Pharmac. Ther. Vol. 52, pp. 35-84, 1991
`Printed in Great Britain. All rights reserved
`
`Specialist Subject Editor: E. HAMEL
`
`0163-7258/91 S0.00 + 0.50
`© 1992 Pergamon Press pie
`
`THE CLINICAL PHARMACOLOGY AND USE OF
`ANTIMICROTUBULE AGENTS IN CANCER
`CHEMOTHERAPEUTICS
`
`ERIC K. RoWINSKY and Ross C. DoNEHoWER
`Division of Pharmacology and Experimental Therapeutics, The Johns Hopkins Oncology Center,
`600 North Wolfe Street, Baltimore, Maryland 21205, U.S.A.
`
`Abstract-Although there has been a rapid expansion of the number of classes of compounds with
`antineoplastic activity, few have played a more vital role in the curative and palliative treatment of cancers
`than the antimicrotubule agents. Although the vinca alkaloids have been the only subclass of antimicro(cid:173)
`tubule agents that have had broad experimental and clinical applications in oncologic therapeutics over
`the last several decades, the taxanes, led by the prototypic agent taxol, are emerging as another very active
`class of antimicrotubule agents. After briefly reviewing the mechanisms of antineoplastic action and
`resistance, this article comprehensively reviews the clinical pharmacology, therapeutic applications, and
`clinical toxicities of selected antimicrotubule agents.
`
`CONTENTS
`
`I. Introduction
`2. Vinca Alkaloids
`2.1. General
`2.2. Mechanisms of action
`2.3. Mechanisms of resistance
`2.4. Vincristine
`2.4.1. Clinical pharmacology
`2.4.2. Dose and schedule
`2.4.3. Clinical applications
`2.4.4. Toxicities
`2.5. Vinblastine
`2.5.1 Clinical pharmacology
`2.5.2. Dose and schedule
`2.5.3. Clinical applications
`2.5.4. Toxicities
`2.6. Vindesine
`2.6.1. Clinical pharmacology
`2.6.2. Dose and schedule
`2.6.3. Clinical trials
`2.6.4. Toxicities
`2.7. Vinorelbine (Navelbine)
`2.7.1. Preclinical
`2.7.2. Clinical pharmacology
`2. 7.3. Dose and schedule
`2. 7.4. Clinical trials
`2.7.5. Toxicities
`3. Taxanes
`3.1. Taxol
`3.1.1. Mechanisms of action
`3.1.2. Preclinical antineoplastic activity
`3.1.3. Mechanisms of resistance
`3.1.4. Clinical pharmacology
`3.1.5. Dose and schedule
`3.1.6. Clinical trials
`
`36
`36
`36
`37
`37
`38
`38
`39
`40
`43
`46
`46
`46
`46
`49
`so
`50
`SI
`51
`S2
`53
`S3
`54
`54
`54
`55
`56
`56
`56
`57
`58
`58
`59
`59
`
`Abbreviations: ALL = acute lymphocytic leukemia; ANLL = acute nonlymphocytic leukemia; AUC = area under the
`time-versus-concentration curve; DNA = deoxyribose nucleic acid; GM-CFC "' granulocyte-macrophage colony-forming
`cell; GTP = guanosine
`reaction; MAPs = microtubule-associate proteins;
`triphosphate; HSR = hw,rsensitivity
`NCI = National Cancer Institute; NVB"' vinorelbine (Navelbine); SIADH"' syndrome of inappropriate secretion of
`antidiuretic hormone; q = half-life; VBL = vinblastine; VCR= vincristine; VDS = vindesine.
`
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`E. K. Row1NSKY and R. C. DoNEHOWEll
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`3.1.7. Future directions
`3.1.8. Toxicities
`3.2. Taxotere (RP 56976)
`.
`3.3. Novel antimicrotubule agents in preclinical development and conclusion
`References
`
`61
`62
`65
`65
`66
`
`I. INTRODUCTION
`
`Microtubules are among the most strategic sub(cid:173)
`cellular targets of anticancer chemotherapeutics. Like
`DNA, microtubules are ubiquitous to all cells.
