Lymphedema and Trismus after Head and Neck Cancer, and the Impact on Body Image and Quality of Life.

BACKGROUND: To assess the prevalence of chronic lymphedema and trismus in patients > 6 months after head and neck cancer (HNC) treatment, and to explore how the severity of these conditions correlates with body image and quality of life. METHODS: The cross-sectional sample included 59 patients, treated for HNC between six months to three years ago. Physical measurements were performed to assess the presence of external lymphedema and trismus (<36 mm). Furthermore, participants completed two questionnaires regarding body image (BIS) and quality of life (UW-QoL V4). RESULTS: Lymphedema prevalence was 94.1% (95% CI 0.86-0.98), with a median severity score of 9 (range 0-24). Trismus prevalence in this sample was 1.2%. The median BIS score was 2, indicating a positive body image. The UW-QoL score showed a good QOL with a median of 100. Only the domain of saliva and overall related health had a lower median of 70 and 60, respectively. There was no correlation between lymphedema and body image (r = 0.08, p = 0.544). Patients with higher lymphedema scores reported poorer speech with a moderate correlation (r = -0.39, p = 0.003). CONCLUSION: Lymphedema is a highly prevalent, but moderately severe late side-effect of HNC with a limited impact on quality of life domains except for speech, in our cohort.

Organization of head and neck cancer rehabilitation care: a national survey among healthcare professionals in Dutch head and neck cancer centers.

PURPOSE: Head and neck cancer (HNC) treatment often leads to physical and psychosocial impairments. Rehabilitation can overcome these limitations and improve quality of life. The aim of this study is to obtain an overview of rehabilitation care for HNC, and to investigate factors influencing rehabilitation provision, in Dutch HNC centers, and to some extent compare it to other countries. METHODS: An online survey, covering five themes: organizational structure; rehabilitation interventions; financing; barriers and facilitators; satisfaction and future improvements, among HNC healthcare- and financial professionals of Dutch HNC centers. RESULTS: Most centers (86%) applied some type of rehabilitation care, with variations in organizational structure. A speech language therapist, physiotherapist and dietitian were available in all centers, but other rehabilitation healthcare professionals in less than 60%. Facilitators for providing rehabilitation services included availability of a contact person, and positive attitude, motivation, and expertise of healthcare professionals. Barriers were lack of reimbursement, and patient related barriers including comorbidity, travel (time), low health literacy, limited financial capacity, and poor motivation. CONCLUSION: Although all HNC centers included offer rehabilitation services, there is substantial practice variation, both nationally and internationally. Factors influencing rehabilitation are related to the motivation and expertise of the treatment team, but also to reimbursement aspects and patient related factors. More research is needed to investigate the extent to which practice variation impacts individual patient outcomes and how to integrate HNC rehabilitation into routine clinical pathways.

Adaptive FDG-PET/CT guided dose escalation in head and neck squamous cell carcinoma: Late toxicity and oncologic outcomes (The ADMIRE study).

Purpose: To report on the late toxicity and local control (LC) of head and neck cancer patients treated with adaptive FDG-PET/CT response-guided radiotherapy (ADMIRE) with dose escalation (NCT03376386). Materials and methods: Between December 2017 and April 2019, 20 patients with stage II-IV squamous cell carcinoma of the larynx, hypopharynx or oropharynx were treated within the ADMIRE study where FDG-PET/CT response-guided (Week 2&4) dose escalation was applied (total dose 70-78 Gy). Cisplatin or cetuximab was added to radiotherapy in case of T3-4 and/or N2c disease. To compare the LC and late toxicity of the study population, we used an external control group (n = 67) consisting of all eligible patients for the study (but not participated). These patients were treated in our institution during the same period with the current standard of 70 Gy radiotherapy. To reduce the effect of confounding, logistic regression analyses was done using stabilized inverse probability of treatment weighting (SIPTW). Results: After median follow-up of 40 and 43 months for the ADMIRE and control groups, the 3-year LC-rates were 74% and 78%, respectively (adjusted HR after SIPTW 0.80, 95 %CI 0.25-2.52, p = 0.70). The incidences of any late G3 toxicity were 35% and 18%, respectively. The adjusted OR for any late G3 toxicity was 5.09 (95 %CI 1.64-15.8, p = 0.005), for any late G ≥ 2 toxicity was 3.67 (95 %CI 1.2-11.7, p = 0.02), for persistent laryngeal edema was 10.95 (95% CI 2.71-44.29, p = 0.001), for persistent mucosal ulcers was 4.67 (95% CI 1.23-17.7, p = 0.023), and for late G3 radionecrosis was 15.69 (95 %CI 2.43-101.39, p = 0.004). Conclusion: Given the comparable LC rates with increased late toxicity in the ADMIRE group, selection criteria for future adaptive dose escalation trials (preferably randomized) need to be refined to include only patients at higher risk of local failure and/or lower risk of severe late toxicity.

