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1 Department of Otolaryngology, University of Michigan, 1904TC/1500 E. Medical Center Drive, Ann Arbor, Michigan 48109 2 The Johns Hopkins Oncology Center, Medical Oncology, Baltimore, Maryland 3 M.D. Anderson Cancer Center, Houston, Texas 4 University of Chicago Medical Center, Chicago, Illinois 5 National Institute of Health, National Cancer Institute, Rockville, Maryland 6 Memorial Sloan Kettering Cancer Center, New York, New York 7 Centre Oscar Lambret, Lille, France 8 American College of Radiology, Philadelphia, Pennsylvania

The management of advanced cancers of the larynx and hypopharynx has become increasingly complex as different treatment modalities including surgery, radiation, and chemotherapy have been combined with the goal of improving local disease control and disease-specific survival. A union of 17 comprehensive cancer centers in the United States, the National Comprehensive Cancer Network (NCCN), was formed in 1995 to promote state-of-the-art cancer care. To achieve this goal, multidisciplinary panels of experts from member institutions have created disease-specific practice guidelines for the evaluation and treatment of cancer patients, including head and neck cancers. 47 These guidelines, intended to help clarify and standardize care of patients with head and neck cancers, were based, where possible, on the findings of multicenter randomized, controlled trials. Many decision points in patient management have not been evaluated to date in such trials, however, and therefore data from phase II trials and case series also influenced the treatment guidelines. Although detailed analysis of surgical methods and radiation techniques is beyond the scope of this article, the evolving laryngeal preservation strategies for patients with advanced, resectable hypopharyngeal or laryngeal (including supraglottic and glottic) cancers are reviewed, using the relevant sections of the NCCN practice guidelines as a framework for discussion. Until recently in the United States, the conventional therapy given patients with locally advanced laryngeal (T3 or T4) or hypopharyngeal (T2, T3, or T4) cancers has been total laryngectomy with neck dissection followed by postoperative radiation therapy. 54 Unfortunately, patients treated with laryngectomy suffer a complete loss of voice and sometimes impairment of swallowing function, leading to decreased overall quality of life in many aspects, including nutrition, social functioning, and personal hygiene. These problems motivated the development of laryngeal-preservation approaches. Organ-preservation approaches have included induction chemotherapy followed in responding patients by radiation and primary radiation therapy alone with surgery reserved for treatment failures. After resectable, advanced laryngeal or hypopharyngeal cancer has been diagnosed, patients and their treating physicians must choose among three primary treatment modalities that are currently available. The NCCN practice guidelines present these three options as surgery, induction chemotherapy, or definitive radiation therapy (Figs. 1, 2, and 3). Many factors contribute to the decision-making process, including patient preference, performance status, tumor location and stage, and the treatment practices of the patient's physicians. Recently, the Department of Veterans Affairs (VA) and the European Organization for Research and Treatment of Cancer (EORTC) reported two landmark randomized, controlled trials in patients with advanced, resectable laryngeal or hypopharyngeal cancer. These two large trials compared primary surgical management with a laryngeal preservation approach of induction chemotherapy followed by definitive radiation. The trials demonstrated that overall survival was comparable in the two treatment groups. 16,37 Moreover, laryngeal preservation was enjoyed by one half to two thirds of the surviving patients in the chemotherapy plus radiation therapy group but by none of the primary laryngectomy patients at 5 years. Given that data from these two important trials served as a foundation for the critical decision point of choosing primary therapy shown in the NCCN guidelines, an understanding of the treatment algorithms requires careful consideration of the findings in these two trials.

To the Editor: In the report by Posner et al. (Oct. 25 issue)1 on the treatment of head and neck cancer, we question the authors’ implication that the 91-11 trial of the Radiation Therapy Oncology Group and Head and Neck Intergroup showed that cisplatin–fluorouracil (PF) induction followed by radiotherapy for laryngeal preservation is equivalent to or better than concomitant cisplatin and radiotherapy. The 91-11 trial was not designed to show equivalence.2 Both combinations resulted in better laryngectomy-free survival than did radiotherapy alone, but the composite end point does not account for a preserved larynx in patients whose death was not due to laryngeal cancer (over half the deaths). Rates of laryngeal preservation and locoregional control provide a much better assessment, and for both end points, the rates were significantly better with concomitant cisplatin and radiotherapy than with radiotherapy alone or PF induction followed by radiotherapy, whereas overall survival did not differ significantly.2,3 The results of the 91-11 trial do not justify the use of docetaxel–cisplatin–fluorouracil (TPF) sequential therapy for T3 and low-volume T4 laryngeal cancer. Arlene Forastiere, M.D.

Background Local-regional recurrence of disease remains the major obstacle to cure of advanced head and neck cancers. Methods This investigation reviewed data derived from Radiation Therapy Oncology Group (RTOG) protocols #85-03 and #88-24 to identify characteristics of tumors that predicted local-regional recurrence of disease following surgery and postoperative radiotherapy (RT). Results The presence of tumor in two or more lymph nodes, and/or extracapsular spread of nodal disease, and/or microscopic-size tumor involvement of the surgical margins of resection imparts a high risk of local-regional (L-R) relapse. Our data also support the hypothesis that, following surgery, the concurrent addition of chemotherapy (CT) to RT may increase the likelihood of L-R control of disease for patients who have these high-risk characteristics. Conclusion A prospective trial of surgery followed by concurrent RT and CT is warranted for patients who have high-risk characteristics found at surgery. © 1998 John Wiley & Sons, Inc. Head Neck 20: 588–594, 1998.

Background For patients with squamous cell carcinoma of the head and neck (HNSCC), persistence of cervical adenopathy following organ-preservation therapy is a strong predictor of locoregional failure. Squamous cell granulomas of the neck may represent a regressed state of metastatic HNSCC; however, relevant clinicopathologic features of this lesion including its morphologic characteristics, association with therapy, and relationship to disease progression are not well defined. Methods We reviewed 866 consecutive neck dissections performed at The Johns Hopkins Hospital from 1984 to 1996. A total of eight cases showing a foreign-body giant-cell reaction to keratin in the absence of viable tumor formed the basis of this study. Results All eight cases were from patients with stage III or IV HNSCC with concurrent neck masses. Patients were initially treated by chemotherapy (n = 1), radiotherapy (n = 1), or chemotherapy plus radiotherapy (n = 6); and all patients subsequently underwent neck dissection for persistence of their neck masses. Histologically, the neck lesions were characterized by a foreign-body giant-cell reaction to keratin and extensive scarring. None (0%) of the patients developed recurrent regional disease in the treated neck. Two (25%) of the patients had tumor recurrence at the primary site. Two (25%) of the patients developed widely metastatic disease. Conclusions These observations suggest that squamous cell granulomas represent histologic regression of metastatic squamous cell carcinoma in patients with HNSCC treated by chemotherapy and/or radiotherapy. Although persistent cervical adenopathy is an established risk factor for locoregional failure in this group of patients, squamous cell granulomas of the neck paradoxically may reflect enhanced regional tumor sensitivity to cytotoxic agents. © 1998 John Wiley & Sons, Inc. Head Neck20: 515–521, 1998.

