Effectiveness of low-dose radiation therapy on symptoms in patients with knee osteoarthritis: a randomised, double-blinded, sham-controlled trial.

OBJECTIVES: Low-dose radiation therapy (LDRT) for benign disorders such as knee osteoarthritis (OA) is widely used in some parts of the world, despite absence of controlled studies. We evaluated the effect of LDRT on symptoms and inflammation in patients with knee OA. METHODS: In this randomised, double-blinded, sham-controlled clinical trial (RCT), we recruited patients with knee OA (clinical ACR criteria) in the Netherlands, aged ≥50 years, pain score ≥5/10 and non-responding to analgesics and exercise therapy. Patients were randomised 1:1 to receive LDRT (1 Gray per fraction) or sham intervention six times in 2 weeks, stratified by pain (<8 versus ≥8/10). Primary outcome was the proportion of OMERACT-OARSI responders, 3 months postintervention. Secondary outcomes included pain, function and inflammatory signs assessed by ultrasound, MRI and serum inflammatory markers. RESULTS: We randomly assigned 55 patients: 27 (49%) to LDRT and 28 (51%) to sham. At 3 months postintervention, 12/27 patients (44%; 95% CI 26% to 63%) in the LDRT vs 12/28 patients (43%; 95% CI 25% to 61%) in the sham group responded; difference 2% (95% CI 25% to 28%), OR adjusted for the stratifying variable was 1.1 (95% CI 0.4 to 3.2). Also, for clinical and any of the inflammatory signs, no differences were observed. CONCLUSIONS: We found no substantial beneficial effect on symptoms and inflammatory signs of LDRT in patients knee OA, compared with sham treatment. Therefore, based on this RCT and the absence of other high-quality evidence, we advise against the use of LDRT as treatment for knee OA. TRIAL REGISTRATION NUMBER: NTR4574.

Screening for psychological distress before radiotherapy for painful bone metastases may be useful to identify patients with high levels of distress.

BACKGROUND: Psychological distress (PD) has a major impact on quality of life. We studied the incidence of PD before and after radiotherapy for painful bone metastases. Furthermore, we aimed to identify factors predictive for PD. METHODS: Between 1996 and 1998, the Dutch Bone Metastasis Study included 1157 patients with painful bone metastases. Patients were randomized between two fractionation schedules. The study showed a pain response of 74% in both groups. Patients filled out weekly questionnaires for 13 weeks, then monthly for two years. The questionnaires included a subscale for PD on the Rotterdam Symptom Checklist. We used generalized estimating equations and multivariable logistic regression analyses. RESULTS: At baseline, 290 patients (27%) had a high level of PD. For the entire group, the level of PD remained constant over time. The majority of patients with a low level of PD at baseline remained at a low level during follow-up. In patients with a high level of PD at baseline, the mean level of PD decreased after treatment and stabilized around the cutoff level. Female patients, higher age, worse performance, lower pain score and worse self-reported QoL were associated with an increased chance of PD, although the model showed moderate discriminative power. CONCLUSIONS: A substantial proportion of patients had a high level of PD before and after radiotherapy for painful bone metastases. Most patients who reported high levels of PD when referred for palliative radiotherapy remained at high levels thereafter. Therefore, screening of PD prior to treatment seems appropriate, in order to select patients requiring intervention.

Does a decision aid for prostate cancer affect different aspects of decisional regret, assessed with new regret scales? A randomized, controlled trial.

