The optimisation of carboplatin dose in carboplatin, etoposide and bleomycin combination chemotherapy for good prognosis metastatic nonseminomatous germ cell tumours of the testis

Annals of Oncology 3: 291-296, 1992. O 1992 Kluwer Academic Publishers. Printed in the Netherlands.

Original article The optimisation of carboplatin dose in carboplatin, etoposide and bleomycin combination chemotherapy for good prognosis metastatic nonseminomatous germ cell tumours of the testis

Royal Marsden Hospital and Institute for Cancer Research Sutton, UK

Summary. An analysis of carboplatin dose response was performed in 121 patients with good prognosis metastatic nonseminomatous germ cell tumours (NSGCT) of the testis, referred to the Royal Marsden Hospital since 1984, who had been given combination carboplatin, etoposide and bleomycin (CEB) chemotherapy. With a median follow-up of 40 months (range: 7 to 85 months) nine patients (7%) have failed CEB. Carboplatin dose was analysed in all patients using body surface area (BSA) to derive a carboplatin dose per metre squared (mg/m2) and by calculation of a predicted serum concentration x time (AUC: area under the curve) derived from the glomerular filtration rate (GFR), using the formula; Dose = AUC(GFR+25). At a carboplatin dose of 400 mg/m2 or greater 2 out of 58 patients (3.4%) failed treat-

ment while 7 out of 63 patients (11%) who received a dose less than this failed (p > 0.1). At an AUC of 5.0 mg.min/ml or greater, 2 out of 74 patients (2.7%) failed while 7 out of 47 patients (14.9%) who had an AUC less than this failed (p < 0.05). There was evidence for a dose/response relationship at relatively low doses and the failure rate rose to 26% for doses less than 4.5 mgjnin/ml (p < 0.001) or 15.6% for doses less than 350 mg/m2 (p > 0.1). In view of the more precise determination of toxicity and efficacy it is recommended that carboplatin dose be based on the GFR.

Introduction

bone marrow suppression and consequent reduction in dose intensity due to delayed administration of subsequent chemotherapy cycles. Therefore the method used to determine the appropriate dose of carboplatin for an individual patient may be critical for antitumour efficacy and to limit bone marrow toxicity. The clinical relevance of this issue has been highlighted by recent controversy over carboplatin combination chemotherapy in good prognosis germ cell tumours. In a non-randomised pilot study on 76 patients we have reported that carboplatin appears to be equivalent to cisplatin when combined with etoposide and bleomycin and given every three weeks to a total of 4 cycles [2]; carboplatin dose was based on renal clearance. However the prospective randomised trial of CE versus PE by collaborators from the Memorial Sloan-Kettering and Southwest Oncology Groups, in an analysis updated from the abstract [15] found the carboplatin arm to be less effective (p =• 0.08); in this trial carboplatin was given at a dose of 500 mg/m2 on a 4 week cycle. Calvert et al [16, 17] have suggested that the appropriate dose could be judged by calculation of the dose of carboplatin required to achieve a predetermined free plasma carboplatin AUC (area under the serum concentration decay curve:serum concentration x time) based on knowledge of the GRF (Glomerular filtration rate) measured by chromium-51 (Cr-51) labelled EDTA [18, 19]. A pharmacokinetic study, previously

Carboplatin is now employed in the chemotherapy of a broad range of malignant tumours including testicular germ cell tumours [1, 2], ovarian cancer [3], lung cancer [4], and head and neck malignancy [5]. It has usually been reported to have similar efficacy to cisplatin but with less renal, acoustic or peripheral nerve toxicity [6-8], and because IV fluid hydration is not required administration is simplified. The pharmacokinetics of carboplatin differ from cisplatin; it is less extensively protein bound [9], a larger percentage is excreted via the kidneys [10-12], and it has a longer plasma half life [11-13]. The choice of carboplatin dose, either as a single agent or in combination chemotherapy, has usually been based on phase I and II studies which recommended a body surface area dose of 400 mg/m2 in a four week schedule [8], however pharmacokinetic considerations have suggested that this may not be the optimal method of dose judgement in view of the predominant elimination by renal excretion [7-10, 13]. Variations in renal function may influence the biological effects of any particular carboplatin dose leading to increased toxicity in patients with impaired renal function [10, 11, 14] while inadequate antitumour effect secondary to a reduced serum concentration x time may occur in patients with high renal clearance. Furthermore, inadvertant overdosage may lead to prolonged

