Research on Thalidomide in Solid Tumors, Hematologic Malignancies, and Supportive Care

Introduction

Interest in thalidomide (Thalomid) has intensified in recent years as research has identified and elucidated its immunomodulatory, anti-inflammatory, and antiangiogenic properties. In this supplement, we present a selection of abstracts about thalidomide from the 36th Annual Meeting of the American Society of Clinical Oncology. The abstracts are categorized by subject into solid tumors, hematologic malignancies, and supportive care. To place these data into perspective, we have invited Drs. Wen-Jen Hwu, of Memorial Sloan-Kettering Cancer Center, James R. Berenson, of Cedars-Sinai Medical Center and UCLA School of Medicine, and Eduardo Bruera, of The University of Texas M. D. Anderson Cancer Center, to comment on these important abstracts.

Thalidomide, also known as alpha-(N-phthalimido)glutarimide, consists of a two-ringed structure with an asymmetric carbon in the glutarimide ring. Thalidomide exists as an equal mixture of S-(-) and R-(+) enantiomers that interconvert rapidly under physiologic conditions. Thalidomide is sparingly soluble in water and ethanol, which to date has prevented the availability of an intravenous formulation.[1]

Mechanism of Action

Clinical investigations of thalidomide have been conducted in patients with diverse diseases. Even though over the past several years its antiangiogenic properties have been hypothesized to be the major cause of its antitumor activity, thalidomide’s immunomodulatory properties appear to be diverse, and the probable factor in its success as an antitumor agent as compared to other pure antiangiogenic agents.

TNF-alpha Inhibition

Thalidomide reduces phagocytosis by polymorphonuclear leukocytes. This may explain its action in inflammatory processes that involve predominantly mononuclear cell accumulation, such as chronic cutaneous lupus erythematosus.[2] Thalidomide inhibits monocyte phagocytosis without any sign of cytotoxicity in monocytes or polymorphonuclear cells.[2] Thalidomide inefficiently, but selectively, inhibits the production of tumor necrosis factor–alpha (TNF-alpha) in human monocytes in a dose-dependent fashion, with no effect on total protein synthesis or the production of other cytokines.[3,4] The process of inhibition is not a complete one.[4,5] Thalidomide also reduces the half-life of TNF-alpha mRNA from approximately 30 to 17 minutes.[4]

Thalidomide’s ability to inhibit TNF-alpha production may depend on the stimulus or the cellular source of production. In addition, there are difficulties in measuring TNF-alpha levels in patients for several reasons: the normal circulating level of the cytokine has not been defined, its release in response to systemic inflammation is often phasic, and its half-life is short.[6,7]

To complicate matters, there are two active forms of TNF-alpha—a membrane-bound protein and a circulating homotrimer, with only the latter typically being a measurable component.[6,7] Measurements of TNF-alpha levels may detect receptor-bound circulating homotrimer, which may not be active. Thus, serum levels may not accurately reflect TNF-alpha activity.

The ability of thalidomide to inhibit TNF-alpha production in vitro has not always been reproducible in vivo. Indeed, in two studies, increases in serum TNF-alpha levels were seen with thalidomide treatment.[8,9] This discordance might be the case in solid tumor malignancies, and does not appear to have an impact on response. (See Dr. Wen-Jen Hwu’s commentary on thalidomide in solid tumors.)

TNF-alpha plays a critical role in the pathogenesis of plasma-cell dyscrasia such as in multiple myeloma. This molecule might play a central role in the pathogenesis of plasma-cell–related amyloidosis. More importantly, a large number of amyloid patients have congestive heart failure, where the TNF-alpha levels appear to be a central cytokine. Our group has shown that the TNF receptor etanercept (Enbrel) has activity in managing the disease, and certainly a drug such as thalidomide might also result in a significant response in this group of patients with poor prognosis.

Antiangiogenic Activity

Multiple myeloma and other hematologic malignancies are targets to be investigated for therapeutic benefit. In myeloma, cytokines that are secreted into the microenvironment of the marrow—such as interleukin-6, interleukin-1-beta, interleukin-10, and TNF-alpha—modulate the growth and survival of myeloma cells[10]; thalidomide may alter the secretion and biologic activity of such cytokines.[11] D’Amato and colleagues first demonstrated thalidomide’s antiangiogenic activity, which has been postulated to have clinical therapeutic applications in solid tumors and other diseases.[12] This aspect of the action of thalidomide is detailed in Dr. Berenson’s commentary on thalidomide in hematologic malignancies. More recently, experiments have shown that a combination of thalidomide and sulindac—a nonsteroidal anti-inflammatory drug with antiangiogenic activity—inhibited angiogenesis to a greater degree than either agent alone.[13] This observation should be carefully studied, and considered for application in a disease such as colon cancer or its predisposing conditions.

