1 Department of Medicine, Institut Gustave-Roussy, Villejuif; 2 Pharmacokinetic Unit, Centre René-Huguenin, St-Cloud; 3 Lilly France, Saint-Cloud, France
Received 7 January 2002; accepted 14 January 2002
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Abstract |
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The aim of this study was to determine the toxicity profile, the recommended dose (RD) and the pharmacokinetic parameters, and to evaluate the antitumor activity of gemcitabine combined with oxaliplatin in patients with advanced non-small-cell lung cancer (NSCLC) and ovarian carcinoma (OC).
Methods:
Gemcitabine was administered as a 30-min infusion followed by a 2-h infusion of oxaliplatin, repeated every 2 weeks. Doses of gemcitabine and oxaliplatin ranged from 800 to 1500 and 70 to 100 mg/m2, respectively.
Results:
Forty-four patients (26 males, 18 females; median age 55 years) including 35 NSCLC (five platinum pretreated) and nine OC patients (all platinum pretreated) received a total of 355 cycles. All patients were evaluable for toxicity. No dose-limiting toxicity at any dose level occurred during the first two cycles; therefore, the highest dose-level of gemcitabine (1500 mg/m2) and oxaliplatin (85 mg/m2) was considered as the RD. Hematological toxicity was moderate amongst the 22 patients treated (167 cycles) at that dose level. Thirteen cycles were associated with grade 34 non-febrile neutropenia in six patients, and eight cycles with grade 34 thrombocytopenia in two patients. Other toxicities were mild to moderate, consisting of asthenia and peripheral neurotoxicity. Four of the 35 patients treated with oxaliplatin 85 mg/m2 experienced grade 3 neurotoxicity requiring treatment discontinuation at cycle 10. In the range of the doses used, gemcitabine and its main metabolite 2',2'-difluorodeoxyuridine appeared not to be affected by oxaliplatin 70100 mg/m2. Of the 44 patients evaluable for activity, 12 NSCLC patients experienced objective responses (one complete and 11 partial responses) and three OC patients showed tumor stabilization lasting for 6 months with a 50% decrease of CA 125 level. Two partial responses (NSCLC) and one tumor stabilization (OC) occurred in platinum-resistant patients.
Conclusions:
The combination of gemcitabine and oxaliplatin could be safely administered on an out-patient schedule in patients with advanced NSCLC and OC. The RD was gemcitabine 1500 mg/m2 and oxaliplatin 85 mg/m2 every 2 weeks. Promising antitumor activity was reported in patients with NSCLC and platinum-pretreated OC, and thus, deserves further evaluation.
Key words: anti-metabolite, combination chemotherapy, diaminocyclohexane, neurotoxicity
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Introduction |
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Oxaliplatin, a recent diaminocyclohexane platinum compound, acts through DNA damage [12] with partial or no cross-resistance with cisplatin in a wide range of human tumors in vitro and in vivo [13, 14]. Oxaliplatin shows potent in vitro cytotoxic activity against a large variety of human tumor specimens from patients using the human tumor cloning assay including colon, NSCLC and OC [15]. Several European phase II trials have reported encouraging activity and manageable toxicity in malignancies both sensitive and resistant to cisplatin, including colon cancer [16], OC [17, 18] and NSCLC [19]. Oxaliplatin is devoid of renal toxicity and is associated with lower hematological and digestive toxicity than cisplatin, making this compound easily manageable for out-patient combination chemotherapy. Cumulative peripheral neuropathy, consisting of cold-enhanced paresthesia, although reversible in the majority of patients, remains the main toxicity associated with oxaliplatin chemotherapy [20].
As mentioned above, gemcitabine and oxaliplatin are both active in a number of solid tumors, with no overlapping toxicity. In vitro, this combination has been demonstrated to be synergistic in several human cancer cell lines, with a sequence-dependency that favors the administration of gemcitabine followed by oxaliplatin [21]. The basic mechanisms of this synergistic interaction have not yet been elucidated, but it is likely to take place at the DNA level, as the incorporation of the anti-metabolite into DNA may increase platinum binding to DNA [21]. DNA mismatch repair (MMR) protein complexes (including hMLH1 and hMSH2) play a predominant role in genomic stability and are an important factor in cisplatin and carboplatin resistance. In contrast to those of cisplatin, adducts formed by oxaliplatin are not recognized by the MMR system, leading to similar toxicity in MMR-proficient and -deficient cell lines and xenografts [22]. Moreover, the loss of hMLH1 expression has been discussed in ovarian tumor cells that developed resistance to cisplatin [23]. Similarly, gemcitabine showed more potent cytotoxic effects in MMR-deficient than in MMR-proficient cells [24]. Therefore, the combination of gemcitabine with oxaliplatin may maintain antitumor activity in both MMR-proficient and MMR-deficient cancer cells that potentially express resistance to cisplatin.
