Search

Background and purpose To investigate relationships between patient-reported acute gastro-intestinal symptoms in a locally advanced cervical cancer (LACC) prospective cohort and clinical and dosimetric parameters, while also taking spatial dose into account. Material and methods A total of 103 patients was included, receiving radiotherapy based on a plan-library-based plan-of-the-day protocol, combined either with concurrent chemotherapy or with neo-adjuvant chemotherapy and concomitant hyperthermia. Toxicity endpoints were extracted from questionnaires sent out weekly during treatment and regularly in the acute phase after treatment. Endpoints were defined for symptoms concerning obstipation, diarrhea, fecal leakage, bowel cramps and rectal bleeding. Dose surface maps were constructed for the rectum. Clinical parameters and dosimetric parameters of the bowel bag and rectum were collected for all patients. Results The use of concomitant chemotherapy and an increase in Planning Target Volume (PTV) resulted in a significant increase in reported diarrhea. The dose–volume parameters V5Gy–V25Gy of the rectum were found to be significant, unlike dose–volume parameters of the bowel bag. Additionally, a significantly higher dose to the inferior part of the rectum was found for patients reporting diarrhea. No significance was reached for fecal leakage and bowel cramps. Conclusion The significance of results for patients reporting diarrhea symptoms found for PTV volume indicates a potential benefit for a plan-of-the-day protocol. Additionally, the results suggest that a reduction of inferior rectum dose could decrease patient-reported diarrhea symptoms, while the administration of concomitant chemotherapy appears to lead to radiosensitizing effects that increase these symptoms.

Purpose: Many patients experience bowel and bladder toxicity during the acute phase of radiation therapy for prostate cancer. Recent literature indicates that hypofractionation (HF) might increase this acute response but little is known on patient-reported outcome during this phase with HF. We evaluated the course of patient-reported acute symptoms during HF versus standard fractionated (SF) radiation therapy within the hypofractionated irradiation for prostate cancer (HYPRO) trial. Methods and Materials: In the HYPRO trial patients were treated with either 64.4 Gy (HF) in 19 fractions (3 times per week) or 78 Gy (SF) in 39 fractions (5 times per week). Normalized total dose for 2 Gy/fractions (NTD2Gy)for acute toxicity (α/β ratio of 10) for HF was 72.1 Gy with a similar dose rate of 10.2 Gy per week. Among the 794 patients who were previously eligible for acute grade ≥2 toxicity assessment, 717 had filled out ≥1 symptom questionnaires. For each maximum symptom, we scored “any complaint” and “moderate-severe complaint.” Differences were tested by χ2 test, and associations with clinical factors were tested using logistic regression. Significance was set at P ≤ .008 to adjust for multiple testing. Results: We observed significantly higher rates of moderate-severe painful defecation (HF 10.8%, SF 5.3%), any mucus discharge (HF 47.1%, SF 37.4%), any rectal blood loss (HF 16.1%, SF 9.3%), increased daily stool frequency ≥4 and ≥6 (HF 34.6%/13.8%, SF 25.6%/7.0%), and any urinary straining (HF 69.9%, SF 58.0%). At 3 months postradiation therapy, rates dropped considerably with similar levels for HF and SF. Hormonal treatment was associated with less acute gastrointestinal symptoms. Conclusion: The increased patient-reported acute rectal symptoms with HF confirmed the previously reported results on acute grade ≥2 rectal toxicity. The increase in bladder symptoms with HF was not identified previously. These observations contradict the NTD2Gy calculations. We observed no patterns of persisting complaints with HF after the acute period; therefore, HF is well tolerated and only associated with a temporary increase of symptoms.

Background and purpose External beam radiotherapy for prostate cancer deposits incidental dose to a region surrounding the target volume. Previously, an association was identified between tumor control and incidental dose for patients treated with conventional radiotherapy. We investigated whether such an association exists for patients treated using intensity modulated radiotherapy (IMRT) and tighter margins. Materials and methods Computed tomography scans and three-dimensional treatment planning dose distributions were available from the Dutch randomized HYPRO trial for 397 patients in the standard fractionation arm (39 × 2 Gy) and 407 patients in the hypofractionation arm (19 × 3.4 Gy), mainly delivered using online image-guided IMRT. Endpoint was any treatment failure within 5 years. A mapping of 3D dose distributions between anatomies was performed based on distance to the surface of the prostate delineation. Mean mapped dose distributions were computed for patient groups with and without failure, obtaining dose difference distributions. Random patient permutations were performed to derive p values and to identify relevant regions. Results For high-risk patients treated in the conventional arm, higher incidental dose was significantly associated with a higher probability of tumor control in both univariate and multivariate analysis. The locations of the excess dose mainly overlapped with the position of obturator internus muscles at about 2.5 cm from the prostate surface. No such relationship could be established for intermediate-risk patients. Conclusions An association was established between reduced treatment failure and the delivery of incidental dose outside the prostate for high-risk patients treated using conventionally fractionated IMRT.

