Genetic Status Affects Disease-Specific Mortality But Not the Incidence of Local Recurrence in Patients with Uveal Melanoma.

PURPOSE: Increased disease-specific mortality has been observed among patients with local recurrence (LR) from uveal melanoma (UM), but the underlying mechanism is unknown. The purpose of this study was to determine if copy number alterations of chromosomes 3 and/or 8q, at the time of diagnosis, increase the incidence of LR and if disease-specific mortality among patients with LR depends on the chromosome status of the primary tumor. DESIGN: Retrospective cohort study. PARTICIPANTS: The study included 239 consecutive patients with primary UM (choroidal or ciliary body) treated with Ruthenium-106 (Ru-106) brachytherapy from January 2009 to December 2019 at a single national referral center. METHODS: Cox regression modeling and Kaplan-Meier analyses were used to assess the effect of the status of chromosomes 3 and 8q on the incidence of LR and disease-specific mortality after the event of LR. Multistate models were used to illustrate the probabilities over time of patients being alive and disease-free, alive with LR, dead from UM metastases, or dead from other causes split on the status of chromosomes 3 and 8q. MAIN OUTCOME MEASURES: Incidence of LR and disease-specific mortality. RESULTS: Local recurrence was observed in 42 patients (16%). Overall incidence of LR was not affected by aberrations of chromosomes 3 and/or 8q (P = 0.87). Although LR occurred earlier in patients with aberrations of chromosomes 3 and/or 8q compared with patients with a normal copy number of chromosomes 3 and 8q, the median time from primary diagnosis to LR was 1.6 years (interquartile range [IQR], 1.0-2.0) and 3.2 years (IQR, 2.1-5.0), respectively. Cox regression found LR to be an independent risk factor for disease-specific mortality (hazard ratio [HR], 2.7; 95% confidence interval [CI], 1.5-5.0) among all patients, but multistate models demonstrated a low risk of disease-specific death among patients with normal chromosomes 3 and 8q status, even after an LR. CONCLUSIONS: Copy number alterations of chromosome 3 and/or 8q in the primary UM did not increase the overall incidence of LR. However, the development of an LR enhanced the risk of disease-specific mortality among patients with copy number alterations of chromosomes 3 and/or 8q. Even after an LR, disease-specific mortality remained low among patients with normal copy numbers of chromosomes 3 and 8q. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Training and external validation of pre-treatment FDG PET-CT-based models for outcome prediction in anal squamous cell carcinoma.

OBJECTIVES: The incidence of anal squamous cell carcinoma (ASCC) is increasing worldwide, with a significant proportion of patients treated with curative intent having recurrence. The ability to accurately predict progression-free survival (PFS) and overall survival (OS) would allow for development of personalised treatment strategies. The aim of the study was to train and external test radiomic/clinical feature derived time-to-event prediction models. METHODS: Consecutive patients with ASCC treated with curative intent at two large tertiary referral centres with baseline FDG PET-CT were included. Radiomic feature extraction was performed using LIFEx software on the pre-treatment PET-CT. Two distinct predictive models for PFS and OS were trained and tuned at each of the centres, with the best performing models externally tested on the other centres' patient cohort. RESULTS: A total of 187 patients were included from centre 1 (mean age 61.6 ± 11.5 years, median follow up 30 months, PFS events = 57/187, OS events = 46/187) and 257 patients were included from centre 2 (mean age 62.6 ± 12.3 years, median follow up 35 months, PFS events = 70/257, OS events = 54/257). The best performing model for PFS and OS was achieved using a Cox regression model based on age and metabolic tumour volume (MTV) with a training c-index of 0.7 and an external testing c-index of 0.7 (standard error = 0.4). CONCLUSIONS: A combination of patient age and MTV has been demonstrated using external validation to have the potential to predict OS and PFS in ASCC patients. CLINICAL RELEVANCE STATEMENT: A Cox regression model using patients' age and metabolic tumour volume showed good predictive potential for progression-free survival in external testing. The benefits of a previous radiomics model published by our group could not be confirmed on external testing. KEY POINTS: • A predictive model based on patient age and metabolic tumour volume showed potential to predict overall survival and progression-free survival and was validated on an external test cohort. • The methodology used to create a predictive model from age and metabolic tumour volume was repeatable using external cohort data. • The predictive ability of positron emission tomography-computed tomography-derived radiomic features diminished when the influence of metabolic tumour volume was accounted for.

