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Annals of Oncology Advance Access originally published online on November 16, 2006
Annals of Oncology 2007 18(3):461-467; doi:10.1093/annonc/mdl415
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© 2006 European Society for Medical Oncology

lung cancer

Randomized phase II three-arm trial with three platinum-based doublets in metastatic non-small-cell lung cancer. An Italian Trials in Medical Oncology study

P Bidoli1, N Zilembo1, D Cortinovis1, L Mariani2, L Isa3, E Aitini4, D Cullurà3, F Pari4, P Nova1, M Mancin1, B Formisano1 and E Bajetta1,*

1 Medical Oncology Unit 2
2 Medical Statistics and Biometry Unit, Fondazione IRCCS "Istituto Nazionale dei Tumori" i, Milan, Italy
3 Department of Oncology, H. Serbelloni, Gorgonzola (MI), Italy
4 Department of Medical Oncology, H.C. Poma, Mantova, Italy

* Correspondence to: Dr E. Bajetta, S.C. Oncologia Medica 2, Fondazione IRCCS "Istituto Nazionale dei Tumori", Via Venezian 1, 20133 Milano, Italy. Tel: +39 02 23902500; Fax: +39 02 23902149; E-mail: emilio.bajetta{at}istitutotumori.mi.it


   Abstract
Top
 Abstract
introduction
 patients and methods
 results
 discussion
 Acknowledgements
 References
 
Background: Many patients with advanced non-small-cell lung cancer (NSCLC) do not tolerate cisplatin-based regimens because of its nonhemathological toxicity.

Patients and methods: We evaluated the response rate safety of new platinum analogue regimens, randomizing 147 patients with nonoperable IIIB/IV NSCLC to (i) carboplatin (area under the curve = 5 mg min/ml) on day 1 plus gemcitabine (GEM) (1000 mg/m2) on days 1 and 8 for six cycles; (ii) same regimen for three cycles followed by docetaxel (Taxotere) (40 mg/m2) on days 1 and 8 plus GEM (1250 mg/m2) on days 1 and 8 for three cycles; (iii) oxaliplatin (130 mg/m2) on day 1 plus GEM (1250 mg/m2) on days 1 and 8 for six cycles.

Results: Intention-to-treat objective response rates were 25%, 25% and 30.6% in arms A, B and C, respectively. Median survival was 11.9, 9.2 and 11.3 months in arms A, B and C, respectively. Grade 3/4 neutropenia/anemia occurred in 29%/12.5%, 10%/16.5% and 8%/6% of arms A, B and C, respectively; grade 3/4 thrombocytopenia in 20.5%, 16.5% and 6%; grade 1/2 neurological toxicity in 43% of arm C.

Conclusions: Oxaliplatin/GEM (arm C) had similar activity to carboplatin/GEM (arm A), but milder hematological toxicity and may be worth testing in a phase III study against carboplatin/GEM in patients not suitable for cisplatin. The sequential regimen gave no additional benefit.

Key words: first-line chemotherapy, NSCLC, phase II study, platinum analogs


   introduction
Top
 Abstract
 introduction
patients and methods
 results
 discussion
 Acknowledgements
 References
 
Platinum-based chemotherapy is considered the standard treatment of locally advanced or metastatic non-small-cell lung cancer (NSCLC). The combination cisplatin plus gemcitabine (GEM) is one of the most active, with an overall response rate of 30%–38%, and median survival of 8–10 months in phase III trials [1, 2]. Although other doublets have produced similar results in several randomized trials [3, 4], a recent meta-analysis indicated that, in combination with a platinum agent, GEM confers a survival advantage over other drugs, with an absolute 1-year survival benefit of 3.9% compared with other platinum-containing regimens [5].

Unfortunately, many patients with advanced NSCLC do not tolerate cisplatin/GEM because of its nonhematological toxicity. In addition, the complexity of administration contraindicate cisplatin in a substantial proportion of patients, particularly older ones and those with comorbid conditions or multiorgan metastases. To improve current results in advanced NSCLC, it is therefore necessary to develop new treatment strategies characterized by milder toxicity profile.