Purpose: The phase 3 Hypofractionated Irradiation for Prostate Cancer trial compared hypofractionated radiation therapy with conventionally fractionated radiation therapy in patients with localized prostate cancer. Similar 5-year relapse-free survival rates were achieved in both groups, but noninferiority of hypofractionation was not confirmed for genitourinary and gastrointestinal toxicity. Here, we present the secondary trial endpoint on patient-reported quality of life. Methods and Materials: A total of 820 patients with intermediate-risk or high-risk prostate cancer were randomized to hypofractionation (19 fractions of 3.4 Gy) or conventional fractionation (39 fractions of 2.0 Gy). Quality of life was measured using a validated questionnaire, the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Prostate Cancer 25 module. Subscales (score range, 0-100) on urinary symptoms, gastrointestinal symptoms, symptoms related to androgen deprivation therapy, sexual function, and sexual activity were analyzed. Changes from baseline of at least 5 points were considered clinically relevant. Inferiority of hypofractionation for separate subscales was rejected if the mean difference in the 3-year incidence of clinically relevant deterioration between treatments was

Background/purpose: To determine the efficacy and toxicity profile of a stereotactic body radiotherapy (SBRT) boost as a first line treatment in patients with oropharyngeal squamous cell carcinoma ...

To investigate prognostic factors for death within 6 months of stereotactic body radiotherapy (SBRT) for patients with peripheral early-stage non-small cell lung cancer (NSCLC).This analysis included 586 NSCLC patients with peripheral tumors treated with SBRT. Potential patient and tumor prognostic factors, including the Charlson Comorbidity Index (CCI) and Cumulative Illness Rating Scale (CIRS), were analyzed by logistic regression analysis for association with early mortality (death6 months after SBRT). Additionally, CCI and CIRS were compared with respect to their predictive ability for early mortality by comparing multivariate models with each comorbidity index, and assessing their respective discriminatory abilities (C-index).A total of 36 patients (6.1%) died within 6 months of the start of SBRT. With a median follow-up of 25 months, 3-year overall survival was 54%. CIRS and tumor diameter were significant predictors of early mortality on multivariate analysis (p = .001). Patients with a CIRS score of 8 or higher and a tumor diameter over 3 cm had a 6-month survival of 70% versus 97% for those lacking these two features (p .001). CCI was not predictive for early mortality on univariate nor multivariate analysis; the model containing CCI had a C-index of 0.65 versus 0.70 for the model containing CIRS.CIRS and tumor diameter predict for early-mortality in peripheral early-stage NSCLC treated with SBRT. CIRS may be a more useful comorbidity index than CCI in this population when assessing short-term life expectancy.

Background: Currently, radiation-oncologists generally evaluate a single treatment plan for each patient that is possibly adapted by the planner prior to final approval. There is no systematic exploration of patient-specific trade-offs between planning aims, using a set of treatment plans with a-priori defined (slightly) different balances. To this purpose, we developed an automated workflow and explored its use for prostate cancer. Materials and Methods: For each of the 50 study patients, seven plans were generated, including the so-called clinical plan, with currently clinically desired ≥99% dose coverage for the low-dose planning target volume (PTVLow). The six other plans were generated with different, reduced levels of PTVLow coverage, aiming at reductions in rectum dose and consequently in predicted grade≥2 late gastro-intestinal (GI) normal tissue complication probabilities (NTCPs), while keeping other dosimetric differences small. The applied NTCP model included diabetes as a non-dosimetric predictor. All plans were generated with a clinically applied, in-house developed algorithm for automated multi-criterial plan generation. Results: With diabetes, the average NTCP reduced from 24.9 ± 4.5% for ≥99% PTVLow coverage to 17.3 ± 2.6% for 90%, approaching the NTCP (15.4 ± 3.0%) without diabetes and full PTVLow coverage. Apart from intended differences in PTVLow coverage and rectum dose, other differences between the clinical plan and the six alternatives were indeed minor. Obtained NTCP reductions were highly patient-specific (ranging from 14.4 to 0.1%), depending on patient anatomy. Even for patients with equal NTCPs in the clinical plan, large differences were found in NTCP reductions. Conclusions: A clinically feasible workflow has been proposed for systematic exploration of patient-specific trade-offs between various treatment aims. For each patient, automated planning is used to generate a limited set of treatment plans with well-defined variations in the balances between the aims. For prostate cancer, trade-offs between PTVLow coverage and predicted GI NTCP were explored. With relatively small coverage reductions, significant NTCP reductions could be obtained, strongly depending on patient anatomy. Coverage reductions could also make up for enhanced NTCPs related to diabetes as co-morbidity, again dependent on the patient. The proposed system can play an important role in further personalization of patient care.

