Multicenter Phase II Trial of Weekly Paclitaxel in Women
`With Metastatic Breast Cancer
`
`By Edith A. Perez, Charles L. Vogel, David H. Irwin, Jellrey J. Kirshner, and Ravi Patel
`
`Purpose: We evaluated the safety and efficacy of
`weekly paclitaxel therapy in women with metastafic
`breast cancer in a phase II multicenter trial. Entry crite-
`ria were relatively liberal to reflect the heterogeneity of
`metastatic breast cancer in clinical practice.
`Patients and Methods: Patients had histologically
`confirmed and measurable metastatic breast cancer.
`Up to two prior chemotherapy regimens for metastatic
`disease, including prior therapy with anthracyclines
`and taxanes and prior high-dose therapy, were al-
`lowed. Paclitaxel 80 mg/m2 was administered weekly
`for 4 weeks per 4-week cycle.
`Results: We enrolled 2| 2 patients; 21 1 were assess-
`able for toxicity and 177 were assessable for response.
`Ninety percent of patients had received prior chemo-
`therapy (adiuvant, metastatic, or both), 46% of patients
`had three or more involved metastatic sites, and 60% of
`patients had visceral-dominant disease. Responses
`were documented on two occasions and were indepen-
`
`N THE YEAR 2001, it is estimated that 192,200 women
`in the United States will be newly diagnosed with breast
`cancer and 40,200 women will die of their disease.I Al-
`though advances in breast cancer detection and treatment
`have improved the odds of long-ten'rr survival, breast cancer
`remains the second most common cause of cancer-related
`
`death in women, surpassed only by lung cancer.1 With
`current treatment modalities, the long-term prognosis for
`women with early-stage disease is generally very good.
`However,
`few patients with metastatic disease will be
`long-term disease-free survivors.2 In the United States,
`metastatic disease as an initial diagnosis accounts for
`approximately 1% to 5% of new breast cancer cases.
`However,
`it
`is estimated that 20% to 30% of patients
`
`From the Mayo Clinic, Jacksonville; Columbia Cancer Research
`Network, Aventura, FL; Alta Bates Comprehensive Cancer Center,
`Berkeley: Comprehensive Blood and Cancer Center. Bakersfield. CA;
`and Hematology/Oncology Associates of Central New York, syracuse,
`NY.
`Submitted September 26, 2000; accepted June 26, 2001.
`Supported by grants from Bristol-Myers Squibb Oncology. Prince-
`ton. NJ, and the Breast Cancer Research Foundation, New York, NY.
`Address reprint requests to Edith A. Perez, MD. Division of
`Hematolognyncology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville,
`FL 32224: email: perez.edith@mayo.edu.
`© 200] by American Society of Clinical Oncology.
`0732-183X/01/1922-42l6f320.00
`
`dently reviewed. The overall response rate (complete
`plus partial response) was 21.5% (95% confidence in-
`terval, 15.4% to 27.5%), with 41.8% of patients having
`disease stabilization. Median time to progression was
`4.7 months, and overall survival in all 212 patients
`enrolled was 12.8 months. Therapy was well tolerated,
`with a 1 5% incidence of grade 3/4 hematologic toxicity
`and a 9% incidence of grade 3 neuratoxicity; other
`serious toxicities were rare. The response rate and
`toxicity profile in the 34% of patients a 65 years of age
`were similar to that of younger patients.
`Conclusion: Weekly paclitaxel therapy was well tol-
`erated and demonstrated reasonable activity in this
`relatively heavily pretreated population with advanced
`disease. Further study of weekly paclitaxel in combina-
`tion therapy is warranted.
`J Clin Oncol 19:4216-4223. 4: 2001 by American
`Society of Clinical Oncology.
`
`initially diagnosed with early-stage disease will eventually
`develop metastatic breast cancer.2
`New treatment options for women with metastatic breast
`cancer are needed. Because many of these patients will have
`previously received chemotherapy, either as adjuvant ther-
`apy or for advanced disease, tolerability of treatment for
`metastatic disease is an important consideration.
