Prevalence and incidence of acute and chronic comorbidity in patients with squamous cell carcinoma of the head and neck.

BACKGROUND: Limited data exist on the burden of comorbidity among patients with squamous cell head and neck cancer (SCCHN) before and during cancer treatment. METHODS: The precancer prevalence and incidence rates of 8 comorbid conditions were estimated among a population-based cohort of 1499 patients with SCCHN in the Netherlands. Patients with cancer, treatments, and comorbidities were identified in the PHARMO Record Linkage System (RLS) using hospital admissions and/or dispensing codes. Prevalence proportions and incidence rates were also compared against a matched cancer-free population. RESULTS: Cardiovascular (41%) and respiratory diseases (12%) were the most prevalent comorbidities. Incidence rates of most comorbidities were highest the first 6 months after cancer diagnosis and decreased over time. Patients receiving chemotherapy-based treatment had significantly higher incidence rates of anemia and other malignant diseases. CONCLUSIONS: High rates of acute and chronic comorbidity were observed; knowledge of comorbidity burden aids in establishing a benefit-risk profile for investigational SCCHN therapies.

A Bayesian hierarchical model for DCE-MRI to evaluate treatment response in a phase II study in advanced squamous cell carcinoma of the head and neck.

OBJECT: Pharmacokinetic parameters from dynamic contrast-enhanced MRI (DCE-MRI) were used to assess the perfusion effects due to treatment response using a tyrosine kinase inhibitor. A Bayesian hierarchical model (BHM) is proposed, as an alternative to voxel-wise estimation procedures, to test for a treatment effect while explicitly modeling known sources of variability. MATERIALS AND METHODS: Nine subjects from a randomized, blinded, placebo-controlled, multicenter, phase II study of lapatinib were examined before and after treatment. Kinetic parameters were estimated, with an extended compartmental model and subject-specific arterial input function, on a voxel-by-voxel basis. RESULTS: The group treated with lapatinib had a decrease in median K(trans) of 0.17 min⁻¹, when averaged across all voxels in the tumor ROIs, compared with no change in the placebo group based on nonlinear regression. A hypothesis test of equality between pre- and posttreatment K (trans) could not be rejected against a one-sided alternative (P = 0.09). Equality between median K(trans) in placebo and lapatinib groups posttreatment could also not be rejected using the BHM (P = 0.32). Across all scans acquired in the study, estimates of K(trans) at one site were greater on average than those at the other site by including a site effect in the BHM. The inter-voxel variability is of similar order (within 15%) when compared to the inter-patient variability. CONCLUSION: Though the study contained a small number of subjects and no significant difference was found, the Bayesian hierarchical model provided estimates of variability from known sources in the study and confidence intervals for all estimated parameters. We believe the BHM provides a straightforward and thorough interrogation of the imaging data at the level of voxels, patients or sites in this multicenter clinical study.

A single-arm, multicenter, open-label phase 2 study of lapatinib as the second-line treatment of patients with locally advanced or metastatic transitional cell carcinoma.

BACKGROUND: The treatment of recurrent transitional cell carcinoma (TCC) remains an unmet clinical need. This study assessed lapatinib, a dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and HER-2, as second-line therapy in patients with locally advanced or metastatic TCC. METHODS: This was a single-arm, multicenter, open-label, prospective phase 2 study. Patients with TCC whose disease progressed on prior platinum-based chemotherapy received lapatinib until disease progression or unacceptable toxicity, with evaluations for response by Response Evaluation Criteria In Solid Tumors criteria performed every 8 weeks. The primary endpoint of the current study was objective tumor response rate. Secondary endpoints included safety, time to disease progression, and overall survival. RESULTS: Fifty-nine patients were enrolled in the study, 25 of whom (42%) could not be evaluated for response. The primary endpoint of an objective response rate (ORR) >10% was observed in 1.7% (95% confidence interval [95% CI], 0.0%-9.1%) of patients; however, 18 (31%; 95% CI, 19%-44%) patients achieved stable disease (SD). The median time to disease progression and overall survival (OS) were 8.6 weeks (95% CI, 8.0 weeks-11.3 weeks) and 17.9 weeks (95% CI, 13.1 weeks-30.3 weeks), respectively. Clinical benefit (ORR and SD) was found to be correlated with EGFR overexpression (P = .029), and, to some extent, HER-2 overexpression. The median OS was significantly prolonged in patients with tumors that overexpressed EGFR and/or HER-2 (P = .0001). Lapatinib was well tolerated. CONCLUSIONS: The study was considered to be negative because it did not meet its primary endpoint; however, further analysis demonstrated an improvement in OS in a subset of patients with tumors overexpressing EGFR and/or HER-2, which is encouraging and warrants further investigation.

Phase I study of lapatinib in combination with chemoradiation in patients with locally advanced squamous cell carcinoma of the head and neck.

PURPOSE: This study (EGF100262) sought to establish the recommended phase II dose of lapatinib with chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). PATIENTS AND METHODS: Patients were enrolled onto cohorts of escalating lapatinib dose (500, 1,000, and 1,500 mg/d). Patients received 1 week of lapatinib alone followed by 6.5 to 7 weeks of the same dose of lapatinib plus radiotherapy 66 to 70 Gy and cisplatin 100 mg/m(2) on days 1, 22, and 43 of radiotherapy. End points included safety/tolerability and clinical activity. RESULTS: Thirty-one patients were enrolled (seven patients in each of the 500- and 1,000-mg cohorts and three in the 1,500-mg cohort; an additional 14 patients were enrolled at 1,500 mg in a safety cohort). Dose-limiting toxicities (DLTs) included perforated ulcer in one patient in the 500-mg cohort and transient elevation of liver enzymes in one patient in the 1,000-mg cohort. No DLTs were observed in the 1,500-mg cohort. Therefore, the recommended phase II dose was defined as lapatinib 1,500 mg/d with chemoradiotherapy. The most common grade 3 to 4 adverse events were radiation mucositis, radiation dermatitis, lymphopenia, and neutropenia. No patients experienced drug-related symptomatic cardiotoxicity, and no interstitial pneumonitis was reported. The overall response rate was 81% (65% at the recommended phase II dose). CONCLUSION: The recommended phase II dose is lapatinib 1,500 mg/d with chemoradiotherapy in patients with LA SCCHN; this regimen is associated with an acceptable tolerability profile. Given these findings, randomized phase II and III studies of lapatinib plus chemoradiotherapy have been initiated.