Predictors of acute grade 4 swallowing toxicity in patients with stages III and IV squamous carcinoma of the head and neck treated with radiotherapy alone

Department of Radiation Oncology, Princess Alexandra Hospital, Qld, Australia.
Radiotherapy and Oncology (Impact Factor: 4.36). 06/2008; 87(2):253-9. DOI: 10.1016/j.radonc.2008.03.010
Source: PubMed


The purpose of the study was to investigate the predictive factors for acute grade 4 swallowing toxicity in an attempt to identify which patients may benefit from early intervention with enteral feeding during curative radiation treatment for localised Stages 3-4 squamous cell carcinoma of the head and neck. It was hypothesised that craniocaudal length of the treatment field to the upper neck and pharynx would correlate with grade 4 swallowing toxicity due to the increased volume of pharynx irradiated.
Toxicity data were collected prospectively as part of a phase III randomised trial (TROG 91:01) that assigned patients to either conventional (CRT) or accelerated radiotherapy (ART). Patients were randomly assigned to either CRT, using a single 2 Gy per day to a dose of 70 Gy in 35 fractions in 49 days or to ART, using 1.8 Gy twice a day to a dose of 59.4 Gy in 33 fractions in 24 days. Treatment allocation was stratified for site and stage. Accrual commenced in 1991 and the trial was closed in 1998 when the target of 350 patients was reached. Potential factors were analysed that predicted for Grade IV swallowing toxicity.
The treatment field lengths >82mm for the second phase increased the probability of requiring intervention with percutaneous endoscopic gastrostomy (PEG) or Nasogastric tube (NGT). The probability of grade 4 swallowing was 36% if the phase 2 treatment length was >82mm vs 16% for less < or = 82mm(p=0.0001). A predictive enteral grading score (PEG score) was derived using the Cox regression coefficients: Field length of the boost volume >82mm scored 3 points, Stage grouping greater than 1 scored 1 point, altered fractionation scored 2 points, ECOG greater than 1 scored 1 point. The PEG score was 45% if the score was 6 and 19% if the score was <6 (p=0.0).
More attention needs to be focused on developing robust dose and volume constraints for the pharyngeal mucosa and the musculature in order to reduce the need for enteral feeding. Patients with PEG score of 6 or greater are at high risk of requiring enteral feeding during radiation treatment and should be considered for prophylactic PEG or NG feeding.

