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We propose an adaptive design for early-phase drug-combination cancer trials with the goal of estimating the maximum tolerated dose (MTD). A nonparametric Bayesian model, using beta priors truncated to the set of partially ordered dose combinations, is used to describe the probability of dose limiting toxicity (DLT). Dose allocation between successive cohorts of patients is estimated using a modified continual reassessment scheme. The updated probabilities of DLT are calculated with a Gibbs sampler that employs a weighting mechanism to calibrate the influence of data vs the prior. At the end of the trial, we recommend one or more dose combinations as the MTD based on our proposed algorithm. We apply our method to a Phase I clinical trial of CB-839 and Gemcitabine that motivated this nonparametric design. The design operating characteristics indicate that our method is comparable with existing methods.

BACKGROUND Multidisciplinary management of head and neck cancer (HNC) must reconcile increasingly sophisticated subspecialty care with timeliness of care. Prior studies examined the individual effects of delays in diagnosis-to-treatment interval, postoperative interval, and radiation interval but did not consider them collectively. The objective of the current study was to investigate the combined impact of these interwoven intervals on patients with HNC. METHODS Patients with HNC who underwent curative-intent surgery with radiation were identified in the National Cancer Database between 2004 and 2013. Multivariable models were constructed using restricted cubic splines to determine nonlinear relations with overall survival. RESULTS Overall, 15,064 patients were evaluated. After adjustment for covariates, only prolonged postoperative interval (P

BACKGROUND: Current nodal staging for salivary gland cancer (SGC) is extrapolated from mucosal head and neck squamous cell carcinoma. However, given their unique biology and clinical behavior, it is possible that a SGC-specific nodal staging system would be more accurate. METHODS: Patients from the National Cancer Database with non-metastatic SGC of the head and neck diagnosed from 2004 to 2013 and undergoing surgical resection and neck dissection removing at least 10 lymph nodes (LN) were included. Multivariable models were constructed to assess the association between survival and nodal factors, including number of metastatic LN, extranodal extension, LN size, and lower LN involvement. RESULTS: Overall, 4,520 patients met inclusion criteria. Increasing number of metastatic LN was strongly associated with worse survival without plateau. The risk of death increased more rapidly up to 4 LN (HR=1.34, 95% confidence interval (CI) 1.27-1.41, P

BACKGROUND There is increasing evidence that primary tumor ablation can improve survival for some cancer patients with distant metastases. This may be particularly applicable to head and neck squamous cell carcinoma (HNSCC) because of its tropism for locoregional progression. METHODS This study included patients with metastatic HNSCC undergoing systemic therapy identified in the National Cancer Data Base. High-intensity local treatment was defined as radiation doses ≥ 60 Gy or oncologic resection of the primary tumor. Multivariate Cox regression, propensity score matching, landmark analysis, and subgroup analysis were performed to account for imbalances in covariates, including adjustments for the number and location of metastatic sites in the subset of patients with this information available. RESULTS In all, 3269 patients were included (median follow-up, 51.5 months). Patients undergoing systemic therapy with local treatment had improved survival in comparison with patients receiving systemic therapy alone in propensity score–matched cohorts (2-year overall survival, 34.2% vs 20.6%; P < .001). Improved survival was associated only with patients receiving high-intensity local treatment, whereas those receiving lower-intensity local treatment had survival similar to that of patients receiving systemic therapy without local treatment. The impact of high-intensity local therapy was time-dependent, with a stronger impact within the first 6 months after the diagnosis (adjusted hazard ratio [AHR], 0.255; 95% confidence interval [CI], 0.210-0.309; P < .001) in comparison with more than 6 months after the diagnosis (AHR, 0.622; 95% CI, 0.561-0.689; P < .001) in the multivariate analysis. A benefit was seen in all subgroups, in landmark analyses of 1-, 2-, and 3-year survivors, and when adjusting for the number and location of metastatic sites. CONCLUSIONS Aggressive local treatment warrants prospective evaluation for select patients with metastatic HNSCC. Cancer 2017. © 2017 American Cancer Society.

