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Background. EGFR and Src are frequently activated in non-small cell lung cancer (NSCLC). In preclinical models, combining EGFR and Src inhibition has additive synergistic effects. We conducted a phase I/II trial of the combination of Src inhibitor dasatinib with EGFR inhibitor erlotinib to determine the maximum tolerated dose (MTD), pharmacokinetic drug interactions, biomarkers, and efficacy in NSCLC. Methods. The phase I 3+3 dose-escalation study enrolled patients with solid tumors to determine the MTD. The phase II trial enrolled patients with advanced NSCLC who had undergone no previous treatments to determine progression-free survival (PFS) and response. Pharmacokinetic and tissue biomarker analyses were performed. Results. MTD was 150 mg of erlotinib and 70 mg of dasatinib daily based on 12 patients treated in the phase I portion. No responses were observed in phase I. The 35 NSCLC patients treated in phase II had an overall disease control rate of 59% at 6 weeks. Five patients (15%) had partial responses; all had activating EGFR mutations. Median PFS was 3.3 months. Epithelial-mesenchymal transition markers did not correlate with outcomes. Conclusion. The combination of erlotinib and dasatinib is safe and feasible in NSCLC. The results of this study do not support use of this combination in molecularly unselected NSCLC.

Tumor hypoxia regulates many cytokines and angiogenic factors (CAF) and is associated with worse prognosis in head and neck squamous cell cancer (HNSCC). Serum CAF profiling may provide information regarding the biology of the host and tumor, prognosis, and response to therapy. We investigated 38 CAFs in HNSCC patients receiving induction therapy on a phase II trial of carboplatin, paclitaxel, and cetuximab. CAFs were measured by multiplex bead assay and enzyme-linked immunosorbent assay in 32 patients. Baseline and postinduction CAF levels were correlated with disease progression (PD) and human papilloma virus (HPV) status by Wilcoxon rank sum test. Baseline levels of eight hypoxia-regulated CAFs (the “high-risk signature” including vascular endothelial growth factor, interleukins 4 and 8, osteopontin, growth-related oncogene-α, eotaxin, granulocyte-colony stimulating factor, and stromal cell–derived factor-1α) were associated with subsequent PD. Elevation in ≥6 of 8 factors was strongly associated with shorter time to progression (P = 0.001) and was 73% specific and 100% sensitive for PD. Increasing growth-related oncogene-α from baseline to week 6 was also associated with PD. Progression-free and overall survival were shorter in patients with HPV-negative tumors (P = 0.012 and 0.046, respectively), but no individual CAF was associated with HPV status. However, among 14 HPV-negative patients, the high-risk CAF signature was seen in all 6 patients with PD, but only 2 of 14 without PD. In conclusion, serum CAF profiling, particularly in HPV-negative patients, may be useful for identifying those at highest risk for recurrence. Mol Cancer Ther; 9(6); 1755–63. ©2010 AACR.

BACKGROUND: Bevacizumab has recently been demonstrated to prolong overall survival when added to carboplatin and paclitaxel for chemotherapy-naive patients with nonsquamous nonsmall-cell lung cancer (NSCLC). However, the effects of combining bevacizumab with other standard, front-line, platinum-based doublets have not been extensively explored. We designed this single treatment arm, phase 2 trial to determine whether the combination of carboplatin, docetaxel, and bevacizumab is tolerable and prolongs progression-free survival of chemotherapy-naive patients with advanced, nonsquamous NSCLC. METHODS: Forty patients were treated with up to 6 cycles of carboplatin (AUC 6), docetaxel (75 mg/m2), and bevacizumab (15 mg/kg) on Day 1 every 21 days. Patients with an objective response or stable disease received maintenance bevacizumab (15 mg/kg) every 21 days until disease progression. The primary endpoint was median progression-free survival. Secondary endpoints included safety, response rates, and overall survival. RESULTS: The median number of chemotherapy and maintenance bevacizumab cycles/patient was 6 and 2, respectively. Grades 3-5 adverse events included febrile granulocytopenia (10%), infections (13%), bleeding (13%), thrombotic events (13%), hypertension (5%), bowel perforation (5%), and proteinuria (3%). Median progression-free survival was 7.9 months and median overall survival was 16.5 months. Partial responses were observed in 21 patients (53%), and stable disease ≥6 weeks occurred in another 17 patients (43%), for a disease control rate of 95%. CONCLUSIONS: Carboplatin, docetaxel, and bevacizumab were feasible and effective for front-line treatment of advanced, nonsquamous NSCLC. These data provide further evidence that bevacizumab may be used in combination with multiple standard, platinum-based doublets in this setting. Cancer 2010. © 2010 American Cancer Society.

BACKGROUND: Irinotecan has significant activity in small-cell lung cancer (SCLC). The authors' previous phase 1 study of alternating weekly therapy with irinotecan/cisplatin (IP), etoposide/cisplatin (EP), and granulocyte–colony-stimulating factor (G-CSF) support was well tolerated and active in patients with SCLC. A phase 2 trial was conducted to estimate the efficacy of this regimen in previously untreated patients with extensive SCLC. METHODS: A total of 33 patients were treated between June 2002 and July 2007. Patients received 12 weeks of therapy with cisplatin (20 mg/m2) on Day 1 and irinotecan (100 mg/m2) on Day 1 and G-CSF on Days 2 to 5 (Weeks 1, 3, 5, 7, 9, and 11) followed by cisplatin (20 mg/m2) on Day 1 and etoposide (60 mg/m2) on Days 1 to 3 with G-CSF on Days 4 to 7 (Weeks 2, 4, 6, 8, 10, and 12). The primary endpoint was 1-year survival rate. RESULTS: Grade 4 neutropenia (toxicities were determined using the National Cancer Institute Common Toxicity Criteria [version 2.0]) was noted in 5 (1.5%) of 343 courses with neutropenic fever in only 5 (1%) of 343 courses. One patient died of neutropenic sepsis. Nonhematologic toxicities grade ≥2 were observed in 15 (4%) of 343 courses and were limited to fatigue, hyponatremia, and diarrhea. The overall objective response rate was 89% in 28 assessable patients (no complete responses and 25 partial responses). The median progression-free and overall survivals were 6.0 months and 10.9 months, respectively. The 1-year survival rate was 33%. CONCLUSIONS: Weekly therapy with IP alternating with EP and G-CSF support was well tolerated in patients with extensive SCLC, but did not demonstrate improved progression-free or overall survival when compared with historical controls at the study institution. Cancer 2010. © 2010 American Cancer Society.