Carboplatin and oxaliplatin, platinum compounds with a mechanism of action similar to that of cisplatin [6], have lower nephro, hematological and gastrointestinal toxicity than cisplatin, are easier to use in the outpatient setting, and do not require specific hydration. Because of these advantages and apparently comparable efficacy, carboplatin and oxaliplatin present as attractive alternatives to cisplatin in combination with GEM in advanced NSCLC.

Carboplatin plus GEM appears to be superior to, or as effective as, other regimens including mitomycin, ifosfamide and cisplatin (MIC) [7] and paclitaxel plus carboplatin [8]. Although meta-analysis data indicate that carboplatin may have lower efficacy than cisplatin [9], no significant survival difference between cisplatin/GEM and carboplatin/GEM was found in other studies [10].

With regard to the combination oxaliplatin/GEM, this regimen has been shown to be synergistic in several human cancer cell lines including NSCLC, but initial results with oxaliplatin/GEM were disappointing, probably because of the heterogeneity of study designs and inclusion criteria [11, 12]. The main toxicity associated with oxaliplatin is a dose-limiting neurological toxicity consisting of generally reversible peripheral neuropathy; however, the drug causes less myelotoxicity than carboplatin and may be active in both cisplatin- and carboplatin-resistant tumors [13].

Since most patients die of progressive disease (PD), even if they initially respond well to chemotherapy, a sequential combination approach, according to the mathematical model of Norton Day and [14] offers the opportunity to use drugs of different mechanisms of action, to reduce the risk of cross-resistance. In this context, docetaxel appears useful, in view of its proven efficacy in NSCLC after platinum failure [15].

We designed an open-label, randomized, multicentric, three-arm phase II study to evaluate the efficacy and tolerability of different platinum combinations in stage IIIB/IV NSCLC. Two of the three arms were determined on the basis of the work of Iaffaioli et al. [16] and preliminary results of two studies from our group [17, 18]. In the first [17], preclinical and clinical findings indicated that administration of carboplatin [area under the curve (AUC) = 5 mg min/ml, day 1] before GEM (1000 mg/m2, days 1–8) gave the better outcome. In the second study [18], performed on a population of highly pretreated patients to determine the appropriate dose of oxaliplatin in association with constant GEM dose, it was found that oxaliplatin can be administered safely at 130 mg/m2 every 3 weeks combined with GEM 1250 mg/m2 on days 1 and 8 of a 21-day cycle. In the third arm, carboplatin/GEM, at the same dose and schedule reported above for three cycles was followed by docetaxel/GEM for three cycles. Docetaxel/GEM is one of best nonplatinum regimens, and appears as a rational alternative to the cisplatin-based doublet in this setting [19].


   patients and methods
Top
 Abstract
 introduction
 patients and methods
results
 discussion
 Acknowledgements
 References
 
patient eligibility
Patients with cytohistologically confirmed stage IIIB/IV NSCLC were eligible for this study, provided they had not received prior chemotherapy. Patients with recurrence after surgery were eligible. Additional eligibility criteria were performance status (PS) of 2 or less according to the Eastern Cooperative Oncology Group scale, age ≤75 years (patients >70 years were eligible if PS ≤1), no brain metastasis, and life expectancy ≥12 weeks. Other requirements included adequate bone marrow (leukocyte count above 4.0 x 109 per l, platelet count above 120 x 109 per l) hepatic and renal function, and negative baseline pregnancy test in women. Patients with a significant history of cardiac disease or evidence of current central or peripheral neuropathy were ineligible. Those with previous cancer were also ineligible (except adequately treated carcinoma of skin or cervix) unless they had been in complete remission for at least 5 years. In addition, patients had to be willing and able to attend for scheduled visits, and comply with the treatment plan, laboratory tests and other trial procedures.

