Paclitaxel and Doxorubicin, a Highly Active Combination in the
`Treatment of Metastatic Breast Cancer
`
`Per Dombernowsky, Julie Gehl, Marianne Boesgaard, Tina P. Jensen, and Benny V. Jensen
`
`The activity of single-agent paclitaxel (Taxol; Bristol-
`Myers Squibb Company, Princeton, NJ) has been docu-
`mented in untreated and previously treated metastatic
`breast cancer, including both patients with anthracy-
`dine-resistant disease and those with extensive pre-
`treatment. Such activity has prompted investigations
`of the optimal doses and schedules of paclitaxel/doxo-
`rubicin combinations. With one exception, paclitaxel
`has been administered as either a 24- or a 3-hour infu-
`
`sion, while the administration times for doxorubicin
`vary from bolus injection to 72-hour infusion. Results
`of these completed phase I and II trials are reviewed.
`Also reported are two European trials that have
`achieved promising results. In Milan, a phase Illl trial
`has shown a preliminary response rate exceeding 90%
`in 32 chemotherapy-naive patients treated with an al-
`ternating schedule of paclitaxel given over 3 hours and
`intravenous bolus doxorubicin. At doses of paclitaxel
`200 mglm2 and doxorubicin 60 mglml, the dose-limiting
`toxicities were neutropenia, oral mucositis, myalgias,
`and peripheral neuropathy. Congestive heart failure oc-
`curred in six patients. A phase II“ study of a 30-minute
`doxorubicin infusion preceding a 3-hour paclitaxel infu-
`sion every 3 weeks in minimally pretreated patients
`also is reported. Of 29 patients evaluable for response,
`l1 have achieved partial responses and seven complete
`responses, for an overall response rate of 83% (95%
`confidence interval, 79% to 99%). Toxicities observed
`were grades 3 to 4 neutropenia and moderate pares-
`thesias, nausea/vomiting, alopecia, myalgia, and muco-
`sitis. Cardiotoxicity also occurred, as l5 patients had a
`significant decrease in left ventricular ejection fraction
`measured by isotope cardiography. Six of these devel-
`oped congestive heart failure. This effect has been ob-
`served only in studies using short infusions of both
`drugs, and it is now being investigated whether low-
`ering the peak doxorubicin concentration will pre-
`clude it.
`
`Copyright © I996 by W.B. Saunders Company
`
`EVERAL chemotherapeutic agents and regi~
`mens are active against breast cancer, but
`fewer than 20% of patients with stage IV breast
`cancer are alive 5 years after distant metastases
`are detected, and the observed overall survival for
`
`patients with metastatic breast cancer has not been
`significantly affected during the last decades. New
`active drugs are therefore needed to improve the
`results for this group of patients. A new and highly
`interesting group of drugs is the taxanes.1 This
`presentation provides a short review of studies of
`both single—agent paclitaxel (Taxol; Bristol—Myers
`
`Squibb Company, Princeton, NJ) and combina~
`tion paclitaxel and doxorubicin in patients with
`advanced breast cancer.
`
`SINGLE-AGENT PACLITAXEL IN PATIENTS
`WITH MINIMAL OR EXTENSIVE PRIOR
`CHEMOTHERAPY
`
`Phase II Trials
`
`In 1991, Holmes et al2 reported a 56% response
`rate (95% confidence interval [CI], 35% to 76%)
`in 25 patients treated with paclitaxel 200 to 250
`mg/m2 given as a 24—hour intravenous (IV) infua
`sion every 3 weeks. Eleven patients had received
`prior chemotherapy for metastatic disease, 14 had
`received adjuvant chemotherapy, and all except
`two had received doxorubicin. The median re;
`
`sponse duration exceeded 5 months (range, 3 to
`13+ months), and three patients obtained com;
`plete responses (CR5). Granulocytopenia was the
`doserlimiting toxicity, but febrile neutropenia was
`rare, observed in only 5% of the courses.