The main trends in food consumption per capita unearthed so far from the Census and other material may be briefly summarized. Only for the meats – pork, beef, and veal – have the estimates been carried back to 1840. It seems not impossible that wheat flour may be extended before 1880, and possibly even the series for dairy products before 1870. In these cases, however, prudence has to date prevailed.

Over the past decades, a number of systemic treatment options for incurable, advanced non-small cell lung cancer have been developed. While untreated patients with this disease typically have a median overall survival of 4.5 months, this figure has exceeded the 12-month mark in the latest randomized phase III trials. Progress in drug development, combination chemotherapy, supportive care, and better selection of patients for specific treatments have contributed to improvements in outcome. In this chapter, we will present the key data that support the use of chemotherapy and biologic agents for the first-line treatment of advanced NSCLC. The following aspects will be discussed: selection and number of chemotherapy agents, duration of therapy, use of biologic drugs (i.e., vascular endothelial growth factor and epidermal growth factor receptor inhibitors), and management of elderly and poor performance status patients.

The purpose of this population-based study is to provide a detailed analysis of survival outcome of patients with stage IIIB and IV non-small cell lung cancer (NSCLC) enrolled in the Surveillance, Epidemiology and End Results (SEER) program.We retrieved, from the SEER database, data on demographics, disease extension (size, extent of primary tumor, and nodal status), histology, primary treatment modality, and survival time of NSCLC cases diagnosed between 1998 and 2003 (n = 138,063). Cases were reclassified into separate T4 (satellite, invasive, or pleural effusion) and M1 (ipsilateral, contralateral, or distant) categories based on the extent of the primary tumor and the location of metastatic disease. Univariate and multivariate analyses were performed to assess the effects of each variable on survival.For stage IIIB NSCLC, T4 satellite had the best prognosis (comparable to T2 lesions), followed by T4 invasive and T4 pleural effusion. For stage IV, M1 ipsilateral had the best prognosis, followed by M1 contralateral and M1 distant. Nodal status remained a powerful determinant of survival, particularly for patients with T4 satellite, T4 invasive, M1 ipsilateral, and, to a less extent, M1 contralateral. Other prognostic variables were identified within each subgroup.In this report, we present the most comprehensive analysis performed to date of patients with stage IIIB and IV NSCLC enrolled in the SEER program. The survival trends observed here suggest that T4 satellite lung cancer cases should be redefined as T2b, and not T3 as recently proposed for the upcoming TNM classification, seventh edition.

Vaccines targeting infections with hepatitis B virus, a risk factor for hepatocellular cancer, and human papillomavirus, a risk factor for cervical cancer, are considered major clinical cancer chemoprevention successes. Molecularly targeted agents can prevent breast cancer (raloxifene and tamoxifen), colorectal adenomas (celecoxib), and prostate cancer (finasteride). Nevertheless, the broad translation of chemoprevention to the clinic is not yet a reality. Continuing research of molecular targets promises to expand the reach of chemoprevention and to personalize it as well.

We previously showed that low-dose fenretinide (200 mg/d) had limited activity in retinoid-resistant oral leukoplakia (34% response rate) possibly because serum drug levels were insufficient to induce retinoid receptor–independent apoptosis. Therefore, we designed the single-arm phase II trial reported here to investigate whether higher-dose fenretinide would improve leukoplakia response over that of our previous study. Leukoplakia patients received fenretinide (900 mg/m2 twice daily) in four 3-week cycles (1 week on drug followed by 2 weeks off). At week 12, clinical responses were determined and blood samples were collected for serum drug level assessments. A planned interim futility analysis led to early trial closure after the initial 15 (of 25 planned) patients because only 3 (20%) had a partial response (stopping rule: ≤4 responses in first 16 patients). Fenretinide was well tolerated—only one grade 3 adverse event (diarrhea) occurred. Serum fenretinide levels changed from 0 (baseline) to 0.122 ± 0.093 μmol/L (week 12). In correlative in vitro studies, high-dose fenretinide inhibited the growth of head and neck cancer cells more and oral leukoplakia cells less than did lower doses of fenretinide. This result is consistent with our clinical finding that high-dose fenretinide did not improve on the historical response rate of lower-dose fenretinide in our previous oral leukoplakia trial.

Purpose To investigate whether retinyl palmitate (RP) alone or plus beta-carotene (BC) would be as effective and less toxic than low-dose 13-cis retinoic acid (13cRA) in treating oral premalignant lesions (OPLs) and reducing the risk of oral cancer. Patients and Methods Initially, patients were randomly assigned to receive low-dose 13cRA or BC plus RP for 3 years (plus 2 years follow-up). After other randomized trials established an adverse effect of BC on lung cancer incidence/mortality, BC was dropped (patients randomly assigned to 13cRA or RP alone). The primary end point was OPL clinical response at 3 months. Results We randomly assigned 162 eligible patients. The 3-month clinical response rate of the combined BC plus RP and RP alone arm (32.5%) was not statistically equivalent to that of 13cRA (48.1%). The clinical response rate of RP alone (20.0%) was significantly lower than that of BC plus RP (42.9%; P = .03). Similar oral cancer–free survival rates were observed across all arms. There was no significant association between 3-month OPL response and subsequent oral cancer development (P = .11). Grades 2 and higher adverse events were more common in the 13cRA than other groups (P < .0001). Conclusion This large chemoprevention trial did not establish the equivalence of RP plus BC or RP alone with low-dose 13cRA in reducing the long-term risk of oral cancer. At present, 13cRA, BC plus RP, and RP alone cannot be recommended for chemoprevention, and new, better agents are needed in this setting. Our results did not establish short-term OPL response as a surrogate end point for oral cancer–free survival.

We discuss the results of the phase III EXTREME (Erbitux in First-Line Treatment of Recurrent or Metastatic Head and Neck Cancer) trial. In this study, 442 untreated patients with advanced squamous cell carcinomas of the head and neck (SCCHN) were randomly assigned to receive platinum and 5-fluorouracil with or without cetuximab. Median overall survival -- the primary end point of the trial -- was improved in the cetuximab arm compared with the chemotherapy-alone arm (10.1 months and 7.4 months, respectively; P = 0.04). This is the first phase III trial in over two decades to exhibit a survival advantage in patients with SCCHN not amenable for curative treatment; however, it raises several considerations for clinical practice and future research directions, such as the optimum choice of chemotherapy to be combined with cetuximab, sequencing of cetuximab with chemotherapy, predictive markers of benefit from cetuximab, as well as implications for patients with locally advanced, potentially curable disease.

