Current role of thalidomide in cancer treatment
`Deborah A. Thomas, MD, and Hagop M. Kantarjian, MD
`
`Thalidomide (Thalidomid, Celgene, Warren, NJ) is a putative
`anti-angiogenesis and immunomodulatory agent that has
`demonstrated activity in various dermatologic and rheumato-
`logic conditions in addition to Crohn’s disease. The biologic
`effects of thalidomide and the clinical trials conducted in solid
`tumors, hematologic malignancies, chronic graft-versus-host
`disease (GVHD), and cancer-related cachexia are reviewed. A
`summary of the preliminary results of ongoing clinical trials is
`presented, and the future directions of thalidomide research in
`the oncology are discussed. Curr Opin Oncol 2000, 12:564–573
`© 2000 Lippincott Williams & Wilkins, Inc.
`
`University of Texas MD Anderson Cancer Center, Department of Leukemia,
`Houston, Texas, USA
`
`Correspondence to Deborah A. Thomas, MD, Assistant Professor, Department
`of Leukemia, University of Texas M. D. Anderson Cancer Center, 1515
`Holcombe Blvd, Box 61, Houston, TX 77030; e-mail: debthomas@mdander-
`son.org
`
`Current Opinion in Oncology 2000, 12:564–573
`
`Abbreviations:
`
`bFGF
`GM
`GVHD
`IL
`TNF-aa
`VEGF
`
`basic fibroblast growth factor
`glioblastoma multiforme
`graft-versus-host disease
`interleukin
`tumor necrosis factor alpha
`vascular endothelial growth factor
`
`ISSN 1040–8746 © 2000 Lippincott Williams & Wilkins, Inc.
`
`564
`
`Historical perspective
`Thalidomide was first introduced in 1953 by Chemie
`Grunenthal as an oral sedative-hypnotic [1]. It had no
`toxicity or addictive properties at therapeutic levels;
`however, peripheral neuritis was noted in some patients
`with long-term use. It was also used to ameliorate
`nausea and vomiting during pregnancy. In 1960, limb
`malformations and abnormalities of internal organs in
`newborns were associated with the maternal use of
`thalidomide. It was thus withdrawn from the market in
`1961 due to its teratogenecity [2].
`
`In 1965, the surprising activity of thalidomide in reac-
`tive lepromatous leprosy (seen during its use as a seda-
`tive-hypnotic) stimulated further study [3]. After a series
`of confirmatory placebo-controlled trials, thalidomide
`was approved by the Food and Drug Administration as
`treatment for the acute cutaneous manifestations of
`erythema nodosum leprosum and as maintenance
`therapy to prevent recurrence. Its immunomodulatory
`properties have been effective in other dermatologic
`diseases such as cutaneous lupus erythematosus, recur-
`rent erythema multiforme, and recurrent aphthous
`ulcers (especially in AIDS patients) [3–7].
`
`The first oncology studies of thalidomide were also
`reported in 1965. Grabstad and Golbey treated 71 patients
`with various malignancies with doses ranging from 300 mg
`to 2 g daily [8]. The one clinical responder had renal cell
`carcinoma metastatic to the lung and was treated after
`nephrectomy. Olson et al. [9] treated 21 patients with
`various solid tumors with doses ranging from 200 mg thrice
`daily up to 1400 mg daily. No tumor regressions were
`noted, but slowing of disease progression was observed in
`two patients, with palliation of symptoms in seven (33%).
`Because of the paucity of objective tumor responses, inter-
`est in thalidomide as an anti-cancer agent waned.
`
`Recently, investigators discovered that the biologic
`effects of thalidomide include inhibition of angiogenesis
`and suppression of tumor necrosis factor alpha (TNF-a).
`Owing to these unique mechanisms of action and favor-
`able side effect profile relative to chemotherapy (Table
`1), the study of thalidomide as a potential anti-tumor
`agent has intensified.
