FDG-PET/CT improves detection of residual disease and reduces the need for examination under anaesthesia in oropharyngeal cancer patients treated with (chemo-)radiation.

PURPOSE: Early detection of residual disease (RD) after (chemo)radiation for oropharyngeal (OPC) is crucial. Surveillance of neck nodes with FDG-PET/CT has been studied extensively, whereas its value for local RD remains less clear. We aim to evaluate the diagnostic value of post-treatment FDG-PET/CT in detecting local RD and the outcome of patients with local RD. METHODS: A cohort (n = 352) of consecutively treated OPC patients at our institute between 2010 and 2017 was evaluated. Patients that underwent FDG-PET/CT at 3 months post-treatment (n = 94) were classified as having complete (CMR) or partial metabolic response (PMR). PMR was defined as visually detectable metabolic activity above the background of surrounding normal tissues. Primary endpoint was diagnostic accuracy in detecting local RD. RESULTS: Local RD was seen in 19/352 patients (5%), all of them were HPV negative. The FDG-PET/CT had a sensitivity of 100% (8/8), specificity 85% (73/86), PPV 38% (8/21), NPV 100% (73/73), and accuracy 86%. Patients with local RD had significantly worse OS at 2 years, compared to those without (10 versus 88%, P < 0.001). In multivariable analysis, local RD remained a significant predictive factor for death with a hazard ratio of 11.9 (95% CI 5.8-24.3). The number of patients that underwent PET/CT increased over time (P < 0.001), whereas the number of patients that underwent EUA declined (P = 0.072). CONCLUSION: FDG-PET/CT has excellent performance for the detection of RD, with the sensitivity and negative predictive value approaching 100%. Due to these excellent results is examination under anaesthesia today in the vast majority of the PET-negative cases not necessary anymore.

Biological PET-guided adaptive radiotherapy for dose escalation in head and neck cancer: a systematic review.

INTRODUCTION: In recent years, the possibility of adapting radiotherapy to changes in biological tissue parameters has emerged. It is hypothesized that early identification of radio-resistant parts of the tumor during treatment provides the possibility to adjust the radiotherapy plan to improve outcome. The aim of this systematic literature review was to evaluate the current state of the art of biological PET-guided adaptive radiotherapy, focusing on dose escalation to radio-resistant tumor. EVIDENCE ACQUISITION: A structured literature search was done to select clinical trials including patients with head and neck cancer of the oral cavity, oropharynx, hypopharynx or larynx, with a PET performed during treatment used to develop biological adaptive radiotherapy by: 1) delineation of sub-volumes suitable for adaptive re-planning; 2) in-silico adaptive treatment planning; or 3) treatment of patients with PET based dose escalated adaptive radiotherapy. EVIDENCE SYNTHESIS: Nineteen articles were selected, 12 articles analyzing molecular imaging signal during treatment and 7 articles focused on biological adaptive treatment planning, of which two were clinical trials. Studied biological pathways include metabolism (FDG), hypoxia (MISO, FAZA and HX4) and proliferation (FLT). CONCLUSIONS: In the development of biological dose adaptation in radiotherapy for head-neck tumors, many aspects of the procedure remain ambiguous. Patient selection, tracer selection for detection of the radio-resistant sub-volumes, timing of adaptive radiotherapy, workflow and treatment planning aspects are discussed in a clinical context.

Orthovoltage X-rays for Postoperative Treatment of Resected Basal Cell Carcinoma in the Head and Neck Area.

