Lack of beneficial effects of low-dose radiation therapy on hand osteoarthritis symptoms and inflammation: a randomised, blinded, sham-controlled trial.

OBJECTIVES: Low-dose radiation therapy (LDRT) is widely used as treatment for osteoarthritis (OA) in some countries, while relatively unknown in others. Systematic literature review displayed a lack of high-level evidence for beneficial effects in clinical practice. The aim was to assess the efficacy of LDRT on symptoms and inflammation in hand OA patients in a randomised, blinded, sham-controlled trial, using validated outcome measures. DESIGN: Hand OA patients, ≥50 years, with pain ≥5 (scale 0-10) and non-responding to conservative therapy were included and randomised 1:1 to receive LDRT (6 × 1 Gy in 2 weeks) or sham (6 × 0 Gy in 2 weeks). Primary outcome was the proportion of OMERACT-OARSI responders, 3 months post-intervention. Secondary outcomes were pain and functioning (Australian/Canadian Hand Osteoarthritis Index; AUSCAN), quality of life (Short Form Health Survey; SF36) and inflammatory outcomes: erythrocyte sedimentation rate and C-reactive protein serum levels, effusion, synovial thickening and power Doppler signal on ultrasound (range 0-3). RESULTS: Fifty-six patients were included. After 3 months, no significant difference in responders was observed between groups (LDRT: 8 (29%); sham: 10 (36%); difference -7% (95%CI -31-17%)). Also, differences in clinical and inflammatory outcomes between groups were small and not significant. CONCLUSIONS: We were unable to demonstrate a substantial beneficial effect of LDRT on symptoms and inflammation in patients with hand OA, compared to sham treatment. Although a small effect can not be excluded, a treatment effect exceeding 20% is very unlikely, given the confidence interval. Therefore, in the absence of other high-level evidence, we advise against the use LDRT as treatment for patients with hand OA. CLINICAL TRIAL REGISTRATION NUMBER: NTR4574 (Dutch Trial Register).

The efficacy and safety of low-dose radiotherapy on pain and functioning in patients with osteoarthritis: a systematic review.

Low-dose radiotherapy (LD-RT) has been widely used for treatment of non-malignant disorders since its introduction and animal studies show anti-inflammatory effects in osteoarthritis (OA). However, the evidence for its effect in clinical practice remains unclear. Therefore, the aim of this study is to systematically summarise the literature on effectiveness of LD-RT on pain and functioning in patients with OA and its safety. Broad search terms were used to search PubMed, EMBASE and Web of Science. Primary inclusion criteria were osteoarthritis as indication, radiotherapy as intervention, written in English, German or Dutch and published since 1980. Study quality was assessed using the EPHPP Quality Assessment Tool for Quantitative Studies (scale: strong, moderate, weak). Seven studies were suitable for inclusion, all with retrospective uncontrolled observational design. Methodological quality of all studies was judged as weak. Most studies used 2-3 RT sessions per week for 2 weeks, some with booster session after 6 weeks. Generally, non-validated single-item measurement instruments were used to evaluate the effect of LD-RT on pain and function. Across the studies, in 25-90 and 29-71 % of the patients pain and functioning improved, respectively. Side effects were described in one study, none were reported. Our results show that there is insufficient evidence for efficacy or to confirm the safety of LD-RT in treatment of OA, due to absence of high-quality studies. Therefore, a well-designed, sham-controlled and blinded randomised trial, using validated outcome measures is warranted to demonstrate the value of LD-RT for OA in clinical practice.

Adjuvant chemotherapy for rectal cancer patients treated with preoperative (chemo)radiotherapy and total mesorectal excision: a Dutch Colorectal Cancer Group (DCCG) randomized phase III trial.