`
`Role for thalidomide in oncology:
`anti-angiogenesis
`In 1971, Folkman [10] determined that angiogenesis
`was essential for tumor development. Progressive
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`Current role of thalidomide in cancer treatment Thomas and Kantarjian 565
`
`Table 1. Rationale for thalidomide in oncology
`
`Parameter
`
`Onset at effect
`
`Chemotherapy
`
`Rapid
`
`Mechanism of action
`
`Specific to agent
`
`Thalidomide
`
`Slower
`
`Inhibits bFGF- and VEGF-angiogenesis
`Inhibits TNF-a
`, IL-12, IL-6
`Stimulates IL-2, IFN-g
`Stimulates CD8+ T cells
`Alters adhesion molecules
`
`Drug resistance
`
`Commonly acquired
`
`Less likely due to multiple targets without cross resistance
`
`Toxicity
`Alopecia
`Gastrointestinal
`Myelosuppression
`Wound healing
`Teratogenicity
`Secondary
`MDS/AML
`Neurologic
`
`Frequent
`Mucositis, nausea, diarrhea
`Frequent
`Delayed
`Known with specific agents
`Risk with some agents (eg,etoposide)
`Specific to agent (ara-C, ataxia; vincristine, peripheral
`neuropathy)
`
`Rare
`Constipation
`Rare, more common in HIV, GVHD
`Delayed
`Severe
`No known mutagenicity, carcinogenicity
`Somnolence; peripheral neuropathy with long-term use
`
`Clinical trial endpoint
`Phase I
`Phase II
`Combination
`
`Maximum tolerated dose
`Maximum biologic effect
`Tumor reduction
`Time to progression and survival
`Overlapping toxicities, reduced doses required for drug
`Synergy with chemotherapy, XRT, other
`combinations
`antiangiogenesis agents
`AML, acute myelogenous leukemia; bFGF, basic fibroblast growth factor; GVHD, graft-versus-host disease; IFN-g, interferon- g; IL-6, interleukin-6;
`IL-12, interleukin-12; MDS, myelodysplasia; TNF-a, tumor necrosis factor-alpha; VEGF, vascular endothelial growth factor; XRT, radiation therapy.
`
`recruitment of blood vessels to the tumor site resulted
`in proliferation and allowed cancer cells access to the
`vascular system for hematogenous spread. The degree
`of tumor vascularization is an independent prognostic
`factor for survival in carcinomas of the breast [11,12],
`lung [13], prostate [14,15], and esophagus [16]. The
`tumor vascular density also correlates with increased
`metastases, recurrences, or worse prognosis for carcino-
`mas of the bladder [17,18], colon [19], and stomach [20],
`and for melanoma [21].
`
`For hematologic malignancies, the pathologic correlate
`of tumor vascularization is bone marrow microvessel
`density. Studies in childhood acute lymphocytic
`leukemia [22], multiple myeloma [23–25], agnogenic
`myeloid metaplasia [26], and other acute and chronic
`leukemias [27] have shown increased marrow microves-
`sel density to correlate with poor risk features.
`Promoters of angiogenesis such as vascular endothelial
`growth factor (VEGF), basic fibroblast growth factor
`(bFGF), and TNF-a
`are elevated in several hematopoi-
`etic malignancies [28,29].
`
`In 1994, D’Amato et al. [30] showed that thalidomide
`inhibited bFGF-induced angiogenesis in a rabbit cornea
`micropocket assay. It also inhibited VEGF in a murine
`model of corneal vascularization [31]. In preclinical
`studies using a murine breast cancer model, thalidomide
`monotherapy did not reduce tumor size, but when
`combined with chemotherapy, prevention of distant
`
`lung and liver metastasis was observed compared with
`chemotherapy alone [32]. Other investigators have
`confirmed the anti-angiogenic effects of thalidomide
`after metabolic activation [33].
`
`Cytokine modulation and other biologic
`effects of thalidomide
`The level of TNF-a
`is elevated in various malignancies
`and other pathologic processes such as rheumatoid arthri-
`tis [34] and Crohn’s disease [34]. It enhances neo-angio-
`genesis, interacts with other proliferative cytokines such
`as interleukin (IL)-6, and contributes to many of the
`systemic symptoms of advanced malignancy. TNF-a
`can
`induce endothelial production and secretion of collage-
`nase, urokinase-type plasminogen activator, and plas-
`minogen activator inhibitor (PAI)-1 to promote tumor
`expansion and metastasis. It induces bFGF mRNA (and
`collagenase and IL-6 mRNA) in human omental
`microvascular cells [35]. Soluble receptors for TNF-a
`are
`present in human ovarian and breast carcinomas [36,37].