BACKGROUND A number of single agents have been tested in patients with carcinoma of the head and neck receiving palliative treatment. In general, 15-30% of patients achieve a partial response lasting 3-4 months. Treatment has not been shown to alter survival rates. It is clear that new drugs with potentially greater activity need to be identified. For this purpose, the Eastern Cooperative Oncology Group conducted a Phase II evaluation of paclitaxel. METHODS Patients with recurrent, metastatic, or locally advanced, incurable squamous cell carcinoma of the head and neck were eligible. The dose and schedule tested was the maximum tolerable dose of 250 mg/m2 determined from Phase I trials using a 24-hour infusion schedule and granulocyte-colony stimulating factor support. Courses were given at 3-week intervals until progression of disease was documented. Dose modifications were specified for hematologic toxicity and for neurotoxicity. RESULTS Thirty-four patients were registered on study and 30 were eligible. Severe or life-threatening granulocytopenia was the most frequent toxicity observed, occurring in 91% of patients. Prior to response evaluation, one patient died of sepsis and one died of a myocardial infarct. Response was observed in 40% of eligible patients (4 complete and 8 partial responses). The median duration of response was 4.5 months (range, 2-20 months), with a median survival of 9.2 months and a 1-year survival rate of 33%. CONCLUSIONS These results indicate that paclitaxel is an active agent for the treatment of squamous cell carcinoma of the head and neck. Studies evaluating alternative infusion schedules and combination regimens currently are underway. Cancer 1998;82:2270-2274. © 1998 American Cancer Society.

PURPOSE The Southwest Oncology Group (SWOG) coordinated an Intergroup study with the participation of Radiation Therapy Oncology Group (RTOG), and Eastern Cooperative Oncology Group (ECOG). This randomized phase III trial compared chemoradiotherapy versus radiotherapy alone in patients with nasopharyngeal cancers. MATERIALS AND METHODS Radiotherapy was administered in both arms: 1.8- to 2.0-Gy/d fractions Monday to Friday for 35 to 39 fractions for a total dose of 70 Gy. The investigational arm received chemotherapy with cisplatin 100 mg/m2 on days 1, 22, and 43 during radiotherapy; postradiotherapy, chemotherapy with cisplatin 80 mg/m2 on day 1 and fluorouracil 1,000 mg/m2/d on days 1 to 4 was administered every 4 weeks for three courses. Patients were stratified by tumor stage, nodal stage, performance status, and histology. RESULTS Of 193 patients registered, 147 (69 radiotherapy and 78 chemoradiotherapy) were eligible for primary analysis for survival and toxicity. The median progression-free survival (PFS) time was 15 months for eligible patients on the radiotherapy arm and was not reached for the chemo-radiotherapy group. The 3-year PFS rate was 24% versus 69%, respectively (P < .001). The median survival time was 34 months for the radiotherapy group and not reached for the chemo-radiotherapy group, and the 3-year survival rate was 47% versus 78%, respectively (P = .005). One hundred eighty-five patients were included in a secondary analysis for survival. The 3-year survival rate for patients randomized to radiotherapy was 46%, and for the chemoradiotherapy group was 76% (P < .001). CONCLUSION We conclude that chemoradiotherapy is superior to radiotherapy alone for patients with advanced nasopharyngeal cancers with respect to PFS and overall survival.

Arlene A. Forastiere, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD Andy Trotti, Radiation Therapy Department, University of South Florida, Tampa, FL David G. Pfister, Head and Neck Medical Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY Jennifer R. Grandis, Department of Otolaryngology, School of Medicine, Univeristy of Pittsburgh, Pittsburgh, PA

Over the past decade and a half, several strategies have been developed to improve the survival of patients with esophageal cancer. Two strategies employ either neoadjuvant chemotherapy or chemoradiotherapy followed by surgery to improve local-regional control and decrease the incidence of distant metastases. A third strategy uses nonsurgical therapy as definitive treatment for patients without metastatic disease. Single-institution pilot trials and randomized comparative trials have been conducted evaluating each approach. The rationale for these trials, results, and current recommendations are presented.

To examine associations between quality of care, survival, and costs in elderly patients treated for laryngeal squamous cell cancer (SCCA).Retrospective analysis of Surveillance, Epidemiology, and End Results Medicare data.We evaluated 2,370 patients diagnosed with laryngeal SCCA from 2004 to 2007 using multivariate regression and survival analysis. Using quality indicators derived from guidelines for recommended care, summary measures of quality were calculated for diagnosis, initial treatment, surveillance, treatment of recurrence, end-of-life care, performance, and an overall summary measure of quality.High-quality care was associated with significant differences in survival for diagnosis [HR = 0.80, 95% CI (0.66-0.97)], initial treatment [HR = 0.75 (0.63-0.88)], surveillance [HR = 0.54 (0.44-0.66)], treatment of recurrence [HR = 1.54 (1.26-1.89)], end-of-life care [HR = 0.69 (0.52-0.92)], performance [HR = 0.41 (0.33-0.52)], and an overall summary measure of quality [HR = 0.66 (0.54-0.80)], which was significantly associated with lower mean incremental costs [-$24,958 (-$35,873 - -$14,042)]. There was a significant survival advantage for initial treatment with surgery and postoperative radiation [HR = 0.66 (0.53-0.82)] and high-volume surgical care [HR = 0.64 (0.43-0.96)] after controlling for all other variables, including quality of care.High-quality larynx cancer care in elderly patients was associated with improved survival and reduced costs; however, high-quality care for treatment of recurrence was associated with poorer survival. These data suggest that survival outcomes in elderly patients with laryngeal cancer are not entirely explained by differences in the receipt of quality care using existing treatment and performance quality indicators and also suggest a need to develop sensitive and valid quality indicators of larynx cancer care in this population.

OBJECTIVES/HYPOTHESIS To examine associations between treatment, survival, and costs in elderly patients with oropharyngeal squamous cell cancer (OPSCC). STUDY DESIGN Retrospective cross-sectional analysis of Surveillance, Epidemiology, and End Results-Medicare data. METHODS We evaluated 666 patients diagnosed with OPSCC from 2004 to 2007 using cross-tabulations, multivariate logistic and generalized linear regression modeling, and survival analysis. RESULTS The majority of patients were nonsmokers (79%), had advanced-stage disease (59%), and received chemoradiation (38%) or radiation (28%). Surgery with postoperative radiation (hazard ratio [HR]: 0.33 [95% CI: 0.20-0.53]) and chemoradiation (HR: 0.45 [95% CI: 0.29-0.71]) were associated with improved survival, whereas stage IV disease was associated with poorer survival (HR: 1.95 [95% CI: 1.13-3.38]). Additional cancer-directed treatment after primary treatment was more likely following chemoradiation (odds ratio [OR]: 3.44 [95% CI: 1.78-6.63]). Salvage surgery was performed in 25% of patients undergoing subsequent additional cancer-directed treatment, and was associated with high-volume hospitals (OR: 2.81 [95% CI: 1.07-7.74]). Additional radiation (HR: 0.47 [95% CI: 0.31-0.72]) and salvage surgery (HR: 0.61 [95% CI: 0.38-0.99]) were associated with improved overall survival when performed >6 months following initial treatment, whereas salvage neck dissection alone was not significantly associated with survival after controlling for time to salvage (HR: 0.38 [95% CI: 0.05-2.78]). Treatment and 5-year overall costs were highest for chemoradiation, surgery with postoperative radiation, and additional cancer-directed treatment. CONCLUSIONS Multimodality treatment in elderly OPSCC patients was associated with improved survival and increased costs. Chemoradiation was associated with an increased likelihood of additional cancer-directed treatment. Salvage surgery was centralized at high-volume hospitals, and was associated with improved survival when performed >6 months after last initial treatment date, but was performed in

to 0.86; P .001) was demonstrated for concomitant treatment. 3 Nooverallsurvivalbenefitwasidentifiedfromtheinductionchemotherapyschedules,althoughamarginalimprovementwasseenin those trials using the fluorouracil and cisplatin combination. Patterns of failure differed between the two treatment schedules. Induction chemotherapy significantly improved the rate of distant metastases (HR, 0.73; 95% CI, 0.61 to 0.88; P .001) but did not influence locoregional failure. The concomitant schedules markedly improved the locoregional control (HR, 0.74; 95% CI, 0.70 to 0.79; P .001) with a significant but less impressive improvement in distant control (HR, 0.88; 95% CI, 0.77 to 1.00; P .04). These reports solidified concomitant chemoradiotherapy as a treatment standard in the definitive management of locoregionally advanced HNSCC. Induction chemotherapy remained investigational except in the larynx preservation setting. Thisclearimpactondistantmetastasesfueledcontinuedinterest

