with surgery and pelvic radiotherapy (RT) or surgery alone in a multicenter randomized trial. Methods and Materials: The Postoperative Radiation Therapy in Endometrial Carcinoma (PORTEC) trial included patients with endometrial cancer confined to the uterine corpus, either Grade 1 or 2 with more than 50% myometrial invasion, or Grade 2 or 3 with less than 50% myometrial invasion. Surgery consisted of an abdominal hysterectomy and oophorectomy, without lymphadenectomy. After surgery, patients were randomized to receive pelvic RT (46 Gy), or no further treatment. A total of 715 patients were randomized. Treatment complications were graded using the French‐Italian glossary. Results: The analysis was done at a median follow-up duration of 60 months. 691 patients were evaluable. Five-year actuarial rates of late complications (Grades 1‐ 4) were 26% in the RT group and 4% in the control group (p < 0.0001). Most were Grade 1 complications, with 5-year rates of 17% in the RT group and 4% in the control group. All severe (Grade 3‐ 4) complications were observed in the RT group (3%). Most complications were of the gastrointestinal tract. The symptoms resolved after some years in 50% of the patients. Grade 1‐2 genitourinary complications occurred in 8% of the RT patients, and 4% of the controls. Bone complications occurred in 4 RT patients (1%). Seven patients (2%) discontinued their RT due to acute RT-related symptoms. Patients with acute morbidity had an increased risk of late RT complications (p 0.001). The 4-field box technique was associated with a lower risk of late complications (p 0.06). Conclusion: Pelvic RT increases the morbidity of treatment in Stage I endometrial cancer. In the PORTEC trial, severe complications occurred in 3% of treated patients, and over 20% experienced mild (mostly Grade 1) symptoms. Patients with acute RT-related morbidity had an increased risk of late complications. As pelvic RT in Stage I endometrial carcinoma was shown to significantly reduce the rate of locoregional recurrence, but without a survival benefit, its use in the adjuvant setting requires careful patient selection (treating those at increased risk of relapse), and the use of treatment schemes with the lowest risk of morbidity.