Comparison of unilateral versus bilateral intensity-modulated radiotherapy for surgically treated squamous cell carcinoma of the palatine tonsil.

BACKGROUND: The authors hypothesized that unilateral intensity-modulated radiotherapy (IMRT) would decrease toxicity compared with bilateral IMRT for patients with lateralized palatine tonsillar cancer and a neck classification of N0 to N2b, with similar oncological outcomes. METHODS: A total of 154 patients were treated with postoperative IMRT from 1997 through 2013. Data were collected prospectively from 2005 to 2013 and retrospectively collected before 2005. Of those patients with lateralized primary and N0 to N2b disease, 48 received unilateral IMRT (group 1) and 59 received bilateral IMRT (group 2); a total of 47 patients had nonlateralized primary or N2c to N3 disease and received bilateral IMRT (group 3). RESULTS: The median follow-up was 5.5 years. The 5-year locoregional control rates were similar in group 1, group 2, and group 3 (100%, 96%, and 94%, respectively; pooled comparison: P = .39 and group 1 vs group 2 comparison: P = .19). The 5-year overall survival rates were similar in group 1, group 2, and group 3 (85%, 79%, and 76%, respectively; pooled comparison: P = .60 and group 1 vs group 2 comparison: P = .25). There were no contralateral neck recurrences noted among unilaterally treated patients. Unilateral IMRT reduced acute toxicity and improved patient-reported quality of life compared with bilateral IMRT. CONCLUSIONS: Unilateral IMRT appears to reduce acute toxicity and achieves oncological outcomes similar to those of bilateral IMRT in selected patients with lateralized palatine tonsillar cancer with a neck classification of N0 to N2b. Cancer 2017;123:4594-4607. © 2017 American Cancer Society.

Comparison of onboard low-field magnetic resonance imaging versus onboard computed tomography for anatomy visualization in radiotherapy.

BACKGROUND: Onboard magnetic resonance imaging (OB-MRI) for daily localization and adaptive radiotherapy has been under development by several groups. However, no clinical studies have evaluated whether OB-MRI improves visualization of the target and organs at risk (OARs) compared to standard onboard computed tomography (OB-CT). This study compared visualization of patient anatomy on images acquired on the MRI-(60)Co ViewRay system to those acquired with OB-CT. MATERIAL AND METHODS: Fourteen patients enrolled on a protocol approved by the Institutional Review Board (IRB) and undergoing image-guided radiotherapy for cancer in the thorax (n = 2), pelvis (n = 6), abdomen (n = 3) or head and neck (n = 3) were imaged with OB-MRI and OB-CT. For each of the 14 patients, the OB-MRI and OB-CT datasets were displayed side-by-side and independently reviewed by three radiation oncologists. Each physician was asked to evaluate which dataset offered better visualization of the target and OARs. A quantitative contouring study was performed on two abdominal patients to assess if OB-MRI could offer improved inter-observer segmentation agreement for adaptive planning. RESULTS: In total 221 OARs and 10 targets were compared for visualization on OB-MRI and OB-CT by each of the three physicians. The majority of physicians (two or more) evaluated visualization on MRI as better for 71% of structures, worse for 10% of structures, and equivalent for 14% of structures. 5% of structures were not visible on either. Physicians agreed unanimously for 74% and in majority for > 99% of structures. Targets were better visualized on MRI in 4/10 cases, and never on OB-CT. CONCLUSION: Low-field MR provides better anatomic visualization of many radiotherapy targets and most OARs as compared to OB-CT. Further studies with OB-MRI should be pursued.

Eliminating radiotherapy to the contralateral retropharyngeal and high level II lymph nodes in head and neck squamous cell carcinoma is safe and improves quality of life.

