RAPID PUBLICATION
`
`Paclitaxel by 3-Hour Infusion in Combination With
`Bolus Doxorubicin in Women With Untreated Metastatic
`Breast Cancer: High Antitumor Efficacy and Cardiac
`Effects in a Dose-Finding and Sequence-Finding Study
`
`By Luca Gianni, Elisabetta Munzone, Giuseppe Capri, Fabio Fulfaro, Emiliana Tarenzi, Fabrizio Villani,
`Carlo Spreafico, Alberto Laflranchi, Augusto Caraceni, Cinzia Martini, Marco Stefanelli,
`Pinuccia Valagussa, ancl Gianni Bonadonna
`
`Pur ose: To define the maximum-tolerated dose
`(MTD) and better tolerated sequence of paclitaxel by 3-
`hour infusion plus bolus doxorubicin (DOX) and to evalu-
`ate antitumor efficacy.
`Patients and Methods: Thirty-five women with meta-
`static breast cancer (dominant visceral metastases in
`56%, and involvement of 2 three sites in 67%) who never
`received chemotherapy of any type were studied. Pacli-
`taer every 3 weeks (125 mg/m2 starting dose) was in-
`creased by 25-mg/m1 steps in subsequent cohorts of pa-
`tients. DOX (60 mg/m2 fixed dose) was administered 15
`minutes before the start of or after the end of paclitaxel
`for a maximum of eight cycles. Subsequently, patients in
`continuous response could receive single-agent pacli-
`taxel (175 to 200 mg/m2 every 3 weeks). The drug se-
`quence was alternated in consecutive patients and in the
`first two cycles.
`Results: Severe neutropenia that lasted greater than
`7 ays (n = 4), febrile neutropenia (n = 7) and grade III
`oral mucositis (n = 6) defined the MTD of paclitaxel at
`
`200 mg/m2 in 34 assessable patients. Grade II periph-
`eral neuropathy occurred in 33% of patients. Six women
`(18%) developed clinically reversible congestive heart
`failure (CHF) after a median of 480 mg/m2 total DOX.
`Drug sequence had no effect on toxicities. High efficacy
`on all metastatic sites in 32 assessable patients ac-
`counted for a 41% complete response (CR) rate (95% con-
`fidence interval
`[CI], 24% to 59%) and 94% overall-
`response rate (95% CI, 79% to 99%). After a median
`follow-up of 12 months (range 3 to 18), the median re-
`sponse duration is 8 months (range, 2+ to 18+) for com-
`plete responders and 11 months (range 1+ to 15+) for
`partial responders.
`Conclusion: The rate of CR and incidence of CHF may
`be an expression of therapeutic and toxic enhancement
`due to the schedule used in this trial. Until clarification
`
`of this possibility, this promising combination should be
`used in investigational trials.
`J Clin Oncol 13:2688-2699. © 1995 by American So-
`ciety of Clinical Oncology.
`
`ACLITAXEL is a highly active new drug in the treat—
`ment of women with advanced breast cancer when
`
`used as first- or second—line chemotherapy.‘ The antitu-
`mor activity of the taxane is lower in more heavily pre-
`treated patients,2 which suggests at least partial cross-
`resistance with conventional chemotherapy.‘ However,
`despite the involvement of taxanes and anthracyclines in
`the multidrug—resistance phenotype,3 paclitaxel induced
`objective responses in 20% to 40% of women who failed
`to respond to prior treatment with anthracyclines.2‘4’5
`
`From the Divisions of Medical Oncology, Cardiology, Palliative
`Therapies, and Diagnostic Radiology, Istituto Nazionale Tumori,
`Milano, Italy.
`Submitted May 16, 1995; accepted July 31, 1995.
`Supported in part by grants no. 93.02309.PF39 and 94. 01274. PF39
`from the Italian National Research Council, Rome, Italy, by a grant
`from the Associazione Italiana Ricerca sul Cancro, Milan, Italy, and
`by Bristol Myers Squibb, Princeton, NJ.
`Address reprint requests to Luca Gianni, MD, Divisione di Onco-
`logia Medica A, Istituto Nazionale Tumori, Via Venezian I, 20133
`Milano, Italy.
`© 1995 by American Society of Clinical Oncology.
`0732—1 83X/95/131 I -0003$3.00/0
`
`Given the important role of doxorubicin (DOX) and its
`analogs in the treatment of breast cancerf”7 the lack of
`complete clinical cross-resistance with paclitaxel justifies
`the development of combination regimens to exploit fully
`the therapeutic potential of the two drugs.
`Several early trials suggested that the combination of
`paclitaxel with other drugs may be complicated by phar-
`macokinetic
`and/or pharmacodynamic
`interferences.
