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Locally recurrent nasopharyngeal carcinoma (NPC) presents substantial challenges in clinical management. Although postoperative re-irradiation (re-RT) has been acknowledged as a potential treatment option, standardized guidelines and consensus regarding the use of re-RT in this context are lacking. This article provides a comprehensive review and summary of international recommendations on postoperative management for potentially resectable locally recurrent NPC, with a special focus on postoperative re-RT. A thorough search was conducted to identify relevant studies on postoperative re-RT for locally recurrent NPC. Controversial issues, including resectability criteria, margin assessment, indications for postoperative re-RT, and the optimal dose and method of re-RT, were addressed through a Delphi consensus process. The consensus recommendations emphasize the need for a clearer and broader definition of resectability, highlighting the importance of achieving clear surgical margins, preferably through an en bloc approach with frozen section margin assessment. Furthermore, these guidelines suggest considering re-RT for patients with positive or close margins. Optimal postoperative re-RT doses typically range around 60 Gy, and hyperfractionation has shown promise in reducing toxicity. These guidelines aim to assist clinicians in making evidence-based decisions and improving patient outcomes in the management of potentially resectable locally recurrent NPC. By addressing key areas of controversy and providing recommendations on resectability, margin assessment, and re-RT parameters, these guidelines serve as a valuable resource for clinical experts involved in the treatment of locally recurrent NPC., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: One main advantage of proton therapy versus photon therapy is its precise radiation delivery to targets without exit dose, resulting in lower dose to surrounding healthy tissues. This is critical, given the proximity of head and neck tumors to normal structures. However, proton planning requires careful consideration of factors, including air-tissue interface, anatomic uncertainties, surgical artifacts, weight fluctuations, rapid tumor response, and daily variations in setup and anatomy, as these heterogeneities can lead to inaccuracies in targeting and creating unwarranted hotspots to a greater extent than photon radiation. In addition, the elevated relative biological effectiveness at the Bragg peak's distal end can also increase hot spots within and outside the target area., Methods and Materials: The purpose of this study was to evaluate for a difference in positron emission tomography (PET) standard uptake value (SUV) after definitive treatment, between intensity modulated proton therapy (IMPT) and intensity modulated photon therapy (IMRT). In addition, we compared the biologic dose between PET areas of high and low uptake within the clinical target volume-primary of patients treated with IMPT. This work is assuming that the greater SUV may potentially result in greater toxicities. For the purposes of this short communication, we are strictly focusing on the SUV and do not have correlation with toxicity outcomes. To accomplish this, we compared the 3- and 6-month posttreatment fluorodeoxyglucose PET scans for 100 matched patients with oropharyngeal cancer treated definitively without surgery using either IMPT (n = 50) or IMRT (n = 50)., Results: Our study found a significant difference in biologic dose between the high- and low-uptake regions on 3-month posttreatment scans of IMPT. However, this difference did not translate to a significant difference in PET uptake in the clinical target volume-primary at 3 and 6 months' follow-up between patients who received IMPT versus IMRT., Conclusions: Studies have proposed that proton's greater relative biological effectiveness at the Bragg peak could lead to tissue inflammation. Our study did not corroborate these findings. This study's conclusion underscores the need for further investigations with ultimate correlation with clinical toxicity outcomes., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Reirradiation for locally recurrent nasopharyngeal carcinoma (NPC) is challenging because prior radiation dose delivered in the first course is often close to the tolerance limit of surrounding normal structures. A delicate balance between achieving local salvage and minimizing treatment toxicities is needed. However, high-level evidence is lacking because available reports are mostly retrospective studies on small series of patients. Pragmatic consensus guidelines, based on an extensive literature search and the pooling of opinions by leading specialists, will provide a useful reference to assist decision-making for these difficult decisions., Methods and Materials: A thorough review of available literature on recurrent NPC was conducted. A set of questions and preliminary draft guideline was circulated to a panel of international specialists with extensive experience in this field for voting on controversial areas and comments. A refined second proposal, based on a summary of the initial voting and different opinions expressed, was recirculated to the whole panel for review and reconsideration. The current guideline was based on majority voting after repeated iteration for final agreement., Results: The initial round of questions showed variations in clinical practice even among the specialists, reflecting the lack of high-quality supporting data and the difficulties in formulating clinical decisions. Through exchange of comments and iterative revisions, recommendations with high-to-moderate agreement were formulated on general treatment strategies and details of reirradiation (including patient selection, targets contouring, dose prescription, and constraints)., Conclusion: This paper provides useful reference on radical salvage treatment strategies for recurrent NPC and optimization of reirradiation through review of published evidence and consensus building. However, the final decision by the attending clinician must include full consideration of an individual patient's condition, understanding of the delicate balance between risk and benefits, and acceptance of risk of complications., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Activation of the PI3K/mTOR signaling pathway is common in head and neck squamous cell carcinoma (HNSCC). BYL719 is an α-specific PI3K inhibitor that is synergistic and efficacious when combined with cetuximab, a Food and Drug Administration-approved radiosensitizing agent in the treatment of HNSCC. The agent independently has been shown to enhance radiosensitivity. This study evaluates the addition of BYL719 to cetuximab and radiation in the treatment of locally advanced HNSCC., Methods and Materials: This is a single-institution, phase 1 study. Patients with American Joint Committee on Cancer seventh edition stage III to IVB HNSCC received standard cetuximab (400 mg/m 2 intravenous loading dose) before intensity modulated radiation therapy (IMRT) followed by 250 mg/m 2 weekly infusions during IMRT. BYL719 was given orally during IMRT in 3 dose levels: (1) 200 mg/d, (2) 250 mg/d, or (3) 300 mg/d in a standard 3 + 3 dose-escalation design., Results: Eleven patients were evaluable. Dose level 2 was the maximum tolerated dose for BYL719. Two patients on dose level 3 had dose-limiting toxicities of oral mucositis that required a dose reduction of BYL719. One patient on dose level 2 had a dose-limiting toxicity of nausea that led to withdrawal of on-study treatment. Related grade 3 or higher adverse events consisted of decreased lymphocyte count, oral mucositis, dysphagia, hyperglycemia, maculopapular rash, and palmar-plantar erythrodysesthesia syndrome. All 11 patients had a complete response on posttreatment imaging, and 10 remain disease free. Of the 8 patients with mutational analysis, 1 had an activating PIK3CA mutation associated with a rapid response on serial intratreatment magnetic resonance imaging scans., Conclusions: The recommended phase 2 dose of BYL719 is 250 mg/d in combination with cetuximab and IMRT in patients with locally advanced HNSCC. Further evaluation of the addition of BYL719 to the platinum-sparing regimen of cetuximab and IMRT in the treatment of locally advanced HNSCC is warranted., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: The treatment of nasopharyngeal carcinoma requires high radiation doses. The balance of the risks of local recurrence owing to inadequate tumor coverage versus the potential damage to the adjacent organs at risk (OARs) is of critical importance. With advancements in technology, high target conformality is possible. Nonetheless, to achieve the best possible dose distribution, optimal setting of dose targets and dose prioritization for tumor volumes and various OARs is fundamental. Radiation doses should always be guided by the As Low As Reasonably Practicable principle. There are marked variations in practice. This study aimed to develop a guideline to serve as a global practical reference., Methods and Materials: A literature search on dose tolerances and normal-tissue complications after treatment for nasopharyngeal carcinoma was conducted. In addition, published guidelines and protocols on dose prioritization and constraints were reviewed. A text document and preliminary set of variants was circulated to a panel of international experts with publications or extensive experience in the field. An anonymized voting process was conducted to rank the proposed variants. A summary of the initial voting and different opinions expressed by members were then recirculated to the whole panel for review and reconsideration. Based on the comments of the panel, a refined second proposal was recirculated to the same panel. The current guideline was based on majority voting after repeated iteration for final agreement., Results: Variation in opinion among international experts was repeatedly iterated to develop a guideline describing appropriate dose prioritization and constraints. The percentage of final agreement on the recommended parameters and alternative views is shown. The rationale for the recommendations and the limitations of current evidence are discussed., Conclusions: Through this comprehensive review of available evidence and interactive exchange of vast experience by international experts, a guideline was developed to provide a practical reference for setting dose prioritization and acceptance criteria for tumor volumes and OARs. The final decision on the treatment prescription should be based on the individual clinical situation and the patient's acceptance of optimal balance of risk., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To identify imaged regions in which dose is associated with radiation-induced trismus after head and neck cancer radiation therapy (HNRT) using a novel image-based data mining (IBDM) framework., Methods and Materials: A cohort of 86 HNRT patients were analyzed for region identification. Trismus was characterized as a continuous variable by the maximum incisor-to-incisor opening distance (MID) at 6 months after radiation therapy. Patient anatomies and dose distributions were spatially normalized to a common frame of reference using deformable image registration. IBDM was used to identify clusters of voxels associated with MID (P ≤ .05 based on permutation testing). The result was externally tested on a cohort of 35 patients with head and neck cancer. Internally, we also performed a dose-volume histogram-based analysis by comparing the magnitude of the correlation between MID and the mean dose for the IBDM-identified cluster in comparison with 5 delineated masticatory structures., Results: A single cluster was identified with the IBDM approach (P < .01), partially overlapping with the ipsilateral masseter. The dose-volume histogram-based analysis confirmed that the IBDM cluster had the strongest association with MID, followed by the ipsilateral masseter and the ipsilateral medial pterygoid (Spearman's rank correlation coefficients: R s = -0.36, -0.35, -0.32; P = .001, .001, .002, respectively). External validation confirmed an association between mean dose to the IBDM cluster and MID (R s = -0.45; P = .007)., Conclusions: IBDM bypasses the common assumption that dose patterns within structures are unimportant. Our novel IBDM approach for continuous outcome variables successfully identified a cluster of voxels that are highly associated with trismus, overlapping partially with the ipsilateral masseter. Tests on an external validation cohort showed an even stronger correlation with trismus. These results support use of the region in HNRT treatment planning to potentially reduce trismus., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Limited data exist to guide the treatment technique for reirradiation of recurrent or second primary squamous carcinoma of the head and neck. We performed a multi-institution retrospective cohort study to investigate the effect of the elective treatment volume, dose, and fractionation on outcomes and toxicity., Methods and Materials: Patients with recurrent or second primary squamous carcinoma originating in a previously irradiated field (≥40 Gy) who had undergone reirradiation with intensity modulated radiation therapy (IMRT); (≥40 Gy re-IMRT) were included. The effect of elective nodal treatment, dose, and fractionation on overall survival (OS), locoregional control, and acute and late toxicity were assessed. The Kaplan-Meier and Gray's competing risks methods were used for actuarial endpoints., Results: From 8 institutions, 505 patients were included in the present updated analysis. The elective neck was not treated in 56.4% of patients. The median dose of re-IMRT was 60 Gy (range 39.6-79.2). Hyperfractionation was used in 20.2%. Systemic therapy was integrated for 77.4% of patients. Elective nodal radiation therapy did not appear to decrease the risk of locoregional failure (LRF) or improve the OS rate. Doses of ≥66 Gy were associated with improvements in both LRF and OS in the definitive re-IMRT setting. However, dose did not obviously affect LRF or OS in the postoperative re-IMRT setting. Hyperfractionation was not associated with improved LRF or OS. The rate of acute grade ≥3 toxicity was 22.1% overall. On multivariable logistic regression, elective neck irradiation was associated with increased acute toxicity in the postoperative setting. The rate of overall late grade ≥3 toxicity was 16.7%, with patients treated postoperatively with hyperfractionation experiencing the highest rates., Conclusions: Doses of ≥66 Gy might be associated with improved outcomes in high-performance patients undergoing definitive re-IMRT. Postoperatively, doses of 50 to 66 Gy appear adequate after removal of gross disease. Hyperfractionation and elective neck irradiation were not associated with an obvious benefit and might increase toxicity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: The therapeutic ratio of reirradiation for recurrent or second primary (RSP) squamous carcinoma of the head and neck may be improved in the intensity modulated radiation therapy (IMRT) era. However, patient selection for reirradiation remains challenging. We performed a multi-institution cohort study to investigate modern outcomes after IMRT-based reirradiation and to identify prognostic subgroups., Patients and Methods: Patients with RSP squamous carcinoma originating in a previously irradiated field (≥40 Gy) who underwent reirradiation with IMRT (≥40 Gy re-IMRT) were included. Locoregional failure and late toxicity were calculated using the Gray competing risk method. Cox proportional hazards regression was used to identify factors associated with overall survival (OS). Factors associated with OS were entered into a recursive partitioning analysis (RPA) for OS., Results: From 7 institutions, 412 patients were included. The median dose of re-IMRT was 60 Gy, and the median time between RT courses was 2.4 years. Chemotherapy was used in 76% of patients. The rates of grade ≥3, grade ≥4, and grade 5 acute toxicities were 19%, 4.4%, and 1.2%, respectively. The 2-year cumulative incidence of grade ≥3 late toxicity adjusted for the competing risks of recurrence or death was 14.2%. RPA identified 3 prognostic subgroups with distinct and homogenous OS (P<.001): class I included patients >2 years from their initial course of RT with resected tumors (2-year OS, 61.9%); class II included patients >2 years with unresected tumors or those ≤2 years and without feeding tube or tracheostomy dependence (2-year OS, 40.0%), and the remaining patients formed class III (2-year OS, 16.8%). Fifty-nine percent of class III patients underwent postoperative re-irradiation., Conclusions: This study informs outcomes and expectations with IMRT-based reirradiation. The RPA classification identifies 3 distinct subgroups, which can guide patient selection for therapy and clinical trial design. RPA class III patients are not ideal candidates for protracted chemoradiation regardless of resection status., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Two modern methods of reirradiation, intensity modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT), are established for patients with recurrent or second primary squamous cell carcinoma of the head and neck (rSCCHN). We performed a retrospective multi-institutional analysis to compare methods., Methods and Materials: Data from patients with unresectable rSCCHN previously irradiated to ≥40 Gy who underwent reirradiation with IMRT or SBRT were collected from 8 institutions. First, the prognostic value of our IMRT-based recursive partitioning analysis (RPA) separating those patients with unresectable tumors with an intertreatment interval >2 years or those with ≤2 years and without feeding tube or tracheostomy dependence (class II) from other patients with unresected tumors (class III) was investigated among SBRT patients. Overall survival (OS) and locoregional failure were then compared between IMRT and SBRT by use of 2 methods to control for baseline differences: Cox regression weighted by the inverse probability of treatment and subset analysis by RPA classification., Results: The study included 414 patients with unresectable rSCCHN: 217 with IMRT and 197 with SBRT. The unadjusted 2-year OS rate was 35.4% for IMRT and 16.3% for SBRT (P<.01). Among SBRT patients, RPA classification retained an independent association with OS. On Cox regression weighted by the inverse probability of treatment, no significant differences in OS or locoregional failure between IMRT and SBRT were demonstrated. Analysis by RPA class showed similar OS between IMRT and SBRT for class III patients. In all class II patients, IMRT was associated with improved OS (P<.001). Further subset analysis demonstrated comparable OS when ≥35 Gy was delivered with SBRT to small tumor volumes. Acute grade ≥4 toxicity was greater in the IMRT group than in the SBRT group (5.1% vs 0.5%, P<.01), with no significant difference in late toxicity., Conclusions: Reirradiation both with SBRT and with IMRT appear relatively safe with favorable toxicity compared with historical studies. Outcomes vary by RPA class, which informs clinical trial design. Survival is poor in class III patients, and alternative strategies are needed., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Definitive treatment of nasopharyngeal carcinoma (NPC) is challenging owing to its rarity, complicated regional anatomy, and the intensity of therapy. In contrast to other head and neck cancers, the effect of facility volume has not been well described for NPC., Methods and Materials: The National Cancer Database was queried for patients with stage II-IVB NPC diagnosed from 2004 to 2014 and treated with definitive radiation. Patients with incomplete staging, unknown receipt or timing of treatment, unknown follow-up duration, incomplete socioeconomic information, or treatment outside the reporting facility were excluded. High-volume facilities (HVFs) were defined as the top 5% of facilities according to the annual facility volume., Results: The present analysis included 3941 NPC patients treated at 804 facilities with a median follow-up duration of 59.4 months, including 1025 patients (26.0%) treated at HVFs. Treatment at HVFs was associated with significantly improved overall survival (OS) on multivariable analysis (hazard ratio 0.79, 95% confidence interval 0.69-0.90; P=.001). In propensity score-matched cohorts, 5-year OS was 69.1% versus 63.3% at HVFs versus lower volume facilities (LVFs), respectively (P=.003). Similar results were seen when facility volume was analyzed as a continuous variable. The effect of facility volume on survival varied by academic status (P=.002 for interaction). At academic centers, the propensity score-matched cohorts had 5-year OS of 71.4% compared with 62.4% (P<.001) at HVFs and LVFs, respectively. In contrast, the 5-year OS was 63.5% versus 67.9% (P=.68) in propensity score-matched patients at nonacademic HVFs and LVFs., Conclusions: Treatment at HVFs was associated with improved OS for patients with NPC, with the effect exclusively seen at academic centers., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To characterize the patterns of care and potential barriers to access to care for elderly patients with oral cavity cancer in the adjuvant setting., Methods and Materials: We performed a retrospective cohort study using the National Cancer Data Base and identified patients with resected oral cavity squamous cell carcinoma diagnosed between 2004 and 2012, who survived for ≥3 months after surgery. We used logistic regression models to assess the association between age (<70, 70-79, and ≥80 years) and the receipt of adjuvant therapy within 3 months of surgery. We additionally assessed the association between patient and tumor characteristics and the receipt of adjuvant therapy among those aged ≥70 years., Results: A total of 25,829 patients were included in the study. Compared with those aged <70 years, older patients were more likely to have no neck dissection or have fewer lymph nodes dissected and were less likely to receive adjuvant therapy than younger patients. Among our cohort, 11,361 patients (44%) had pathologic T3-T4 disease or N2-N3 disease, and 4185 patients (16%) had extracapsular nodal extension or positive surgical margins. In multivariate analyses controlling for comorbidity and demographic characteristics, older age was independently associated with lower odds of receiving adjuvant radiation therapy in the subgroup with T3 or T4 disease or N2 or N3 disease and adjuvant chemoradiation therapy in the positive extracapsular nodal extension or positive surgical margin subgroup. Among elderly patients, both greater patient distance from reporting facility and older age were associated with lower odds of receiving both adjuvant radiation therapy (odds ratio 0.66; 95% confidence interval, 0.55-0.81) and chemoradiation therapy (odds ratio 0.56; 95% confidence interval, 0.40-0.79)., Conclusions: In a national hospital-based cohort of patients with oral cavity cancer, elderly patients were less likely to receive adjuvant radiation or chemoradiation therapy. Greater patient distance from reporting facility, in addition to older age, was associated with lower odds of receiving both adjuvant radiation therapy and adjuvant chemoradiation therapy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Reirradiation therapy (re-RT) is the only potentially curative treatment option for patients with locally recurrent head and neck cancer (HNC). Given the significant morbidity with head and neck re-RT, interest in proton beam radiation therapy (PBRT) has increased. We report the first multi-institutional clinical experience using curative-intent PBRT for re-RT in recurrent HNC., Methods and Materials: A retrospective analysis of ongoing prospective data registries from 2 hybrid community practice and academic proton centers was conducted. Patients with recurrent HNC who underwent at least 1 prior course of definitive-intent external beam radiation therapy (RT) were included. Acute and late toxicities were assessed with the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 and the Radiation Therapy Oncology Group late radiation morbidity scoring system, respectively. The cumulative incidence of locoregional failure was calculated with death as a competing risk. The actuarial 12-month freedom-from-distant metastasis and overall survival rates were calculated with the Kaplan-Meier method., Results: Ninety-two consecutive patients were treated with curative-intent re-RT with PBRT between 2011 and 2014. Median follow-up among surviving patients was 13.3 months and among all patients was 10.4 months. The median time between last RT and PBRT was 34.4 months. There were 76 patients with 1 prior RT course and 16 with 2 or more courses. The median PBRT dose was 60.6 Gy (relative biological effectiveness, [RBE]). Eighty-five percent of patients underwent prior HNC RT for an oropharynx primary, and 39% underwent salvage surgery before re-RT. The cumulative incidence of locoregional failure at 12 months, with death as a competing risk, was 25.1%. The actuarial 12-month freedom-from-distant metastasis and overall survival rates were 84.0% and 65.2%, respectively. Acute toxicities of grade 3 or greater included mucositis (9.9%), dysphagia (9.1%), esophagitis (9.1%), and dermatitis (3.3%). There was 1 death during PBRT due to disease progression. Grade 3 or greater late skin and dysphagia toxicities were noted in 6 patients (8.7%) and 4 patients (7.1%), respectively. Two patients had grade 5 toxicity due to treatment-related bleeding., Conclusions: Proton beam re-RT of the head and neck can provide effective tumor control with acceptable acute and late toxicity profiles likely because of the decreased dose to the surrounding normal, albeit previously irradiated, tissue, although longer follow-up is needed to confirm these findings., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: Local control in oropharyngeal cancer has improved to unprecedented rates with combined modality therapy; as a result, distant metastases are becoming a principal challenge. We aimed to determine the impact of diabetes mellitus and metformin use on clinical outcomes in a large population of oropharyngeal cancer patients treated in the modern era., Methods and Materials: We identified 1745 consecutive patients with oropharyngeal cancer treated at 2 large cancer centers with external beam radiation therapy from 1998 to 2011. A total of 184 patients had diabetes mellitus at the time of diagnosis, of whom 102 were taking metformin. The outcomes assessed included local failure-free survival (LFFS), regional failure-free survival (RFFS), distant metastasis-free survival (DMFS), and overall survival (OS)., Results: The median follow-up time was 4.3 years. The 5-year actuarial rates of DMFS were 89.6% for nondiabetic patients and 78.7% for diabetic nonmetformin users (P=.011) and of OS were 83.0% for nondiabetic patients and 70.7% for diabetic nonmetformin users (P=.048). Diabetic metformin users had 5-year DMFS (90.1%) and OS (89.6%) similar to those of nondiabetic patients. Multivariate analysis (diabetic nonmetformin users as reference) demonstrated improved DMFS for nondiabetic patients (adjusted hazard ratio 0.54; 95% confidence interval 0.32-0.93; P=.03) and a trend toward improved DMFS with metformin use (adjusted hazard ratio 0.46; 95% confidence interval 0.20-1.04; P=.06). LFFS and RFFS were high in all groups and were not significantly different by diabetic status or metformin use., Conclusions: Diabetic patients not using metformin independently have significantly higher rates of distant metastases than do nondiabetic patients, whereas metformin users have rates of distant metastases similar to those of nondiabetic patients. Further prospective investigation is warranted to validate the benefit of metformin in oropharyngeal cancer., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: Elevated expression of eukaryotic protein synthesis initiation factor 4E (eIF4E) in histologically cancer-free margins of resected head and neck squamous cell carcinomas (HNSCCs) is mediated by mammalian target of rapamycin complex 1 (mTORC1) and has been associated with increased risk of disease recurrence. Preclinically, inhibition of mTORC1 with everolimus sensitizes cancer cells to cisplatin and radiation., Methods and Materials: This was single-institution phase 1 study to establish the maximum tolerated dose of daily everolimus given with fixed dose cisplatin (30 mg/m(2) weekly × 6) and concurrent intensity modulated radiation therapy for patients with locally and/or regionally advanced head-and-neck cancer. The study had a standard 3 + 3 dose-escalation design., Results: Tumor primary sites were oral cavity (4), salivary gland (4), oropharynx (2), nasopharynx (1), scalp (1), and neck node with occult primary (1). In 4 of 4 cases in which resected HNSCC surgical pathology specimens were available for immunohistochemistry, elevated expression of eIF4E was observed in the cancer-free margins. The most common grade ≥3 treatment-related adverse event was lymphopenia (92%), and dose-limiting toxicities (DLTs) were mucositis (n=2) and failure to thrive (n=1). With a median follow up of 19.4 months, 2 patients have experienced recurrent disease. The maximum tolerated dose was everolimus 5 mg/day., Conclusions: Head-and-neck cancer patients tolerated everolimus at therapeutic doses (5 mg/day) given with weekly cisplatin and intensity modulated radiation therapy. The regimen merits further evaluation, especially among patients who are status post resection of HNSCCs that harbor mTORC1-mediated activation of eIF4E in histologically negative surgical margins., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The clearance of nonirradiated tumors after localized radiation therapy is known as the abscopal effect. Activation of an antitumor immune response has been proposed as a mechanism for the abscopal effect. Here we report a patient with metastatic melanoma who received palliative radiation to his primary tumor with subsequent clearance of all his nonirradiated in-transit metastases. Anti-MAGEA3 antibodies were found upon serological testing, demonstrating an association between the abscopal effect and a systemic antitumor immune response. A brain recurrence was then treated with a combination of stereotactic radiosurgery and immunotherapy with ipilimumab. The patient experienced a complete remission that included resolution of nodal metastases, with a concomitant increase in MAGEA3 titers and a new response to the cancer antigen PASD1. This case supports the immune hypothesis for the abscopal effect, and illustrates the potential of combining radiotherapy and immunotherapy in the treatment of melanoma., (Published by Elsevier Inc.)

