C URRENT OPINION
`
`
`
`
`
`
`Thalidomide in Cancer
`Poten tial Uses an d Limitation s
`
`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(cid:173)
`lidomide has antiangiogenic activity. It has been investigated in a number of
`cancers including multiple myeloma, myelodysplastic syndromes, gliomas,
`Kaposi 's sarcoma, renal cell carcinoma, advanced breast cancer, and colon cancer.
`Its role has been best explored in myeloma, ·where, at daily doses of 100 to 800mg,
`it is remarkably active, causing clinically meaningful responses in one-third of
`exlensively pretreated patients and in over half of patients treated early in the
`course of the disease. It also acts synergistically wilh corticosteroids and chemo(cid:173)
`therapy in myeloma. Thalidomide produces improvement of cytopenias charac(cid:173)
`teristic of myelodysplastic syndrome, resulting in the reduction or elimination of
`transfusion dependence in some patients. Responses have also been seen in one(cid:173)
`third of patients with Kaposi's sarcoma, in a small proportion of patients with
`renal cell carcinoma and high grade glioma and, in combination with irinotecan,
`in some patients with colon cancer. Thalidomide is being investigated currently
`in a number of clinical trials for cancer. Drowsiness, constipation and fatigue are
`common adverse effects seen in 75% of patients. Symptoms of peripheral neu(cid:173)
`ropathy and skin rash are seen in 30%. A minority of patients experience brady(cid:173)
`cardia and thrombotic phenomena. Despite lhe 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 patients
`with myeloma who are unresponsive to or relapse after standard therapy. In olher
`malignant diseases, the most appropriate way to use the dmg is in the setting of
`well designed clinical trials. In U1e absence of access to such studies, thalidomide
`could be considered singly or in combination wilh standard therapy in patients
`with no meaningful therapeutic options.
`
`Thalidomide, a synthetic glutamic acid derivative,
`was originally introduc d as a sedative-hypnotic in
`Europe and Canada in the late 1950s. Belated rec(cid:173)
`ognition of s ver teratogenic effects resulted in its
`withdrawal in the early 1960s.Pl Subsequently, tl1e
`
`drug was found to possess diverse immunomodula(cid:173)
`tory and anti-inflanunatory properties,L2-41 which are,
`at least in part, responsible for its activily in erythema
`nodosum leprosuml5l and graft-versus-host disease
`(GVHD).L6J
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`164
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`The limited early efforts exploring thalidomide
`in cancer were inconclusive. [7.sJ The description of
`its powerful activity in patients with end-stage my(cid:173)
`eloma by Singhal et at.C9l has given rise to investi(cid:173)
`gation of thalidomide in a number of malignant
`disorders. The purpose of this review is to summa(cid:173)
`rise the limited data available on the use of thalid(cid:173)
`omide in cancerP 0-391 and to provide some practical
`guidelines for its use based on our experience.
`
`1. Mechanism of Action
`
`While the exact mechanism of the antimalign(cid:173)
`ancy action of thalidomide is not known, it is likely
`that angiogenesis inhibition, immunomodulation
`and cytokine modulation,140-601 individually or in
`combination, underlie its antitumour activity. The ra(cid:173)
`pid tempo of response in some myeloma patients[91
`suggests that thalidomide may have some direct
`cytotoxic effect on plasma cells. Table I summa(cid:173)
`rises some of the properties of the drug which may
`contribute to its activity in cancer.
`Thalidomide inhibits the production of tumour
`necrosis factor (TNF)-a by monocytes as well as T
`cells. 14o,4i,51.55,56-581 Inhibition of TNF a production
`is not associated with inhibition of other cytokines
`such as interleukin (IL)-2. In fact, thalidomide en(cid:173)
`hances the production of IL -2 ,146·481 which itself
`may possess anti tumour activities or may modulate
`
`Table I. Potential mechanisms of action of tha lidomide in ca nce r
`
`the immune system to induce anticancer activity.