BACKGROUND: The discussion on the role of adjuvant chemotherapy for rectal cancer patients treated according to current guidelines is still ongoing. A multicentre, randomized phase III trial, PROCTOR-SCRIPT, was conducted to compare adjuvant chemotherapy with observation for rectal cancer patients treated with preoperative (chemo)radiotherapy and total mesorectal excision (TME). PATIENTS AND METHODS: The PROCTOR-SCRIPT trial recruited patients from 52 hospitals. Patients with histologically proven stage II or III rectal adenocarcinoma were randomly assigned (1:1) to observation or adjuvant chemotherapy after preoperative (chemo)radiotherapy and TME. Radiotherapy consisted of 5 × 5 Gy. Chemoradiotherapy consisted of 25 × 1.8-2 Gy combined with 5-FU-based chemotherapy. Adjuvant chemotherapy consisted of 5-FU/LV (PROCTOR) or eight courses capecitabine (SCRIPT). Randomization was based on permuted blocks of six, stratified according to centre, residual tumour, time between last irradiation and surgery, and preoperative treatment. The primary end point was overall survival. RESULTS: Of 470 enrolled patients, 437 were eligible. The trial closed prematurely because of slow patient accrual. Patients were randomly assigned to observation (n = 221) or adjuvant chemotherapy (n = 216). After a median follow-up of 5.0 years, 5-year overall survival was 79.2% in the observation group and 80.4% in the chemotherapy group [hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.62-1.39; P = 0.73]. The HR for disease-free survival was 0.80 (95% CI 0.60-1.07; P = 0.13). Five-year cumulative incidence for locoregional recurrences was 7.8% in both groups. Five-year cumulative incidence for distant recurrences was 38.5% and 34.7%, respectively (P = 0.39). CONCLUSION: The PROCTOR-SCRIPT trial could not demonstrate a significant benefit of adjuvant chemotherapy with fluoropyrimidine monotherapy after preoperative (chemo)radiotherapy and TME on overall survival, disease-free survival, and recurrence rate. However, this trial did not complete planned accrual. REGISTRATION NUMBER: Dutch Colorectal Cancer group, CKTO 2003-16, ISRCTN36266738.

Quality of life after prostate cancer treatments in patients comparable at baseline.

BACKGROUND: Previous studies on the effects of different prostate cancer treatments on quality of life, were confounded because patients were not comparable. This study examined treatment effects in more comparable groups. METHODS: From 2008-2011, 240 patients with localised prostate cancer were selected to be eligible for both radical prostatectomy (RP) and external beam radiotherapy (EBRT). Brachytherapy (BT) was a third option for some. Health-related quality of life was measured by expanded prostate cancer index composite (EPIC) up to 12 months after treatment. RESULTS: In the sexual domain, RP led to worse summary scores (P<0.001) and more often to a clinically relevant deterioration from baseline than BT and EBRT (79%, 33%, 34%, respectively). In the urinary domain, RP also led to worse summary scores (P=0.014), and more deterioration from baseline (41%, 12%, 19%, respectively). Only on the irritative/obstructive urinary scale, more BT patients (40%) showed a relevant deterioration than RP (17%) and EBRT patients (11%). In the bowel domain, the treatment effects did not differ. CONCLUSION: This study provides a more unbiased comparison of treatment effects, as men were more comparable at baseline. Our results suggest that, for quality of life, radiotherapy is as least as good an option as RP for treating localised prostate cancer.

The role of physical activity and physical fitness in postcancer fatigue: a randomized controlled trial.

PURPOSE: Patients suffering from postcancer fatigue have both an inferior physical activity and physical fitness compared to non-fatigued cancer survivors. The aims of this study were (1) to examine the effect of cognitive behavior therapy, an effective treatment for postcancer fatigue, on physical activity and physical fitness and (2) to examine whether the effect of cognitive behavior therapy on postcancer fatigue is mediated by physical activity and/or physical fitness. METHODS: Severely fatigued cancer survivors were randomly assigned to either the intervention (cognitive behavior therapy) or the waiting list condition. After assigning 23 patients in the intervention condition and 14 patients in the waiting list condition, they were assessed both at baseline and 6 months later. Physical activity was assessed via actigraphy and physical fitness was assessed by a maximal exercise test. A nonparametric bootstrap approach was used to test the statistical significance of the mediation effects. RESULTS: A significant increase in physical activity was observed in the intervention group from baseline to follow-up, whereas physical activity did not change from baseline to follow-up in the waiting list group. Physical fitness did not significantly change after cognitive behavior therapy or after 6 months of waiting for therapy. Fatigue decreased more significantly in the intervention group than in the waiting list group. The mediation hypotheses were rejected. CONCLUSIONS: Cognitive behavior therapy effectively reduced postcancer fatigue and increased physical activity but did not change physical fitness. The effect of cognitive behavior therapy on postcancer fatigue is not mediated by a change in physical activity or physical fitness.

Maximal exercise performance in patients with postcancer fatigue.