All eligible patients were assessed before registration by physical examination; chest X-ray; computed tomography of the chest, upper abdomen and brain; abdominal ultrasonography; bone scan or skeletal X-ray; fiberoptic bronchoscopy if indicated and complete blood determination. Signed and dated informed consent was obtained from all registered patients indicating that the patient (or a legally acceptable representative) had been informed of all pertinent aspects of the trial. The study was approved by the National Cancer Institute of Milan Ethics Committee and by the ethics committee of each participating center. The study was conducted in accordance with ethical principles embodied in the Declaration of Helsinki and good clinic practice guidelines.

treatment plan
Eligible patients were registered centrally and randomized to receive one of the three schedules (Figure 1). Patients in arm A received carboplatin (AUC = 5 mg min/ml) on day 1 plus GEM (1000 mg/m2) on days 1 and 8 for six cycles. Patients in arm B received the same regimen for three cycles followed by docetaxel (40 mg/m2) on days 1 and 8 plus GEM (1250 mg/m2) on days 1 and 8 for three cycles. Patients in arm C received oxaliplatin (130 mg/m2) on day 1 plus GEM (1250 mg/m2) on days 1 and 8 for six cycles. Blood counts were performed on days 1 and 8 before infusion, then weekly. Hepatic and renal functions were evaluated at each cycle on day 1. Cycles were repeated every 3 weeks if absolute granulocyte count (AGC) was ≥1.5 x 109 per l and platelet count was ≥100 x 109 per l. If grade ≥2 hematological toxicity occurred on day 1, treatment could be delayed for 1 week. If toxicity persisted, the treatment was administered as follows: if AGC was between 1.0 and 1.5 x 109 per l and platelet count between 75 and 100 x 109 per l, doses were reduced by 25%; if AGC was ≤1.0 x 109 per l and platelet counts ≤75 x 109 per l, treatment was delayed by a further week; subsequently if AGC remained low, the cycle was considered concluded. If grade ≥2 hematological toxicity was documented on day 8, treatment was delayed for 1 week. In the event of persistent toxicity, the treatment cycle was considered concluded and the patient was restarted on the next cycle at the third week. Patients were not allowed any other anticancer drugs. Growth factor support, antiemetics and therapy for sensory neuropathies were permitted at the investigator's discretion. In responding patients and patients with stable disease (SD), a maximum of six cycles of chemotherapy was given. Patients were removed from the study for PD, unacceptable toxicity (as defined by the protocol or determined by the treating physician) or patient refusal.


Figure 1
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  		Figure 1. Study design.

 
assessment of efficacy and toxicity
The primary end points of this phase II study were the response rate and toxicity of the three regimens. Disease extent was assessed at baseline; patients were then evaluated every three cycles to assess objective response according to World Health Organization criteria [20]. Complete response (CR) was defined as disappearance of all disease. For patients with measurable disease, a partial response (PR) was defined as ≥50% decrease of the sum of the products of the largest perpendicular diameters of all measurable lesions. For CR and PR, confirmation by assessment not less than 4 weeks after the initial observation was necessary. SD was defined as <50% decrease or <25% increase in the sum of the products of the diameters of the lesions with no new lesions appearing. PD was defined as a >25% size increase of at least one measurable lesion, or appearance of a new lesion. Patients could be assessed at any time in the event of suspected disease progression.

Secondary end points were time to progression (TtP) and overall survival (OS). TtP was the time from randomization to disease progression, death or last known follow-up. OS was time from randomization to death or last known follow-up. Intention-to-treat analyses of response rate, TtP and OS were performed. Duration of response was defined as time from initial documentation of response to failure (disease progression or death).