Key words: germ cell tumour, non-seminoma, testis carboplatin, pharmacokinetics, chemotherapy

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W. J. Childs, E. J. NichoUs & A. Horwich

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Patients and methods Since 1984, patients referred to the Royal Marsden Hospital with good prognosis testicular teratoma have been entered into a single arm study to evaluate the use of the combination of carboplatin, etoposide and bleomycin. This study is an analysis of results from these patients relating the methods of carboplatin dosing to the treatment outcome and bone marrow toxicity. The dosing of carboplatin was initially based on the body surface area derived from height and weight nomogTams. The dose was escalated in a series of steps, 12 patients were given 300 mg/m2, 4 patients were given 350 mg/m2, 6 patients received 400 mg/m2 and 4 patients were given 450 mg/m2. The dose of carboplatin given to each patient was not adjusted on subsequent cycles unless severe toxicity occurred. Following pharamacokinetic studies on 4 of these patients confirming the accuracy of predicting the observed AUC 119], carboplatin dose was given according to the formula; Carboplatin dose (mg) - desired AUC(EDTA renal clearance+25) [16]. The carboplatin dose was calculated to achieve an AUC of 4.6 mg min/ml in 20 patients and an AUC of 5.0 mg.min/ml in 75 patients. In the later part of this study a 10% increment of the carboplatin dose was made in subsequent cycles if the platelet nadir was greater than 100,000/(iL or the white cell count greater than 2,000/u.L and a 10% reduction made when the platelet count was less than 50,000/uL or the white cell nadir was less than 1,000/u.L. Etoposide was given intravenously (i.v.) at a dose of 120 mg/m2 per day on days 1 to 3 inclusive and bleomycin 30 U. i.v. on days 2, 9 and 16 of each cylce which was repeated every 21 days to a total of 4 cycles. The doses of etoposide and bleomycin were kept constant in each patient throughout all treatment cycles and no patient had any cycle delays beyond day 21. Patients were staged according to the RMH criteria [21] as shown in Table 1, however eligibility for analysis as good prognosis in this study was based on the factors determined by the recent MRC prognostic factor analysis study |22|. Patients having a nodal mass greater than 10 cm in the largest diameter, more than 20 lung metastases, liver bone or brain metastases, an alphafetoprotein of greater than 1,000 IU/L or betaHCG greater than 10,000 IU/L were excluded from our study. All patients had histological evidence of non-seminoma or seminoma with significantly elevated markers; an AFP of gTeater than 30 IU/1 or HCG greater than 500 IU/1 was presumed to indicate the presence of non-seminomatous component. Prior to treatment all patients were staged with a chest x-ray, CT scan of chest, abdomen and pelvis, tumour markers and biochemistry. Renal function was determined by the clearance of chromium51 labelled (CR-51) EDTA [18, 19]. In addition all patients had measurement of serum creatinine and electrolytes. During chemotherapy a weekly haemaglobin, white cell count, platelet count and tumour marker assays were undertaken.

A total of 121 patients treated prior to June 1990 were eligible for analysis. The age range at the time of presentation to the Royal Marsden Hospital was 10 to 62 years with a median age of 27 years.

Results One hundred twenty-one patients with good prognosis metastatic nonseminomatous germ cell tumours (NSGCT) of the testis were given CEB chemotherapy. With a median follow-up of 40 months (range of 7 to 85 months) from the start of chemotherapy 118 patients remain alive and no patients have died from progressive germ cell rumour. One patient died 3 years after chemotherapy from ischaemic heart disease; this has been classified as death due to coincidental disease. Two patients have been classified as having disease related deaths, one patient died from bleomycin pneumonitis one month after completing chemotherapy, and another died in remission during replacement of an aortic graft, the result of complications of previous surgery undertaken for residual TD following CEB chemotherapy six years earlier. The cause-specific survival was 98% with 95% confidence interval of 95.5% to 100% (Table 2). The clinical details of the nine patients (7%) who failed CEB chemotherapy are shown in Table 3. Five of these patients had persistent tumour Table I. Stage distribution of patients. RMH Stage

