Heterogeneity of colorectal cancer (CRC) in reference to KRAS proto-oncogene utilizing WAVE technology.

BACKGROUND: New drugs targeting specific genes required for unregulated growth and metastases have improved survival rates for patients with metastatic colorectal cancer. Resistance to monoclonal antibodies specific for the epidermal growth factor receptor (EGFR) has been attributed to the presence of activating point mutations in the proto-oncogene KRAS. The use of EGFR inhibitor monotherapy in patients that have KRAS wild type has produced response rates of only 10-20%. The molecular basis for clinical resistance remains poorly understood. We propose two possible explanations to explain these low response rates; 1) levels of resistant CRC cells carrying mutated KRAS are below the sensitivity of standard direct sequencing modalities (<5%) or 2) the standard practice of analyzing a single area within a heterogeneous tumor is a practice that can overlook areas with mutated KRAS. METHODS: In a collaborative effort with the surgical and molecular pathology departments, 3 formalin fixed paraffin embedded tissue blocks of human CRC were obtained from the human tissue bank maintained by the Lifespan Pathology Department and/or the human tissue bank maintained by the Molecular Pathology Core of the COBRE for Cancer Research Development. The three specimens previously demonstrated KRAS mutations detected by the Applied Biosystems Kit. The Wave system 4500 (high performance ion-pairing liquid chromatography (IP-HPLC)) was utilized to evaluate tissue for the presence of KRAS proto-oncogene mutations at codons 12 and 13. RESULTS: Initially, the sensitivity of WAVE technology was compared with direct sequencing by evaluating a dilutional series. WAVE detected mutant alleles at levels of 2.5% compared to 20% performed with standard direct sequencing. Samples from three patients were evaluated by WAVE technology. Eight samples from patient 1 were analyzed. In two of eight samples, no mutations were detected at concentrations as low as 5%. In one sample a mutation was noted by WAVE and not by direct sequencing. All four samples from patient 2 tested positive for Exon 12/13 mutations. Of the seven samples from patient 3, five were positive for Exon 12/13 mutations and two were negative for Exon 12/13 mutations. CONCLUSION: In these studies the analysis of three patients' colorectal cancer tissues were analyzed utilizing the WAVE technology. Results demonstrated a greater degree of sensitivity in mutation detection when compared to standard sequencing. These studies also demonstrated heterogeneity of expression of KRAS mutations between areas of the tissue samples at a genomic level. The low clinical response rates to EGFR inhibition might be explained by the variation in mutation presence, which was dependent upon the region examined. The heterogeneity demonstrated in these studies provides another phenotypic variant that will impact clinical care.

A randomized, placebo-controlled phase 2 study of ganitumab (AMG 479) or conatumumab (AMG 655) in combination with gemcitabine in patients with metastatic pancreatic cancer.

BACKGROUND: We evaluated the efficacy and safety of ganitumab (a mAb antagonist of insulin-like growth factor 1 receptor) or conatumumab (a mAb agonist of human death receptor 5) combined with gemcitabine in a randomized phase 2 trial in patients with metastatic pancreatic cancer. PATIENTS AND METHODS: Patients with a previously untreated metastatic pancreatic adenocarcinoma and an Eastern Cooperative Oncology Group (ECOG) performance status ≤1 were randomized 1 : 1 : 1 to i.v. gemcitabine 1000 mg/m(2) (days 1, 8, and 15 of each 28-day cycle) combined with open-label ganitumab (12 mg/kg every 2 weeks [Q2W]), double-blind conatumumab (10 mg/kg Q2W), or double-blind placebo Q2W. The primary end point was 6-month survival rate. Results In total, 125 patients were randomized. The 6-month survival rates were 57% (95% CI 41-70) in the ganitumab arm, 59% (42-73) in the conatumumab arm, and 50% (33-64) in the placebo arm. The grade ≥3 adverse events in the ganitumab, conatumumab, and placebo arms, respectively, included neutropenia (18/22/13%), thrombocytopenia (15/17/8%), fatigue (13/12/5%), alanine aminotransferase increase (15/5/8%), and hyperglycemia (18/2/3%). CONCLUSIONS: Ganitumab combined with gemcitabine had tolerable toxicity and showed trends toward an improved 6-month survival rate and overall survival. Additional investigation into this combination is warranted. Conatumumab combined with gemcitabine showed some evidence of activity as assessed by the 6-month survival rate.

