De-escalation of radiotherapy after primary chemotherapy in cT1-2N1 breast cancer (RAPCHEM; BOOG 2010-03): 5-year follow-up results of a Dutch, prospective, registry study.

BACKGROUND: Primary chemotherapy in breast cancer poses a dilemma with regard to adjuvant locoregional radiotherapy, as guidelines for locoregional radiotherapy were originally based on pathology results of primary surgery. We aimed to evaluate the oncological safety of de-escalated locoregional radiotherapy in patients with cT1-2N1 breast cancer treated with primary chemotherapy, according to a predefined, consensus-based study guideline. METHODS: In this prospective registry study (RAPCHEM, BOOG 2010-03), patients referred to one of 17 participating radiation oncology centres in the Netherlands between Jan 1, 2011, and Jan 1, 2015, with cT1-2N1 breast cancer (one to three suspicious nodes on imaging before primary chemotherapy, of which at least one had been pathologically confirmed), and who were treated with primary chemotherapy and surgery of the breast and axilla were included in the study. The study guideline comprised three risk groups for locoregional recurrence, with corresponding locoregional radiotherapy recommendations: no chest wall radiotherapy and no regional radiotherapy in the low-risk group, only local radiotherapy in the intermediate-risk group, and locoregional radiotherapy in the high-risk group. Radiotherapy consisted of a biologically equivalent dose of 25 fractions of 2 Gy, with or without a boost. During the study period, the generally applied radiotherapy technique in the Netherlands was forward-planned or inverse-planned intensity modulated radiotherapy. 5-year follow-up was assessed, taking into account adherence to the study guideline, with locoregional recurrence rate as primary endpoint. We hypothesised that 5-year locoregional recurrence rate would be less than 4% (upper-limit 95% CI 7·8%). This study was registered at ClinicalTrials.gov, NCT01279304, and is completed. FINDINGS: 838 patients were eligible for 5-year follow-up analyses: 291 in the low-risk group, 370 in the intermediate-risk group, and 177 in the high-risk group. The 5-year locoregional recurrence rate in all patients was 2·2% (95% CI 1·4-3·4). The 5-year locoregional recurrence rate was 2·1% (0·9-4·3) in the low-risk group, 2·2% (1·0-4·1) in the intermediate-risk group, and 2·3% (0·8-5·5) in the high-risk group. If the study guideline was followed, the locoregional recurrence rate was 2·3% (0·8-5·3) for the low-risk group, 1·0% (0·2-3·4) for the intermediate-risk group, and 1·4% (0·3-4·5) for the high-risk group. INTERPRETATION: In this study, the 5-year locoregional recurrence rate was less than 4%, which supports our hypothesis that it is oncologically safe to de-escalate locoregional radiotherapy based on locoregional recurrence risk, in selected patients with cT1-2N1 breast cancer treated with primary chemotherapy, according to this predefined, consensus-based study guideline. FUNDING: Dutch Cancer Society. TRANSLATION: For the Dutch translation of the abstract see Supplementary Materials section.

Early Weight Loss during Chemoradiotherapy Has a Detrimental Impact on Outcome in NSCLC.

OBJECTIVES: The aim of this study was to assess the effect of early weight loss before the onset of radiation esophagitis on overall survival (OS) in patients with non-small cell lung cancer treated with concurrent chemoradiotherapy. METHODS: Characteristics (e.g., patient weight, radiation esophagitis score, sex, World Health Organization performance status, chemotherapy dose, nodal status, and gross tumor volume) of 151 patients who received concurrent chemoradiotherapy (in 2006-2013) were retrospectively correlated with OS. Early weight loss was defined as weight loss of more than 5% between the start and third week of radiotherapy in patients whose weight was stable before treatment initiation. RESULTS: In 17% of the patients early weight loss was observed. Median OS (95% confidence interval [CI]) was significantly shorter in the early weight loss group (OS = 13.0 months, 95% CI: 2.0-24.0) versus in the non-early weight loss group (OS = 23.0 months, 95% CI: 14.7-31.3) (hazard ratio [HR] = 1.8, 95% CI: 1.12-2.96, p = 0.017). On multivariate analysis sex (HR = 2.1, 95% CI: 1.33-3.29, p = 0.001), World Health Organization performance status (HR = 1.9, 95% CI: 1.20-2.97, p = 0.006), nodal status (HR = 2.9, 95% CI: 1.38-6.01, p = 0.005), and early weight loss (HR = 1.9, 95% CI: 1.10-3.19, p = 0.022) were associated with OS. CONCLUSIONS: Early weight loss in patients with non-small cell lung cancer was found to be associated with worse prognosis. These data warrant further investigation into the efficacy of tailored intervention to prevent early weight loss.