Different benefits of adaptive radiotherapy for different histologies of NSCLC.

BACKGROUND: Adenocarcinoma (AC) and squamous cell carcinoma (SCC) are the most frequent histological subtypes of non-small cell lung cancer (NSCLC). The aim of this study was to investigate how patients with AC and SCC benefit from image-guided adaptive radiotherapy (ART) with tumour match. MATERIAL AND METHODS: Consecutive patients diagnosed with AC or SCC of the lung treated with definitive chemo-radiotherapy before and after the implementation of ART and tumour match were retrospectively included for analyses. Data collection included baseline patient and treatment characteristics in addition to clinical data on radiation pneumonitis (RP), failure, and survival. Patients were divided into four categories based on their histology and treatment before (n = 173 [89 AC and 84 SCC]) and after implementation of ART (n = 240 [141 AC and 99 SCC]). RESULTS: Median follow-up was 5.7 years for AC and 6.3 years for SCC. Mean lung dose decreased for both histologies with ART, whereas mean heart dose only decreased for patients with AC. Incidences of grade 3 and 5 RP decreased for both histologies with ART. Loco-regional failure (LRF) rates decreased significantly for patients with SCC after ART (p = .04), no significant difference was observed for AC. Overall survival (OS) increased significantly for SCC after ART (p < .01): the 2-year OS increased from 31.0% (95% confidence interval [CI] [22.5-42.6]) to 54.5% (95% CI [45.6-65.3]). No significant effect on OS was observed for patients with AC. CONCLUSION: ART and tumour match in the radiotherapeutic treatment of patients with locally advanced NSCLC primarily led to decreased LRF and improved OS for patients with SCC.

European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer consensus on re-irradiation: definition, reporting, and clinical decision making.

Re-irradiation can be considered for local recurrence or new tumours adjacent to a previously irradiated site to achieve durable local control for patients with cancer who have otherwise few therapeutic options. With the use of new radiotherapy techniques, which allow for conformal treatment plans, image guidance, and short fractionation schemes, the use of re-irradiation for different sites is increasing in clinical settings. Yet, prospective evidence on re-irradiation is scarce and our understanding of the underlying radiobiology is poor. Our consensus on re-irradiation aims to assist in re-irradiation decision making, and to standardise the classification of different forms of re-irradiation and reporting. The consensus has been endorsed by the European Society for Radiotherapy and Oncology and the European Organisation for Research and Treatment of Cancer. The use of this classification in daily clinical practice and research will facilitate accurate understanding of the clinical implications of re-irradiation and allow for cross-study comparisons. Data gathered in a uniform manner could be used in the future to make recommendations for re-irradiation on the basis of clinical evidence. The consensus document is based on an adapted Delphi process and a systematic review of the literature was done according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

Prognostic factors for patients with anal cancer treated with conformal radiotherapy-a systematic review.

AIMS: Anal cancer is primarily treated using concurrent chemoradiotherapy (CRT), with conformal techniques such as intensity modulated radiotherapy (IMRT) and volumetric arc therapy (VMAT) now being the standard techniques utilised across the world. Despite this, there is still very limited consensus on prognostic factors for outcome following conformal CRT. This systematic review aims to evaluate the existing literature to identify prognostic factors for a variety of oncological outcomes in anal cancer, focusing on patients treated with curative intent using contemporary conformal radiotherapy techniques. MATERIALS AND METHODS: A literature search was conducted using Medline and Embase to identify studies reporting on prognostic factors for survival and cancer-related outcomes after conformal CRT for anal cancer. The prognostic factors which were identified as significant in univariable and multivariable analysis, along with their respective factor effects (where available) were extracted. Only factors reported as prognostic in more than one study were included in the final results. RESULTS: The results from 19 studies were analysed. In both univariable and multivariable analysis, N stage, T stage, and sex were found to be the most prevalent and reliable clinical prognostic factors for the majority of outcomes explored. Only a few biomarkers have been identified as prognostic by more than one study - pre-treatment biopsy HPV load, as well as the presence of leukocytosis, neutrophilia and anaemia at baseline measurement. The results also highlight the lack of studies with large cohorts exploring the prognostic significance of imaging factors. CONCLUSION: Establishing a set of prognostic and potentially predictive factors for anal cancer outcomes can guide the risk stratification of patients, aiding the design of future clinical trials. Such trials will in turn provide us with greater insight into how to effectively treat this disease using a more personalised approach.