Purpose We hypothesized that the addition of gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, to docetaxel would enhance therapeutic efficacy in squamous cell carcinoma of the head and neck (SCCHN). Patients and Methods Patients with recurrent or metastatic SCCHN with Eastern Cooperative Oncology Group (ECOG) performance status of 2, or patients with ECOG performance status of 0 to 2 but were previously treated with chemotherapy, were randomly assigned to receive weekly docetaxel plus either placebo (arm A) or gefitinib 250 mg/d, orally (arm B) until disease progression. At the time of progression, patients in the placebo arm could receive single-agent gefitinib. EGFR, c-MET, and KRAS mutations and polymorphisms in drug metabolizing enzymes and transporters were evaluated by pyrosequencing. Results Two hundred seventy patients were enrolled before the study was closed early at interim analysis (arm A, n = 136; arm B, n = 134). Median overall survival was 6.0 months in arm A versus 7.3 months in arm B (hazard ratio, 0.93; 95% CI, 0.72 to 1.21; P = .60). An unplanned subset analysis showed that gefitinib improved survival in patients younger than 65 years (median 7.6 v 5.2 months; P = .04). Also, there was a trend for improved survival in patients with c-MET wild-type (5.7 v 3.6 months; P = .09) regardless of treatment. Grade 3/4 toxicities were comparable between the two arms except that grade 3/4 diarrhea was more common with docetaxel/gefitinib. Of 18 eligible patients who received gefitinib after disease progression in arm A, one patient had a partial response. Conclusion The addition of gefitinib to docetaxel was well tolerated but did not improve outcomes in poor prognosis but otherwise unselected patients with SCCHN.

PURPOSE A phase I and pharmacologic study was performed to evaluate the feasibility of administering the topoisomerase I (topo I) inhibitor topotecan (TPT) in combination with cisplatin (CDDP) in minimally pretreated adults with solid tumors. The study was designed to evaluate the magnitude of the toxicologic and pharmacologic differences between the two sequences of drug administration. MATERIALS AND METHODS TPT was administered as a 30-minute infusion daily for 5 days and CDDP was given either before TPT on day 1 or after TPT on day 5. Each patient was treated with both schedules on an alternating basis every 3 weeks. Sequential dose escalation of TPT or CDDP resulted in three dosage permutation of TPT/CDDP (mg/m2): 0.75/50, 1/50, and 0.75/75. After the maximum-tolerated dose (MTD) level was achieved, the feasibility of using granulocyte colony-stimulating factor (G-CSF) to permit further dose escalation was studied. To examine the interaction of TPT and CDDP in vitro, human A549 lung cancer cells were exposed to these agents concurrently and sequentially. RESULTS Dose-limiting neutropenia and thrombocytopenia resulted after the doses of TPT or CDDP were increased to greater than 0.75 and 50 mg/m2, respectively, without and with G-CSF. The sequence of CDDP before TPT induced significantly worse neutropenia and thrombocytopenia than the alternate sequence. In vitro studies failed to provide any evidence for the differences in the cytotoxicity of these two sequences. Instead, pharmacokinetic studies suggested that the differences in toxicity were due, in part, to lower TPT clearance and exposure when CDDP preceeds TPT, possibly due to subclinical renal tubular toxicity induced by CDDP. CONCLUSION The sequence of CDDP before TPT at doses of 50 and 0.75 mg/m2, respectively, is recommended for subsequent clinical trials in tumor types in which both agents have significant single-agent activity. The potential for sequence-dependent cytotoxic, toxicologic, and pharmacologic effects should be evaluated in concurrent clinical and laboratory studies in the course of developing combination chemotherapy regimens that consist of topo I-targeting agents and other antineoplastic agents, particularly DNA-damaging agents.

PURPOSE To determine the toxicities, pharmacokinetics, and recommended doses of the topoisomerase I inhibitor, topotecan, in patients with varying degrees of renal excretory dysfunction. PATIENTS AND METHODS Fourteen patients with normal renal function [creatinine clearance (CrCl) > or = 60 mL/min] and 28 patients with varying degrees of renal dysfunction were treated with topotecan 0.4 to 2.0 mg/m2/d as a 30-minute infusion for 5 consecutive days every 3 weeks. Plasma and urine samples were obtained to determine the disposition of topotecan. RESULTS In patients with mild renal dysfunction (CrCl = 40 to 59 mL/min), dose-limiting hematologic toxicity was observed in three of eight patients receiving topotecan 1.0 mg/m2/d and in two of five patients receiving topotecan 1.5 mg/m2/d. In patients with moderate renal dysfunction (CrCl = 20 to 39 mL/min), dose-limiting hematologic toxicity was observed in three of eight patients who received topotecan 0.5 mg/m2/d, and in two of four patients receiving topotecan 1.0 mg/m2/d; these events were more frequently observed in extensively pretreated patients. Pharmacokinetic analyses showed significant correlations between CrCl and the plasma clearance of both total topotecan [Spearman's correlation coefficient (r2) = 0.65, P = .00001] and topotecan lactone (r2 = 0.65, P = .00003). Mean systemic plasma clearance of total topotecan was significantly reduced in patients with mild (P = .04) and moderate (P = .00006) renal dysfunction. There was no evidence of changes in the pharmacodynamic relationship between topotecan exposure (AUC) and myelotoxicity. CONCLUSION Dose adjustments are required in patients with moderate, but not mild, renal impairment. For patients with moderate renal dysfunction, the recommended starting dose of topotecan is 0.75 mg/m2/d for 5 days every 3 weeks. Moreover, extensively pretreated patients need further dose reductions.

During the past 25 years, the Radiation Therapy Oncology Group (RTOG) has played a major role in head and neck cancer clinical research. The major research themes for recent and currently active trials have been: (a) combined modality therapy, (b) altered fractionation radiotherapy, (c) hypoxic cell sensitizers, (d) organ preservation, (e) chemoprevention, and (f) clinical/laboratory correlations. For advanced operable disease, the RTOG showed improved local-regional control with postoperative radiotherapy as compared to preoperative radiotherapy for carcinoma of the supraglottic larynx and hypopharynx. This established the use of surgery followed by postoperative radiotherapy as the standard treatment in subsequent RTOG and Intergroup trials for operable disease. For advanced inoperable disease, the RTOG demonstrated the feasibility of testing altered fractionation radiotherapy in a multiinstitutional clinical trials setting. A Phase III trial comparing hyperfractionation and accelerated fractionation to conventional fractionation is now in progress. Phase I/II combined modality studies established the efficacy of concurrent high-dose cisplatin and radiotherapy in the treatment of advanced disease and provided the basis for further testing in Phase III trials for nasopharyngeal carcinoma, larynx preservation, and high-risk advanced operable disease. Analysis of the extensive RTOG Head and Neck Cancer database established the incidence of second malignancies and their adverse impact on patients whose initial tumors were cured by radiotherapy, and provided the basis for chemoprevention trials. Recursive partitioning analysis identified 6 distinct prognostically homogeneous patient groups based on pretreatment tumor or patient characteristics and/or treatment variables. Retrospective analysis identified tumor p105 antigen density as an independent prognostic indicator in patients irradiated for head and neck cancer. Future trials will continue to focus on the reduction of morbidity and mortality, and improvement of the quality of life of head and neck cancer patients through innovative radiotherapy delivery, multimodality approaches, use of chemical and biological modifiers, and other novel therapies, identification of clinical and biological prognostic indicators, and prevention or diminution of acute morbidity and late complications of the disease and its treatment.

