Systemic Immune-Inflammatory Index Association with Survival in Patients Undergoing Trimodality Therapy for Lung Cancer.

PURPOSE: The systemic immune-inflammation index (SII) is correlated with patient survival in various solid malignancies including non-small-cell lung cancer (NSCLC). However, limited information is available on the prognostic implication of the SII in patients undergoing trimodality therapy for stage III NSCLC. METHODS: At our institution, 81 patients underwent curative intent trimodality therapy (neoadjuvant chemoradiotherapy followed by surgical resection) for stage III NSCLC from 2004 to 2019. The SII was calculated at the time of diagnosis as platelet count × neutrophil count/lymphocyte count. χ2 analysis was used to compare categorical variables. A Kaplan-Meier analysis was performed to estimate disease-free survival (DFS), overall survival (OS), and freedom from recurrence (FFR) rates, with Cox regression used to determine absolute hazards. RESULTS: Patients underwent neoadjuvant radiation therapy to a median dose of 4,500 cGy concurrent with a median of 3 cycles of chemotherapy (most commonly carboplatin and paclitaxel) followed by surgical resection (86.4% lobectomy and 13.6% pneumonectomy) with mediastinal lymph node dissection. At a median follow-up of 68.4 months, a low SII (<1,260) at diagnosis was independently associated with an improved OS (hazard ratio [HR]: 0.448, p = 0.004), DFS (HR: 0.366, p < 0.001), and FFR (HR: 0.325, p = 0.002). CONCLUSIONS: We identified that a low SII was associated with improved OS, DFS, and FFR in patients undergoing trimodality therapy for stage III NSCLC. The interplay of the immune system and lung cancer outcomes remains an active area of investigation for which further study is warranted.

NCCN Guidelines® Insights: Head and Neck Cancers, Version 1.2022.

The NCCN Guidelines for Head and Neck Cancers address tumors arising in the oral cavity (including mucosal lip), pharynx, larynx, and paranasal sinuses. Occult primary cancer, salivary gland cancer, and mucosal melanoma (MM) are also addressed. The specific site of disease, stage, and pathologic findings guide treatment (eg, the appropriate surgical procedure, radiation targets, dose and fractionation of radiation, indications for systemic therapy). The NCCN Head and Neck Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding management of HPV-positive oropharynx cancer and ongoing research in this area.

Head and Neck Cancers, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.

Treatment is complex for patients with head and neck (H&N) cancers with specific site of disease, stage, and pathologic findings guiding treatment decision-making. Treatment planning for H&N cancers involves a multidisciplinary team of experts. This article describes supportive care recommendations in the NCCN Guidelines for Head and Neck Cancers, as well as the rationale supporting a new section on imaging recommendations for patients with H&N cancers. This article also describes updates to treatment recommendations for patients with very advanced H&N cancers and salivary gland tumors, specifically systemic therapy recommendations.

NCCN Guidelines Insights: Head and Neck Cancers, Version 1.2018.

The NCCN Guidelines for Head and Neck (H&N) Cancers provide treatment recommendations for cancers of the lip, oral cavity, pharynx, larynx, ethmoid and maxillary sinuses, and salivary glands. Recommendations are also provided for occult primary of the H&N, and separate algorithms have been developed by the panel for very advanced H&N cancers. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding evaluation and treatment of nasopharyngeal carcinoma.

