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

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

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

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).

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

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 1195651 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

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.

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

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)

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

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

Results - baseline PRE ASSAY CHANGE POST ASSAY CHANGE Number of Patients 44 53 Median age (range) 68.41 (45-87) 67.66 (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

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%)

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%)

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%)

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?

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