Characterization of cerebral radiation necrosis following the treatment of sinonasal malignancies.

Objectives: Our study aims to determine the incidence and potential risk factors for cerebral radiation necrosis (CRN) following treatment of sinonasal malignancies. Methods: One hundred thirty-two patients diagnosed with sinonasal malignancies over an 18-year period were identified at two institutions. Forty-six patients meeting inclusion criteria and treated with radiation therapy were included for analysis. Demographic and clinical-pathologic characteristics were collected and reviewed. Post-treatment magnetic resonance imaging (MRI) at least 1 year following treatment was reviewed to determine presence or absence of CRN. Results: CRN was identified on MRI in 8 of 46 patients (17.4%) following radiation treatment. Patients with a history of reirradiation were more likely to develop CRN (50% vs. 10.5%, p < .05). The BEDs of radiation were also higher in CRN patients compared to non-CRN patients, but this difference was not significant (p > .05). CRN patients had a higher proportion of tumors with skull base involvement than non-CRN patients (100% vs. 57.9%, p = .037). Demographics, comorbidities, pathology, primary tumor subsite, chemotherapy use, and stage of disease demonstrated no significant increase in risk of CRN. Conclusions: Reirradiation and tumor skull base involvement were significant risk factors associated with CRN. Higher average total prescribed and BEDs of radiation were seen in the CRN groups, but these differences were not statistically significant. Gender, comorbidities, tumor subsite, tumor location, and treatment type were not significantly different between groups. Level of evidence: Level 3.

Early Experience of the First Single-Room Gantry Mounted Active Scanning Proton Therapy System at an Integrated Cancer Center.

Introduction: Review the early experience with a single-room gantry mounted active scanning proton therapy system. Material and Methods: All patients treated with proton beam radiotherapy (PBT) were enrolled in an institutional review board-approved patient registry. Proton beam radiotherapy was delivered with a 250 MeV gantry mounted synchrocyclotron in a single-room integrated facility within the pre-existing cancer center. Demographic data, cancer diagnoses, treatment technique, and geographic patterns were obtained for all patients. Treatment plans were evaluated for mixed modality therapy. Insurance approval data was collected for all patients treated with PBT. Results: A total of 132 patients were treated with PBT between March 2018 and June 2019. The most common oncologic subsites treated included the central nervous system (22%), gastrointestinal tract (20%), and genitourinary tract (20%). The most common histologies treated included prostate adenocarcinoma (19%), non-small cell lung cancer (10%), primary CNS gliomas (8%), and esophageal cancer (8%). Rationale for PBT treatment included limitation of dose to adjacent critical organs at risk (67%), reirradiation (19%), and patient comorbidities (11%). Patients received at least one x-ray fraction delivered as prescribed (36%) or less commonly due to unplanned machine downtime (34%). Concurrent systemic therapy was administered to 57 patients (43%). Twenty-six patients (20%) were initially denied insurance coverage and required peer-to-peers (65%), written appeals (12%), secondary insurance approval (12%), and comparison x-ray to proton plans (8%) for subsequent approval. Proton beam radiotherapy approval required a median of 17 days from insurance submission. Discussion: Incorporation of PBT into our existing cancer center allowed for multidisciplinary oncologic treatment of a diverse population of patients. Insurance coverage for PBT presents as a significant hurdle and improvements are needed to provide more timely access to necessary oncologic care.

A Phase 2 Trial of Alternative Volumes of Oropharyngeal Irradiation for De-intensification (AVOID): Omission of the Resected Primary Tumor Bed After Transoral Robotic Surgery for Human Papilloma Virus-Related Squamous Cell Carcinoma of the Oropharynx.

