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`Review
`
`Annals of Oncology 8: 15-25, 1997.
`© 1997 Kluwer Academic Publishers Printed in the Netherlands.
`
`Dose intensity for bolus versus infusion chemotherapy administration:
`Review of the literature for 27 anti-neoplastic agents
`
`J. Lokich & N. Anderson
`Cancer Center of Boston in Boston, Plymouth and Framingham, MA, USA
`
`Summary
`
`Problem: The dose intensity (DI) and the maximum tolerated
`dose (MID) of anti-neoplastic agents is assumed to be a critical
`factor for achieving optimal therapeutic benefit. Each of these
`factors may be influenced by the schedule of drug administra-
`tion, specifically infusional or bolus delivery.
`Objective: To review the literature for selected antineoplastic
`drugs to analyze the relative DI and MTD for bolus vs. infu-
`sional administration schedules.
`Methods: Clinical reports of bolus and infusional delivery of
`chemotherapeutic drugs in the categories of antimetabolites;
`alkylating agents; antibiotics; plant alkaloids and platinum
`analogues were collected focusing on phase I studies establish-
`ing the MTD per cycle and the DI. Infusional schedules were
`defined as continuous parenteral administration for more than
`24 hours or, in some instances, daily bolus dosing for one hour
`for 3 to 5 days. Bolus schedules were defined as administration
`over minutes up to 24 hours and also included daily dosing in
`some cases.
`Results: For antimetabolites, the infusional schedule gener-
`ally decreases the MTD and DI relative to bolus administration
`but for 5-FU, the MTD and DI both increase. For alkylating
`agents and the platinum analogues, the MTD and DI for bolus
`and infusional delivery are generally comparable; but infusional
`
`administration results in a slightly increased MTD for thiotepa
`and for ifosfamide, the MTD is increased depending upon the
`duration of the infusion. For the antibiotics and the plant
`alkaloids, the MTD and DI of infusional administration is
`variable related to the specific agent and the infusion duration
`and may be increased, decreased or comparable to the MTD of
`bolus schedules.
`Conclusions: The MTD and DI for most cytotoxic agents
`administered by bolus versus infusional schedules is unpredict-
`able and variable and is influenced by the infusion duration and
`the interval between treatment cycles (for example three versus
`four week intervals). The MTD and DI increase substantially
`with infusional delivery for thiotepa, 5-FU and VM26 (the latter
`in leukemia specifically) and decrease substantially for the anti-
`metabolites FUDR, ara-C, methotrexate and 6MP. For most
`other agents and in all four drug categories, the MTD and DI
`are relatively comparable although for ifosfamide and topote-
`can, the duration of infusion determines whether the MTD and
`DI increases, decreases or stays the same relative to bolus
`administration. The use of cytokines may substantially change
`the MTD and DI especially for bolus administration since dose
`limiting toxicity is hematologic for many agents.
`
`Key words: bolus chemotherapy, dose intensity, infusion
`
`Introduction
`
`Some anti-neoplastic agents are administered as a con-
`tinuous 24-hour infusion for five or more days routinely,
`such as 5-fluorouracil and cladrabine. Some agents, for
`example, fludarabine and etoposide are administered as a
`daily bolus for three to five days emulating an infusional
`schedule and may be considered as a type of infusion in
`spite of bolus administration because of the constancy of
`delivery. The rationale for infusional administration for
`chemotherapeutic agents is generally based upon observ-
`ing schedule dependency in experimental systems and
`drug pharmacology in which a short plasma half-life
`following bolus administration would limit tumor cell
`exposure (Table 1) [1]. Furthermore, the infusion schedule
`may mitigate the acute and chronic toxicities commonly
`associated with high peak levels.
`Infusional schedules employ various durations of
`administration including 24-hour infusion repeated at
`
`weekly or longer intervals; 96-120-hour infusions; 7- or
`14-day infusions; and finally the protracted infusion for
`weeks or months. The selection of a duration of infusion
`is often arbitrary or based on achieving specific objectives
`such as decreasing allergic, gastrointestinal or other ad-
`verse effects. The dose intensity (DI) and the maximum
`tolerated dose (MTD) for infusional schedules may be
`different from those achieved with bolus administration
`and as such may influence the clinical effectiveness of the
`therapy.