BACKGROUND The treatment of head and neck cancers is complex and associated with significant morbidity, requiring multidisciplinary care and physician expertise. Thus, facility characteristics, such as clinical volume and academic status, may influence outcomes. METHODS The current study included 46,567 patients taken from the National Cancer Data Base who were diagnosed with locally advanced invasive squamous cell carcinomas of the oropharynx, larynx, and hypopharynx and were undergoing definitive radiotherapy. High-volume facilities (HVFs) were defined as the top 1% of centers by the number of patients treated from 2004 through 2012. Multivariable Cox regression and propensity score matching were performed to account for imbalances in covariates. RESULTS The median follow-up was 55.1 months. Treatment at a HVF (hazard ratio, 0.798; 95% confidence interval, 0.753-0.845 [P

We present a cancer phase I clinical trial design of a combination of two drugs with the goal of estimating the maximum tolerated dose curve in the two-dimensional Cartesian plane. A parametric model is used to describe the relationship between the doses of the two agents and the probability of dose limiting toxicity. The model is re-parameterized in terms of the probabilities of toxicities at dose combinations corresponding to the minimum and maximum doses available in the trial and the interaction parameter. Trial design proceeds using cohorts of two patients receiving doses according to univariate escalation with overdose control (EWOC), where at each stage of the trial, we seek a dose of one agent using the current posterior distribution of the MTD of this agent given the current dose of the other agent. The maximum tolerated dose curve is estimated as a function of Bayes estimates of the model parameters. Performance of the trial is studied by evaluating its design operating characteristics in terms of safety of the trial and percent of dose recommendation at dose combination neighborhoods around the true MTD curve and under model misspecifications for the true dose-toxicity relationship. The method is further extended to accommodate discrete dose combinations and compared with previous approaches under several scenarios. Copyright © 2016 John Wiley & Sons, Ltd.

BACKGROUND: Early marrow blast clearance 14 days after induction chemotherapy is an independent prognostic indicator of outcomes in acute myeloid leukemia (AML). METHODS: We evaluated the relationship between time to peripheral blood blast clearance after induction and disease status as assessed by day 14 and day 30 marrow biopsies in 162 patients with AML. Day 6 after induction was the optimal cutoff point determined by a receiver operating characteristic analysis and was selected to divide patients into early blast clearance (EBC; ≤6 days; n = 119) and delayed blast clearance (DBC; >6 days; n = 43) groups. RESULTS: DBC patients were older, but otherwise the 2 groups were comparable. Marrow blast clearance on day 14 after induction chemotherapy was observed in 84% of patients in the EBC group and 60% in the DBC group. With a median follow-up of 1538 days, both relapse-free survival (RFS) (442 vs 202 days, P = .0017) and overall survival (OS) (930 vs 429 days, P < .0001) were longer in the EBC group, and a multivariable analysis showed that EBC independently predicted clearance of marrow blasts at day 14 (P = .0018), remission (P = .0179), RFS (P = .0171), and OS (P = .0122). CONCLUSIONS: Early clearance of peripheral blood blasts after induction chemotherapy predicts for early marrow blast clearance, complete remission, RFS, and OS. Cancer 2012. © 2012 American Cancer Society.

