1. Carboplatin and Creatinine Have we got it right?
Dr Emma Cattell
Medical Oncologist, Musgrove Park
Sept 2015

2. Background
In Feb 2013, it was noted that there had been a general reduction in serum creatinine levels.
Most patients appeared to have dropped approximately 20 µmol/l.
Contacted Biochemistry - ? Reason

3. Measuring serum creatinine
Historically – colorimetric ‘Jaffe’ method used.
This was calibrated against a reference method, but remained concerns over specificity.
Interactions – bilirubin, drugs etc
New ‘enzymatic’ method which should give reference method results.
All UK labs assessed on performance against ref method values- so likely to be a UK wide/international issue

4. Impact
Instigating dose reductions for renally cleared drugs eg cisplatin and capecitabine.
Calculation of carboplatin doses which are based on the calvert formula
Dose = Target AUC x(GFR+25).

5. International concerns
In October 2010 the NCI (National Cancer Institute) Cancer Therapy Evaluation programme recognised the issue and published a letter recommending that carboplatin doses were capped at a GFR of 125ml/min.
GOG also recommended using a minimum creatinine of 0.7mg/dl(?61 umol/l) , using pre-op not post-op Cr and adjusted ideal not actual body weight if BMI>25
AUC
Max carboplatin dose 4
600 5
750 6
900

6. Initials
MRN
Cr Dec12/Jan13
CrCl
AUC6
Cr Mar/Apr13
CrCl4
AUC65
% difference DB
281805 72 49
444 69 53
468
5.4 KF
136285 82
114
834 63
149
1044
25.2 PN 87 60
510 74
582
14.1 PO
217515 84 55
480 70
564
17.5 HP
YDH
28.6
321.6 81 33
348
8.2 FS
220960 61
516 79
624
20.9 JW
508839 86 91
696 64
122
882
26.7 EC
204932 77 66 80
630
11.7 JP
422186 57
123
888 44
171
1176
32.4 CR
789731 68
558 96
-8.6 DC
228543 99 89
534
11.3 JK
420634 73
642 45
132
942
46.7

7. PREVIOUS AUDIT
Following these concerns, we increased the number of patients having an isotope GFR (esp for ICON8 patients.)
Looked at all the patients who had had an isotope GFR from March to Dec 2013, and calculated the dose of carboplatin they would have received using cockcroft and gault calculated clearance, at AUC5 and AUC6.
Also looked at alternatives such as wright formula.

8. Difference between carboplatin dose using isotope GFR and calculated clearance using AUC5 and AUC6.

9. Actions
For most patients, esp with low creatinine, consider starting at AUC 5 and increase to AUC6 according to toleration.
Cap CrCl at 125 ml/min
Audit of toxicity in pts having carboplatin.
Consider Isotope GFR (for all!!??, if Cr <50)

10. Excluded patients on ICON8, as all had an isotope GFR.
AUDIT OF CARBOPLATIN DOSES BEFORE AND AFTER THE CHANGE IN CREATININE MEASUREMENTS.
All patients with a gynae cancer who commenced carboplatin based chemotherapy for 2 time periods.
1st June 2011 to 1st June 2012
1st April 2013 to 1st April 2014
Excluded patients on ICON8, as all had an isotope GFR.
Assay changed Feb 2013

11. Data collected Age of patient Primary Line of therapy. Interval debulk
Response
Dose of carboplatin.
Dose Reductions
Dose Delays.

12. Results - baseline PRE ASSAY CHANGE POST ASSAY CHANGE
Number of Patients 44 53
Median age (range)
(45-87)
(44-88)
Primary Site
Ovarian/Fall tube
29 (66%)
33 (62%)
Primary Peritoneal
8 (18%)
9 (17%)
Endometrial
4 (9%)
10 (19%)
Cervix/vaginal
3 (7%)
1 (2%)
Treatment given
Carbo alone
17 (39%)
18 (34%)
Carbo-taxol
26 (59%)
28 (53%)
Carbo-gem 1 5
Carbo-caelyx 2

13. Results – Baseline PRE ASSAY CHANGE POST ASSAY CHANGE
Line of treatment 1
35 (79%)
37 (69%) 2
7 (16 %)
15 (28%) 3+
2 (4 %)
Intent
Palliative
23 (52%)
28 (53%)
Adjuvant
13 (24.5%)
14 (26.4%)
Neo adjuvant – complete debulk
4 (9%)
7 (13%)
Neoadjuvant- incomplete debulk
4 (7.5%)
Response
Progression
5 (11%)
Stable Disease
2 (4.5%)
5 (9%)
Partial response
21 (47%)
23 (43%)
Complete response
4 (7%)

14. Results – Dose intensity
PRE ASSAY CHANGE
POST ASSAY CHANGE
Median AUC at C1
5.8
4.7
Median AUC at C6
5.22
4.6
Number starting at AUC 6
36 (82%)
2 (4%)
Number starting at AUC 5
7 (16%)
37 (70%)
Number starting at ≤AUC4
1 (2%)
12 (23%)
Number capped at CrCl of 125ml/min
5 (9%)

15. Results – Impact on Doses
PRE ASSAY CHANGE
POST ASSAY CHANGE
Dose Delays
No of pts delayed
1 week
7 (16%)
15 (28%)
2 wks
2 (4%)
6 (11%)
≥ 3 wks
4 (9%)
Delays due to low neutrophils
4 (7.5%)
Delays due to low platelets
6 (13.5%)
11 (21%)
Delay – other reasons
6 (14%)
5 (9%)
Dose modifications
Carbo Dose Reductions
8 (15%)
Carbo Dose increases
1 (2%)
3 (6%)
Stopped early due to toxicity
9 (20%)

16. Conclusions
Since the change in creatinine measurements, we have been far more likely to give AUC5 than AUC6 when prescribing carboplatin.
Allowing for differences in primaries and line of treatment, no obvious differences in response rates or interval debulking outcomes.
Similar dose reductions and delays.
Slightly less likely to stop early due to toxicity?

17. Discussion Feels safe – but ? In line with other centres.
Small patient group - ? Look at progression free survival - ? Numbers to be meaningful.
Are we disadvantaging some pts..? Should we be increasing dose more often if tolerating