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    • "The volume of RT-treated swallowing structures is a prognostic factor. In the Trans Tasman Radiation Oncology Group (TROG) 91.01 trial, the volume of irradiated pharynx (which included the mucosa and underlying pharyngeal constrictor muscles) was correlated to the probability of requiring enteral feeding [37]. "
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    ABSTRACT: Progress in head and neck cancer (HNC) therapies has improved tumor response, loco-regional control, and survival. However, treatment intensification also increases early and late toxicities. Dysphagia is an underestimated symptom in HNC patients. Impairment of swallowing process could cause malnutrition, dehydration, aspiration, and pneumonia. A comprehensive literature review finalized in May 2012 included searches of electronic databases (Medline, Embase, and CAB abstracts) and scientific societies meetings materials (American Society of Clinical Oncology, Associazione Italiana Radioterapia Oncologica, Associazione Italiana di Oncologia Cervico-Cefalica, American Head and Neck Society, and European Society for Medical Oncology). Hand-searches of HNC journals and reference lists were carried out. Approximately one-third of dysphagia patients developed pneumonia requiring treatment. Aspiration pneumonia associated mortality ranged from 20% to 65%. Unidentified dysphagia caused significant morbidity, increased mortality, and decreased the quality of life. In this review we underline definition, causes, predictive factors of dysphagia and report on pretreatment and on-treatment evaluation, suggesting some key points to avoid underestimation. A multi-parameter assessment of swallowing problems may allow an earlier diagnosis. An appropriate evaluation might lead to a better treatment of both symptoms and cancer.
    Full-text · Article · Sep 2013 · Clinical and Experimental Otorhinolaryngology
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    • "Given the likely relationship of radiotherapy-induced toxicity with the target volume and administered dose, this toxicity might be significantly reduced by a selective irradiation approach. In the TROG 91:01 trial, which included 350 head and neck cancer patients, Poulsen et al. [23] reported that the target volume in the second phase of treatment had the strongest influence on the development of odynophagia and need for aggressive nutritional intervention (gastrotomy or insertion of nasogastric tube), finding that the likelihood of developing grade-4 (G-4) odynophagia was 36% when the volume was > 82 mm and 16% when it was <18 mm (p = 0.0001). "
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    ABSTRACT: Background In cervical postoperative radiotherapy, the target volume is usually the same as the extension of the previous dissection. We evaluated a protocol of selective irradiation according to the risk estimated for each dissected lymph node level. Methods Eighty patients with oral/oropharyngeal cancer were included in this prospective clinical study between 2005 and 2008. Patients underwent surgery of the primary tumor and cervical dissection, with identification of positive nodal levels, followed by selective postoperative radiotherapy. Three types of selective nodal clinical target volume (CTV) were defined: CTV0, CTV1, and CTV2, with a subclinical disease risk of <10%, 10-25%, and 25% and a prescribed radiation dose of <35 Gy, 50 Gy, and 66–70 Gy, respectively. The localization of node failure was categorized as field, marginal, or outside the irradiated field. Results A consistent pattern of cervical infiltration was observed in 97% of positive dissections. Lymph node failure occurred within a high-risk irradiated area (CTV1-CTV2) in 12 patients, marginal area (CTV1/CTVO) in 1 patient, and non-irradiated low-risk area (CTV0) in 2 patients. The volume of selective lymph node irradiation was below the standard radiation volume in 33 patients (mean of 118.6 cc per patient). This decrease in irradiated volume was associated with greater treatment compliance and reduced secondary toxicity. The three-year actuarial nodal control rate was 80%. Conclusion This selective postoperative neck irradiation protocol was associated with a similar failure pattern to that observed after standard neck irradiation and achieved a significant reduction in target volume and secondary toxicity.
    Full-text · Article · Apr 2013 · Radiation Oncology
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    • "radiation volume, fractionation, and chemotherapy), and patient related factors (e.g. performance and baseline weight loss) [13] [14] [15]. Clinical data sets on normal tissue complications often include a large number of variables, many of which we would like to incorporate in a model because they are possibly related to a given complication. "
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    ABSTRACT: PURPOSE: Multivariate modeling of complications after radiotherapy is frequently used in conjunction with data driven variable selection. This study quantifies the risk of overfitting in a data driven modeling method using bootstrapping for data with typical clinical characteristics, and estimates the minimum amount of data needed to obtain models with relatively high predictive power. MATERIALS AND METHODS: To facilitate repeated modeling and cross-validation with independent datasets for the assessment of true predictive power, a method was developed to generate simulated data with statistical properties similar to real clinical data sets. Characteristics of three clinical data sets from radiotherapy treatment of head and neck cancer patients were used to simulate data with set sizes between 50 and 1000 patients. A logistic regression method using bootstrapping and forward variable selection was used for complication modeling, resulting for each simulated data set in a selected number of variables and an estimated predictive power. The true optimal number of variables and true predictive power were calculated using cross-validation with very large independent data sets. RESULTS: For all simulated data set sizes the number of variables selected by the bootstrapping method was on average close to the true optimal number of variables, but showed considerable spread. Bootstrapping is more accurate in selecting the optimal number of variables than the AIC and BIC alternatives, but this did not translate into a significant difference of the true predictive power. The true predictive power asymptotically converged toward a maximum predictive power for large data sets, and the estimated predictive power converged toward the true predictive power. More than half of the potential predictive power is gained after approximately 200 samples. Our simulations demonstrated severe overfitting (a predicative power lower than that of predicting 50% probability) in a number of small data sets, in particular in data sets with a low number of events (median: 7, 95th percentile: 32). Recognizing overfitting from an inverted sign of the estimated model coefficients has a limited discriminative value. CONCLUSIONS: Despite considerable spread around the optimal number of selected variables, the bootstrapping method is efficient and accurate for sufficiently large data sets, and guards against overfitting for all simulated cases with the exception of some data sets with a particularly low number of events. An appropriate minimum data set size to obtain a model with high predictive power is approximately 200 patients and more than 32 events. With fewer data samples the true predictive power decreases rapidly, and for larger data set sizes the benefit levels off toward an asymptotic maximum predictive power.
    Full-text · Article · Jan 2012 · Radiotherapy and Oncology
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