BACKGROUND: Bortezomib has demonstrated efficacy in patients with relapsed B-cell non-Hodgkin lymphoma (NHL) both alone and in combination with other agents; however, limited data exist regarding its toxicity in combination with common frontline therapies for indolent NHL. A phase 1 study of bortezomib combined with rituximab, cyclophosphamide, doxorubicin, modified vincristine, and prednisone (R-CHOP) was conducted in patients with untreated follicular lymphoma (FL) and other indolent NHLs. METHODS: Nineteen patients, including 10 patients with FL, were enrolled. The median patient age was 59 years (range, 29-71 years). Seven patients had a FL International Prognostic Index score ≥3. R-CHOP with the vincristine dose capped at 1.5 mg was administered on a 21-day cycle for 6 to 8 cycles, and 1 of 3 dose levels of bortezomib (1.0 mg/m2 [n = 1], 1.3 mg/m2 [n = 6], or 1.6 mg/m2 [n = 12]) was administered on days 1 and 8 of each cycle using a Bayesian algorithm for dose escalation. RESULTS: The maximum tolerated dose (MTD) of bortezomib with modified R-CHOP was reached at 1.6 mg/m2. Dose-limiting toxicity was observed in 5 patients (1 patient at a bortezomib dose of 1.0 mg/m2, 1 patient at a bortezomib dose of 1.3 mg/m2, and 3 patients at a bortezomib dose of 1.6 mg/m2). Neuropathy occurred in 16 patients (84%), including 2 patients (11%) who experienced grade 3 sensory neuropathy. Grade 4 hematologic toxicity occurred in 4 patients. Of 19 evaluable patients, 100% responded, and the complete response rate was 68%. At a median follow-up of 32 months, the 3-year progression-free survival rate was 89.5%. CONCLUSIONS: Bortezomib combined with modified R-CHOP produced high response rates without substantial increases in toxicity. A phase 2 study of R-CHOP and bortezomib given at this established MTD is currently ongoing. Cancer 2012;3538–3548. © 2012 American Cancer Society.

An antibody simultaneously targeting epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), two major tumor growth-driving machineries, may provide a novel effective strategy for optimizing tumor targeting and maximizing potential clinical benefits. Human domain antibodies selected against VEGF and EGFR were formatted into a fully human dual-targeting IgG (DT-IgG) to directly target both antigens in a single molecule. We evaluated the efficacy of DT-IgG in comparison with bevacizumab and cetuximab alone and in combination in the lung cancer cell line A549 (low EGFR expression and KRAS mutant) and the head and neck squamous cell carcinoma (HNSCC) cell line Tu212 (high EGFR expression and KRAS wild type) in vitro and in vivo. DT-IgG suppressed Tu212 and A549 cell growth, inhibited EGFR activation and induced apoptosis as effectively as cetuximab, and neutralized VEGF as effectively as bevacizumab. DT-IgG induced EGFR-dependent VEGF internalization, constituting a novel antiangiogenesis mechanism. In xenograft models with lung and head and neck cancer cell lines, DT-IgG displayed efficacy equivalent to bevacizumab in diminishing tumor growth despite its short serum half-life (36 hr in rats) and both agents may constitute preferable alternatives to cetuximab in KRAS-mutant tumors. Immunofluorescence staining revealed that localization of DT-IgG was similar to that of cetuximab, largely associated with EGFR+tumor cells. Our proof of principle study suggests a DT-IgG against EGFR and VEGF as an alternative therapeutic strategy with potentially enhanced clinical benefit.

BACKGROUND: High-dose cytarabine (HiDAC) is safe and very effective in younger patients with acute myeloid leukemia (AML), but it generally is not well tolerated in the elderly. METHODS: The authors explored the safety and tolerability of a modified HiDAC induction regimen consisting of 6 daily doses of cytarabine at 2 g/m2 in combination with 3 daily doses of daunorubicin at 45 mg/m2 in 59 consecutive patients aged >60 years who had de novo AML diagnosed between July 1996 and February 2005. RESULTS: The median patient age was 68 years (range, 60-86 years). The regimen was well tolerated. Infections were common and occurred in 39% of patients, but cerebellar toxicities occurred in only 7% of patients and were reversible. The day-30 induction-related mortality rate was 10%. Overall, 69% of patients achieved complete remissions (CR), and 80% received up to 3 consolidations with HiDAC. The median follow-up for surviving patients was 53 months (range, 17-114 months). The median overall survival was 15.3 months (range, 1-114 months), and the relapse-free survival was 13.8 months (range, 1-113 months). Survival for patients who achieved CR was 27 months (range, 2-114 months). CONCLUSIONS: The modified HiDAC regimen was well tolerated in patients aged >60 years with AML and was associated with low induction mortality and high rates of CR. Nevertheless, these high remissions still were associated with poor overall outcomes. Cancer 2011;. © 2011 American Cancer Society.

