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

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

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

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

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

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 mesna 2400 mg/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 Ifosfamide was given at a dose of 14gm/m2 divided in 7 doses. The loading dose of mesna was given with the 1st dose of ifosfamide. The remainder of mesna was given simultaneously with alkaline fluids.

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 An additional 3 liters of alkaline IVF is given with the mesna infusion. Once the mesna infusion was complete the alkaline IVF is increased to a total of 6 liters a day. We watch electrolytes closely and make daily adjustments to the IVF to balance electrolytes.

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

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

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 This is an example of the type of plot seen. The bar shows +/- SE at each time point. 3. Fix Age = 30, Cycle =1 and baseline creatinine level = 0.8. The curve shown is for the “No Dopamine” Group. Make point: The line is curvilinear and so is best estimated by a quadratic function of time over each cycle.

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 This set of curves shows the effect of age and baseline creatinine during cycle 1. The dashed curve is the group without dopamne. The solid curve is the group with dopamine. Note first that in each panel, the no dopamine group has higher creatinine levels. The effect of age, seen by moving from left to right, also increases creatinine levels to a minor degree. The effect of baseline creatinine , seen by moving from the top panel to the bottom panel is much greater than the age effect.

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 Similar findings are seen on course 2…..

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 and on course 3. Note that for all courses, all ages, and all baseline creatinine levels, the patients treated with dopamine did better.

Fitted Linear Mixed Model for Creatinine Levels Statistical Results Fitted Linear Mixed Model for Creatinine Levels Variable Coefficient SE P-value Time x Cycle — < 0.0001 Baseline Creatinine 0.788 0.067 Age 0.002 0.001 0.103 Dopamine -0.082 * 0.031 0.014 Creatinine level is obviously a time-dependent variable. There is no significant cumulative toxicity during the 3 cycles. Baseline creatinine is the most highly correlated variable with subsequent creatinine levels, and the effect of age, separate from its correlation with baseline creatinine is not significant. The coefficient measures the the magnitude of the effect. A positive value is correlated with higher creatinine. A negative value with lower creatinine, Note that dopamine gives significant protection (p=0.014), but the magnitude of the dopamine effect is only about 1/10 that of the effect of baseline creatinine. * A negative sign corresponds to a lower creatinine level

Ignoring Baseline Creatinine Accounting for Baseline Creatinine Dopamine No Dopamine No Dopamine Dopamine Ignoring baseline creatinine, the dopamine group is slightly worse than the no-dopamine group, but the curves are statistically indistinguishable. 2.In contrast, correcting for baseline creatinine, the dopamine effect is highly significant. P = 0.715 P = 0.014

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