`Rowinsky et al8 showed that the order of administration of
`paclitaxel and cisplatin was associated with significantly
`better tolerability when the taxane preceded cisplatin.
`When DOX was administered by 48-hour infusion and
`paclitaxel by 24-hour infusion, the maximum-tolerated
`dose (MTD) of the two drugs was higher with the se-
`quence of DOX before paclitaxel than with the opposite
`sequence.9 A similar sequence—dependent tolerability was
`reported for administration of bolus DOX and paclitaxel
`by 24-hour infusion.” Furthermore, the MTD was rela—
`tively high when paclitaxel and DOX were administered
`concomitantly as a 72-hour infusion.”
`The effects of the order of drug administration on the
`tolerability of the combination of paclitaxel and DOX
`have so far been described with use of 24-hour or longer
`
`2688
`
`h
`Journal of Clinical Oncology, Vol 13, No l 1 (November), 19956p11268_8-2699 G
`e trion v.
`Information downloaded from jco.ascopubs.org and provided by at Reprints Desk on August 4, 2016 from 216.185.156.28H)l{2017_01122
`Copyright © 1995 American Society of Clinical Oncology. All rights reserved.
`Genentech Exhibit 2015
`
`enentec
`
`

`

`SHORT-INFUSION PACLITAXEL PLUS BOLUS DOXORUBICIN
`
`2689
`
`infusions of paclitaxel. However, a multicenter random-
`ized study in patients with ovarian carcinoma showed that
`the tolerability of paclitaxel was schedule—dependent, in
`that the taxane caused significantly less hematologic tox-
`icity when administered by 3-hour as compared with 24-
`hour infusion.12 In this study, there was no significant
`difference in efficacy. Since the taxane is a phase-specific
`drug, it is important to rule out a negative impact of the
`3—hour infusion of paclitaxel on its antitumor activity in
`breast cancer. Preliminary studies in heavily pretreated
`and anthracycline-resistant patients indicate no differ-
`ence,5’13 and a prospective controlled study of 3-hour ver-
`sus 24-hour paclitaxel is nearly completed. However, a
`clear definition of the best infusion duration should take
`
`into account that paclitaxel over 96 hours may be superior
`to the shorter infusion schedule in patients with breast
`cancer refractory to anthracyclines,14 and is active in pa-
`tients resistant to the taxane given on a 3—hour schedule.15
`To develop a fully outpatient regimen of DOX plus
`paclitaxel, we therefore conducted a dose—finding study
`with a fixed bolus dose of DOX in combination with
`
`paclitaxel infused over 3 hours. We also wanted to assess
`whether the order of drug administration had any effect
`on the tolerability of the two drugs.
`
`PATIENTS AND METHODS
`
`Patients
`
`From June 1993 to October 1994, 35 patients with metastatic
`breast cancer were accrued into this open-label dose-finding study
`in which therapeutic doses of DOX and paclitaxel were used. The
`trial was approved by the ethical committee of the Istituto Nazionale
`Tumon’. All patients provided witnessed, informed consent.
`Criteria for inclusion were as follows: histologic proof of breast
`cancer; age 18 to 70 years; performance status 0 to 2 (Eastern Coop-
`erative Oncology Group [ECOG] scale), absolute neutrophil count
`(ANC) a 2,000/aL and platelet count 2 100,000/,uL; normal func—
`tion tests for liver (bilirubin level 5 1.25 times upper normal limit)
`and kidneys (creatinine concentration 3 1.25 times upper normal
`limit); left ventricular ejection fraction (LVEF) 2 normal limit of
`50% by echocardiograph or radionuclide cineangiography; presence
`of at least one neoplastic lesion bidimensionally measurable by phys-
`ical examination or instrumental studies (central CNS or bone metas-
`tases as the only site of disease were excluded); and no prior chemo-
`therapy.
`
`Drug Administration and Dose Modifications
`Paclitaxel
`(Taxol) was
`supplied by Bristol Myers Squibb
`(Princeton, NJ) as a sterile solution in vials that contained 30 mg
`of drug formulated in 5 mL of 50% polyoxyethylated castor oil
`(Cremophor EL; PEG 35 castor oil; BASF, Parsippany, NJ) and
`50% dehydrated alcohol United States Pharmacopeia. The drug was
`diluted in 5% dextrose to a final concentration not greater than
`0.6 mg/mL. All solutions were filtered through a 22-,am pore—size
`cellulose acetate filter (IVEX HP; Millipore, Molsheim, France).
