Dopamine May Decrease Nephrotoxicity in Patients Receiving High-Dose Ifosfamide

1. Dopamine May Decrease Nephrotoxicity in Patients Receiving High-Dose Ifosfamide L Johnetta Blakely, SR Patel, PF Thall, X Wang, TA Simmons, JL Beach, TL Armen, LL Chen, MA Burgess, JC Trent, and RS Benjamin UT MD Anderson Cancer Center Houston, United States

2. Background Ifosfamide is one of the most commonly used and most effective chemotherapeutic agents for sarcoma Complications with high-dose ifosfamide: • Renal Toxicity • Neurotoxicity • Neutropenia / Fever

3. Background Dopamine • Low doses have been shown to increase blood flow and GFR • Some evidence suggests a renal protective effect in cancer patients receiving immunotherapy

4. Giving Dopamine with Ifosfamide:Rationale and Possible Benefits • Decrease in “subclinical” nephrotoxicity • Decrease in clinical nephrotoxicity • Decrease in other adverse side effects • Decrease in length of hospital stay • Increase in the initial dose and possibly subsequent doses of ifosfamide • Increase in cure rate and expected survival

5. Methods • Randomized phase III study in progress, with 34/36 patients enrolled • 2 patients were excluded from this analysis due to abnormal baseline renal function • The full data, including creatinine level over 3 courses of therapy, on 29 patients currently are available. These data were used for this statistical analysis

6. Methods: Chemotherapy Ifosfamide 2000 mg/m2 in 500 ml NS over 2 hr q 12 h x 7 doses Mesna • 400 mg/m2 mixed w. first Ifosfamide dose • Simultaneously, start mesna2400mg/m2 in 2 liters D5W w. 150 mEq/l Sodium Acetate + 20 mEq/l K Acetate over 24 hrs daily x 4 days via pump Dopamine • Patients randomized to receive or not receive dopamine 3mcg/kg/min after 4 hours of IV fluids

7. Methods: Chemotherapy IV Fluids • D5W + 150 mEq /l Sodium Acetate + 4 mEq/l MgSO4 + 40 mEq / l K Acetate + 20 mEq / l KCl at 125 ml / hr for 4 hr prior to and continuing with chemotherapy and mesna • At completion of MESNA infusion, increase IV fluid rate to 250 ml / hr • Daily adjustments to keep patient alkaline and balance electrolytes

8. Patient Characteristics • 29 patients randomized • 13 (45%) received dopamine • 16 (55%) received no dopamine • Age • Median 35 years • Range 18 - 62 • Sex • 10 (34%) females • 19 (66%) males

9. Statistical Methods Daily creatinine level was measured during and immediately after ifosfamide over 3 cycles of therapy, 21 days per cycle A longitudinal mixed effects linear regression model was fit, accounting for : • Variation of Creatinine, over time within cycle • Patient Age • Baseline Creatinine • Treatment (Dopamine vs. No Dopamine) • Within-Patient Correlation, among the repeated creatinine measurements

10. Predicted Creatinine Levels Over Cycle 1 for a 30-year-old Patient with Baseline Creatinine Level 0.8 Results 95% confidence intervals given by vertical lines

11. Predicted Creatinine Levels for the Dopamine and No Dopamine Groups by Age (30 vs 52 ) and Baseline Creatinine Level (0.8 vs 1.1 ) in Cycle 1 No Dopamine Dopamine

12. Predicted Creatinine Levels for the Dopamine and No Dopamine Groups by Age (30 vs 52 ) and Baseline Creatinine Level (0.8 vs 1.1 ) in Cycle 2 No Dopamine Dopamine

13. Predicted Creatinine Levels for the Dopamine and No Dopamine Groups by Age (30 vs 52 ) and Baseline Creatinine Level (0.8 vs 1.1 ) in Cycle 3 No Dopamine Dopamine

14. Statistical Results Fitted Linear Mixed Model for Creatinine Levels *A negative sign corresponds to a lower creatinine level

15. Ignoring Baseline Creatinine Accounting for Baseline Creatinine Dopamine No Dopamine No Dopamine Dopamine P = 0.715 P = 0.014

16. Conclusions • Dopamine may offer significant protection from ifosfamide nephrotoxicity • The relative magnitude of the effect of baseline creatinine on subsequent creatinine levels is approximately 10-fold that of dopamine • If we had ignored baseline creatinine in our model, we would have missed the beneficial effects of dopamine