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 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.

7. Methods: Chemotherapy
IV Fluids
D5W mEq /l Sodium Acetate + 4 mEq/l MgSO 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.

8. Patient Characteristics
29 patients randomized
13 (45%) received dopamine
16 (55%) received no dopamine
Age
Median 35 years
Range
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
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.

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
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.

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
Similar findings are seen on course 2…..

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

14. Fitted Linear Mixed Model for Creatinine Levels
Statistical Results
Fitted Linear Mixed Model for Creatinine Levels
Variable
Coefficient SE
P-value
Time x Cycle —
<
Baseline Creatinine
0.788
0.067
Age
0.002
0.001
0.103
Dopamine *
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

15. 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

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