A multi-center phase II study of BMS-247550 (Ixabepilone) by two schedules in patients with metastatic gastric adenocarcinoma previously treated with a taxane.

PURPOSE: Ixabepilone is one of the epothilones, a new class of cytotoxics, that function as microtubule-stabilizing agents. With the primary endpoint of assessing ixabepilone's response rate against metastatic gastric cancer previously treated with a taxane, we performed a multi-center phase II trial. PATIENTS AND METHODS: Patients with histologically documented metastatic gastric or gastroesophageal adenocarcinoma, who had previously received a taxane, were eligible. Patients were required to have near normal organ function, > or =18 years of age, ECOG performance status of 0 or 1. A written informed consent was obtained from all patients. Ixabepilone was administered over one hour intravenously at a dose of 50 mg/m2 every 21 days (23 patients; cohort A) and 24 subsequent patients were treated with an amended protocol schedule to receive 6 mg/m2 intravenously on days 1-5 every 21 days (cohort B). RESULTS: A total of 47 patients were treated. Most patients were men with a median performance status of 1. Two of 23 patients in cohort A achieved a confirmed partial response (9%, 95% CI 1.1-28%) but none of the 24 patients in cohort B achieved a response. A higher proportion of patients in cohort A experienced Grade 3/4 toxicities compared with those in cohort B. CONCLUSIONS: Ixabepilone, on a once every 21-day schedule, is modestly active against metastatic gastric cancer previously treated with a taxane. The days 1-5 every 21 days schedule had a more favorable safety profile but no activity. The results of this study suggest that once every 21-day ixabepilone schedule should be pursued further in untreated gastric or gastroesophageal adenocarcinoma patients.

Phase II study of the farnesyl transferase inhibitor R115777 in patients with sensitive relapse small-cell lung cancer.

BACKGROUND: R115777 (tipifarnib, Zarnestra) is a farnesyl transferase inhibitor that blocks the farnesylation of proteins involved in signal transduction pathways critical for cell proliferation and survival. This multicenter phase II study was conducted to determine the efficacy, tolerability and pharmacokinetics of R115777 in patients with relapsed small-cell lung cancer (SCLC). PATIENTS AND METHODS: Patients who had a partial or complete response to their initial chemotherapy regimen, followed by at least 3 months off treatment before relapse (sensitive relapse) were eligible. R115777 was administered in 3-week cycles at a dose of 400 mg orally twice daily for 14 consecutive days followed by 7 days off treatment. RESULTS: Twenty-two patients were enrolled. The median progression-free survival was 1.4 months and median overall survival was 6.8 months. Non-hematological toxicities were predominantly grade 1-2 and included nausea (64%) and fatigue (60%). Grade 3-4 granulocytopenia and thrombocytopenia occurred in 27% and 23% of patients, respectively. Febrile neutropenia was not observed. Pharmacokinetic studies demonstrated peak plasma concentrations of R115777 2.6-4.5 h after oral dosing and no significant drug accumulation. The trial was terminated because no objective responses were observed in 20 patients evaluable for response. CONCLUSIONS: R115777 showed no significant antitumor activity as a single agent in sensitive-relapse SCLC.

Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer.

PURPOSE: To determine whether addition of the farnesyltransferase inhibitor tipifarnib (Zarnestra, R115777; Johnson and Johnson Pharmaceutical Research and Development, Beerse, Belgium) to standard gemcitabine therapy improves overall survival in advanced pancreatic cancer. PATIENTS AND METHODS: This randomized, double-blind, placebo-controlled study compared gemcitabine + tipifarnib versus gemcitabine + placebo in patients with advanced pancreatic adenocarcinoma previously untreated with systemic therapy. Tipifarnib was given at 200 mg bid orally continuously; gemcitabine was given at 1,000 mg/m(2) intravenously weekly x 7 for 8 weeks, then weekly x 3 every 4 weeks. The primary end point was overall survival; secondary end points included 6-month and 1-year survival rates, progression-free survival, response rate, safety, and quality of life. RESULTS: Six hundred eighty-eight patients were enrolled. Baseline characteristics were well balanced between the two treatment arms. No statistically significant differences in survival parameters were observed. The median overall survival for the experimental arm was 193 v 182 days for the control arm (P =.75); 6-month and 1-year survival rates were 53% and 27% v 49% and 24% for the control arm, respectively; median progression-free survival was 112 v 109 days for the control arm. Ten drug-related deaths were reported for the experimental arm and seven for the control arm. Neutropenia and thrombocytopenia grade > or = 3 were observed in 40% and 15% in the experimental arm versus 30% and 12% in the control arm. Incidences of nonhematologic adverse events were similar in two groups. CONCLUSION: The combination of gemcitabine and tipifarnib has an acceptable toxicity profile but does not prolong overall survival in advanced pancreatic cancer compared with single-agent gemcitabine.

