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Phase II trial of thalidomide as maintenance therapy for extensive stage small cell lung cancer after response to chemotherapy
Lung Cancer (2007) 56, 377—381
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Phase II trial of thalidomide as maintenance therapy for extensive stage small cell lung cancer after response to chemotherapy Afshin Dowlati ∗, Shanmuga Subbiah, Matthew Cooney, Kimberly Rutherford, Tarek Mekhail, Pingfu Fu, Robert Chapman, Anne Ness, Tania Cortas, Joel Saltzman, Nathan Levitan, Gregory Warren Division of Hematology/Oncology, Case Western Reserve University and University Hospitals of Cleveland, CASE Comprehensive Cancer Center, Cleveland, Ohio and Henry Ford Hospital, Detroit, MI, United States Received 16 November 2006; received in revised form 17 January 2007; accepted 22 January 2007 Presented in part at the American Society of Clinical Oncology, Annual Meeting, Orlando, 2005
KEYWORDS Small cell lung cancer; Thalidomide; Phase II
Summary Background: Extensive-stage small cell lung cancer (SCLC) is a highly aggressive malignancy for which little therapeutic progress has been made over the past 20 years. SCLC is a highly angiogenic tumor and targeting angiogenesis is being investigated. The putative mechanism of action of thalidomide is through inhibition of new blood vessel formation. This trial was designed to evaluate thalidomide in ES-SCLC. Patients and methods: Patients who had received first-line chemotherapy without disease progression were eligible. Patients received thalidomide 200 mg daily as maintenance therapy starting 3—6 weeks after completion of chemotherapy. Results: Thirty patients were enrolled. Toxicity was minimal with grade 1 neuropathy in 27% of patients and only one case of grade 3 neuropathy. Median survival from time of initiation of induction chemotherapy was 12.8 months (95% CI: 10.1—15.8 months) and 1-year survival of 51.7% (95% CI: 32.5—67.9%). Median duration on thalidomide was 79 days. Conclusion: Thalidomide 200 mg daily is well tolerated when given as maintenance therapy for ES-SCLC after induction chemotherapy. Further evaluation of anti-angiogenic agents in SCLC is warranted. © 2007 Elsevier Ireland Ltd. All rights reserved.
∗
Corresponding author at: Division of Hematology/Oncology, University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, OH 44106, United States. Tel.: +1 216 844 1228; fax: +1 216 844 5234. E-mail address: [email protected] (A. Dowlati). 0169-5002/$ — see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2007.01.020
378
1. Introduction Small cell lung cancer (SCLC) remains a lethal neoplasm despite known initial high response rates to systemic chemotherapy. Most patients present with distant metastases and are considered to have extensive-stage SCLC (ES-SCLC) [1]. Chemotherapy as first-line treatment results in a response rate of about 70%, the majority being partial responses. For patients who have stable disease or a response to four cycles of induction treatment (i.e. absence of progression on first-line treatment) a median overall survival of 11.2 months with a 1-year survival of 40.3% can be expected [2]. Unfortunately all patients will progress, with a median time to relapse of 2.3 months upon completion of first line chemotherapy [3]. In attempts to improve survival for this disease investigators have modified the upfront chemotherapeutic regimens [4] or have added a third [5] or have investigated the concept of sequential non-cross resistant therapy [3]. Unfortunately none of the above has resulted in improved survival. The addition of novel targeted therapies has recently been investigated with very disappointing results. These include vaccine based trials [6], as well as agents targeting c-kit [7] and bcl-2 [8]. Small cell lung cancer is a highly angiogenic tumor. A number of pro-angiogenic circulating factors have been implicated in this disease. High pre-treatment serum level of vascular endothelial growth factor (VEGF) is associated with poor outcome in SCLC [9] and serum VEGF levels correlate better with tumor stage than albumin, neuron-specific enolase or lactate dehydrogenase [10]. High pre-treatment serum concentration of basic fibroblast growth factor (bFGF) is also a predictor of poor prognosis in SCLC [11]. The multi-targeted kinase inhibitor SU5416 inhibits SCLC and angiogenesis in murine xenograft models, in part by blocking Kit-mediated VEGF expression [12]. Thalidomide has been shown to modulate angiogenesis [13]. The antitumor activity of thalidomide may also be related the enhancement of natural killer cell activity [14], enhancement of cytotoxic T-lymphocyte function [15] as well as general increase in Th1-type cellular immunity [16]. In addition, anecdotal reports suggested possible benefit to this approach in SCLC. Long-term survival of a patient with SCLC following treatment with thalidomide and combination chemotherapy has been reported [17]. Given the above we evaluated the potential role of thalidomide in patients with ES-SCLC in remission after induction therapy.