`Paclitaxel
`is an effective agent
`in the treatment of
`metastatic breast cancer. Overall response rates of 21% to
`62% have been reported in phase 11 and phase III trials
`evaluating paclitaxel at doses of 135 to 250 mg/m2 admin-
`istered by either 3- or 24-hour infusion as initial or subse-
`quent therapy to women with metastatic breast cancer?'3
`Neutropenia is generally the most common toxicity reported
`among these studies, although neuropathy can be dose-
`limiting, particularly with short infusions of paclitaxel.
`Recent reports of the activity and tolerability of weekly
`dosing of paclitaxel have generated much clinical interest.
`In women with metastatic breast cancer, studies administer-
`ing paclitaxel weekly by 1-hour infirsion at doses ranging
`fi'om 80 to 100 mg/m2 have reported overall response rates
`of 50% to 68%.14'20 In general, weekly paclitaxel therapy
`has been quite well tolerated, causing minimal myelosup-
`pression and no apparent cumulative myelosuppression.
`Neuropathy, when present, is usually of mild or moderate
`severity and generally reversible.
`Although the results of these trials of weekly paclitaxel in
`metastatic breast cancer have been encouraging, the indi-
`
`4216
`
`Joumal of Clinical Oncology, Vol 19, No 22 (November 15), 2001: pp 4216-4223
`
`Information downloaded from jeo.ascopubs.org and provided b at Reprints Desk on August 31, 2016 from 216.185.156.28
`Copyright © 2001 American Society of
`linical Oncology. All rights reserved.
`
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`

`

`WEEKLY PACLITAXEL IN METASTATlC BREAST CANCER
`
`4217
`
`vidual trials reported to date have been relatively small,
`enrolling 30 or fewer patients. We conducted this large
`multicenter phase II trial of weekly paclitaxel to more fully
`characterize the activity and safety of this therapy in women
`with metastatic breast cancer. Given that several
`large
`clinical trials in breast cancer are currently investigating
`weekly paclitaxel-based regimens, the efficacy and toxicity
`information of weekly single-agent paclitaxel provided by
`this study may provide an important perspective for the
`interpretation of these clinical trials.
`
`PATIENTS AND METHODS
`
`Eligibility Criteria
`
`Women with histologically or cytologically confirmed metastatic
`breast cancer with bidimensionally measurable or otherwise assessable
`and documentable disease, such as mediastinal or pleural-based masses
`or lytic bone metastases, were eligible for enrollment. Patients were
`required to be 2 l8 years of age; have an Eastern Cooperative
`Oncology Group performance status of 0 to 2; have adequate bone
`marrow, renal, and liver function (absolute granulocyte count 2' 1,500
`p.L, platelets 2 100,000 uL, serum creatinine and total bilirubin 5 two
`times the upper normal limit, and AST or ALT s 2.5 times the upper
`normal
`limit); and provide informed consent per institution review
`board guidelines. Women of childbearing potential must have had a
`negative prestudy pregnancy test and practice appropriate contracep-
`tion while on study.
`Patients may have received up to two prior chemotherapy regimens
`for metastatic disease, and in addition may have received prior adjuvant
`chemotherapy, hormonal therapy, radiation therapy, and immunother—
`apy. Patients who had been treated with high-dose chemotherapy with
`stem-cell support were also eligible. Previous treatment with a taxane
`was allowed provided administration was on a Z 3-week schedule.
`Patients with asymptomatic brain metastases were eligible provided
`they had completed cranial irradiation more than 4 weeks before study
`entry therapy and had other assessable sites of disease. Prestudy
`evaluation included a complete history and physical examination,
`complete blood cell count with differential, platelet count, senJm
`chemistries, ECG, and tumor measurement and appropriate radio-
`graphic or CT imaging for disease assessment.
`Exclusion criteria included major surgery, radiation, chemotherapy,
`or immunotherapy within 3 weeks of study entry (5 weeks for prior
`nitrosourea, melphalan, or mitomycin therapy), or prior radiation to
`more than 30% of bone marrow. Patients with bone metastases as their
`only site of assessable disease were not eligible if bisphosphonate
`therapy had been initiated less than 2 months before enrollment.
