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Phase III Double-Blind, Placebo-Controlled Study of Thalidomide in Extensive-Disease Small-Cell Lung Cancer After Response to Chemotherapy: An Intergroup Study FNCLCC cleo04–IFCT 00-01

Jean Louis Pujol, Jean Luc Breton, Radj Gervais, Marie-Laure Tanguy, Elisabeth Quoix, Philippe David, Henri Janicot, Virginie Westeel, Sabine Gameroff, Jean Genève, Dominique Maraninchi

From the Centre Hospitalier Universitaire, Montpellier; Hôpital de Belfort, Belfort; Centre Régional de Lutte Contre le Cancer, François Baclesse, Caen; Service de Biostatistique et d'Information Médicale, Hôpital la Pitié-Salpêtrière, Assistance Publique des Hôpitaux de Paris; Hôpital du Kremlin Bicêtre, Assistance Publique des Hôpitaux de Paris; Bureau des Études Cliniques et Thérapeutiques, Fédération Nationale des Centres de Lutte Contre le Cancer, Paris; Hôpital Universitaire de Strasbourg, Strasbourg; Hôpital Universitaire de Clermont Ferrand, Clermont Ferrand; Hôpital Universitaire de Besançon, Besançon; and Institut Contre le Cancer Paoli Calmette, Marseille, France

Address reprint requests to Jean Louis Pujol, MD, PhD, Hôpital Universitaire Arnaud de Villeneuve, 34295 Montpellier Cedex 5, France; e-mail: jl-pujol{at}chu-montpellier.fr

	ABSTRACT

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Purpose This randomized, double-blind, placebo-controlled phase III study aimed to determine whether thalidomide prolongs survival of patients with extensive-disease small-cell lung cancer (SCLC).

Patients and Methods One hundred nineteen patients received two courses of etoposide, cisplatin, cyclophosphamide, and 4'-epidoxorubicin (PCDE). Responder patients who had recovered from chemotherapy toxicity were randomly assigned to receive four additional PCDE cycles plus thalidomide (400 mg daily) or placebo.

Results After the first two PCDE cycles, objective response rate was 81.5%, and 92 patients were randomly assigned to placebo (n = 43) or thalidomide (n = 49). Median exposure duration to placebo was 4.5 months, and median exposure to thalidomide was 4.9 months. Patients treated with thalidomide had a longer survival compared with patients who received placebo, although the difference was not statistically significant (minimal follow-up, 3 years; median survival time, 11.7 v 8.7 months, respectively; log-rank test: hazard ratio [HR] = 0.74; 95% CI, 0.49 to 1.12; P = .16). Patients with a performance status (PS) of 1 or 2 who received thalidomide had a significantly longer survival (HR = 0.59; 95% CI, 0.37 to 0.92; P = .02). The disease also progressed slower in patients with PS of 1 or 2 receiving thalidomide (HR = 0.54; 95% CI, 0.36 to 0.87; P = .02), whereas the difference did not reach statistical significance for the whole population (HR = 0.74; 95% CI, 0.49 to 1.12; P = .15). Neuropathy occurred more frequently in the thalidomide group compared with the placebo group (33% v 12%, respectively).

Conclusion Treatment with thalidomide was not associated with a significant improvement in survival of SCLC patients. There was pronounced heterogeneity in survival outcomes between groups of patients. Some benefit was observed among patients with a PS of 1 or 2 (exploratory analyses), deserving further studies targeting angiogenesis in this disease.

	INTRODUCTION

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Chemotherapy remains the backbone of small-cell lung cancer (SCLC) therapy, particularly in extensive-disease SCLC (ED-SCLC).¹ Despite the high chemotherapy sensitivity of SCLC, 2- and 5-year survival rates are low because of the frequent occurrence of chemotherapy-resistant relapses. The circumvention of the secondary chemotherapy resistance has been addressed using different treatment modalities. One of them is to intensify induction treatment; another is to contain the residual disease as dormant by maintenance therapy.

Etoposide and cisplatin combination might be considered as an emerging worldwide accepted regimen, even if no standard regimen can be unerringly defined for ED-SCLC.¹ More aggressive regimens remain controversial, and recent attempts at increasing dose-intensity have been restricted to patients with a more favorable presentation.^2-6 Despite all efforts in improving induction chemotherapy, including targeting c-Kit receptor tyrosine kinases,⁷ survival rates remained low.