`Although they are primarily recognized as being
`important in mitotic functions, microtubules also
`play critical roles in many interphase and mainten(cid:173)
`ance functions in cells such as maintenance of cell
`shape and scaffolding, intracellular transport, se(cid:173)
`cretion, and possible relay of signals between cell
`surface receptors and the nucleus (Edelman, 1976;
`Dustin, 1980; Crossin and Carney, 1981; Otto et al.,
`1981 ). Interestingly, antimicrotubule agents are all
`structurally complex natural products or semi(cid:173)
`synthetic compounds. They are among the most
`important of anticancer drugs and have significantly
`contributed to the therapy of most curable neoplasms
`such as Hodgkin's and non-Hodgkin's lymphomas,
`germ cell tumors and childhood leukemia (Loehrer et
`al., 1988b; DeVita et al., 1989; Hellman et al., 1989;
`Henderson et al., 1990). They are also extremely
`useful in the palliative treatment of many other
`cancers. Despite their promise, only a few antimicro(cid:173)
`tubule agents have been developed over the last
`decade and only two vinca alkaloids, vincristine and
`vinblastine, are officially approved for use and are
`widely available for oncologic therapy in North
`America and Europe. However, there has recently
`been a resurgence of interest in these compounds.
`This has led to the identification and development of
`several novel vinca alkaloids like vinorelbine (Navel(cid:173)
`bine), as well as new classes of antimicrotubule agents
`such as taxanes, dolostatins, and rhizoxin which
`possess novel mechanisms of cytotoxic action, unique
`antitumor spectra in vitro and/or in the clinic, and
`potentially improved therapeutic indices. This review
`will focus on those vinca alkaloids and taxanes in
`which ample clinical and preclinical experience exists.
`
`2. VINCA ALKALOIDS
`2. l. GENERAL
`
`The vinca alkaloids are natural or semisynthetic
`compounds which are present in minute quantities in
`the plant Catharanthus roseus G. Don (formerly
`Vinca rosea Linn.), commonly called the periwinkle.
`The compounds were originally screened by pharma(cid:173)
`ceutical chemists because of their use as hypoglycemic
`agents in several parts of the world. However, their
`hypoglycemic activity turned out to be of miniscule
`importance compared to their cytotoxic properties.
`
`Since the 1960s, only two vinca alkaloids, vincristine
`(VCR) and vinblastine (VBL), have been officially
`approved for the treatment of malignant disorders in
`the United States. Both VCR and VBL are large,
`dimeric compounds with similar but complex struc(cid:173)
`tures (Fig. 1). They are composed of an indole
`nucleus (the catharanthine portion) and a dihydroin(cid:173)
`dole nucleus (the vindoline portion). VCR and VBL
`are structurally identical with the exception of the
`substitutent attached to the nitrogen of the vindoline
`nucleus where VCR possesses a formyl group and
`VBL has a methyl group. However, VCR and VBL
`differ dramatically in their antitumor spectrum and
`clinical toxicities.
`A third vinca alkaloid analog, vindesine (VDS;
`desacetyl vinblastine carboxyamide), a synthetic de(cid:173)
`rivative and human metabolite of VBL, was intro(cid:173)
`duced into clinical trials in the 1970s. Although VDS
`has demonstrated activity against several malignan(cid:173)
`cies, most notably non-small cell lung cancer, it has
`only been available for investigational purposes and
`its future is uncertain. Other vinca alkaloids with
`antitumor activity include vinleurosine and vinro(cid:173)
`sidine; however, further clinical development of these
`
`F10.
`
`I. Structures of vincristine and vinblastine (A);
`vindesine (B).
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`Antimic:rotubule agents in canc:er chemotherapy
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`37
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`agents has been abandoned due to their exceptional
`toxicities (Creasey, 1975). Recently, semi-synthetic
`derivatives of VBL, specifically vinorelbine (Navel(cid:173)
`bine; NVB) and vinzolidine, have also entered clinical
`development and appear to be excitins for several
`reasons. These compounds, especially NVB, have
`demonstrated activity in neoplasms that are refrac(cid:173)
`tory to conventional agents. In addition, both NVB
`and vin.zolidine arc oral preparations in contrast to
`all other available vinca alkaloids which can only be
`administered by parenteral routes.
`The clinical pharmacology, toxicology, and clinical
`applications of the vinca alkaloids, VCR, VBL, VDS,
`and NVB, will be discussed in this section. Relevant
`aspects of vinzolidine's clinical pharmacology and
`early phase 1/11 trials have been published (Dudman
`et al., 1984; Kreis et al., 1986; Taylor et al., 1990;
`Dudman et al., 1991). Extensive reviews of the
`identification, isolation, and characterization of the
`vinca alkaloids arc also available (Johnson et al.,
`1963; Neuss et al., 1964; Creasy et al., 1975).