Safety was evaluated in all patients who received at least one cycle. Adverse events were graded according to National Cancer Institute Common Toxicity Criteria version 2.0 [21].

statistical analysis
The trial was conducted using the Bryant and Day [22] two-stage design. For the sample size calculation, type I and II errors were assumed as 0.10; a response rate of 40% and severe acute toxicity rate (grades 3 and 4) of ≤10% were considered sufficient to warrant further investigation, whereas a response rate of 20% and severe acute toxicity rate of 30% were considered unacceptable. Stage I of the study required 17 patients to be enrolled in each arm; if ≤4 responses or ≥5 severe acute toxic effects were observed on either arm, the trial was to be prematurely closed. Otherwise, the trial would proceed to stage II and accrual continues until 46 eligible patients were enrolled in each arm. If ≥13 responses and ≤10 severe acute toxic effects occurred in any arm, the regimen of that arm was considered worthy of further testing.

Statistical analysis included simple descriptive statistics (medians for continuous variables and proportions for categorical data). Confidence intervals (CIs) of proportions were calculated from the exact binomial distribution. Progression-free survival and OS curves were estimated with the Kaplan-Meier method.


   results
Top
 Abstract
 introduction
 patients and methods
 results
discussion
 Acknowledgements
 References
 
patient characteristics
From October 2001 to November 2004, 147 patients (49 in arm A, 48 in arm B and 50 in arm C) were enrolled in the study from six Italian centers (Figure 2). On review, two patients were ineligible and were excluded from the analysis: one (arm A) did not receive the study drugs because of deterioration in PS and the other (arm C) had brain metastases. The three arms were reasonably well balanced as indicated by patient characteristics (Table 1). A total of 132 (90.3%) of 145 assessable patients had stage IV disease. The most prominent histology was adenocarcinoma (64%) with male predominance (72%). Median age was 62 years, range 27–75. Seventeen patients were >70 years of age.


Figure 2
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  		Figure 2. Flow of participants through each stage of study.

 

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  		Table 1. Patient characteristics

 
efficacy
Intent-to-treat responses in each study arm, together with objective response rates (ORRs), are given in Table 2. Per protocol ORRs were 26.7% (95% CI 14.6–41.9) in arm A, 27.9% (95% CI 15–43.7) in arm B and 33.3% (95% CI 20–49) in arm C. Median response duration was 8.2 months (range 5.9–9.6) in arm A, 6.3 months (range 5.0–15.0) in arm B, 5.4 months (range 3.4–9.3) in arm C. With a median follow-up of 27 months, median TtPs were 6.4 (range 4.9–8.2), 4.9 (range 4.0–7.2) and 5.8 (range 4.5–7.8) months in arms A, B and C, respectively (Figure 3). Median survival times were 11.9 (range 9.7–15.8), 9.2 (range 7.5–12.2) and 11.3 months (range 8.3–13.4) in arms A, B and C, respectively (Figure 4).


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  		Table 2. Intent-to-treat responses in the three treatment arms

 

Figure 3
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  		Figure 3. Progression-free survival.

 

Figure 4
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  		Figure 4. Overall survival.

 
Estimated 1- and 2-year survival rates were 48.5% (95% CI 36.0–65.4) and 24.9% (95% CI 14.4–43.2) in arm A; 36.3% (95% CI 24.7–53.3) and 13.4% (95% CI 5.7–31.8) in arm B and 48.1% (95% CI 35.4–65.3) and 14.1 (95% CI 6.1–32.5) in arm C.

treatment administration and safety
A total of 652 cycles were administered: 230 in arm A, 199 in arm B and 223 in arm C. Details of treatment administration including dose intensity and dose delay are shown in Table 3. Hematological toxicity is shown in Table 4. Grade 3–4 neutropenia occurred in 29% of patients in arm A, 10% in arm B and 8% in arm C. Grade 3–4 anemia occurred in 12.5%, 6% and 2% of patients in arms A, B and C, respectively. Grade 3–4 thrombocytopenia occurred in 20.5%, 16.5% and 6% of patients in arms A, B and C, respectively. Symptomatic bleeding was not observed in any arm. Nonhematological toxicity was generally mild, with grade 4 toxicity in never more than 2% of patients. Grade 3 toxicity was also fairly infrequent and mainly manifested as nausea/vomiting and asthenia (Table 5). In arm C, neurological toxicity, related to the use of oxaliplatin, occurred in 43% of patients and consisted of grade 1–2 reversible paresthesia in all cases. In patients >70 years, no grade 3/4 toxicity was observed.