Multi-institutional experience of stereotactic body radiotherapy for large (≥5 centimeters) non-small cell lung tumors.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is the standard of care for patients with nonoperative, early-stage non-small cell lung cancer (NSCLC) measuring < 5 cm, but its use among patients with tumors measuring ≥5 cm is considerably less defined, with the existing literature limited to small, single-institution reports. The current multi-institutional study reported outcomes evaluating the largest such population reported to date. METHODS: Clinical/treatment characteristics, outcomes, toxicities, and patterns of failure were assessed in patients with primary NSCLC measuring ≥5 cm without evidence of distant/lymph node metastasis who underwent SBRT using ≤5 fractions. Statistics included Kaplan-Meier survival analyses and univariate/multivariate Cox proportional hazards models. RESULTS: A total of 92 patients treated from 2004 through 2016 were analyzed from 12 institutions. The median follow-up was 12 months (15 months in survivors). The median age and tumor size among the patients were 73 years (range, 50-95 years) and 5.4 cm (range, 5.0-7.5 cm), respectively. The median dose/fractionation was 50 Gray/5 fractions. The actuarial local control rates at 1 year and 2 years were 95.7% and 73.2%, respectively. The disease-free survival rate was 72.1% and 53.5%, respectively, at 1 year and 2 years. The 1-year and 2-year disease-specific survival rates were 95.5% and 78.6%, respectively. The median, 1-year, and 2-year overall survival rates were 21.4 months, 76.2%, and 46.4%, respectively. On multivariate analysis, lung cancer history and pre-SBRT positron emission tomography maximum standardized uptake value were found to be associated with overall survival. Posttreatment failures were most commonly distant (33% of all disease recurrences), followed by local (26%) and those occurring elsewhere in the lung (23%). Three patients had isolated local failures. Grade 3 to 4 toxicities included 1 case (1%) and 4 cases (4%) of grade 3 dermatitis and radiation pneumonitis, respectively (toxicities were graded according to the Common Terminology Criteria for Adverse Events [version 4.0]). Grades 2 to 5 radiation pneumonitis occurred in 11% of patients. One patient with a tumor measuring 7.5 cm and a smoking history of 150 pack-years died of radiation pneumonitis. CONCLUSIONS: The results of the current study, which is the largest study of patients with NSCLC measuring ≥5 cm reported to date, indicate that SBRT is a safe and efficacious option. Cancer 2017;123:688-696. © 2016 American Cancer Society.

NCCN Guidelines Insights: Head and Neck Cancers, Version 2.2017.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers provide treatment recommendations for cancers of the lip, oral cavity, pharynx, larynx, ethmoid and maxillary sinuses, and salivary glands. Recommendations are also provided for occult primary of the head and neck (H&N), and separate algorithms have been developed by the panel for very advanced H&N cancers. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding the increase in human papillomavirus-associated oropharyngeal cancer and the availability of immunotherapy agents for treatment of patients with recurrent or metastatic H&N cancer.

A Review and Update of Treatment Options and Controversies in the Management of Hepatocellular Carcinoma.

OBJECTIVE: To review the current management, outline recent advances and address controversies in the management of hepatocellular carcinoma (HCC). SUMMARY OF BACKGROUND DATA: The treatment of HCC is multidisciplinary involving hepatologists, surgeons, medical oncologists, radiation oncologists, radiologists, interventional radiologists, and other disciplines. Each of these disciplines brings its unique perspective and differing opinions that add to controversies in the management of HCC. METHODS: A focused literature review was performed to identify recent studies on the management of HCC and thereby summarize relevant information on the various therapeutic modalities and controversies involved in the treatment of HCC. RESULTS: The main treatment algorithms continue to rely on hepatic resection or transplantation with controversies involving patients harboring early stage disease and borderline hepatic function. The other treatment strategies include locoregional therapies, radiation, and systemic therapy used alone or in combination with other treatment modalities. Recent advances in locoregional therapies, radiation, and systemic therapies have provided better therapeutic options with curative intent potential for some locoregional therapies. Further refinements in combination therapies such as algorithms consisting of locoregional therapies and systemic or radiation therapies are likely to add additional options and improve survival. CONCLUSIONS: The management of HCC has witnessed significant strides with advances in existing options and introduction of several new treatment modalities of various combinations. Further refinements in these treatment options combined with enrollment in clinical trials are essential to improve the management and outcomes of patients with HCC.

Occult primary, version 3.2014.

The NCCN Guidelines for Occult Primary tumors provide recommendations for the evaluation, workup, management, and follow-up of patients with occult primary tumors (cancers of unknown primary). These NCCN Guidelines Insights summarize major discussion points of the 2014 NCCN Occult Primary panel meeting. The panel discussed gene expression profiling (GEP) for the identification of the tissue of origin and concluded that, although GEP has a diagnostic benefit, a clinical benefit has not been demonstrated. The panel recommends against GEP as standard management, although 20% of the panel believes the diagnostic benefit of GEP warrants its routine use. In addition, the panel discussed testing for actionable mutations (eg, ALK) to help guide choice of therapy, but declined to add this recommendation.

Current concepts in the management of small cell lung cancer.

Small cell lung cancer (SCLC) has a clinical course that is distinct from its more common counterpart non-small cell lung cancer. SCLC continues to be a major clinical problem, with an aggressive clinical course and short disease-free duration after initial therapy. Current optimal treatment consists of chemotherapy with platinum-etoposide, given concurrently with thoracic irradiation in patients with limited stage disease and chemotherapy alone in those with extensive stage. Prophylactic cranial irradiation (PCI) is recommended for patients who have responded to initial therapy, as it not only decreases the risk of brain metastases and but also improves overall survival. Newer targeted agents are currently being evaluated for this disease.