`Doxorubicin (Adriblastina) was purchased from Pharrnacia (Milan,
`
`Italy) as lyophilized powder in 10— or 50—mg vials and dissolved
`with normal saline to a final concentration not greater than 3 mg/
`mL. The dose of DOX was fixed at 60 mg/m2. The anthracycline
`was administered intravenously as a 5-minute bolus either 15 min-
`utes before the start or after the end of paclitaxel infusion. The initial
`dose of paclitaxel was 125 mg/mz, and was increased by 25-mg/m2
`steps in subsequent cohorts of at least three patients until dose-
`limiting toxicity (DLT). The DLT was defined by the occurrence of
`any of the following: ANC less than SOD/til. for more than 7 days;
`ANC less than lOO/nL for more than 3 days; febrile neutropenia
`(ANC < SOC/ML and fever > 38°C); World Health Organization
`(WHO) grade III mucositis; grade III peripheral neuropathy; any
`other major organ toxicity greater than grade II.
`The two-drug combination was administered in the outpatient
`clinic every 21 days after premedication that consisted of oral predni—
`sone (25 mg) given 12 hours before treatment; and intramuscular
`chlorpheniramine (10 mg), intravenous cimetidine (300 mg), and
`intravenous hydrocortisone (250 mg) given 30 minutes before pacli-
`taxel administration.
`The sequence of DOX and paclitaxel administration was alternated
`for every other patient. Within each patient. the sequence was alter-
`nated during course 2. From the third cycle on, each patient received
`the drugs in the order of administration that was better tolerated in
`the first two cycles. In the absence of objective differences between
`sequences, patients were asked to choose their own preferred se—
`quence. Administration of the combination was planned for a maxi-
`mum of eight cycles, which corresponded to a total dose of 480 mg/
`m2 of DOX. Patients in continuous response could continue with
`single—agent paclitaxel.at..an...ini.tial»dese~of1'75 mglmz (later in-
`creased to 200 mg/mz). In case of complete response (CR), patients
`received four additional cycles of the combination or of single-agent
`paclitaxel after the eighth cycle of the combination. Patients who
`achieved a partial response (PR) continued for four cycles after
`response stabilization or until a maximum of 12 cycles of single-
`agent paclitaxel. Patients with stable disease (SD) continued pacli-
`taxel until tumor progression or the twelfth cycle. Patients with
`progressive disease (PD) were immediately taken off study. The
`dose of DOX was not reduced during the entire trial. However, DOX
`was discontinued if patients had a decreaSe to less than 50% of
`LVEF, a decrease of greater than 15% of LVEF with respect to
`pretreatment values, or congestive heart failure (CHF) of any grade.
`The dose of paclitaxel was reduced in steps of 25 mg/m2 from course
`3 onward if the DLT was observed in a previous course. If patients
`could not tolerate a dose of 100 mg/m2 in combination with 60 mg/
`m2 of DOX, they were taken off study.
`
`Patient Monitoring
`All patients were initially evaluated with a collection of history,
`physical examination, chest x-ray, complete blood cell (CBC) count,
`liver and kidney function tests, ECG and echocardiography, liver
`echography, and bone scan. Computed tomography (CT) of the
`chest, liver, abdomen, or head; nuclear magnetic resonance imaging
`(MRI) studies; and x-ray studies of selected osseous segments were
`performed when clinically indicated.
`During the paclitaxel infusion, patient vital signs (blood pressure,
`heart rate, and respiratory rate) were monitored every 15 minutes
`for the first hour and every 30 minutes for the following 2 hours.
`All patients had a CBC count twice per week, and renal and liver
`function tests and physical examinations every 3 weeks. Toxicities
`were recorded according to WHO criteria.16 Cardiac monitoring con-
`sisted of ECG recording every cycle, and echocardiography exami-
`
`lnformation downloaded from jco.ascopubs.org and provided by at Reprints Desk on August 4, 2016 from 216.185.156.28
`Copyright © 1995 American Society of Clinical Oncology. All rights reserved.
