US Pharm.2008;33(7)(Oncology suppl):3-13.

ABSTRACT: Thalidomide, a drug once thought to have no clinical benefit due to its significant toxicity, has now become a potential agent for the treatment of hematologic malignancies and some solid tumors. Thalidomide in combination with dexamethasone is approved for use in multiple myeloma. Current study data show promising results for hepatocellular carcinoma, prostate, neuroendocrine, and ovarian cancers, but larger studies are needed to fully define the role of thalidomide in these cancers.

The serendipitous discovery of novel uses for medications is not a new phenomenon. Drugs such as minoxidil and finasteride for hair growth, nitroglycerin for vasodilation, and warfarin for blood thinning effects all have their own unique development story. Thalidomide, a drug once thought to have no clinical benefit due to its significant toxicity, is approved for use in multiple myeloma and has now become a potential agent for the treatment of various cancers. This article aims to educate pharmacists about the history, mechanism of action, indications, toxicities, and special dispensing requirements for thalidomide.

History of Thalidomide
Thalidomide was first introduced in Germany in 1957 as an OTC sedative. It was also marketed in 46 countries for the treatment of morning sickness in pregnant patients.1 Over the next few years, case reports of severe birth defects started to appear. The most significant adverse events were amelia (lack of a limb) and phocomelia (seal limb) in children whose mothers had taken thalidomide during pregnancy. Other reported adverse events included deformities of the heart, kidney, and eyes; absent or abnormal ears; cleft lip or palate; spinal cord defects; and disorders of the gastrointestinal tract.1 It is estimated that 8,000 to 12,000 infants were affected worldwide.2 The United States was not as widely affected as other countries due to delayed approval of the drug by the FDA over concerns of peripheral neuropathy. During the delayed approval process, evidence of the severe teratogenicity became apparent and the product was removed from the worldwide market in 1962.1,2

In 1965, Sheskin et al reported symptom resolution of erythema nodosum leprosum (ENL), an inflammatory complication of leprosy, in a patient who was treated with thalidomide for his insomnia.3 This eventually led the FDA to approve thalidomide for the use of ENL in 1998.1 Due to its various postulated mechanisms of action, thalidomide was soon being investigated for use in a variety of cancers.

Pharmacology
The mechanism of action of thalidomide has not been fully elucidated. However, it is known that thalidomide possesses immunomodulatory, anti-inflammatory, and antiangiogenic properties. The immunologic effects are caused by a suppression of excessive tumor necrosis factor-alpha production and a down-regulation of selected cell surface adhesion molecules that are involved in white blood cell migration. Other anti-inflammatory properties come from suppression of macrophage involvement in prostaglandin synthesis, and modulation of interleukin-10 and interleukin-12 production by monocytes and lymphocytes. Thalidomide has also been shown to increase the number of circulating natural killer cells, level of interferon gamma, and level of interleukin-2.4 The anti-angiogenic properties of thalidomide are thought to be caused by inhibition of vascular endothelial growth factor and basic fibroblast growth factor.5 The combination of these effects are thought to be responsible for the anticancer activity of thalidomide.

Approved Uses in Cancer
Thalidomide in combination with dexamethasone is currently FDA approved for use in patients with newly diagnosed multiple myeloma. It is important to note that this indication is based on response rates in clinical trials. To date, no increase in survival has been shown in clinical trials.4 The use of thalidomide for multiple myeloma was first reported by Singhal et al in 1999 in patients with relapsed/refractory multiple myeloma.6 Subsequent single-agent studies showed response rates of 15% to 48%.7 Additional studies showed that thalidomide doses of up to 400 mg daily plus pulse-dose dexamethasone (20 mg/m2 for 4 days beginning on days 1, 9, and 17, repeated for 3 cycles) increased the response rate by approximately 20% in relapsed/refractory patients.7,8

Clinical trials in previously untreated patients have also shown good response rates with the combination of thalidomide and dexamethasone. The ECOG E1A00 and MM003 trials showed statistically significant partial response rates (63% and 69%, respectively), a complete response of 4% (ECOG E1A00), and at least a very good partial remission (almost complete disappearance of the tumor but still a suspicion that some tumor remains) of 43.8% (MM003) when compared to high-dose dexa­ methasone alone.9,10 These two studies also showed a longer progression-free survival period with the combination of thalidomide and dexamethasone compared to high-dose dexamethasone.9,10

