Thalidomide in patients with malignant pleural mesothelioma

Lung Cancer (2005) 48, 291—296

Thalidomide in patients with malignant pleural mesothelioma Paul Baasa,∗, Willem Boogerdb, Otilia Dalesioc, Annebeth Haringhuizena, Frank Custersa, Nico van Zandwijka a

Department of Thoracic Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands b Department of Neurology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands c Department of Biostatistics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands Received 29 July 2004 ; received in revised form 27 September 2004; accepted 4 October 2004 KEYWORDS Mesothelioma; Thalidomide; Anti-angiogenesis

Summary Objectives: The purpose of this study was to describe the experience with the antiangiogenic 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. © 2004 Elsevier Ireland Ltd. All rights reserved.

1. Introduction * Corresponding author. Tel.: +31 205122958;

fax: +31 205122573. E-mail address: [email protected] (P. Baas).

Malignant pleural mesothelioma (MPM) is a nearly invariably lethal tumor of the pleura or peritoneum

0169-5002/$ — see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2004.10.005

292 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—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—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.

2. Materials and methods 2.1. 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

P. Baas et al. least 4 weeks before registration was allowed, with the exception of palliative radiotherapy to painful lesions or to prevent the development of metastases along biopsy tracks. Performance status had to be ≤2 (WHO criteria, after palliative measures like pleural drainage), patients were >18 years, had adequate bone marrow reserve, hepatic function and renal function. Special attention was given to women in the childbearing age or spouses with a partner with childbearing potential. A negative pregnancy test was requested and adequate contraception was advised during the study period and 9 months there after. Patients with signs of grade II or more neuropathy, pregnancy, prior treatment with thalidomide or a life expectancy of <3 months were considered ineligible. The study was approved by the medical ethical committee.

2.2. Treatment Thalidomide was given as a tablet of 100 mg for the first 2 weeks at night. If this was well tolerated, the dose was increased to 200 mg for an additional 2 weeks and finally to 400 mg per day. When patients experienced drowsiness or other side effects considered unacceptable by the patient the dose was reduced to the previous level. Regular neurological examination was performed at baseline and repeated every 2 months. In addition, serial nerve conduction studies were performed prior to start and after every 4 months or sooner in case of neurological complaints. These studies included sensory nerve conduction velocity and sensory nerve action potential (SNAP) amplitude of unilateral sural and median nerve. Motor conduction velocity and compound muscle action potential of the median nerve, and latency and amplitude of the H-reflex in the soleus muscle were both measured. During the last procedure, the skin temperature was maintained above 32 ◦ C. In case of moderate paresthesias or interfering with function, a dose modification of 50% of thalidomide was advised. When repeated testing showed stabilization or improvement, this dose was maintained. In all other cases, the thalidomide treatment was discontinued. Thalidomide treatment was interrupted for any surgical intervention until complete healing of the surgical wound, with a maximum of 4 weeks.

2.3. Endpoints and Statistical methods It was not expected that thalidomide would be able to induce significant responses but could be

Thalidomide in patients with malignant pleural mesothelioma effective in preventing progression. Therefore, the proportion of patients without progression at 6 months after start of the treatment was considered the main endpoint of the study. The Kaplan Meier technique was used to construct the overall survival curve of this group. Patients visited the outpatient clinic on a monthly basis and were screened by chest X-ray and CT scan every 2 months or when indicated for signs of response or progression. Toxicity was scored according to the NCIC/CTC guidelines. In addition, the incidence and severity of peripheral neuropathy including the usefulness of serial neurological and neurophysiological examinations for the detection of thalidomide-induced neuropathy was examined.

3. 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. Table 1

Patient characteristics

Male/female Age (range) WHO 0/1/2/3

34/6 62 (42—78) 5/30/4/1

Pathology Epithelial/other

36/4

Stage (IMIG) I/II III/IV

15 25

Previous treatment No Yes (surgery/RT/chemotherapy)

