Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. The content is also available on www.palliativedrugs.com and will feature in future editions of the Hospice and Palliative Care Formulary USA and its British and Canadian counterparts. The series editors welcome feedback on the articles ([email protected]).
Abbreviations/Key
†Off-label indication
GIGastrointestinal
GVHDGraft vs. host disease
HIVHuman immunodeficiency virus
PGProstaglandin
VTEVenous thrombo-embolism
Class: Biologic response modifier.
Indications: Multiple myeloma (with concurrent dexamethasone), cutaneous manifestations of lepromatous leprosy (erythema nodosum leprosum), †graft versus host disease (GVHD), †recurrent aphthous stomatitis in HIV infection and connective tissue disease (Behcet’s syndrome), †paraneoplastic sweating, †paraneoplastic and uremic pruritus, †cachexia in HIV and cancer, †intractable GI bleeding, †intractable irinotecan-induced diarrhea, †discoid lupus erythematosus, †rheumatoid arthritis, †prevention of graft rejection.
1
, 2
Contraindications: Because it causes severe congenital abnormalities (absent or shortened limbs), thalidomide is contraindicated in pregnant women and in women with childbearing potential unless strict contraception is implemented (see Dose and Use).
3
Treatment should not be initiated with an absolute neutrophil count of <750/mm3.Pharmacology
Thalidomide is an immunomodulator with anticytokine, anti-integrin, and anti-angiogenic properties.
4
, 5
It was withdrawn from use as a non-barbiturate hypnotic with antiemetic properties in the early 1960s after it became apparent that it was teratogenic.6
Subsequently, it has been found to have immunomodulatory properties with potential for the treatment of various conditions.7
However, its use is closely monitored and it is prohibitively expensive (see Supply).Thalidomide inhibits the synthesis of the pro-inflammatory cytokine tumor necrosis factor α (TNF-α) by monocytes,
8
and stimulates interleukin-2 and interferon-γ production (thereby stimulating human T lymphocytes).9
It also inhibits chemotaxis of neutrophils and monocytes. Thalidomide also has antiproliferative and pro-apoptotic activity in tumor cells.10
Thalidomide antagonizes PGE2, PGF2, histamine, serotonin, and acetylcholine.
11
It also affects several other mechanisms associated with inflammation and immunomodulation.12
These properties probably account for the prevention of irinotecan-induced diarrhea,13
and for the amelioration of paraneoplastic sweating14
and paraneoplastic pruritus.15
Thalidomide also inhibits angiogenesis, a property that is the basis for investigational studies in oncology.
16
, 17
Thalidomide suppresses vascular endothelial growth factor (VEGF), a potent angiogenic factor secreted by cancer cells in response to hypoxia. This property also provides the rationale underlying the use of thalidomide in refractory GI bleeding.18
, 19
, 20
, 21
Analogues of thalidomide with similar anti-angiogenic, immunomodulatory and anti-inflammatory properties have been developed.
22
For example, lenalidomide is approved in the USA and Europe for certain myelodysplastic syndromes that cause transfusion-dependent anemia23
, 24
, 25
and, with concurrent dexamethasone, as a second-line treatment in multiple myeloma.26
However, lenalidomide is also presumed to carry serious teratogenic risk, is restricted in its availability, is expensive, and in multiple myeloma is associated with an increased risk of VTE. Further, there is a dearth of experience with lenalidomide in symptom management and palliative care, and no obvious advantage over thalidomide.The metabolism of thalidomide is by non-enzymatic hydrolysis in plasma. Hepatic metabolism is minor.
3
Studies in patients with hepatic and renal impairment have not been performed.Bioavailability: 67–93% PO in animals, no data in humans.
Onset of action: varies from 2 days for lepromatous leprosy and paraneoplastic sweating to 1–2 months for GVHD and 2–3 months for rheumatoid arthritis.
Time to peak plasma concentration: 2–6 h, delayed by food.
Plasma half-life: 6 h (200 mg/24 h)–18 h (800 mg/24 h).
12
Duration of action: 24 h.
Cautions
For full list, see manufacturer’s Prescribing Information.
Treat as a “cytotoxic” when handling. Thalidomide potentiates the sedative properties of barbiturates and alcohol, and increases the likelihood of extrapyramidal effects with chlorpromazine and reserpine.
11
Thalidomide should be used cautiously with other drugs that cause drowsiness, neuropathy or reduce the effectiveness of oral contraception (e.g., HIV protease inhibitors, rifampin, rifabutin, phenytoin and carbamazepine).11
, 27
Undesirable Effects
For full list, see manufacturer’s Prescribing Information.
Low-grade peripheral neuropathy occurs in >80% of patients receiving thalidomide, and severe neuropathy in 3–5%, generally after treatment lasting >6 months.
