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Thalidomide

Open AccessPublished:October 22, 2010DOI:https://doi.org/10.1016/j.jpainsymman.2010.10.001
      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
      GI
      Gastrointestinal
      GVHD
      Graft vs. host disease
      HIV
      Human immunodeficiency virus
      PG
      Prostaglandin
      VTE
      Venous 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.
      • Calabrese L.
      • Fleischer A.
      Thalidomide: current and potential clinical applications.
      • Chen M.
      • Doherty S.D.
      • Hsu S.
      Innovative uses of thalidomide.
      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).
      • Celgene
      Prescribing information for Thalomid® thalidomide (THALPI.013 02/10 CG).
      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.
      • Jacobson J.
      Thalidomide: a remarkable comeback.
      • De Sanctis J.B.
      • Mijares M.
      • Suárez A.
      • et al.
      Pharmacological properties of thalidomide and its analogues.
      It was withdrawn from use as a non-barbiturate hypnotic with antiemetic properties in the early 1960s after it became apparent that it was teratogenic.
      • Marriott J.B.
      • Muller G.
      • Dalgleish A.G.
      Thalidomide as an emerging immunotherapeutic agent.
      Subsequently, it has been found to have immunomodulatory properties with potential for the treatment of various conditions.
      • Peuckmann V.
      • Fisch M.
      • Bruera E.
      Potential novel uses of thalidomide: focus on palliative care.
      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,
      • Sampaio E.P.
      • Sarno E.N.
      • Galilly R.
      • Cohn Z.A.
      • Kaplan G.
      Thalidomide selectively inhibits tumour necrosis factor alpha production by stimulated human monocytes.
      and stimulates interleukin-2 and interferon-γ production (thereby stimulating human T lymphocytes).
      • Corral L.G.
      • Kaplan G.
      Immunomodulation by thalidomide and thalidomide analogues.
      It also inhibits chemotaxis of neutrophils and monocytes. Thalidomide also has antiproliferative and pro-apoptotic activity in tumor cells.
      • Hideshima T.
      • Chauhan D.
      • Shima Y.
      • et al.
      Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy.
      Thalidomide antagonizes PGE2, PGF2, histamine, serotonin, and acetylcholine.
      • Radomsky C.
      • Levine N.
      Thalidomide.
      It also affects several other mechanisms associated with inflammation and immunomodulation.
      • Bousvaros A.
      • Mueller B.
      Thalidomide in gastrointestinal disorders.
      These properties probably account for the prevention of irinotecan-induced diarrhea,
      • Govindarajan R.
      • Heaton K.M.
      • Broadwater R.
      • et al.
      Effect of thalidomide on gastrointestinal toxic effects of irinotecan.
      and for the amelioration of paraneoplastic sweating
      • Deaner P.
      The use of thalidomide in the management of severe sweating in patients with advanced malignancy: trial report.
      and paraneoplastic pruritus.

      Smith JC, Astley A, Johnstone S. Use of thalidomide in the treatment of intractable itch. Poster abstract 21. Palliative Care Congress, Sheffield, UK, 2002.

      Thalidomide also inhibits angiogenesis, a property that is the basis for investigational studies in oncology.
      • Eisen T.
      Thalidomide in solid tumors: the London experience.
      • Eleutherakis-Papaiakovou V.
      • Bamias A.
      • Dimopoulos M.A.
      Thalidomide in cancer medicine.
      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.
      • Bauditz J.
      • Schachschal G.
      • Wedel S.
      • Lochs H.
      Thalidomide for treatment of severe intestinal bleeding.
      • Craanen M.E.
      • van Triest B.
      • Verheijen R.H.
      • Mulder C.J.
      Thalidomide in refractory haemorrhagic radiation induced proctitis.
      • Karajeh M.A.
      • Hurlstone D.P.
      • Stephenson T.J.
      • Ray-Chaudhuri D.
      • Gleeson D.C.
      Refractory bleeding from portal hypertensive gastropathy: a further novel role for thalidomide therapy?.
      • Lambert K.
      • Ward J.
      The use of thalidomide in the management of bleeding from a gastric cancer.
      Analogues of thalidomide with similar anti-angiogenic, immunomodulatory and anti-inflammatory properties have been developed.
      • Li S.
      • Gill N.
      • Lentzsch S.
      Recent advances of IMiDs in cancer therapy.
      For example, lenalidomide is approved in the USA and Europe for certain myelodysplastic syndromes that cause transfusion-dependent anemia
      • List A.
      • Kurtin S.
      • Roe D.J.
      • et al.
      Efficacy of lenalidomide in myelodysplastic syndromes.
      • Giagounidis A.A.
      • Germing U.
      • Aul C.
      Biological and prognostic significance of chromosome 5q deletions in myeloid malignancies.
      • Naing A.
      • Sokol L.
      • List A.F.
      Developmental therapeutics for myelodysplastic syndromes.
      and, with concurrent dexamethasone, as a second-line treatment in multiple myeloma.
      • Richardson P.
      • Mitsiades C.
      • Laubach J.
      • et al.
      Lenalidomide in multiple myeloma: an evidence-based review of its role in therapy.
      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.
      • Celgene
      Prescribing information for Thalomid® thalidomide (THALPI.013 02/10 CG).
      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).
      • Bousvaros A.
      • Mueller B.
      Thalidomide in gastrointestinal disorders.
      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.
      • Radomsky C.
      • Levine N.
      Thalidomide.
      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).
      • Radomsky C.
      • Levine N.
      Thalidomide.
      • Thomas D.
      • Kantarjian H.
      Current role of thalidomide in cancer treatment.

