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Forty-three patients with local-regional squamous-cell carcinoma of the esophagus or adenocarcinoma of the esophagus, cardia, or gastroesophageal junction were treated with concurrent cisplatin, vinblastine, fluorouracil (5-FU), and radiation therapy (RT) over 21 days. A transhiatal esophagectomy (THE) was planned on day 42. Seventy-nine percent had T2 primaries by clinical staging and 56% had enlarged regional nodes (N) on computed tomographic (CT) scan. Forty-one patients completed the preoperative treatment and went to surgery (95% operability rate), and 36 (84%) were completely resected. Ten of the 41 operative candidates had no evidence of tumor in the resected esophagus and nodal tissue (tumor0 node0; T0N0), 24% complete response (CR). Myelosuppression was the major toxicity with grade 3 or 4 leukopenia in 93% of patients and two preoperative treatment-related deaths. At a median follow-up of 26 months, the median survival time (MST) of all 43 patients registered on study has not been reached. The MST of the 36 completely resected patients and the 10 complete responders has not been reached; 70% and 100%, respectively, are alive at 24 months. The MST by histology is 21 months for the 22 squamous patients and has not been reached for the 21 adenocarcinoma patients registered on study. In a prognostic factor analysis, clinical N status, histology, and the percent of cisplatin and vinblastine tolerated were significant predictors for survival. These survival results suggest a significant improvement over the 14-month MST observed in our previous trial using preoperative chemotherapy only in a similar patient population, and a 12-month MST in a historic control group undergoing THE. A randomized trial is now in progress to convincingly determine if survival is prolonged by this therapy.

Purpose The feasibility of combining concomitant boost-accelerated radiation regimen (AFX-C) with cisplatin was previously demonstrated in this Phase II trial. This article reports the long-term toxicity, relapse patterns, and survival in patients with advanced head and neck carcinoma. Methods and Materials Between April and November 2000, 84 patients with Stage III–IV HNC were enrolled, and 76 patients were analyzable. Radiation consisted of 72 Gy over 6 weeks. Cisplatin dose was 100 mg/m 2 on Days 1 and 22. Tumor and clinical status were assessed, and acute-late toxicities were graded. Results The median follow-up for surviving patients is 4.3 years. The 2- and 4-year locoregional failure rates were 33% and 36%, respectively, and the 2- and 4-year survival rates were 70% and 54%, respectively. The worst overall late Grade 3 or 4 toxicity rate was 42%. The prevalence rates of a gastrostomy at any time during follow-up, at 12 months, and at 48 months were 83%, 41%, and 17%, respectively. Five of 36 patients (14%) alive and without disease at last follow-up were gastrostomy-tube dependent. Conclusion These data of long-term follow-up of patients treated with AFX-C with cisplatin show encouraging results with regard to locoregional disease control and survival, with few recurrences after 2 years. The late toxicity rates are relatively high. However, although prolonged dysphagia was noted in our preliminary report, its prevalence does decreased over time. A Phase III trial comparing AFX-C plus cisplatin against standard radiation plus cisplatin has completed accrual.

The abrogation of function of the tumor-suppressor protein p53 as a result of mutation of its gene, TP53, is one of the most common genetic alterations in cancer cells. We evaluated TP53 mutations and survival in patients with squamous-cell carcinoma of the head and neck.A total of 560 patients with squamous-cell carcinoma of the head and neck who were treated surgically with curative intent were enrolled in our prospective multicenter, 7-year study. TP53 mutations were analyzed in DNA from the tumor specimens with the use of the Affymetrix p53 chip and the Surveyor DNA endonuclease and denaturing high-performance liquid chromatography. Mutations were classified into two groups, disruptive and nondisruptive, according to the degree of disturbance of protein structure predicted from the crystal structure of the p53-DNA complexes. TP53 mutational status was compared with clinical outcome.TP53 mutations were found in tumors from 224 of 420 patients (53.3%). As compared with wild-type TP53, the presence of any TP53 mutation was associated with decreased overall survival (hazard ratio for death, 1.4; 95% confidence interval [CI], 1.1 to 1.8; P=0.009), with an even stronger association with disruptive mutations (hazard ratio, 1.7; 95% CI, 1.3 to 2.4; P0.001) and no significant association with nondisruptive mutations (hazard ratio, 1.2; 95% CI, 0.9 to 1.7; P=0.16). In multivariate analyses a disruptive TP53 alteration, as compared with the absence of a TP53 mutation, had an independent, significant association with decreased survival (hazard ratio, 1.7; 95% CI, 1.2 to 2.4; P=0.003).Disruptive TP53 mutations in tumor DNA are associated with reduced survival after surgical treatment of squamous-cell carcinoma of the head and neck.

The combination of chemotherapy, fluorouracil and cisplatin, and radiation has improved outcome for patients with esophageal cancer. A randomized controlled trial confirmed a long-term survival benefit when this chemotherapy was added to radiotherapy for squamous cell carcinoma, but the approach has not been definitively assessed in patients with adenocarcinoma. Preoperative chemoradiotherapy has been tested in numerous phase II studies and underpowered or flawed phase III studies. Nevertheless, collectively, the evidence strongly suggests that preoperative chemoradiotherapy improves outcome, and thus, this strategy has become a standard treatment option. Attempts to improve outcome by intensifying conventional cytotoxic drugs or increasing the radiation dose have not been successful. Camptothecin and taxane-based regimens combined with radiation have altered the toxicity profile, but substantial improvement in survival outcomes has yet to be demonstrated. Future improvements will likely require the incorporation of targeted agents that add minimally to existing toxicity, the use of molecular predictors of response to individualize selection of the chemotherapeutic regimen, and early identification of responders such that therapy might be altered dynamically.

