Thalidomide (Thalomid) is recognized to have antiangiogenic properties and has been shown to be effective in the treatment of refractory myeloma. As a result, thalidomide is now being investigated for use in a number of malignancies, including breast,
Thalidomide (Thalomid) is recognized to haveantiangiogenic properties and has been shown to be effective in the treatment ofrefractory myeloma. As a result, thalidomide is now being investigated foruse in a number of malignancies, including breast, lung, and renal cellcarcinoma, as well as melanoma. The following is an account of a patient withtwo unrelated disorders (one malignant, one benign), both of which haveresponded to thalidomide.
An active 77-year-old man in otherwise good health was referred to thesurgical department in July 1996 because of a large, protuberant abdominal mass.The patient described a 1- to 2-year history of abdominal bloating and earlysatiety, and reported that the mass became larger following meals. In addition,he had lost 5 to 10 lb over the preceding 7 months. The patient also had ahistory of Osler-Weber-Rendu disease (hereditary hemorrhagic telangiectasia),reporting nosebleeds every night as well as some rectal bleeding. His hematocrittypically ranged from the high 20s to low 30s. A prior computed tomography (CT)scan had shown cystic lesions in the liver. On physical examination, the patienthad lesions consistent with this disease on his lips and tongue.
An abdominal ultrasound taken in June 1996 showed a 16-cm mass in the rightupper quadrant, displacing the kidney and pancreas. The ultrasound was positivefor ascites. A cystic mass was also discovered in the dome of the right upperlobe of the liver. A CT scan confirmed both masses (Figure1). Fine-needleaspiration of the abdominal mass removed a large amount of bloody fluid, which,at the time, was negative for malignant cells. Aspiration reduced the size ofthe mass somewhat, but the mass did not resolve completely.
Series of Surgeries
In July 1996, the patient underwent surgery to remove the abdominal mass.Macroscopically, the tumor appeared to be highly vascular. The mass was purplishin color and was attached to one of the mesenteric arteries of the transversecolon. There were numerous satellite cystic lesions throughout the abdomen.Pathology revealed that the mass was a grade II epithelioid leiomyosarcoma, with5 to 10 mitoses per high-powered field. All margins of all specimens, whichincluded a portion of the omentum, were positive for tumor cells. Adjuvantchemotherapy was not recommended, based predominantly on concerns abouttolerability.
The patient later developed nodules in the area of the abdominal incision.Following a CT scan, a second operation, performed in April 1998, removed thegall bladder and a portion of the diaphragm due to tumor involvement. Twoadditional operations were performed in September 1998 and June 1999 to removeprogressive tumor growth. On each occasion, numerous small lesions(approximately 1 mm) were seen throughout the abdominal cavity. Following thefinal operation, the patient developed a pulmonary embolus that was mild butlengthened recovery time. This was treated by placement of a vena caval filter,as anticoagulation therapy was contraindicated.
Thalidomide Therapy Initiated
Due to the vascularity of the tumors, and in an attempt to circumvent theneed for additional surgery, antiangiogenic therapy was considered. In August1999, the patient was started on thalidomide, 250 mg/d. Adverse events reportedby the patient included mild peripheral neuropathy in the fingers and toes,which, although mild, resulted in a dose reduction to 150 mg/d. The patientgenerally took the medication at night, and the mild sedative effects were notproblematic.
In September 2000, the patient presented to the emergency room withcomplaints of abdominal pain. Surgery was again performed, and tumor wasdebulked. However, the numerous small lesions found during all previous surgicalprocedures were not observed. The few lesions present were well-formed, olderlesions that had been present at the time of the previous operation, althoughthey appeared to be somewhat smaller in size.
The patient currently has no symptoms, and is being followed closely. A CTscan confirmed shrinkage of existing lesions (Figure2). Thus, the time betweensurgeriesinitially every 6 to 8 monthshas slowed considerably sincethalidomide therapy was initiated. After this last surgery, the thalidomide dosewas increased to 200 mg/d; the patient is tolerating it well.