`We undertook to review the literature with regard to
`the phase I and/or phase II studies for selected antineo-
`plastic agents in order to compare the MTD and DI of
`bolus and infusional administration. We define bolus
`administration as a less than 24-hour administration
`period and infusional administration as a 24-hour or
`more continuous administration. Phase I and/or phase
`II studies of single agent administration without the
`planned use of cytokines were part of the criteria for
`
`AVENTIS EXHIBIT 2070
`Mylan v. Aventis, IPR2016-00712
`
`

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`16
`
`Table 1. Phannacologic half of selected antineoplastic agents.
`
`5-Fluorouracil (5-FU)
`
`The fluoropyrimidines (5-FU and 5-FUDR) represent
`classic, if not quintessential, anti-metabolites commonly
`administered utilizing an infusion schedule. For 5-FU,
`short-term infusions for 24 or 48 hours on a weekly basis
`as well as 5-day, 7-day, 14-day and protracted infusion
`schedules have been reported [2-6]. The most common
`bolus schedule is daily x 5 repeated at 5-week intervals
`with an MTD of 500 mg/m2/d or 2500 mg/m2/cycle. Dose
`limiting toxicity (DLT) is leukopenia. For
`infusional
`5-FU, the MTD for a 5-day infusion is 5 g/m2 and for the
`protracted infusion for 28 days 8.4 g/m2 [7]. The pro-
`tracted infusion dose limiting toxicity was established in
`a phase I trial in which the DLT was manifest as hand-
`foot syndrome in 25% to 30% of patients in those receiv-
`ing the infusion at a rate of 300 mg/m2/day for more than
`30 days. For this fluoropyrimidine, therefore, the infu-
`sional schedule results in a substantial increase in the dose
`intensity by a factor of 4 and the dose limiting toxicity is
`substantially changed from bone marrow suppression to
`stomatitis or hand-foot syndrome most probably related
`to differences in phannacologic distribution of the drug,
`sparing the bone marrow.
`
`Floxuridine (5-FUDR)
`
`Floxuridine is most commonly applied in the setting of
`hepatic arterial infusion. Studies of systemic bolus versus
`infusional administration for five days revealed a marked
`decrease in the MTD with infusional delivery [8]. Pro-
`tracted infusions of 5-FUDR for 14 days demonstrated
`that the MTD was only 0.15 mg/kg/day which translated
`to a cumulative dose of 777 mg/m2 for a cycle [9]. In
`contrast to 5-FU, the dose intensity for infusional deliv-
`ery of 5-FUDR decreases by a factor of greater than 7
`relative to bolus administration but dose limiting toxicity
`is similar to that on the bolus schedule.
`
`Cytosine arabinoside
`
`This agent is virtually never employed in a bolus schedule
`and even the high dose ara-C bolus regimens utilize an
`every 12 hours delivery for six or more doses emulating
`an infusion. Nonetheless, a phase I trial by Frei et al.
`demonstrated a substantial decrease in the MTD for
`ara-C administered on the infusional schedule compared
`to bolus delivery [10]. Dose limiting toxicity is non
`hematologic since bone marrow suppression is the ex-
`pected therapeutic effect and is manifest as neurologic
`toxicity particularly cerebellar dysfunction but hepatic
`toxicity and dermatologic toxicity can also be observed.
`Dose intensity is decreased by a factor of 10 or more in
`the transition from the high dose 'bolus' regimens to the
`7-day infusional regimen but the comparison is com-
`plicated by the fact that the bolus schedule is tantamount
`to infusional administration and a case may be made for
`the high dose regimen simply being a special type of
`infusion.
`
`Drug class
`
`TA (hours)
`
`0.16
`2-4
`10
`
`14
`
`-20
`
`30
`
`.83 (Gamma)
`
`4-6.5
`15
`
`20
`
`.75
`1.6
`1.3-1.7 (Beta)
`1 (Beta)
`
`3.3
`18
`23-42
`36
`l-A (Beta)
`
`5.8 (Beta)
`6-8 (Terminal)
`8 (Terminal)
`2.6 (Mean)
`23-85 (Gamma)
`20-64 (Gamma)
`18-49 (Gamma)
`20-24 (Gamma)
`
`Anti-metabolites
`5-Fluorouracil
`Methotrexate
`Fludarabine
`Ara-C
`2 CD A
`Hydroxyurea
`6Mercaptopurine
`Alkylating agents and platinums
`Cyclophosphamide
`Ifosfamide
`Melphalan
`Mitomycin C
`Thiotepa
`Carboplatin
`Cisplatin
`Antibiotics
`Doxombicin
`Epirubicin
`Mitoxantrone
`Actinomycin
`Bleomycin
`Plant alkaloids
`Paclitaxel
`Etoposide
`Teniposide
`Topotecan
`Vincristine
`Vinblastine
`Vinorelbine
`Vindesine
`
`Modified from Vogelzang, J Clin Oncol 1984; 2: 1289 [1].