Purpose Taxane-based concurrent chemoradiotherapy (CCR) for head and neck cancers has proven to have a favorable toxicity profile compared with cisplatin and radiation. This phase II multi-institutional trial evaluates taxane-based induction chemotherapy followed by CCR for organ preservation in resectable stage III/IVA and IVB larynx and oropharynx (OP) cancer patients. Patients and Methods Eligibility required resectable stage T2N+, or T3-T4N0-3M0 biopsy-proven squamous carcinoma, age at least 18 years, PS 0 to 2, good organ function, and no prior chemotherapy or radiation. Treatment was induction paclitaxel 175 mg/m2 and carboplatin area under the concentration-time curve (AUC) 6 for two cycles every 21 days followed by concurrent paclitaxel 30 mg/m2 every 7 days with 70 Gy if no evidence of tumor progression. Weekly erythropoietin alpha 40 kU was used for suboptimal hemoglobin (< 14 gm/dL men, < 13 gm/dL women). The primary end point was organ preservation (freedom from primary site salvage surgery or primary tumor recurrence). Results One hundred five of 111 patients (36 larynx, 69 OP) were eligible. Median follow-up was 36.7 months. Ninety-four percent received full-dose radiotherapy and 91% received at least five cycles of concurrent paclitaxel. No patient progressed while receiving chemotherapy. Organ preservation was 81% at 2 years after completion of therapy (larynx 74%, OP 84%). Thirteen patients required primary-site salvage surgery (seven larynx, six OP), and six of these have progressed and died (three larynx, three OP). Thirteen patients developed distant metastases (seven larynx, six OP; P = .02) and 10 of 36 larynx and 11 of 69 OP patients have died as a result of their disease. Two-year survival is 76% (63% larynx v 83% OP). Conclusion A high organ preservation rate was obtained with this regimen for OP but not for larynx patients. Toxicity was low, and induction chemotherapy did not preclude delivery of concurrent chemoradiotherapy.

Barrett’s esophagus is a premalignant condition in which normal squamous epithelium of the esophagus is replaced by specialized columnar mucosa. It occurs as a result of chronic gastroesophageal reflux and is associated with an increased risk of developing esophageal adenocarcinoma. The incidence of esophageal adenocarcinoma in the United States is rapidly increasing (1–4). The 5-year survival rate after surgical resection of esophageal cancer is approximately 24% (5). Although clinical trials evaluating potential new agents and new approaches in the treatment of esophageal adenocarcinoma are underway, this disease remains associated with high morbidity and mortality. Strategies to prevent or reverse esophageal tumorigenesis include antireflux surgery, aggressive medical management of acid secretion, and ablation of premalignant tissue (6–8). With the exception of Barrett’s mucosal ablation with photodynamic therapy for patients with high-grade dysplasia, most strategies have not been effective (9). Photodynamic therapy can ablate high-grade dysplasia and substantially decrease the incidence of adenocarcinoma, but it is expensive and associated with adverse reactions, including prolonged photosensitivity, chest pain, and esophageal stricture (9). Hence, there is an urgent need for newer agents and/or methods to decrease the risk of progression from dysplasia to this deadly cancer. Several epidemiologic studies (10–13) have found that, among patients at risk for esophageal cancer, treatment with aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a decreased risk of esophageal cancer. One potential mechanism for chemoprevention is inhibition of cyclooxygenase (COX), an enzyme that is crucial to the synthesis of prostaglandins (PGs) from arachidonic acid (14). Esophageal tumorigenesis has been associated with overexpression of the inducible COX isoform COX-2 (15). Treatment with a COX-2 inhibitor led to a reduction in esophageal adenocarcinomas in an animal model of Barrett’s esophagus (16). We report the results of Chemoprevention for Barrett’s Esophagus Trial (CBET), a phase IIb randomized, parallel treatment, placebo-controlled, double-masked multicenter trial evaluating the long-term administration of celecoxib, a selective COX-2 inhibitor, in Barrett’s esophagus patients with lowor high-grade dysplasia.

6022 Background: The addition of B, an anti-VEGF monoclonal antibody, to chemotherapy has improved outcomes in several solid tumors. Pemetrexed plus B in R/M SCCHN showed promising efficacy but sig...

e17036 Background: In preclinical HNSCC models, combined EGFR and Src inhibition with radiation has additive and possibly synergistic effects. We conducted a 3+3 standard Ph1 trial to determine the...

Purpose To develop a clinical practice guideline for treatment of laryngeal cancer with the intent of preserving the larynx (either the organ itself or its function). This guideline is intended for use by oncologists in the care of patients outside of clinical trials. Methods A multidisciplinary Expert Panel determined the clinical management questions to be addressed and reviewed the literature available through November 2005, with emphasis given to randomized controlled trials of site-specific disease. Survival, rate of larynx preservation, and toxicities were the principal outcomes assessed. The guideline underwent internal review and approval by the Panel, as well as external review by additional experts, members of the American Society of Clinical Oncology (ASCO) Health Services Committee, and the ASCO Board of Directors. Results Evidence supports the use of larynx-preservation approaches for appropriately selected patients without a compromise in survival; however, no larynx-preservation approach offers a survival advantage compared with total laryngectomy and adjuvant therapy with rehabilitation as indicated. Recommendations All patients with T1 or T2 laryngeal cancer, with rare exception, should be treated initially with intent to preserve the larynx. For most patients with T3 or T4 disease without tumor invasion through cartilage into soft tissues, a larynx-preservation approach is an appropriate, standard treatment option, and concurrent chemoradiotherapy therapy is the most widely applicable approach. To ensure an optimum outcome, special expertise and a multidisciplinary team are necessary, and the team should fully discuss with the patient the advantages and disadvantages of larynx-preservation options compared with treatments that include total laryngectomy.

Summary Head and neck cancers are a complex group of diseases defined by variations in histological features, anatomical location, and cause. Once the realm of surgeons and radiation oncologists, the treatment of locally advanced disease now involves medical oncologists. Major developments include primary chemoradiotherapy for unresectable disease and organ preservation, the addition of chemotherapy to adjuvant radiotherapy, improvement in surgical and radiation techniques, and biological therapies. Concomitant chemoradiotherapy consistently improves locoregional control. However, control of distant metastases is poor, resulting in an increasing proportion of deaths from systemic recurrence. Given this shift in site of recurrence, therapeutic strategies to suppress distant metastases may be the next goal for further improvement of survival. One approach that merits reassessment is the use of induction chemotherapy in the setting of locally advanced disease—both resectable and unresectable. In this review we summarise data for the use of induction chemotherapy to define better which patients will likely benefit from this approach now and which questions are important in the design of future clinical trials.

Claudins are components of tight junctions important in intercellular barriers and cell polarity. The authors identified upregulation of Claudins 3, 4, and 7 in gastric adenocarcinoma using Affymetrix U-133 oligonucleotide microarrays and immunohistochemistry (IHC). While normal gastric mucosa lacked Claudin 3, 4, and 7 expression, intestinal metaplasia and dysplasia showed these proteins. The authors hypothesized that Claudins would be similarly overexpressed in Barrett's esophagus (BE)/adenocarcinoma. Claudins 3, 4, and 7 gene expression was analyzed by Affymetrix U-133 microarrays in three esophageal adenocarcinomas, one case of BE, and three normal esophagi. IHC validation was performed using tissue microarrays constructed from esophageal resection specimens containing squamous (44 cases), gastric (40 cases), and non-dysplastic BE (16 cases), low-grade and high-grade dysplasia (16 and 26 cases), adenocarcinoma (58 cases), and nodal metastases (27 cases). IHC staining was scored semiquantitatively (0+ to 4+). By microarray analysis, Claudin 3 showed a marked increase in mRNA expression compared with normal esophagus (approximately 100-fold). Claudins 4 and 7 were modestly increased (2.2- and 1.3-fold). By IHC, Claudin 3 expression was 1+ in most (>95%) normal squamous or gastric tissues and 2+ to 4+ in more than 80% of high-grade dysplasia, adenocarcinoma, and metastases specimens. Claudin 4 protein expression was 2+ or less in most squamous and gastric mucosa (>90%) but 3+ or 4+ in BE, low- and high-grade dysplasia, adenocarcinoma, and metastases specimens (>90%). Claudin 7 expression was minimal in squamous and gastric mucosa but strong (3+ to 4+) in BE and low-grade dysplasia. In high-grade dysplasia, adenocarcinoma, and metastases, Claudin 7 was less intense, with 60% to 70% staining 3+ or 4+ and 30% to 40% staining weakly (1+ or 2+). The findings suggest that alterations in Claudin proteins are an early event in tumorigenesis and may provide targets for diagnosis and directed therapy for esophageal adenocarcinoma and its precursors.

Factors predicting sensitivity to epidermal growth factor receptor (EGFR) blockade are largely unknown and new strategies are being sought to individualize cancer therapy. This study evaluated the variation in the expression of the early response gene c-fos as a distal effect of EGFR inhibition and its relationship to antitumor effects. The growth-inhibitory and c-fos–modulating effects of gefitinib and erlotinib in human cancer cell lines (A431, CAL27, HN11, HuCCT1, and Hep2) were determined. Next, these cell lines were xenografted in mice and treated for 14 days with gefitinib (A431 and HuCCT1) or erlotinib (CAL27, HN11, and Hep2). Fine needle aspiration biopsy of tumors was done at baseline and after 14 days of therapy for c-fos assessment. In addition, we tested the feasibility of analyzing this marker in five paired tumor samples from a clinical trial of gefitinib in patients with solid tumors. In culture, gefitinib and erlotinib decreased c-fos mRNA levels in the susceptible cell lines A431, CAL27, and HN11; however, both drugs failed to achieve c-fos inhibition in resistant cells. Gefitinib or erlotinib abrogated the increase in c-fos expression in vivo in EGFR-sensitive A431, CAL27, and HN11 tumors but not in resistant strains. Ex vivo evaluation was feasible and predicted in vivo effects. The feasibility study in paired human tumor biopsies showed that this biomarker can be reliably measured in clinical materials. In summary, variations in c-fos expression reflect the pharmacologic actions of EGFR inhibitors in in vitro and in vivo models. (Cancer Res 2006; 66(4): 2385-90)

Background. Malignant tumors of the salivary glands make up approximately 5% of head and neck cancers. The Eastern Cooperative Oncology Group (ECOG) initiated a phase II evaluation of paclitaxel in patients with locally recurrent or metastatic salivary gland malignancies. Methods. Chemo-naive patients with histologically confirmed recurrent or metastatic carcinoma of salivary gland origin (mucoepidermoid, adenocarcinoma, or adenoid cystic) were eligible. Patients were treated with paclitaxel, 200 mg/m2 IV, every 21 days for a minimum of four cycles. Results. Forty-five patients were treated. Eight partial responses were seen among the 31 patients with mucoepidermoid or adenocarcinoma histologic findings for a response rate of 26%. No responses were seen in the adenoid cystic carcinoma group. No significant difference in overall survival was found among these three histologic subgroups. Conclusion. Paclitaxel demonstrates moderate activity in salivary gland tumors of mucoepidermoid and adenocarcinoma histology. The poor response rate in adenoid cystic carcinoma is consistent with prior reports in this chemoresistant histologic subtype. © 2006 Wiley Periodicals, Inc. Head Neck28: 197–204, 2006

Purpose Therapy of recurrent/metastatic squamous cell carcinoma of the head and neck results in median progression-free survival (PFS) of 2 months. These cancers are rich in epidermal growth factor receptor (EGFR). We wished to determine whether the addition of cetuximab, which inhibits activation of EGFR, would improve PFS. Patients and Methods Patients with recurrent/metastatic squamous cell carcinoma of the head and neck were randomly assigned to receive cisplatin every 4 weeks, with weekly cetuximab (arm A) or placebo (arm B). Tumor tissue was assayed for EGFR expression by immunohistochemistry. The primary end point was PFS. Secondary end points of interest were response rate, toxicity, overall survival, and correlation of EGFR with clinical end points. Results There were 117 analyzable patients enrolled. Median PFS was 2.7 months for arm B and 4.2 months for arm A. The hazard ratio for progression of arm A to arm B was 0.78 (95% CI, 0.54 to 1.12). Median overall survival was 8.0 months for arm B and 9.2 months for arm A (P = .21). The hazard ratio for survival by skin toxicity in cetuximab-treated patients was 0.42 (95% CI, 0.21 to 0.86). Objective response rate was 26% for arm A and 10% for arm B (P = .03). Enhancement of response was greater for patients with EGFR staining present in less than 80% of cells. Conclusion Addition of cetuximab to cisplatin significantly improves response rate. There was a survival advantage for the development of rash. Progression-free and overall survival were not significantly improved by the addition of cetuximab in this study.

The gene that encodes methylthioadenosine phosphorylase (MTAP), an enzyme involved in adenine and methionine salvage pathways, is located on chromosome 9p21 telomeric to the p16INK4A/CDKN2A tumor suppressor gene. Inactivation of the p16INK4A/CDKN2A gene occurs by three different mechanisms: hypermethylation of the gene promoter, intragenic mutation coupled with loss of the second allele, and homozygous deletion. Immunohistochemical labeling for the p16INK4A/CDKN2A gene product parallels gene status but does not elucidate the mechanism of gene inactivation. Since the MTAP gene is often co-deleted with p16INK4A/CDKN2A, concurrent immunolabeling for both proteins can identify cases with homozygous p16INK4A/CDKN2A gene deletion. MTAP loss itself has therapeutic implications since it may confer selective sensitivity to inhibitors of de novo purine biosynthesis, such as L-alanosine. Twelve tissue microarrays were constructed from 92 cases of Barrett-associated adenocarcinomas and precursor lesions and 112 cases of gastric adenocarcinoma and precursor lesions comprising 1161 individual cores. Multiple cores were arrayed from any given case, and when available, included the entire histologic spectrum of intestinal metaplasia-dysplasia-carcinoma. Tissue microarrays were labeled with monoclonal antibodies against MTAP protein (clone 6.9, Salmedix, Inc) and p16 (clone 16P07, Neomarkers). Complete loss of labeling was considered negative, while any labeling (p16: nuclear; MTAP: cytoplasmic and nuclear) was considered positive. Loss of MTAP labeling occurred exclusively in conjunction with loss of p16 labeling, confirming that the previous findings from this group that concurrent loss of MTAP and p16 labeling is a surrogate marker of 9p21 homozygous deletions. Complete loss of MTAP and p16 was seen in 4 of 25 (16%) patients with Barrett's esophagus, 4 of 18 (22%) with low-grade dysplasia, 5 of 39 (13%) with high-grade dysplasia, 17 of 78 (22%) with invasive adenocarcinoma, and 8 of 36 (22%) of metastases. There were 7 cases of esophageal adenocarcinoma with loss of both MTAP and p16 for which precursor lesions were available. In 6 on these 7 cases (85%), the precursor lesion(s) had loss of both MTAP and p16. Lack of MTAP and p16 expression was seen in 11 of 106 (10%) cases of gastric adenocarcinoma. All metaplastic (30 biopsies from 20 cases) and dysplastic (15 biopsies from 13 cases) gastric tissues had both intact MTAP and p16INK4A/CDKN2A gene products. No precursor lesions were available from the gastric cancers that had loss of both MTAP and p16. Two benign gastric hyperplastic polyps also had intact p16 and MTAP. Concurrent MTAP and p16 loss detected by immunohistochemistry can serve as a convenient surrogate for p16INK4A/CDKN2A gene homozygous deletion in archival tissues. Inactivation of p16INK4A/CDKN2A by homozygous deletion appears to be an early event in Barrett carcinogenesis, occurring in noninvasive precursor lesions, including nondysplastic Barrett mucosa, in subsets of cases. In the absence of MTAP, cells depend exclusively on the de novo synthesis pathway for production of adenosine. This loss of MTAP during 9p21 homozygous deletion might be exploited therapeutically using de novo purine synthesis antimetabolites to treat a subset of invasive gastroesophageal adenocarcinomas and esophageal precursor lesions.

Purpose To determine the response rate, survival and toxicity of infusional cisplatin plus fluorouracil (CF) versus cisplatin plus paclitaxel (CP) in patients with incurable squamous cell cancer of the head and neck, with the hypothesis that CP is superior. Patients and Methods Two hundred eighteen patients with locally advanced, recurrent, or metastatic disease were randomly assigned to CF (cisplatin 100 mg/m2 day 1 and fluorouracil 1,000 mg/m2/24 hours by continuous intravenous infusion day 1 through 4) or CP (cisplatin 75 mg/m2 day 1 and paclitaxel 175 mg/m2 over 3 hours on day 1). Cycles were repeated every 3 weeks until progression or a minimum of 6 cycles with complete response or stable disease. The primary outcome was overall survival. Secondary outcomes included response rate and toxicity. Results No significant difference in overall survival or response rate was seen. Estimated median survival was 8.7 months in the CF group and 8.1 month in the CP group. Objective response rate (complete response plus partial response) was 27% in the CF group and 26% in the CP group. Toxicity was similar between groups, with the most frequent including myelosuppression, thrombocytopenia, anemia, nausea, vomiting, and stomatitis. A total of 12 deaths occurred (CF, seven; CP, five) during treatment; eight from infection, two from hemorrhage, one from cardiac causes and one from unknown causes. Gastrointestinal and hematologic toxicities were more common in the CF group, whereas neurotoxicity was equivalent between groups. Conclusion This phase III, randomized, multicenter trial showed no difference in survival between patients treated with CF or CP.

Esophageal adenocarcinoma arises through well-defined precursor lesions (Barrett esophagus), although only a subset of these lesions advances to invasive adenocarcinoma. The lack of markers predicting progression in Barrett esophagus, typical presentation at advanced stage, and limitations of conventional chemotherapy result in90% mortality for Barrett-associated adenocarcinomas. To identify potential prognostic markers and therapeutic targets, we compared gene expression profiles from Barrett-associated esophageal adenocarcinoma cell lines (BIC1, SEG1, KYAE, OE33) and normal esophageal epithelial scrapings utilizing the Affymetrix U133_A gene expression platform. We identified 560 transcripts with3-fold up-regulation in the adenocarcinoma cell lines compared with normal epithelium. Utilizing tissue microarrays composed of normal esophageal squamous mucosa (n = 20), Barrett esophagus (n = 10), low-grade dysplasia (n = 14), high-grade dysplasia (n = 27), adenocarcinoma (n = 59), and node metastases (n = 27), we confirmed differential up-regulation of three proteins (Cdc2/Cdk1, Cdc5, and Igfbp3) in adenocarcinomas and Barrett lesions. Protein expression mirrored histologic progression; thus, 87% of low-grade dysplasias had at least focal surface Cdc2/Cdk1 and 20% had5% surface staining; 96% of high-grade dysplasias expressed abundant surface Cdc2/Cdk1, while invasive adenocarcinoma and metastases demonstrated ubiquitous expression. Esophageal adenocarcinoma cell lines treated with the novel CDC2/CDK1 transcriptional inhibitor, tetra-O-methyl nordihydroguaiaretic acid (EM-1421, formerly named M4N) demonstrated a dose-dependent reduction in cell proliferation, paralleling down-regulation of CDC2/CDK1 transcript and protein levels. These findings suggest a role for CDC2/CDK1 in esophageal adenocarcinogenesis, both as a potential histopathologic marker of dysplasia and a putative treatment target.

Purpose of review Head and neck cancer remains a significant cause of morbidity worldwide, with approximately 400,000 new cases per year. Ongoing advances in multidisciplinary management of this complex and multivaried disease process are resulting in improved function, quality of life, and survival. This review presents selected advances in primary research in head and neck cancer during the year 2003. Recent findings Successful management of head and neck cancer now requires a cooperative approach among a broad group of medical disciplines that includes head and neck surgery, radiation oncology, medical oncology, medical imaging, clinical pathology and lab medicine, social work, nutrition, and others. Translation of continued advances in these fields by cooperative work will continue to yield incremental advances in diagnosis, staging, treatment, follow-up, supportive care, and quality of life. Accordingly, this review aims to include facets of each individual field. Diagnosis and staging continue to evolve with the inclusion of nuclear medicine and in vivo molecular imaging based on the technology of positron emission tomography and single photon emission computed tomographic scanning. Multimodality approaches remain the forefront of intervention for patients with advanced disease. Facets that continue to be defined and studied include the best treatment order of the three disciplines of surgery, radiation, and chemotherapy; the refinement of radiation by altering fraction dose, sequence, and time course; radiosensitization by chemo- and biologic therapy; and the addition of novel, biologically targeted agents to these disciplines. Following from the side effects of these intensive treatments to a functionally critical part of the body are ongoing advances in supportive care and quality of life. Summary Head and neck cancer represents a collection of diseases that, although seemingly united by location and histology, on closer inspection represent a diverse collection of subcategories that often differ in pathogenesis, tumor biology, sublocation within the head and neck region, diagnosis, prognosis, treatment, and effect on quality of life. Given this complexity, it is not surprising that clinical management is also complicated and requires a cooperative effort among multiple subspecialties. This review of the current standard of care for patients with head and neck cancer aims to assist this diverse group of practitioners in caring for this complex group of patients.