Benefits of Thalidomide Therapy
Surprisingly, the patient’s symptoms related to Osler-Weber-Rendu diseasehave also diminished, in terms of both frequency and severity. The patient’shematocrit has now stabilized in the low 40s, and nosebleeds occur lessfrequently. Before receiving thalidomide, the patient experienced three to fournosebleeds daily. With therapy, the frequency has been reduced to one nosebleedevery 2 to 3 days. In addition, the nosebleeds are lighter and more easilystopped, lasting on average 1 to 2 minutes, as opposed to 45 to 90 minutes priorto thalidomide. Although these findings are anecdotal, it is intriguing toobserve the antiangiogenic properties of thalidomide in a patient whose tumor isresponding to this agent.
Further investigation into the effects of thalidomide in solid malignanciesas well as in certain vascular disorders such as Osler-Weber-Rendu diseasecertainly appears warranted.
RONALD KURSTIN, MD
Assistant Clinical Professor
George Washington University Medical School
Georgetown University Medical School
Research Director, Sibley Hospital
The over-the-counter marketing of thalidomide in Europeduring the late 1950s for the treatment of pregnancy-associated morning sicknesswas a tragic sentinel event in the history of drug development. As early as1961, reports of teratogenicity and dysmelia (stunted limb growth) associatedwith thalidomide use prompted its subsequent withdrawal.[1,2]
The return of thalidomide as therapy for certain conditions stems from itsbroad array of pharmacoimmunologic effects. This rehabilitation was reflectedby its approval in 1998 by the Food and Drug Administration for the short-termtreatment of cutaneous manifestations of moderate-to-severe erythema nodosumleprosum (ENL), together with its use as maintenance therapy to prevent andsuppress cutaneous manifestations of ENL recurrence. Thalidomide has sincebecome the treatment of choice for ENL, and its wide spectrum of activity hasfostered its application in a variety of disease states (Table1).[3-5] Givenits teratogenic effects, thalidomide is now used only under strict guidelines toensure that no fetal exposure to the drug occurs.
In the field of medical oncology, the discovery of thalidomide’santiangiogenic properties coincided with the emerging importance ofantiangiogenesis in tumor growth and progression. Thalidomide has proven toinhibit angiogenesis induced by beta-fibroblast growth factor in a rabbit corneamicropocket assay and by vascular endothelial growth factor (VEGF) in a murinemodel of corneal vascularization.[6,7]
In human studies, the drug appears to undergo activation to metabolites viaantiangiogenic activity. Given these antiangiogenic properties, thalidomideis currently being evaluated for the treatment of various solid tumors, multiplemyeloma, and other hematologic malignancies.[9-13] Results in multiple myelomaare particularly promising, although its precise mechanisms of action in thisdisease are not completely understood, and its antiangiogenic effects arebelieved to be only part of the means by which its antimyeloma activity occurs.These other potential actions include modulation of adhesion molecules,inhibition of tumor necrosis factor (TNF)-alpha, down-regulation of lymphocytesurface molecules, lowering of CD4-to-CD8 peripheral lymphocyte ratios, anddirect effects on myeloma cells themselves.[10,14-18]
Sedation and constipation appear to be the most common adverse effectsreported by cancer patients,[9,13,19] with peripheral neuropathy being the mostserious adverse effect associated with thalidomide. Use of this drug mayalso increase the incidence of thromboembolic events, although such events arerare when the drug is used as a single agent. However, recent reports have shownthromboembolic complications develop more frequently when thalidomide iscombined with steroids and, in particular, with anthracycline-basedchemotherapy. One study exploring a combination of thalidomide with liposomaldoxorubicin (Doxil) and dexamethasone was terminated prematurely due tothromboembolic complications.[21,22]
The possible cardiovascular effects of thalidomide include bradycardia andhypotension. The risk of adverse cardiovascular events associated withthalidomide therapy appears to be greater when consumed together with multipleblood pressure-lowering medications by older patients with coronarydisease. It is well known that thalidomide must never be used duringpregnancy, and recommended contraceptive practices must be followed by both menand women of childbearing potential. The System for Thalidomide Education andPrescribing Safety (STEPS), implemented to ensure the safe distribution ofthalidomide, requires that patients comply with contraception guidelines andmandatory surveillance procedures. In addition, all health-care providers whoplan to prescribe and/or dispense thalidomide must be registered with theprogram.