2. Patients and methods 2.1. Study endpoints and eligibility criteria The primary endpoint of this phase II trial was the 1year survival rate with a secondary end-point of toxicity of thalidomide in this patient population. Eligibility criteria included histologically confirmed ES-SCLC patients who have achieved a complete or partial response or stable disease after four to six cycles of induction chemotherapy. Extensive stage SCLC is defined as disease not meaning the definition of limited stage disease (limited stage defined as disease confined to one hemithorax without pericardial or pleural
A. Dowlati et al. effusion and thus encompassable by a single radiotherapy port) [18]. Further eligibility requirements were age ≥18 years, ECOG performance status of ≤2 and estimated life expectancy of ≥2 months. Women who were pregnant, lactating or not using adequate contraception were excluded from the study. Negative pregnancy test was required in all women of child bearing age. This study was approved by the institutional review boards of each participating center. Written informed consent was obtained from all patients.
2.2. Treatment Patients received thalidomide as a single dose of 200 mg at bedtime starting 3—6 weeks after completion of induction chemotherapy. Since constipation was an expected side effect of treatment with thalidomide, a bowel regime with bisacodyl was routinely given to all patients. Treatment was continued for a maximum of 12 months or until unacceptable toxicity, patient refusal, intercurrent illness preventing continuation of therapy, progressive disease or death occurred.
2.3. Baseline and treatment assessments A complete history and physical exam, performance status evaluation, complete blood counts with differential, blood chemistry, tumor measurements with CT scan of thorax and abdomen, bone scan and other appropriate tests as indicated were done at screening, followed by 3 monthly intervals and at the end of the study (12 months). Toxicity was evaluated according to National Cancer Institute Common Toxicity Criteria version 2.0. RECIST criteria were used for evaluation of disease progression [19].
2.4. Statistical analysis This open-label, single-agent, multicenter study evaluated whether thalidomide increases overall and 1-year survival compared to historical control. Extensive SCLC patients who have been treated with chemotherapy and respond or have stable disease have a 1-year survival rate of 40.3% [2]. This was used as the historical control. A 60% 1-year survival was expected with the addition of thalidomide. With type I error of 0.05, a power of 80%, 18 months of accrual and a followup period of 12 months the estimated sample size needed for the study are 28 patients based on one-sided exponential MLE test. Time to progression for thalidomide was measured from the date of starting thalidomide to the date of death or disease progression. Overall survival was measured from the date of chemotherapy treatment (date of cycle 1 of induction chemotherapy) until death and censored at the date of last follow-up for survivors. Progression free survival and overall survival were estimated by Kaplan—Meier method [20]. Thus, 1-year overall survival was compared with that from the historical controls. Ninety-five percent confidence intervals were calculated.
3. Results A total of 30 patients were enrolled onto the study between November 2002 and September 2005 at two Cancer Centers.
Phase II trial of thalidomide as maintenance therapy Table 1
379
Patient characteristics
Characteristic
Number of patients
Age (years) Median Range
63 50—78
Sex Male Female
11 19
ECOG performance status 0 1 2
8 21 1
Sites of metastatic disease Liver Bone Brain Adrenal Other Prior therapy Chemotherapy Cisplatin/etoposide Carboplatin/etoposide Cisplatin/irinotecan Carboplatin/irinotecan Radiotherapy Brain Bone
13 8 8 4 4
11 17 1 1 4 1
Response to prior induction Chemotherapy Complete response (CR) Partial response (PR) Stable disease (SD)
1 28 1
Number of metastatic sites 1 2 ≥3
8 7 15
Fig. 1 Kaplan—Meier estimation of overall survival with 95% confidence intervals; overall survival was measured from start of induction chemotherapy to death and censored at last followup for survivors.
(95% CI: 32.5—67.9%). The median time to disease progression from initiation of thalidomide was 2.4 months (95% CI: 1.8—3 months). The median duration on thalidomide therapy was 79 days (95% CI: 34—85 days).
3.2. Toxicity Table 2 summarizes the main drug-related toxicities that were observed during this study. The major side effects were peripheral neuropathy and constipation, reported in 30% and 16% of the patients, respectively, although the severity was mild in majority of the patients. One patient developed grade 3 peripheral neuropathy, which gradually improved with stopping the drug and eventually the neuropathy disappeared. Other toxicities reported as possibly related to thalidomide included rash, fatigue and weakness, pulmonary embolism and dizziness. These were infrequent and were easily managed. The primary reason for discontinuation of study drug was progressive disease.
4. Discussion Patient characteristics are shown in Table 1. Median age was 63 years (range 50—78) with ECOG performance status 0 or 1 in 96% of patients. Of these patients one patient was not evaluable for toxicity or survival since the patient never took study drug. All the patients received platinum based induction chemotherapy, 28 (93%) patients had partial response to their chemotherapy, 1 (3%) patient had complete response and the other (3%) had stable disease. Sites of metastases at the time of enrollment included liver (36%), brain (26%) and bone (26%). Five patients (16%) had received prior radiotherapy to metastatic sites, including four patients (13%) had whole brain radiation therapy.