Disease outcome and associated factors after definitive platinum based chemoradiotherapy for advanced stage HPV-negative head and neck cancer.

BACKGROUND: Definitive concomitant cisplatin-based chemoradiotherapy (CRT) is the current gold standard for most patients with advanced stage head and neck squamous cell carcinoma (HNSCC) of the pharynx and larynx. Since previous meta-analysis on CRT outcomes in HNSCC have been reported, advances have been made in radiotherapy techniques and clinical management, while HPV-status has been identified as a strong confounding prognostic factor in oropharyngeal cancer. Here, we present real-world outcome data from a large multicenter cohort of HPV-negative advanced stage HNSCC treated with CRT using contemporary IMRT-based techniques. METHOD: Retrospective data were collected from a multicenter cohort of 513 patients treated with definitive concurrent platinum-based CRT with curative intent between January 2009 and August 2017. Only patients with HPV-negative advanced stage (III-IV) HNSCC were included. A prognostic model for outcome was developed based on clinical parameters and compared to TNM. RESULTS: Nearly half of the 513 patients (49%) had an oropharyngeal tumor, often locally advanced (73.3% T3-T4b) and with involvement of the regional lymph nodes (84%). Most patients (84%) received cisplatin as single agent. In total 66% received the planned number of cycles and 75% reached a cumulative cisplatin dose of ≥200 mg/m2. Locoregional control was achieved in 324 (63%) patients during follow-up, and no association with tumor sites was observed (p = 0.48). Overall survival at 5 year follow-up was 47%, with a better survival for laryngeal cancer (p = 0.02) compared to other sites. A model with clinical variables (gender, high pre-treatment weight loss, N2c/N3-stage and <200 mg/m2 dose of cisplatin) provided a noticeably stronger association with overall survival than TNM-staging (C- index 0.68 vs 0.55). Simultaneous Integrated Boosting (SIB) significantly outperformed Sequential Boosting (SEQ) to reduce the development of distant metastasis (SEQ vs SIB: OR 1.91 (1.11-3.26; p = 0.02). CONCLUSION: Despite advances in clinical management, more than a third of patients with HPV-negative HNSCC do not complete CRT treatment protocols due to cisplatin toxicity. A model that consists of clinical variables and treatment parameters including cisplatin dose provided the strongest association with overall survival. Since cisplatin toxicity is a major obstacle in completing definitive CRT, the development of alternative and less toxic radiosensitizers is therefore warranted to improve treatment results. The association of RT-boost technique with distant metastasis is an important finding and requires further study.

The impact of hyperbaric oxygen therapy on late irradiation injury in oral microcirculation.

BACKGROUND: Late side effects of radiotherapy in patients with head and neck cancer (HNCPs) result in decreased tissue vascularity, a compromised healing capacity and spontaneous breakdown of tissue. The aim of this study was to examine the in vivo effect of hyperbaric oxygen therapy (HBOT) on the microcirculation in irradiated oral tissue. METHODS: Using a handheld microscope, the effect of HBOT on oral mucosal microcirculation parameters was measured in 34 previously irradiated HNCPs prior to HBOT and at 4 weeks and 6 months posttreatment. RESULTS: A significant increase in mean buccal vessel density and decrease in buccal vessel diameter was found 6 months after HBOT compared to baseline, 22 ± 11 versus 25 ± 7 cpll/mm2 (p < 0.05) and 20 ± 4 versus 16 ± 5 µm (p < 0.05), respectively. CONCLUSION: Our results indicate that oral microcirculation histopathology associated with irradiation is able to respond to HBOT by redirecting oral microcirculation parameters towards values consistent with healthy tissue.

