Thalidomide (Thalomid) has made
a big comeback into clinical
practice. It is actively being investigated for the treatment of a wide variety
of malignant and nonmalignant conditions in the United States and around the
world. Although the US Food and Drug Administration (FDA) has licensed
thalidomide only for use in erythema nodosum leprosum (a type of immune reaction
seen in leprosy), most prescriptions written today are for the treatment of
various cancers, particularly multiple myeloma. Over the last 2 to 3 years,
there has been a substantial increase in the number of studies of this agent for
the treatment of cancer, and the results are being reported ongoingly. This
article reviews the history, pharmacology, and current status of thalidomide in
the treatment of cancer. Other related uses, including its role in the treatment
of cancer cachexia, insomnia, and graft-vs-host disease, are beyond the scope of
this review and are not discussed.
Thalidomide was first introduced into clinical practice as a
sedative. Beginning in the late 1950s, it was marketed in more than 40
countries. In the United States, the FDA was concerned about nerve damage and
did not approve thalidomide for clinical use. In countries in which it was
available, thalidomide became popular because of its association with good sleep
quality and an unusually low risk of fatal overdose (unlike other sedatives
marketed at the time).
Subsequently, thalidomide was found to be effective in the
treatment of pregnancy-related morning sickness. Unfortunately, many women took
thalidomide before its severe teratogenic potential was realized in 1961. As a
result, almost 10,000 children worldwide were born with birth defects. The fetal
malformations associated with thalidomide involved the extremities (phocomelia),
ears, eyes, and the gastrointestinal tract.[1,2] Thalidomide was withdrawn from
the market in 1962.
Pregnant women are vulnerable to its teratogenic effects between
days 27 and 40 of gestation. The mechanism of its teratogenicity is unclear, but
may be related to its antiangiogenic properties or inhibition of tumor necrosis
factor-alpha (TNF-alpha) production. Free-radical-mediated oxidative
damage to DNA has also been postulated as a mechanism of its teratogenic
effects. A single pill (50 mg) may be sufficient to cause the teratogenic
Despite its tragic past, thalidomide has reentered clinical
practice due to its immunomodulatory and antiangiogenic properties. It was
reported to be effective in the treatment of erythema nodosum leprosum in the
mid-1960s. Over the past 10 years, studies of thalidomide have confirmed its
efficacy in the treatment of AIDS-related cachexia and aphthous ulcers. It has
also been effective in the treatment of aphthous ulcers in patients with Behçet’s
disease and in the treatment of chronic graft-vs-host disease. In 1998, the FDA
approved thalidomide for use in erythema nosodum leprosum, with substantial
Thalidomide began to be studied as an anticancer agent within
months of the discovery that it caused teratogenicity. In 1962, only 4 months
after the initial reports of its severe teratogenicity, Rogerson questioned
whether a drug with such remarkable inhibitory powers on growing tissues can be
used as an anticancer agent. Within a week, Woodyatt responded that he had
used thalidomide to treat a woman with a malignant mixed mesodermal tumor of the
uterus, and was waiting to see if it demonstrated any activity.
Over the next few years, interest in studying the drug as an
anticancer agent persisted, and led to the initiation of at least two trials in
the early 1960s. The Eastern Cooperative Oncology Group (ECOG) administered
thalidomide to 21 patients with 14 types of advanced cancer, at doses ranging
from 600 to 2,000 mg/d. Included in the ECOG study were two patients
with multiple myeloma. Although no tumor responses were noted, significant
subjective palliation of symptoms was seen in seven patients (33%). The
researchers also noted that there probably was a slowing of tumor growth in two
patients with rapidly progressive disease. They concluded that further study was
Grabstad and Golbey reported on 71 patients who received
treatment with thalidomide for a variety of cancers. Doses ranged from 300 to
2,000 mg/d. One patient with renal cell carcinoma achieved resolution of
pulmonary metastases. No other responses were seen. In addition to these two
published studies, there was at least one other investigation conducted in more
than 100 patients with advanced cancer, which failed to show any response to
It is not clear whether the lack of response seen in these
trials was due to the advanced stage of the disease in the patients receiving
treatment or whether it was just a reflection of the inadequate imaging methods
used to measure response. In any case, following the completion of these initial
trials, interest in thalidomide as an anticancer agent diminished greatly.