Chemotherapy has an expanding role in the treatment of squamous cell carcinoma of the head and neck. Patients with recurrent or metastatic disease that have a good performance status should receive combination therapy with cisplatin and 5-fluorouracil or enter investigational protocols. Neoadjuvant chemotherapy should be offered to patients with laryngeal carcinoma as an alternative to surgery. Adjuvant chemotherapy should be considered in patients with an increased risk for relapse. Combined chemoradiotherapy may improve locoregional control and impact on survival. Chemoradiotherapy warrents further investigation through clinical trials and should be considered for patients at high risk for relapse. As the biology of these tumors becomes better defined, so too will our ability to define subsets of patients who may benefit from combined modality treatment.

6066Background: Multiple standard of care options exist for locally advanced SCCHN. We analyzed treatment plans submitted for commercially insured patients by practicing medical oncologists for pre...

Although epidemiologic studies have long associated tobacco and alcohol use with the development of squamous-cell carcinoma of the head and neck, the molecular targets of these carcinogens have yet to be identified. We performed a molecular analysis to determine the pattern of mutations in the p53 gene in neoplasms from patients with squamous-cell carcinoma of the head and neck and a history of tobacco or alcohol use.Sequence analysis of the conserved regions of the p53 gene was performed in tumor samples from 129 patients with primary squamous-cell carcinoma of the head and neck. We then used statistical analysis to identify any patient characteristics associated with mutation of the p53 gene.We found p53 mutations in 42 percent of the patients (54 of 129). Fifty-eight percent of the patients who smoked cigarettes and used alcohol (37 of 64; 95 percent confidence interval, 45 to 70 percent), 33 percent of the patients who smoked but abstained from alcohol (13 of 39; 95 percent confidence interval, 19 to 50 percent), and 17 percent of the patients who neither smoked nor drank alcohol (4 of 24, 95 percent confidence interval, 5 to 37 percent) had p53 mutations (P = 0.001). (Two patients used alcohol but did not smoke, and neither had a p53 mutation.) Furthermore, 100 percent of the mutations in the patients who neither drank nor smoked occurred at sites containing cytidine phosphate guanosine dinucleotides (potentially representing endogenous mutations) within the p53 gene (5 of 5 mutations; 95 percent confidence interval, 48 to 100 percent), whereas only 23 percent of those in cigarette smokers consisted of such changes (12 of 53 mutations; 95 percent confidence interval, 12 to 36 percent; P = 0.001).In our study, a history of tobacco and alcohol use was associated with a high frequency of p53 mutations in patients with squamous-cell carcinoma of the head and neck. Preliminary evidence linked cigarette smoking to p53 mutations at nonendogenous mutation sites. Our findings suggest a role for tobacco in the molecular progression of squamous-cell carcinoma of the head and neck and support the epidemiologic evidence that abstinence from smoking is important to prevent head and neck cancer.

Background Constitutive activation of nuclear factor κB (NF-κB) is associated with poor prognosis. Irinotecan demonstrates single-agent activity in head and neck cancer but activates NF-κB, promoting cell survival and resistance. Bortezomib is a proteasome inhibitor that inactivates NF-κB. Patients and Methods We performed a randomized phase II trial of bortezomib on days 1, 4, 8, and 11 and irinotecan on days 1 and 8 of each 21-day cycle or single-agent bortezomib on days 1, 4, 8, and 11 on a 21-day cycle. The addition of irinotecan to bortezomib was allowed in patients who progressed on bortezomib alone. Results The response rate of bortezomib and irinotecan was 13%. One patient had a partial response to bortezomib alone (response rate 3%). No responses were seen in patients with addition of irinotecan at time of progression on bortezomib. Conclusions The bortezomib-based regimens evaluated in this study have minimal activity in recurrent or metastatic head and neck cancer. Head Neck, 2013

Purpose: Erlotinib, an orally active selective inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, has synergistic activity with radiation and with cisplatin. The EGFR is overexpressed in the majority of head and neck cancers. The primary objective of this phase I study was to determine the maximum-tolerated dose (MTD) of erlotinib in combination with low-dose daily cisplatin and radiotherapy. We also sought evidence of biologic activity of erlotinib alone using serial 18-FDG positron emission tomography (PET) imaging. Experimental Design: Oral erlotinib was taken daily starting with a 14-day run-in and continued until radiation therapy (RT) was completed. Low-dose daily cisplatin, 6 mg/m2 i.v. was given concurrently with standard fractionation RT to a total dose of 66 to 70 Gy. Dose escalation followed a modified Fibonacci dose escalation design. Results: Twenty-two patients were enrolled and 18 patients received therapy on protocol. MTD of the combination of erlotinib, cisplatin, and RT was not reached. The recommended phase II dose of erlotinib is 150 mg per day in combination with cisplatin and RT, the highest dose of erlotinib evaluated in this study. 18F-FDG PET showed evidence for metabolic response to single-agent erlotinib. Per PERCIST criteria, the overall metabolic response rate at day 14 was 38.8% (95% CI: 17.3–64.3). On completion of concurrent chemoradiotherapy, overall response rate derived from tumor measurements based on imaging studies was 83% for all dose levels combined. Conclusions: Erlotinib in combination with low-dose daily cisplatin and RT is well tolerated and shows evidence of clinical efficacy. The combination should be evaluated further. Clin Cancer Res; 18(6); 1735–42. ©2012 AACR.

To define the roles of radiotherapy and chemotherapy on the risk of Grade 3+ mucositis during intensity-modulated radiation therapy (IMRT) for oropharyngeal cancer.164 consecutive patients treated with IMRT at two institutions in nonoverlapping treatment eras were selected. All patients were treated with a dose painting approach, three dose levels, and comprehensive bilateral neck treatment under the supervision of the same radiation oncologist. Ninety-three patients received concomitant chemotherapy (cCHT) and 14 received induction chemotherapy (iCHT). Individual information of the dose received by the oral mucosa (OM) was extracted as absolute cumulative dose-volume histogram (DVH), corrected for the elapsed treatment days and reported as weekly (w) DVH. Patients were seen weekly during treatment, and peak acute toxicity equal to or greater than confluent mucositis at any point during the course of IMRT was considered the endpoint.Overall, 129 patients (78.7%) reached the endpoint. The regions that best discriminated between patients with/without Grade 3+ mucositis were found at 10.1 Gy/w (V10.1) and 21 cc (D21), along the x-axis and y-axis of the OM-wDVH, respectively. On multivariate analysis, D21 (odds ratio [OR] = 1.016, 95% confidence interval [CI], 1.009-1.023, p0.001) and cCHT (OR = 4.118, 95% CI, 1.659-10.217, p = 0.002) were the only independent predictors. However, V10.1 and D21 were highly correlated (rho = 0.954, p0.001) and mutually interchangeable. cCHT would correspond to 88.4 cGy/w to at least 21 cc of OM.Radiotherapy and chemotherapy act independently in determining acute mucosal toxicity; cCHT increases the risk of mucosal Grade 3 toxicity ≈4 times over radiation therapy alone, and it is equivalent to an extra ≈6.2 Gy to 21 cc of OM over a 7-week course.

