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Concurrent Weekly Cisplatin Chemotherapy and Radiotherapy in a Haemodialysis Patient with Locally Advanced Cervix Cancer
Clinical Oncology (2008) 20: 6e11 doi:10.1016/j.clon.2007.10.007
Original Article
Concurrent Weekly Cisplatin Chemotherapy and Radiotherapy in a Haemodialysis Patient with Locally Advanced Cervix Cancer M. A. Zahra*, A. Taylory, G. Mouldy, C. Coles*, R. Crawfordz, L. T. Tan* *Department of Oncology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Trust, Cambridge, UK; yDepartment of Biochemistry, Royal Surrey County Hospital, Guildford, UK; zDepartment of Gynae-oncology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Trust, Cambridge, UK
ABSTRACT: Aims: Concurrent cisplatin chemo-radiotherapy improves outcome in cervical carcinoma. In haemodialysis patients, cisplatin is potentially hazardous. We report the treatment of a haemodialysis patient with cervix cancer using cisplatinbased chemo-radiation. Mathematical modelling using toxicity data from a range of cisplatin dosages and schedules reported in published studies was undertaken. Materials and methods: The patient was treated using weekly cisplatin chemotherapy 25 mg/m2. The serum platinum levels were measured. Correlations between reported toxicity and platinum levels for a variety of cisplatin schedules in published studies were evaluated. Results: Treatment was completed with no interruptions and minimum acute toxicity. The platinum levels rose progressively. The elimination half-life was prolonged at 6.6e7.5 days. The percentage extraction varied between 7.7 and 41.0%. The cumulative cisplatin dose correlated with neurotoxicity (P [ 0.002). Myelotoxicity correlated with the peak cisplatin level in the first 15 days of treatment (P [ 0.01). With an elimination half-life of 7.5 days, 35 mg/m2 weekly is predicted to have the same risk of myelotoxicity and neurotoxicity as 40 mg/m2 weekly in a patient with normal renal function. Conclusions: Weekly cisplatin chemotherapy 25 mg/m2 can be delivered safely in a haemodialysis patient. Dialysis is effective in eliminating platinum even if carried out more than 3 h after infusion, but it should commence as soon as possible after cisplatin infusion, as the incidence of myelotoxicity is related to the peak platinum level. Zahra, M. A. et al. (2008). Clinical Oncology 20, 6e11 ª 2007 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Cervix, cisplatin, dialysis, radiotherapy
Introduction Radiotherapy with concurrent cisplatin chemotherapy is now the standard treatment for locally advanced carcinoma of the cervix. The addition of chemotherapy to radiotherapy results in an absolute improvement in overall survival of 10% and significantly reduces local recurrence [1]. Cisplatin acts as a radiosensitiser and may also have an independent cytotoxic effect as the incidence of distant metastases is reduced [1]. It has been estimated that each cycle of chemotherapy contributes an equivalent of 2e4 Gy10 to the treatment [2]. There is some evidence that the benefit from chemotherapy is apparent as long as patients receive at least three cycles of cisplatin at a dose of 40 mg/m2 weekly [3,4]. Cisplatin is a highly potent anti-neoplastic agent with a broad spectrum of activity in many solid tumours [5]. It is usually given intravenously and excretion is predominantly renal. The drug undergoes extensive (O90%) plasma protein 0936-6555/08/200006þ06 $35.00/0
binding, resulting in a biphasic pattern of decay. After administration, there is initially rapid elimination of nonprotein bound intact drug and metabolites (half-life 20e45 min). As extensive protein binding occurs, clearance declines rapidly, resulting in a prolonged excretory phase (terminal half-life w5 days) [5]. Cisplatin has a number of significant toxicities, including a high emetic potential, nephrotoxicity, neurotoxicity and ototoxicity. Toxicity is dose and schedule dependent and is also usually cumulative [6]. Pre-treatment hydration is recommended to minimise nephrotoxicity. Neurotoxicity is one of the major dose-limiting toxicities of cisplatin therapy and becomes clinically manifest at cumulative doses of 300e600 mg/m2 [7]. Haematological toxicity is less pronounced compared with other chemotherapeutic agents. An overdose of cisplatin can result in death [6], usually from renal failure or myelosuppression. Published reports [8,9] suggest that in the event of an overdose, haemodialysis is effective in clearing out the drug
ª 2007 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
CISPLATIN CHEMOTHERAPY AND RADIOTHERAPY IN A HAEMODIALYSIS PATIENT WITH CERVIX CANCER
only if carried out within 3 h of administration due to the extensive protein binding. In renal failure, the half-life of cisplatin is prolonged and dose modification is recommended. The Royal College of Radiologists’ chemotherapy guidelines [10] suggest using full doses of cisplatin if the creatinine clearance is above 50 ml/min, a proportional reduction if the clearance is between 30 and 50 ml/min and omission of cisplatin if the clearance is below 30 ml/min. The British Columbia Cancer Agency guidelines [5], which have been adopted in many clinical trials, are more stringent and suggest 75% of the usual dose if the creatinine clearance is 45e59 ml/min and omission of the drug if the clearance is !45 ml/min. There are no guidelines for cisplatin dose modification in patients on dialysis. Previous reports of cisplatin use in this group of patients were mostly single case reports involving different tumour sites within a palliative setting using a variety of drug doses (ranging from 10 to 80 mg/m2) and dialysis regimens. The most common adverse events reported were myelotoxicity and emesis [8,11e16]. This study evaluated the pharmacokinetics and acute toxicity of concurrent cisplatin chemotherapy with radiotherapy in the radical treatment of a haemodialysis patient with carcinoma of the cervix. Mathematical modelling of toxicity data from a wide range of cisplatin dosages and schedules reported in published studies was undertaken to guide the future use of cisplatin in dialysis patients.