BACKGROUND: Surgery is the golden standard for treating basal cell carcinomas. In case of positive tumor margins or recurrent disease, postoperative adjuvant or salvaging therapy is suggested to achieve good local control. OBJECTIVE: To retrospectively report on local control and toxicity of postoperative radiotherapy by means of orthovoltage X-rays for residual or recurrent basal cell carcinoma after surgery in the head and neck area. METHODS: Sixty-six surgically resected residual or recurrent basal cell carcinomas of the head and neck region were irradiated postoperatively by means of orthovoltage X-rays at the Netherlands Cancer Institute between January 2000 and February 2015. RESULTS: After a median follow-up duration of 30.5 months, only 5 recurrences were reported. The 5-year local control rates at 1, 3, and 5 years were 100%, 87%, and 87%, respectively. The 5-year local control rate was 92% for immediate postoperative radiotherapy of incompletely resected basal cell carcinomas, 90% for recurrences after 1 previously performed excision, and 71% for multiple recurrences, namely, a history of more than 1 excision ( P = .437). Acute toxicity healed spontaneously within 3 months. Late toxicities were mild. CONCLUSION: Radiotherapy by means of orthovoltage X-ray is an excellent alternative for re-excision in case of incompletely resected or recurrent basal cell carcinomas that are at risk of serious functional and cosmetic impairments after re-excision, with a 5-year local control rate of 87% and a low toxicity profile.

Prospective clinical study on long-term swallowing function and voice quality in advanced head and neck cancer patients treated with concurrent chemoradiotherapy and preventive swallowing exercises.

Concurrent chemoradiotherapy (CCRT) for advanced head and neck cancer (HNC) is associated with substantial early and late side effects, most notably regarding swallowing function, but also regarding voice quality and quality of life (QoL). Despite increased awareness/knowledge on acute dysphagia in HNC survivors, long-term (i.e., beyond 5 years) prospectively collected data on objective and subjective treatment-induced functional outcomes (and their impact on QoL) still are scarce. The objective of this study was the assessment of long-term CCRT-induced results on swallowing function and voice quality in advanced HNC patients. The study was conducted as a randomized controlled trial on preventive swallowing rehabilitation (2006-2008) in a tertiary comprehensive HNC center with twenty-two disease-free and evaluable HNC patients as participants. Multidimensional assessment of functional sequels was performed with videofluoroscopy, mouth opening measurements, Functional Oral Intake Scale, acoustic voice parameters, and (study specific, SWAL-QoL, and VHI) questionnaires. Outcome measures at 6 years post-treatment were compared with results at baseline and at 2 years post-treatment. At a mean follow-up of 6.1 years most initial tumor-, and treatment-related problems remained similarly low to those observed after 2 years follow-up, except increased xerostomia (68%) and increased (mild) pain (32%). Acoustic voice analysis showed less voicedness, increased fundamental frequency, and more vocal effort for the tumors located below the hyoid bone (n = 12), without recovery to baseline values. Patients' subjective vocal function (VHI score) was good. Functional swallowing and voice problems at 6 years post-treatment are minimal in this patient cohort, originating from preventive and continued post-treatment rehabilitation programs.

Predictive factors for pharyngocutaneous fistulization after total laryngectomy.

OBJECTIVES: Postoperative complications, especially pharyngocutaneous fistulization (PCF), are more frequent after total laryngectomy (TL) performed for salvage after (chemo)radiotherapy than after primary TL. The aim of this study was to identify the incidence of PCF, predictive factors for PCF, and the relationship of PCF to survival. METHODS: We performed a retrospective chart review of 217 consecutive patients treated with TL between 2000 and 2010. Univariate and multivariable analysis with logistic regression was used to identify factors associated with PCF. We used a Kaplan-Meier survival analysis. RESULTS: The overall incidence of PCF was 26.3% (57 of 217 cases). The incidence of PCF after primary TL was 17.1% (12 of 70), that after salvage TL was 25.5% (25 of 98), that after TLE for a second primary was 37.5% (9 of 24), and that after TL for a dysfunctional larynx was 44.0% (11 of 25). The predictive factors for PCF were hypopharynx cancer (odds ratio [OR], 3.67; 95% confidence interval [CI], 1.74 to 7.71; P = .001), an albumin level of less than 40 g/L (OR, 2.20; 95% CI, 1.12 to 4.33; P = .022), previous chemoradiotherapy (OR, 3.38; 95% CI, 1.34 to 8.52; P = .010), more-extended pharyngeal resection (P = .001), and pharynx reconstruction (P = .002). The median duration of survival was 30 months (95% CI, 17.5 to 42.5); the 2-year overall survival rate was 54%. The median duration of survival of patients with PCF was 23 months (95% CI, 9.4 to 36.6), and that of those without PCF was 31 months (95% CI, 15.0 to 47.0; P = .421). The 2-year overall survival rate was 48% in patients with PCF and 57% in those without PCF (P = .290). CONCLUSIONS: Incidence of PCF after TL is significantly higher in patients with hypopharynx cancer, previous chemoradiotherapy, a low albumin level, more-extended pharyngeal resection, or pharynx reconstruction. The occurrence of PCF does not influence the rate of survival.