`Supplemented and updated from Chabner BA and Longo DL, Cancer
`Chemotherapy and Biotherapy, 2nd Edition 1995, Lippencott-Raven
`Philadelphia, New York.
`
`selection of the drugs to be studied. l\venty-seven agents
`were identified for review within four categories, including
`antimetabolites, alkylating agents, antitumor antibiotics
`and plant alkaloids.
`
`Antimetabolites
`
`Antimetabolites as a group are cycle specific agents and
`schedule dependent for the most part in experimental
`systems and in clinical usage. Some of the agents are
`provided in an oral formulation and routinely are ad-
`ministered on a schedule emulating parenteral infusion,
`for example 6mercaptopurine and hydroxyurea. Five of
`the agents (ara-C, hydroxyurea, 6MP, fludarabine and
`cladribine) have been employed almost exclusively in the
`treatment of hematologic malignancies with dose limit-
`ing toxicity manifest as bone marrow suppression but the
`therapeutic goal within the context of treating these
`malignancies is also marrow suppression. For hydrox-
`yurea and cladaribine, no bolus dosing studies have been
`reported (Table 2).
`
`

`
`Table 2. Antimetabolites: Comparison of maximum tolerated dose (MTD) per treatment cycle and dose intensity (DI) for bolus versus infusion
`administration.
`
`17
`
`Bolus
`
`Infusion
`
`Reference
`
`MTDmg/m2
`
`DI mg/m2/wk
`
`MTD mg/m2
`
`DI mg/m2/wk
`
`Agent
`
`5-FU'
`
`2000-2500
`
`500-525
`
`5-FUdRb
`Ara-Cc
`Hydroxyurea (HU)d
`6Mercaptopurinee
`Fludarabine
`Cladribine
`Methotrexatef
`
`5500
`36000
`ND
`2400
`160
`107.5
`200
`
`1387.5
`9000
`ND
`800
`40
`28
`200
`
`50001
`84002
`111
`2800
`10000
`210-350
`110 to 125
`49
`21
`
`1250
`2100
`194.2
`700
`3333
`52.5-87.5
`27.5-31
`12
`5.25
`
`2-6
`
`8,9
`10
`11-13
`14-17
`18,19
`20
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`° Weekly bolus (500 mg/m2) or daily x 5 (525 mg/m2) versus 5 day infusion1 or protracted 28-day infusion2 (2.1 g).
`b Mg/kg transposed to mg/m2 using multiple factor of 37.
`c Bolus 3 g/m2 over 3 hours q 12 h x 12 doses versus infusion x 7 days at 200 to 400 mg/m2/d.
`d Infusion for 120 hours; No data for parenteral bolus.
`' Bolus = 24-hour infusion in AML or 48-hour infusion in solid tumors.
`r Infusion for 28 days. Bolus without leucovorin rescue.
`Abbreviation: ND - no data.
`
`Hydroxyurea (HU)
`
`A direct comparison of bolus and infusional administra-
`tion of hydroxyurea has not been reported in part because
`the parenteral formulation has not yet been approved by
`the FDA but also because bolus administration is not a
`common usage. Early studies of short term infusion by
`Belt et al. [11] and Blumenreich et al. [12] of 72-hour
`or longer duration infusions have been reported and
`Doroshow [13] has completed a phase I study of 120-
`hour infusional HU with dose limiting toxicity manifest
`as bone marrow suppression. For the 72-hour schedule,
`the MTD was 324 g/m2 (oral) or 778 g/m2 (intravenous)
`with DLT manifest as leukopenia. For the Blumenreich
`study, the study objective was to determine the maximum
`duration of infusion at different doses and at 500 mg/m2/
`day HU could be administered indefinitely similar to the
`experience with protracted 5-FU infusion. However, ac-
`cording to Doroshow, for the 5-day infusion the maxi-
`mum cumulative dose was 12.5 g/m2 with DLT of skin
`rash and neutropenia and the DI, which may require
`cytokine support, is 3.25 g/m2/week. Therefore, prolong-
`ing the infusion from 72 to 120 hours apparently results in
`a substantial decrease in MTD but low daily dose rates
`can permit extension of the infusion duration.