Purpose To evaluate the outcome of elderly patients with head and neck cancer undergoing palliative chemotherapy. Patients and Methods We analyzed combined data from two mature phase III randomized trials conducted by the Eastern Cooperative Oncology Group (ECOG; trial E1393, which compared cisplatin plus paclitaxel at two dose levels, and trial E1395, which compared cisplatin plus fluorouracil to cisplatin plus paclitaxel) to evaluate the toxicity, objective response rates, and survival of patients 70 years or older versus their younger counterparts. All patients had previously untreated recurrent or metastatic squamous cell carcinoma of the head and neck and ECOG performance status 0 or 1. Results Fifty-three elderly patients were enrolled from a total of 399 eligible participants (13%). Elderly patients had similar objective response rates (28% v 33%) and median time to progression (5.25 v 4.8 months) compared with younger patients. The median survival was 5.3 v 8 months (Wilcoxon P = .06; log-rank P = .17) and the 1-year survival 26% v 33% for elderly and younger patients, respectively. Elderly patients had a significantly higher incidence of severe nephrotoxicity, diarrhea, and thrombocytopenia. A higher rate of toxic deaths was noted in the elderly but did not reach statistical significance (13% v 8%; P = .29). Conclusion Elderly patients were underrepresented in these studies. Fit elderly patients with recurrent or metastatic head and neck cancer sustained increased toxicities with cisplatin-based doublets but had comparable survival outcomes compared with younger patients. Strategies to ameliorate toxicities should be pursued in the elderly.

Barrett's esophagus is a premalignant condition in which normal squamous epithelium of the esophagus is replaced by metaplastic columnar epithelium. It is a known risk factor for the development of esophageal adenocarcinoma. With the incidence of esophageal adenocarcinoma rising, it is reasonable to study Barrett's esophagus as a potential target for therapy that may prevent, delay and/or reverse ongoing tumorigenic processes. Epidemiologic and animal studies support the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in the chemoprevention of several cancers, including esophageal cancer. Cyclo-oxygenase-2 (COX-2) inhibitors are a new class of NSAIDs that inhibit prostaglandin synthesis by selectively blocking the COX-2 enzyme. The COX-2 enzyme has been reported to be over-expressed in premalignant and malignant states, including in Barrett's esophagus and esophageal adenocarcinoma. The Chemoprevention for Barrett's Esophagus Trial (CBET) is a phase IIb, multicenter, randomized, double-masked, placebo-controlled study of the selective COX-2 inhibitor, celecoxib, in patients with Barrett's dysplasia. The sample size is 200 patients with high or low grade Barrett's dysplasia. Celecoxib is administered orally, 200 mg twice per day; the dosing schedule for placebo is the same. Randomization is stratified by dysplasia grade and by clinic. Endoscopy with biopsies is performed at specified time intervals according to the highest grade of dysplasia determined at randomization. The primary outcome measure is the change from baseline to 1 year in the proportion of biopsies exhibiting dysplasia. Secondary outcomes include change from baseline in the maximal grade, extent and surface area of dysplasia. Tertiary outcomes will include measurements of various relevant biomarkers.

We investigated aberrant methylation patterns in esophageal adenocarcinoma and correlated the findings to patient survival and tumor recurrence.Gene promoter methylation was performed in 82 samples from 41 esophagectomy patients consisting of 41 adenocarcinoma samples, each with its adjacent nonmalignant tissue, which included one sample with Barretts metaplasia. The methylation status of seven genes was determined. Epigenetic silencing was confirmed using immunohistochemical staining. Kaplan-Meier plots were constructed using disease-specific survival as the primary end point and the interval from surgery to tumor recurrence as the secondary end point. The association of clinicopathological and biomolecular risk factors to survival and recurrence was performed using the Log-rank test and Cox proportional hazards model for multivariate analysis.Methylation frequencies of the genes analyzed were APC, 68%; E-cadherin, 66%; O(6)-methylguanine DNA methyltransferase, 56%; ER, 51%; p16, 39%; DAP-kinase, 19%; and TIMP3, 19%. DNA methylation of some genes individually showed only trends toward diminished survival, whereas patients whose tumors had50% of their gene profile methylated had both significantly poorer survival (P = 0.04) and earlier tumor recurrence (P = 0.05) than those without positive methylation. By multivariate analysis, the hazard ratios (HRs) with positive methylation status were more powerful predictors of survival [HR 2.7 (1.14-6.45; 95% confidence interval)] and tumor recurrence [HR 2.5 (1.11-5.6)] than age (HR 2.03 and 1.96, respectively) or stage (HR 1.48 and 1.67, respectively).Our data suggest that positive methylation status for multiple genes in esophageal adenocarcinoma is a predictor of poor prognosis.

Objective To evaluate the incidence of morbidity, mortality, and disease control for patients requiring salvage total laryngectomy (TL) following organ preservation therapy. Design Patients entered into a 3-arm randomized prospective multi-institutional trial for laryngeal preservation who required TL following initial treatment. Setting The Radiation Therapy Oncology Group 91-11 trial for laryngeal preservation. Patients From 1992 to 2000, 517 evaluable patients were randomized to receive chemotherapy followed by radiation therapy (arm 1), concomitant chemotherapy and radiation therapy (arm 2), or radiation therapy alone (arm 3). Results Overall, TL was required in 129 patients. The incidence was 28%, 16%, and 31% in arms 1, 2, and 3, respectively ( P = .002). Of these, 7 patients (5%) required TL for aspiration or necrosis. Following TL, the incidence of major and minor complications ranged from 52% to 59% and did not differ significantly among the 3 arms. Pharyngocutaneous fistula was lowest in arm 3 (15%) and highest in arm 2 (30%) ( P >.05). There was 1 perioperative death. Local-regional control following salvage TL was 74% for arms 1 and 2 and 90% for arm 3. At 24 months, the overall survival was 69% (arm 1), 71% (arm 2), and 76% (arm 3) ( P >.73). Conclusions Laryngectomy following organ preservation treatment is associated with acceptable morbidity. Perioperative mortality is low but up to one third of patients will develop a pharyngocutaneous fistula. Local-regional control is excellent for this group of patients. Survival following salvage TL was not influenced by the initial organ preservation treatment.