`
`The binding of the vinca alkaloids to tubulin, in
`tum, prevents the polymerization of these subunits
`into microtubules. The subunits then form highly
`ordered paracrystalline arrays of tubulin that arc
`of\cn termed 'paracrystals' (Bryan, 1972b; Manfredi
`and Horowitz, 1984a) which contain one mole
`of bound drug per mole of tubulin (Bensch and
`Malawiata, 1969). The net effects of these processes
`include the blockage of the polymerization of tubulin
`into microtubules which may eventually lead to
`the inhibition of vital cellular processes and cell
`death.
`Although moat evidence indicates that mitotic ar(cid:173)
`rest is the principal cytotoxic effect of the vinca
`alkaloids, there is also evidence suggesting that the
`lethal effects of these agents may be attributable
`in part to effects on other phases of the cell cycle.
`The vinca alkaloids appear to be cytotoxic to non(cid:173)
`proliferating cells in vitro and in vivo in both G 1 and
`S cell cycle phases (Madoc-Jones and Mauro, 1968;
`Strychmana et al., 1973; Rosner et al., 1975).
`
`2.2. MECHANISMS OF ACTION
`
`2.3. MECHANISMS OF REslSTANCB
`
`The vinca alkaloids induce cytotoxicity by direct
`interactions with tubulin which is the basic protein
`subunit of microtubules (Johnson et al., 1963; Olm(cid:173)
`stead and Borisy, 1973; Luduena et al., 1977; Dustin,
`1980). Other biochemical effects that have been re(cid:173)
`ported for the vinca alkaloids include: (a) compe(cid:173)
`tition for transport of amino acids into cells; (b)
`inhibition of purine biosynthesis; (c) inhibition of
`RNA, DNA, and protein synthesis; (d) disruption of
`lipid metabolism; (e) inhibition of glycolysis; (f)
`alterations in the release of antidiuretic hormone; (g)
`inhibition of release of histamine by mast cells and
`enhanced release of epinephrine; and (h) disruption in
`the integrity of the cell membrane and membrane
`functions. Comprehensive reviews on these various
`effects have been published (Creasy, 1975, Beck,
`1984).
`Microtubules are ubiquitous in eukaryotic cells
`and vital to the performance of many critical func(cid:173)
`tions including maintenance of cell shape, mitosis,
`meiosis, secretion, intracellular transport, and axonal
`transport. Many of the unique pharmacologic inter(cid:173)
`actions of drugs with microtubules are due to a
`dynamic equilibrium between microtubules and tubu(cid:173)
`lin dimers (Bryan, 1974; Dustin, 1980). Critical mess(cid:173)
`ages in the cell, including those related to cell cycle
`traverse, influence net microtubule polymerization.
`Vinca alkaloids exert their antimicrotubule effects by
`binding to a site on tubulin that is distinctly different
`from the binding sites of colchicine, podophyllotoxin,
`and taxol (Bryan, 1972a; Owellen et al., 1972; Wilson
`et al., 1975; Bhattacharyya and Wolff, 1976; Huang
`et al., 1985). The vinca alkaloids bind to specific sites
`on tubulin with a binding constant of 5.6 x 10-5 M
`(Na and Timashelf, 1986) and initiate a sequence
`of events that lead to disruption of microtubules.
