Peter G. Hawkins

Sparing all salivary glands with IMRT for head and neck cancer: Longitudinal study of patient-reported xerostomia and head-and-neck quality of life

BACKGROUND AND PURPOSE While parotid-sparing intensity modulated radiotherapy (IMRT) has demonstrated superiority to conventional RT in terms of observer-rated xerostomia, patient-reported outcome measures (PROMs) have only marginally improved. We investigated how sparing all salivary glands affects PROMs. MATERIALS AND METHODS Patients treated to the bilateral neck with all-gland-sparing IMRT answered xerostomia (XQ) and head-and-neck quality of life (HNQOL) questionnaires. Longitudinal regression was used to assess the relationship between questionnaire scores and mean bilateral parotid gland (bPG), contralateral submandibular gland (cSMG), and oral cavity (OC) doses. Marginal R2 and Akaike information criterion (AIC) were used for model evaluation. RESULTS 252 patients completed approximately 600 questionnaires. On univariate analysis, bPG, cSMG, and OC doses significantly correlated with XQ-summary, XQ-eating, and HNQOL-eating scores. On multivariate analysis, bPG and OC doses significantly correlated with XQ-summary, XQ-eating, and HNQOL-eating scores; and cSMG dose with HNQOL-summary. Combining doses to all three structures yielded the highest R2 for XQ-summary, XQ-rest, XQ-eating, and HNQOL-eating. In the 147 patients who received a mean cSMG dose ≤39Gy, there were no failures in contralateral level IB. CONCLUSIONS Reducing doses to all salivary glands maximizes PROMs. A cSMG dose constraint of ≤39Gy does not increase failure risk.

Organ-Sparing in Radiotherapy for Head-and-Neck Cancer: Improving Quality of Life

This is an overview of select studies characterizing the effect of radiation on normal tissues in the treatment of head-and-neck cancer. Recommendations for organ-at-risk dose constraints aiming to reduce risks of xerostomia and dysphagia, the factors which have the highest effect on patient quality of life, are discussed, along with their supporting evidence. Recent advances in technology and biology, and their implications for reducing toxicity are explored. Considerations related to organ-sparing in the setting of treatment deintensification for good-prognosis head-and-neck cancer are also discussed.

Individualizing Radiation Dose in Locally Advanced Non–Small Cell Lung Cancer Patients Using Pretreatment Serum MicroRNA Signatures

RTOG 0915 was open, and closed on April 15; 2015 after accruing a total of 98 patients. All patients received planned SBRT treatment. Median follow-up was 27 months. In follow-up; 10 patients were lost to follow-up; 1 was in arm 1 and 9 in arm 2. Baseline patient and tumor characteristics were balanced between both arms. Thirteen (27%) patients on arm 1 and 16 (33%) patients on arm 2 experienced RTOG grade 3 AEs; there were no grade 4 AEs. Thoracic grade 3 AEs were experienced by 8 (16%) patients on arm 1 and 6 (12%) patients on arm 2. There were no differences in OS or PFS survival, log-rank PZ.44 and .99, respectively. OS at 2 years was 71% (95% CI; 55-82%) for arm 1 and 61% (95% CI; 44-78%) for arm 2. PFS at 2 years was 63% (95% CI; 46-75%) for arm 1 and 51% (95% CI; 34-65%) for arm 2. Conclusion: This randomized phase 2 study demonstrated that 30 Gy in one fraction was equivalent to 60 Gy in three fractions in terms of toxicity, progression-free survival, and overall survival. Author Disclosure: A.K. Singh: None. J. Gomez Suescun: None. K.L. Stephans: None. J.A. Bogart: None. T. Lili: None. H. Malhotra: None. G.M. Videtic: None. A. Groman: None.