PURPOSE: The aim of this study is to examine whether physical fitness of severely fatigued and non-fatigued cancer survivors, as measured by maximal exercise performance, is different between both groups and, if so, whether this difference can be explained by differences in physical activity, self-efficacy regarding the exercise test, and/or social support. METHODS: Severely fatigued (n = 20) and sex- and age-matched non-fatigued (n = 20) disease-free cancer survivors, who completed treatment for a malignant, solid tumor at least 1 year earlier, participated in this case-control study. Maximal oxygen consumption was measured during an incremental cycling exercise test. Physical activity was assessed via actigraphy. Self-efficacy regarding the test and social support were assessed via questionnaires to study its relationship with physical fitness. RESULTS: Maximal oxygen consumption was significantly lower in fatigued compared to non-fatigued participants. Actual physical activity, self-efficacy regarding the test, and negative interactions of social support were significantly different between both groups. However, after inclusion of these three variables in linear regression analyses, the difference in physical fitness between fatigued and non-fatigued cancer survivors persisted. CONCLUSIONS: Maximal oxygen consumption, a measure for physical fitness, was reduced in severely fatigued compared to non-fatigued cancer survivors. The inferior maximal exercise performance cannot fully be explained by differences in physical activity, self-efficacy, or social support between both groups. Other currently still unknown factors, such as a disturbance in the cardiopulmonary circuit, may play a role.

Continuing medical education in Europe: towards a harmonised system.

One of the first reports on the state of medical education was published in 1910 in North America, with the support of the Carnegie Foundation, showing that the interest for this issue dates back at least a century. Doctors (and nurses) are among the few professionals who managed to avoid for a long time any sort of evaluation of their knowledge and competence after the achievement of their diploma. But concern has been rising in society about the fast obsolescence of medical knowledge, particularly in the last 50 years when the development of research and technology in the field has been so fast. The concept of Continuing Medical Education gained growing interest after the Second World War as a necessity for health professionals, but also as a form of protection of patients, who have the right to be treated by competent and knowledgeable doctors and nurses. The United States (US)-based Josiah Macy Foundation recently sponsored a conference exploring the state of continuing education and the result is 'a picture of a disorganised system of education with obvious foci of excellence (most in universities) but with most commercially supported events shading more towards product promotion and the welfare of doctors than prioritised dedication to enhancing the care of patients'. Despite the fact that there is a lot to be learned from the US experience, Europe has to find its own way. Considerable progress was made since 1995 when UEMS (Union Européenne des Médecins Spécialistes) started to structure CME activities in Europe at translational level. A workshop on the issue was jointly organised by the European School of Oncology (ESO) and the Accreditation Council of Oncology in Europe (ACOE) in Berlin in September 2009.

In primary breast cancer the mitotic activity yields similar prognostic information as the histological grade: a study with long-term follow-up.

We evaluated with long-term follow-up, the prognostic value of the mitotic activity index (MAI) and the volume corrected mitotic index (M/V-index) compared with that of the histological grade in breast cancer patients not treated with adjuvant systemic therapy. Of 739 consecutive patients living in the city of Nijmegen, the Netherlands, 477 patients with primary unilateral breast cancer were not treated with adjuvant systemic therapy and eligible for the study. In multivariate survival analyses the MAI and M/V-index showed similar hazard ratios (HRs) compared to HRs of histological grade for overall survival (OS) (HR: 1.45, 1.48, and grade II versus grade I (GII/GI) 1.34, grade III versus grade I (GIII/GI) 1.53, respectively) and for breast cancer specific survival (BCSS) (HR: 1.27, 1.57, and (GII/GI) 1.57 (GIII/GI) 2.32, respectively). Other independent prognostic variables for OS and BCSS were age at diagnosis, tumour size, and number of positive lymph nodes. In the present study with long term follow-up, we compared the prognostic value of mitotic activity with that of histological grade and found no advantage for the mitotic activity in predicting either BCSS or OS and concluded that histological grade and the mitotic activity were equally informative in predicting patient outcome. As histological grade is a well established and widely used prognosticator we do not have arguments to replace the histological grade by the mitotic indices MAI or M/V-index.

What the clinician wants to know: radiation oncology perspective.

The delineation of the target volume, i.e. the volume which should be irradiated with a therapeutic dose of irradiation, is of utmost importance in radiotherapy. Modern imaging techniques cannot be missed in this process. Diagnosticians and radiation oncologists therefore should understand each other's needs and potential.