Materials and Methods The patient was a 38-year-old woman who presented with a 6-month history of vaginal bleeding. Examination under anaesthesia showed a 6 5 cm cervical tumour extending to the lower third vagina. There was bilateral parametrial involvement to both pelvic sidewalls. Cystoscopy showed involvement of the posterior bladder wall and her disease
7
was staged as FIGO IVa. Biopsy showed poorly differentiated squamous cell carcinoma. Staging magnetic resonance imaging (Fig. 1a) showed no evidence of pelvic or paraaortic lymphadenopathy. The patient developed renal failure after an episode of pyelonephritis at the age of 3 years and commenced renal dialysis at the age of 14 years. She underwent her first cadaveric renal transplant at the age of 16 years, which lasted for 8 years. A second living related renal transplant was carried out when she was 24 years old, which lasted for 9 years. At the time of diagnosis, she had resumed dialysis for 5 years and was awaiting a third renal transplant. She was on long-term erythropoietin treatment. The patient consented to radical radiotherapy with weekly cisplatin chemotherapy, and additional blood sampling to measure serum platinum levels. Radiotherapy was given in two phases, 45 Gy in 25 fractions over 5 weeks to the whole pelvis using parallel opposed fields, followed by a boost of 20 Gy in 10 fractions over 2 weeks to the primary tumour. Cisplatin 25 mg/m2 (¼ 40 mg) in 1 l of normal saline was infused over 1 h once a week during radiotherapy. The cisplatin dose was chosen empirically based on previous experience with patients with renal impairment. Ondansetron and dexamethasone were given to prevent emesis. Hydration was omitted to avoid unnecessary fluid overload as nephrotoxicity was not relevant in this patient. Acute toxicity was graded prospectively at weekly intervals using National Cancer Institute Common Toxicity Criteria (CTC). Full blood count and serum biochemistry were monitored twice weekly. Haemodialysis was undertaken three times a week for 4 h at a time, using a FX8 (Fresenius Medical Care) polyolefine hollow fibre dialyser (1.4 m2 surface area) with A/105 dialysis solution, as per the patient’s pre-treatment schedule. On the days of chemotherapy, dialysis was commenced within 1 h of completing cisplatin infusion. Venous blood samples for platinum levels were obtained immediately
Fig. 1 e Sagittal T2-weighted magnetic resonance images of the patient. (a) Pre-treatment image showing the tumour extending to the lower third vagina and invading the posterior bladder wall. (b) Post-treatment image showing O50% reduction in tumour volume.
CLINICAL ONCOLOGY
before and after each dialysis session during radiotherapy. Total platinum levels were measured by inductively coupled plasma-mass spectrometry at the University of Surrey Trace Elements Laboratory. The excretion half-life was estimated using WinNonlin (version 5) software.
Mathematical Modelling A search of published studies was carried out to identify studies reporting toxicity data from a wide range of cisplatin dosages and schedules. For each study, the dose intensity (mg/m2/week) and the total dose given (mg/m2) were recorded. The peak cisplatin level (mg/m2) after one cycle, and at the end of treatment, was calculated using the equation [17]: ln Ct ¼ ln Cmax kelim t where Ct is the cisplatin level after time interval t, Cmax is the maximum cisplatin level after drug infusion, taking into account incomplete clearance from previous infusions and kelim is the elimination constant and is equal to 0.693/T½ where T½ is the terminal half-life of cisplatin (assumed to be 5 days for patients with normal renal function [5]). The correlations between cisplatin doses and reported toxicity were assessed using Spearman’s correlation coefficient (r) and two-sided significance testing.
Results The patient completed her radiotherapy without any interruptions. She received seven cycles of cisplatin as planned (total dose 280 mg ¼ 175 mg/m2). On day 8 of her treatment, she developed grade 2 anaemia (haemoglobin 8.6 g/dl) and subsequently received three blood transfusions (a total of 8 units) over the course of her radiotherapy. After the second week of treatment, she developed shortness of breath associated with evidence of fluid overload and her dialysis sessions were increased to four times a week. During the fifth week of treatment, she developed a small area of radiation dermatitis (maximum CTC grade ¼ 2) over the natal cleft within the radiotherapy field. On day 44, she developed grade 1 leucopoenia (white cell count 3.1 109/l), which did not deteriorate and did not require growth factor support. She had no nausea, vomiting, bowel or urinary toxicity during her treatment. She did not report any symptoms of neurotoxicity or ototoxicity at the end of treatment or on subsequent follow-up. Magnetic resonance imaging 3 months after completing radiotherapy (Fig. 1b) showed a partial response with O50% reduction in tumour volume, but repeat imaging after 9 months of treatment showed progressive disease in the pelvis. The patient died of disease progression 15 months after treatment.
Pharmacokinetics The elimination half-life of cisplatin in our patient was estimated to be between 6.6 and 7.5 days. The percentage
Platinum levels (nmols/l)
8
12000 10000 8000 6000 4000 2000 0
C
0
C
C
7
14
C
21
C
28
C
35
42
Treatment days Fig. 2 e Changes in serum platinum levels. -, pre-dialysis platinum; ,, post-dialysis platinum; D, dialysis; , chemotherapy; , trendline pre-dialysis levels immediately , trendline post-dialysis levels 100 h postpost-infusion; infusion; , rebound.
extraction of cisplatin by dialysis varied between 7.7 and 41.0% (median ¼ 21.0%). The variation in drug extraction did not correlate with the timing of dialysis relative to cisplatin infusion, the absolute platinum levels or the serum albumin levels. There was a progressive rise in plasma platinum levels with each cycle of chemotherapy (Fig. 2). This rise was seen in the pre-dialysis levels measured 2 h after cisplatin infusion, and in the levels measured after three to four dialysis sessions before the next cisplatin infusion. Episodes of rebound in platinum levels between dialysis sessions, which were not related to drug administration, were observed.
Toxicity Modelling Myelotoxicity data from eight published studies [5,18e22] and neurotoxicity (grade 3e4) data from 10 studies [5,18,20,22e26] were used for toxicity modelling. The correlations between these data and cisplatin doses are shown in Table 1. The incidence of myelotoxicity reported in the studies ranged between 25 and 100%. There was a significant correlation between the incidence of myelotoxicity and the calculated peak level of cisplatin in the first 15 days of treatment (Fig. 3: r ¼ 0.81, P ¼ 0.01). There was no correlation between myelotoxicity and cumulative dose (P ¼ 0.69). The incidence of grade 3e4 neurotoxicity ranged between 0 and 50% and was significantly correlated with the cumulative dose given (r ¼ 0.84, P ¼ 0.002) and the calculated peak level at the end of treatment (Fig. 4: r ¼ 0.81, P ¼ 0.004). Both myelotoxicity and neurotoxicity showed no correlation with the dose intensity of the treatment regimen. Using the elimination half-life values for our patient, we estimated that a dose of 40 mg/m2 in normal renal function (half-life 5 days) is equivalent to 35 mg/m2 if the half-life is prolonged to 6.6e7.5 days. By extrapolating these doses to the toxicity plots in Figs. 3 and 4, the prolonged elimination half-life is predicted to increase the risk of myelotoxicity but not neurotoxicity. For example, for a dose of 40 mg/m2
CISPLATIN CHEMOTHERAPY AND RADIOTHERAPY IN A HAEMODIALYSIS PATIENT WITH CERVIX CANCER
9
Table 1 e Correlations of platinum dose with toxicity
Toxicity Myelotoxicity any grade (n ¼ 8) Neurotoxicity grade 3e4 (n ¼ 10)
Dose intensity (mg/m2/week)
Cumulative dose (mg/m2)
Peak dose in period day 1e15 (mg/m2)
Peak dose at end of treatment (mg/m2)
r ¼ 0.58 P ¼ 0.13 r ¼ 0.35 P ¼ 0.32
r ¼ 0.17 P ¼ 0.69 r ¼ 0.84 P ¼ 0.002
r ¼ 0.81 P ¼ 0.014 r ¼ 0.62 P ¼ 0.054
r ¼ 0.70 P ¼ 0.056 r ¼ 0.81 P ¼ 0.004
r, Spearman’s correlation coefficient with two-tailed significance testing.