`
`Thalidomide inhibits TNF-a production by stimulated
`monocytes, macrophages, and neutrophils [38]. Proposed
`mechanisms include (1) decreased synthesis by acceler-
`ated degradation of TNF-a mRNA, (2) binding to a
`1-acid
`glycoproteins with intrinsic anti-TNF-a
`activity, and (3)
`decreased binding activity of NFkB, which controls the
`activation of the TNF-a gene [38–41]. Thalidomide also
`inhibits monocyte IL-12 production, enhances synthesis
`of IL-2, and inhibits IL-6 [42–44].
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`566 Therapeutic modalities
`
`Immunomodulatory effects on lymphocytes include (1)
`differential CD8+ T-cell stimulation resulting in
`decreased CD4/CD8 ratio, (2) shift from Th1 to Th2 T-
`cell responses, and (3) inhibition of T-cell proliferation
`in stimulated lymphocytes [45–48]. Thalidomide also
`inhibits neutrophil chemotaxis and modifies expression
`of surface adhesion molecules such as integrin receptors
`on leukocytes [49–51]. Direct anti-tumor effects of
`thalidomide include morphologic differentiation of the
`human leukemia cell line K562 in vitro [52].
`
`Pharmacology and toxicity
`Thalidomide is a racemate; the S and R isomer forms
`represent derivatives of l- and d-glutamic acid, respec-
`tively. The S isomer has been linked to teratogenicity,
`whereas the R isomer appears responsible for the seda-
`tive properties [53]. At physiologic pH, these isomers
`rapidly interconvert in vivo. The absolute bioavailability
`has not been characterized because of poor aqueous
`solubility. In studies of healthy volunteers and subjects
`with Hansen’s disease, the mean time to peak plasma
`concentrations ranged from 2.9 to 5.7 hours, indicating
`that it is slowly absorbed from the gastrointestinal tract
`[54••]. The influence of food on the rate or extent of
`absorption has not been determined.
`
`Side effects of thalidomide include somnolence,
`nausea, dry mouth and skin, skin rashes, constipation,
`increased appetite, headache, hypertension, bradycar-
`dia, dizziness and orthostatic hypotension, altered
`temperature sensitivity, irregularities in menstrual
`cycles, hypothyroidism, edema of lower extremities,
`teratogenicity, and peripheral neuropathy [54••].
`Constipation can be controlled with an aggressive laxa-
`tive regimen. Rash and leukopenia appear to be more
`common in AIDS patients and recipients of allogeneic
`bone marrow transplant. The immunomodulatory
`action of thalidomide has not been associated with an
`increased incidence of infections.
`
`Adverse effects such as somnolence, nausea, and skin
`rashes are dose-dependent and generally resolve with
`discontinuation of therapy. Tachyphylaxis has been
`observed to the somnolence and can be minimized by
`administration at bedtime. Thalidomide appears to
`enhance the sedative effects of barbiturates and alcohol
`and the catatonic effects of chlorpromazine and reser-
`pine. Thalidomide-induced sedation can be antagonized
`with the central nervous system stimulants
`methylphenidate and methylamphetamine.
`
`Thalidomide-associated neuropathy is generally charac-
`terized by painful symmetric paresthesias in the toes and
`feet, and electrophysiologic findings are often consistent
`with axonal degeneration without demyelination [55–57].
`Other associated symptoms include muscle cramps or
`
`weakness, signs of pyramidal tract involvement, and
`carpal tunnel syndrome. Rapid improvement is usually
`observed with discontinuation of therapy; however, cases
`of irreversible or longstanding sensory loss have been
`reported. The incidence of neuropathy appears to be
`increased in older patients and after administration of
`high cumulative doses; there may be a relation between
`slow acetylation and development of neuropathy.
`
`Thalidomide is teratogenic and should never be used by
`women who are pregnant or who could become pregnant
`while taking the drug. Major human fetal abnormalities
`have been documented: amelia (absence of limbs),
`phocomelia (short limbs), hypoplasticity of the bones,
`absence of bones, abnormalities or absence of organs
`(kidney, spleen, gallbladder), external ear abnormalities,
`facial palsies, eye abnormalities, and congenital heart
`defects. The highest risk occurs when the thalidomide is
`ingested during days 35 to 50 of pregnancy; severe effects
`can occur even with a single 100-mg dose. Thus, the drug
`must not be used at any time during pregnancy, and
`recommended contraceptive methods must be used by
`both women and men of child-bearing potential. Females
`on rifampin, rifabutin, barbiturates, steroids, phenytoin or
`carbamazepine should not rely on hormonal contracep-
`tion, since efficacy is reduced. Studies of the plasma phar-
`macokinetics of oral contraceptives given concomitantly
`with thalidomide do not indicate reduced efficacy [58].