`
`6Mercaptopurine (6MP)
`
`Like hydroxyurea, 6MP has been employed predomi-
`nantly in hematologic malignancies, with an oral formu-
`lation mimicking infusion, and the FDA has not yet
`approved the use of the parenteral form of the drug.
`Nonetheless, short term infusion studies have been re-
`ported, although for relatively short periods less than 48
`hours [14, 15], and for longer periods in solid tumors in
`relatively older trials [16]. Thus, the bolus doses defined in
`Table 2 for 6MP actually represent 24- or 48-hour infu-
`
`sions and the data for more protracted infusions are
`limited to one study in which 6MP was administered for
`up to 10 days in an experimental design that provides
`inconclusive data. In the latter study, patients received up
`to 35 mg/m2/d for 6 to 10 days by continuous infusion. A
`minor proportion of patients achieved DLT with leuko-
`penia and it may well be that substantially higher doses
`are achievable. These data suggest that the
`infusion
`schedule decreases the MTD and DI for 6MP but a
`more modern and sophisticated phase I trial for infusion
`is necessary. Such a phase I study with a classical exper-
`imental design is ongoing utilizing the parenteral formu-
`lation with a 14-day infusion duration. A preliminary
`analysis indicates that the MTD for a 14-day infusion is
`420 mg/m2 with a dose intensity of 105 mg/m2/week
`[17]. The dose limiting toxicity is neutropenia and hyper-
`bilirubinemia.
`
`Fludarabine
`
`Fludarabine is a schedule dependent antimetabolite in
`experimental systems and is employed as a therapy for
`low grade lymphomas with the dose limiting toxicity and
`therapeutic effect being bone marrow suppression. Phase
`I trials have utilized a 48-hour infusion schedule [18] or a
`daily x five schedule emulating an infusion [19]. The total
`cumulative dose per cycle of approximately 125 mg/m
`for the daily x 5 bolus can be compared to 110 mg/m2 for
`the loading dose - 2-day infusion schedule and the single
`bolus dose schedule which is 160 mg/m2. The MTD for
`the three schedules increases as the duration of admin-
`istration decreases from five to three to one day.
`
`Cladribine (2CDA)
`
`2-Chlorodeoxyadenosine is an antipurine which is ad-
`ministered as a continuous infusion for seven days as
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`
`Table 3. Alkylating agents and platinum analogues: Comparison of MTD per treatment cycle and DI for bolus versus infusional administration.
`
`Agent
`
`Bolus
`
`Infusion
`
`Reference
`
`MTD mg/m2
`
`DI mg/m2/wk
`
`MTD mg/m2
`
`DI mg/m2/wk
`
`Cyclophosphamide'
`Ifosfamide
`
`Thiotepab
`
`Cisplatinc
`
`Carboplatind
`
`2000
`7500
`
`14
`
`100
`200
`400-600
`
`666
`1875
`
`4.1
`
`25
`50
`80-120
`
`2000
`70002
`180003
`60'
`1122
`100
`
`375'
`3502
`
`666
`1750
`4500
`15
`28
`25
`
`75
`70
`
`22-25
`26-29
`
`30
`
`31
`
`32-34
`
`* Infusion 120 hours or 28 days.
`b Infusion 120 hours or 28 days.
`c Infusion 5 days.
`d Use of dosing formula based on creatinine clearance and the delayed asymetric leukopenia-thrombocytopenia complicate the DI calculation for
`both bolus and infusional administration.
`1 5-Day infusion.
`2 14-Day infusion.
`3 4-Day infusion.
`
`a standard schedule based upon experimental in vitro
`studies which demonstrate schedule dependency and a
`pharmacology profile with a short plasma half-life of only
`6.7 hours. Bolus schedules have been explored using a
`daily x 5 schedule [20]. Dose limiting toxicity for the
`infusion schedule is bone marrow suppression which is
`also the intended therapeutic effect but neurologic effects
`are observed as well. In contrast, daily bolus dosing
`obviates or minimizes the neurologic effects. The MTD
`for a 7-day infusion is 49 mg/m2 compared to 107.5 mg/m2
`for the 5-day bolus schedule.