`
`Resistance to the vinca alkaloids develops fairly
`rapidly in vitro in the presence of these agents. To
`date, two mechanisms of resistance have been de(cid:173)
`scribed. The first mechanism involves mutations in
`either the alpha or beta subunits of tubulin, leading
`to decreased vinca alkaloid binding (Cabral et al.,
`1986; Brewer and Warr, 1987). The second, more well
`characterized mechanism of resistance involves the
`general multi-drug resistance (mdr) phenotype that
`confers broad resistance to many unrelated classes of
`large, bulky natural product antineoplastic agents
`including the antitumor antibiotics, vinca alkaloids,
`colchicine, and taxol, and the epipodophyllotoxins
`(Juliano and Ling, 1976; Wilkoff and Dulmadge,
`1978; Beck et al., 1979; Riordan and Ling, 1979;
`Inaba et al., 1984; Cooter and Beck, 1984; Gupta,
`1985; Beck, 1987; Fojo et al., 1987a,b; Greenberger
`et al., 1987; Hamada et al., 1987; Choi et al., 1988;
`Moscow and Cowan, 1988). Cells with mdr pheno(cid:173)
`type possess an increased capacity to expel natural
`products by virtue of increased amounts of mem(cid:173)
`brane phosphoglycoproteins (P-glycoproteins) such
`as the P-170 membrane glycoprotein that functions as
`a drug efflux pump (Hamada et al., 1987). A substan(cid:173)
`tial number of unrelated compounds, including cal(cid:173)
`cium channel antagonists (Tsuruo, 1983; Brewer and
`Warr, 1987), phenothiazines and other 'calmodulin
`antagonists' (Tsuruo et al., 1983; Akiyama et al.,
`1986), antiarrhythmic agents such as quinidine and
`amiodarone (Tsuruo et al., 1984;
`Inaba and
`Earuyama, 1988), cephaloaporins (Gosland et al.,
`1989), and cyclosporin A (Slater et al., 1986) have
`been demonstrated to reverse drug resistance related
`to the mdr phenotype. Interestingly, the ability of the
`calcium channel blocker verapamil or cyclosporin A
`to reverse mdr resistance does not aooear to be
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`38
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`E. K. ROWINSKY and R. C. DoNEHOWER
`
`related to either calcium channel antagonism or
`immunomodulation since inactive isomers are con(cid:173)
`siderably more active in reversing this type of resist(cid:173)
`ance (Gruber et al., 1988; Twentyman, 1988).
`
`2.4. VINCRISTINE
`
`2.4. l. Clinical Pharmacology
`
`Relative to their broad clinical use, there are
`limited data available about the pharmacology of the
`vinca alkaloids in humans compared to other classes
`of antineoplastic agents. This has primarily been due
`to a lack of sensitive assays capable of measuring
`minute plasma concentrations which result from the
`wide distribution of mg doses of these agents. Early
`animal and human studies used radiolabeled vinca
`alkaloids, with further separation of parent drug and
`metabolites by high-pressure liquid chromatography
`(HPLC) (Castle et al., 1976; Bender et al., 1977; Culp
`et al., 1977; El Dareer et al., 1977; Owellen et al.,
`1977a,b; Jackson et al., 1978; Owellen and Hartke,
`1985). More recently, studies using sensitive radio(cid:173)
`immunoassays (RIA) and enzyme-linked immuno(cid:173)
`sorbent assay (ELISA) methods, which may be able
`to detect picomolar concentrations, have been able
`to overcome these problems (Nelson et al., 1979,
`1980; Hande et al., 1980; Jackson et al., 1980, 1981a;
`Sethi et al., 1981b; Sethi and Kimball, 1981; Nelson,
`1982; Hacker et al., 1984; Rahmani et al., 1985;
`Labinjoki et al., 1986; Ratain and Vogelzang, 1986,
`1987).
`Following standard doses of VCR administered as
`a bolus intravenous injection, peak plasma VCR
`levels approach 0.4 µM (Bender et al., 1977). VCR's
`plasma distribution is characterized by triexponential
`kinetics with a distribution (alpha) half-life (t½) ofless
`than 5 min owing to extensive and rapid tissue bind(cid:173)
`ing. Beta phase q values have been reported to range
`from 50 to 155 min and terminal tt values have varied
`even more profoundly, from 23 ± 17 to 85 ± 65 hr
`(Owellen et al., 1977b; Nelson et al., 1980; Jackson
`et al., 1981b; Sethi et al., 1981b; Nelson, 1982).
`Similar pharmacokinetic parameters have been noted
`in children (Sethi and Kimball, 1982). When the
`pharmacologic behavior of VCR has been studied
`using 3H-VCR coupled with purification by HPLC,
`alpha, beta, and terminal tt have been determined to
`be 0.85, 7.4, and 64min, respectively (Bender et al.,
`1977). In one comparative pharmacokinetic study of
`VCR, VBL, and VDS, VCR had the longest terminal
`t½, 85.0 ± 68.9 hr, versus 24.8 ± 7.5 hr for VBL and
`24.2 ± 10.4 hr for VDS (Nelson et al., 1980; Nelson,
`1982). The apparent volumes of distribution (Vd)
`have also been high ( Vdcentral of 0.328 ± 0.1061/kg
`and Vdgamma, 8.42 ± 3.17 I/kg for VCR), indicating
`extensive tissue binding (Nelson et al., 1980; Nelson,
`1982). In addition, marked differences in serum clear(cid:173)
`ance rates have been noted with VCR having the
`slowest clearance (0.106 ± 0.061 I/kg-hr), VBL the
`
`highest (0. 740 ± 0.317 1/kg-hr), and VOS an inter(cid:173)
`mediate value (0.252 ± 0.100 I/kg-hr) (Nelson et al.,
`1980; Nelson, 1982). It has been postulated that
`VCR's longer terminal half-life and lower plasma
`clearance rate compared to other vinca alkaloids
`might account for its greater neurotoxic effects
`(Nelson et al., 1980; Nelson 1982).