`The S.T.E.P.S. program has been instituted to reduce
`fetal exposure; access is controlled by registration of
`prescribing physicians, dispensing pharmacies, and
`patients [59•]. A comprehensive consent process with
`educational materials is mandatory.
`
`Clinical trials in solid tumor malignancies
`High-grade gliomas
`Two early phase II studies have shown promising activ-
`ity of thalidomide in patients with recurrent high-grade
`gliomas (highly vascular tumors with high microvessel
`density are an adverse prognostic factor) such as
`anaplastic mixed glioma, anaplastic astrocytoma, or
`glioblastoma multiforme (GBM). Fine et al. [60••]
`administered 800 mg to 1200 mg daily to patients previ-
`ously treated with external radiation therapy with or
`without chemotherapy. Two of 36 patients (6%) had
`partial responses, two (6%) had minor responses, and 12
`(33%) had stable disease. Median time to progression
`was only 10 weeks for the entire group, but it was 33
`weeks for the responders, 15 for those with stable
`disease, and 8 weeks for the nonresponders. Median
`survivals were 74, 30, and 22 weeks, respectively.
`Increases in bFGF correlated with progression and
`shorter survival. Adverse events were grade 4 seizures in
`four patients with prior history of seizures or tumor
`progression. Somnolence and constipation were the
`main toxicities attributable to thalidomide.
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`Current role of thalidomide in cancer treatment Thomas and Kantarjian 567
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`In another single-agent trial, 37 patients with recurrent
`GBM were treated with doses ranging from 100 mg to
`500 mg daily [61]. Of the 34 patients evaluable, 5 (15%)
`had a partial response, 11 (32%) had stable disease, and
`18 (53%) had progressive disease. No correlation
`between VEGF levels and outcome was observed. In a
`combination trial, 46 patients with recurrent high-grade
`gliomas were treated with carboplatin (AUC 8) and
`thalidomide 300 mg/m2 daily [62]. Five partial responses
`(12%) were observed and 28 (70%) patients had stable
`disease with a median response duration of 24 weeks
`and estimated survival of 40 weeks. Hematologic toxic-
`ity was prominent in patients receiving prior nitrosurea.
`Major nonhematologic toxicities attributable to thalido-
`mide were constipation and drowsiness. Complete
`results of these two trials are not yet published.
`
`Kaposi’s sarcoma
`Recent data indicate that thalidomide is active in AIDS-
`related Kaposi’s sarcoma. Fife et al. [63] conducted a
`phase II study of 100 mg daily for 8 weeks in 17 patients
`with cutaneous AIDS-related Kaposi’s sarcoma. Six of 17
`patients achieved a partial response (35%), and 8 patients
`withdrew from therapy because of toxicity (n=6),
`progression (n=1), or noncompliance (n=1). Interestingly,
`human herpesvirus 8 DNA load became undetectable in
`three of the five assessable partial responders.
`
`Preliminary results of two additional studies have been
`reported. Politi et al. [64] treated 12 patients with doses
`ranging from 200 to 600 mg daily. Two of 12 patients
`(17%) responded at doses of 200 and 400 mg per day,
`respectively; 7 patients (58%) had stable disease. The
`partial responses lasted for 3+ and 8 months. The
`median time to disease progression was 4 months. Dose-
`dependent somnolence was observed, requiring cessa-
`tion of therapy in two of three patients treated at 600 mg
`per day. Rash, headache, and paresthesias were
`observed. Yarchoan et al. [65] treated 13 patients with
`AIDS-related Kaposi’s sarcoma in an escalating fashion
`beginning with 200 mg up to 1000 mg as tolerated. Four
`of 11 evaluable patients (36%) achieved a partial
`response. Two maintained their response at 30+ and 50+
`weeks, whereas two progressed at 16 and 49 weeks. Five
`patients (45%) had stable disease ranging from 12 to 52
`weeks. Rash, neutropenia, depression, and sedation
`were reported.
