Chemo-IMRT of Oropharyngeal Cancer Aiming to Reduce Dysphagia: Swallowing Organs Late Complication Probabilities and Dosimetric Correlates

Abstract

Purpose Assess dosimetric correlates of long-term dysphagia after chemo-IMRT of oropharyngeal cancer (OPC) sparing parts of the swallowing organs. Patients and Methods Prospective longitudinal study: weekly chemotherapy concurrent with IMRT for stages III/IV OPC, aiming to reduce dysphagia by sparing non-involved parts of swallowing-related organs: pharyngeal constrictors (PC), glottic and supraglottic larynx (GSL), and esophagus, as well as oral cavity and major salivary glands. Dysphagia outcomes included patient-reported Swallowing and Eating Domain scores, Observer-based (CTCAEv.2) dysphagia, and videofluoroscopy (VF), before and periodically after therapy through 2 years. Relationships between dosimetric factors and worsening (from baseline) of dysphagia through 2 years were assessed by linear mixed-effects model. Results 73 patients participated. Observer-based dysphagia was not modeled because at >6 months there were only four grade ≥2 cases (one of whom feeding-tube dependent). PC, GSL, and esophagus mean doses, as well as their partial volume doses (VDs), were each significantly correlated with all dysphagia outcomes. However, the VDs for each organ inter-correlated and also highly correlated with the mean doses, leaving only mean doses significant. Mean doses to each of the parts of the PCs (superior, middle and inferior) were also significantly correlated with all dysphagia measures, with superior PCs demonstrating highest correlations. For VF-based strictures, most significant predictor was esophageal mean doses (48±17 Gy in patients with, vs 27±12 in patients without strictures, p=0.004). Normal tissue complication probabilities (NTCPs) increased moderately with mean doses without any threshold. For increased VF-based aspirations or worsened VF summary scores, TD50 and TD25 were 63Gy and 56Gy for PC, and 56Gy and 39Gy for GSL, respectively. For both PC and GSL, patient-reported swallowing TDs were substantially higher than VF-based TDs. Conclusions Swallowing organs mean doses correlated significantly with long-term worsening of swallowing. Different methods assessing dysphagia resulted in different NTCPs, and none demonstrated a threshold.

Dysphagia and trismus after concomitant chemo-Intensity-Modulated Radiation Therapy (chemo-IMRT) in advanced head and neck cancer; dose–effect relationships for swallowing and mastication structures

“…Feng et al published 2 prospective studies that included patients with oropharyngeal and/or nasopharyngeal cancer, and found significant correlations between dysphagia endpoints (i.e. assessed with videofluoroscopy and questionnaires) and the doses to the pharyngeal constrictors (IC, MC, and SC) [9,25]. These authors also found a significant association between the swallowing related quality of life scores (HNQOL and UWQOL) and the mean doses to the pharyngeal constrictors.…”

“…However, patients that already show functional problems at baseline are at higher risk of developing dysphagia/trismus, because even with IMRT it is impossible to avoid the relevant structures and at the same time deliver the required doses to the primary tumor. In this respect, it is important to provide these patient information and start with preventive therapy as Feng et al [25] also stated: "it is unlikely that technology alone will completely eliminate dysphagia and that additional strategies like customization of treatment intensity to predictors of tumor control, improved cytoprotection, better targeted radio sensitization, and prompt swallow therapy when indicated are required for additional progress. "…”

“…In the literature, no clear thresholds were reported either [9,29]. Feng et al also looked at dose-volume effects, and concluded that patients aspirating after 3 months had received mean pharyngeal constrictor doses >60 Gy or a V65> 50% [9,25]. In addition, Schwartz et al investigated candidate dosimetric predictors of the long-term objective (videofluoroscopy) and subjective swallowing dysfunction in oropharyngeal cancer patients [30].…”

A Multi-institution Pooled Analysis of G-Tube Dependence in Patients With Oropharyngeal Cancer Treated With Definitive IMRT

“…The latter hypothesis has been founded in the observation that long-term swallowing dysfunction is independently associated with the mean dose to the pharyngeal constrictor muscles and larynx, as well as the volume of structures receiving between 50-70 Gy. [16][17][18][19] Multiple randomized trials are currently investigating the use of transoral surgery +/− adjuvant therapy in the setting of de-intensifying treatment for HPV-positive disease (ECOG 3311, ADEPT), as well as in the setting of multimodality treatment intensification for HPVnegative disease (RTOG 1221).…”

NTCP reduction for advanced head and neck cancer patients using proton therapy for complete or sequential boost treatment versus photon therapy

“…Biological evaluation was done for several clinical endpoints based on modern NTCP models with both, underlying patient characteristics and treatment procedures similar to the presented study: Incidence of acute oral mucositis (grade Ն 3) [9], aspiration assessed by videofl uoroscopy [10], xerostomia 12 months after therapy [11], subjective and objective swallowing dysfunction [12], late larynx edema (grade Ն 2) [13] and trismus assessed as jaw-opening Ͻ 35 mm [14], cf. Jakobi et al [5] for details.…”