Thalidomide in Cancer

Thalidomide in CancerPotential Uses and Limitations

Seema Singhal and Jayesh Mehta

Division of Hematology/Oncology, Northwestern University Medical School, Chicago, Illinois, USA

Abstract In addition to immunomodulatory and cytokine-modulatory properties, tha-lidomide has antiangiogenic activity. It has been investigated in a number ofcancers including multiple myeloma, myelodysplastic syndromes, gliomas,Kaposi’s sarcoma, renal cell carcinoma, advanced breast cancer, and colon cancer.Its role has been best explored inmyeloma, where, at daily doses of 100 to 800mg,it is remarkably active, causing clinically meaningful responses in one-third ofextensively pretreated patients and in over half of patients treated early in thecourse of the disease. It also acts synergistically with corticosteroids and chemo-therapy in myeloma. Thalidomide produces improvement of cytopenias charac-teristic of myelodysplastic syndrome, resulting in the reduction or elimination oftransfusion dependence in some patients. Responses have also been seen in one-third of patients with Kaposi’s sarcoma, in a small proportion of patients withrenal cell carcinoma and high grade glioma and, in combination with irinotecan,in some patients with colon cancer. Thalidomide is being investigated currentlyin a number of clinical trials for cancer. Drowsiness, constipation and fatigue arecommon adverse effects seen in 75% of patients. Symptoms of peripheral neu-ropathy and skin rash are seen in 30%. Aminority of patients experience brady-cardia and thrombotic phenomena. Despite the high frequency of adverse effects,those severe enough to necessitate cessation of therapy are seen in only 10 to 15%of patients. A therapeutic trial of thalidomide should be considered in all patientswith myeloma who are unresponsive to or relapse after standard therapy. In othermalignant diseases, the most appropriate way to use the drug is in the setting ofwell designed clinical trials. In the absence of access to such studies, thalidomidecould be considered singly or in combination with standard therapy in patientswith no meaningful therapeutic options.

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Thalidomide, a synthetic glutamic acid derivative,was originally introduced as a sedative-hypnotic inEurope and Canada in the late 1950s. Belated rec-ognition of severe teratogenic effects resulted in itswithdrawal in the early 1960s.[1] Subsequently, the

drug was found to possess diverse immunomodula-tory and anti-inflammatory properties,[2-4] which are,at least in part, responsible for its activity in erythemanodosum leprosum[5] and graft-versus-host disease(GVHD).[6]

The limited early efforts exploring thalidomidein cancer were inconclusive.[7,8] The description ofits powerful activity in patients with end-stage my-eloma by Singhal et al.[9] has given rise to investi-gation of thalidomide in a number of malignantdisorders. The purpose of this review is to summa-rise the limited data available on the use of thalid-omide in cancer[10-39] and to provide some practicalguidelines for its use based on our experience.

1. Mechanism of Action

While the exact mechanism of the antimalign-ancy action of thalidomide is not known, it is likelythat angiogenesis inhibition, immunomodulationand cytokine modulation,[40-60] individually or incombination, underlie its antitumour activity. The ra-pid tempo of response in some myeloma patients[9]suggests that thalidomide may have some directcytotoxic effect on plasma cells. Table I summa-rises some of the properties of the drug which maycontribute to its activity in cancer.Thalidomide inhibits the production of tumour

necrosis factor (TNF)-α by monocytes as well as Tcells.[40,41,51,55,56,58] Inhibition of TNFα productionis not associated with inhibition of other cytokinessuch as interleukin (IL)-2. In fact, thalidomide en-hances the production of IL-2,[46,48] which itselfmay possess antitumour activities or maymodulate

the immune system to induce anticancer activity.Data on its effects on interferon (IFN)-γ productionhave been variable[45,51,55,56] but more reports haveshown it to increase IFN-γ production than to in-hibit it. Thalidomide inhibits IL-6, IL-10 and IL-12production[50,51,56] and enhances IL-4 and IL-5 pro-duction.[45] IL-6 is a potent growth factor for malig-nant plasma cells and its inhibition may be partlyresponsible for the action of thalidomide in my-eloma. In addition to increasing total lymphocytecounts as well as CD4+ and CD8+ T cells,[48,60] tha-lidomide is a potent costimulator of T lympho-cytes.[52]Angiogenesis is important in tumour progres-

sion and correlates with prognosis in a number ofmalignant diseases.[61,62] D’Amato et al.[43] were thefirst to show the angiogenesis inhibitory activity ofthalidomide in a rabbit model of corneal neovas-cularisation induced by basic fibroblast growthfactor. These data have subsequently been con-firmed in other studies,[49,53,54,57] and the combina-tion of thalidomide and sulindac,[59] a nonsteroidalanti-inflammatory agent with antiangiogenic activ-ity, has been shown to be synergistic in inhibitingangiogenesis.