`Patients with New York Heart Association class 3 or 4 heart disease
`were excluded, as were patients with preexisting peripheral neuropathy
`more than grade 1 and those with a corrected serum calcium level of E
`12 mgldL at study entry. Patients with other serious medical conditions
`potentially compromising study participation were also excluded.
`
`Study Design
`
`Paclitaxel 80 mg/m2 was administered over 1 hour weekly for 4
`weeks per 4-week cycle. Premedications consisted of diphenhydramine
`50 mg administered intravenously (IV) and an H2 blocker (such as
`cimetidine 300 mg 1V), both administered 30 to 60 minutes before
`therapy. along with dexamethasone 20 mg administered either orally 12
`
`and 6 hours prior or IV 30 to 60 minutes before paclitaxel. If no
`hypersensitivity reactions occurred after the first paclitaxel dose,
`dexamethasone dose reductions were permitted. Treatment continued
`until disease progression or prohibitive toxicity. The use of hemato-
`poietic colony-stimulating factors was discouraged. In the event of
`serious hematologic toxicity (absolute granulocyte count 5 800 uL or
`platelets 5 50,000 [.LL), treatment was held until recovery and the
`weekly paclitaxel dose was decreased by 10 mg/m’. For grade 2 motor
`or sensory neuropathy, the weekly paclitaxel dose was decreased by l0
`mg/m2 without interruption of therapy. For all other nonhematologic
`grade 2 toxicities, treatment was held until toxicity diminished to 5
`grade I and subsequent weekly doses were decreased by 10 mg/m2.
`Patients experiencing grade 3 nonhematologic toxicities were removed
`from study, as were those who could not tolerate therapy afier two dose
`reductions or 60 mg/m2 weekly. Patients requiring a treatment delay of
`more than 2 weeks were also removed from study.
`
`Response and Toxicity Assessment
`
`Complete blood cell counts, platelet counts, and toxicity assessment
`were performed weekly, with performance status and semm chemis-
`tries assessed before each cycle (every 4 weeks). Toxicity was
`evaluated according to National Cancer Institute common toxicity
`criteria guidelines.
`Tumor measurements for response assessment were obtained every
`three cycles ( l2 weeks), and all responses had to be confirmed by a
`second measurement after an additional 4 weeks. All response claims
`were independentiy reviewed. Patients must have completed at least
`one required on—study evaluation of their disease to be considered
`assessable for response. However, patients removed from study for
`disease progression before their first response assessment at 12 weeks
`were included as assessable provided they had received at least three
`weekly paclitaxel doses. Response criteria were as follows: complete
`response was defined as the disappearance of all clinical and radio-
`graphic evidence of disease determined on two observations at least 4
`weeks apart, partial response was defined as a 2 50% decrease in the
`sum of products of the biperpendicular diameters of measurable lesions
`or a 2 50% decrease in the size of assessable lesions (agreed on by two
`investigators) confirmed on two evaluations at least 4 weeks apart and
`no increase in or appearance of new lesions, stable disease was defined
`as a less than 50% decrease in the in the sum of products of the
`biperpendicular diameters of measurable lesions or in the size of
`assessable lesions and no increase in or appearance of new lesions, and
`progressive disease was defined as a 2 25% increase in lesion size or
`the appearance of any new lesion.
`
`Statistical Methods
`
`The primary study end point was response rate. We estimated that a
`total sample size of 200 patients would be required to allow for 179
`assessable patients. This sample size was required to demonstrate an
`anticipated response rate of 35% with confidence intervals of 28% to
`42% at an alpha of 0.05. Comparison of response rates among different
`patient subgroups, including number of prior regimens for metastatic
`disease, prior taxane versus no prior taxane, prior anthracycline versus
`no prior anthracycline, prior high-dose therapy versus all other prior
`therapies, visceral dominant disease versus nonvisceral dominant
`disease, and presence of three or more three metastatic sites versus
`fewer than three metastatic sites were evaluated by the x2 test.
`Duration of response was calculated fi'om the day the response was
`first recorded until day of disease progression. Time to progression and
`overali survival were calculated from the day of study entry until the
`
`Information downloaded from jco.ascopubs.org and provided b at Reprints Desk on August 31, 2016 from 216.185.156.28
`Copyright © 2001 American Society of
`linical Oncology. All rights reserved.