PURPOSE: This trial tested the safety and efficacy of a novel, deintensified radiation therapy (RT) approach after initial surgical resection for patients with human papilloma virus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). METHODS AND MATERIALS: This single-arm phase 2 prospective clinical trial enrolled 60 patients with stage pT1-pT2 N1-3 HPV-associated OPSCC treated with transoral robotic surgery (TORS) and selective neck dissection at a single institution between May 2014 and September 2017. Patients had favorable features at the primary site (negative surgical margins ≥2 mm, no perineural invasion, and no lymphovascular invasion) but required adjuvant therapy based on lymph node involvement. Surgeries were all performed at a high-volume head and neck cancer center with expertise in TORS. Patients received postoperative RT to at-risk areas in the involved neck (60-66 Gy) and uninvolved neck (54 Gy). The resected primary site was treated as an active avoidance structure in the treatment planning of postoperative RT. Concurrent chemotherapy was administered for patients with extranodal extension. RESULTS: Median follow-up of the 60 patients enrolled was 2.4 years (range, 8.5-53.8 months). A single patient recurred at the primary site, for 2-year local control of 98.3%. One patient (1.7%) developed a regional neck recurrence, and 2 patients (3.3%) developed distant metastases. Measured 2-year local recurrence-free survival was 97.9% (95% confidence interval, 86.1%-99.7%). Overall survival was 100% at the time of analysis. The mean radiation dose to the primary site was 36.9 Gy (standard deviation, 10.3 Gy). Two patients (3.3%) experienced late soft tissue necrosis in the primary site surgical bed that resolved within 2 months. Feeding tube dependence rates were 0% during RT, 3.3% temporarily during follow-up, and 0% at last follow-up. CONCLUSIONS: Deintensified postoperative RT that avoids the resected primary tumor site and targets only the at-risk neck after TORS for selected patients with HPV-associated OPSCC may be safe and is worthy of further study.

Conditional Reprogramming for Patient-Derived Cancer Models and Next-Generation Living Biobanks.

Traditional cancer models including cell lines and animal models have limited applications in both basic and clinical cancer research. Genomics-based precision oncology only help 2-20% patients with solid cancer. Functional diagnostics and patient-derived cancer models are needed for precision cancer biology. In this review, we will summarize applications of conditional cell reprogramming (CR) in cancer research and next generation living biobanks (NGLB). Together with organoids, CR has been cited in two NCI (National Cancer Institute, USA) programs (PDMR: patient-derived cancer model repository; HCMI: human cancer model initiatives. HCMI will be distributed through ATCC). Briefly, the CR method is a simple co-culture technology with a Rho kinase inhibitor, Y-27632, in combination with fibroblast feeder cells, which allows us to rapidly expand both normal and malignant epithelial cells from diverse anatomic sites and mammalian species and does not require transfection with exogenous viral or cellular genes. Establishment of CR cells from both normal and tumor tissue is highly efficient. The robust nature of the technique is exemplified by the ability to produce 2 × 106 cells in five days from a core biopsy of tumor tissue. Normal CR cell cultures retain a normal karyotype and differentiation potential and CR cells derived from tumors retain their tumorigenic phenotype. CR also allows us to enrich cancer cells from urine (for bladder cancer), blood (for prostate cancer), and pleural effusion (for non-small cell lung carcinoma). The ability to produce inexhaustible cell populations using CR technology from small biopsies and cryopreserved specimens has the potential to transform biobanking repositories (NGLB: next-generation living biobank) and current pathology practice by enabling genetic, biochemical, metabolomic, proteomic, and biological assays, including chemosensitivity testing as a functional diagnostics tool for precision cancer medicine. We discussed analyses of patient-derived matched normal and tumor models using a case with tongue squamous cell carcinoma as an example. Last, we summarized applications in cancer research, disease modeling, drug discovery, and regenerative medicine of CR-based NGLB.

Phase I Trial Using Induction Ciplatin, Docetaxel, 5-FU and Erlotinib Followed by Cisplatin, Bevacizumab and Erlotinib With Concurrent Radiotherapy for Advanced Head and Neck Cancer.