`There has been a considerable interest in the
`administration of VCR on protracted continuous
`infusion schedules based on the likelihood that these
`schedules more closely simulate optimal in vitro con(cid:173)
`ditions required for cytotoxicity compared to bolus
`schedules (Jackson, 1990). The cytotoxicity of the
`vinca alkaloids appears to be dependent not only on
`drug concentration, but on duration of treatment
`(Jackson and Bender, 1979; Hill and Whelan, 1980;
`Ferguson et al., 1984; Ludwig et al., 1984; Jackson,
`1990). VCR concentrations in the range of 100 nM are
`only briefly achieved after intravenous bolus injec(cid:173)
`tions and levels typically decline to less than IO nM by
`2 to 4 hr approaching I nM by 48 to 72 hr (Nelson
`et al., 1980; Jackson et al., 1981b). When compared
`to conditions required for cytotoxicity in vitro,
`though, treatment with 100 nM VCR for 3 hr is
`required to kill 50% ofLl210 murine or CEM human
`lymphoblastic leukeinias, whereas 6 to 12 hr of treat(cid:173)
`ment is required to achieve this degree of cytotoxicity
`at 10 nM and no lethal effects occurs with VCR
`concentrations below 2 nM (Jackson and Bender,
`1979). Interestingly, a 0.5 mg intravenous bolus injec(cid:173)
`tion of VCR followed by a continuous infusion at
`doses of 0.5 to 1.0 mg/m2/day for 5 consecutive days
`has typically produced steady-state VCR concen(cid:173)
`trations ranging from I nM to 10 nM and half-lives
`after discontinuation of the infusions have ranged
`from 10.5 hr (1.0 mg/m2)
`to 21.7 hr (0.5 mg/m2)
`(Jackson et al., 1981b). Although peak VCR plasma
`concentrations achieved with continuous infusions
`have generally been lower than levels achieved with
`bolus injections, continuous infusions have produced
`greater total drug exposure above a critical threshold
`concentration (Jackson et al., 1981b).
`The tissue distribution of VCR has been investi(cid:173)
`gated in several animal species. In the dog and the rat,
`the spleen appears to concentrate VCR to a greater
`extent than any other tissue (Owellen and Donigian,
`1972; Castle et al., 1976). In the monkey, the tissue
`with the highest VCR concentration has been the
`pancreas (El Dareer et al., 1977). Although VCR has
`been demonstrated to rapidly enter the central ner(cid:173)
`vous system of primates after intravenous injection,
`with VCR levels above 1 nM maintained in cere(cid:173)
`brospinal fluid for longer than 72 hr in one study (El
`Dareer et al., 1977), most investigations using rats,
`dogs, monkeys, and humans have indicated that VCR
`penetrates poorly through the blood-brain barrier
`(Castle et al., 1976; El Dareer et al., 1977; Jackson
`et al., 1980, 1981a). In humans, cerebrospinal fluid
`levels have been 20- to 30-fold lower than concurrent
`plasma concentrations and have never exceeded
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`Antimicrotubule agents in cancer chemotherapy
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`1.1 11M (Jackson et al., 1981a). Approximately 48% of
`VCR is bound to serum proteins (Bender et al., 1977).
`VCR also undergoes extensive binding to formed
`blood elements, especially platelets and red blood
`cells, which has led to the use of VCR-loaded platelets
`for treating disorders of platelet consumption such as
`idiopathic thrombocytopenia purpura (see Section
`2.4.3, Clinical Applications).
