Thalidomide in patients with malignant pleural mesothelioma

doi:10.1016/j.lungcan.2004.10.005

Lung Cancer

Volume 48, Issue 2, May 2005, Pages 291-296

https://doi.org/10.1016/j.lungcan.2004.10.005 Get rights and content

Summary

Objectives:

The purpose of this study was to describe the experience with the anti-angiogenic agent thalidomide in the treatment of patients with a malignant pleural mesothelioma (MPM).

Materials and methods:

Patients with a histological confirmed diagnosis of malignant mesothelioma received thalidomide orally at night. Increasing doses of 100, 200 or maximally 400 mg were given till progression or unacceptable toxicity. Patients that did not show signs of progression for ≥6 months were considered responders. Neurological examination included the use a sensory nerve action potential (SNAP) test.

Results:

Forty patients were evaluable for toxicity and efficacy. Twenty of them (50%) had received prior treatment. Thirty patients (75%) received a dose of 400 mg, 11 (37%) required dose reduction and 10 patients were confined to a dose of 200 mg or less. The major toxicity elicited by thalidomide concerned constipation (18/40 grade I and II) and two patients developed grade II neurotoxicity. A decline in SNAP test (>50%) did not seem to be related to the extent of neurological complaints. Eleven patients (27.5%) showed disease stabilization for >6 months and the median survival was 230 days (CI 130-330).

Conclusions:

The advised dose for future studies in these patients is 200 mg/day. At this dose level, the toxicity is mild and routine monitoring of neurological toxicity (SNAP test) can be omitted. The percentage of patients seen with prolonged disease stabilization upon thalidomide treatment warrants phase III studies in MPM.

Introduction

Malignant pleural mesothelioma (MPM) is a nearly invariably lethal tumor of the pleura or peritoneum which origin is closely linked to the exposure of asbestos fibres [1]. In general, the survival is dismal with a median of 7–11 months after diagnosis [2].

MPM is notoriously refractory to therapy. Neither surgery nor radiotherapy alone has resulted in increased survival. Long-term survivors are occasionally seen.

So far most studies on chemotherapy have been disappointing [3], [4], [5], but recently a phase III study has reported a survival advantage for the combination of pemetrexed plus cisplatin over cisplatin alone [6]. However, no long-term improvement was obtained. It is, therefore, obvious that new therapies have to be explored.

MPM is a disease characterized by distinct angiogenesis and an increased vessel density has been correlated with a worse outcome [7]. Malignant mesothelioma cells often express vascular endothelial growth factor (VEGF) and to some extent basic fibroblast growth factor (b-FGF) [8], [9]. These factors are closely related with the formation of new vasculature in embryogenesis, wound healing, diabetic neuropathy and tumor progression. Inhibition of tumor-induced angiogenesis should prevent growth and could play an important role in further management of this disease. Although it is not expected that the use of these drugs will completely eradicate tumors, it is hoped they can inhibit progressive growth [10], [11], [12], [13].

Thalidomide has been used in the late fifties as a sedative especially during pregnancy. Unfortunately, teratogenic effects (focomelia) prohibited further use of the drug and its application was abandoned. In recent years, thalidomide has been revisited, using strict contra-conceptive measures. Its major toxicity is peripheral sensory neuropathy and constipation. Recently, its toxicity and efficacy has been described in patients with refractory multiple myeloma and recurrent high-grade gliomas [14], [15].

We have examined the efficacy and toxicity of increasing doses of thalidomide in patients with MPM.