Dose summation and image registration strategies for radiobiologically and anatomically corrected dose accumulation in pelvic re-irradiation.

BACKGROUND: Re-irradiation (reRT) is a promising technique for patients with localized recurrence in a previously irradiated area but presents major challenges. These include how to deal with anatomical change between two courses of radiotherapy and integration of radiobiology when summating original and re-irradiation doses. The Support Tool for Re-Irradiation Decisions guided by Radiobiology (STRIDeR) project aims to develop a software tool for use in a commercial treatment planning system to facilitate more informed reRT by accounting for anatomical changes and incorporating radiobiology. We evaluated three approaches to dose summation, incorporating anatomical change and radiobiology to differing extents. METHODS: In a cohort of 21 patients who previously received pelvic re-irradiation the following dose summation strategies were compared: (1) Rigid registration (RIR) and physical dose summation, to reflect the current clinical approach, (2) RIR and radiobiological dose summation in equivalent dose in 2 Gy fractions (EQD2), and (3) Patient-specific deformable image registration (DIR) with EQD2 dose summation. RESULTS: RIR and physical dose summation (Strategy 1) resulted in high cumulative organ at risk (OAR) doses being 'missed' in 14% of cases, which were highlighted by EQD2 dose summation (Strategy 2). DIR (with EQD2 dose summation; Strategy 3) resulted in improved OAR overlap and distance to agreement metrics compared to RIR (with EQD2 dose summation; Strategy 2) and was consistently preferred in terms of clinical utility. DIR was considered to have a clinically important impact on dose summation in 38% of cases. CONCLUSION: Re-irradiation cases require individualized assessment when considering dose summation with the previous treatment plan. Fractionation correction is necessary to meaningfully assess cumulative doses and reduce the risk of unintentional OAR overdose. DIR can add clinically relevant information in selected cases, especially for significant anatomical change. Robust solutions for cumulative dose assessment offer the potential for future improved understanding of cumulative OAR tolerances.

Dose-Response and Normal Tissue Complication Probabilities after Proton Therapy for Choroidal Melanoma.

PURPOSE: Normal tissue complication probability (NTCP) models could aid the understanding of dose dependence of radiation-induced toxicities after eye-preserving radiotherapy of choroidal melanomas. We performed NTCP-modeling and established dose-response relationships for visual acuity (VA) deterioration and common late complications after treatments with proton therapy (PT). DESIGN: Retrospective study from single, large referral center. PARTICIPANTS: We considered patients from Nice, France, diagnosed with choroidal melanoma and treated primarily with hypofractionated PT (52 Gy physical dose in 4 fractions). Complete VA deterioration information was available for 1020 patients, and complete information on late complications was available for 991 patients. METHODS: Treatment details, dose-volume histograms (DVHs) for relevant anatomic structures, and patient and tumor characteristics were available from a dedicated ocular database. Least absolute shrinkage and selection operator (LASSO) variable selection was used to identify variables with the strongest impact on each end point, followed by multivariate Cox regressions and logistic regressions to analyze the relationships among dose, clinical characteristics, and clinical outcomes. MAIN OUTCOME MEASURES: Dose-response relationship for VA deterioration and late complications. RESULTS: Dose metrics for several structures (i.e., optic disc, macula, retina, globe, lens, ciliary body) correlated with clinical outcome. The near-maximum dose to the macula showed the strongest correlation with VA deterioration. The near-maximum dose to the retina was the only variable with clear impact on the risk of maculopathy, the dose to 20% of the optic disc had the largest impact on optic neuropathy, dose to 20% of cornea had the largest impact on neovascular glaucoma, and dose to 20% of the ciliary body had the largest impact on ocular hypertension. The volume of the ciliary body receiving 26 Gy was the only variable associated with the risk of cataract, and the volume of retina receiving 52 Gy was associated with the risk of retinal detachment. Optic disc-to-tumor distance was the only variable associated with dry eye syndrome in the absence of DVH for the lachrymal gland. CONCLUSIONS: VA deterioration and specific late complications demonstrated dependence on dose delivered to normal structures in the eye after PT for choroidal melanoma. VA deterioration depended on dose to a range of structures, whereas more specific complications were related to dose metrics for specific structures.

Outcome measures in multimodal rectal cancer trials.

There is a large variability regarding the definition and choice of primary endpoints in phase 2 and phase 3 multimodal rectal cancer trials, resulting in inconsistency and difficulty of data interpretation. Also, surrogate properties of early and intermediate endpoints have not been systematically assessed. We provide a comprehensive review of clinical and surrogate endpoints used in trials for non-metastatic rectal cancer. The applicability, advantages, and disadvantages of these endpoints are summarised, with recommendations on clinical endpoints for the different phase trials, including limited surgery or non-operative management for organ preservation. We discuss how early and intermediate endpoints, including patient-reported outcomes and involvement of patients in decision making, can be used to guide trial design and facilitate consistency in reporting trial results in rectal cancer.

Tumour control probability after Ruthenium-106 brachytherapy for choroidal melanomas.

Purpose: Ruthenium-106 (Ru-106) brachytherapy is a common eye-preserving treatment for choroidal melanomas. However, a dose-response model describing the relationship between the actual delivered tumour dose and tumour control has, to the best of our knowledge, not previously been quantified for Ru-106 brachytherapy; we aimed to rectify this.Material and methods: We considered consecutive patients with primary choroidal melanomas, treated with Ru-106 brachytherapy (2005-2014). Dosimetric plans were retrospectively recreated using 3D image-guided planning software. Pre-treatment fundus photographies were used to contour the tumour; post-treatment photographies to determine the accurate plaque position. Patient and tumour characteristics, treatment details, dose volume histograms, and clinical outcomes were extracted. Median follow-up was 5.0 years. The relationship between tumour dose and risk of local recurrence was examined using multivariate Cox regression modelling, with minimum physical tumour dose (D99%) as primary dose metric.Results: We included 227 patients with median tumour height and largest base dimension of 4 mm (range 1-12, IQR 3-6) and 11 mm (range 4-23, IQR 9-13). The estimated 3 year local control was 82% (95% CI 77-88). Median D99% was 105 Gy (range 6-783, IQR 65-138); this was the most significant factor associated with recurrence (p < .0001), although tumour height, combined TTT and Ru-106 brachytherapy, and sex were also significant. The hazard ratio (HR) for a 10 Gy increase in D99% was 0.87 (95% CI 0.82-0.93). Using biological effective dose in the model resulted in no substantial difference in dose dependence estimates. Robustness cheques with D1-99% showed D99% to be the most significant dose metric for local recurrence.Conclusion: The minimum tumour dose correlated strongly with risk of tumour recurrence, with 100 Gy needed to ensure at least 84% local control at 3 years.

Feasibility of preference-driven radiotherapy dose treatment planning to support shared decision making in anal cancer.

PURPOSE/OBJECTIVE: Chemo-radiotherapy is an established primary curative treatment for anal cancer, but clinically equal rationale for different target doses exists. If joint preferences (physician and patient) are used to determine acceptable tradeoffs in radiotherapy treatment planning, multiple dose plans must be simultaneously explored. We quantified the degree to which different toxicity priorities might be incorporated into treatment plan selection, to elucidate the feasible decision space for shared decision making in anal cancer radiotherapy. MATERIAL AND METHODS: Retrospective plans were generated for 22 anal cancer patients. Multi-criteria optimization handles dynamically changing priorities between clinical objectives while meeting fixed clinical constraints. Four unique dose distributions were designed to represent a wide span of clinically relevant objectives: high-dose preference (60.2 Gy tumor boost and 50.4 Gy to elective nodes with physician-defined order of priorities), low-dose preference (53.75 Gy tumor boost, 45 Gy to elective nodes, physician-defined priorities), bowel sparing preference (lower dose levels and priority for bowel avoidance) and bladder sparing preference (lower dose levels and priority for bladder avoidance). RESULTS: Plans satisfied constraints for target coverage. A senior oncologist approved a random subset of plans for quality assurance. Compared to a high-dose preference, bowel sparing was clinically meaningful at the lower prescribed dose [median change in V45Gy: 234 cm3; inter-quartile range (66; 247); p < .01] and for a bowel sparing preference [median change in V45Gy: 281 cm3; (73; 488); p < .01]. Compared to a high-dose preference, bladder sparing was clinically meaningful at the lower prescribed dose [median change in V35Gy: 13.7%-points; (0.3; 30.6); p < .01] and for a bladder sparing preference [median change in V35Gy: 30.3%-points; (12.4; 43.1); p < .01]. CONCLUSIONS: There is decision space available in anal cancer radiotherapy to incorporate preferences, although tradeoffs are highly patient-dependent. This study demonstrates that preference-informed dose planning is feasible for clinical studies utilizing shared decision making.