`
`Renal cell carcinoma
`In a large phase II study, Eisen et al. [66•] treated 66
`advanced cancer (ovarian, melanoma, renal, breast)
`patients with thalidomide 100 mg daily. Three of 18
`patients (17%) with renal cell carcinoma had partial
`responses, and 3 had stable disease for 3 months or
`longer. Two of the responders had failed bioim-
`munochemotherapy; tumor shrinkage was observed
`
`within 2 weeks of starting thalidomide. No other objec-
`tive responses were observed, but patients had reduced
`insomnia and stabilization of weight loss. Toxicities
`included grade 2 lethargy (n=8), grade 2 neuropathy
`(n=2), and skin rashes. Progression correlated with
`increasing serum and urine levels of VEGF. Preliminary
`results of another phase II study in 15 patients with
`renal cell carcinoma used higher doses ranging from 400
`mg to 1200 mg daily [67]. Of the 12 patients evaluable
`for response (at least 4 weeks of therapy), 1 had a partial
`response for 11+ months after failing IL-2, 1 had a minor
`response for 3+ months, 3 had stable disease, and 7
`patients had progressive disease. Full results of this trial
`are not yet available.
`
`Prostate cancer
`Figg et al. [68] reported preliminary data of thalidomide
`in 63 patients with metastatic prostate cancer who had
`failed combined androgen blockade as well as antiandro-
`gen withdrawal. The drug was administered at either a
`low dose (n=50, 200 mg daily) or high dose (n=13, titra-
`tion to 1200 mg). Declines in prostate-specific antigen
`were observed in 58% and 68% of patients on the low-
`dose and high-dose arms, respectively. Eighteen percent
`treated with low-dose thalidomide had greater than 50%
`reductions in prostate-specific antigen, the longest
`maintained for 1.5 years. No objective tumor reductions
`were observed, but two patients had both symptomatic
`and radiographic improvement of bone scan lesions.
`Reduced bFGF levels were seen in responders. The
`most prevalent complaints were constipation, dizziness,
`edema, fatigue, xerostomia, and neurocortical symp-
`toms. Peripheral neuropathy was observed with long-
`term use (> 9 months). Thalidomide upregulates
`prostate-specific antigen secretion in the human
`prostate cell line LNCaP [69], indicating that additional
`end points may be required to determine response in
`future trials.
`
`Hepatocellular carcinoma
`Patt et al. [70] studied patients with nonresectable hepa-
`tocellular carcinoma beginning at 400 mg daily with esca-
`lation to 1000 mg by week 5 (one-third dose was adminis-
`tered in the afternoon and two-thirds at bedtime).
`Twenty-seven patients were treated; 21 were evaluable
`for response. Preliminary results included one partial
`response and one minor response; 10 patients (48%) had
`stable disease for at least 2 months. Somnolence was
`observed in all patients, and grade 3–4 skin reactions
`were observed in 20%. One patient developed an exfolia-
`tive dermatitis. Combination trials with chemotherapeu-
`tic agents such as capecitabine are planned.
`
`Melanoma
`Reported thalidomide experience is limited in
`melanoma. Eisen et al. [66•] treated 17 patients with
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`568 Therapeutic modalities
`
`advanced melanoma with low-dose thalidomide (100 mg
`daily). No objective responses were observed, but 4
`patients (24%) had stable disease for up to 5 months.
`One patient was noted to have significant symptom
`control of his leg deposits.
`
`Breast and ovarian cancer
`Eisen et al. [66•] treated 12 patients with advanced
`breast cancer and 19 with ovarian carcinoma with low-
`dose thalidomide (100 mg daily); no objective responses
`were observed in these groups. Nguyen et al. [32]
`treated advanced breast cancer patients (n=7) with
`thalidomide (100 to 300 mg daily) in combination with
`cyclophosphamide, doxorubicin, and fluorouracil (CAF).
`Three patients had partial response, one had stable
`disease, two had progressive disease, and one was lost to
`follow-up.
`
`Long et al. [71] treated seven patients with breast cancer
`after intensive chemotherapy and autologous stem cell
`transplant with thalidomide 400 mg orally daily begin-
`ning at hematologic recovery until day 180. Fatigue and
`mild somnolence were observed at the time of the
`report. Modulation of VEGF was noted. Full results of
`this study were not available; accrual was ongoing.
