1 Medical Oncology Unit B, 2 Unit of Experimental Oncology C, 3 Unit of Medical Statistics and Biometry, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy
Received 27 May 2002; revised 9 August 2002; accepted 11 September 2002
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Abstract |
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To explore the activity and tolerability of gemcitabine (GEM) and carboplatin (CBDCA) in non-small-cell lung cancer (NSCLC) we tested four administration sequences on H460 NSCLC cells, and at the same time performed a randomized phase II trial using analogous schedules.
Patients and methods:
GEM was given first in two in vitro sequences, and CBDCA first in the other two; interaction was quantified calculating a combination index. Eighty-eight chemotherapy-naïve, stage IV NSCLC patients were randomly assigned to receive either: GEM (1000 mg/m2) on days 1 and 8 and CBDCA (AUC 5 mg·min/ml) on day 1, 4 h before GEM (arm A); same as arm A except CBDCA given 4 h after GEM (arm B); GEM on days 1 and 8 and CBDCA on day 2 (arm C); GEM on days 2 and 9 and CBDCA on day 1 (arm D). Courses were repeated every 21 days.
Results:
In the preclinical study, CBDCA given before GEM produced a synergistic cytotoxic effect. Two complete and 29 partial responses occurred in 86 of 88 treated patients (intention-to-treat analysis 35%; 95% confidence interval 25.5% to 46.8%). One- and 2-year survivals were 44% and 11%, respectively. Grade 3/4 thrombocytopenia occurred in 11%; grade 3/4 neutropenia in 17%; and non-hematological toxicity was insignificant. Median survival was 11 months (range 718+), but better in patients receiving CBDCA first (arms A and D) (13 versus 9 months) than in patients receiving GEM first (arms B and C). The response was greater (50% versus 31%) in arm A than in the other arms.
Conclusions:
The CBDCA/GEM combination is safe and active against stage IV NSCLC. Our preclinical and clinical findings suggest that administration of CBDCA before GEM gives the better outcome.
Key words: carboplatin, gemcitabine, non-small-cell lung cancer
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Introduction |
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GEM is an analog of deoxycytidine, well-known for its mild toxicity profile and for its activity against many kinds of malignant cells. Once activated by deoxycytidine kinase, GEM is incorporated into DNA where it inhibits exonuclease and DNA repair [4].
Carboplatin (CBDCA) acts, like cisplatin, by forming platinumDNA adducts and has similar antitumor activity to cisplatin; however, CBDCA lacks the nephrotoxicity of the latter and does not require large volume hydration [5]. Preclinical studies have shown synergistic effects when GEM and platinum are delivered in combination. This synergism might be due to GEMs ability to inhibit DNA repair after platinum-induced damage, or cisplatins ability to inhibit ribonucleotide reductase and so enhance the phosphorylation and activation of GEM [6, 7]. The best sequence of administration of the two drugs is still unclear. Furthermore, the GEM plus CBDCA combination has not been sufficiently explored in NSCLC; only a few studies with small numbers of patients have been published, while more recent larger studies have so far reported preliminary data only and none has specifically addressed the problem of sequence of administration [813].
We designed the present study to evaluate the activity and tolerability of CBDCA plus GEM in the treatment of stage IV NSCLC. We used four different administration schedules in a preclinical study and at the same time we began a randomized phase II study to investigate the best administration sequence.
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Material and methods |
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Median effect analysis. The approach proposed by Chou and Talalay [16] was used to determine the nature of the interaction between GEM and CBDCA. The drugs were always combined in the same concentration mass ratio (GEM:CBDCA = 1:700). The interaction was quantified by calculating the combination index at increasing levels of cell kill. Combination indices of less than or greater than 1 indicated synergy or antagonism, respectively, whereas a combination index of 1 indicated additivity. The range of concentrations tested to calculate the IC50 was 2.5100 µg/ml for CBDCA and 0.0110 µg/ml for GEM.
Phase II study
From September 1998 to March 2001, 88 consecutive patients with stage IV NSCLC, were enrolled in our single-center trial. The study was approved by the Ethics Committee of the National Cancer Institute of Milan and conducted according to the ethical principles laid down in the latest version of the Declaration of Helsinki and the Guidelines for Good Clinical Practice.
Eligibility criteria. Eligibility criteria were: histologically or cytologically confirmed NSCLC, stage IV; age <75 years; no prior chemotherapy; an Eastern Cooperative Oncology Group performance status 2 or less; at least one measurable lesion; no brain metastases as assessed by computed tomography (CT) or magnetic resonance imaging (MRI); adequate bone marrow reserve, defined as white blood cell count >4000/mm3, neutrophils >2000/mm3, platelets >120 000/mm3 and hemoglobin >11 g/dl; adequate renal and liver function (creatinine <1.5 mg/dl, creatinine clearance >60 ml/min, bilirubin <2 mg/dl); life expectancy at least 12 weeks; no concomitant serious illness; no prior malignancies except in situ cervical carcinoma and non-melanotic skin neoplasms. Women of childbearing potential were required to use an approved form of contraception over the study period. All patients had to sign an informed consent before enrolment.