In this context, the authors present an intriguing and informative case of apatient with abdominal epithelioid leiomyosarcoma and a prior history ofOsler-Weber-Rendu disease. After initial diagnosis in 1996, the patientunderwent repeated surgery for his truncal sarcoma until 1999 when, withwidespread locoregionally recurrent disease, oral antiangiogenic therapy waspursued with thalidomide at a starting dose of 250 mg/d. Mild peripheralneuropathy prompted a dose reduction to 150 mg/d, but the drug was subsequentlywell tolerated, with a recent dose increase to 200 mg/d and treatment ongoing.
In terms of disease response, the widespread smaller vascular lesionspreviously seen at laparotomy reportedly disappeared, and the intervals betweensurgery have diminished. Moreover, the patient’s symptoms related toOsler-Weber-Rendu disease have markedly diminished, with reduced bleeding and astable hematocrit.
Mechanisms of Action
D’Amato et al postulated that thalidomide acted as an antiangiogenic agentthrough the interruption of processes induced by beta-FGF and/or VEGF.[6,7,19]Moreover, in vitro studies suggested that the antiangiogenic effect ofthalidomide was due to specific metabolites and not the parent compound.
Another important property of thalidomide is that it selectively inhibits TNF-alphaproduction while leaving the immune system otherwise intact, thus leading toits application in various disorders characterized by abnormal TNF-alphaactivity. The exact mechanism of thalidomide-induced TNF-alpha inhibition isunclear, but it appears to be different from that of other TNF-alpha inhibitorssuch as pentoxyfylline (Trental) and dexamethasone.[25,26] One possiblemechanism postulated by Moreira and colleagues is that thalidomide inhibits TNF-alphasynthesis by accelerating degradation of TNF-alpha messenger ribonucleic acid,resulting in significant although incomplete suppression of TNF-alpha proteinproduction.[25,27]
Of particular interest is the recent demonstration that thalidomide decreasesthe binding activity of nuclear factor kappaB, which in turn controls activationof the TNF-alpha gene. It has also been postulated that thalidomide’seffect on angiogenesis may be through TNF-alpha inhibition, because TNF-alphahas proangiogenic effects. However, the absence of a demonstrable TNF-alphaeffect in experimental models of angiogenesis, coupled with the inability ofstrong TNF-alpha inhibitors to directly influence angiogenesis, suggests thatthalidomide’s antiangiogenic activity is not related to TNF-alpha inhibitionalone.[6,7] Thus, the clinical effect on the vasculature described in this caseis especially intriguing and is commensurate with thalidomide’s proposedmechanisms of action on new vessel formation and perhaps the down-regulation ofcytokines such as TNF-alpha, which activate endothelium.
We would concur, therefore, with the author’s conclusions that studies ofthalidomide in such vascular disorders and in angiogenesis-dependent tumors arewarranted, with analysis of appropriate surrogate vascular markers to betterdefine the mechanisms of action and efficacy in such specific disease settings.
PAUL RICHARDSON, MD
KENNETH ANDERSON, MD
Jerome Lipper Multiple Myeloma Center
Dana-Farber Cancer Institute
1. Singhal S, Mehta J, Desikan R, et al: Antitumor activity of thalidomide inrefractory multiple myeloma. N Engl J Med 341:1565-1571, 1999.
1. Lenz W: The susceptible period for thalidomide malformations in man andmonkey. Ger Med Mon 4:197-198, 1968.
2. Lenz W: Malformations caused by drugs in pregnancy. Am J Dis Child2:99-106, 1996.
3. Hales BF: Thalidomide on the comeback trail. Nat Med 5:489-490, 1999.
4. Zeldis JB, Williams BA, Thomas SD, et al: STEPS: A comprehensive programfor controlling and monitoring access to thalidomide. Clin Ther 21:319-330,1999.
5. Stirling DI: Thalidomide and its impact in dermatology. Semin Cutan MedSurg 17:231-242, 1998.
6. D’Amato RJ, Loughnan MS, Flynn E, et al: Thalidomide is an inhibitor ofangiogenesis. Proc Natl Acad Sci U S A 91:4082-4085, 1994.
7. Kenyon BM, Browne F, D’Amato RJ: Effects of thalidomide and relatedmetabolites in a mouse corneal model of neovascularization. Exp Eye Res64:971-978, 1997.
8. Bauer KS, Dixon SC, Figg WD: Inhibition of angiogenesis by thalidomiderequires metabolic activation, which is species-dependent. Biochem Pharmacol55:1827-1834, 1998.