Early oral intake after total laryngectomy does not increase pharyngocutaneous fistulization.

Timing of oral intake after total laryngectomy (TLE) is mostly delayed until postoperative day 10-12, under the assumption that this limits the incidence of pharyngocutaneous fistulization (PCF). However, early oral intake could be advantageous and could reduce costs, providing that it does not lead to increased PCF. Comparison of PCF incidence in traditional 'late' oral intake protocol (start at postoperative day 10-12; LOI) and in early oral intake protocol (start at postoperative day 2-4; EOI). Retrospective cohort study comparing two different oral intake protocols in 247 consecutive patients laryngectomized between early 2000 until mid 2006 (LOI; N = 140), and mid 2006 until mid 2012 (EOI; N = 107). Both groups were comparable in terms of sex, age, origin of tumor, and TLE indication, except for the American Society of Anesthesiologists score (ASA), which was slightly more favorable in the LOI group (p = 0.047). Compliance with the oral intake protocols during both periods was good: the median day of starting oral intake was day 11 (range 6-103) in the LOI group vs. day 3 (range 2-84) in the EOI group (p = 0.001). The incidence of PCF was not significantly different between the two groups (25% for LOI and 32% for EOI; Fisher's exact: p = 0.255). In addition, no association was observed between the timing of oral intake and PCF (HR = 0.995; CI 0.98-1.01; p = 0.364). This study suggests that early oral intake is safe and does not increase pharyngocutaneous fistulization.

A multicentric randomized controlled phase III trial of adaptive and 18F-FDG-PET-guided dose-redistribution in locally advanced head and neck squamous cell carcinoma (ARTFORCE).

BACKGROUND AND PURPOSE: This multicenter randomized phase III trial evaluated whether locoregional control of patients with LAHNSCC could be improved by fluorodeoxyglucose-positron emission tomography (FDG-PET)-guided dose-escalation while minimizing the risk of increasing toxicity using a dose-redistribution and scheduled adaptation strategy. MATERIALS AND METHODS: Patients with T3-4-N0-3-M0 LAHNSCC were randomly assigned (1:1) to either receive a dose distribution ranging from 64-84 Gy/35 fractions with adaptation at the 10thfraction (rRT) or conventional 70 Gy/35 fractions (cRT). Both arms received concurrent three-cycle 100 mg/m2cisplatin. Primary endpoints were 2-year locoregional control (LRC) and toxicity. Primary analysis was based on the intention-to-treat principle. RESULTS: Due to slow accrual, the study was prematurely closed (at 84 %) after randomizing 221 eligible patients between 2012 and 2019 to receive rRT (N = 109) or cRT (N = 112). The 2-year LRC estimate difference of 81 % (95 %CI 74-89 %) vs. 74 % (66-83 %) in the rRT and cRT arm, respectively, was not found statistically significant (HR 0.75, 95 %CI 0.43-1.31,P=.31). Toxicity prevalence and incidence rates were similar between trial arms, with exception for a significant increased grade ≥ 3 pharyngolaryngeal stenoses incidence rate in the rRT arm (0 versus 4 %,P=.05). In post-hoc subgroup analyses, rRT improved LRC for patients with N0-1 disease (HR 0.21, 95 %CI 0.05-0.93) and oropharyngeal cancer (0.31, 0.10-0.95), regardless of HPV. CONCLUSION: Adaptive and dose redistributed radiotherapy enabled dose-escalation with similar toxicity rates compared to conventional radiotherapy. While FDG-PET-guided dose-escalation did overall not lead to significant tumor control or survival improvements, post-hoc results showed improved locoregional control for patients with N0-1 disease or oropharyngeal cancer treated with rRT.