The role of thalidomide in asymptomatic patients is not clear and so far no overall survival benefit has been demonstrated. Current guidelines suggest that thalidomide should not be used in asymptomatic patients until a survival benefit is clearly demonstrated.11

Thalidomide is the adjunct therapy of choice to add to the standard of care of melphalan plus prednisone in elderly patients. A clear increase in overall survival in previously untreated elderly patients was seen in a study by Facon et al when melphalan/prednisone plus thalidomide was compared to melphalan/prednisone alone or with reduced-intensity stem cell transplantation using melphalan.12 Of the 447 patients recruited, 196 received melphalan/prednisone (0.25 mg/kg melphalan + 2 mg/kg prednisone given orally for 4 days in each of 12 six-week cycles), 125 received melphalan/prednisone/thalidomide (0.25 mg/kg melphalan + 2 mg/kg prednisone given orally for 4 days in each of 12 six-week cycles, plus thalidomide 400 mg/day), and 126 received reduced-intensity stem cell transplantation using melphalan 100 mg/m2.

Currently, there are over 15 clinical trials investigating thalidomide as treatment or part of a treatment regimen for both newly diagnosed and refractory/relapsed patients with multiple myeloma.13 Results of these trials will help determine the role of thalidomide in all stages of multiple myeloma.


Investigational Uses in Cancer
After a benefit in multiple myeloma was seen with thalidomide, researchers began investigating the drug for activity in other cancers. The results so far have been mixed and no new FDA-approved indications have been developed. Clinical trials in breast cancer, renal cell carcinoma, and small cell lung cancer have not shown a benefit.14-17 However, trials in prostate cancer, hepatocellular carcinoma, some neuroendocrine cancers, and ovarian cancer have demonstrated positive results.18-24

Prostate Cancer: For patients who have progressed to androgen independent or hormone refractory prostate cancer, the addition of thalidomide to docetaxel may provide benefit. Several studies comparing docetaxel alone to docetaxel plus thalidomide have been published. One study showed a 53% response rate for the combination therapy compared to a 37% response rate for docetaxel alone, and median progression free survival for the combination arm was 5.9 months (survival of 25.9 months) compared to progression free survival of 3.7 months (survival 14.7 months) in the docetaxel only arm.18 Another docetaxel plus thalidomide study showed 18 month survival in 69.3% of patients compared to 47.2% of patients treated with docetaxel alone (P <.05).19 These findings led Dahut et al to conclude that combination therapy with docetaxel and thalidomide represents a promising new area of treatment for metastatic androgen independent prostate cancer, but additional studies are needed to define thalidomideexact role.18

Hepatocellular Carcinoma: Several phase II studies with single-agent thalidomide have been published in recent years. These studies were undertaken after anecdotal evidence suggested that patients who were refractory to or ineligible for traditional chemotherapy might have a good response with thalidomide.20,21 Phase II trials by Patt et al and Lin et al showed only a modest response rate of 5% to 7%, which suggests that, as a single agent, the use of thalidomide mostly offers disease stabilization in patients with hepatocellular carcinoma.20,22 The authors added that the combination of thalidomide with other antiangiogenesis medications or chemotherapy agents could prove to be beneficial in this patient population, and further studies are warranted.20 In a study by Hsu et al, patients who had a high tumor vascularity index, identified by power Doppler ultrasound, had the best response to thalidomide.23 Therefore, using this diagnostic procedure may identify the best candidates to receive thalidomide therapy.

Neuroendocrine Cancers: Neuroendocrine cancers represent a family of malignancies that are often characterized by hormonal excess. To date, systemic therapies have not been very effective at destroying these tumors. However, the use of temozolomide, a cytotoxic alkylating agent, has shown benefit in these types of tumors.24 Because of its antiangiogenic properties, thalidomide is a good theoretical choice to add to temozolomide therapy. Kulke et al administered temozolomide (150 mg/m2 for 7 days, every other week) plus thalidomide (50-400 mg daily) to 29 neuroendocrine cancer patients. An overall radiologic response rate (defined according to Response Evaluation Criteria in Solid Tumors guidelines) of 25%, a biochemical response rate (decrease in chromogranin A by 50% or more from baseline) of 40%, and a two-year survival rate of 70% were noted in these patients. The authors suggested that this combination may provide good benefit to this patient population, but further studies are needed to define the exact role of temozolomide and thalidomide.24