Phase II study of external irradiation and weekly paclitaxel for nonmetastatic, unresectable pancreatic cancer: RTOG-98-12.

Unresectable cancer of the pancreas was treated with the combination of weekly paclitaxel and external beam irradiation in an effort to improve palliation and extend life expectancy. One hundred twenty-two patients were entered in a multicentered protocol. Thirteen patients were either ineligible, cancelled, or had delinquent data, thus providing 109 for analysis. Unresectable cancer was based on imaging studies (computed tomography or magnetic resonance imaging), all had histologic proof of adenocarcinoma, and none had evidence of metastatic disease or peritoneal seeding. Image-guided radiotherapy treatment consisted of 50.4 Gy in 28 fractions over 5.5 weeks with coplanar anterior/posterior and lateral ports. An initial dose of 45 Gy was given to fields covering the primary tumor plus the regional peripancreatic, celiac, and porta hepatis lymph nodes. A cone down field was used for the last three fractions to encompass the gross tumor volume with a 1- to 1.5-cm margin. Paclitaxel was administered weekly with irradiation in a dosage of 50 mg/m2 as a 3-hour infusion. The median age was 63 and 53% were female. The Karnofsky performance status was greater than or equal to 80 in 81%. Eighty percent were classified T3 or 4; 20% had N1 disease. The primary tumor was located in the pancreatic head in 65%. Eighty-five percent received all six cycles of paclitaxel per protocol, whereas 93% received irradiation with acceptable protocol variation. Field placement, total dose, fractionation, and overall treatment time were given per protocol in greater than or equal to 90%. Acute toxicity (worst per patient) occurred in 39% with grade III (35% of these were asymptomatic neutropenia), 5% with grade IV, and one patient died of infection during the fourth cycle of chemotherapy (grade V). The median follow-up time for alive patients is 20.6 months (range 5-30). The median survival is 11.2 months (95% CI 10.1, 12.3) with estimated 1- and 2-year survivals of 43% and 13%, respectively. External irradiation plus concurrent weekly paclitaxel is well tolerated when given with large-field radiotherapy. The median survival is better than historical results achieved with irradiation and fluoropyrimidines. These data provide the basis for a new Radiation Therapy Oncology Group trial using paclitaxel and irradiation combined with a second radiation sensitizer, gemcitabine, now under way.

Overexpression of the HER-2/neu oncogene in pancreatic adenocarcinoma.

Novel systemic treatments are needed in pancreatic cancer. The authors sought to establish the frequency of overexpression of the HER-2/neu oncogene in patients with pancreatic adenocarcinoma to determine the potential role of trastuzumab (Herceptin) as a therapeutic agent in this disease. Tumor specimens from patients with pancreatic adenocarcinoma were analyzed by staining for p185HER2 protein using the DAKO immunohistochemical assay. Patients with and without HER-2/neu overexpression by immunohistochemistry were compared with respect to clinical and pathologic characteristics. HER-2/neu gene amplification was also evaluated by fluorescence in situ hybridization (FISH). Thirty-two of 154 patients (21%) had pancreatic adenocarcinoma that demonstrated HER-2/neu overexpression by immunohistochemistry. At initial diagnosis, 16% of resectable cancers, 17% of locally advanced cancers, and 26% of metastatic cancers were determined to have HER-2/neu overexpression. Three of 11 (27%) patients with HER-2/neu overexpression by immunohistochemistry had gene amplification by FISH. HER-2/neu overexpression occurs in a subset of pancreatic cancer. Evaluation of the efficacy of trastuzumab for patients with pancreatic cancer who overexpress HER-2/neu appears indicated.

Surgical resection is necessary to maximize tumor control in function-preserving, aggressive chemoradiation protocols for advanced squamous cancer of the head and neck (stage III and IV).