MR and CT based treatment planning for mTHPC mediated interstitial photodynamic therapy of head and neck cancer: description of the method.

BACKGROUND AND OBJECTIVE: Interstitial photodynamic therapy is a potentially important tool in the management of voluminous or deep-seated recurrent head and neck cancers. STUDY DESIGN/METHODS: The described treatment algorithm in this manuscript consists of the treatment simulation, implantation of light sources, verification, modification of the treatment plan if necessary, and illumination. The tumor is delineated on imaging sections (CT, MRI, and/or PET/CT) and the treatment is simulated by virtually introducing light sources to the tumor volume on specially modified brachytherapy software. This enables us to determine if the treatment is technically feasible, and information about approximate number and location of light sources necessary. Following implantation of catheters in which the light sources will be introduced, CT or MR scan is performed to verify the actual location of the implanted catheters. The verification-CT is imported to the software and co-registered with pre-treatment images to observe the deviations from the simulation. The simulation is run again with the actual position of the light sources to determine if any additional light sources are necessary and adaptation of the source length in order to cover the tumor volume (modification). Thereafter the tumor is illuminated. RESULTS: This method has the potential to help with identifying iPDT feasible patients by simulating before the actual treatment. The suboptimal placement of light sources can be identified and corrected. The simulations were documented and saved for subsequent evaluation of the technique. CONCLUSION: The proposed technique can help standardize and document iPDT.

Surgical site complications of isolated salvage neck dissection post-radiotherapy and post-chemoradiotherapy - A cohort analysis (1997-2017).

INTRODUCTION: This study aims to quantify surgical site complications (SSC) after isolated salvage neck dissection (ND) compared with primary ND. PATIENTS AND METHODS: Between 1997 and 2017 in the Netherlands Cancer Institute - Antoni van Leeuwenhoek, a total of 323 isolated NDs were performed in 308 patients: primary ND (n = 144), post-radiotherapy (RT) ND (n = 53) and post-chemoradiotherapy (CRT) ND (n = 126). Patient, tumor and therapy characteristics were recorded. SSCs were scored according to the Clavien-Dindo Classification (CDC). RESULTS: 101 NDs (31%) were complicated by at least one SSC. In total, 189 different SSCs occurred. Translated to CDC, 45 complications were grade 2, 25 grade 3a and 31 grade 3b. No significant difference in occurrence of SSC (CDC >1) was found between all groups. However, post-CRT, selective (SND) and modified radical ND and radical ND (MRND/RND) (p = 0.005), resection of sternocleidomastoid muscle (SCM) (p = 0.039) and duration of super selective ND surgery (p = 0.048) were significantly associated with more SSC. SCM muscle removal was associated with more surgical site infection (p = 0.045) and necrosis (p = 0.036). From week 10 post-RT/CRT, no difference in complication frequency with primary ND was seen. CONCLUSION: Post-CRT SND, MRND/RND and SCM muscle resection were associated with an increased incidence of SSCs. If oncologically possible, limit the extent of ND and when an MRND is inevitable, preserve the SCM muscle for optimal prevention of SSC. Concerning SSC, optimal timing of salvage ND is minimal 10 weeks after RT/CRT.

Defining High-Quality Integrated Head and Neck Cancer Care Through a Composite Outcome Measure: Textbook Outcome.

OBJECTIVES/HYPOTHESIS: To further improve the quality of head and neck cancer (HNC) care, we developed a composite measure defined as "textbook outcome" (TO). METHODS: We analyzed a retrospective cohort of patients after curvative-intent primary surgery, radiotherapy (RT), or chemoradiation (CRT) for HNC between 2015 and 2018 at the Netherlands Cancer Institute. TO was defined as 1) the start of treatment within 30 days, 2a) satisfactory pathologic outcomes, without 30-day postoperative complications, for the surgically treated group, and 2b), for RT and CRT patients, no unexpected or prolonged hospitalization and toxicity after the completion of treatment as planned. RESULTS: In total, 392 patients with HNC were included. An overall TO was achieved in 9.6% of patients after surgery, 20.6% after RT, and 2.2% after CRT. Two indicators (margins >5 mm and start treatment <30 days) reduced TO radically for both groups. CONCLUSION: TO can aid the evaluation of the quality of care for HNC patients and guide improvement processes. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:78-87, 2022.

