Routine administration of a single dose of cisplatin ≥ 75 mg/m ² after short hydration in an outpatient lung-cancer clinic

ARTICLE

bdc.2012.1555

Auteur(s) : Armelle Lavolé¹ armelle.lavole@tnn.aphp.fr, Sophie Danel¹, Laurence Baudrin², Valérie Gounant¹, Anne-Marie Ruppert¹, Christelle Epaud¹, Laure Belmont¹, Lise Rosencher¹, Jacques Cadranel¹, Bernard Milleron²

¹ Hôpital Tenon, AP-HP, département de pneumologie et réanimation respiratoire, unité fonctionnelle d’oncologie thoracique, 4, rue de la Chine, 75970 Paris, France

² Unité de biostatistiques, intergroupe francophone d’oncologie thoracique, 10, rue de la Grange-Batelière, 75009 Paris, France

Reprint: A. Lavolé

Introduction

A cisplatin-based combination therapy is currently considered the most active treatment option for several types of solid tumors, including lung cancer. In phase III trials, the association of cisplatin with one of the third-generation agents (paclitaxel, docetaxel, gemcitabine, vinorelbine, or pemetrexed [restricted to non-squamous histologies for the latter]) has demonstrated efficacy in patients with locally advanced and metastatic non-small-cell lung cancer (NSCLC) [1-4]. Moreover, cisplatin-based chemotherapy also significantly increased overall survival rates of patients with completely resected NSCLC [5-7]. Thus, a large proportion of patients with NSCLC are being treated with cisplatin-based chemotherapy. When cisplatin was first approved for commercial use in 1978, major causes of toxicity included severe nausea and vomiting and a high incidence of renal dysfunction. These adverse effects were reduced by the use of 5HT3-receptor antagonists and hydration [8].

Most instructions concerning hydration recommend the use of a pre-treatment regimen with 1 to 2 L of fluid infused for 8 to 12 h, with the drug diluted in 2 L of 5% dextrose, in half or one third normal saline containing 37.5 g of mannitol, and infused over a 6- to 8-h period (US Food, BC Cancer Agency). It is also recommended that hydration and control of diuresis are maintained during the following 24 h, eventually with a diuretic. Nevertheless, no consistent data exist concerning the specific protective effect of either mannitol or furosemide, or the duration of hydration [8, 9]. Ambulatory oncological care has been widely developed to reduce time spent in the hospital unit, one of the most important concerns for cancer patients [10, 11]. In addition, the safety of cisplatin administration to outpatients has been queried. Moreover, conventional cisplatin administration usually requires complete hospitalization in most countries. Therefore, we carried out retrospective evaluation of the safety and tolerance of treating outpatients with cisplatin between 2001 and 2007. Nephrotoxicity was considered in this report as the primary criterion for safety analysis, and the toxicity scale of NCI was based on creatinine level, as this is used in all therapeutic trials and reflects our daily oncological routine.

Patients and methods

Selection of patients

Patients eligible for the retrospective study (between January 2001 and May 2007) had NSCLC or small-cell lung cancer (SCLC) and were treated at the outpatient clinic of Tenon University Hospital with a chemotherapy regimen that included cisplatin ≥ 75 mg/m² with a pre-planned short hydration protocol delivered intravenously in 2 h. Patients who were consecutively treated with fractionated cisplatin ≥ 75 mg/m² were excluded. Study parameters included age, gender, and weight before and after each course of treatment, performance status (PS) according to the Eastern Cooperative Oncology Group (ECOG) scale, typing of tumor histology, stage of disease, co-morbidity (high blood pressure, cardiac insufficiency and coronary disease, diabetes, and hypercholesterolemia) and associated treatments (diuretics, angiotensin-converting enzymes [ACE] or both).

Nephrotoxicity was defined as ≥ grade 1 according to National Cancer Institute (NCI) common toxicity criteria. Creatininemia was measured every week and the nadir was used for evaluation of the nephrotoxicity. Rate of creatinine clearance (ΔCC) was defined as the difference between the initial calculated CC and the minimal CC recorded up to completion of the last course with cisplatin. CC was calculated using the Cockcroft and Gault formula.