PURPOSE In 1990 we published the results of an intensive 3-week preoperative chemoradiation regimen for locoregional esophageal cancer that suggested improved survival compared with historical controls. We now report the long-term results at a median follow-up of 78.7 months. PATIENTS AND METHODS Forty-three patients with locoregional squamous cell carcinoma or adenocarcinoma of the esophagus or cardia were treated with fluorouracil (5-FU), cisplatin, and bolus vinblastine concurrent with radiation administered over 21 days. Transhiatal esophagectomy was performed on day 42. RESULTS Forty-one patients (95%) completed the preoperative treatment, and 36 (84%) had a potentially curative resection. Ten of 41 (24%) had no tumor in the resected esophagus and nodal tissues (path-negative group). The median survival duration of all 43 patients registered on study was 29 months; 34% were alive at 5 years. By histology, median survival durations were 32 months for 21 adenocarcinoma patients and 23 months for 22 squamous cell patients, with corresponding 5-year survival rates of 34% and 31%, respectively. Analysis of the 36 patients who underwent a potentially curative resection demonstrated median survival durations of 32 and 44 months and 5-year survival rates of 36% and 43%, respectively, for adenocarcinoma and squamous cell histologies. Path-negative (complete response [CR]) patients had a median survival duration of 70 months and 60% were alive at 5 years, while those patients with residual tumor in the resected esophagus had a median survival duration of 26 months and 32% were alive at 5 years (P = .114 by the log-rank test and P = .04 by the Wilcoxon test). CONCLUSION The results of this regimen appear improved over those reported with surgery alone, with an approximate doubling of the 5-year survival rate. Thirty-two percent of patients with residual tumor in the esophageal specimen are long-term survivors, which suggests a benefit from esophagectomy. A randomized trial is in progress to compare this preoperative regimen with immediate surgery.

Background Cellular immune deficiency is a consistent finding in patients with advanced head and neck cancer. Interleukin-2 and alpha-interferon are modulators of the immune system. Methods Eleven patients with recurrent head and neck cancer were treated in a Phase II study of recombinant human interleukin-2 (rIL-2) and alpha-2a-interferon (Roferon-A, Hoffmann-La Roche, Inc., Nutley, NJ). Each course consisted of rIL-2, 3 x 10(6) U/m2/day, as a continuous intravenous infusion over 24 hours for 4 days, and recombinant alpha-2a-interferon, 5 x 10(6) U/m2/day intramuscularly or subcutaneously daily for 4 days. This treatment was repeated weekly for 4 weeks, and then a second cycle was given after a 2-week break. Results Two patients (18%) achieved a partial response. Toxic effects were substantial. Three of 11 patients experienced Grade 3 hypotension, 3 patients had Grade 3 oliguria, and Grade 3 fatigue was one of the most common reasons for withdrawal from the study. There were no deaths or need for intensive care monitoring. Conclusions In view of the 18% response rate, additional investigation of biologic therapy in advanced head and neck cancer is warranted.

to characterize contemporary patterns of thyroid surgical care and variables associated with access to high-volume care.cross-sectional analysis.maryland Health Service Cost Review Commission database.adults who underwent surgery for thyroid disease in Maryland between January 1, 1990, and July 1, 2009.overall, 21 270 thyroid surgical procedures were performed by 1034 surgeons at 51 hospitals. Procedures performed by high-volume surgeons increased from 15.7% in 1990-1999 to 30.9% in 2000-2009 (odds ratio [OR], 3.69; P.001), while procedures performed at high-volume hospitals increased from 11.9% to 22.7% (3.46; P.001). High-volume surgeons were more likely to perform total thyroidectomy (OR, 2.50; P.001) and neck dissection (1.86; P.001), had a shorter length of hospitalization (0.44; P.001), and had a lower incidence of recurrent laryngeal nerve injury (0.46; P = .002), hypocalcemia (0.62; P.001), and thyroid cancer surgery (0.89; P = .01). After controlling for other variables, thyroid surgery in 2000-2009 was associated with high-volume surgeons (OR, 1.76; P.001), high-volume hospitals (2.93; P.001), total thyroidectomy (2.67; P.001), and neck dissection (1.28; P = .02) but was less likely to be performed for cancer (0.83; P.001).the proportion of thyroid surgical procedures performed by high-volume surgeons and in high-volume hospitals increased significantly from 1990-1999 to 2000-2009, with an increase in total thyroidectomy and neck dissection. Surgeon volume was significantly associated with complication rates. Thyroid cancer surgery was less likely to be performed by high-volume surgeons and in 2000-2009 despite an increase in surgical cases. Further investigation is needed to identify factors contributing to this trend.

Positive volume-outcome relationships exist for diseases treated with technically complex surgery. Contemporary patterns of laryngeal cancer surgery by hospital and surgeon volume are poorly defined.The Maryland Health Service Cost Review Commission database was queried for hospital and surgeon laryngeal cancer surgical case volumes from 1990 to 2009.Overall, 1,981 laryngeal cancer surgeries were performed by 288 surgeons at 41 hospitals. Cases performed by high-volume surgeons increased from 19% in 1990 to 1999 to 35% in 2000 to 2009 (odds ratio [OR] = 3.0, P.001), whereas cases performed at high-volume hospitals increased from 33% to 39% (OR = 2.0, P.001). High-volume surgeons were more likely to perform total laryngectomy (OR = 1.7, P = .001) and neck dissection (OR = 1.7, P = .002). High-volume hospitals were significantly associated with total laryngectomy (OR = 2.0, P = .003), neck dissection (OR = 1.8, P = .038), flap reconstruction (OR = 5.1, P = .021), prior radiation (OR = 3.0, P = .031), and increased mortality risk scores (OR = 3.2, P = .006). After controlling for other variables, laryngeal cancer surgery in 2000 to 2009 was associated with increased access to high-volume surgeons (OR = 1.9, P.001) and high-volume hospitals (OR = 1.3, P = .040), a decrease in partial and total laryngectomy procedures (OR = 0.2, P.001), an increase in neck dissection (OR = 2.2, P0.001), an increase in prior radiation (OR = 3.0, P.001), increased case complexity scores (OR = 5.7, P.001), and an increase in wound fistula or dehiscence (OR = 2.0, P = .015) compared with 1990 to 1999.The proportion of laryngeal cancer surgery patients treated by high-volume surgeons and hospitals increased significantly in 2000 to 2009 compared with 1990 to 1999, with a decrease in laryngectomy procedures and an increase in wound complications. These findings may be due to changing trends in primary management of laryngeal cancer.