`Reichman et al3 studied paclitaxel as first/line
`chemotherapy in 26 patients with stage IV breast
`cancer. Paclitaxel 250 mg/m2 was administered as
`a 24-hour IV infusion every 3 weeks, together with
`human granulocyte colony’stimulating factor (Ga
`CSF) given days 3 to 10. The response rate was
`62% (95% CI, 41% to 80%), including 12% CR5.
`Ten of 16 patients (63%) had received prior adjua
`vant chemotherapy. Five of the responses were
`achieved in eight patients who had received prior
`doxorubicin—containing
`chemotherapy. Febrile
`neutropenia was observed in 4%.
`The Memorial Sloan’Kettering Cancer Center
`(New York, NY) also treated patients with pacli—
`taxel 200 to 250 mg/m2 as a 24—hour infusion, with
`added GrCSF.4 This group of patients was heavily
`
`
`From the Departments of Oncology and Clinical Physiology, Herr
`lev Hospital and Rigshospitalet, University of Copenhagen, Dena
`mark.
`
`Address reprint requests to Per Dombernowsky, MD, Depart;
`ment of Oncology, Herlev Hospital, University of Copenhagen,
`DKr273O Herkv, Denmark.
`Copyright © 1996 by W.B. Saunders Company
`OO93¢7754/96/230l»0103$05.00/O
`
`Celltrion v. Genentech
`
`Seminars in Oncology, Vol 23, No l, Suppl
`
`| (February), I996: pp l3-l8
`
`IPR2017-01122 .3
`
`Genentech Exhibit 2013
`
`

`

`I4
`
`DOMBERNOWSKY ET AL
`
`pretreated, having received a median of two
`(range,
`two to six) chemotherapy regimens,
`in—
`cluding high—dose chemotherapy in 15%. The
`overall response rate among these 76 patients was
`33% (95% Cl, 14% to 37%), with a median re—
`
`sponse duration of 7 months. Responses were
`found to be at least as likely in patients prospec—
`tively classified as de novo resistant to anthracy—
`clines (32%) as in patients classified as having
`initial sensitivity (acquired resistance) to anthra—
`cyclines (30%).
`In an MD. Anderson Cancer Center (Houston,
`
`TX) study of 12 patients, three partial responses
`(PRs) were seen with paclitaxel 135 to 150 mg/
`m2 given as a 24—hour infusion without G—CSF
`support? All patients had received prior doxorubi—
`cin as adjuvant and/or metastatic therapy and were
`pretreated with at least three prior chemotherapy
`regimens.
`A study of short, 3—hour infusions of paclitaxel
`175 mg/m2 given as salvage chemotherapy also has
`been completed at the Memorial Sloan—Kettering
`Cancer Center.6 Definite results are not yet avail—
`able, but the preliminary response among 24 pa—
`tients with prior anthracycline treatment is 21%
`(95% CI, 7% to 42%).
`
`The results of a phase I/II trial of paclitaxel
`given by 96—hour infusion to doxorubicin— or mi—
`toxantrone—refractory breast cancer patients re—
`cently have been published.7 In that study, patients
`had received a median of two prior regimens for
`metastatic disease. The paclitaxel dose ranged from
`120 to 140 mg/mz, and 21 of the 33 patients in—
`cluded also received G—CSF. Results showed that
`
`48% (95% CI, 31% to 66%) achieved a PR and
`that the response duration was 7 months. Dose—
`limiting toxicity consisted of mucositis and grade
`4 granulocytopenia.
`Two recently reported major trials also have
`confirmed the activity of paclitaxel
`in patients
`with breast cancer and prior therapy with anthra—
`cyclines. In the first, a National Cancer Institute
`(Bethesda, MD) treatment referral center study,8
`paclitaxel 135 to 175 mg/m2 given over 24 hours
`resulted in an overall response rate of 23% (95%
`CI, 17% to 30%), and the response rate among
`153 patients, whose disease had progressed either
`during doxorubicin treatment or within 6 months
`after its completion, was 24%. The second study,
`performed by the Milan group, used paclitaxel
`
`doses ranging from 175 to 225 mg/m2 given as a
`3—hour infusion.9 Response to paclitaxel was found
`in 38% (95% CI, 25% to 53%) of 50 patients with
`prior anthracycline treatment, given either for
`metastatic disease or in the adjuvant/neoadjuvant
`setting.