Cisplatin administration

Starting at 8 a.m., patients were prehydrated with 2 L of G5%, with 4 g/L NaCl, 2 g/L KCl, 1 g/L MgCl₂, and 1 g/L CaCl₂, without control of diuresis. Cisplatin was infused in 250 mL of saline solution at 1 mg/min. Neither mannitol nor diuretics were administered. Patients were able to return home at 3 p.m. The duration at the outpatient clinic was at least 6 h. Patients were advised to drink large quantities of liquids during the days following chemotherapy.

Statistical analyses

All quantitative variables of the study were converted into categorical variables using the median as the cut-off point. Proportions were compared by the Chi² test or Fisher's exact test, as appropriate. A backward logistic regression was performed to assess the relationship between the patients’ demography, disease characteristics, cisplatin dose, and nephrotoxicity. The fit of the logistic regression was assessed by the Hosmer and Lemeshow goodness-of-fit test. A good fit to the data was indicated by non-significance of the test. A P-level < 0.05 was considered significant. All analyses were carried out using SAS software version 9.1 (SAS Institute Inc., Cary, NC, USA).

Results

Patients

The data from 357 consecutive patients with NSCLC or SCLC were analyzed. The patients’ characteristics are shown in table 1. Among the 357 patients, 250 were men. The median age was 58 years (range: 25-81 years) and 7% were aged > 70 years. The ECOG PS was 0 in 80% of cases, 1 in 19% of cases, and 2 in 1% of cases. The subtype histology was NSCLC in 340 patients (adenocarcinoma: 47%, squamous cell: 27%, large cell: 10%, and others: 16%), and SCLC in 17 patients. For NSCLC, disease stage was I-II in 20% and III-IV in 80% of cases. For SCLC, the disease was localized in 45% and was disseminated in 55%. Co-morbidities (one or more) were noted in 95 patients (26.5%). Arterial hypertension was the most frequently noted risk factor for nephrotoxicity (n = 88), followed by diabetes (n = 30), obesity (n = 6), hypercholesterolemia (n = 20), and heart disease (n = 8). Forty-one patients (11.5%) had concurrent medication therapy (diuretics and/or ACE inhibitors).

Table 1 Patients’ characteristics.

SCLC: small cell lung cancer; NSCLC: non-small cell lung cancer; ACE: angiotensin-converting enzymes; PS: performance status.

Treatment

On average, 3.6 chemotherapy cycles (range: 1-6) were administered to each patient. The median total cumulative dose of cisplatin received at the outpatient clinic was 282 mg/m² (range: 80-600). Cisplatin was combined with gemcitabine in 275 patients, with vinorelbine in 34 patients, with docetaxel in 25 patients, and with etoposide in 23 patients. All patients received the same hydration regimen, which was well tolerated, with no episodes of edema or heart failure. Grades 3 and 4 hematologic toxicities occurred in 49.5% of patients, and grade 3 or 4 digestive toxicity occurred in 18.5% of patients.

Renal function

Nephrotoxicity grade 1 or more according to NCIC common toxicity criteria

Twenty-one out of 357 patients (6%) experienced nephrotoxicity ≥ grade 1 according to the NCIC (table 2). Grade 1 (1 N ≤ SC < 1.5 N) was noted in most cases (95%). Grade 3 was noted in only one patient (5%). Grade 1 nephrotoxicity was observed after the first cycle in one patient, after the second cycle in two patients, after the fifth cycle in five patients, and after the sixth cycle in 12 patients, whereas grade 3 nephrotoxicity was observed after the third cycle in one patient. Among the 20 patients with grade 1 nephrotoxicity, 12 returned to grade 0 after completing treatment (median of 141 days, range: 31-448). The grade 3 nephrotoxicity observed in one patient, spontaneously improved to grade 2 by 2 months after completing treatment with cisplatin.