3.1. Time-to-event measures At the time of this analysis only one patient remains alive. Median survival from initial treatment (chemotherapy cycle1) for all 29 patients was 12.8 months (95% CI: 10.1—15.8 months) (Fig. 1). The 1-year survival was 51.7%
Although ES-SCLC is initially chemo-responsive, it will ultimately relapse. Dose intensification strategies unfortunately have failed to improve survival [1]. Trial designs evalu-
Table 2 grade
Selected drug-related toxicity by maximum CTC CTC grade
Neuropathy Constipation Fatigue/weakness Rash Dyspnea Pulmonary embolism Dizziness Dry mouth
1
2
3
4
8 (27%) 5 (16%) 1 (3)% 1 (3%) 1 (3%) 0 1 (3%) 1 (3%)
0 0 0 1 (3%) 0 0 0 0
1 (3%) 0 1 (3%) 0 0 0 0 0
0 0 0 0 0 1 (3%) 0 0
380 Table 3
A. Dowlati et al. Comparison of reported trials of maintenance thalidomide in SCLC
Author
Patients
Thalidomide dose (mg)
Concurrent with chemotherapy
Median overall survival (months)
1-Year survival (%)
Phase II Dowlati Lee
30 26
200 100
No Yes
12.8 10.2
51.7 42
49 43
400 Placebo
Yes (after cycle 2) —
11.7 8.7
49 30.2
Phase III Pujol
ating novel targeted agents in SCLC have included the so-called window of opportunity design where new agents have been given to patients who are chemotherapy-na¨ıve. However, this approach has been problematic for these new agents as most patients have had rapid progression of their disease [7]. Another strategy to test novel therapeutics in SCLC is targeting the residual disease after initial debulking chemotherapy. At this stage of disease, tumor volume will be at its minimum and thus the experimental agent has a potentially improved chance of efficacy. Many investigators are thus using the concept of maintenance therapy in patients having obtained a response as the best way to test novel targeted agents in SCLC [21]. Given the importance of angiogenesis in SCLC and the success with thalidomide or its analogues in variety of other cancers we tested this agent in the setting of ES-SCLC as maintenance therapy. A Hoosier Oncology Group (HOG) trial treated patients with ES-SCLC with four cycles of induction chemotherapy [2]. After four cycles patients with progressive disease were removed from trial. In the non-progressing group (response or stable disease to induction treatment), they were then randomized to observation or oral etoposide as maintenance treatment. A total of 72 patients went on the observation arm. The authors of this trial reported the median and 1year survival (from the start of induction chemotherapy) of the observation arm to be 11.2 months (95% CI: 9.8—12.3 months) and 40.3%, respectively. Thus the observation arm of this trial meaning those patients who received four cycles of chemotherapy without progression prior to randomization were used as our historical control and basis of comparison to our study population. Our study population was similar to this historical control in terms of number of metastases (approximately 50% of patients having ≥3 sites of metastases) but differed in terms of gender where 33% of the HOG trial participants were female as opposed to 63% in our trial. Our study showed an overall median survival of 12.8 months and 1-year survival of 51.7%. It did not, however, meet our predefined primary endpoint of a 60% 1-year survival and our TTP was only 2.4 months similar to the observation arm on E7593 [3]. Further recent data on thalidomide in this setting has also been reported (Table 3). In a recent randomized phase III trial presented in abstract form by Pujol et al. at ASCO 2006 [22] the arm receiving thalidomide had a significantly higher overall survival (11.7 months, hazard ratio for death of 0.48) as compared to the arm randomized to placebo (8.7 months). In addition, the survival achieved on the thalidomide arm of Pujol trial was very similar to that
seen in our study. There are however differences between these two trials. Our trial used a dose of thalidomide of 200 mg while Pujol et al. used 400 mg. This higher dose explains the increased toxicity observed by Pujol where a grades 2—4 neuropathy rate of 32.6% was observed while this was 3% on our trial. Another difference is that Pujol et al. added thalidomide starting from cycle 3 after documenting a response to chemotherapy after cycle number 2. In yet another study of thalidomide in SCLC, Lee and colleagues treated 26 patients with induction chemotherapy and concurrent thalidomide at 100 mg daily for up to six cycles and continuing thalidomide in responding or stable disease patients for up to 2 years or until progression [23]. Median survival of 10.2 months and a 1-year survival of 42% were observed. Table 3 shows all three mentioned thalidomide trials in comparison. Doses of thalidomide have ranged between 100 and 400 mg with no obvious dose benefit. However median and 1-year survivals are very similar across all three trials. These results have led to a large randomized trial of more than 700 patients comparing the addition of thalidomide or not to the treatment of SCLC in the United Kingdom. In conclusion, thalidomide 200 mg daily as maintenance therapy for ES-SCLC patients who have stable disease or a response following platinum-based induction chemotherapy was well tolerated. Further exploration of thalidomide and its analogues in SCLC are warranted.
Conflict of interest Supported by a research grant from Celgene Inc.
References [1] Johnson BE, Janne PA. Basic treatment considerations using chemotherapy for patients with small cell lung cancer. Hematol Oncol Clin North Am 2004;18:309—22. [2] Hanna NH, Sandler AB, Loehrer PJ, Ansari R, Jung SH, Lane K, et al. Maintenance daily oral etoposide versus no further therapy following induction chemotherapy with etoposide plus ifosfamide plus cisplatin in extensive small-cell lung cancer: a Hoosier Oncology Group randomized study. Ann Oncol 2002;13:95—102. [3] Schiller JH, Adak S, Cella D, DeVore 3rd RF, Johnson DH. Topotecan versus observation after cisplatin plus etoposide in extensive-stage small-cell lung cancer: E7593—–a phase III trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2001;19:2114—22.
