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Plan evaluation is a key step in the radiotherapy treatment workflow. Central to this step is the assessment of treatment plan quality. Hence, it is important to agree on what we mean ...by plan quality and to be fully aware of which parameters it depends on. We understand plan quality in radiotherapy as the clinical suitability of the delivered dose distribution that can be realistically expected from a treatment plan. Plan quality is commonly assessed by evaluating the dose distribution calculated by the treatment planning system (TPS). Evaluating the 3D dose distribution is not easy, however; it is hard to fully evaluate its spatial characteristics and we still lack the knowledge for personalising the prediction of the clinical outcome based on individual patient characteristics. This advocates for standardisation and systematic collection of clinical data and outcomes after radiotherapy. Additionally, the calculated dose distribution is not exactly the dose delivered to the patient due to uncertainties in the dose calculation and the treatment delivery, including variations in the patient set-up and anatomy. Consequently, plan quality also depends on the robustness and complexity of the treatment plan. We believe that future work and consensus on the best metrics for quality indices are required. Better tools are needed in TPSs for the evaluation of dose distributions, for the robust evaluation and optimisation of treatment plans, and for controlling and reporting plan complexity. Implementation of such tools and a better understanding of these concepts will facilitate the handling of these characteristics in clinical practice and be helpful to increase the overall quality of treatment plans in radiotherapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Defining margins around the Gross Tumour Volume (GTV) to create a Clinical Target Volume (CTV) for head and neck cancer radiotherapy has traditionally been based on presumed knowledge of anatomical ...routes of spread. However, using a concentric geometric expansion around the GTV may be more reproducible. The purpose of this study was to analyse the inter-observer consistency of geometric CTV delineation with adaptation for anatomical boundaries versus anatomically defined CTVs.
Radiation oncologists at four Danish cancer centres delineated high, intermediate and elective dose CTVs (CTV1, CTV2 and CTV3, respectively) in a patient-case template (stage IV squamous cell carcinoma of the oropharynx), first using mainly anatomical margins (original standard) and then using concentric geometric expansion (new standard). Each centre made a dummy-run radiotherapy plan based on the delineated CTVs. The difference between the CTV contours and the radiotherapy plans was evaluated across the centres.
Anatomy-based contours were significantly more heterogenous and showed larger volume differences between centres than geometric margins. Dice similarity coefficient increased by 0.29 and mean surface distance decreased by 4mm for CTV1. Use of consistent CTV volumes resulted in more consistent irradiated volumes between centres.
Introduction of geometric margins resulted in more uniform CTV1 and CTV2 delineation. Geometric CTV expansion was easier, left less room for misinterpretation, and resulted in more uniform treatment plans with similar irradiated high and intermediate dose volumes across all centres.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
•64 HNSCC outcome prediction models containing clinical variables were reviewed.•Model performance measures and full model information were poorly reported.•Most model publications were at high risk ...of bias due to methodological issues.•The methodological issues may affect model accuracy in heterogeneous populations.•External validation and clinical impact studies are essential before clinical use.