`
`

`

`4218
`
`day of documented disease progression or death, respectively. Overall
`survival was calculated from the date of study enrollment until death.
`Patients who died without documented disease progression were
`censored on the day of death or last follow-up. Patients who did not
`expire were censored at the time they were last known to be alive. Time
`to progression and overall survival distributions were estimated using
`the Kaplan-Meier method.2|
`
`Quality-of-Life Analysis
`
`The Functional Assessment of Cancer Therapy (FACT)-B and
`FACT—Taxane questionnaires were used to assess quality of life?“3
`Data were obtained at study entry, before each cycle of therapy for the
`first six cycles, and then every three cycles thereafter. 0n the prede-
`termined visits, patients completed the questionnaires before their
`meeting with the physician and the start of the paclitaxel infusion,
`although some patients may have started their premedication regimen.
`Both the FACT—B and the FACT-Taxane had five main subscales:
`physical well-being, socialffamily well-being, emotional well-be—
`ing, relationship with physician, and functional well-being; an
`additional concerns subscale was also assessed. The additional
`concerns of the FACT-B Were specific to breast cancer, and the
`additional concerns of the FACT-Taxane were specific for taxane
`treatment. Differences were assessed using paired I tests, with type
`1 error not adjusted for most comparisons.
`
`RESULTS
`
`The study enrolled 212 patients at 27 participating insti-
`tutions. Patient characteristics are listed in Table 1. The
`
`majority of patients (88%) had an Eastern Cooperative
`Oncology Group performance status of 0 or 1, with com-
`parable percentages for patients younger and older than 65
`years. Nearly half of the patients had three or more sites of
`metastatic disease. Hepatic and/or visceral metastases were
`present in 72% of patients and were the dominant site of
`disease in 60% of patients. The time from diagnosis of
`breast cancer to study entry was more than 12 months in 183
`patients (86%), 6 to 12 months in 11 patients (5%), and less
`than 6 months in 18 patients (9%).
`The majority (90%) of patients had received prior che-
`motherapy, either as adjuvant treatment, therapy for meta-
`static disease, or both (Table 1). Prior treatment with
`anthracyclines was reported for 152 patients (72%). Anthra-
`cyclines were administered in the adjuvant or neoadjuvant
`setting in 67 of these patients, as therapy for metastatic
`disease in 76 patients, and as both adjuvant and metastatic
`therapy in nine patients. Time from prior anthracycline
`therapy was less than 3 months for 39 patients, 3 to 6
`months for 14 patients, 6 to 12 months for 16 patients, and
`more than 12 months for 83 patients. The median number of
`days from prior anthracycline therapy was 462 (range, 21 to
`3,185 days). A total of 54 patients (25%) had received prior
`taxane therapy; 38 patients had received paclitaxel, 15
`patients had received docetaxel, and one patient had re-
`ceived both. The taxanes were administered primarily for
`
`Table 1. Patient Characteristics (N = 212)
`
`Age, years
`Mean
`Range
`Patients 2 age 65 years
`ECOG performance status
`0
`1
`2
`No. at metastatic sites involved (n = 211)
`1
`2
`3+
`Site of metastasis
`Visceral (not including hepatic)
`Hepatic
`Salt tissue
`Bone
`Brain
`Other
`Prior chemotherapy
`Adiuvant therapy only
`Metastatic therapy only
`Both adiuvant and metastatic
`No prior chemotherapy
`No. 01 chemotherapy regimens lor metastatic disease
`0
`1
`2
`Prior therapy
`Anthracycline
`Taxane
`High-dose with stem-cell support
`Hormonal
`Radiation
`
`PEREZ ET AL
`
`No.
`
`%
`
`60
`31 -88
`
`73
`
`88
`99
`25
`
`55
`59
`97
`
`1 14
`90
`1 15
`122
`24
`9
`
`44
`73
`74
`21
`
`66
`106
`41
`
`152
`54
`20
`1 54
`143
`
`34
`
`41
`47
`1 2
`
`26
`28
`46
`
`54
`42
`54
`58
`1 1
`4
`
`21
`34
`35
`10
`
`31
`50
`1 9
`
`72
`25
`9
`73
`68
`
`Abbreviation: ECOG, Eastern Cooperative Oncology Group.
