Sex-Specific Cut-Off Values for Low Skeletal Muscle Mass to Identify Patients at Risk for Treatment-Related Adverse Events in Head and Neck Cancer

A low skeletal muscle index (SMI), defined with cut-off values, is a promising predictor for adverse events (AEs) in head and neck squamous cell cancer (HNSCC) patients. The aim was to generate sex-specific SMI cut-off values based on AE to diagnose low SMI and to analyse the relationship between low SMI and AEs in HNSCC patients. In this present study, HNSCC patients were prospectively included in a large oncological data-biobank and SMI was retrospectively measured using baseline neck scans. In total, 193 patients were included and were stratified according to treatment modality: (chemo-)radiotherapy ((C)RT) (n = 135) and surgery (n = 61). AE endpoints were based on the occurrence of clinically relevant toxicities (Common Terminology Criteria for Adverse Events grade ≥ III) and postoperative complications (Clavien–Dindo Classification grade ≥ II). Sex-specific SMI cut-off values were generated with receiver operating characteristic curves, based on the AE endpoints. The relationship of the baseline characteristics and AEs was analysed with logistic regression analysis, with AEs as the endpoint. Multivariable logistic analysis showed that low SMI (OR 3.33, 95%CI 1.41–7.85) and tumour stage (OR 3.45, 95%CI 1.28–9.29) were significantly and independently associated to (C)RT toxicity. Low SMI was not related to postoperative complications. To conclude, sex-specific SMI cut-off values, were generated based on the occurrence of AEs. Low SMI and tumour stage were independently related to (C)RT toxicity in HNSCC patients

Impact of sarcopenia on acute radiation-induced toxicity in head and neck cancer patients

Background and purpose: Sarcopenia is related to late radiation-induced toxicities and worse survival in head and neck cancer (HNC) patients. This study tested the hypothesis that sarcopenia improves the performance of current normal tissue complication probability (NTCP) models of radiation-induced acute toxicity in HNC patients. Material/methods: This was a retrospective analysis in a prospective cohort of HNC patients treated from January 2007 to December 2018 with (chemo)radiotherapy. Planning CT scans were used for evaluating skeletal muscle mass. Characteristics of sarcopenic and non-sarcopenic patients were compared. The impact of sarcopenia was analysed by adding sarcopenia to the linear predictors of current NTCP models predicting physician- and patient-rated acute toxicities. Results: The cut-off values of sarcopenia in the study population (n = 977) were established at skeletal muscle index = 2, p = 3 dysphagia (week 3-6 during RT, p 0.99). Conclusion: Sarcopenia in HNC patients was an independent prognostic factor for radiation-induced physician-rated acute grade >= 3 dysphagia, which might be explained by its impact on swallowing muscles. However, addition of sarcopenia did not improve the NTCP model performance. (c) 2022 The Author(s). Published by Elsevier B.V. Radiotherapy and Oncology 170 (2022) 122-128 This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Relatieve bijdrage van bestralingsdosis op stamcelrijke en niet-stamcelrijke regio binnen de glandula parotis in het voorspellen van xerostomie bij hoofd-halskankerpatiënten

INTRODUCTIE Ondanks alle ontwikkelingen in de radiotherapie ervaren hoofd-halskankerpatiënten nog steeds xerostomie ten gevolge van speekselklierbestraling. De parotisstamcellen, met name gelokaliseerd rond de grote afvoergangen (stamcelrijke regio), hebben een cruciale rol in de radiatierespons van de glandula parotis. Kennis over het relatieve belang van dosis op deze stamcelrijke regio en dosis op het overig deel van de parotis (niet-stamcelrijke regio) is essentieel voor optimalisatie van een bestralingsplan. Daarom kwantificeert deze studie de relatieve bijdrage van bestralingsdosis op de stamcelrijke en de niet-stamcelrijke regio in het ontstaan van bijwerkingen. METHODE De studiepopulatie bestond uit 102 hoofd-halskankerpatiënten die eerder hadden deelgenomen aan een gerandomiseerde studie naar het effect van stamcelsparende radiotherapie. Gemeten bijwerkingen waren patiënt-gescoorde xerostomie overdag en tijdens eten, en arts-gescoorde xerostomie op 6, 12 en 24 maanden na radiotherapie. De dosis ratio van de glandula parotis a in Deff (effectieve bestralingsdosis) = Dgem (gemiddelde bestralingsdosis) stamcelrijke regio + a * Dgem niet-stamcelrijke regio, waarbij Deff de beste voorspeller was voor bijwerkingen, werd bepaald met multivariabele logistische regressie. RESULTATEN Bestralingsdosis op de contralaterale parotis (sub)structuren was significant geassocieerd met de gemeten bijwerkingen. Deff is gelijk aan Dgem glandula parotis voor a = 3,6, dit betekent dat Dgem niet-stamcelrijke regio 3,6 keer zoveel bijdraagt als Dgem stamcelrijke regio. Terwijl de bijdrage van Dgem stamcelrijke regio aan het ontstaan van bijwerkingen juist groter is voor a < 3,6. Voor alle bijwerkingen, behalve xerostomie tijdens eten op 24 maanden (a=4.49), was de dosis ratio a kleiner dan 3,6 (variërend van 0,00 tot 1,23). Derhalve was de relatieve bijdrage van Dgem stamcelrijke regio aan het ontstaan van xerostomie na radiotherapie 2,1 tot 4,6 keer groter dan aangegeven door Dgem glandula parotisCONCLUSIE Risicoreductie van bijwerkingen door schade aan de glandula parotis, is met name te bereiken door het verminderen van bestralingsdosis op het stamcelrijke gebied