20 20

Asbestos exposure No Yes

1 39

Previous surgerya Previous chemotherapyb

6 13

The mean duration of thalidomide dosing was 4.7 months, the median was 3.5 months, and 30 of the 40 patients (75%) tolerated a dose of 400 mg thalidomide daily. Eleven out of these 30 experienced side effects during treatment that resulted in a dose reduction to 200 mg per day. There was no significant difference in duration of treatment with thalidomide between patients who had been pretreated or not. Toxicity was relatively mild, two patients experienced an allergic reaction (grade 2), which prohibited further treatment with thalidomide in one patient. No grade 3 neurotoxicity was observed with this study. Five patients reported mild, and apparently transient paresthesias starting at a low median cumulative dose of 14.6 gm (range 12.8—17.4 gm), and subsiding spontaneously without dose adjustments. Six patients experienced persisting mild to moderate paresthesias, starting at a median cumulative dose of 66.3 gm (range 14.6—94 gm). Two of these patients developed a grade 2 peripheral neurotoxicity (Table 2) after cumulative doses of 104 and 121 gm. Dose reduction to 100 mg thalidomide per day was applied in these patients resulting in a stable neurological condition at last moment of follow-up after 3 months in one patient. In the other patient, treatment was stopped after 3 weeks because of progressive disease. The SNAP index decreased more than 50% from baseline in six patients who developed grade 1 or 2 neurotoxicity, and in two patients without neurotoxicity. There was no relationship between the date of measured SNAP decrease and occurrence of neurological complaints, i.e. SNAP decrease preceded, coincided, but also lagged behind clinical symptoms. In the two patients with neurotoxicity grade 2 the SNAP decrease preceded the Table 2

Sensory neurotoxicity

Common Toxicity Criteria version 2.0 final 1/30/98 revised by NCI 3/23/98 Grade 0 Grade I Grade II

Grade III

a

Hyperthermic chemolavage after pleurectomy/pleuropneumonectomy. b Methotrexate/doxorubicin (n = 7); raltitrexed (n = 3); gemcitabin/cisplatin (n = 2); vinorelbine (n = 1).

293

Grade IV

Normal Loss of deep tendon reflexes or paresthesia (including tingling) but not interfering with function Objective sensory loss or paresthesia (including tingling), interfering with function, but not interfering with activities of daily living Sensory loss or paresthesia interfering with activities of daily living Permanent sensory loss that interferes with function

294

P. Baas et al.

Table 3

Duration of therapy

Months Pats

1 2

2 16

3 4

4 3

5 3

6 1

7 1

8 1

9 3

10 2

stage of interference with function for 4 months in one patient, and coincided with that moment in the other one. No association between neurological complaints and other neurophysiological parameters (nerve conduction, H-reflex) was found. Eleven out of 40 patients (27.5%) were free of progression after 6 months (range 6—27 months). Details are presented in Table 3. There were 18 patients that stopped treatment within 2 months. Of these patients, two refused treatment with thalidomide; the remaining 16 progressed within 2 months. Sites of failure were local in 90% of the cases. The median survival time was 230 days (95%CI 130—330 days; Fig. 1). Response according to stage of disease and pretreatment status was analyzed and no statistically significant association was detected.

11 —

12 2

13 1

16 —

18 —

20 —

22 —

24 1

26 —

4. 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 antitumor 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 vessel density has been proven to be of prognostic value [16]. Changes in serum levels of b-FGF correlated well with the time to tumor progression and overall survival. In this study, it has not been possible to measure VEGF, bFGF or other biological determinants.

Fig. 1 Survival of all patients.

Thalidomide in patients with malignant pleural mesothelioma Thalidomide has been proven active in multiple myeloma and high-grade gliomas, where paraprotein levels were reduced by at least 90% and durable responses were recorded [14,15,17]. Complications noted were mild to moderate constipation, weakness or fatigue, comparable to our observations. Toxicity reported was predominantly non haematological with, grade 3 or 4, neuropathy (16%), sedation (13%) and constipation (6%), but in these studies the high doses of thalidomide used (800—1200 mg per day) could explain the higher rate of side effects. Based on this experience, the maximal dose of thalidomide selected for this study was 400 mg per day. Even with this planned dose, only 75% (30 patients) reached this level. One-third of them (11 patients) required a dose reduction to 200 mg during the course of the treatment. A preliminary report from Australia confirms this observation [18]. To our knowledge, this is the first report on the activity of thalidomide in malignant pleural mesothelioma. Toxicity was mild with only two patients who developed a grade 2 neuropathy (12%). A dose reduction with 50% prevented further neurological deterioration. No relationship between mild complaints of neuropathy and a decrease of the SNAP index was found. A number of patients complained of paresthesias already after a cumulative dose of about 15 gm, without striking abnormalities on neurological and neurophysiological examination. Dose adjustments were not carried out in these patients and the complaints resolved spontaneously. Based on these findings, we do not subscribe the guidelines for use of thalidomide in the United Kingdom that propose that thalidomide should be stopped immediately either upon development of paresthesias or if the SNAP index declines by more than 40% [19]. Pathogenesis and risk factors of thalidomide neuropathy are not clearly understood. Our results suggest some relationship with the cumulative dose. An allergic reaction (grade 3) occurred in two patients and prevented us from further treatment with Thalidomide. A morbilliform rash was present in both cases and was successfully treated with prednisone. Nijsten et al. have been the first to report this type of side effect [20]. The drug however is considered to be an effective agent in dermatological conditions that are based on immunological and inflammatory disorders [21]. The overall activity, defined as a progression free interval of at least 6 months was 27.5%. Most patients that did not respond to the treatment had disease progression within 2 months of treatment. In this study, we have not been able to identify factors that were associated with stabilization of dis-

