Alfons C.M. van den Bergh

Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial

BACKGROUND Postoperative radiotherapy for International Federation of Gynaecology and Obstetrics (FIGO) stage-1 endometrial carcinoma is a subject of controversy due to the low relapse rate and the lack of data from randomised trials. We did a multicentre prospective randomised trial to find whether postoperative pelvic radiotherapy improves locoregional control and survival for patients with stage-1 endometrial carcinoma. METHODS Patients with stage-1 endometrial carcinoma (grade 1 with deep [> or =50%] myometrial invasion, grade 2 with any invasion, or grade 3 with superficial [<50%] invasion) were enrolled. After total abdominal hysterectomy and bilateral salpingo-oophorectomy, without lymphadenectomy, 715 patients from 19 radiation oncology centres were randomised to pelvic radiotherapy (46 Gy) or no further treatment. The primary study endpoints were locoregional recurrence and death, with treatment-related morbidity and survival after relapse as secondary endpoints. FINDINGS Analysis was done according to the intention-to-treat principle. Of the 715 patients, 714 could be evaluated. The median duration of follow-up was 52 months. 5-year actuarial locoregional recurrence rates were 4% in the radiotherapy group and 14% in the control group (p<0.001). Actuarial 5-year overall survival rates were similar in the two groups: 81% (radiotherapy) and 85% (controls), p=0.31. Endometrial-cancer-related death rates were 9% in the radiotherapy group and 6% in the control group (p=0.37). Treatment-related complications occurred in 25% of radiotherapy patients, and in 6% of the controls (p<0.0001). Two-thirds of the complications were grade 1. Grade 3-4 complications were seen in eight patients, of which seven were in the radiotherapy group (2%). 2-year survival after vaginal recurrence was 79%, in contrast to 21% after pelvic recurrence or distant metastases. Survival after relapse was significantly (p=0.02) better for patients in the control group. Multivariate analysis showed that for locoregional recurrence, radiotherapy and age below 60 years were significant favourable prognostic factors. INTERPRETATION Postoperative radiotherapy in stage-1 endometrial carcinoma reduces locoregional recurrence but has no impact on overall survival. Radiotherapy increases treatment-related morbidity. Postoperative radiotherapy is not indicated in patients with stage-1 endometrial carcinoma below 60 years and patients with grade-2 tumours with superficial invasion.

Survival after relapse in patients with endometrial cancer: results from a randomized trial☆

OBJECTIVE The aim of this study was to determine the rates of local control and survival after relapse in patients with stage I endometrial cancer treated in the multicenter randomized PORTEC trial. METHODS The PORTEC trial included 715 patients with stage 1 endometrial cancer, either grade 1 or 2 with deep (>50%) myometrial invasion or grade 2 or 3 with <50% invasion. In all cases an abdominal hysterectomy was performed, without lymphadenectomy. After surgery, patients were randomized to receive pelvic RT (46 Gy) or no further treatment. RESULTS The analysis was done by intention-to-treat. A total of 714 patients were evaluated. At a median follow-up of 73 months, 8-year actuarial locoregional recurrence rates were 4% in the RT group and 15% in the control group (P < 0.0001). The 8-year actuarial overall survival rates were 71 (RT group) and 77% (control group, P = 0.18). Eight-year rates of distant metastases were 10 and 6% (P = 0.20). The majority of the locoregional relapses were located in the vagina, mainly in the vaginal vault. Of the 39 patients with isolated vaginal relapse, 35 (87%) were treated with curative intent, usually with external RT and brachytherapy, and surgery in some. A complete remission (CR) was obtained in 31 of the 35 patients (89%), and 24 patients (77%) were still in CR after further follow-up. Five patients subsequently developed distant metastases, and 2 had a second vaginal recurrence. The 3-year survival after first relapse was 51% for patients in the control group and 19% in the RT group (P = 0.004). The 3-year survival after vaginal relapse was 73%, in contrast to 8 and 14% after pelvic and distant relapse (P < 0.001). At 5 years, the survival after vaginal relapse was 65% in the control group compared to 43% in the RT group. CONCLUSION Survival after relapse was significantly better in the patient group without previous RT. Treatment for vaginal relapse was effective, with 89% CR and 65% 5-year survival in the control group, while there was no difference in survival between patients with pelvic relapse and those with distant metastases. As pelvic RT was shown to improve locoregional control significantly, but without a survival benefit, its use should be limited to those patients at sufficiently high risk (15% or over) for recurrence in order to maximize local control and relapse-free survival.