BACKGROUND: Radiation treatment volumes in head and neck squamous cell carcinoma (HNSCC) are controversial. The authors report the outcomes, patterns of failure, and quality of life (QOL) of patients who received treatment for HNSCC using intensity-modulated radiation therapy (IMRT) that eliminated the treatment of contralateral retropharyngeal lymph nodes (RPLNs) in the clinically uninvolved neck. METHODS: A prospective institutional database was used to identify patients who had primary oral cavity, oropharyngeal, hypopharyngeal, laryngeal, and unknown primary HNSCC for which they received IMRT. There were 3 temporal groups (generations 1-3). Generation 1 received comprehensive neck IMRT with parotid sparing, generation 2 eliminated the contralateral high level II (HLII) lymph nodes, and generation 3 further eliminated the contralateral RPLNs in the clinically uninvolved neck. Patterns of failure and survival analyses were completed, and QOL data measured using the MD Anderson Dysphagia Inventory were compared in a subset of patients from generations 1 and 3. RESULTS: In total, 748 patients were identified. Of the 488 patients who received treatment in generation 2 or 3, 406 had a clinically uninvolved contralateral neck. There were no failures in the spared RPLNs (95% confidence interval, 0%-1.3%) or in the high contralateral neck (95% confidence interval, 0%-0.7%). QOL data were compared between 44 patients in generation 1 and 51 patients in generation 3. QOL improved both globally and in all domains assessed for generation 3, in which reduced radiotherapy volumes were used (P < .007). CONCLUSIONS: For patients with locally advanced HNSCC, eliminating coverage to the contralateral HLII lymph nodes and contralateral RPLNs in the clinically uninvolved side of the neck is associated with minimal risk of failure in these regions and significantly improved patient-reported QOL.

Quantitative FDG-PET/CT predicts local recurrence and survival for squamous cell carcinoma of the anus.

PURPOSE: 18F-fluorodeoxyglucose (FDG) positron emission tomography-(PET)/computed tomography (CT) imaging is used for staging and treatment planning of patients with anal cancer. Quantitative pre- and posttreatment metrics that are predictive of recurrence are unknown. We evaluated the association between pre- and posttreatment FDG-PET/CT parameters and outcomes for patients with squamous cell carcinoma of the anus (SCCA). METHODS AND MATERIALS: The records of 110 patients treated between 2003 and 2013 with definitive radiation therapy for SCCA were reviewed under an institutional review board-approved protocol. The median radiation therapy dose was 50.4 Gy (range, 35-60 Gy). Concurrent chemotherapy was administered for 109 of 110 patients and generally consisted of 5-fluorouracil and mitomycin C (n = 94). All patients underwent pretreatment FDG-PET/CT and 101 of 110 underwent posttreatment FDG-PET/CT 3 months after completion of radiation therapy. The maximum standard uptake value (SUVmax) was analyzed, in addition to multiple patient and treatment factors, by univariate and multivariate Cox regression for correlation with local recurrence (LR) and overall survival (OS). RESULTS: The median follow-up was 28.6 months. LR occurred in 1 of 15 (6.7%), 5 of 47 (10.6%), and 6 of 48 (12.5%) patients with stage I, II, and III disease, respectively. On univariate analysis, a significant association was observed between reduced LR and posttreatment SUVmax <6.1 (P = .0095) and between increased OS and posttreatment SUVmax <6.1 (P = .0086). On multivariate analysis, a significant association was observed between reduced LR and posttreatment SUVmax <6.1 (P = .0013) and the use of intensity modulated radiation therapy (P < .001). A significant multivariate association was observed between increased OS and posttreatment SUVmax <6.1 (P = .0373) and the use of 5-fluorouracil/mitomycin C chemotherapy (P = .001). CONCLUSION: Posttreatment SUVmax <6.1 is associated with reduced LR and increased OS after chemoradiation therapy for SCCA independent of T and N stage on multivariate analysis. Greater follow-up is required to confirm this association with late patterns of failure.

High E6 Gene Expression Predicts for Distant Metastasis and Poor Survival in Patients With HPV-Positive Oropharyngeal Squamous Cell Carcinoma.