2. Clinical Studies

2.1 Multiple Myeloma/Plasma Cell Disorders

Thalidomide was administered to patients withterminal myeloma[9] on the basis of observationsthat bone marrow angiogenesis was prominent inactive myeloma[63] and thalidomide inhibited an-giogenesis.[43] After treating 5 patients on a compas-sionate basis, Singhal et al.[9] treated 84 additionalpatients with thalidomide as a single agent for 2 to465 days on a US Food and Drug Administration-approved protocol.Most patients had relapsed aftera preceding autotransplant. The starting dose of200mg daily was increased by 200mg every 2weeks to amaximumof 800mg. 32%of the patientsresponded, with the serum or urine paraprotein lev-els declining by ≥90% in 8 patients (including 2complete remissions), ≥75% in 6, ≥50% in 7, and≥25% in 6. Paraprotein reduction was evident

Table I. Potential mechanisms of action of thalidomide in cancer

Action References

Inhibition of angiogenesis 43,49,53,54,57,59

Alteration of adhesion molecule expression 42,44,47

Selective inhibition of tumour necrosisfactor-α production

40,41,51,55,56,58

Induction of Th2 cytokine production (IL-4and IL-5)

45

Variable effects of interferon-γ production 45,51,55,56

Increase in the synthesis of IL-2 bymononuclear cells

46

Increase in soluble IL-2 receptor levels 48

Inhibition of IL-6, IL-10 and IL-12 production 50,51,56

Increase in total lymphocyte and CD4+ andCD8+ T cell numbers

48,60

Costimulation of T lymphocytes 52

IL = interleukin; Th = helper T lymphocyte.

164 Singhal & Mehta

© Adis International Limited. All rights reserved. BioDrugs 2001; 15 (3)

within 2months in 78%of the responders. Responseswere associated with reduction in marrow plas-macytosis. The actuarial 1-year overall and event-free survival was 58% and 22%, respectively. Cur-rently, after more than 2 years of follow-up, 60%of responding patients have relapsed.These encouraging data have now been repli-

cated by a number of other groups.[19-23,25,27,28,32,33]The response rates described have varied between20 and 70%. It is clear that not all patients respondto thalidomide, and that a number of respondingpatients eventually relapse. The combination ofthalidomide with dexamethasone[27,39] or chemo-therapy[18,20,24] (‘angiochemotherapy’) has beenfound to be active under these circumstances. The2 noteworthy combinations are DT-PACE (dexa-methasone, thalidomide, cisplatin, doxorubicin,cyclophosphamide, etoposide)[18] and BLT-D (cla-rithromycin, thalidomide, dexamethasone).[39] DT-PACE (2 cycles) resulted in ≥50% paraprotein de-cline in almost 70% of previously treated patients.However, the mortality was considerable, with 3 of43 patients dying of toxicity.[18] BLT-D was toler-ated well by 17 patients with myeloma (n = 14) orWaldenstrom’s macroglobulinaemia (n = 3), withall 14 evaluable patients showing a response [in-cluding 3 complete responses (CR)].[39] The dailydose of thalidomide used in the DT-PACE regimenwas 200 to 400mg, and that in the BLT-D regimen,50 to 200mg.How thalidomide is best used in a patient with

relapsedmyeloma depends on the tempo of diseaseprogression and bone marrow reserves. For in-stance, if the disease is slowly progressive, thalid-omide can be used as a single agent. Chemotherapyor corticosteroids can be added if there is no re-sponse. On the other hand, if the disease is rapidlyprogressive, a combination of agents may have tobe used from the beginning.We have used thalidomide as a single agent at

the dose of 200 to 400mg to treat 12 previouslyuntreated patients who refused standard therapy.Paraprotein declined by ≥50% in 8 patients, andthis response has been sustained on continued ther-apy for over 8 months in 7 patients (unpublished

observations). More data are required before thedrug can be recommended as first-line therapy ofmyeloma outside the setting of a comparative clin-ical trial. However, in patients refusing standardtherapy, thalidomide is a reasonable choice.Thalidomide can be administered as maintenance

therapy following autologous stem cell tranplanta-tion as a means of prolonging remission duration.We use thalidomide for post-transplant mainte-nance in patients who cannot tolerate IFN-α ordexamethasone, have poor marrow function, orhave disease that was unresponsive to dexametha-sone or responsive to thalidomide before the trans-plant (table II).Thalidomide has been effective as a single agent

400mg daily in previously treated patients withWaldenstrom’s macroglobulinaemia (A. Zomas,personal communication). The BLT-D combina-tion regimen has also been reported to be effectivein this indication.[39] We have used thalidomide ina patient with Castleman’s disease with excellentresponse. The disease activity declined on thalido-mide despite the reduction of prednisone from100mg daily to 5mg daily and was accompaniedby normalisation of a grossly elevated IL-6 level.There are no reports on the use of thalidomide inamyloidosis or POEMS (Polyneuropathy, Or-ganomegaly, Endocrine abnormalities, Monoclonalprotein, Skin changes) syndrome.

