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Annals of Oncology Advance Access published online on March 9, 2007
Annals of Oncology, doi:10.1093/annonc/mdm061
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© 2007 European Society for Medical Oncology

Phase III study in stage IV non-small-cell lung cancer patients treated with two courses of cisplatin/gemcitabine followed by a randomization to three additional courses of the same combination or gemcitabine alone

S Novello1,*, P Bruzzi2, C Barone3, R Buosi4, A Masotti5, G Michetti6, M Fioretti7, S Barbera8, M Spatafora9, L Garetto10, P Mazzanti11, V Dongiovanni3, G Selvaggi1, L Crinò12 and GV Scagliotti1

1 Department of Clinical and Biological Sciences, Thoracic Oncology Unit, San Luigi Hospital, University of Turin, Orbassano, Turin
2 National Cancer Research Institute, Genoa
3 Division of Medical Oncology, S. Giovanni Battista Hospital, Torino
4 Division of Medical Oncology, Novara
5 Division of Respiratory Diseases, Borgo Trento Hospital, Verona
6 Division of Respiratory Diseases, Ospedali Riuniti, Varese
7 Division of Respiratory Diseases, Ospedale di Circolo, Varese
8 Division of Respiratory Diseases, Mariano Santo Hospital, Cosenza
9 Division of Respiratory Diseases, Cervello Hospital, Palermo
10 Division of Medical Oncology, IRCC Candiolo, Torino
11 Division of Medical Oncology, Ospedale Civile, Ancona
12 Division of Medical Oncology, Silvestrini Hospital, Perugia, Italy

* Correspondence to: Dr S. Novello, University of Turin, Department of Clinical and Biological Sciences, Thoracic Oncology Unit, San Luigi Hospital, Regione Gonzole 10, 10043 Orbassano, Torino, Italy. Tel: +39-011-9026-978; Fax: +39-011-9038-616; E-mail: silvia.novello{at}unito.it


   Abstract
Top
 Abstract
introduction
 patients and methods
 results
 discussion
 Acknowledgements
 References
 
Background: This randomised phase III study investigated if in responsive and stable disease (SD) stage IV patients after two courses of cisplatin and gemcitabine, single-agent gemcitabine (experimental arm) was not inferior in terms of overall survival (OS) to cisplatin–gemcitabine (standard arm).

Patients and methods: Noninferiority was defined as an increase in the hazard of death (HR) ≤1.33 in the experimental arm. From January 2001 to February 2004, 340 patients were registered and 250 were randomised. Cisplatin was administered on day 1 at 75 mg/m2 and Gemcitabine on days 1 and 8 at 1250 mg/m2 every 3 weeks.

Results: Response rate after two courses was 29%. The 1-year progression-free survival was 13% in both arms. One-year survival was 52% in the standard and 42% in the experimental arm for an HR of 1.21 [90% confidence interval (CI) 0.97–1.51]. Postprogression survival was in favour of the standard arm (HR 1.30, 95% CI 0.99–1.70, P = 0.051). Grades 3–4 toxicity favoured in the experimental arm.

Conclusion: In responsive and SD patients with stage IV non-small-cell lung cancer it was not possible to demonstrate that three courses of gemcitabine alone are not inferior, in terms of OS, to the standard approach of three courses of cisplatin–gemcitabine.

chemotherapy, cisplatin, gemcitabine, metastatic disease, non-small-cell lung cancer


   introduction
Top
 Abstract
 introduction
patients and methods
 results
 discussion
 Acknowledgements
 References
 
Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related mortality and ~30%–40% of the newly diagnosed cases present with locally advanced or metastatic disease [1]. For stage IV patients with good performance status (PS) and without significant weight loss, cisplatin-based chemotherapy remains the cornerstone of treatment [2], although the survival benefit is limited [3] and sometimes overweighed by toxicity. The best response to chemotherapy is usually observed within the first two to three cycles and two randomised trials in patients with advanced NSCLC showed that prolongation of chemotherapy beyond three to four courses does not offer additional clinical benefit but only increases toxicity and these data are consistent with a retrospective analysis carried out previously using phase II data [4–6]. If cisplatin administration is required for the whole program of chemotherapy is an issue not still addressed.