Positive margins matter regardless of subsequent resection findings.

OBJECTIVES: In the resection of oral cavity squamous cell carcinoma (OCSCC), an intraoperative positive surgical margin (SM) communicated to the head and neck surgeon necessitates further resection of the area of identified involvement to achieve a final negative SM. The prognostic implication of initial positive SM when the final SM is negative is understudied. MATERIALS AND METHODS: We retrospectively reviewed 249 patients with non-metastatic (stage I-IVB) OCSCC who underwent a resection from 2010 to 2019 to assess the prognostic impact of an initial positive SM. Chi-squared analysis was used to evaluate the association between an initial positive SM and clinicopathologic parameters. A Kaplan-Meier analysis was performed to estimate patient outcomes with Cox regression analysis used to determine absolute hazards. RESULTS: At a median follow-up of 28.4 months, the 2-year freedom from local recurrence (FFLR), disease-free survival (DFS), and overall survival (OS) rates were 82.1%, 63.5%, and 78.5%, respectively. Fifty patients (20.1%) had an initial positive SM which was revised to a negative SM on frozen and permanent sections by resecting further tissue while 12 patients (4.8%) had a final positive SM. An initial positive SM was independently associated with a worse FFLR (HR: 2.696, p = 0.004), DFS (HR: 1.57, p = 0.044), and OS (HR: 1.72, p = 0.029). CONCLUSION: An initial positive SM is independently associated with worse disease control and patient survival. A positive SM may be a surrogate for diffusely infiltrative disease as further malignancy identified on the re-resection specimen was associated with worse outcomes.

NCCN Clinical Practice Guidelines Occult primary.

Occult primary tumors, or cancers of unknown primary (CUPs), are defined as histologically proven metastatic malignant tumors whose primary site cannot be identified during pretreatment evaluation. They have a wide variety of clinical presentations and a poor prognosis in most patients. Patients with occult primary tumors often present with general complaints, such as anorexia and weight loss. Clinical absence of primary tumor, early dissemination, aggressiveness, and unpredictability of metastatic pattern are characteristic of these tumors. Life expectancy is very short, with a median survival of 6 to 9 months. In most patients, occult primary tumors are refractory to systemic treatments, and chemotherapy is only palliative and does not significantly improve long-term survival. However, certain clinical presentations of these tumors are associated with a better prognosis. Special pathologic studies can identify subsets of patients with tumor types that are more responsive to chemotherapy. Treatment options should be individualized for this selected group of patients to achieve improved response and survival rates.

Systemic inflammation is associated with inferior disease control and survival in stage III non-small cell lung cancer.

BACKGROUND: The systemic immune-inflammation index (SII) correlates with patient survival in various types of solid malignancies, including non-small cell lung cancer (NSCLC). However, limited information is available on the prognostic implication and disease-specific survival of SII in patients undergoing definitive chemoradiation therapy (CRT) for stage III NSCLC. METHODS: We retrospectively reviewed 125 patients who underwent curative intent CRT for stage III NSCLC with sufficient laboratory assessment from 2010-2019. SII was calculated at the time of diagnosis as platelet count × neutrophil count/lymphocyte count. Chi-squared analysis was used to compare categorical variables. A Kaplan-Meier analysis was performed to estimate progression-free survival (PFS), disease specific survival (DSS), and overall survival (OS) rates, with Cox regression used to determine absolute hazards. RESULTS: At a median follow-up of 19.7 months, 5-year OS, DSS, and PFS rates were 22.6%, 30.9%, and 13.4%, respectively. A low SII (<1,266) at diagnosis was independently associated with an improved OS (HR: 0.399, 95%, CI: 0.247-0.644, P<0.001), DSS (HR: 0.383, 95%, CI: 0.228-0.645, P<0.001), and PFS (HR: 0.616, 95%, CI: 0.407-0.932, P=0.022). We did not detect an association between SII and freedom from recurrence (FFR), freedom from locoregional recurrence (FFLRR), or freedom from distant recurrence (FFDR). NSAID (1,483.4 vs. 2,302.9, P=0.038) and statin usage (1,443.9 vs. 2,201.7, P=0.046) were associated with a lower SII while COPD exacerbations (2,699.7 vs. 1,573.7, P=0.032) and antibiotic prescriptions (2,384.6 vs. 1,347.9, P=0.009) were associated with an elevated SII. These factors were not independently associated with improved survival outcomes. CONCLUSIONS: Low SII scores were independently associated with improved OS, DSS, and PFS rates in patients with stage III NSCLC undergoing definitive CRT. NSAIDs and statin usage may be associated with lower SII at diagnosis of NSCLC. This study suggests that SII may be an effective prognostic indicator of patient mortality. Further investigation of the therapeutic potential of these agents in patients with an elevated SII in this setting may be warranted.