`Data on its effects on interferon (IFN)-y production
`have been variablel45·51 ·55-56l but more reports have
`shown it to increase IFN-y production than to in(cid:173)
`hibit it. Thalidomide inhibits IL-6, IL-10 and IL-12
`productionl50·51·561 and enhances IL-4 and IL-5 pro(cid:173)
`duction.C451 IL-6 is a potent growth factor for malig(cid:173)
`nant plasma cells and its inhibition may be partly
`responsible for the action of thalidomide in my (cid:173)
`eloma. In addition to increasing total lymphocyte
`cmmts as well as CD4+ and CD8+ Tcells,l48.60J tha(cid:173)
`lidomide is a potent costimulator of T lympho(cid:173)
`cytes.1521
`Angiogenesis is important in tumour progres(cid:173)
`sion and correlates with prognosis in a number of
`malignant diseases.l61·62l D ' Amato et aI.l43l were the
`first to show the angiogenesis inhibitory activity of
`thalidomide in a rabbit model of corneal neovas(cid:173)
`cularisation induced by basic fibroblast growth
`factor. These data have subsequently been con(cid:173)
`fim1ed in other studies,[49.53.54.571 and the combina(cid:173)
`tion of thalidomide and sulindac,l59l a nonsteroidal
`anti -inflammatory agent with antiangiogenic activ(cid:173)
`ity, has been shown to be synergistic in inhibiting
`angiogenesis.
`
`2. Clinical Studies
`
`2.1 Multiple Myeloma/Plasma Cell Disorders
`
`Thalidomide was administered to patients with
`terminal myeloma191 on the basis of observations
`that bone marrow angiogenesis was prominent in
`active myeloma1631 and thalidomide inhibited an(cid:173)
`giogenesis.C43l After treating 5 patients on a compas(cid:173)
`sionate basis, Singha! et al.l91 treated 84 additional
`patients with thalidomide as a single agent for 2 to
`465 days on a US Food and Dmg Administration(cid:173)
`approved protocol. Most patients had relapsed after
`a preceding autotransplant. The starting dose of
`200mg daily was increased by 200mg every 2
`weeks to a maximum of800mg. 32% of the patients
`responded, with the serum or urine paraprotein lev(cid:173)
`els declining by ~90% in 8 patients (including 2
`complete remissions), ~75% in 6, ~50% in 7, and
`~25% in 6. Paraprotein reduction was evident
`
`References
`Action
`Inhibition of angiogenesis
`43,49,53,54,57,59
`Alteration of adhesion molecule expression 42,44,47
`Selective inhibition of tumour necrosis
`40,41 ,51 ,55,56,58
`factor-a production
`Induction ofTh2 cytokine production (IL-4
`and IL-5)
`Variable effects of interferon-y production
`Increase in the synthesis of IL-2 by
`mononuclear ce lls
`48
`Increase in soluble IL-2 receptor levels
`Inhibition of IL-6, IL-10 and IL-12 production 50,51,56
`Increase in total lymphocyte and CD4+ and 48,60
`CD8+ T cell numbers
`Costimulation of T lymphocytes
`IL = interleukin ; Th = helper T lymphocyte.
`
`45
`
`45,51,55.56
`46
`
`52
`
`
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`Thalidomide i.n Cane r
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`165
`
`within 2 months in 78% of the responders. Responses
`were associated with reduction in marrow plas(cid:173)
`macytosis. The actuarial 1-year overall and event(cid:173)
`free survival was 58% and 22%, respectively. Cur(cid:173)
`rently, after more than 2 years of follow-up, 60%
`of responding patients have relapsed.
`These encouraging data have now been repli(cid:173)
`cated by a number of other groups.l 19-23,25,27,28,32,33 J
`The response rates described have varied between
`20 and 70%. It is clear that not all patients respond
`to thalidomide, and that a number of responding
`patients evenh1ally relapse. The combination of
`thalidomide with dexamethasonel27,391 or chemo(cid:173)
`therapyC 18·20·241 ('angiochemotherapy ' ) has been
`found to be active under these circumstances. The
`2 noteworthy combinations are OT-PACE (dexa(cid:173)
`methasone, thalidomide, cisplatin, doxonibicin,
`cyclophospham.ide, etoposide)fl 8l and BLT-0 (cla(cid:173)
`rithromycin, thalidomide, dexamethasone). l39l OT(cid:173)
`PACE (2 cycles) resulted in ~50% paraprotein de(cid:173)
`cline in almost 70% of previously treated patients.
