Int J Clin Oncol (2010) 15:82–87 DOI 10.1007/s10147-009-0015-3
ORIGINAL ARTICLE
Effect of calcium and magnesium on neurotoxicity and blood platinum concentrations in patients receiving mFOLFOX6 therapy: a prospective randomized study Keiichiro Ishibashi • Norimichi Okada Tatsuya Miyazaki • Motohiko Sano • Hideyuki Ishida
•
Received: 10 April 2009 / Accepted: 28 September 2009 / Published online: 29 January 2010 Ó Japan Society of Clinical Oncology 2010
Abstract Background Whether the administration of calcium (Ca) and magnesium (Mg) can reduce oxaliplatin-related neurotoxicity remains controversial. In addition, little is known about the effects of Ca/Mg on the blood level of platinum or objective tumor progression. Patients and methods Patients receiving modified FOLFOX6 for metastatic colorectal cancer were double-blinded and randomized to receive additional treatment with Ca/Mg or placebo before and after the administration of oxaliplatin. The plasma and ultrafiltrable concentrations of platinum during the first and fifth cycles of treatment were determined using inductively coupled plasma spectrometry. Results Patients were randomized to receive Ca/Mg (Ca/Mg group, n = 17) or placebo (placebo group, n = 16) before and after the administration of oxaliplatin (85 mg/ m2). The incidence of neurotoxicity after six cycles was not significantly different between the two groups. Blood concentrations of platinum at each time and the area under the curve were also not significantly different between the two groups. Furthermore, the response rate (RR) and disease control rate (DCR) did not differ significantly between K. Ishibashi (&) N. Okada T. Miyazaki H. Ishida Department of Gastrointestinal and General Surgery, Saitama Medical Center, Saitama Medical University, 1981 Kamoda-Zujidocho, Kawagoe, Saitama 350-8550, Japan e-mail:
[email protected] M. Sano Department of Pharmaceutical Services, Saitama Medical Center, Saitama Medical University, 1981 Kamoda-Zujidocho, Kawagoe, Saitama 350-8550, Japan
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the two groups (Ca/Mg group: RR 36%, DCR 73%. Placebo group: RR 40%, DCR 70%, P [ 0.99). The median progression-free survival time was 9.2 months in the Ca/ Mg group and 8.1 months in the control group; these survival times were not significantly different (P = 0.56). Conclusion These data are insufficient to conclude with any certainty that the administration of Ca/Mg is not neuroprotective; however, the administration of Ca/Mg may not have any influence on antitumor activity and the blood concentration profile of platinum in patients receiving oxaliplatin-based chemotherapy. Keywords Calcium gluconate Magnesium sulfate Neurotoxicity Oxaliplatin Platinum
Introduction FOLFOX therapy [the administration of a combination of oxaliplatin, 5-fluorouracil (5-FU), and l-leucovorin (l-LV)] is a standard treatment for unresectable advanced colorectal cancer [1–3]. Nevertheless, the continuation of FOLFOX therapy is reportedly difficult because of the development of neurotoxicity, which is a dose-limiting toxicity of oxaliplatin [4]. Although the mechanism underlying peripheral neuropathy is still unclear, Gamelin et al. [5] performed a retrospective study that revealed a decrease in neuropathy among patients who had received an infusion of calcium gluconate (Ca) and magnesium sulfate (Mg). Ca/Mg infusion was suggested to decrease antitumor activity [6]. In Western countries, large-scale clinical studies, including the NEUROXA study [7] and the Combined Oxaliplatin Neuropathy Prevention Trial (CONCEPT) study [8], have been performed to evaluate the usefulness and safety of Ca/Mg infusion. Nonetheless,
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the influence of the Ca/Mg infusion on the blood platinum concentration during oxaliplatin administration has not been reported. We performed a prospective, randomized, double-blind controlled trial in patients receiving modified FOLFOX6 (mFOLFOX6) therapy to determine whether the infusion of Ca/Mg was effective against oxaliplatin-related neurotoxicity and whether it influenced the antitumor activity of this regimen.
and after the administration of oxaliplatin, or to the control group, which received a placebo infusion (100 mL of 5% glucose alone) before and after the administration of oxaliplatin. Patients were randomly assigned to either the Ca/ Mg group or the control group in a double-blinded fashion, using centralized allocation via a random-number randomization system. Adverse events were evaluated before the start of administration according to the National Cancer Institute’s Common Toxicity Criteria (NCI-CTC) version 3.0 [10].