`
`treatment of metastatic disease, although five patients re-
`ceived paclitaxel as adjuvant therapy. Prior taxane therapy
`was administered on an every-3-to—4-weeks schedule except
`in two patients who received only one dose. Time from prior
`taxane therapy was less than 3 months for 28 patients, 3 to
`6 months for 6 patients, 6 to 12 months for 9 patients, and
`more than 12 months for 11 patients. The median number of
`days from prior taxane therapy was 83 (range, 21 to 1,047
`days). In addition, 20 patients (9%) had undergone prior
`high-dose therapy with stem-cell support.
`A total of 1,068 cycles of therapy were administered to
`211 patients (one patient refirsed treatment). The median
`number of cycles delivered was four (range, 1 to 29)(Fig 1),
`with a mean weekly delivered dose of 77 mg/m2. Only 14%
`of doses were delayed or reduced, with 7% being delayed or
`reduced because of toxicity and 7% because of social or
`other reasons.
`
`Information downloaded from jco.ascopubs.org and provided by at Reprints Desk on August 31, 2016 from 216.185.156.28
`Copyright © 2001 American Society of Clinical Oncology. All rights reserved.
`
`

`

`WEEKLY PACUTAXEL IN METASTATIC BREAST CANCER
`
`4219
`
`developed grade 3 neuropathy afier five and 11 courses of
`therapy. Overall, the incidence of any grade of neuropathy
`was 69%; however, grade 3 neuropathy was encountered in
`only 20 patients (9%), and no patient experienced grade 4
`neuropathy. The median number of courses of therapy until
`development of grade 2 or 3 neuropathy, including patients
`with preexisting grade 1
`toxicity, was five courses (20
`weeks) for either, and ranged from one to 13 courses.
`Grade 3 asthenia and arthralgia/myalgia occurred in 4%
`and 2% of patients, respectively. Other grade 3 nonhema—
`tologic toxicities were quite uncommon, occurring in no
`more than 1% of patients. Grade 4 nonhematologic toxicity
`was limited to one patient who experienced a severe
`anaphylactic reaction.
`Given that 34% of patients enrolled were 2 65 years of
`age, we compared the incidence of toxicities in this group
`with that of patients who were younger than 65 years. There
`were no substantial differences in the overall
`toxicity
`incidence or the incidence of grade 3 or 4 toxicities between
`the two age groups.
`
`Response
`
`Of the 212 patients enrolled, 177 (83%) were fully
`eligible for response evaluation. Thirty-five patients were
`deemed ineligible for response evaluation for the following
`reasons: therapy refusal (seven patients), treatment discon-
`tinuation before first scheduled response evaluation (nine
`patients, including three because of hypersensitivity reac-
`tions with their first
`treatment), physician decision to
`withdraw patient from study (seven patients, several of
`
`35
`
`20
`
`NumberatPatients 10
`
`15
`
`5 0
`
`1 2 3 4 5 B 7 B 91011121314151817181920212223242526272829
`Cycles Delivered
`
`Fig l. Cycles of weekly paclitaxel administered (n = 211); each cycle =
`4 weeks.
`
`Toxicilies
`
`Toxicity data were available for 211 patients who had
`received at least one dose of paclitaxel. Overall. therapy
`was generally well
`tolerated and manageable on an
`outpatient basis (Table 2). Grade 3 or 4 neutropenia
`occurred in 31 patients (15%). All but two patients who
`developed grade 3 or 4 neutropenia had received prior
`chemotherapy, and five of these patients had received
`prior high-dose chemotherapy. Grade 3 anemia was
`encountered in 18 patients (9%), and one patient each
`experienced grades 3 and 4 thrombocytopenia.
`There were 30 patients (14%) enrolled with preexisting
`grade 1 neuropathy. Two of these patients eventually
`
`Table 2. Highest Degree of Treatment-Related Toxicity Observed (N = 2111'
`Grade 1
`Grade 2
`Grade 3
`Grade 4
`No.
`%
`Na.
`‘1
`No.
`3;
`Na.