Correlation of dosimetric factors with the development of symptomatic radiation pneumonitis in stereotactic body radiotherapy.

BACKGROUND: The development of radiation pneumonitis (RP) after Stereotactic Body Radiotherapy (SBRT) is known to be associated with many different factors, although historical analyses of RP have commonly utilized heterogeneous fractionation schemes and methods of reporting. This study aims to correlate dosimetric values and their association with the development of Symptomatic RP according to recent reporting standards as recommended by the American Association of Physicists in Medicine. METHODS: We performed a single-institution retrospective review for patients who received SBRT to the lung from 2010 to 2017. Inclusion criteria required near-homogeneous tumoricidal (α/ß = 10 Gy) biological effective dose (BED10) of 100-105 Gy (e.g., 50/5, 48/4, 60/8), one or two synchronously treated lesions, and at least 6 months of follow up or documented evidence of pneumonitis. Symptomatic RP was determined clinically by treating radiation oncologists, requiring radiographic evidence and the administration of steroids. Dosimetric parameters and patient factors were recorded. Lung volumes subtracted gross tumor volume(s). Wilcoxon Rank Sums tests were used for nonparametric comparison of dosimetric data between patients with and without RP; p-values were Bonferroni adjusted when applicable. Logistic regressions were conducted to predict probabilities of symptomatic RP using univariable models for each radiation dosimetric parameter. RESULTS: The final cohort included 103 treated lesions in 93 patients, eight of whom developed symptomatic RP (n = 8; 8.6%). The use of total mean lung dose (MLD) > 6 Gy alone captured five of the eight patients who developed symptomatic RP, while V20 > 10% captured two patients, both of whom demonstrated a MLD > 6 Gy. The remaining three patients who developed symptomatic RP without exceeding either metric were noted to have imaging evidence of moderate interstitial lung disease, inflammation of the lungs from recent concurrent chemoradiation therapy to the contralateral lung, or unique peri-tumoral inflammatory appearance at baseline before treatment. CONCLUSIONS: This study is the largest dosimetric analysis of symptomatic RP in the literature, of which we are aware, that utilizes near-homogenous tumoricidal BED fractionation schemes. Mean lung dose and V20 are the most consistently reported of the various dosimetric parameters associated with symptomatic RP. MLD should be considered alongside V20 in the treatment planning process. TRIAL REGISTRATION: Retrospectively registered on IRB 398-17-EP.

Adjuvant chemotherapy following SBRT for early stage non-small cell lung cancer (NSCLC) in older patients.

Adjuvant chemotherapy improves overall survival (OS) following stereotactic body radiotherapy (SBRT) in patients with early stage non-small cell lung cancer and tumors ≥four cm. Here, we aim to evaluate its role following SBRT in older patients. Patients >70 years diagnosed with clinical stages I-II NSCLC, (N0 disease), who received SBRT, were identified using the National Cancer Database (n = 7042). The Kaplan-Meier method was used to estimate OS, and the log-rank test was used to compare distributions by treatment strategy overall and within clinical stages I and II. There were 3533 female patients (50.2%), and 6074 (86.3%) had stage I disease. Among stage I patients, 643 (10.6%) received adjuvant chemotherapy, compared to 372 stage II patients (38.4%). Median OS was better with SBRT in patients with stage I disease (25.4 vs. 20.3 months; p < .001); while patients with stage II NSCLC had better OS with SBRT + chemotherapy (20.2 vs. 14.2 months; p < .001). On multivariate analysis, patients with stage I NSCLC who received SBRT alone had better overall survival (HR: 0.79; 95% CI, 0.73, 0.87). SBRT alone was associated with an increased risk of death in patients with stage II disease (HR: 1.34; 95% CI, 1.15, 1.55). Patients with tumors ≥4 cm had better OS with SBRT + chemotherapy (18.5 vs. 15.5 months; p = .003), while patients with tumors <4 cm did better with SBRT (median OS of 24.1 vs. 20.3 months; p < .001). In >70 years old patients with tumors ≥4 cm, adjuvant chemotherapy following SBRT was associated with improved OS.