`Table 1 summarizes five of the above—mentioned
`
`studies of patients with prior anthracycline expo—
`sure. As can be seen, a considerable fraction (24%
`
`to approximately 50%) of patients with prior an—
`thracycline exposure, or resistance to these drugs,
`do respond to second— or third—line paclitaxel ther—
`apy, although the definition of resistance varies
`considerably among the different studies.
`
`Phase III Trials
`
`A European/Canadian randomized trial com—
`pared paclitaxel 135 and 175 mg/rnz, given by 3—
`hour infusion.lo Preliminary results are available
`for the first 245 patients of 471 included. Overall,
`31% of the patients had received previous adj uvant
`chemotherapy only, 37% had been given prior
`treatment for metastatic disease, and 32% had re—
`
`ceived therapy for both adjuvant and metastatic
`disease. Currently, 234 patients are evaluable for
`response. The overall preliminary response rate is
`26% (eight CRs and 52 PR5). The response rate
`was 32% in patients who had received previous
`adjuvant chemotherapy only and 20% in those
`with previOus chemotherapy for metastatic disease.
`According to dose level, 29% of the patients who
`received the higher dose and 22% treated at the
`lower dose level responded. At both dose levels
`treatment was well tolerated and demonstrated the
`
`safety and efficacy of paclitaxel administered as a
`3—h0ur infusion.
`
`COMBINATION CHEMOTHERAPY WITH
`PACLITAXEL AND DOXORUBICIN
`
`Based on initial reports demonstrating a high
`activity level of single—agent paclitaxel in patients
`having had only minimal chemotherapy for meta—
`static breast cancer, it was of great interest to test
`paclitaxel in combination with other drugs.
`Doxorubicin, currently the most active agent
`against metastatic breast cancer, was the obvious
`first choice for combination chemotherapy. Of par—
`ticular clinical relevance was the observation of
`
`at least a partially clinical non—cross—resistance
`
`

`

`PACLITAXEL AND DOXORUBICIN IN MBC
`
`
`
`l5
`
`Holmes et aI2
`
`Dose (mg/m1)/
`Schedule (hr)
`
`200—250/24
`
`No. of Evaluable
`Patients
`
`* Including two of six refractory patients (ie, progression/relapse on anthracycline or relapse within 6 months).
`
`Definition of Prior Anthracycline Exposure
`
`23 have received prior doxorubicin, including
`|
`l for metastatic disease and II adjuvant
`Progression/relapse on doxorubicin or
`relapse within I2 mo
`Failure to achieve CR (27%) or failure to
`respond (73%) to doxorubicin or
`mitoxantrone
`
`Progression on doxorubicin or relapse within
`6 mo
`
`Progression/relapse on doxorubicin (six
`patients adjuvant, I9 neoadjuvant, and 26
`for metastatic disease)
`
`Seidman et al‘
`
`200-250/24
`
`Wilson et al7
`
`I 20- I40/96
`
`Abrams et aI‘3
`
`I35- I 75/24
`
`Gianni et al9
`
`I 75-225/3
`
`between paclitaxel and doxorubicin in patients
`with metastatic breast cancer, as detailed above.
`Several trials, some now finished and some on—
`
`going, aimed at defining the optimal dose and
`schedule of paclitaxel in combination with doxo—
`rubicin. Some of these studies are summarized here.