Based on the above rationale, we designed a phase III dose escalation study in tumors that were thought to be sensitive to either gemcitabine or to oxaliplatin alone, such as advanced NSCLC and OC. The goal of this trial was to determine the recommended dose (RD) of this combination given on an every other week out-patient schedule. Based on the literature and clinical experience, the every other week schedule was selected in order to optimize synergistic interaction between gemcitabine and oxaliplatin, and to allow the maintenance of gemcitabine dose intensity. Secondary end points consisted of describing the toxicity profile, the pharmacokinetic parameters and the antitumor activity of this combination.
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Patients and methods |
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Study design
This study was an open-label phase III dose escalation single center study. This study was performed according to the French national guidelines, conducted in compliance with the Helsinki declaration and following good clinical practice. The protocol was approved by the ethical review committee of the University of Kremlin-Bicêtre, France.
Pretreatment and follow-up examination
Baseline investigations before treatment included clinical history, physical exam, complete white blood cell count with differential, serum chemistry analysis (sodium, potassium, chloride, bicarbonate, calcium, phosphorus, magnesium, creatinine, urea, uric acid, bilirubin, AST, ALT, alkaline phosphatase, total protein and albumin), electrocardiogram and chest X-ray. Tumor measurement was assessed by clinical exam, ultrasound, computed tomography (CT) scan and/or MRI as appropriate. Baseline CA 125 assessment was performed for OC patients. Physical exam, evaluation of drug-related toxicity according to the WHO Common Toxicity Criteria (CTC) [26], blood hematology and biochemistry were repeated on a weekly basis. CA 125 was repeated each month. In patients with measurable disease, response evaluation was performed according to the WHO criteria [27] every four cycles (every 2 months of treatment). The occurrence of an objective response had to be confirmed by a second evaluation 1 month after the first documentation of the response. Survival was calculated using the KaplanMeier method and comparisons used the log rank test. Treatment was continued until evidence of disease progression or occurrence of an unacceptable toxicity.
Drug administration
Gemcitabine was supplied by Lilly France (St-Cloud, France) and oxaliplatin by Sanofi-Synthelabo (Gentilly, France). Gemcitabine was diluted with normal saline to obtain a final solution containing 10 mg/ml or less, and given as an intravenous infusion over 30 min, followed by oxaliplatin diluted in 5% glucose solution given intravenously over 2 h. Both drugs were administered every 2 weeks. In all patients, pre-medication consisted of 8 mg i.v. ondansetron combined with 80 mg i.v. methylprednisolone, administered 30 min before the start of gemcitabine infusion.
Dose-escalation procedures
The starting doses of gemcitabine (800 mg/m2 every 2 weeks) and oxaliplatin (70 mg/m2 every 2 weeks) were determined on the basis of literature and previous clinical data. Six dose levels (IVI) were explored escalating gemcitabine/oxaliplatin doses as follows: 800/70, 1000/70, 1000/85, 1200/85, 1200/100 and 1500/85 mg/m2. No intra-patient dose escalation was allowed. In this study, dose-limiting toxicity (DLT) was defined, using the WHO CTC [26], as any of the following events occurring during the first two cycles of treatment (first month of treatment): (i) grade 4 neutropenia lasting >7 days and/or associated with fever 38.5°C; (ii) grade 4 thrombocytopenia; (iii) grade 3 thrombocytopenia associated with hemorrhage; (iv) grade 3 non-hematological toxicity (excluding alopecia, nausea and vomiting); and (v) persistence of non-hematological toxicity (excluding alopecia) of CTC >2 at the scheduled retreatment. For oxaliplatin-induced neurotoxicity, the oxaliplatin-specific scale [28] was used. In the latter, grade 2 is described as permanent paresthesia between cycles, and grade 3 as permanent paresthesia associated with minor functional impairment. Grade 3 neuropathy was considered as a DLT. For each dose level, if one of the initial three patients showed a limiting toxicity, further evaluation was performed by treating three additional patients. The maximal tolerated dose (MTD) was defined as the dose level at which at least two of three, or three of six patients experienced DLT during the first two cycles. The RD was defined as the dose immediately below the MTD. If the MTD could not be reached at dose level VI, then the latter would be considered as the RD.