Table II. Our criteria for selection of patients for thalidomide main-tenance after autotransplantation (based on unpublished observa-tions)

Clinical situation Patient selection

Already autografted 1. History of response to thalidomide inthe past

2. Intolerance of dexamethasone andinterferon

3. No response to dexamethasone in thepast (alternative to interferon)

4. Poor marrow function (alternative todexamethasone)

Not autografted yet Pretransplant therapeutic trial ofthalidomide for 6 weeks: responders canreceive thalidomide after transplant,whereas nonresponders should receivedexamethasone and/or interferon

Thalidomide in Cancer 165


2.2 Myelodysplastic Syndromes

Intramedullary apoptosis of bone marrow cells,probably mediated by TNFα,[64] is responsible forthe cytopenias that characterise myelodysplasticsyndromes (MDS). In an attempt to exploit the se-lective TNFα-inhibitory effect of thalidomide,Raza et al.[38] treated 61 patients with MDS withthalidomide 100 to 400mg for 12 weeks. 22 patientshad refractory anaemia (RA), 13 had RA withringed sideroblasts, 19 had RA with excess blasts(RAEB), 4 had RAEB in transformation, and 3 hadchronic myelomonocytic leukaemia. At the time ofthe report, 11 had stopped therapy, 25 had not re-ceived the drug long enough, and 17 of the remain-ing 25 evaluable patients had shown improvementin cytopenia (3 trilineage, 4 bilineage, 10 single lin-eage). The best responses were seen in the erythroidseries, with a number of patients becoming trans-fusion-independent. Longer follow-up is requiredto see how long these responses are sustained.Thalidomide-containing angiochemotherapy

combinations may be active in RAEB, RAEB intransformation and secondary acute myeloid leu-kaemia. These combinations (liposomal anthracy-cline with topotecan or cytarabine; with or with-out thalidomide) are being studied currently.[29]

2.3 Kaposi’s Sarcoma

Soler et al.[13] described a 14-year-old girl withHIV infection and subcutaneous Kaposi’s sarcoma(KS) who received thalidomide for aphthous ul-cers. This resulted in regression of KS lesions, dis-appearance of KS-associated herpesvirus (KSHV)DNA from blood, and reduced viral load in tumourtissue. Fife et al.[15] administered 100mg thalido-mide daily for 8 weeks to 17 patients with AIDS-related KS. Six patients achieved a partial response,and viral DNA load decreased to undetectablelevels in 3 of the 5 responders assessed virologi-cally.Little et al.[36] treated 20 HIV-positive patients

who had progressive KS with 200mg thalidomidein a phase II study. The dose was escalated to1000mg for up to a year. Eight patients had partial

response and 2 had stabilisation of progressive dis-ease. The median drug dose at the time of responsewas 500mg. The median duration of therapy was6.3 months, and the median time to progression 7.3months. KSHV DNA titres were not studied. Thedisappearance of viral DNA in responding patientsis of interest in the context of the activity of thalid-omide in myeloma and the fact that some groupshave isolated KSHV DNA in patients with my-eloma.[65]

2.4 Breast Cancer

Eisen et al.[30] studied 12 patients with breastcancer as part of a group of 66 patients with variouscancers who received 100mg thalidomide daily.No objective response was seen in any of these12 patients. Baidas et al.[37] studied the efficacy ofthalidomide in 28 women with heavily pretreated,progressive metastatic breast cancer who wererandomised to receive either 200 or 800mg thalid-omide daily. No response was seen in any patient.13 of 14 patients receiving 800mg thalidomide ex-perienced progressive disease within 8 weeks, com-pared with 12 of 14 in the 200mg arm. Two patientsin the 200mg arm had stable disease at 8 weeks.Nguyen et al.[14] administered 100 to 300mg

thalidomide daily for 4 weeks in addition to stand-ard chemotherapy in 7 women with breast cancer.With a follow-up of 1 to 6months, patients with stage4 disease had either a partial response or stabilisa-tion of disease. However, the disease eventually pro-gressed in the 2 patients with the longest follow-up(5 and 6 months).These studies included patients with advanced

disease and used the drug as a single agent or for alimited duration. More benefit might be seen if tha-lidomide is combined with chemotherapy and thencontinued as maintenance therapy for an extendedperiod, although such an approach requires system-atic investigation.

2.5 Glioma

Because malignant gliomas are vascular tu-mours, angiogenesis inhibition may be therapeuti-cally beneficial. Fine et al.[31] administered thalid-

166 Singhal & Mehta


omide to 39 patients with anaplastic mixed glioma,anaplastic astrocytoma or glioblastoma multi-forme who had radiological evidence of progres-sion after external-beam radiation with or withoutchemotherapy. The drug was started at the dailydose of 800mg and increased by 200mg every 2weeks to 1200mg. Among the 36 evaluable pa-tients, there were 2 radiologically evident partialresponses (6%), 2 minor responses (6%) and 12patients (33%) with stable disease. Eight patientswere alive over a year after starting therapy, mostwith progressive disease. Once again, it is likelythat thalidomide will have to be used as part of amultimodality treatment plan if it is to be of anybenefit in this setting.

2.6 Colon Cancer

Govindarajan et al.[35] treated 9 colon cancer pa-tients with irinotecan (325 to 350 mg/m2 every 3weeks) and 400mg thalidomide daily as second-line therapy. None of the patients had been treatedwith irinotecan in the past. Thalidomide was foundto eliminate the dose-limiting gastrointestinal sideeffects of irinotecan, especially nausea and diar-rhoea, almost completely, permitting 8 of 9 pa-tients to complete therapy. Of the 7 patients evalu-able for response, 1 attained complete remission and2 partial remission. These data have important im-plications for the tolerability as well as efficacy ofangiochemotherapy in colon cancer.

2.7 Renal Cell Carcinoma

Among 18 patients with renal cell carcinomawhich was progressive despite biochemotherapy, 3partial responses were noted with thalidomidemonotherapy. One lasted 5 months, and the othertwo were ongoing at 5 and 11 months at the timeof the report. 13 of the remaining 16 patients expe-rienced disease stabilisation for 1 to 3 months (10)or >3 months (3).[30]

2.8 Other Cancers

Responses to thalidomide as a single agent atthe dose of 200 to 400mg daily have been seen in

Hodgkin’s disease relapsing after autotransplanta-tion (unpublished observations), Langerhans cellhistiocytosis,[10-12,16] hepatocellular carcinoma,[34]and chronic myeloproliferative disorders.[29] Noresponses were seen in ovarian cancer and advancedmelanoma.[30]

2.9 Graft-versus-Host Disease

Thalidomide is immunomodulatory rather thanimmunosuppressive in its action. In fact, thalidomideincreases total lymphocyte counts as well as CD4+and CD8+ lymphocytes. It is likely that its benefi-cial effect in treating established chronic GVHD[6]is a result of TNFα inhibition. Thalidomide haslittle effect on acute GVHD,[66] and prophylacticuse of the drug, paradoxically, has been shown toresult in increased chronic GVHD.[67] This may bebecause of some immunostimulatory effects.GVHD and graft-versus-tumour effects are of-

ten closely linked. Thus, when GVHD resolves withsuccessful immunosuppression, the underlyingmalignant disease often recurs. It was anecdotallyobserved in a small series that the patients whoseGVHD resolved with thalidomide treatment didnot relapse.[66] If this interesting observation isconfirmed, it could mean that the immunomodula-tory and/or antiangiogenesis effects of thalidomidemay allow separation of GVHD and graft-versus-tumour effects in patients with established chronicGVHD.

2.10 Cancer Cachexia

High levels of TNFα have been linked with can-cer cachexia and malaise. Because of its effects onTNFα, thalidomide was explored in 72 terminalcancer patients who were not receiving any cyto-toxic therapy at the dose of 100mg at night for 10days. Among the 37 evaluable patients, 44 to 69%reported significant improvement in insomnia,nausea, appetite and sensation of well-being.

3. Dosage and Administration

No systematic dose escalation studies of thalid-omide have been performed in any disease. The



doses used have varied widely between 50 and1200mg daily, and responses have been seen at alldose levels. Dose escalation in the myeloma studywas time-dependent, and thus the effect of the du-ration of therapy was inseparable from the effect ofdose.[9] Based on the effect of dose adjustment onthe extent of response in myeloma, we have ob-served a clear dose-response relationship in somepatients.When used off-protocol, the drug should be

started at the dose of 100 to 200mg daily and esca-lated in 50 to 100mg steps every week to a targetdose of 400 to 800mg. The optimum dose for agiven patient is one that is best tolerated by thatindividual.Most studies have used the drug as a single bed-

time dose. In the myeloma study, this was changedonly occasionally to divided doses in patients withexcessive drowsiness in the morning. Although wehave not noticed any effect of divided doses, a Swe-dish group has reported faster and better responsesin myeloma patients receiving the drug in divideddoses.[33] Since the half-life of thalidomide is 6 to7 hours, this may be preferable to single daily doseadministration of the drug.

4. Adverse Effects

Severe teratogenicity, historically the most im-portant adverse effect of thalidomide, is less rele-vant in cancer patients undergoing chemotherapythan in other patient populations. To minimise therisk of teratogenicity, Celgene Corporation (War-ren,New Jersey,USA), theAmericanmanufacturerof thalidomide, has developed a programme calledSTEPS (System for Thalidomide Education andPrescribing Safety) for controlling and monitoringaccess to thalidomide.[68] The programme ensureseducation of physicians, pharmacists and patientson precautions to avoid teratogenicity.Drowsiness, constipation, weakness, fatigue,

tingling and/or numbness in the hands and the feet,dizziness and skin rash are the predominant ad-verse effects of thalidomide. In the study of Singhalet al.,[9] 75% of patients experienced some adverseeffect at the minimum dose of 200mg daily, whereas

over 90% of patients experienced adverse effectsat the maximum dose of 800mg daily. Most adverseeffects were WHO grade I or II, and only 10% ofpatients discontinued the drug because of adverseeffects. Because sedation is the outstanding ad-verse effect, the use of sedatives and tranquillisersin patients taking thalidomide should be mini-mised.There is some concern that thrombotic phenom-

ena occur more commonly in patients receivingthalidomide,[18,28,69] although it must be borne inmind that the underlying diseases are also associ-ated with a predisposition to thrombosis.The occurrence of symptoms of peripheral neu-