`
`Phase 1 Trials of Doxorubicin Given as a
`Continuous Infusion
`
`Holmes11 has assessed paclitaxel and doxorubi—
`cin administered sequentially to patients who had
`received no prior chemotherapy for metastatic dis—
`ease, but who may have received adjuvant chemo—
`therapy including doxorubicin. Paclitaxel 125 to
`210 mg/m2 was given as a 24—hour infusion on day
`1, followed by doxorubicin 60 mg/m2 given as a
`48—hour infusion starting on day 2, with the addi—
`tion of G—CSF. Because of severe and dose—limiting
`mucositis and a high incidence of febrile neutro—
`penia, the sequence of administration of the two
`drugs was inverted. The maximum tolerated doses
`(MTDS) of paclitaxel and doxorubicin were 125
`and 48 mg/m2, respectively, in the original sched—
`ule. With the reverse schedule, 60 mg/m2 doxoru—
`bicin and 150 mg/m2 paclitaxel were the MTDs
`achieved, with neutropenic fever as the dose—lim—
`iting toxicity. The response rate was 80% (95%
`CI, 44% to 98%) in the 10 patients treated with
`paclitaxel followed by doxorubicin, and 57% (95%
`CI, 34% to 78%) in the 21 patients treated with
`the reverse schedule. The median response dura—
`tion in both series was greater than 6.5 months.
`
`A parallel pharmacokinetic study indicated that
`therapy with a 24—hour infusion of paclitaxel prior
`to the start of the 48—hour doxorubicin infu—
`sion decreased doxorubicin metabolite clearance
`
`by 32%.12
`In a National Cancer Institute study, the MTDs
`of paclitaxel and doxorubicin administered as a
`simultaneous IV infusion over 72 hours every 3
`weeks, together with G—CSF, were 160 mg/m2 and
`75 mg/m2, respectively.13 In this phase I trial, the
`response rate was 62% in 18 patients, and the
`median response duration was more than 8
`months. Again, the patients were minimally pre—
`treated, and only four patients had received prior
`adjuvant chemotherapy. The dose—limiting toxic—
`ity was diarrhea, and abdominal pain due to clini—
`cal typhlitis was reported in three patients. Other
`significant toxicities included grade 3 diarrhea at
`the higher dose levels and grade 4 neutropenia in
`all cases. No differences were observed in pacli—
`taxel or doxorubicin pharmacokinetics when the
`drugs were administered alone versus in combina—
`tion.14
`
`PHASE I STUDIES WITH DOXORUBICIN
`
`AS RAPID AND BOLUS INJECTION
`
`In a multicenter phase II study, paclitaxel and
`doxorubicin were administered using an alternat—
`ing schedule.15 To be eligible, patients must have
`received no more than one prior non—anthracy—
`Cline—containing regimen for metastatic disease or
`as adjuvant therapy. Paclitaxel was administered
`
`

`

`I6
`
`DOMBERNOWSKY ET AL
`
`at a dose of 200 mg/m2 as a 24rhour infiision, fol—
`lowed after 3 weeks by bolus injection of doxorubi—
`Cin 75 mg/m2. With this regimen, there were two
`CRs and five PR5 in 12 patients. Neutropenia was
`the major toxicity and was more severe following
`paclitaxel administration. In contrast, however,
`thrombocytopenia was more pronounced following
`doxorubicin.
`
`A second Eastern Cooperative Oncology Group
`trial evaluated doxorubicin as an IV push and
`paclitaxel as a 24—hour continuous infusion.16 The
`sequence of drug administration was alternated
`both among the patients and in individual patients
`to evaluate the effect of administration sequence
`on toxicity. Granulocyte colony—stimulating factor
`was used in this study. The two dose levels evalu—
`ated were paclitaxel 150 and 175 mg/m2 and doxor
`rubicin 50 and 60 mg/m2, respectively. Of note,
`mucositis of any grade and grade 3/4 were more
`frequent when paclitaxel preceded doxorubicin
`than vice versa. Responses were seen in five of 12
`patients, with a median duration of 11 months.