`
`Squamous cell carcinoma of the head and neck and
`non-small cell lung cancer
`Preliminary results of a phase II trial of escalating
`thalidomide (200 to 1200 mg) in 17 heavily pretreated
`patients with recurrent or metastatic squamous cell
`carcinoma of the head and neck was recently reported
`[72]. No objective tumor responses were observed, with
`94% of the patients discontinuing thalidomide due to
`progressive disease. The median survival of 5.4 months
`was similar to that of historical control subjects.
`
`A pilot study of thalidomide in combination with pacli-
`taxel 225 mg/m2 over 3 hours with carboplatin (AUC 6)
`was conducted in patients with advanced non-small cell
`lung cancer (unresectable stage IIIA, IIIB, or stage IV)
`[73]. Thalidomide was given 200 mg daily and escalated
`to 1000 mg as tolerated. Patients with stage III disease
`without pleural effusion received two cycles of combina-
`tion therapy followed by external radiation therapy plus
`thalidomide; those with a pleural effusion or stage IV
`disease received six cycles of combination therapy
`without external radiation therapy. Preliminary results
`in nine patients showed no objective responses; all six
`patients receiving two cycles of chemotherapy had
`stable disease. One stage IIIB patient with a pleural
`effusion had progressive disease. The regimen was well
`tolerated, with fatigue, myalgias, constipation, and grade
`I neuropathy the most common complaints. The mean
`tolerated dose of thalidomide was 711 mg. Accrual was
`ongoing at the time of the report.
`
`Miscellaneous solid tumor malignancies
`The Food and Drug Administration summarized the
`results of a physician survey regarding 575 single-
`patient Investigative New Drug applications issued for
`thalidomide in 1997 and 1998 [74]. Of the 544 practi-
`tioners surveyed, 359 (66%) responded to yield data on
`480 patients whose age ranged from 11 to 90 years
`(median 52 years). The most common malignancies
`treated were those of the breast, central nervous system
`(GBM), prostate, skin (melanoma), colon, pancreas, and
`kidneys (renal cell carcinoma). Thalidomide was given
`in doses up to 2400 mg daily, with 400 mg the most
`common dose (33%), followed by 200 mg (26%), 800
`mg (18%), and 1200 mg (15%). Fifty-eight patients
`(31%) were prescribed thalidomide in combination with
`chemotherapy. Responses were observed in 36 patients
`(7.5%), 10 of those with combination therapy. Most
`patients (53%) discontinued therapy for progressive
`disease, whereas only 10% ceased thalidomide because
`of toxicity. The most common side effects reported
`were somnolence, constipation, rash, fatigue, and
`mental status changes. Overall it appeared that thalido-
`mide was well tolerated with no increased toxicities
`attributable to combination therapy.
`
`Clinical trials in hematologic malignancies
`Multiple myeloma, plasma cell leukemia,
`Waldenstrom’s macroglobulinemia
`The remarkable efficacy of single-agent thalidomide in
`84 patients with refractory or relapsed multiple
`myeloma (90% relapsed after high-dose chemotherapy)
`was reported recently by Singhal et al. [75••]. The initial
`dose was 200 mg daily with escalation by 200 mg every 2
`weeks to a maximum dose of 800 mg. The maximum
`tolerable dose was then continued until progressive
`disease. Median duration of therapy was 52 days (range,
`2 to 465) with 80% receiving at least 4 weeks of therapy.
`
`Reduction in paraprotein levels (for at least 6 weeks) was
`observed in 32% of the patients. Two patients achieved a
`complete response. Responses in paraprotein correlated
`with reduction in plasma cells and improvements in
`hemoglobin levels and were apparent within 2 months in
`78% of the patients. Mild to moderate constipation,
`weakness, fatigue, or somnolence occurred in one third of
`the patients; 11% discontinued therapy due to intoler-
`ance. Neurologic side effects included somnolence, dizzi-
`ness, confusion, tremors, incoordination, tingling, and
`numbness. Decreases in marrow marrow microvessel
`density were observed; no direct correlation with
`response could be demonstrated. An update by Barlogie
`summarizing the Arkansas experience with thalidomide
`in multiple myeloma in over 300 patients (single-agent
`and combination therapy) confirmed the activity of
`thalidomide monotherapy in an additional 85 patients
`(total 169 patients) [76]. Eighty-four percent of the
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`Current role of thalidomide in cancer treatment Thomas and Kantarjian 569
`
`patients had some reduction in paraproteinemia (36% had
`‡25% reduction, 28%
`‡ 50% reduction, 20% ‡75% reduc-
`tion). Complete response or near-complete response was
`achieved in 12% of these patients. The activity of thalido-
`mide in refractory or relapsed multiple myeloma has been
`confirmed by other investigators [77,78].