Gemcitabine has not only shown single-agent activity in advanced NSCLC [7–9], but it is a reference drug for the treatment of NSCLC in the elderly [10], it has an excellent tolerability and it is commonly used in combination with cisplatin in the front-line treatment of advanced NSCLC [11–13].

This paper reports about a phase III study in which nonprogressing patients with stage IV NSCLC after two courses of gemcitabine/cisplatin were randomised to receive three additional courses of the same combination or gemcitabine alone. The trial had overall survival (OS) as the primary end point and was designed as a noninferiority study. This was an institution-initiated study and was exclusively funded by the University of Torino, Department of Clinical and Biological Sciences which acted as the sponsor of the study.


   patients and methods
Top
 Abstract
 introduction
 patients and methods
results
 discussion
 Acknowledgements
 References
 
patient selection
Patients eligible for the study had to have clinically evaluable stage IV disease as defined by objective imaging studies and supported by a histologic or cytologic diagnosis of NSCLC. The presence of at least one unidimensional measurable disease was mandatory and bidimensionally measurable disease was preferable. Radiation therapy was permitted if concluded at least 4 weeks before entering the study (as long as the irradiated site was not the only site of measurable disease), and prior surgery was allowed if the patient met all the other criteria specified. Patients were required to have an Eastern Cooperative Oncology Group PS of zero to two and a life expectancy of at least 12 weeks. Additional eligibility criteria included adequate bone marrow reserve [absolute neutrophil count (ANC) ≥2.0 x 109/l, platelets ≥100 x 109/l, haemoglobin ≥10 g/l, and haematocrit ≥30%], liver, and renal function (creatinine <1.5 times the upper normal limits).

Patients were excluded from the study for active infection, symptomatic central nervous system metastases requiring emergency radiotherapy and/or corticosteroids, serious concomitant systemic disorders, second primary malignancy (except in situ carcinoma of the cervix or nonmelanomatous skin cancers), and severe cardiovascular diseases. Patients who were pregnant or breast-feeding were not entered into the study. Patients with clinically relevant weight loss (>5% in the 6 months before entering the study) were also excluded.

Written informed consent was obtained from each patient before entering the study. The study was conducted under the approval of the appropriate ethical review boards and the guidelines for good clinical practice. The recommendations of the Declaration of Helsinki for biomedical research involving human subjects were also followed.

treatment schedule and randomization
All patients were registered at the time of study entry and they received two courses of cisplatin 75 mg/m2 on day 1 and gemcitabine 1250 mg/m2 on days 1 and 8 every 21 days. After two courses, all patients underwent full clinical and computed tomography (CT) scan evaluation including brain, chest, and upper abdomen, and in case of objective response or stable disease (SD) were randomised to receive three additional courses of the same combination (standard arm) or gemcitabine alone at the same dose and schedule (experimental arm). Standard intravenous hydration was administered along with cisplatin and antiemetic prophylactic therapy according to hospital policy was delivered during chemotherapy infusion.

No dose reduction was planned for haematological toxicity but a treatment delay of 1 week was requested if ANC was <1.5 x 109/l and/or platelet count <100 x 109/l and/or creatinine clearance <45 ml/min. If treatment was delayed for >2 weeks patients were discontinued from the study. Gemcitabine on day 8 was omitted if ANC was <1.5 x 109/l and/or platelet count <100 x 109/l.

Treatment was continued until there was documented progression of the neoplastic disease, unacceptable toxicity, or a maximum of five cycles in patients achieving objective response or SD. Poststudy treatments were not planned and left to the discretion of each investigator participating in the study.

baseline and treatment evaluation
Before entering the study, patients underwent a medical history, physical examination and tumour measurement of neoplastic lesions. Full blood count (FBC), blood chemistries, urinalysis, electrocardiogram, vital signs and calculated creatinine clearance were collected within 7 days before starting treatment. Four to six weeks before entering the study all patients underwent brain, chest, and upper abdomen CT scan. Additional prestudy assessments included other imaging tests [e.g. resonance imaging (magnetic resonance imaging)], if necessary for tumour measurement or if clinical or laboratory data suggested evidence of disease in a site not evaluable by other imaging modalities. The same assessment method used to determine disease status at baseline was used consistently for efficacy evaluation throughout the study.

