Tetsuro Wakasugi

Incidence and Risk Factors of Hypomagnesemia in Head and Neck Cancer Patients Treated with Cetuximab

Background Hypomagnesemia is a common adverse event during cetuximab (Cmab) treatment. However, few reports have investigated the incidence and risk factors of hypomagnesemia in head and neck cancer patients treated with Cmab. Methods We retrospectively reviewed 131 head and neck cancer patients who received Cmab-containing therapy. Main eligibility criteria were ≥3 Cmab administrations, no prior EGFR-directed therapy, and no prophylactic Mg supplementation. Results Median baseline serum Mg level and number of Cmab administrations were 2.2 mg/dl and 8, respectively. Overall incidence of hypomagnesemia was 50.4% (grade 1, 46.6%; grade 2, 3.1%; grade 3, 0%; and grade 4, 0.8%) and differed between patients treated with palliative chemotherapy and bioradiation (Cmab and radiation) (63 versus 24%; P < 0.01). Independent risk factors were low baseline serum Mg [odds ratio (OR) 161.988, 95% confidence interval (CI) 9.436–2780.895], ≥7 Cmab administrations (OR 3.56, 95% CI 1.16–13.98), and concurrent administration of platinum (cisplatin; OR 23.695, 95% CI 5.219–107.574, carboplatin; OR 5.487, 95% CI 1.831–16.439). Respective incidence of hypomagnesemia in patients in high- (concurrent platinum and ≥7 Cmab administrations) and low-risk (no concurrent platinum and <7 Cmab administrations) groups was 66.0 and 6.6% (P < 0.001, OR 28.0). Conclusion Cmab is associated with a significant risk of hypomagnesemia in patients with head and neck cancer with longer term administration and concurrent platinum therapy. High-risk patients should be treated with particular care.

Gene expression profiling to predict recurrence of advanced squamous cell carcinoma of the tongue: discovery and external validation

Objectives To establish a prognostic signature for locally advanced tongue squamous cell carcinoma (TSCC) patients treated with surgery. Results In the discovery study, unsupervised hierarchical clustering analysis identified two clusters which differentiated the Kaplan-Meier curves of RFS [median RFS, 111 days vs. not reached; log-rank test, P = 0.023]. The 30 genes identified were combined into a dichotomous PI. In the validation cohort, classification according to the PI was associated with RFS [median RFS, 754 days vs. not reached; log-rank test, P = 0.026 in GSE31056] and DSS [median DSS, 540 days vs. not reached; log-rank test, P = 0.046 in GSE42743 and 443 days vs. not reached; P < 0.001 in GSE41613]. Among genes, positive immunohistochemical staining of cytokeratin 4 was associated with favorable prognostic values for RFS (hazard ratio (HR), 0.591, P = 0.045) and DSS (HR, 0.333, P = 0.004). Materials and methods We conducted gene expression profiling of 26 clinicopathologically homogeneous advanced TSCC tissue samples using cDNA microarray as a discovery study. Candidate genes were screened using clustering analysis and univariate Cox regression analysis for relapse-free survival (RFS). These were combined into a prognostic index (PI), which was validated using three public microarray datasets of tongue and oral cancer (123 patients). Some genes identified in discovery were immunohistochemically examined for protein expression in another 127 TSCC patients. Conclusion We identified robust molecular markers that showed significant associations with prognosis in TSCC patients. Gene expression profiling data were successfully converted to protein expression profiling data.OBJECTIVES To establish a prognostic signature for locally advanced tongue squamous cell carcinoma (TSCC) patients treated with surgery. RESULTS In the discovery study, unsupervised hierarchical clustering analysis identified two clusters which differentiated the Kaplan-Meier curves of RFS [median RFS, 111 days vs. not reached; log-rank test, P = 0.023]. The 30 genes identified were combined into a dichotomous PI. In the validation cohort, classification according to the PI was associated with RFS [median RFS, 754 days vs. not reached; log-rank test, P = 0.026 in GSE31056] and DSS [median DSS, 540 days vs. not reached; log-rank test, P = 0.046 in GSE42743 and 443 days vs. not reached; P < 0.001 in GSE41613]. Among genes, positive immunohistochemical staining of cytokeratin 4 was associated with favorable prognostic values for RFS (hazard ratio (HR), 0.591, P = 0.045) and DSS (HR, 0.333, P = 0.004). MATERIALS AND METHODS We conducted gene expression profiling of 26 clinicopathologically homogeneous advanced TSCC tissue samples using cDNA microarray as a discovery study. Candidate genes were screened using clustering analysis and univariate Cox regression analysis for relapse-free survival (RFS). These were combined into a prognostic index (PI), which was validated using three public microarray datasets of tongue and oral cancer (123 patients). Some genes identified in discovery were immunohistochemically examined for protein expression in another 127 TSCC patients. CONCLUSION We identified robust molecular markers that showed significant associations with prognosis in TSCC patients. Gene expression profiling data were successfully converted to protein expression profiling data.