Patients and methods
Criteria for delay/discontinuation and resumption of chemotherapy
Eligibility All of the subjects had histologically confirmed colorectal cancer and either had unresectable metastases or had already undergone resections for metastatic lesions. The bone marrow, liver, and kidney functions of all of the patients were normal, and in each case their World Health Organization (WHO) performance status was 0–2. The patients ranged in age from 18 to 75 years, and none of them had multiple cancers or a history of radiotherapy. This study was approved by the institutional review board of the Saitama Medical Center, Saitama Medical University; written consent was obtained from each patient. Treatment and randomization According to the mFOLFOX6 treatment schedule, a 5hydroxytryptamine-3 (5-HT3)-receptor antagonist (KytrilÒ, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan) was administered prior to the start of treatment. Subsequently, 200 mL of 5% glucose containing l-LV (IsovorinÒ, Wyeth K.K., Tokyo, Japan) (200 mg/m2) and oxaliplatin (ElplatÒ, Yakult Honsha Co., Ltd., Tokyo, Japan) (85 mg/m2) were administered by intravenous infusion over 2 h, followed by the rapid intravenous infusion of 5-FU (5FUÒ, Kyowa Hakko Kirin Co., Ltd., Tokyo, Japan) (400 mg/m2) and then the slow infusion of 5-FU (2400 mg/m2) over 46 h. This regimen was repeated every 2 weeks. In the patients with unresectable cancer, treatment was continued until tumor progression [9] or unacceptable toxicity, or until surgery was performed because the metastatic disease had become resectable. When mFOLFOX6 was performed as an adjuvant therapy after the resection of metastases, it was discontinued if no new lesions were detected after six cycles of treatment. Patients were randomly assigned to either the Ca/Mg group, which received 100 mL of 5% glucose containing calcium gluconate of 850 mg (CalcicolÒ, 10 mL; Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan) and magnesium sulfate of 720 mg (Conclyte MgÒ, 10 mL; Nipro Pharm Co., Ltd., Osaka, Japan) before
Treatment was delayed or discontinued in patients with grade 3 or 4 hematological toxicity or neurotoxicity and in patients with grade 2 or worse nonhematological toxicity other than neurotoxicity. Chemotherapy was resumed once the hematological toxicity or neurotoxicity had decreased to Bgrade 2 or once the nonhematological toxicity other than neurotoxicity had decreased to Bgrade 1. When chemotherapy was resumed, the doses of each drug were reduced to 70% of the previous dose level. Endpoints The primary endpoint of the study was the incidence and severity of neurotoxicity. The secondary endpoints were antitumor activity, progression-free survival, and the plasma levels of platinum. Evaluation of neurotoxicity The development and severity of neurotoxicity were evaluated during each cycle of therapy according to the NCICTC criteria [10] and the Debiopharm Neurotoxicity Scale (DEB-NTS) criteria [11]. The severity of the neurotoxicity was evaluated by nurses and pharmacists in the outpatient chemotherapy center. Evaluation of treatment outcome In patients with evaluable lesions, the effect of mFOLFOX6 therapy was evaluated according to the RECIST criteria [9] and was compared between the Ca/Mg and control groups. Progression-free survival was also compared between the two groups. Platinum concentration To measure the plasma platinum level, blood samples were collected at 5 min, 1 and 3 h, and 2 weeks after oxaliplatin administration during the first cycle, as well as before
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oxaliplatin administration and at 5 min, 1 h, and 2 weeks after oxaliplatin administration during the fifth cycle. Approximately 10 mL of blood was collected at each time point and the samples were centrifuged at 10009g for 10 min at 4°C. The plasma was then collected from the upper layer and used as the plasma sample, while the residual plasma was centrifuged through a filter (Amicon CentrifreeTM; Millipore Co., Bedford, MA, USA) at 10009g for 30 min at 4°C to provide a plasma ultrafiltrate sample. All samples were stored at -70°C until subsequent analysis using inductively coupled plasma mass spectrometry (ICP-MS) [12]. At each analysis point during the first and fifth cycles, the platinum concentration was compared with each sample of plasma and the ultrafiltrate. The area under the blood concentration–time curve (AUC) was measured for the platinum concentrations in the ultrafiltrate during the first cycle and was compared between the Ca/Mg treatment and control groups, as well as between the two groups stratified according to grade 2 neurotoxicity (DEB-NTS) [11] after the completion of the sixth cycle and between the two groups stratified according to tumor response.