Outcome of High-Risk Stage IC, Grade 3, Compared With Stage I Endometrial Carcinoma Patients: The Postoperative Radiation Therapy in Endometrial Carcinoma Trial

PURPOSE Stage IC, grade 3 endometrial cancer is regarded as a high-risk category. Stage IC, grade 3 patients were not eligible for the randomized Postoperative Radiation Therapy in Endometrial Carcinoma (PORTEC) trial, but were registered and received postoperative radiotherapy. PATIENTS AND METHODS The PORTEC trial included 715 patients with stage IC, grade 1 or 2, and stage IB, grade 2 or 3 endometrial cancer. Patients were randomly assigned after surgery to receive pelvic radiotherapy (RT) or no further treatment. A total of 104 patients with stage IC, grade 3 endometrial cancer were registered, of whom 99 could be evaluated. Patterns of relapse and survival were compared with PORTEC patients receiving RT. Median follow-up was 83 months. RESULTS The actuarial 5-year rates of locoregional relapse were 1% to 3% for PORTEC patients who received RT, compared with 14% for stage IC, grade 3 patients. Five-year distant metastases rates were 3% to 8% for grade 1 and 2 tumors; 20% for stage IB, grade 3 tumors; and 31% for stage IC, grade 3 tumors. Overall survival rates were 83% to 85% for grades 1 and 2; 74% for stage IB, grade 3; and 58% for stage IC, grade 3 patients (P <.001). In multivariate analysis grade 3 was the most important adverse prognostic factor for relapse and death as a result of endometrial cancer (hazard ratios, 5.4 and 5.5; P <.0001). CONCLUSION Patients with stage IC, grade 3 endometrial carcinoma are at high risk of early distant spread and endometrial carcinoma-related death. Novel strategies for adjuvant therapy should be explored to improve survival for this patient group.

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.

Quality assurance in the 22991 EORTC ROG trial in localized prostate cancer: Dummy run and individual case review

INTRODUCTION EORTC trial 22991 was designed to evaluate the addition of concomitant and adjuvant short-term hormonal treatments to curative radiotherapy in terms of disease-free survival for patients with intermediate risk localized prostate cancer. In order to assess the compliance to the 3D conformal radiotherapy protocol guidelines, all participating centres were requested to participate in a dummy run procedure. An individual case review was performed for the largest recruiting centres as well. MATERIALS AND METHODS CT-data of an eligible prostate cancer patient were sent to 30 centres including a description of the clinical case. The investigator was requested to delineate the volumes of interest and to perform treatment planning according to the protocol. Thereafter, the investigators of the 12 most actively recruiting centres were requested to provide data on five randomly selected patients for an individual case review. RESULTS Volume delineation varied significantly between investigators. Dose constraints for organs at risk (rectum, bladder, hips) were difficult to meet. In the individual case review, no major protocol deviations were observed, but a number of dose reporting problems were documented for centres using IMRT. CONCLUSIONS Overall, results of this quality assurance program were satisfactory. The efficacy of the combination of a dummy run procedure with an individual case review is confirmed in this study, as none of the evaluated patient files harboured a major protocol deviation. Quality assurance remains a very important tool in radiotherapy to increase the reliability of the trial results. Special attention should be given when designing quality assurance programs for more complex irradiation techniques.

Cognitive functioning in patients treated for nonfunctioning pituitary macroadenoma and the effects of pituitary radiotherapy

Context and objective  Cognitive deterioration is reported in patients with a nonfunctioning pituitary macroadenoma (NFA) and after pituitary radiotherapy. However, reported results are inconsistent and are potentially confounded by different underlying pituitary disorders. The aim of this study was to examine cognitive functions in patients previously treated for NFA with or without radiotherapy.

Radiation optic neuropathy after external beam radiation therapy for acromegaly.

Acromegaly is an uncommon disease, mostly caused by a growth hormone (GH)-secreting pituitary adenoma. Its incidence has been estimated at 2.8–6 cases per million and its prevalence at 38–68 cases per million [2,10,64]. A GH-secreting pituitary adenoma does not only lead to clinical signs and symptoms, like acral enlargement and soft tissue swelling, but may also be accompanied by visual field defects and acuity loss caused by tumour compression on the optic nerves or chiasm, often seen in combination with pituitary hormone insufficiencies. Surgery, drug therapy with somatostatin analogs and external beam radiation therapy are currently the available treatment options [61]. External beam radiation therapy is available since the beginning of the 20th century [12,35]. It became clear, however, that radiation therapy alone often results in insufficient biochemical control, which means a decline but not a normalisation of GH hypersecretion [3,4, 24,29,56]. Consequently, surgery became the initial treatment of choice. According to some experts drug therapy may be the first treatment of choice for selected patients [61]. Postoperative radiation therapy is performed in many centres to reduce the postoperative time span of medical treatment, to normalise remaining GH hypersecretion, and to prevent regrowth of residual tumour [75]. Radiation optic neuropathy (RON) was for the first time reported by Forrest et al. in 1956 [30]. They defined RON as a sudden and profound irreversible vision loss due to damage of the optic nerves or damage of the chiasm caused by radiation therapy. Kline et al. and Parsons et al. defined the following criteria for diagnosing RON [49,65]: (a) irreversible visual loss with visual field defects, indicating optic nerve or chiasmal dysfunction; (b) absence of visual pathway compression due to recurrence or progression of tumour, radiation-induced neoplasm, arachnoidal adhesions around the chiasm, radiation retinopathy or any other apparent ophthalmological disease; (c) absence of optic disc edema and (d) optic atrophy within 6–8 weeks after onset of symptoms. In the past decades many reports on RON have appeared in the literature. The last review of RON in acromegaly was published by Eastman et al. in 1992 [25]. The radiation dose level for the occurrence of RON is not known. Moreover the dose–response relationship for RON has not been firmly established due to the small numbers of events in most series [46,65]. It has been suggested that the maximal steepness of the sigmoid dose–response curve for RON is between 50 and 60 Gy [46,65]. The occurrence of RON after doses as low as 45–50 Gy administered in fractions of 1.67–2 Gy seems to be a problem unique to patients with pituitary tumours, and probably reflects pre-existing optic nerve and chiasm compression and vascular compromise secondary to a mass effect or due to surgery [46,65]. Some authors propose that the optic system in acromegalic patients might be more sensitive to radiation damage compared to patients irradiated for non-functioning pituitary adenomas [5,6,13,39]. This may be caused by vascular and hormonal changes in relation to acromegaly [5], but this opinion is not uniformly accepted [23,25].