Section snippets

Eligibility

Patients with a histological confirmed diagnosis of MPM were eligible for this study. All tumor stages (IMIG staging) were allowed when one or more target lesions could be measured according to the RECIST criteria. Prior surgery, radiotherapy, chemotherapy (including intra-cavitary therapies) was allowed as long as there was evidence of disease progression. No anti-cancer therapy within the least 4 weeks before registration was allowed, with the exception of palliative radiotherapy to painful

Results

Between July 2001 and November 2002, a total of 42 patients were enrolled in the study. One patient refused medication after registration for psychological reasons and another patient stopped within 5 days because he preferred experimental surgical treatment of his mesothelioma. These two patients are excluded from further analysis. Characteristics of the 40 patients analyzed are presented in Table 1. Half of the patients had received previous (chemo) therapy and the majority was male. The mean

Discussion

Of the available anti-angiogenic drugs, thalidomide is the most extensively tested drug and has predictable toxicity. Although its proper working mechanism is not fully elucidated, the possible anti-tumor mechanisms of action involve: inhibition of angiogenesis, modulation of the cytokine-mediated pathways, alteration of adhesion molecules, the inhibition of cyclooxygenase-2 and stimulation of the immuno response. Expression of VEGF and bFGF in patients with MPM is considered to be high and

Acknowledgement

The authors wish to thank Professor J. Beijnen Pharmacist of the Slotervaart Hospital for the preparation and distribution of the thalidomide tablets.

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Citation Excerpt :
Unsurprisingly, the maximum tolerated doses of thalidomide combined with bortezomib are significantly lower than single-agent doses, with peripheral neuropathy as a key dose-limiting toxicity [99]. Nerve conduction studies demonstrate reduced SNAP amplitudes with relatively preserved conduction velocities, in keeping with a sensory axonal neuropathy [95]. Thalidomide neuropathy has been associated with genes governing repair mechanisms and inflammation in the peripheral nervous system like ABCA1, ICAM1, PPARD, SERPINB2 and SLC12A6 [46].
Chemotherapy induced peripheral neuropathy (CIPN) is a potentially dose limiting side effect of commonly used chemotherapeutic agents like taxanes, vinca-alkaloids, platinum compounds, bortezomib and thalidomide.
Supposed pathogenetic mechanisms of CIPN are axonopathy through dying back axon damage and neuronopathy in which the cell bodies of the dorsal root ganglia are involved. The exact pathophysiology however is not clear and different underlying mechanisms have been proposed for different classes of anti-cancer drugs.
Sensory symptoms, like pain, numbness and tingling are most common, but motor weakness, autonomic dysfunction and even cranial nerve involvement may occur. CIPN can be painful and/or disabling, causing significant loss of functional abilities and decreasing quality of life. This can lead to dose reductions, discontinuation of treatment and may thus, ultimately, affect survival.
Risk factors for CIPN include dose per cycle, cumulative dose, treatment schedule, duration of infusion, administration of other chemotherapeutics, comorbidity and pre-existing peripheral neuropathy.
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In this review we describe the different drug-related characteristics of CIPN, pharmacogenomic studies, neurophysiological findings, treatment and outcome, and neuroprotective strategies.
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Citation Excerpt :
This study does not allow us to comment on the effect of thalidomide in less fit patients, nor a possible response to thalidomide in patients who progressed after first-line chemotherapy. We were reluctant to include these patients in our study, since in the preceding phase 2 study15 no partial responses were seen in this particular group. In our opinion inclusion of patients with progressive disease would not have been ethical, since they had had a 50% chance of treatment with active supportive care only and probably had no chance of response with thalidomide.
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Dutch Cancer Society (KWF), Eli Lilly, NSW Dust Disease Compensation Board, University of Sydney, and Cancer Australia.

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Thalidomide in patients with malignant pleural mesothelioma

Summary

Objectives:

Materials and methods:

Results:

Conclusions:

Introduction

Section snippets

Eligibility

Results

Discussion

Acknowledgement

Ann Oncol

Mayo Clin Proc

Prognostic factors in patients with pleural mesothelioma The EORTC experience

J Clin Oncol

Chemotherapy in malignant pleural mesothelioma: a review

J Clin Oncol

Malignant pleural mesothelioma: a disease unaffected by current therapeutic manoeuvres

JCO

Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma

J Clin Oncol

Angiogenesis is an independent prognostic factor in malignant mesothelioma

Br J Cancer

Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis

Nature

Correlations of bFGF expression levels with degree of malignancy and vascularity in human gliomas

J Neurosurg