Phase II trial of thalidomide as maintenance therapy [4] Hanna N, Bunn Jr PA, Langer C, Einhorn L, Guthrie Jr T, Beck T, et al. Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol 2006;24:2038—43. [5] Niell HB, Herndon JE, Miller AA, Watson DM, Sandler AB, Kelly K, et al. Randomized phase III intergroup trial of etoposide and cisplatin with or without paclitaxel and granulocyte colonystimulating factor in patients with extensive-stage small-cell lung cancer: Cancer and Leukemia Group B Trial 9732. J Clin Oncol 2005;23:3752—9. [6] Giaccone GC, Debruyne C, Felip E, Chapman PB, Grant SC, Millward M, et al. Phase III study of adjuvant vaccination with Bec2/bacille Calmette-Guerin in responding patients with limited-disease small-cell lung cancer (European Organisation for Research and Treatment of Cancer 08971-08971B; Silva Study). J Clin Oncol 2005;23:6854—64. [7] Soria JC, Johnson BE, Chevalier TL. Imatinib in small cell lung cancer. Lung Cancer 2003;41(Suppl. 1):S49—53. [8] Rudin CM, Kozloff M, Hoffman PC, Edelman MJ, Karnauskas R, Tomek R, et al. Phase I study of G3139, a bcl-2 antisense oligonucleotide, combined with carboplatin and etoposide in patients with small-cell lung cancer. J Clin Oncol 2004;22:1110—7. [9] Salven P, Ruotsalainen T, Mattson K, Joensuu H. High pretreatment serum level of vascular endothelial growth factor (VEGF) is associated with poor outcome in small-cell lung cancer. Int J Cancer 1998;79:144—6. [10] Mall JW, Schwenk W, Philipp AW, Meyer-Kipker C, Mall W, Muller J, et al. Serum vascular endothelial growth factor levels correlate better with tumour stage in small cell lung cancer than albumin, neuron-specific enolase or lactate dehydrogenase. Respirology 2002;7:99—102. [11] Ruotsalainen T, Joensuu H, Mattson K, Salven P. High pretreatment serum concentration of basic fibroblast growth factor is a predictor of poor prognosis in small cell lung cancer. Cancer Epidemiol Biomark Prev 2002;11:1492—5. [12] Litz J, Sakuntala Warshamana-Greene G, Sulanke G, Lipson KE, Krystal GW. The multi-targeted kinase inhibitor SU5416 inhibits small cell lung cancer growth and angiogenesis, in part by blocking Kit-mediated VEGF expression. Lung Cancer 2004;46:283—91. [13] Teo SK. AAPS J 22:E14-19; 2005.
381 [14] Davies FE, Raje N, Hideshima T, Lentzsch S, Young G, Tai YT. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood 2001;98:210—6. [15] Haslett PAJ, Corral LG, Albert M, Kaplan G. Thalidomide costimulates primary human T lymphocytes, preferentially inducing proliferation, cytokine production, and cytotoxic responses in CD8+ subset. J Exp Med 1998;187:1885—92. [16] Corral LG, Haslett PAJ, Muller GW, Chen R, Wong LM, Ocampo CJ, et al. Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-␣. J Immunol 1999;163:380—6. [17] Mall JW, Philipp AW, Mall W, Pollmann C. Long-term survival of a patient with small-cell lung cancer (SCLC) following treatment with thalidomide and combination chemotherapy. Angiogenesis 2002;5:11—3. [18] Mascaux C, Paesmans M, Berghmans T, Branle F, Lafitte JJ, Vallot F, et al. A systematic review of the role of etoposide and cisplatin in the chemotherapy of small cell lung cancer with methodology assessment and meta-analysis. Lung Cancer 2000;30:23—36. [19] Therasse P, Arbuck S, Eisenhauer E, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000;92:205—16. [20] Kaplan EL, Meier P. Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457—81. [21] Pandya J, Levy DE, Hidalgo M, Cohen RB, Lee MW, Schiller JH, et al. A randomized, phase II ECOG trial of two dose levels of temsirolimus (CCI-779) in patients with extensive stage small cell lung cancer in remission after induction chemotherapy. A preliminary report. J Clin Oncol 2005;23(16S) [2005 ASCO Annual Meeting Proceedings. Part I of II (June 1 Suppl.) abstract 7005]. [22] Pujol JL, Breton JL, Gervais R, Tanguy M, Quoix E, David P, et al. A prospective randomized phase II, double blind, placebocontrolled study of thalidomide in extensive-disease small cell lung cancer patients after response to chemotherapy. J Clin Oncol 2006;24(18S) [2006 ASCO Annual Meeting Proceedings. Part I (June 20 Suppl.), abstract 7057]. [23] Lee SM, James LE, Mohamed-Ali V, Boschoff C, Snee M, Brock C, et al. A phase II study of carboplatin/etoposide with thalidomide in small cell lung cancer. Proc Am Soc Clin Oncol 2002;21 [abstract 1251].
