Personalized neck irradiation guided by sentinel lymph node biopsy in patients with squamous cell carcinoma of the oropharynx, larynx or hypopharynx with a clinically negative neck: (Chemo)radiotherapy to the PRIMary tumor only. Protocol of the PRIMO study.

Background: Elective neck irradiation (ENI) is performed in head and neck cancer patients treated with definitive (chemo)radiotherapy. The aim is to eradicate nodal metastases that are not detectable by pretreatment imaging techniques. It is conceivable that personalized neck irradiation can be performed guided by the results of sentinel lymph node biopsy (SLNB). It is expected that ENI can be omitted to one or both sides of the neck in 9 out of 10 patients, resulting in less radiation side effects with better quality of life. Methods/design: This is a multicenter randomized controlled trial aiming to compare safety and efficacy of treatment with SLNB guided neck irradiation versus standard bilateral ENI in 242 patients with cN0 squamous cell carcinoma of the oropharynx, larynx or hypopharynx for whom bilateral ENI is indicated. Patients randomized to the experimental-arm will undergo SLNB. Based on the histopathologic status of the SLNs, patients will receive no ENI (if all SLNs are negative), unilateral neck irradiation only (if a SLN is positive at one side of the neck) or bilateral neck irradiation (if SLNs are positive at both sides of the neck). Patients randomized to the control arm will not undergo SLNB but will receive standard bilateral ENI. The primary safety endpoint is the number of patients with recurrence in regional lymph nodes within 2 years after treatment. The primary efficacy endpoint is patient reported xerostomia-related quality of life at 6 months after treatment. Discussion: If this trial demonstrates that the experimental treatment is non-inferior to the standard treatment in terms of regional recurrence and is superior in terms of xerostomia-related quality of life, this will become the new standard of care.

Muscarinic inhibition of salivary glands with glycopyrronium bromide does not reduce the uptake of PSMA-ligands or radioiodine.

RATIONALE: Salivary glands are highly perfused and express the prostate-specific membrane antigen (PSMA) receptor as well as the sodium-iodide symporter. As a consequence, treatment with 177Lu/225Ac-PSMA for prostate cancer or 131I for thyroid cancer leads to a high radiation dose in the salivary glands, and patients can be confronted with persistent xerostomia and reduced quality of life. Salivation can be inhibited using an antimuscarinic pharmaceutical, such as glycopyrronium bromide (GPB), which may also reduce perfusion. The primary objective of this work was to determine if inhibition with GPB could provide a considerable (> 30%) reduction in the accumulation of administered 123I or 68Ga-PSMA-11 in salivary glands. METHODS: Ten patients who already received a whole-body 68Ga-PSMA-11 PET/CT scan for (re)staging of prostate cancer underwent a repeat PET/CT scan with tracer administration at 90 min after intravenous injection of 0.2 mg GPB. Four patients in follow-up after thyroid cancer, who had been treated with one round of ablative 131I therapy with curative intent and had no signs of recurrence, received 123I planar scintigraphy at 4 h after tracer administration without GPB and a repeated scan at least one week later, with tracer administration at 30 min after intramuscular injection of 0.4 mg GPB. Tracer uptake in the salivary glands was quantified on PET and scintigraphy, respectively, and values with and without GPB were compared. RESULTS: No significant difference in PSMA uptake in the salivary glands was seen without or with GPB (Mean SULmean parotid glands control 5.57, intervention 5.72, p = 0.50. Mean SULmean submandibular glands control 6.25, intervention 5.89, p = 0.12). Three out of 4 patients showed increased 123I uptake in the salivary glands after GPB (Mean counts per pixel control 8.60, intervention 11.46). CONCLUSION: Muscarinic inhibition of salivation with GPB did not significantly reduce the uptake of PSMA-ligands or radioiodine in salivary glands, and can be dismissed as a potential strategy to reduce toxicity from radionuclide therapies.

Laryngo-esophageal dysfunction free survival and propensity score matched analysis comparing organ preservation and total laryngectomy in hypopharynx cancer.

AIMS: To assess the functional outcomes of patients treated for hypopharynx cancer and to obtain an unbiased estimate of survival difference between patients treated with chemoradiotherapy (CRT) or total laryngectomy (TL). METHODS: Retrospective cohort study of all patients treated with curative intent for T1-T4 squamous cell carcinoma of the hypopharynx in The Netherlands Cancer Institute (1990-2013). Functional outcome following radiotherapy (RT) or CRT was measured using laryngo-esophageal dysfunction free survival rate (LDFS). Using propensity score (PS) matched analysis, we compared survival outcome of TL to CRT in T2-T4 patients. RESULTS: We included 343 patients with T1T4 hypopharynx cancer. LDFS 2 and 5-years following CRT was respectively 44 and 32%. Following RT this was 39 and 30%. Patients were matched on the following variables: age, gender, TNM classification, subsite of tumor, decade of diagnosis, prior cancer, smoking, ACE27 score, BMI hemoglobin, albumin, and leukocyte level. With PS matching, we were able to match 26 TL patients with 26 CRT patients. The OS rates for TL and CRT in this matched cohort were respectively 56% and 46% at 5 years and 35% and 17% at 10 years. CONCLUSION: In conclusion, functional outcomes following RT or CRT are suboptimal and require improved treatment strategies or rehabilitation efforts. The OS results challenge the preposition that CRT and TLE are equivalent in terms of survival.