The dosimetric and clinical advantages of the GTV-CTV-PTV margins reduction by 6 mm in head and neck squamous cell carcinoma: Significant acute and late toxicity reduction.

PURPOSE: We aim to identify the dosimetric and clinical impact of reducing the total GTV-CTV-PTV margins in head-and-neck squamous cell carcinoma (HNSCC) treated with definitive (chemo)radiation. MATERIALS AND METHODS: The acute and late toxicity and outcomes of 155 consecutive patients treated between February 2017 and March 2019 with GTV-CTV-PTV margins of 9 mm were compared to those of 155 consecutive patients treated with total margin of 15 mm margin, before April 2015. All patients were treated with VMAT with daily-image guidance using CBCT. RESULTS: Reducing the GTV-CTV-PTV by 6 mm resulted in significant reduction of total irradiated volume (PTV-total) by a median of 28.1% and significant reduction of doses to all salivary glands (largest reduction ipsilateral parotid gland; median -9.6 Gy) and constrictor muscle (-6.1 Gy) with subsequent reduction of the incidence of overall acute grade 3 toxicity (47.7% for 9 mm and 66.5% for 15 mm groups, p = 0.001), grade 3 mucositis (18.1% vs. 35.5%, p < 0.001) and feeding tube-dependency at the end of treatment (24.5% vs. 40%, p = 0.005). The incidence of late grade ≥ 2 xerostomia and dysphagia were also significantly lower in the 9 mm group (31.7% vs. 58.6% p < 0.001, and 15.4% vs. 26.7%, p = 0.04). The 2-year rates of loco-regional control, disease-free and overall survival were 78.8% vs.75.8%, 70.9% vs. 64.4%, and 83.8% vs. 67.6%, (p > 0.05, all). CONCLUSION: Reduction of the total GTV-CTV-PTV margins from 15 to 9 mm in HNSCC significantly reduced the irradiated volumes and the dose to salivary glands and constrictor muscle with significant reduction of radiation-related toxicity. The loco-regional control rates of both groups were comparable.

Development and external validation of a prediction model for tube feeding dependency for at least four weeks during chemoradiotherapy for head and neck cancer.

BACKGROUND & AIMS: Patients who receive chemoradiotherapy or bioradiotherapy (CRT/BRT) for locally advanced head and neck squamous cell carcinoma (LAHNSCC) often experience high toxicity rates interfering with oral intake, causing tube feeding (TF) dependency. International guidelines recommend gastrostomy insertion when the expected use of TF exceeds 4 weeks. We aimed to develop and externally validate a prediction model to identify patients who need TF ≥ 4 weeks and would benefit from prophylactic gastrostomy insertion. METHODS: A retrospective multicenter cohort study was performed in four tertiary head and neck cancer centers in the Netherlands. The prediction model was developed using data from University Medical Center Utrecht and the Netherlands Cancer Institute and externally validated using data from Maastricht University Medical Center and Radboud University Medical Center. The primary endpoint was TF dependency ≥4 weeks initiated during CRT/BRT or within 30 days after CRT/BRT completion. Potential predictors were extracted from electronic health records and radiotherapy dose-volume parameters were calculated. RESULTS: The developmental and validation cohort included 409 and 334 patients respectively. Multivariable analysis showed predictive value for pretreatment weight change, texture modified diet at baseline, ECOG performance status, tumor site, N classification, mean radiation dose to the contralateral parotid gland and oral cavity. The area under the receiver operating characteristics curve for this model was 0.73 and after external validation 0.62. Positive and negative predictive value for a risk of 90% or higher for TF dependency ≥4 weeks were 81.8% and 42.3% respectively. CONCLUSIONS: We developed and externally validated a prediction model to estimate TF-dependency ≥4 weeks in LAHNSCC patients treated with CRT/BRT. This model can be used to guide personalized decision-making on prophylactic gastrostomy insertion in clinical practice.