Definition

1M

Rising postorchidectomy markers

II

Number of patients 9

A B C

Abdominal lymphadenopathy <2 cm Abdominal lymphadenopathy 2-5 cm Abdominal lymphadenopathy >5 cm

21 31 9

O A B C

Supradiaphragmatic lymphadenopathy No abdominal disease Abdominal lymphadenopathy <2 cm Abdominal lymphadenopathy 2-5 cm Abdominal lymphadenopathy >5 cm

1 1 5 1

Extralymphatic metastases <4 lung metastases >3 lung metastases all <2 cm >3 lung metastases one or more >2 cm

27 12 3

III

IV LI L2 L3

Table 2. Outcome of treatment. Number of patients

Median follow up months (range)

121

36 months 9 (3-81) (7%)

1

Treatment failures* (%)

Alive and disease free

Cause specific survival11

118

98% (95.5-100) c

4 patients relapsed after complete remission and 5 patients had persistent malignancy at surgery. b 1 death from coincidental disease and 2 deaths from treatment related toxicity. ' 95% confidence interval.

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undertaken on a number of patients included in this report, has confirmed that the formula: carboplatin dose (mg) = desired AUC x(EDTA renal clearance+25) [16] can accurately predict the observed AUC [20]. However the question remains whether the carboplatin dose to achieve a predicted AUC using this formula is a more accurate determinant of antitumour effect and of bone marrow toxicity than the simpler dose calculation based on body surface area (BSA). We have analysed treatment results and toxicity in 121 patients treated with CEB chemotherapy for good prognosis NSCGT of the testis, including the 76 patients previously reported [1, 2], and present an analysis of carboplatin dose response comparing two methods of dose calculation using BSA or AUC.

293 Table 3. Treatment failures.

Table 4. Haematological toxicity by WHO grade.

Age

Dose' m:

AUC

Stage

Histology

Type of failure

1

30

300

3.6

IVBL1

2

36

300

3.4

IVBL1

Seminoma MTI Seminoma

3

42

300

3.9

IIIB

MTI

4

17

300

2.6

IVOL2

MTI

5 6

20 30

300 350

3.8 4.0

IVCL2 IVOL1

7

22

470

4.9

IIB

MTI Seminoma/ MTU MTI

R

24

420

5.0

IIIO

MTI

9

28

375

5.0

IVBL1

MTU

Residual MTU (lung) Relapse (markers) Residual MTI (abdominal) Residual MTI (lung) Relapse (lung) Residual MTU (lung) Residual MTI (pelvic nodes) Relapse (neck node) Relapse (lung)

0

1

2

3

4

9 (8%) 2 (2%)

27 (23%) 4 (4°,;,)

60 (52%) 42 (38°;,)

19 (16%) 59 (55°;.)

1 ( I"*') 1 (1%)

Platelet toxicity Toxicity on cycle n - 116 1 nadir Maximum toxicity n - 108 on any cycle

73 (63%) 33 (30%)

21 (18%) 17 (16%)

7 (6%) 19 (18%)

15 (13%) 31 (29%)

0

Haemaglobin toxicit) Maximum nadir n - 108 per patient

29 (27%)

29 (27%)

37 (34%)

12 (11%)

1 (1%)