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 cumulative dose of cisplatin on outcome of patients with head and neck squamous cell carcinoma.

Despite the wide use of cisplatin-based concomitant chemoradiotherapy (CCRT) for head and neck squamous cell carcinoma (HNSCC), data on the optimal regimen and cumulative dose are scarce and frequently conflicting. We aimed to evaluate the compliance and the impact of the cumulative dose of cisplatin on overall survival (OS), disease-free survival (DFS), loco-regional control (LRC), and distant-metastasis-free survival (DMFS) in a retrospective study. Between 2008 and 2015, 279 patients with HNSCC scheduled for CCRT (three courses of 3-week 100 mg/m2 cisplatin) were identified. Of the whole group, 14% did not receive any cisplatin and 26% received daily cisplatin. In patients planned for three courses (n = 167), 56% received 3, 20% received 2, and 24% received one course. After median follow-up of 31.6 months, the actuarial OS, DFS, LRC, and DMFS rates at 3 years for patients received cumulative dose of ≥200 mg/m2 were significantly better compared to those received <200 mg/m2; 74 vs. 51% for OS, 73 vs. 49% for DFS, 80 vs. 58% for LRC (p < 0.001), and 85 vs. 76% for DMFS (p = 0.034). At multivariate analysis, the cumulative cisplatin dose (≥200 vs. <200 mg/m2) was significantly predictive for OS (HR 2.05; 95% CI 1.35-3.13, p = <0.001). Borderline GFR (60-70 mL/min) at baseline predicts compliance for ≥two courses (p = 0.003). In conclusion, considerable proportion of patients did not receive all pre-planned courses of cisplatin. Patients receiving cumulative cisplatin dose ≥200 mg/m2 had significantly better outcome than those receiving <200 mg/m2 and cumulative dose <200 mg/m2 might even be detrimental. These findings increased the bulk of slowly growing evidence on the optimal cumulative dose of cisplatin. Baseline GFR might predict compliance.

Elective unilateral nodal irradiation in head and neck squamous cell carcinoma: A paradigm shift.

There is a long-standing convention to irradiate the great majority of head and neck squamous cell carcinoma (HNSCC) electively to both sides of the neck, to reduce the theoretically increased risk of contralateral regional failure (cRF). With the currently available diagnostic imaging techniques this treatment paradigm means, in our opinion, an overtreatment in considerable proportion of these patients. From all the published studies (n = 11, with 1116 patients treated in total), the incidence of cRF in patients with oropharyngeal cancer treated to one side of the neck is 2.4%. The incidence was higher in patients with tumours involving the midline (12.1%). The low incidence of cRF was also seen in patients with HNSCC treated by local excision combined with unilateral neck dissection or sentinel node procedure. It seems clear from the aggregated data of these studies that a less conservative approach with regard to the selection of patients for unilateral elective nodal irradiation is justified. The fear of leaving the contralateral neck untreated in well-selected groups of patients with HNSCC needs nowadays to be mitigated since the incidence of cRF in lateralised tumours extending to but not crossing the midline is low. Furthermore, the obviously improved diagnostic imaging nowadays could help us to guide the selection of considerable proportion of patients with lateralised HNSCC for unilateral elective nodal irradiation with significant reduction of radiation-related toxicity and improved quality of life.

[Pain as the primary symptom of a malignant parotid tumour]. / Pijn als primair symptoom van een maligne parotistumor.

The differential diagnosis of peri-auricular pain is comprehensive and arriving at a correct diagnosis is not always easy, which may result in a delay of treatment or even malpractice. Two patients presented themselves with facial peri-auricular pain. After a period of follow-up and control this pain turned out to be related to a malignant tumor in the glandula parotidea. These two cases show the importance for the dentist to refer patients with peri-auricular pain, with or without concomitant facial nerve palsy, to a specialist in a timely manner.

The Impact of the Overall Radiotherapy Time on Clinical Outcome of Patients with Nasopharyngeal Carcinoma; A Retrospective Study.