`
`Combination therapy strategies are being explored in
`multiple myeloma. Weber et al. [79] reported on the effi-
`cacy of thalidomide in combination with pulse dexam-
`ethasone. Initially, 44 patients with relapsed or refractory
`multiple myeloma were treated with single-agent thalido-
`mide with an overall response rate of 25%. Nonresponders
`were treated with dexamethasone 20 mg/m2 for 4 days—
`days 1 through 4, 9 through 12, and 17 through 20—along
`with their maximum tolerated thalidomide dose. Four of
`10 patients (40%) with primary resistant disease and 5 of
`16 patients (31%) with resistant relapse achieved a partial
`response. The combination of thalidomide with
`chemotherapy (DT-PACE [dexamethasone, cisplatin,
`doxorubicin, cyclophosphamide, and etoposide]) has also
`proved an effective strategy for plasma cell leukemia and
`fulminant multiple myeloma [80•].
`
`Preliminary results in Waldenstrom’s macroglobulinemia
`have been reported [81]. Eight patients were treated with
`thalidomide at doses from 200 mg up to 600 mg daily;
`seven were evaluable for response. Results indicated that
`three patients had at least 50% reduction of serum mono-
`clonal protein, one had stable disease, and three had
`progressive disease. Reductions in organomegaly and
`splenomegaly were noted in responders.
`
`Myelodysplasia, acute leukemias, and chronic
`leukemias
`Raza et al. [82] reported preliminary results of thalido-
`mide in early myelodysplasia in 61 patients treated with
`100 to 400 mg of thalidomide. Of these, 22 had refractory
`anemia (RA), 13 had refractory anemia with ringed sider-
`oblasts, 19 had refractory anemia with excess blasts, 4 had
`refractory anemia with excess blasts in transformation,
`and 3 had chronic myelomonocytic leukemia. Of the 25
`patients evaluable for response, 17 (68%) responded and
`8 (32%) failed. Trilineage (n=3), bilineage (n=4), and
`monolineage (n=10) responses were observed. Criteria for
`responses were not clearly defined. Transfusion indepen-
`dence was reported, and some responses were not mani-
`fested until after 3 months of therapy.
`
`At the MD Anderson Cancer Center, thalidomide has
`been studied in relapsed or refractory myelodysplasia
`(refractory anemia with excess blasts, refractory anemia
`with excess blasts in transformation), acute myelogenous
`leukemia, chronic myelomonocytic leukemia, and chronic
`myelogenous leukemia [83,84]. Of the 14 patients with
`relapsed or refractory acute myelogenous leukemia, one
`
`had significant hematologic improvement (clearance of
`peripheral blasts, reduction in marrow leukemia infiltrate,
`and recovery of neutrophil count). Of the 10 patients with
`advanced myelodysplasia, one patient achieved a
`complete response. Transient reductions in marrow
`leukemic infiltrate were observed in three patients. Two
`of six patients with chronic myelomonocytic leukemia
`had hematologic improvements with reductions in
`splenomegaly and resolution of leukemia cutis. Of six
`patients with chronic myelogenous leukemia, one late
`chronic phase patient had a partial cytogenetic response;
`another had a complete hematologic response. All
`patients with chronic myelogenous leukemia–chronic
`phase had a reduction in requirements of concomitant
`cytoreductive agents such as hydroxyurea and anagrelide.
`Patients with rapidly progressive disease prior to institu-
`tion of thalidomide were unlikely to complete therapy.
`Toxicities included dose-limiting fatigue (59%),
`reversible neurotoxicity (46%), constipation (30%), and
`rash or skin dryness (19%). One third of the patients
`developed infections, usually occurring in the nonrespon-
`ders with prolonged neutropenia because of their under-
`lying disease. Randomized trials of anthracycline and ara-
`C induction chemotherapy with or without thalidomide
`are being conducted in poor-risk patients with acute
`myelogenous leukemia [83].