Purpose: Cyclooxygenase-2 (COX-2)–specific inhibition suppresses carcinogenesis in preclinical models and is a promising strategy for preventing oral cancer. In this pilot randomized phase II study, we evaluated the efficacy and safety of the COX-2 inhibitor celecoxib in patients with oral premalignant lesions (OPL). Experimental Design: Patients were randomly assigned to placebo (n = 18), celecoxib 100 mg twice daily (n = 17), or celecoxib 200 mg twice daily (n = 15) for 12 weeks. Six additional patients received celecoxib (400 mg twice daily) in an unblinded extension of the study. Biopsies were obtained at baseline and week 12. All patients entering the study were required to have at least one histologically confirmed early (atypical hyperplasia, atypical hyperkeratosis, or mild dysplasia) or advanced (moderate to severe dysplasia) OPL. Results: Forty-nine patients (46 of 50 randomized and 3 of 6 open label) were evaluable for efficacy analyses. There were no statistically significant differences between the response rates of the randomly assigned arms: placebo, 33.3% (6 of 18); celecoxib 100 mg twice daily, 41.2% (7 of 17); and celecoxib 200 mg twice daily, 20.0% (3 of 15). Two patients responded on celecoxib 400 mg twice daily. Celecoxib was generally well tolerated. Patients with higher baseline COX-2 mRNA levels had an increased risk of disease progression within 3 months. Conclusions: Celecoxib at 100 or 200 mg twice daily was ineffective in controlling OPLs in this randomized controlled trial. This result and cardiovascular toxicity results of other (large scale) randomized controlled trials of selective COX-2 inhibitors have discouraged the continued investigation of these agents in oral cancer chemoprevention. Better methods for identifying high-risk patients and more active interventions are needed for future oral cancer chemoprevention trials.

Background: LY2606368 is a CHK1/2 inhibitor. In addition to its role in DNA damage response, CHK1 also phosphorylates multiple downstream targets that regulate DNA replication, chromosome alignment, spindle checkpoints, and exit from cytokinesis. Since potent inhibition of CHK1 is predicted to generate DNA damage and mitotic catastrophe, LY2606368 was evaluated as a single agent in expansion cohorts of patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN). Methods: This was a phase I, multicenter, nonrandomized, open-label study in patients with advanced cancer (NCT01115790). Based on results from the dose-escalation phase, dose-expansion cohorts were comprised of patients with SCC given LY2606368 at the maximum tolerated dose (MTD) of 105 mg/m2 on day 1 of a 14-day schedule. Cohorts were defined by tumor location and by line of treatment. Patients were assessed for safety, tolerability, and preliminary efficacy. Pretreatment biopsies were obtained for pharmacogenomic analysis, including human papillomavirus (HPV) status. Aggregate results from patients with recurrent/metastatic SCCHN are presented. Results: Fifty-seven patients with recurrent/metastatic SCCHN were enrolled in the dose-expansion phase. Over 50% of patients had received ≥2 prior lines of treatment (median of 3 cycles; range: 1 to 5) in the recurrent/metastatic setting. The most frequently reported adverse event (AE) was a transient (typically 10% of patients included thrombocytopenia (44%), anemia (25%), fatigue (23%), and headache (14%). The majority of non-hematologic AEs were grade 1 or 2 (per Common Terminology Criteria) in severity. Three patients (5%) had a partial response and 25 patients (44%) had stable disease for at least 3 cycles. The duration of response ranged from 4.8-7.8+ months, and the median progression-free survival (PFS) was 1.6 months (90% confidence interval: 1.4, 2.8). Biopsy samples were evaluable from 34 patients. The median PFS by HPV status was 4.5 months in 15 patients who were HPV positive, and 1.4 months in 19 patients who were HPV negative (log-rank test, p = .0012). Conclusions: LY2606368 has an acceptable safety profile and demonstrates modest preliminary activity in a subset of patients with recurrent/metastatic SCCHN. The MTD of 105 mg/m2 is confirmed as the recommended dose for phase II testing. Citation Format: Johanna Bendell, Stefan Grant, Filip Janku, Jeffrey Infante, William N. William, Todd M. Bauer, Sarina Piha-Paul, Ricardo Martinez, Sameera Wijayawardana, Ji Lin, Lisa Golden, Aimee Bence Lin, David Hong. Checkpoint kinase (CHK) 1/2 inhibitor LY2606368 in a phase I dose-expansion study in patients with squamous cell carcinoma of the head and neck. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT240. doi:10.1158/1538-7445.AM2015-CT240

6001 Background: We designed a randomized phase II trial to determine the efficacy of two induction chemotherapy (ICT) cetuximab (C) containing regimens with demonstrated efficacy and acceptable to...

7530 Background: Substantial genomic heterogeneity of lung cancers between different patients, reflecting distinct genetic background and potentially different carcinogen exposures in different pat...

6081 Background: ACC is chemotherapy refractory and there is no standard of care treatment for patients (pts) with metastatic disease. ACC genotyping revealed alterations in the Notch (N) pathway i...

6016 Background: Epithelial-to-mesenchymal transition (EMT) is associated with poor prognosis and resistance to EGFR inhibitors. To determine molecular alterations and novel targets associated with...

9573 Background: Pericardial effusion is a common finding in cancer patients and can be related to the tumor infiltration of the pericardial space or can be secondary to cancer therapy (chemotherap...

Background: Epithelial-to-mesenchymal transition (EMT) is a marker of resistance to specific targeted drugs in non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSC), and other epithelial cancer and may be associated with poor patient outcomes. Here we performed an integrated molecular analysis in 1934 tumors representing 11 different cancer types in the Cancer Genome Atlas (TCGA) and 1264 representative cell lines to investigate new potential therapeutic targets (PTTs) in mesenchymal tumors. Methods: For each tumor, we correlated the EMT score (based on expression of an EMT gene signature) with mutation status, copy number alterations (CNA), mRNA, miRNA, and protein expression. PTTs expressed in mesenchymal tumors were investigated in vitro using publically available drug sensitivity datasets (DSDs) by correlating IC50s with EMT score. Results: Most cancer types exhibited a range of EMT scores that included both epithelial and mesenchymal tumors, with the exception of kidney clear cell carcinoma (KIRC) (all mesenchymal) and ovarian serous cystadenocarcinoma (OV) (primarily epithelial). Patients with mesenchymal OV and HNSC experienced shorter overall survival (p=0.029 and 0.076, respectively). BAP1 and PP2R1A mutations were more frequent in mesenchymal tumors, independent of primary site (adjusted p value 0.3). PTTs commonly expressed in mesenchymal tumors included AXL, PDGFRA/B, MMP2 and DDR2 (r>0.6). Of these, investigation of the DSDs supported in vitro sensitivity of mesenchymal cell lines overall to PDGFR and GSK3 inhibitors, but resistance to drugs targeting ErbB family members, including the dual VEGF/EGFR inhibitor vandetanib (p Conclusions: Application of the EMT signature to diverse tumor types identifies highly conserved patterns of gene and miRs expression, including high miR-199a expression in mesenchymal cancers. While mutational landscape and CNAs were most often driven by tumor type, protein expression and drug sensitivity were influenced by a combination of tumor type and EMT status. New associations between drug response and EMT were identified, such as the sensitivity of mesenchymal cancers to PDGFR and GSK3 inhibitors, that warrant further investigation. Citation Format: Pan Tong, Milena P. Mak, Lixia Diao, Jing Wang, Patrick Kwok-Shing Ng, You-hong Fan, William N. William, John V. Heymach, Kevin R. Coombes, Lauren Averett Byers. An integrated analysis of EMT across diverse cancer types identifies new potential therapeutic targets. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1040. doi:10.1158/1538-7445.AM2014-1040

11032 Background: Individual cancers are composed of populations of cells with distinct molecular and phenotypic features, a phenomenon termed ITH. ITH may have profound impacts on biopsy strategy,...