Positive volume-outcome relationships exist for diseases treated with technically complex surgery. Contemporary patterns of oropharyngeal cancer surgery by hospital and surgeon volume are poorly defined.The Maryland Health Service Cost Review Commission database was queried for hospital and surgeon oropharyngeal cancer surgical case volumes from 1990 to 2009.Overall, 1,534 oropharyngeal cancer surgeries were performed by 238 surgeons at 41 hospitals. Cases performed by high-volume surgeons increased from 18.9% in 1990 to 1999 to 24.8% in 2000 to 2009 (odds ratio [OR] = 1.5, P = .002), whereas cases performed at high-volume hospitals increased from 35.0% to 41.8% (OR = 1.7, P.001). High-volume surgeons were significantly associated with university hospitals (OR = 25.9, P.001) and were more likely to perform partial glossectomy (OR = 1.8, P = .002), total glossectomy (OR = 3.8, P.001), and neck dissection (OR = 2.3, P.001). High-volume hospitals were significantly associated with tonsillectomy (OR = 3.0, P.001), partial glossectomy (OR = 1.4, P = .044), total glossectomy (OR = 4.3, P.001), neck dissection (OR = 3.1, P.001), flap reconstruction (OR = 1.9, P = .028), and prior radiation (OR = 5.0, P.001). After controlling for other variables, oropharyngeal cancer surgery in 2000 to 2009 was associated with increased utilization of university hospitals (OR = 1.7, P.001), increased mortality risk scores (OR = 3.1, P = .022), prior radiation (OR = 4.9, P = .011), and a decrease in partial glossectomy (OR = 0.5, P.001), total glossectomy (OR = 0.4, P = .004), pharyngectomy (OR = 0.6, P = .007), and mandibulectomy (OR = 0.6, P = .022) procedures.The proportion of oropharyngeal cancer surgery patients treated by high-volume surgeons and hospitals increased significantly from 1990 to 1999 to 2000 to 2009, with a decrease in partial glossectomy, total glossectomy, pharyngectomy, and mandibulectomy procedures. These findings may be due to changing trends in the primary management of oropharyngeal cancer.

Purpose We investigated the impact of race, in conjunction with gender and partner status, on locoregional control (LRC) and overall survival (OS) in three head and neck trials conducted by the Radiation Therapy Oncology Group (RTOG). Methods and Materials Patients from RTOG studies 9003, 9111, and 9703 were included. Patients were stratified by treatment arms. Covariates of interest were partner status (partnered vs. non-partnered), race (white vs. non-white), and sex (female vs. male). Chi-square testing demonstrated homogeneity across treatment arms. Hazards ratio (HR) was used to estimate time to event outcome. Unadjusted and adjusted HRs were calculated for all covariates with associated 95% confidence intervals (CIs) and p values. Results A total of 1,736 patients were analyzed. Unpartnered males had inferior OS rates compared to partnered females (adjusted HR = 1.22, 95% CI, 1.09–1.36), partnered males (adjusted HR = 1.20, 95% CI, 1.09–1.28), and unpartnered females (adjusted HR = 1.20, 95% CI, 1.09–1.32). White females had superior OS compared with white males, non-white females, and non-white males. Non-white males had inferior OS compared to white males. Partnered whites had improved OS relative to partnered non-white, unpartnered white, and unpartnered non-white patients. Unpartnered males had inferior LRC compared to partnered males (adjusted HR = 1.26, 95% CI, 1.09–1.46) and unpartnered females (adjusted HR = 1.30, 95% CI, 1.05–1.62). White females had LRC superior to non-white males and females. White males had improved LRC compared to non-white males. Partnered whites had improved LRC compared to partnered and unpartnered non-white patients. Unpartnered whites had improved LRC compared to unpartnered non-whites. Conclusions Race, gender, and partner status had impacts on both OS and locoregional failure, both singly and in combination.

The curative treatment of locally advanced head and neck squamous cell cancer has advanced greatly in recent years, with the establishment of standard of care indications for chemoradiation (CRT). At the same time, there have been advances in each modality, including intensity-modulated radiation therapy, sequential chemotherapy and more tailored combination therapies. However, with new therapies come new challenges. This review will discuss some of the novel approaches to treating head and neck squamous cell cancer, particularly the introduction of biological agents into treatment paradigms, and some of the challenges arising as the field advances.A number of recent clinical trials have focused on reducing the disadvantages of concurrent CRT, specifically acute toxicity, lack of compliance and potential for late effects affecting quality of life and function. In particular, the use of biological agents as radiosensitizers has led to the investigation of new combination therapies, such as epidermal growth factor receptor inhibitors administered concurrently with CRT. These new therapies have potential for improving overall survival and lowering locoregional recurrence rates.Combination therapies hold promise for improving outcomes of patients with head and neck squamous cell cancer, both human papilloma virus-associated and human papilloma virus-negative tumors. The introduction of intensity modulated radiation therapy and biological agents into CRT treatment approaches may reduce some of the disadvantages of more traditional radiation and CRT treatments. Although many challenges remain, the possibility of improving survival with reduced toxicity through treatment selection based on risk stratification and prognostic biomarkers is incrementally evolving.

Background: We hypothesized that a serum proteomic profile predictive of survival benefit in non–small cell lung cancer patients treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) reflects tumor EGFR dependency regardless of site of origin or class of therapeutic agent. Methods: Pretreatment serum or plasma from 230 patients treated with cetuximab, EGFR-TKIs, or chemotherapy for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) or colorectal cancer (CRC) were analyzed by mass spectrometry. Each sample was classified into “good” or “poor” groups using VeriStrat, and survival analyses of each cohort were done based on this classification. For the CRC cohort, this classification was correlated with the tumor EGFR ligand levels and KRAS mutation status. Results: In the EGFR inhibitor–treated cohorts, the classification predicted survival (HNSCC: gefitinib, P = 0.007 and erlotinib/bevacizumab, P = 0.02; CRC: cetuximab, P = 0.0065) whereas the chemotherapy cohort showed no survival difference. For CRC patients, tumor EGFR ligand RNA levels were significantly associated with the proteomic classification, and combined KRAS and proteomic classification provided improved survival classification. Conclusions: Serum proteomic profiling can detect clinically significant tumor dependence on the EGFR pathway in non–small cell lung cancer, HNSCC, and CRC patients treated with either EGFR-TKIs or cetuximab. This classification is correlated with tumor EGFR ligand levels and provides a clinically practical way to identify patients with diverse cancer types most likely to benefit from EGFR inhibitors. Prospective studies are necessary to confirm these findings. Cancer Epidemiol Biomarkers Prev; 19(2); 358–65

PURPOSE The Southwest Oncology Group (SWOG) conducted a randomized comparison of cisplatin plus fluorouracil (5-FU) and carboplatin plus 5-FU versus single-agent methotrexate (MTX) in patients with recurrent and metastatic squamous-cell carcinoma (SCC) of the head and neck. The primary objective was to compare separately the response rates of each combination regimen to standard weekly MTX. PATIENTS AND METHODS Two hundred seventy-seven patients diagnosed with SCC of the head and neck were randomized to one of three treatments: (1) cisplatin 100 mg/m2 intravenously (IV) on day 1 and 5-FU 1,000 mg/m2 per day for a 96-hour continuous infusion repeated every 21 days; (2) carboplatin 300 mg/m2 IV on day 1 and 5-FU 1,000 mg/m2 per day for a 96-hour continuous infusion repeated every 28 days; and (3) MTX 40 mg/m2 IV given weekly. RESULTS All three treatment regimens were well tolerated. However, both hematologic and nonhematologic toxicities were significantly greater with cisplatin plus 5-FU compared with MTX (P = .001). Toxicity from carboplatin plus 5-FU was intermediate compared with the other regimens. The complete and partial response rates were 32% for cisplatin plus 5-FU, 21% for carboplatin plus 5-FU, and 10% for MTX. The comparison of cisplatin plus 5-FU to MTX was statistically significant (P less than .001), and the comparison of carboplatin plus 5-FU to MTX was of borderline statistical significance (P = .05). Median response durations and median survival times were similar for all three treatment groups. Logistic regression models showed that only treatment assigned was associated significantly with response (P = .001). Cox proportional hazards models indicated that only performance status was associated significantly with survival (P less than .01). CONCLUSIONS We conclude that combination chemotherapy resulted in improved response rates but was associated with an increased toxicity and no improvement in overall survival. Therefore, new treatments that may alter the course of disease in recurrent head and neck cancer patients still need to be identified.