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/lungcan
Phase II trial of thalidomide as maintenance therapy for extensive stage small cell lung cancer after response to chemotherapy Afshin Dowlati ∗, Shanmuga Subbiah, Matthew Cooney, Kimberly Rutherford, Tarek Mekhail, Pingfu Fu, Robert Chapman, Anne Ness, Tania Cortas, Joel Saltzman, Nathan Levitan, Gregory Warren Division of Hematology/Oncology, Case Western Reserve University and University Hospitals of Cleveland, CASE Comprehensive Cancer Center, Cleveland, Ohio and Henry Ford Hospital, Detroit, MI, United States Received 16 November 2006; received in revised form 17 January 2007; accepted 22 January 2007 Presented in part at the American Society of Clinical Oncology, Annual Meeting, Orlando, 2005
KEYWORDS Small cell lung cancer; Thalidomide; Phase II
Summary Background: Extensive-stage small cell lung cancer (SCLC) is a highly aggressive malignancy for which little therapeutic progress has been made over the past 20 years. SCLC is a highly angiogenic tumor and targeting angiogenesis is being investigated. The putative mechanism of action of thalidomide is through inhibition of new blood vessel formation. This trial was designed to evaluate thalidomide in ES-SCLC. Patients and methods: Patients who had received first-line chemotherapy without disease progression were eligible. Patients received thalidomide 200 mg daily as maintenance therapy starting 3—6 weeks after completion of chemotherapy. Results: Thirty patients were enrolled. Toxicity was minimal with grade 1 neuropathy in 27% of patients and only one case of grade 3 neuropathy. Median survival from time of initiation of induction chemotherapy was 12.8 months (95% CI: 10.1—15.8 months) and 1-year survival of 51.7% (95% CI: 32.5—67.9%). Median duration on thalidomide was 79 days. Conclusion: Thalidomide 200 mg daily is well tolerated when given as maintenance therapy for ES-SCLC after induction chemotherapy. Further evaluation of anti-angiogenic agents in SCLC is warranted. © 2007 Elsevier Ireland Ltd. All rights reserved.
∗
Corresponding author at: Division of Hematology/Oncology, University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, OH 44106, United States. Tel.: +1 216 844 1228; fax: +1 216 844 5234. E-mail address: [email protected] (A. Dowlati). 0169-5002/$ — see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2007.01.020
378
1. Introduction Small cell lung cancer (SCLC) remains a lethal neoplasm despite known initial high response rates to systemic chemotherapy. Most patients present with distant metastases and are considered to have extensive-stage SCLC (ES-SCLC) [1]. Chemotherapy as first-line treatment results in a response rate of about 70%, the majority being partial responses. For patients who have stable disease or a response to four cycles of induction treatment (i.e. absence of progression on first-line treatment) a median overall survival of 11.2 months with a 1-year survival of 40.3% can be expected [2]. Unfortunately all patients will progress, with a median time to relapse of 2.3 months upon completion of first line chemotherapy [3]. In attempts to improve survival for this disease investigators have modified the upfront chemotherapeutic regimens [4] or have added a third [5] or have investigated the concept of sequential non-cross resistant therapy [3]. Unfortunately none of the above has resulted in improved survival. The addition of novel targeted therapies has recently been investigated with very disappointing results. These include vaccine based trials [6], as well as agents targeting c-kit [7] and bcl-2 [8]. Small cell lung cancer is a highly angiogenic tumor. A number of pro-angiogenic circulating factors have been implicated in this disease. High pre-treatment serum level of vascular endothelial growth factor (VEGF) is associated with poor outcome in SCLC [9] and serum VEGF levels correlate better with tumor stage than albumin, neuron-specific enolase or lactate dehydrogenase [10]. High pre-treatment serum concentration of basic fibroblast growth factor (bFGF) is also a predictor of poor prognosis in SCLC [11]. The multi-targeted kinase inhibitor SU5416 inhibits SCLC and angiogenesis in murine xenograft models, in part by blocking Kit-mediated VEGF expression [12]. Thalidomide has been shown to modulate angiogenesis [13]. The antitumor activity of thalidomide may also be related the enhancement of natural killer cell activity [14], enhancement of cytotoxic T-lymphocyte function [15] as well as general increase in Th1-type cellular immunity [16]. In addition, anecdotal reports suggested possible benefit to this approach in SCLC. Long-term survival of a patient with SCLC following treatment with thalidomide and combination chemotherapy has been reported [17]. Given the above we evaluated the potential role of thalidomide in patients with ES-SCLC in remission after induction therapy.
2. Patients and methods 2.1. Study endpoints and eligibility criteria The primary endpoint of this phase II trial was the 1year survival rate with a secondary end-point of toxicity of thalidomide in this patient population. Eligibility criteria included histologically confirmed ES-SCLC patients who have achieved a complete or partial response or stable disease after four to six cycles of induction chemotherapy. Extensive stage SCLC is defined as disease not meaning the definition of limited stage disease (limited stage defined as disease confined to one hemithorax without pericardial or pleural
A. Dowlati et al. effusion and thus encompassable by a single radiotherapy port) [18]. Further eligibility requirements were age ≥18 years, ECOG performance status of ≤2 and estimated life expectancy of ≥2 months. Women who were pregnant, lactating or not using adequate contraception were excluded from the study. Negative pregnancy test was required in all women of child bearing age. This study was approved by the institutional review boards of each participating center. Written informed consent was obtained from all patients.