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  		Table 3. Treatments administered

 

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  		Table 4. Hematologic toxic effects in patients who received at least one cycle of treatment

 

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  		Table 5. Nonhematological toxic effects for patients who received at least one cycle of treatment

 

   discussion
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
Acknowledgements
 References
 
This three-arm randomized phase II study was carried out to indicate hypotheses regarding efficacy and tolerability in the widely used doublet carboplatin/GEM, in oxaliplatin/GEM and in a sequential carboplatin/GEM followed by the nonplatinum regimen docetaxel/GEM.

The carboplatin/GEM combination is increasingly used in Europe and the United States as a consistently effective first-line chemotherapy in advanced NSCLC [23]. Two meta-analyses [9, 24] found that cisplatin-based was superior to carboplatin-based chemotherapy in terms of responses but this did not translate into better survival. By contrast, a meta-analysis to assess the feasibility of substituting carboplatin for cisplatin in combination with GEM or docetaxel showed no marked differences in efficacy between cisplatin- and carboplatin-containing regimens, although a slight trend favoring carboplatin/GEM was observed. Furthermore, a comparison of toxicity profiles indicated that carboplatin/GEM was less toxic [25].

In the present trial, we had an ORR of 25% (2 CR and 10/48 PR) with carboplatin/GEM. This is within the range 19.6%–33.3% obtained in other trials using similar schedules (not all randomized) [10, 26–29], but lower than reported by other experiences [7, 28] in which the ORR was >40%. The present ORR was also lower than that obtained in our previous single-institution study of four carboplatin/GEM schedules (35%), and much lower than the 50% ORR obtained in the same study when carboplatin was given before GEM. However, the latter finding was probably a random overestimate, arising from the selection process in which this regimen was chosen as the best of the four tested.

In spite of this disappointing ORR, median survival time and 1-year and 2-year survival in the carboplatin/GEM arm of present study were somewhat better than in our previous experience [17]: 11.9 months, 48.5% and 24.9% versus 11 months, 44% and 11%. Furthermore, median and 1-year survival in this study were similar to those reported using more intensive carboplatin/GEM regimens, in which GEM was given at a higher dose (1250 mg/m2) [26, 27].

Similar median and 1- to 2-year survival results were obtained recently in a phase III randomized study conducted by the London Lung Cancer Group. In this study, carboplatin/GEM was significantly more effective than MIC with low-dose cisplatin (50 mg/m2) [7]. Moreover, the smaller randomized phase III study of the Czech Lung Cancer Cooperative Group, which compared a 3-week carboplatin/GEM schedule with cisplatin (80 mg/m2)/GEM did not translate the longer duration of response of the cisplatin/GEM arm into a significant survival advantage [10].

Although well tolerated, easy to administer in the outpatient setting, and associated with less nonhematological toxicity than cisplatin, carboplatin/GEM is often associated with secondary hematological effects, principally thrombocytopenia [7, 10, 27]. Our experience was that carboplatin/GEM was associated with grade 3/4 neutropenia, anemia and thrombocytopenia in 29%, 12.5% and 20.5% of patients, respectively. These results appear worse than those obtained in the sequential and oxaliplatin/GEM arms.

With regard to our sequential arm results, we note that the docetaxel/GEM combination has recently been shown to produce similar OS to the well-known cisplatin/vinorelbine regimen but with less toxicity [19]. However, in our study, which employed this promising regimen in sequence after carboplatin/GEM, there was no additional benefit relative to the doublet alone (ORR 25% in both arms, median survival 11.9 and 11.3 months). Furthermore, the toxicity profile of the sequential arm was intermediate between that of carboplatin/GEM and oxaliplatin/GEM. Moreover, while not experiencing clinically significant toxicity, arm B (sequential arm) patients were characterized by lower compliance resulting in premature discontinuation in some cases (total cycles given 199, versus 230 in arm A and 223 in arm C). Our results with the sequential regimen are consistent with recent experience with carboplatin/GEM followed sequentially by docetaxel alone [29] in which the sequential regimen results were similar to those obtained with other standard doublets and did not represent a significant improvement in the treatment of advanced NSCLC.

