1 Department of Pharmacology, All India Institute of Medical Sciences, New Delhi; 2 Institute of Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
Received 25 October 2001; revised 21 February 2002; accepted 27 March 2002
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Abstract |
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Key words: adverse reaction, doseduration relationship, multiple myeloma, thalidomide
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Introduction |
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The worldwide withdrawal of thalidomide in the early 1960s was based on its unwanted teratogenic effects and not because of ineffectiveness; this study was undertaken to assess the safety of high doses (800 mg/day) of thalidomide given over a long period (>15 months) in Indian patients with refractory or relapsed MM.
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Materials and methods |
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Results |
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Ankle edema was noted in 70% of patients. In 50% of these it occurred at a dose of 200 mg/day, 14 days after initiation of therapy. Some of these patients suffered multiple episodes of peripheral edema that was responsive to diuretic therapy, and reduction or discontinuation of thalidomide was not required. One patient, a non-responder to thalidomide, had marked generalized edema that was non-responsive to diuretic therapy. Renal, cardiac or hepatic causes were ruled out.
Dry skin and dry mouth were problematic in 65% of patients. The severity was dose- and duration-dependent (Table 3). Pruritus was reported in 22% of patients and occurred only at a dose of 400 mg/day.
No significant neutropenia was seen, and total leukocyte count (TLC) ranged between 2500 and 6000/mm3 in all the patients throughout the course of therapy. Thirteen episodes of inter-current infections, chiefly involving the respiratory tract, were reported, and during these the TLC remained the same or higher than the range given above. Maximum episodes occurred at a dose of 800 mg/day after 2 months of therapy. All patients were treated symptomatically. Two patients died due to septicemia secondary to pneumonia. The third patient had septicemia secondary to infection of an in situ Hickmans catheter. Removal of the catheter and antibiotics led to recovery.
Generalized weakness/fatigue was reported with an incidence of 52%, but did not significantly alter the daily routine of the patients. In all but one patient, this occurred 1.5 months after initiation of therapy at a dose of 600 mg/day. The severity of fatigue was dose- and duration-dependent. Headache with no doseduration correlation was noted in 30% of patients.
Despite the fact that thalidomide was launched as a drug for morning sickness, nausea and vomiting occurred in 26% of patients. In four patients it was reported at a dose of 200 mg/day within the first 15 days of therapy.
Skin eruptions of a vesicular type occurred at a dose of 400 mg/day or more after >1 month of therapy, but before the end of 8 weeks, in 22% of patients. The vesicles were distributed in the anterior part of the chest, forelimbs, hands and the beard area, and were 5 x 5 mm in size, painless, and associated with itching, and subsided spontaneously without thalidomide interruption. In the first patient with vesicles, thalidomide was discontinued and the lesions disappeared within 15 days. Upon re-challenge, a fresh crop of vesicles surfaced but subsided spontaneously even though thalidomide was continued. In 17% of patients, skin rash occurred at a dose of 800 mg/day after >2 months of therapy. The rash was in the form of erythematous macules, 2 x 3 mm in size on the abdomen and limbs, and associated with itching. Subsequent dermatological examination ruled out other skin conditions. The rash subsided without treatment after 15 days. Discontinuation of treatment was not required.
Heart-burn was reported by 21.73% (n = 5) and tremors by 13% of patients; neither had a correlation to dose or duration of thalidomide.
At the end of 10 months of therapy, one patient reported weakness of the lower limbs manifested as difficulty in climbing the stairs. Similarly, two patients at the end of 1 year had similar complaints. Nerve conduction studies were done and all three patients reported peripheral motor and sensory neuropathy. All these patients had received a total dose of >200 g and were receiving 800 mg/day at the time of diagnosis of neuropathy. These patients showed more sensory loss than motor loss; lower limb involvement was greater than upper limb. Hence, the incidence of peripheral neuropathy is 13%.
Blood urea ranged between 14 and 43 mg/dl, and creatinine between 0.1 and 1.6 mg/dl in all patients, except one who developed acute renal failure, for whom these values ranged between 20 and 89 mg/dl, and 0.9 and 4.5 mg/dl, respectively. AST and ALT ranged between 17 and 50 IU, and 14 and 96 IU, respectively in all patients except one, who had acute hepatitis C; thalidomide was discontinued in this patient.
Hypertensive and diabetic patients did not require change in drug or the dosage of treatment. None of these patients reported any symptom related to thyroid dysfunction.
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Discussion |
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Incidence of sedation (87%) is similar to that reported earlier (range 25100%) [35], with no doseduration relationship. With increased dose, patients developed tolerance, although mild daytime somnolence persisted. Although earlier studies reported that patients were unable to lead active daily lives [4, 5], in the present study, despite the high dose and longer duration of therapy, patients led active lives and most of them continued with their professional work, e.g. a surgeon receiving thalidomide was able to operate.
Ankle edema with no doseduration relationship was a significant side effect (incidence 70%), which is in variance with earlier studies (incidence 622%) [3, 4]. There were multiple episodes of peripheral edema (pitting type). This high incidence demonstrates Indian predisposition to stasis of blood in extremities when on thalidomide, although no cases of deep vein thrombosis were reported.
Dose-dependent dryness of skin and mouth (incidence 65%), which was not reported in earlier studies, was treated with emollients. It is possible that tolerance developed to this, as there was reduction in severity of dryness.
Multiple episodes of inter-current infections reported may be related to the immunomodulator effects of thalidomide. Severity of generalized weakness or fatigue increased in a linear manner, with dose as well as duration of therapy.
Thalidomide resulted in nausea and vomiting, which was more apparent when therapy was initiated. Skin rash showed a dose-dependent relationship. It was apparent only at dose of 400 mg/day or more. However, no treatment or dose reduction was required, as the rash subsided without treatment, and did not warrant discontinuation of thalidomide.
Peripheral neuropathy, a serious and dose-limiting side effect of thalidomide, has been conspicuous by its low incidence and its late onset in Indian patients [3, 4]. Also noteworthy is the fact that one patient with diagnosed sensory and motor peripheral neuropathy before starting thalidomide did not show any worsening of his condition despite being on high-dose therapy for 9 months.
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Conclusions |
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Acknowledgements |
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Footnotes |
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References |
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2. Fermand JP. High dose therapy and autologous bone stem cell transplantation vs conventional treatment in multiple myeloma. Results of a randomized trial in 191 patients 55 to 65 years of age. Presented at the Eighth International Multiple Myeloma Workshop, Stockholm, Sweden, September 1999.
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6. Julieusson G, Celsing F, Turesson I et al. Frequent good partial remissions from thalidomide including best response ever in patients with advanced refractory and relapsed myeloma. Br J Haematol 2000; 109: 8996.[ISI][Medline]