Numerous studies have shown cisplatin-based chemotherapy to be effective in the treatment of head and neck cancer. Cisplatin/5-fluorouracil (5-FU) is the most frequently used combination regimen, but neurotoxicity, ototoxicity, and renal toxicity limit repeated dosing (for long-term treatment of responding patients) and dose intensification. In studies to date, the analogue carboplatin appears to have activity similar to cisplatin, the advantage of no significant neurotoxicity, ototoxicity, or renal toxicity, and less emetic potential. Two randomized trials have shown cisplatin/5-FU and carboplatin/5-FU superior in terms of response rate compared to single-agent therapy. Treatment with combinations of carboplatin/methotrexate and carboplatin/cisplatin is feasible, but myelosuppression is dose-limiting. As an induction regimen, carboplatin/5-FU yields response rates similar to cisplatin/5-FU. Overall, carboplatin has a more favorable toxicity profile for treating head and neck cancer patients who often have multiple medical problems when presenting for palliation of cancer. Reversible myelosuppression is dose-limiting. However, the availability of hematopoietic growth factors may allow investigators to safely intensify dosing, particularly in combined-modality curative treatment regimens for the newly diagnosed patient.

Purpose: Detect tumor-related DNA using LigAmp in histologically clear margins and associate results with clinical outcome. Experimental Design: Patients with head and neck cancer were registered for molecular analysis of surgical margins. Adequacy of resection was ensured using histologic margin analysis. Further margins were then harvested and DNA extracted. TP53 mutations in tumor were determined using Affymetrix p53 GeneChip. Margins were analyzed by Ligamp in comparison with standard curves for quantification of mutant DNA. Ligation used two oligonucleotides to isolate DNA targeting the mutation. Ligated DNA was amplified using real-time PCR. The quantity of mutation in the margin was determined as percent of mutant species relative to plasmid and relative to tumor. Cutpoints were identified and defined groups were evaluated for local failure-free, cancer-specific, and overall survival. Study margins were examined for presence of tumor by light microscopy. Results: Tissue from 95 patients with common mutations was analyzed. Fifteen experienced local recurrence. Cutpoints of 0.15% for mutant species relative to plasmid and 0.5% for mutant species relative to tumor were chosen as most selective of recurrent cases. LigAmp had slightly better area under the receiver operator characteristic curve (P = 0.09) than light microscopy correctly predicting 9 of 15 recurrent tumors. There were 6 false negative cases and 26 false positive results. No statistically significant distinctions were observed in cancer-specific or overall survival in this limited cohort. Conclusions: Ligamp provides quantifiable, sensitive detection of mutant DNA in histologically normal margins. Detection of mutant species in margins may identify patients at risk of local recurrence. (Clin Cancer Res 2009;15(24):7658–65)

To assess volumetric changes of selected organs at risk (OAR) during intensity-modulated radiotherapy (IMRT) for oropharyngeal carcinoma.Twenty-six consecutive patients that were treated with definitive IMRT ± chemotherapy between November 2007 and November 2008 were selected for the present study. As part of an internal quality assurances program, a repeat kilovolt (KV) computed tomography was planned weekly during the 7-week treatment course. On each available scan, a single observer contoured the parotid submandibular, and thyroid glands (PG/SMG/TG), larynx (L), and constrictor, masticatory, and sternocleidomastoid muscles (CM/MM/SCM) as appropriate. The volume at each scan was compared with the one at planning CT in a pair-wise fashion. p values0.05 after correction for multiple testing were considered significant.A total of 159 scans was obtained during treatment for a total of 185 scans, including the baseline imaging. All OARs showed statistically significant changes over baseline by week 5. At week 7, the PG showed the largest absolute change with an average reduction of ∼10 mL followed by both the SCM and MM (∼-5 mL). The largest (∼-30%) relative change was observed for the salivary glands. L and CM showed a ∼15% increase in volume during treatment.All selected OAR undergo significant volumetric changes during a course of IMRT for oropharyngeal squamous cell carcinoma.

Background: Preclinical evidence suggests synergy between docetaxel and irinotecan, two drugs active in esophagogastric cancer. We previously demonstrated the safety of docetaxel 35 mg/m 2 and irinotecan 50 mg/m 2 given on days 1 and 8 of a 21-day schedule. Materials and methods: Patients who had unresectable/metastatic squamous cell carcinoma or adenocarcinoma of the esophagus, measurable disease, Eastern Cooperative Oncology Group performance status of zero to two, and normal bilirubin were eligible. Tumor assessment was carried out every three cycles. Results: We enrolled 29 chemotherapy-naive (CN) and 15 chemotherapy-exposed (CE) eligible patients. Principal toxic effects were diarrhea, neutropenia, and hyperglycemia. There were no toxic deaths. There was one early death, from myocardial infarction. Among 26 CN and assessable patients, there were seven (26.9%) with a partial response (PR) and one (3.8%) with a complete response (CR). There were two PRs and one CR among the patients with CE disease. Median time to progression for CN patients was 4.0 months and for CE patients 3.5 months. Median survival for CN eligible patients was 9.0 months and for CE patients 11.4 months. Conclusions: Docetaxel–irinotecan combination given on a weekly · 2 of 3 schedule is promising in the treatment of

Untreated and minimally pretreated solid tumor patients received alternating sequences of taxol and cisplatin. Sequential dose escalation of each agent using taxol doses of 110 or 135 mg/m2 and cisplatin doses of 50 or 75 mg/m2 resulted in four dosage permutations that induced grades 3 and 4 neutropenia in 72% to 84% and 50% to 53% of courses, respectively. Neutropenia was brief, and hospitalization for neutropenia and fever was required in 13% to 24% of courses. However, further escalation of taxol to 170 or 200 mg/m2 induced grade 4 neutropenia in 79% to 82% of courses. At the highest taxol-cisplatin dose level (200 mg/m2 to 75 mg/m2), the mean neutrophil count nadir was 98/microL, and hospitalization for neutropenia and fever was required in 64% of courses. The sequence of cisplatin before taxol, which has less antitumor activity in vitro, induced more profound neutropenia than the alternate sequence. Pharmacologic studies indicated that this difference was probably due to 25% lower taxol clearance rates when cisplatin preceded taxol. Although neurotoxicity was initially thought to be a potentially serious effect of the combination, mild to modest neurotoxicity occurred in only 27% of patients. Adverse effects also included myalgias, alopecia, vomiting, diarrhea, bradycardia, and asymptomatic ventricular tachycardia. Objective responses were noted in melanoma, as well as non-small-cell lung, ovarian, breast, head and neck, colon, and pancreatic carcinomas. Based on these results, the sequence of taxol before cisplatin at doses of 135 and 75 mg/m2, respectively, is recommended for phase II/III trials, with escalation of taxol to 170 mg/m2 if treatment is well tolerated.

The incorporation of chemotherapy into a combined modality approach for treating newly diagnosed, advanced head and neck cancer has been under evaluation since the 1970s. In this review, the criteria for a well-designed prospective randomized trial are delineated based on prognostic factors determined from singleinstitution induction chemotherapy trials. The results of randomized controlled trials conducted from 1978 to the present are discussed with respect to their impact on survival, locoregional disease control, and the development of distant metastasis. Each study is then critiqued for its design, conduct, and interpretation. Organ preservation, improved locoregional control, and survival are important goals for future trials.