We found that arm C (oxaliplatin/GEM) had an ORR of 30.6% (1 CR and 14/49 PR) which is slightly better than the 25% ORR of the other two arms. It is noteworthy, in addition, that we were able to deliver the planned therapy to most patients in arm C: median dose intensity 0.88 versus 0.79 in arm A (carboplatin/GEM); delayed cycles 10.3% versus 19.1% in arm A (Table 3). This result is also slightly better than the ORR of 25% and median survival of 7.3 months reported by another Italian trial—the only one with a comparable chemo-naive patient population (85% stage IV) [30]. Our better results may be due to the fact that the other Italian study used a lower GEM dose (2000 mg/m2 versus 2500 mg/m2) and included 6.7% of patients with brain metastases, while we excluded patients with unfavorable prognostic factors. The toxicity profile of both experiences was similar, with transient grade 3/4 neutropenia and thrombocytopenia in 8% and 6%, respectively, in our study compared with 11.7% and 8.3%, respectively, in the other study [31].

Our findings in this phase II randomized study are, therefore, that the carboplatin and oxaliplatin doublets show encouraging antitumor efficacy in patients with advanced NSCLC; while, despite strong theoretical and biological rationales, the sequential strategy gives no additional benefit. Survival in arm A appeared slightly better than in the other two arms of the present study, although the trial did not have the power to reveal survival differences. Importantly, the favorable toxicity profile of oxaliplatin/GEM, in the context of similar survival and efficacy to carboplatin/GEM, indicates that the former may be worth testing in a noninferiority phase III study against carboplatin/GEM particularly in patients with advanced NSCLC not suitable for cisplatin. Finally, in view of their ease of administration, oxaliplatin and carboplatin doublets may, in this patient setting, lend themselves to integration with new targeted therapies (e.g. antibodies to growth factors and growth factor receptors) which promise to be the future in advanced NSCLC.


   Acknowledgements
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 Acknowledgements
References
 
Additional participating personnel and their institutes: Sergio Pessa, Unità di Oncologia Medica, Ospedale "Cà Foncello", Treviso; Italo Stifani, Unità di Pneumologia, Istituti Ospitalieri di Cremona, Cremona; Giuseppe Nastasi, Unità di Oncologia Medica, Ospedale Pesenti Fenaroli, Alzano Lombardo (Bergamo). The authors thank the Scientific Office of Italian Trials in Medical Oncology for assistance in preparing the manuscript and DC Ward for help with English. Presented in preliminary forms at: ECCO-11 (European Cancer Conference in Oncology) Meeting, Lisbon, Portugal, October 2001; AIOM (Associazione Italiana di Oncologia Medica) Meeting, Naples, Italy, November 2001; 16th ICACT (International Congress on Anti Cancer Treatment) Congress, Paris, France, February 2005; 41st Annual Meeting of ASCO (American Society of Clinical Oncology), Orlando, USA, May 2005; 11th World Conference on Lung Cancer (IASLC International Association for the Study of Lung Cancer), Barcelona, Spain, July 2005; AIOM (Associazione Italiana di Oncologia Medica) Meeting, Naples, Italy, October 2005.

Received for publication May 24, 2006. Revision received September 25, 2006. Accepted for publication October 5, 2006.