Postoperative radiotherapy in stage I-III Merkel cell carcinoma.

BACKGROUND: Postoperative radiotherapy (PORT) is currently recommended for the treatment of Merkel cell carcinoma. Nevertheless, deviations occur frequently due to the generally elderly and frail patient population. We aimed to evaluate the influence of PORT on survival in stage I-III MCC patients treated in the Netherlands. METHODS: Patients were included retrospectively between 2013 and 2018. Fine-Gray method was used for cumulative incidence of recurrence and MCC-related death, cox regression was performed for overall mortality. Analyses were performed in patients with clinical (sentinel node biopsy [SN] not performed) stage I/II (c-I/II-MCC), pathologic (SN negative) stage I/II (p-I/II-MCC) and stage III MCC (III-MCC), separately. Propensity score matching (PSM) was performed to assess confounding by indication. RESULTS: In total 182 patients were included, 35 had p-I/II-MCC, 69 had c-I/II-MCC and 78 had III-MCC. Median follow up time was 53.5 (IQR 33.4-67.4), 30.5 (13.0-43.6) and 29.3 (19.3-51.0) months, respectively. Multivariable analysis showed PORT to be associated with less recurrences and reduced overall mortality, but not with MCC-related mortality. In stage III-MCC, extracapsular extension (sub-distribution hazard [SDH] 4.09, p = 0.012) and PORT (SDH 0.45, p = 0.044) were associated with recurrence, and ≥ 4 positive lymph nodes (SDH 3.24, p = 0.024) were associated with MCC-related mortality. CONCLUSIONS: PORT was associated with less recurrences and reduced overall mortality in patients with stage I-III MCC, but not with MCC-related mortality. Trends in overall survival benefit are likely to be caused by selection bias suggesting further refinement of criteria for PORT is warranted, for instance by taking life expectancy into account.

Comparisons of normal tissue complication probability models derived from planned and delivered dose for head and neck cancer patients.

BACKGROUND AND PURPOSE: Normal tissue complication probability (NTCP) models are typically derived from the planned dose distribution, which can deviate from the delivered dose due to anatomical day-to-day variations. The aim of this study was to compare NTCP models derived from the planned and the delivered dose for head and neck cancer (HNC) patients. MATERIAL AND METHOD: 322 HNC patients who received radiotherapy with daily CBCT guidance were included in this retrospective study. The delivered dose was estimated by deformably accumulating dose from daily CBCT to planning anatomy. We used a Lyman-Kutcher-Burman NTCP model, to relate the equivalent uniform dose (EUD) of organs at risk (OAR) with oral mucositis, xerostomia and dysphagia respectively. We compared the model parameters and performances. RESULTS: The median differences between planned and delivered EUD to the OARs were significantly larger for patients with toxicity than without for acute dysphagia (≥G2 and ≥G3) and late dysphagia (≥G3) (p < 0.05). Those differences resulted in small differences in steepness and agreement to the data between delivered- and planned-fitted NTCP curves, and the differences were not significant. The differences in AUC were less than 0.01. CONCLUSION: Differences between delivered and planned dose did not lead to significant differences in NTCP curves. The additional clinical relevance of NTCP models using accumulated dose for oral mucositis, xerostomia and dysphagia in HNC radiotherapy is likely to be limited.

Deterioration of Intended Target Volume Radiation Dose Due to Anatomical Changes in Patients with Head-and-Neck Cancer.