Purpose: To analyze the effect of primary gross tumor volume (pGTV) and nodal gross tumor volume (nGTV) on treatment outcomes in patients treated with definitive intensity-modulated radiation therapy (IMRT) for oropharyngeal cancer (OPC)., Methods and Materials: Between September 1998 and April 2009, a total of 442 patients with squamous cell carcinoma of the oropharynx were treated with IMRT with curative intent at our center. Thirty patients treated postoperatively and 2 additional patients who started treatment more than 6 months after diagnosis were excluded. A total of 340 patients with restorable treatment plans were included in this present study. The majority of the patients underwent concurrent platinum-based chemotherapy. The pGTV and nGTV were calculated using the original clinical treatment plans. Cox proportional hazards models and log-rank tests were used to evaluate the correlation between tumor volumes and overall survival (OS), and competing risks analysis tools were used to evaluate the correlation between local failure (LF), regional failure (RF), distant metastatic failure (DMF) vs. tumor volumes with death as a competing risk., Results: Median follow-up among surviving patients was 34 months (range, 5-67). The 2-year cumulative incidence of LF, RF and DF in this cohort of patients was 6.1%, 5.2%, and 12.2%, respectively. The 2-year OS rate was 88.6%. Univariate analysis determined pGTV and T-stage correlated with LF (p < 0.0001 and p = 0.004, respectively), whereas nGTV was not associated with RF. On multivariate analysis, pGTV and N-stage were independent risk factors for overall survival (p = 0.0003 and p = 0.0073, respectively) and distant control (p = 0.0008 and p = 0.002, respectively)., Conclusions: In this cohort of patients with OPC treated with IMRT, pGTV was found to be associated with overall survival, local failure, and distant metastatic failure., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: Dynamic contrast-enhanced MRI (DCE-MRI) can provide information regarding tumor perfusion and permeability and has shown prognostic value in certain tumors types. The goal of this study was to assess the prognostic value of pretreatment DCE-MRI in head and neck squamous cell carcinoma (HNSCC) patients with nodal disease undergoing chemoradiation therapy or surgery., Methods and Materials: Seventy-four patients with histologically proven squamous cell carcinoma and neck nodal metastases were eligible for the study. Pretreatment DCE-MRI was performed on a 1.5T MRI. Clinical follow-up was a minimum of 12 months. DCE-MRI data were analyzed using the Tofts model. DCE-MRI parameters were related to treatment outcome (progression-free survival [PFS] and overall survival [OS]). Patients were grouped as no evidence of disease (NED), alive with disease (AWD), dead with disease (DOD), or dead of other causes (DOC). Prognostic significance was assessed using the log-rank test for single variables and Cox proportional hazards regression for combinations of variables., Results: At last clinical follow-up, for Stage III, all 12 patients were NED. For Stage IV, 43 patients were NED, 4 were AWD, 11 were DOD, and 4 were DOC. K(trans) is volume transfer constant. In a stepwise Cox regression, skewness of K(trans) (volume transfer constant) was the strongest predictor for Stage IV patients (PFS and OS: p <0.001)., Conclusion: Our study shows that skewness of K(trans) was the strongest predictor of PFS and OS in Stage IV HNSCC patients with nodal disease. This study suggests an important role for pretreatment DCE-MRI parameter K(trans) as a predictor of outcome in these patients., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To update the Memorial Sloan-Kettering Cancer Center's experience with intensity-modulated radiotherapy (IMRT) in the treatment of oropharyngeal cancer (OPC)., Methods and Materials: Between September 1998 and April 2009, 442 patients with histologically confirmed OPC underwent IMRT at our center. There were 379 men and 63 women with a median age of 57 years (range, 27-91). The disease was Stage I in 2%, Stage II in 4%, Stage III in 21%, and Stage IV in 73% of patients. The primary tumor subsite was tonsil in 50%, base of tongue in 46%, pharyngeal wall in 3%, and soft palate in 2%. The median prescription dose to the planning target volume of the gross tumor was 70 Gy for definitive (n = 412) cases and 66 Gy for postoperative cases (n = 30). A total 404 patients (91%) received chemotherapy, including 389 (88%) who received concurrent chemotherapy, the majority of which was platinum-based., Results: Median follow-up among surviving patients was 36.8 months (range, 3-135). The 3-year cumulative incidence of local failure, regional failure, and distant metastasis was 5.4%, 5.6%, and 12.5%, respectively. The 3-year OS rate was 84.9%. The incidence of late dysphagia and late xerostomia ≥Grade 2 was 11% and 29%, respectively., Conclusions: Our results confirm the feasibility of IMRT in achieving excellent locoregional control and low rates of xerostomia. According to our knowledge, this study is the largest report of patients treated with IMRT for OPC., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To correlate proton magnetic resonance spectroscopy ((1)H-MRS), dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and (18)F-labeled fluorodeoxyglucose positron emission tomography ([(18)F]FDG PET) of nodal metastases in patients with head and neck squamous cell carcinoma (HNSCC) for assessment of tumor biology. Additionally, pretreatment multimodality imaging was evaluated for its efficacy in predicting short-term response to treatment., Methods and Materials: Metastatic neck nodes were imaged with (1)H-MRS, DCE-MRI, and [(18)F]FDG PET in 16 patients with newly diagnosed HNSCC, before treatment. Short-term patient radiological response was evaluated at 3 to 4 months. Correlations among (1)H-MRS (choline concentration relative to water [Cho/W]), DCE-MRI (volume transfer constant [K(trans)]; volume fraction of the extravascular extracellular space [v(e)]; and redistribution rate constant [k(ep)]), and [(18)F]FDG PET (standard uptake value [SUV] and total lesion glycolysis [TLG]) were calculated using nonparametric Spearman rank correlation. To predict short-term responses, logistic regression analysis was performed., Results: A significant positive correlation was found between Cho/W and TLG (ρ = 0.599; p = 0.031). Cho/W correlated negatively with heterogeneity measures of standard deviation std(v(e)) (ρ = -0.691; p = 0.004) and std(k(ep)) (ρ = -0.704; p = 0.003). Maximum SUV (SUVmax) values correlated strongly with MRI tumor volume (ρ = 0.643; p = 0.007). Logistic regression indicated that std(K(trans)) and SUVmean were significant predictors of short-term response (p < 0.07)., Conclusion: Pretreatment multimodality imaging using (1)H-MRS, DCE-MRI, and [(18)F]FDG PET is feasible in HNSCC patients with nodal metastases. Additionally, combined DCE-MRI and [(18)F]FDG PET parameters were predictive of short-term response to treatment., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Despite progress in surgical and reconstructive techniques, as well as advances in radiotherapy delivery methods, a significant proportion of patients irradiated for head-and-neck cancer develop locoregional recurrence. These patients are also at high risk of developing new second primary cancers of the head and neck. Because of the heterogeneity of this population with respect to disease-related and patient-related factors, such as previous treatment, tumor recurrence site, disease extent, and performance status, the optimal treatment of locoregionally recurrent or second primary cancers of the head and neck remains to be defined. Although surgical resection typically constitutes the mainstay of treatment, effective salvage therapy is often precluded by anatomic inaccessibility and the risk of perioperative complications. Although chemotherapy alone has traditionally been considered an alternative to surgery, the response rates have been poor, with nearly all patients dying of disease progression within months. Similarly, salvage therapy using re-irradiation has historically been avoided because of concerns regarding toxicity. Although the results of more recent studies using contemporary treatment techniques and conformal delivery methods have been somewhat more promising, the role of re-irradiation after previous full-course radiotherapy is still considered investigational by many. Numerous questions remain unanswered, and practical guidelines for clinical decision-making are sparse., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: Osteoradionecrosis (ORN) is a known complication of radiation therapy to the head and neck. However, the incidence of this complication with intensity-modulated radiation therapy (IMRT) and dental sequelae with this technique have not been fully elucidated., Methods and Materials: From December 2000 to July 2007, 168 patients from our institution have been previously reported for IMRT of the oral cavity, nasopharynx, larynx/hypopharynx, sinus, and oropharynx. All patients underwent pretreatment dental evaluation, including panoramic radiographs, an aggressive fluoride regimen, and a mouthguard when indicated. The median maximum mandibular dose was 6,798 cGy, and the median mean mandibular dose was 3,845 cGy. Patient visits were retrospectively reviewed for the incidence of ORN, and dental records were reviewed for the development of dental events. Univariate analysis was then used to assess the effect of mandibular and parotid gland dosimetric parameters on dental endpoints., Results: With a median clinic follow-up of 37.4 months (range, 0.8-89.6 months), 2 patients, both with oral cavity primaries, experienced ORN. Neither patient had preradiation dental extractions. The maximum mandibular dose and mean mandibular dose of the 2 patients were 7,183 and 6,828 cGy and 5812 and 5335 cGy, respectively. In all, 17% of the patients (n = 29) experienced a dental event. A mean parotid dose of >26 Gy was predictive of a subsequent dental caries, whereas a maximum mandibular dose >70 Gy and a mean mandibular dose >40 Gy were correlated with dental extractions after IMRT., Conclusions: ORN is rare after head-and-neck IMRT, but is more common with oral cavity primaries. Our results suggest different mechanisms for radiation-induced caries versus extractions., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To assess noninvasively the tumor microenvironment of neck nodal metastases in patients with head-and-neck cancer by investigating the relationship between tumor perfusion measured using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and hypoxia measured by (18)F-fluoromisonidazole ((18)F-FMISO) positron emission tomography (PET)., Methods and Materials: Thirteen newly diagnosed head-and-neck cancer patients with metastatic neck nodes underwent DCE-MRI and (18)F-FMISO PET imaging before chemotherapy and radiotherapy. The matched regions of interests from both modalities were analyzed. To examine the correlations between DCE-MRI parameters and standard uptake value (SUV) measurements from (18)F-FMISO PET, the nonparametric Spearman correlation coefficient was calculated. Furthermore, DCE-MRI parameters were compared between nodes with (18)F-FMISO uptake and nodes with no (18)F-FMISO uptake using Mann-Whitney U tests., Results: For the 13 patients, a total of 18 nodes were analyzed. The nodal size strongly correlated with the (18)F-FMISO SUV (rho = 0.74, p < 0.001). There was a strong negative correlation between the median k(ep) (redistribution rate constant) value (rho = -0.58, p = 0.042) and the (18)F-FMISO SUV. Hypoxic nodes (moderate to severe (18)F-FMISO uptake) had significantly lower median K(trans) (volume transfer constant) (p = 0.049) and median k(ep) (p = 0.027) values than did nonhypoxic nodes (no (18)F-FMISO uptake)., Conclusion: This initial evaluation of the preliminary results support the hypothesis that in metastatic neck lymph nodes, hypoxic nodes are poorly perfused (i.e., have significantly lower K(trans) and k(ep) values) compared with nonhypoxic nodes., (Copyright 2010 Elsevier Inc. All rights reserved.)