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mean ± standard deviation (SD). To compare discrete variables, either the chi-square test or the Fisher exact probability test was used. To compare continuous variables, the Mann–Whitney test was used. The progression-free survival curves were generated using the Kaplan–Meier method, and the differences in the curves were compared using a log-rank test. A P value of less than 0.05 was considered significant.
Results Patient characteristics and treatment
The incidence of Cgrade 2 (DEB-NTS) [11] neurotoxicity after six cycles of mFOLFOX6 therapy was 20% in the Ca/ Mg group and 50% in the control group in a retrospective study conducted between April 2005 and September 2006 at our institute. In a study that investigated the neurotoxicities of various agents, including oxaliplatin, the incidence of Cgrade 2 (NCI-CTC) [10] neurotoxicity was 5% in the Ca/Mg group and 54% in the control group when the mean total dose of oxaliplatin was 500–550 mg/m2 (equivalent to six cycles at an oxaliplatin dose of 85 mg/ m2) [5]. The number of patients per group required to reproduce these results was calculated using a type I error (a) of 0.05, a type II error (b) of 0.2, and a control-totreated data number ratio of 1:1. As a result, the numbers of patients required to reproduce the results of our previous study and those of Gamelin et al. [5] were found to be 31 and 8, respectively. Therefore, the number of subjects for this study was set at 35 per group to allow for a 10% dropout rate.
Thirty-three patients who started mFOLFOX6 therapy between October 2006 and September 2007 were enrolled in the present study. According to the interim report of the CONCEPT study [7], published in September 2007, the results of the treatment were poorer in the Ca/Mg group than in the control group, so the subsequent enrollment of patients was discontinued. As a result, 17 patients from the Ca/Mg group and 16 patients from the control group were included in the present analysis. In the Ca/Mg group, three patients received adjuvant chemotherapy and 14 patients were treated for unresectable/recurrent colorectal cancer (first-line therapy in 12 patients, second-line therapy in one patient, and third-line therapy in one patient). In the control group, one patient received adjuvant chemotherapy and 15 patients were treated for unresectable/recurrent colorectal cancer (first-line therapy in all 15 patients). In the one patient who underwent mFOLFOX6 as a second-line therapy, tegafururacil (UFTÒ, Taiho Pharmaceutical Co., Ltd., Tokyo, Japan) and calcium folinate (LeucovorinÒ, Wyeth K.K., Tokyo, Japan) had been administered as the first-line therapy. In the one patient who underwent mFOLFOX6 as a third-line therapy, tegafur-uracil and calcium folinate had been administered as the first-line chemotherapy and tegafur, gimeracil, and oteracil potassium (TS-1Ò, Taiho Pharmaceutical Co., Ltd., Tokyo, Japan) had been administered as the second-line therapy. No differences in age (P = 0.80), sex (P = 0.73), the number of mFOLFOX6 cycles (P = 0.90), the relative dose intensity (P = 0.27), or the number of metastatic organs (P = 0.38) were observed between the two groups (Table 1).