Late side effects of short-course preoperative radiotherapy combined with total mesorectal excision for rectal cancer: increased bowel dysfunction in irradiated patients--a Dutch colorectal cancer group study.

PURPOSE: Preoperative short-term radiotherapy improves local control in patients treated with total mesorectal excision (TME). This study was performed to assess the presence and magnitude of long-term side effects of preoperative 5 x 5 Gy radiotherapy and TME. Also, hospital treatment was recorded for diseases possibly related to late side effects of rectal cancer treatment. PATIENTS AND METHODS: Long-term morbidity was assessed in patients from the prospective randomized TME trial, which investigated the efficacy of 5 x 5 Gy before TME surgery for mobile rectal cancer. Dutch patients without recurrent disease were sent a questionnaire. RESULTS: Results were obtained from 597 patients, with a median follow-up of 5.1 years. Stoma function, urinary function, and hospital treatment rates did not differ significantly between the treatment arms. However, irradiated patients, compared with nonirradiated patients, reported increased rates of fecal incontinence (62% v 38%, respectively; P < .001), pad wearing as a result of incontinence (56% v 33%, respectively; P < .001), anal blood loss (11% v 3%, respectively; P = .004), and mucus loss (27% v 15%, respectively; P = .005). Satisfaction with bowel function was significantly lower and the impact of bowel dysfunction on daily activities was greater in irradiated patients compared with patients who underwent TME alone. CONCLUSION: Although preoperative short-term radiotherapy for rectal cancer results in increased local control, there is more long-term bowel dysfunction in irradiated patients than in patients who undergo TME alone. Rectal cancer patients should be informed on late morbidity of both radiotherapy and TME. Future strategies should be aimed at selecting patients for radiotherapy who are at high risk for local failure.

Comparative analysis of risk factors for pathological fracture with femoral metastases.

A number of risk factors based upon mostly retrospective surgical data, have been formulated in order to identify impending pathological fractures of the femur from low-risk metastases. We have followed up patients taking part in a randomised trial of radiotherapy, prospectively, in order to determine if these factors were effective in predicting fractures. In 102 patients with 110 femoral lesions, 14 fractures occurred during follow-up. The risk factors studied were increasing pain, the size of the lesion, radiographic appearance, localisation, transverse/axial/circumferential involvement of the cortex and the scoring system of Mirels. Only axial cortical involvement >30 mm (p = 0.01), and circumferential cortical involvement >50% (p = 0.03) were predictive of fracture. Mirels' scoring system was insufficiently specific to predict a fracture (p = 0.36). Our results indicate that most conventional risk factors overestimate the actual occurrence of pathological fractures of the femur. The risk factor of axial cortical involvement provides a simple, objective tool in order to decide which treatment is appropriate.

Updated European core curriculum for radiotherapists (radiation oncologists). Recommended curriculum for the specialist training of medical practitioners in radiotherapy (radiation oncology) within Europe.

AIM: To produce updated state-of-the-art recommendations for harmonised medical specialist training in radiotherapy within Europe. MATERIAL AND METHODS: The Minimum Curriculum for the Theoretical Education in Radiation Oncology in Europe from 1991 was updated under consideration of new developments in medicine in general, and in radiotherapy and its basic sciences in particular. Recent medical developments, national guidelines and training programmes from European countries, as well as equivalent documents from the USA and Australia were reviewed by an expert panel jointly appointed by the European Society of Therapeutic Radiology and Oncology and the European Board of Radiotherapy. A draft document prepared by this group was circulated among the national and professional societies for radiotherapy in Europe for review before a European consensus conference took place in Brussels in December 2002. RESULTS: The updated European Core Curriculum for Radiotherapists (Radiation Oncologists) was endorsed by representatives of 35 European nations during the Brussels consensus conference on December 14, 2002. Compared to the earlier version the updated document contains specific recommendations not only for the 5 year training curriculum but also for organisatoric and infrastructural aspects of teaching departments, and for supplementation of the training by formal teaching courses. CONCLUSION: The updated European core curriculum is an important step on the way to fully harmonise medical specialist training in Europe and to guarantee equal access for all European citizens to highest quality medical care. The responsibility for the implementation of the standards and guidelines set in the updated Core Curriculum for radiotherapy (radiation oncology) will lie with the local and/or national training bodies and authorities.