A 47-year-old woman with nuclear protein in testis midline carcinoma masquerading as a sinus infection: a case report and review of the literature.

BACKGROUND: Nuclear protein in testis midline carcinoma is a rare, highly metastatic undifferentiated carcinoma that typically arises in midline structures and is characterized by having a fusion involving the nuclear protein in testis, NUT, gene. Nuclear protein in testis midline carcinoma has been identified in patients of all ages and is often initially misdiagnosed due to the rapid timeline of symptom onset. CASE PRESENTATION: Here we report the case of a 47-year-old Caucasian woman with a nuclear protein in testis midline carcinoma that was initially mistaken for a sinus infection. After symptom progression while on an aggressive antibiotic regimen, the source of her symptoms was correctly identified as a sella mass. Comprehensive analysis of the tumor was performed, and standard cytogenetic analysis identified a translocation of 15q and 19p. Further testing identified a NUT-BRD4 fusion and confirmed the diagnosis of nuclear protein in testis midline carcinoma. Despite definitive diagnosis and surgical, radiation, and, ultimately, systemic therapy, she progressed rapidly, developing widespread metastases, and ultimately died from the disease 5 months after diagnosis. CONCLUSIONS: Based on this and other previous reports, aggressive therapy should be initiated once nuclear protein in testis midline carcinoma is diagnosed and close surveillance employed in an attempt to prevent and/or recognize metastases as early as possible. Aggressive therapy has shown little efficacy such that the average overall survival for patients with nuclear protein in testis midline carcinoma is very short, often less than 6 months. Thus, early enrollment into clinical trials testing novel therapies for the treatment of nuclear protein in testis midline carcinoma should be considered. Finally, additional reports of nuclear protein in testis midline carcinoma are needed to fully characterize this rare and highly aggressive cancer.

Adjuvant Systemic Therapy in Patients With Early-Stage NSCLC Treated With Stereotactic Body Radiation Therapy.

INTRODUCTION: Stereotactic body radiation therapy (SBRT) is commonly used to treat nonsurgical patients with early-stage NSCLC. There are no prospective data on the role of adjuvant chemotherapy in this setting. METHODS: Patients (≥18 years) diagnosed with clinical stages I-II NSCLC from 2004 to 2013 were identified using the National Cancer Database (n = 11,836). The Kaplan-Meier method was used to estimate overall survival (OS) distributions and the log-rank test was used to compare distributions by treatment strategy. Clinical stages I and II were subdivided according to the TNM staging and log-rank tests was used to compare survival distributions by treatment strategy within each subgroup. RESULTS: In patients with T2bN0, median OS in the SBRT alone and SBRT plus adjuvant chemotherapy groups were 16.5 months versus 24.2 months, respectively (95% confidence interval [CI]: 14.1-20.1 months and 18.8-33.3 months, respectively; p < .001); whereas for T3N0, median OS times were 13 months and 20.1 months, respectively (95% CI: 11.7-14.5 mohths and 17.7-21.9 months, respectively; p < .001). For tumors 4 cm or larger and node-negative disease, median OS was 15.9 months in the SBRT-alone group, and 19 months in the SBRT-plus-chemotherapy group (95% CI: 15.1-16.8 months and 17.9-20.8 months, respectively; p < .001). For patients with tumors less than 4 cm and node-negative disease, the median OS was 28.5 months in the SBRT-alone group and 24.3 months in the SBRT-plus-chemotherapy group (95% CI: 27.4-29.4 months and 22.8-26.1 months, respectively; p < .001). CONCLUSIONS: SBRT followed by adjuvant chemotherapy was associated with improved OS in comparison with SBRT alone in patients with T greater than or equal to 4 cm, similar to that seen after surgery.

National Practice Patterns for Clinical T1N0 Nasopharyngeal Cancer in the Elderly: A National Cancer Data Base Analysis.