      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.
      • Dimopoulos M.A.
      • Eleutherakis-Papaiakovou V.
      Adverse effects of thalidomide administration in patients with neoplastic diseases.
      • Mileshkin L.
      • Stark R.
      • Day B.
      • et al.
      Development of neuropathy in patients with myeloma treated with thalidomide: patterns of occurrence and the role of electrophysiologic monitoring.
      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.
      • Mileshkin L.
      • Stark R.
      • Day B.
      • et al.
      Development of neuropathy in patients with myeloma treated with thalidomide: patterns of occurrence and the role of electrophysiologic monitoring.
      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.
      • Wulff C.H.
      • Høyer H.
      • Asboe-Hansen G.
      • Brodthagen H.
      Development of polyneuropathy during thalidomide therapy.
      Although some studies have found a relationship between the cumulative dose and the occurrence of neuropathy,
      • Fullerton P.
      • O’Sullivan D.
      Thalidomide neuropathy: a clinical, electrophysiological, and histological follow up study.
      others have not.
      • Chapon F.
      • Lechevalier B.
      • da Silva D.C.
      • et al.
      [Neuropathies caused by thalidomide].
      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.
      • Gardner-Medwin J.M.
      • Smith N.J.
      • Powell R.J.
      Clinical experience with thalidomide in the management of severe oral and genital ulceration in conditions such as Behcet’s disease: use of neurophysiological studies to detect thalidomide neuropathy.
      • Ochonisky S.
      • Verroust J.
      • Bastuji-Garin S.
      • Gherardi R.
      • Revuz J.
      Thalidomide neuropathy incidence and clinico-electrophysiologic findings in 42 patients.
      Some 80% of patients experience a mild decrease in bowel motility; this may reflect autonomic dysfunction, and can exacerbate constipation.
      • Grover J.K.
      • Uppal G.
      • Raina V.
      The adverse effects of thalidomide in relapsed and refractory patients of multiple myeloma.
      Somnolence or sedation may also occur and is the reason for taking the daily thalidomide dose at bedtime.
      • Palumbo A.
      • Rajkumar S.V.
      • Dimopoulos M.A.
      • et al.
      Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma.
      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.
      • Palumbo A.
      • Rajkumar S.V.
      • Dimopoulos M.A.
      • et al.
      Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma.
      • Uaprasert N.
      • Voorhees P.M.
      • Mackman N.
      • Key N.S.
      Venous thromboembolism in multiple myeloma: current perspectives in pathogenesis.
      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.
      • Kaur A.
      • Yu S.S.
      • Lee A.J.
      • Chiao T.B.
      Thalidomide-induced sinus bradycardia.
      Severe sinus bradycardia occurs in only 1–3% of patients.
      • Eisen T.
      Thalidomide in solid tumors: the London experience.
      Mild peripheral edema has been reported in 15%.
      • Sampaio E.P.
      • Sarno E.N.
      • Galilly R.
      • Cohn Z.A.
      • Kaplan G.
      Thalidomide selectively inhibits tumour necrosis factor alpha production by stimulated human monocytes.
      Orthostatic hypotension and dizziness also have been reported with thalidomide.
      • Clark T.E.
      • Edom N.
      • Larson J.
      • Lindsey L.J.
      Thalidomid (Thalidomide) capsules: A review of the first 18 months of spontaneous postmarketing adverse event surveillance, including off-label prescribing.
      A dose-dependent decrease in supine systolic and diastolic pressures is seen up to 2 h after dosing.
      • Noormohamed F.H.
      • Youle M.S.
      • Higgs C.J.
      • et al.
      Pharmacokinetics and hemodynamic effects of single oral doses of thalidomide in asymptomatic human immunodeficiency virus-infected subjects.
      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.
      • Ng S.S.
      • Brown M.
      • Figg W.D.
      Thalidomide, an antiangiogenic agent with clinical activity in cancer.
      Severe skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, may also occur.
      • Rajkumar S.V.
      • Gertz M.A.
      • Witzig T.E.
      Life-threatening toxic epidermal necrolysis with thalidomide therapy for myeloma.
      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.
      • Chanan-Khan A.
      • Miller K.C.
      • Takeshita K.
      • et al.
      Results of a phase 1 clinical trial of thalidomide in combination with fludarabine as initial therapy for patients with treatment-requiring chronic lymphocytic leukemia (CLL).
      Other undesirable effects include seizures,
      • Clark T.E.
      • Edom N.
      • Larson J.
      • Lindsey L.J.
      Thalidomid (Thalidomide) capsules: A review of the first 18 months of spontaneous postmarketing adverse event surveillance, including off-label prescribing.
      altered temperature sensitivity, irregular menstrual cycles, and hypothyroidism. Thalidomide can increase HIV viral load.
      • Marriott J.B.
      • Cookson S.
      • Carlin E.
      • et al.
      A double-blind placebo-controlled phase II trial of thalidomide in asymptomatic HIV-positive patients: clinical tolerance and effect on activation markers and cytokines.
      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).
      • Davis M.
      • Dickerson E.
      Thalidomide: dual benefits in palliative medicine and oncology.
      Female patients prescribed thalidomide must be counseled about the need for contraception, and male patients must use a condom. Written consent should be obtained.
      • Powell R.
      • Gardner-Medwin J.
      Guideline for the clinical use and dispensing of thalidomide.
      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.
      • Teo S.K.
      • Harden J.L.
      • Burke A.B.
      • et al.
      Thalidomide is distributed into human semen after oral dosing.
      Table 1Potential Uses of Thalidomide in Palliative Care
      Thalidomide is not the first-line treatment for any of these indications.
      IndicationDoseReference
      Aphthous ulcers in HIV+ disease100–200 mg at bedtime for 10 days
      • Jacobson J.M.
      • Greenspan J.S.
      • Spritzler J.
      • et al.
      Thalidomide for the treatment of oral aphthous ulcers in patients with human immunodeficiency virus infection.
      Paraneoplastic sweating100–200 mg at bedtime
      • Deaner P.
      Thalidomide for distressing night sweats in advanced malignant disease.
      • Calder K.
      • Bruera E.
      Thalidomide for night sweats in patients with advanced cancer.
      Paraneoplastic and uremic pruritus100–200 mg at bedtime