At baseline and before each cycle, patients completed the Lung Cancer Symptom Score questionnaire and received a limited medical history, physical examination, and a chest X-ray. During each cycle, patients underwent blood chemistries on day 1 and FBC weekly. At the end of each cycle, patients were assessed for toxicity according to the National Cancer Institute Common Toxicity Criteria version 1 (see http://www.fda.gov/cder/cancer/toxicityframe.htm).

statistical considerations
The study was designed as a noninferiority study. The primary end point of the trial was the OS, while secondary end points included the response rate, 1-year survival rate, evaluation of toxicity profile, and of quality-of-life assessment using the Lung Cancer Symptom Scale. OS was computed from randomization to death or last follow-up, whichever first. Noninferiority was defined as an increase in the hazard of death (HR) ≤1.33 in the experimental arm, as compared with the standard arm. This difference was chosen because, due to the palliative nature of the treatment, only a nonmarginal increase in the risk of death was deemed worth the toxicity associated with three more cycles of the two-drugs regimen. One-year survival rate was expected to be ≥33% in the standard arm, and, under the null hypothesis, 23% in the experimental arm. The 1-year survival estimation in the standard arm was on the basis of the mean of the median survival observed in two recently published randomised trials in advanced NSCLC [14, 15].

In order to have a 80% power of rejecting the null hypothesis of inferiority (HR = 1.33) at the 5%, one-sided, significance level, under the alternative hypothesis that the experimental arm was associated with no increase in the hazard of death (HR = 1) it was necessary to observe 220 events (i.e. deaths). One-sided tests are often used in noninferiority trials, as the difference in the other direction (i.e. HR >> 1.33) has no clinical interest. The final analysis was planned when the 220th event was observed. On the basis of 220 events, the 90% confidence intervals (CI) of the observed hazard ratio were expected to range between */÷ 1.30. It was planned to enrol 308 patients in a 2-year period, with an additional follow-up of 2 years.

Randomization was carried out at the end of the second cycle to exclude patients with progression of the disease during the first two cycles of therapy. At time of the randomization, patients were stratified according to centre and PS (0–1 versus 2).

With the exception of the primary test of the null hypothesis of inferiority, all tests of hypotheses were conducted at the {alpha} = 0.05 level (one sided), with a 95% CI. All patients who were randomised were included in all analyses according to the intention-to-treat principle. Estimates of time-to-event end points were calculated using the Kaplan–Meier method and compared using the log-rank test. Responses were compared using the Pearson's chi-square test. The effects of baseline factors (PS, brain metastases, squamous cell histology, number of metastatic sites, and disease stage) were assessed for time-to-event end points using the Cox's proportional hazards model and for response using logistic regression. A final model was developed using a backward selection strategy. Treatment was added to the final model to assess its effect when adjusted for the presence of relevant prognostic factors.

assessment of response
The assessment of response was carried out after two courses of chemotherapy and at the end of treatment (after cycle 5) using standard World Health Organisation criteria [16], still commonly used when the study was initiated. In this study, responsive patients did not undergo to repeated imaging evaluation 4 weeks later to confirm the response.

Lung Cancer Symptom Score
Quality-of-life assessment was completed by patients using the Lung Cancer Symptom Scale (LCSS). The instrument has been already fully validated in its original form and normative data have also been published for the measure [17, 18].

Before patients started the treatment and at the end of every cycle with the exclusion of the evaluation at the end of cycle 5, physicians handed out the questionnaire to each patient.

