Anand K. Sharma

Cisplatin and Radiotherapy With or Without Erlotinib in Locally Advanced Squamous Cell Carcinoma of the Head and Neck: A Randomized Phase II Trial

PURPOSE The combination of cisplatin and radiotherapy is a standard treatment for patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). Cetuximab-radiotherapy is superior to radiotherapy alone in this population, validating epidermal growth factor receptor (EGFR) as a target. Erlotinib is a small-molecule inhibitor of EGFR. Adding EGFR inhibition to standard cisplatin-radiotherapy may improve efficacy. PATIENTS AND METHODS Patients with locally advanced SCCHN were randomly assigned to receive cisplatin 100 mg/m(2) on days 1, 22, and 43 combined with 70 Gy of radiotherapy (arm A) or the same chemoradiotherapy with erlotinib 150 mg per day, starting 1 week before radiotherapy and continued to its completion (arm B). The primary end point was complete response rate (CRR), evaluated by central review. The secondary end point was progression-free survival (PFS). Available tumors were tested for p16 and EGFR by fluorescent in situ hybridization. RESULTS Between December 2006 and October 2011, 204 patients were randomly assigned. Arms were well balanced for all patient characteristics including p16, with the exception of more women on arm A. Patients on arm B had more rash, but treatment arms did not differ regarding rates of other grade 3 or 4 toxicities. Arm A had a CRR of 40% and arm B had a CRR of 52% (P = .08) when evaluated by central review. With a median follow-up time of 26 months and 54 progression events, there was no difference in PFS (hazard ratio, 0.9; P = .71). CONCLUSION Erlotinib did not increase the toxicity of cisplatin and radiotherapy in patients with locally advanced HNSCC but failed to significantly increase CRR or PFS.

Effect of body mass index on chemoradiation outcomes in head and neck cancer.

Objective: To investigate the association between initial body mass index (BMI) and chemoradiation therapy (CRT) outcomes in head and neck cancer patients.

A comparison of outcomes using intensity-modulated radiation therapy and 3-dimensional conformal radiation therapy in treatment of oropharyngeal cancer.

IMPORTANCE Approximately 50% of head and neck cancer survivors experience dysphagia and related morbidity. Intensity-modulated radiation therapy (IMRT) is increasingly used to treat oropharyngeal cancers with excellent oncologic outcomes, but few studies have compared it with conventional 3-dimensional conformal radiation therapy (3D-CRT) to determine whether it can decrease treatment-related toxic and adverse effects. OBJECTIVE To determine whether IMRT improves percutaneous endoscopic gastrostomy (PEG) tube and treatment-related toxicity outcomes compared with 3D-CRT in patients with oropharyngeal squamous cell carcinoma. DESIGN, SETTING, AND PARTICIPANTS Retrospective review of 159 patients with oropharyngeal primary tumors with no history of chemotherapy, radiation therapy, or surgery of the head and neck who underwent definitive treatment with radiotherapy for oropharyngeal squamous cell carcinoma at the Hollings Cancer Center outpatient clinic, Medical University of South Carolina, from 2000 to 2009. INTERVENTION Doses of 70 Gy in 35 daily fractions of radiotherapy delivered via IMRT or 3D-CRT. MAIN OUTCOMES AND MEASURES Primary end points included PEG tube dependence 1 year after radiotherapy start, weight loss during treatment, and change in Eastern Cooperative Oncology Group performance status. Secondary end points included overall and disease-free survival, disease recurrence, and toxic effect profiles. RESULTS The IMRT group (n = 103) had a significantly lower rate of PEG tube dependence 1 year after treatment initiation than the 3D-CRT group (n = 56) for all patients (P = .02) and for those with advanced T stage (P = .01) and a shorter time to PEG tube removal (P < .001). Acute grade 3 or greater toxic effects to skin and mucous membranes occurred less frequently in the IMRT group (P = .02 and P < .001, respectively). The 2 groups did not differ significantly in weight loss, treatment failure (hazard ratio, 0.82 [95% CI, 0.47-1.41]), overall survival (P = .45), or disease-free survival (P = .26). CONCLUSIONS AND RELEVANCE The use of IMRT significantly improves PEG tube and toxicity-related outcomes compared with 3D-CRT in the treatment of oropharyngeal primary cancers. Given the association between mucosal toxic effects, PEG tube dependence, and dysphagia, these findings may be an indication of improved swallowing outcomes with IMRT.