`However, the mortality was considerable, with 3 of
`43 patients dying of tox.icity.P 81 BLT-0 was toler(cid:173)
`ated well by 17 patients with myeloma (n = 14) or
`Waldenstrom's macroglobulinaemia (n = 3), with
`all 14 evaluable patients showing a response [in(cid:173)
`cluding 3 complete responses (CR)].1391 The daily
`dose of thalidomide used in the OT-PACE regimen
`was 200 to 400mg, and that in the BLT-0 regimen,
`50 to 200mg.
`How thalidomide is best used in a patient with
`relapsed myeloma depends on the tempo of disease
`progression and bone marrow reserves. For in(cid:173)
`stance, if the disease is slowly progressive , thalid(cid:173)
`omide can be used as a single agent. Chemotherapy
`or corticosteroids can be added if there is no re(cid:173)
`sponse. On the other hand, if the disease is rapidly
`progressive, a combination of agents may have to
`be used from the beginning.
`We have used thalidomide as a single agent at
`the dose of 200 to 400mg to treat 12 previously
`untreated patients who refused standard therapy.
`Paraprotein declined by ~50% in 8 patients, and
`this response has b en sustained on continued ther(cid:173)
`apy for over 8 months in 7 patients (unpublished
`
`observations). More data are required before the
`drug can be recommended as first-line therapy of
`myeloma outside the setting of a comparative clin(cid:173)
`ical trial. However, in patients refusing standard
`therapy, thalidomide is a reasonable choice .
`Thalidomide can be administered as maintenance
`therapy following autologous stem cell tranplanta(cid:173)
`tion as a means of prolonging remission duration.
`We use thalidomide for post-transplant mainte(cid:173)
`nance in patients who cannot tolerate IFN-a or
`dexamethasone, have poor marrow function, or
`have disease that was unresponsive to dexametha(cid:173)
`sone or responsive to thalidomide before the trans(cid:173)
`plant (table 11).
`Thalidomide has been effective as a single agent
`400mg daily in previously treated patients with
`Waldenstrom 's macroglobulinaemia (A. Zomas,
`personal communication) . The BLT-0 combina(cid:173)
`tion regimen has also been reported to be effective
`in this indication.l39l We have used thaJidomide in
`a patient with Castleman 's disease with excellent
`response. The disease activity declined on thalido(cid:173)
`mide despite the reduction of prednisone from
`100mg daily to 5mg daily and was accompanied
`by nonnalisation of a grossly elevated IL-6 level.
`There are no reports on the use of thalidomide in
`amyloidosis or POEMS (Polyneuropathy, Or(cid:173)
`ganomegaly, Endocrine abnonnalities, Monoclonal
`protein, Skin changes) syndrome.
`
`Table II. Our criteria for selection of patients for thalidomide main(cid:173)
`tenance after autotransplantation (based on unpublished observa(cid:173)
`tions)
`
`Clinical situation
`Already autografted
`
`Not autografted yet
`
`Patient selection
`1. History of response to thalidomide in
`the past
`2. Intolerance of dexamethasone and
`interferon
`3. No response to dexamethasone in the
`past (alternative to interferon)
`4. Poor marrow function (alternative to
`dexamethasone)
`Pretransplant therapeutic trial of
`thalidomide for 6 weeks: responders can
`receive thalidomide after transplant,
`whereas nonresponders should receive
`dexamethasone and/or interferon
`
`
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`2.2 Myelodysplastic Syndromes
`
`IntrameduJ lary apoptosis of bone marrow eel Is,
`probably mediated by TNFa,l64l is responsible for
`the cytopenias that characterise myelodysplastic
`syndromes (MDS). In an attempt to exploit the se(cid:173)
`lective TNFa-inhibitory effect of thalidomide,
`Raza et aJ.l38l treated 61 patients with MDS with
`thalidomide 100 to 400mg for 12 weeks. 22 patients
`had refractory anaemia (RA) , 13 had RA with
`ringed sideroblasts, 19 had RA ·with excess blasts
`(RAEB), 4 had RAEB in transfonnation, and 3 had
`chronic myelomonocytic leukaemia. At the time of
`the report, 11 had stopped therapy, 25 had not re(cid:173)
`ceived the drug long enough, and 17 of the remain(cid:173)
`ing 25 evaluable patients had shown improvement
`in cytopenia (3 trilineage, 4 bilineage, 10 single Lin(cid:173)
`eage). The best responses were seen in the erythroid
`series, with a number of patients becoming trans(cid:173)
`f11sion-independent. Longer follow-up is required
`to see how long these responses are sustained.