Treatment plan. GEM 1000 mg/m2 and CBDCA AUC 5 mg·min/ml were both administered as 30-min infusions in 250 ml normal saline. The patients were randomized to one of the following schedules: arm A, GEM on days 1 and 8 with CBDCA on day 1 given 4 h before GEM; arm B, same schedule but with CBDCA given 4 h after GEM; arm C, GEM on days 1 and 8 with CBDCA on day 2; and arm D, GEM on days 2 and 9, with CBDCA on day 1. The courses were repeated every 21 days. Antiemetic prophylaxis with anti-5-hydroxytryptamine type 3 receptor and steroids was given.
Patient evaluation. At baseline, a history was taken and all patients received physical examination, chest and abdominal CT, brain CT or MRI, bone scan, complete blood cell count, serum biochemistry and ECG. The hemochrome was checked before each infusion and repeated in the event of fever. Tumor response was assessed and blood tests were repeated, every three cycles. Responses were assessed according to WHO criteria [17]: complete response (CR) was defined as the complete disappearance of all the known lesions, in the absence of new ones. Partial response (PR) was defined as a reduction of the sum of the products of the perpendicular diameters of all measurable lesions by >50%. CR and PR had to persist for at least 4 weeks. Stable disease (SD) was defined as <50% reduction or <25% increase in tumor size. Patients with a response or SD after three courses received additional treatment up to a maximum of six cycles; patients with progressive disease were withdrawn from the study and received second-line chemotherapy or supportive care depending on their clinical status.
After the end of treatment patients were checked every 2 months. The duration of response was measured from the date of documentation of first response to the date of first evidence of progressive disease. Time to progression was measured from the date of initial treatment to the date of disease progression. Overall survival was measured from the date of initial treatment to the date of death or latest follow-up examination. Toxicity was evaluated according to the National Cancer Institute Common Toxicity Criteria [18]. Palliative radiotherapy was given to some patients with progressive or symptomatic disease.
Statistical methods. The 95% confidence interval (CI) values for the response rate were calculated from the binomial distribution as described by Atkinson and Brown [19]. Progression-free and overall survival were estimated by the product-limit method of Kaplan and Meier. Simons two-stage minimax design [20] was adopted as the trial design, with response rate as the main end point. It was decided prospectively that if less than nine patients responded among the first 42 recruited, the study would be terminated for inefficacy. Otherwise, 77 patients would have to be recruited to achieve a 90% power of verifying the hypothesis that the true response rate is greater than 35% and of rejecting the hypothesis that the true response rate is less than 20% at the 5% significance level. In fact 88 patients were randomized and 86 treated. With such a sample size, the hypothesis that the true response rate was less than 20% could be rejected if there were at least 25 responses.
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Results |
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The interaction between GEM and CBDCA was analyzed using different treatment schedules. Figure 1 shows plots of the combination indices for the interaction between the two drugs as a function of the treatment schedule, each data point is the mean of nine determinations. Sequential treatment with GEM for 4 h followed by CBDCA for an additional 4 or 24 h produced simply additive effects, as indicated by combination indices very close to 1. Conversely, when the inverse sequence (CBDCA for 4 h followed by GEM for an additional 4 or 24 h) was used, a supra-additive/synergistic effect was consistently observed at different levels of cell kill (Figure 1).
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By intention-to-treat analysis, reported in Table 2, the overall response rate was 31 of 88 (35%; 95% CI 25.5% to 46.8%); 35 patients (40%) achieved SD of median duration 5 months (range 39+). Eighty-one patients of the 86 who entered the trial were evaluable for response, because five patients did not complete the first three cycles required for the evaluation of clinical response, four because of early progression and one because he decided to be treated elsewhere. The overall response rate was 31 of 81 (38%; 95% CI 29.5% to 50.6%). The response analysis is given in Table 3. The response was slightly greater in the arms in which CBDCA was given before GEM [arms A and D, 18 of 41 (44%), versus arms B and C, 13 of 40 (32.5%)]. Similarly, median duration of response and time to progression were longer when CBDCA was administered first (arms A and D, 8 and 10 months, respectively, versus arms B and C, 5 and 8 months, respectively); median survival was also better in the group that received CBDCA first (13 versus 9 months), although neither difference was statistically significant (Figure 2). In particular, the arm A sequence seems to be the best (PR 50% and median duration of response 10 months), but the difference was not significant by the chi-square test (on treatment analysis, P = 0.3362).