PURPOSE: Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) have a favorable prognosis. As a result, de-escalation clinical trials are under way. However, approximately 10% of patients will experience distant recurrence even with standard-of-care treatment. Here, we sought to identify novel biomarkers to better risk-stratify HPV-positive patients with OPSCC. METHODS AND MATERIALS: Gene expression profiling by RNA sequencing (RNA-seq) and quantitative polymerase chain reaction was performed on HPV-positive OPSCC primary tumor specimens from patients with and without distant metastasis (DM). RESULTS: RNA-seq analysis of 39 HPV-positive OPSCC specimens revealed that patients with DM had 2-fold higher E6 gene expression levels than did patients without DM (P=.029). This observation was confirmed in a validation cohort comprising 93 patients with HPV-positive OPSCC. The mean normalized E6 expression level in the 17 recurring primary specimens was 13 ± 2 compared with 8 ± 1 in the remaining 76 nonrecurring primaries (P=.001). Receiver operating characteristic analysis established an E6 expression level of 7.3 as a cutoff for worse recurrence-free survival (RFS). Patients from this cohort with high E6 gene expression (E6-high) (n=51, 55%) had more cancer-related deaths (23% vs 2%, P<.001) and DM (26% vs 5%, P<.001) than did patients with low E6 gene expression (E6-low) (n=42, 45%). Kaplan-Meier survival analysis revealed that E6-high had worse RFS (95% vs 69%, P=.004) and cancer-specific survival (97% vs 79%, P=.007). E6-high maintained statistical significance in multivariate regression models balancing surgery, chemotherapy, nodal stage, and smoking status. Gene set enrichment analysis demonstrated that tumors with high E6 expression were associated with P53, epidermal growth factor receptor, activating transcription factor-2, and transforming growth factor-ß signaling pathways. CONCLUSION: High E6 gene expression level identifies HPV-positive OPSCC patients with 5-fold greater risk of distant disease recurrence and worse cancer-specific survival. Validation in a multi-institutional prospective clinical trial is required to assess the utility of E6 gene expression as a clinically useful prognostic biomarker.

Reevaluation of postoperative radiation dose in the management of human papillomavirus-positive oropharyngeal cancer.

BACKGROUND: The purpose of this study was to compare outcomes of patients with p16-positive oropharyngeal squamous cell carcinoma (SCC) treated with postoperative intensity-modulated radiotherapy (IMRT) before and after an institutional dose reduction policy effective on February 2009. METHODS: Between 1998 and 2013, 175 consecutive patients with p16-positive oropharyngeal SCC with extracapsular extension (ECE) and/or close or positive margins were treated postoperatively to 66 Gy (n = 109) or 60 Gy (n = 66) in 2 Gy/fx. RESULTS: Between the 66 and 60 Gy groups, there was no difference in tumor classification (pT4 vs pT1-T3; p = .181) and nodal classification (pN2c-N3 vs pN0-N2b; p = .704), and American Joint Committee on Cancer (AJCC) group stage (IV vs I-III; p = .473). Median follow-up was 5.9 years overall (66 Gy: 7.4 years; 60 Gy: 4.0 years). There was no difference in locoregional recurrence-free survival (2-year: 98.1% vs 98.5%; p = .421). CONCLUSION: This study suggests that treating p16-positive oropharyngeal SCC with ECE and/or close or positive margins with postoperative IMRT to 60 Gy may not compromise locoregional recurrence-free survival compared to 66 Gy. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1708-1716, 2016.

Prognostic value of 18F-FDG PET metabolic parameters in oropharyngeal squamous cell carcinoma.

OBJECTIVE: To evaluate whether pretreatment metabolic parameters obtained from positron emission tomography (PET) with [18F]fluorodeoxyglucose (FDG) can improve risk prediction for patients with oropharyngeal squamous cell carcinoma (OPSCC) treated with definitive intensity-modulated radiation therapy (IMRT). METHODS: Between 2003 and 2009, 86 patients with OPSCC had FDG-PET/CT prior to treatment with definitive IMRT. Chemotherapy was administered to 90 % of the patients. Metabolic tumor volume (MTV), total lesion glycolysis (TLG), maximum standardized uptake value (SUVmax), mean SUV (SUVmean), and inverse coefficient of variation (1/CoV) were analyzed for the primary tumor alone and the total of the primary tumor and involved lymph nodes. RESULTS: Median follow-up time for surviving patients was 41 months. On univariate analysis, total MTV and total TLG were significant predictors of disease-free survival (DFS) and overall survival (OS). SUVmax, SUVmean, and 1/CoV failed to predict DFS or OS. On multivariate analysis controlling for T- and N-classification, total MTV remained a significant predictor of DFS and OS. The optimal cutpoint for total MTV was 20.5 ml. A total MTV >20.5 ml was associated with a 4.13-fold increased risk of death (95 % confidence interval [CI], 2.12-8.05; p < 0.0001). Total MTV remained a significant predictor of DFS and OS for the subgroups with p16-positive (n = 25) and p16-negative (n = 18) cancer. CONCLUSION: Total MTV is an independent predictor of DFS and OS for patients with OPSCC treated with definitive radiotherapy. Total MTV remained predictive of DFS and OS for both p16-positive and p16-negative cancer.