Background Prognostication tools for early-stage non-small cell lung cancer (NSCLC) patients treated with stereotactic body radiotherapy (SBRT) are currently lacking. The purpose of this study was to develop and externally validate a nomogram to predict overall survival in individual patients with peripheral early-stage disease. Methods A total of 587 NSCLC patients treated with biologically effective dose > 100 Gy10 were eligible. A Cox proportional hazards model was used to build a nomogram to predict 6-month, 1-year, 3-year and 5-year overall survival. Internal validation was performed using bootstrap sampling. External validation was performed in a separate cohort of 124 NSCLC patients with central tumors treated with SBRT. Discriminatory ability was measured by the concordance index (C-index) while predictive accuracy was assessed with calibration slope and plots. Results The resulting nomogram was based on six prognostic factors: age, sex, Karnofsky Performance Status, operability, Charlson Comorbidity Index, and tumor diameter. The slope of the calibration curve for nomogram-predicted versus Kaplan-Meier-estimated overall survival was 0.77. The C-index of the nomogram (corrected for optimism) was moderate at 0.64. In the external validation cohort, the model yielded a C-index of 0.62. Conclusions We established and validated a nomogram which can provide individual survival predictions for patients with early stage lung cancer treated with SBRT. The nomogram may assist patients and clinicians with treatment decision-making.

PUROSE Ethiopia has one cobalt radiotherapy (RT) machine to serve a population of more than 100 million. The purpose of this study was to report on patterns of palliative RT of bone metastasis in a severely low-capacity setting. PATIENTS AND METHODS Patient and treatment characteristics of patients irradiated for palliation of symptomatic bone metastasis were extracted from a retrospective database of patients treated between May 2015 and January 2018. This database included a random sample of 1,823 of the estimated 4,000 patients who were treated with RT within in the study period. Associations between the applied RT schedule and patient and tumor characteristics were evaluated with the χ2 test. Hypothetical savings of RT sessions and time were compared in the case of a single-fraction policy. RESULTS From the database, 234 patients (13%) were treated for bone metastasis. Most patients were ≤ 65 years of age (n = 189; 80%) and female (n = 125; 53%). The most common primary sites were breast (n = 82; 35%) and prostate (n = 36; 15%). Fractionated regimens were preferred over single fraction: 20 Gy in 5 fractions (n = 192; 82.1%), 30 Gy in 10 fractions (n = 7; 3%), and 8 Gy in 1 fraction (n = 28; 12%). Factors associated with single-fraction RT included nonaxial sites of bone metastasis ( P < .01) and an address outside Addis Ababa ( P ≤ .01). If single-fraction RT would have been given uniformly for bone metastasis, this would have resulted in a 78% reduction in the number of RT sessions and 76% reduction in total RT time. CONCLUSION The pattern of palliative RT for bone metastasis in Ethiopia favors fractionated regimens over single fraction. Efforts should be made to adopt evidence-based and cost-effective guidelines.