ropathy in women taking thalidomide was the rea-son that the drug was not approved for use in USinitially. We have found symptoms of neuropathyin approximately 30% of patients who take thalid-omide, but only half have had objective changes onnerve conduction studies. Thalidomide-inducedperipheral neuropathy is typically symmetrical andis characterised by painful paraesthesias of thehands and feet, often accompanied by sensory lossin the feet. The symptoms apparently do not correl-ate with the duration of treatment or the dose,[70-72]and women and older persons are at greater risk.[70]There is some suggestion that slow acetylators maybe more predisposed to neuropathy.[71] We havefound pyridoxine (vitamin B6) to relieve neuro-pathic symptoms in a number of patients at the doseof 200mg daily. Prophylactic use of pyridoxine100mg daily with thalidomide appears to reducethe frequency of such symptoms (unpublished ob-servations).In general, if the adverse effects are tolerable,

patients should be encouraged to continue the drugat the same dosage. If the symptoms are difficultto tolerate, a step-wise reduction in dose to find alevel that is better tolerated is reasonable. Occa-sionally, the drug may need to be discontinued fora period of 2 to 3 weeks and then restarted at alower dose.Table III shows our approach to managing spe-

cific adverse events. The skin and cardiac eventsmentioned in the table need some elaboration.

168 Singhal & Mehta


Most patients who develop a rash have maculopap-ular lesions. However, a rash resembling Stevens-Johnson syndrome is seen in approximately 1% ofpatients. In the first such patient,[25] rechallengeresulted in recurrence of Stevens-Johnson syndromewhich was fatal. In the subsequent patient, the drugwas not reintroduced and the reaction did not recur.Recently, life-threatening toxic epidermal necrolysishas been described in newly diagnosed myelomapatients treated with the combination of thalido-mide and dexamethasone.[73] The investigators ad-vocated caution in the use of this drug combinationin newly diagnosed patients.[73] Toxic epidermalnecrolysis has also been described in 1 patient withglioblastoma who was receiving thalidomide.[74]

We have seen bradycardia of unclear aetiologyin approximately 5% of patients treated with tha-lidomide. Since there have been no blood pressurefluctuations in these patients, it is unclear if thisrepresents a form of autonomic neuropathy. How-ever, caution is warranted if bradycardia develops,especially if patients are already on drugs such asβ-blockers for hypertension.

5. Conclusions

The use of thalidomide in myeloma providedthe crucial proof of principle that a drug apparentlylacking conventional cytotoxic activity could havemeaningful antimalignancy action. It is now im-portant to ensure that patients likely to benefit from

Table III. Suggested approach to managing specific adverse effects of thalidomide therapy

Adverse event Type/severity Management Comments

Bradycardia Mild: decrease in resting heartrate by 10-20/min; rate >60

Watch carefully; counsel patient to monitorpulse daily; continue thalidomide

Avoid concomitant β-blocker usage

Moderate: rate 50-60 As above; check ECG; continue thalidomideif no hypotension or syncopal episodes andnormal ECG; stop thalidomide if there aresymptoms or ECG abnormalities

As above

Severe: rate <50 Stop thalidomide immediately; check ECG;evaluation for sick sinus syndrome orautonomic neuropathy may be necessary

Consider pacemaker implantation ifthalidomide considered unavoidable

Skin rash Erythematous, maculopapular,itchy lesions

Local corticosteroid cream; if no relief,decrease dose gradually or stop the drugand restart at a lower dose

Erythema multiforme(Stevens-Johnson syndrome)

Discontinue thalidomide; absolutecontraindication for repeat administration ofthe drug

Peripheralneuropathy

Mild symptoms Increase pyridoxine dose to 200mg daily;additional vitamin B1, B12 and folate may behelpful in some patients; continuethalidomide

Baseline nerve conduction studiesmay be useful in patients withpre-existing neuropathic symptoms

Moderate symptoms As above; continue thalidomide if symptomsintermittent; stop thalidomide if symptomscontinuous

As above; thalidomide may berestarted if symptoms abate

Severe symptoms As above; stop thalidomide; nerveconduction studies to evaluate extent ofneuropathic changes

As above; thalidomide may berestarted at a lower dose ifsymptoms abate and therapyconsidered unavoidable

Thrombosis Deep vein thrombosis Therapeutic anticoagulation Consider prophylactic warfarin inpatients with a prior history of deepvein thrombosis



thalidomide have access to it, and that it is evalu-ated systematically in other cancers. In diseasessuch as myeloma, where its activity is undisputed,thalidomide should be considered as salvage ther-apy at the appropriate time (relapsed or refractorydisease). Its use in early disease is best confined toclinical studies or any situation where more con-ventional therapy is not feasible. In disease wherethe action of thalidomide has not been conclusivelyshown, it should be used in the setting of well de-signed clinical trials. In the absence of such studies,its use singly or in combination with standard ther-apy could be considered in patients in whom nostandard therapeutic options or alternative clinicalstudies of salvage therapy are available.

Acknowledgements

Disclosure: Drs Singhal andMehta own stock in CelgeneCorporation, the company which manufactures and marketsthalidomide in USA.