OBJECTIVES: Bevacizumab (avastin) and erlotinib (tarceva) had shown early clinical activity against head and neck cancer (HNC). We initiated a phase I trial of induction cisplatin, docetaxel, 5-fluorouracil and erlotinib (TPF-E) followed by cisplatin, bevacizumab and erlotinib (PA-E) with radiotherapy (XRT) for advanced HNC. The goal was to determine maximum tolerated erlotinib dose. METHODS: Eligible patients had stage IVA or higher HNC with good performance status, hematologic, and renal reserve. Two cycles of induction TPF-E were administered. XRT was administered with concurrent weekly cisplatin and bevacizumab every 2 weeks. Initial erlotinib dose was 50 mg daily from start of induction chemotherapy until radiotherapy completion. Erlotinib dose escalations to 100 and 150 mg were planned. RESULTS: Thirteen patients with previously untreated locoregional disease (11 patients) or oligometastatic (2 patients) HNC were enrolled. Totally, 11 of 13 patients completed XRT as planned. Four of 8 patients in cohort 1 (erlotinib 50 mg), 3 of 4 patients in cohort 2 (100 mg), and 0 of 1 patients in cohort 3 (150 mg) completed the regimen. Two patients had significant gastrointestinal complications (bleeding and perforation), and 1 had dose-limiting diarrhea. Maximum tolerated dose was reached at 50 mg erlotinib. At median 23.4 months follow-up, 5 patients (38%) have no evidence of disease, and 2 (15%) have stable but measurable disease. CONCLUSIONS: Erlotinib in combination with induction TPF followed by erlotinib, cisplatin, and bevacizumab with XRT is active but toxic. Gastrointestinal toxicities partly caused high rates of study withdrawal. All doses studied in this protocol caused unexpected toxicities and we do not recommend advancement to phase II.

Quality of Life of Postoperative Photon versus Proton Radiation Therapy for Oropharynx Cancer.

PURPOSE: Quality of life (QOL) for patients with oropharyngeal squamous cell cancer is negatively affected by conventional radiation (RT) owing to radiation exposure to normal tissues. Proton therapy, via pencil beam scanning (PBS), can better spare many of these tissues, and may thereby improve QOL. PATIENTS AND METHODS: Patient-reported outcomes were prospectively collected from patients treated from April 2013 to April 2015. Patients were treated with PBS or intensity-modulated radiation therapy (IMRT) via volumetric arc therapy after transoral robotic surgery. Validated QOL questionnaires were collected before RT, and 3, 6, and 12 months post RT. RESULTS: Sixty-four patients were treated with adjuvant RT after transoral robotic surgery, 33 (52%) with volumetric arc therapy, and 31 (48%) with PBS. Both groups were similar in terms of age, site, stage, and dose delivered. Patients receiving PBS had significantly less dose to many normal structures than those receiving IMRT. These dosimetric advantages with PBS were reflected in higher scores in head and neck specific, as well as general, QOL measures. Most notable was significantly less xerostomia with PBS, on multiple patient-reported outcomes at multiple timepoints (6 and 12 months). CONCLUSION: Pencil beam scanning, when compared to IMRT, confers a significant dosimetric advantage to many normal organs at risk, with a corresponding benefit in multiple patient-reported QOL parameters in patients receiving adjuvant RT for oropharyngeal squamous cell cancer.

Lesion oxygenation associates with clinical outcomes in premalignant and early stage head and neck tumors treated on a phase 1 trial of photodynamic therapy.

BACKGROUND: We report on a Phase 1 trial of photodynamic therapy (PDT) for superficial head and neck (H&N) lesions. Due to known oxygen dependencies of PDT, translational measurements of lesion hemoglobin oxygen saturation (StO2) and blood volume (tHb) were studied for associations with patient outcomes. METHODS: PDT with aminolevulinc acid (ALA) and escalating light doses was evaluated for high-grade dysplasia, carcinoma-in-situ, and microinvasive carcinomas of the H&N. Among 29 evaluable patients, most (18) had lesions of the tongue or floor of mouth (FOM). Disease was intact in 18 patients and present at surgical margins in 11 patients. In 26 patients, lesion StO2 and tHb was measured. RESULTS: Local control (LC) at 24 months was 57.5% among all patients. In patients with tongue/FOM lesions LC was 42.7%, and it was 50.1% for those with intact lesions. Lesion tHb was not associated with 3-month complete response (CR), but StO2 was higher in patients with CR. In tongue/FOM lesions, baseline StO2 [mean(SE)] was 54(4)% in patients (n=12) with CR versus 23(8)% in patients (n=6) with local recurrence/persistence (p=0.01). Similarly, for intact disease, baseline StO2 was 54(3)% in patients (n=10) with CR versus 28(8)% in patients (n=5) without CR (p=0.03). In patients with intact disease, higher baseline StO2 associated with 24-month local control (p=0.02). CONCLUSIONS: Measurement of the physiologic properties of target lesions may allow for identification of patients with the highest probability of benefiting from PDT. This provides opportunity for optimizing light delivery based on lesion characteristics and/or informing ongoing clinical decision-making in patients who would most benefit from PDT.