`
`Philadelphia-negative myeloproliferative disorders and
`myelofibrosis
`Preliminary results of thalidomide (escalating from 200
`mg to 800 mg) in 18 patients with either Ph-negative
`myeloproliferative disorders or myelofibrosis (primary or
`secondary) were recently reported [85]. Of twelve evalu-
`able patients, 8 (67%) responded with hematologic
`improvements in at least one of the following: (1) reduc-
`tion of splenomegaly or hepatomegaly by 50% or greater,
`(2) achievement of transfusion-independence and/or
`increase in hemoglobin by at least 2 g/dL, or (3) normal-
`ization of platelet count (> 100 · 109/L) with prior throm-
`bopenia. Most responders (88%) had improvements in at
`least two of the categories. Responses were gradual;
`reduction in organomegaly could take 3 months to
`achieve. Those with proliferative disease had a reduced
`need for concomitant cytoreductive agents. Grade 1 to 2
`toxicities included fatigue (72%), constipation (44%), skin
`rash (39%), and reversible neurologic difficulties such as
`incoordination, paresthesias, and tremors (28%). Therapy
`was discontinued in 39% of the patients for either toxicity
`(n=3) or progression (n=4). Continued study is planned.
`
`Supportive care
`Chronic graft-versus-host disease after allogeneic bone
`marrow transplant
`To determine whether thalidomide prophylaxis could
`prevent GVHD after allogeneic bone marrow transplant,
`a double-blind, randomized trial was conducted in 59
`
`DR. REDDY’S LABS., INC. EX. 1005 PAGE 6
`
`

`

`570 Therapeutic modalities
`
`patients [86]. Thalidomide was given in a dose of 200
`mg twice daily starting day 80. Surprisingly, a higher
`rate of GVHD was observed with thalidomide compared
`with placebo (82% vs 54%, respectively, P = 0.06) in
`addition to a higher mortality (39% vs 8%, P = 0.0006).
`
`istration, and continued for 3 months or 6 months in
`patients with complete response or partial response,
`respectively. Fourteen patients (32%) had a complete
`response, 12 (27%) had a partial response, and 18 (41%)
`failed. Toxicities were reported to be minimal.
`
`Vogelsang et al. [87] reported on 23 patients with chronic
`GVHD and 21 with high-risk chronic GVHD (defined
`as two of three risk factors: evolution from acute GVHD,
`lichenoid skin or mucous-membrane changes, or hepatic
`dysfunction). Thalidomide was given at a dose that
`produced a plasma level of 5 µg/mL 2 hours after admin-
`
`Parker et al. [88] studied 80 patients with thalidomide for
`patients with either progressive GVHD despite at least 1
`month of cyclosporin and/or prednisone (n=31), stable but
`persistent GVHD after at least 2 months of therapy (n=40),
`GVHD responsive to therapy but flaring after taper
`(requiring at least 20 mg prednisone, n=7), or medical
`
`Table 2. Examples of current or planned clinical trials of thalidomide in oncology
`
`Disease type
`
`Solid tumors
`Gastrointestinal
`Colorectal
`Biliary carcinoma
`Hepatocellular
`
`Eligibility
`
`Regimen
`
`Resected disease after recurrence
`Variable
`Variable
`
`Adjuvant vs. placebo
`Thalidomide
`Thalidomide + capecitabine
`
`SCCa head and neck
`
`Recurrent or metastatic disease
`
`Thalidomide
`
`Site(s)
`
`NCI
`MDACC
`MDACC
`
`MDACC
`
`Nonsmall cell lung
`
`Stage III
`
`Carboplatin, paclitaxel, XRT ± thalidomide
`
`NCI
`
`Prostate adenocarcinoma
`Androgen-independent
`
`Androgen-dependent
`
`Metastatic
`Metastatic
`Stage IV nonmetastatic; hormonal ablation
`
`Weekly docetaxel ± thalidomide
`Paclitaxel + estramustine + thalidomide
`Thalidomide vs. placebo
`
`Locally advanced
`
`Surgical candidate
`
`Pre-op thalidomide followed by RRP
`
`Ovarian epithelial
`
`Stage IC-IV
`
`Carboplatin ± thalidomide
`
`Renal cell carcinoma
`
`IL-2