References1. Annas GJ, Elias S. Thalidomide and the Titanic: reconstructing

the technology tragedies of the twentieth century. Am J PublicHealth 1999; 89: 98-101

2. Koch HP. Thalidomide and congeners as anti-inflammatoryagents. Prog Med Chem 1985; 22: 165-242

3. Zwingenberger K, Wnendt S. Immunomodulation by thalido-mide: systematic review of the literature and of unpublishedobservations. J Inflamm 1995; 46: 177-211

4. Corral LG, Kaplan G. Immunomodulation by thalidomide andthalidomide analogues. Ann Rheum Dis 1999; 58 Suppl. 1:I107-13

5. Sheskin J. The treatment of lepra reaction in lepromatous lep-rosy. Fifteen years’experience with thalidomide. Int J Dermatol1980; 19: 318-22

6. Vogelsang GB, Farmer ER, Hess AD, et al. Thalidomide for thetreatment of chronic graft-versus-host disease. N Engl J Med1992; 326: 1055-8

7. Olson KB, Hall T, Horton J, et al. Thalidomide (N-phthaloyl-glutamide) in the treatment of advanced cancer. Clin Phar-macol Ther 1965; 6: 292-7

8. Grabstad H, Golbey R. Clinical experiences with thalidomidein patients with cancer. Clin Pharmacol Ther 1965; 6: 298-302

9. Singhal S, Mehta J, Desikan R, et al. Antitumor activity of tha-lidomide in refractory multiple myeloma. N Engl JMed 1999;341: 1565-71

10. Bensaid P, Machet L, Vaillant L, et al. Langerhans-cell histio-cytosis in the adult: regressive parotid involvement follow-ing thalidomide therapy. Ann Dermatol Venereol 1992; 119:281-3

11. Thomas L, Ducros B, Secchi T, et al. Successful treatment ofadult’s Langerhans cell histiocytosis with thalidomide. Reportof two cases and literature review. Arch Dermatol 1993; 129:1261-4

12. Dallafior S, Pugin P, Cerny T, et al. Successful treatment of acase of cutaneous Langerhans cell granulomatosis with 2-chlorodeoxyadenosine and thalidomide. Hautarzt 1995; 46:553-60

13. Soler RA, Howard M, Brink NS, et al. Regression of AIDS-re-lated Kaposi’s sarcoma during therapy with thalidomide. ClinInfect Dis 1996; 23: 501-3

14. Nguyen M, Tran C, Barsky S, et al. Thalidomide and chemo-therapy combination: preliminary results of preclinical andclinical studies. Int J Oncol 1997; 10: 965-9

15. Fife K, Howard MR, Gracie F, et al. Activity of thalidomide inAIDS-related Kaposi’s sarcoma and correlation with HHV8titre. Int J STD AIDS 1998; 9: 751-5

16. Lair G, Marie I, Cailleux N, et al. Langerhans histiocytosis inadults: cutaneous and mucous lesion regression after treat-ment with thalidomide. Rev Med Intern 1998; 19: 196-8

17. Figg WD, Raje S, Bauer KS, et al. Pharmacokinetics of thalid-omide in an elderly prostate cancer population. J Pharm Sci1999; 88: 121-5

18. Munshi N, Desikan R, Zangari M, et al. Chemoangiotherapywith DT-PACE for previously treated multiple myeloma(MM) [abstract]. Blood 1999; 94 Suppl. 1: no. 540

19. Neben K, Hawighorst H, Moehler TM. Clinical response tothalidomide monotherapy correlates with improvement in dy-namic magnetic resonance (d-MRI) angiogenesis parameters[abstract]. Blood 1999; 94 Suppl. 1: no. 545

20. Moehler TM, Neben K, Egerer G, et al. Thalidomide plus CED-chemotherapy in patients with poor prognosis multiple my-eloma [abstract]. Blood 1999; 94 Suppl. 1: no. 547

21. Sabir T, Raza S, Anderson L, et al. Thalidomide is effective inthe treatment of recurrent, refractorymultiplemyeloma (MM)[abstract]. Blood 1999; 94 Suppl. 1: no. 548

22. Cheng D, Kini AR, Rodriguez J, et al. Microvascular densityand cytotoxic T cell activation correlate with response to tha-lidomide therapy in myeloma patients [abstract]. Blood 1999;94 Suppl. 1: no. 1408

23. Rajkumar SV, Fonseca R, Dispenzieri A, et al. Thalidomide inthe treatment of relapsed and refractory myeloma [abstract].Blood 1999; 94 Suppl. 1: no. 1414

24. Munshi N, Desikan R, Anaissie E, et al. Peripheral blood stemcell collection (PBSC) after CAD + G-CSF as part of TotalTherapy II in newly diagnosed multiple myeloma (MM): in-fluence of thalidomide (THAL) administration [abstract].Blood 1999; 94 Suppl. 1: no. 2577

25. Desikan R, Munshi N, Zeldis J, et al. Activity of thalidomide(THAL) in multiple myeloma (MM) confirmed in 180 pa-tients with advanced disease [abstract]. Blood 1999; 94 Suppl.1: no. 2685

26. Bruera E, Neumann CM, Pituskin E, et al. Thalidomide in pa-tients with cachexia due to terminal cancer: preliminary re-port. Ann Oncol 1999; 10: 857-9

27. Weber DM, Gavino M, Delasalle K, et al. Thalidomide alone orwith dexamethasone for multiple myeloma [abstract]. Blood1999; 94 Suppl. 1: no. 2686