Angiogenesisthe formation of new blood vesselsoccurs
physiologically during embryonal growth, wound healing, and in the female
genital system during the menstrual cycle. Angiogenesis is critical for the
proliferation and metastases of most malignant neoplasms. In the absence of
angiogenesis, tumors cannot grow beyond 1 to 2 mm in size. Increased
angiogenesis is an adverse prognostic factor in several tumors, including
hematologic malignancies such as myeloma.[11-15]
Over the past few years, there has been a marked interest in
tumor angiogenesis, especially after the discovery of angiostatin and
endostatin, two potent antiangiogenic compounds.[16,17] Enthusiasm for studying
thalidomide as an anticancer agent has paralleled the increased interest in
tumor angiogenesis due to reports suggesting that the drug possessed potent
Single-Agent Therapy in
Singhal and colleagues at the University of Arkansas conducted
the first trial investigating the activity of thalidomide in relapsed
myeloma. Most patients in this study had failed stem cell transplantation.
Treatment consisted of oral doses of thalidomide at 200 mg/d initially for 2
weeks, then increased by 200 mg/d every 2 weeks, up to a maximum daily
dose of 800 mg/d, depending on toxicity. The overall response rate was 32%.
Median time to response was 1 month. Approximately 10% of patients achieved
³ 90% reduction in paraprotein levels. Paraprotein responses were
accompanied by improvements in anemia and other symptoms.
Among the 48 patients who underwent repeat bone marrow analysis
after thalidomide therapy, 81% had confirmation of paraprotein responses. The
best predictor of response was a plasma cell labeling index < 0.2. Median
duration of response had not been reached after 14.5 months of follow-up.
Considering that 90% of patients in this study had failed transplantation, these
results are impressive. An update to this study confirmed the activity
of thalidomide in 169 patients with relapsed myeloma.[20,21] Overall
survival at 18 months was 55%, and event-free survival was 30%.
We reported on 16 patients with relapsed myeloma treated at the
Mayo Clinic on a similar schedule of thalidomide.[22,23] Of these patients, 25%
had failed prior stem cell transplantation; 88% had received two or more
chemotherapy regimens prior to beginning thalidomide therapy, including 25% who
had failed four or more regimens. Four patients (25%) achieved a partial
response to therapy, thus confirming the initial results obtained at the
University of Arkansas. A larger Mayo Clinic phase II study of thalidomide in
relapsed myeloma reconfirmed these findings.
Several other groups have also demonstrated the single-agent
activity of thalidomide in relapsed and refractory myeloma.[21, 23-34] Table 1
summarizes the results of the major trials of single-agent thalidomide in
relapsed myeloma.[21,23-34] Response rates ranged from 25% to 75%. Based on the
evidence thus far, thalidomide can clearly be recommended for the treatment of
relapsed myeloma, although the FDA has not yet approved it for this indication.
Combination Therapy in
Ongoing studies are assessing the efficacy of thalidomide in
combination with other effective agents for myeloma (Table 2).[33,35,36] In one
investigation conducted by Weber and colleagues, 24 of 47 patients (52%) with
resistant myeloma responded to the combination of thalidomide and
dexamethasone. Single-agent therapy with dexamethasone and thalidomide had
previously failed in many (46%) of these patients, suggesting a synergistic
effect with this combination.
Barlogie and colleagues have used thalidomide in a combination
chemotherapy regimen known as DT-PACE (dexamethasone, thalidomide, cisplatin
[Platinol], doxorubicin [Adriamycin], cyclophosphamide [Cytoxan, Neosar],
etoposide) for patients with aggressive myeloma and plasma cell leukemia.
Responses were observed in four of five patients, including three who achieved a
complete response. Updated results reported for 43 patients indicate a 40%
response rate after two cycles of therapy, and no unfavorable effects on
subsequent stem cell harvest.
Coleman and colleagues are studying the combination of
thalidomide, low-dose dexamethasone, and clarithromycin (Biaxin). Preliminary
results show significant activity. More data are needed, however, and the
role of clarithromycin in the combination needs to be clarified. Kropff and
colleagues are evaluating a combination of hyperfractionated cyclophosphamide,
pulsed dexamethasone, and thalidomide.
Previously Untreated Myeloma
Given the activity of thalidomide in relapsed myeloma, studies
are now evaluating the effect of this agent as first-line therapy in previously
untreated patients with myeloma (Table 1). Preliminary results from an ongoing
Mayo Clinic study showed that the combination of thalidomide and dexamethasone
is very active in this setting, with a response rate of 77%. The initial
protocol called for escalation of the dose of thalidomide up to 800 mg/d.
However, among the first seven patients treated, two developed grade 3/4 skin
toxicity including one patient with toxic epidermal necrolysis. The protocol
was then amended to stop dose escalation of thalidomide, and keep the dose
constant at 200 mg for the subsequent 19 patients studied.
Major grade 3/4 toxicities included the development of a rash in
three patients, and syncope, sedation, constipation, arrhythmia, and myalgia in
one patient each. This regimen may be an appropriate oral alternative to
infusional chemotherapy with VAD (vincristine, doxorubicin [Adriamycin],
dexamethasone) as initial treatment of myeloma in preparation for stem cell
transplantation. However, these results are preliminary and require further
ECOG is developing a randomized trial of thalidomide plus
dexamethasone vs dexamethasone alone in newly diagnosed symptomatic myeloma.
This study will help confirm the activity of combination therapy with
thalidomide plus dexamethasone in previously untreated myeloma and determine if
there is any significant excess toxicity associated with this regimen. An
ongoing randomized study at the University of Arkansas is investigating whether
the addition of thalidomide to a chemotherapy regimen has a role in the
management of newly diagnosed myeloma, and whether thalidomide has a role in
Thalidomide is also being studied as a single agent in patients
with previously untreated asymptomatic myeloma. Initial reports show a response
rate of approximately 35%.[33,34] However, because the main goal of therapy in
patients with smoldering and indolent myeloma is to delay the need for
chemotherapy, more data on the durability of response are needed before this
strategy can be recommended for standard clinical practice. Moreover, the effect
of prolonged thalidomide therapy on stem cell harvest is unknown.
Summary of Thalidomide
Therapy in Myeloma
It is clear from the data discussed above that thalidomide is
effective in the treatment of relapsed and refractory myeloma. In patients who
are refractory to thalidomide, the addition of dexamethasone may induce a
response, even if patients have previously failed steroid therapy. Studies are
ongoing to define the role of thalidomide alone or in combination with other
chemotherapeutic agents or dexamethasone in previously untreated myeloma. In
light of toxicity concerns, previously untreated patients should receive
thalidomide therapy primarily in the context of carefully conducted clinical
trials. Further studies are needed to determine whether thalidomide has a role
in maintenance therapy following transplantation.
1. Lenz W: Thalidomide and congenital abnormalities. Lancet
2. McBride WG: Thalidomide and congenital abnormalities. Lancet
3. Argiles JM, Carbo N, Lopez-Soriano FJ: Was tumour necrosis
factor-alpha responsible for the fetal malformations associated with thalidomide
in the early 1960s? Med Hypotheses 50:313-318, 1998.
4. Parman T, Wiley MJ, Wells PG: Free radical-mediated oxidative
DNA damage in the mechanism of thalidomide teratogenicity. Nat Med 5:582-585,
5. Iyer CG, Languillon J, Ramanujam K, et al: WHO coordinated
short-term double-blind trial with thalidomide in the treatment of acute lepra
reactions in male lepromatous patients. Bull World Health Organ 45:719-732,
6. Rogerson G: Thalidomide and congenital abnormalities. Lancet
7. Woodyatt PB: Thalidomide. Lancet 1:750, 1962.
8. Olson KB, Hall TC, Horton J, et al: Thalidomide
(N-phthaloylglutamimide) in the treatment of advanced cancer. Clin Pharmacol
Ther 6:292-297, 1965.