6007 Background: Loss of heterozygosity (LOH) profiles predict oral cancer (OC) risk in patients (pts) with oral premalignant lesions (OPL). We conducted a randomized, multi-center, double-blind, placebo-controlled, personalized medicine trial of the EGFR inhibitor erlotinib in pts with OPLs defined as high risk by molecular criteria. Our primary hypothesis was that erlotinib would improve oral cancer-free survival (OCFS) in the high-risk, LOH+ population. Methods: Pts with histological evidence of an OPL (with or without a prior history of invasive OC) underwent LOH profiling at 3p14, 9p21, 4q, 8p, 11p, 13q, 17p. LOH+ pts were defined as those with prior OC and LOH at 3p14 and/or 9p21; or those without prior OC and LOH at 3p14 and/or 9p21 plus an additional chromosomal site. LOH- pts received no treatment. LOH+ pts were stratified by history of OC, then randomized (1:1) to erlotinib 150 mg po daily for 12 months or placebo and were assessed every 3-6 months for development of invasive OC. Primary endpoin...

6086 Background: Human immunodeficiency virus (HIV)-infected individuals are at increased risk for head and neck cancer (HNC). Poor survival is associated with low CD4 counts, larynx/hypopharynx si...

Background: Targeted therapy for head and neck squamous cell carcinoma (HNSCC) is currently limited to EGFR inhibition with agents such as cetuximab. We and others have previously demonstrated that epithelial to mesenchymal transition (EMT) is associated with resistance to EGFR inhibitors in HNSCC and lung cancers but greater sensitivity to other targeted drugs, such as AXL inhibitors. Here, we apply a previously published EMT signature to identify novel potential therapeutic targets (PTTs) in mesenchymal HNSCC tumors (MHNTs). Methods: A high-throughput analysis of gene and protein expression in HNSCC tumors from The Cancer Genome Atlas (TCGA) (A, n=113) was performed to identify PTTs in MHNTs. Specifically, the EMT signature score for each tumor was correlated with marker expression levels by Pearson correlation (mRNA, protein) or t-test (mutation, HPV status). PTTs were validated in an independent cohort of high-risk, resected tumors (B, n=105) and HNSCC cell lines (C, n=60). PTTs were defined as druggable targets found on recent HNSCC publications, our in-house targeted sequencing panel of 202 genes and publicly available cancer cell lines drug sensitivity datasets (DSDs). Results: At a false discovery rate of 1% (p0.5) and confirmed in our independent cohort included DDR2, FGFR1, KDR, MMP14, MMP2, PDGFRA, PDGFRB and TGFBR2. Targets that were overexpressed in both tumors and cell lines included NOTCH4 (A and B p Conclusions: An integrated analysis of EMT and expression data from two independent cohorts identifies previously unrecognized, candidate PTTs in mesenchymal HNSCC tumors. Validation of the PTTs at the protein level is ongoing. The approach described may identify patient subsets, beyond mutational status, for whom targeted therapy can be successful. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A131. Citation Format: Milena P. Mak, Lixia Diao, Jing Wang, Patrick KS Ng, You-Hong Fan, Michael D. Story, William N. William, John V. Heymach, John N. Weinstein, Kevin R. Coombes, Lauren A. Byers. Identification of candidate therapeutic targets in mesenchymal head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A131.

8079 Background: Many clinical trials in metastatic NSCLC patients who failed first-line chemotherapy have utilized pre-treatment, diagnostic tissues for marker assessment. BATTLE was a randomized, biopsy-driven clinical study in patients with metastatic NSCLC previously treated with systemic therapy. Fresh biopsies were obtained at the time of enrollment for biomarker evaluation. We hypothesized that molecular abnormalities found at the time of enrolment in BATTLE would differ from baseline, pre-chemotherapy, diagnostic tissue. Methods: We isolated DNA (SPRI-TE-based DNA recovery and cleanup methodology) from 82 matched pre-chemotherapy and BATTLE formalin-fixed paraffin-embedded specimens. Mutations were assessed by MALDI-TOF MS (MassArray, Sequenom Inc) using a lung cancer panel of 16 genes/140 assays (AKT1, BRAF, CTNNB1, EGFR, ERBB2, FGFR3, HRAS, KRAS, MEK1, MEK2, MET, NRAS, PIK3CA, PIK3R1, PTEN, and STK11) and were compared between pre-chemotherapy versus BATTLE samples. Results: Mutations were identified in 25 pre-chemotherapy samples (14 K-RAS, 5 EGFR, 3 PIK3CA, 1 STK11, 1 PTEN, 1 HRAS, 1 CTNNB1). Conversely, 29 BATTLE samples had at least one mutation (14 K-RAS, 7 EGFR, 5 PIK3CA, 2 STK11, 1 PTEN, 1 HRAS, 1 CTNNB1). For the matched pair analysis, 46 patients had wild-type tumors both in pre-chemotherapy and BATTLE samples. 11 patients had wild-type tumors in pre-chemotherapy samples, but had a mutation identified in BATTLE samples (4 K-RAS, 4 EGFR, 2 PIK3CA, 1 STK11). 7 patients had a mutation in pre-chemotherapy samples, but no mutations in BATTLE samples (4 K-RAS, 2 EGFR, 1 HRAS). The remaining 18 patients had mutations in both the pre-chemotherapy and BATTLE samples; of these, 2 had different mutations in the paired samples (both within the same genes, 1 KRAS, 1 PIK3CA). Overall, there was a 24% gene mutation discordance rate between pre-chemotherapy and BATTLE samples. Conclusions: Profiling of fresh biopsies may more accurately reflect molecular abnormalities present in the tumor at the time of initiation of salvage therapy, underscoring the importance of real time tissue collection in biomarker-driven studies in this setting (V Foundation, DoD).