Purpose: To present our single-institution experience of intensity-modulated radiotherapy (IMRT) for oral cavity cancer., Methods and Materials: Between September 2000 and December 2006, 35 patients with histologically confirmed squamous cell carcinoma of the oral cavity underwent surgery followed by postoperative IMRT. The sites included were buccal mucosa in 8, oral tongue in 11, floor of the mouth in 9, gingiva in 4, hard palate in 2, and retromolar trigone in 1. Most patients had Stage III-IV disease (80%). Ten patients (29%) also received concurrent postoperative chemotherapy with IMRT. The median prescribed radiation dose was 60 Gy., Results: The median follow-up for surviving patients was 28.1 months (range, 11.9-85.1). Treatment failure occurred in 11 cases as follows: local in 4, regional in 2, and distant metastases in 5. Of the 5 patients with distant metastases, 2 presented with dermal metastases. The 2- and 3-year estimates of locoregional progression-free survival, distant metastasis-free survival, disease-free survival, and overall survival were 84% and 77%, 85% and 85%, 70% and 64%, and 74% and 74%, respectively. Acute Grade 2 or greater dermatitis, mucositis, and esophageal reactions were experienced by 54%, 66%, and 40% of the patients, respectively. Documented late complications included trismus (17%) and osteoradionecrosis (5%)., Conclusion: IMRT as an adjuvant treatment after surgical resection for oral cavity tumors is feasible and effective, with promising results and acceptable toxicity.