Radiotherapeutic management of cervical lymph node metastases from an unknown primary site.

OBJECTIVE: To determine whether ipsilateral radiotherapy affects overall survival, cause-specific survival, or local control in patients with a cancer from an unknown primary of the head and neck compared with comprehensive radiotherapy. DESIGN: Retrospective medical record review. SETTING: Academic tertiary care hospital. PATIENTS: The study population comprised 46 patients with cervical metastases from an unknown primary cancer treated with radiotherapy from 1989 through 2008. Median follow-up was 4.6 years. INTERVENTIONS: All patients were treated with radiation therapy. Radiotherapy target volumes were categorized as either ipsilateral neck only (IPSI) or comprehensive (COMP), including both the potential mucosal surfaces and ipsilateral or bilateral neck. Human papillomavirus (HPV) status, as determined by p16 immunohistochemical analysis, was evaluated for 36 patients (74%). MAIN OUTCOME MEASURES: Overall survival, cause-specific survival, locoregional control, and rate of distant metastases were analyzed. RESULTS: Overall survival at 2 years and 5 years was 87% and 77%, respectively. Cause-specific survival at 2 years and 5 years was 89% and 81%, respectively. There were no ipsilateral neck failures. There was no difference in overall survival between patients treated with IPSI or COMP radiation therapy. The contralateral neck was controlled in all patients receiving bilateral neck irradiation and in 95% receiving ipsilateral neck irradiation. Of the 34 patients evaluated with p16 immunohistochemical analysis, results for 16 (47%) were positive. There was a nonsignificant trend toward improved overall survival in p16-positive patients (P = .06). CONCLUSION: IPSI radiation therapy demonstrated excellent locoregional control with no adverse effect on disease-free survival or overall survival.

Cervical cancer histology and tumor differentiation affect 18F-fluorodeoxyglucose uptake.

BACKGROUND: This study aimed to evaluate the variation in cervical cancer glucose metabolism for different tumor histologies and levels of differentiation, as measured by the uptake of 18F-fluorodeoxyglucose (FDG) by positron emission tomography (PET). METHODS: The study population consisted of 240 patients with International Federation of Gynecology and Obstetrics stages Ib1 through IVb cervical cancer, who underwent a pretreatment FDG-PET. Tumor histology included 221 squamous cell (SC), 4 adenosquamous (AS), and 15 adenocarcinoma (AC) tumors. There were 14 well, 145 moderately, and 81 poorly differentiated tumors. The stage distribution was as follows: 70 stage I tumors (9 AC, 2 AS, and 59 SC), 102 stage II tumors (3 AC, 1 AS, and 98 SC), 64 stage III tumors (3 AC, 1 AS, and 60 SC), and 4 stage IV tumors (4 SC). From the FDG-PET, maximal standardized uptake value (SUVmax) was determined. The variation in SUVmax was analyzed for differences based on tumor histology and differentiation. RESULTS: For all patients, the mean SUVmax was 11.62 (range, 2.50-50.39). The mean SUVmax by histology was as follows: SC, 11.91 (range, 2.50-50.39); AS, 8.85 (range, 6.53-11.26); and AC, 8.05 (range, 2.83-13.92). Squamous versus nonsquamous tumors demonstrated a significant difference in SUVmax (P=.0153). SUVmax and tumor volume were not found to be correlated (R2=0.013). The mean SUVmax was 8.58 for well-differentiated, 11.56 for moderately differentiated, and 12.23 for poorly differentiated tumors. The mean SUVmax was significantly different for well-differentiated versus poorly differentiated cervical tumors (P=.0474). CONCLUSIONS: Cervical tumor FDG uptake varied by histology and differentiation. SC tumors demonstrated a significantly higher SUVmax compared with nonsquamous cell tumors, and poorly differentiated tumors also had a higher SUVmax.