Guidelines for the infrastructure of training institutes and teaching departments for radiotherapy in Europe.

AIM: To develop guidelines for the infrastructure of training institutes and teaching departments for medical specialist training in radiotherapy within Europe. MATERIAL AND METHODS: Guidelines for teaching departments were developed under consideration of the updated European Core Curriculum for Radiotherapists (Radiation Oncologists) by an expert panel jointly appointed by the European Union of Medical Specialists and the European Society of Therapeutic Radiology and Oncology. The group approached national professional and scientific societies for information on national requirements for teaching departments. Based on this information, a draft document was circulated among the national and professional societies for radiotherapy in Europe for review before a European consensus conference took place in Brussels in December 2002. RESULTS: The guidelines for the infrastructure of training institutes and teaching departments for medical specialist training in radiotherapy within Europe were endorsed by representatives of 35 European nations during the Brussels consensus conference on December 14, 2002. CONCLUSION: The infrastructure guidelines represent an important instrument that can be used by teaching departments for comparison of their situation with that of other departments in Europe as a basis for negotiations with authorities on resources provided for training.

Radiotherapy does not compensate for positive resection margins in rectal cancer patients: report of a multicenter randomized trial.

PURPOSE: Circumferential resection margin (CRM) involvement is a prognostic factor for local recurrence in rectal cancer. In a randomized trial comparing preoperative radiotherapy (5 x 5 Gy), followed by total mesorectal excision (TME) with TME alone, we demonstrated the beneficial effect of short-term preoperative radiotherapy on local recurrences. Here we evaluate the effect of radiotherapy on local recurrence rates in patients with different CRM involvements. METHODS AND MATERIALS: Circumferential margins were defined as positive (< or =1 mm), narrow (1.1-2 mm), or wide (>2 mm). Postoperative radiotherapy was mandatory for surgery-only patients with a positive CRM, but was not always administered and enabled us to compare local recurrence rates for patients with or without postoperative radiotherapy. Furthermore, the effect of preoperative radiotherapy was assessed in the different margin groups. RESULTS: Of 120 patients in the surgery-only group with a positive CRM, 47% received postoperative radiotherapy. There was no difference in the local recurrence rate between the irradiated and nonirradiated patients (17.3% vs. 15.7%, p = 0.98). Preoperative radiotherapy was effective in patients with a narrow CRM (0% vs. 14.9%, p = 0.02) or wide CRM (0.9 vs. 5.8%, p < 0.0001), but not in patients with positive margins (9.3% vs. 16.4%, p = 0.08). CONCLUSION: Preoperative hypofractionated radiotherapy has a beneficial effect in patients with wide or narrow resection margins, but cannot compensate for microscopically irradical resections resulting in positive margins.

Radiation-induced changes in gene expression and distribution of atrial natriuretic peptide (ANP) in different anatomical regions of the rat heart.

PURPOSE: To examine the effects of whole-heart irradiation on gene expression and distribution of atrial natriuretic peptide (ANP) in atrial appendages and left ventricles of the rat heart. MATERIAL AND METHODS: Female Sprague-Dawley rats were irradiated with a single dose of 0, 15 or 20 Gy locally to the heart. At intervals up to 16 months post-irradiation, the localization of ANP was examined using immunohistochemical techniques. Absolute mRNA concentrations were determined using the competitive PCR assay. RESULTS: Histological and immunohistochemical studies demonstrated that whole-heart irradiation caused a reduction of atrial ANP, which is due to a substantial loss of ANP-producing atrial myocytes and accumulation of collagen (replacement fibrosis). On the other hand, ANP became detectable in the subendocardium of the irradiated left ventricles. Positive staining of ANP was mainly found in the proximity of injured areas consisting of degeneration of myocytes and fibrosis. At the transcriptional level, reduction of atrial ANP expression at 1 month post-irradiation was followed by recovery at 3 months. Thereafter, ANP mRNA concentrations followed the mRNA pattern of controls and even appeared to increase at 16 months. In the left ventricle, dose-dependent and progressive elevation of ANP gene expression could be observed during the observation period and reached a 20-fold increase as compared with sham-irradiated age-matched controls. CONCLUSIONS: The distribution of ANP after local irradiation of the rat heart depends on the severity of the pathological/structural changes (i.e. myocyte degeneration and fibrosis). In radiation-induced heart disease, elevated ANP expression in the left ventricle is most probably involved in the observed chronic elevation of plasma ANP levels.