28. Alexanian R, Weber D. Thalidomide for resistant and relapsingmyeloma. Semin Hematol 2000; 37 Suppl. 3: 22-5

29. Thomas DA. Pilot studies of thalidomide in acute myelogenousleukemia, myelodysplastic syndromes, and myeloprolifera-tive disorders. Semin Hematol 2000; 37 Suppl. 3: 26-34

30. Eisen T, Boshoff C, Mak I, et al. Continuous low dose thalido-mide: a phase II study in advancedmelanoma, renal cell, ovar-ian and breast cancer. Br J Cancer 2000; 82: 812-7

170 Singhal & Mehta


31. Fine HA, Figg WD, Jaeckle K, et al. Phase II trial of the anti-angiogenic agent thalidomide in patients with recurrent high-grade gliomas. J Clin Oncol 2000; 18: 708-15

32. Kneller A, Raanani P, Hardan I, et al. Therapy with thalidomidein refractory multiple myeloma patients – the revival of anold drug. Br J Haematol 2000; 108: 391-3

33. Juliusson G, Celsing F, Turesson I, et al. Frequent good partialremissions from thalidomide including best response ever inpatients with advanced refractory and relapsed myeloma. BrJ Haematol 2000; 109: 89-96

34. Patt YZ, Hassan MM, Lozano RD, et al. Durable clinical re-sponse of refractory hepatocellular carcinoma to orally ad-ministered thalidomide. Am J Clin Oncol 2000; 23: 319-21

35. Govindarajan R, Heaton KM, Broadwater R, et al. Effect ofthalidomide on gastrointestinal toxic effects of irinotecan.Lancet 2000; 356: 566–7

36. Little RF, Wyvill KM, Pluda JM, et al. Activity of thalidomidein AIDS-related Kaposi’s sarcoma. J Clin Oncol 2000; 18:2593-602

37. Baidas SM, Winer EP, Fleming GF, et al. Phase II evaluation ofthalidomide in patients with metastatic breast cancer. J ClinOncol 2000; 18: 2710-7

38. Raza A, Liask K, Andrews C, et al. Encouraging improvementin cytopenias of patients with myelodysplastic syndromes(MDS) with thalidomide [abstract]. Proc ASCO 2000; no. 111

39. Coleman M, Leonard JP. BLT-D (biaxin, low-dose thalidomideand dexamethasone) produces consistent responses in my-eloma and Waldenstrom’s macroglobulinemia [abstract].Proc ASCO 2000; no. 27

40. Sampaio EP, Sarno EN, Galilly R, et al. Thalidomide selectivelyinhibits tumor necrosis factor alpha production by stimulatedhuman monocytes. J Exp Med 1991; 173: 699-703

41. Moreira AL, Sampaio EP, Zmuidzinas A, et al. Thalidomideexerts its inhibitory action on tumor necrosis factor alphaby enhancing MRNA degradation. J Exp Med 1993; 177:1675-80

42. Neubert R, Nogueira AC, Neubert D. Thalidomide derivativesand the immune system. I. Changes in the pattern of integrinreceptors and other surface markers on T lymphocyte sub-populations of marmoset blood. Arch Toxicol 1993; 67: 1-17

43. D’Amato RJ, Loughnan MS, Flynn E, et al. Thalidomide is aninhibitor of angiogenesis. Proc Natl Acad Sci U SA1994; 91:4082-5

44. Nogueira AC, Neubert R, Helge H, et al. Thalidomide and theimmune system. 3. Simultaneous up- and down-regulation ofdifferent integrin receptors on human white blood cells. LifeSci 1994; 55: 77-92

45. McHugh SM, Rifkin IR, Deighton J, et al. The immunosuppres-sive drug thalidomide induces T helper cell type 2 (Th2) andconcomitantly inhibits Th1 cytokine production in mitogen-and antigen-stimulated human peripheral blood mononuclearcell cultures. Clin Exp Immunol 1995; 99: 160-7

46. Shannon EJ, Sandoval F. Thalidomide increases the synthesisof IL-2 in cultures of human mononuclear cells stimulatedwith concanavalin-A, staphylococcal enterotoxin A, and pu-rified protein derivative. Immunopharmacology 1995; 31:109-16

47. Geitz H, Handt S, Zwingenberger K. Thalidomide selectivelymodulates the density of cell surface molecules involved inthe adhesion cascade. Immunopharmacology 1996; 31: 213-21

48. Haslett P, Hempstead M, Seidman C, et al. The metabolic andimmunologic effects of short-term thalidomide treatment ofpatients infected with the human immunodeficiency virus.AIDS Res Hum Retrovir 1997; 13: 1047-54

49. Kenyon BM, Browne F, D’Amato RJ. Effects of thalidomideand related metabolites in a mouse corneal model ofneovascularization. Exp Eye Res 1997; 64: 971-8

50. Moller DR,WysockaM,Greenlee BM, et al. Inhibition of IL-12production by thalidomide. J Immunol 1997; 159: 5157-61

51. Moreira AL, Tsenova-Berkova L,Wang J, et al. Effect of cytok-ine modulation by thalidomide on the granulomatous re-sponse in murine tuberculosis. Tuber Lung Dis 1997; 78:47-55

