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Paclitaxel for Breast Cancer: The Memorial Sloan-Kettering Cancer Center Experience

Paclitaxel for Breast Cancer: The Memorial Sloan-Kettering Cancer Center Experience

ABSTRACT: The proven safety profile and antitumor activity of paclitaxel (Taxol) in the treatment of metastatic breast cancer led investigators at Memorial Sloan-Kettering Cancer Center (MSKCC) to further examine the agent's potential in the treatment of advanced breast cancer. Efficacy and tolerability studies of paclitaxel as single-agent therapy were undertaken, along with parallel investigations of quality-of-life parameters. The studies examined the effects of 96-hour infusion schedules of paclitaxel and are currently assessing the feasibility of a weekly 1-hour infusion schedule. Researchers at MSKCC also compared the results of a variety of two- and three-drug paclitaxel-containing regimens to determine possible synergism and better define safety profiles. They examined the combination of paclitaxel and edatrexate, as well as a promising combination of paclitaxel and a monoclonal antibody directed at growth factor receptors. The latter ongoing trial will include both laboratory studies that examine possible cellular mechanisms for the combination's observed synergy and a clinical trial that combines paclitaxel with a monoclonal antibody directed against the epidermal growth factor. In conclusion, the investigators discuss the optimal integration of paclitaxel into doxorubicin/cyclophosphamide (Cytoxan, Neosar)-based adjuvant therapy for node-positive stage II-III resectable breast cancer. [ONCOLOGY 11(Suppl):20-28, 1997]

Introduction

In the management of patients with metastatic breast cancer, paclitaxel
(Taxol) has demonstrated safety and significant antitumor activity.[1-5]
To fully characterize the drug's potential in the treatment of advanced
breast cancer, we have conducted a series of phase II clinical trials evaluating
its efficacy and tolerability as single-agent therapy (Table
1
).

Paclitaxel has been studied in various doses and schedules among patients
with metastases who have not received previous chemotherapy for advanced
disease, as well as among those who have had moderate and extensive prior
therapy.[1,3-5] In heavily pretreated patients, we have conducted a formal
parallel investigation of quality-of-life (QOL) parameters to better assess
the palliative potential of paclitaxel among patients who receive this
agent with the primary intent of symptom control.[6] We are presently incorporating
these variables into a prospective study that addresses economic (charges/costs)
and QOL outcomes, in addition to classic tumor response and toxicity assessments,
in patients receiving single-agent paclitaxel.[7]

Our studies were influenced by preclinical data demonstrating schedule-dependent
cytokinetic variability in resistance profiles to the taxanes,[8-10] as
well as clinical documentation of the efficacy and safety of a 96-hour
infusion schedule against anthracycline-refractory breast cancer.[11] These
investigations led us to perform a phase II and pharmacologic trial assessing
the activity and toxicity profile of this prolonged infusion schedule in
patients with documented progression of disease during shorter taxane exposure.[12]

Data supporting the feasibility and efficacy of more frequent, shorter-duration
taxane infusions[13] has motivated our ongoing trial, which is evaluating
a weekly 1-hour infusion paclitaxel schedule in patients who have received
one or two prior regimens for breast cancer (including adjuvant therapy).[14]
Collaborative laboratory investigations aimed at characterizing clinically
relevant mechanisms of resistance to paclitaxel are well underway in studies
involving biopsied human breast cancer tissue.

Combinations of paclitaxel and other cytotoxic agents are being studied.
A variety of two- and three-drug paclitaxel-containing regimens are in
clinical trials to define possible synergism, as well as to illuminate
safety profiles. At Memorial Sloan-Kettering Cancer Center (MSKCC), we
have investigated the combination of paclitaxel and edatrexate, a dihydrofolate
reductase inhibitor with preclinical advantages over methotrexate[15] and
proven single-agent activity against metastatic breast cancer.[16-17] The
trial design derives from schedule-dependent synergy observed in vitro
in mammary carcinoma cells.[18,19]

A promising avenue of translational research pertains to the observed
synergy between paclitaxel and monoclonal antibodies (MoAbs) directed at
various growth factor receptors in human breast carcinoma xenografts.[20,21]
While laboratory studies addressing possible cellular mechanisms for this
effect are ongoing, we are conducting a clinical trial combining paclitaxel
with a MoAb directed against the epidermal growth factor.

The preserved activity of paclitaxel after anthracycline threapy has
stimulated its evaluation as a component of an adjuvant sequential chemotherapy
regimen for node-positive stage II-III resectable breast cancer.[22] We
recently evaluated the optimal integration of paclitaxel into doxorubicin/cyclophosphamide
(Cytoxan, Neosar)-based adjuvant therapy in a randomized clinical trial.[23]

This article will review 6 years of experience with paclitaxel in the
treatment of breast cancer at MSKCC and describe ongoing and planned studies.