`VCR is primarily metabolized in the liver and
`excreted in the feces (Bender et al., 1977; Jackson et
`al., 1978). Within 72 hr after the administration of
`radiolabeled VCR, 12% of the total labeled material
`is excreted in the urine, 50% of which consists of
`metabolites; and approximately 70% is excreted in
`the feces, 40% of which consists of metabolites
`(Bender et al., 1977). VCR rapidly concentrates in the
`bile with an initial bile : plasma concentration ratio
`of 100: l which declines to 20: l at 72 hr post-injec(cid:173)
`tion (Jackson et al., 1978). Metabolic products ac(cid:173)
`cumulate rapidly in the bile such that only 46.5% of
`the total biliary product is the urunetabolized parent
`compound (Jackson et al., 1978). Many studies in
`both man (Bender et al., 1977, Jackson et al., 1978,
`Sethi et al., 198la,b) and animals (Castle et al., 1976,
`Houghton et al., 1984) have demonstrated that ap(cid:173)
`proximately 6 to 11 metabolites are produced. The
`structures of all these metabolites have not been
`definitely identified; however, analytical studies of
`the products formed by incubating VCR with dog
`bile have identified 4-deacety!VCR as a principal
`metabolite (Sethi and Thimmaiah, 198S; Thimmaiah
`and Sethi, 1990). In addition, 4-deacetylvincristine
`(Houghton et al., 1984) and N-deformy!VCR (Sethi
`et al., 1981a) have been isolated from human bile.
`4'-Deoxy-3'-hydroxyVCR and 3',4'-epoxyvincristine
`N-oxide have also been tentatively identified from
`in vitro incubation of VCR with bile from dogs
`(Thimmaiah and Sethi, 1990).
`
`2.4.2. Dose and Schedule
`
`VCR is routinely administered to children as a
`bolus intravenous injection at doses of 2.0 mg/m2
`weekly (Livingston and Carter, 1970). For adults, the
`conventional weekly dose is 1.4 mg/m2• A restriction
`of the absolute single dose of VCR to 2.0 mg/m2 has
`been adopted by many clinicians over the last several
`decades, presumptively based on reports of excep(cid:173)
`tional neurotoxicity at higher doses. Nevertheless, the
`origin of this restriction has recently been investi(cid:173)
`gated and felt to be largely based on empiricism
`(Sulkes and Collins, 1987). Available evidence
`suggests that this absolute restriction should be re(cid:173)
`considered (Sulkes and Collins, 1987). It has readily
`been appreciated that cumulative dose may be a more
`critical variable than single dose; however, wide
`interpatient variability exists and some patients are
`able to tolerate much higher VCR doses with little or
`no toxicity (Costa et al., 1962, Holland et al., 1973).
`This may be due to significant interindividual differ-
`
`ences in areas under the time-versus-concentration
`curves (AUC) which have been found to vary by as
`much as 11-fold (Desai et al., 1982; Van den Berg
`et al., 1982). However, this explanation does not
`justify capping VCR doses at 2.0 mg.
`It is commonly believed that subsequent doses of
`VCR should be adjusted based on toxicity; however,
`doses should not be reduced for a mild peripheral
`neuropathy, particularly if VCR is being used in
`a regimen with curative intent. Instead, VCR may
`have to be held for signs and symptoms indicative
`of more serious neurotoxicity,
`including severe
`symptomatic sensory changes, motor and/or cranial
`nerve deficits, and ileus, until these toxicities resolve.
`In clearly palliative settings, more liberal attitudes
`about dose reduction or lengthening dosing intervals
`may be justified for moderate neurotoxicity.
`Based on in vitro data indicating that the duration
`of VCR treatment above a critical threshold concen(cid:173)
`tration is an important determinant for cytotoxicity
`(Jackson and Bender, 1979), phase I/II trials in adults
`have evaluated prolonged continuous infusion sched(cid:173)
`ules (Jackson, 1990). Following a 0.5 mg/m2 intra(cid:173)
`venous injection of VCR, total daily VCR doses of
`0.2S to 0.50 mg/m2 as a continuous infusion for 5
`consecutive days have generally been well tolerated
`(Weber et al., 1979; Hopkins et al., 1983; Jackson
`et al., 1984b, 198Sa,b, 1986a; Pinkerton et al., 198S;
`Yau et al., 1985; Jackson, 1990). In pediatric patients,
`the continuous infusion of VCR for S consecutive
`days has permitted a twofold increase in the dose
`that could be safely administered without major
`toxicity compared to bolus administration schedules
`(Pinkerton et al., 1988).