SCLC clinically behaves aggressively, with a rapid growth and metastatic spread. Because both features are thought to be angiogenesis-dependent processes, therapy targeting angiogenesis could be considered as a potential new approach. Thalidomide, a glutamic acid derivative, inhibits angiogenesis by repression of key angiogenic genes and downregulation of vascular endothelial growth factor and basic fibroblast growth factor secretions.⁸ Thalidomide has shown promising activity in hematologic malignancies^9,10 and various solid tumors such as melanoma, Kaposi's sarcoma,¹¹ and renal cell carcinoma,¹² although more data are needed to firmly establish the role of this antiangiogenic therapy in solid tumors.

We hypothesized that the combination of an active chemotherapy and a maintenance therapy using an antiangiogenic compound could improve the outcome of patients with ED-SCLC. Therefore, we designed a two-step study. First, patients received two cycles of chemotherapy. Then, responders entered the second step and were randomly allocated to receive four additional chemotherapy cycles plus thalidomide or a placebo until progression or unacceptable toxicity. We present here the final results of this French intergroup, prospective, randomized, phase III, double-blind, placebo-controlled study of thalidomide in ED-SCLC patients after response to chemotherapy.

	PATIENTS AND METHODS

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Patients
Enrollment criteria (step 1). Patients with newly diagnosed, histologically confirmed SCLC with extensive disease (defined according to the Veteran's Administration Lung Cancer Group¹³) and at least one bidimensionally measurable lesion took part in this study. Other eligibility criteria consisted of Eastern Cooperative Oncology Group performance status (PS) of 2 or less; age less than 75 years; weight loss less than 10% during the previous 3 months; baseline neutrophil count of 2,000/µL; platelet count of 100,000/µL; levels of bilirubin, alkaline phosphatase, and transaminases less than 1.5x the normal upper limits (except in case of liver metastases); sodium more than 125 mmol/L; normal calcemia; creatinine clearance 60 mL/min; left ventricular ejection fraction more than 50%; no prior treatment; and no symptomatic brain metastases. For women, an age of 50 years or older was required together with a postmenopausal status. Signed informed consent had to be obtained before random assignment, and the study was approved by a national ethics committee (Montpellier University, Montpellier, France).

For all patients, evaluation before receiving any drug treatment included clinical examination, CBC, blood chemistry including lactate dehydrogenase measurements, isotopic or echographic ventricular ejection measurement, standard chest x-ray, computed tomography (CT) scan of chest and brain, CT or ultrasonography of the upper abdomen, fiberoptic bronchoscopy, bone scan, and bone marrow biopsy.

Criteria at random assignment (step 2). After two cycles of etoposide, cisplatin, cyclophosphamide, and 4'-epidoxorubicin (PCDE), patients who had achieved a complete or a partial response and who had recovered from any toxicity greater than grade 1 were planned to continue chemotherapy until the sixth cycle.

Treatments
Chemotherapy consisted of 4'-epidoxorubicin 40 mg/m² on day 1, cisplatin 100 mg/m² on day 2, and etoposide 100 mg/m² and cyclophosphamide 400 mg/m² on days 1 through 3, administered every 28 days, as previously described.⁵ Considering the toxicity observed in this previous study, granulocyte colony-stimulating factor (G-CSF) support was recommended. Dose reduction modalities and schedule of administration have been previously described in detail.⁵ The decision as to what treatment to propose to patients who had experienced relapse was left to the discretion of each center's policy.

Thalidomide (and placebo) was presented as a capsule containing 100 mg on a 28-capsule blister (Laphal Industries Laboratory, Allauch, Marseille, France). Responder patients who had recovered from toxicity were randomly assigned to receive four additional cycles of PCDE plus daily oral thalidomide at 400 mg/d or its placebo (double-blinded) all at once in the first half of the day. Random assignment was determined with stratification by center according to a labeled therapeutic batch system. A two-step decrease of thalidomide dose was planned according to tolerance (200 mg daily, then 100 mg daily). The following toxicities were considered as requiring dose reduction: neuropathy (grade 2), constipation (grade 2), drowsiness (grade 2), and electrophysiologic decrease in nerve conduction velocities of at least 20%. Two dose reductions were allowed, but treatment withdrawal was required for patients experiencing long-lasting toxicity (or grade 3 to 4 toxicity), unacceptable adverse effects interfering with daily activity, or putative life-threatening events such as thromboembolic disease. The on-study drug was planned for a maximal duration of 2 years.