Technological advances in radiotherapy of rectal cancer: opportunities and challenges.

PURPOSE OF REVIEW: This review summarizes the available evidence for the use of modern radiotherapy techniques for chemoradiotherapy for rectal cancer, with specific focus on intensity-modulated radiotherapy (IMRT) and volumetric arc therapy (VMAT) techniques. RECENT FINDINGS: The dosimetric benefits of IMRT and VMAT are well established, but prospective clinical studies are limited, with phase I-II studies only. Recent years have seen the publication of a few larger prospective patient series as well as some retrospective cohorts, several of which include much needed late toxicity data. Overall results are encouraging, as toxicity levels - although varying across reports - appear lower than for 3D conformal radiotherapy. Innovative treatment techniques and strategies which may be facilitated by the use of IMRT/VMAT include simultaneously integrated tumour boost, adaptive treatment, selective sparing of specific organs to enable chemotherapy escalation, and nonsurgical management. SUMMARY: Few prospective studies of IMRT and VMAT exist, which causes uncertainty not just in regards to the clinical benefit of these technologies but also in the optimal use. The priority for future research should be subgroups of patients who might receive relatively greater benefit from innovative treatment techniques, such as patients receiving chemoradiotherapy with definitive intent and patients treated with dose escalation.

High-dose chemoradiotherapy and watchful waiting for distal rectal cancer: a prospective observational study.

BACKGROUND: Abdominoperineal resection is the standard treatment for patients with distal T2 or T3 rectal cancers; however, the procedure is extensive and mutilating, and alternative treatment strategies are being investigated. We did a prospective observational trial to assess whether high-dose radiotherapy with concomitant chemotherapy followed by observation (watchful waiting) was successful for non-surgical management of low rectal cancer. METHODS: Patients with primary, resectable, T2 or T3, N0-N1 adenocarcinoma in the lower 6 cm of the rectum were given chemoradiotherapy (60 Gy in 30 fractions to tumour, 50 Gy in 30 fractions to elective lymph node volumes, 5 Gy endorectal brachytherapy boost, and oral tegafur-uracil 300 mg/m(2)) every weekday for 6 weeks. Endoscopies and biopsies of the tumour were done at baseline, throughout the course of treatment (weeks 2, 4, and 6), and 6 weeks after the end of treatment. We allocated patients with complete clinical tumour regression, negative tumour site biopsies, and no nodal or distant metastases on CT and MRI 6 weeks after treatment to the observation group (watchful waiting). We referred all other patients to standard surgery. Patients under observation were followed up closely with endoscopies and selected-site biopsies, with surgical resection given for local recurrence. The primary endpoint was local tumour recurrence 1 year after allocation to the observation group. This study is registered with ClinicalTrials.gov, number NCT00952926. Enrolment is closed, but follow-up continues for secondary endpoints. FINDINGS: Between Oct 20, 2009, and Dec 23, 2013, we enrolled 55 patients. Patients were recruited from three surgical units throughout Denmark and treated in one tertiary cancer centre (Vejle Hospital, Vejle, Denmark). Of 51 patients who were eligible, 40 had clinical complete response and were allocated to observation. Median follow-up for local recurrence in the observation group was 23·9 months (IQR 15·3-31·0). Local recurrence in the observation group at 1 year was 15·5% (95% CI 3·3-26·3). The most common acute grade 3 adverse event during treatment was diarrhoea, which affected four (8%) of 51 patients. Sphincter function in the observation group was excellent, with 18 (72%) of 25 patients at 1 year and 11 (69%) of 16 patients at 2 years reporting no faecal incontinence at all and a median Jorge-Wexner score of 0 (IQR 0-0) at all timepoints. The most common late toxicity was bleeding from the rectal mucosa; grade 3 bleeding was reported in two (7%) in 30 patients at 1 year and one (6%) of 17 patients at 2 years. There were no unexpected serious adverse reactions or treatment-related deaths. INTERPRETATION: High-dose chemoradiotherapy and watchful waiting might be a safe alternative to abdominoperineal resection for patients with distal rectal cancer. FUNDING: CIRRO-The Lundbeck Foundation Center for Interventional Research in Radiation Oncology and The Danish Council for Strategic Research.

Dose-response of acute urinary toxicity of long-course preoperative chemoradiotherapy for rectal cancer.