Purpose: External beam radiotherapy (EBRT) plays a controversial role in the management of nonanaplastic thyroid cancer. We reviewed our institution's outcomes in patients treated with EBRT for advanced or recurrent nonanaplastic thyroid cancer., Methods and Materials: Between April 1989 and April 2006, 76 patients with nonanaplastic thyroid cancer were treated with EBRT. The median follow-up for the surviving patients was 35.3 months (range, 4.2-178.4). The lesions were primarily advanced and included Stage T2 in 5 (7%), T3 in 5 (7%), and T4 in 64 (84%) patients. Stage N1 disease was present in 60 patients (79%). Distant metastases before EBRT were identified in 27 patients (36%). The median total EBRT dose delivered was 6,300 cGy. The histologic features examined included medullary in 12 patients (16%) and nonmedullary in 64 (84%). Of the 76 patients, 71 (93%) had undergone surgery before RT, and radioactive iodine treatment was used in 56 patients (74%)., Results: The 2- and 4-year overall locoregional control rate for all histologic types was 86% and 72%, respectively, and the 2- and 4-year overall survival rate for all patients was 74% and 55%, respectively. No significant differences were found in locoregional control, overall survival, or distant metastases-free survival for patients with complete resection, microscopic residual disease, or gross residual disease. Grade 3 acute mucositis and dysphagia occurred in 14 (18%) and 24 (32%) patients, respectively. Late adverse toxicity was notable for percutaneous endoscopic gastrostomy tube use in 4 patients (5%)., Conclusion: The results of our study have shown that EBRT is effective for locoregional control of selected locally advanced or recurrent nonanaplastic thyroid malignancies, with acceptable acute toxicity.