in normal renal function, the predicted upper limit of the incidence of myelotoxicity and neurotoxicity is 44 and 0%, respectively. If the half-life is prolonged to 7.5 days, the upper limit of the predicted incidence of myelotoxicity is 60% if the dose is 40 mg/m2, 47% if the dose is 35 mg/m2, and 36% if the dose is 30 mg/m2. However, the incidence of neurotoxicity is predicted to be !3% even if the dose is maintained at 40 mg/m2.
Fig. 3 e Correlation between the incidence of myelotoxicity and the calculated peak cisplatin level in the first 15 days of treatment for eight published studies of varying cisplatin dosages and schedules: 75 mg/m2 day 1 every 3 weeks [5]; 70 mg/m2 day 1 every 4 weeks [19]; 40 mg/m2 weekly [18]; 50 mg/m2 days 1, 8, 15 every 4 weeks [20]; 100 mg/m2 day 1 every 3 weeks [25]; 70 mg/m2 days 1, 8, 15 every 4 weeks [22]; 70 mg/m2 days 1, 8, 15 every 4 weeks [20]; 30 mg/m2 days 1e5 every 4 weeks [21].
Discussion We have shown that concurrent cisplatin chemotherapy with radiotherapy can be delivered in a patient on haemodialysis with minimal toxicity. The pharmacokinetic
Fig. 4 e Correlation between the incidence of grade 3e4 neurotoxicity and the calculated peak cisplatin level at the end of treatment for 10 published studies of varying cisplatin dosages and schedules: 40 mg/m2 weekly, cumulative dose 200 mg/m2 [19]; 50 mg/m2 days 1, 8, 15 every 4 weeks, cumulative dose 300 mg/m2 [20]; 20 mg/m2 days 1e5 every 4 weeks, cumulative dose 400 mg/ m2 [23]; 75 mg/m2 day 1 every 4 weeks, cumulative dose 450 mg/ m2 [5]; 70 mg/m2 days 1, 8, 15 every 4 weeks, cumulative dose 420 mg/m2 [20]; 70 mg/m2 days 1, 8, 15 every 4 weeks, cumulative dose 420 mg/m2 [22]; 100 mg/m2 days 1, 8 every 4 weeks, cumulative dose 600 mg/m2 [24]; 100 mg/m2 day 1 every 3 weeks, cumulative dose 600 mg/m2 [25]; 40 mg/m2 days 1e5 every 4 weeks, cumulative dose 800 mg/m2 [23]; 40 mg/m2 days 1e5 every 4 weeks, cumulative dose 600 mg/m2 [26].
10
CLINICAL ONCOLOGY
data for our patient showed prolonged clearance and progressive accumulation of cisplatin, which is in agreement with previous case reports of cisplatin use in dialysis patients [12,13,15]. The variation in percentage drug extraction by haemodialysis (8e40%) is similar to that reported by Ribrag et al. [16] (8e21%). The variation could be due to changes in a patient’s biochemistry in between dialysis sessions, which could affect the degree of protein binding and the amount of free cisplatin that could be dialysed. This wide variation precludes the use of an initial test dose to establish the optimal dose for individual dialysis patients [16]. The amount of platinum removed by dialysis was not related to the timing of dialysis relative to drug infusion, in contrast with previous reports [8,9] that suggested that dialysis is ineffective in eliminating platinum if carried out more than 3 h after infusion. Our data showed that dialysis after the 3 h limit still resulted in marked reductions in platinum levels. On the basis of our data and that from Lagrange et al. [27], who reported a significant reduction in platinum levels from dialysis initiated 7 days after an accidental overdose, dialysis is an appropriate treatment option for accidental overdose even if delayed beyond 3 h. The phenomenon of rebound in plasma platinum levels between dialysis sessions as seen in our patient has only been described in one other report [27]. This finding cannot be explained by analytical imprecision, as all our samples were analysed in a single batch, and is postulated to be due to the release of platinum from the tissues. In accidental overdose, repeated dialysis may therefore be necessary to maintain the reduction in serum platinum levels. The incidence and severity of cisplatin toxicity is known to be dose and schedule dependent. Our modelled data confirm that the incidence of grade 3e4 neurotoxicity is significantly correlated with the cumulative dose. There is also a significant correlation with the peak drug level at the end of treatment, which depends on both the dose given and the scheduling. This is in keeping with the finding by Cavaletti et al. [28], who reported that patients treated to an identical cumulative dose with 75 mg/m2 every 3 weeks had 38.6% incidence of neuropathy compared with 11e21% for patients treated with 50 mg/m2 weekly. Animal studies [29] have also shown that tissue platinum concentrations are related to the time interval between administrations as well as the total dose given. In contrast, we did not find a correlation between myelotoxicity and cumulative dose. It is known that cisplatin-induced myelosuppression usually manifests itself by day 18e23 [5] and we have assumed that any cisplatin delivered in the first 15 days of treatment would contribute to the myelotoxic effect. Our modelled data suggest that this peak level in the first 15 days of treatment is the most significant factor influencing the incidence of myelotoxicity in the published studies. The pharmacokinetic model we have used assumes that the main difference in drug metabolism between patients with normal renal function and patients on dialysis is the prolonged half-life. We have not allowed for the effects of the dialysis parameters, or the altered physiological parameters in patients on dialysis, such as low serum albumin
levels. Bearing in mind these limitations, the model suggests that a weekly cisplatin dose of 35 mg/m2 in a haemodialysis patient with a prolonged elimination half-life of 7.5 days would be expected to induce the same incidence of myelotoxicity as seen with 40 mg/m2 weekly in a patient with normal renal function. The prolonged elimination halflife is not predicted to have any significant effect on the incidence of severe neurotoxicity.