`
`

`

`2690
`
`GlANNI ET AL
`
`nation for LVEFl7 at the following intervals: baseline and after the
`third, fifth, and eighth cycles during combination therapy; every
`three courses during single-agent paclitaxel; and at 3-month intervals
`during follow-up evaluation. ECG-Holter monitoring was recorded
`for 24 hours before and 24 hours during and after the infusion of
`the first two cycles of the combination. Supraventricular arrhythmias
`were classified according to Villani et all8 into five categories, as
`follows: 0, no ventricular arrhythmia; 1A, less than 30 supraventricu-
`lar premature beats per hour; 1B, 2 30 supraventricular ectopic
`beats per hour; 2, supraventricular couplets; 3, 2 one episode of
`supraventricular tachycardia; and 4, flutter or atrial fibrillation. For
`the purposes of this study, categories 1A and 1B were described as
`the single category 1. Ventricular arrhythmia was classified ac—
`cording to the Lawn classification into the following categories: 0,
`no ventricular arrhythmia; 1, less than 30 ventricular premature beats
`per hour; 2, 2 30 ventricular premature beats per hour; 3, multiform
`ventricular premature beats; 4, repetitive ventricular premature beats;
`and S ventricular premature beats with R on T phenomenon. For the
`purpose of the present analysis, no distinction was made between
`categories 1A and 1B of the original Lown classification, and cate-
`gory 4 corresponds to the 4A category (ventricular couplets), since
`no patient experienced 4B arrhythmia. In selected patients, the neuro-
`logic examination included monitoring of the neurophysiology of
`the optic pathways, as described previously.”
`
`Response Assessment
`Response of measurable and assessable sites of disease was as-
`sessed according to WHO criteria every two cycles.” All responses
`were reviewed by an independent panel of experts. For responses
`of bone metastases, osteoblastic lesions only or the combination of
`osteoblastic and lytic lesions were always considered as assessable,
`but not measurable. The definition of response adhered to the criteria
`outlined by Miller et all.” In our trial, this set of criteria was modified
`to include that all responses required the same type of assessment
`by two different radiologic techniques (bone x-ray and CT scan,
`MRI, or scintigraphy).
`
`Statistical Analysis
`The duration of response was calculated from first demonstration
`of response to disease progression. Freedom from progression and
`total survival were calculated from the first drug administration using
`the Kaplan-Meier product-limit method. Nineteen patients were cen-
`sored without evidence of disease progression. Details on the censor-
`ing of patients and reasons for censoring are described in the Results.
`The comparison of activity and toxicity results between different
`groups was performed using the X2 test. The t test for paired data
`was used for within-patient comparison of continuous measures per—
`formed at different
`intervals before, during, and after therapy.
`Within—patient comparisons of toxicity grade was performed using
`the test of mean scores for repeated measures of ordinal data.20 All
`reported values are for two-tailed tests.
`
`Patients and Treatment
`
`RESULTS
`
`Thirty-five patients with metastatic breast cancer were
`included in this study (Table 1). One patient was lost for
`follow-up evaluation after the first course of treatment.
`Two patients were assessable for drug toxicity only. They
`
`%
`
`85
`9
`6
`
`18
`
`47
`23
`12
`
`56
`
`25
`19
`
`9
`25
`66
`
`78
`22
`
`60
`40
`
`69
`31
`
`Table 1. Patient and Treatment Characteristics
`Characteristic
`No.
`
`Total patients
`Assessable for toxicity
`Assessable for antitumor activity
`Age, years
`Median
`
`Range
`ECOG performance status
`0
`1
`2
`
`Prior anticancer therapy'
`None
`
`Breast surgery
`Local radiotherapy
`Hormonal therapy
`Dominant site of disease
`Visceral
`Liver
`
`Lung
`Other viscera
`Bone
`Soft tissues
`Metastatic lesions
`1
`2
`2 3
`Visceral lesions
`1
`2
`
`Cycles of therapy
`DOX and paclitaxel
`Median per patient
`Range
`DOX before paclitaxel
`Paclitaxel before DOX
`Median days between cycles
`Range
`Paclitaxel alone (in 26 patients)
`Median per patient
`Range
`Dose of 175 mg/m2
`Dose of 200 mg/m2
`Median days between cycles
`Range
`Dose-intensity
`DOX (mg/mz/mo)
`Median
`Range
`Paclitaxel (% of planned at each dose level)
`Median
`Range
`Cumulative dose of DOX (mg/m2):
`Median
`Range
`
`35
`34
`32
`
`29
`3
`2
`
`6
`
`16
`8
`4
`
`18
`9
`
`1 1
`1
`8
`6
`
`3
`8
`21
`
`14
`4
`
`229
`
`138
`91
`
`109
`
`75
`34
`
`50
`
`26-63
`
`8
`1-8
`
`22
`20-42
`
`4
`28
`
`22
`20-53
`
`82
`68—87
`
`93
`70-100
`
`420
`120~480
`
`‘None of the patients received adiuvant chemotherapy or chemotherapy
`for metastatic disease.
`
`Information downloaded from jco.ascopubs.org and provided by at Reprints Desk on August 4, 2016 from 216.185.156.28
`Copyright © 1995 American Society of Clinical Oncology. All rights reserved.
`
`

`

`SHORT-INFUSION PACLITAXEL PLUS BOLUS DOXORUBICIN
`
`269i
`
`went off study because of toxicity (described later) after
`they had received two and one course of chemotherapy
`with paclitaxel at 150 and 200 mg/mz, respectively. They
`both had evidence of a nonconfirmed PR. The group had a
`median age of 50 years, and a median ECOG performance
`status of 0. None of the patients had received any type
`of prior chemotherapy, and six women were at first diag-
`nosis of breast cancer. All patients had measurable dis-
`ease. The majority had three or more involved sites
`(66%), and 18 (56%) had dominant visceral disease (Ta—
`ble 1). In four patients, there was concomitant involve-
`ment of the liver and lung. Patients received a median of
`eight cycles of the combination (range, two to eight).
`The dose of paclitaxel was never reduced during the
`first two cycles. From the third cycle on, the dose was
`reduced by 75 mg/m2 in four patients (eight cycles), by
`50 mg/m2 in four (nine cycles), and by 25 mg/m2 in three.
`The median interval between cycles was 22 days (range,
`20 to 42) (Table 1). A 1-week treatment delay occurred
`in one patient only (one cycle). Two- to 3—week delays
`occurred in four patients (four cycles). The reasons for
`dose reduction and/or treatment delay were neutropenia
`and/or mucositis. Two obese patients had the dose of DOX
`adjusted to their lean body weight after the first two cycles.
`The median dose-intensity of DOX was 82 mg/m2 per
`month (range, 68 to 87 mg/m2 per month). Paclitaxel in
`the combination was given at a median of 93% (range,
`70% to 100%) of the planned dose-intensity at any given
`dose level. Following discontinuation of DOX, 26 patients
`received 109 cycles of paclitaxel alone (median, four cy-
`cles; range, two to eight). Initially, the dose was set at 175
`mg/m2 (75 cycles). The protocol was amended to give a
`dose of 200 mg/m2 after six patients had received the same
`dose of paclitaxel in combination with DOX.
`
`Definition of Paclitaxel MTD and Better Tolerated
`Sequence of Drug Administration
`
`Three subsequent cohorts of three patients each re-
`ceived paclitaxel at 125, 150, and 175 mg/mz, respec-
`
`tively. Twenty—five women received paclitaxel at 200 mg/
`m2 (Table 1). All 34 women were assessable for toxicity.
`However, the last five patients at 200 mg/m2 were accrued
`after the definition of the paclitaxel MTD and received
`granulocyte colony-stimulating factor
`(G—CSF)
`and,
`therefore, were not taken into account in the evaluation of
`
`neutropenia. After the first cycle, one patient had febrile
`neutropenia that lasted 4 days and was followed by Liste-
`ria sepsis and pneumonitis, as well as systemic candidosis
`due to central venous catheter contamination (grade IV
`infection). She went off study thereafter, and was taken
`into account for the definition of the paclitaxel MTD only.
`The DLTs of the combination were neutropenia and
`mucositis (Table 2). The MTD of paclitaxel in combina-
`tion with 60 mg/m2 of DOX was reached at 200 mg/m2
`and defined by the following: grade IV neutropenia for
`more than 7 days in four of 20 assessable patients (20%)
`and 10 of 135 assessable cycles (7%); febrile neutropenia
`in seven of 25 patients (28%) and nine of 151 cycles
`(6%); and grade III mucositis in six of 25 patients (24%)
`and nine cycles (6%) (Table 2). Six of eight patients with
`episodes of febrile neutropenia had liver metastases. Four
`of them had concomitant alteration of liver transaminases.
`
`Febrile neutropenia required hospitalization in only one
`woman. In all other patients, prophylactic oral antibiotics
`were given at home.