Purpose: Although Radiation Therapy Oncology Group protocols have proposed a limiting dose to the brachial plexus for patients undergoing intensity-modulated radiotherapy for head-and-neck cancer, essentially no recommendations exist for the delineation of this structure for treatment planning., Methods and Materials: Using anatomic texts, radiologic data, and magnetic resonance imaging, a standardized method for delineating the brachial plexus on 3-mm axial computed tomography images was devised. A neuroradiologist assisted with identification of the brachial plexus and adjacent structures. This organ at risk was then contoured on 10 consecutive patients undergoing intensity-modulated radiotherapy for head-and-neck cancer. Dose-volume histogram curves were generated by applying the proposed brachial plexus contour to the initial treatment plan., Results: The total dose to the planning target volume ranged from 60 to 70 Gy (median, 70). The mean brachial plexus volume was 33 +/- 4 cm(3) (range, 25.1-39.4). The mean irradiated volumes of the brachial plexus were 50 Gy (17 +/- 3 cm(3)), 60 Gy (6 +/- 3 cm(3)), 66 Gy (2 +/- 1 cm(3)), 70 Gy (0 +/- 1 cm(3)). The maximal dose to the brachial plexus was 69.9 Gy (range, 62.3-76.9) and was >/=60 Gy, >/=66 Gy, and >/=70 Gy in 100%, 70%, and 30% of patients, respectively., Conclusions: This technique provides a precise and accurate method for delineating the brachial plexus organ at risk on treatment planning computed tomography scans. Our dosimetric analysis suggest that for patients undergoing intensity-modulated radiotherapy for head-and-neck cancer, brachial plexus routinely receives doses in excess of historic and Radiation Therapy Oncology Group limits.