52. Haslett PA, Corral LG, Albert M, et al. Thalidomide cos-timulates primary human T lymphocytes, preferentially in-ducing proliferation, cytokine production, and cytotoxicresponses in the CD8+ subset. J Exp Med 1998; 187: 1885-92

53. Kruse FE, Joussen AM, Rohrschneider K, et al. Thalidomideinhibits corneal angiogenesis induced by vascular endothelialgrowth factor. Graefes Arch Clin Exp Ophthalmol 1998; 236:461-6

54. Or R, Feferman R, Shoshan S. Thalidomide reduces vasculardensity in granulation tissue of subcutaneously implantedpolyvinyl alcohol sponges in guinea pigs. Exp Hematol 1998;26: 217-21

55. Partida-Sanchez S, Favila-Castillo L, Pedraza-Sanchez S, et al.IgG antibody subclasses, tumor necrosis factor and IFN-gamma levels in patients with type II lepra reaction on tha-lidomide treatment. Int Arch Allergy Immunol 1998; 116:60-6

56. Rowland TL, McHugh SM, Deighton J, et al. Differential reg-ulation by thalidomide and dexamethasone of cytokine ex-pression in human peripheral blood mononuclear cells.Immunopharmacology 1998; 40: 11-20

57. Moreira AL, Friedlander DR, Shif B, et al. Thalidomide and athalidomide analogue inhibit endothelial cell proliferation invitro. J Neurooncol 1999; 43: 109-14

58. Rowland TL, McHugh SM, Deighton J, et al. Selective down-regulation of T cell- and non-T cell-derived tumour necrosisfactor alpha by thalidomide: comparisons with dexametha-sone. Immunol Lett 1999; 68: 325-32

59. Verheul HM, Panigrahy D, Yuan J, et al. Combination therapywith thalidomide and sulindac inhibits tumour growth in rab-bits. Br J Cancer 1999; 79: 114-8

60. Walchner M, Meurer M, Plewig G, et al. Clinical and immuno-logic parameters during thalidomide treatment of lupus ery-thematosus. Int J Dermatol 2000; 39: 383-8

61. Battegay EJ. Angiogenesis: mechanistic insights, neovasculardiseases, and therapeutic prospects. J Mol Med 1995; 73:333-46

62. Folkman J. Angiogenesis in cancer, vascular, rheumatoid, andother disease. Nature Med 1995; 1: 27-31

63. Vacca A, Ribatti D, Roncali L, et al. Bonemarrow angiogenesisand progression in multiple myeloma. Br J Haematol 1994;87: 503-8

64. Mundle SD, Ali A, Cartlidge JD, et al. Evidence for involve-ment of tumor necrosis factor-alpha in apoptotic death ofbone marrow cells in myelodysplastic syndromes. Am JHematol 1999; 60: 36-47

65. Rettig MB, Ma HJ, Vescio RA, et al. Kaposi’s sarcoma-associ-ated herpesvirus infection of bone marrow dendritic cellsfrom multiple myeloma patients. Science 1997; 276: 1851-4

66. Kulkarni S, Powles R, Mehta J, et al. Thalidomide in GVHD –is anti-GVHD effect separable from the antiangiogenesis?Blood 1998; 92 Suppl. 1: 344b

67. Chao NJ, Parker PM, Niland JC, et al. Paradoxical effect ofthalidomide prophylaxis on chronic graft-vs.-host disease.Biol Blood Marrow Transplant 1996; 2: 86-92



68. Zeldis JB, Williams BA, Thomas SD, et al. S.T.E.P.S.: a com-prehensive program for controlling and monitoring access tothalidomide. Clin Ther 1999; 21: 319-30

69. Flageul B, Wallach D, Cavelier-Balloy B, et al. Thalidomideand thrombosis. Ann Dermatol Venereol 2000; 127: 171-4

70. Ochonisky S, Verroust J, Bastuji-Garin S, et al. Thalidomideneuropathy incidence and clinico-electrophysiologic findingsin 42 patients. Arch Dermatol 1994; 130: 66-9

71. Harland CC, Steventon GB, Marsden JR. Thalidomide-inducedneuropathy and genetic differences in drug metabolism. EurJ Clin Pharmacol 1995; 49: 1-6

72. Hess CW, Hunziker T, Kupfer A, et al. Thalidomide-inducedperipheral neuropathy. A prospective clinical, neurophysio-logical and pharmacogenetic evaluation. J Neurol 1986; 233:83-9

73. Rajkumar SV, Gertz MA,Witzig TE. Life-threatening toxic epi-dermal necrolysis with thalidomide therapy for myeloma. NEngl J Med 2000; 343: 972-3

74. Horowitz SB, Stirling AL. Thalidomide-induced toxic epider-mal necrolysis. Pharmacotherapy 1999; 19: 1177-80

Correspondence and offprints: Dr Seema Singhal, Divisionof Hematology/Oncology, Northwestern University Med-ical School, 676 N St. Clair Street, Suite 850, Chicago, IL60611, USA.E-mail: [email protected]

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