Risk of lymph node metastasis and recommendations for elective nodal treatment in squamous cell carcinoma of the nasal cavity and maxillary sinus: a SEER analysis.

BACKGROUND: Risk of nodal involvement in patients with squamous cell carcinomas (SCC) of the nasal cavity and maxillary sinus has not been well defined, especially by risk factors beyond local T-stage. Additional criteria defining patients at highest risk, as well as specific nodal levels at highest risk, has been limited in small retrospective series. We describe a population-based assessment of specific nodal involvement in this group. MATERIAL AND METHODS: The Surveillance, Epidemiology and End Results (SEER) database from 2004 to 2010 identified 1283 eligible patients with SCC of the nasal cavity or maxillary sinus. Neck involvement and individual nodal level involvement at presentation were assessed, and comparison made with a contemporaneous cohort of patients with a borderline clinically significant risk of nodal involvement and recurrence. RESULTS: Among 1283 patients, 182 (14.2%) had nodal involvement at presentation (4-27% by site and local extension). T-stage alone was associated with higher rates of nodal involvement in maxillary sinus SCC, while higher T-stage and size >2 cm were associated with higher rates of nodal involvement in nasal cavity SCC on multivariable analysis. Facial nodes and cervical nodes at levels 1 and 2 have the highest rates of involvement in T4a nasal cavity SCC, whereas nodal levels 1, 2, and/or 3 have the highest rates of involvement in T2 or higher maxillary sinus SCC when compared with a clinical reference standard. CONCLUSION: In this population-based study, there are high rates of initial nodal involvement when stratified by local extent determined by T-stage in nasal cavity SCC and maxillary sinus SCC, and independently by size in nasal cavity SCC. Involvement of the facial and nodal levels 1-3 varies depending on site and local extent of tumor involvement. These observations may help guide treatment decision making in the inclusion of and extent of elective nodal treatment fields.

Benefit of particle therapy in re-irradiation of head and neck patients. Results of a multicentric in silico ROCOCO trial.

BACKGROUND AND PURPOSE: In this multicentric in silico trial we compared photon, proton, and carbon-ion radiotherapy plans for re-irradiation of patients with squamous cell carcinoma of the head and neck (HNSCC) regarding dose to tumour and doses to surrounding organs at risk (OARs). MATERIAL AND METHODS: Twenty-five HNSCC patients with a second new or recurrent cancer after previous irradiation (70Gy) were included. Intensity-modulated proton therapy (IMPT) and ion therapy (IMIT) re-irradiation plans to a second subsequent dose of 70Gy were compared to photon therapy delivered with volumetric modulated arc therapy (VMAT). RESULTS: When comparing IMIT and IMPT to VMAT, the mean dose to all investigated 22 OARs was significantly reduced for IMIT and to 15 out of 22 OARs (68%) using IMPT. The maximum dose to 2% volume (D2) of the brainstem and spinal cord were significantly reduced using IMPT and IMIT compared to VMAT. The data are available on www.cancerdata.org. CONCLUSIONS: In this ROCOCO in silico trial, a reduction in mean dose to OARs was achieved using particle therapy compared to photons in the re-irradiation of HNSCC. There was a dosimetric benefit favouring carbon-ions above proton therapy. These dose reductions may potentially translate into lower severe complication rates related to the re-irradiation.

A Single-institution Comparison of Cetuximab, Carboplatin, and Paclitaxel Induction Chemotherapy Followed by Chemoradiation (CRT) Versus CRT for Locally Advanced Squamous Cell Carcinoma of the Head and Neck (LA-SCCHN).