Ovarian Cancer: A recent study by Downs et al comparing topotecan to topotecan plus thalidomide in recurrent ovarian cancer patients showed promising results for the combination arm.25 The overall response rate was 21% for topotecan and 47% for topotecan plus thalidomide. The progression free survival time was four months for topotecan and six months for thalidomide. Both the response rates (P = .03) and progression free survival times (P = .02) were statistically significant. The median overall survival was 14.8 months for topotecan and 18.8 months for topotecan plus thalidomide, although this was not statistically significant (P = .67). The study authors concluded that further phase III trials in women with recurrent ovarian cancer should be conducted.25

Adverse Events
The most common side effects seen in clinical trials were sedation, rash, dizziness, constipation, tremor, and headache.26 While thalidomide carries a black box warning and a pregnancy category X for its well-known teratogenicity, two other significant toxicities have also emerged: peripheral neuropathy and venous thromboembolism (VTE). Peripheral neuropathy associated with thalidomide use is a well-known and feared adverse event, which commonly leads to drug discontinuation. The most common complaint is paresthesias with tingling sensation and slight loss of tactile and pain response at limb extremities. It is reported to variable degrees (14% to 70% of cases) in clinical trials, and previous use of neurotoxic agents may increase the risk.27

In general, VTE is a major complication of cancer, occurring in 4% to 20% of patients, and certain medications have been found to increase this risk.28 Thalidomide-associated VTE is a common toxicity associated with treatment. One study reported VTE in 22.5% of thalidomide/dexamethasone-treated patients with multiple myeloma.28 It is estimated that patients on thalidomide are 2.6 times more likely to develop VTE, and patients on combination therapy with thalidomide and dexamethasone are eight times more likely to develop VTE.28 This increased risk has led the American Society of Clinical Oncology to recommend that myeloma patients treated with thalidomide and chemotherapy or dexa­ methasone receive either low-molecular weight heparins or warfarin (to an international normalized ratio of ~1.5) as prophylaxis against VTE.29

S.T.E.P.S Program
Due to the teratogenic effects of thalidomide, the FDA and Celgene, the manufacturer of thalidomide (Thalomid), created the System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.) program.30 The S.T.E.P.S. program is a restricted distribution program that involves the patient, physician, and pharmacist. Both the physician and the pharmacy must register with the S.T.E.P.S. program before medication can be dispensed. Pharmacist responsibilities are listed in Table 1. Additional information about the S.T.E.P.S. program can be found at: www.thalomid.com/steps_program.aspx.

Patient responsibilities include signing all consent forms and adhering to the S.T.E.P.S. program. For female patients of childbearing age, two forms of birth control are mandated throughout the treatment course. While not part of the specific S.T.E.P.S. program, men are advised to wear condoms while being treated with thalidomide.30

A recent study revealed that 0.7% of patients received a prescription in violation of a black box warning, which further increases the importance of programs like S.T.E.P.S.31 This program has been extremely successful in preventing the tragic birth defects seen in the 1950s and 1960s. To date, of the 145,000 patients who have been enrolled in the S.T.E.P.S. program, only three pregnancies have been reported.30


The Pharmacist's Role
As the treatment of certain cancers transition to oral therapies, the role of the pharmacist becomes increasingly important. Being up to date on the appropriate use, adverse effects, and special dispensing requirements is essential for pharmacists to help manage these patients appropriately. By participating in programs like S.T.E.P.S., pharmacists are taking a more active role in patient care. As has been seen with the S.T.E.P.S. program, when patients, pharmacists, and physicians work together, tragic events like those seen in the 1950s and 1960s are avoided.

Conclusion
Thalidomide in combination with dexamethasone is now accepted as a treatment of choice for both treated and untreated patients with multiple myeloma. While initial clinical experience in hepatocellular carcinoma, prostate, neuroendocrine, and ovarian cancers is promising, the exact role of thalidomide in these cancers is still being determined. Currently, there are over 15 clinical trials evaluating thalidomide's benefit in cancer. Once these studies are published, clinicians will have a better understanding of the exact role thalidomide will play as an antineoplastic agent.

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