BACKGROUND: Long-course preoperative chemoradiotherapy (chemo-RT) improves outcomes for rectal cancer patients, but acute side effects during treatment may cause considerable patient discomfort and may compromise treatment compliance. We developed a dose-response model for acute urinary toxicity based on a large, single-institution series. MATERIAL AND METHODS: In total 345 patients were treated with (chemo-)RT for primary rectal cancer from January 2007 to May 2012. Urinary toxicity during RT was scored prospectively using the CTCAE v 3.0 cystitis score (grade 0-5). Clinical variables and radiation dose to the bladder were related to graded toxicity using multivariate ordinal logistic regression. Three models were optimized, each containing all available clinical variables and one of three dose metrics: Mean dose (Dmean), equivalent uniform dose (EUD), or relative volume given x Gy or above (dose cut-off model, Vx). The optimal dose metric was chosen using the Akaike Information Criterion (AIC). RESULTS: Grade 1 cystitis was experienced by 138 (40%), grade 2 by 39 (11%) and grade 3 by two (1%) patients, respectively. Dose metrics were significantly correlated with toxicity in all models, but the dose cut-off model provided the best AIC value. The only significant clinical risk factors in the Vx model were male gender (p = 0.006) and brachytherapy boost (p = 0.02). Reducing the model to include gender, brachytherapy boost and Vx yielded odds ratios ORmale = 1.82 (1.17-2.80), ORbrachy = 1.36 (1.02-1.80 for each 5 Gy), x = 35.1 Gy (28.6-41.5 Gy). The predicted risk of grade 2 and above cystitis ranged from 2% to 26%. CONCLUSION: Acute cystitis correlated significantly with radiation dose to the bladder; the dose-cut-off model (V35Gy) was superior to Dmean and EUD models. Male gender and brachytherapy boost increased the risk of toxicity. Wide variation in predicted risks suggests room for treatment optimization using individual dose constraints.

Cell-free DNA in healthy individuals, noncancerous disease and strong prognostic value in colorectal cancer.

The purpose was to investigate total cell-free DNA (cfDNA) in colorectal cancer (CRC) patients during treatment with second-line chemotherapy and in healthy controls and patients with different comorbidities. Patient treated with second-line irinotecan for metastatic CRC (n = 100), a cohort of healthy controls with and without comorbidity (n = 70 and 100, respectively) were included. cfDNA was quantified by an in-house developed quantitative polymerase chain reaction from plasma samples drawn prior to the first cycle of chemotherapy and at time of progression. cfDNA levels were significantly higher in CRC compared to controls, with a clear capability for discriminating between the groups (receiver operation curve analysis; area under the curve 0.82, p < 0.0001). Patients with high levels had a shorter survival from irinotecan compared to those with lover levels. The cohort independent upper normal limit divided patients into high and low risk groups. The progression-free survival (PFS) was 2.1 months [95% confidence interval (CI) 2.0-3.4] and 6.5 (95% CI 4.2-7.2) months [hazard ratio (HR) 2.53; 95% CI 1.57-4.06, p < 0.0001] and overall survival (OS) 7.4 months (95% CI 4.3-8.7) and 13.8 months (95% CI 11.9-18.9; HR 2.52; 95% CI 1.54-4.13, p < 0.0000), respectively. Cox regression multivariate analysis showed a PFS HR of 1.4 (95% CI 1.1-1.7) for each increase in cfDNA quartile, p = 0.03 and 1.6 (1.3-2.0) for OS, p < 0.0001, respectively. A combined marker analysis with plasma KRAS mutations added further prognostic impact, which was consistent when performed on the samples drawn at time of progression. In conclusion, cfDNA measurement holds important clinical information and could become a useful tool for prediction of outcome from chemotherapy in mCRC.

Towards individualized dose constraints: Adjusting the QUANTEC radiation pneumonitis model for clinical risk factors.

