DNA Damage Measured by the Comet Assay in Head and Neck Cancer Patients Treated with Tirapazamine

AbstractTirapazamine (TPZ) [3-amino -1,2,4-benzotriazine 1,4-dioxide, SR4233, WIN 59075, and Tirazone™] is a novel anticancer drug that is selectively activated by the low oxygen environment in solid tumors. By killing the radioresistant hypoxic cells, TPZ potentiates the antitumor efficacy of fractionated irradiation of transplanted tumors in mice. As this cell kill is closely correlated with TPZ-induced DNA damage, we investigated whether human head and neck cancers would show DNA damage similar to that seen in mouse tumors following TPZ administration. TPZ-induced DNA damage in both transplanted tumors in mice and in neck nodes of 13 patients with head and neck cancer was assessed using the alkaline comet assay on cells obtained from fine-needle aspirates. The oxygen levels of the patients' tumors were also measured using a polarographic oxygen electrode. Cells from the patients' tumors showed DNA damage immediately following TPZ administration that was comparable to, or greater than, that seen with transplanted mouse tumors. The heterogeneity of DNA damage in the patients' tumors was greater than that of individual mouse tumors and correlated with tumor hypoxia. The similarity of TPZinduced DNA damage in human and rodent tumors suggests that tirapazamine should be effective when added to radiotherapy or to cisplatin-based chemotherapy in head and neck cancers

Phase III Randomized Trial of Chemotherapy With or Without Bevacizumab in Patients With Recurrent or Metastatic Head and Neck Cancer.

PURPOSE: We evaluated the addition of bevacizumab, a humanized monoclonal antibody that targets vascular endothelial growth factor, to platinum-based chemotherapy in recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Patients with chemotherapy-naïve (or with prior platinum as part of multimodal therapy completed ≥ 4 months earlier) recurrent or metastatic SCCHN were randomly assigned to receive a platinum-based chemotherapy doublet with or without bevacizumab 15 mg/kg given intravenously every 3 weeks until disease progression. Chemotherapy could be discontinued after six cycles if a maximum response was achieved. RESULTS: The study randomly assigned 403 patients. Median overall survival (OS) was 12.6 months with bevacizumab plus chemotherapy (BC) and 11.0 months with chemotherapy alone (hazard ratio, 0.87; 95% CI, 0.70 to 1.09; P = .22). At 2, 3, and 4 years, the OS rates were 25.2% v 18.1%, 16.4% v 10.0%, and 11.8% v 6.4% for BC versus chemotherapy, respectively. In an analysis of 365 eligible patients who started treatment, the hazard ratio was 0.82 (95% CI, 0.65 to 1.04; P = .10), with a median OS of 14.2 months on BC v 11.1 months on chemotherapy. Median progression-free survival with BC was 6.0 months v 4.3 months with chemotherapy (P = .0014). Overall response rates were 35.5% with BC and 24.5% with chemotherapy (P = .016). There was increased toxicity, including a higher rate of treatment-related grade 3 to 5 bleeding events (6.7% v 0.5%; P \u3c .001) and treatment-related deaths (9.3% v 3.5%; P = .022) with BC versus chemotherapy. CONCLUSION: The addition of bevacizumab to chemotherapy did not improve OS but improved the response rate and progression-free survival with increased toxicities. These results encourage biomarker-driven studies of angiogenesis inhibitors with better toxicity profiles in select patients with SCCHN

Doubleâ blind, randomized phase 3 trial of lowâ dose 13â cis retinoic acid in the prevention of second primaries in head and neck cancer: Longâ term followâ up of a trial of the Eastern Cooperative Oncology Groupâ ACRIN Cancer Research Group (C0590)

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139904/1/cncr30920.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139904/2/cncr30920_am.pd

Phase III randomized trial of chemotherapy with or without bevacizumab (B) in patients (pts) with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN): Survival analysis of E1305, an ECOG-ACRIN Cancer Research Group trial