`
`Methotrexate
`The antifolate compound methotrexate represents an anti-
`metabolite which is most commonly employed in breast
`cancer as part of the CMF regimen at a dose of 40 to 60
`mg/m2 parenteral bolus twice monthly or in the context
`of lymphomas or head and neck cancer tumors utilizing
`'intermediate' or high dose regimens weekly. The MTD
`indicated in Table 2 for the bolus schedule represents
`the 'intermediate' high dose methotrexate regimen which
`may be administered without the need for leucovorin
`rescue and can be delivered on a weekly basis. Dose
`limiting toxicity is stomatitis. For the infusion regimen, a
`phase I trial of protracted 14-day infusion of methotrexate
`resulted in dose limiting toxicity of stomatitis and throm-
`bocytopenia [21]. The dose intensity is reduced by a factor
`of almost 40 on the infusion schedule compared to the
`bolus schedule or even higher if the high methotrexate
`doses administered with leucovorin rescue are considered.
`
`Alkylating agents and platinums
`
`The alkylating agents are a diverse group of compounds
`only three of which are parenterally formulated and
`stable enough to be administered as an infusion (cyclo-
`
`phosphamide, ifosfamide and thiotepa) (Table 3). Mel-
`phalan is stable for only three hours and is therefore not
`practical for ambulatory infusion and the nitrosoureas
`are also unstable with the exception of streptozocin.
`There are also oral formulations of some of the alkylat-
`ing agents (melphalan, chlorambucil, cyclophosphamide)
`which are often utilized in a schedule which emulates
`parenteral infusional delivery. The two major platinum
`analogues, cisplatin and carboplatin, are considered non
`classical alkylating agents and although both have been
`administered on an infusional schedule, the current ra-
`tionale for infusional administration based upon pharma-
`cology or an improved therapeutic index has not been
`established for either of these agents. In fact, although
`some experimental data suggests that for some alkylating
`agents an infusional schedule may be advantageous, there
`is no clinical data supporting an advantage for an infu-
`sional schedule and there have been no randomized
`comparative trials of infusional versus bolus administra-
`tion of single agents. Dose limiting toxicity for all the
`alkylating agents as well as carboplatin is bone marrow
`suppression and for cisplatin is neurologic and renal
`complications.
`
`Cyclophosphamide
`
`Infusional cyclophosphamide has been studied in 72-hour
`[22], 120-hour [23, 24] and protracted infusion for 14 days
`or more [25]. The maximum tolerated dose for all of these
`durations of infusion was approximately 2000 mg/m2
`with dose limiting toxicity manifest as leukopenia with
`minimal thrombocytopenia. In the two studies address-
`ing the five day infusion, one was carried out in refractory
`leukemia and one in solid tumors the latter focusing on
`pharmacology studies. The study in solid tumors demon-
`strated that the area under the curve (AUC) for phos-
`pheramide mustard is three times higher with the infu-
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`19
`
`sional administration of cyclophosphamide compared to
`bolus dosing. Another pharmacodynamic aspect of this
`agent is the requirement for microsomal activation which
`may obscure possible differences between infusion and
`bolus administration.
`It is evident from these studies that for cyclophospha-
`mide the dose intensity is comparable whether one uses
`an infusional delivery or bolus administration.
`
`lfosfamide
`
`The analogue of cyclophosphamide is most commonly
`administered as a daily bolus or as a continuous infusion
`over five days. In order to obviate the problem of hemor-
`rhagic cystitis with bolus dosing, a common administra-
`tion schedule is as a fractionated bolus daily for five days
`with concomitant Mesna administration. In a phase I
`study of 4-day continuous infusion ifosfamide along with
`Mesna uroprotection, dose escalation to a maximum dose
`of 18 g/m2 was possible and dose limiting toxicity was
`renal insufficiency and central nervous system toxicity
`[26]. For 10-day infusion periods, the maximum cumula-
`tive dose decreased to 12 to 13 g/m2 [27] and in a phase I
`trial of protracted infusion of ifosfamide for 14 days, the
`MTD was 7 g/m2 per cycle [28]. Therefore, the MTD and
`DI for infusional ifosfamide may be increased or de-
`creased relative to bolus delivery depending on the dura-
`tion of infusion. Although phase III trials of infusional
`versus bolus ifosfamide have not been carried out, one
`study did analyze a sequential group of patients receiv-
`ing ifosfamide as a bolus and subsequent entries as an
`infusion in conjunction with a combination chemother-
`apy regimen for metastatic sarcoma and there was a
`higher response rate in the group receiving bolus ifosfa-
`mide [29].