T Cells

Another important aspect of thalidomide’s proposed mechanism of action is its influence on T cells. In healthy volunteers, thalidomide decreases the ratio of circulating helper T cells to suppressor T cells, because of a reduction in helper T cells and an apparent increase in suppressor T cells.[14] Its effect may be mediated at the level of cytokine regulation. A potent and specific effect on cytokine production relating to helper T cells has been shown.[15] In peripheral blood mononuclear cell cultures, thalidomide enhances the production of interleukin-4 and -5 and inhibits interferon gamma production.[15] Thalidomide is a potent costimulator of human

T cells in vitro.[16] The drug’s effects are synergistic with stimulation by means of the T-cell receptor complex, thereby increasing interleukin-2–mediated cell proliferation and interferon gamma production. Costimulation is more pronounced in CD8 lymphocytes than in CD4 lymphocytes. Based on these findings, the combination of thalidomide and other cytokines is currently being investigated, especially in malignancies that have shown some response to interferons and interleukins.

Oxidative Damage

Another mechanism that may be important in the management of malignancies is related to thalidomide’s ability to cause oxidative damage to DNA mediated by free radicals, which probably has a role in the teratogenicity of thalidomide.[17] Thalidomide, by modulating the profile of adhesion molecules, may influence the growth and survival of tumor cells.[18] The adhesion of malignant plasma cells to bone marrow stromal cells triggers the secretion of cytokines, augmenting the growth and survival of myeloma cells and inducing drug resistance in them.[10,19]

Dosage and Toxicity

As my colleagues have emphasized, there does not appear to be an identified dose or schedule that should be followed when using thalidomide. Several studies are focusing on defining this important aspect.

Toxicity related to thalidomide use is a critical issue that more often than not results in premature discontinuation of an effective therapy. From our experience, and that of others, it does appear that the drug is not well tolerated when used in patients with poor performance status, or when the dose is escalated in a rapid fashion. Careful patient evaluation and education results in continuing therapy in over 98% of the patients at the Cleveland Clinic. The most common adverse effects are dose-dependent somnolence and dizziness.[1,20] To minimize these complications, we administer thalidomide as a once-daily dose in the evening, initiated at low doses (50–100 mg/d). The dose is escalated at 50–100 mg/wk to the maximum dose specified according to the disease or the protocol followed.

Relative to the dizziness, which appears to be related to the hypotensive effect of the drug, special care should be taken to ensure the patient’s fluid intake is increased. Patients should also be advised to sit upright for a few minutes before standing from a recumbent position. This is particularly important in diseases such as multiple myeloma, where dehydration and low hemoglobin due to different factors are common events. Tolerance to thalidomide’s sedative properties usually develops over time.

Constipation is a common side effect experienced by 3% to 30% of patients. Narcotics, decreased mobility, and electrolyte imbalances worsen constipation. In our experience, initiating all patients on two Senokot-S a day, to be titrated up to eight tablets according to their symptoms, has eliminated this side effect. Chronic thalidomide therapy can produce peripheral neuropathy. The neuropathy results from axonal degeneration without demyelination in the sensory fibers of the lower and occasionally upper extremities. Risk of peripheral neuropathy appears to rise with patient age and cumulative dose of thalidomide, resulting in an incidence of approximately 25% in nonlepromatous patients on chronic thalidomide therapy.[21]

We have shown that 35% to 40% of patients with plasma-cell dyscrasia have a functional vitamin B12 and folate deficiency.[22] Detecting and treating this deficiency generally results in the drug being better tolerated. Thalidomide-induced erythematous macular rash, usually involving the trunk and back, has been reported. This rash is not likely to be pruritic[1]; it usually occurs within 2 to 13 days after initiation and reverses after discontinuation, with or without the use of antihistamines.[21] Severe, life-threatening epidermal damage has been reported.[1,21] Our policy is to observe the patients carefully, and discontinue the drug only if the rash worsens.