BACKGROUND: Understanding the dose-response of the lung in order to minimize the risk of radiation pneumonitis (RP) is critical for optimization of lung cancer radiotherapy. We propose a method to combine the dose-response relationship for RP in the landmark QUANTEC paper with known clinical risk factors, in order to enable individual risk prediction. The approach is validated in an independent dataset. MATERIAL AND METHODS: The prevalence of risk factors in the patient populations underlying the QUANTEC analysis was estimated, and a previously published method to adjust dose-response relationships for clinical risk factors was employed. Effect size estimates (odds ratios) for risk factors were drawn from a recently published meta-analysis. Baseline values for D50 and γ50 were found. The method was tested in an independent dataset (103 patients), comparing the predictive power of the dose-only QUANTEC model and the model including risk factors. Subdistribution cumulative incidence functions were compared for patients with high/low-risk predictions from the two models, and concordance indices (c-indices) for the prediction of RP were calculated. RESULTS: The reference dose- response relationship for a patient without pulmonary co-morbidities, caudally located tumor, no history of smoking, < 63 years old, and receiving no sequential chemotherapy was estimated as D50(0) = 34.4 Gy (95% CI 30.7, 38.9), γ50(0) = 1.19 (95% CI 1.00, 1.43). Individual patient risk estimates were calculated. The cumulative incidences of RP in the validation dataset were not significantly different in high/low-risk patients when doing risk allocation with the QUANTEC model (p = 0.11), but were significantly different using the individualized model (p = 0.006). C-indices were significantly different between the dose-only and the individualized model. CONCLUSION: This study presents a method to combine a published dose-response function with known clinical risk factors and demonstrates the increased predictive power of the combined model. The method allows for individualization of dose constraints and individual patient risk estimates.

Individual lymph node position variation for rectal cancer patients treated with long course chemoradiotherapy.

Background and purpose: Delivery of high precision radiotherapy lymph node boosts requires detailed information on the interfraction positional variation of individual lymph nodes. In this study we characterized interfraction positional shifts of suspected malignant lymph nodes for rectal cancer patients receiving long course radiotherapy. Furthermore, we investigated parameters which could affect the magnitude of the position variation. Materials and Methods: Fourteen patients from a prospective clinical imaging study with a total of 61 suspected malignant lymph nodes in the mesorectum, presacral, and lateral regions, were included. The primary gross tumor volume (GTVp) and all suspected malignant lymph nodes were delineated on six magnetic resonance imaging scans per patient. Positional variation was calculated as systematic and random errors, based on shifts of center-of-mass, and estimated relative to either bony structures or the GTVp using a hierarchical linear mixed model. Results: Depending on location and direction, systematic and random variations (relative to bony structures) were within 0.6-2.8 mm and 0.6-2.9 mm, respectively. Systematic and random variations increased when evaluating position relative to GTVp (median increase of 0.6 mm and 0.5 mm, respectively). Correlations with scan time-point and relative bladder volume were found in some directions. Conclusions: Using linear mixed modeling, we estimated systematic and random positional variation for suspected malignant lymph nodes in rectal cancer patients treated with long course radiotherapy. Statistically significant correlations of the magnitude of the lymph node shifts were found related to scan time-point and relative bladder volume.

Technical note: Optimization functions for re-irradiation treatment planning.

BACKGROUND: Although re-irradiation is increasingly used in clinical practice, almost no dedicated planning software exists. PURPOSE: Standard dose-based optimization functions were adjusted for re-irradiation planning using accumulated equivalent dose in 2-Gy fractions (EQD2) with rigid or deformable dose mapping, tissue-specific α/ß, treatment-specific recovery coefficients, and voxelwise adjusted EQD2 penalization levels based on the estimated previously delivered EQD2 (EQD2deliv ). METHODS: To demonstrate proof-of-concept, 35 Gy in 5 fractions was planned to a fictitious spherical relapse planning target volume (PTV) in three separate locations following previous prostate treatment on a virtual human phantom. The PTV locations represented one repeated irradiation scenario and two re-irradiation scenarios. For each scenario, three re-planning strategies with identical PTV dose-functions but various organ at risk (OAR) EQD2-functions was used: 1) reRTregular : Regular functions with fixed EQD2 penalization levels larger than EQD2deliv for all OAR voxels. 2) reRTreduce : As reRTregular , but with lower fixed EQD2 penalization levels aiming to reduce OAR EQD2. 3) reRTvoxelwise : As reRTregular and reRTreduce , but with voxelwise adjusted EQD2 penalization levels based on EQD2deliv . PTV near-minimum and near-maximum dose (D98% /D2% ), homogeneity index (HI), conformity index (CI) and accumulated OAR EQD2 (α/ß = 3 Gy) were evaluated. RESULTS: For the repeated irradiation scenario, all strategies resulted in similar dose distributions. For the re-irradiation scenarios, reRTreduce and reRTvoxelwise reduced accumulated average and near-maximum EQD2 by ˜1-10 Gy for all relevant OARs compared to reRTregular . The reduced OAR doses for reRTreduce came at the cost of distorted dose distributions with D98% = 92.3%, HI = 12.0%, CI = 73.7% and normal tissue hot spots ≥150% for the most complex scenario, while reRTregular (D98% = 98.1%, HI = 3.2%, CI = 94.2%) and reRTvoxelwise (D98%  = 96.9%, HI = 6.1%, CI = 93.7%) fulfilled PTV coverage without hot spots. CONCLUSIONS: The proposed re-irradiation-specific EQD2-based optimization functions introduce novel planning possibilities with flexible options to guide the trade-off between target coverage and OAR sparing with voxelwise adapted penalization levels based on EQD2deliv .