`VCR is a potent vesicant and should not be
`administered intramuscularly, subcutaneously, or
`intraperitoneally. VCR has been accidentally admin(cid:173)
`istered into the cerebrospinal fluid resulting in rapid
`death (Slyter et al., 1980; Gaidys et al., 1983;
`Williams et al., 1983; Dyke, 1989). VCR (0.4 mg/day
`for 5 consecutive days) has also been administered by
`the hepatic intra-arterial route to 6 patients with
`metastatic liver disease (colon cancer (S); non(cid:173)
`Hodgkin's lymphoma (I)) (Jackson et al., 1984c). No
`objective responses were observed, and toxicities,
`including substantial neurotoxicity (confusion, weak(cid:173)
`ness, ileus, aphasia, postural hypotension, urinary
`incontinence), were very severe in some patients.
`Diarrhea, a rare toxicity of VCR on bolus schedules,
`was also observed in one third of the patients.
`Although it has not been carefully evaluated, an
`apparently major role of the liver in the disposition
`and metabolism of VCR (see Section 2.4.1., Clinical
`Pharmacology) indicates that dose modifications
`should be considered for patients with hepatic dys(cid:173)
`function (Van den Berg et al., 1982). To date, firm
`guidelines for dose modifications have not been es(cid:173)
`tablished; however, a 50% dose reduction is often
`recommended for patients with plasma in bilirubin
`concentrations above 3 mg/di.
`
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`40
`
`E. K. ROWINSKY and R. C. DONEHOWER
`
`2.4.3. Clinical Applications
`
`2.4.3.1. Leukemia. The recognition of VCR's signifi(cid:173)
`cant activity in acute lymphocytic leukemia (ALL) in
`the 1960s was one of the events that opened the door
`to the modern era of cancer chemotherapy. The
`combination of VCR and prednisone continues to be
`the cornerstone of remission induction treatment for
`ALL in children and adults. VCR can be given in
`optimal therapeutic doses to patients with ALL with
`only mild inhibition of granulopoiesis and thrombo(cid:173)
`poiesis. Although many trials of VCR administered
`on various schedules and doses for remission induc(cid:173)
`tion have been conducted, a single intravenous bolus
`dose of 2 mg/m2 weekly has become the consensus
`schedule of administration, with the qualification
`expressed by many that the total weekly dose not
`exceed 2 mg (see Section 2.4.2., Dose and Schedule).
`More frequent bolus injection (Carbone et al., 1963)
`and continuous infusion schedules have greater
`antitumoc activity in this disease (Greenberg and
`Holland, 1976), but the increased toxicity of these
`regimens has exceeded any increases in antitumor
`activity. The combination of VCR and prednisone as
`initial therapy is capable of including complete remis(cid:173)
`sions in over 85% of pediatric patients with ALL
`(Mauer and Simone, 1976; Aur et al., 1978) and
`between 36% and 67% in adults (Amadori et al.,
`1980; Willemze et al., 1980; Hess and Zirkle, 1982).
`However, the combination of VCR and prednisone
`is rarely used alone as initial induction therapy since
`the rate and duration of these responses have
`been demonstrated to be increased by the addition of
`other agents such as L-asparaginase and the anthracy(cid:173)
`clines (Hagbin et al., 1974; Ortega et al., 1977;
`Sachman-Muriel et al., 1978; Willemze et al., 1980;
`Gottlieb et al., 1984). On the other hand, VCR with
`or without corticosteroids, has yet to establish itself
`in remission maintenance therapy (Colebach et al.,
`1968), but may add to the maintenance afforded by
`antimetabolites when given intermittently (Chevalier
`and Glidewell, 1967; Jones et al., 1977; Leiken et al.,
`1968).
`Similar VCR-prednisone-based regimens have also
`been used to treat acute lymphoblastic crisis of
`chronic myelogenous leukemia (Rosenthal et al.,
`1977) and Philadelphia chromosome positive child(cid:173)
`hood ALL (Crist et al., 1990). VCR is not as active
`in the treatment of acute nonlymphocytic leukemia
`(ANLL), especially in adults. In early studies in
`ANLL, single agent therapy with VCR was associ(cid:173)
`ated with a 21 % complete response rate and a 51 %
`overall response rate, but the majority of the re(cid:173)
`sponses occurred in children (Livingston and Carter,
`1970).Although VCR has been incorporated into
`several induction and post-remission therapies for
`adult ANLL (Glucksberg et al., 1981; Yates et al.,
`1982; Weinstein et al., 1983; Sauter et al., 1984;
`Priester et al., 1987), the drug is not generally used in
`most conventional treatment regimens. VCR is more
`
`commonly employed, albeit infrequently, in child(cid:173)
`hood ANLL in combination with other agents,
`principally cytosine arabinoside, an anthracycline
`(usually daunorubicin), 6-thioguanine, and 5-azacy(cid:173)
`tidine.