Multiple outcome prediction models have been developed for Head and Neck Squamous Cell Carcinoma (HNSCC). This systematic review aimed to identify HNSCC outcome prediction model studies, assess their methodological quality and identify those with potential utility for clinical practice. Inclusion criteria were mucosal HNSCC prognostic prediction model studies (development or validation) incorporating clinically available variables accessible at time of treatment decision making and predicting tumour-related outcomes. Eligible publications were identified from PubMed and Embase. Methodological quality and risk of bias were assessed using the checklist for critical appraisal and data extraction for systematic reviews of prediction modelling studies (CHARMS) and prediction model risk of bias assessment tool (PROBAST). Eligible publications were categorised by study type for reporting. 64 eligible publications were identified; 55 reported model development, 37 external validations, with 28 reporting both. CHARMS checklist items relating to participants, predictors, outcomes, handling of missing data, and some model development and evaluation procedures were generally well-reported. Less well-reported were measures accounting for model overfitting and model performance measures, especially model calibration. Full model information was poorly reported (3/55 model developments), specifically model intercept, baseline survival or full model code. Most publications (54/55 model developments, 28/37 external validations) were found to have high risk of bias, predominantly due to methodological issues in the PROBAST analysis domain. The identified methodological issues may affect prediction model accuracy in heterogeneous populations. Independent external validation studies in the local population and demonstration of clinical impact are essential for the clinical implementation of outcome prediction models.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We compare outcomes in two large‐scale contemporaneously treated HPV‐positive (HPV+) oropharynx cancer (OPC) cohorts treated with definitive radiotherapy/chemoradiotherapy (RT/CRT). p16‐confirmed ...HPV+ OPC treated between 2007 and 2015 at PMH and DAHANCA were identified. Locoregional failure (LRF), distant metastasis (DM), and overall survival (OS) were compared. Multivariable analysis (MVA) calculated adjusted‐hazard‐ratio (aHR) with 95% confidence interval (95% CI), adjusting for cohort, age, gender, performance status, smoking pack‐years, T‐category and N‐category and chemotherapy. Compared to PMH (n = 701), DAHANCA (n = 1174) contained lower TNM‐8T‐categories (T1‐T2: 77% vs 56%), N‐categories (N0‐N1: 77% vs 67%) and stages (stage I: 63% vs 44% (all P < .001). PMH used standard‐fractionation CRT in 69% (481) while 31% (220) received hypofractionated or moderately accelerated RT‐alone. All DAHANCA patients were treated with moderately accelerated RT; 96% (1129) received nimorazole (NIM) and 73% (856) concurrent weekly cisplatin. DAHANCA had shorter overall‐treatment‐time (P < .001), lower gross tumor (66‐68 vs 70 Gy) and elective neck (50 vs 56 Gy) doses. Median follow‐up was 4.8 years. DAHANCA had higher 5‐year LRF (13% vs 7%, aHR = 0.47 0.34‐0.67), comparable DM (7% vs 12%, aHR = 1.32 0.95‐1.82), but better OS (85% vs 80%, aHR = 1.30 1.01‐1.68). CRT patients had a lower risk of LRF (aHR 0.56 0.39‐0.82), DM (aHR 0.70 0.50‐1.00) and death (aHR 0.39 0.29‐0.52) vs RT‐alone. We observed exemplary outcomes for two large‐scale trans‐Atlantic HPV+ OPC cohorts treated in a similar manner. Concurrent chemotherapy was a strong, independent prognostic factor for all endpoints. Our findings underscore the need for a very careful approach to de‐intensification of treatment for this disease.
What's new?
HPV‐positive oropharyngeal cancer (OPC) represents a unique subgroup which has very different epidemiology, molecular biology, and response to radiotherapy/chemo‐radiotherapy (RT/CRT) than HPV‐negative squamous cell carcinoma of the head and neck (HNSCC). In this study, the authors compared two large cohorts of HPV‐positive OPC, and found significantly better outcomes in patients that routinely received concurrent chemoradiotherapy with cisplatin compared with radiotherapy alone. The authors conclude that these findings underscore the need for a cautious approach to efforts aimed at de‐intensifying treatment for this disease.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The objective of this study was to evaluate whether patient biological sex influences treatment outcomes in patients with metastatic melanoma (MM) undergoing first-line immune checkpoint inhibitor ...(ICI) therapy.
The Danish Metastatic Melanoma Database (DAMMED) was employed to identify patients who underwent first-line ICI therapy for MM in Denmark from 2013 to 2021. Excluding adjuvant treatment, uveal and mucosal histological subtypes, the study conducted univariable and multivariable analyses to evaluate the influence of patient sex in survival analyses. Further, landmark survival of this real-world national cohort was described for progression free survival (PFS), overall survival (OS) and melanoma-specific survival (MSS).
The analysis encompassed a cohort of 1378 patients with MM. Compared to male sex, females had significantly improved OS (p = 0.003) when tested in univariable testing. Multivariable analyses, controlling for age, performance status, lactate dehydrogenase level, BRAF status, M-stage, and number of metastatic sites revealed significant favourable outcomes associated with female sex irrespective of the considered survival metrics (pPFS = 0.014, pOS = 0.002, and pMSS = 0.03). The observed five-year OS rates of the entire cohort were 47% and 38%, while melanoma-specific survival were 50% and 45% for female and male, respectively.