`The most common toxicities of the combination ob—
`
`served at the different dose levels of paclitaxel are listed
`in Table 3. Neutropenia was infrequently associated with
`other hematologic side effects, and the rare instances of
`thrombocytopenia were of no clinical importance. With
`the exception of mucositis, which contributed to the defi-
`nition of the paclitaxel MTD in the combination, other
`nonhematologic toxicities were similar in frequency and
`severity to those described with the use of paclitaxel alone
`at similar doses by 3-hour infusion.13 The more disturbing
`symptoms were myalgias and arthralgias, which usually
`started on day 3 after administration of the drugs and
`lasted for approximately 3 days. Peripheral neuropathy
`
`Table 2. Incidence of DLTs at Different Dose Levels of Paclitaxel
`
`ANC < 500 ML
`
`Febrile Neutropenia
`
`Grade Ill Mucositis
`
`Dose
`[mg/m2]
`l 25
`l 50
`l 75
`200
`
`Total
`
`No. of
`Patients
`3
`3
`3
`25
`
`34
`
`No. of
`Cycles
`24
`l 8
`24
`l 51
`
`217
`
`No. of
`Patients
`2
`3
`2
`20‘
`
`27
`
`No. of
`Cycles
`3
`i 2
`7
`60‘
`
`82
`
`Days
`
`Median
`5
`6
`4
`5'
`
`Range
`5-7
`37
`2-7
`2‘] 2
`
`No. of
`Patients
`-
`l
`-—-
`7
`
`8
`
`No. of
`Cycles
`-
`l
`—-
`8
`
`9
`
`No. of
`Patients
`-
`l
`——
`6
`
`7
`
`No. at
`Cycles
`--
`l
`—
`9
`
`l 0
`
`Range
`
`Median
`
`Days
`
`—
`7
`
`6
`
`3-l 0
`
`‘The last 5 patients received G-CSF and were therefore omitted from this evaluation, which took into account 135 assessable cycles in 20 patients.
`
`Information downloaded from jco.ascopubs.org and provided by at Reprints Desk on August 4, 2016 from 216.185.156.28
`Copyright © 1995 American Society of Clinical Oncology. All rights reserved.
`
`

`

`2692
`
`GIANNI ET AL
`
`Table 3. Main Acute and Subacute Toxicities of Combination Paclitaxel and DOX
`
`No. of Patients ldose/grade)
`% oi Assessable Cycles (dose/grade)
`l25-I75 mg/m2 (n = 9)
`200 mg/m2 (n = 25)
`125475 mg/m2 (n = 66)
`200 mg/m2 (n = 164)
` IV I II III IV I II III IV
`
`
`
`
`I
`IV
`I
`Toxicity
`II
`III
`II
`III
`
`
`
`
`
`
`
`
`
`—
`2
`I
`3
`I
`3
`5
`3
`
`-—-
`2
`—
`4
`4
`4
`3
`—
`
`2
`—
`-——
`I
`I
`—
`—
`—
`
`7
`I
`—
`—
`—
`—
`—
`—
`
`I
`I
`4
`I 2
`8
`I5
`I 6
`I I
`
`2
`I
`I
`9
`7
`5
`8
`5
`
`3
`--
`A
`2
`6
`——
`—
`—
`
`I9
`7‘
`-
`——
`—-
`—
`—
`—
`
`7
`5
`I
`48
`I8
`I5
`60
`6
`
`2I
`3
`—
`2i
`9
`8
`I
`—
`
`36
`—
`—
`I
`I
`—
`—
`—
`
`33
`I
`——-
`—
`—
`—
`——
`—
`
`6
`< I
`8
`45
`I 6
`34
`69
`22
`
`I3
`< I
`7
`I 9
`I I
`A
`I 0
`7
`
`23
`—
`2
`3
`6
`-
`—
`—
`
`50
`5
`—
`'—
`—
`-—
`—
`—
`
`Neulropenia
`Infection
`Thrombocytopenia
`Anemia
`MUCOSiiiS
`Arthralgia/myalgia
`Neuropathy
`Prurilus
`Nausea and
`
`-—43vomiting ~ 6 8 6 -— I 8 9 — — 27 2i 8
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`‘Gracle IV infection was any instance of febrile neutropenia even in the absence of documented site-specific infection.
`
`tended to be more severe with the highest dose of pacli-
`taxel, and was significantly associated with the number
`of administered cycles. Using the test of mean scores for
`repeated measures,20 a within-patient comparison of the
`grade of neurotoxicity showed a significant worsening of
`the symptoms after the fourth versus the first cycle (P <
`.001), the eighth versus the first (P < .001), and the eighth
`versus the fourth (P < .01), respectively. A majority
`of patients (Table 3) also described pruritus, which was
`occasionally distressing, and required medication with
`antihistamines with only partial relief. Most likely be-
`cause of the premedication with corticosteroids and anti-
`histamines, nausea and vomiting were not as pronounced
`as expected from the administration of bolus DOX alone.
`By the end of the second cycle, all patients had complete
`reversible alopecia.