OBJECTIVE: To develop and validate new regret scales and examine whether a decision aid affects different aspects of regret in the treatment choice for prostate cancer. METHODS: This was a multicentre trial (three sites) with imbalanced randomization (1 : 2). From 2008 to 2011, patients with localized prostate cancer were randomized 1 : 2 to usual care (N = 77) or usual care plus a decision aid presenting risks and benefits of different treatments (N = 163). The treatments were surgery and (external or interstitial) radiotherapy. Regret was assessed before, and 6 and 12 months after treatment, using the Decisional regret scale by Brehaut et al. (Medical Decision Making, 23, 2003, 281), and three new scales focusing on process, option and outcome regret. The relation between decision aid and regret was analysed by anova. RESULTS: The concurrent validity of the new regret scales was confirmed by correlations between regret and anxiety, depression, decision evaluation scales and health-related quality of life. With a decision aid, patient participation was increased (P = 0.002), but regret was not. If anything, in patients with serious morbidity the decision aid resulted in a trend to less option regret and less Brehaut regret (P = 0.075 and P = 0.061, with effect sizes of 0.35 and 0.38, respectively). Exploratory analyses suggest that high-risk patients benefitted most from the decision aid. CONCLUSION: The new regret scales may be of value in distinguishing separate aspects of regret. In general, regret was not affected by the decision aid. In patients with serious morbidity, a trend to lower option regret with a decision aid was observed.

The effect of carbogen breathing and nicotinamide added to standard (chemo)radiation treatment of advanced cervical cancer in Indonesia.

OBJECTIVE: Chemoradiation is the standard therapy for advanced stages of cervical cancer. In developing countries, where 80% of cervical cancers occur, this is not always available. Carbogen breathing and oral nicotinamide (CON) therapy, aimed at overcoming tumor hypoxia, has shown to improve treatment efficacy in some epithelial tumors. This study investigates the effect of CON during (chemo)radiation of advanced stages of cervical cancer on overall survival, local and regional control, and toxicity. METHODS: From December 2006 to February 2010, 139 patients with stage IB2 to IVA cervical cancer were nonrandomly assigned to receive radiotherapy (RT) or chemoradiation (CRT) with or without CON. Differences in overall survival, local and regional control after 1 year, and toxicity were assessed in 113 evaluable patients. Thirty-two patients received RT, 16 received CRT, 45 received CON-RT, and 20 received CON-CRT. RESULTS: The CON-RT and RT groups contained significantly more patients with a poor performance status and IIIB and IVA tumors. Despite these differences in baseline characteristics, overall survival and local and regional control at 1 year were not significantly different (P = 0.10 and P = 0.19, respectively). Toxicity scores also did not differ (P = 0.60 and P = 0.73 for acute and late toxicity). CONCLUSIONS: Addition of CON to standard (chemo)radiation gives comparable survival and control rates. The effect of CON might be underestimated due to differences in baseline characteristics. Because chemotherapy cannot always be (completely) administered in low-resource settings, CON could be a worthy substitute. The CON treatment is feasible and safe.

Is increasing physical activity necessary to diminish fatigue during cancer treatment? Comparing cognitive behavior therapy and a brief nursing intervention with usual care in a multicenter randomized controlled trial.

BACKGROUND: Two interventions for fatigue were given during curative cancer treatment. The aim of this multicenter randomized controlled trial (RCT) with three conditions was to demonstrate the efficacy and to determine the contribution of physical activity. METHODS: Recruited from seven hospitals, 220 patients with various malignancies participated in a RCT. The brief nursing intervention (BNI) consisted of two 1-hour sessions, 3 months apart, given by 12 trained nurses, focusing only on physical activity. Cognitive behavior therapy (CBT) consisted of up to ten 1-hour sessions, within 6 months, provided by two therapists, focusing on physical activity and psychosocial elements. The control group received only usual care (UC). Assessments took place before and at least 2 months after cancer treatment, when patients had recovered from acute fatigue. Fatigue was the primary outcome. Efficacy was tested using analyses of covariance. A nonparametric bootstrap approach was used to test whether the effect on fatigue was mediated by physical activity. RESULTS: The CBT group was significantly less fatigued than the UC group. Between the BNI and the UC groups, no significant difference was found in fatigue. The mediation hypothesis was rejected. DISCUSSION: CBT given during curative cancer treatment proved to be an effective intervention to reduce fatigue at least 2 months after cancer treatment. The BNI was not effective. Contrary to what was expected, physical activity did not mediate the effect of CBT on fatigue. Thus, the reduction in fatigue elicited by CBT was realized without a lasting increase in physical activity.

Offering a treatment choice in the irradiation of prostate cancer leads to better informed and more active patients, without harm to well-being.

PURPOSE: To examine, in prostate cancer patients, the effect of (1) being offered a choice between radiation doses in three-dimensional conformal radiotherapy, and of (2) accepting or declining the possibility to choose. METHODS AND MATERIALS: A total of 150 patients with localized prostate cancer (T1-3N0M0) were offered a choice with a decision aid between two radiation doses (70 and 74 Gy). A control group of 144 patients received a fixed radiation dose without being offered a choice. Data were collected at baseline (before choice), before treatment (after choice), and 2 weeks and 6 months after treatment completion. RESULTS: Compared with the control group, the involvement group, receiving the decision aid, showed increased participation in decision making (p < 0.001), increased knowledge (p < 0.001), and improved risk perception (p < 0.001); they were more satisfied with the quality of information (p = 0.002) and considered their treatment a more appropriate treatment (p = 0.01). No group differences were found in well-being (e.g., general health, European Organization for Research and Treatment of Cancer quality of life, anxiety). Within the involvement group, accepting or declining the option to choose did not affect well-being either. CONCLUSIONS: Offering a choice of radiation dose, with a decision aid, increased involvement in decision making and led to a better-informed patient. In contrast to earlier suggestions, a strong increase in involvement did not result in improved well-being; and in contrast to clinical concerns, well-being was not negatively affected either, not even in those patients who preferred to leave the decision to their physician. This study shows that older patients, such as prostate cancer patients, can be informed and involved in decision making.

Evidence and research in rectal cancer.

The main evidences of epidemiology, diagnostic imaging, pathology, surgery, radiotherapy, chemotherapy and follow-up are reviewed to optimize the routine treatment of rectal cancer according to a multidisciplinary approach. This paper reports on the knowledge shared between different specialists involved in the design and management of the multidisciplinary ESTRO Teaching Course on Rectal Cancer. The scenario of ongoing research is also addressed. In this time of changing treatments, it clearly appears that a common standard for large heterogeneous patient groups have to be substituted by more individualised therapies based on clinical-pathological features and very soon on molecular and genetic markers. Only trained multidisciplinary teams can face this new challenge and tailor the treatments according to the best scientific evidence for each patient.

Effectiveness and toxicity of conventional radiotherapy treatment for painful spinal metastases: a detailed course of side effects after opposing fields versus a single posterior field technique.

BACKGROUND: Conventional radiotherapy for painful spinal metastases can be delivered with a single posterior-anterior (PA) or two opposed anterior-posterior (APPA) fields. We studied the effectiveness and toxicity of both techniques and studied whether treatment technique was predictive for abdominal and skin toxicity. PATIENTS AND METHODS: Within the Dutch Bone Metastasis Study, 343 patients received 8 Gray in a single fraction or 24 Gray in six fractions for painful spinal metastases. Treatment technique was not randomized. At baseline and weekly during follow-up, patients reported pain and other physical complaints. Any complaint increasing within 4 weeks after treatment was noted as a side effect. Pain response was calculated according to international standards, taking into account changes in pain score and medication. Repeated measurement analyses and multivariate logistic analyses were performed. RESULTS: Patients were mainly treated on the thoracic (34%) and lumbar (53%) spine and 73% received a PA field. Pain response was similar between both techniques (74%). In patients treated at the thoraco-lumbar and lumbar spine, with multiple fractions, significantly more abdominal complaints were noticed. In multivariate analysis, radiotherapy technique did not predict for side effects. CONCLUSION: Conventional radiotherapy of painful spinal metastases provides limited toxicity. Radiotherapy technique is not an independent predictor of abdominal and skin toxicity of irradiation.

Local recurrences after different treatment strategies for ductal carcinoma in situ of the breast: a population-based study in the East Netherlands.