Patients were assessed for tumor response every other cycle (systematically using CT scan and all other tests characterizing the disease) and at the end of chemotherapy or at the time when any symptoms of possible progression occurred. After completion of the treatment program, patients were observed every 3 months using CT scan. Tumor response evaluation and toxicity assessment were carried out according to the WHO recommendations.¹⁴

Statistical Considerations
The hypothesis was that a 20% improvement in the survival at 7 months (ie, 9 months after registration) could be achieved in the thalidomide group, taking into account previous results with PCDE.⁵ The planned accrual was 200 randomly assigned patients, taking into account a ß risk of 20% and an risk of 5%. Random assignment was stratified according to center. All analyses were performed on an intent-to-treat basis. All statistical tests were two sided.

Overall survival was defined as the time from random assignment to the date of death. Progression-free survival was defined as the period lasting from random assignment to the date of the first observation of progressive disease or death. Probability of survival was estimated using the Kaplan-Meier method,¹⁵ and survival difference was analyzed using log-rank tests. Associations between the treatment groups, potential prognostic variables (eg, sex, liver metastatic involvement, PS), and survival were tested using a Cox model.¹⁶ The selection of variables to be tested in the model was made using the results of univariate analysis. We also included in the model an interaction term between PS and treatment group. The classic forward selection of variable procedure was used. P < .05 was considered significant. SAS software packages (SAS Institute, Cary, NC) were used.

The distribution of qualitative variables between groups was compared using the ² test or the Fisher's exact test. For each patient, the dose-intensity was calculated taking into account the actual time of treatment plus 4 weeks. Relative dose-intensity, for each drug, was defined as the ratio of the actual mean dose per unit of time to the planned mean dose per unit of time.¹⁷ Treatment durations were compared with the Mann-Whitney U test.

	RESULTS

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Patients
Because of a low accrual rate, the study was shortened, with final analysis performed in January 2007. From October 2000 to January 2004, 119 patients were accrued by 21 French institutions, and 92 patients were randomly assigned. At inclusion (step 1), 81.5% of patients were male (97 of 119 patients). Eastern Cooperative Oncology Group PS was 0 in 37 patients (31.4%), 1 in 70 patients (59.3%), and 2 in 11 patients (9.3%). The mean weight loss ± standard deviation during the 3 previous months was 3.2% ± 3.4% of the body weight. Seven patients (5.9%) were ineligible as a result of limited disease (n = 2), hypercalcemia (n = 1), weight loss more than 10% (n = 1), and low creatinine clearance and thrombocytopenia (n = 2); in addition, one woman was less than 50 years old. Metastatic profile is shown in Table 1, with liver metastases presented as the most frequent site with a trend towards a higher frequency of this disease characteristic in the thalidomide group.

Random Assignment
Figure 1 describes the flow diagram of the clinical trial. Among the 119 registered patients, 97 achieved a response at the end of step 1. Among the 22 remaining patients, one patient did not receive the planned treatment because of limited disease, seven had SD or progressive disease, nine experienced toxicity or intercurrent disease precluding response evaluation, one did not undergo disease evaluation, and four died as a result of treatment toxicity. Among the 97 responder patients, five were ineligible because of lack of toxicity recovery. A patient who did not fit full eligibility criteria at the end of step 1 was inadvertently randomly assigned, and one of the eligible patients withdrew his consent. Therefore, 92 patients were randomly allocated to the placebo (n = 43) or thalidomide group (n = 49). Patient demographics and disease characteristics at the time of random assignment did not significantly differ between the two groups (Table 1).

View larger version (20K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Flow diagram of the randomized, phase III, double-blind, placebo-controlled study of thalidomide versus placebo in extended-disease small-cell lung cancer patients. PD, progressive disease.

View larger version (17K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Overall survival from date of random assignment. HR, hazard ratio.

View larger version (16K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Progression-free survival from date of random assignment. HR, hazard ratio.

	DISCUSSION

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This study could be discussed taking three different slants of its design: the timing of introduction of the antiangiogenic therapy, the choice of the chemotherapy program, and finally, the planned dose of thalidomide.