9. Grabstad H, Golbey R: Clinical experience with thalidomide in
patients with cancer. Clin Pharmacol Ther 6:298-302, 1965.
10. Folkman J: Seminars in Medicine of the Beth Israel Hospital,
Boston. Clinical applications of research on angiogenesis. N Engl J Med
11. Fox SB: Tumour angiogenesis and prognosis. Histopathology
12. Weidner N, Semple JP, Welch WR, et al: Tumor angiogenesis
and metastasiscorrelation in invasive breast carcinoma. N Engl J Med 324:1-8,
13. Dickinson AJ, Fox SB, Persad RA, et al: Quantification of
angiogenesis as an independent predictor of prognosis in invasive bladder
carcinomas. Br J Urol 74:762-766, 1994.
14. Rajkumar SV, Leong T, Roche PC, et al: Prognostic value of
bone marrow angiogenesis in multiple myeloma. Clin Cancer Res 6:3111-3116, 2000.
15. Rajkumar SV, Witzig TE: A review of angiogenesis and
antiangiogenic therapy with thalidomide in multiple myeloma. Cancer Treat Rev
16. O’Reilly MS, Holmgren L, Chen C, et al: Angiostatin
induces and sustains dormancy of human primary tumors in mice. Nat Med
17. O’Reilly MS, Boehm T, Shing Y, et al: Endostatin: An
endogenous inhibitor of angiogenesis and tumor growth. Cell 88:277-285, 1997.
18. D’Amato RJ, Loughnan MS, Flynn E, et al: Thalidomide is an
inhibitor of angiogenesis. Proc Natl Acad Sci USA 91:4082-4085, 1994.
19. Singhal S, Mehta J, Desikan R, et al: Antitumor activity of
thalidomide in refractory multiple myeloma. N Engl J Med 341:1565-1571, 1999.
20. Barlogie B: Thalidomide (T) in the management of multiple
myeloma (MM): The Arkansas Experience in > 300 patients (pts) with
single-agent (SA) and combination chemotherapy (CT) (abstract 28). Proc Am Soc
Clin Oncol 19:9a, 2000.
21. Barlogie B, Spencer T, Tricot G, et al: Long-term follow-up
of 169 patients in a phase II trial of single-agent thalidomide for advanced and
refractory multiple myeloma. Blood 96:514a, 2000.
22. Rajkumar SV, Fonseca R, Dispenzieri A, et al: Thalidomide in
the treatment of relapsed and refractory myeloma. Blood 94(suppl 1):316a, 1999.
23. Rajkumar SV, Fonseca R, Dispenzieri A, et al: Thalidomide in
the treatment of relapsed multiple myeloma. Mayo Clin Proc 75:897-902, 2000.
24. Rajkumar SV, Fonseca R, Dispenzieri A, et al: A phase II
trial of thalidomide in the treatment of relapsed multiple myeloma with
laboratory correlative studies. Blood 96:168a, 2000.
25. Yakoub-Agha I, Attal M, Dumontet C, et al: Thalidomide in
patients with advanced myeloma: Survival prognostic factors. Blood 96:167a,
26. Weber DM, Gavino M, Delasalle K, et al: Thalidomide alone or
with dexamethasone for multiple myeloma. Blood 94(suppl 1):604a, 1999.
27. Raza SN, Veksler Y, Sabir T, et al: Durable response to
thalidomide in relapsed/refractory multiple myeloma. Blood 96:168a, 2000.
28. Durie BGM, Stepan DE: Efficacy of low-dose thalidomide (T)
in multiple myeloma. Blood 94(suppl 1):316a, 1999.
29. Juliusson 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 109:89-96, 2000.
30. Kneller A, Raanani P, Hardan I, et al: Therapy with
thalidomide in refractory multiple myelomathe revival of an old drug. Br J
Haematol 108:391-393, 2000.