PURPOSE: Outcomes after different treatment strategies for ductal carcinoma in situ (DCIS) of the breast were analyzed for a geographically defined population in the East Netherlands. METHODS AND MATERIALS: A total of 798 patients with a first diagnosis of DCIS between January 1989 and December 2003 were included and their medical records were reviewed. Survival rates for ipsilateral recurrences were calculated by the Kaplan-Meier method and a multivariate Cox proportional hazards regression model was used to evaluate the prognostic significance of different variables. RESULTS: The 5-year recurrence-free survival was 75% for breast conserving surgery (BCS) alone (237 patients) compared with 91% for BCS followed by radiation therapy (RT; 153 patients) and 99% for mastectomy (408 patients, p < 0.01). Independent risk factors for local recurrences were treatment strategy, symptomatically detected DCIS, and presence of comedo necrosis. Margin status reached statistical significance only for patients treated by BCS (hazard ratio, 2.0; 95% confidence interval, 1.1-4.0) whereas significance of other prognostic variables did not change. CONCLUSIONS: In a defined population outside a trial setting, RT after BCS for DCIS lowered recurrence rates. Besides the use of RT, a microscopically complete excision of DCIS is essential. This is especially true for patients with symptomatically detected DCIS and with tumors that contain comedo necrosis, as these groups are at particular high risk for recurrent disease.

Reduced late rectal mucosal changes after prostate three-dimensional conformal radiotherapy with endorectal balloon as observed in repeated endoscopy.

PURPOSE: The aim of this study was to investigate prospectively the rectal wall (Rwall) spatial dose distribution, toxicity, and mucosal changes after prostate cancer radiotherapy with or without an endorectal balloon (ERB). METHODS AND MATERIALS: A total of 24 patients with ERB and 24 without ERB (No-ERB) were treated with three-dimensional conformal radiotherapy (3D-CRT) to a dose of 67.5 Gy. The Rwall was divided into 16 mucosal areas and Rwall dose surface maps were constructed. After 3 months, 6 months, 1 year, and 2 years a rectosigmoidoscopy was performed, and each mucosal area was scored on telangiectasia, congestion, ulceration, stricture, and necrosis. Late rectal toxicity was correlated with the endoscopic findings. RESULTS: The ERB significantly reduced the Rwall volume exposed to doses >40 Gy. Late rectal toxicity (grade >or=1, including excess of bowel movements and slight rectal discharge) was reduced significantly in the ERB group. A total of 146 endoscopies and 2,336 mucosal areas were analyzed. Telangiectases were most frequently seen and appeared after 6 months. At 1 and 2 years, significantly less high-grade telangiectasia (T 2-3) was observed in the ERB group at the lateral and posterior part of the Rwall. In mucosal areas exposed to doses >40 Gy, less high-grade telangiectases (T 2-3) were seen in the ERB group compared with the No-ERB group. CONCLUSIONS: An ERB reduced the Rwall volume exposed to doses >40 Gy, resulting in reduction of late rectal mucosal changes and reduced late rectal toxicity. Although further analysis is needed, these data suggest an ERB-induced increased tolerance for late Rwall damage.

Radiotherapy of non-malignant disorders: where do we stand?

During a consensus meeting in Nice the role of radiotherapy in benign disorders was discussed. Based on this meeting we categorized the indication into three categories: (A) accepted indication; (B) only accepted in clinical trial; (C) not accepted. The results of this consensus meeting are presented for disorders of the eye, joints and bones, brain and soft tissue.

Impact of short-term preoperative radiotherapy on health-related quality of life and sexual functioning in primary rectal cancer: report of a multicenter randomized trial.

BACKGROUND: Few prospective studies have been performed about the impact of preoperative radiotherapy (PRT) or total mesorectal excision (TME) on health-related quality of life (HRQL) and sexual functioning in patients with resectable rectal cancer. This report describes the HRQL and sexual functioning of 990 patients who underwent TME and were randomly assigned to short-term PRT (5 x 5 Gy). PATIENTS AND METHODS: The Rotterdam Symptom Check List supplemented with additional items was used with questionnaires before treatment and at 3, 6, 12, 18, and 24 months after surgery. Patients without a recurrence the first 2 years were analyzed (n = 990). RESULTS: Few differences were found in HRQL between patients treated with or without PRT. Daily activities were significantly less for PRT patients 3 months postoperatively. Irradiated patients recovered slower from defecation problems than TME-only patients (P = .006). PRT had a negative effect on sexual functioning in males (P = .004) and females (P < .001). Irradiated males had more ejaculation disorders (P = .002), and erectile functioning deteriorated over time (P < .001). PRT had similar effects in patients who underwent a low anterior resection (LAR) versus an abdominoperineal resection (APR). Patients with an APR scored better on the physical (P = .004) and psychologic dimension (P = .007) than LAR patients, but worse on voiding (P = .0007). CONCLUSION: Short-term PRT leads to more sexual dysfunction, slower recovery of bowel function, and impaired daily activity postoperatively. However, this does not seriously affect HRQL. The comparison between LAR and APR patients demonstrates that the existence of a permanent stoma is not the only determinant of HRQL.