Pharmacokinetics of initial full and subsequent reduced doses of S-1 in patients with locally advanced head and neck cancer—effect of renal insufficiency

Background S-1 is a combination of tegafur [metabolized to 5-fluorouracil (5-FU)] with the modulators gimeracil (5-chloro-2,4-dihydroxypyridine) and oteracil potassium. 5-Chloro-2,4-dihydroxypyridine maintains plasma 5-FU concentrations by inhibiting dihydropyrimidine dehydrogenase, a pyrimidine catabolism enzyme that degrades 5-FU. As 50% of 5-chloro-2,4-dihydroxypyridine is excreted in urine, renal insufficiency may increase its blood level, increasing 5-FU concentrations. We investigated whether special dose modification is needed in the presence of renal insufficiency. Objective We compared steady state pharmacokinetics of 5-FU for the initial S-1 dose and reduced doses in patients with head and neck cancer requiring dose reduction due to renal and non-renal toxicities. Methods Chemoradiotherapy with S-1 and cisplatin was administered every 5 weeks for two courses with a radiation dose totaling 70 Gy over 33-35 fractions. Two additional courses of adjuvant chemotherapy were administered in the case of an objective response. The S-1 and/or cisplatin dose was reduced in response to renal, hematologic or other toxicities. The primary endpoint was the change in area under the plasma concentration-versus-time curve from time 0-10 hours (5-FU AUCss 0-10) between the initial and reduced S-1 doses. Results Although the mean 5-FU levels in patients with non-renal toxicities significantly decreased between the full and reduced dose, the full-dose and reduced-dose mean maximum 5-FU plasma concentrations at steady state (Css max) and AUCss 0-10 in patients with renal insufficiency were similar. Conclusions Standard S-1 dose reduction for renal toxicity did not result in a significant decrease in 5-FU levels at steady state. A greater reduction to lower plasma 5-chloro-2,4-dihydroxypyridine may be necessary in patients with renal insufficiency.

998PINCIDENCE AND RISK FACTORS OF HYPOMAGNESEMIA IN HEAD AND NECK CANCER PATIENTS TREATED WITH CETUXIMAB

ABSTRACT Aim: Hypomagnesemia is an adverse event during cetuximab treatment. However, the incidence and risk factors of hypomagnesemia in head and neck cancer patients have not been clarified. The aim of this study is to identify clinical features and risk factors of hypomagnesemia caused by cetuximab-containing therapy in head and neck cancer patients. Methods: We retrospectively reviewed 113 head and neck cancer patients who received cetuximab-containing therapy from February 2012 to March 2014. Main eligibility criteria were ≥3 cetuximab administrations, no prior EGFR-directed therapy, and no prophylactic Mg supplementation. Results: Median baseline serum Mg level and number of cetuximab administrations were 2.2 mg/dl (range 1.8-2.6) and 8 (range 3-25), respectively. Overall incidence of hypomagnesemia was 46.9% (grade 1, 43.3%; grade 2, 2.6%; grade 3, 0%; grade 4, 0.8%) and differed between patients treated with bioradiation (cetuximab and radiation) and palliative chemotherapy (26% vs. 58%; p Conclusions: While prophylactic Mg supplementation is not absolutely necessary, special attention should be given to high-risk patients, namely those with low baseline Mg level, high number of cetuximab administrations, and concurrent platinum. Hypomagnesemia in high- and low- risk groups High-risk group Low-risk group (n = 53) (n = 15) p-value OR Median baseline Mg [mg/dl] (range) 2.2 (1.8, 2.6) 2.3 (1.9, 2.6) p = 0.23 - Median Δ Mg* [mg/dl] (range) -0.5 (0, -1.2) -0.3 (0, -0.8) p - Median Δ Mg %** [%] (range) -25 (0, -67) -13 (0, -31) p - Hypomagnesemia*** 66.0% 6.6% p 27.2 *Minimum Mg - Baseline Mg, **Δ Mg / Baseline Mg, ***All grades †Mann-Whitney U test, ‡Fishers exact test. Disclosure: All authors have declared no conflicts of interest.