Purpose In the multicenter, phase 3, HYpofractionated irradiation for PROstate cancer trial, hypofractionated (HF) radiation therapy was compared with conventionally fractionated (CF) radiation therapy. In previous reports, we could not demonstrate the postulated superiority of hypofractionation in terms of relapse-free survival at 5 years. The frequent use of long-term androgen deprivation therapy might have had substantial effects on relapse-free survival. In the current analysis, we provide updated 7-year relapse-free survival outcomes. Methods and Materials We enrolled patients with intermediate- to high-risk T1b-T4NX-N0MX-M0 localized prostate cancer. Patients were randomly assigned (1:1) to either HF (64.6 Gy in 19 fractions) or CF (78.0 Gy in 39 fractions) radiation therapy. Based on an estimated α/β ratio for prostate cancer of 1.5 Gy, the EQD2 was 90.4 Gy for HF versus 78.0 Gy for CF radiation therapy. The primary endpoint of the present analysis is relapse-free survival at 7 years. Results A total of 820 patients were enrolled, of whom 804 were assessable for the current evaluation (407 HF versus 397 CF). Median follow-up was 89 months (interquartile range, 83-99). Concomitant androgen deprivation therapy was prescribed for 537 (67%) of 804 patients for a median duration of 32 months (interquartile range, 10-44). Treatment failure at 7 years was reported in 220 (27.4%) of 804 patients, 107 (26.3%) in HF versus 113 (28.5%) in CF radiation therapy. Seven-year relapse-free survival was 71.7% (95% confidence interval [CI], 66.4-76.4) for HF versus 67.6% (95% CI, 62.0-72.5) for CF (P = .52). Overall survival was 80.8% (95% CI, 76.5-84.4) in HF versus 77.6% (95% CI, 73.0-81.5) in CF radiation therapy (P = .17). Conclusions The current results of 7-year relapse-free survival confirmed our previous findings that the hypothesized dose escalation in the HF arm did not translate to superior tumor control compared with the CF arm.

International audience; For decades, dose-volume information for segmented anatomy has provided the essential data for correlating radiotherapy dosimetry with treatment-induced complications. Dose-volume information has formed the basis for modelling those associations via normal tissue complication (NTCP) models and for driving treatment planning. Limitations to this approach have been identified. Many studies have emerged demonstrating that the incorporation of information describing the spatial nature of the dose distribution, and potentially its correlation with anatomy, can provide more robust associations with toxicity and seed more general NTCP models. Such approaches are culminating in the application of computationally intensive processes such as machine learning and the application of neural networks. The opportunities these approaches have for individualising treatment, predicting toxicity and expanding the solution space for radiation therapy are substantial and have clearly widespread and disruptive potential. Impediments to reaching that potential include issues associated with data collection, model generalisation and validation. This review examines the role of spatial models of complication and summarises relevant published studies. Sources of data for these studies, appropriate statistical methodology, frameworks for processing spatial dose information and extracting relevant features are described. Spatial complication modelling is consolidated as a pathway to guiding future developments towards effective, complication-free radiotherapy treatment.

Background: To investigate the location of recurrences with respect to the radiation fields in oropharynx cancer after intensity-modulated radiotherapy and stereotactic body radiotherapy (SBRT) boost. Methods: Local and regional recurrences were delineated on diagnostic scans which were rigidly coregistered with treatment planning scans, then classified based on the location of the center of mass (COM) as well as volumetrically. Results: In 195 patients, the 5-year local and regional control were 90% and 93%, respectively. By COM, 76% of local recurrences were in-field; 24% were out-of-field, significantly higher than 0%-5% in the literature for conventional regimens (P < 0.01). Regional recurrences (19 in 12 patients) were largely within unirradiated neck levels (47%) and electively irradiated regions (42%). Conclusions: The regimen with biological equivalent dose intensification provides excellent overall and in-field local control. The highly conformal boost technique was, however, associated with increased out-of-field local failure.

Purpose The phase 3 HYpofractionated irradiation for PROstate cancer (HYPRO) trial randomized patients with intermediate- to high-risk localized prostate cancer to conventionally fractionated (78 Gy in 39 fractions) or hypofractionated (64.6 Gy in 19 fractions) radiation therapy. Differences in techniques and treatment protocols were present between participating centers. This study aimed to compare dose parameters and patient-reported gastrointestinal symptoms between these centers. Methods and Materials From the trial population, we selected patients (N=572) from 4 treatment centers who received image guided (IG) intensity modulated radiation therapy (IMRT). Center A (n=242) applied planning target volume (PTV) margins of 5 to 6 mm and was considered the reference center. In center B (n=170, 7-mm margins), magnetic resonance imaging (MRI) was integrated in treatment planning. An endorectal balloon (ERB) was applied in center C (n=85, 7-mm margins). Center D (n=75) applied the largest PTV margins of 8 mm. The study protocol provided identical anorectal dose constraints, and local protocols were applied for further treatment optimization. Anorectal dose-surface histograms were compared by applying t tests. Rectal complaints during follow-up (6 months to 4 years) were compared in a generalized linear model, adjusting for age, follow-up, treatment arm, and hormone therapy. Results Favorable anorectal dose distributions were found for center B (MRI delineation) and center C (ERB application) as compared with centers A and D. These were associated with significantly lower incidences of patient-reported complaints of rectal incontinence, use of incontinence pads, and rectal discomfort in these centers. Furthermore, lower incidences of increased stool frequency (≥4 per day) and mucous loss were observed for center C. Conclusions Despite comparable IG-IMRT techniques and predefined dose constraints, pronounced differences in dose distributions and toxicity rates were observed. MRI delineation and ERB application were associated with favorable rectal dose parameters and toxicity profiles, whereas a 2- to 3-mm difference in PTV margins did not translate into observed differences. We conclude that choices for treatment optimization of IG-IMRT are important and clinically relevant for patients since these affect symptoms experienced in daily life.