Conclusion We have shown that weekly cisplatin chemotherapy 25 mg/m2 with radiotherapy can be delivered with minimal toxicity in a haemodialysis patient. Mathematical modelling suggests that the cisplatin dose can be increased to 35 mg/m2 weekly with comparable myelotoxicity and neurotoxicity as 40 mg/m2 in a patient with normal renal function. Dialysis sessions should commence as soon as possible after cisplatin infusion as the incidence of myelotoxicity is related to the peak platinum level after infusion. Acknowledgements. The Royal College of Radiologists Clinical Oncology Research Fellowship is funding the salary of M. A. Zahra and the Gynaecological Cancer Fund, Addenbrooke’s Hospital funded the platinum analysis. Author for correspondence: L. T. Tan, Department of Oncology, Box 193, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, UK. Tel: þ44-1223-763337; Fax: þ44-1223-763120; E-mail: [email protected] Received 16 October 2006; received in revised form 14 September 2007; accepted 12 October 2007
References 1 Green JA, Kirwan JM, Tierney JF, et al. Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: a systematic review and meta-analysis. Lancet 2001;358:781e786. 2 Jones B, Dale RG. The potential for mathematical modelling in the assessment of the radiation dose equivalent of cytotoxic chemotherapy given concomitantly with radiotherapy. Br J Radiol 2005;78:939e944. 3 Grigsby PW. Cervical cancer: combined modality therapy. Cancer J 2001;7(Suppl 1):S47eS50. 4 Peters WA 3rd, Liu PY, Barrett RJ 2nd, et al. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 2000;18:1606e1613. 5 British Columbia Cancer Agency. Cancer drug manual. British Columbia Cancer Agency; 2006. 6 Go RS, Adjei AA. Review of the comparative pharmacology and clinical activity of cisplatin and carboplatin. J Clin Oncol 1999; 17:409e422. 7 Mollman JE. Cisplatin neurotoxicity. N Engl J Med 1990;322: 126e127. 8 Gorodetsky R, Vexler A, Bar-Khaim Y, Biran H. Plasma platinum elimination in a hemodialysis patient treated with cisplatin. Ther Drug Monit 1995;17:203e206.
CISPLATIN CHEMOTHERAPY AND RADIOTHERAPY IN A HAEMODIALYSIS PATIENT WITH CERVIX CANCER 9 Brivet F, Pavlovitch JM, Gouyette A, Cerrina ML, Tchernia G, Dormont J. Inefficiency of early prophylactic hemodialysis in cis-platinum overdose. Cancer Chemother Pharmacol 1986;18: 183e184. 10 Guidelines for cytotoxic chemotherapy in adults. A document for local expert groups in the United Kingdom preparing chemotherapy policy documents. Clin Oncol (R Coll Radiol) 2001;13:s209es248. 11 Hirai K, Ishiko O, Sumi T, Kanaoka Y, Ogita S. Kinetics of plasma platinum in a hemodialysis patient receiving repeated doses of cisplatin. Oncol Rep 2000;7:1243e1245. 12 Kurisu A, Hata T, Owada A. Full-dose chemotherapy for esophageal cancer patient under hemodialysis. Nephron 2002;92:960. 13 Watanabe R, Takiguchi Y, Moriya T, et al. Feasibility of combination chemotherapy with cisplatin and etoposide for haemodialysis patients with lung cancer. Br J Cancer 2003;88: 25e30. 14 Tomita M, Kurata H, Aoki Y, Tanaka K, Kazama JJ. Pharmacokinetics of paclitaxel and cisplatin in a hemodialysis patient with recurrent ovarian cancer. Anticancer Drugs 2001;12: 485e487. 15 Tanabe N, Goto M, Morita H, et al. Pharmacokinetics of cisdiammine-dichlor-platin in a hemodialysis patient. Cancer Invest 1991;9:629e635. 16 Ribrag V, Droz JP, Morizet J, Leclercq B, Gouyette A, Chabot GG. Test dose-guided administration of cisplatin in an anephric patient: a case report. Ann Oncol 1993;4:679e682. 17 Greenblatt DJ. Elimination half-life of drugs: value and limitations. Annu Rev Med 1985;36:421e427. 18 Tan LT, Russell S, Burgess L. Acute toxicity of chemoradiotherapy for cervical cancer: the Addenbrooke’s experience. Clin Oncol (R Coll Radiol) 2004;16:255e260. 19 Petrioli R, Frediani B, Manganelli A, et al. Comparison between a cisplatin-containing regimen and a carboplatin-containing regimen for recurrent or metastatic bladder cancer patients. A randomized phase II study. Cancer 1996;77:344e351.
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20 van der Burg ME, de Wit R, van Putten WL, et al. Weekly cisplatin and daily oral etoposide is highly effective in platinum pretreated ovarian cancer. Br J Cancer 2002;86:19e25. 21 Legha SS, Dimery IW. High-dose cisplatin administration without hypertonic saline: observation of disabling neurotoxicity. J Clin Oncol 1985;3:1373e1378. 22 de Jongh FE, van Veen RN, Veltman SJ, et al. Weekly high-dose cisplatin is a feasible treatment option: analysis on prognostic factors for toxicity in 400 patients. Br J Cancer 2003;88: 1199e1206. 23 Nichols CR, Williams SD, Loehrer PJ, et al. Randomized study of cisplatin dose intensity in poor-risk germ cell tumors: a Southeastern Cancer Study Group and Southwest Oncology Group protocol. J Clin Oncol 1991;9:1163e1172. 24 Gandara DR, DeGregorio MW, Wold H, et al. High-dose cisplatin in hypertonic saline: reduced toxicity of a modified dose schedule and correlation with plasma pharmacokinetics. A Northern California Oncology Group Pilot Study in nonsmall-cell lung cancer. J Clin Oncol 1986;4:1787e1793. 25 Muggia FM, Braly PS, Brady MF, et al. Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a gynecologic oncology group study. J Clin Oncol 2000;18:106e115. 26 Benedetti Panici P, Greggi S, Scambia G, et al. Efficacy and toxicity of very high-dose cisplatin in advanced ovarian carcinoma: 4-year survival analysis and neurological followup. Int J Gynecol Cancer 1993;3:44e53. 27 Lagrange JL, Cassuto-Viguier E, Barbe V, et al. Cytotoxic effects of long-term circulating ultrafiltratable platinum species and limited efficacy of haemodialysis in clearing them. Eur J Cancer 1994;30A:2057e2060. 28 Cavaletti G, Marzorati L, Bogliun G, et al. Cisplatin-induced peripheral neurotoxicity is dependent on total-dose intensity and single-dose intensity. Cancer 1992;69:203e207. 29 Cavaletti G, Tredici G, Pizzini G, Minoia A. Tissue platinum concentrations and cisplatin schedules. Lancet 1990;336:1003.
