Weekly Docetaxel, Cisplatin, and Cetuximab in Palliative Treatment of Patients with Squamous Cell Carcinoma of the Head and Neck.

LESSONS LEARNED: Chemotherapy for recurrent, metastatic squamous cell carcinoma of the head and neck need not be known for extreme toxicity.The weekly regimen studied here has been demonstrated to be tolerable and effective. BACKGROUND: The objective of this study was to establish the response rate, progression-free survival (PFS) and overall survival (OS), and safety profile of weekly docetaxel, platinum, and cetuximab (TPC) in patients with relapsed or metastatic squamous cell carcinoma of the head and neck (SCCHN). MATERIALS AND METHODS: Twenty-nine patients with metastatic or recurrent SCCHN with an Eastern Cooperative Oncology Group (ECOG) performance status <3 were enrolled in an institutional review board-approved phase II trial. This study permitted prior chemoradiation, radiation, and/or surgery, provided that 3 months had elapsed since the end of the potentially curative treatment. Patients received cisplatin 30 mg/m2 or carboplatin area under the curve (AUC) 2, docetaxel 30 mg/m2, and cetuximab 250 mg/m2 weekly for 3 weeks, followed by a break during the fourth week, for a 28-day cycle. Planned intrapatient dose modifications were based on individual toxicity. RESULTS: Twenty-seven patients received TPC and were evaluable for response and toxicity. Rates of complete response (CR), partial response (PR), and confirmed PR were 3%, 52%, and 30%, respectively. The overall objective response rate was 56%. Estimated median PFS and OS were 4.8 and 14.7 months, respectively. The rates of grade 3 and 4 worst-grade adverse events (AEs) per patient were 85% and 7%, respectively. Dose density through cycle 4 was preserved for all patients; however, treatment beyond cycle 6 with the TPC regimen proved unfeasible. CONCLUSION: Weekly docetaxel, cisplatin, and cetuximab is an effective regimen for patients with metastatic or recurrent SCCHN. Response rates, PFS, and OS compare favorably with other combination chemotherapy treatments. Grade 4 toxicity rates observed in this study were substantially lower than those described with regimens using less frequent, higher-dose chemotherapy schedules.

In search for optimal induction chemotherapy for advanced nasopharyngeal cancer: Standard dosing of Docetaxel, Platinum, and 5-Fluorouracil (TPF) followed by chemoradiation.

OBJECTIVES: A phase II = design is used to evaluate the efficacy and feasibility of full dose docetaxel, platinum, and 5-fluorouracil (TPF) in a sequential chemoradiation treatment locally advanced (LA) or oligometastatic (OM) NPC patients. MATERIALS AND METHODS: Twenty patients with LANPC (M0 cohort) and six patients with OMNPC (M1 cohort) received induction standard dose T (75 mg/m2) P (75 mg/m2) F (750 mg/m2 IVCI x 5days) x 3 followed by weekly cisplatin (40 mg/m2) or carboplatin (AUC 1.5) x 6 concurrent with radiation therapy of 70 Gy over 6.5-7 weeks. The first five patients received bevacizumab as part of an exploratory objective of hypoxia modification using correlative fluoromisonidasole (18F-MISO) PET CT scanning. RESULTS: The 18F-MISO imaging failed to reveal adequate levels of baseline hypoxia necessary to evaluate for changes with chemotherapy and bevacizumab. Ninety percent of M0 patients and 83% of M1 patients received the full-intended TPF and radiation dose. Eighty-five percent of M0 patients and all M1 patients received at least 60% of the full-intended concurrent platinum dose. The 2-year progression free survival (PFS) rate for the M0 cohort was 90% (95% CI: 77.8%- 100%), and was sustained at 5 years. The 2-year PFS rate for the M1 cohort was 66.7% (95% CI: 37.9%- 100%). The 2-year overall survival (OS) rates for the M0 and M1 cohorts were 100% and 83.3% (95% CI: 58.3%- 100%), respectively. At five years, OS was 94.4% for the M0 cohort. CONCLUSION: Administration of standard-dose TPF as induction chemotherapy in this NPC patient population is both feasible and effective when coupled with definitive concurrent chemoradiation. CLINICALTRIALS.GOV IDENTIFIER: NCT00896181.

FAT/CD36 Participation in Human Skeletal Muscle Lipid Metabolism: A Systematic Review.