Background LKB1 loss is associated with invasive carcinoma and metastasis. In head and neck squamous cell carcinoma (HNSCC), lymph node metastasis status is the strongest predictor of survival. Methods LKB1 immunohistochemistry was performed on primary tumors from patients with HNSCC who never developed metastases, patients with metastases, and their paired lymph node metastasis to determine whether LKB1 was associated with HNSCC metastasis. Results LKB1 was expressed in the nucleus and cytoplasm of tumor cells and HNSCC cell lines. Primary tumors from patients with metastatic carcinoma had decreased nuclear, but not cytoplasmic, LKB1 compared to patients with nonmetastatic cancer. Nuclear LKB1 levels correlated with lymph node metastasis grade and primary tumor site. The percentage of tumor cells negative for nuclear LKB1 staining was greatest in the primary metastatic tumor group, and decreased nuclear LKB1 trended toward worse disease-free survival. Conclusion Decreased nuclear LKB1 levels correlate with HNSCC metastasis and suggest a nuclear function of LKB1 in repressing HNSCC metastasis. Head Neck, 2010

BACKGROUND One proposed mechanism of extracorporeal photopheresis (ECP) in reducing chronic graft-versus-host disease (cGVHD) is alteration in numbers of circulating dendritic cells (DCs). This hypothesis was tested by correlating numbers of DC precursors and T cells in the blood before and during ECP therapy with response of cGVHD.

This study was to explore whether the efficacy of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 (Z, Iressa, gefitinib) plus chemotherapeutic agents docetaxel (D) and cisplatin (P) may benefit from sequencing of the combination.Three head and neck cancer cell lines were used to study the effect of various combinations of and relative sequencing of D, P, and Z in cell growth inhibition. A population pharmacokinetic stimulation study was conducted on Z in silico and used together with the growth inhibition data to derive principles for future in vivo use of this drug combination.The inhibitory effects of Z on combinations of D and P were sequence dependent. Treatment simultaneously with DPZ or with DP followed by Z (DP--Z) showed synergistic effects in all 3 cell lines. However, sequencing with Z followed by DP (Z--DP), gave an antagonistic effect, suggesting that D and P should be administered when the effect of Z is low. The induction of apoptosis was also sequence dependent. The in silico pharmacokinetic study suggested the feasibility of deriving a 5-day-on/2-day-off regimen for Z, in which D and P administration commences when levels of Z are low, allowing levels of Z to accumulate sufficiently during the remainder of the cycle.These data suggests that it is feasible to design clinical trials with these settings to maximize the efficacy of this combined drug regimen.

Background Nanotechnology-based drug delivery approaches may help increase therapeutic efficacy and decrease side effects of chemotherapeutics. We investigated expression levels of folate receptor in squamous cell carcinoma of the head and neck (SCCHN) to evaluate folate receptor as a target for nanotherapy. Methods Folate receptor expression levels in archival SCCHN tissues were analyzed by immunohistochemistry and correlated with clinical parameters. Results Folate receptor was detected in 45% of primary tumors and 40% of corresponding lymph node metastases. Folate receptor expression in primary tumors of the metastatic group strongly correlated with the corresponding lymph node metastases (p = .0002). Folate receptor expression was inversely correlated with disease-free survival in nonmetastatic (p = .0048), metastatic (p = .0127), and lymph node metastases (p

We examine a large class of prior distributions to model the dose-response relationship in cancer phase I clinical trials. We parameterize the dose-toxicity model in terms of the maximum tolerated dose (MTD) gamma and the probability of dose limiting toxicity (DLT) at the initial dose rho(0). The MTD is estimated using the EWOC (escalation with overdose control) method of Babb et al. We show through simulations that a candidate joint prior for (rho0,gamma) with negative a priori correlation structure results in a safer trial than the one that assumes independent priors for these two parameters while keeping the efficiency of the estimate of the MTD essentially unchanged.