`Thalidomide-containing angiochemotherapy
`combinations may be active in RAEB , RAEB in
`transformation and secondary acute myeloid leu(cid:173)
`kaemia. These combinations (liposomal anthracy(cid:173)
`cline with topotecan or cytarabine ; with or with(cid:173)
`out thalidomide) are being studied currently.[291
`
`2.3 Kaposi's Sarcoma
`
`Soler et al.[1 31 described a 14-year-old girl with
`HIV infection and subcutaneous Kaposi 's sarcoma
`(KS) who received thalidomide for aphthous ul(cid:173)
`cers. This resulted in regression of KS lesions dis(cid:173)
`appearance of KS-associated herpesvirns (KSHV)
`DNA from blood and reduced viral load in tumour
`tissue. Fife et al.P51 administered 100mg thalido(cid:173)
`mide daily for 8 weeks to 17 patients ,•,rith AIDS(cid:173)
`related KS. Six patients achieved a partial response
`and viral DNA load decreased to undetectable
`levels in 3 of the 5 responders assessed virologi(cid:173)
`cally.
`Little et al.1361 treated 20 HIV-positive patients
`who had progressive KS with 200mg thalidomide
`in a phase II study. The dose was escalated to
`1000mg for up to a year. Eight patients had partial
`
`response and 2 had stabilisation of progressive dis(cid:173)
`ease. The median drng dose at the time of response
`was 500mg. The median duration of therapy was
`6.3 months, and the median time to progression 7.3
`months. KSHV DNA titres were not studied. The
`disappearance of viral DNA in responding patients
`is of interest in the context of the activity of thalid(cid:173)
`omide in myeloma and the fact that some groups
`have isolated KSHV DNA in pati.ents with my (cid:173)
`eloma.l651
`
`2.4 Breast Cancer
`
`Eisen et at.l3°J studied 12 patients with breast
`cancer as part of a group of 66 patients with various
`cancers who received 100mg thalidomide daily.
`No objective response was seen in any of these
`12 patients. Baidas et al. C3 7l studied the efficacy of
`thalidomide in 28 women with heavily pretreated,
`progressive metastatic breast cancer who were
`randomised to receive either 200 or 800mg thalid(cid:173)
`omide daily. No response was seen in any patient.
`13 of 14 patients receiving 800mg thalidomide ex(cid:173)
`perienced progressive disease within 8 weeks, com(cid:173)
`pared with 12 of 14 in the 200mg arm. Two patients
`in the 200mg arm had stable disease at 8 weeks.
`Nguyen et al.1 141 administered 100 to 300mg
`thalidomide daily for 4 weeks in addition to stand(cid:173)
`ard chemotherapy in 7 women with breast cancer.
`With a follow-up of 1 to 6 months, patients with stage
`4 disease had either a partial response or stabilisa(cid:173)
`tion of disease. However, the disease eventually pro(cid:173)
`gressed in the 2 patients with the longest follow-up
`(5 and 6 months).
`These studies included patients with advanced
`disease and used the drng as a single agent or for a
`limited duration. More benefit might be seen if tha(cid:173)
`lidomide is combined with chemotherapy and then
`continued as maintenance therapy for an extended
`period, although such an approach requires system(cid:173)
`atic investigation.
`
`2.5Glioma
`
`Because malignant gliomas are vascular tu(cid:173)
`mours, angiogenesis inhibition may be therapeuti(cid:173)
`cally beneficial. Fine et al.f3 IJ administered thalid-
`
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`omide to 3 9 patients with anaplastic mixed glioma,
`anaplastic astrocytoma or glioblastoma multi(cid:173)
`forme who had radiological evidence of progres(cid:173)
`sion after external-beam radiation with or without
`chemotherapy. The drug was started at the daily
`dose of 800mg and increased by 200mg every 2
`weeks to 1200mg. Among the 36 evaluable pa(cid:173)
`tients, there were 2 radiologically evident partial
`responses (6%), 2 minor responses (6%) and 12
`patients (33%) with stable disease. Eight patients
`were alive over a year after starting therapy, most
`with progressive disease. Once again, it is likely
`that thalidomide will have to be used as part of a
`multimodaJity treatment plan if it is to be of any
`benefit in this setting.