Original Article
Concurrent Weekly Cisplatin Chemotherapy and Radiotherapy in a Haemodialysis Patient with Locally Advanced Cervix Cancer M. A. Zahra*, A. Taylory, G. Mouldy, C. Coles*, R. Crawfordz, L. T. Tan* *Department of Oncology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Trust, Cambridge, UK; yDepartment of Biochemistry, Royal Surrey County Hospital, Guildford, UK; zDepartment of Gynae-oncology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Trust, Cambridge, UK
ABSTRACT: Aims: Concurrent cisplatin chemo-radiotherapy improves outcome in cervical carcinoma. In haemodialysis patients, cisplatin is potentially hazardous. We report the treatment of a haemodialysis patient with cervix cancer using cisplatinbased chemo-radiation. Mathematical modelling using toxicity data from a range of cisplatin dosages and schedules reported in published studies was undertaken. Materials and methods: The patient was treated using weekly cisplatin chemotherapy 25 mg/m2. The serum platinum levels were measured. Correlations between reported toxicity and platinum levels for a variety of cisplatin schedules in published studies were evaluated. Results: Treatment was completed with no interruptions and minimum acute toxicity. The platinum levels rose progressively. The elimination half-life was prolonged at 6.6e7.5 days. The percentage extraction varied between 7.7 and 41.0%. The cumulative cisplatin dose correlated with neurotoxicity (P [ 0.002). Myelotoxicity correlated with the peak cisplatin level in the first 15 days of treatment (P [ 0.01). With an elimination half-life of 7.5 days, 35 mg/m2 weekly is predicted to have the same risk of myelotoxicity and neurotoxicity as 40 mg/m2 weekly in a patient with normal renal function. Conclusions: Weekly cisplatin chemotherapy 25 mg/m2 can be delivered safely in a haemodialysis patient. Dialysis is effective in eliminating platinum even if carried out more than 3 h after infusion, but it should commence as soon as possible after cisplatin infusion, as the incidence of myelotoxicity is related to the peak platinum level. Zahra, M. A. et al. (2008). Clinical Oncology 20, 6e11 ª 2007 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Cervix, cisplatin, dialysis, radiotherapy
Introduction Radiotherapy with concurrent cisplatin chemotherapy is now the standard treatment for locally advanced carcinoma of the cervix. The addition of chemotherapy to radiotherapy results in an absolute improvement in overall survival of 10% and significantly reduces local recurrence [1]. Cisplatin acts as a radiosensitiser and may also have an independent cytotoxic effect as the incidence of distant metastases is reduced [1]. It has been estimated that each cycle of chemotherapy contributes an equivalent of 2e4 Gy10 to the treatment [2]. There is some evidence that the benefit from chemotherapy is apparent as long as patients receive at least three cycles of cisplatin at a dose of 40 mg/m2 weekly [3,4]. Cisplatin is a highly potent anti-neoplastic agent with a broad spectrum of activity in many solid tumours [5]. It is usually given intravenously and excretion is predominantly renal. The drug undergoes extensive (O90%) plasma protein 0936-6555/08/200006þ06 $35.00/0
binding, resulting in a biphasic pattern of decay. After administration, there is initially rapid elimination of nonprotein bound intact drug and metabolites (half-life 20e45 min). As extensive protein binding occurs, clearance declines rapidly, resulting in a prolonged excretory phase (terminal half-life w5 days) [5]. Cisplatin has a number of significant toxicities, including a high emetic potential, nephrotoxicity, neurotoxicity and ototoxicity. Toxicity is dose and schedule dependent and is also usually cumulative [6]. Pre-treatment hydration is recommended to minimise nephrotoxicity. Neurotoxicity is one of the major dose-limiting toxicities of cisplatin therapy and becomes clinically manifest at cumulative doses of 300e600 mg/m2 [7]. Haematological toxicity is less pronounced compared with other chemotherapeutic agents. An overdose of cisplatin can result in death [6], usually from renal failure or myelosuppression. Published reports [8,9] suggest that in the event of an overdose, haemodialysis is effective in clearing out the drug
ª 2007 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
CISPLATIN CHEMOTHERAPY AND RADIOTHERAPY IN A HAEMODIALYSIS PATIENT WITH CERVIX CANCER
only if carried out within 3 h of administration due to the extensive protein binding. In renal failure, the half-life of cisplatin is prolonged and dose modification is recommended. The Royal College of Radiologists’ chemotherapy guidelines [10] suggest using full doses of cisplatin if the creatinine clearance is above 50 ml/min, a proportional reduction if the clearance is between 30 and 50 ml/min and omission of cisplatin if the clearance is below 30 ml/min. The British Columbia Cancer Agency guidelines [5], which have been adopted in many clinical trials, are more stringent and suggest 75% of the usual dose if the creatinine clearance is 45e59 ml/min and omission of the drug if the clearance is !45 ml/min. There are no guidelines for cisplatin dose modification in patients on dialysis. Previous reports of cisplatin use in this group of patients were mostly single case reports involving different tumour sites within a palliative setting using a variety of drug doses (ranging from 10 to 80 mg/m2) and dialysis regimens. The most common adverse events reported were myelotoxicity and emesis [8,11e16]. This study evaluated the pharmacokinetics and acute toxicity of concurrent cisplatin chemotherapy with radiotherapy in the radical treatment of a haemodialysis patient with carcinoma of the cervix. Mathematical modelling of toxicity data from a wide range of cisplatin dosages and schedules reported in published studies was undertaken to guide the future use of cisplatin in dialysis patients.