`% ’
`
`
`5
`lo
`10
`21
`l 8
`38
`22
`46
`Neutropenla
`t: l
`l
`< l
`l
`l
`3
`24
`50
`Thrombocytopenia
`0
`0
`9
`l 8
`37
`79
`45
`96
`Anemia
`0
`0
`0
`0
`2
`5
`l
`2
`Infection
`0
`0
`l
`3
`0
`0
`0
`0
`Febrile neutropenia
`< l
`l
`< l
`l
`l
`2
`< l
`l
`Anaphylaxis
`0
`0
`9
`20
`21
`44
`38
`8l
`Neuropalhy
`0
`0
`2
`4
`6
`12
`18
`37
`Arthralgia/myalgia
`0
`0
`4
`8
`l 8
`39
`26
`54
`Asthenia
`0
`0
`< l
`l
`7
`l 4
`9
`l 9
`Edema
`0
`0
`l
`3
`3
`6
`22
`47
`Nausea
`O
`0
`l
`3
`l
`3
`8
`16
`Vomiting
`0
`0
`< l
`l
`4
`8
`18
`39
`Diarrhea
`0
`0
`Q l
`1
`4
`8
`l6
`33
`Slomaiitis
`0
`0
`0
`0
`30
`64
`l 2
`26
`Aiopecia
`0
`0
`0
`0
`3
`6
`17
`36
`Nail disorder
`
`
`
`
`
`
`
`
`Rush 0 27 l 3 l0 5 l < l 0
`
`'Toxicity assessed according to the National Cancer Institute common toxicity criteria.
`
`Information downloaded from jco.ascopubs.org and provided by at Reprints Desk on August 31. 2016 from 216.185.156.28
`Copyright © 2001 American Society of Clinical Oncology. All rights reserved.
`
`

`

`
`Table 3. Response to Therapy and Survival Times in Assessable Patients
`No. of Prior Metastatic Therapy Regimens
`All patients (N -— 177)
`None in = 51)
`One In — 93)
`Two (n = 33)
`Best Response
`No.
`%
`i.
`No.
`%
`No.
`%
`
`
`PEREZ ET AL
`
`Complete response
`Partial response
`Stable disease
`Progressive disease
`2.7
`4.6
`5.7
`4.7
`Median time to progression, months
`
`Median overall survival, months 12.7 12.8 18.6 12.5
`
`
`
`
`4
`34
`74
`65
`
`2.3
`19.2
`41.8
`36.7
`
`2.0
`23.5
`51.0
`23.5
`
`3
`17
`37
`36
`
`3.2
`15.3
`39.8
`38.7
`
`0
`5
`1 1
`17
`
`0
`15.2
`33.3
`51.5
`
`whom were switched to trastuzumab therapy), and protocol
`violations (12 patients), including use of additional thera-
`pies such as bisphosphonates in patients with bone-only
`disease, intervening surgery, incomplete disease documen-
`tation before study entry, and prior therapy history outside
`entry criteria specifications.
`All responses had to be documented on two occasions at
`least 4 weeks apart, and all reported responses were inde-
`pendently reviewed. In the 177 assessable patients, there
`were four complete responses (2.3%) and 34 partial re-
`sponses (19.2%), for an overall response rate of 21.5%
`(95% confidence interval, 15.4% to 27.5%)(Table 3). The
`median duration of response was 251 days. Stable disease
`was achieved in 74 patients (41.8%).
`In 19 patients, initial response observations were not
`documented on a second occasion as required. For 10 of
`these patients, it was because follow-up evaluations were
`not performed 4 weeks later, and these patients were
`classified as having stable disease. However, if responses
`documented on one occasion were to be considered, the
`potential response rate in the 177 assessable patients
`would be 32.2% (95% confidence interval, 25.3% to
`39.1%), with six complete responses (3.4%) and 51
`partial responses (28.8%).
`The overall response rates did not differ among patients
`with zero, one, or two prior chemotherapy regimens for
`metastatic disease (Table 3). Responses occurred in 23
`(17.6%) of the 131 assessable patients who had received
`prior anthracycline therapy and in seven (15.6%) of the 45
`assessable patients who had received prior taxane therapy.