      Smith JC, Astley A, Johnstone S. Use of thalidomide in the treatment of intractable itch. Poster abstract 21. Palliative Care Congress, Sheffield, UK, 2002.

      • Goncalves F.
      Thalidomide for the control of severe paraneoplastic pruritus associated with Hodgkin’s disease.
      • Silva S.R.
      • Viana P.C.
      • Lugon N.V.
      • et al.
      Thalidomide for the treatment of uremic pruritus: a crossover randomized double-blind trial.
      Cachexia in HIV+ disease and cancer100–200 mg at bedtime
      • Boasberg P.
      • O’Day S.
      • Weisberg M.
      • et al.
      Thalidomide induced cessation of weight loss and improved sleep in advanced cancer patients with cachexia.
      • Mantovani G.
      • Macciò A.
      • Massa E.
      • Madeddu C.
      Managing cancer-related anorexia/cachexia.
      • Gordon J.N.
      • Trebble T.M.
      • Ellis R.D.
      • et al.
      Thalidomide in the treatment of cancer cachexia: a randomised placebo controlled trial.
      GI bleeding associated with angiodysplasia/radiation proctitis100–300 mg at bedtime
      • Lambert K.
      • Ward J.
      The use of thalidomide in the management of bleeding from a gastric cancer.
      Intractable irinotecan-induced diarrhea400 mg at bedtime
      • Govindarajan R.
      • Heaton K.M.
      • Broadwater R.
      • et al.
      Effect of thalidomide on gastrointestinal toxic effects of irinotecan.
      • Govindarajan R.
      Irinotecan and thalidomide in metastatic colorectal cancer.
      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.

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