Materials and Methods The patient was a 38-year-old woman who presented with a 6-month history of vaginal bleeding. Examination under anaesthesia showed a 6 5 cm cervical tumour extending to the lower third vagina. There was bilateral parametrial involvement to both pelvic sidewalls. Cystoscopy showed involvement of the posterior bladder wall and her disease
7
was staged as FIGO IVa. Biopsy showed poorly differentiated squamous cell carcinoma. Staging magnetic resonance imaging (Fig. 1a) showed no evidence of pelvic or paraaortic lymphadenopathy. The patient developed renal failure after an episode of pyelonephritis at the age of 3 years and commenced renal dialysis at the age of 14 years. She underwent her first cadaveric renal transplant at the age of 16 years, which lasted for 8 years. A second living related renal transplant was carried out when she was 24 years old, which lasted for 9 years. At the time of diagnosis, she had resumed dialysis for 5 years and was awaiting a third renal transplant. She was on long-term erythropoietin treatment. The patient consented to radical radiotherapy with weekly cisplatin chemotherapy, and additional blood sampling to measure serum platinum levels. Radiotherapy was given in two phases, 45 Gy in 25 fractions over 5 weeks to the whole pelvis using parallel opposed fields, followed by a boost of 20 Gy in 10 fractions over 2 weeks to the primary tumour. Cisplatin 25 mg/m2 (¼ 40 mg) in 1 l of normal saline was infused over 1 h once a week during radiotherapy. The cisplatin dose was chosen empirically based on previous experience with patients with renal impairment. Ondansetron and dexamethasone were given to prevent emesis. Hydration was omitted to avoid unnecessary fluid overload as nephrotoxicity was not relevant in this patient. Acute toxicity was graded prospectively at weekly intervals using National Cancer Institute Common Toxicity Criteria (CTC). Full blood count and serum biochemistry were monitored twice weekly. Haemodialysis was undertaken three times a week for 4 h at a time, using a FX8 (Fresenius Medical Care) polyolefine hollow fibre dialyser (1.4 m2 surface area) with A/105 dialysis solution, as per the patient’s pre-treatment schedule. On the days of chemotherapy, dialysis was commenced within 1 h of completing cisplatin infusion. Venous blood samples for platinum levels were obtained immediately
Fig. 1 e Sagittal T2-weighted magnetic resonance images of the patient. (a) Pre-treatment image showing the tumour extending to the lower third vagina and invading the posterior bladder wall. (b) Post-treatment image showing O50% reduction in tumour volume.
CLINICAL ONCOLOGY
before and after each dialysis session during radiotherapy. Total platinum levels were measured by inductively coupled plasma-mass spectrometry at the University of Surrey Trace Elements Laboratory. The excretion half-life was estimated using WinNonlin (version 5) software.
Mathematical Modelling A search of published studies was carried out to identify studies reporting toxicity data from a wide range of cisplatin dosages and schedules. For each study, the dose intensity (mg/m2/week) and the total dose given (mg/m2) were recorded. The peak cisplatin level (mg/m2) after one cycle, and at the end of treatment, was calculated using the equation [17]: ln Ct ¼ ln Cmax kelim t where Ct is the cisplatin level after time interval t, Cmax is the maximum cisplatin level after drug infusion, taking into account incomplete clearance from previous infusions and kelim is the elimination constant and is equal to 0.693/T½ where T½ is the terminal half-life of cisplatin (assumed to be 5 days for patients with normal renal function [5]). The correlations between cisplatin doses and reported toxicity were assessed using Spearman’s correlation coefficient (r) and two-sided significance testing.
Results The patient completed her radiotherapy without any interruptions. She received seven cycles of cisplatin as planned (total dose 280 mg ¼ 175 mg/m2). On day 8 of her treatment, she developed grade 2 anaemia (haemoglobin 8.6 g/dl) and subsequently received three blood transfusions (a total of 8 units) over the course of her radiotherapy. After the second week of treatment, she developed shortness of breath associated with evidence of fluid overload and her dialysis sessions were increased to four times a week. During the fifth week of treatment, she developed a small area of radiation dermatitis (maximum CTC grade ¼ 2) over the natal cleft within the radiotherapy field. On day 44, she developed grade 1 leucopoenia (white cell count 3.1 109/l), which did not deteriorate and did not require growth factor support. She had no nausea, vomiting, bowel or urinary toxicity during her treatment. She did not report any symptoms of neurotoxicity or ototoxicity at the end of treatment or on subsequent follow-up. Magnetic resonance imaging 3 months after completing radiotherapy (Fig. 1b) showed a partial response with O50% reduction in tumour volume, but repeat imaging after 9 months of treatment showed progressive disease in the pelvis. The patient died of disease progression 15 months after treatment.
Pharmacokinetics The elimination half-life of cisplatin in our patient was estimated to be between 6.6 and 7.5 days. The percentage
Platinum levels (nmols/l)
8
12000 10000 8000 6000 4000 2000 0
C
0
C
C
7
14
C
21
C
28
C
35
42
Treatment days Fig. 2 e Changes in serum platinum levels. -, pre-dialysis platinum; ,, post-dialysis platinum; D, dialysis; , chemotherapy; , trendline pre-dialysis levels immediately , trendline post-dialysis levels 100 h postpost-infusion; infusion; , rebound.
extraction of cisplatin by dialysis varied between 7.7 and 41.0% (median ¼ 21.0%). The variation in drug extraction did not correlate with the timing of dialysis relative to cisplatin infusion, the absolute platinum levels or the serum albumin levels. There was a progressive rise in plasma platinum levels with each cycle of chemotherapy (Fig. 2). This rise was seen in the pre-dialysis levels measured 2 h after cisplatin infusion, and in the levels measured after three to four dialysis sessions before the next cisplatin infusion. Episodes of rebound in platinum levels between dialysis sessions, which were not related to drug administration, were observed.
Toxicity Modelling Myelotoxicity data from eight published studies [5,18e22] and neurotoxicity (grade 3e4) data from 10 studies [5,18,20,22e26] were used for toxicity modelling. The correlations between these data and cisplatin doses are shown in Table 1. The incidence of myelotoxicity reported in the studies ranged between 25 and 100%. There was a significant correlation between the incidence of myelotoxicity and the calculated peak level of cisplatin in the first 15 days of treatment (Fig. 3: r ¼ 0.81, P ¼ 0.01). There was no correlation between myelotoxicity and cumulative dose (P ¼ 0.69). The incidence of grade 3e4 neurotoxicity ranged between 0 and 50% and was significantly correlated with the cumulative dose given (r ¼ 0.84, P ¼ 0.002) and the calculated peak level at the end of treatment (Fig. 4: r ¼ 0.81, P ¼ 0.004). Both myelotoxicity and neurotoxicity showed no correlation with the dose intensity of the treatment regimen. Using the elimination half-life values for our patient, we estimated that a dose of 40 mg/m2 in normal renal function (half-life 5 days) is equivalent to 35 mg/m2 if the half-life is prolonged to 6.6e7.5 days. By extrapolating these doses to the toxicity plots in Figs. 3 and 4, the prolonged elimination half-life is predicted to increase the risk of myelotoxicity but not neurotoxicity. For example, for a dose of 40 mg/m2
CISPLATIN CHEMOTHERAPY AND RADIOTHERAPY IN A HAEMODIALYSIS PATIENT WITH CERVIX CANCER
9
Table 1 e Correlations of platinum dose with toxicity
Toxicity Myelotoxicity any grade (n ¼ 8) Neurotoxicity grade 3e4 (n ¼ 10)
Dose intensity (mg/m2/week)
Cumulative dose (mg/m2)
Peak dose in period day 1e15 (mg/m2)
Peak dose at end of treatment (mg/m2)
r ¼ 0.58 P ¼ 0.13 r ¼ 0.35 P ¼ 0.32
r ¼ 0.17 P ¼ 0.69 r ¼ 0.84 P ¼ 0.002
r ¼ 0.81 P ¼ 0.014 r ¼ 0.62 P ¼ 0.054
r ¼ 0.70 P ¼ 0.056 r ¼ 0.81 P ¼ 0.004
r, Spearman’s correlation coefficient with two-tailed significance testing.