6000 Background: The addition of B, an anti-VEGF monoclonal antibody, to chemotherapy has improved outcomes in several solid tumors. Pemetrexed plus B showed promising efficacy in R/M SCCHN (Argiris et al. JCO 2011). E1305 was designed to evaluate the addition of B to a platinum doublet in R/M SCCHN. Methods: B-eligible pts with performance status 0-1, not having received chemotherapy for R/M SCCHN (prior chemotherapy for locally advanced disease allowed ≥ 4 months) and without factors predisposing to bleeding (history of bleeding due to SCCHN, anticoagulation, central cavitary lung metastasis, carotid invasion) were randomized to: A) one of 4 regimens (investigator's choice) given every 3 weeks: A1, cisplatin (C) 100 mg/m 2 , 5-FU 1000 mg/m 2 /day x 4 days; A2, carboplatin (Cb) AUC 6, 5-FU 1000 mg/m 2 /day x 4 days; A3, C 75 mg/m 2 , docetaxel (D) 75 mg/m 2 ; A4, Cb AUC 6, D 75 mg/m 2 , or B) the same regimen (B1, B2, B3, B4) plus B 15 mg/Kg IV, every 3 weeks, until progression. Chemotherapy could be stopped after 6 cycles after maximum response. All pts received prophylactic antibiotics. The primary endpoint was overall survival (OS). Control median OS of 8.5 months (mo) was projected; the addition of B was hypothesized to increase median OS to 11.5 mo with a hazard ratio (HR) of 0.74. Results: 403 pts were randomized (200 in arm A; 203 in arm B). Baseline characteristics were well balanced. 38% in arm A/42% in arm B had an oropharyngeal primary; 87% received C or Cb plus D. With a median follow-up of 23.1 mo, median OS was 11 mo in arm A and 12.6 mo in arm B; HR 0.84 (95% CI 0.67-1.05), p = 0.13. The 1-, 2-, 3-, and 4-year OS were 46% vs 51%, 18% vs 26%, 8% vs 16%, 6% vs 13%, in arm A vs B, respectively. Median PFS was 4.4 mo in arm A and 6.1 mo in arm B (HR 0.71, 95% CI 0.58-0.87; p = 0.0012). Objective response rate was 25% in arm A vs 36% in arm B (p = 0.013). Grade 3-5 bleeding occurred in 3.5% in arm A vs 7.7% in arm B (p = 0.08). Conclusions: B added to a standard platinum doublet improved response rate and PFS but not OS in first-line treatment of R/M SCCHN. The control arm in this study performed better than expected. Clinical trial information: NCT00588770

T cell receptor repertoire among women who cleared and failed to clear cervical human papillomavirus infection: An exploratory proof-of-principle study.

It is unknown why a minority of women fail to clear human papillomavirus (HPV) and develop precancer/cancer. Differences in T-cell receptor (TCR) repertoires may identify HPV16-infected women at highest-risk for progression to cancer. We conducted a proof-of-principle study nested within the Guanacaste HPV Natural History Study to evaluate the utility of next-generation sequencing for interrogating the TCR repertoires among women who cleared and failed to clear cervical HPV16.TCR repertoires of women with HPV16-related intraepithelial neoplasia grade 3 or higher (CIN3+; n = 25) were compared to women who cleared an incident HPV16 infection without developing precancer/cancer (n = 25). TCR diversity (richness and evenness) and relative abundance (RA) of gene segment (V [n = 51], D [n = 2], J [n = 13]) usage was evaluated; receiver operating curve analysis assessed the ability to differentiate case-control status.TCR repertoire richness was associated with CIN3+ status (P = 0.001). Relative abundance (RA) of V-gene segments was enriched for associations between cases and controls. A single V-gene (TRBV6-7) was significantly associated with CIN3+ status (RA = 0.11%, 0.16%, among cases and controls, respectively, Bonferroni P = 0.0008). The estimated area under the curve using richness and V-gene segment RA was 0.83 (95% confidence interval: 0.73-0.90).Substantial differences in TCR repertoire among women with CIN3+ compared to women who cleared infection were observed.This is the first study to use next-generation sequencing to investigate TCR repertoire in the context of HPV infection. These findings suggest that women with HPV16-associated cervical lesions have significantly different TCR repertoires from disease-free women who cleared HPV16 infection

TCR diversity and relative abundance of the V gene usage within the TCR together strongly differentiated women with HPV16-related CIN3+ (cases) from women who cleared an incident cervical HPV16 infection without precancer/cancer development (controls).

<p>Receiver operating curves (ROC) were generated using random forest together with the leave-one-out (LOO) procedure for i) relative abundances (RA) of V genes (red line); ii) TCR repertoire richness (dotted blue line); and iii) RA of V genes and TCR repertoire richness combined (dotted purple line). Reported AUCs and their confidence intervals were based on resampling without replacement.</p