28
, 29
The incidence is higher in elderly patients, women, and in patients with pre-existing neuropathy or who are treated with neurotoxic chemotherapy, e.g., vincristine, cisplatin, paclitaxel.29
Generally, the peripheral neuropathy presents as distal paresthesia or dysesthesia with or without sensory loss. Physical examination may be normal or show mildly decreased sensation in the distal limbs. Strength is usually preserved, but reflexes, particularly ankle jerks, may be depressed or absent. These symptoms, which are progressive, typically begin in the distal lower limbs and extend proximally and into the upper limbs.30
Although some studies have found a relationship between the cumulative dose and the occurrence of neuropathy,
31
others have not.32
Nerve conduction studies typically show results consistent with a sensory axonal neuropathy. If a patient develops symptomatic neuropathy, thalidomide should be stopped to decrease the likelihood of chronic painful neuropathy.33
, 34
Some 80% of patients experience a mild decrease in bowel motility; this may reflect autonomic dysfunction, and can exacerbate constipation.
35
Somnolence or sedation may also occur and is the reason for taking the daily thalidomide dose at bedtime.36
Thalidomide (and lenalidomide) increase the risk of VTE in patients with multiple myeloma, particularly when used in combination with high-dose dexamethasone and/or anthracycline-based chemotherapy, and thromboprophylaxis is recommended.
36
, 37
There is insufficient evidence to warrant routine thromboprophylaxis when thalidomide is used in symptom control, but close monitoring would be prudent in patients at high risk of VTE.Thalidomide is associated with arrhythmia, hypotension, and edema. Sinus bradycardia, generally mild, has been reported in ≤25% of patients.
38
Severe sinus bradycardia occurs in only 1–3% of patients.16
Mild peripheral edema has been reported in 15%.8
Orthostatic hypotension and dizziness also have been reported with thalidomide.39
A dose-dependent decrease in supine systolic and diastolic pressures is seen up to 2 h after dosing.40
However, symptom control doses should not affect blood pressure.A pruritic and maculopapular rash may occur 10–14 days after starting treatment, starting on the trunk and extending to the back and proximal limbs. This is generally mild and resolves with the use of an emollient and dose reduction.
41
Severe skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, may also occur.42
Skin complications seem more likely when thalidomide is combined with dexamethasone.Tumor flare (a temporary increase in size of a cancerous lesion) may occur. When thalidomide is used to treat chronic lymphocytic leukemia, some patients have experienced increased lymphadenopathy, enlargement of the spleen, and an increased lymphocyte count.
43
Other undesirable effects include seizures,
39
altered temperature sensitivity, irregular menstrual cycles, and hypothyroidism. Thalidomide can increase HIV viral load.44
Myelosuppression is rare.Dose and Use
Thalidomide is prohibitively expensive and cost alone will severely limit its use. In palliative care, thalidomide should never be considered as a first-line treatment. Its use should be considered only when more conventional treatments have failed and a full review of the potential benefits and harms has been undertaken with specialist colleagues.
There are several potential uses for thalidomide in palliative care (Table 1).
45
Female patients prescribed thalidomide must be counseled about the need for contraception, and male patients must use a condom. Written consent should be obtained.46
Contraception should be used for ≥4 weeks before starting, during, and for 4 weeks after stopping treatment. Regular pregnancy testing is advised throughout treatment. Because thalidomide is present in the semen of men treated with the drug, even after vasectomy a latex condom must be used during sexual intercourse with women of childbearing potential.47
Table 1Potential Uses of Thalidomide in Palliative Care
Indication | Dose | Reference |
---|---|---|
Aphthous ulcers in HIV+ disease | 100–200 mg at bedtime for 10 days | 48 |
Paraneoplastic sweating | 100–200 mg at bedtime | 49 , 50 |
Paraneoplastic and uremic pruritus | 100–200 mg at bedtime | 15 , 51 , 52 |
Cachexia in HIV+ disease and cancer | 100–200 mg at bedtime | 53 , 54 , 55 |
GI bleeding associated with angiodysplasia/radiation proctitis | 100–300 mg at bedtime | 21 |
Intractable irinotecan-induced diarrhea | 400 mg at bedtime | 13 , 56 |
a Thalidomide is not the first-line treatment for any of these indications.
Supply
Thalidomide is available in some countries through a strictly monitored program: in the USA, the System for Thalidomide Education and Prescribing Safety (STEPS) and, in Canada, the Canadian Thalomid Access Program (CANTAP). Clinicians wishing to use thalidomide must be registered with the program.
Lenalidomide is available through a similar distribution program, RevAssist in the USA (www.REVLIMID.com) and RevAid in Canada (www.RevAid.ca).
Thalidomide
Thalomid® (Celgene)
Capsules 50 mg, 100 mg, 150 mg, 200 mg, 28 days @ 200 mg at bedtime=$7,056.
Lenalidomide
Revlimid® (Celgene)
Capsules 5 mg, 10 mg, 15 mg, 25 mg, 28 days @ 10 mg once daily=$10,800.
References
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- Recent advances of IMiDs in cancer therapy.Curr Opin Oncol. 2010 Aug 4; ([Epub ahead of print])
- Efficacy of lenalidomide in myelodysplastic syndromes.N Engl J Med. 2005; 352: 549-557
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- Developmental therapeutics for myelodysplastic syndromes.J Natl Compr Canc Netw. 2006; 4: 78-82
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Article info
Publication history
Published online: October 22, 2010
Accepted:
September 27,
2010
AHFS 92:2000Footnotes
Series Co-Editors: Andrew Wilcock, DM, FRCP, and Robert Twycross, DM, FRCP
Identification
Copyright
© 2011 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc.