1 Department of Medical Oncology, University General Hospital of Heraklion, Crete; 2 Department of Pharmacology, Medical School, University of Ioannina, Ioannina, Greece
Received 2 May 2002; revised 5 July 2002; accepted 18 July 2002
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Abstract |
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Gemcitabine and oxaliplatin have broad antineoplastic activity and favorable toxicity. We conducted a phase I study to determine the maximum tolerated doses (MTDs) and dose-limiting toxicities (DLTs) of the combination in patients with advanced solid tumors.
Patients and methods:
Sixty-eight patients with advanced stage solid tumors were enrolled. Treatment was first-line for 35% of patients, second-line for 27%, and third-line for 38%. Gemcitabine was administered at escalating doses of 10002000 mg/m2 as a 30-min intravenous (i.v.) infusion on days 1 and 8 and oxaliplatin at 60130 mg/m2 as a 4-h i.v. infusion on day 8 every 21 days without growth factor support.
Results:
The MTD was defined at gemcitabine 1800 mg/m2 on days 1 and 8 and oxaliplatin 130 mg/m2 on day 8. Twelve dose levels were evaluated and DLTs occurring during the first cycle consisted of grade 4 neutropenia, grade 3 asthenia or mucositis and grade 13 neutropenia or thrombocytopenia resulting in treatment delays. A total of 266 cycles were administered with only one episode of febrile neutropenia and no toxic deaths. Seven (3%) and 26 (10%) cycles were complicated by grade 4 and 3 neutropenia, respectively, three (1%) and 13 (5%) by grade 4 and 3 thrombocytopenia, and eight (3%) by grade 3 anemia. The most common non-hematological toxicity was grade 2/3 asthenia observed in 23% of cycles. Responses were observed in patients with a variety of epithelial neoplasms. The pharmacokinetic study revealed no significant interaction between the two drugs.
Conclusions:
The combination of gemcitabine and oxaliplatin has excellent tolerability and promising activity in patients with advanced solid tumors. As the MTD exceeds the recommended single-agent dose for gemcitabine, and a doseresponse effect has not been established, we recommend using both drugs at full doses, e.g. gemcitabine 12001400 mg/m2 on days 1 and 8 and oxaliplatin 130 mg/m2 on day 8 for further phase II studies.
Key words: gemcitabine, oxaliplatin, phase I, solid tumors
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Introduction |
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Oxaliplatin (Eloxatin; Sanofi, Paris, France) is a new platinum derivative characterized by a 1,2-diaminocyclohexane carrier ligand, which confers important advantages in terms of activity and toxicity compared with cisplatin and carboplatin. Oxaliplatin lacks the nephrotoxicity of cisplatin and causes less myelosuppression than carboplatin, while it may be active in tumors with intrinsic or acquired resistance to cisplatin [6, 7]. This partial cross-resistance with cisplatin and carboplatin is presumably attributable to a different mechanism of action or resistance, as demonstrated in a National Cancer Institute cytotoxicity screening study [8]. Oxaliplatin induces adducts that are more effective at inhibiting DNA synthesis and mechanisms of resistance include defects in mismatch repair and enhanced replicative bypass [6]. In clinical practice, oxaliplatin used alone or in combination with 5-fluorouracil (5-FU) and leucovorin has produced high response rates and long progression-free survival in patients with advanced colorectal cancer [9]. Although oxaliplatin is not licensed in the United States, it is approved in many European countries for the treatment of advanced colorectal cancer in combination with 5-FU and leucovorin. Oxaliplatin is also active in ovarian cancer, NSCLC, breast cancer, non-Hodgkins lymphomas and gastrointestinal tumors [10]. The recommended dose is 130 mg/m2 administered as a 26 h i.v. infusion every 3 weeks. Because of the lack of nephrotoxicity, oxaliplatin can be given without pre- or post-hydration. The DLT is dose-dependent and cumulative peripheral neuropathy, triggered or enhanced by exposure to cold, and manifested as paresthesia and dysesthesia in the extremities [11]. However, unlike the neurotoxicity typically seen with cisplatin administration, oxaliplatins neurotoxicity is reversible after discontinuation of treatment. Other toxicities are usually mild and uncommon. Hematological toxicity is limited to grade 1/2 neutropenia or thrombocytopenia even at doses up to 200 mg/m2 [12]. Nausea and vomiting can be easily controlled with standard antiemetic pretreatment, and diarrhea, alopecia and ototoxicity are uncommon.
Growth inhibition studies using the human CEM leukemia cell line and the colon cancer cell lines HCT 116 and Colo 320 DM revealed that the gemcitabineoxaliplatin combination displayed supra-additive effects and that the cytotoxic effects of the combination were better than or equal to those of gemcitabinecisplatin combinations [13]. Based on the different mechanisms of action of the two drugs, the in vitro evidence of enhanced activity when combined together, the broad spectrum of antineoplastic activity with favorable non-overlapping toxicity, we conducted a dose-escalation and pharmacokinetic study to determine the maximum tolerated doses (MTD) and the DLTs of the combination in patients with advanced solid tumors.
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Patients and methods |
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Treatment
Treatment schedule and dose-escalation levels are shown in Table 1. Gemcitabine was administered as a 30-min i.v. infusion on days 1 and 8 at escalated doses ranging from 1000 to 2000 mg/m2. Oxaliplatin was administered on day 8, following gemcitabine administration, as a 4-h i.v. infusion, without pre- or post-hydration, at escalated doses ranging from 60 to 130 mg/m2. Treatment cycles were repeated every 3 weeks without prophylactic administration of hematopoietic growth factors. The standard antiemetic regimen included ondansentron 16 mg, dexamethasone 8 mg and diazepam 5 mg given i.v. 30 min before chemotherapy administration.
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Dose escalation
As shown in Table 1 the following 12 dose-escalation levels for gemcitabine/oxaliplatin have been evaluated: 1000/60; 1200/70; 1200/80; 1400/80; 1400/90; 1600/90; 1600/100; 1600/110; 1600/120; 1600/130; 1800/130; 2000/130 (mg/m2). No intra-patient dose escalation was allowed. At least three patients were enrolled at each dose level. If a DLT was observed in one of the first three patients, then three additional patients were enrolled at the same dose level. DLTs were assessed during the first chemotherapy cycle. DLT was defined as the occurrence of any of the following: grade 4 hematological toxicity; grade 3/4 neutropenia with fever >38.2°C; grade 3/4 non-hematological toxicity, excluding nausea/vomiting; and any treatment delay because of toxicity. Dose escalation was discontinued and the DLT dose level was reached if at least 50% of the patients treated at that level developed a DLT (e.g. at least two of three, or three of six patients). The MTD dose level was defined as the first level below the DLT dose level.
Pharmacokinetic methods
The pharmacokinetic parameters of gemcitabine and oxaliplatin were assessed for 12 patients on day 8 of the first cycle at dose levels 6, 7, 8, 9, 10, 11 and 12. Samples from two patients were collected for each dose level except levels 6 and 7 where samples from only one patient were analyzed. For gemcitabine measurements blood samples were drawn in tubes containing tetrahydrouridine before starting and immediately following the end of the i.v. infusion and then at 1, 4, 8 and 24 h thereafter. A reversed-phase HPLC method was used to separate and quantify gemcitabine [15]; the chromatographic system (Shimadzu LC-10A/10Avp; Shimadzu Deutschland GmbH, Duisburg, Germany) consisted of an LC10AD pump, an SCL-10Avp controller, an SIL-10Avp automatic sample injector and an SPD-M10Avp UV detector. Calculation of gemcitabine concentration was based on a standard calibration curve using standard solutions of gemcitabine (Eli Lilly) with good linearity (r2 = 0.9996). The detection limit was determined as 0.078 mg/l of plasma. For oxaliplatin concentration measurements blood samples were drawn before starting, in the middle of, and immediately following the end of the i.v. infusion and then at 30 min, 1, 2, 4, 6 and 24 h thereafter. Aliquots for total oxaliplatin were diluted with 25% Triton X-100 and 20 µl were used for the measurement [16]. Ultrafiltrated samples (considered as oxaliplatin plasma fraction free from proteins) obtained by centrifugation at 2000 g for 30 min at 4°C using Centrex UF2 micropartition devices of 30 000 Da cut-off (Schleicher & Schuell, Dassel, Germany) were measured immediately after filtration without any preparation [16, 17]. Different oxaliplatin levels were determined by flameless atomic absorption spectrophotometry with deuterium correction, on a Shimadzu system of an AA-6800 spectrophotometer and a GFA-EX 7 graphite furnace at 265.9 nm. Standard platinum concentrations (FLUCA, Buchs, Switzerland) and a standard calibration curve (range 12.896.0 µg/l, with good linearity, r2 = 0.9998), were used for calculation of oxaliplatin concentrations. All the within-day values of both free and total oxaliplatin were less than 7%. All pharmacokinetic calculations were made according to Human Drug Kinetics (Saunders L, Ingram D, Jackson SHD Eds, IRL Press, Oxford, UK, 1989), and by using PRISM (v2.0) GraphPad Software (PRISM, San Diego, USA).
Tumor response
Although patients were not required to have bidimensionally measurable disease to enter the study, response was assessed according to the standard WHO criteria for those who did [14]. Patients evaluable for response were the patients who had measurable disease and had completed at least two cycles of chemotherapy.
Statistical methods
Differences of the nadir hematological parameters between cycles (cycle 1 versus cycle 3) and dose levels (1, 2, etc.) were examined by a two-way analysis of variance; this allowed also the assessment of an interaction effect between cycles and dose levels.
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Results |
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Non-hematological toxicity was generally mild. Table 5 shows the non-hematological toxicity in all cycles and per first courses at the different dose levels. Across all dose levels the most common toxicity was asthenia, which was grade 2 in 47 cycles (18%) corresponding to 21 patients (31%) and grade 3 in 14 cycles (5%) corresponding to 11 patients (16%). Similarly, grade 2 peripheral sensory neurotoxicity was observed in 14 cycles (5%) corresponding to six patients (9%) and grade 3 in two cycles (1%) corresponding to two patients (3%). Grade 3 vomiting, diarrhea and mucositis were rarely seen. Grade 1/2 edema and transient maculopapular rash were observed in 14 (21%) and eight (12%) patients, respectively. A flu-like syndrome was reported by eight patients (12%) in 10 cycles (4%). Onycholysis was observed in five patients (7%).
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Based on the above measurements, the pharmacokinetic profile of both drugs does not seem to be modified when the two drugs are administered concomitantly according to the schedule evaluated in the present study.
Antitumor activity
Twelve patients were not evaluable for response for the following reasons: lack of bidimensionally measurable disease (n = 7), treatment discontinuation after the first cycle (n = 3), lost to follow-up (n = 2). Among 56 patients who were evaluable for response, we observed 10 with partial response, 16 with stable disease and 30 with progressive disease. Responses were observed at dose levels 1, 2, 6, 10, 11 and 12 including two patients with breast cancer (third-line treatment), two patients with bladder cancer (second-line treatment), two patients with adenocarcinoma of unknown primary (first-line treatment), one patient with NSCLC (third-line treatment) and one patient with each of the following: endometrial cancer, fallopian tube cancer and carcinoid tumor of the intestine (all first-line treatment). The median duration of response was 3.5 months (range 1.517.5) and the median time to tumor progression was 5.5 months (range 419).
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Discussion |
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Since the purpose of our study was to determine the MTD and DLT of the combination, doses of both drugs were escalated based on the predefined study criteria. Based on these the DLT dose level was reached if at least 50% of the patients treated at that level developed a DLT (e.g. at least two of three, or three of six patients). This is a liberal and arbitrarily defined criterion used in many studies and has obvious shortcomings since it accepts a DLT incidence of up to 49%. The MTD was reached at gemcitabine 1800 mg/m2 administered on days 1 and 8 and oxaliplatin 130 mg/m2 on day 8 every 21 days. These doses are considered to be tolerable based on the predefined study criteria for DLTs encountered during the first cycle of treatment. For oxaliplatin this represents the recommended dose for single-agent administration and for gemcitabine it exceeds the monotherapy recommended dose. Although we did not observe any cumulative effect on either hematological or non-hematological toxicity even at the higher dose levels (data not shown), we cannot recommend the MTD doses to be used in future phase II trials since a doseresponse effect has not been established for any of the used agents and the responses observed in our study occurred across all dose levels. However, based on our results, the administration of both agents at full doses, e.g. gemcitabine 12001400 mg/m2 on days 1 and 8 and oxaliplatin 130 mg/m2 on day 8, should be well tolerated and represent our recommendation for further phase II testing.
The observed low toxicity of this regimen was expected since both drugs have very favorable toxicity profiles and present different DLTs [5, 11]. Therefore the low amount of toxicity observed in this study can be explained by the mild and non-overlapping toxicities of the individual agents. The good tolerance of the regimen is especially important in view of the characteristics of the study population (median age 64 years; 38% of patients had two prior regimens). Despite these adverse parameters, clinically significant grade 3/4 neutropenia and thrombocytopenia complicated 13% and 6% of the treatment cycles overall, and less than 25% and 15% of the cycles at any dose level, respectively. Moreover, there was only one episode of febrile neutropenia observed at dose level 10. Although neutropenia was the most common dose-limiting event, asthenia was the most common non-hematological toxicity complicating approximately one-quarter of the treatment cycles. The observed low incidence of peripheral sensory neurotoxicity may be attributable to the relatively low cumulative oxaliplatin dose (median cumulative administered dose for oxaliplatin 329 mg/m2). It has been reported that nearly all patients are expected to experience some degree of neurosensory toxicity at cumulative oxaliplatin dose levels of 540 mg/m2 [11]. However, this neurotoxicity is also reported to be highly reversible, as 82% of patients have their neuropathy regress within 46 months, and 41% experience complete recovery within 68 months. In our study neurotoxicity reversed in four out of five evaluable patients after 36 months of follow-up. This recovery is in contrast with the cisplatin-induced neuropathy, which usually tends to progress after treatment without signs of reversibility [21].
All pharmacokinetic parameters measured in the present study were dose-independent. This may be due to the large interindividual variation observed with both drugs. The obvious explanation for this is the small number of patients tested and the substantial variability that exists between different individual patients. We made every effort to avoid technical problems (e.g. blood sampling, problems with assays) associated with drug concentration measurements. Alternatively, the investigation of a wider range of doses may be necessary in order to demonstrate a dose-dependent correlation of pharmacokinetic parameters. Indeed, Abbruzzese et al. [15] reported a proportional increase of both Cmax and AUC of gemcitabine in the dose range of 531000 mg/m2. Moreover, Graham et al. [22] reported increased values for plasma Cmax and AUC of oxaliplatin in a dose-related manner for doses ranging from 20 to 180 mg/m2. Since samples were analyzed for a limited number of patients for each dose level, the pharmacokinetic data of our study should be interpreted with caution. Therefore the unusually high AUC observed in dose levels 8 and 11 for both oxaliplatin and gemcitabine may be explained by the small number of patients tested. Since this was not observed in the other dose levels it is unlikely to represent interaction between the two drugs in terms of their pharmacodynamics. Our preliminary conclusion, based on these data, is that the pharmacokinetic profile of both drugs does not seem to be modified when the two drugs are administered concomitantly according to the schedule evaluated in this trial.
In previous studies, both gemcitabine and oxaliplatin have shown single-agent activity in refractory neoplasms such as breast cancer, ovarian cancer, bladder cancer, germ cell tumors and lymphomas [2328]. Furthermore, oxaliplatin was shown to have comparable activity but with a better toxicity profile than cisplatin in poor-prognosis NSCLC patients [29]. Therefore, its combination with other active agents such as gemcitabine may be preferable to cisplatin combinations for the treatment of NSCLC and deserve evaluation in phase II studies. Finally, because loss of DNA mismatch repair results in resistance to cisplatin but not to oxaliplatin [30], and because oxaliplatin is active in cisplatin-resistant as well as cisplatin-sensitive tumors [31], oxaliplatin-based combinations should be tested in platinum-sensitive and -resistant neoplasms. In a recently published phase II study of the combination in patients with advanced pancreatic adenocarcinoma, gemcitabine was administered at 1000 mg/m2 as a 10 mg/m2/min infusion on day 1 and oxaliplatin at 100 mg/m2 on day 2 in cycles every 2 weeks [32]. Only 11% of patients developed each of grade 3/4 neutropenia, thrombocytopenia and peripheral neuropathy and the overall response rate was 30%. Although using a different administration schedule than our study, these results confirm our findings regarding the promising activity and favorable toxicity of this combination.
To the best of our knowledge this is the first dose-escalation and pharmacokinetic study reported for the gemcitabineoxaliplatin combination. In this study the combination was evaluated extensively in terms of toxicity in a large cohort of patients receiving many cycles of treatment across a wide range of doses. Based on the observed excellent tolerability and promising activity, this regimen deserves further testing in phase II trials in various types of tumors. Although higher doses may be well tolerated, the recommended doses are gemcitabine 12001400 mg/m2 on days 1 and 8 and oxaliplatin 130 mg/m2 on day 8 without growth factor support or prophylactic antibiotic administration.
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Acknowledgements |
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Footnotes |
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References |
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