`
`2.6 Colon Cancer
`
`Govindarajan et al.f35l treated 9 colon cancer pa(cid:173)
`tients with irinotecan (325 to 350 mg/m2 every 3
`weeks) and 400mg thalidomide daily as second(cid:173)
`line therapy. None of the patients had been treated
`with irinotecan in the past. Thalidomide was found
`to eliminate the dose-limiting gastrointestinal side
`effects of irinotecan, especially nausea and diar(cid:173)
`rhoea, almost completely, pennitting 8 of 9 pa(cid:173)
`tients to complete therapy. Of the 7 patients evalu(cid:173)
`able for response, 1 attained complete remission and
`2 partial remission. These data have important im(cid:173)
`plications for the tolerability as well as efficacy of
`angiochemotherapy in colon cancer.
`
`Hodgkin's disease relapsing after autotransplanta(cid:173)
`tion (unpublished observations), Langerhans cell
`histiocytosis,r10· 12-16l hepatocellular carcinoma,f341
`and chronic myeloproliferative disorders.f29l No
`responses were seen in ovarian cancer and advanced
`melanoma. [3o1
`
`2.9 Graft-versus-Host Disease
`
`Thalidomide is irnmunomodulatory rather than
`imrnunosuppressive in its action. In fact, thalidomide
`increases total lymphocyte counts as well as CD4+
`and CD8+ lymphocytes. It is likely that its benefi(cid:173)
`cial effect in treating established chronic GVHDl6J
`is a result of TNFa inhibition. Thalidomide has
`little effect on acute GVHD,[661 and prophylactic
`use of the drug, paradoxically, has been shown to
`result in increased chronic GVHD.f671 This may be
`because of some immunostimulatory effects.
`GVHD and graft-versus-tumour effects are of(cid:173)
`ten closely linked. Thus, when GVHD resolves with
`successful immunosuppression, the underlying
`malignant disease often recurs. It was anecdotally
`observed in a small series that the patients whose
`GVHD resolved with thalidomide treatment did
`not relapse.C66l If this interesting observation is
`confinned, it could mean that the immunomodula(cid:173)
`tory and/or antiangiogenesis effects ofthalidom.ide
`may allov,1 separation of GVHD and gTaft-versus(cid:173)
`tumour effects in patients with established chronic
`GVHD.
`
`2.7 Renal Cell Carcinoma
`
`2.10 Cancer Cachexia
`
`Among 18 patients ·with renal cell carcinoma
`which was progressive despite biochemotherapy, 3
`partial responses were noted with thalidomide
`monotherapy. One lasted 5 months, and the other
`two were ongoing at 5 and 11 months at the time
`of the report. 13 of the remaining 16 patients expe(cid:173)
`rienced disease stabilisation for 1 to 3 months (10)
`or >3 months (3).L30J
`
`High levels ofTNFa have been linked with can(cid:173)
`cer cachexia and malaise. Because of its effects on
`TNFa, thalidomide was explored in 72 terminal
`cancer patients who were not receiving any cyto(cid:173)
`toxic therapy at the dose of 100mg at night for 10
`days. Among the 37 evaluable patients, 44 to 69%
`reported significant improvement in insomnia,
`nausea, appetite and sensation of well-being.
`
`2.8 Other Cancers
`
`3. Dosage and Administration
`
`Responses to thalidomide as a single agent at
`the dose of 200 to 400mg daily have been seen in
`
`No systematic dose escalation studies of thalid(cid:173)
`omide have been performed in any disease. The
`
`
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`doses used have varied v.ridely between 50 and
`1200mg daily, and responses have been seen at all
`dose levels. Dose escalation in the myeloma study
`was time-dependent, and thus the effect of the du(cid:173)
`ration of therapy was inseparable from the effect of
`dose.191 Based on the effect of dose adjustment on
`the extent of response in myeloma, we have ob(cid:173)
`served a clear dose-response relationship in some
`patients.