`A phase I/II study to define the optimal dose
`and MTD of paclitaxel given as a 3’hour infusion
`combined with bolus doxorubicin recently has
`been finalized by Gianni et al at the Istituto Nazio—
`nale Tumori in Milan (personal communications,
`June 1995).17 In that trial, previously untreated
`patients with metastatic breast cancer were given
`paclitaxel at a starting dose of 125 mg/mz, escalated
`by 25—mg increments to a maximum dose of 200
`mg/mz. Doxorubicin was administered as an IV
`bolus in a fixed dose of 60 mg/m2 before or after
`the paclitaxel infusion to assess the role played by
`drug sequence. Patients were assigned to receive
`either paclitaxel followed by doxorubicin or doxo’
`rubicin followed by paclitaxel in the first cycle and
`then were crossed over to the other sequence in
`the second cycle.
`This combination of drugs was found to be very
`active. Among 32 patients evaluable for activity,
`12 CR5 and 18 PRs were observed, for an overall
`response rate of 94% (95% CI, 79% to 99%). The
`main toxicities of the combination were neutror
`
`penia, oral mucositis, myalgias, and peripheral neu—
`ropathy. The sequence of administration of pacli’
`taxel and doxorubicin had no significant effect on
`the tolerability of the combination. Neutropenia
`and peripheral neuropathy tended to be more se
`vere after repeated cycles, whereas nausea and
`
`vomiting requiring treatment occurred in only 4%
`of cycles. The MTD of paclitaxel was reached at
`200 mg/m2 with severe neutropenia (<O.5 X 109/
`L for >7 days) in four patients and 10 cycles,
`febrile neutropenia in six patients and eight cycles,
`and grade 3 mucositis in six patients and eight
`cycles. Six patients developed congestive heart
`failure, five after cumulative doxorubicin doses of
`480 mg/m2 and one after 120 mg/m2 and irradia—
`tion involving the heart.
`In a phase l/II study implemented in November
`1993 and currently ongoing in Copenhagen,
`women with metastatic breast cancer who had re
`
`ceived no more than one prior adjuvant chemov
`therapy regimen and no prior anthracycline treatv
`ment were given doxorubicin as a 30vminute
`infusion followed by paclitaxel as a 3ahour infusion
`every 3 weeks. At this time, 30 patients are evalu’
`able for toxicity and 29 for response. Three pa—
`tients have received dose level 1 (doxorubicin 50
`trig/mZ and paclitaxel 155 mg/mz), 21 patients have
`received dose level 2 (doxorubicin 60 mg/m2 and
`paclitaxel 175 mg/mz), and five patients have re—
`ceived dose level 3 (doxorubicin 60 mg/m2 and
`paclitaxel ZOO rag/m2). The median age of the pa;
`tients was 50 years (age range, 32 to 69), and the
`median Eastern Cooperative Oncology Group per—
`formance status was 1 (range, 0 to Z). Most patients
`have extensive disease, and 83% have bone and/
`or Visceral metastases.
`
`More than 260 treatment cycles have been
`given. Toxicities observed are grade 3/4 neutro’
`penia and moderate paresthesias, nausea and vom»
`iting, alopecia, myalgia, and mucositis. Cardiotox’
`icity has been observed frequently. Fifteen patients
`have had a significant decrease in left ventricular
`ejection fraction as measured by isotope cardiogra'
`phy, and six of those patients have developed conr
`gestive heart failure. Due to neurotoxicity, three
`patients went off study after three courses. Twenty—
`nine patients are currently evaluable for response.
`Of these, 17 patients achieved a PR and seven a
`CR, for an overall response rate of 83% (95% CI,
`79% to 99%). Time to progression was approxi—
`mately 9 months (range, 2 to 19+ months). The
`response rates at the different dose levels are shown
`in Table 2.