BACKGROUND: The role of surgery in aggressive chemoradiation protocols for advanced head and neck cancer has been questioned because of the quoted high clinical response rates in many series. METHODS: The role of surgical resection was examined in an aggressive neoadjuvant protocol of weekly paclitaxel, carboplatin, and radiation for stage III and IV with completion of radiation to 72 Gy if biopsy at the primary site was negative after administration of 45 Gy. Of 43 patients enrolled, 38 completed the protocol. The clinical response was 100% (including 18 complete and 20 partial responses). RESULTS: The complete pathologic response (negative primary site biopsy at 45 Gy) was 25 of 38 (66%). Of patients who presented with N1 to N3 nodes, neck dissection revealed residual nodal metastases in 22%. Surgical resection of the primary site was required in 13 patients, including 5 with larynx cancer and 2 with base of tongue cancers. Four patients had resection with reconstruction for advanced mandible floor of mouth cancer, and one had resection of nasal-maxillary cancer. Functional resection was performed in 9 of 12 patients. The median progression free and overall survival was 64% and 68%, respectively, at median follow-up of 50 months. Nine patients developed recurrence (three local and six distant). There were no failures in the neck. Salvage surgery was performed in one patient with local and one with distant disease. CONCLUSIONS: Surgical resection is an essential component of aggressive chemoradiation protocols to ensure tumor control at the primary site and in the neck.

Paclitaxel, cisplatin, and concurrent radiation for esophageal cancer.

Paclitaxel is an active agent for adenocarcinomas and squamous cell carcinomas of the esophagus and is a radiation sensitizer. We sought to investigate the toxicity and complete response rate of paclitaxel, cisplatin, and concurrent radiation for esophageal cancer. Forty-one patients with esophageal cancer were studied, 29 with adenocarcinomas and 12 with squamous cell cancers. Twelve patients had tumor extension into the proximal stomach and/or abdominal adenopathy. Patients received paclitaxel 60 mg/m2 by 3-hour intravenous (i.v.) infusion, and cisplatin 25 mg/m2 weekly on days 1, 8, 15, and 22. Radiation was administered concurrently to a total dose of 39.60 Gy, in 1.80 Gy fractions, for 22 treatments. Patients with medical or surgical contraindications to esophagectomy received 2 additional weeks of paclitaxel with a radiation boost to 50.4 Gy. Neutropenia was the most common grade 3/4 toxicity occurring in 10 patients (24%). Only 2 patients (5%) had grade 4 esophagitis requiring parenteral nutrition. Twelve patients (29%) obtained a complete response. The 2-year progression-free and overall survival rates were 40% and 42%, respectively. Esophagitis was less severe than expected and prophylactic enteral feeding tubes were not necessary. Additional effective systemic treatments are needed to reduce the development of distant metastases.

Paclitaxel and concurrent radiation for locally advanced pancreatic cancer.

PURPOSE: To determine the activity and toxicity of paclitaxel and concurrent radiation for pancreatic cancer. METHODS AND MATERIALS: Forty-four patients with locally unresectable pancreatic cancer were studied. Patients received paclitaxel, 50 mg/m(2) by 3 h i.v. (IV) infusion, weekly, on Days 1, 8, 15, 22 and 29. Radiation was administered concurrently to a total dose of 50.4 Gy, in 1.80 Gy fractions, for 28 treatments. RESULTS: Nausea and vomiting were the most common toxicities, Grade 3 in five patients (12%). Two patients (5%) had Grade 4 hypersensitivity reactions to their first dose of paclitaxel. Of 42 evaluable patients, the overall response rate was 26%. The median survival was 8 months, and the 1-year survival was 30%. CONCLUSION: Concurrent paclitaxel and radiation demonstrate local-regional activity in pancreatic cancer. Future investigations combining paclitaxel with other local-regional and systemic treatments are warranted.

p53 mutations do not predict response to paclitaxel in metastatic nonsmall cell lung carcinoma.