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.

Cost-Effectiveness of Surgery Versus Organ Preservation in Advanced Laryngeal Cancer.

OBJECTIVE: Treatment decision-making for patients with laryngeal cancer consists of a complex trade-off between survival and quality of life. For decision makers on coverage and guidelines, costs come in addition to this equation. Our aim was to perform a cost-effectiveness analysis of surgery (laryngectomy with or without radiotherapy) versus organ preservation (OP: radiotherapy, chemo- and/or bioradiation) in advanced laryngeal cancer patients from a healthcare perspective. METHODS: A cost-effectiveness analysis was conducted using a Markov model. For each modality, data on survival and quality-adjusted life years (QALYs) were sourced from relevant articles in agreement with experts, and national benchmark cost prices were included regarding treatment, follow-up, adverse events, and rehabilitation. RESULTS: Total QALYs of the surgical approach (6.59) were substantially higher compared to the OP approach (5.44). Total lifetime costs were higher for the surgical approach compared to the OP approach, namely €95,881 versus €47,233. The surgical approach was therefore more effective and more costly compared to OP, resulting in an incremental cost-effectiveness ratio of €42,383/QALY. CONCLUSION: Based on current literature, surgical treatment was cost-effective compared to OP in advanced laryngeal cancer within most willingness-to-pay thresholds. The study provides information on the survival adjusted for quality of life in combination with costs of two different approaches for advanced laryngeal cancer, relevant for patients, physicians, and policy makers. As financial toxicity is a relevant aspect in this population, collection of real-world data on country-specific costs and utilities is strongly recommended to enable further generalization. LEVEL OF EVIDENCE: N/A. Laryngoscope, 131:E509-E517, 2021.

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.

Patient-reported swallowing function after treatment for early-stage oropharyngeal carcinoma: Population-based study.

BACKGROUND: Single-modality treatment (surgery or radiotherapy [RT]) is a curative treatment option for early-stage oropharyngeal carcinoma (OPC) with comparable (excellent) oncological outcomes. This study aimed to compare self-reported swallowing function. METHODS: Participants with a T1-2N0-2bM0 OPC who were offered single-modality treatment and were recruited to the Head and Neck 5000 study were included. Prospectively collected self-reported swallowing function was compared between surgery and RT. RESULTS: Those offered RT (n = 150) had less favorable baseline characteristics than those offered surgery (n = 150). At 12-month follow up, RT participants reported more swallowing problems (35% vs 23%, RR 1.3; 95% CI 0.8-2.3, P = .277) in models adjusted for baseline characteristics. In those allocated to surgery who received adjuvant therapy (n = 78, 52%), the proportion with swallowing problems was similar to those allocated to RT alone. CONCLUSIONS: Participants offered surgery alone had similar mortality but improved swallowing, although this was not statistically significant. However, over half of participants offered surgery alone received surgery and adjuvant therapy.

Disease course after the first recurrence of head and neck squamous cell carcinoma following (chemo)radiation.

PURPOSE: Recurrent head and neck squamous cell carcinoma (HNSCC) after chemoradiation is a challenging clinical problem. Salvage surgery (SS) is often extensive and mutilating. Oncological outcomes of SS are relatively well known, but little is published about the course of disease after the first recurrence, especially in patients without salvage possibilities. The aim of this study was to analyze the course of disease in patients with recurrent HNSCC after chemoradiation. METHODS: We retrospectively analyzed and descriptively reported the disease course in 198 patients with recurrent HNSCC after chemoradiation in the time period after the first recurrence. We scored any type of event, salvage treatment, systemic treatment and overall survival (OS). RESULTS: Of the 198 patients with recurrent HNSCC, salvage surgery was attempted in 104 (53%). SS was more frequently given in patients with recurrent laryngeal cancer, isolated regional failure (p < 0.001) and HPV-positive disease (p = 0.09). The 2-year OS of the whole group was 31% and was significantly different by tumor site, type of failure and SS. HPV-positive disease and salvaged recurrences were significantly predictive for better survival. One third of that salvaged patients was still alive without second recurrence. Median survival in patients that received any palliative systemic treatment without surgery, compared to those were no treatment was given, was 6 and 3 months, respectively (p = 0.006). CONCLUSIONS: Main factors influencing the course of disease in recurrent HNSCC are the possibilities for SS and HPV-status. Therefore, SS should always be considered and discussed. In patients without possibilities for SS, overall survival is 3-6 months.