`
`These preliminary results suggest that combined
`administration of doxorubicin and paclitaxel
`is
`well tolerated and that few patients need hospital—
`
`

`

`PACLITAXEL AND DOXORUBICIN IN MBC
`
`
`
`l7
`
`Dose Level
`Doxorubicinl
`
`Paclitaxel (mg/m2)
`
`No. of
`Patients
`
`PR
`
`CR
`
`Response PR
`+ CR (%)
`
`
`
`I (33)
`50/l55
`I 8 (86)
`60/ I 75
`5 (IOO)
`60/200
`24 (83)
`Total
`
`
`ization due to adverse effects caused by the treat—
`ment. Furthermore, the efficacy of the drug combi—
`nation seems high, as preliminary response rates
`in the Milan and Copenhagen studies are 94% and
`83%, respectively.
`An ongoing, randomized intergroup phase III
`study has been designed to evaluate the efficacy
`and tolerability of paclitaxel and doxorubicin both
`alone and in combination. The study regimens are
`(1) paclitaxel 175 mg/m2 given as a 24—hour infu—
`sion, (2) doxorubicin 60 mg/m2 given as an IV
`bolus, and (3) combination doxorubicin 50 mg/m2
`IV bolus followed 4 hours later by paclitaxel 150
`mg/m2 as a 24—hour infusion. The drugs are given
`as first—line chemotherapy. At present, more than
`400 patients have been included in this study, but
`no data are available yet.16
`
`CONCLUSION
`
`Paclitaxel given as single agent has been shown
`to be active in both minimally pretreated and
`heavily pretreated patients with metastatic breast
`cancer. As activity was also observed in doxorubi—
`cin—resistant patients, several groups of investiga—
`tors have now combined paclitaxel and doxorubi—
`cin in attempts to improve the patient benefit.
`However, it is still unknown whether, optimally,
`paclitaxel and doxorubicin should be given con—
`comitantly or in sequence and what the optimal
`dose or infusion duration of each drug is.
`Data from the Copenhagen and Milan studies,
`both of which apply short infusions of both pacli—
`taxel and doxorubicin, strongly indicate that clini—
`cal cardiotoxicity is a significant problem associ—
`ated with this combination, when the drugs are
`administered as in these studies. This implication
`is in contrast to other studies of the combination
`
`in which neither congestive heart failure nor sig—
`nificant decreases in left ventricular ejection frac—
`tion have been described. Whether the solution
`
`to the problem involves lowering the peak concen—
`tration of doxorubicin by decreasing the drug dos—
`ages or by prolonging the infusion duration is at
`present unknown. Ongoing studies explore the im—
`pact of the interval between doxorubicin and
`paclitaxel administration by treating patients at
`increasing intervals. In these studies the recom—
`mended cumulative dose of doxorubicin is 360
`
`mg/mz.
`
`REFERENCES
`
`1. Rowinsky BK, Onetto N, Canetta RM, et al: Taxol: The
`first of the taxanes, an important new class of antitumor agents.
`Semin Oncol 191646—662, 1992
`2. Holmes FA, Walters RS, Theriault RL, et al: Phase II
`trial of Taxol, an active drug in the treatment of metastatic
`breast cancer. J Natl Cancer Inst 83:1797—1805, 1991
`3. Reichman BS, Seidman AD, Crown JPA, et al: Paclitaxel
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`as initial chemotherapy for metastatic breast cancer. J Clin
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`4. Seidman AD, Reichman BS, Crown JPA, et al: Paclitaxel
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`1994
`8. Abrams JS, Vena DA, Baltz J, et al: Paclitaxel activity in
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`interim analysis. Onkologie 17:86—90, 1994
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`12. Holmes FA, Newman RA, Madden T, et al: Schedule
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`

`

`l8
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`DOMBERNOWSKY ET AL
`
`tor in patients with metastatic breast cancer. Monogr Natl
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`86:143445, 1994
`15. Sledge G, Sparano J, McCaskill—Stevens W, et a1: Pilot
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`
`161 Sledge GW, Robert N, Sparano JA, et a1: Paclitaxel
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`
`breast cancer patients. Proc Am Soc Clin Oncol 13:74, 1994
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`
`