BACKGROUND: The standard of care for T1N0 nasopharyngeal cancer (NPC) is definitive radiation therapy (RT). However, practice patterns in the elderly may not necessarily follow national guidelines. Herein, we investigated national practice patterns for T1N0 NPC. MATERIALS AND METHODS: The National Cancer Data Base (NCDB) was queried for clinical T1N0 primary NPC cases (2004-2013) in patients ≥70 years old. Patient, tumor, and treatment parameters were extracted. Kaplan-Meier analysis was used to compare overall survival (OS) between patients receiving RT versus those under observation. Logistic regression was used to examine variables associated with receipt of RT. Cox proportional hazards modeling determined variables associated with OS. Landmark analysis of patients surviving 1 year or more was performed to assess survival differences between groups. RESULTS: In total, data of 147 patients were analyzed. RT was delivered to 89 patients (61%), whereas 58 (39%) patients underwent observation. On multivariable analysis, older patients were less likely to receive RT (p=0.003), but there were no differences between groups in terms of Charlson-Deyo comorbidity index. Median and 5-year OS in patients receiving RT versus those under observation were 71 and 33 months, and 59% and 48% (p=0.011), respectively. For patients surviving 1 year or more (n=96), there was a strong trend showing that receipt of RT was associated with better median and 5-year OS. CONCLUSION: This National Data Base analysis shows that observation is relatively common for T1N0 NPC in the elderly, but is associated with poorer survival.

The features and prognostic impact of extracranial metastases in patients with epidermal growth factor receptor-mutant lung adenocarcinoma.

AIMS: We have previously demonstrated that brain metastases were more common among patients with epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma. However, the association of EGFR mutation and extracranial metastases (ECM) remains inconclusive. In this study, we explored the potential association between EGFR mutation and the risk of ECM. PATIENTS AND METHODS: Between March 2007 and December 2014, 234 patients were analyzed for the potential association between EGFR mutation and ECM. STATISTICAL ANALYSIS USED: Multivariate Cox regression analysis. RESULTS: There were no associations between the EGFR mutation and metastases in different organs, except for bone. The frequency of EGFR mutation was statistically higher for patients with bone metastases (BMs) at the initial diagnosis (P = 0.039) and at the last follow-up (P = 0.018) as compared to those with wild-type EGFR. In multivariate logistic regression analysis, EGFR mutation significantly increased the risk of BM at the initial diagnosis (P = 0.036). Among those patients without BM at initial diagnosis, 1- and 2-year accumulative rates of subsequent BM were significantly higher in patients with EGFR-mutant disease (P = 0.026). EGFR mutation was an independent risk factor for subsequent BM (P < 0.05). In addition, patients with finial BM and EGFR-mutant disease had longer median survival as compared to those with wild-type disease (P = 0.020). CONCLUSIONS: Only BM in patients with ECM was significantly correlated with EGFR mutation during their disease course. EGFR mutation was an independent predictive and prognostic factor for developing BM, which was also a positive predictive factor for overall survival of patients who developed BM.

Phase 1b/2a Trial of the Superoxide Dismutase Mimetic GC4419 to Reduce Chemoradiotherapy-Induced Oral Mucositis in Patients With Oral Cavity or Oropharyngeal Carcinoma.

PURPOSE: To assess the safety of the superoxide dismutase mimetic GC4419 in combination with radiation and concurrent cisplatin for patients with oral cavity or oropharyngeal cancer (OCC) and to assess the potential of GC4419 to reduce severe oral mucositis (OM). PATIENTS AND METHODS: Patients with locally advanced OCC treated with definitive or postoperative intensity modulated radiation therapy (IMRT) plus cisplatin received GC4419 by 60-minute intravenous infusion, ending <60 minutes before IMRT, Monday through Friday for 3 to 7 weeks, in a dose and duration escalation study. Oral mucositis was assessed twice weekly during and weekly after IMRT. RESULTS: A total of 46 patients received GC4419 in 11 separate dosing and duration cohorts: dose escalation occurred in 5 cohorts receiving 15 to 112 mg/d over 3 weeks (n=20), duration escalation in 3 cohorts receiving 112 mg/d over 4 to 6 weeks (n=12), and then 3 additional cohorts receiving 30 or 90 mg/d over 6 to 7 weeks (n=14). A maximum tolerated dose was not reached. One dose-limiting toxicity (grade 3 gastroenteritis and vomiting with hyponatremia) occurred in each of 2 separate cohorts at 112 mg. Nausea/vomiting and facial paresthesia during infusion seemed to be GC4419 dose-related. Severe OM occurred through 60 Gy in 4 of 14 patients (29%) dosed for 6 to 7 weeks, with median duration of only 2.5 days. CONCLUSIONS: The safety of GC4419 concurrently with chemoradiation for OCC was acceptable. Toxicities included nausea/vomiting and paresthesia. Doses of 30 and 90 mg/d administered for 7 weeks were selected for further study. In an exploratory analysis, severe OM seemed less frequent and briefer than expected.