PURPOSE: In Yogyakarta, nasopharyngeal carcinoma (NPC) shows a poor response to radiotherapy treatment. Previous study showed a prolonged overall treatment time (OTT), due to interruptions during treatment. This study explores the association between clinical outcome and OTT. Secondary, the relation between clinical outcome and disease stage, waiting time to radiation (WT) and chemotherapy schedule was explored. METHODS: In this retrospective cohort, 142 patients who started curative intent radiotherapy for NPC between March 2009 and May 2014, with or without chemotherapy, were included. The median follow up time was 1.9 years. Data was collected on WT, OTT, disease stage, and chemotherapy schedule. Time factors were log-transformed. Clinical outcome was defined as therapy response, loco-regional control (LRC), disease free survival (DFS) and overall survival (OS). RESULTS: The median WT was 117 days (range 12-581) and OTT was 58 days (43-142). OTT and disease stage were not associated to any of the clinical outcome parameters. The log-WT was associated to poor therapy outcome (HR 1.68; 95% ci: 1.09-2.61), LRC (HR 1.66; 95% ci: 1.15-2.39), and DFS (HR 1.4; 95% ci: 1.09-1.81). In the multivariable analysis, significant hazard risk for poor therapy response, LRC, DFS and OS were seen for patients who didn't received concurrent chemotherapy. CONCLUSION: Not receiving concurrent chemotherapy showed the strongest risk for poor outcome. Since the choice of chemotherapy is related to a variety of factors, like the WT and patient's physical condition when radiation can start, careful interpretation is needed. Reason for not finding a relation between OTT and clinical outcome might be the low number of patients who finished radiotherapy within 7 weeks, or by a stronger detrimental effect of other factors.

Dietary counselling and nutritional support in oropharyngeal cancer patients treated with radiotherapy: persistent weight loss during 1-year follow-ups.

BACKGROUND/OBJECTIVES: The need for dietary counselling and nutritional support in oropharyngeal cancer patients is generally accepted. However, evidence for the effectiveness is sparse. The aim of this study was to describe dietary counselling, nutritional support, body weight and toxicity during and after treatment, and investigate the effect of pre-treatment body mass index (BMI) on survival in oropharyngeal cancer patients. SUBJECTS/METHODS: A retrospective chart review was made in 276 oropharyngeal cancer patients treated with radiotherapy (RT). End points were dietary consultations, weight loss, toxicity, overall survival and disease-free survival. RESULTS: Almost all oropharyngeal cancer patients received dietary counselling (94%) and nutritional support (99%). Dietary counselling decreased sharply shortly after treatment to 38% at 1 year after treatment. Overall weight loss increased during the first year of follow-up and ranged from 3% at start of RT, until 11% at 1 year after RT. Overall survival was significantly longer for patients with a BMI above average (P=0.01). Acute dysphagia (P=0.001), mucositis (P=0.000) and toxicity grade 3 (P=0.002) were significantly more prevalent in patients who had lost 10% or more of their body weight. CONCLUSIONS: This study showed that patients continue to lose body weight during and until 1 year after treatment, despite nutrition support and frequent dietetic consultation. A BMI above average appears to increase survival time. Future studies, preferably randomized trials, are needed to compare standard dietary counselling with more intensive dietary counselling that consists of earlier and/or prolonged treatment.

Radiotherapy for T1-2N0 glottic cancer: a multivariate analysis of predictive factors for the long-term outcome in 1050 patients and a prospective assessment of quality of life and voice handicap index in a subset of 233 patients.

OBJECTIVES: To evaluate the outcomes of patients with early stage glottic cancer (GC) treated with radiotherapy (RT). DESIGN, SETTING AND PARTICIPANTS: The current study report on a retrospective analysis of oncologic outcome of 1050 patients with T1-2N0 glottic cancer treated with radiotherapy. Prospective assessment of quality of life (QoL) and voice handicap index (VHI) was performed in all patients treated from 2006 onwards (n = 233). MAIN OUTCOME MEASURES: Local control (LC), regional control (RC), disease-free survival (DFS), overall survival (OS), quality of life and voice handicap index. RESULTS: After a median follow-up of 90 months (range 3-309), the actuarial rates of local control, regional control, disease-free survival and overall survival were 85%, 99%, 84% and 81% at 5 years and 82%, 98%, 80% and 61% at 10 years, respectively. On multivariate analysis, T2 tumours, smoking after radiotherapy and conventional radiation scheme correlated significantly with poor local control. Patients who continued smoking after radiotherapy had also significantly lower overall survival rates (OR 4.3, P < 0.001). Hypothyroidism was reported in 18% of patients. Slight and temporary deterioration of quality of life scores was reported. Patient-reported xerostomia and dysphagia at 48 months were -7.1 and -6.5, compared with baseline, respectively. Voice handicap index improved significantly from 37 at baseline to 18 at 48 months. Patients with T2b and those who continued smoking had significantly worse voice handicap index. CONCLUSIONS: In the current study, excellent outcome with good quality of life and voice handicap index scores were reported. T2 tumours, in particular T2b, and continuing smoking after radiotherapy correlated significantly with poor local control and worse voice handicap index.