Table 2 Nephrotoxicity grade ≥ 1 according to NCIC criteria for common toxicity.

SC: serum creatinine.

Rate of creatinine clearance during cisplatin treatment

Among the group without nephrotoxicity and ≥ grade 1 according to the NCIC (n = 336), mean initial CC before starting chemotherapy was 92 mL/min (range: 41-216).

Mean ΔCC was 10 mL/min (range: -57 to 95). ΔCC was negative or stable in 73 patients (22%), slightly elevated (0 < ΔCC ≤ 10) in 118 patients (36%), moderately elevated (10 < ΔCC ≤ 20) in 70 patients (21%). ΔCC of > 20 mL/min was noted in 68 patients (20.5%).

Among the group with nephrotoxicity that was ≥ grade 1 according to the NCIC (n = 21), mean initial CC before starting chemotherapy was 80 mL/min (range: 54-143).

Mean ΔCC was 18.5 mL/min (range: 3-76). ΔCC was slightly elevated (0 < ΔCC ≤ 10) in two patients (9.5%), and moderately elevated (10 < ΔCC ≤ 20) in 10 patients (21%). ΔCC > 20 mL/min was noted in nine patients (41%).

Factors predictive for nephrotoxicity ≥ grade 1 according to NCIC

In univariate analysis, co-morbidity, histological subtype, initial SC, cisplatin dose by cycle, and cumulative cisplatin dose were associated with nephrotoxicity ≥ grade 1 according to NCIC common toxicity (tables 3 and 4). Age, gender, treatment, stage of disease, PS, initial CC, hematological or digestive toxicity, and number of cycles, were not predictive of nephrotoxicity (table 3). Associated co-morbidity (OR = 4.97 CI 95% [1.8-13.7] P = 0.0020), initial SC ≥ 100 μmol/L (OR = 8.3 CI 95% [2.55-27.4] P = 0.0005) and dose and first-cycle cisplatin dose 100 mg/m² (OR = 10.8 CI 95% [3.6-32.5]) were the only independent factors predictive for nephrotoxicity (table 4).

Table 3 Factors predictive for nephrotoxicity grade ≥ 1 (univariate analysis).

* SC: serum creatinine value (μmol/L) before initiating CDDP (mL/min); ** CC: creatinine clearance value before initiating CDDP; C1: first cycle.

Table 4 Factors predictive for nephrotoxicity grade ≥ 1 (multivariate analysis).

Hosmer and Lemeshow goodness-of-fit test: P = 0.776.

Discussion

Among the 357 patients evaluated in this study, only 21 (6%) had nephrotoxicity grade ≥ 1 according to NCIC criteria. Among these 21 patients, toxicity was minor (grade 1, 1N < SC ≤ 1.5N) in 20 patients (95% of cases). Moreover, nephrotoxicity returned to grade 0 after completion of treatment in 12 patients out of 20 (data not shown). Only one patient had nephrotoxicity grade 3, which returned to grade 2 after completion of treatment. We selected the NCIC criteria as the definition for nephrotoxicity because these are used in all phase III therapeutics trials and are a simple test. However, although ΔCC is probably more specific, interestingly, mean ΔCC was only 10 mL/min in 96% of all patients.

Instructions concerning most commercially available cisplatin formulas recommend the use of a pretreatment hydration regimen, with 1 or 2 L of fluid infused for 8 or 12 h and maintained during the following 24 h; however, few data are available on the optimal volume and duration of fluid intake, and practices are heterogeneous [12]. In a retrospective study of 425 patients, those receiving a high volume of hydration did not have less nephrotoxicity [13]. Moreover, the hydration volume was not correlated with reduced kidney-cortex platinum concentrations upon human autopsies [14]. A few studies have suggested the possibility of an outpatient short hydration regimen for intermediate-to-high dose (≥ 75 mg/m²) cisplatin-based chemotherapy [15, 16]. Brock and Alberts noted nephrotoxicity in only five patients out of 147 (3.6%) cancer patients [16]. In the second study, nephrotoxicity of grade ≥ 1 according to NCIC criteria was observed in only five patients out of 107 [15]. No prospective study exists that compares ambulatory with conventional hospital administration for cisplatin therapy. However, several phase III studies have been carried out concerning the renal toxicity of cisplatin during conventional hospitalization, according to the NCI scale. Nephrotoxicity of grade ≥ 1 was observed in 5-38% of cases in those studies [1, 17, 18].