31. Shima Y, Treon SP, Yoshizaki K, et al: Clinical and
biological activity of thalidomide (THAL) in multiple myeloma. Blood 94(suppl
32. Neben K, Hawighorst H, Moehler TM, et al: Clinical response
to thalidomide monotherapy correlates with improvement in dynamic magnetic
resonance (d-MRI) angiogenesis parameters. Blood 94(suppl 1):124a, 1999.
33. Rajkumar SV, Hayman S, Fonseca R, et al: Thalidomide plus
dexamethasone (Thal/Dex) and thalidomide alone (Thal) as first-line therapy for
newly diagnosed myeloma (abstract 722). Blood 96:168a, 2000.
34. Weber DM, Rankin K, Gavino M, et al: Angiogenesis factors
and sensitivity to thalidomide in previously untreated multiple myeloma
(abstract 724). Blood 96:168a, 2000.
35. Weber DM, Rankin K, Gavino M, et al: Thalidomide with
dexamethasone for resistant multiple myeloma (abstract 719). Blood 96:167a,
36. Coleman M, Leonard JP, Nahum K: Non-myelosuppressive therapy
with BLT-D ([Biaxin], low-dose thalidomide, and dexamethasone) is highly active
in Waldenstrom’s macroglobulinemia and myeloma (abstract 720). Blood 96:167a,
37. Barlogie B, Desikan R, Munshi N, et al: Single course
DT-PACE antiangiochemotherapy effects CR in plasma cell leukemia and fulminant
multiple myeloma. Blood 92(suppl 1):273b, 1998.
38. Munshi N, Desikan R, Zangari M, et al: Chemoangiotherapy
with DT-PACE for previously treated multiple myeloma. Blood 94(suppl 1):123a,
39. Kropff MH, Innig G, Mitterer M, et al: Hyperfractionated
cyclophosphamide in combination with pulsed dexamethasone and thalidomide
(hyper-CDT) in primary refractory or relapsed multiple myeloma. Blood 96:168a,
40. Rajkumar SV, Gertz MA, Witzig TE: Life-threatening toxic
epidermal necrolysis with thalidomide therapy for myeloma. N Engl J Med
41. Dimopoulos MA, Viniou N, Zomas A, et al: Treatment of
Waldenstrom’s macroglobulinemia with thalidomide. Blood 96:286b, 2000.
42. Raza A, Lisak L, Little L, et al: Thalidomide as a single
agent or in combination with topotecan, pentoxifylline, and/or Enbrel in
myelodysplastic syndromes. Blood 96:146a, 2000.
43. Thomas DA: Pilot studies of thalidomide in acute myelogenous
leukemia, myelodysplastic syndromes, and myeloproliferative disorders. Semin
Hematol 37(suppl 3):26-34, 2000.
44. Estey E, Albitar M, Cortes J, et al: Addition of thalidomide
to chemotherapy did not increase remission rate in poor prognosis AML/MDS. Blood
45. Piccaluga PP, Finelli C, Ricci P, et al: Antiangiogenic
therapy with thalidomide improves anemia, thrombocytopenia, hyperleucocytosis,
splenomegaly in idiopathic myelofibrosis. Blood 96:746a, 2000.
46. Barosi G, Grossi A, Comotti B, et al: Thalidomide in
patients with myelofibrosis with myeloid metaplasia. Blood 96:746a, 2000.
47. Tefferi A, Elliot MA: Serious myeloproliferative reactions
associated with the use of thalidomide in myelofibrosis with myeloid metaplasia.
Blood 96:4007, 2000.
48. Hirschfeld S, Wilson C, Pelosi M: The FDA experience on the
use of thalidomide in advanced malignancies (abstract 2391). Proc Am Soc Clin
Oncol 19:607a, 2000.
49. Baidas SM, Winer EP, Fleming GF, et al: Phase II evaluation
of thalidomide in patients with metastatic breast cancer. J Clin Oncol
50. Little RF, Wyvill KM, Pluda JM, et al: Activity of
thalidomide in AIDS-related Kaposi’s sarcoma. J Clin Oncol 18:2593-2602, 2000.