Radiation-induced lung toxicity in non-small-cell lung cancer: Understanding the interactions of clinical factors and cytokines with the dose-toxicity relationship

BACKGROUND AND PURPOSE Current methods to estimate risk of radiation-induced lung toxicity (RILT) rely on dosimetric parameters. We aimed to improve prognostication by incorporating clinical and cytokine data, and to investigate how these factors may interact with the effect of mean lung dose (MLD) on RILT. MATERIALS AND METHODS Data from 125 patients treated from 2004 to 2013 with definitive radiotherapy for stages I-III NSCLC on four prospective clinical trials were analyzed. Plasma levels of 30 cytokines were measured pretreatment, and at 2 and 4weeks midtreatment. Penalized logistic regression models based on combinations of MLD, clinical factors, and cytokine levels were developed. Cross-validated estimates of log-likelihood and area under the receiver operating characteristic curve (AUC) were used to assess accuracy. RESULTS In prognosticating grade 3 or greater RILT by MLD alone, cross-validated log-likelihood and AUC were -28.2 and 0.637, respectively. Incorporating clinical features and baseline cytokine levels increased log-likelihood to -27.6 and AUC to 0.669. Midtreatment cytokine data did not further increase log-likelihood or AUC. Of the 30 cytokines measured, higher levels of 13 decreased the effect of MLD on RILT, corresponding to a lower odds ratio for RILT per Gy MLD, while higher levels of 4 increased the association. CONCLUSIONS Although the added prognostic benefit from cytokine data in our model was modest, understanding how clinical and biologic factors interact with the MLD-RILT relationship represents a novel framework for understanding and investigating the multiple factors contributing to radiation-induced toxicity.

Prediction of Radiation Esophagitis in Non–Small Cell Lung Cancer Using Clinical Factors, Dosimetric Parameters, and Pretreatment Cytokine Levels

Radiation esophagitis (RE) is a common adverse event associated with radiotherapy for non–small cell lung cancer (NSCLC). While plasma cytokine levels have been correlated with other forms of radiation-induced toxicity, their association with RE has been less well studied. We analyzed data from 126 patients treated on 4 prospective clinical trials. Logistic regression models based on combinations of dosimetric factors [maximum dose to 2 cubic cm (D2cc) and generalized equivalent uniform dose (gEUD)], clinical variables, and pretreatment plasma levels of 30 cytokines were developed. Cross-validated estimates of area under the receiver operating characteristic curve (AUC) and log likelihood were used to assess prediction accuracy. Dose-only models predicted grade 3 RE with AUC values of 0.750 (D2cc) and 0.727 (gEUD). Combining clinical factors with D2cc increased the AUC to 0.779. Incorporating pretreatment cytokine measurements, modeled as direct associations with RE and as potential interactions with the dose-esophagitis association, produced AUC values of 0.758 and 0.773, respectively. D2cc and gEUD correlated with grade 3 RE with odds ratios (ORs) of 1.094/Gy and 1.096/Gy, respectively. Female gender was associated with a higher risk of RE, with ORs of 1.09 and 1.112 in the D2cc and gEUD models, respectively. Older age was associated with decreased risk of RE, with ORs of 0.992/year and 0.991/year in the D2cc and gEUD models, respectively. Combining clinical with dosimetric factors but not pretreatment cytokine levels yielded improved prediction of grade 3 RE compared to prediction by dose alone. Such multifactorial modeling may prove useful in directing radiation treatment planning.

Dosimetric impact of interfractional organs at risk variation during high-dose rate interstitial brachytherapy for gynecologic malignancies