Acute side effects and complications after short-term preoperative radiotherapy combined with total mesorectal excision in primary rectal cancer: report of a multicenter randomized trial.

PURPOSE: Total mesorectal excision (TME) surgery in the treatment of rectal cancer has been shown to result in a reduction in the number of local recurrences in retrospective studies. Reports on improved local control after preoperative, hypofractionated radiotherapy (RT) have led to the introduction of a prospective randomized multicenter trial, in which the effect of TME surgery with or without preoperative RT were evaluated. Any benefit in regard to a reduced local recurrence rate and possible improved survival must be weighed against potential adverse effects in both the short-term and the long-term. The present study was undertaken to assess the acute side effects of short-term, preoperative RT in rectal cancer patients and to study the influence of five doses of 5 Gy on surgical parameters, postoperative morbidity and mortality in patients randomized in the Dutch TME trial. PATIENTS AND METHODS: We analyzed 1,530 Dutch patients entered onto a prospective randomized trial, comparing preoperative RT with five doses of 5 Gy followed by TME surgery with TME surgery alone, of which 1,414 patients were assessable. Toxicity from RT, surgery characteristics, and postoperative complications and mortality were compared. RESULTS: Toxicity during RT hardly occurred. Irradiated patients had 100 mL more blood loss during the operation (P <.001) and showed more perineal complications (P =.008) in cases of abdominoperineal resection. The total number of complications was slightly increased in the irradiated group (P =.008). No difference was observed in postoperative mortality (4.0% v 3.3%) or in the number of reinterventions. CONCLUSION: Preoperative hypofractionated RT is a safe procedure in patients treated with TME surgery, despite a slight increase in complications when compared with TME surgery only.

Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer.

BACKGROUND: Short-term preoperative radiotherapy and total mesorectal excision have each been shown to improve local control of disease in patients with resectable rectal cancer. We conducted a multicenter, randomized trial to determine whether the addition of preoperative radiotherapy increases the benefit of total mesorectal excision. METHODS: We randomly assigned 1861 patients with resectable rectal cancer either to preoperative radiotherapy (5 Gy on each of five days) followed by total mesorectal excision (924 patients) or to total mesorectal excision alone (937 patients). The trial was conducted with the use of standardization and quality-control measures to ensure the consistency of the radiotherapy, surgery, and pathological techniques. RESULTS: Of the 1861 patients randomly assigned to one of the two treatment groups, 1805 were eligible to participate. The overall rate of survival at two years among the eligible patients was 82.0 percent in the group assigned to both radiotherapy and surgery and 81.8 percent in the group assigned to surgery alone (P=0.84). Among the 1748 patients who underwent a macroscopically complete local resection, the rate of local recurrence at two years was 5.3 percent. The rate of local recurrence at two years was 2.4 percent in the radiotherapy-plus-surgery group and 8.2 percent in the surgery-only group (P<0.001). CONCLUSIONS: Short-term preoperative radiotherapy reduces the risk of local recurrence in patients with rectal cancer who undergo a standardized total mesorectal excision.

Isolated late local recurrences with high mitotic count and early local recurrences following breast-conserving therapy are associated with increased risk on distant metastasis.

PURPOSE: Local recurrence (LR) after breast-conserving therapy (BCT) is associated with an increased risk for the development of distant metastasis. We studied risk factors for distant metastasis risk (DMR) and poor prognosis within a group of patients with LR as first event. PATIENTS AND METHODS: From a cohort of 1481 breast carcinomas treated with BCT in the period 1980-1994, a total of 68 pT1-3 N0-1 patients developed LR as first event. We have studied risk factors for the development of distant metastasis within this group of patients with LR. In addition to clinical factors (age at BCT and LR, mode of detection, location of LR, and treatment of LR), the histology slides of the primary and the recurrent tumor were reviewed. Immunohistochemical staining was performed for the following proteins: bcl-2, cyclin D1, E-cadherin, EGF receptor, ER, PR, Ki-67, c-erbB-2/neu, and p53. Statistical analyses were performed using conditional logistic regression. RESULTS: At a median follow-up after LR of 5.6 years, the 5-year DMR was 53%. In univariate analysis, none of the factors of the primary tumor was found to be associated with DMR after LR. Of the recurrent tumor the following factors were found to be risk factors for high DMR after LR: interval between treatment of the primary tumor and LR at 2 years or less (relative risk, 2.38; 95% confidence interval, 1.22-4.76; p = 0.008) and high mitotic count (relative risk, 2.51; 95% confidence interval, 1.03-6.15; p = 0.04). All patients with noninvasive recurrent tumor were alive at the time of analysis. Patients with an interval of greater than 2 years and a recurrent tumor with high mitotic count were found to have an equally poor prognosis compared to patients with LRs detected after a short interval. CONCLUSION: LR after BCT is associated with higher DMR and poor prognosis. Patients with LR within 2 years after BCT are especially at high risk. Late recurrences with high mitotic count have the same poor prognosis as early recurrences. For these patients, systemic treatment at time of the detection of LR should be considered.