STAT3 Regulation by S-Nitrosylation: Implication for Inflammatory Disease

AIMS S-nitrosylation and S-glutathionylation, redox-based modifications of protein thiols, are recently emerging as important signaling mechanisms. In this study, we assessed S-nitrosylation-based regulation of Janus-activated kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway that plays critical roles in immune/inflammatory responses and tumorigenesis. RESULTS Our studies show that STAT3 in stimulated microglia underwent two distinct redox-dependent modifications, S-nitrosylation and S-glutathionylation. STAT3 S-nitrosylation was associated with inducible nitric oxide synthase (iNOS)-produced nitric oxide (NO) and S-nitrosoglutathione (GSNO), whereas S-glutathionylation of STAT3 was associated with cellular oxidative stress. NO produced by iNOS or treatment of microglia with exogenous GSNO inhibited STAT3 activation via inhibiting STAT3 phosphorylation (Tyr(705)). Consequently, the interleukin-6 (IL-6)-induced microglial proliferation and associated gene expressions were also reduced. In cell-free kinase assay using purified JAK2 and STAT3, STAT3 phosphorylation was inhibited by its selective preincubation with GSNO, but not by preincubation of JAK2 with GSNO, indicating that GSNO-mediated mechanisms inhibit STAT3 phosphorylation through S-nitrosylation of STAT3 rather than JAK2. In this study, we identified that Cys(259) was the target Cys residue of GSNO-mediated S-nitrosylation of STAT3. The replacement of Cys(259) residue with Ala abolished the inhibitory role of GSNO in IL-6-induced STAT3 phosphorylation and transactivation, suggesting the role of Cys(259) S-nitrosylation in STAT3 phosphorylation. INNOVATION Microglial proliferation is regulated by NO via S-nitrosylation of STAT3 (Cys(259)) and inhibition of STAT3 (Tyr(705)) phosphorylation. CONCLUSION Our results indicate the regulation of STAT3 by NO-based post-translational modification (S-nitrosylation). These findings have important implications for the development of new therapeutics targeting STAT3 for treating diseases associated with inflammatory/immune responses and abnormal cell proliferation, including cancer.

Results of a phase II trial of gemcitabine plus doxorubicin in patients with recurrent head and neck cancers: Serum C 18-ceramide as a novel biomarker for monitoring response

Purpose: Here we report a phase II clinical trial, which was designed to test a novel hypothesis that treatment with gemcitabine (GEM)/doxorubicin (DOX) would be efficacious via reconstitution of C18-ceramide signaling in head and neck squamous cell carcinoma (HNSCC) patients for whom first-line platinum-based therapy failed. Experimental Design: Patients received GEM (1,000 mg/m2) and DOX (25 mg/m2) on days 1 and 8, every 21 days, until disease progression. After completion of 2 treatment cycles, patients were assessed radiographically, and serum samples were taken for sphingolipid measurements. Results: We enrolled 18 patients in the trial, who were evaluable for toxicity, and 17 for response. The most common toxicity was neutropenia, observed in 9 of 18 patients, and there were no major nonhematologic toxicities. Of the 17 patients, 5 patients had progressive disease (PD), 1 had complete response (CR), 3 exhibited partial response (PR), and 8 had stable disease (SD). The median progression-free survival was 1.6 months (95% CI: 1.4–4.2) with a median survival of 5.6 months (95% CI: 3.8–18.2). Remarkably, serum sphingolipid analysis revealed significant differences in patterns of C18-ceramide elevation in patients with CR/PR/SD in comparison with patients with PD, indicating the reconstitution of tumor suppressor ceramide generation by GEM/DOX treatment. Conclusions: Our data suggest that the GEM/DOX combination could represent an effective treatment for some patients with recurrent or metastatic HNSCC, and that serum C18-ceramide elevation might be a novel serum biomarker of chemotherapy response. Clin Cancer Res; 17(18); 6097–105. ©2011 AACR.