We sought to develop a framework for the identification and management of patients at risk for organs at risk (OARs) overdosing due to interfractional anatomic variation during high-dose rate interstitial brachytherapy for gynecologic malignancies. We analyzed 40 high-dose rate interstitial brachytherapy fractions from 10 patients. Planned OAR doses were compared to delivered doses, which were calculated from computed tomography scans obtained prior to each treatment fraction. Doses were converted to equivalent doses in 2 Gy fractions (EQD2) and doses to the most exposed 2 cm3 (D2cc) were reviewed. Patients were risk-stratified by identifying dose thresholds corresponding to a 10% or lower risk of receiving an OAR dose exceeding the corresponding planning constraint. For each OAR, 30% to 62.5% of patients received total doses greater than planned, although the magnitude of these differences was <4 Gy in over 75% of cases. Using EMBRACE II guidelines, one patient who had met the planning constraint for bladder and one for small bowel were found to have received doses exceeding the recommended limits. We next calculated thresholds for estimating the risk of OAR overdosing in individual patients and developed a framework based on these thresholds to direct time- and resource-intensive imaging and replanning efforts toward patients who are most likely to derive benefit. In summary, differential OAR dosing due to interfractional anatomic variation is common but likely rarely clinically meaningful. The proposed framework could decrease toxicity and maximize clinical efficiency.

Submandibular gland sparing when irradiating neck level IB in the treatment of oral squamous cell carcinoma

Patients with oral squamous cell carcinoma (OSqCCA) frequently require postoperative radiation (PORT), which may include contralateral level IB within the clinical target volume (CTV). The submandibular gland (SMG) is typically included within the level IB CTV; however, the SMG does not contain lymph nodes or lymphatic vessels. We hypothesized that level IB could be adequately irradiated while sparing the SMG to reduce xerostomia. Twelve patients with OSqCCA receiving PORT, which included the contralateral level IB within the planning target volume (PTV), were retrospectively reviewed and replanned using volumetric modulated arc therapy. CTV contouring, including contralateral level IB, was in accordance with the consensus contouring atlas but excluded the SMG. The contralateral neck PTVs were planned to 54 Gray (Gy) (PTV54). Dose requirements were per Radiation Therapy Oncology Group-1008: PTV54 D95% >54 Gy, with an allowable variation of >48.6 Gy. The dose constraint for the SMG was mean dose ≤39 Gy based on published dose-effect data for the SMGs. Mean SMG and PTV54 doses were 38.5 Gy and 56.3 Gy, respectively. Median PTV54 D95% was 53.0 Gy (range 52.5 to 54.6 Gy), with all cases meeting our allowable coverage goal. When assessing the portion of the PTV associated with level IB only (PTV_IB), mean PTV_IB dose was 54.4 Gy and median PTV_IB D95% was 43.3 Gy (range 42.5 to 52.2). Median D95% to CTV_IB was 50.2 Gy. SMG sparing resulted in 10% to 20% underdosing of the part of the PTV corresponding to level IB, as a portion of the PTV lies within the SMG. The SMG can be spared to a mean dose ≤39 Gy with slight underdosing of the surrounding PTV where the PTV overlaps with the SMG. Clinical trials evaluating SMG sparing are warranted.

Individualized survival prediction for patients with oropharyngeal cancer in the human papillomavirus era: Assessment of OPSCC Survival Calculators

Accurate, individualized prognostication in patients with oropharyngeal squamous cell carcinoma (OPSCC) is vital for patient counseling and treatment decision making. With the emergence of human papillomavirus (HPV) as an important biomarker in OPSCC, calculators incorporating this variable have been developed. However, it is critical to characterize their accuracy prior to implementation.

MINI01.13: Prediction of Lung Toxicity in the Definitive Radiotherapy of Non–Small Cell Lung Cancer using Clinical, Dosimetric and Biologic Factors: Topic: Radiation Oncology

Methods: Patients treated with definitive intent SBRT at our institution from 2013-2016 were identified. Twenty-three (23) of these patients consented to accrue to our IRB-approved biorepository. For these patients, peripheral blood was collected prior to treatment, and analyzed for levels of 17 different serum angiogenesis biomarkers. All biomarkers were assayed on the Luminex platform, and were part of the Human Angiogenesis/Growth Factor Panel from EMD Millipore. Log-rank tests were performed in R or SPSS v22 to calculate PFS (defined as freedom from any local, regional or distant progression) and distant metastasis free survival (DMFS). Cutoff thresholds were calculated using an in-house algorithm to optimize significance.