OBJECTIVES: Comparisons of induction chemotherapy (IC) against upfront chemoradiation (CRT) for locally advanced head and neck cancer (LA-HNSCC) have demonstrated no differences except greater toxicity with IC. Effective induction regimens that are less toxic are therefore warranted. To inform future efforts with IC, we present our institutional experience comparing a less toxic IC regimen to CRT. METHODS: We included patients with LA-HNSCC treated with organ-preservation CRT (+/-induction) between 2008 and 2011. Patients were of age above 18 years, ECOG performance status 0-1, and had minimum 6 months follow-up. IC consisted of 8 weekly cycles of cetuximab, carboplatin, and paclitaxel followed by CRT. The CRT regimen was platinum based, with cetuximab reserved for patients contraindicated to receive platinum. RESULTS: Of 118 patients, 24 (20%) received IC and 94 (80%) received CRT. Median follow-up was 17 (IC) and 19 (CRT) months (P=0.05). There were no differences in toxicity between the groups. IC patients were more likely male, with more advanced tumor and nodal stage. Even when controlling for these factors, IC was still associated with worse locoregional control (HR=3.6, P=0.02), distant metastasis-free survival (HR=5.3, P=0.02), and overall survival (HR=5.1, P<0.01). CONCLUSIONS: IC patients had greater disease burden than those receiving CRT. IC was well tolerated, but with significant rates of locoregional and systemic failures. Given the retrospective nature of the study, our findings are not meant to be definitive or conclusive, but rather suggestive in directing future efforts with IC. For now, we favor CRT as the standard option for treatment of inoperable LA-HNSCC.

Endoscopy versus imaging: Analysis of surveillance methods in sinonasal malignancy.

BACKGROUND: The purpose of this study was to assess the utility of imaging and endoscopy in posttreatment surveillance of sinonasal malignancies. METHODS: We conducted a retrospective analysis of primary sinonasal malignancies diagnosed between 2000 and 2014. Posttreatment surveillance included nasal endoscopy and imaging (MRI, CT, and positron emission tomography [PET]/CT). Positive predictive value (PPV), negative predictive value (NPV), specificity, and sensitivity were calculated for each modality and compared. RESULTS: One hundred nine sinonasal malignancies were identified with 30 recurrences. Endoscopy showed a sensitivity and specificity of 24% and 89%, respectively, whereas imaging was 76% and 90%, respectively. Identifying suspicious symptoms significantly improved the PPV of both endoscopy and imaging. MRI demonstrates the highest PPV when compared with other imaging modalities. CONCLUSION: Both modalities are necessary in posttreatment surveillance. MRI shows the highest PPV, whereas endoscopy trends toward a higher specificity. PET/CT scans have a high false-positive rate and should be reserved for tumors with a high propensity for distant metastases. © 2016 Wiley Periodicals, Inc. Head Neck 38:1229-1233, 2016.

Effects of full-neck volumetric-modulated arc therapy vs split-field intensity-modulated head and neck radiation therapy on low neck targets and structures.

OBJECTIVE: While split-field intensity-modulated radiation therapy (SF-IMRT) decreases dose to low neck (LAN) structures such as the glottic larynx compared with full-neck intensity-modulated radiation therapy (IMRT), it is unknown whether SF-IMRT affords superior dose avoidance to organs than whole neck-field volumetric-modulated arc therapy (WF-VMAT). METHODS: 10 patients treated definitively with radiation for oropharyngeal, oral cavity or nasopharyngeal carcinoma were compared. Only patients ideally suited for SF-IMRT plans were included. The glottic larynx, supraglottic larynx, arytenoids, pharyngeal constrictors, oesophagus, brachial plexus and target volume coverage in the LAN were compared between WF-VMAT and SF-IMRT. RESULTS: Volumetric-modulated arc therapy (VMAT) yielded statistically significant decreases in maximum dose to the arytenoids and mean dose to the oesophagus. There was no difference in dose to the glottic larynx, supraglottic larynx, pharyngeal constrictors and brachial plexus. WF-VMAT led to improved coverage to 50/2 Gy fraction equivalent in LAN compared with SF-IMRT using an anteroposterior (AP) LAN field but no difference to the 60/2 Gy fraction equivalent between SF-IMRT and WF-VMAT using AP/posterior-anterior LAN boost. CONCLUSION: WF-VMAT affords equivalent glottic and supraglottic larynx dose and lower dose to the arytenoids and oesophagus. WF-VMAT better covers most LAN target structures. Given these findings as well as concerns with matchline cold spots or hotspots with SF-IMRT, patients requiring comprehensive elective nodal irradiation should typically be treated with WF-VMAT. ADVANCES IN KNOWLEDGE: SF-IMRT for larynx sparing has better dosimetric results to normal structures than whole-neck IMRT, but with increased matchline recurrence risk. We show dosimetric equivalence or superiority of WF-VMAT compared with SF-IMRT.