in normal renal function, the predicted upper limit of the incidence of myelotoxicity and neurotoxicity is 44 and 0%, respectively. If the half-life is prolonged to 7.5 days, the upper limit of the predicted incidence of myelotoxicity is 60% if the dose is 40 mg/m2, 47% if the dose is 35 mg/m2, and 36% if the dose is 30 mg/m2. However, the incidence of neurotoxicity is predicted to be !3% even if the dose is maintained at 40 mg/m2.
Fig. 3 e Correlation between the incidence of myelotoxicity and the calculated peak cisplatin level in the first 15 days of treatment for eight published studies of varying cisplatin dosages and schedules: 75 mg/m2 day 1 every 3 weeks [5]; 70 mg/m2 day 1 every 4 weeks [19]; 40 mg/m2 weekly [18]; 50 mg/m2 days 1, 8, 15 every 4 weeks [20]; 100 mg/m2 day 1 every 3 weeks [25]; 70 mg/m2 days 1, 8, 15 every 4 weeks [22]; 70 mg/m2 days 1, 8, 15 every 4 weeks [20]; 30 mg/m2 days 1e5 every 4 weeks [21].
Discussion We have shown that concurrent cisplatin chemotherapy with radiotherapy can be delivered in a patient on haemodialysis with minimal toxicity. The pharmacokinetic
Fig. 4 e Correlation between the incidence of grade 3e4 neurotoxicity and the calculated peak cisplatin level at the end of treatment for 10 published studies of varying cisplatin dosages and schedules: 40 mg/m2 weekly, cumulative dose 200 mg/m2 [19]; 50 mg/m2 days 1, 8, 15 every 4 weeks, cumulative dose 300 mg/m2 [20]; 20 mg/m2 days 1e5 every 4 weeks, cumulative dose 400 mg/ m2 [23]; 75 mg/m2 day 1 every 4 weeks, cumulative dose 450 mg/ m2 [5]; 70 mg/m2 days 1, 8, 15 every 4 weeks, cumulative dose 420 mg/m2 [20]; 70 mg/m2 days 1, 8, 15 every 4 weeks, cumulative dose 420 mg/m2 [22]; 100 mg/m2 days 1, 8 every 4 weeks, cumulative dose 600 mg/m2 [24]; 100 mg/m2 day 1 every 3 weeks, cumulative dose 600 mg/m2 [25]; 40 mg/m2 days 1e5 every 4 weeks, cumulative dose 800 mg/m2 [23]; 40 mg/m2 days 1e5 every 4 weeks, cumulative dose 600 mg/m2 [26].
10
CLINICAL ONCOLOGY
data for our patient showed prolonged clearance and progressive accumulation of cisplatin, which is in agreement with previous case reports of cisplatin use in dialysis patients [12,13,15]. The variation in percentage drug extraction by haemodialysis (8e40%) is similar to that reported by Ribrag et al. [16] (8e21%). The variation could be due to changes in a patient’s biochemistry in between dialysis sessions, which could affect the degree of protein binding and the amount of free cisplatin that could be dialysed. This wide variation precludes the use of an initial test dose to establish the optimal dose for individual dialysis patients [16]. The amount of platinum removed by dialysis was not related to the timing of dialysis relative to drug infusion, in contrast with previous reports [8,9] that suggested that dialysis is ineffective in eliminating platinum if carried out more than 3 h after infusion. Our data showed that dialysis after the 3 h limit still resulted in marked reductions in platinum levels. On the basis of our data and that from Lagrange et al. [27], who reported a significant reduction in platinum levels from dialysis initiated 7 days after an accidental overdose, dialysis is an appropriate treatment option for accidental overdose even if delayed beyond 3 h. The phenomenon of rebound in plasma platinum levels between dialysis sessions as seen in our patient has only been described in one other report [27]. This finding cannot be explained by analytical imprecision, as all our samples were analysed in a single batch, and is postulated to be due to the release of platinum from the tissues. In accidental overdose, repeated dialysis may therefore be necessary to maintain the reduction in serum platinum levels. The incidence and severity of cisplatin toxicity is known to be dose and schedule dependent. Our modelled data confirm that the incidence of grade 3e4 neurotoxicity is significantly correlated with the cumulative dose. There is also a significant correlation with the peak drug level at the end of treatment, which depends on both the dose given and the scheduling. This is in keeping with the finding by Cavaletti et al. [28], who reported that patients treated to an identical cumulative dose with 75 mg/m2 every 3 weeks had 38.6% incidence of neuropathy compared with 11e21% for patients treated with 50 mg/m2 weekly. Animal studies [29] have also shown that tissue platinum concentrations are related to the time interval between administrations as well as the total dose given. In contrast, we did not find a correlation between myelotoxicity and cumulative dose. It is known that cisplatin-induced myelosuppression usually manifests itself by day 18e23 [5] and we have assumed that any cisplatin delivered in the first 15 days of treatment would contribute to the myelotoxic effect. Our modelled data suggest that this peak level in the first 15 days of treatment is the most significant factor influencing the incidence of myelotoxicity in the published studies. The pharmacokinetic model we have used assumes that the main difference in drug metabolism between patients with normal renal function and patients on dialysis is the prolonged half-life. We have not allowed for the effects of the dialysis parameters, or the altered physiological parameters in patients on dialysis, such as low serum albumin
levels. Bearing in mind these limitations, the model suggests that a weekly cisplatin dose of 35 mg/m2 in a haemodialysis patient with a prolonged elimination half-life of 7.5 days would be expected to induce the same incidence of myelotoxicity as seen with 40 mg/m2 weekly in a patient with normal renal function. The prolonged elimination halflife is not predicted to have any significant effect on the incidence of severe neurotoxicity.