Inter-reader reproducibility of dynamic contrast-enhanced magnetic resonance imaging in patients with non-small cell lung cancer treated with bevacizumab and erlotinib.

UNLABELLED: Objectives When evaluating anti-tumor treatment response by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) it is necessary to assure its validity and reproducibility. This has not been well addressed in lung tumors. Therefore we have evaluated the inter-reader reproducibility of response classification by DCE-MRI in patients with non-small cell lung cancer (NSCLC) treated with bevacizumab and erlotinib enrolled in a multicenter trial. MATERIALS AND METHODS: Twenty-one patients were scanned before and 3 weeks after start of treatment with DCE-MRI in a multicenter trial. The scans were evaluated by two independent readers. The primary lung tumor was used for response assessment. Responses were assessed in terms of relative changes in tumor mean trans endothelial transfer rate (K(trans)) and its heterogeneity in terms of the spatial standard deviation. Reproducibility was expressed by the inter-reader variability, intra-class correlation coefficient (ICC) and dichotomous response classification. RESULTS: The inter-reader variability and ICC for the relative K(trans) were 5.8% and 0.930, respectively. For tumor heterogeneity the inter-reader variability and ICC were 0.017 and 0.656, respectively. For the two readers the response classification for relative K(trans) was concordant in 20 of 21 patients (k=0.90, p<0.0001) and for tumor heterogeneity in 19 of 21 patients (k=0.80, p<0.0001). CONCLUSIONS: Strong agreement was seen with regard to the inter-reader variability and reproducibility of response classification by the two readers of lung cancer DCE-MRI scans.

Improved progression free survival for patients with diabetes and locally advanced non-small cell lung cancer (NSCLC) using metformin during concurrent chemoradiotherapy.

BACKGROUND AND PURPOSE: The aim was to investigate whether the use of metformin during concurrent chemoradiotherapy (cCRT) for locally advanced non-small cell lung cancer (NSCLC) improved treatment outcome. MATERIAL AND METHODS: A total of 682 patients were included in this retrospective cohort study (59 metformin users, 623 control patients). All received cCRT in one of three participating radiation oncology departments in the Netherlands between January 2008 and January 2013. Primary endpoint was locoregional recurrence free survival (LRFS), secondary endpoints were overall survival (OS), progression-free survival (PFS) and distant metastasis free survival (DMFS). RESULTS: No significant differences in LRFS or OS were found. Metformin use was associated with an improved DMFS (74% versus 53% at 2 years; p=0.01) and PFS (58% versus 37% at 2 years and a median PFS of 41 months versus 15 months; p=0.01). In a multivariate cox-regression analysis, the use of metformin was a statistically significant independent variable for DMFS and PFS (p=0.02 and 0.03). CONCLUSIONS: Metformin use during cCRT is associated with an improved DMFS and PFS for locally advanced NSCLC patients, suggesting that metformin may be a valuable treatment addition in these patients. Evidently, our results merit to be verified in a prospective trial.

In vivo quantification of hypoxic and metabolic status of NSCLC tumors using [18F]HX4 and [18F]FDG-PET/CT imaging.

PURPOSE: Increased tumor metabolism and hypoxia are related to poor prognosis in solid tumors, including non-small cell lung cancer (NSCLC). PET imaging is a noninvasive technique that is frequently used to visualize and quantify tumor metabolism and hypoxia. The aim of this study was to perform an extensive comparison of tumor metabolism using 2[(18)F]fluoro-2-deoxy-d-glucose (FDG)-PET and hypoxia using HX4-PET imaging. EXPERIMENTAL DESIGN: FDG- and HX4-PET/CT images of 25 patients with NSCLC were coregistered. At a global tumor level, HX4 and FDG parameters were extracted from the gross tumor volume (GTV). The HX4 high-fraction (HX4-HF) and HX4 high-volume (HX4-HV) were defined using a tumor-to-blood ratio > 1.4. For FDG high-fraction (FDG-HF) and FDG high-volume (FDG-HV), a standardized uptake value (SUV) > 50% of SUVmax was used. We evaluated the spatial correlation between HX4 and FDG uptake within the tumor, to quantify the (mis)match between volumes with a high FDG and high HX4 uptake. RESULTS: At a tumor level, significant correlations were observed between FDG and HX4 parameters. For the primary GTV, the HX4-HF was three times smaller compared with the FDG-HF. In 53% of the primary lesions, less than 1 cm(3) of the HX4-HV was outside the FDG-HV; for 37%, this volume was 1.9 to 12 cm(3). Remarkably, a distinct uptake pattern was observed in 11%, with large hypoxic volumes localized outside the FDG-HV. CONCLUSION: Hypoxic tumor volumes are smaller than metabolic active volumes. Approximately half of the lesions showed a good spatial correlation between the PET tracers. In the other cases, a (partial) mismatch was observed. The addition of HX4-PET imaging has the potential to individualize patient treatment.