No downstaging after short-term preoperative radiotherapy in rectal cancer patients.

PURPOSE: In retrospective studies, total mesorectal excision (TME) surgery has been demonstrated to result in a reduction in the number of local recurrences of rectal cancer. Reports on improved local control after preoperative, hypofractionated radiotherapy have led to the introduction of a randomized multicenter trial to evaluate the effect of TME surgery with and without preoperative radiotherapy. Treatment with preoperative radiotherapy might have an effect on the pathologic characteristics that determine staging of rectal cancer. We investigated the occurrence of downstaging in rectal cancer patients treated with and without preoperative radiotherapy. PATIENTS AND METHODS: We analyzed the differences in tumor size, number of examined lymph nodes, tumor-node-metastasis stage, and histopathologic features in 1,321 patients entered onto a randomized trial. The trial compared preoperative radiotherapy (5 x 5 Gy) followed by TME surgery with TME surgery alone. Patients who had an interval of more than 10 days between the start of radiotherapy and surgery were excluded from analysis. RESULTS: Differences were observed in tumor size (P <.001) and total number of examined lymph nodes (P <.001). No difference in tumor or node classification was detected. The irradiated group demonstrated more poorly differentiated tumors as well as more mucinous tumors. CONCLUSION: In rectal cancer patients, short-term, preoperative radiotherapy with 5 x 5 Gy does not lead to downstaging if the interval between the start of radiotherapy and surgery does not exceed 10 days.

Circulating atrial natriuretic peptide plasma levels as a marker for cardiac damage after radiotherapy.

PURPOSE: To investigate whether plasma concentrations of atrial natriuretic peptide (ANP) could be used to identify patients with radiation mediated cardiac dysfunction. MATERIALS AND METHODS: Circulating levels of ANP were measured in patients who have been irradiated on a large part of the heart (50-80%; Hodgkin's disease) or smaller part of the heart (20-30%; primary breast cancer). C-terminal ANP was determined by radioimmunoassay (RIA) using a commercial kit. RESULTS: In this study ANP plasma levels of 121 patients (Hodgkin's disease, 73 patients; breast cancer, 48 patients) and 67 controls were examined. ANP plasma levels of both Hodgkin patients (28.8+/-2.2, P=0.003) and breast cancer patients (20.4+/-2.8 ng/l, P=0.01) were significantly elevated when compared to age-matched controls (13.5+/-1.2 ng/l). Both for the Hodgkin (R=0.42, P=0.05) and breast cancer group (R=0.50, P=0.09) a positive relation between ANP plasma values and age was found. However, no clear relation between ANP plasma levels and time post treatment could be demonstrated. Patients with clinical symptoms of cardiovascular disease (n=25) had significantly higher ANP plasma levels (P<0.001) compared to patients in the same treatment group without evidence of cardiac disease (50.2+/-7.5 vs. 23.3+/-1.3 ng/l, P<0.001, and 38.2+/-12.4 vs. 16.3+/-1.6 ng/l, P<0.001, for Hodgkin's disease and breast cancer, respectively). Eight patients suffered from essential hypertension (n=8), whereas the remaining group of 17 patients showed a variety of cardiac disorders (i.e. myocardial infarction, decreasing ventricular function, and atrial fibrillations). In 11 patients cardiac problems were manifest either before or within a few years after mediastinal therapy. In two patients treated for Hodgkin's disease, and in four patients treated for breast cancer cardiac problems became manifest a long time (>10 years) after radiotherapy. Probably in this group of patients cardiac problems are related to the therapy. CONCLUSIONS: The present study indicates that ANP plasma levels could be used to identify patients with radiation induced cardiac dysfunction.