Publisher Summary Organ-function preservation is applied to those situations in which the alternative treatment strategy is a surgery that results in substantial impairment of speech or swallowing function. Organ preservation, or more precisely, organ function conservation, can be achieved by combining chemotherapy and radiotherapy and reserving surgery to manage the neck, when indicated. The two nonsurgical strategies that have been tested extensively are induction chemotherapy followed by radiotherapy in responding patients and concurrent radiotherapy and chemotherapy. A combination of chemotherapy with a platinum agent and 5-fluorouracil has been utilized in the majority of clinical trials demonstrating benefits in local control and survival. However, this combination of chemotherapy is frequently associated with significant local-regional toxicity as well as hematologic toxicity. Concomitant, single-agent, low-dose daily cisplatin is an alternative to combination chemotherapy, as this regimen has demonstrated improved local control, progression-free survival, distant metastasis-free survival, and overall survival in two well-controlled trials when administered with conventional fractionation or hyperfractionated radiotherapy.

Background . Data suggest that preoperative chemoradiation improves survival in patients with stage II and III esophageal tumors. Whether preoperative therapy increases postesophagectomy morbidity and mortality has not been determined. This study evaluates our postoperative results after chemoradiation therapy. Methods . From 1989 through 1998, 120 consecutive patients underwent chemoradiation therapy followed by esophagectomy at our institution. The medical records for these patients were reviewed to determine patient age, sex, race, cell type, operative technique, complications, deaths, and length of hospital stay (LOS). Results . There were 106 (88%) men and 14 (12%) women with a mean age of 58 (32 to 77) years. White patients predominated (114 of 120, 95%); 98 (82%) had adenocarcinoma and 22 (18%) had squamous cell carcinoma. Operative technique was transhiatal in 91 (76%) patients, three-incision in 23 (19%), Ivor-Lewis in 4 (3%), and thoracoabdominal in 2 (2%). There was 1 death. Complications developed in 44 (37%) patients; 59% (13 of 22) of squamous cell carcinoma patients and 32% (31 of 98) of adenocarcinoma patients developed complications. Respiratory complications occurred in 32% (7 of 22) of squamous cell carcinoma patients and in 3% (3 of 98) of adenocarcinoma patients. Mean length of stay after surgery was 15 days (range 7 to 163). Conclusions . Postesophagectomy results after chemoradiation therapy are comparable to those reported after esophagectomy alone. Squamous cell carcinoma patients are nearly twice as likely to develop postoperative complications and are more likely to have respiratory complications than adenocarcinoma patients.

PURPOSE: To assess the antitumor activity and toxicity of docetaxel plus cisplatin chemotherapy in patients with recurrent or incurable squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Patients with recurrent or incurable SCCHN were eligible if they were chemotherapy naive or if they had received one prior regimen as neoadjuvant or concurrent treatment with radiation. Patients who had received chemotherapy for recurrence or prior taxanes were ineligible. Patients received docetaxel 75 mg/m2 and cisplatin 75 mg/m2 on day 1; cycles were repeated every 21 days. RESULTS: Toxic effects and length of survival were assessable in 36 patients and tumor response was assessable in 32, for whom the overall response rate was 40% (13 of 32) (6% complete response and 34% partial response). Median time to response was 5 weeks, and median duration was 4.9 months. In the intent to treat population (n = 36), median time to disease progression was 4 months. Median survival (n = 36) was 9.6 months, and the 12-month survival rate was 27%. Grade 4 neutropenia was observed in 71% of patients. Two patients (6%) experienced serious fever during grade 4 neutropenia (without documented infection) that required intravenous antibiotics, and an additional four patients had grade 3 infection. Other severe (grades 3 and 4) toxic effects were asthenia (25%), nausea (11%), fever (8%), vomiting (8%), severe hypersensitivity reactions (8%), and diarrhea (8%). Severe stomatitis (grade 3) occurred in only one patient. CONCLUSION: Docetaxel plus cisplatin is an effective regimen with an acceptable safety profile for palliation of recurrent SCCHN. Relative to the standard regimen of cisplatin/fluorouracil, this regimen may offer higher tumor response and survival rates with short outpatient administration and a lower incidence of severe mucosal toxicity.

Head and neck cancers include neoplasms of the oral cavity, pharynx, and larynx. The risk of these cancers is strongly associated with smoking and alcohol ingestion. There have been important advances in understanding of the molecular pathogenesis and progression of head and neck cancer and also in approaches to therapy, which include innovations in surgery, radiation therapy, and cytotoxic-drug therapy.

245 Background: Multiple studies have demonstrated equivalence of single vs. multi-fraction regimens for palliation of uncomplicated bone metastases, but single fraction (SF) radiotherapy (RT) remains under-utilized in the United States. To increase physician and patient awareness of RT options for bone metastases, both AAHPM and ASTRO participated in the “Choosing Wisely” campaign. AAHPM recommended 8 Gy X 1 for uncomplicated bone metastases. ASTRO recommended against routine use of courses > 10 fractions and supported strong consideration for the use of SF RT for patients with limited prognosis or transportation difficulties. To identify possible changes in prescribing patterns following “Choosing Wisely”, we evaluated utilization rates of SF (8 Gy x 1) for treatment of bone metastases via treatment requests submitted for preauthorization over a 3 year period. Methods: A proprietary web-based application (eviti Connect ) enables oncology providers to obtain real time automated precertification for patients insured by payers across the U.S. that utilize the platform. All preauthorization requests for RT of bone metastases were evaluated for the prescription of 8 Gy X 1. The overall rate of SF use was calculated as were quarterly rates within the study period. Results: From 6/1/11-6/30/14 7,524 requests were submitted; 658 were for bone metastases. Overall SF was used in 7.6 % of cases. Prior to Q4 of 2012 no prescriptions for 8 Gy X 1 were used. In 2013 SF was prescribed in 9.6% of cases (30/314): 2.8%, 7.3%, 7% and 20% for Q1, Q2, Q3, and Q4 respectively. During 2014 use of 8 Gy X 1 was 23.9% in Q1 and 19.5% in Q2. Protracted schedules > 10 treatments were prescribed in 31% of cases, but decreased over the study period (from 40% prior to Q4 2012, to 28% in 2013, and to 23% in the first half of 2014). Conclusions: Within this unique dataset of working aged insured patients, utilization of 8 Gy X 1 for treatment of bone metastases has increased. Increases were most pronounced in 2013. This coincides with the announcement and dissemination of the “Choosing Wisely” initiatives. Longer follow-up is needed to determine if increased provider uptake of SF RT as a componant of patient-centered quality care persists.