6030 Background: Preclinical evidence supports clinical investigation of IGF-1R inhibitors alone, or combined with EGFR inhibitors, in SCCHN patients (pts). CIX and CET monoclonal antibodies block ligand binding to IGF-1R and EGFR, respectively. CIX mono and CIX+CET combo were studied in pts with chemotherapy-refractory R/M-SCCHN. Methods: This open-label phase II trial randomized 97 pts with R/M-SCCHN, ECOG PS 0-2 and disease progression following (2 (Arm B) every 2 wks. Time to recurrence from last anti-EGFR exposure had to be >90 days; pts were stratified by prior CET exposure. Primary endpoint was median PFS (RECIST assessments every 8 wks). Efficacy endpoints in the CET-naïve patients, immunohistochemical analysis of 10 relevant markers on tumor specimens, and cytokine/angiogenic factor profiling of blood samples obtained serially through treatment were also examined. Results: 47 Arm A and 44 arm B pts were treated: median age: 60.0 y (35 - 81), PS 0/1/2: 17.6%/62.6%/19.8%, male (80.2%), tumors originating mainly from oropharynx (67.1%), supraglottic (9.9%) and oral cavity (13.2%), with 33% moderately and 36.3% poorly differentiated tumors, previous therapy: 98.9% chemotherapy and 82.4% radiotherapy indicating no baseline differences. Most common tx-emergent AEs were fatigue (55.3 vs. 61.4%), dermatitis acneiform (6.4 vs 63.6%), nausea (29.8 vs. 34.1%), weight decreased (25.5 vs. 29.5%), hyperglycemia (25.5% vs. 29.5%), vomiting (21.3 vs. 20.5%), and headache (17 vs. 25%). Efficacy: See Table. Conclusions: Targeting IGF-1R alone with CIX or co-targeting IGF-1R and EGFR with CIX and CET did not result in improved PFS compared to historical data with CET alone in patients with chemotherapy-refractory R/M-SCCHN. The results of this study do not support CIX single-agent activity in this patient population. Therapy on both arms was feasible. There was no apparent exacerbation of CET toxicity by concurrent CIX exposure. Clinical trial information: NCT00617734. [Table: see text]

6087 Background: Evidence from small cohorts suggests that level of LNM predicts survival in patients with HNSCC. This study sought to investigate the prognostic value of level of LNM in a large populational database and contrast it with the current AJCC classification of lymph node involvement. Methods: SEER registry was queried for patients with stage I-IVB HNSCC of oral cavity (OC), oropharynx (OP), larynx (LAR) and hypopharynx (HP) diagnosed from 2004 to 2009 (N=39,699, median follow-up 2.3 years). Each anatomic group was divided into 3 subgroups based on level of LNM (no LNM, LNM to levels 1-3, 4 or 5), and 4 subgroups based on AJCC classification (N0, N1, N2, N3). Overall survival (OS) in each subgroup was computed (Kaplan-Meier method) and compared (log-rank test). Concordance statistics (C-index) were used to assess the accuracy of LNM classification by level vs AJCC in predicting OS. Results: Both AJCC and level of LNM-based classifications predicted OS in patients with OC, LAR, and HP cancers. For OP, neither AJCC nor level of LNM-based classification predicted OS as expected (lower OS for N0 vs N1/2 or levels 1-3/4) (Table). The performance of level of LNM-based classification was comparable to AJCC N staging for OC, LAR and HP. Conclusions: Level of LNM is a prognostic factor for OC, LAR and HP HNSCC. Classification by level of LNM reached similar accuracy as AJCC N staging in predicting OS for OC, LAR and HP. Neither classification is satisfactory for OP, illustrating the need to refine the staging system in this subgroup. [Table: see text]

Purpose Head and neck (H&N) cancers arising in previously irradiated volumes were rarely treated with radiotherapy due to concerns of toxicity. With improved precision in planning and delivery, reirradiation has been increasingly used. We reviewed our institutional experience using IMRT in the management of previously irradiated H&N carcinoma. Materials and methods The records of 136 patients treated with IMRT reirradiation at U.T. M.D. Anderson Cancer Center for H&N cancer between 1999 and 2012 were retrospectively reviewed. Reirradiation was defined as any overlap between the two radiation treatment volumes. Severe toxicity related to reirradiation included events requiring hospitalization, urgent intervention, or death. Survival estimates were calculated using the Kaplan–Meier algorithm, excluding those patients treated with palliative intent. Results Thirty-three (24%) patients underwent surgical resection and 70 (51%) patients received chemotherapy. Twenty of these patients received radiation with palliative intent. Median time interval between initial radiation and reirradiation was 23 months. Median follow-up after reirradiation was 33 months. Median reirradiation dose was 60 Gy (range 15–70 Gy), while the median cumulative radiation dose was 120 Gy. The 2- and 5-year overall survival and locoregional control rates were 58% and 63%, and 39% and 51%, respectively. Re-treatment doses ⩾66 Gy trended towards improved LRC ( p = 0.14). Severe reirradiation related toxicity occurred in 35 patients (26%), including three treatment-related deaths. Severe toxicity did not correlate with total or re-treatment dose but was associated with retreatment volumes >150 cc. Conclusions IMRT yields promising local control and survival outcomes in select patients receiving reirradiation for H&N cancer. However, treatment related toxicity continues to be significant despite the increased conformality of IMRT over 3D conformal radiation. Alternative treatment strategies, including the possible use of stereotactic radiotherapy, to further improve conformality and thereby increase the therapeutic ratio, may be explored in the future.