`In the 26 women who received paclitaxel alone after
`discontinuation of DOX, the drug was well tolerated (Ta-
`ble 4). There was no significant difference between the
`two doses of paclitaxel used (data not shown). The rela-
`tively high incidence of neuropathy and myalgias is ex-
`plained by taking into account that all patients had already
`
`Table 4. Main Acute and Subacute Toxicities of Single-Agent Paclitaxel
`in 26 Patients Receiving I75 or 200 mg/m2 Per Cycle After
`Discontinuation of DOX
`
`Toxicity
`
`Neutropenia
`Anemia
`Mucositis
`
`Arthralgia/myalgia
`Neuropathy
`Pruritus
`
`Nausea and vomiting
`
`I
`
`I8
`2O
`I
`
`36
`71
`15
`
`7
`
`96 of Assessable Cycles
`(N = I09) (grade)
`II
`III
`
`27
`5
`—
`
`2
`23
`—-
`
`I
`
`I8
`-—
`—
`
`—
`——
`——
`
`——
`
`IV
`
`—
`—
`—
`
`—
`—
`—-
`
`—
`
`received paclitaxel for a median of eight courses in com-
`bination with DOX. After the observation of visual symp-
`toms in a concomitant study of single-agent paclitaxel,19
`patients were routinely interrogated about their visual
`acuity and the experience of scotomata. The latter symp-
`tom was described by nine patients, while reduction of
`visual acuity was reported by 10. However, in only one
`woman was there a corresponding alteration of the mea—
`sure of visual-evoked potentials, as previously de—
`scribed.19
`
`One major goal of the study was to define the optimal
`sequence of the two drugs. For simplicity, we report here
`the results of the 24 assessable patients treated with 200
`mg/m2 of paclitaxel (20 only in the case of neutropenia)
`(Table 5). Results were identical when the nine patients
`treated with lower doses of the taxane were also included.
`
`The neutrophil counts at nadir were not significantly dif—
`ferent when paclitaxel was given before or after DOX
`(data not shown). The sequence also had no effect on
`other toxicities that could be measured by categories of
`the WHO scale,
`ie, neutropenia, mucositis, peripheral
`neuropathy, and myalgia/arthralgia (Table 5), and the du-
`ration of neutropenia and mucositis were also not affected
`by drug—sequence. From the third cycle, 12 women con—
`tinued with paclitaxel before DOX and 19 with DOX
`before paclitaxel. A comparison of all cycles administered
`with paclitaxel before DOX (n = 91) versus all cycles
`administered with the opposite sequence (n = 138) did not
`show any statistically significant difference of tolerability
`(data not shown).
`
`Cardiac Effects and Toxicity of the Combination
`
`The effects of paclitaxel and DOX on cardiac rhythm
`were investigated in 29 patients in the first two cycles
`with Holter monitoring for 24 hours during and after
`
`Information downloaded from jco.ascopubs.org and provided by at Reprints Desk on August 4, 2016 from 216.185.156.28
`Copyright © 1995 American Society of Clinical Oncology. All rights reserved.
`
`

`

`SHORT-INFUSION PACLITAXEL PLUS BOLUS DOXORUBICIN
`
`2693
`
`Table 5. Effect of Order of Drug Administration on Toxicities of Box Combination With Paclitaxel at 200 mg/m2
`Neutrophil Nadir
`Mucositis
`Myalgia/Anhralgia
`Neuropathy
`l" = 20)
`in = 24)
`in = 24)
`ln = 24)
`Grade
`T—tD
`D’9T
`T—>D
`D—tT
`T—tD
`D—tT
`T—'D
`D—'T
`
`
`0
`l
`ll
`Ill
`lV
`
`l
`—
`3
`6
`l0
`
`l
`3
`2
`4
`l0
`
`20
`3
`-
`l
`—
`
`18
`2
`3
`l
`—
`
`l3
`9
`2
`—
`—
`
`12
`12
`—
`—
`—
`
`9
`14
`3
`l
`—
`
`l l
`13
`l
`—
`—
`
`
`
`.l785 . l 933 .7626P' .l630
`
`
`
`
`
`
`
`NOTE. Toxicities graded according to WHO scale.
`Abbreviations: T -> D, sequence of paclitaxel followed by DOX; D —> T, sequence of Box followed by paclitaxel.
`’Within-patient comparison was performed using the test of mean scores for repeated measures of ordinal data.”
`
`paclitaxel infusion, and compared with basal recording
`performed on the day before treatment. Bradycardia that
`ranged from 30 to 50 beats per minute was recorded in
`four patients. In three of them, there also was a mild
`prolongation of the QT interval. None of the patients had
`an atlioventiicular block of any grade. Figure 1 summa-
`rizes the results of the monitoring of supraventricular
`(SV) and ventricular arrhythmias. A within—patient com-
`parison of arrhythmia before versus during and after ther-
`apy was highly significant for SV alterations only (P <
`.001 by test for repeated measures). Four patients had
`nonsustained runs of SV tachycardia that were not present
`previously, and one patient had a transient episode (2
`minutes) of atrial fibrillation. Six patients had multiform
`(class 3) or repetitive (class 4) ventricular premature
`
`beats, but in five the arrhythmia was already present be-
`fore therapy (Fig 1). None of the recorded alterations was
`symptomatic, and none of the patients required antiar—
`rhythmic therapy during the entire period of chemother-
`apy and follow-up evaluation.