Role of mitomycin in upper digestive tract stricture

Mitomycin C is an anti‐fibroblast chemotherapeutic agent that has demonstrated promise in the treatment of head and neck cancer‐related cervical stenosis. The present study investigates whether the application of mitomycin C at the time of dilation is both safe and effective in the treatment of head and neck cancer‐related upper digestive tract stricture.

TOXICITY AND SURVIVAL OUTCOMES OF HYPERFRACTIONATED SPLIT-COURSE REIRRADIATION AND DAILY CONCURRENT CHEMOTHERAPY IN LOCOREGIONALLY RECURRENT, PREVIOUSLY IRRADIATED HEAD AND NECK CANCERS

Reirradiation of locoregionally recurrent, previously irradiated head/neck cancer may be considered in situations of unresectability, medical inoperability, or adverse pathologic features found at salvage resection.

Proximal Esophageal Stenosis in Head and Neck Cancer Patients after Total Laryngectomy and Radiation

Background: There has been an increasing focus on late functional effects of head and neck cancer (HNC) treatment. This study was undertaken to evaluate the incidence of late proximal esophageal stricture in patients undergoing total laryngectomy (TL) and radiation therapy (RT). Material and Methods: An institutional retrospective review of HNC patients treated between 1995 and 2003 with TL and RT was undertaken. Thirty-three patients with stage II–IV disease were included; 25 patients had TL and postoperative RT (group 1), while 8 patients had definitive RT with salvage laryngectomy (group 2). Results: The median follow-up was 28 months. At the last follow-up, 25 patients (76%) were alive and disease free. Four had died and 3 developed distant metastasis. Dysphagia or stenosis developed in 40% in group 1 and 75% in group 2 patients. The median time to dysphagia was 5.5 months for all patients. Conclusions: The incidence of esophageal stenosis was 33% for all patients. Contributing factors for esophageal stenosis after TL and RT include continued alcohol and tobacco use, the dose-volume relationship of the RT and normal tissue damage from the tumor and the treatment.

Cisplatin/Irinotecan Versus Carboplatin/Paclitaxel as Definitive Chemoradiotherapy for Locoregionally Advanced Esophageal Cancer

Objective:To compare toxicities, disease control, and survival outcomes for patients treated with either cisplatin/irinotecan versus carboplatin/paclitaxel concurrent chemoradiotherapy for locally advanced esophageal cancer. Methods:Single-institution retrospective comparison between treatment groups: the cisplatin/irinotecan group was treated with 2 cycles of induction chemotherapy followed by concurrent chemoradiotherapy, whereas the carboplatin/paclitaxel group began with chemoradiotherapy followed by 2 additional cycles of chemotherapy. Acute toxicities, response rates, disease control, survival outcomes, and patterns of failure were compared between the groups. Results:Between January 2000 and December 2007, 57 patients were identified for inclusion in the present study (38 cisplatin/irinotecan and 19 carboplatin/paclitaxel). Groups were well-balanced by clinical-, pathologic-, staging-, and treatment-related factors. Thirty-five patients (92%) in the cisplatin/irinotecan group and 18 patients (95%) in the carboplatin/paclitaxel group completed the concurrent phase of chemoradiotherapy. There were no significant differences in hematologic or nonhematologic toxicities between the groups. At a median survivor follow-up of 37.6 months (range: 7.3–59.3 months) for the entire population, 22 patients were alive (16 without evidence of disease). The 3-year overall survival estimates was 19.7% for the cisplatin/irinotecan group versus 56.1% for the carboplatin/paclitaxel group (P = 0.022). Estimated 3-year cancer-specific survivals were 24.6% for the cisplatin/irinotecan group versus 59.3% for the carboplatin/paclitaxel group (P = 0.033). Conclusion:Concurrent chemoradiotherapy with carboplatin/paclitaxel is well-tolerated and provided superior overall and disease-specific survival compared with cisplatin/irinotecan chemoradiotherapy in the present study population. Further investigation is warranted.

Cervical esophageal cancer: a population-based study.

The purpose of this study was to present our analysis of outcomes, prognostic factors, and treatment for cervical esophageal carcinoma using the Surveillance, Epidemiology, and End Results (SEER) database.