2.2. Treatment Patients received thalidomide as a single dose of 200 mg at bedtime starting 3—6 weeks after completion of induction chemotherapy. Since constipation was an expected side effect of treatment with thalidomide, a bowel regime with bisacodyl was routinely given to all patients. Treatment was continued for a maximum of 12 months or until unacceptable toxicity, patient refusal, intercurrent illness preventing continuation of therapy, progressive disease or death occurred.
2.3. Baseline and treatment assessments A complete history and physical exam, performance status evaluation, complete blood counts with differential, blood chemistry, tumor measurements with CT scan of thorax and abdomen, bone scan and other appropriate tests as indicated were done at screening, followed by 3 monthly intervals and at the end of the study (12 months). Toxicity was evaluated according to National Cancer Institute Common Toxicity Criteria version 2.0. RECIST criteria were used for evaluation of disease progression [19].
2.4. Statistical analysis This open-label, single-agent, multicenter study evaluated whether thalidomide increases overall and 1-year survival compared to historical control. Extensive SCLC patients who have been treated with chemotherapy and respond or have stable disease have a 1-year survival rate of 40.3% [2]. This was used as the historical control. A 60% 1-year survival was expected with the addition of thalidomide. With type I error of 0.05, a power of 80%, 18 months of accrual and a followup period of 12 months the estimated sample size needed for the study are 28 patients based on one-sided exponential MLE test. Time to progression for thalidomide was measured from the date of starting thalidomide to the date of death or disease progression. Overall survival was measured from the date of chemotherapy treatment (date of cycle 1 of induction chemotherapy) until death and censored at the date of last follow-up for survivors. Progression free survival and overall survival were estimated by Kaplan—Meier method [20]. Thus, 1-year overall survival was compared with that from the historical controls. Ninety-five percent confidence intervals were calculated.
3. Results A total of 30 patients were enrolled onto the study between November 2002 and September 2005 at two Cancer Centers.
Phase II trial of thalidomide as maintenance therapy Table 1
379
Patient characteristics
Characteristic
Number of patients
Age (years) Median Range
63 50—78
Sex Male Female
11 19
ECOG performance status 0 1 2
8 21 1
Sites of metastatic disease Liver Bone Brain Adrenal Other Prior therapy Chemotherapy Cisplatin/etoposide Carboplatin/etoposide Cisplatin/irinotecan Carboplatin/irinotecan Radiotherapy Brain Bone
13 8 8 4 4
11 17 1 1 4 1
Response to prior induction Chemotherapy Complete response (CR) Partial response (PR) Stable disease (SD)
1 28 1
Number of metastatic sites 1 2 ≥3
8 7 15
Fig. 1 Kaplan—Meier estimation of overall survival with 95% confidence intervals; overall survival was measured from start of induction chemotherapy to death and censored at last followup for survivors.
(95% CI: 32.5—67.9%). The median time to disease progression from initiation of thalidomide was 2.4 months (95% CI: 1.8—3 months). The median duration on thalidomide therapy was 79 days (95% CI: 34—85 days).
3.2. Toxicity Table 2 summarizes the main drug-related toxicities that were observed during this study. The major side effects were peripheral neuropathy and constipation, reported in 30% and 16% of the patients, respectively, although the severity was mild in majority of the patients. One patient developed grade 3 peripheral neuropathy, which gradually improved with stopping the drug and eventually the neuropathy disappeared. Other toxicities reported as possibly related to thalidomide included rash, fatigue and weakness, pulmonary embolism and dizziness. These were infrequent and were easily managed. The primary reason for discontinuation of study drug was progressive disease.
4. Discussion Patient characteristics are shown in Table 1. Median age was 63 years (range 50—78) with ECOG performance status 0 or 1 in 96% of patients. Of these patients one patient was not evaluable for toxicity or survival since the patient never took study drug. All the patients received platinum based induction chemotherapy, 28 (93%) patients had partial response to their chemotherapy, 1 (3%) patient had complete response and the other (3%) had stable disease. Sites of metastases at the time of enrollment included liver (36%), brain (26%) and bone (26%). Five patients (16%) had received prior radiotherapy to metastatic sites, including four patients (13%) had whole brain radiation therapy.