`These overall response rates were not different between
`patients who had received prior therapy with either an
`anthracycline or a taxane and those who did not. Response
`rates were not different among patients who had received
`prior adjuvant therapy, those who had received prior high-
`dose therapy, those with visceral dominant disease, or those
`with three or more sites of metastatic disease compared with
`those who did not. Because of sample-size considerations,
`the power to detect significant differences in theses subset
`
`analyses was limited. This limited power and the fact that
`baseline characteristics among the subsets were not neces-
`sarily balanced precluded more in-depth analyses.
`In the cohort of 56 assessable patients age 2 65 years,
`there were 1 1 partial responses (19.6%) and 28 patients with
`stable disease (50%). The rate of response observed in this
`patient subgroup was similar to that observed in patients
`younger than 65 years.
`Median follow-up time was 336 days (11 months) and
`ranged from 8 to 997 days. The median time to progression
`for assessable patients was 142 days (4.7 months)(Fig 2).
`Median times to progression for patients who had received
`no prior chemotherapy for metastatic disease, one prior
`regimen, and two prior regimens were 174 days (5.7
`months), 140 days (4.6 months), and 85 days (2.7 months),
`respectively. The median time to progression for patients
`age 2 65 years was 214 days (7.0 months).
`The median overall survival for all 212 patients was 387
`days (12.8 months)(Fig 3). Median overall survival times
`were 562 days (18.6 months) for patients who had received
`
`1,
`
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`
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`
`Fig 2. Kaplan-Meier analysis of time to progression. Median time to
`progression = 142 days.
`
`Information downloaded from jco.ascopubs.org and provided b at Reprints Desk on August 31, 2016 from 216.185.156.28
`Copyright © 2001 American Society of
`linical Oncology. All rights reserved.
`
`

`

`WEEKLY PACUTAXEL IN MEIASTATIC BREAST CANCER
`
`4221
`
`828
`5'.
`
`
`
`
`
`SurvivalDI-trlbumnFunction8f.B2".3...~.__.
`
`g
`
`
`
`mmmsooemmooommo
`WWW)
`
`Fig 3. Kaplan-Meier analysis of overall survival. Median overall survival
`time = 387 days.
`
`no prior chemotherapy for metastatic disease, 378 days
`(12.5 months) for patients with one prior regimen, and 296
`days (9.7 months) for patients with two prior regimens. The
`median overall survival time for patients 2 65 years of age
`was 384 days (12.7 months).
`
`Quality of Life
`
`Compliance in completing the quality-of-life question-
`naires was good. Baseline and subsequent data were avail-
`able for 145 (78%) of 187 patients at cycle 2, 120 (75%) of
`160 patients at cycle 3, 95 (77%) of 124 patients at cycle 4,
`68 (71%) of 96 patients at cycle 5, 55 (75%) of 73 patients
`at cycle 6, and 16 (32%) of 50 patients at cycle 7. There
`were no differences in FACT-B total scores between base-
`
`line and any subsequent cycle. For the FACT-Taxane
`analysis, significant differences were noted between base—
`line and course 4 (P = .045) and baseline and course 5 (P
`= .015). In both cases, the mean total score was higher at
`baseline, indicating a higher quality of life.
`For subscale analyses, significant differences were noted
`between baseline and all subsequent cycles for emotional
`well-being, with P values ranging from less than .001 to
`.02]. Significant differences from baseline scores in the
`socialffamily well-being subscale were seen at cycles 3, 4,
`and 5 (P = .006, .026, and .010, respectively). For func-
`tional well~being, a significant difference was noted only
`between baseline and cycle 5 (P = .029). In all cases, mean
`scores were higher at baseline. There were no differences
`between baseline and subsequent cycles for the additional
`concems—breast subscale. However, the additional concem-
`s—taxane subscale did show significant differences between
`baseline and cycles 3 through 7, with P values ranging from
`less than .001 to .044.
`
`,
`
`J
`
`('
`
`Analyses were also performed to determine potential
`differences in scores among patients achieving complete or
`partial remission, stable disease, and those with disease
`progression. For patients achieving a complete or partial
`response compared with patients with stable disease or
`those with disease progression,
`the total mean FACT-B
`scores were significantly higher at cycles 3 and 5 (P = .026
`and .013,
`respectively).