BACKGROUND: In vitro data and animal studies suggest that paclitaxel may have a unique ability to activate tumor cell apoptosis in the absence of wild-type p53 function. The authors previously demonstrated that response to paclitaxel and concurrent radiation was not affected by p53 mutations in nonsmall cell lung carcinoma (NSCLC). We sought to determine whether p53 mutations affect response to paclitaxel alone in patients with metastatic NSCLC. METHODS: Twenty-five patients with metastatic NSCLC who participated in Brown University Oncology Group protocols utilizing single-agent weekly paclitaxel had tumor tissue that was adequate for p53 analysis. Tumor tissue was evaluated for p53 gene mutations in exons 5 through 8 by single-strand conformation polymorphism analysis. Mutations were confirmed by direct sequencing of altered mobility polymerase chain reaction products. RESULTS: Mutations in p53 were found in 8 of 25 patients (32%). The response rates of 75% for patients with tumors with p53 mutations and 47% for patients with wild-type p53 do not differ significantly (P = 0.12). The 1-year survival rates for patients with and without p53 mutation after treatment with weekly paclitaxel were 63% (95% confidence interval [CI], 31-100%) and 53% (95% CI, 33-86%), respectively. CONCLUSIONS: p53 mutations do not adversely affect response to paclitaxel as a single agent in metastatic NSCLC. These results provide clinical support for in vitro observations that paclitaxel can bypass mutant p53 and lead to tumor cell death by alternate pathway(s). Paclitaxel should be considered as a component of treatment for patients with metastatic NSCLC with tumors that have p53 mutations.

Paclitaxel and concurrent radiation for gastric cancer.

PURPOSE: To determine the activity and toxicity of paclitaxel and concurrent radiation for gastric cancer. METHODS AND MATERIALS: Twenty-seven patients were studied. Twenty-five had proximal gastric cancers, two had distal cancers. Eight had esophageal extension, 6 had celiac adenopathy, and 7 had retroperitoneal adenopathy. Patients received paclitaxel, 50 mg/m(2) by 3-hour intravenous (IV) infusion, weekly, on days 1, 8, 15, 22, and 29. Radiation was administered concurrently to a total dose of 45.0 Gy, in 1.80 Gy fractions, for 25 treatments. Patients who were medically or surgically inoperable received a sixth week of paclitaxel with a radiation boost to 50.4 Gy. RESULTS: Esophagitis and gastritis were the most important toxicities, Grade 3 in four patients (15%), and Grade 4 in three patients (11%). Five patients (19%) had Grade 3 nausea. The overall response rate was 56%, including three patients (11%) with a complete response. The 2-year progression-free and overall survival rates were 29% and 31%, respectively. CONCLUSION: Concurrent paclitaxel and radiation demonstrates substantial local-regional activity in gastric cancer. Future investigations combining paclitaxel and radiation with other local-regional and systemic treatments are warranted.

Role of p53 and p16 gene alterations in determining response to concurrent paclitaxel and radiation in solid tumor.

Molecular genetic alterations that disturb cell cycle regulation in tumor cells can affect their response to chemotherapeutic agents and radiation. Many genes that regulate the critical cell cycle checkpoint at G1S are altered in human tumors. These genetic changes can result in uncontrolled cellular proliferation, genetic instability, and altered response to radiation and chemotherapy. The p53 tumor suppressor gene serves a critical role at the G1S transition, where it can either block entry into S phase or activate programmed cell death (apoptosis) in response to DNA damage. p53 Gene mutations are common in human tumors and interfere with the activation of apoptosis in response to most chemotherapeutic agents. Paclitaxel is a potent chemotherapeutic agent that interferes with mitotic spindle function to block cells at G2M, the most radiosensitive phase of the cell cycle. Utilization of paclitaxel as a radiation sensitizer in vivo to treat aggressive, locally advanced neoplasms has resulted in high response rates and acceptable toxicity in protocols for non-small cell lung carcinoma, upper gastrointestinal tract carcinoma, and other malignancies. Recent evidence suggests that paclitaxel is unique in its ability to activate apoptosis in tumor cells with p53 mutations in vitro and in vivo. The p16(INK4a) (MTS-1, CDKN2) gene product acts in the same pathway as p53 to inhibit cell cycle progression at G1/S. p16(INK4a) is deleted and/or mutated in a significant fraction of human tumors, including pancreatic carcinoma. The effects of p16(INK4a) alterations in response to paclitaxel/radiation and the risk of systemic relapse are currently being evaluated. Information about molecular genetic alterations in individual tumors ultimately may be a critical factor in choosing between therapeutic options.

Paclitaxel and concurrent radiation therapy for locally advanced adenocarcinomas of the pancreas, stomach, and gastroesophageal junction.