34 Background: Current evidence-based guidelines for management of rectal cancer (RC) caution against routine use of IMRT and do not address the role of IGRT. To explore patterns of care and cost implications for treatment of RC in commercially insured patients, we assessed treatment requests submitted for preauthorization through eviti Connect. Methods: A proprietary web-based application enables oncology providers to obtain automated precertification for patients insured by payers across the US that use the platform. All requests for pelvic radiation for treatment of RC submitted from 6/1/11-5/31/14 were reviewed. Treatment delivery costs for 3D CRT + weekly port films and for IMRT + IGRT were calculated based on average reimbursement rates from 3 payers for a typical course of 50.4 Gy/28 fractions. Results: A total of 195 cases for treatment of RC were submitted. At submission, 50.3% (98/195) of cases met evidence based standards and received automated preauthorization; 49.7% required treatment justification. Ninety-eight percent of deviations involved use of IMRT and/or IGRT. Upon review, 34.9% (68/195) had a medical rationale for the variance. Justification for IMRT/IGRT use included treatment volumes comparable to anal cancer, inadequate bowel displacement by routine techniques, and obesity. Fifteen percent (29/195) contained unwarranted deviations. In 23/29 cases peer to peer discussion resulted in the provider altering the plan to be compliant. Providers did not agree to changes in the other 6 cases. Cost for a course of 3D CRT + weekly port films was $6,591 vs. $32,292 for IMRT + daily IGRT. For these 195 cases, the estimated cost of overutilization of IMRT/IGRT was $745,000 ($25,700 X 29). Conclusions: Despite lack of endorsement by consensus group guidelines, IMRT and IGRT were prescribed for treatment of RC in nearly 50% of cases. Case review and peer to peer discussion clarified the rationale for treatment deviations from guidelines and allowed providers to bring plans into compliance with evidence based practices, reducing inappropriate use of IMRT/IGRT from 15% to 3%. Reduction in unwarranted use of high cost technologies can improve quality and yield significant cost savings.

6035 Background: TP53 is the most commonly mutated gene in HNSCC. The specific mutations in TP53 can be prognostic of patient survival. Thus, a framework to predict patient survival from previously...

e19515 Background: Follicular Lymphoma remains an incurable B-cell lymphoproliferative disorder with many treatment options, rituximab being the single most common therapy. Methods: In order to est...

6563 Background: As one solution to reducing costs and medical bankruptcies, experts such as the Institute of Medicine and ASCO have suggested patients and physicians should discuss the cost of car...

137 Background: Evidence informing current guidelines advising postoperative chemotherapy following trimodality therapy for esophageal cancer are limited. Our objective was to identify patients with locally advanced esophageal adenocarcinoma treated with trimodality therapy who may benefit from adjuvant chemotherapy. Methods: A single institution retrospective study was performed in 308 patients with esophageal adenocarcinoma who underwent neoadjuvant chemoradiation followed by surgery between 1989-2012. Kaplan-Meier analysis compared postoperative survival by clinical response to trimodality therapy and the use of adjuvant chemotherapy. Cox proportional hazards regression models estimated the association of adjuvant chemotherapy with survival. Results: After trimodality treatment, 93 out of 308 patients(30%) received adjuvant chemotherapy. Partial response to trimodality treatment was observed in 150(48%) patients; 50 of whom received adjuvant therapy. The median survival for partial responders who received adjuvant therapy vs. those receiving trimodality therapy alone was 53.2 vs. 27.6 months, respectively (p=0.047). Patients with complete response or no response to trimodality therapy showed no difference in median survival with the addition of adjuvant chemotherapy. Univariate Cox regression revealed a 26% decrease in relative hazard for long-term survival amongst patients who received adjuvant chemotherapy compared to no adjuvant therapy (HR=0.74, 95% CI 0.55-0.98). This association remained stable after adjusting for clinical response to trimodality therapy, age, and ASA score (aHR=0.75, 95% CI 0.55-1.01). Conclusions: Adjuvant therapy for patients with locally advanced esophageal adenocarcinoma was associated with a 26% decrease in relative hazard for mortality compared to trimodality treatment alone. Long-term survival following adjuvant therapy was dependent on initial response to trimodality therapy. Partial responders may benefit most from adjuvant chemotherapy.

PURPOSE: A pilot study of 43 patients with potentially resectable esophageal carcinoma treated with an intensive regimen of preoperative chemoradiation with cisplatin, fluorouracil, and vinblastine before surgery showed a median survival of 29 months in comparison with the 12-month median survival of 100 historical controls treated with surgery alone at the same institution. We designed a randomized trial to compare survival for patients treated with this preoperative chemoradiation regimen versus surgery alone. MATERIALS AND METHODS: One hundred patients with esophageal carcinoma were randomized to receive either surgery alone (arm I) or preoperative chemoradiation (arm II) with cisplatin 20 mg/m2/d on days 1 through 5 and 17 through 21, fluorouracil 300 mg/m2/d on days 1 through 21, and vinblastine 1 mg/m2/d on days 1 through 4 and 17 through 20. Radiotherapy consisted of 1.5-Gy fractions twice daily, Monday through Friday over 21 days, to a total dose of 45 Gy. Transhiatal esophagectomy with a cervical esophagogastric anastomosis was performed on approximately day 42. RESULTS: At median follow-up of 8.2 years, there is no significant difference in survival between the treatment arms. Median survival is 17.6 months in arm I and 16.9 months in arm II. Survival at 3 years was 16% in arm I and 30% in arm II (P = .15). This study was statistically powered to detect a relatively large increase in median survival from 1 year to 2.2 years, with at least 80% power. CONCLUSION: This randomized trial of preoperative chemoradiation versus surgery alone for patients with potentially resectable esophageal carcinoma did not demonstrate a statistically significant survival difference.