`In the FACT-Taxane analysis,
`scores for patients achieving a complete or partial response
`were significantly higher at cycles 2, 3, and 5 compared
`with patients with either stable disease or disease progres-
`sion (P = .018, .013, and .021, respectively).
`
`DISCUSSION
`
`In this phase multicenter 11 study, we endeavored to
`enroll a population of patients reflective of that seen in
`general clinical practice. Entry criteria allowed patients to
`have received up to two prior chemotherapy regimens for
`metastatic disease in addition to adjuvant chemotherapy.
`Nearly 70% of patients enrolled had received at least one
`prior chemotherapy regimen for metastatic disease. Also,
`9% of patients had undergone prior high-dose therapy with
`stem—cell support. The disease burden of the patient popu-
`lation was substantial, as approximately half of the patients
`enrolled had three or more involved metastatic sites, 60% of
`patients had visceral-dominant disease, and 1 1% of patients
`had brain metastases.
`
`With weekly paclitaxel therapy, we observed an overall
`response rate of 21.5% in women with metastatic breast
`cancer, with all responses documented on two occasions and
`independently reviewed. Disease stabilization occurred in
`41.8% of patients; thus it may be considered that 63.3% of
`the patients who received weekly paclitaxel had some
`benefit from therapy. Responses were observed with equal
`frequency in all subgroups assessed, including patients who
`had received prior anthracycline or taxane therapy, those
`with visceral dominant disease, and those with three or more
`involved metastatic sites.
`
`Direct comparison of response rates from one trial to
`another is inherently difficult, given that studies often
`differ with respect to entry criteria and population char-
`acteristics. Nevertheless, overall response rates of 21% to
`49% have been reported from other multicenter trials of
`single-agent paclitaxel administered at doses of 135 to
`250 mga’m2 by 3- or 24-hour infusion every 3 weeks in
`women with metastatic breast cancer.” In all but one of
`
`these studies, patients were limited to one prior chemo-
`therapy regimen for metastatic disease. Thus our re-
`sponse results are within the range observed in other
`trials of paclitaxel, particularly if prior treatment charac-
`teristics and extent of disease are considered.
`
`Information downloaded from jco.ascopubs.org and provided by at Reprints Desk on August 31, 2016 from 216.185.156.28
`Copyright © 2001 American Society of Clinical Oncology. All rights reserved.
`
`

`

`4222
`
`PEREZ ET AL
`
`We found weekly paclitaxel therapy to be well toler-
`ated by the majority of patients, supported by the facts
`that the median duration of therapy was 16 weeks and
`few patients required dose delays or adjustments.
`In
`agreement with other studies of weekly paclitaxel, few
`patients (15%) encountered serious hematologic toxicity.
`Grade 3 neuropathy, occurring in 9% of patients, devel-
`oped after a median of 20 weeks of therapy. Other serious
`toxicities were uncommon.
`
`An important finding is that patients 2 65 years of age
`had an equivalent overall response rate and no greater
`incidence of toxicity compared with younger patients. As
`the population ages, clinicians will be increasingly faced
`with the decision treating older patients with chemother-
`apy. On the basis of our results, weekly paclitaxel can be
`considered as safe to use in older patients as it
`is in
`younger patients, and response expectations should not
`be diminished.
`
`in
`Quality of life was maintained relatively well
`patients treated with weekly paclitaxel, reflected by the
`fact that there were no significant differences between
`total scores at baseline and any subsequent cycle for the
`FACT-B instrument. Differences from baseline quality of
`life assessed by the FACT-Taxane instrument appeared
`only in cycles 4 and 5, or after 16 weeks of therapy.
`There were significant differences from baseline in sev-
`eral subscales, including social well-being and function
`well-being; however, overall quality of life was reason-
`
`ably well maintained throughout the course of therapy.
`Quality-of-life scores improved with therapy for patients
`achieving complete or partial responses, a finding that
`has been observed in other breast cancer studies.”25
`
`Therapy with weekly paclitaxel was well tolerated and
`demonstrated activity in metastatic breast cancer patients.
`Although the response rate we observed is lower than that of
`previously reported single-institution trials