Quantitative assessment of anatomical change using a virtual proton depth radiograph for adaptive head and neck proton therapy.

The aim of this work is to demonstrate the feasibility of using water-equivalent thickness (WET) and virtual proton depth radiographs (PDRs) of intensity corrected cone-beam computed tomography (CBCT) to detect anatomical change and patient setup error to trigger adaptive head and neck proton therapy. The planning CT (pCT) and linear accelerator (linac) equipped CBCTs acquired weekly during treatment of a head and neck patient were used in this study. Deformable image registration (DIR) was used to register each CBCT with the pCT and map Hounsfield units (HUs) from the planning CT (pCT) onto the daily CBCT. The deformed pCT is referred as the corrected CBCT (cCBCT). Two dimensional virtual lateral PDRs were generated using a ray-tracing technique to project the cumulative WET from a virtual source through the cCBCT and the pCT onto a virtual plane. The PDRs were used to identify anatomic regions with large variations in the proton range between the cCBCT and pCT using a threshold of 3 mm relative difference of WET and 3 mm search radius criteria. The relationship between PDR differences and dose distribution is established. Due to weight change and tumor response during treatment, large variations in WETs were observed in the relative PDRs which corresponded spatially with an increase in the number of failing points within the GTV, especially in the pharynx area. Failing points were also evident near the posterior neck due to setup variations. Differences in PDRs correlated spatially to differences in the distal dose distribution in the beam's eye view. Virtual PDRs generated from volumetric data, such as pCTs or CBCTs, are potentially a useful quantitative tool in proton therapy. PDRs and WET analysis may be used to detect anatomical change from baseline during treatment and trigger further analysis in adaptive proton therapy.

Toxicities and early outcomes in a phase 1 trial of photodynamic therapy for premalignant and early stage head and neck tumors.

OBJECTIVES: Management of early superficial lesions in the head and neck remains complex. We performed a phase 1 trial for high-grade premalignant and early superficial lesions of the head and neck using photodynamic therapy (PDT) with Levulan (ALA). MATERIALS AND METHODS: Thirty-five subjects with high grade dysplasia, carcinoma in situ, or microinvasive (⩽1.5mm depth) squamous cell carcinoma were enrolled. Cohorts of 3-6 patients were given escalating intraoperative light doses of 50-200J/cm(2) 4-6h after oral administration of 60mg/kg ALA. Light at 629-635nm was delivered in a continuous (unfractionated) or fractionated (two-part) schema. RESULTS: PDT was delivered to 30/35 subjects, with 29 evaluable. There was one death possibly due to the treatment. The regimen was otherwise tolerable, with a 52% rate of grade 3 mucositis which healed within several weeks. Other toxicities were generally grade 1 or 2, including odynophagia (one grade 4), voice alteration (one grade 3), and photosensitivity reactions. One patient developed grade 5 sepsis. With a median follow-up of 42months, 10 patients (34%) developed local recurrence; 4 of these received 50J/cm(2) and two each received 100, 150, and 200J/cm(2). Ten (34%) patients developed recurrence adjacent to the treated field. There was a 69% complete response rate at 3months. CONCLUSIONS: ALA-PDT is well tolerated. Maximum Tolerated Dose appears to be higher than the highest dose used in this study. Longer followup is required to analyze effect of light dose on local recurrence. High marginal recurrence rates suggest use of larger treatment fields.

Nodal metastasis and elective nodal level treatment in sinonasal small-cell and sinonasal undifferentiated carcinoma: a surveillance, epidemiology and end results analysis.