The aim of this study was to explore circulating tumor cell (CTC) detection in advanced non-small cell lung cancer (NSCLC). CTCs may not only serve as a prognostic marker in selected tumor types, but may also be useful as pharmacodynamic marker in drug development.Fourty-six advanced NSCLC patients and fourty-six healthy controls were included in the study and 8.0 ml of peripheral blood was obtained from each of the participants. Immunomagnetic bead enrichment for cells expressing epithelial cell adhesion molecule (EpCAM) was performed, followed by multi-marker quantitative real-time PCR of a panel of marker genes: cytokeratin 7 (CK7), cytokeratin 19 (CK19), human epithelial glycoprotein (EGP) and fibronectin 1 (FN1). Using quadratic discriminant analysis (QDA), expression values were combined into a single score, which indicated CTC-positivity or -negativity. Test characteristics were assessed using receiver operating characteristic (ROC) curve analysis.ROC curve analysis showed capability of discrimination between advanced NSCLC patients and healthy controls (area=0.712; 95% CI 0.606-0.819; P0.001). A cut-off minimizing overall misclassification for QDA-positivity reached a sensitivity of 46% (95% CI 31-61) and a specificity of 93% (95% CI 82-99).In this exploratory study, an assay was developed for discriminating CTCs in peripheral blood samples of advanced NSCLC patients from healthy controls. The assay demonstrated an acceptable sensitivity in combination with good specificity. Further validation studies should take place in NSCLC patients and a matched control group.

bladder were 0.33 0.13 cm, for prostate were 0.41 0.22 cm and for rectum were 0.52 0.31 cm. Conclusions: Mean DSC values indicate a promising degree of conformity between standard CBCT and sCBCT. The centroid shift was found to be greatest for the rectum (mean 0.52 cm, maximum 1.38 cm). This may represent true organ motion between CBCT and sCBCT acquisition. Intraobserver outlining variability and contouring uncertainties resulting from poorer image quality of sCBCT may also contribute to this. The bladder measurements exhibited the highest level of conformity, with the highest DSC value and the lowest centroid shift. This suggests that the bladder exhibits less organ motion between CBCTand sCBCTacquisition, possibly as a result of increased stability due to the empty bladder protocol. The bladder may also be more reliably visualised than the other organs, due to its density and increased homogeneity, reducing variability on contouring. Outlining target and organ at risk volumes on sCBCT in clinical practice is feasible. Ultimately intra-fraction imaging would allow organ localisation during treatment, with more accurate calculation of target/OAR doses. This has the potential to enhance correlation with clinical outcomes and toxicity, in addition to increasing centre throughput and efficiency. Author Disclosure: C.J. Thompson: None. S. Mayes: None. A. Maikenhead: None. J. Logue: None. J. Wylie: None. P.A. Elliot: None. J. Livsey: None. C. Coyle: None. N. Alam: None. A. Tran: None. J. Stratford: None. C. Boylan: None. A. Choudhury: None.

6.8 months (IQR 6.2-7.5). Within the prostate & pelvis group, 61/62 received 74Gy to prostate, 49/62 (79%) received 60Gy to pelvis, 11 dose reduced to 55Gy (permitted in protocol), 1 received 50Gy, and 1 no RT to pelvis. Acute RTOG toxicity grades are shown in Figure. At week 18, 2/59 (3.4%; 90%CI 0.6-10.3) prostate alone & 3/60 (5.0%, 90%CI 1.4-12.4) prostate & pelvis patients had G≥2 GI toxicity. No G3/4 RTOG GI toxicities were reported at week 18. Moderate/severe bowel symptoms were reported by 10/46 (22%) prostate alone & 16/53 (30%) of prostate & pelvis patients according to the IBDQ at week 18. On the Gulliford scale at week 18, moderate/severe bowel 'bother' was reported in 4/59 (7%) prostate alone & 2/60 (3%) prostate & pelvis patients.