Single-Agent Paclitaxel

First-Line Therapy

Subsequent to the M. D. Anderson Cancer Center report of the promising
antitumor activity of paclitaxel against metastatic breast cancer,[2] we
performed a confirmatory phase II trial of the agent as first-line chemotherapy
for stage IV disease.[3] In this study, 28 patients who had not received
prior chemotherapy for metastatic disease were treated with paclitaxel,
250 mg/m² via a 24-hour infusion every 3 weeks. Because the first
two patients we treated on this protocol experienced significant myelosuppression
(which was dose-limiting in the previous trial[2]), the protocol was amended
so that all subsequent patients received prophylactic granulocyte colony-stimulating
factor (G-CSF [Neupogen]), 5 µg/kg/d subcutaneously, on days 3 to
10 of each cycle.

A 62% response rate (95% confidence interval [CI], 41% to 80%) was noted,
including three complete responses.[3] Responses were as common among women
who had received prior adjuvant therapy, including doxorubicin-containing
regimens, as among those who had not. Treatment was well tolerate; adverse
effects included generalized alopecia in all patients, and grade 3 or 4
nonhematologic toxicities were uncommon. Of 178 cycles administered, there
were 8 admissions (4%) for febrile neutropenia, involving 6 (21%) of 28
patients.

Administration of recombinant human granulocyte colony stimulating factor
(rh-G-CSF) resulted in a median duration with an absolute neutrophil count
less than 500 cells/µL of 2 days, which was shorter than that previously
reported (7 days)[1] without concomitant growth factor support. Fifty-eight
percent of cycles were delivered at modestly reduced doses, primarily due
to significant neutropenia or febrile neutropenia. Because drug supply
was a consideration at this time in the agent's development, the clinical
trial design specified the length of treatment to be two cycles beyond
the best response, with a maximum of 10 cycles per patient. Thus, response
duration was not a valid end point of this trial.

After Prior Chemotherapy

Following this confirmation of paclitaxel's marked antitumor activity
in patients with minimal prior therapy, we evaluated patients who had received
extensive prior chemotherapy for metastatic breast cancer.[4] Fifty-one
patients who had previously received two or more prior chemotherapy regimens
for metastatic disease (median number of regimens, three; range, two to
six; all with prior anthracycline therapy) entered our second phase II
trial.

The median Karnofsky performance score (KPS) for these patients was
70% (range, 60% to 90%). Fourteen percent had received prior high-dose
chemotherapy regimens sufficiently myelotoxic as to require the reinfusion
of autologous bone marrow and/or peripheral blood progenitor cells; two-thirds
of these patients had received radiotherapy for metastatic disease. Paclitaxel
was administered at 200 mg/m² (a lower starting dose was chosen in
anticipation of significant toxicity in these more heavily pretreated patients)
via a 24-hour infusion every 3 weeks with G-CSF, as previously described.

Partial responses were observed in 14 patients (27.5%; 95% CI, 16% to
42%), with a median response duration of 7 months. Hospitalization for
febrile neutropenia occurred in 24 (8%) of the first 312 cycles and in
9 (18%) of 51 patients. No patient was removed from the trial due to toxicity.

Our next trial evaluated the higher 250-mg/m² dose, again via a
24 hour infusion every 3 weeks, in patients who had received only one prior
chemotherapy regimen for metastatic disease (with or without prior adjuvant
therapy).[4] Nine partial and two complete responses were noted among 25
evaluable patients (44%; 95% CI, 24% to 65%).

Significantly, in this and the previous trial, prior demonstrated sensitivity
or resistance to an anthracycline did not predict the likelihood of subsequent
response to paclitaxel. This lack of significant clinical cross-resistance
between paclitaxel and doxorubicin, an observation corroborated by others,
was particularly gratifying because preclinical data suggest significant
in vitro cross-resistance between paclitaxel and other agents for which
p-glycoprotein-mediated multidrug resistance is considered relevant.[24,25]

These observations have motivated our ongoing studies characterizing
pre- and post-paclitaxel human tumor tissue biopsies for mdr expression,
tubulin alterations, and genomic changes. It is hoped that such studies
will expand the understanding of clinically relevant mechanisms of taxane
resistance, which may then guide the development of efficient strategies
to overcome resistance and, potentially, the development of superior analogs.

Shorter Infusion Schedule

Renewed interest in the shorter, more convenient 3-hour infusion schedule
coincided with our next two phase II trials, which addressed the safety
and efficacy of this schedule as salvage chemotherapy in heavily treated
patients and as initial chemotherapy for stage IV disease. In the previously
treated patients (two or more prior regimens for metastatic disease, including
an anthracycline), paclitaxel was administered at a starting dose of 175
mg/m² via a 3-hour infusion every 3 weeks. Since 3-hour infusions
are associated with less significant myelosuppression than 24-hour infusions,
G-CSF was not administered prophylactically.

Sixty-four percent of the patients had predominantly visceral disease,
and the median KPS was 70%. After the 111 cycles were delivered (median,
3; range, 1 to 8), five partial responses were observed in 24 evaluable
patients (20.8%; 95% CI, 7% to 42%),[5] with a median response duration
of 4 months (range, 2 to 11 months).

Paclitaxel treatment was well tolerated; the only grade 3 or 4 nonhematologic
toxicities noted were myalgia (4%) and mucositis (4%). Grade 3 or 4 neutropenia
was seen in one-third of patients, grade 3 or 4 thrombocytopenia in 8%,
and grade 3 or 4 anemia in 13%. Dose reduction was required in 21% of patients,
and dose escalation was possible in only 4%.