Early body weight loss during concurrent chemo-radiotherapy for non-small cell lung cancer.

BACKGROUND AND PURPOSE: Radiation-esophagitis and weight loss are frequently observed toxicities in patients treated with concurrent chemo-radiotherapy (CT-RT) for non-small cell lung cancer (NSCLC) and might be related. The purpose was to investigate whether weight loss already starts early after initiation of CT-RT and precedes radiation-esophagitis. MATERIALS AND METHODS: In a retrospective cohort, weight and esophagitis grade ≥2 were assessed during the first weeks of (CT-)RT in patients treated with concurrent (n = 102) or sequential (n = 92) therapy. In a prospective validation study, data on body weight, esophagitis grade ≥2, nutritional intake and muscle strength were obtained before, during and following CT-RT. RESULTS: In the retrospective cohort, early weight loss was observed in concurrently treated patients (p = 0.002), independent of esophagitis ≥ grade 2. Early weight loss was also observed in the prospective cohort (p = 0.003) and was not accompanied by decreases in nutritional intake. In addition lower limb muscle strength rapidly declined (p = 0.042). In the later weeks of treatment, further body weight loss occurred (p < 0.001) despite increased nutritional supplementation and body weight was only partly recovered after 4 weeks post CT-RT (p = 0.003). CONCLUSIONS: Weight loss during concurrent CT-RT for NSCLC starts early and prior to onset of esophagitis, requiring timely and intense nutritional rehabilitation.

Does routine psychosocial screening improve referral to psychosocial care providers and patient-radiotherapist communication? A cluster randomized controlled trial.

OBJECTIVE: This study tests whether using a screening instrument improves referral to psychosocial care providers (e.g. psychologist) and facilitates patient-radiotherapist communication. METHODS: A cluster randomized controlled trial was used. Fourteen radiotherapists were randomly allocated to the experimental or control group and 568 of their patients received care in accordance with the group to which their radiotherapist was allocated. Patients in the experimental group were asked to complete a screening instrument before and at the end of the radiation treatment period. All patients were requested to complete questionnaires concerning patient-physician communication after the first consultation and concerning psychosocial care 3 and 12 months post-intervention. RESULTS: Patients who completed the screening instrument were referred to social workers at an earlier stage than patients who did not (P<0.01). No effects were observed for numbers of referred patients, or for improved patient-radiotherapist communication. CONCLUSIONS: Our results suggest that a simple screening procedure can be valuable for the timely treatment of psychosocial problems in patients. Future efforts should be directed at appropriate timing of screening and enhancing physicians' awareness regarding the importance of identifying, discussing and treating psychosocial problems in cancer patients. PRACTICE IMPLICATIONS: Psychosocial screening can be enhanced by effective radiotherapist-patient communication.

Psychosocial screening effects on health-related outcomes in patients receiving radiotherapy. A cluster randomised controlled trial.

OBJECTIVE: This study examined the short-term and long-term effects of using a screening instrument on psychological distress and health-related quality of life (HRQoL) among cancer patients receiving radiotherapy. In addition, we investigated the effect of early psychosocial treatment on patients' overall health-related outcomes as previous research showed that patients in the screening condition were referred to a psychosocial caregiver at an earlier stage. METHODS: A cluster randomised controlled trial with a randomisation at the levels of 14 radiotherapists, 568 patients was conducted. Patients were asked to complete questionnaires at 3 and 12 months follow-up. RESULTS: Mixed models analyses showed no significant intervention effects on patients' overall extent of psychosocial distress and HRQoL, both on the short and long terms. Post-hoc analyses revealed significant interactions of the intervention with early referral and improved HRQoL and anxiety, suggesting that earlier referral might influence short-term HRQoL and experienced anxiety in patients. CONCLUSIONS: Our results suggest that the use of a psychosocial screening instrument among patients receiving radiotherapy in itself does not sufficiently improve patients' health-related outcome. The effective delivery of psychosocial care depends upon several components such as identification of distress and successful implementation of screening procedures. One of the challenges is to get insight in the effects of early referral of cancer patients for psychosocial support because early referral might have a favourable effect on some of the patients' health-related outcomes.