Delivered radiation dose can differ from intended dose. This study quantifies dose deterioration in targets, identifies predictive factors, and compares dosimetric to clinical patient selection for adaptive radiotherapy in head-and-neck cancer patients. One hundred and eighty-eight consecutive head-and-neck cancer patients treated up to 70 Gy were analyzed. Daily delivered dose was calculated, accumulated, and compared to the planned dose. Cutoff values (1 Gy/2 Gy) were used to assess plan deterioration in the highest/lowest dose percentile (D1/D99). Differences in clinical factors between patients with/without dosimetric deterioration were statistically tested. Dosimetric deterioration was evaluated in clinically selected patients for adaptive radiotherapy with CBCT. Respectively, 16% and 4% of patients had deterioration over 1 Gy in D99 and D1 in any of the targets, this was 5% (D99) and 2% (D1) over 2 Gy. Factors associated with deterioration of D99 were higher baseline weight/BMI, weight gain early in treatment, and smaller PTV margins. The sensitivity of visual patient selection with CBCT was 22% for detection of dosimetric changes over 1 Gy. Large dose deteriorations in targets occur in a minority of patients. Clinical prediction based on patient characteristics or CBCT is challenging and dosimetric selection tools seem warranted to identify patients in need for ART, especially in treatment with small PTV margins.

Reduction of GTV to high-risk CTV radiation margin in head and neck squamous cell carcinoma significantly reduced acute and late radiation-related toxicity with comparable outcomes.

BACKGROUND AND PURPOSE: We aim to retrospectively investigate whether reducing GTV to high-risk CTV margin will significantly reduce acute and late toxicity without jeopardizing outcome in head-and-neck squamous cell carcinoma (HNSCC) treated with definitive (chemo)radiation. MATERIALS AND METHODS: Between April 2015 and April 2019, 155 consecutive patients were treated with GTV to high-risk CTV margin of 10 mm and subsequently another 155 patients with 6 mm margin. The CTV-PTV margin was 3 mm for both groups. All patients were treated with volumetric-modulated arc therapy with daily image-guidance using cone-beam CT. End points of the study were acute and late toxicity and oncologic outcomes. RESULTS: Overall acute grade 3 toxicity was significantly lower in 6 mm, compared to 10 mm group (48% vs. 67%, respectively, p < 0.01). The same was true for acute grade 3 mucositis (18% vs. 34%, p < 0.01) and grade ≥ 2 dysphagia (67% vs. 85%, p < 0.01). Also feeding tube-dependency at the end of treatment (25% vs. 37%, p = 0.02), at 3 months (12% and 25%, p < 0.01), and at 6 months (6% and 15%, p = 0.01) was significantly less in 6 mm group. The incidence of late grade 2 xerostomia was also significantly lower in the 6 mm group (32% vs. 50%, p < 0.01). The 2-year rates of loco-regional control, disease-free and overall survival were 78.7% vs. 73.1%, 70.6% vs. 61.4%, and 83.2% vs. 74.4% (p > 0.05, all). CONCLUSION: The first study reporting on reduction of GTV to high-risk CTV margin from 10 to 6 mm showed significant reduction of the incidence and severity of radiation-related toxicity without reducing local-regional control and survival.

National Protocol for Model-Based Selection for Proton Therapy in Head and Neck Cancer.

In the Netherlands, the model-based approach is used to identify patients with head and neck cancer who may benefit most from proton therapy in terms of prevention of late radiation-induced side effects in comparison with photon therapy. To this purpose, a National Indication Protocol Proton therapy for Head and Neck Cancer patients (NIPP-HNC) was developed, which has been approved by the health care authorities. When patients qualify according to the guidelines of the NIPP-HNC, proton therapy is fully reimbursed. This article describes the procedures that were followed to develop this NIPP-HNC and provides all necessary information to introduce model-based selection for patients with head and neck cancer into routine clinical practice.

[18F]-HX4 PET/CT hypoxia in patients with squamous cell carcinoma of the head and neck treated with chemoradiotherapy: Prognostic results from two prospective trials.