Study protocol of a prospective multicenter study comparing (cost-)effectiveness of a tailored interdisciplinary head and neck rehabilitation program to usual supportive care for patients treated with concomitant chemo- or bioradiotherapy.

BACKGROUND: Since 2011, a tailored, interdisciplinary head and neck rehabilitation (IHNR) program, covered by the basic healthcare insurance, is offered to advanced head and neck cancer (HNC) patients in the Netherlands Cancer Institute (NKI). This program is developed to preserve or restore patients' functioning, and to optimize health-related quality of life (HRQoL). It applies an integrated approach to define patients' individual goals and provide rehabilitation care throughout the cancer care continuum. The aim of the current study is to assess the (cost-) effectiveness of the IHNR approach compared to usual supportive care (USC) consisting of monodisciplinary and multidisciplinary care in advanced HNC patients. METHODS: This multicenter prospective observational study is designed to compare (cost-)effectiveness of the IHNR to USC for advanced HNC patients treated with chemoradiotherapy (CRT) or bioradiotherapy (BRT). The primary outcome is HRQoL represented in the EORTC QLQ-C30 summary score. Functional HRQoL, societal participation, utility values, return to work (RTW), unmet needs (UN), patient satisfaction and clinical outcomes are secondary outcomes, assessed using the EORTC QLQ-H&N35, USER-P, EQ-5D-5 L, and study-specific questionnaires, respectively. Both patient groups (required sample size: 64 per arm) are requested to complete the questionnaires at: diagnosis (baseline; T0), 3 months (T1), 6 months (T2), 9 months (T3) and 12 months (T4) after start of medical treatment. Differences in outcomes between the intervention and control group will be analyzed using mixed effects models, Chi-square test and descriptive statistics. In addition, a cost-effectiveness analysis (CEA) will be performed by means of a Markov decision model. The CEA will be performed using a societal perspective of the Netherlands. DISCUSSION: This prospective multicenter study will provide evidence on the effectiveness and cost-effectiveness of IHNR compared to USC. RTW and societal participation, included as secondary outcomes, have not been studied sufficiently yet in cancer rehabilitation. Interdisciplinary rehabilitation has not yet been implemented as usual care in all centers, which offers the opportunity to perform a controlled clinical study. If demonstrated to be (cost-)effective, national provision of the program can probably be advised. TRIAL REGISTRATION: The study has been retrospectively registered in the Netherlands Trial Registry on April 24th 2018 ( NTR7140 ).

Incidence of contralateral regional failure in the electively irradiated contralateral neck of patients with head and neck squamous cell carcinoma.

BACKGROUND: The vast majority of patients with head and neck squamous cell carcinoma (HNSCC) routinely undergo elective nodal irradiation (ENI) to both sides of the neck. Little is known about the extent to which bilateral ENI prevents regional failure (RF) and contralateral RF (cRF) in particular, while such knowledge is necessary to evaluate the results of more selective approaches like unilateral ENI. We investigated the rate and pattern of RF after bilateral ENI, the rate of cRF in the electively irradiated contralateral neck, and tried to identify risk factors for development of cRF. MATERIALS AND METHODS: Retrospective cohort study of a consecutive series of 605 patients with T1-4N0-3 HNSCC treated between 2008 and 2017 with primary (chemo)radiation and bilateral ENI. RESULTS: Median follow-up was 43 months (range 1.4-126). Three-year cumulative incidence of RF was 12.7%. Three-year cumulative incidences of ipsilateral RF (iRF) and cRF were 10.6% and 2.8%, respectively. All cRF occurred within the electively treated volume. Salvage treatment was possible in 65% and 59% of patients with iRF and cRF, respectively (p = 0.746). The 3-year overall survival rates after RF in patients with iRF and cRF were 27.4% and 41.2%, respectively (p = 0.713). Three-year cancer-specific survival rates were 31.6% and 48.1%, respectively (p = 0.634). In multivariate analysis, no significant predictive factors were identified for cRF after bilateral ENI. CONCLUSION: Contralateral regional failure is rare, but still occurs in 2.8% of patients treated with bilateral ENI. The possibilities for salvage treatment, the rates of overall survival and cancer-specific survival were comparable to patients with iRF.