OBJECTIVE: Risk of nodal involvement in patients with sinonasal small-cell carcinoma and sinonasal undifferentiated carcinoma (SNUC) has not been well defined because of their rarity. We describe a population-based assessment of specific nodal level involvement in this group of rare neuroectodermal tumours. METHODS: The Surveillance, Epidemiology and End Results (SEER) database from 2004 to 2011 identified patients with SNUC and sinonasal small-cell carcinoma. Overall neck involvement and individual nodal level involvement at presentation were assessed, and comparison was made with a contemporaneous cohort of patients with a borderline clinically significant risk of nodal involvement and recurrence. RESULTS: Of 141 patients, 31 (22%) had gross nodal involvement at presentation (range 14-33% by site and histology). Non-nasal, non-ethmoid site with SNUC histology has the highest rates of initial nodal involvement, whereas higher stage and size do not predict for higher nodal involvement rates. Bilateral Levels 2-3 for all sinonasal small cell; Levels 2-3 for nasal or ethmoid SNUC; and bilateral Levels 1-3 in non-nasal/non-ethmoid SNUC have the highest rates of involvement compared with a clinical reference standard. CONCLUSION: We found high rates of initial nodal involvement in all SNUC and sinonasal small-cell carcinoma. We found higher initial involvement of Levels 2 and 3 and in certain cases to the Level 1 nodal levels, hypothesizing benefit for elective treatment to those levels. ADVANCES IN KNOWLEDGE: With small single-institution series reporting conflicting nodal involvement rates, our data support high rates of nodal presentation at diagnosis, hypothesizing benefit for elective nodal treatment in this cohort.

HPV-related oropharyngeal cancer: Risk factors for treatment failure in patients managed with primary transoral robotic surgery.

BACKGROUND: The purpose of this study was to determine clinical factors that predict locoregional recurrence or distant metastasis in patients with human papillomavirus (HPV)-positive oropharyngeal cancer treated with surgery and guideline-indicated adjuvant therapy. METHODS: We identified all presumed HPV-positive patients with oropharyngeal cancer in our health system from January 2010 to August 2012 treated with surgery and guideline-indicated adjuvant therapy. Statistical analysis was performed to identify clinical predictors associated with treatment failure. RESULTS: One hundred fourteen p16+ oropharyngeal cancers managed with initial surgical resection were identified. Median follow-up was 17 months. Two-year locoregional failure was 3.3% and distant failure was 8.4%. Statistical analysis found that conventional poor prognostic features did not predict treatment failure. CONCLUSION: Locoregional recurrence and development of distant metastatic disease are uncommon in patients who are appropriately selected for surgical management of p16+ oropharyngeal cancer regardless of the presence or absence of conventional poor prognostic features.

Total Laryngectomy Versus Larynx Preservation for T4a Larynx Cancer: Patterns of Care and Survival Outcomes.

PURPOSE: To examine practice patterns and compare survival outcomes between total laryngectomy (TL) and larynx preservation chemoradiation (LP-CRT) in the setting of T4a larynx cancer, using a large national cancer registry. METHODS AND MATERIALS: Using the National Cancer Database, we identified 969 patients from 2003 to 2006 with T4a squamous cell larynx cancer receiving definitive treatment with either initial TL plus adjuvant therapy or LP-CRT. Univariate and multivariable logistic regression were used to assess predictors of undergoing surgery. Survival outcomes were compared using Kaplan-Meier and propensity score-adjusted and inverse probability of treatment-weighted Cox proportional hazards methods. Sensitivity analyses were performed to account for unmeasured confounders. RESULTS: A total of 616 patients (64%) received LP-CRT, and 353 (36%) received TL. On multivariable logistic regression, patients with advanced nodal disease were less likely to receive TL (N2 vs N0, 26.6% vs 43.4%, odds ratio [OR] 0.52, 95% confidence interval [CI] 0.37-0.73; N3 vs N0, 19.1% vs 43.4%, OR 0.23, 95% CI 0.07-0.77), whereas patients treated in high case-volume facilities were more likely to receive TL (46.1% vs 31.5%, OR 1.78, 95% CI 1.27-2.48). Median survival for TL versus LP was 61 versus 39 months (P<.001). After controlling for potential confounders, LP-CRT had inferior overall survival compared with TL (hazard ratio 1.31, 95% CI 1.10-1.57), and with the inverse probability of treatment-weighted model (hazard ratio 1.25, 95% CI 1.05-1.49). This survival difference was shown to be robust on additional sensitivity analyses. CONCLUSIONS: Most patients with T4a larynx cancer receive LP-CRT, despite guidelines suggesting TL as the preferred initial approach. Patients receiving LP-CRT had more advanced nodal disease and worse overall survival. Previous studies of (non-T4a) locally advanced larynx cancer showing no difference in survival between LP-CRT and TL may not apply to T4a disease, and patients should be counseled accordingly.