Normal tissue complication probability (NTCP) models for late rectal bleeding, stool frequency and fecal incontinence after radiotherapy in prostate cancer patients.

BACKGROUND AND PURPOSE Curative radiotherapy for prostate cancer may lead to anorectal side effects, including rectal bleeding, fecal incontinence, increased stool frequency and rectal pain. The main objective of this study was to develop multivariable NTCP models for these side effects. MATERIAL AND METHODS The study sample was composed of 262 patients with localized or locally advanced prostate cancer (stage T1-3). Anorectal toxicity was prospectively assessed using a standardized follow-up program. Different anatomical subregions within and around the anorectum were delineated. A LASSO logistic regression analysis was used to analyze dose volume effects on toxicity. RESULTS In the univariable analysis, rectal bleeding, increase in stool frequency and fecal incontinence were significantly associated with a large number of dosimetric parameters. The collinearity between these predictors was high (VIF>5). In the multivariable model, rectal bleeding was associated with the anorectum (V70) and anticoagulant use, fecal incontinence was associated with the external sphincter (V15) and the iliococcygeal muscle (V55). Finally, increase in stool frequency was associated with the iliococcygeal muscle (V45) and the levator ani (V40). No significant associations were found for rectal pain. CONCLUSIONS Different anorectal side effects are associated with different anatomical substructures within and around the anorectum. The dosimetric variables associated with these side effects can be used to optimize radiotherapy treatment planning aiming at prevention of specific side effects and to estimate the benefit of new radiation technologies.

The impact of gastrointestinal and genitourinary toxicity on health related quality of life among irradiated prostate cancer patients

PURPOSE To determine the impact of late radiation-induced toxicity on health-related quality of life (HRQoL) among patients with prostate cancer. PATIENTS AND METHODS The study sample was composed of 227 patients, treated with external beam radiotherapy. Common Terminology Criteria for Adverse Events version 3.0 were used to grade late genitourinary and gastrointestinal toxicity. The European Organization for Research and Treatment of Cancer Quality of life Questionnaire C30 (EORTC QLQ-C30) was used to assess HRQoL at baseline, and 6, 12 and 24 months after completion of radiotherapy. Statistical analysis was performed using a multivariate analysis of variance (MANOVA). RESULTS Urinary incontinence and rectal discomfort significantly affected HRQoL. The impact of urinary incontinence on HRQoL was most pronounced 6 months after radiotherapy and gradually decreased over time. The impact of rectal discomfort on HRQoL was predominant at 6 months after radiotherapy, decreased at 12 months and increased again 2 years after radiotherapy. No significant impact on HRQoL was observed for any of the other toxicity endpoints, or non-toxicity related factors such as hormonal therapy, radiotherapy technique or age. CONCLUSION Urinary incontinence and rectal discomfort have a significant impact on HRQoL. Prevention of these side effects may likely improve quality of life of prostate cancer patients after completion of treatment.

Neuroticism and Responses to Social Comparison Among Cancer Patients

The present study examined how the effects of three audiotapes containing different types of social comparison information on the mood of cancer patients depended on the level of neuroticism. On the procedural tape, a man and woman discussed the process of radiation therapy, on the emotion tape, they focussed on emotional reactions to their illness and treatment, while on the coping tape they focussed on the way they had been coping. A validation study among 115 students showed that the tapes were perceived as they were intended. The main study was conducted among 226 patients who were about to undergo radiation therapy. Compared to patients in the control group, as patients were higher in neuroticism, they reported less negative mood after listening to the procedural and the coping tape. Furthermore, as patients were higher in neuroticism, they reported less negative mood after listening to the coping tape than to the emotion tape. Copyright