Organ Function Preservation Failure after (Chemo)Radiotherapy in Head and Neck Cancer: A Retrospective Cohort Analysis.

OBJECTIVE: The aim of the current study was to determine the incidence of organ function preservation failure (OFPF) in patients with head and neck squamous cell carcinoma (HNSCC) treated by (chemo)radiotherapy and to identify its risk factors. STUDY DESIGN: Retrospective cohort analysis. SETTING: Tertiary cancer care center. SUBJECTS AND METHODS: A single-center retrospective cohort analysis was done (n = 703) in which OFPF after (chemo)radiotherapy was assessed. OFPF was defined as local failure or pure functional failure in the absence of local failure because of major surgical intervention (total laryngectomy, commando resection, permanent tracheostomy) or feeding tube dependence >2 years. RESULTS: OFPF occurred in 153 patients (21.8%). Reasons for OFPF were local failure in 103 patients (14.6%) and functional failure in 50 patients (7.2%). Evidence of functional failure included need for total laryngectomy (n = 9, 1.3%), commando resection (n = 2, 0.3%), permanent tracheostomy (n = 16, 2.3%), and/or long-term feeding tube for functional reasons (n = 23, 3.3%). In a Cox proportional hazards model, OFPF was worse for patients with T4 tumors (hazard ratio [HR] <0.5 and P < .001 for all other stages), for laryngeal vs oropharyngeal cancer (HR, 1.83; 95% confidence interval [CI], 1.20-2.79, P = .005, hypopharyngeal not significant), and for smokers (HR, 1.68; 95% CI, 1.10-2.56, P = .015). Exploratory multivariate analysis by tumor site showed that T4 tumor and pretreatment tracheostomy were the strongest predictive factors for OFPF in laryngeal and hypopharyngeal carcinoma while T4 tumor and smoking were predictive for poor OFPF in oropharyngeal carcinoma. CONCLUSION: This work shows a detrimental effect of smoking on functional outcomes after (chemo-)radiotherapy for HNSCC. Moreover, T4 tumor, laryngeal subsite, and pretreatment tracheostomy are strong predictors of OFPF.

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.

The impact of margin reduction on outcome and toxicity in head and neck cancer patients treated with image-guided volumetric modulated arc therapy (VMAT).

BACKGROUND AND PURPOSE: In recent decades, outcomes of patients with head and neck cancer (HNC) have improved as a result of implementing several strategies, such as chemoradiation. However, these improvements were achieved at the cost of increased toxicity. One way to reduce radiation-related toxicity is by reducing the margins. MATERIALS AND METHODS: Between 2013 and 2016, 206 consecutive patients were treated with CTV-PTV margin of 5 mm and subsequently 208 patients with 3 mm margin. This study evaluates the impact of reducing clinical target volume (CTV) to planning target volume (PTV) margin on outcome and toxicity. RESULTS: All patients were treated with volumetric modulated arc therapy (VMAT) with daily-image guidance using cone-beam CT (CBCT). Overall acute grade 3 toxicity was significantly lower in 3 mm-group, compared to 5 mm-group (53.8% vs. 65%, respectively, p = 0.032). The same was true for acute grade 3 mucositis (30.8% vs. 42.2%, p = 0.008) and for acute grade 3 dysphagia (feeding tube-dependence) (22.1% vs. 33.5%, p = 0.026). The incidence of ongoing feeding tube-dependence after 3 months of radiotherapy was 11.1% and 20.4%, respectively (p = 0.012). The 2-year incidence of late grade ≥2 xerostomia was 15.8% and 19.4% (p = 0.8). The 2-year loco-regional control rates of patients treated in 3 mm and 5 mm-groups were 79.9% and 79.2% (p = 1.0). The figures for disease-free survival were 71.5% and 72.7 (p = 0.6) and for overall survival were 75.2% and 75.1% (p = 0.9). CONCLUSION: Reducing the CTV-PTV margin from 5 to 3 mm combined with daily CBCT-guided VMAT reduced the severity, frequency, and duration of radiation-related toxicity without jeopardizing outcome.