PURPOSE: To determine dose-response effects and the activity of paclitaxel combined with cisplatin in patients with incurable squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: Two hundred ten patients with locally advanced, recurrent, or metastatic disease were randomly placed in either Arm A, paclitaxel 200 mg/m2 (24-hour infusion) + cisplatin 75mg/m2 + granulocyte colony-stimulating factor, or Arm B, paclitaxel 135 mg/m2 (24-hour infusion) + cisplatin 75 mg/m2. Cycles were repeated every 3 weeks until progression or a total of 12 cycles for complete responses. Primary outcomes were event-free and overall survival. RESULTS: No significant differences in outcomes were observed between the high- and low-dose paclitaxel regimens. The estimated median survival was 7.3 months (95% confidence interval, 6.0 to 8.6). The 1-year survival rate was 29%, and event-free survival was 4.0 months. The objective response rate (complete response plus partial response) was 35% for the high-dose patients and 36% for the low-dose patients. Myelosuppression was the most frequent toxicity: grade 3 or 4 granulocytopenia, 70% of patients in Arm A and 78% in Arm B; febrile neutropenia, 27% of patients in Arm A and 39% in Arm B. Grade 5 toxicities occurred in 22 patients (10.5%). Treatment was terminated early in 31% because of excessive toxicity or patient refusal. CONCLUSION: This phase III multicenter trial showed (1) no advantage for high-dose paclitaxel and (2) excessive hematologic toxicity associated with both regimens. Therefore, neither of the paclitaxel regimens evaluated in this trial can be recommended.

Esophageal cancers are aggressive tumors that tend to present in an advanced stage and that historically have been associated with poor survival despite therapy. There are two reasons a chapter on esophageal cancer is pertinent in this text on geriatric surgery. The first is that esophageal cancer is primarily a disease of the elderly Thomas and Sobin,1 reporting the Surveillance, Epidemiology, and End Results (SEER) data from the National Cancer Institute, demonstrated that the peak incidence for presentation of esophageal cancer occurred in patients over age 65 regardless of histologic cell type or gender (Fig. 38.1). The second reason is that esophageal cancer most frequently presents with dysphagia, weight loss, and fatigue, all of which threaten an elderly patient’s personal and financial independence. Despite the fact that historically the outlook has been bleak for many patients with esophageal tumors, advancements in the identification of prema-lignant pathology, diagnosis and staging of tumors, therapeutic options, treatment safety, and survival have introduced a note of optimism into the management of this disease.

There are three traditional therapeutic modalities employed in the treatment of esophageal cancer; surgery, radiation therapy, and chemotherapy. These modalities have been utilized, either in combination or alone, as primary or adjuvant therapy for locally advanced disease as well as palliative therapy for metastatic disease. A thorough review of the incidence, risk factors and clinical presentation of esophageal cancer is described elsewhere in this book. However, it remains critically important to emphasize the changing epidemiology of this disease. The incidence of adenocarcinoma of the esophagus and gastric cardia in the United States and parts of Western Europe is rising, while squamous cell carcinoma of the esophagus remains the dominant histologic type in Asia and Africa (1,2). Although there are current efforts to stratify therapy based on histology, the existing studies are not adequate to support histology-specific therapeutic recommendations. Therefore, the treatment modalities discussed in this chapter are for both types of esophageal cancer.

Neoadjuvant chemoradiation (NAC) therapy protocols were developed to improve survival in patients with resectable esophageal cancer. Our experience with two consecutive NAC therapy trials is reviewed. Both studies included patients with localized squamous cell cancer and adenocarcinoma. Patients were treated with cisplatinum 26 mg/m2/day (days 1–5 and 26–30), 5-Flourouracil (5-FU) 300 mg/m2/day (days 1–30), concurrent radiotherapy (4400 cGy) followed by esophagectomy. In the second trial, adjuvant taxol was added. The first protocol had 50 patients. Two patients died, both before surgery, one from sepsis. There was no residual viable tumor (CR) in 19 (40%) patients. The median sur-vial time was 31 months. The 5-year survival rate of 36% compared favorably with concurrent 5-year survival of 18% for surgery alone. Fourty-one patients were enrolled in the second trial. All underwent surgery. There were no treatment or operative deaths. Survival data for this group is maturing. Combined results from both protocols are: treatment mortality of 2.2%, complete response rate of 37%, and a median and 3-year disease-specific survival of 42 months and 54%, respectively. We conclude that NAC followed by surgery improves survival over surgery alone and that CR is predictive of improved survival.

Controlled trials testing the concept of laryngeal preservation for patients with locally advanced stage III and IV cancers of the larynx or hypopharynx were initiated in the mid-1980s. Three randomized trials, evaluating the same cisplatin plus 5-fluorouracil induction chemotherapy regimen and conventional radiotherapy compared with surgery and radiotherapy, have been completed, and the results of two are published. In addition, a meta-analysis of these three trials was completed. The studies are critically reviewed. Conclusions from these trials are that the induction approach is feasible; local and regional control are not improved, whereas distant metastases are delayed; there is no evidence of a difference in overall survival; and of the patients alive at 3 and 5 years, a functional larynx can be preserved in 67% and 58%; there are not enough data to know if there are differences in outcome by subsite. Several unanswered questions are being addressed in phase III trials. These include defining the precise contribution of chemotherapy by comparing induction chemotherapy and radiotherapy to treatment with radiotherapy alone; determining if elective neck dissection for patients with N2N3 neck disease would improve survival; and determining whether local control can be improved by using concomitant or alternating chemotherapy and radiotherapy.

The incidence of esophageal adenocarcinoma has increased markedly in the past two decades, but the genetic alterations in this cancer and its precursor, Barrett mucosa, have not been characterized extensively. DNA replication errors and allelic losses of chromosomes 17p, 18q, and 5q were studied in 36 resected adenocarcinomas arising in the esophagus and esophagogastric junction, 56 Barrett adenocarcinomas, and 11 dysplasias in Barrett esophagus. The results were compared with clinical and pathological characteristics, including patient survival. Replication error positive cancer was rare (5.4%) in esophageal adenocarcinomas and was not found in Barrett mucosa. There was an increase in the prevalence of chromosomal losses in the Barrett mucosa–columnar dysplasia–adenocarcinoma sequence: 17p loss occurred in 14% of Barrett mucosae, 42% of low-grade dysplasias, 79% of high-grade dysplasias, and 75% of adenocarcinomas, respectively; loss of 18q in 32%, 42%, 73%, and 69%; and loss of 5q in 10%, 21%, 27%, and 46%. Clinical stage was a very strong prognostic factor for survival, and adenocarcinomas with allelic loss of both 17p and 18q had worse survival than cancers with no or one allelic loss (P = 0.002). Our results indicate that accumulation of genetic alterations follows the dysplasia–adenocarcinoma sequence in the esophagus and that losses of 18q and 17p occur earlier than 5q loss. Allelic loss of both 17p and 18q in esophageal adenocarcinoma identifies patients with poor prognosis.