`When used off-protocol , the drug should be
`started at the dose of 100 to 200mg daily and esca(cid:173)
`lated in 50 to 100mg steps every week to a target
`dose of 400 to 800mg. The optimum do se for a
`given patient is one that is best tolerated by that
`individual.
`Most studies have used the dmg as a single bed(cid:173)
`time dose. In the myeloma study, tltis was changed
`only occasionally to divided dos s in patients with
`excessive drowsiness in th morning. Although we
`have not noticed any effect of divided doses, a Swe(cid:173)
`dish group has reported faster and better responses
`in myeloma patients receiving the dmg in divided
`doses.l33l Since the half-life of thalidomide is 6 to
`7 hours, tltis may be preferable to single daily dose
`admi1tistration of the drug.
`
`4. Adverse Effects
`
`Severe teratogenicity, historically the most im(cid:173)
`portant adverse effect of thalidomide, is less rele(cid:173)
`vant in cancer patients undergoing chemotherapy
`than in other patient populations. To minimise the
`risk of teratogenicity Celgene Corporation (War(cid:173)
`ren, New Jersey, USA), the American manufacturer
`of thalidomide, has developed a progra1mne called
`STEPS (System for Thalidomide Education and
`Prescribing Safety) for controlling and monitoring
`access to thalidontide.f681 The programme ensures
`education of physicians pharmacists and patients
`on 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(cid:173)
`verse effects of thalidomide. In the study of Singhal
`et al. ,(91 75% of patients experienced some adverse
`effect at the 1ninimmn dose of 200mg daily, whereas
`
`over 90% of patients experienced adverse effects
`at the maximum dose of800mg daily. Most adverse
`effects were WHO grade I or II, and only 10% of
`patients discontinued the drug because of adverse
`effects. Because sedation is the outstanding ad(cid:173)
`verse effect, the use of sedatives and tranquillisers
`in patients taking thalidomide should be mini(cid:173)
`mised.
`There is some concern that thrombotic phenom(cid:173)
`ena occur more commonly in patients receiving
`thalidomide,118,28,691 although it must be borne in
`mind that the underlying diseases are also associ(cid:173)
`ated with a predisposition to thrombosis.
`The occurrence of symptoms of peripheral neu(cid:173)
`ropathy in women taking thalidomide was the rea(cid:173)
`son that the dmg was not approved for use in US
`initially. We have found symptoms of neuropathy
`in approximately 30% of patients who take thalid(cid:173)
`omide, but onJy half have had objective changes on
`nerve conduction studies. Thalidomide-induced
`peripheral neuropathy is typically symmetrical and
`is characterised by painful paraesthesias of the
`hands and feet, often accompanied by sensory loss
`in the feet. The symptoms apparently do not correl(cid:173)
`ate with the duration of treatment or the dose,170-721
`and women and older persons are at greater risk.17°1
`There is some suggestion that slow acetylators may
`be more predisposed to neuropathy.L71 l We have
`found pyridoxine (vitamin B6) to relieve neuro(cid:173)
`pathic symptoms in a number of patients at the dose
`of 200mg daily. Prophy lactic use of pyridoxine
`100mg daily with thalidomide appears to reduce
`the frequency of such symptoms (unpublished ob(cid:173)
`servations).
`In general, if the adverse effects are tolerable,
`patients should be encouraged to continue the drug
`at the same dosage . If the symptoms are difficult
`to tolerate, a step-v.1ise reduction in dose to find a
`Level that is better to lerated is reasonable. Occa(cid:173)
`sionally, the drng may need to be discontinued for
`a period of 2 to 3 weeks and then restarted at a
`lower dose.
`Table III shows our approach to managing spe(cid:173)
`cific adverse events. The skin and cardiac events
`mentioned in the table need some elaboration.