In this nationwide cohort of patients with MM undergoing first-line ICI treatment females exhibited superior treatment outcomes compared to males. Sex was identified as an independent predictive variable for treatment outcomes, irrespective of the chosen outcome measures considered. Our analyses are not able to conclude whether the differences in outcome is attributable to differences in biology or to treatment strategy.
•The impact of patient sex on treatment outcome for metastatic melanoma is debatable.•National, observational cohort study.•1378 metastatic melanoma patients analysed undergoing first-line ICI treatment.•Female biological sex associated with significant improved PFS, OS, and MSS.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•Intensification of RT is needed to improve tumor control in high-risk HNSCC.•Dose escalation is possible using hyperfractionation.•Combining hyperfractionation, acceleration, cisplatin and ...nimorazole was feasible.•Toxicity was slightly enhanced compared to standard chemo-radiotherapy, but manageable.•The combination schedule yielded favorable tumor control.
A phase I–II study to evaluate the feasibility and efficacy of intensified, primary radiotherapy (RT) for Locally Advanced Head and Neck Squamous Cell Carcinoma (LAHNSCC) employing dose escalation by hyperfractionation, acceleration of treatment time, concomitant chemotherapy and hypoxic modification.
Patients with HPV/p16- LAHNSCC receiving primary hyperfractionated, accelerated RT, 76 Gy/56 fx, 10 fx/week for 5½ weeks, concomitant weekly cisplatin (40 mg/m2) and nimorazole (HART-CN) were included. Primary endpoint was locoregional failure (LRF). Secondary endpoints were overall survival (OS) and toxicity.
50 patients received HART-CN from 2013 to 2017. Median age was 60 years. Most patients had stage IV hypo- or oropharynx cancer with a heavy smoking history. All oropharyngeal cancers were HPV/p16-negative. Ninety-eight percent of patients completed RT, but compliance to cisplatin and nimorazole was lower. Median observation time was 44 months. LRF was diagnosed in 10 patients. All LRFs were in the high-dose CTV. The 3-year actuarial LRF was 21%, and OS was 74%. The peak incidence of acute toxicity showed that 67% of patients experienced severe dysphagia, 61% severe mucositis, and 78% were equipped with feeding tubes. Late severe morbidity was seen in 7 of 29 recurrence-free patients with at least 3 years of followup, who presented with either severe dysphagia (n = 2), severe xerostomia (n = 1), severe fibrosis of the neck (n = 3) or osteoradionecrosis (n = 1). Three were still tube dependent.
HART-CN is feasible in patients with HPV/p16- LAHNSCC in good health. Although acute toxicity was pronounced, the proportion of patients with late toxicity was acceptable and outcome at 3 years encouraging.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A high‐quality treatment plan aims to best achieve the clinical prescription, balancing high target dose to maximise tumour control against sufficiently low organ‐at‐risk dose for acceptably low ...toxicity. Treatment planning (TP) includes multiple steps from simulation/imaging and segmentation to technical plan production and reporting. Consistent quality across this process requires close collaboration and communication between clinical and technical experts, to clearly understand clinical requirements and priorities and also practical uncertainties, limitations and compromises. TP quality depends on many aspects, starting from commissioning and quality management of the treatment planning system (TPS), including its measured input data and detailed understanding of TPS models and limitations. It requires rigorous quality assurance of the whole planning process and it links to plan deliverability, assessable by measurement‐based verification. This review highlights some factors influencing plan quality, for consideration for optimal plan construction and hence optimal outcomes for each patient. It also indicates some challenges, sources of difference and current developments. The topics considered include: the evolution of TP techniques; dose prescription issues; tools and methods to evaluate plan quality; and some aspects of practical TP. The understanding of what constitutes a high‐quality treatment plan continues to evolve with new techniques, delivery methods and related evidence‐based science. This review summarises the current position, noting developments in the concept and the need for further robust tools to help achieve it.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
•18F-FAZA imaging was used in a prospective trial of 38 HNSCC patients completing radiotherapy.•Within 5 years of follow-up, nine locoregional treatment failures were observed.•A high tumor-muscle ...ratio of tracer uptake (TMR ≥1.6) was associated with a higher risk of locoregional failure.•This association remained significant, when accounting for HPV/p16-positivity.•FAZA PET likely identifies cases, where treatment intensification is indicated.