Purpose: To evaluate long-term outcomes and toxicity in patients with unresectable paranasal sinus carcinoma treated with radiotherapy, with or without chemotherapy., Methods and Materials: Between January 1990 and December 2006, 39 patients with unresectable Stage IVB paranasal sinus carcinoma were treated definitively with chemotherapy plus radiotherapy (n = 35, 90%) or with radiotherapy alone (n = 4, 10%). Patients were treated with three-dimensional conformal radiotherapy (n = 18, 46%), intensity-modulated radiotherapy (n = 12, 31%), or conventional radiotherapy (n = 9, 23%) to a median treatment dose of 70 Gy. Most patients received concurrent platinum-based chemotherapy (n = 32, 82%) and/or concomitant boost radiotherapy (n = 29, 74%)., Results: With a median follow-up of 90 months, the 5-year local progression-free survival, regional progression-free survival, distant metastasis-free survival, disease-free survival, and overall survival were 21%, 61%, 51%, 14%, and 15%, respectively. Patients primarily experienced local relapse (n = 25, 64%), mostly within the irradiated field (n = 22). Nine patients developed neck relapses; however none of the 4 patients receiving elective neck irradiation had a nodal relapse. In 13 patients acute Grade 3 mucositis developed. Severe late toxicities occurred in 2 patients with radionecrosis and 1 patient with unilateral blindness 7 years after intensity-modulated radiation therapy (77 Gy to the optic nerve). The only significant factor for improved local progression-free survival and overall survival was a biologically equivalent dose of radiation >/=65 Gy., Conclusions: Treatment outcomes for unresectable paranasal sinus carcinoma are poor, and combined-modality treatment is needed that is both more effective and associated with less morbidity. The addition of elective neck irradiation may improve regional control.

Purpose: To analyze the recent experience of patients with adenoid cystic carcinoma treated with radiation therapy at Memorial Sloan-Kettering Cancer Center., Methods and Materials: From 1990 to 2004, a total of 59 patients with a diagnosis of primary adenoid cystic carcinoma of the head and neck received radiation therapy at our institution. The subsite distribution was oral cavity, 28% (n = 17); paranasal sinuses, 22% (n = 13); parotid, 14% (n = 8); submandibular, 14% (n = 8); oropharynx, 10% (n = 6); sublingual, 3% (n = 2); nasopharynx, 3% (n = 2); and other, 5% (n = 3). T Stage distribution was T1, 34% (n = 20); T2, 19% (n = 11); T3, 14% (n = 8); and T4, 34% (n = 20). Twenty-nine percent of patients (n = 17) were treated with intensity-modulated radiation therapy; 25% (n =15), with three-dimensional conformal therapy, and the remainder, with conventional techniques. Ninety percent (n = 53) of patients received treatment including the base of skull., Results: Median follow-up for surviving patients was 5.9 years. Five-year and 10-year rates of local control and distant metastases-free survival were 91%/81% and 81%/49%, respectively. Five-year and 10-year rates of disease-free and overall survival were 76%/40% and 87%/65%, respectively. On univariate analysis, stage T4 (p = 0.004) and gross/clinical nerve involvement (p = 0.002) were associated with decreased progression free survival, whereas stage T4 and lymph node involvement were associated with decreased overall survival (p = 0.046 and p < 0.001, respectively)., Conclusions: Radiation therapy in combination with surgery produces excellent rates of local control, although distant metastases account for a high proportion of failures. Routine treatment to the base of skull reduces the significance of histologic perineural invasion, but major nerve involvement remains an adverse prognostic factor.

Purpose: Unknown primary head and neck cancers often require comprehensive mucosal and bilateral neck irradiation. With conventional techniques, significant toxicity can develop. Intensity-modulated radiotherapy (IMRT) has the potential to minimize the toxicity., Methods and Materials: Between 2000 and 2005, 21 patients underwent IMRT for unknown primary head and neck cancer at our center. Of the 21 patients, 5 received IMRT with definitive intent and 16 as postoperative therapy; 14 received concurrent chemotherapy and 7 IMRT alone. The target volumes included the bilateral neck and mucosal surface. The median dose was 66 Gy. Acute and chronic toxicities, esophageal strictures, and percutaneous endoscopic gastrostomy tube dependence were evaluated. Progression-free survival, regional progression-free survival, distant metastasis-free survival, and overall survival were estimated with Kaplan-Meier curves., Results: With a median follow-up of 24 months, the 2-year regional progression-free survival, distant metastasis-free survival, and overall survival rate was 90%, 90%, and 85%, respectively. Acute grade 1 and 2 xerostomia was seen in 57% and 43% of patients, respectively. Salivary function improved with time. Percutaneous endoscopic gastrostomy tube placement was required in 72% with combined modality treatment and 43% with IMRT alone. Only 1 patient required percutaneous endoscopic gastrostomy support at the last follow-up visit. Two patients treated with combined modality and one treated with IMRT alone developed esophageal strictures, but all had improvement or resolution with dilation., Conclusion: The preliminary analysis of IMRT for unknown primary head and neck cancer has shown acceptable toxicity and encouraging efficacy. The analysis of the dosimetric variables showed excellent tumor coverage and acceptable doses to critical normal structures. Esophageal strictures developed but were effectively treated with dilation. Techniques to limit the esophageal dose could help further minimize this complication.

Purpose: To discuss the implications of three examples of periparotid recurrence after definitive intensity-modulated radiotherapy (IMRT) for head and neck cancer (HNC)., Methods and Materials: We present 3 patients with HNC who underwent definitive IMRT with concurrent chemotherapy and later had treatment failure in or near a spared parotid gland. Two patients had bilateral multilevel nodal disease, and all had Level II nodal disease ipsilateral to the site of recurrence. The patients were treated using dose-painting IMRT with a dose of 70 Gy to the gross tumor volume and 59.4 Gy or 54 Gy to the high-risk or low-risk clinical tumor volume, respectively. The parotid glands were spared bilaterally. The patients had not undergone any surgical treatment for HNC before radiotherapy., Results: All patients had treatment failure in the region of a spared parotid gland. Failure in the 2 patients with bilateral multilevel nodal involvement occurred in the periparotid lymph nodes. The third patient developed a dermal metastasis near the tail of a spared parotid gland. On pretreatment imaging, the 2 patients with nodal failure had small nonspecific periparotid nodules that showed no hypermetabolic activity on positron emission tomography., Conclusion: For HNC patients receiving definitive IMRT, nonspecific positron emission tomography-negative periparotid nodules on pretreatment imaging should raise the index of suspicion for subclinical disease in the presence of multilevel or Level II nodal metastases. Additional evaluation of such nodules might be indicated before sparing the ipsilateral parotid gland.

Purpose: To report the clinical outcome of patients treated with combined-modality approaches for sinonasal undifferentiated carcinoma (SNUC) of the head and neck., Methods and Materials: The records of 21 patients with SNUC treated with curative intent at the University of California, San Francisco between 1990 and 2004 were analyzed. Patient age ranged from 33 to 71 years (median, 47 years). Primary tumor sites included the nasal cavity (11 patients), maxillary sinus (5 patients), and ethmoid sinus (5 patients). All patients had T3 (4 patients) or T4 (17 patients) tumors. Local-regional treatment included surgery followed by postoperative radiotherapy (PORT) with or without adjuvant chemotherapy for 17 patients; neoadjuvant chemoradiotherapy followed by surgery for 2 patients; and definitive chemoradiotherapy for 2 patients. Median follow-up among surviving patients was 58 months (range, 12-70 months)., Results: The 2- and 5-year estimates of local control were 60% and 56%, respectively. There was no difference in local control according to initial treatment approach, but among the 19 patients who underwent surgery the 5-year local control rate was 74% for those with gross tumor resection, compared with 24% for those with subtotal tumor resection (p = 0.001). The 5-year rates of overall and distant metastasis-free survival were 43% and 64%, respectively. Late complications included cataracts (2 patients), lacrimal stenosis (1 patient), and sino-cutaneous fistula (1 patient)., Conclusion: The suboptimal outcomes suggest a need for more effective therapies. Gross total resection should be the goal of all treatments whenever possible.