INTRODUCTION: The presence of hypoxia in head-and-neck squamous cell carcinoma is a negative prognostic factor. PET imaging with [18F] HX4 can be used to visualize hypoxia, but it is currently unknown how this correlates with prognosis. We investigated the prognostic value of [18F] HX4 PET imaging in patients treated with definitive radio(chemo)therapy (RTx). MATERIALS AND METHODS: We analyzed 34 patients included in two prospective clinical trials (NCT01347281, NCT01504815). Static [18F] HX4 PET-CT images were collected, both pre-treatment (median 4 days before start RTx, range 1-16), as well as during RTx (median 13 days after start RTx, range 3-17 days). Static uptake at both time points (n = 33 pretreatment, n = 28 during RTx) and measured changes in hypoxic fraction (HF) and hypoxic volume (HV) (n = 27 with 2 time points) were analyzed. Univariate cox analyses were done for local progression free survival (PFS) and overall survival (OS) at both timepoints. Change in uptake was analyzed by comparing outcome with Kaplan-Meier curves and log-rank test between patients with increased and decreased/stable hypoxia, similarly between patients with and without residual hypoxia (rHV = ratio week 2/baseline HV with cutoff 0.2). Voxelwise Spearman correlation coefficients were calculated between normalized [18F] HX4 PET uptake at baseline and week 2. RESULTS: Analyses of static images showed no prognostic value for [18F] HX4 uptake. Analysis of dynamic changes showed that both OS and local PFS were significantly shorter (log-rank P < 0.05) in patients with an increase in HV during RTx and OS was significantly shorter in patients with rHV, with no correlation to HPV-status. The voxel-based correlation to evaluate spatial distribution yielded a median Spearman correlation coefficient of 0.45 (range 0.11-0.65). CONCLUSION: The change of [18F] HX4 uptake measured on [18F] HX4 PET early during treatment can be considered for implementation in predictive models. With these models patients with a worse prognosis can be selected for treatment intensification.

Long-term swallowing, trismus, and speech outcomes after combined chemoradiotherapy and preventive rehabilitation for head and neck cancer; 10-year plus update.

BACKGROUND: The objective of this study was to explore the 10-year plus outcomes of Intensity Modulated Radiotherapy with concomitant chemotherapy (CRT) combined with preventive swallowing rehabilitation (CRT+) for head and neck cancer (HNC). METHODS: Subjective and objective swallowing, trismus, and speech related outcomes were assessed at 10-year plus after CRT+. Outcomes were compared to previously published 6-year results of the same cohort. RESULTS: Fourteen of the 22 patients at 6-year follow-up were evaluable. Although objective swallowing-related outcomes showed no deterioration (eg, no feeding tube dependency and no pneumonia), swallowing-related quality of life slightly deteriorated over time. No patients had or perceived trismus. Voice and speech questionnaires showed little problems in daily life. Overall quality of life (QOL) was good. CONCLUSIONS: After CRT with preventive rehabilitation exercises for advanced HNC, swallowing, trismus, and speech related outcomes moderately deteriorated from 6 to 10 years, with an on average good overall QOL after.

Randomized controlled trial to identify the optimal radiotherapy scheme for palliative treatment of incurable head and neck squamous cell carcinoma.

BACKGROUND: No randomized controlled trials (RCT) have yet identified the optimal palliative radiotherapy scheme in patients with incurable head and neck squamous cell carcinoma (HNSCC). We conducted RCT to compare two radiation schemes in terms of efficacy, toxicity and quality-of-life (QoL). MATERIALS AND METHODS: Patients with locally-advanced HNSCC who were ineligible for radical treatment and those with limited metastatic disease were randomly assigned in 1:1 ratio to arm 1 (36 Gy in 6 fractions, twice a week) or arm 2 (50 Gy in 16 fractions, four times a week). RESULTS: The trial was discontinued early because of slow accrual (34 patients enrolled). Objective response rates were 38.9% and 57.1% for arm 1 and 2 respectively (p = 0.476). The median time to loco-regional progression was not reached. The loco-regional control rates at 1 year was 57.4% and 69.3% in arm 1 and 2 (p = 0.450, HR = 0.56, 95%CI 0.12-2.58). One-year overall survival was 33.3% and 57.1%, with medians of 35.4 and 59.5 weeks, respectively (p = 0.215, HR = 0.55, 95%CI 0.21-1.43). Acute grade ≥3 toxicity was lower in arm 1 (16.7% versus 57.1%, p = 0.027), with the largest difference in grade 3 mucositis (5.6% versus 42.9%, p = 0.027). However, no significant deterioration in any of the patient-reported QoL-scales was found. CONCLUSION: No solid conclusion could be made on this incomplete study which is closed early. Long-course radiotherapy did not show significantly better oncologic outcomes, but was associated with more acute grade 3 mucositis. No meaningful differences in QoL-scores were found. Therefore, the shorter schedule might be carefully advocated. However, this recommendation should be interpreted with great caution because of the inadequate statistical power.