Results of the Dutch National study of the palliative effect of irradiation using two different treatment schemes for non-small-cell lung cancer.

PURPOSE: A national multicenter randomized study compared the efficacy of 2 x 8 Gy versus our standard 10 x 3 Gy in patients with inoperable stage IIIA/B (with an Eastern Cooperative Oncology Group score of 3 to 4 and/or substantial weight loss) and stage IV non-small-cell lung cancer. PATIENTS AND METHODS: Between January 1999 and June 2002, 297 patients were eligible and randomized to receive either 10 x 3 Gy or 2 x 8 Gy by external-beam irradiation. The primary end point was a patient-assessed score of treatment effect on seven thoracic symptoms using an adapted Rotterdam Symptom Checklist. Study sample size was determined based on an average total symptom score difference of more than one point over the initial 39 weeks post-treatment. The time course of symptom scores were also evaluated, and other secondary end points were toxicity and survival. RESULTS: Both treatment arms were equally effective, as the average total symptom score over the initial 39 weeks did not differ. However, the pattern in time of these scores differed significantly (P < .001). Palliation in the 10 x 3-Gy arm was more prolonged (until week 22) with less worsening symptoms than in 2 x 8-Gy. Survival in the 10 x 3-Gy arm was significantly (P = .03) better than in the 2 x 8-Gy arm with 1-year survival of 19.6% (95%CI, 14.1% to 27.3%) v 10.9% (95%CI, 6.9% to 17.3%). CONCLUSION: The 10 x 3-Gy radiotherapy schedule is preferred over the 2 x 8-Gy schedule for palliative treatment, as it improves survival and results in a longer duration of the palliative response.

Systematic review of the effect of radiation dose on tumor control and morbidity in the treatment of prostate cancer by 3D-CRT.

PURPOSE: A higher radiation dose is believed to result in a larger probability of tumor control and a higher risk of side effects. To make an evidence-based choice of dose, the relation between dose and outcome needs to be known. This study focuses on the dose-response relation for prostate cancer. METHODS AND MATERIALS: A systematic review was carried out on the literature from 1990 to 2003. From the selected studies, the radiation dose, the associated 5-year survival, 5-year bNED (biochemical no evidence of disease), acute and late gastrointestinal (GI) and genitourinary (GU) morbidity Grade 2 or more, and sexual dysfunction were extracted. With logistic regression models, the relation between dose and outcome was described. RESULTS: Thirty-eight studies met our criteria, describing 87 subgroups and involving up to 3000 patients per outcome measure. Between the (equivalent) dose of 70 and 80 Gy, various models estimated an increase in 5-year survival (ranging from 10% to 11%), 5-year bNED for low-risk patients (5-7%), late GI complications (12-16%), late GU complications (8-10%), and erectile dysfunction (19-24%). Only for the overall 5-year bNED, results were inconclusive (range, 0-18%). CONCLUSIONS: The data suggest a relationship between dose and outcome measures, including survival. However, the strength of these conclusions is limited by the sometimes small number of studies, the incompleteness of the data, and above all, the correlational nature of the data. Unambiguous proof for the dose-response relationships can, therefore, only be obtained by conducting randomized trials.

IMRT boost dose planning on dominant intraprostatic lesions: gold marker-based three-dimensional fusion of CT with dynamic contrast-enhanced and 1H-spectroscopic MRI.