Purpose Patients with advanced, incurable thyroid cancer not amenable to surgery or radioactive iodine (131I) therapy have few satisfactory therapeutic options. This multi-institutional study assessed the activity and safety of axitinib, an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3 in patients with advanced thyroid cancer. Patients and Methods Patients with thyroid cancer of any histology that was resistant or not appropriate for 131I were enrolled onto a single-arm phase II trial to receive axitinib orally (starting dose, 5 mg twice daily). Objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors was the primary end point. Secondary end points included duration of response, progression-free survival (PFS), overall survival, safety, and modulation of soluble (s) VEGFR. Results Sixty patients were enrolled. Partial responses were observed in 18 patients, yielding an ORR of 30% (95% CI, 18.9 to 43.2). Stable disease lasting ≥ 16 weeks was reported in another 23 patients (38%). Objective responses were noted in all histologic subtypes. Median PFS was 18.1 months (95% CI, 12.1 to not estimable). Axitinib was generally well tolerated, with the most common grade ≥ 3 treatment-related adverse event being hypertension (n = 7; 12%). Eight patients (13%) discontinued treatment because of adverse events. Axitinib selectively decreased sVEGFR-2 and sVEGFR-3 plasma concentrations versus sKIT, demonstrating its targeting of VEGFR. Conclusion Axitinib is a selective inhibitor of VEGFR with compelling antitumor activity in all histologic subtypes of advanced thyroid cancer.

Purpose Concurrent chemoradiotherapy (CCRT) for squamous cell carcinoma of the head and neck (SCCHN) increases both local tumor control and toxicity. This study evaluates clinical factors that are associated with and might predict severe late toxicity after CCRT. Methods Patients were analyzed from a subset of three previously reported Radiation Therapy Oncology Group (RTOG) trials of CCRT for locally advanced SCCHN (RTOG 91-11, 97-03, and 99-14). Severe late toxicity was defined in this secondary analysis as chronic grade 3 to 4 pharyngeal/laryngeal toxicity (RTOG/European Organisation for the Research and Treatment of Cancer late toxicity scoring system) and/or requirement for a feeding tube ≥ 2 years after registration and/or potential treatment-related death (eg, pneumonia) within 3 years. Case-control analysis was performed, with a multivariable logistic regression model that included pretreatment and treatment potential factors. Results A total of 230 patients were assessable for this analysis: 99 patients with severe late toxicities and 131 controls; thus, 43% of assessable patients had a severe late toxicity. On multivariable analysis, significant variables correlated with the development of severe late toxicity were older age (odds ratio 1.05 per year; P = .001); advanced T stage (odds ratio, 3.07; P = .0036); larynx/hypopharynx primary site (odds ratio, 4.17; P = .0041); and neck dissection after CRT (odds ratio, 2.39; P = .018). Conclusion Severe late toxicity after CCRT is common. Older age, advanced T-stage, and larynx/hypopharynx primary site were strong independent risk factors. Neck dissection after CCRT was associated with an increased risk of these complications.

Whether postoperative radiotherapy improves survival compared with surgery alone in patients with head and neck cancer remains unclear. This Practice Point commentary discusses the findings of a study by Kao et al. who used the Surveillance, Epidemiology, and End Results database to look for evidence of improved overall survival in patients with node-positive head and neck cancer. The analysis included 5,297 eligible patients who were treated with first-line surgery, of whom 4,307 (81%) received adjuvant radiotherapy. On multivariate analysis, adjuvant radiotherapy, age, primary tumor site, tumor and nodal stage were significant predictors of overall survival. While these results show an association between the use of adjuvant radiotherapy and improved overall survival in a selected group of patients, several aspects of the study limit its interpretation. Whether there is a causal relationship between postoperative radiotherapy and the observed overall survival benefit remains undetermined.

Objective Utilizing data obtained during a multicenter investigation, this paper illustrates how the use of covariates and careful modeling techniques can be useful in assessing whether a negative outcome from a small multicenter clinical trial could be due to imbalance in baseline characteristics. The Chemoprevention for Barrett's Esophagus Trial (CBET) was a phase IIb, multicenter, randomized, placebo-controlled trial of celecoxib in patients with Barrett's esophagus. The primary outcomes for the original study were the proportion of biopsy samples exhibiting dysplasia in the celecoxib and placebo groups. The secondary and tertiary outcomes included histologic change and measurements of biologically relevant markers, including COX-1 and − 2 mRNA, prostanoid levels, and methylation of tumor suppressor genes p16, APC, and E-cadherin. The original study reported no significant differences in primary, secondary or tertiary outcomes. In this paper, we focus on the results of one of the secondary measures, quantitative endoscopy (QE). Design The study utilizes data from 56 patients in the CBET for whom baseline (BL) QE and one-year follow-up QE (F04) studies were performed. Of these, 29 were treated with celecoxib (200 mg twice daily for a minimum of 48 weeks) and 27 received the placebo. These patients are segmented as to the presence or absence of circumferential, tongues or islands of Barrett's. Measurements The response of interest is total affected area at one year (Total F04); affected area at baseline (Total BL) is used as a covariate. Results Controlling for complexity and clinic, there is a significant treatment effect. In addition, there is significant evidence that the area of Barrett's involvement decreased for patients in the treatment group. Conclusions That there was a decrease for the celecoxib over the placebo group adds to the body of evidence that relates COX-2 specific inhibitors and cancer incidence.

Head and neck cancers account for less than 5% of all cancers and for less than 3% of all cancer deaths in the United States. The populations at risk for head and neck cancers are those who have a long-standing history of smoking and alcohol use. More recently, the incidence of oropharyngeal cancer in younger populations has been increasing and is associated with exposure to the human papillomavirus. This subset of patients appears to have a better overall prognosis and to respond better to treatment. This review is limited to head and neck cancers of squamous cell histology, which constitute more than 90% of head and neck cancers. Because treatment of head and neck cancers is complex and involves multiple modalities, a multidisciplinary approach is needed. This review focuses on the goal of organ preservation and postoperative treatment of high-risk patients with the concurrent use of chemotherapy and radiation therapy. This review also highlights recent advances in treatment using molecularly targeted therapies, specifically the role of inhibitors of the epidermal growth factor receptor in locally advanced and recurrent/metastatic squamous cell cancer of the head and neck. Studies in the English language were identified by searching the MEDLINE, EMBASE database (1980-2007) using the search terms head and neck, squamous cell, carcinoma, chemotherapy, radiation, human papillomavirus, epidermal growth factor receptor, and targeted therapy.

The Chemoprevention for Barrett’s Esophagus Trial (CBET) was a phase IIb, multicenter, randomized, placebo-controlled trial of celecoxib in patients with Barrett’s esophagus. The overall outcome of the study was that there were no significant differences in primary, secondary, or tertiary outcomes. The purpose of the current study is to focus on results related to the method of measuring lesion size called quantitative endoscopy (QE). The design includes a review of a total number of studies and then restricts analyses to the four clinics that enrolled more than four patients each for whom a baseline and 1-year QE study was performed, comparing intra- and inter-patient and clinic differences in Barrett’s esophagus. Measurements include the number of total QEs and adverse events, changes in areas from baseline to 1 year and other intervals, classification of Barrett’s lesion type with respect to patients, clinics, and treatment. A total of 309 QE studies were completed with no adverse events. Differences in surface area measurements over time for a particular patient are smaller than the differences for randomly selected patients. The complexity mix (as defined by the mix of circumferential, tongues, and islands) of the Barrett’s lesions varied with different clinics. In conclusion, QE is an efficient, safe, and accurate way to measure the area of Barrett’s lesions variation between different clinical sites may be attributable to a subtle type of selection bias at the individual clinics rather than to regional differences.