`
`Thiotepa
`
`The alkylating agent thiotepa is uncommonly used but
`has been employed as an alkylating agent in the treatment
`of Hodgkin's disease replacing nitrogen mustard because
`of the absence of gastrointestinal toxicity and it has also
`been used as part of a combination chemotherapy regi-
`men for breast cancer. Dose limiting toxicity for bolus
`administration is bone marrow suppression as it is for
`infusional delivery. Only a single phase I trial has been
`carried out for thiotepa using a continuous
`infusion
`schedule. The cumulative dose for a 5-day infusion is 60
`mg/m2 and for the more protracted infusion of 28 days,
`the cumulative dose is almost doubled to 112 mg/m2 [30].
`Therefore, for this particular alkylating agent, the MTD
`and dose intensity is increased by a factor of 4 to 7 on the
`infusion schedule compared to the bolus schedule.
`
`Platinum analogues
`
`The two major platinum analogues are cisplatin and
`carboplatin, each of which demonstrate a different dose
`limiting toxicity and toxicity which is generally not altered
`
`with the use of the infusional schedule. For cisplatin, the
`continuous infusion schedule was introduced as a poten-
`tial option for decreasing extra-medullary toxicity such
`as renal, neurologic toxicity and gastrointestinal toxicity
`[31]. However, the same pattern and frequency of toxic-
`ities are observed on the infusional schedule as the bolus
`schedule and the doses achieved per cycle are similar
`with a comparable dose intensity.
`For carboplatin, the dose limiting toxicity is bone
`marrow suppression with markedly reduced gastrointes-
`tinal and renal toxicity compared to cisplatin. Bolus
`dosing is commonly guided by the Calvert formula and
`the MTD for bolus scheduling varies between 400 and
`600 mg/m2 and could be higher. The infusional schedule
`has been explored in a phase I study with a decrease in
`the cumulative dose per cycle and a modest decrease in
`the dose intensity [32]. Other studies of continuous infu-
`sion carboplatin have suggested that the dose intensity
`may in fact be increased. For example, in the study by
`Smit et al. [33], the cumulative dose for a 21-day infusion
`was 630 mg/m2. However, because of the delayed pattern
`of hematologic toxicity associated with carboplatin, this
`infusional schedule could only be administered at 6-week
`intervals. Thus, the dose intensity is calculated to be
`approximately 105 mg/m2 which is comparable or slightly
`less than that achieved with bolus administration depend-
`ing upon the Calvert formula calculation.
`The trials of continuous infusion carboplatin in refrac-
`tory leukemia utilized a cumulative dose of 1500 mg/m2
`per cycle [34]. Although demonstrating activity in acute
`leukemia, the precise calculation of the dose intensity for
`carboplatin is complicated by the pattern of delayed and
`protracted myelosuppression. Nonetheless, assuming an
`interval of up to 6 or 7 weeks between cycles of treatment,
`the potential dose intensity nearly doubles to 200 mg/m2
`per week with infusional delivery compared to bolus
`administration at least in the trials involving carboplatin
`for leukemia.
`
`Antibiotics and anthracenediones
`
`A comprehensive review of infusion administration of
`antineoplastic antibiotics has been previously published
`[35]. The antibiotic agents that have been studied using an
`infusion schedule include the anthracycline analogues
`doxorubicin and epirubicin and the, anthracendione,
`mitoxantrone and three unrelated antibiotics mitomycin
`C, actimycin D and bleomycin (Table 4).
`Doxorubicin was the earliest anthracycline to be intro-
`duced and is the most commonly employed agent in this
`category in the United States while epirubicin is popular
`in Europe. The acute dose limiting toxicity is bone mar-
`row suppression and stomatitis and the cumulative dose
`for both analogues is limited by cardiac effects and
`particularly cardiomyopathy. Short term and protracted
`infusion schedules were actually developed in order to
`obviate the problem of cumulative cardiac toxicity and
`dose rate limiting toxicity for both the acute and chronic
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`
`Table 4. Antibiotics: Comparison of MTD per treatment cycle and DI for botus versus infusional administration.