   References
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 Acknowledgements
 References
 
1. Crinò L, Scagliotti GV, Ricci S, et al. (1999) Gemcitabine and cisplatin versus mitomycin, ifosfamide, and cisplatin in advanced non-small-cell lung cancer: a randomized phase III study of the Italian Lung Cancer Project. J Clin Oncol 17:3522–3530.[Abstract/Free Full Text]

2. Scagliotti GV, De Marinis F, Rinaldi M, et al. (2002) Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell-lung cancer. J Clin Oncol 20:4285–4291.[Abstract/Free Full Text]

3. Kelly K, Crowley J, Bunn PA Jr, et al. (2001) Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non-small-cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol 19:3210–3218.[Abstract/Free Full Text]

4. Rosell R, Gatzemeier U, Betticher DC, et al. (2002) Phase III randomised trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients with advanced non-small-cell lung cancer: a cooperative multinational trial. Ann Oncol 13:1539–1549.[Abstract/Free Full Text]

5. Le Chevalier T, Scagliotti GV, Natale R, et al. (2005) Efficacy of gemcitabine plus platinum chemotherapy compared with other platinum containing regimens in advanced non-small-cell lung cancer: a meta-analysis of survival outcomes. Lung Cancer 47:69–80.[CrossRef][ISI][Medline]

6. Cosaert J and Quoix E. (2002) Platinum drugs in the treatment of non-small-cell lung cancer. Br J Cancer 87:825–833.[CrossRef][ISI][Medline]

7. Rudd RM, Gower NH, Spiro SG, et al. (2005) Gemcitabine plus carboplatin versus mitomycin, ifosfamide, and cisplatin in patients with stage IIIB or IV non-small-cell lung cancer: a phase III randomized study of the London Lung Cancer Group. J Clin Oncol 23:142–153.[Abstract/Free Full Text]

8. Treat J, Belani CP, Edelman MJ, et al. (2005) A randomized phase III trial of gemcitabine (G) in combination with carboplatin (C) or paclitaxel (P) versus paclitaxel plus carboplatin in advanced (Stage IIIB, IV) Non-Small Cell Lung Cancer (NSCLC): update of the Alpha Oncology trial (A1-99002L). ASCO Annual Meeting (Abstr 7025).

9. Hotta K, Matsuo K, Ueoka H, et al. (2004) Meta-analysis of randomized clinical trials comparing cisplatin to carboplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol 22:3852–3859.[Abstract/Free Full Text]

10. Zatloukal P, Petruzelka L, Zemanova M, et al. (2003) Gemcitabine plus cisplatin vs GEM plus carboplatin in stage IIIb and IV non-small cell lung cancer: a phase III randomized trial. Lung Cancer 41:321–331.[CrossRef][ISI][Medline]

11. Faivre S, Le Chevalier T, Monnerat C, et al. (2002) Phase I-II and pharmacokinetic study of gemcitabine combined with oxaliplatin in patients with advanced non-small-cell lung cancer and ovarian carcinoma. Ann Oncol 13:1479–1489.[Abstract/Free Full Text]

12. Franciosi V, Barbieri R, Aitini E, et al. (2003) Gemcitabine and oxaliplatin: a safe and active regimen in poor prognosis advanced non-small cell lung cancer patients. Lung Cancer 41:101–106.[CrossRef][ISI][Medline]

13. Raymond E, Chaney SG, Taamma A, et al. (1998) Oxaliplatin: a review of preclinical and clinical studies. Ann Oncol 9:1053–1071.[Abstract/Free Full Text]

14. Norton L and Day R. (1991) Potential innovations in scheduling of cancer chemotherapy. In DeVita VT, Hellman S, Rosemberg SA (Eds.). Important Advances in Oncology(Lipincott Williams & Wilkins, Philadelphia) pp. 57–72.