OC-0109 Functional dose to the parotid gland: a new regional based dose metric in NTCP models for xerostomia

Purpose or Objective Despite improvements, HNC patients still experience xerostomia due to RT-induced salivary gland damage. The parotid gland’s (PG) stem cells, concentrated in the gland’s main ducts (stem cell rich (SCR) region), play a critical role in the PG’s response to radiation. However, treatment optimization requires dose metrics accounting for the relative contributions of dose to this SCR region and dose to the remainder of the gland (non-SCR region) to the risk of xerostomia. This study aimed to develop such dose metric: the functional dose. Subsequently, NTCP models including additional contributions of other risk factors were constructed using multivariable logistic regression analyses. Materials and Methods Treatment and toxicity data of 1,013 HNC patients treated with definitive RT was obtained from our prospective data registration program. Xerostomia was measured with the EORTC QLQ-H&N35, the Groningen Radiotherapy-Induced Xerostomia questionnaire and the CTCAE version 4. For xerostomia endpoints associated with PG dose, functional dose (Dfunc) to the PG was defined as Dfunc,PG = Dmean,SCR + r * Dmean,non-SCR. In our cohort for weighting factor r = 3.6, Dfunc,PG corresponds to Dmean,PG. This reflects the difference in volume between the SCR and the non-SCR region. A value of r < 3.6 indicates an enhanced contribution of Dmean,SCR to the risk of xerostomia. The value of r for which Dfunc,PG was the best predictor for xerostomia endpoints, was estimated in a subset of 102 patients included in a previously-published randomized controlled trial testing stem cell sparing RT(1). Next, for each endpoint Dfunc,PG, dose to other organs and clinical factors were used to develop multivariable NTCP models in 663 patients. Finally, these models were validated in the remaining 350 patients. Results Dose to contralateral PG (sub)structures was significantly associated with patient-rated daytime, eating-related and physician-rated grade ≥2 xerostomia. No associations with patient-rated general, activity-related and nighttime xerostomia were found.The estimations of r were smaller than 3.6 for most xerostomia endpoints (Table 1), demonstrating that Dmean,PG underestimates the contribution of dose to the SCR region to the risk of xerostomia. The most-frequently additional risk factors identified in multivariable modeling were pretreatment xerostomia and Dmean oral cavity (Table 1). The models showed moderate-to-good discrimination and calibration after internal and external validation (Table 2). Conclusion We developed a new dose metric to account for the larger contribution of dose to the stem cell rich region to the risk of xerostomia. This new dose metric was subsequently used to develop novel multivariable models that can be used for the routine implementation of stem cell sparing RT. (1) Steenbakkers, RJHM et al. Parotid Gland Stem Cell Sparing Radiation Therapy for Patients with Head and Neck cancer: A Double-Blind Randomized Controlled Trial. Int. J. Radiat. Oncol. 112, 306-316 (2022)

Impact of sarcopenia on survival and late toxicity in head and neck cancer patients treated with RT

Purpose/Objective Sarcopenia, defined as the loss of skeletal muscle mass and strength, is emerging as an adverse prognostic factor for both survival and complication risk in cancer patients. The aim of this study was to determine the impact of sarcopenia on several survival parameters and late toxicity in a large cohort of patients with head and neck squamous cell carcinoma (HNSCC) treated with primary radiotherapy (RT). Material/methods Patients with HNSCC who were treated with definitive RT with or without systemic treatment from January 2007 to June 2016 were included. Prospectively collected variables were retrospectively analysed. The planning CT-scan was used to measure the cross-sectional area (CSA) of skeletal muscles at the level of the third cervical vertebra (C3). The prediction rule by Swartz et al. was used to estimate CSA at the third lumbar vertebra (L3). L3 skeletal muscle index (SMI) was calculated. The impact of sarcopenia on overall survival (OS) and disease-free survival (DFS) was investigated using univariate (Kaplan Meier) and multivariate (Cox proportional hazards regression) analysis. To analyse the association of sarcopenia with physician-rated grade ≥2 toxicity (i.e. xerostomia and dysphagia) and with moderate-to-severe patient-rated xerostomia, multivariable logistic regression analyses were performed to create association models. Results The study population was composed of 750 patients with HNSCC. The cut-off value of sarcopenia was set at SMI &lt;42.4 cm2/m2 (men) and &lt;30.6 cm2/m2 (women) corresponding with the lowest gender specific quartile. Patients with sarcopenia had significantly poorer survival rates than others. The 3-year OS in sarcopenic patients was 53% compared to 73% in non-sarcopenic patients (p&lt;0.001) and the 3-year DFS was resp. 59% and 76% (p&lt;0.001). However, sarcopenia was only significantly associated with OS and DFS in patients with WHO performance score (WHO-score)&gt;0 (resp. p&lt;0.001 and p=0.003) and in those with locally advanced disease (stage III-IV) (both p&lt;0.001) (Figure 1 OS stratified by stage of disease). The multivariate analysis showed that sarcopenia was an independent adverse prognostic factor for OS (p=0.004), next to age, WHO-score, tumour stage and primary tumour site and for DFS (p=0.013), next to age, WHO-score and tumour stage (Table 1). In the univariate analysis, sarcopenia was associated with more radiation-induced xerostomia and dysphagia at six and twelve months after treatment, but no such association was found in multivariate analysis after correcting for confounders. Conclusion In this prospective cohort study, sarcopenia was significantly associated with poorer OS and DFS, for patients with lower performance (WHO-score &gt;0) and locally advanced disease (stage III-IV), with similar prognostic value as WHO-score, tumour stage and primary tumour site. Given that the SMI can be easily assessed on planning-CT scan, clinical introduction is easy and adds important and clinically relevant information to assess patient outcome