Statistics
Neurotoxicity
The data analysis and the calculation of the sample size was performed using the statistical software packages SPSS version 7.5 (SPSS Inc., Chicago, IL, USA) and Fisher for Windows (Nakayama-shoten, Tokyo, Japan) on a Windows personal computer, respectively. The results were expressed as the median and range or
According to the DEB-NTS criteria [11], the incidences of Cgrade 1, 2, and 3 neurotoxicity after the completion of the sixth cycle were 100, 71, and 6% in the Ca/Mg group, respectively, and 94, 56, and 0% in the control group, respectively. No significant differences in these incidences were observed between the two groups (grade 1: P = 0.48,
Sample size
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Table 1 Patient characteristics
Age (years)a
Ca/Mg (n = 17)
Control (n = 16)
P value
63 (32–74)
64 (35–73)
0.80 0.73
Male:female
9:8
7:9
Cycles of mFOLFOX6a
9 (5–16)
10 (4–20)
0.90
Relative dose intensitya
75.0 (54.5– 100)
72.8 (38– 93.3)
0.27
Chemotherapy for unresectable lesions
14
15
1st line
12
15
2nd line
1
0
3rd line
1
0
Adjuvant chemotherapy
3
1
Single
7
8
Two
7
6
Three
0
1
Fig. 1 Progression-free survival
Number of metastatic organs
Target lesions Liver
a
6
8
Lung
3
1
Peritoneum
5
9
Lymph node
3
3
Local
3
1
0.38
Median (range)
patients from the Ca/Mg group and 12 patients from the control group had measurable lesions that could be evaluated to assess the efficacy of treatment according to the RECIST criteria [9]. In the Ca/Mg group, partial response (PR), stable disease (SD), and progressive disease (PD) were noted in four patients (33%) each. In the control group, a complete response (CR), PR, SD, and PD were noted in one patient (8%), four patients (33%), three patients (25%), and four patients (33%), respectively. Neither the response rates (RRs) (P [ 0.99) nor the disease control rates (P [ 0.99) of the two groups were significantly different. The median progression-free survival time was 9.2 months in the Ca/Mg group (n = 12) and 8.1 months in the control group (n = 12); these survival times were not significantly different (P = 0.56) (Fig. 1).
Table 2 Neurotoxicity after six cycles of mFOLFOX6 Ca/Mg (n = 17)
Placebo (n = 16)
P value
CGrade 1
17 (100%)
15 (94%)
CGrade 2
12 (71%)
9 (56%)
CGrade 3
1 (6%)
0 (0%)
CGrade 1
17 (100%)
15 (94%)
CGrade 2
1 (6%)
1 (6%)
[0.99
CGrade 3
1 (6%)
0 (0%)
[0.99
DEB-NTS 0.48 0.48 [0.99
NCI-CTC 0.48
grade 2: P = 0.48, grade 3: P [ 0.99) (Table 2). According to the NCI-CTC criteria [10], the incidences of Cgrade 1, 2, and 3 neurotoxicity were 100, 6, and 6% in the Ca/Mg group, respectively, and 94, 6, and 0% in the control group, respectively. Again, no significant differences in these incidences were observed between the two groups (grade 1: P = 0.48, grade 2: P [ 0.99, grade 3: P [ 0.99) (Table 2). Efficacy of treatment Among the 27 patients who received first-line mFOLFOX6 therapy for the treatment of unresectable tumors, 12
Platinum concentration Although the plasma platinum concentration during the first cycle tended to be higher in the control group at 3 h after oxaliplatin administration (P = 0.06), the plasma platinum concentration was not significantly different between the two groups at any other time point (Fig. 2a). The plasma ultrafiltrate concentration of platinum during the first cycle also was not significantly different between the two groups at any time point (Fig. 2b). The plasma platinum concentration during the fifth cycle was not significantly different between the two groups at any time point (Fig. 3a). The plasma ultrafiltrate concentration of platinum during the fifth cycle also was not significantly different between the two groups at any time point (Fig. 3b). A comparison of the AUCs for the plasma ultrafiltrate during the first cycle showed no significant difference between the Ca/Mg group (27.6 ± 13.6 lg h/mL) and the control group (27.0 ± 18.2 lg h/mL) (P = 0.92). When the AUC of platinum in the plasma ultrafiltrate during the first cycle was compared with respect to the presence of grade 2 neurotoxicity (DEB-NTS) [11] after the completion of the sixth cycle, no significant difference was
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Fig. 2 a Plasma concentration of platinum during the first cycle; b plasma ultrafiltrate concentration of platinum during the first cycle
observed between the patients with grade 2 or greater neurotoxicity (27.6 ± 17.7 lg h/mL) and those without neurotoxicity (27.0 ± 13.8 lg h/mL) (P = 0.85). When the AUC was compared with respect to the response to treatment, the values were 25.5 ± 5.3 and 25.8 ± 16.3 lg h/mL for the patients with CR/PR and those with SD/PD, respectively; these values were not significantly different (P = 0.73).