15. Shepherd FA, Dancey J, Ramlau R, et al. (2000) Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 18:2095–2103.[Abstract/Free Full Text]

16. Iaffaioli RV, Tortoriello A, Facchini G, et al. (1999) A phase I-II study of gemcitabine and carboplatin in stage IIIB-IV non-small-cell lung cancer. J Clin Oncol 17:921–926.[Abstract/Free Full Text]

17. Bajetta E, Stani SC, De Candis D, et al. (2003) Preclinical and clinical evaluation of four GEM plus carboplatin schedules as front-line treatment for stage IV non-small-cell lung cancer. Ann Oncol 14:242–247.[Abstract/Free Full Text]

18. Bidoli P, Stani SC, Mariani L, et al. (2004) Phase I study of escalating doses of oxaliplatin in combination with fixed dose GEM in patients with non-small cell lung cancer. Lung Cancer 43:203–208.[CrossRef][ISI][Medline]

19. Pujol JL, Breton JL, Gervais R, et al. (2005) Gemcitabine plus docetaxel for advanced or metastatic non-small cell lung cancer: similar survival to cisplatin plus vinorelbine and less toxicity. Cancer Treat Rev 31:571–576.[CrossRef][ISI][Medline]

20. World Health Organization. (1979) WHO Handbook for Reporting Results of Cancer Treatment. (WHO, WHO Offset Publication No. 48. Geneva, Switzerland).

21. National Cancer Institute. Cancer Therapy Evaluation Program Common Toxicity Criteria, Version 2.0. [on-line] 1998; http://ctep.info.nih.gov/reporting/index.html (1 and 7 November 2006, date last accessed).

22. Bryant J and Day R. (1995) Incorporating toxicity considerations into the design of two-stage phase II clinical trials. Biometrics 51:1372–1383.[CrossRef][ISI][Medline]

23. Cullen M. (2005) The development of gemcitabine and carboplatin in the treatment of non-small-cell lung cancer. Lung Cancer 50:S5–S7.

24. Ardizzoni A, Tiseo M, Boni L, et al. (2006) CISCA (cisplatin vs. carboplatin) meta-analysis: an individual patient data meta-analysis comparing cisplatin versus carboplatin-based chemotherapy in first-line treatment of advanced non-small cell lung cancer (NSCLC). J Clin Oncol 24:366S (Abstr 7011).

25. Natale RB. (2004) Gemcitabine-containing regimens vs other in first-line treatment of NSCLC. Oncology 18:27–31.

26. Thomas P, Robinet G, Gouva S, et al. (2006) Randomized multicentric phase II study of carboplatin/gemcitabine and cisplatin/vinorelbine in advanced non-small cell lung cancer GFPC 99-01 study (Groupe francais de pneumo-cancerologie). Lung Cancer 51:105–114.[CrossRef][ISI][Medline]

27. Sederholm C, Hillerdal G, Lamberg K, et al. (2005) Phase III trial of GEM plus carboplatin versus single-agent GEM in the treatment of locally advanced or metastatic non-small-cell lung cancer: the Swedish Lung Cancer Study Group. J Clin Oncol 23:8380–8388.[Abstract/Free Full Text]

28. Danson S, Middleton MR, O'Byrne KJ. (2003) Phase III trial of gemcitabine and carboplatin versus mitomycin, ifosfamide, and cisplatin or mitomycin, vinblastine, and cisplatin in patients with advanced non-small cell lung carcinoma. Cancer 98:542–553.[CrossRef][ISI][Medline]

29. Chiappori A, Simon G, Williams C, et al. (2005) Phase II study of first-line sequential chemotherapy with GEM-carboplatin followed by docetaxel in patients with advanced non-small cell lung cancer. Oncology 68:382–390.[CrossRef][ISI][Medline]

30. Mazzanti P, Massacesi C, Rocchi MB, et al. (2003) Randomized, multicenter, phase II study of gemcitabine plus cisplatin versus gemcitabine plus carboplatin in patients with advanced non-small cell lung cancer. Lung Cancer 41:81–89.[ISI][Medline]

31. Cappuzzo F, Novello S, De Marinis F, et al. (2005) Phase II study of gemcitabine plus oxaliplatin as first-line chemotherapy for advanced non-small-cell lung cancer. Br J Cancer 93:29–34.[CrossRef][ISI][Medline]


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