This trial was designed as a two-step study. The first step allowed patient selection to propose random assignment to patients with reduced tumor burden. Patients with SD only were not considered as eligible, taking into account the negative prognostic significance of the lack of response to chemotherapy.^1,5 Considering responder patients as eligible for random assignment was decided to avoid exposing poor prognostic patients to an adjuvant treatment associated with potential toxicity. This introduced a survival bias because a selected population of responders is also one that yields a better prognosis. Another possible study design would have been to complete a shortened chemotherapy program ( four cycles) before random assignment. Such a design was applied in the North Central Cancer Treatment Group study with interferon gamma versus observation in SCLC responder patients¹⁸ and in as study of marimastat.¹⁹ The advantage of the sequential design (chemotherapy followed by maintenance therapy) is to avoid potential overlap of toxicity. In our study, the three-fold higher rate of grade 2 neurotoxicity observed in the thalidomide group compared with the placebo group could have been favored by the combined effects of cisplatin and thalidomide. The rationale for starting the thalidomide therapy early in the treatment was the potential synergistic antitumor effect of thalidomide and cytotoxic agents, as has been observed for patients suffering from multiple myeloma,²⁰ and the possibility of starting the adjuvant therapy as soon as possible because progression-free survival observed in ED-SCLC patients is usually too short to investigate a sequential schedule.

The case of intensive chemotherapy in ED-SCLC is still debatable. Many opinion leaders have pointed out that, because of the poor prognosis of patients suffering from extensive disease at the time of diagnosis, a doublet regimen consisting of cisplatin-etoposide or carboplatin-etoposide could be considered as reasonable chemotherapy.¹ However, disease extent is only one factor among other important determinants of poor prognosis.^21,22 ED-SCLC patients for whom the disease extent is the sole poor prognostic determinant could be referred for more aggressive chemotherapy.^23-25 The four-drug chemotherapy regimen with recommended G-CSF support adopted in this thalidomide study produced a high response rate, including complete response, in a short period of time, allowing the eligibility of a high proportion of patients with minimal burden at the time of random assignment.

Targeted therapies have recently been proposed as a possible alternatives to maintenance chemotherapy.²⁶ Until now, noncytotoxic agents, such as interferons or metalloproteinase inhibitors, have failed to prolong SCLC patient survival.^18,19,27-29 The recent research regarding thalidomide therapy in cancer suggests that the daily doses adopted at the beginning of its use (400 mg or more) were too high and were responsible for a high incidence of toxicity and a poor safety profile. Currently, doses less than 400 mg daily are considered as well tolerated, with most adverse effects ranging from mild to moderate in severity. This would promote a new schedule of administration beginning with low dosage and subsequent individual increase in the dose according to tolerance. There is a trend toward the use of a dosage as low as 100 mg daily³⁰ in different diseases including multiple myeloma.²⁰ Nevertheless, at least in the setting of myeloma, some studies have suggested the possibility of a dose-response effect. At the time when this study was designed, there was no standard dosage for thalidomide therapy in cancer, but the optimal dose for each patient was considered to be the highest dose that patients could tolerate with the least amount of adverse effects, which, in most patients, was thought to range between 200 and 400 mg daily.

In conclusion, the poor safety profile of thalidomide precludes its routine use in SCLC. Mature results of our study with 3-year minimal follow-up did not demonstrate survival benefit by adding thalidomide to chemotherapy at time of tumor response. Pronounced heterogeneity in survival outcomes between groups of patients, with some evidence of benefit among PS 1 to 2 patients, is a clue in favor of the angiogenesis process as a therapeutic window in SCLC therapy and deserves further research in the same setting, evaluating more modern antiangiogenic agents with better safety profile.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: N/A Research Funds: N/A Testimony: N/A Other: Elisabeth Quoix, GlaxoSmithKline

	AUTHOR CONTRIBUTIONS

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Conception and design: Jean Louis Pujol, Dominique Maraninchi

Administrative support: Sabine Gameroff, Jean Genève, Dominique Maraninchi

Provision of study materials or patients: Jean Louis Pujol, Jean Luc Breton, Radj Gervais, Elisabeth Quoix, Philippe David, Henri Janicot, Virginie Westeel

Collection and assembly of data: Sabine Gameroff, Jean Genève

Data analysis and interpretation: Jean Louis Pujol, Marie-Laure Tanguy, Sabine Gameroff

Manuscript writing: Jean Louis Pujol, Marie-Laure Tanguy

Final approval of manuscript: Jean Louis Pujol, Jean Luc Breton, Radj Gervais, Marie-Laure Tanguy, Elisabeth Quoix, Philippe David, Henri Janicot, Virginie Westeel, Sabine Gameroff, Jean Genève, Dominique Maraninchi

Other: Jean Louis Pujol [Chairman of FNCLCC cleo04-IFCT 00-01 phase III study]

	NOTES

 
Supported by the French League Against Cancer.

Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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Submitted March 24, 2007; accepted May 29, 2007.

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