Pharmacokinetic study
Pharmacokinetic parameters of gemcitabine in plasma were analyzed at the first cycle (17 patients, starting at a dose level of 800 mg/m2). Peripheral blood (5 ml) from distant site of gemcitabine infusion was collected in heparinized tubes in the presence of tetrahydrouridine (Calbiochem, San Diego, CA, USA) immediately before drug administration, and 30 min, and 3, 4, 6, 8, 12 and 24 h from the start of the infusion (eight blood samples). After performing preliminary analysis in the first 10 patients, additional blood samples were drawn at 60 and 90 min, and 2 h from the start of the infusion for the dose level gemcitabine 1500 mg/m2 (11 blood samples in seven patients). Tetrahydrouridine was added to samples to inhibit the conversion of gemcitabine to its metabolite 2',2'-difluorodeoxyuridine (dFdU) by deoxycytidine deaminase. Whole blood samples were centrifuged immediately (3500 rpm for 10 min) and plasma was frozen at 20°C for subsequent analysis.
The levels of gemcitabine and its main deaminated metabolite dFdU were determined by the method described previously by Freeman et al. [29]. Separation and quantification of gemcitabine and dFdU in the plasma was achieved with an isocratic reverse-phase high-performance liquid chromatography (HPLC) system that consisted of a 515 Waters pump (Milford, MA, USA), a 484 Waters detector set at 272 nm and a 717+ Waters automatic injection system. The samples were injected onto a µBondapack C18 Waters column (particle size 10 µm) with a flow rate of 1 ml/min. Peak area were quantified using the data acquisition program Millenium, version 3.2 (Waters). Retention times of gemcitabine and dFdU were 4.8 and 6 min, respectively. The limit of quantification was 50 ng/ml for both gemcitabine and dFdU.
The area under the concentrationtime curve (AUC) from t0 (start of infusion) to infinity t was calculated using the linear trapezoidal rule for non-compartmental analysis according to the Micropharm computer program (S. Urien, INSERM, St-Cloud, France). At doses ranging from 800 to 1200 mg/m2, available data allowed calculation of pharmacokinetic parameters Cmax, AUC and terminal half life only for dFdU. At the dose gemcitabine 1500 mg/m2, both gemcitabine and dFdU pharmacokinetic parameters could be calculated.
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Results |
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Non-hematological toxicity
Nausea/vomiting was mainly restricted to grade 2 and occurred in one, one, four, three and eight patients treated at dose levels I, II, IV, V and VI, respectively. Nausea/vomiting was satisfactorily treated and prevented by the addition of metoclopramide to the ondansetron/steroid cocktail for subsequent cycles.
No mucositis or alopecia was reported. Grade 12 asthenia was frequently observed (45% of patients, 18% of cycles) and appeared to increase with the number of cycles. Grade 3 asthenia was reported in a total of three patients treated, respectively, at dose levels I (one patient at cycle 7), IV (one patient at cycle 3 who recovered for further cycles) and VI (one patient at cycle 6). Sustained grade 3 asthenia caused treatment discontinuation in two patients, aged 57 and 78 years. One patient presented a gemcitabine-related grade 2 flu-like syndrome.
As expected with oxaliplatin, cold-enhanced paresthesia were reported in several patients receiving four or more cycles. Although not significant, an increasing severity trend was observed with higher doses (85 versus 70 mg/m2). Paresthesia were cumulative, grade 3 being observed after a median of 10 cycles (range 1012). Figure 1 shows the probability of occurrence of the neurotoxicity as a function of time from the first oxaliplatin administration for all patients treated in this study. Grade 3 peripheral neurotoxicity was reported in four patients (9%), with minor functional impairment occurring at cycle 911 that prompted us to stop oxaliplatin. Among these four patients with NSCLC, three were chemotherapy-naïve and one had previously received a cumulative dose of cisplatin of 200 mg/m2. With a follow-up ranging from 6 to 12 months, all but one patient with grade 3 neurotoxicity recovered partially or completely. Table 4 summarizes worst non-hematological toxicity per patient according to dose level.
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Pharmacokinetic study
Because of the short terminal half-life (t) of gemcitabine ranging from 10 to 20 min [30], only the end of infusion peak plasma levels of gemcitabine could be measured for dosage ranging from 800 to 1200 mg/m2. For gemcitabine, the pharmacokinetic profiles could only be obtained for the highest dosage (1500 mg/m2) due to the limit of quantification of the HPLC method (50 ng/ml). The calculated pharmacokinetic parameters were: Cmax 34.7 ± 19.1 µg/ml; AUC 21.3 ± 11.4 µg/ml·h; clearance 86.2 ± 37.9 l/h/m2; and t 0.39 ± 0.17 h.
Peak gemcitabine levels in the plasma showed important interpatient variability, with a median value of 34.7 µg/ml (range 18.659.8 µg/ml) at the recommended dose level of 1500 mg/m2.
Because of the longer persistence of the deaminated inactive product dFdU in plasma, a full pharmacokinetic profile could be evaluated (Figure 2). Peak dFdU concentrations were observed at the end of gemcitabine infusion and an increasing trend was observed with the dose. The AUC of dFdU in plasma showed inter-patient variability (Table 5). The AUC of dFdU was not correlated with the gemcitabine dose (r2 = 0.221). Although a limited number of patients underwent pharmacokinetics within dose levels I to V, it seemed that saturation occurred for gemcitabine metabolization into dFdU by deoxycytidine kinase (Figure 3). The elimination of dFdU followed a biphasic profile in all patients. In contrast to gemcitabine, the t of dFdU was delayed between 9.7 and 16 h, with a variation between patients ranging from 30% to 54%. Table 5 summarizes the pharmacokinetic results.
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In patients with NSCLC, 11 of 33 patients with measurable diseases had objective response (1/3, 1/2, 1/1, 3/6, 1/3 and 4/20 for dose levels I, II, III, IV, V and VI, respectively). This included one patient with stage IIIB disease who experienced a complete response that lasted for 6 months with disappearance of primary tumor and mediastinal lymph nodes. Three partial responses were observed in platinum-pretreated patients (two responses occurred in patients who had disease progression within 6 months following cisplatin-based chemotherapy). In addition, one non-measurable patient experienced bone pain disappearance, significant regression of lung metastasis at CT scan and bone metastasis at bone scan that was considered as a partial response. Two patients with NSCLC experienced minor responses measured as a 46% tumor regression. Figure 4 represents the best tumor response observed per measurable patient.
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In this study, the overall median duration of response and time to progression were 8.1 months [95% confidence interval (CI) 3.910.7 months] and 4.8 months (95% CI 3.68.2 months), respectively (Figure 5). Time to progression and duration of response were not significantly different at the recommended dose and among all dose levels (P = 0.9 and 0.3, respectively).
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Discussion |
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This regimen was remarkably well tolerated regarding hematological, digestive and renal toxicity. In this study, no DLT was observed during the first two cycles up to the highest dose level. Therefore, the RD for phase II studies was gemcitabine 1500 mg/m2 combined with oxaliplatin 85 mg/m2 every 2 weeks. The administration of this regimen every 2 weeks allowed the maintenance of the dose intensity. At the recommended dose, 99% of planned cycles were effectively received by the patients. The main cause of treatment delay was thrombocytopenia. Cumulative toxicities were asthenia and paresthesia, as previously reported with gemcitabine and oxaliplatin, respectively. At the RD, hematological toxicity was limited to infrequent episodes of grade 34 neutropenia and thrombocytopenia in 7.8% and 4.8% of cycles, respectively. Neither sepsis nor bleeding was observed, and no transfusion was required. Digestive toxicity was easily manageable with classical anti-emetics. None of the patients presented alopecia or mucositis. Since oxaliplatin has no renal toxicity, this allowed us to give treatment on an out-patient basis.