PURPOSE: To demonstrate the theoretical feasibility of integrating two functional prostate magnetic resonance imaging (MRI) techniques (dynamic contrast-enhanced MRI [DCE-MRI] and 1H-spectroscopic MRI [MRSI]) into inverse treatment planning for definition and potential irradiation of a dominant intraprostatic lesion (DIL) as a biologic target volume for high-dose intraprostatic boosting with intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: In 5 patients, four gold markers were implanted. An endorectal balloon was inserted for both CT and MRI. A DIL volume was defined by DCE-MRI and MRSI using different prostate cancer-specific physiologic (DCE-MRI) and metabolic (MRSI) parameters. CT-MRI registration was performed automatically by matching three-dimensional gold marker surface models with the iterative closest point method. DIL-IMRT plans, consisting of whole prostate irradiation to 70 Gy and a DIL boost to 90 Gy, and standard IMRT plans, in which the whole prostate was irradiated to 78 Gy were generated. The tumor control probability and rectal wall normal tissue complication probability were calculated and compared between the two IMRT approaches. RESULTS: Combined DCE-MRI and MRSI yielded a clearly defined single DIL volume (range, 1.1-6.5 cm3) in all patients. In this small, selected patient population, no differences in tumor control probability were found. A decrease in the rectal wall normal tissue complication probability was observed in favor of the DIL-IMRT plan versus the plan with IMRT to 78 Gy. CONCLUSION: Combined DCE-MRI and MRSI functional image-guided high-dose intraprostatic DIL-IMRT planned as a boost to 90 Gy is theoretically feasible. The preliminary results have indicated that DIL-IMRT may improve the therapeutic ratio by decreasing the normal tissue complication probability with an unchanged tumor control probability. A larger patient population, with more variations in the number, size, and localization of the DIL, and a feasible mechanism for treatment implementation has to be studied to extend these preliminary tumor control and toxicity estimates.

Patients with a favourable prognosis are equally palliated with single and multiple fraction radiotherapy: results on survival in the Dutch Bone Metastasis Study.

BACKGROUND AND PURPOSE: In the prospectively, randomized Dutch Bone Metastasis Study on the effect of a single fraction of 8 Gy versus 24 Gy in six fractions on painful bone metastases, 28% of the patients survived for more than 1 year. Purpose of the present study was to analyze the palliative effect of radiotherapy in long-term surviving patients, and to identify prognostic factors for survival. MATERIAL AND METHODS: Response rates were compared in all patients surviving>52 weeks. The Cox proportional hazards model stratified by primary tumour was used for multivariate (MV) analyses of prognostic factors for survival. RESULTS: In 320 patients surviving>52 weeks, responses were 87% after 8 Gy and 85% after 24 Gy (P=0.54). Duration of response and progression rates were similar. For all primary tumours, prognostic factors for survival were a good Karnofsky Performance Score, no visceral metastases, and non-opioid analgesics intake (all factors, MV P<0.001). CONCLUSIONS: Single fraction radiotherapy should be the standard dose schedule for all patients with painful bone metastases, including patients with an expected favourable survival. General prognosticators as the Karnofsky Performance Score and metastatic tumour load are useful in predicting survival.

Enhancing patient participation by training radiation oncologists.

OBJECTIVE: Several studies have shown that patients' active participation to their medical interaction is beneficial for their information processing and their quality of life. Unfortunately, cancer patients often act rather passively in contact with their oncologists. We investigated whether cancer patients' participation in radiation therapy consultations could be enhanced by specific communicative behaviours of the radiation oncologists (ROs). METHODS: Eight ROs and 160 patients participated; 80 patients in the pre training group and 80 patients in the post training group. The ROs were trained to use specific communicative behaviours that are supposed to encourage patient participation. In the training special attention was paid to communicative requirements in the first minutes of the consultation. The communicative behaviours of the ROs and the cancer patients were measured by the Roter Interaction Analysis System, and compared before and after the RO training. RESULTS: From the start throughout the entire consultation, patients in the post training group participated more in interactions than patients in the pre training group: they discussed more psychosocial issues, expressed more concerns and contributed more to decision-making. CONCLUSION: Cancer patients' participation in the initial radiation oncology consultations can be increased by training of ROs. PRACTICE IMPLICATIONS: The results suggest that doctors working with cancer patients should receive communication training and feedback on a regular base.