Measuring the Physiologic Properties of Oral Lesions Receiving Fractionated Photodynamic Therapy.

Photodynamic therapy (PDT) can treat superficial, early-stage disease with minimal damage to underlying tissues and without cumulative dose-limiting toxicity. Treatment efficacy is affected by disease physiologic properties, but these properties are not routinely measured. We assessed diffuse reflectance spectroscopy (DRS) for the noninvasive, contact measurement of tissue hemoglobin oxygen saturation (St O2 ) and total hemoglobin concentration ([tHb]) in the premalignant or superficial microinvasive oral lesions of patients treated with 5-aminolevulinic acid (ALA)-PDT. Patients were enrolled on a Phase 1 study of ALA-PDT that evaluated fluences of 50, 100, 150 or 200 J cm(-2) delivered at 100 mW cm(-2) . To test the feasibility of incorporating DRS measurements within the illumination period, studies were performed in patients who received fractionated (two-part) illumination that included a dark interval of 90-180 s. Using DRS, tissue oxygenation at different depths within the lesion could also be assessed. DRS could be performed concurrently with contact measurements of photosensitizer levels by fluorescence spectroscopy, but a separate noncontact fluorescence spectroscopy system provided continuous assessment of photobleaching during illumination to greater tissue depths. Results establish that the integration of DRS into PDT of early-stage oral disease is feasible, and motivates further studies to evaluate its predictive and dosimetric value.

Carotid intima-media thickness measurement promises to improve cardiovascular risk evaluation in head and neck cancer patients.

BACKGROUND: Radiation-treated head and neck cancer (HNC) patients are at high risk for developing radiation vasculopathy, as evidenced by an increased stroke risk. The benefits of screening and assessing the cardiovascular (CV) risk of HNC patients using carotid intima-media thickness (CIMT) ultrasound are not known. Our objective was to determine the prevalence of high CV risk in patients without known CV diseases who received radiation for HNC, determine the percentage of screened patients who had a change in clinical management as a result of an increased CIMT, and to compare this risk-assessment tool to patients' risk classification using the Framingham Risk Score (FRS) and Pooled Cohort Atherosclerotic Cardiovascular Disease (ASCVD) Risk Equation (recommended by American College of Cardiology/American Heart Association Guidelines on the Assessment of Cardiovascular Risk). HYPOTHESIS: Risk calculators may not accurately predict risk in this population with a unique risk factor. Carotid IMT may be used to detect radiation vasculopathy in HNC patients. METHODS: Retrospective medical chart review was conducted on 134 radiation-treated HNC patients. The main outcome measures were CV risk (as determined by CIMT) and clinical management. Also, the FRS and the Pooled Cohort ASCVD Risk Equation were used to compare classification with CIMT. RESULTS: Approximately 74% of the cases were at high CV risk using CIMT technique. Approximately half of the HNC patients screened had a change in clinical management characterized by recorded initiation of aspirin and recorded initiation or increase of statin therapies. The FRS and the Pooled Cohort ASCVD Risk Equation failed to detect 40% to 50% of cases found to be at high risk using the CIMT technique. CONCLUSIONS: Carotid IMT identified a much greater percentage of radiation-treated HNC patients at high CV risk compared with standard CV-risk calculators. By more accurately identifying the patients at high risk, this may lead to more effective prevention, and therefore a reduction in CV events.