Thalidomide is a complex immunomodulatory agent whose role in oncology practice is as yet not fully clear. Studies to define the dose, schedule, and role in combination with other cytokines and chemotherapy are underway.

References:

1. Thalomid capsules (thalidomide) prescription product insert. Celgene, Warren, NJ, revised August 1998.

2. Barnhill RL, Doll NJ, Millikan LE, et al: Studies on the anti-inflammatory properties of thalidomide: Effects on polymorphonuclear leukocytes and monocytes. J Am Acad Dermatol 11:814-819, 1984.

3. Sampaio EP, Sarno EN, Galilly R, et al: Thalidomide selectively inhibits tumor necrosis factor-a production by stimulated human monocytes. J Exp Med 173:699-703, 1991.

4. Moriera AL, Sampaio EP, Zmuidzinas A, et al: Thalidomide exerts its inhibitory action on tumor necrosis factor-a by enhancing mRNA degradation J Exp Med 177:1675-1680, 1993.

5. Klausner JD, Freedman VH, Kaplan G: Thalidomide as an anti-TNF-a inhibitor: Implications for clinical use. Clin Exp Immunol 81:219-223, 1996.

6. Strieter RM, Kunkel SJ, Bone RC: Role of tumor necrosis factor-a in disease states and inflammation. Crit Care Med 21:S447-S463, 1993.

7. Davidsen SK, Summers JB: Inhibitors of TNF-a synthesis. Exp Opin Ther Pats 5:1087-1100, 1995.

8. Jacobson JM, Greenspan JS, Spritzler J, et al: Thalidomide for the treatment of oral aphthous ulcers in patients with human immunodeficiency virus infection. N Engl J Med 336:1487-1493, 1997.

9. Wolkenstein P, Latarject J, Roujeau JC: Randomized comparison of thalidomide versus placebo in toxic epidermal necrolysis. Lancet 352:1586-1589, 1998.

10. Hallek M, Leif Bergsagel P, Anderson KC: Multiple myeloma: Increasing evidence for a multistep transformation process. Blood 91:3-21, 1998.

11. Corral LG, Haslett PA, Muller GW, et al: Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha. J Immunol 163:380-386, 1999.

12. D’Amato RJ, Loughnan MS, Flynn E, et al: Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA 91:4082-4085, 1994.

13. Verheul HM, Panigrahy D, Yuan J, et al: Combination therapy with thalidomide and sulindac inhibits tumour growth in rabbits. Br J Cancer 79:114-118, 1999.

14. Gad SM, Shannon EJ, Krotoski WA, et al: Thalidomide induces imbalances in T-lymphocyte sub-populations in the circulating blood of healthy males. Lepr Rev 56:35-39, 1985.

15. McHugh SM, Rifkin IR, Deighton J, et al: The immunosuppressive drug thalidomide induces T helper cell type 2 (Th2) and concomitantly inhibits Th1 cytokine production in mitogen- and antigen-stimulated human peripheral blood mononuclear cell cultures. Clin Exp Immunol 99:160-167, 1995.

16. Haslett PA, Corral LG, Albert M, et al: Thalidomide costimulates primary human T lymphocytes, preferentially inducing proliferation, cytokine production, and cytoxic responses in the CD8+ subset. J Exp Med 187:1885-1892, 1998.

17. Parman T, Wiley MJ, Wells PG: Free radical-mediated oxidative DNA damage in the mechanism of thalidomide teratogenicity. Nat Med 5:582-585, 1999.

18. Geitz H, Handt S, Zwingenberger K: Thalidomide selectively modulates the density of cell surface molecules involved in the adhesion cascade. Immunopharmacol 31:213-221, 1996.

19. Damiano JS, Cress AE, Hazelhurst LA, et al: Cell adhesion mediated drug resistance (CAM-DR): Role of integrins and resistance to apoptosis in human myeloma cell lines. Blood 93:1658-1667, 1999.

20. Tseng S, Pak G, Washenik K, et al: Rediscovering thalidomide: A review of its mechanism of action, side effects, and potential uses. J Am Acad Dermatol 35: 969-979, 1996.

21. Celgene. Request for Medical Information. Thalomid and cancer. Document #702. Revised February 1999.

22. Beckmann MJ, Hussein MA, Lichtin A, et al: Low serum vitamin B12 in patients with plasma cell myeloma is associated with true functional cobalamin deficiency (abstract 97). Am J Clin Pathol 104:350, 1995.