`
`2.4.3.2. Hodgkin's lymphoma. VCR has also had a
`substantial impact on the curative treatment of both
`Hodgkin's and non-Hodgkin's lymphomas in adults
`and children. In early studies of VCR used as a single
`agent in all forms of lymphoma, responses were
`observed in 50% to 60% of patients (Livingston and
`Carter, 1970). As with the leukemias, however, the
`incidences of complete and durable responses have
`been substantially lower with single agent therapy
`(Costa et al., 1962; Bohannon et al., 1963; Carbone
`et al., 1963; Gailani, 1963; Shaw et al., 1964; Selawry
`et al., 1968; Livingston and Carter, 1970). In 1967,
`however, a report on the use of VCR (Oncovin) in
`combination with nitrogen mustard, procarbazine,
`and prednisone (MOPP) demonstrated that combi(cid:173)
`nation chemotherapy could produce a high rate
`(80%) of complete remissions in advanced Hodgkin's
`disease (a four-fold increase over the best results
`achieved with single agents), and remissions were
`durable (DeVita and Serpick, 1967; DeVita et al.,
`1970; Lowenbraun et al., 1970; DeVita, 1981). Each
`agent in MOPP was selected based on single agent
`antitumor activity and to minimize potential overlap(cid:173)
`ping toxicities. Although VBL may have been the
`favored vinca alkaloid in lymphomas at that time,
`VCR was selected because it was associated with less
`myelosuppression. A 20 year follow-up report of the
`original series of patients treated with MOPP re(cid:173)
`vealed that the original study population was even
`slanted towards poorer prognostic variables (Longo
`et al., 1986). Of those patients who achieved a
`complete remission, 64% and 54% have remained
`alive and continuously disease free, respectively, after
`20 years. In the original MOPP regimen, VCR was
`administered as a 1.4 mg/m2
`intravenous bolus
`weekly for two consecutive weeks every 28 days
`without dose capping at 2.0 mgs. A sliding scale
`based on neurotoxic symptoms was used to adjust
`VCR dose. Despite considerable acute peripheral
`neurotoxicity observed in the original study, toxicity
`slowly resolved
`in most patients after
`therapy
`was discontinued and no patients were permanently
`paralyzed.
`In the decade following the success of MOPP,
`many other regimens were designed to reduce the
`side-effects of MOPP by substituting or adding ad(cid:173)
`ditional drugs and to improve on MOPP's antitumor
`activity by either increasing dose intensity and/or
`alternating MOPP with other non-cross resistant
`regimens. Almost all of these modified regimens
`included a vinca alkaloid, either VCR or VBL. Of
`those modified regimens containing VCR, none have
`consistently demonstrated superiority to MOPP.
`Modified MOPP alternatives containing VCR that
`
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`Antimicrotubule agents in cancer chemotherapy
`
`41
`
`have been evaluated in Hodgkin's disease include
`COPP (cyclophosphamide, VCR, procarbazine and
`prednisone) (Cooper et al., 1984; Propert et al., 1986);
`LOPP (chlorambucil, VCR, procarbazine and pred(cid:173)
`nisone) (Hancock, 1986); and 8-MOPP (bleomycin
`added to MOPP) (Coltman et al., 1985). Non-cross
`resistant
`alternative
`regimens
`have
`included
`MOPP-ABVD (MOPP alternating with ABVD
`(Adriamycin, bleomycin, VBL and dacarbazine)
`(Santoro et al., 1982a; Bonadonna et al., 1986; Canel(cid:173)
`los et al., 1988); MOP-BAP (nitrogen mustard, VCR,
`bleomycin, adriamycin, prednisone) (Jones et al.,
`1983); and MOPP-ABV, a MOPP-ABVD variant
`in which dacarbazine is omitted and all the agents
`are given in the first 8 days rather than alternating on
`a monthly basis (Klimo and Connors, 1985a).
`
`2.4.3.3