HNSCC is a common, deadly, and disfiguring disease. While combinations of radiotherapy, surgery, and chemotherapy are highly effective in HNSCC, there is significant morbidity associated with the disease and recurrence is common. There is great interest in identifying molecular events and pathways which drive HNSCC progression in order that targeted therapies may be developed. The loss of the tumor suppressor function such as p53 and NOTCH1, as well as activation of the STAT3 and STAT5 pathways, has been implicated in HNSCC progression. We have identified interactions between STAT3, STAT5, and the novel tumor suppressor SOCS2 to be important in HNSCC. To extend these findings to humans, we performed experiments to identify prognostic markers in HNSCC and to investigate the expression of STAT3, STAT5, and SOCS2 in HNSCC tissue. Immunohistochemistry was performed on tissue microarrays from resected tumor specimens of 123 stage I-IVB oral cavity SCC patients (treated with surgery +/- adjuvant radiation therapy) with annotated clinical outcome information from a median follow up of 76 months collected at the UT/MD Anderson Cancer Center. The array was screened with antibodies against STAT5, STAT3, and SOCS2, and scored in a blinded fashion by a pathologist. SOCS2 expression (present vs. absent) correlated significantly with recurrence-free survival in both the univariate (hazard ratio 0.24, p=0.0003; Cox proportional hazards model) and multivariate (hazard ratio 0.24, p=0.0004) analyses. Notably all patients who lacked SOCS2 tumor expression recurred within 45 months. There was a trend towards a correlation of SOCS2 expression with overall survival (HR 0.50, p=0.11) and disease-specific survival (HR 0.52, p=0.28). SOCS2 expression did not significantly correlate with tumor stage and extracapsular extension emphasizing that its absence is an independent marker of poor prognosis. Our prior published work demonstrates that STAT5 drives SOCS2 expression. The expression of SOCS2 in these patient samples positively correlated with total and phosphoSTAT5 (r=0.29 and 0.21 respectively; p This work was supported The University of Texas SPORE in Head and Neck Cancer (P50 CA097007), The Cancer Center Support Grant, and the ASCO Cancer Foundation Young Investigator Award (WW). Citation Format: Courtney Nicholas, Maria I. Nunez, Nusrat Harun, J. Jack Lee, Jeffrey Myers, Ignacio I. Wistuba, Banibrata Sen, Adel K. El-Naggar, Stephen Y. Lai, Faye M. Johnson, William N. William. SOCS2 (suppressor of cytokine signaling protein 2) is a prognostic indicator of progression-free survival in head and neck squamous cell carcinoma (HNSCC) patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5578. doi:10.1158/1538-7445.AM2013-5578

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background : We have previously shown that gene expression profiles of oral leukoplakia (OL) may improve the prediction of oral cancer (OC) risk. In order to identify new targets for prevention of oral cancer, we performed a systematic survey of transcripts overlapping between those associated with an increased risk of OC and those overexpressed in oral cancer versus normal mucosa (NM). Material and Methods: We used gene expression profiles of: i-86 OLs enrolled in a chemoprevention trial that used the incidence of OC development as a prespecified endpoint; ii-26 OC and 12 NM ([GSE9844][1]); and iii-22 paired head and neck squamous cell carcinoma (HNSCC) and NM ([GSE6631][2]) downloaded from public repositories. Total MET expression was evaluated using immunohistochemistry in 120 OLs from the same chemoprevention trial, using a score from 0 to 4. In vitro sensitivity to ARQ 197, a selective inhibitor of MET, and to erlotinib, an EGFR inhibitor, was studied in 4 immortal human keratinocytes that serve as models of preneoplasia (MSKLeuk1, MSKLeuk1s, HaCaT, and HOK-16B) and in 19 OC cell lines using MTT assay. Results : Venn diagram of 572 transcripts associated with an increased risk of OC (cox proportional hazard ratio > 1, P 0.5, P < 0.01) led to the identification of 115 overlapping transcripts, including MET. High MET gene expression in HNSCC versus NM was validated in an independent set of samples ([GSE6631][2]; paired samples t -test P

193 Background: Adherence to clinical guidelines, such as those developed by the National Comprehensive Cancer Network (NCCN), can serve as a quality measure for delivered care. We aimed to assess multidisciplinary conference (MC) treatment recommendations’ adherence to NCCN head and neck cancer guidelines, while identifying potential areas for quality improvement. Methods: Patients presented with previously un-treated head and neck cancers are being prospectively accrued as they are presented at weekly MC. The charts of patients presented between 10/20/2011 and 6/31/2012 were retrospectively reviewed for clinical data leading up to MC to allow us to assess whether, based on the available information, the recommendations of conference are compliant with NCCN treatment guidelines. Results: We identified 231 eligible patients. TNM staging was documented in 90.9% of MC notes and treatment recommendations were documented for 93.5% of patients; the remainder of presented patients required further evaluation before a treatment plan could be determined. Of 196 enrolled patients, 53% had oropharyngeal cancer, 25% had oral cavity cancer, 18.4% had laryngeal cancer, and 3.6% had nasopharyngeal cancer. For the entire cohort, the mean age at presentation was 59.5 years. One hundred fifty nine patients (81.1%) were men. The recommendations of conference were compliant with NCCN treatment guidelines for 92.3% patients. The main reasons for non-compliance in 15 patients were treatment of T1/2N2 oropharyngeal cancer with definitive radiation alone (6 patients), incomplete documentation (4 patients), and recommended over-use of adjuvant therapy (3 patients) and induction chemotherapy (2 patients). Conclusions: NCCN guideline compliance can be used to evaluate the quality of head and neck cancer care. Although most cases involving deviation resulted from incomplete MC documentation, areas for improvement were identified. Further study is needed to evaluate how care that deviates from NCCN guidelines affects patient outcomes.

202 Background: Adherence to clinical guidelines, such as those developed by the National Comprehensive Cancer Network (NCCN), can serve as a quality measure for delivered care. We aimed to determine NCCN guideline compliance of and concordance between multidisciplinary conference (MC) treatment recommendations and treatment received. Methods: A retrospective review of 71 consecutive previously untreated patients from 1/1 to 4/1/2006 evaluated whether MC recommendations were compliant with 2006 NCCN treatment guidelines, what treatment was actually provided, and whether this treatment was congruent with MC recommendations and/or adhered to 2006 NCCN guidelines. Results: TNM staging was documented in 94.4% of MC notes and treatment recommendations were documented for 98.6% of patients. Of enrolled patients, 53% had oropharyngeal cancer, 22.7% had oral cavity cancer, 18.2% had laryngeal cancer, and 6.1% had nasopharyngeal cancer. The mean age at presentation was 57.4 years. Forty-eight patients (72.7%) were men. MC recommendations were not compliant with NCCN guidelines in 7 (10.6%) patients. Reasons for non-compliance were recommended definitive radiation alone for T1/2N2 oropharyngeal cancer (3 patients), recommended over-use of induction chemotherapy (2 patients) or adjuvant therapy (1 patient), and incomplete documentation (1 patient). Actual treatment deviated from MC recommendations in 25 (38.5%) patients, although in 14 of these patients, treatment remained guideline-adherent. Actual treatment was not compliant with guidelines in 9 patients; 4 of these patients had treatment congruent with MC recommendations, which were not NCCN guideline-compliant. Reasons for guideline-discordance in the remaining patients were individual. Conclusions: Discordance with NCCN guidelines for head and neck cancer treatment planning and delivery was observed in this cohort; while some deviations were due to incomplete documentation, areas for improvement were identified. Further study is warranted to determine whether treatment deviating from NCCN guidelines impacts patient outcome.