The usefulness and feasibility of a screening instrument to identify psychosocial problems in patients receiving curative radiotherapy: a process evaluation.

BACKGROUND: Psychosocial problems in cancer patients are often unrecognized and untreated due to the low awareness of the existence of these problems or pressures of time. The awareness of the need to identify psychosocial problems in cancer patients is growing and has affected the development of screening instruments. This study explored the usefulness and feasibility of using a screening instrument (SIPP: Screening Inventory of Psychosocial Problems) to identify psychosocial problems in cancer patients receiving curative radiotherapy treatment (RT). METHODS: The study was conducted in a radiation oncology department in The Netherlands. Several methods were used to document the usefulness and feasibility of the SIPP. Data were collected using self-report questionnaires completed by seven radiotherapists and 268 cancer patients. RESULTS: Regarding the screening procedure 33 patients were offered to consult a psychosocial care provider (e.g. social worker, psychologist) during the first consultation with their radiotherapist. Of these patients, 31 patients suffered from at least sub-clinical symptoms and two patients hardly suffered from any symptoms. Patients' acceptance rate 63.6% (21/33) was high. Patients were positive about the content of the SIPP (mean scores vary from 8.00 to 8.88, out of a range between 0 and 10) and about the importance of discussing items of the SIPP with their radiotherapist (mean score = 7.42). Radiotherapists' perspectives about the contribution of the SIPP to discuss the different psychosocial problems were mixed (mean scores varied from 3.17 to 4.67). Patients were more positive about discussing items of the SIPP if the radiotherapists had positive attitudes towards screening and discussing psychosocial problems. CONCLUSIONS: The screening procedure appeared to be feasible in a radiotherapy department. In general, patients' perspectives were at least moderate. Radiotherapists considered the usefulness and feasibility of the SIPP generally to be lower, but their evaluations were mixed. A positive attitude to using screening instruments like the SIPP needs to be encouraged among radiotherapists, as this may not only improve the usefulness of a screening instrument, but also patients' satisfaction with care. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00859768.

Compliance to technical guidelines for radiotherapy treatment in relation to patient safety.

OBJECTIVE: To determine the compliance of radiation technologists to technical guidelines in daily practice for radiotherapy treatment and whether there are differences in compliance across organizational units. DESIGN: On the basis of consensus, radiation technologists constructed a flowchart describing the work procedure of the irradiation of patients with breast cancer. Using video recordings, technologists in two units were observed to determine whether treatment was conducted in accordance with the flowchart. SETTING: Data have been collected on one linear accelerator at the MAASTRO clinic, a radiotherapy clinic in the Netherlands. PARTICIPANTS: Fifty-six treatments for breast cancer were analyzed in two treatment units. MAIN OUTCOME MEASURE: Percentage compliance to the most important issues for patient safety. RESULTS: An overall compliance of 59% (range: 2-100%) was shown on the 18 most important tasks for patient safety. Between the two units, the compliance varied from 21% to 81%. Tasks considered important by independent assessment had higher levels of compliance. CONCLUSIONS: Video-taped observation proved to be an effective tool for determining compliance in daily practice. A large variation in practice within and across units was detected by the video observations suggesting a need for standard operating procedures to improve the safety of radiotherapy.

Psychometric properties of the Dutch version of the Mental Adjustment to Cancer scale in Dutch cancer patients.

OBJECTIVES: The measurement of adjustment to cancer is relevant for research purposes and daily practice. In this study, the psychometric properties of the original five subscales and the two recently proposed summary scales of the Mental Adjustment to Cancer (MAC) scale were examined in Dutch cancer patients. METHODS: Data from 289 cancer patients were assessed with the Dutch version of the MAC scale and the Hospital and Anxiety Depression scale (HADS); 259 patients completed the MAC scale for a second time. RESULTS: In total, 85.5% of the participants completed the full MAC scale. The internal consistency of the five subscales and the summary scales were mostly similar to the original versions. The test-retest reliability of the Fighting Spirit, Helplessness/Hopelessness, Anxious Preoccupation, Summary Positive Adjustment and Summary Negative Adjustment subscales were moderate and the test-retest reliability of the Fatalism and Avoidance subscales were low. Correlations between the original and the two summary scales of the MAC scale and the depression and anxiety subscales of the HADS indicated good convergent validity. The structure of the five original subscales as well as the structure of the two proposed summary scales was adequate as shown by construct validity using confirmatory factor analyses. CONCLUSION: The Dutch version of the MAC scale is a feasible questionnaire and appeared to have comparable psychometric properties as demonstrated by studies in the UK. The psychometric properties of the summary scales and Fighting Spirit and Helplessness/Hopelessness subscales seem to be acceptable. This supports the cross-national usefulness of the MAC scale.