`The myocardial contractility was investigated in all
`women before and at different intervals during and after
`the entire course of treatment by echocardiography evalu—
`ation of the LVEF. Table 6 lists the findings of the investi-
`gation according to National Cancer Institute common
`toxicity criteria (CTC). Thirty-one of 33 assessable pa-
`tients had a decrease in LVEF. In 25 of them (Table 6),
`the reduction of LVEF was within 15% units of basal
`
`values (grade I toxicity) and was the only sign of reduced
`heart contractility. Six patients developed symptomatic
`
`(A) Supraventricular
`I.
`Fig
`(classified according to Villani et
`all") and (B) ventricular arrhyth-
`mias
`(lown classification)
`re-
`corded before and for 24 hours
`during and after treatment. Su-
`praventricular arrhythmias in-
`creased
`significantly
`during
`therapy (P < .00], within-pa-
`tient analysis by test of repeated
`measures of ordinal data).
`
`A
`
`arrhythmia
`
`class
`
`i-a
`
`after
`
`Information downloaded from jco.ascopubs.org and provided by at Reprints Desk on August 4, 2016 from 216.185.156.28
`Copyright © 1995 American Society of Clinical Oncology. All rights reserved.
`
`

`

`2694
`
`GlANNl ET AL
`
`Table 6. Cardiac Function as Worse Per Patient Toxicity and Overall
`Incidence per Cycle
`Cycles
`Patients
`CTC — —
`Grade‘
`Not
`%
`No.
`96
`
`0
`l
`ll
`ill
`
`Total
`
`2
`25
`—
`6
`
`33
`
`6
`76
`—
`l8
`
`lOO
`
`23
`l )0
`7
`6
`
`136
`
`16
`75
`5
`4
`
`100
`
`’Common toxicity criteria: grade 0, no toxicity; grade I, asymptomatic
`decline of resting LVEF by < 20% of baseline values; grade II, asymptomatic
`decline of LVEF by > 20%, grade "I, mild CHF responsive to therapy.
`
`CHF after a median of eight cycles and 480 mg/m2 of
`cumulative DOX (Table 7). Three had class III and three
`had class 11 CHF according to the classification of the
`New York Heart Association. In none of them was the
`
`decline of LVEF predictive of CHF. They all had some
`type of cardiac risk factor (Table 7). The onset of symp-
`toms was within 1 year after the first administration of
`DOX and concomitant with a decrease of the LVEF. A
`
`woman with controlled hypertension and obesity devel-
`oped class 11 CHF after she had received two cycles (120
`mg/m2 cumulative DOX). She was concomitantly irradi-
`ated to the ninth thoracic vertebra, and a perfusional scan
`showed a reduction of contractility limited to the posterior
`heart wall that was included within the irradiation field.
`
`She was the only patient taken off study for cardiac rea-
`sons, and was considered assessable for toxicity only in
`spite of initial evidence of major response of liver metas-
`tases, lytic bone lesions, and inflammatory breast involve-
`ment. All patients responded to treatment with vasodila—
`tors and digoxin. Another woman who started treatment
`with a 52% LVEF had a decrease to less than 50% after
`
`the third cycle and continued on single—agent paclitaxel
`while in CR.
`
`Changes in LVEF at different end points during the
`trial are shown in Fig 2. There was a progressive decline
`
`of the LVEF in all assessable patients during DOX ther-
`apy (Fig 2A). The decrease was already significant after
`a cumulative dose of 180 mg/m2 of DOX (P < .01 by t
`test for paired data), and there was a constant trend toward
`a progressive reduction until the last dose of anthracy-
`cline. Figure 2B shows the comparison of LVEF mea-
`sured before and after the last DOX dose, and after the last
`
`dose of paclitaxel in 21 assessable patients who received
`a median of four cycles of single—agent paclitaxel after
`discontinuation of DOX. The data show an average stable
`myocardial function during single-agent chemotherapy.
`Five women continued paclitaxel after the appearance of
`CHF (Fig 2B). In four of them, the LVEF was unchanged
`or ameliorated, while in one there was a further decrease.
`Overall, LVEF measured after the last dose of DOX and
`
`the last dose of paclitaxel were not significantly different
`(P = .22, t test for paired data), which indicates that the
`taxane had no further negative effect on heart contractil-
`ity. Simil