Introduction: Patients with oral leukoplakia and other oral potentially malignant disorders (OPMD) have an increased risk for oral cancer development. Extensive research efforts are currently directed toward identification of agents which can prevent or delay progression to invasive carcinoma in these high risk patients. Although cancer development is the ideal endpoint to monitor for efficacy, years may elapse before malignant progression. Many clinical trials therefore utilize surrogate endpoints such as clinical appearance or pathologic grade of dysplasia to assess response to study agents. The subjective nature of clinical examination and potential for sampling error with small biopsy samples may limit the ability of oral chemoprevention trials to accurately evaluate the potential efficacy of study agents in patients with OPMD based on clinical examination and/or pathologic evaluation of biopsy samples. The purpose of this study is to evaluate the feasibility of using noninvasive optical imaging approaches for quantitative comparisons of oral lesions in patients participating in an oral cancer chemoprevention trial. Material and Methods: Twenty-three patients with visible oral lesions enrolled on the Erlotinib Prevention of Oral Cancer chemoprevention trial (EPOC) were simultaneously enrolled in diagnostic optical imaging and spectroscopy trials. EPOC is a multicenter trial to test the ability of an epidermal growth factor receptor (EGFR) inhibitor to reduce the incidence of oral cancer in high-risk patients. These 23 patients are also being followed over time with standard clinical examination, autofluorescence imaging (AFI), and optical spectroscopy. The AFI device captures autofluorescence images of a 4-5 cm diameter region of oral mucosa using an excitation wavelength of 405 nm, optical filters, and a camera. The spectroscopy device collects autofluorescence and reflectance spectra from selected sites using a 4 mm diameter fiber optic probe. Normalized red:green fluorescence intensity ratios from AFI and posterior probability risk scores generated by an algorithm from spectroscopy exams are recorded. Objective optical data from successive exams over time are compared to clinical exam and pathologic results from any corresponding biopsies. Results: During the 30-month period from February 2010 to August 2012 a total of 89 in vivo measurement sessions were carried out, producing data from 64 unique oral sites in 23 subjects. Of the 64 sites tracked, there were 45 corresponding histopathologic diagnoses available at some point during the study period. To date, 18 of the patients have been measured over the course of three or more visits. Conclusion: Results illustrate a potential for objective optical diagnostic evaluations to assist in monitoring response to test agents during oral chemoprevention trials. Citation Format: Jana M. Howe, Sharon Mondrik, Richard Schwarz, Tim Quang, Vijayashree Bhattar, Sohini Dhar, Mary K. Quinn, William William, Jr., Michelle D. Williams, Rebecca Richards-Kortum, Ann M. Gillenwater. Assessment of quantitative optical measurements of mucosal lesions as a surrogate biomarker in patients participating in an oral cancer chemoprevention trial. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B109.

7047 Background: Tumor size is a known prognostic factor for early stage (I and II) NSCLC, but its significance in node positive or locally advanced NSCLC has not been determined. We sought to evaluate its prognostic value in early and locally advanced NSCLC and create a nomogram incorporating tumor size and other prognostic variables to predict survival. Methods: The SEER registry was queried for patients (pts) with NSCLC, aged 20-103 and diagnosed between 1998 and 2003. Pts with extra-pulmonary metastases or distant lymph node metastases were excluded. Tumor size was analyzed as a continuous variable. Other demographic variables included age, gender, race, histology, primary tumor extension, node status and primary treatment modality (surgery vs radiation). Log-rank test was performed to evaluate the relationship between these variables and overall survival (OS). Cox proportional hazard model was used to evaluate whether tumor size was an independent prognostic factor. Results: 52,287 eligible pts were divided into 16 subgroups based on primary tumor extension and node status. For example, in group 1, tumor was confined to one lung with no nodes involved; pts in group 12 had tumor invading the mediastinum (T4 by extent) and positive ipsilateral mediastinal nodes. Tumor size had a significant effect on OS in almost all groups after adjustment for age, sex, race, histology, node status, primary tumor extension and primary treatment modality. Our model incorporating tumor size had significantly better predictive accuracy (larger C index) than our alternative model not including this information (p

e17009 Background: Pemetrexed is a novel antimetabolite that inhibits both purine and pyrimidine biosynthesis. Because its mechanism of action is similar to that of both methotrexate and 5-FU, it may also have activity in recurrent/metastatic HNSCC, a disease with limited treatment options and very poor median survival. Pemetrexed is traditionally prescribed with steroids due to skin toxicities observed in early studies; however vitamin supplementation (B12 and folic acid) was not standard at the time of those studies. No study to date has evaluated the optimal use of steroids with pemetrexed in the era of vitamin supplementation. Methods: All patients had metastatic or recurrent HNSCC, were treated with at least one prior chemotherapy regimen, and had ECOG PS of 0–2. The first cohort of patients received pemetrexed 500 mg/m2 every 3 weeks and the next receiving 600 mg/m2 based on a predefined standard dose escalation design. Within each dose level, patients were randomized to one of 3 premedication regimens: no dexamethasone, 20 mg IV on day 1, or standard 4 mg orally bid for 3 days. All patients received vitamin supplementation. The primary endpoint of the study was to determine the maximum tolerated dose of pemetrexed based on steroid premedication. Results: From October 2005 to March 2008, 36 patients were enrolled and 31 were available for evaluation. Median age was 57 years (range 42–82). 51.5% of patients had more than one prior chemotherapy regimens, 81.8% of patients had prior radiation therapy, and 48.5% of patients had prior surgery. Incidence of rash and combined skin toxicities were: 1/11 (9%) and 3/11 (27%) of patients without steroids, 1/11 (9%) and 3/11 (27%) with single IV dose, and 4/9 (44%) and 5/9 (55%) with oral steroids. No treatment-related grade 3 toxicities were observed. One patient initially received no steroid and required dose reduction and addition of steroid due to grade 2 rash. A partial response was observed in one patient (3.2%), and stable disease in 8 patients (25.8%) for a disease control rate of 29%. Conclusions: This is the first study to report the role of steroids as a premedication for pemetrexed. Our data suggests that no steroid premedication is needed with pemetrexed and vitamin supplementation. [Table: see text]

11085 Background: Mammalian target of rapamycin (mTOR) plays a central role in carcinogenesis by coupling intracellular growth stimuli through tyrosine kinase receptors to cell-cycle progression. AMPK has been proposed to act as a cellular fuel sensor allosterically activated under conditions that decrease the ATP/AMP ratio. AMPK is also regulated by phosphorylation following activation of the upstream serine-threonine kinase LKB1. Besides contributing to energy metabolism control, AMPK has been shown to inhibit cell growth via mTOR suppression, thus suggesting a possible role in carcinogenesis. Methods: We determined the distribution of p-AMPK protein levels in tumor specimens from 277 patients (55% female) with non-small cell lung cancer (NSCLC) [94%] or SCLC [6%], using high throughput Western tissue microarrays, and evaluated its impact on survival. Biomarker expression levels in pre-specified subgroups were compared by Wilcoxon and Kruskal-Wallis tests. Survivals between the groups were compared usin...