Two other phase I trials have reported preliminary data on gemcitabineoxaliplatin combinations using different schedules. Mavroudis et al. [31] used gemcitabine 10001600 mg/m2 on days 1 and 8, combined with oxaliplatin 60120 mg/m2 on day 8, every 21 days, in patients with advanced solid tumors. Early results indicate that the DLTs are grade 34 neutropenia, thrombocytopenia and asthenia. Overall, the incidence of grade 34 hematological toxicity was comparable to that for our study. Interestingly, in the Mavroudis et al. [31] study, the median age of patients was 65 years, and 42% of patients had been treated with two previous regimens. In this population, the combination was well tolerated up to gemcitabine 1600 mg/m2 on days 1 and 8, with oxaliplatin 120 mg/m2 on day 8, every 21 days, as no DLT was observed. These data are consistent with our results showing that the combination of gemcitabine with oxaliplatin can be well tolerated in both untreated and previously treated patients. The California Consortium trial has recently reported preliminary results for gemcitabine 7001750 mg/m2 on days 1 and 8, plus a fixed dose of oxaliplatin 130 mg/m2 on day 1, every 21 days, in patients with advanced solid tumors [32, 33]. In this study, the DLTs occurring at the dose of gemcitabine 1250 mg/m2 were grade 4 thrombocytopenia and grade 3 confusion. This schedule appears to be associated with more severe grade 34 hematotoxic toxicity in about 30% to 33% of cycles. The authors are currently exploring doses of gemcitabine 1000 mg/m2 plus oxaliplatin 130 mg/m2 as an RD.
The pharmacokinetic parameters investigated in this study indicated a non-linear pharmacokinetic behavior of the gemcitabine main metabolite dFdU within the range of doses used. Although oxaliplatin pharmacokinetic evaluation has not been carried out in this study, gemcitabine and dFdU disposition appeared to be unaffected by oxaliplatin, since our data were consistent with those obtained in previous studies investigating the pharmacokinetic parameters of gemcitabine given as single agent and combinations [3437]. The limited occurrence of toxic events during the first two cycles did not permit us to explore pharmacodynamic interactions in this study.
In our study, gemcitabine combined with oxaliplatin achieved a number of objective responses. Activity was reported in chemotherapy-naïve and pretreated NSCLC and OC patients. Interestingly, responses were observed in two patients with NSCLC, and tumor stabilization in one patient with OC considered as resistant to classical platinum compounds. At the recommended dose, five of 20 patients with NSCLC showed objective responses and two of two patients with OC showed 6-month tumor stabilization. In this study, the duration of response reached a median of 8.1 months, and the time to progression a median of 4.8 months. Duration of response and time to progression appeared to be not significantly different at the RD and among all dose levels. The inclusion criteria in our study did not allow us to describe the activity of the combination in heavily pretreated patients. This was explored in another study, which found evidence of activity illustrated by a 13% response rate reported in patients having received one or two previous lines of chemotherapy [31].
Several studies have reported on the combination of gemcitabine with cisplatin. This regimen was recently acknowledged as one of the standard options for the treatment of patients with advanced NSCLC [3840]. The main toxicity of gemcitabine combined with cisplatin was grade 34 thrombocytopenia, occurring in 48% to 64% of patients and requiring platelets transfusion in 15% to 20% of cases [3840]. Grade 34 anemia also occurred in 29% to 65% of patients and required red blood cell transfusion in 38% of patients [3840]. Other toxicities were related to cisplatin. Grade 34 nausea and vomiting were reported in 18% to 37% and grade 34 renal toxicity in 1% to 9% of patients. Grade 34 neurotoxicity occurred in 2% to 16% of patients. Overall, treatment discontinuation caused by toxicity was as high as 28% in the randomized controlled Eastern Cooperative Oncology Group (ECOG) trial reported by Schiller et al. [40]. Although no comparison study is available, gemcitabine combined with oxaliplatin seems to be associated with a lower rate of nausea/vomiting, alopecia, hematological and renal toxicity. In contrast to cisplatin-induced neurotoxicity, most of the cases of oxaliplatin-induced neurotoxicity were reported as reversible in our study, as described previously [20].
In summary, this trial shows that gemcitabine combined with oxaliplatin on an every other week out-patient schedule has manageable toxicity. The recommended dose is gemcitabine 1500 mg/m2 combined with oxaliplatin 85 mg/m2 every 2 weeks. This combination shows promising antitumor activity and should be investigated in patients with NSCLC and OC. Other tumors currently treated with the gemcitabinecisplatin regimen, such as pancreatic and bladder cancer, might also benefit from this regimen and could be evaluated. Phase II studies are underway in these tumor types.
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Acknowledgements |
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Footnotes |
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