Purpose: Hypoxia renders tumor cells radioresistant, limiting locoregional control from radiotherapy (RT). Intensity-modulated RT (IMRT) allows for targeting of the gross tumor volume (GTV) and can potentially deliver a greater dose to hypoxic subvolumes (GTV(h)) while sparing normal tissues. A Monte Carlo model has shown that boosting the GTV(h) increases the tumor control probability. This study examined the feasibility of fluorine-18-labeled fluoromisonidazole positron emission tomography/computed tomography ((18)F-FMISO PET/CT)-guided IMRT with the goal of maximally escalating the dose to radioresistant hypoxic zones in a cohort of head and neck cancer (HNC) patients., Methods and Materials: (18)F-FMISO was administered intravenously for PET imaging. The CT simulation, fluorodeoxyglucose PET/CT, and (18)F-FMISO PET/CT scans were co-registered using the same immobilization methods. The tumor boundaries were defined by clinical examination and available imaging studies, including fluorodeoxyglucose PET/CT. Regions of elevated (18)F-FMISO uptake within the fluorodeoxyglucose PET/CT GTV were targeted for an IMRT boost. Additional targets and/or normal structures were contoured or transferred to treatment planning to generate (18)F-FMISO PET/CT-guided IMRT plans., Results: The heterogeneous distribution of (18)F-FMISO within the GTV demonstrated variable levels of hypoxia within the tumor. Plans directed at performing (18)F-FMISO PET/CT-guided IMRT for 10 HNC patients achieved 84 Gy to the GTV(h) and 70 Gy to the GTV, without exceeding the normal tissue tolerance. We also attempted to deliver 105 Gy to the GTV(h) for 2 patients and were successful in 1, with normal tissue sparing., Conclusion: It was feasible to dose escalate the GTV(h) to 84 Gy in all 10 patients and in 1 patient to 105 Gy without exceeding the normal tissue tolerance. This information has provided important data for subsequent hypoxia-guided IMRT trials with the goal of further improving locoregional control in HNC patients.

Purpose: Hypoxia is one of the main causes of the failure to achieve local control using radiotherapy. This is due to the increased radioresistance of hypoxic cells. (18)F-fluoromisonidazole ((18)F-FMISO) positron emission tomography (PET) is a noninvasive imaging technique that can assist in the identification of intratumor regions of hypoxia. The aim of this study was to evaluate the reproducibility of (18)F-FMISO intratumor distribution using two pretreatment PET scans., Methods and Materials: We enrolled 20 head and neck cancer patients in this study. Of these, 6 were excluded from the analysis for technical reasons. All patients underwent an (18)F-fluorodeoxyglucose study, followed by two (18)F-FMISO studies 3 days apart. The hypoxic volumes were delineated according to a tumor/blood ratio >or=1.2. The (18)F-FMISO tracer distributions from the two (18)F-FMISO studies were co-registered on a voxel-by-voxel basis using the computed tomography images from the PET/computed tomography examinations. A correlation between the (18)F-FMISO intensities of the corresponding spatial voxels was derived., Results: A voxel-by-voxel analysis of the (18)F-FMISO distributions in the entire tumor volume showed a strong correlation in 71% of the patients. Restraining the correlation to putatively hypoxic zones reduced the number of patients exhibiting a strong correlation to 46%., Conclusion: Variability in spatial uptake can occur between repeat (18)F-FMISO PET scans in patients with head and neck cancer. Blood data for one patient was not available. Of 13 patients, 6 had well-correlated intratumor distributions of (18)F-FMISO-suggestive of chronic hypoxia. More work is required to identify the underlying causes of changes in intratumor distribution before single-time-point (18)F-FMISO PET images can be used as the basis of hypoxia-targeting intensity-modulated radiotherapy.

Purpose: To perform a retrospective review of laryngeal/hypopharyngeal carcinomas treated with concurrent chemotherapy and intensity-modulated radiotherapy (IMRT)., Methods and Materials: Between January 2002 and June 2005, 20 laryngeal and 11 hypopharyngeal carcinoma patients underwent IMRT with concurrent platinum-based chemotherapy; most patients had Stage IV disease. The prescription of the planning target volume for gross, high-risk, and low-risk subclinical disease was 70, 59.4, and 54 Gy, respectively. Acute/late toxicities were retrospectively scored using the Common Toxicity Criteria scale. The 2-year local progression-free, regional progression-free, laryngectomy-free, distant metastasis-free, and overall survival rates were calculated using the Kaplan-Meier method., Results: The median follow-up of the living patients was 26 months (range, 17-58 months). The 2-year local progression-free, regional progression-free, laryngectomy-free, distant metastasis-free, and overall survival rate was 86%, 94%, 89%, 92%, and 63%, respectively. Grade 2 mucositis or higher occurred in 48% of patients, and all experienced Grade 2 or higher pharyngitis during treatment. Xerostomia continued to decrease over time from the end of RT, with none complaining of Grade 2 toxicity at this analysis. The 2-year post-treatment percutaneous endoscopic gastrostomy-dependency rate for those with hypopharyngeal and laryngeal tumors was 31% and 15%, respectively. The most severe late complications were laryngeal necrosis, necrotizing fascitis, and a carotid rupture resulting in death 3 weeks after salvage laryngectomy., Conclusion: These preliminary results have shown that IMRT achieved encouraging locoregional control of locoregionally advanced laryngeal and hypopharyngeal carcinomas. Xerostomia improved over time. Pharyngoesophageal stricture with percutaneous endoscopic gastrostomy dependency remains a problem, particularly for patients with hypopharyngeal carcinoma and, to a lesser extent, those with laryngeal cancer. Strategies using IMRT to limit the dose delivered to the esophagus/inferior constrictor musculature without compromising target coverage might be useful to further minimize this late complication.

Purpose: To compare clinical outcomes of patients with carcinomas of the paranasal sinuses and nasal cavity according to decade of radiation treatment., Methods and Materials: Between 1960 and 2005, 127 patients with sinonasal carcinoma underwent radiotherapy with planning and delivery techniques available at the time of treatment. Fifty-nine patients were treated by conventional radiotherapy; 45 patients by three-dimensional conformal radiotherapy; and 23 patients by intensity-modulated radiotherapy. Eighty-two patients (65%) were treated with radiotherapy after gross total tumor resection. Nineteen patients (15%) received chemotherapy. The most common histology was squamous cell carcinoma (83 patients)., Results: The 5-year estimates of overall survival, local control, and disease-free survival for the entire patient population were 52%, 62%, and 54%, respectively. There were no significant differences in any of these endpoints with respect to decade of treatment or radiotherapy technique (p > 0.05, for all). The 5-year overall survival rate for patients treated in the 1960s, 1970s, 1980s, 1990s, and 2000s was 46%, 56%, 51%, 53%, and 49%, respectively (p = 0.23). The observed incidence of severe (Grade 3 or 4) late toxicity was 53%, 45%, 39%, 28%, and 16% among patients treated in the 1960s, 1970s, 1980s, 1990s, and 2000s, respectively (p = 0.01)., Conclusion: Although we did not detect improvements in disease control or overall survival for patients treated over time, the incidence of complications has significantly declined, thereby resulting in an improved therapeutic ratio for patients with carcinomas of the paranasal sinuses and nasal cavity.

Purpose: To evaluate the incidence of nodal relapses from carcinomas of the salivary glands among patients with clinically negative necks in an attempt to determine the potential utility of elective neck irradiation (ENI)., Methods and Materials: Between 1960 and 2004, 251 patients with clinically N0 carcinomas of the salivary glands were treated with surgery and postoperative radiation therapy. None of the patients had undergone previous neck dissection. Histology was: adenoid cystic (84 patients), mucoepidermoid (60 patients), adenocarcinoma (58 patients), acinic cell (21 patients), undifferentiated (11 patients), carcinoma ex pleomorphic adenoma (7 patients), squamous cell (7 patients), and salivary duct carcinoma (3 patients); 131 patients (52%) had ENI. Median follow-up was 62 months (range, 3-267 months)., Results: The 5- and 10-year actuarial estimates of nodal relapse were 11% and 13%, respectively. The 10-year actuarial rates of nodal failure were 7%, 5%, 12%, and 16%, for patients with T1, T2, T3, and T4 disease, respectively (p = 0.11). The use of ENI reduced the 10-year nodal failure rate from 26% to 0% (p = 0.0001). The highest crude rates of nodal relapse among those treated without ENI were found in patients with squamous cell carcinoma (67%), undifferentiated carcinoma (50%), adenocarcinoma (34%), and mucoepidermoid carcinoma (29%). There were no nodal failures observed among patients with adenoid cystic or acinic cell histology., Conclusion: ENI effectively prevents nodal relapses and should be used for select patients at high risk for regional failure.

