2018 ASCO Annual Meeting!
Session: Patient and Survivor Care
Type: Poster Session
Time: Monday June 4, 1:15 PM to 4:45 PM
Location: Hall A
Pharmacokinetic (PK) modeling of serum platinum to reveal extent of long-term exposure and associated comorbidities after cisplatin treatment.
Late and Long-Term Effects
Patient and Survivor Care
2018 ASCO Annual Meeting
Poster Board Number:
Poster Session (Board #46)
J Clin Oncol 36, 2018 (suppl; abstr 10058)
Author(s): Omar El Charif, Zepeng Mu, Eric R Gamazon, Paul C Dinh, Shirin Ardeshirrouhanifard, Patrick O. Monahan, Darren R. Feldman, Lawrence H. Einhorn, Robert James Hamilton, David J. Vaughn, Neil E. Martin, Chunkit Fung, Sophie D. Fossa, Lois B. Travis, M. Eileen Dolan; The University of Chicago, Chicago, IL; Vanderbilt University, Nashville, TN; Indiana University School of Medicine, Indianapolis, IN; Memorial Sloan Kettering Cancer Center, New York, NY; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; University of Pennsylvania, Philadelphia, PA; Dana-Farber Cancer Institute/ Brigham and Women's Hospital, Boston, MA; University of Rochester Medical Center, Rochester, NY; Oslo University Hospital, University of Oslo, Oslo, Norway; University of Chicago, Chicago, IL
Background: Platinum (Pt) is detectable for years after cisplatin treatment completion, but few studies have examined the extent of long-term exposure to Pt and associated co-morbidities. Methods: Eligible testicular cancer survivors (TCS, n = 633) given 300 or 400 ± 15 mg/m2 cisplatin underwent lab tests and extensive audiometry, and completed questionnaires at follow-up (median 5 y, range 1-35). Since subject-level PK parameters cannot be estimated in cross-sectional designs, we regressed log(Pt) on dose and follow-up time in the entire cohort. Each subject’s PK trait was defined as the deviation from the average concentration-time curve (the residual). High values indicate Pt levels exceeding the expected value, i.e. slower elimination. The Pt reference interval (RI) used (central 95% of 147 non-Pt exposed patients) was 8-47 ng/L (JALM 2016; 1:2, 143). Linear regression at α = 0.05 was used for associations with co-morbidities. Hearing loss was quantified as the geometric mean of thresholds: 4-12 kHz (JCO 2016; 34, 2712). Sensory neuropathy was self-reported using EORTC-CIPN20. Cardiovascular (CV) burden was defined as angina, angioplasty, stroke, DVT, PE, CAD, and/or MI > 1 month after therapy. Serum Pt, LDL, HDL, and creatinine (used to estimate creatinine clearance [CrCl] with the Cockroft-Gault formula) were measured. Results: Only 35 TCS (5.6%) were within the RI (median follow-up for this group: 20 y, range: 10-35). The estimated time to reach RI upper limit was 18 and 21 y after 300 and 400 mg/m2 cisplatin respectively (time to RI median: 46 and 57 y). The Pt PK phenotype was strongly negatively associated with CrCl (p < 10-9), and positively associated with age (p < 10-8), neuropathy (p = 0.002; age-adjusted p = 0.04), and HDL (age-adjusted p < 0.001). When adjusted for age, no associations were apparent with LDL, CV burden, or hearing loss. Conclusions: Circulating Pt persists for decades and may contribute to adverse outcomes. We previously showed that hearing loss, but not neuropathy, is associated with cumulative cisplatin dose. In conjunction with our findings here, this suggests differential kinetics of ototoxicity and neurotoxicity.