`
`Agent
`
`Bolus
`
`Infusion
`
`Reference
`
`MTD mg/m2
`
`DI mg/m2/wk
`
`MTD mg/m2
`
`DI mg/m2/wk
`
`Doxorubicin*
`
`Epirubicinb
`Mitoxantrone0
`Mitomycin C
`Actinomycin Db
`Bleomycin
`
`75
`
`120
`14
`20
`1.5
`20-60
`
`25
`
`40
`4.6
`3.6
`0.3
`10-15
`
`* Infusion durations 96 hours' and protracted 28 days2.
`b Infusion 21 days.
`c Infusion 14 days.
`d Bolus daily x 5, infusion over 5 days.
`
`60'
`842
`126
`21
`17.5 to 21
`2.5
`75-125
`
`20
`21
`42
`5.25
`2.6 to 3.5
`0.5
`18-31
`
`36,37
`
`41
`42
`43
`44
`45
`
`effects of the infusion schedule include stomatitis and
`hand-foot syndrome [36, 37]. Phase III comparative trials
`of the infusion versus the bolus schedule have been
`reported for doxorubicin and do demonstrate a decrease
`in the cardiac toxicity but these studies are methodo-
`logically problematic [38, 39]. Nonetheless, an analysis of
`the collected data on cardiac toxicity consistently demon-
`strates a decrease in this pattern of toxicity with an infu-
`sional schedule as well as the capacity to extend the
`maximum cumulative dose of doxorubicin that may be
`administered [40].
`The bolus dosage of doxorubicin has been increased
`with the use of cytokines but the MTD has generally been
`in the range of 75 to 100 mg/m2 when the drug is ad-
`ministered as a single agent every three weeks. For the
`short term 96-hour infusion and the protracted infusion
`for 28 or more days, the dose intensity is comparable or
`decreased by approximately 20% for the infusion sched-
`ule relative to bolus administration.
`Epirubicin is a closely related analogue of doxorubicin
`developed because of lesser cardiac toxicity. The bolus
`dose of epirubicin as a single agent is 120 mg/m2 and the
`infusional schedule for 21 days has an MTD based upon
`acute toxicity of 126 mg/m2 [41]. The data suggests that
`infusion decreases the MTD for doxorubicin but does not
`affect the MTD for epirubicin.
`Mitoxantrone is not an antibiotic but a synthesized
`anthracene analogue of the parent compound doxoru-
`bicin. A phase I trial of infusional administration for 14
`days established an MTD of 21 mg/m2 which is approx-
`imately 50% higher than the bolus dose used for therapy
`in lymphoma or solid tumors [42].
`Mitomycin C and actinomycin D are two agents which
`have been studied in only single reports of infusional
`delivery [43, 44]. Mitomycin C is an alkylating agent which
`is generally administered as a bolus at 6-week intervals
`with acute DLT manifest as bone marrow suppression
`and chronic exposure may lead to pulmonary insuffi-
`ciency or renal failure. For a 7-day infusion, generally
`repeated at 5- or 6-week intervals, the MTD is 21 mg/m2
`with a dose intensity of 2.6 mg/m2/week [42]. In contrast,
`the bolus DI for mitomycin C is 3.6 mg/m2/week. Actino-
`
`mycin D has been studied in a 5-day infusion in 18
`patients with an MTD of 2.5 mg/m2 and a DI of 0.5 vagi
`m2/week [43]. The DLT for infusional actinomycin D is
`stomatitis and bone marrow suppression with an increase
`in the DI on the infusion schedule as compared to the
`bolus schedule.
`Bleomycin is a unique anti-tumor antibiotic composed
`of a mixture of peptides that does not have a classic acute
`DLT in that there are no acute gastrointestinal or marrow
`suppression effects but rather two forms of pulmonary
`toxicity are recognized. The acute pulmonary insuffi-
`ciency is idiosyncratic and not related to dose and the
`fibrosis process is chronic and related to a cumulative
`dose of more than 450 mg. The usual bolus dose for
`Hodgkin's disease is 10 U/m2 on day 1 and 15 and for
`testicular cancer is 30 units per week. Infusional sched-
`ules for lymphoma and for testicular cancer have been
`employed to decrease pulmonary toxicity but may in-
`crease the toxicity if used in conjunction with radiation
`[45, 46]. The MTD is apparently increased with the
`infusion schedule but with increased toxicity as well
`including hypertension and hyperbilirubinemia [45].