3.1. Time-to-event measures At the time of this analysis only one patient remains alive. Median survival from initial treatment (chemotherapy cycle1) for all 29 patients was 12.8 months (95% CI: 10.1—15.8 months) (Fig. 1). The 1-year survival was 51.7%
Although ES-SCLC is initially chemo-responsive, it will ultimately relapse. Dose intensification strategies unfortunately have failed to improve survival [1]. Trial designs evalu-
Table 2 grade
Selected drug-related toxicity by maximum CTC CTC grade
Neuropathy Constipation Fatigue/weakness Rash Dyspnea Pulmonary embolism Dizziness Dry mouth
1
2
3
4
8 (27%) 5 (16%) 1 (3)% 1 (3%) 1 (3%) 0 1 (3%) 1 (3%)
0 0 0 1 (3%) 0 0 0 0
1 (3%) 0 1 (3%) 0 0 0 0 0
0 0 0 0 0 1 (3%) 0 0
380 Table 3
A. Dowlati et al. Comparison of reported trials of maintenance thalidomide in SCLC
Author
Patients
Thalidomide dose (mg)
Concurrent with chemotherapy
Median overall survival (months)
1-Year survival (%)
Phase II Dowlati Lee
30 26
200 100
No Yes
12.8 10.2
51.7 42
49 43
400 Placebo
Yes (after cycle 2) —
11.7 8.7
49 30.2
Phase III Pujol
ating novel targeted agents in SCLC have included the so-called window of opportunity design where new agents have been given to patients who are chemotherapy-na¨ıve. However, this approach has been problematic for these new agents as most patients have had rapid progression of their disease [7]. Another strategy to test novel therapeutics in SCLC is targeting the residual disease after initial debulking chemotherapy. At this stage of disease, tumor volume will be at its minimum and thus the experimental agent has a potentially improved chance of efficacy. Many investigators are thus using the concept of maintenance therapy in patients having obtained a response as the best way to test novel targeted agents in SCLC [21]. Given the importance of angiogenesis in SCLC and the success with thalidomide or its analogues in variety of other cancers we tested this agent in the setting of ES-SCLC as maintenance therapy. A Hoosier Oncology Group (HOG) trial treated patients with ES-SCLC with four cycles of induction chemotherapy [2]. After four cycles patients with progressive disease were removed from trial. In the non-progressing group (response or stable disease to induction treatment), they were then randomized to observation or oral etoposide as maintenance treatment. A total of 72 patients went on the observation arm. The authors of this trial reported the median and 1year survival (from the start of induction chemotherapy) of the observation arm to be 11.2 months (95% CI: 9.8—12.3 months) and 40.3%, respectively. Thus the observation arm of this trial meaning those patients who received four cycles of chemotherapy without progression prior to randomization were used as our historical control and basis of comparison to our study population. Our study population was similar to this historical control in terms of number of metastases (approximately 50% of patients having ≥3 sites of metastases) but differed in terms of gender where 33% of the HOG trial participants were female as opposed to 63% in our trial. Our study showed an overall median survival of 12.8 months and 1-year survival of 51.7%. It did not, however, meet our predefined primary endpoint of a 60% 1-year survival and our TTP was only 2.4 months similar to the observation arm on E7593 [3]. Further recent data on thalidomide in this setting has also been reported (Table 3). In a recent randomized phase III trial presented in abstract form by Pujol et al. at ASCO 2006 [22] the arm receiving thalidomide had a significantly higher overall survival (11.7 months, hazard ratio for death of 0.48) as compared to the arm randomized to placebo (8.7 months). In addition, the survival achieved on the thalidomide arm of Pujol trial was very similar to that
seen in our study. There are however differences between these two trials. Our trial used a dose of thalidomide of 200 mg while Pujol et al. used 400 mg. This higher dose explains the increased toxicity observed by Pujol where a grades 2—4 neuropathy rate of 32.6% was observed while this was 3% on our trial. Another difference is that Pujol et al. added thalidomide starting from cycle 3 after documenting a response to chemotherapy after cycle number 2. In yet another study of thalidomide in SCLC, Lee and colleagues treated 26 patients with induction chemotherapy and concurrent thalidomide at 100 mg daily for up to six cycles and continuing thalidomide in responding or stable disease patients for up to 2 years or until progression [23]. Median survival of 10.2 months and a 1-year survival of 42% were observed. Table 3 shows all three mentioned thalidomide trials in comparison. Doses of thalidomide have ranged between 100 and 400 mg with no obvious dose benefit. However median and 1-year survivals are very similar across all three trials. These results have led to a large randomized trial of more than 700 patients comparing the addition of thalidomide or not to the treatment of SCLC in the United Kingdom. In conclusion, thalidomide 200 mg daily as maintenance therapy for ES-SCLC patients who have stable disease or a response following platinum-based induction chemotherapy was well tolerated. Further exploration of thalidomide and its analogues in SCLC are warranted.
Conflict of interest Supported by a research grant from Celgene Inc.
References [1] Johnson BE, Janne PA. Basic treatment considerations using chemotherapy for patients with small cell lung cancer. Hematol Oncol Clin North Am 2004;18:309—22. [2] Hanna NH, Sandler AB, Loehrer PJ, Ansari R, Jung SH, Lane K, et al. Maintenance daily oral etoposide versus no further therapy following induction chemotherapy with etoposide plus ifosfamide plus cisplatin in extensive small-cell lung cancer: a Hoosier Oncology Group randomized study. Ann Oncol 2002;13:95—102. [3] Schiller JH, Adak S, Cella D, DeVore 3rd RF, Johnson DH. Topotecan versus observation after cisplatin plus etoposide in extensive-stage small-cell lung cancer: E7593—–a phase III trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2001;19:2114—22.