295

ease. The small sample size and the fact that all patient had signs of disease progression at start of treatment have to be taken into consideration. We conclude that thalidomide given in a daily dose of 200 mg in patients with MPM is feasible and the stabilization of the disease suggests some activity. These results have already resulted in the initiation of a multicenter phase III in the Netherlands. Patients, who have had a stabilization or response to first line chemotherapy with pemetrexed, are randomized to receive adjuvant thalidomide treatment or standard follow-up. The toxicity is considered acceptable and manageable at a daily dose of 200 mg for longer periods. Neurological examination using SNAP testing at this dose is only indicated when signs or symptoms interfering with function develop.

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

References [1] IUCC Report and Recommendations of the Aorking group on asbestos and cancer. Ann NY Acad Sci 1965;132:706—721. [2] Curran D, Sahmoud T, Therasse P, van Meerbeeck J, Postmus PE, Giaccone G. Prognostic factors in patients with pleural mesothelioma The EORTC experience. J Clin Oncol 1998;16:145—52. [3] Baas P, Schouwink H, Zoetmulder FAN. Malignant pleural mesothelioma. A review. Ann Oncol 1998;9:139—49. [4] Ong ST, Vogelenzang NJ. Chemotherapy in malignant pleural mesothelioma: a review. J Clin Oncol 1996;14:1007—17. [5] Alberts AS, Falkson G, Goedhals L, Vorobiof DA, Van der Merwe CA. Malignant pleural mesothelioma: a disease unaffected by current therapeutic manoeuvres. JCO 1998;6:527—35. [6] Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Denham C, Kaukel E, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003;21(14):2636—44. [7] Edwards JG, Cox G, Andi A, Jones JL, Walker RA, Waller DA, et al. Angiogenesis is an independent prognostic factor in malignant mesothelioma. Br J Cancer 2001;85(6):863—8. [8] Shweiki D, Itin A, Soffer D, Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxiainitiated angiogenesis. Nature 1992;359:843—5. [9] Takahashi J, Fukumoto M, Igorshi K, Oda Y, Kikuchi H, Hatanaka M. Correlations of bFGF expression levels with degree of malignancy and vascularity in human gliomas. J Neurosurg 1992;76:792—8. [10] Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285:1182—6.

296 [11] Toi M, Inada K, Suzuki H, Tominaga T. Tumor angiogenesis in breast cancer: its importance as a prognostic indicator and the association with VEGF expression. Breast Cancer Res Treat 1995;36:193—204. [12] Plate KH, Breier G, Weich HA, Mennel HD, Risau W. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 1992;359:845—8. [13] Zagzag D, Miller D, Sato Y, Rifkin DB, Burstein DE. Immunohistochemical localization of bFGF in astrocytomas. Cancer Res 1990;50:7393—8. [14] Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999;341(21):1565— 609. [15] Fine HA, Figg WD, Jaeckle K, Wen PY, Kyritsis AP, Loeffler JS, et al. Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas. J Clin Oncol 2000;18(4):708—15. [16] Ohta Y, Shridhar V, Bright RK, Kalemkerian GP, Du W, Carbone M, et al. Pass HI. VEGF and VEGF type C play an important role in angiopgenesis and lymphangiogene-

P. Baas et al.

[17]

[18]

[19] [20]

[21]

sis in human malignant mesothelioma tumors. Br J Cancer 1999;81(1):54—61. Kumar S, Gertz MA, Dispenzieri A, Lacy MQ, Geyer SM, Iturria NL, et al. Response rate, durability of response, and survival after thalidomide therapy for relapsed multiple myeloma. Mayo Clin Proc 2003;78(1):34—9. Pavlakis N, Abraham R, Harvie R. Thalidomide alone or in combination with Cisplatin/Gemcitabine in malignant pleural mesothelioma(MM): interim results of two parallel non randomised phase II studies. Oral presentation O-26 during the 10th World Conference on Lung Cancer published in Lung Cancer 2003 August;41(S2) S11. Powell RJ, Gardner-Medwin JM. Guideline for the clinical use and dispensing of thalidomide. Postgrad Med J 1994;70:901—4. Nijsten T, Meuleman L, Schroyens W, Lambert J. Thalidomide-induced morbilliform rash: diagnosis and continuation of therapy, premedicated with methylprednisolone. Dermatology 2002;204(4):365—7. Wines NY, Cooper AJ, Wines MP. Quiz 239-40 Thalidomide in dermatology. Aust J Dermatol 2002;43(4):229—38.