`
`
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`Thalidomide i.n Cane r
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`Table 111. Suggested approach to managing specific adverse effects of thalidomide therapy
`
`Adverse event
`
`Type/severity
`
`Management
`
`Comments
`
`Bradycardia
`
`Mild: decrease in resting heart
`rate by 10-20/min; rate >60
`
`Watch carefully; counsel patient to monitor
`pulse daily; continue thalidomide
`
`Avoid concomitant ~-blocker usage
`
`As above; check ECG; continue thalidomide As above
`if no hypotension or syncopal episodes and
`normal ECG; stop thalidomide if there are
`symptoms or ECG abnormalities
`
`Moderate: rate 50-60
`
`Severe: rate <50
`
`Skin rash
`
`Erythematous, maculopapular,
`itchy lesions
`
`Erythema multiforme
`(Stevens-Johnson syndrome)
`
`Peripheral
`neuropathy
`
`Mild symptoms
`
`Moderate symptoms
`
`Severe symptoms
`
`Stop thalidomide immediately; check ECG;
`evaluation for sick sinus syndrome or
`autonomic neuropathy may be necessary
`
`Local corticosteroid cream; if no re lief,
`decrease dose gradually or stop the drug
`and restart at a lower dose
`
`Discontinue tha lidomide; absolute
`contraindication for repeat administration of
`the drug
`
`Increase pyri doxine dose to 200mg daily;
`additional vitamin 81 , 812 and fo late may be
`helpful in some patients; continue
`thalidom ide
`
`As above; continue thalidomide if symptoms
`intermittent; stop thalidomide if symptoms
`continuous
`
`As above; stop thalidomide; nerve
`conduction studies to evaluate extent of
`neuropathic changes
`
`Consider pacemaker implantation if
`thalidomide considered unavoidable
`
`Baseline nerve conduction studies
`may be useful in patients with
`pre-existing neuropathic symptoms
`
`As above; thalidomide may be
`restarted if symptoms abate
`
`As above; thalidomide may be
`restarted at a lower dose if
`symptoms abate and therapy
`considered unavoidable
`
`Consider prophylactic warfarin in
`patients with a prior history of deep
`vein thrombosis
`
`Thrombosis
`
`Deep vein thrombosis
`
`Therapeutic anticoagulation
`
`Most patients who develop a rash have maculopap(cid:173)
`ular lesions. However, a rash resembling Stevens(cid:173)
`Johnson syndrome is seen in approximately 1 % of
`patients. In the firs t such patient,1251 rechallenge
`resulted in recurrence of Stevens-Jolmson syndrome
`which was fatal. In the subsequent patient, the drug
`was not reintroduced and the reaction did not recur.
`Recently, life-threatening toxic epidennal necrolysis
`has been described in newly diagnosed myeloma
`patients treated with the combination of thalido(cid:173)
`mide and dexamethasone.1731 The investigators ad(cid:173)
`vocated caution in the us of this drug combination
`in newly diagnosed patients.1731 Toxic epidermal
`necrolysis has also been described in 1 patient with
`glioblastoma who was receiving thalidomide.C741
`
`We have seen bradycardia of unclear aetiology
`in approximately 5% of patients treated with tha(cid:173)
`lidomide. Since there have been no blood pressure
`:fluctuations in these patients, it is unclear if this
`represents a form of autonomic neuropathy. How(cid:173)
`ever, caution is warranted if bradycardia develops,
`especially if patients are already on drugs such as
`[3-blockers for hypertension.
`
`5. Conclusions
`
`The use of thalidomide in myeloma provided
`the crucial proof of principle that a drug apparently
`lacking conventional cytotoxic activity could have
`meaningful antimalignancy action. It is now im(cid:173)
`portant to ensure that patients likely to benefit from
`
`
`
`BioDrugs 2001 ; 15 (3)
`
`DR. REDDY’S LABS., INC. EX. 1032 PAGE 7
`
`

`

`170
`
`Singha/ & M ehta
`
`thalidomide have access to it, and that it is evalu(cid:173)
`ated systematically in other cancers. In diseases
`such as myeloma where its activity is undisputed,
`thalidomide should be considered as salvage ther(cid:173)
`apy at the appropriate time (relapsed or refractory
`disease) . Its use in early disease is best confined to
`clinical studies or any situation where more con(cid:173)
`ventional therapy is not feasible . In disease where
`the action of thalidomide has not been conclusively
`shown, it should be used in the setting of well de(cid:173)
`signed clinical trials . In the absence of such studies,
`its use singly or in combination with standard ther(cid:173)
`apy could be considered in patients in whom no
`standard therapeutic options or alternative clinical
`studies of salvage therapy are avai lable.
`
`Acknowledgements
`
`Disclosure: Drs Singha! and Mehta own stock in Celgene
`Corporation, the company which manufactures and markets
`thalidomide in USA.
`
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