Although controlled prospective clinical trials are lacking, available data indicate that the frequency and severity of cisplatin nephrotoxicity may be reduced by slow infusion rates (1 mg/min). Moreover, cisplatin should be infused with physiological serum as the chloride-containing vehicle, such as 0.9% sodium chloride, which may prevent aquation or hydroxylation of cisplatin and reduce its toxicity [19]. We did not use diuretics or mannitol because they may increase cisplatin nephrotoxicity [9, 12].

In contrast, magnesium (Mg) depletion is a known side effect of cisplatin treatment [20, 21] and one study indicated a substantial additive effect of Mg depletion on cisplatin-induced renal toxicity [22]. All patients in our unit received Mg supplementation during treatment. Finally, novel anti-emetic agents, such as the antagonist aprepitant, have improved prevention of chemotherapy-induced nausea and vomiting, thus decreasing the risk of dehydration and reducing the nephrotoxicity of cisplatin. In a retrospective study, the use of ondansetron reduced the incidence of nephrotoxicity with cisplatin [23].

We found three independent factors predictive for nephrotoxicity. The first was cisplatin at a dose ≥ 100 mg/m² during the first cycle (HR = 9.5, CI = 3.2-28). Acute cisplatin nephrotoxicity is considered dose-dependent [24, 25]. Some authors observed more nephrotoxicity with a cisplatin dose of 100 mg/m² than with a dose of 75 or 80 mg/m² [1, 17]. Various studies have demonstrated that cisplatin-induced nephrotoxicity is related to peak plasma concentration and/or the area under the plasma concentration (the time curve of non-protein-bound cisplatin) [26-28].

The second independent factor predictive of cisplatin nephrotoxicity in our study was the association with co-morbidity (diabetes, arterial hypertension, heart disease). To our knowledge, this has not been previously reported in the literature. In a retrospective study (n = 425 patients), a history of diabetes, hypertension, or atherosclerosis was not associated with increased cisplatin nephrotoxicity [13]. Medication-associated administration (diuretics or ECA) was linked to nephrotoxicity only in univariate analysis. In a retrospective study (n = 62 patients), medication (albeturol, atenolol, hydrochlorothiazide, and multivitamins) was associated with an increased incidence of nephrotoxicity, but co-morbidity was not studied because of the small number of subjects with co-existing illness [23].

The third factor predictive of cisplatin nephrotoxicity was an initial creatininemia level of > 100 μmol/L; however, this has been poorly described in the literature.

An age of > 70 years did not affect nephrotoxicity in our study. However, cisplatin use in elderly patients remains controversial as physiological renal function is known to gradually decrease with age, with diminished glomerular-filtration rate, renal flow, and tubular function. Thyss et al. studied a series of 35 patients aged > 80 years treated with 60-100 mg/m² of cisplatin. Renal function remained stable or slightly deteriorated in 91% of these patients [29]. Cubillo et al. [30] and Lichtman et al. [31] studied 49 and 34 patients, respectively, who were > 70 years old and were treated with cisplatin. They concluded that their cisplatin toxicity profiles were “acceptable”.

In conclusion, brief cisplatin hydration enabled unfractionated administration at doses ranging from 75-100 mg/m² in an outpatient setting: treatment was entirely feasible and had minimal risk for the patient. Such an approach to patient management is likely to both decrease the cost of medical care [32] and improve the quality of life of cancer patients. A prospective study that seeks to validate this hypothesis is presently in progress at our unit.

Conflict of interest: none.

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