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Discussion |
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The association of CBDCA with GEM has been less well studied, although a number of trials have been published recently [1115, 21, 22]; however, the real impact of the dosing schedule on the feasibility and tolerability of this combination in unknown [8]. Very high rates of thrombocytopenia, ranging from 40% to 60%, were observed initially [8, 2325]. In all of these trials GEM was administered on days 1, 8 and 15 with courses every 28 days. In the Hoosier Oncology Group trials hematological toxicity led to discontinuation after the recruitment of only seven patients [24]; nevertheless in the first study a response rate of 33% was reported, suggesting the need to improve the administration schedule [23]. In the latest phase I trial, GEM was no longer given on day 15 leading to a marked decrease in thrombocytopenia (grade 3/4 in 12% of cases) [26]. The authors of the latter study concluded that the combination of CBDCA (AUC 5 mg·min/ml) on day 8 with GEM (1100 mg/m2) on days 1 and 8, every 28 days, was feasible provided that grade 13 thrombocytopenia in 50% of patients was acceptable; within the limits of the phase I design, they observed an objective response in 50% of patients, most of whom were stage IIIb. More recently, preliminary data on two phase II studies have appeared [9, 10]. These used sequential CBDCA plus GEM followed by paclitaxel. Both studies found that the schedule is effective and well-tolerated, and in particular that the severe thrombocytopenia was much reduced. Three other preliminary studies, which did not address sequence, found that the combination was superior to GEM alone, as active as other standard combinations, but better tolerated, although thrombocytopenia remains a worry [1113]. A recently published study comparing GEM (1000 mg/m2 days 1 and 8) plus CBCDA (300 mg/m2) with a first-generation cisplatin schedule found that GEM/CBCDA was associated with better 1-year survival, but had a similar toxicity profile [22].
For the present trial, we also chose a relatively low GEM dose (1000 mg/m2), hoping to reduce or eliminate thrombocytopenia in our stage IV patients. We also chose a 21-day schedule that allowed the planned dose intensity to be given to all patients. Grade III/IV thrombocytopenia occurred in only 11% of cases. Non-hematological toxicity was not clinically relevant in any of the cases.
The phase I studies of Iaffaioli et al. [26] and of Gajra et al. [27] employed a schedule in which GEM was followed by CBDCA. This choice was based on cytokinetic considerations that the initial agent would attack proliferating cells, and this would be followed by a cycle-specific agent to destroy residual non-proliferating cells. This scheme was also supported by the results of a regression analysis of data from six studies which employed cisplatin with GEM [28].
However, in spite of the known synergism between platinum and GEM, the best sequence of administration has not been clearly established [29]. Our in vitro experiments suggested that a synergistic effect could be obtained when CBDCA was administered first, while only an additive effect or less was found when the sequence was inverted. Our clinical regimen followed the sequence of the preclinical study and aimed to explore the activity and tolerability of these two drugs in four combinations: two with CBDCA before GEM and two with the inverse sequence. The overall results (intention-to-treat analysis response rate 35%, 1-year survival 44%, 2-year survival 11%) are encouraging especially when we consider that only stage IV patients were enrolled, in most of whom (81%) there were more than two sites of disease at diagnosis. The CBDCA/GEM combination did not worsen the performance status in most patients, with very low grades of fatigue and no hospitalization for any kind of toxicity. This might have contributed to the good survival rates seen in our series.
The clinical outcomes supported the experimental observations in that the best results were obtained when GEM was given on day 1, 4 h after CBDCA (arm A). However, there were imbalances in gender and histology distributions among the four treatment arms (Table 1) and the study was powered to evaluate the overall response rate of the combination. Therefore, this phase II study could not show which of the four treatment arms was superior. However, the group that received CBDCA first (arms A and D) had a better response rate, better median duration of response, and better median survival than those who did not, although the differences were not statistically significant. We suggest that ribonucleotide reductase inhibition by platinum results in depletion of deoxycytidine triphosphate (dCTP). Since dCTP inhibits deoxycytidine kinase, which is the rate-limiting enzyme for GEM phosphorylation, the effect of dCTP depletion might be both to enhance GEM phosphorylation and, by reduced competition, to increase GEM-triphosphate incorporation into DNA [30].
We conclude from this study that in view of its efficacy and good tolerability the CBDCA and GEM combination may be a valid alternative to cisplatin-based chemotherapy as front-line treatment for stage IV NSCLC. We have begun a phase III study to verify whether the order of administration of CBDCA and GEM is important and in particular whether CBDCA administered before GEM may be superior.
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Acknowledgements |
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Footnotes |
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