`
`Plant alkaloids and topoisomerase inhibitors
`
`The diverse group of compounds encompassing the plant
`aklaloids and the topoisomerase I and II inhibitors rep-
`resent some of the more recently available antineoplastic
`compounds as well as some of the oldest neoplastic drugs
`(Table 5). The nine selected agents have all been evaluated
`in phase I—II trials of infusional delivery and the spectrum
`of dose limiting toxicities include bone marrow suppres-
`sion, neurotoxicity and stomatitis. Schedule dependency
`is established for some in experimental systems and for at
`least one agent (etoposide) in clinical trials as well.
`
`Periwinkle plant alkaloids
`
`Vincristine, vinblastine, vindesine and vinorelbine are
`analogs with different dose limiting toxicities. Vincristine
`is associated with neurologic toxicity without bone mar-
`
`

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` by guest on June 5, 2016
`
`21
`
`Table 5. Plant alkaloids and topoisomerase inhibitors: Comparison of MTD per treatment cycle and DI for bolus versus infusional administration.
`
`Agent
`
`Bolus
`
`Infusion
`
`Reference
`
`MTD mg/m2
`
`DI mg/m2/wk
`
`MTD mg/m2
`
`DI mg/m2/wk
`
`48
`49
`50
`51
`52-54
`
`55
`56
`
`57-60
`
`61-63
`
`2 3
`
`.3
`12
`2
`100
`125
`187
`50
`
`3.9
`1.14
`35
`
`6
`10
`48
`6
`300'
`420b
`750
`150
`
`14.7'
`3.42
`140
`
`1.4
`5-7
`20
`2
`125
`
`32
`100
`115
`1.9
`2.7
`50
`
`_ - -
`
`4-8
`500
`
`130
`100 (weekly)
`350 (q 3 weeks)
`7.5'
`8.32
`200-250
`
`Vincristinec
`Vinblastine0
`Vinorelbined
`Vindesine
`Etoposidee
`
`Tenposider
`Irinotecan
`
`Topotecanb
`
`Paclitaxel*
`
`* Infusion 96 hours.
`b Bolus x 5 days' or x 1 days2.
`c Infusion x 21 days' or 5 days2.
`d Bolus schedule generaly weekly.
`e Infusion schedule for 4 days (96 h) repeated every 3 weeks with preinfusion bolus dose.
`f Infusion for 5' or 212 days.
`' In childhood leukemia.
`
`row suppression while the other three are associated with
`bone marrow suppression and a lesser incidence of neuro-
`toxicity. All of these anti microtubular agents are generally
`administered on a bolus schedule often weekly and there-
`fore the DI generally reflects the weekly bolus dose [47,
`48]. For vincristine, the MTD is cumulative neurotoxicity
`and the DI is comparable for both the bolus and infusion
`schedules [48]. For vinblastine, the weekly bolus schedule
`has a similar DLT to that of the infusion schedule with an
`increase in the DI [49]. For vinorelbine, however, the 96
`hour infusion results in a decrease in the MTD and DI
`relative to bolus dosing [50]. Finally, for vindesine, the
`MTD and DI are quite comparable for the bolus and
`infusion schedules [51].
`
`Topoisomerase 2 inhibitors (etoposide (VP16) and
`tenopiside (VM26))
`
`Infusional schedules have been studied in the phase I
`setting for both VP16 and VM26 although the standard
`schedule for both agents is a daily x 3 or 5 bolus
`schedule. For etoposide, particularly the bolus scheduling
`is designed to emulate infusion by this multi-fractionated
`daily bolus system. The MTD for bolus etoposide is 500
`mg/m2 with a dose intensity of 125 mg/m /week. Con-
`flicting phase I studies of short term infusion for five days
`yielded a lower or comparable dose intensity [52, 53] at
`100 to 125 mg/m2/week which was similar with prolonga-
`tion of the infusion to 21 days [54]. The DLT for etoposide
`is bone marrow suppression and stomatitis for both bolus
`and infusion schedules. Teniposide has been studied by
`infusion for a duration of only 72 hours and applied in
`the treatment of refractory leukemia [55]. Therefore,
`although the MTD and the DI increase with infusional
`administration for teniposide, the clinical setting is one
`
`in which bone marrow suppression (the DLT in solid
`tumors) is the intended therapeutic effect.
`
`Topoisomerase I inhibitors
`
`Topotecan has been the most extensively studied topoiso-
`merase 1 inhibitor on the infusion schedule while infu-
`sional irinotecan (CPT 11) has been evaluated in a single
`clinical tria