White cell toxicity Toxicity on cycle I nadir Maximum toxiciu on any cycle

TnA

following 4 cycles of chemotherapy and four patients relapsed following an apparent complete remission on CEB. In the five patients who had a partial response the presence of residual malignancy was confirmed on the histology of the surgically-resected tumour mass. One of these patients had relapsed in the pelvic bone before the commencement of salvage chemotherapy. These five patients have remained in remission following their surgery and salvage chemotherapy. Four patients relapsed after obtaining a complete remission on CEB, with a median time to relapse from the start of the original treatment of 7 months and a range of 6 to 29 months. Only one relapse occurred more than 12 months from the start of CEB chemotherapy. Three of the patients who relapsed remain disease free following salvage chemotherapy, and one patient who had been in remission for 42 months after successful salvage chemotherapy required further chemotherapy for a second primary tumour (malignant teratoma undifferentiated) in the contralateral testis. The toxicity of CEB chemotherapy was generally mild to moderate and there were no serious complications (Table 4). Following the first cycle of treatment 20 patients (17%) had WHO grade 3 or 4 leucopaenia whereas 60 patients (56%) experienced WHO grade 3 or 4 leucopaenia at their worst nadir on any cycle. Eight patients (7%) experienced one episode of fever and neutropaenia requiring broad spectrum IV antibiotics. Fifteen patients (13%) had a WHO grade 3 or 4 platelet nadir following the first cycle of treatment and 39 patients (36%) had WHO grade 3 or 4 platelet toxicity on their worst nadir. There were no recorded episodes of spontaneous bruising or haemorrhage in any patient during treatment. Progressive anaemia occurred in most patients with 50 (46%) having a haemoglobin fall to less than 9.5 gm/dL however only 18 patients (15%) were recorded as having a blood transfusion. The pattern of blood count fall was consistently a nadir of leucopenia and thrombocytopenia at 2 weeks which had recovered by 3 weeks, and all courses in all patients were repeated on a 21 day cycle.

n - 116 n - 108

rplohnnc

;TYTA I

8 (7%)

»p

onn

body surface area demonstrated that for any given body surface area there was a wide range of EDTA renal clearance resulting in a low correlation coefficient (R — 0.161). This would not be unexpected in small patients with very good renal function or large patients with renal impairment, however in this study most patients were not in these extremes. Eleven patients (9%) had impaired renal function as defined by an EDTA renal clearance of less than 100 mls/min. Therefore the correlation coefficient between calculated carboplatin AUC and carboplatin dose per metre squared is low (Fig. 1: R = 0.199). Seven of the nine failures occurred in patients who received a dose of less than 400 mg/m2 of carboplatin and also seven of nine failures occurred in patients who received carboplatin with an AUC of less than 5.0 mg.min/ml (Fig. 1). The mean carboplatin AUC in patients who had successful treatment was 4.85 mg.min/ ml and 4.02 mg.min/ml in those patients who failed CEB treatment (p = 0.0002 two tailed t-test). Where carboplatin dose was expressed by body surface area the mean dose was 388 mg/m2 in patients having sucRELATIONSHIP BETWEEN CALCULATED CARBOPLATIN AUC AND CARBOPLATIN DOSE PER BODY SURFACE AREA o

Tn

•

Tn

88»

:-p O

O

o

o o*

OO

O

• • • ooooo

4 DOSE

-OO

Q O

O OO

o

5

6

AUC (mg.mln m2)

Hg. 1. Correlation of carboplatin dose based on body surface area (BSAJ with calculated AUC. R' 2 - 0.199.