Fatty acid translocase/cluster of differentiation 36 (FAT/CD36) is a multifunctional membrane protein activated by a high-fat diet, physical exercise, fatty acids (FAs), leptin, and insulin. The principal function of FAT/CD36 is to facilitate the transport of long-chain fatty acids through cell membranes such as myocytes, adipocytes, heart, and liver. Under high-energy expenditure, the different isoforms of FAT/CD36 in the plasma membrane and mitochondria bind to the mobilization and oxidation of FAs. Furthermore, FAT/CD36 is released in its soluble form and becomes a marker of metabolic dysfunction. Studies with healthy animals and humans show that physical exercise and a high-lipid diet increase FAT/CD36 expression and caloric expenditure. However, several aspects such as obesity, diabetes, Single Nucleotide polymorphisms (SNPs), and oxidative stress affect the normal FAs metabolism and function of FAT/CD36, inducing metabolic disease. Through a comprehensive systematic review of primary studies, this work aimed to document molecular mechanisms related to FAT/CD36 in FAs oxidation and trafficking in skeletal muscle under basal conditions, physical exercise, and diet in healthy individuals.

Discordance in routine second opinion pathology review of head and neck oncology specimens: A single-center five year retrospective review.

OBJECTIVES: Second opinion review of pathology specimens is a common institutional practice, supported by large retrospective studies demonstrating significant histologic discordance. Since the most recent study of head and neck-specific pathology review was conducted, routine HPV and EBV testing is now recommended for certain specimens. We describe the frequency of and reasons for discordant reports and their potential impact on treatment recommendations and prognosis in a five-year retrospective cohort study at a single academic referral institution from 2005 to 2010. MATERIALS AND METHODS: Following institutional review board review, 1003 cases referred to the Head and Neck Oncology Service were identified using a retrospective database search. Discordance between outside and second review pathology report was assessed by a board-certified medical oncologist. RESULTS: 667 cases were included, of which 22% were discordant. Discordance was associated with adenocarcinomas (AOR [adjusted odds ratio] 0.09, 95% CI 0.03-0.31; p<0.001), poorly differentiated carcinomas (AOR 0.14, 95% CI 0.06-0.39; p<0.001), and specimens of uncommon histology (AOR 0.18, 95% CI 0.07-0.45; p<0.001) but not biopsy site in a multivariate model. The most common reasons for discordance included histology (61%), followed by the results of special studies (36%), and the presence or absence of stromal invasion (14%). Differences in tumor HPV status comprised 16% of discordant cases and were associated with better prognosis (p<0.001) following second opinion review. CONCLUSIONS: Routine second opinion pathology review may lead to clinically significant differences in treatment recommendations and prognosis.

Hearing evaluation of patients with head and neck cancer: Comparison of Common Terminology Criteria for Adverse Events, Brock and Chang adverse event criteria in patients receiving cisplatin.

BACKGROUND: The purpose of this study was to compare Common Terminology Criteria for Adverse Events (CTCAE), Brock and Chang hearing loss grading in patients with head and neck cancer receiving cis-diamminedichloroplatinum (CDDP). Endpoints were baseline distribution of hearing loss, interobserver consistency, and sensitivity to hearing loss after CDDP treatment. METHODS: Four hundred sixty single ear audiograms in 110 patients with head and neck cancer were graded. Hearing loss at baseline, interobserver agreement rates, and changes in hearing loss after CDDP were evaluated. RESULTS: The Chang and Brock tools' baseline hearing loss distribution was concentrated at grade 0 (57% and 41%, respectively), whereas 47%, per the CTCAE, had grade 3 baseline hearing loss. Interobserver agreement was highest for the Brock scale (≥90%) followed by the Chang (≥89%) and CTCAE (≥75%) scales. Detection of change after CDDP was highest for Chang (48%) followed by Brock (45%) and the CTCAE (32%). CONCLUSION: The Brock and Chang tools may be superior to the CTCAE in patients with head and neck cancer receiving CDDP using baseline hearing loss distribution, interobserver agreement, and detection of hearing loss grade change as performance indicators.

Targeting CD137 enhances the efficacy of cetuximab.

Treatment with cetuximab, an EGFR-targeting IgG1 mAb, results in beneficial, yet limited, clinical improvement for patients with head and neck (HN) cancer as well as colorectal cancer (CRC) patients with WT KRAS tumors. Antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells contributes to the efficacy of cetuximab. The costimulatory molecule CD137 (4-1BB) is expressed following NK and memory T cell activation. We found that isolated human NK cells substantially increased expression of CD137 when exposed to cetuximab-coated, EGFR-expressing HN and CRC cell lines. Furthermore, activation of CD137 with an agonistic mAb enhanced NK cell degranulation and cytotoxicity. In multiple murine xenograft models, including EGFR-expressing cancer cells, HN cells, and KRAS-WT and KRAS-mutant CRC, combined cetuximab and anti-CD137 mAb administration was synergistic and led to complete tumor resolution and prolonged survival, which was dependent on the presence of NK cells. In patients receiving cetuximab, the level of CD137 on circulating and intratumoral NK cells was dependent on postcetuximab time and host FcyRIIIa polymorphism. Interestingly, the increase in CD137-expressing NK cells directly correlated to an increase in EGFR-specific CD8+ T cells. These results support development of a sequential antibody approach against EGFR-expressing malignancies that first targets the tumor and then the host immune system.