Tissue Platinum Concentration and Tumor Response in Non–Small-Cell Lung Cancer

Abstract

A B S T R A C T PurposePlatinum resistance is a major limitation in the treatment of advanced non-small-cell lung cancer (NSCLC). Reduced intracellular drug accumulation is one of the most consistently identified features of platinum-resistant cell lines, but clinical data are limited. We assessed the effects of tissue platinum concentrations on response and survival in NSCLC. Patients and MethodsWe measured total platinum concentrations by flameless atomic absorption spectrophotometry in 44 archived fresh-frozen NSCLC specimens from patients who underwent surgical resection after neoadjuvant platinum-based chemotherapy. Tissue platinum concentration was correlated with percent reduction in tumor size on post-versus prechemotherapy computed tomography scans. The relationship between tissue platinum concentration and survival was assessed by univariate and multicovariate Cox proportional hazards regression model analysis and Kaplan-Meier analysis. ResultsTissue platinum concentration correlated significantly with percent reduction in tumor size (P Ͻ .001). The same correlations were seen with cisplatin, carboplatin, and all histology subgroups. Furthermore, there was no significant impact of potential variables such as number of cycles and time lapse from last chemotherapy on platinum concentration. Patients with higher platinum concentration had longer time to recurrence (P ϭ .034), progression-free survival (P ϭ .018), and overall survival (P ϭ .005) in the multicovariate Cox model analysis after adjusting for number of cycles. ConclusionThis clinical study established a relationship between tissue platinum concentration and response in NSCLC. It suggests that reduced platinum accumulation might be an important mechanism of platinum resistance in the clinical setting. Further studies investigating factors that modulate intracellular platinum concentration are warranted.

Intratumoral injection of cisplatin in various concentrations of ethanol for cisplatin-resistant lung tumors

“…Consistently, previous studies by Kim et al (9) and Tang et al (10) reported that decreased platinum accumulation in NSCLC tumor tissues and SCLC cells may be an important mechanism underlying platinum resistance in NSCLC and SCLC cells in the clinical setting.…”

Organic cation transporter 6 directly confers resistance to anticancer platinum drugs

“…Indeed, tissue platinum concentration is significantly associated with tumor response and survival in non-small cell lung cancer patients (13). Although OCTs play a critical role in the cellular uptake of platinum drugs, the relationship between OCTs and drug resistance is not fully understood.…”

Chemotherapy Resistance in Lung Cancer

“…The same relationship was seen individually in cisplatin and carboplatin groups. Patients with lower platinum concentration also had shorter time to recurrence, progression-free survival (PFS) and overall survival (OS) [ 7 ]. Furthermore, there was no signifi cant impact of potential variables such as the type of platinum compound, number of cycles, cumulative dose and time lapse from last chemotherapy, which strongly suggests that certain resistance-inducing transport factors, are likely modulating intratumoral platinum accumulation.…”

“…Reduced uptake of cisplatin has also been demonstrated in resistant NSCLC cells [ 4 -6 ]. To clinically validate reduced drug accumulation as a signifi cant mechanism of platinum resistance in NSCLC, a recent study established correlation between intratumoral tissue platinum concentrations and tumor response in NSCLC [ 7 ]. A signifi cant relationship between tissue platinum concentrations and percent reduction in tumor size was demonstrated.…”