Phase II trial of thalidomide with chemotherapy and as maintenance therapy for patients with poor prognosis small-cell lung cancer

doi:10.1016/j.lungcan.2007.08.032

Lung Cancer

Volume 59, Issue 3, March 2008, Pages 364-368

https://doi.org/10.1016/j.lungcan.2007.08.032 Get rights and content

Summary

Background

Despite the high response rates achieved following standard chemotherapy for small-cell lung cancer (SCLC), the majority of patients will subsequently die from disease progression.

Materials and methods

We examined the efficacy and toxicity of thalidomide, an anti-angiogenic agent, in combination with carboplatin and etoposide and as maintenance therapy in patients with untreated SCLC. Twenty-five chemotherapy-naive patients with extensive disease (ED) or limited disease (LD) SCLC were enrolled in a single-arm phase II study. Carboplatin and etoposide were given every 3 weeks for 6 cycles with concurrent thalidomide 100 mg orally daily. The treatment with thalidomide was continued as maintenance for up to 2 years.

Results

Median progression free and overall survival were 8.3 months and 10.1 months, respectively. One-year survival was 40% and the 1-year progression-free survival was 36%. The overall response rate was 68% (95% CI 46–85%) with four complete remissions (20%) and 13 partial remissions (48%). We observed no increase in chemotherapy related toxicity. Thalidomide was well-tolerated and median time on thalidomide treatment was 7.6 months.

Conclusion

Concurrent thalidomide with chemotherapy followed by maintenance thalidomide appears to be well tolerated. The results on tumour response rate and survival led us to initiate a randomised phase III trial in the United Kingdom.

Introduction

Small-cell lung cancer (SCLC) continues to remain a major therapeutic challenge. Despite the high response rates achieved following treatments with conventional agents, the majority of patients will subsequently die.

Since tumour growth and metastasis are angiogenesis-dependent [1], therapeutic strategies aimed at inhibiting angiogenesis are theoretically attractive. Thalidomide can inhibit this process by interfering with the basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) [2], [3]. Since high pre-treatment levels of VEGF and bFGF in patients with SCLC have been demonstrated to be associated with shorter survival and poor response to chemotherapy [4], [5], it is possible that this property of thalidomide may benefit patients when combined with chemotherapy. Other advantages of thalidomide are its potential anti-tumour, anti-cachexia and immunomodulatory effects which can counter the disease-related and treatment-induced cachexia seen frequently in SCLC patients [6], [7], [8]. Anti-tumour activity has mainly been reported in multiple myeloma but activity is also seen in glioma, renal-cell carcinoma, hepatoma, hormone-refractory prostate cancer and HIV-related Kaposi sarcoma [9], [10], [11], [12]. In addition, preclinical models of thalidomide have demonstrated synergistic activity when combined with cytotoxic agents and studies in animal models show a reduction in the incidence of lung metastases from primary Lewis lung carcinoma [13], [14], [15]. Improved responses were seen when thalidomide was combined with BCNU to treat high-grade gliomas [16]. It has also been suggested that administering anti-angiogenic agent concurrently with chemotherapy may decrease tumoural vascular permeability and interstitial fluid pressure, thereby improving chemotherapy delivery and tumoural cell-killing [17], [18], [19].

Here, we report the results of a single-arm multicentre phase II study in which we examined the role of thalidomide when added to standard combination chemotherapy and as maintenance treatment for SCLC.

Section snippets

Patients and methods

Patients were enrolled into an open-label single-arm phase II study. Eligibility included: measurable or evaluable disease, those with either extensive or poor prognosis limited disease (we defined this as ECOG performance status ≥2 and alkaline phosphatase > 1.5 times the upper limit of normal range according to Souhami et al. [20]), age 18–75 years, ECOG performance status of 0–3 and no previous treatment with chemotherapy or radiotherapy, no prior history of malignant tumour, no medical

Results

Twenty-five patients were enrolled into the study, and their baseline characteristics are summarised in Table 1.

Eighty percent of patients (20/25) completed the planned 6 cycles of chemotherapy, two patients (8%) each completed two and three courses of chemotherapy and one patient (4%) received 1 cycle of chemotherapy. The reasons for stopping chemotherapy early were death (three patients), progressive disease (one patient), and refusal to continue with chemotherapy (one patient). Sixteen

Discussion

This trial suggests that low dose thalidomide as a component of standard chemotherapy and as maintenance therapy was well tolerated with a median survival of 10.1 months, consistent with other studies on thalidomide. A phase II study of 30 patients reported a median overall survival of 12.8 months when using 200 mg thalidomide as maintenance treatment after chemotherapy [22]. A randomised trial of 92 patients, all of which had a tumour response after 2 cycles of chemotherapy, showed a difference

Conflict of interest

The study was funded by a grant from Cancer Research UK. The authors indicated no other potential conflicts of interest.

Acknowledgements

Supported by a grant from Cancer Research, UK. Presented in part at the American Society of Clinical Oncology Annual Meeting, Atlanta 2002 and the 10th World Conference on Lung Cancer, Vancouver 2003.

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Phase II trial of thalidomide with chemotherapy and as maintenance therapy for patients with poor prognosis small-cell lung cancer

Summary

Background

Materials and methods

Results

Conclusion

Introduction

Section snippets

Patients and methods

Results

Discussion

Conflict of interest

Acknowledgements

Exp Eye Res

Lung Cancer

Nutrition

Eur J Cancer

Lung Cancer

Lung Cancer

Tumor angiogenesis: therapeutic implications

N Engl J Med

Thalidomide is an inhibitor of angiogenesis

Proc Natl Acad Sci USA

High pre-treatment serum level of vascular endothelial growth factor (VEGF) is associated with poor outcome in small-cell lung cancer

Int J Cancer

Effects of thalidomide on HIV-associated wasting syndrome: a randomized, double-blind, placebo-controlled clinical trial

AIDS

Anti-cytokine approaches to the treatment of anorexia and cachexia

Semin Oncol

Antitumor activity of thalidomide in refractory multiple myeloma

N Engl J Med