Organ-preservation (chemo)radiotherapy for T4 laryngeal and hypopharyngeal cancer: is the effort worth?

PURPOSE: We aimed to analyze the oncological and functional outcomes of chemoradiation for T4 laryngeal and hypopharyngeal cancer. METHODS: Patients treated between 2008 and 2015 with chemoradiation (n = 39) were retrospectively analyzed for oncological and functional (laryngo-esophageal dysfunction-free survival, LED-FS) outcomes and compared with 32 consecutive patients treated primarily with total laryngectomy (TL). LED was scored as event in case of local failure, TL for any reason, persistent tracheotomy and/or feeding tube dependency 2 years after chemoradiation. RESULTS: The 5-year local control (LC) rates in the chemoradiation and TL groups were 64 and 87%, respectively (p = 0.030). The disease-free survival was 54 and 59% (p = 0.810), and overall survival (OS) was 46 and 47% (p = 1.00). In the chemoradiation group, the 5-year cumulative incidence of LED-FS was 46%, but was significantly worse in patients with poor pre-treatment laryngeal function, compared to those without (20% and 74%, respectively, p = 0.001). Furthermore, patients with LED have significantly worse OS compared to those without (32% and 65%, respectively, p = 0.041). Multivariate analysis showed that primary treatment type is significantly predictive for LC, while tumor site and extra-capsular extension were predictive for OS. Poor pre-treatment laryngeal function is the only significant predictive factor for LED. CONCLUSIONS: TL resulted in significantly better LC, as compared to chemoradiation in T4 laryngeal and hypopharyngeal cancer patients and the LED-FS is worse in patients with poor pre-treatment laryngeal function. These patients might benefit more from primary treatment with TL followed by radiotherapy. These issues should be taken into consideration, as patients are counseled about different primary treatment options.

Protocolised way to cope with anatomical changes in head & neck cancer during the course of radiotherapy.

INTRODUCTION: During a course of radiotherapy for head-and-neck-cancer (HNC), non-rigid anatomical changes can be observed on daily Cone Beam CT (CBCT). To objectify responses to these changes, we use a decision support system (traffic light protocol). Action levels orange and red may lead to re-planning. The purpose of this study was to evaluate how often re-planning was done for non-rigid anatomical changes, which anatomical changes led to re-planning and in which subgroups of patients treatment adaptation was deemed necessary. MATERIALS AND METHODS: A consecutive series of 388 HNC patients were retrospectively selected using the digital log of CBCT scans. The logs were analyzed for the number of new plans on an original planning CT scan (O-pCT) or a new pCT scan (N-pCT). Reasons for re-planning were categorized into: target volume increase/decrease, body contour decrease/increase and local shift of target volume. Subgroup analysis was performed to investigate relative differences of re-planning between treatment modalities. RESULTS: For 33 patients the treatment plan was adapted due to anatomical changes, resulting in 37 new plans in total. Re-planning on a N-pCT with complete re-delineation was done 22 times. In fifteen cases a new plan was created after adjustment of contours on the O-pCT. Main reasons for re-planning were target volume increase, body contour decrease and local shifts of target volume. Most re-planning (23%) was seen in patients treated with chemoradiotherapy. CONCLUSION: Visual detection of anatomical changes on CBCT during treatment of HNC, results in re-planning in 1 out of 10 patients.