Data were analyzed on an intention-to-treat basis and reported as mean value ± standard deviation as cumulative data for the first two cycles and as separated data for the randomised part of the study. To demonstrate trends, the baseline score for each item and for the average score was subtracted from that of the subsequent visits and then categorised as declined (>10 mm), preserved (–10 mm to 10 mm) or improved (<–10 mm). Trends of symptoms in the two arms were compared, at each assessment, by means of the chi-square test for trend.


   results
Top
 Abstract
 introduction
 patients and methods
 results
discussion
 Acknowledgements
 References
 
registered patients
From January 2001 to February 2004, 340 patients from 41 Italian centres were enrolled and 10 centres, enrolling 10+ patients each, accounted for 222 patients (65%). Median age was 62 years (range 35–76), 78% were male, 94% of enrolled patients had PS of zero or one. Main patient and tumour characteristics are summarised in Table 1.


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  		Table 1. Patient's characteristics of registered and randomised patients

 
Thirty-two patients were not assessable at the end of cycle 2 because of early withdrawal for patient's decision (n = 10), protocol violation (one case), unacceptable toxicity (five cases), worsening of symptoms (six cases), and death after the inclusion in the protocol (three cases) and were considered as early progression. Among all registered patients, response status after two courses of cisplatin and gemcitabine (GC) was 1% complete response (CR), 28% partial response (PR), 47% SD, 24% progressive disease (PD). Seven patients with objective response or SD were not randomised (four for patient's decision and three deaths).

Up to May 2006 among 340 registered patients, 311 patients died and 335 progressed.

randomised patients
Two hundred and fifty patients (73% of the registered patients) were subsequently randomised (Supplemental Table 1, available online). There were more patients with PR allocated to the standard arm (n = 52) rather than to the experimental arm (n = 41). Twenty-six patients with asymptomatic brain metastases were randomised. At the time of the final analysis among randomised patients, 225 deaths (111 in the standard arm, 113 in the experimental arm) already occurred.

Among randomised patients, the distribution of the response rate (CR/PR/SD) after two courses of induction chemotherapy was as follows: experimental arm 2%/31%/67%; standard arm 0/42%/58% (Pearson chi-square P = 0.08). Noteworthy, in the standard arm there were more patients with more than one metastatic site (51% versus 41%) and brain metastases (14% versus 6%) although neither difference was statistically significant. However, response rate at cycle 2 did not differ according to the number of metastatic sites and presence/absence of brain metastases (data not shown).

At the end of cycle 5 when a second assessment of the tumour response was carried out, the distribution of responses was as follows (CR/PR/SD/PD): experimental arm 0/14.5%/62.5%/23%; standard arm: 1%/26%/50%/24% (Pearson chi-square, P = 0.06). The overall objective response rate was 21% and it was independent of the number of metastatic sites (P = 0.84). Responsive patients were 26% in the group with brain metastases and 20% in those without brain metastases (P = 0.41).

OS and progression-free survival
At the time of the analysis, 224 patients had died, 113 in the experimental arm and 111 in the standard arm. Overall 1-year survival rate was 52% in the standard arm and 42% in the experimental arm for a hazard ratio of 1.21 (90% CI 0.97–1.51) (Figure 1). As a consequence, it was not possible to reject the null hypothesis of a 33% increase in the hazard of death in the experimental arm. The 1-year progression-free survival was 13% in both arms (HR = 1.00, 95% CI 0.77–1.28) (Supplemental Figure 1, available online).


Figure 1
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  		Figure 1. Overall survival rate in the standard arm (dotted line) and the experimental arm (continuous line). One-year survival was 52% in the standard arm and 42% in the experimental arm [hazard of death (HR) = 1.21, 90% confidence interval (CI) 0.97–1.51].

 
At the multivariable analysis, the only significant prognostic variable associated with survival was PS. Objective response after two cycles was not found to be an independent prognostic factor (P = 0.47). After adjustment for PS, the hazard ratio for the experimental arm was 1.26 (95% CI 0.96–1.64).

A longer survival after progression was observed in the standard arm and the difference was close to statistical significance (HR = 1.30, 95% CI 0.99–1.70, P = 0.051) (Figure 2).


Figure 2
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  		Figure 2. Survival after progression in the standard arm (dotted line) and the experimental arm (continuous line). Difference was close to statistical significance [hazard of death (HR) = 1.30, 95% confidence interval (CI) 0.99–1.70, P = 0.051].

 
toxicity
The toxicity profiles are shown in Tables 2 and 3. Generally, toxicity was mild and favoured the experimental arm in terms of haematological as well non-haematological toxicity.