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Patient number

294

over four treatment cycles. Similar results for risk of treatment failure are seen when the dose analysis is apCarboplatin TreatRisk of Chi square Total plied to the mean dose level over four cycles of treatno. of ment with Yates1 dose parameter failure ment in each patient. patients failures correction The carboplatin dose calculated from body surface AUC of 5.0 mg.min/ area or to achieve a particular AUC correlated poorly 0.027 ml or greater 74 2 X2-4.57 with the absolute platelet nadir on the first cycle of AUC of less than 0.149 5.0 mg.min/ml 47 7 0.05 > p > 0.01 treatment; the correlation coefficient for both is low (AUC R = 0.256 and dose/m2 R - 0.167) as illustrated AUC of 4.5 mg.min/ ml or greater 98 3 0.031 X 2 - 11.22 in Fig. 2. AUC of less than The correlation coefficient did not improve when 4 5 mg.min/ml 23 6 0.261 p < 0.001 the AUC or the BSA dose was related to the percent2 1 0.036 450 mg/m or greater 28 X2-0.23 age platelet reduction on the first treatment cycle nadir 0.086 Less than 450 mg/m2 93 8 p>0.1 (AUC R = 0.117) and dose/m2 R = 0.158). Over the 2 0.034 400 mg/m or greater 58 2 X2-1.59 commonly prescribed dose range there was a wide Less than 400 mg/m2 63 7 0.111 p>0.1 range of platelet nadir at any given dose of carboplatin. 2 0.045 350 mg/m or greater 89 4 X2-2.78 The correlation of both dose parameters with the maxi0.156 Less than 350 mg/m2 32 5 p>0.1 mum absolute platelet nadir on any cycles was also low (AUC R = 0.124 and dose/m2 R - 0.201) with a wide 2 cessful treatment and 346 mg/m in those who failed variation of maximum platelet nadir resulting from any (p = 0.0775). The risk of failure has been analysed for given dose of carboplatin within the dose range used. carboplatin dose calculated by AUC and body surface There was no significant correlation of carboplatin area (Table 5). The treatment failure rate in patients dose with the total white cell nadir on the first cycle of who received a carboplatin dose of less than 400 mg/ treatment or with the maximum white cell nadir on any m2 was 11% (7 out of 63 patients) and for those receiv- cycle. Both dose parameters also correlated poorly ing a dose of 400 mg/m2 or greater the failure rate was with the haemaglobin nadir (R - 0.176 for dose/m2 3.4% (2 out of 54 patients). and R = 0.113 for AUC). Similarly patients who received a carboplatin dose less than 350 mg/m2 had a failure rate of 15.6% while the failure rate was only 4.5% in those patients who re- Discussion ceived a dose greater than this. Both these differences do not reach statistical significance using chi squared This study confirms earlier reports [1, 2] regarding the with Yates' correction (p > 0.1). Where the calculated efficacy and reduced toxicity when carboplatin is subcarboplatin AUC was 5.0 mg.min/ml or greater the stituted for cisplatin in the combination cisplatin, etorisk of failure was 2.7% (2 out of 74 patients) while at poside and bleomycin (BEP) regimen for good progan AUC of less than 5.0 mg.min/ml the risk was 14.9% nosis NSGCT of the testis. This study, with a larger (7 out of 47 patients). This difference is statistically sig- number of patients and longer follow-up, is continuing nificant (Chi squared with Yates' correction for small to substantiate that CEB will achieve the very high cure numbers p < 0.05) and also remains highly significant if rate reported with established treatments [23, 24]. It a threshold AUC of 4.5 mg.min/ml is used (p < 0.001). During treatment there was no adjustment of BleoCORRELATION OF CAflBOPLATIN DOSE mycin or Etoposide doses, but dose adjustments of CALCULATED FROM BODY SURFACE AREA WITH PLATELET NADIR ON FIRST CYCLE carboplatin were made to achieve defined total white OF TREATMENT. cell and platelet nadirs; 42 patients had a carboplatin o T» dose increment of which 19 patients had a total increment of 10% or less over subsequent cycles of treat• TMMUn ment and 23 had a total increment of greater than 10% over subsequent cycles of treatment. Thirty-two patients I °o had a total decrease of carboplatin dose (13 patients dose decrease of 10% or less and 19 patients dose decrease of greater than 10%) on subsequent cycles. Seven patients had both increases and decreases on subsequent cycles of treatment. To take account of this • I o.° 8 ° o o oo « . variation the mean body surface area dose and mean AUC for the four treatment cycles in each patient was compared with the initial dose on cycle one. For paCAHBOPLATTM BSA DOSE (mg.'ml) tients where a dose adjustment was made there was generally only a small difference between the initial Fig. 2. Correlation of carboplatin dose calculated from body surAUC or BSA dose and the mean AUC or BSA dose face area with platelet nadir on first cycle of treatment. Table 5. Analysis of treatment failure.