Discussion The present study was terminated prior to the completion of enrollment because an interim analysis of the CONCEPT study reported that treatment with Ca/Mg decreased antitumor activity [6]. In the present study, Ca/Mg infusion was not shown to be useful for reducing the neurotoxicity of FOLFOX therapy, but it had no adverse influence on the antitumor activity of this therapy. The final results of the CONCEPT study have recently been reported in the American Society of Clinical Oncology (ASCO) [8]. Contrary to the results of the interim report, the final report
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concluded that the effect of FOLFOX ? bevacizumab therapy was not influenced by Ca/Mg infusion. Nikcevich et al. [13] performed a randomized controlled trial that investigated the effect of Ca/Mg on neurotoxicity in stage II or III colon cancer patients receiving FOLFOX as adjuvant chemotherapy. Similar to the present study, their study was also discontinued after the release of the interim results of the CONCEPT study [6]. However, they reported that Ca/Mg significantly alleviated Cgrade 2 neurotoxicity (NCI-CTC) [10]. Gamelin et al. [7] published an interim report describing a randomized controlled study of FOLFOX ? bevacizumab with or without Ca/Mg that was performed by the French Oncology Research Group (GERCOR). According to their report, no differences in the objective RR, progression-free survival, or overall survival were observed between the Ca/Mg-treated group and the untreated group, while the incidence of neurotoxicity was significantly lower in the Ca/Mg-treated group. Reports have also been published concerning the alleviation of neurotoxicity by methods other than Ca/Mg infusion. A stop-and-go strategy study [14] and the CONCEPT study [8] both showed that the temporary withdrawal of oxaliplatin was useful for alleviating neurotoxicity. Furthermore, the development of neurotoxicity was reportedly decreased by prolonging the duration of oxaliplatin administration. Petriori et al. [15] suggested that a longer duration of administration would reduce the peak plasma concentration of platinum, resulting in a decrease in neurotoxicity. Several reports have been published concerning the profiles of the plasma and plasma ultrafiltrate concentrations of platinum after oxaliplatin administration [16, 17]. However, to our knowledge, only the present study has investigated the relation between the platinum concentration or the AUC and the response to treatment or the onset of peripheral neuropathy. The results of the present study indicated that the plasma concentration of platinum was not related to the efficacy of treatment or the occurrence of peripheral neuropathy. There may be an argument that the sample size of this study is too small to clarify any clinical significance of administrating Ca/Mg. We calculated the sample size based on two different studies evaluating the incidence of Cgrade 2 (DEB-NTS [11] and NCI-CTC [10]). Subsequently, the number of enrolled patients per group (n = 17 for Ca/Mg group, n = 16 for control group) exceeded the number (n = 8, per group) required to reproduce the results reported by Gamelin and associates [5]. However, because of the discontinuance of the study, the number of enrolled patients did not reach the required number (n = 31, per group) calculated based on our previous study. Therefore, we cannot conclude with any certainly that administration of Ca/Mg is not neuroprotective in
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Fig. 3 a Plasma concentration of platinum during the fifth cycle; b plasma ultrafiltrate concentration of platinum during the fifth cycle
patients receiving oxaliplatin-based chemotherapy. Nevertheless, the present study suggests that the administration of Ca/Mg may not have any influence on antitumor activity or the blood concentration profile of platinum in patients receiving oxaliplatin-based chemotherapy. Conflict of interest statement interest.
No author has any conflict of
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