The effectiveness of the Screening Inventory of Psychosocial Problems (SIPP) in cancer patients treated with radiotherapy: design of a cluster randomised controlled trial.

BACKGROUND: The Screening Inventory of Psychosocial Problems (SIPP) is a short, validated self-reported questionnaire to identify psychosocial problems in Dutch cancer patients. The one-page 24-item questionnaire assesses physical complaints, psychological complaints and social and sexual problems. Very little is known about the effects of using the SIPP in consultation settings. Our study aims are to test the hypotheses that using the SIPP (a) may contribute to adequate referral to relevant psychosocial caregivers, (b) should facilitate communication between radiotherapists and cancer patients about psychosocial distress and (c) may prevent underdiagnosis of early symptoms reflecting psychosocial problems. This paper presents the design of a cluster randomised controlled trial (CRCT) evaluating the effectiveness of using the SIPP in cancer patients treated with radiotherapy. METHODS/DESIGN: A CRCT is developed using a Solomon four-group design (two intervention and two control groups) to evaluate the effects of using the SIPP. Radiotherapists, instead of cancer patients, are randomly allocated to the experimental or control groups. Within these groups, all included cancer patients are randomised into two subgroups: with and without pre-measurement. Self-reported assessments are conducted at four times: a pre-test at baseline before the first consultation and a post-test directly following the first consultation, and three and 12 months after baseline measurement. The primary outcome measures are the number and types of referrals of cancer patients with psychosocial problems to relevant (psychosocial) caregivers. The secondary outcome measures are patients' satisfaction with the radiotherapist-patient communication, psychosocial distress and quality of life. Furthermore, a process evaluation will be carried out. Data of the effect-evaluation will be analysed according to the intention-to-treat principle and data regarding the types of referrals to health care providers and patient satisfaction about the with radiotherapists will be analysed by means of descriptive techniques. The process evaluation data will also be analysed by means of descriptive techniques. DISCUSSION: Using the SIPP may prevent underdiagnosis of early symptoms reflecting psychosocial problems, should facilitate communication between physicians and patients about psychosocial distress and may contribute to adequate referral to relevant (psychosocial) caregivers. TRIAL REGISTRATION: NCT00859768.

Evaluation of three different CT simulation and planning procedures for the preoperative irradiation of operable rectal cancer.

PURPOSE: To find the best procedure regarding quality and work load for treatment planning in operable non-locally advanced rectal cancer using 3D CT-based information. METHODS: The study population consisted of 62 patients with non-locally advanced tumours, as defined by MRI in the lower (N=16), middle (N=25) and upper (N=21) rectum referred for preoperative short-course radiotherapy. In procedure 1 (Pr1), planning in one central plane was performed (field borders/shielding based on bony anatomy). In procedure 2 (Pr2), field borders were determined by 2 markers for the extension of the CTV in the cranial and ventral direction. Dose optimization was performed in one central and two border planes. In procedure 3(Pr3) the PTV volume (CTV was contoured on CT) received conformal treatment (3D dose optimization). RESULTS: Conformity index reached 1.6 for Pr3 vs. 2.2 for Pr2 (p<0.001). PTV coverage was 87%, 94%, 99% in Pr1, Pr2, Pr3, respectively (p=0.001). In Pr2 target coverage was below 95% for low/middle tumours. PTV coverage was reduced by narrow field borders (18-23%) and shielding (28%). A total of 43.5% (1-100) of the bladder volume was treated in Pr2 in contrast to 16% (0-68) in Pr3 (p<0.001). The maximum dose was exceeded in 10 patients (26-298 cc) and 2 patients (21-36 cc) in procedures 1 and 2, respectively. The overall time spent by technologists was 86 min for Pr3 vs 17 min in Pr2 and Pr1 (p<0.001), for radiation oncologists this difference was 24 vs 4 min (p<0.001). CONCLUSIONS: Pr1 does not fulfill todays quality requirements. Pr3 provides the best quality at the cost of working time. Pr2 is less time consuming, however, the PTV coverage was insufficient, with also much larger treatment volumes. An optimization of the PTV coverage in Pr2 even further enlarged the treatment volume.