We then evaluated a 250-mg/m² dose administered via a 3-hour infusion,
again without prophylactic G-CSF, as first-line chemotherapy for metastatic
breast cancer. Among 25 evaluable patients,1 complete and 7 partial responses
were noted (32%; 95% CI, 15% to 53%).[5]

Myalgias, arthralgias, and neuropathy appeared to be more significant
than in our prior experience with this dose delivered over 24 hours to
a similar group of patients. Several patients experienced photopsia[26]
at paclitaxel doses of 250 mg/m² or more over 3 hours, a phenomenon
that may represent an optic neuropathy.[27] These trials provided pilot
data for the design of ongoing randomized trials by the Cancer and Leukemia
Group B (CALGB) and National Surgical Adjuvant Breast and Bowel Project
(NSABP).

Additional Effects of Prolonged Treatment

In the course of these trials, it became obvious to us that many patients
experiencing symptomatic relief of bone pain and radiographic healing of
osteolytic metastases on plain x-rays, CT, or MRI had transient worsening
on nuclear scintigraphic evaluation of the skeleton.[28] This radiographic
"flare" on bone scan was followed by further clinical improvement
in skeletal pain and recalcification of destructive bone lesions in one-third
of patients.

Another phenomenon became apparent with prolonged paclitaxel treatment
(in some cases, beyond 20 courses). Among a series of 52 patients experiencing
continued response of visceral, osseous, and soft-tissue metastases during
paclitaxel treatment, 6 experienced disease progression in the central
nervous system in the absence of other evidence of treatment failure. This
manifested as both parenchymal brain metastases and leptomeningeal disease.
Thus, the central nervous system does appear to be a sanctuary site in
many women receiving paclitaxel for the management of metastatic breast
cancer.[29]

Schedule-Dependent Activity

Our next phase II clinical and pharmacologic trial was motivated by
in vitro data showing less resistance to paclitaxel in p-glycoprotein-overexpressing
MCF-7 breast cancer cells with longer drug exposure time.[8] Further support
of this phenomenon came from other preclinical studies[9,10,30,31] and
encouraging clinical experience with prolonged paclitaxel infusion in patients
with anthracycline-resistant breast cancer.[11]

In this study, we evaluated the possibility of schedule-dependent activity
by administering paclitaxel via a 96-hour continuous infusion specifically
to patients with disease that had demonstrated clinical resistance to short
taxane exposure.[12] A total of 27 such patients with disease progression
had recently received 3-hour paclitaxel (N = 24), 1-hour docetaxel (Taxotere;
N = 2), or both (N = 1). Per protocol, all patients received paclitaxel
via a 96-hour infusion at 140 mg/m² (35 mg/m²/d ×4), with
a starting dose of 120 mg/m²/d for patients with impaired hepatic
function. Because early data had suggested that the omission of steroid
and H1- and H2-receptor antagonist premedication was not associated with
significant hypersensitivity-like reactions with this dose and schedule,[11]
these drugs were not given in our study.

With 195 cycles administered, seven partial responses were noted in
26 evaluable patients (26.9%; 95% CI, 11.6% to 47.8%), with acceptable
hematologic and nonhematologic toxicity. Despite the omission of standard
premedication, no cases of hypersensitivity-like reactions occurred. This
suggests that the slower rate of exposure to paclitaxel--and possibly to
the polyoxyethylated castor oil (Cremophor EL) formulation--may not precipitate
mast-cell degranulation and other cellular phenomena associated with hypersensitivity
reactions.

Serum paclitaxel concentrations were assayed in 23 patients by high-performance
liquid chromatography at 24, 48, 72, and 96 hours of the infusion. The
median steady-state paclitaxel concentration (Css) was .047 µM (range,
.023 to .176 µM). For 11 patients experiencing grade 4 neutropenia,
median Css was .068 µM (range, .032 to .176 µM), as compared
with .039 µM (.023 to .098 µM) in 12 patients with less severe
neutropenia (P less than .05). Median Css and absolute neutrophil count
(ANC) nadirs were .094 µM (range, .074 to .176 µM) and 300
cells/mm³, respectively, in four patients with baseline elevation
of hepatic transaminases vs .041 µM (.023 to .102 µM) and 800
cells/mm³ in 19 patients with normal transaminases (Css, P less than
.01; ANC, not significant).[12]

No relationship between steady-state level and tumor response was noted
with this limited sample size. To further define the significance of infusion
duration for paclitaxel, a recently completed multi-institution trial led
by the M. D. Anderson Cancer Center randomized patients with refractory
metastatic breast cancer to receive paclitaxel via either a 3- or 96-hour
infusion schedule. It is noteworthy that there are greater pharmacologic
differences between the 3- and 96-hour infusion schedules than between
the 3- and 24-hour schedules, and many preclinical data suggest the importance
of paclitaxel exposure duration in breast carcinoma cells. Thus, this trial
should provide the most definitive information about the impact of paclitaxel
infusion duration on efficacy and toxicity.

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