Purpose: To perform a retrospective analysis of patients with paranasal sinus (PNS) cancer treated with postoperative radiotherapy (RT) at Memorial Sloan-Kettering Cancer Center., Methods and Materials: Between January 1987 and July 2005, 85 patients with PNS and nasal cavity cancer underwent postoperative RT. Most patients had squamous cell carcinoma (49%; n = 42), T4 tumors (52%; n = 36), and the maxillary sinus (53%; n = 45) as the primary disease site. The median radiation dose was 63 Gy. Of the 85 patients, 76 underwent CT simulation and 53 were treated with either three-dimensional conformal RT (27%; n = 23) or intensity-modulated RT (35%; n = 30). Acute and late toxicities were scored according to the Radiation Therapy Oncology Group radiation morbidity scoring criteria., Results: With a median follow-up for surviving patients of 60 months, the 5-year estimates of local progression-free, regional progression-free, distant metastasis-free, disease-free, and overall survival rates were 62%, 87%, 82%, 55%, and 67%, respectively. On multivariate analysis, squamous cell histology and cribriform plate involvement predicted for an increased likelihood of local recurrence, and squamous cell histologic features predicted for worse overall survival. None of the patients who underwent CT simulation and were treated with modern techniques developed a Grade 3-4 late complication of the eye., Conclusion: Complete surgical resection followed by adjuvant RT is an effective and safe approach in the treatment of PNS cancer. Emerging tools, such as three-dimensional conformal treatment and, in particular, intensity-modulated RT for PNS tumors, may minimize the occurrence of late complications associated with conventional RT techniques. Local recurrence remains a significant problem.

Tumors invading the skull base pose a difficult problem for the treating radiation oncologist. When confronting these highly complex tumors where the gross tumor abuts the optic apparatus or brain stem, the physician often has to make a difficult choice regarding coverage of the tumor, i.e., underdosing portions of the tumor to protect the critical normal tissues versus accepting the risk of late complication while ensuring full coverage of the tumor. This situation is often encountered in advanced T4 disease originating either in the paranasal sinuses or the nasopharynx. In this case report, the author presents a case in which difficult decisions were made when treating a complex, locally advanced, T4 nasopharyngeal cancer that invaded the skull base.

Purpose: The aim of this study was to compare toxicity/efficacy of conventional radiotherapy using delayed accelerated concomitant boost radiotherapy (CBRT) vs. intensity-modulated radiotherapy (IMRT) in the setting of concurrent chemotherapy (CT) for locally advanced oropharyngeal carcinoma., Methods and Materials: Between September 1998 and June 2004, a total of 293 consecutive patients were treated at our institution for cancer of the oropharynx. Of these, 112 had Stage III/IV disease and squamous cell histology. In all, 41 were treated with IMRT/CT and 71 were treated with CBRT/CT, both to a median dose of 70 Gy. Most common CT was a planned two cycles given every 3 to 4 weeks of cisplatin, 100 mg/m2 i.v., but an additional cycle was given to IMRT patients when possible. Both groups were well-matched for all prognostic factors., Results: Median follow-up was 46 months (range, 3-93 months) for the CBRT patients and 31 months (range, 20-64 months) for the IMRT group. Three-year actuarial local-progression-free, regional-progression-free, locoregional progression-free, distant-metastases-free, disease-free, and overall survival rates were 85% vs. 95% (p = 0.17), 95% vs. 94% (p = 0.90), 82% vs. 92% (p = 0.18), 85% vs. 86% (p = 0.78), 76% vs. 82% (p = 0.57), and 81% vs. 91% (p = 0.10) for CBRT and IMRT patients, respectively. Three patients died of treatment-related toxicity in the CBRT group vs. none undergoing IMRT. At 2 years, 4% IMRT patients vs. 21% CBRT patients were dependent on percutaneous endoscopic gastrostomy (p = 0.02). Among those who had > or =20 months follow-up, there was a significant difference in Grade > or =2 xerostomia as defined by the criteria of the Radiation Therapy and Oncology Group, 67% vs. 12% (p = 0.02), in the CBRT vs. IMRT arm., Conclusion: In the setting of CT for locally advanced oropharyngeal carcinoma, IMRT results in lower toxicity and similar treatment outcomes when compared with CBRT.

Purpose: To review the Memorial Sloan-Kettering Cancer Center's experience in using intensity-modulated radiation therapy (IMRT) for the treatment of oropharyngeal cancer., Methods and Materials: Between September 1998 and June 2004, 50 patients with histologically confirmed cancer of the oropharynx underwent IMRT at our institution. There were 40 men and 10 women with a median age of 56 years (range, 28-78 years). The disease was Stage I in 1 patient (2%), Stage II in 3 patients (6%), Stage III in 7 (14%), and Stage IV in 39 (78%). Forty-eight patients (96%) received definitive treatment, and 2 (4%) were treated in the postoperative adjuvant setting. Concurrent chemotherapy was used in 43 patients (86%). Patients were treated using three different IMRT approaches: 76% dose painting, 18% concomitant boost with IMRT in both am and pm deliveries, and 6% concomitant boost with IMRT only in pm delivery. Regardless of the approach, the average prescription dose to the gross tumor planning target volume was 70 Gy, while the average dose delivered to the subclinical volume was 59.4 Gy in the dose painting group and 54 Gy in the concomitant boost group. Percutaneous endoscopic gastrostomy feeding tubes (PEGs) were placed before the beginning of treatment in 84% of the patients. Acute and late toxicity were graded according to the Radiation Therapy Oncology Group (RTOG) radiation morbidity scoring criteria. Toxicity was also evaluated using subjective criteria such as the presence of esophageal stricture, and the need for PEG usage. The local progression-free, regional progression-free, and distant metastases-free rates, and overall survival were calculated using the Kaplan-Meier method., Results: Three patients had persistent locoregional disease after treatment. The 2-year estimates of local progression-free, regional progression-free, distant metastases-free, and overall survival were 98%, 88%, 84%, and 98%, respectively. The worst acute mucositis experienced was Grade 1 in 4 patients (8%), Grade 2 in 27 (54%), and Grade 3 in 19 (38%). Xerostomia decreased with increasing time interval from the end of radiotherapy, and among the patients with at least 9 months of follow-up there was 67% Grade 0-1 and 33% Grade 2 toxicity. Of the 42 patients who required upfront PEG placement, 6 were still using PEG for nutrition at the time of this analysis. Three patients had cervical esophageal strictures, and of these, 1 was still PEG dependent 1 year after treatment. Two of these patients were treated with the IMRT concomitant boost am and pm approach, whereas the other was treated with the dose painting technique., Conclusions: Intensity-modulated radiotherapy achieved encouraging local control rates in patients with oropharyngeal carcinoma. Treatment toxicity was acceptable even in the setting of concurrent chemotherapy. Long-term follow-up is needed to confirm these preliminary findings.

Purpose: Intensity-modulated radiation therapy (IMRT) enables highly conformal treatment for thyroid cancer (TC). In this study, we review outcomes/toxicity in a series of TC patients treated with IMRT., Methods and Materials: Between July 2001 and January 2004, 20 nonanaplastic TC patients underwent IMRT. Mean age was 55. There were 3 T2 and 17 T4 patients. Sixteen patients had N1 disease. Seven patients had metastases before RT. Fifteen underwent surgery before RT. Radioactive iodine (RAI) and chemotherapy were used in 70% and 40%, respectively. Median total RT dose was 63 Gy., Results: With two local failures, 2-year local progression-free rate was 85%. There were six deaths, with a 2-year overall survival rate of 60%. For patients with M0 disease, the 2-year distant metastases-free rate was 46%. The worst acute mucositis and pharyngitis was Grade 3 (n = 7 and 3, respectively). Two patients had Grade 3 acute skin toxicity and 2 had Grade 3 acute laryngeal toxicity. No significant radiation-related late effects were reported., Conclusions: IMRT for TC is feasible and effective in appropriately selected cases. Acute toxicity is manageable with proactive clinical care. Ideal planning target volume doses have yet to be determined. Additional patients and long-term follow-up are needed to confirm these preliminary findings and to clarify late toxicities.