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  		Table 2. Grades 3–4 hematological toxicity by cycle in the induction and randomised phases of the study

 

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  		Table 3. Non-hematological toxicity by cycle in the induction and randomised phases of the study

 
During the induction phase, the percentage of cycle delays was 4% mainly secondary to haematological toxicity, while gemcitabine administration on day 8 was omitted in <1% of the cases. Among the 250 randomised patients, only in 3% of the cases there was a cycle delay during the three additional courses of chemotherapy, without significant difference between two arms. No toxic deaths were reported.

quality of life
As shown in Table 4 at baseline, quality-of-life data were obtained in 71% of the registered patients and at cycle 3 in 61% of the randomised patients. The lower numbers of questionnaires at cycles 1 and 2 are mainly related to the dropouts. Time trends (Supplemental Table 2, available online) indicate a better improvement for disease-related symptoms (cough, dyspnoea, haemoptysis) in both arms, without significant differences, while systemic symptoms such as fatigue remained overall unchanged. No significant difference was seen between the two treatment arms at either assessment in any of the considered symptoms. Overall quality-of-life assessment indicates that quality of life did not deteriorate during chemotherapy without any difference between the two arms.


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  		Table 4. Descriptive statistics for Lung Cancer Symptom Scale scores and items (results are reported as mean values ± standard deviation for each cycle of therapy)

 
second-line therapy
Second-line treatment was administered to 25% of registered and nonrandomised patients and they mainly received single-agent docetaxel. Among randomised patients, 48% in both arms received a single-agent second-line treatment being docetaxel (standard arm 50%, experimental arm 44%), vinorelbine (standard 26%, experimental 21%) and gefitinib (standard 14%, experimental 11%) the commonest administered drugs without significant differences between the two arms.


   discussion
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
Acknowledgements
 References
 
Therapeutic guidelines in stage IV NSCLC for the duration of therapy indicate no more than four cycles with the possibility to administer two additional cycles in responsive patients [2].

The present randomised study was carried out in the setting of an Italian network of community hospitals with specific interest in thoracic oncology. Its aim was to investigate in patients with stage IV NSCLC, responsive or with disease stabilisation after two courses of cisplatin–gemcitabine if a treatment with single-agent gemcitabine was an acceptable regimen when compared with the classical approach of three additional courses of cisplatin–gemcitabine, the latter being the most frequently used approach in the centres involved in the study. The study was conducted in a way resembling daily clinical practice and did not conform to standards of a classical phase II and III cancer clinical trials, for instance objective response confirmation was not obtained 4 weeks after the first assessment after two courses of chemotherapy but only at the end of the study treatment. Once more for practical purposes, in case of residual toxicity on day 21, the subsequent course of chemotherapy was not dose reduced but delayed for 1 week.

The objective response rate after two courses of cisplatin–gemcitabine, as evaluated by the investigators, was 29%. This percentage is quite close to that previously reported for the same doublet in another randomised clinical study carried out in Italy [13]. Even if with the limitations related to a limited sample of patients in the present trial, we were able to confirm that patients with clinically stable brain metastases benefit from cytotoxic chemotherapy similarly to any other patient with stage IV NSCLC without brain metastases as already previously reported [12].

The data from this study indicate that although the progression-free survival rate was 13% in both arms, a decreased survival was observed in the experimental arm and the null hypothesis of its inferiority as compared with the standard arm could not be rejected. In this regard, an apparent limitation of this study lies in the fact that only 250 patients were randomised instead of the planned 308, as projected in the study design. However, it should be noted that the number of events required in the original study design to achieve an 80% power was 220. As a consequence the present analysis, on the basis of 224 events, had full power to detect the noninferiority.

The observed difference in OS contrasts with the identical progression-free survival in the two study groups and is entirely due to a difference in survival after progression. Analysis of postprogression survival shows an even higher difference favouring the standard arm approaching the boundary of the hazard ratio for the superiority. This difference may not be ascribed to differences in the type of second-line treatment because no differences were seen in relation to the type and amount of drugs administered in second line.