Conclusion We have shown that weekly cisplatin chemotherapy 25 mg/m2 with radiotherapy can be delivered with minimal toxicity in a haemodialysis patient. Mathematical modelling suggests that the cisplatin dose can be increased to 35 mg/m2 weekly with comparable myelotoxicity and neurotoxicity as 40 mg/m2 in a patient with normal renal function. Dialysis sessions should commence as soon as possible after cisplatin infusion as the incidence of myelotoxicity is related to the peak platinum level after infusion. Acknowledgements. The Royal College of Radiologists Clinical Oncology Research Fellowship is funding the salary of M. A. Zahra and the Gynaecological Cancer Fund, Addenbrooke’s Hospital funded the platinum analysis. Author for correspondence: L. T. Tan, Department of Oncology, Box 193, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, UK. Tel: þ44-1223-763337; Fax: þ44-1223-763120; E-mail: [email protected] Received 16 October 2006; received in revised form 14 September 2007; accepted 12 October 2007
References 1 Green JA, Kirwan JM, Tierney JF, et al. Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: a systematic review and meta-analysis. Lancet 2001;358:781e786. 2 Jones B, Dale RG. The potential for mathematical modelling in the assessment of the radiation dose equivalent of cytotoxic chemotherapy given concomitantly with radiotherapy. Br J Radiol 2005;78:939e944. 3 Grigsby PW. Cervical cancer: combined modality therapy. Cancer J 2001;7(Suppl 1):S47eS50. 4 Peters WA 3rd, Liu PY, Barrett RJ 2nd, et al. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 2000;18:1606e1613. 5 British Columbia Cancer Agency. Cancer drug manual. British Columbia Cancer Agency; 2006. 6 Go RS, Adjei AA. Review of the comparative pharmacology and clinical activity of cisplatin and carboplatin. J Clin Oncol 1999; 17:409e422. 7 Mollman JE. Cisplatin neurotoxicity. N Engl J Med 1990;322: 126e127. 8 Gorodetsky R, Vexler A, Bar-Khaim Y, Biran H. Plasma platinum elimination in a hemodialysis patient treated with cisplatin. Ther Drug Monit 1995;17:203e206.
CISPLATIN CHEMOTHERAPY AND RADIOTHERAPY IN A HAEMODIALYSIS PATIENT WITH CERVIX CANCER 9 Brivet F, Pavlovitch JM, Gouyette A, Cerrina ML, Tchernia G, Dormont J. Inefficiency of early prophylactic hemodialysis in cis-platinum overdose. Cancer Chemother Pharmacol 1986;18: 183e184. 10 Guidelines for cytotoxic chemotherapy in adults. A document for local expert groups in the United Kingdom preparing chemotherapy policy documents. Clin Oncol (R Coll Radiol) 2001;13:s209es248. 11 Hirai K, Ishiko O, Sumi T, Kanaoka Y, Ogita S. Kinetics of plasma platinum in a hemodialysis patient receiving repeated doses of cisplatin. Oncol Rep 2000;7:1243e1245. 12 Kurisu A, Hata T, Owada A. Full-dose chemotherapy for esophageal cancer patient under hemodialysis. Nephron 2002;92:960. 13 Watanabe R, Takiguchi Y, Moriya T, et al. Feasibility of combination chemotherapy with cisplatin and etoposide for haemodialysis patients with lung cancer. Br J Cancer 2003;88: 25e30. 14 Tomita M, Kurata H, Aoki Y, Tanaka K, Kazama JJ. Pharmacokinetics of paclitaxel and cisplatin in a hemodialysis patient with recurrent ovarian cancer. Anticancer Drugs 2001;12: 485e487. 15 Tanabe N, Goto M, Morita H, et al. Pharmacokinetics of cisdiammine-dichlor-platin in a hemodialysis patient. Cancer Invest 1991;9:629e635. 16 Ribrag V, Droz JP, Morizet J, Leclercq B, Gouyette A, Chabot GG. Test dose-guided administration of cisplatin in an anephric patient: a case report. Ann Oncol 1993;4:679e682. 17 Greenblatt DJ. Elimination half-life of drugs: value and limitations. Annu Rev Med 1985;36:421e427. 18 Tan LT, Russell S, Burgess L. Acute toxicity of chemoradiotherapy for cervical cancer: the Addenbrooke’s experience. Clin Oncol (R Coll Radiol) 2004;16:255e260. 19 Petrioli R, Frediani B, Manganelli A, et al. Comparison between a cisplatin-containing regimen and a carboplatin-containing regimen for recurrent or metastatic bladder cancer patients. A randomized phase II study. Cancer 1996;77:344e351.
11
20 van der Burg ME, de Wit R, van Putten WL, et al. Weekly cisplatin and daily oral etoposide is highly effective in platinum pretreated ovarian cancer. Br J Cancer 2002;86:19e25. 21 Legha SS, Dimery IW. High-dose cisplatin administration without hypertonic saline: observation of disabling neurotoxicity. J Clin Oncol 1985;3:1373e1378. 22 de Jongh FE, van Veen RN, Veltman SJ, et al. Weekly high-dose cisplatin is a feasible treatment option: analysis on prognostic factors for toxicity in 400 patients. Br J Cancer 2003;88: 1199e1206. 23 Nichols CR, Williams SD, Loehrer PJ, et al. Randomized study of cisplatin dose intensity in poor-risk germ cell tumors: a Southeastern Cancer Study Group and Southwest Oncology Group protocol. J Clin Oncol 1991;9:1163e1172. 24 Gandara DR, DeGregorio MW, Wold H, et al. High-dose cisplatin in hypertonic saline: reduced toxicity of a modified dose schedule and correlation with plasma pharmacokinetics. A Northern California Oncology Group Pilot Study in nonsmall-cell lung cancer. J Clin Oncol 1986;4:1787e1793. 25 Muggia FM, Braly PS, Brady MF, et al. Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a gynecologic oncology group study. J Clin Oncol 2000;18:106e115. 26 Benedetti Panici P, Greggi S, Scambia G, et al. Efficacy and toxicity of very high-dose cisplatin in advanced ovarian carcinoma: 4-year survival analysis and neurological followup. Int J Gynecol Cancer 1993;3:44e53. 27 Lagrange JL, Cassuto-Viguier E, Barbe V, et al. Cytotoxic effects of long-term circulating ultrafiltratable platinum species and limited efficacy of haemodialysis in clearing them. Eur J Cancer 1994;30A:2057e2060. 28 Cavaletti G, Marzorati L, Bogliun G, et al. Cisplatin-induced peripheral neurotoxicity is dependent on total-dose intensity and single-dose intensity. Cancer 1992;69:203e207. 29 Cavaletti G, Tredici G, Pizzini G, Minoia A. Tissue platinum concentrations and cisplatin schedules. Lancet 1990;336:1003.