An effective locoregional therapy is needed for adenocarcinomas of the pancreas, stomach, and gastroesophageal junction. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) may enhance the effect of radiation therapy (RT). Paclitaxel synchronizes cells at G2/M, a relatively radiosensitive phase of the cell cycle. We have shown that response to paclitaxel and concurrent RT (paclitaxel/RT) was not affected by p53 mutations in non-small cell lung cancer. This finding suggested that paclitaxel/RT was a rational treatment approach for other malignancies that frequently harbor p53 mutations, such as upper gastrointestinal malignancies. We completed a phase I study of paclitaxel/RT for locally advanced pancreatic and gastric cancer. The maximum tolerated dose of paclitaxel was 50 mg/m2/wk for 6 weeks with abdominal RT. The dose-limiting toxicities were abdominal pain within the radiation field, nausea, and anorexia. Phase II studies are now under way. Twenty-five patients with locally advanced pancreatic cancer have been entered at the phase II dose level of paclitaxel 50 mg/m2/wk with concurrent RT (total dose, 50 Gy). Thus far, the only grade 3/4 toxicities have been hypersensitivity reactions (n = 2), asymptomatic grade 4 neutropenia (n = 3), and nonneutropenic biliary sepsis (n = 1). Of the first 18 assessable patients with pancreatic cancer treated on the phase II study, six obtained a partial response, for a preliminary response rate of 33%. In the phase II study for locally advanced gastric cancer, 20 patients have been enrolled. Of the first 19 patients who have completed treatment, nine (47%) had grade 3/4 toxicities, including nausea, anorexia, esophagitis, and gastritis. Of the first 16 patients with gastric cancer, complete and partial responses have been observed in one and eight patients, respectively, for a preliminary response rate of 56%. We have also completed treatment on 24 patients with potentially resectable adenocarcinomas of the gastroesophageal junction with neoadjuvant paclitaxel 60 mg/m2 and cisplatin 25 mg/m2, weekly for 4 weeks, with concurrent RT (total dose, 40 Gy) followed by surgical resection. Ten patients (41%) had grade 3/4 toxicities, including neutropenia, nausea, and dehydration. Of 24 patients, four complete responses (17%) and 14 partial responses (58%) were observed, for an overall response rate of 75%. Severe esophagitis was uncommon, making this a well-tolerated outpatient regimen for adenocarcinomas of the distal esophagus. These findings demonstrate that paclitaxel-based chemoradiation for locally advanced upper gastrointestinal malignancies is well-tolerated with substantial activity.

Chemoradiotherapy for advanced inoperable head and neck cancer: A phase II study.

The beneficial effects of chemotherapy in patients with advanced head and neck cancer remain controversial in terms of survival, but have shown some promise in improving locoregional control and quality of life. In an effort to improve locoregional control and survival, a prospective phase II study was initiated using paclitaxel and carboplatin with concurrent conventional fractionated external-beam radiotherapy. Paclitaxel and carboplatin have both shown excellent radiosensitization through two discrete mechanisms, cell blockage in G2/M phase and inhibition of DNA repair, respectively. Patients were stratified as either operable or inoperable. This report pertains to the inoperable patient group, who received eight cycles of weekly paclitaxel (60 mg/m2), carboplatin (area under the concentration-time curve of 1) with conventional radiotherapy (72 Gy). Chemoradiotherapy was followed by neck dissection for those patients who presented with clinically palpable lymph nodes. Thirty-three patients were enrolled in this group (23 men and 10 women with a median age of 56 years). Eleven patients (33%) had stage III disease; 22 (67%), stage IV disease. The median follow-up period was 14 months. Clinical complete response occurred in 20 patients (60%) and partial response occurred in 10 (30%), for an overall response rate of 90%. Following completion of therapy, 18 patients have undergone biopsy at the primary tumor site and 17 were negative. Eight of the 16 patients with clinically palpable neck nodes at presentation underwent neck dissection; five (63%) had negative nodes. Mucositis was the most common toxicity. Grade 3 or 4 mucositis occurred in 30 of the 33 (90%) patients. Other grade 3 or 4 toxicities included skin (22%), candidiasis (19%), neutropenia (9%), and dehydration (6%). One patient with laryngeal carcinoma who had pathologic complete response developed cartilage necrosis and is undergoing hyperbaric oxygen therapy. Survival data are early but encouraging. Concurrent paclitaxel, carboplatin, and external-beam radiotherapy yielded excellent clinical and pathologic responses. Mucositis remains the most common and significant morbidity. The study will continue for necessary accrual.