A potential explanation for the increased survival in the standard arm might be the unbalance in the proportion of responders allocated in the experimental and standard arm (33% and 42%, respectively). However, when considered in a multivariable Cox model, response to therapy after two courses was not an independent prognostic factor for survival.

Another explanation to be considered is the potential inferior antitumour activity of gemcitabine alone in comparison to cisplatin–gemcitabine. Against this hypothesis there are the similar progression rates at the response reassessment after cycle 5 (standard arm 24%, experimental arm 23%) and the lack of any difference in overall progression-free survival.

Data about second-line therapies were recorded, making a difference in treatments after progression an unlikely explanation for the observed difference in postprogression survival. Alternatively, it could be speculated that a more prolonged exposure to cisplatin can eradicate a superior percentage of chemosensitive clones or can make the tumour less aggressive even after cisplatin withdrawal.

Concerning the toxicity profile in the two treatment arms, there was no evidence of any type of cumulative toxicity or any significant worsening of the toxicity profile in the arm receiving five courses of cisplatin–gemcitabine. However, the more frequent grades III–IV haematological toxicity observed in this arm was clinically manageable.

Cisplatin is still a backbone agent in advanced NSCLC and, theoretically, the best study design would have considered the inclusion of a third arm of two courses of cisplatin/gemcitabine followed by three additional courses of cisplatin alone. However, this hypothesis was considered not fully appropriate because of historical data showing a lower single-agent activity for cisplatin than for gemcitabine.

In conclusion, five courses of cisplatin and gemcitabine are superior to two courses with both drugs followed by three courses of gemcitabine alone and the results of this trial fail to support the hypothesis that a conservative approach of two courses of cisplatin-based chemotherapy followed by three additional courses of gemcitabine alone can be considered clinically equivalent (noninferior) to the standard regimen. Despite the identical progression-free survival, a nonstatistically significant superiority in OS for the standard approach of five courses of cisplatin–gemcitabine was observed both in univariate and multivariate analyses. On the basis of the results of the present randomised clinical trial, the experimental approach of two courses of cisplatin–gemcitabine followed by three courses of single-agent gemcitabine is not recommended and this approach should only be considered for those patients with poor tolerability to cisplatin-based chemotherapy, particularly in terms of non-hematological toxic effects.


   Acknowledgements
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 Acknowledgements
References
 
Preliminary results of this study have been presented at the 40th and 41st annual meeting of the American Society of Clinical Oncology, 5–8 June 2004 in New Orleans, LA and 14–17 May 2005 in Orlando, FL, USA.

Received for publication October 26, 2006. Revision received January 22, 2007. Accepted for publication January 23, 2007.


   References
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 Acknowledgements
 References
 
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7. Perng R-P, Chen Y-M, Ming-Liu J, et al. (1997) Gemcitabine versus the combination of cisplatin and etoposide in patients with inoperable non-small cell lung cancer in a phase II randomized study. J Clin Oncol 15:2097–2102.[Abstract/Free Full Text]

8. Manegold C, Bergman B, Chemaissani A, et al. (1997) Single-agent gemcitabine versus cisplatin-etoposide: early results of a randomised phase II study in locally advanced or metastatic non-small-cell lung cancer. Ann Oncol 8:525–529.[Abstract/Free Full Text]

9. Vansteenkiste J, Vandebroek J, Nackaerts K, et al. (2001) Clinical benefit response in advanced non-small cell lung cancer. A multicentre prospective randomised phase III study of single agent gemcitabine versus cisplatin-vindesine. Ann Oncol 12:1221–1230.[Abstract/Free Full Text]

10. Gridelli C, Perrone F, Gallo C, et al. (2003) Chemotherapy for elderly patients with advanced non-small cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomised trial. J Natl Cancer Inst 95:362–372.[Abstract/Free Full Text]

11. Le Chevalier T, Scagliotti G, 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 47:169–80.[CrossRef][Web of Science][Medline]

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