Phase II trial of thalidomide as maintenance therapy [4] Hanna N, Bunn Jr PA, Langer C, Einhorn L, Guthrie Jr T, Beck T, et al. Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol 2006;24:2038—43. [5] Niell HB, Herndon JE, Miller AA, Watson DM, Sandler AB, Kelly K, et al. Randomized phase III intergroup trial of etoposide and cisplatin with or without paclitaxel and granulocyte colonystimulating factor in patients with extensive-stage small-cell lung cancer: Cancer and Leukemia Group B Trial 9732. J Clin Oncol 2005;23:3752—9. [6] Giaccone GC, Debruyne C, Felip E, Chapman PB, Grant SC, Millward M, et al. Phase III study of adjuvant vaccination with Bec2/bacille Calmette-Guerin in responding patients with limited-disease small-cell lung cancer (European Organisation for Research and Treatment of Cancer 08971-08971B; Silva Study). J Clin Oncol 2005;23:6854—64. [7] Soria JC, Johnson BE, Chevalier TL. Imatinib in small cell lung cancer. Lung Cancer 2003;41(Suppl. 1):S49—53. [8] Rudin CM, Kozloff M, Hoffman PC, Edelman MJ, Karnauskas R, Tomek R, et al. Phase I study of G3139, a bcl-2 antisense oligonucleotide, combined with carboplatin and etoposide in patients with small-cell lung cancer. J Clin Oncol 2004;22:1110—7. [9] Salven P, Ruotsalainen T, Mattson K, Joensuu H. High pretreatment serum level of vascular endothelial growth factor (VEGF) is associated with poor outcome in small-cell lung cancer. Int J Cancer 1998;79:144—6. [10] Mall JW, Schwenk W, Philipp AW, Meyer-Kipker C, Mall W, Muller J, et al. Serum vascular endothelial growth factor levels correlate better with tumour stage in small cell lung cancer than albumin, neuron-specific enolase or lactate dehydrogenase. Respirology 2002;7:99—102. [11] Ruotsalainen T, Joensuu H, Mattson K, Salven P. High pretreatment serum concentration of basic fibroblast growth factor is a predictor of poor prognosis in small cell lung cancer. Cancer Epidemiol Biomark Prev 2002;11:1492—5. [12] Litz J, Sakuntala Warshamana-Greene G, Sulanke G, Lipson KE, Krystal GW. The multi-targeted kinase inhibitor SU5416 inhibits small cell lung cancer growth and angiogenesis, in part by blocking Kit-mediated VEGF expression. Lung Cancer 2004;46:283—91. [13] Teo SK. AAPS J 22:E14-19; 2005.
381 [14] Davies FE, Raje N, Hideshima T, Lentzsch S, Young G, Tai YT. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood 2001;98:210—6. [15] Haslett PAJ, Corral LG, Albert M, Kaplan G. Thalidomide costimulates primary human T lymphocytes, preferentially inducing proliferation, cytokine production, and cytotoxic responses in CD8+ subset. J Exp Med 1998;187:1885—92. [16] Corral LG, Haslett PAJ, Muller GW, Chen R, Wong LM, Ocampo CJ, et al. Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-␣. J Immunol 1999;163:380—6. [17] Mall JW, Philipp AW, Mall W, Pollmann C. Long-term survival of a patient with small-cell lung cancer (SCLC) following treatment with thalidomide and combination chemotherapy. Angiogenesis 2002;5:11—3. [18] Mascaux C, Paesmans M, Berghmans T, Branle F, Lafitte JJ, Vallot F, et al. A systematic review of the role of etoposide and cisplatin in the chemotherapy of small cell lung cancer with methodology assessment and meta-analysis. Lung Cancer 2000;30:23—36. [19] Therasse P, Arbuck S, Eisenhauer E, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000;92:205—16. [20] Kaplan EL, Meier P. Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457—81. [21] Pandya J, Levy DE, Hidalgo M, Cohen RB, Lee MW, Schiller JH, et al. A randomized, phase II ECOG trial of two dose levels of temsirolimus (CCI-779) in patients with extensive stage small cell lung cancer in remission after induction chemotherapy. A preliminary report. J Clin Oncol 2005;23(16S) [2005 ASCO Annual Meeting Proceedings. Part I of II (June 1 Suppl.) abstract 7005]. [22] Pujol JL, Breton JL, Gervais R, Tanguy M, Quoix E, David P, et al. A prospective randomized phase II, double blind, placebocontrolled study of thalidomide in extensive-disease small cell lung cancer patients after response to chemotherapy. J Clin Oncol 2006;24(18S) [2006 ASCO Annual Meeting Proceedings. Part I (June 20 Suppl.), abstract 7057]. [23] Lee SM, James LE, Mohamed-Ali V, Boschoff C, Snee M, Brock C, et al. A phase II study of carboplatin/etoposide with thalidomide in small cell lung cancer. Proc Am Soc Clin Oncol 2002;21 [abstract 1251].