Hypoxic tumor volumes can be visualized with 18F-FAZA PET/CT. In head and neck squamous cell carcinoma (HNSCC), hypoxia is important for the clinical outcome after primary radiotherapy (RT). The outcome is furthermore heavily influenced by the HPV/p16-positivity of oropharyngeal tumors (OPCp16+ tumors). The study purposes were (1) to report on locoregional failures within five years after primary RT in a prospective cohort stratified by both HPV/p16-status and PET hypoxia and (2) to characterize the failure site and the spatial association to PET hypoxia.
From 2009 to 2011, 38 patients with non-metastatic SCC of the larynx, oro-, hypo- and nasopharynx completing primary RT were included in the prospective DAHANCA 24 trial (NCT01017224). Fifteen patients had OPCp16+ tumors. All were imaged with a static FAZA PET/CT prior to treatment. The hypoxia threshold was determined by a tumor-to-muscle ratio (TMR) of 1.6. Recurrences were documented histologically. Imaging of the recurrence was deformable fused with the pre-treatment FAZA PET/CT. The spatial information of recurrence- and hypoxic volumes were compared visually.
Sixteen patients had more hypoxic tumors (high tracer uptake, TMR ≥1.6) before treatment (42%). With a median follow-up of 7.8 years, nine locoregional recurrences were observed, of which seven were in patients with high-uptake tumors (44% and 9%, respectively, HR 5.8 1.2–28.2). The risk of locoregional recurrence was highest among patients with more hypoxic, non-OPCp16+ tumors (57% 21–94%), with a risk difference of 45% 4–86%, when comparing to less hypoxic, non-OPCp16+ tumors. Eight patients had sufficient imaging of the recurrence for co-registration with the FAZA PET/CT. Six had hypoxic primary tumors, and in two, the recurrence was overlapping the baseline hypoxic subvolume.
HNSCC demonstrating a TMR ≥1.6 at baseline is significantly associated with treatment failure after primary RT. In addition to HPV/p16-status, FAZA PET/CT has potential for the selection of tumors requiring treatment intensification.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
BACKGROUNDThis study investigated changes in body weight, lean body mass (LBM), fat mass (FM), muscle strength and functional performance during radiation treatment in head and neck cancer (HNSCC) ...patients. Secondly, it investigated the impact of cisplatin-based chemoradiation (CCRT) on LBM loss compared with radiation alone.METHODS48 patients (all tumor sites) received either 6 weeks of radiation alone (n = 16) with 66-68 Gy in 33-34 Fx, 5-6 Fx/week or CCRT, adding weekly cisplatin or carboplatin (n = 32). LBM and FM was evaluated using Dual-energy X-ray Absorptiometry bi-weekly from pre- to two weeks post-treatment. Maximal muscle strength (knee extension, leg - and chest press) and functional performance (stair climb, chair rise, and arm curl) were assessed pre- and post-treatment.RESULTSBody weight and LBM had declined significantly already week 2 into treatment and declined significantly further through week 4 and 6 before leveling off after week 6. Bi-weekly, from treatment start to week 2, 2-4, and 4-6, LBM declined 1.2 ± 0.4 kg (p = .002; 95% CI: 0.4;2.0), 2.0 ± 0.4 kg (p < .0001; 1.2;2.8) and 1.4 ± 0.4 kg (p = .001; 0.6;2.2). With a two-week delay, FM declined significantly from week 2-8. All measures of muscle strength declined significantly from pre- to post-treatment. Functional performance was unchanged. LBM loss from pre- to post-treatment was significantly associated with impaired muscle strength (R2 = 0.3-0.5). CCRT patients lost 3.1 ± 0.8 kg of LBM (p = .0001; 1.5;4.7) more from pre- to post-treatment compared with patients receiving radiation alone. Analyses adjusting for nimorazole, tumor stage, baseline BMI, mean radiation dose to constrictor muscles and oral cavity confirmed this.CONCLUSIONAccelerated and substantial LBM loss was already initiated within the first two weeks of treatment - before the onset of radiation-induced mucositis. LBM loss was associated with muscle strength impairment. Patients receiving CCRT experienced significantly larger LBM loss than patients receiving radiation alone. Registered on clinincaltrials.gov (Identifier: NCT05890859).
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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