6005 Background: 36 cytokines and angiogenic factors (C/AFs) were measured in HN patients on a Phase II induction chemotherapy trial to investigate connections between biomarker signatures and clin...

18098 Background: The combination of bevacizumab, paclitaxel and carboplatin has been recently shown to increase response rates and survival in patients (pts) with untreated, metastatic, non-squamous, NSCLC and is currently FDA-approved for this indication. However, there are limited data on the safety and efficacy of bevacizumab in combination with other widely used chemotherapy doublets for NSCLC. This is a single-arm, open-labeled, phase II trial of bevacizumab, docetaxel and carboplatin for pts with NSCLC. Methods: Eligibility criteria included chemotherapy-naïve stage IIIB or IV incurable NSCLC of non-squamous cell histology, PS 0–1, no brain metastases, no history of hemoptysis, no cavitation, stable cardiac condition and no full dose anticoagulation. Treatment consisted of docetaxel 75 mg/m2, carboplatin AUC 6, and bevacizumab 15 mg/kg IV on day 1 every 3 weeks for up to 6 cycles followed by bevacizumab 15 mg/kg alone every 3 weeks until progression. The primary endpoint was progression-free survival. Results: 20 pts (12 females) have been enrolled with a planned sample size of 50 pts. Baseline characteristics were: median age 66 years old (37–77), PS 0 (6 pts) or 1 (14 pts), stage IIIB (1 pt) or IV (19 pts). 19 pts are evaluable for response and toxicity at this time. Severe adverse events (SAEs) included: 4 pts with neutropenia (2 febrile neutropenias), mild hemoptysis in 2 pts (treated with radiotherapy), 1 pt with peritoneal perforation (who had a history of diverticula), 1 pt with pulmonary embolism, and 1 pt with grade 3 hypertension. Partial responses by RECIST have been observed in 14 pts (74%, 13 confirmed), and stable disease in 5 pts (26%, 4 confirmed). Disease control rate (PR+SD) was 100% after 4 cycles of therapy. 9/20 pts are off treatment (3 progressions, 5 SAEs, 1 maximal benefit). Progression-free survival will be reported at the completion of the trial. Conclusions: The combination of bevacizumab, docetaxel and carboplatin appears to be efficacious and tolerable for the first-line treatment of metastatic NSCLC. No significant financial relationships to disclose.

18013 Background: A small subset of patients with metastatic melanoma treated with BioCT may experience LTDFS. Methods: We retrospectively reviewed all patients with stage IV melanoma and a follow-up of at least 12 months (mo) who received BioCT between 1/1998 -1/2005 under the supervision of one of the co-authors (ACB). Treatment consisted of two 3-week-cycles of cisplatin 25 mg/m2 IV D1–3, vinblastine 2 mg/m2 IV D1–3, dacarbazine 800 mg/m2 IV D1, IL-2 9 MIU/m2 IVCI D1–4, and interferon alpha-2b (IFN) 5 MIU SC D1–5. Responding patients received up to 4 additional cycles, depending on tolerance. Metastasectomy was performed for residual disease at the discretion of the attending physician. Results: A total of 57 pts (36 men, median age 45 years, median follow-up 50 months) received 190 cycles of BioCT (median 3 cycles/pt). No deaths occurred during treatment. To date, 48 pts (84%) have recurred and 41 pts (72%) have died. Median time to progression and overall survival were 8 and 17 mo, respectively. Response rates using RECIST: CR 19%, PR 32%, for an overall response rate of 51%. LTDFS, defined as pts alive and recurrence-free at 24+ mo after BioCT, was observed in 8 of the 57 pts treated (29+, 30+, 51+, 58+, 69+, 71+, 80+, and 97+ mo). 4 of the 8 pts were rendered disease-free by surgery following BioCT (2 CR, 1 PR and 1 SD; 3 with viable melanoma at pathology and 1 with pathologic CR). The remaining 4 pts achieved CR and LTDFS with BioCT alone (see Table for clinical characteristics). Conclusions: LTDFS can be achieved in approximately 7% of pts with stage IV melanoma treated with BioCT alone. Although small, this subset of pts justifies the use of BioCT for young and highly selected pts. Further studies such as gene profiling designed to better identify individuals who could potentially benefit most from BioCT are clearly warranted. [Table: see text] No significant financial relationships to disclose.

8038 Background: There are limited data on systemic therapy after progression following BioCT (cisplatin, vinblastine, dacarbazine, interferon-alfa and IL-2) in patients with stage IV melanoma. High-dose IL-2 has a 16% response-rate as first-line therapy, with approximately 5% of the pts achieving long-term survival. Methods: We retrospectively reviewed our experience with high-dose IL-2 in pts who had metastatic melanoma and had progressed during or after BioCT from 1/2000 to 1/2005. One treatment course consisted of IL-2, 600.000 IU/kg IVP q8h for a maximum of 14 doses per cycle, followed by an identical cycle after a one week of rest. Responding patients received 2 additional courses after 6 weeks of rest between courses. All pts were treated in a regular ward setting under the assistance of specialized and trained nurses on high-dose IL-2 therapy. Results: A total of 23 pts (15 male, 8 female); median age 46 (range 21–68) were treated with high-dose IL-2. Two pts received only 1 cycle of therapy due to PD and 1 treatment-related death. The remaining 21 pts received at least 1 full course (2 cycles) of therapy. Median number of cycles was 2 and median number of IL-2 doses/cycle was 10. Response rates using RECIST were as follows: CR, 1 pt (5%); PR, 6 pts (27%). Duration of response was 1, 3, 8, 9, 10, 12, and 18 months. There were no long-term disease-free survivors. Among the 9 patients with a previous response to BioCT, 1 pt had CR and 3 pts had PR to high-dose IL-2. Among the 8 pts whose disease previously progressed on BioCT, 2 pts still achieved a PR. After a median follow-up of 36 months, all pts have presented disease progression and 20 pts have died. Median time to progression and overall survival were 2.5 mo and 9.5 mo, respectively. Conclusions: High-dose IL-2 has modest but definite activity in pts previously treated with BioCT, regardless of the response to the latter treatment, and may be an option in selected pts. No significant financial relationships to disclose.

5607 Background: The role of neoadjuvant chemotherapy followed by chemotherapy administered concurrently with accelerated RT has not been established. We designed a study to evaluate the feasibilit...