Prediction of treatment outcome by cisplatin‐DNA adduct formation in patients with stage III/IV head and neck squamous cell carcinoma, treated by concurrent cisplatin‐radiation (RADPLAT)

Abstract

The purpose of our study was to test the predictive value of cisplatin-DNA adduct levels in head and neck squamous cell carcinoma (HNSCC) patients treated with cisplatin-radiation. Patients with advanced-stage HNSCC were treated within a randomized trial, investigating the optimal route of cisplatin administration, concurrently with radiation. Cisplatin was administered intra-arterially (IA, 150 mg/m 2 , with systemic rescue by sodium thiosulfate) or intravenously (IV, 100 mg/m 2 ). In a subgroup, adducts were quantified in normal tissue and tumor.32 P-postlabeling was used to quantify intrastrand guanosine-guanosine adducts (GG-adducts) and adenosine-guanosine adducts (AG-adducts). Adduct levels were correlated with treatment outcome. Thirty-five patients were included (21 IV and 14 IA). At median follow-up of 27 months, locoregional (LR) control was 75% at 1 and 70% at 2 years. Adduct levels in tumor were 4-5-fold higher than in white blood cells (WBC) for both IA and IV treatment (p 5 0.01). Adduct formation in WBC and buccal cells was higher in IV treated patients compared with IA infusion (p 5 0.049 and 0.005 for GG-adducts in WBC and buccal cells, respectively). Adducts in tumors after IA infusion were not statistically different from those after IV. A strong correlation was observed between GG-and AG-adduct formation (r 5 0.86, p < 0.001). Patients with higher GG adduct levels (>median) in primary tumor had significantly better disease free survival (DFS) than patients with lower ( median) adduct levels (p 5 0.02). For overall survival (OS), a nonsignificant trend was observed, again in favor of patients with higher adduct levels (p 5 0.06). In conclusion, cisplatin-DNA adduct formation in primary tumor appears to be predictive for DFS in HNSCC. No differences were observed in intratumoral adduct levels between IA and IV treatments, despite selective infusion of high-dose cisplatin with the IA procedure. However, systemic adduct levels (WBC and buccal cells) from IV patients were higher than in IA patients, consistent with less systemic exposure after IA administration. ' 2006 Wiley-Liss, Inc.Key words: head and neck cancer; chemoradiation; cisplatin; DNA adducts Outcomes for patients with advanced stage head and neck squamous cell carcinoma (HNSCC) have been unsatisfactory for treatment by radiation alone. Several strategies have been pursued to improve results of radiotherapy, including neoadjuvant chemotherapeutic regimens, adjuvant systemic treatment and the concurrent administration of chemotherapy during the radiation treatment course. In several studies on locally advanced HNSCC, it was shown that cisplatin-based chemotherapy, given concurrently with radiation therapy, improved both locoregional (LR) control and overall survival (OS). [1][2][3][4] This combined treatment is now considered the standard of care not only in advanced stage HNSCC but also in a variety of other solid tumors. [5][6][7][8][9] However, further improvement is warranted since LR recurrence rates of up to 30-40% are observed.I...

A Gynecologic Oncology Group Study of Platinum-DNA Adducts and Excision Repair Cross-Complementation Group 1 Expression in Optimal, Stage III Epithelial Ovarian Cancer Treated with Platinum-Taxane Chemotherapy

“…When expressed as a continuous variable, the levels of platinum-DNA adducts was not associated with PFS, OS, or the results of SLL in this cohort. In contrast, the level of platinum-DNA adducts in buccal cells was shown to be an independent predictor of better OS in NSCLC (20), and the level of platinum-DNA adducts in tumor tissue was shown to be an independent predictor of better PFS but not OS in HNSCC (21). A number of differences exist between these studies that likely contribute, at least in part, to the disparity in results, including the patient population (EOC versus NSCLC versus HNSCC), method for detecting platinum-DNA adducts Although tumor response was not an end point in the study reported herein, SLL was allowed when declared at the time of protocol enrollment and provided an opportunity to evaluate disease status in this population with optimally debulked stage III EOC.…”

“…Previous studies evaluated the relationship between platinum-DNA adducts in peripheral leukocytes and disease response but not PFS or OS in a variety of cancers including ovarian cancer (8)(9)(10)(11)(12)(13)(14)(16)(17)(18) or between platinum-DNA adducts in either buccal cells or tumor and disease response in a variety of cancers (19), OS in NSCLC (20), or with PFS and OS in HNSCC (21). In these studies, platinum-DNA adducts were assessed using an ELISA (8)(9)(10)(11)(12)14) atomic absorbance spectroscopy (12-14, 16, 17), inductively coupled plasma-mass spectroscopy (18), immunocytochemistry (19,20), or 32 P postlabeling (21). This study showed that the presence of platinum-DNA adducts in PBL 20 to 28 h after the first cycle of chemotherapy was associated with better OS, but not with PFS or the results of SLL.…”

“…20) and between platinum-DNA adducts in tumor tissue and better progression-free survival (PFS) in head and neck squamous cell carcinoma (HNSCC; ref. 21).…”

Oxaliplatin-DNA adduct formation in white blood cells of cancer patients

“…Recently, a significantly better disease-free survival was reported for cisplatin-treated head and neck carcinoma patients with higher adduct levels (Hoebers et al, 2006). The feasibility of intraindividual dose escalation of cisplatin based on platinum-DNA adduct levels has been shown in two clinical trials in patients with head and neck cancer (Schellens et al, 2001) and non-small cell lung cancer (Schellens et al, 2003).…”

Intra‐arterial chemotherapy for head and neck cancer

“…5 More recently, Hoebers et al measured cisplatin adduct levels in patients with head and neck cancer receiving either IV or IA cisplatin. 6 Although the level of GG adduct formation was higher in the IA group, this was not statistically significant; however, there were only 5 patients in the IA group and 7 in the IV group. Furthermore, some of the subjects would have received a reduced amount of the total drug infused if they received a bilateral IA infusion.…”