Non-invasive imaging prediction of tumor hypoxia: A novel developed and externally validated CT and FDG-PET-based radiomic signatures.

BACKGROUND: Tumor hypoxia increases resistance to radiotherapy and systemic therapy. Our aim was to develop and validate a disease-agnostic and disease-specific CT (+FDG-PET) based radiomics hypoxia classification signature. MATERIAL AND METHODS: A total of 808 patients with imaging data were included: N = 100 training/N = 183 external validation cases for a disease-agnostic CT hypoxia classification signature, N = 76 training/N = 39 validation cases for the H&N CT signature and N = 62 training/N = 36 validation cases for the Lung CT signature. The primary gross tumor volumes (GTV) were manually defined by experts on CT. In order to dichotomize between hypoxic/well-oxygenated tumors a threshold of 20% was used for the [18F]-HX4-derived hypoxic fractions (HF). A random forest (RF)-based machine-learning classifier/regressor was trained to classify patients as hypoxia-positive/ negative based on radiomic features. RESULTS: A 11 feature "disease-agnostic CT model" reached AUC's of respectively 0.78 (95% confidence interval [CI], 0.62-0.94), 0.82 (95% CI, 0.67-0.96) and 0.78 (95% CI, 0.67-0.89) in three external validation datasets. A "disease-agnostic FDG-PET model" reached an AUC of 0.73 (0.95% CI, 0.49-0.97) in validation by combining 5 features. The highest "lung-specific CT model" reached an AUC of 0.80 (0.95% CI, 0.65-0.95) in validation with 4 CT features, while the "H&N-specific CT model" reached an AUC of 0.84 (0.95% CI, 0.64-1.00) in validation with 15 CT features. A tumor volume-alone model was unable to significantly classify patients as hypoxia-positive/ negative. A significant survival split (P = 0.037) was found between CT-classified hypoxia strata in an external H&N cohort (n = 517), while 117 significant hypoxia gene-CT signature feature associations were found in an external lung cohort (n = 80). CONCLUSION: The disease-specific radiomics signatures perform better than the disease agnostic ones. By identifying hypoxic patients our signatures have the potential to enrich interventional hypoxia-targeting trials.

Privacy-preserving distributed learning of radiomics to predict overall survival and HPV status in head and neck cancer.

A major challenge in radiomics is assembling data from multiple centers. Sharing data between hospitals is restricted by legal and ethical regulations. Distributed learning is a technique, enabling training models on multicenter data without data leaving the hospitals ("privacy-preserving" distributed learning). This study tested feasibility of distributed learning of radiomics data for prediction of two year overall survival and HPV status in head and neck cancer (HNC) patients. Pretreatment CT images were collected from 1174 HNC patients in 6 different cohorts. 981 radiomic features were extracted using Z-Rad software implementation. Hierarchical clustering was performed to preselect features. Classification was done using logistic regression. In the validation dataset, the receiver operating characteristics (ROC) were compared between the models trained in the centralized and distributed manner. No difference in ROC was observed with respect to feature selection. The logistic regression coefficients were identical between the methods (absolute difference <10-7). In comparison of the full workflow (feature selection and classification), no significant difference in ROC was found between centralized and distributed models for both studied endpoints (DeLong p > 0.05). In conclusion, both feature selection and classification are feasible in a distributed manner using radiomics data, which opens new possibility for training more reliable radiomics models.