9. Eisen T, Boshoff C, Vaughan M, et al: Anti-angiogenic treatment ofmetastatic melanoma, renal cell, ovarian and breast cancers with thalidomide: Aphase II study (abstract). Proc Am Soc Clin Oncol 17:441a, 1998.
10. Figg WD, Bergan R, Brawley O, et al: Randomized, phase II study ofthalidomide in androgen-independent prostate cancer (AIPC) (abstract). Proc AmSoc Clin Oncol 16:333a, 1997.
11. Fine HA, Loeffler JS, Kyritsis A, et al: A phase II trial of the anti-angiogenicagent, thalidomide, in patients with recurrent high-grade gliomas (abstract).Proc Am Soc Clin Oncol 16:385a, 1997.
12. Long G, Vredenburgh J, Rizzieri DA, et al: Pilot trial of thalidomidepost-autologous peripheral blood progenitor cell transplantation (PBPC) inpatients with metastatic breast cancer (abstract). Proc Am Soc Clin Oncol17:181a, 1998.
13. Marx GM, Levi JA, Bell DR, et al: A phase I/II trial of thalidomide as anantiangiogenic agent in the treatment of advanced cancer (abstract). Proc Am SocClin Oncol 18:454a, 1999.
14. Geitz H, Handt S, Zwingenberger K: Thalidomide selectively modulates thedensity of cell surface molecules involved in the adhesion cascade.Immunopharmacology 31:213-221, 1996.
15. Sampaio EP, Kaplan G, Miranda A, et al: The influence of thalidomide onthe clinical and immunologic manifestation of erythema nodosum leprosum. JInfect Dis 168:408-414, 1993.
16. Nogueira AC, Neubert R, Helge H, et al: Thalidomide and the immunesystem: Simultaneous up- and down-regulation of different integrin receptors onhuman white blood cells. Life Sci 55:77-92, 1994.
17. Shannon EJ, Ejigu M, Haile-Mariam HS, et al: Thalidomide’seffectiveness in erythema nodosum leprosum is associated with a decrease in CD4+cells in the peripheral blood. Lepr Rev 63:5-11, 1992.
18. Hideshima T, Chauhan D, Shima Y, et al: Thalidomide and its analogsovercome drug resistance of human multiple myeloma cells to conventionaltherapy. Blood 96:2943-2950, 2000.
19. Kotoh T, Dhar DK, Masunaga R, et al: Antiangiogenic therapy of humanesophageal cancers with thalidomide in nude mice. Surgery 125:536-544, 1999.
20. Stirling DI: The pharmacology of thalidomide. Semin Hematol 37:5-14,2000.
21. Weber DM, Rankin K, Gavino M: Thalidomide with dexamethasone forresistant multiple myeloma (abstract). Blood 96:167a, 2000.
22. Osman K, Comenzo R, Rajkumar SV: Deep venous thrombosis and thalidomidetherapy for multiple myeloma. N Engl J Med 21:1951-1952, 2001.
23. Hastings RC, Trautman JR, Enna CD, et al: Thalidomide in the treatment oferythema nodosum leprosum: With a note on selected laboratory abnormalities inerythema nodosum leprosum. Clin Pharmacol Ther 11:481-487, 1970.
24. Dunzendorfer S, Schratzberger P, Reinisch N, et al: Effects ofthalidomide on neutrophil respiratory burst, chemotaxis, and transmigration ofcytokine- and endotoxin-activated endothelium. Naunyn Schmiedebergs ArchPharmacol 356:529-535, 1997.
25. Moreira AL, Sampaio EP, Zmuidzinas A, et al: Thalidomide exerts itsinhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation.J Exp Med 177:1675-1680, 1993.
26. Calderon P, Anzilotti M, Phelps R: Thalidomide in dermatology. Newindications for an old drug. Int J Dermatol 36:881-887, 1997.
27. Sampaio EP, Sarno EN, Galilly R, et al: Thalidomide selectively inhibitstumor necrosis factor alpha production by stimulated human monocytes. J Exp Med173:699-703, 1991.
28. Turk BE, Jiang H, Liu JO: Binding of thalidomide to 1-acid glycoproteinmay be involved in its inhibition of TNF production. Proc Natl Acad SciU S A 93:7552-7556, 1996.