Early radiologic and metabolic tumour response assessment during combined chemo-radiotherapy for locally advanced NSCLC.

Background: The role of early treatment response for patients with locally advanced non-small cell lung cancer (LA-NSCLC) treated with concurrent chemo-radiotherapy (cCRT) is unclear. The study aims to investigate the predictive value of response to induction chemotherapy (iCX) and the correlation with pattern of failure (PoF). Materials and methods: Patients with LA-NSCLC treated with cCRT were included for analyses (n = 276). Target delineations were registered from radiotherapy planning PET/CT to diagnostic PET/CT, in between which patients received iCX. Volume, sphericity, and SUVpeak were extracted from each scan. First site of failure was categorised as loco-regional (LR), distant (DM), or simultaneous LR+M (LR+M). Fine and Gray models for PoF were performed: a baseline model (including performance status (PS), stage, and histology), an image model for squamous cell carcinoma (SCC), and an image model for non-SCC. Parameters included PS, volume (VOL) of tumour, VOL of lymph nodes, ΔVOL, sphericity, SUVpeak, ΔSUVpeak, and oligometastatic disease. Results: Median follow-up was 7.6 years. SCC had higher sub-distribution hazard ratio (sHR) for LRF (sHR = 2.771 [1.577:4.87], p < 0.01) and decreased sHR for DM (sHR = 0.247 [0.125:0.485], p  <  0.01). For both image models, high diagnostic SUVpeak increased risk of LRF (sHR = 1.059 [1.05:1.106], p < 0.01 for SCC, sHR = 1.12 [1.03:1.21], p < 0.01 for non-SCC). Patients with SCC and less decrease in VOL had higher sHR for DM (sHR = 1.025[1.001:1.048] pr. % increase, p = 0.038). Conclusion: Poor response in disease volume was correlated with higher sHR of DM for SCC, no other clear correlation of response and PoF was observed. Histology significantly correlated with PoF with SCC prone to LRF and non-SCC prone to DM as first site of failure. High SUVpeak at diagnosis increased the risk of LRF for both histologies.

Treatment planning for patients with low rectal cancer in a multicenter prospective organ preservation study.

BACKGROUND: Non-surgical management of rectal cancer relies on (chemo)radiotherapy as the definitive treatment modality. This study reports and evaluates the clinical high dose radiotherapy treatment plans delivered to patients with low resectable rectal cancer in a Danish multicenter trial. METHODS: The Danish prospective multicenter phase II Watchful Waiting 2 trial (NCT02438839) investigated definitive chemoradiation for non-surgical management of low rectal cancer. Three Danish centers participated in the trial and committed to protocol-specified treatment planning and delivery requirements. The protocol specified a dose of 50.4 Gy in 28 fractions to the elective volume (CTV-/PTV-E) and a concomitant boost of 62 Gy in 28 fractions to the primary target volume (CTV-/PTV-T). RESULTS: The trial included 108 patients, of which 106 treatment plans were available for retrospective analysis. Dose coverage planning goals for the main target structures were fulfilled for 94% of the treatment plans. However, large intercenter differences in doses to organs-at-risk (OARs) were seen, especially for the intestines. Five patients had a V60Gy>10 cm3 for the intestines and two patients for the bladder. CONCLUSION: Prescribed planning goals for target coverage were fulfilled for 94% of the treatment plans, however analysis of OAR doses and volumes indicated intercenter variations. Dose escalation to 62 Gy (as a concomitant boost to the primary tumor) introduced no substantial high dose volumes (>60 Gy) to the bladder and intestines. The treatment planning goals may be used for future prospective evaluation of highdose radiotherapy for organ preservation for low rectal cancer.