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would also appear that salvage chemotherapy and sur- with respect to the dose per unit body surface area gery will successfully treat a good proportion of the compared to patients in whom the dose is prescribed small number of patients who fail CEB chemotherapy. by body surface area where a lesser number were An MRC-EORTC trial randomising patients between underdosed according to the AUC. However, because BEP (Bleomycin, Etoposide, cisplatin) and CEB the numbers in each of these groups was small it was not possible to determine whether the actual risk of chemotherapy is currently testing these observations. While previous studies have addressed the question relapse is higher if one dose parameter is above the of optimising the dose of carboplatin using the magni- defined threshold while the other is below. tude of bone marrow toxicity [12, 25, 26], especially Previous studies have reported that the dose limiting thrombocytopaenia, the lack of an established rela- toxicity of carboplatin is thrombocytopaenia and that tionship between the degree of thrombocytopaenia and this is correlated with the carboplatin dose [12, 25-28). the probability of achieving tumour cell kill using con- Our study showed a poor correlation of carboplatin ventional doses of carboplatin makes it important to dose with either absolute platelet nadir or percentage analyse dose determination regimens from the point of reduction of platelet count on the first or subsequent view of clinically observed treatment failure rates. If a treatment cycles and confirmed that there was wide relationship does exist between thrombocytopaenia individual variability in the degree of platelet response and carboplatin dose it remains to be established to a particular dose of carboplatin when used in combiwhether there is a clinically useful correlation or that nation with etoposide and bleomycin. With our larger there is an optimum degree of thrombocytopaenia to group of patients the relationship between carboplatin be obtained. Given that optimum dosing of carboplatin dose and platelet nadir is less evident than was preis critical to minimising the risk of treatment failure it is viously reported from an earlier study on a smaller important to establish a dose response curve and the group of these patients [26]. optimum method of dose determination in clinical No relationship was seen between white cell nadir practice that will reliably ensure maximum tumour cell and carboplatin dose which is in keeping with data rekill. Because the total number of adverse events in our ported elsewhere [11, 26]. Most patients developed a study (treatment failure) was small the statistical anal- progressive anaemia during treatment however this ysis should be interpreted with caution, however a clear correlated poorly with the carboplatin dose. Using the dose threshold appears to have been established for dose thresholds defined by body surface area or AUC carboplatin based on body surface area or calculated in our study the chance of serious complations from from a desired AUC. The threshold for increased risk toxicity was small and this was also true for the small of treatment failure by dose based on body surface area number of patients receiving higher doses of over 500 appears to be below 350 mg/m2, although this did not mg/m2 (n = 5) or doses resulting in an AUC of over 6.0 reach statistical significance. Because dose escalation mg.min/ml (n = 4). The outcome of treatment and patabove this level resulted in an acceptable degree of toxi- tern of toxicity within the range of doses used in our city with an even smaller risk of treatment failure, a study, suggest that the practice of establishing a mimidose of between 400 mg/m2 to 450 mg/m2 remains a mum starting dose by either AUC or BSA and then adsafe and appropriate level when prescribing on the justing according to the observed platelet and white cell basis of body surface area and when a dose of 400 mg/ nadirs should avoid any serious marrow toxicity, howm2 is prescribed only a small proportion of patients will ever, the AUC method is preferable since it was more have a predicted AUC of less than 4.5 mg.min/ml. This precise in discriminating treatment failure. study suggests that a higher dose of up to 500 mg/m2 Our study has defined a dose threshold based on could be used without causing dangerously low nadir calculated AUC for carboplatin when used in combiblood counts. nation with etoposide and bleomycin for good progA threshold for the risk of failure has been defined nosis NSGCT of the testis however the thresholds may by the predicted AUC with a significantly increased be suboptimal for more advanced germ cell tumours risk of failure below 4.5 mg.min/ml, however as a level and for other tumours or drug combinations. Though of 5.0 mg.min/ml resulted in a smaller number of fail- higher AUC's did not cause any problems in our study, ures with an acceptable degree of toxicity it remains the an interim analysis of the Memorial/SWOG trial, which 2 suitable level for clinical use. These dose thresholds employed carboplatin at 500/m with etoposide 100 2 have been established using carboplatin in combination mg/m /day for 5 days, reported (in contrast to the with etoposide and bleomycin in good prognosis pa- abstract [15]) that there were more unfavourable retients and are not necessarily appropriate for poor sponses compared with cisplatin + E; this may have prognosis patients or when used in combination with been because the degree of bone marrow suppression led to a long intercycle time (the standard was 4 weeks). other cytotoxic drugs. The results of our current study show that for the When one method of dose determination is used a small proportion of patients will be judged to have been chemotherapy of germ cell tumours and within the underdosed on the basis of the alternative method. dose range studied, bone marrow toxicity would not be Prescribing carboplatin dose by AUC resulted in a a useful predictor of tumour response to carboplatin. In slightly larger proportion of patients being underdosed the small number of patients in our study who failed