51. Fine HA, Figg WD, Jaeckle K, et al: A phase II trial of the
antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas.
J Clin Oncol 18:708-715, 2000.
52. Marx GM, McCowatt S, Boyle F, et al: Phase II study of
thalidomide as an antiangiogenic agent in the treatment of recurrent
glioblastoma multiforme (abstract 613). Proc Am Soc Clin Oncol 19:158a, 2000.
53. Eisen T, Boshoff C, Mak I, et al: Continuous low-dose
thalidomide: A phase II study in advanced melanoma, renal cell, ovarian and
breast cancer. Br J Cancer 82:812-817, 2000.
54. Tseng JE, Glisson BS, Khuri FR, et al: Phase II trial of
thalidomide in the treatment of recurrent and/or metastatic squamous cell
carcinoma of the head and neck (SCHN) (abstract 1645). Proc Am Soc Clin Oncol
55. Patt YZ, Hassan MM, Lozano RD, et al: Durable clinical
response of refractory hepatocellular carcinoma to orally administered
thalidomide. Am J Clin Oncol 23:319-321, 2000.
56. Patt YZ, Hassan MM, Lozano RD, et al: Phase II trial of
Thalomid (thalidomide) for treatment of nonresectable hepatocellular carcinoma
(HCC) (abstract 1035). Proc Am Soc Clin Oncol 19:266a, 2000.
57. Figg WD, Bergan R, Brawley O, et al: Randomized phase II
study of thalidomide in androgen-independent prostate cancer (AIPC) (abstract
1189). Proc Am Soc Clin Oncol 16:333a, 1997.
58. Govindarajan R, Heaton KM, Broadwater R, et al: Effect of
thalidomide on gastrointestinal toxic effects of irinotecan. Lancet 356:566,
59. Stirling DI: Pharmacology of thalidomide. Semin Hematol
60. Kenyon BM, Browne F, D’Amato RJ: Effects of thalidomide
and related metabolites in a mouse corneal model of neovascularization. Exp Eye
Res 64:971-978, 1997.
61. Or R, Feferman R, Shoshan S: Thalidomide reduces vascular
density in granulation tissue of subcutaneously implanted polyvinyl alcohol
sponges in guinea pigs. Exp Hematol 26:217-221, 1998.
62. Minchinton AI, Fryer KH, Wendt KR, et al: The effect of
thalidomide on experimental tumors and metastases. Anticancer Drugs 7:339-343,
63. Bauer KS, Dixon SC, Figg WD: Inhibition of angiogenesis by
thalidomide requires metabolic activation, which is species-dependent. Biochem
Pharmacol 55:1827-1834, 1998.
64. Rajkumar SV, Fonseca R, Witzig TE, et al: Bone marrow
angiogenesis in patients achieving complete response after stem cell
transplantation for multiple myeloma. Leukemia 13:469-472, 1999.
65. Kumar S, Fonseca R, Dispenzieri A, et al: Bone marrow
angiogenesis in multiple myeloma: Effect of therapy and prognostic value. Blood
66. Moreira AL, Sampaio EP, Zmuidzinas A, et al: Thalidomide
exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA
degradation. J Exp Med 177:1675-1680, 1993.
67. Turk BE, Jiang H, Liu JO: Binding of thalidomide to
alpha1-acid glycoprotein may be involved in its inhibition of tumor necrosis
factor alpha production. Proc Natl Acad Sci USA 93:7552-7556, 1996.
68. Haslett PA, Corral LG, Albert M, et al: Thalidomide
costimulates primary human T lymphocytes, preferentially inducing proliferation,
cytokine production, and cytotoxic responses in the CD8+ subset. J Exp Med
69. 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.
70. 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.
71. Hideshima T, Chauhan D, Shima Y, et al: Thalidomide and its
analogs overcome drug resistance of multiple myeloma cells to conventional
therapy. Blood 96:2943-2950, 2000.