296 treatment there was no difference in the magnitude of platelet toxicity compared to those whose treatment was succesful, which suggests that such toxicity may be independent of tumour response to carboplatin. Acknowledgements

References 1. Horwich A. Carboplatin in the treatment of testicular cancer; The Royal Marsden Hospital Testicular Tumour Unit Experience. In Bunn PA, Canetta R, Ozol RF, Rozencweig M (eds): Carboplatin (JM-8) Current perspectives ajid future directions. W. B. Saunders 1990; pp. 53-62. 2. Horwich A, DeamaJey DP, Nicholls J et al. Effectiveness of carboplatin, etoposide and bleomycin combination chemotherapy in good prognosis metastatic testicular nonseminomatous germ cell tumours. J Clin Oncol 1991; 9:62-9. 3. Ten Bokkel Huinink WW, Rodenhuis S, Simonetti G et al. Studies with carboplatin in ovarian cancer Experience of the Netherlands cancer institute and GCCG of the European Organisation for Research and Treatment of Cancer. In Bunn PA, Canetta R, Ozol RF, Rozencweig M (eds): Carboplatin (JM-8) Current perspectives and future directions. W. B. Saunders 1990; pp. 165-74. 4. Smith IE. Carboplatin in Small cell Lung Cancer: The Royal Marsden Hospital Experience. In Bunn PA, Canetta R, Ozol RF, Rozencweig M (eds): Carboplatin (JM-8) Current perspectives and future directions. W. B. Saunders 1990; pp. 243-8. 5. Al-Sarraf M. Management strategies in head and neck cancer The role of carboplatin. In Bunn PA, Canetta R, Ozol RF, Rozencweig M (eds): Carboplatin (JM-8) Current perspectives and future directions. W. B. Saunders 1990; pp. 221-31. 6. Calvert AH, Harland SJ, Newell DR et al. Early clinical studies with cis-diammine-l,l-cyclobutane dicarboxylate platinum II. Cancer Chemother Pharmacol 1982; 9: 140-7. 7. Calvert AH, Harland SJ, Newell DR et al. Phase I studies with carboplatin at the Royal Marsden Hospital. Cancer Treat Rev 1985; 12: 51-7. 8. Van Glabbeke M, Renard J, Pinedo HM et al. Iproplatin and carboplatin induced toxicities: Overview of phase II clinical trials conducted by the EORTC Early Clinical Trials-Cooperative Group (ECTCG). Eur J Cancer Clin Oncol 1988; 24:255-62. 9. Himmelstein KJ, Patton TF, Belt AJ et al. Clinical kinetics of intact cisplatin and some related species. Clin Pharmacol Ther 1981; 29: 658-64. 10. Harland SJ, Newell DR, Siddik ZH et al. Pharmacokinetics of cis-diammine-l,l-cyclobutane dicarboxylate platinum (II) in patients with normal and impaired renal function. Cancer Res 1984; 44: 1693-7. 11. Ostrow S, Egorin MJ, Hahn ET et al. High dose cisplatin therapy using mannitol versus furosemide diuresis: Comparative pharmacokinetics and toxicity. Cancer Treat Rep 1981; 65: 73-8. 12. Van Echo DA, Egorin MJ, Aisner J. The pharmacology' of carboplatin. Sem Oncol 1989; 16 (Suppl 5): 1-6. 13. Deconti RC, Toftness BR, Lange RC et al. Clinical and pharmacological studies with cisdiamminedichloroplatinum II. Cancer Res 1983; 33: 1310-5.

Received 15 October 1991; accepted 20 December 1991. Correspondence to: Professor A. Horwich The Institute of Cancer Research and the Royal Marsden Hospital Dow ns Road Sutton, Suirey SM2 5PT, UK

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W. J. Childs was supported by a Commonwealth Universities Medical Fellowship. The research of the Testicular Tumour Unit is supported by the Cancer Research Campaign and the Bob Champion Cancer Trust.

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