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Vol. 4, /689-1695, July 1998 Clinical Cancer Research 1689
Phase I Trial of Sequential High-Dose Chemotherapy with Escalating
Dose Paditaxel, Melphalan, and Cyclophosphamide, Thiotepa, and
Carboplatin with Peripheral Blood Progenitor Support in
Women with Responding Metastatic Breast Cancer’
Linda T. 2 Kyriakos Papadopoulos,
Casilda Balmaceda, Trish McGovern,
Jane Dunleavy, Elizabeth Kaufman,
Blanche Fung, Thomas Garrett, David Savage,
Amy Tiersten, Janet Ayello, Emilia Bagiella,
Daniel Heitjan, Karen Antman, and
Charles HesdorfferDivision of Medical Oncology and Hematology, Department of
Medicine Columbia University College of Physicians and Surgeons,
New York, New York 10032
ABSTRACT
A single high-dose cycle of chemotherapy with stem cell
support can produce disease-free survival of 15-20% for at
least 3 years in women with responding stage IV breast
cancer. North American Autobogous Bone Marrow Trans-
plant Registry data suggest that a complete response (CR) is
the single most important prognostic factor associated with
prolonged disease-free survival. Therefore, if sequential
high-dose chemotherapy can increase the CR rate, then
perhaps an increased proportion of patients will remain
disease free.
Women with at least a partial response (PR) to induc-
tion chemotherapy received three separate high-dose cycles
of chemotherapy with peripheral blood progenitor support
and granulocyte colony-stimulating factor. The first inten-
sification was a dose escalation of paditaxel (400-825 mg/
m2), the second intensification was melphalan (180 mglm2),
and the third intensification consisted of 6000 mg/m2 cyclo-
mg/m2/day), and 800 mg/m2 carboplatin (200 mglm2/day;
CTCb).
Thirty-six women were enrolled and 31 completed all
three cycles. After the paditaxel infusion most patients de-
veloped reversible predominantly sensory neuropathy. Of
Received 12/5/97; revised 4/15/98; accepted 4/17/98.The costs of publication of this article were defrayed in part by thepayment of page charges. This article must therefore be hereby marked
advertisement in accordance with 18 U.S.C. Section 1734 solely to
indicate this fact.
‘ Supported in part by USPHS Grant P30-CA13696-2l, NCI R21
CA66244-0l , and P20CA66244-0l . L.T.V. is a Michael Cohen Scholar.2 To whom requests for reprints should be addressed, at Blood andMarrow Transplant Unit, Division of Medical Oncology, MHB 6N-435,177 Fort Washington Avenue, New York, NY 10032. Phone: (212)305-2486; Fax: (212) 305-6798.
the 19 patients with measurable disease, 6 converted to CR,
7 converted to a PR* (the complete resolution of all soft
tissue or visceral disease with sclerosis of prior lytic bone
lesions), and 2 had a further PR for an overall response rate
of 79%. Two patients had no further response and disease in
two patients progressed, and thus they were taken off the
study before CTCb. Seventy-eight percent are progression-
free at a median follow-up of 14 months (range, 3-24+).
Three sequential cycles of high-dose chemotherapy are
feasible and were administered in this study with no mor-tality. Single agent pacitaxel at doses up to 825 mg/m2 werewell tolerated with moderate reversible toxicity.
INTRODUCTION
Although breast cancer is considered a highly curable
disease if detected early in its course, disseminated breast cancer
is associated with a grave prognosis with a median survival of
less than 3 years (1, 2). North American Autologous Bone
Marrow Transplant Registry data and multiple single institution
Phase II trials confirm that a single high-dose cycle of chemo-
therapy can produce disease-free survivals of 15-20% for at
least 3 years (3). Furthermore, progression-free survival can be
stratified by response to chemotherapy with patients with tu-
mors responding completely associated with a higher probabil-
ity of remaining progression-free than those with partial or
nonresponding tumors.
Fifteen to twenty percent of patients whose tumors respond
completely to either conventional or high-dose chemotherapy
remain disease-free for up to 10 years (3, 4). The percentage of
patients achieving a CR3 to cytotoxic chemotherapy in Phase II
trials is higher for high-dose chemotherapy than for conven-
tional dose chemotherapy; however, an increased response rate
may not always translate into a similarly increased disease-free
survival rate (5).
In the only published randomized trial of high-dose therapy
versus conventional dose therapy for metastatic breast cancer,
Bezwoda et a!. (6) randomized patients between high-dose
cyclophosphamide, mitoxantrone, and etoposide for two cycles,
compared with conventional dose cyclophosphamide, mitox-
antrone, and vincristine. The disease-free and overall survival of
the women randomized to the high-dose chemotherapy was
significantly improved over their counterparts in the lower dose
3 The abbreviations used are: CR, complete response; PR, partial re-sponse; PR*, complete resolution of all soft tissue or visceral disease
with sclerosis of prior lytic bone lesions; G-CSF, granulocyte colony-
klebsiella pneumonia, staph epidermidis, and xanthomonas mal-
tophilia) in one patient was attributed to contaminated IV solu-
tion, and the other bacterernia was due to xanthomonas malto-
philia.
Cardiac. Two patients developed transient atrial fibrilla-
tion at the 400 and 725 mg/rn2 dose level.
Hepatic. Transient elevations in total bilirubin ranging
from 1.2- 3.9 rng/dl (median, 1.5) was observed in 65% (22 of
34) of patients occurring on day -3 to day +5. Of 34 patients,
32 developed a mild (National Cancer Institute criteria grade I)
to moderate (grade II) transaminitis over the same interval.
Neurological. Neurotoxicity was predominantly sensory,
however, 5 of 18 patients treated at paclitaxel doses �725
mg/rn2 developed weakness. Both the motor and sensory
changes were reversible. Nerve conduction studies revealed
statistically significant decreased amplitude in sensory (median,
ulnar and sural) as well as motor (peroneal >> tibial) nerves
across all dose levels suggesting an axonal neuropathic process.
Gait difficulties resembling ataxia were observed in patients
receiving doses �725 mg/m2. One patient receiving paclitaxel
at 775 mg/rn2 developed an unexplained Horner’s syndrome
between the second and third intensifications (evaluation in-
eluded magnetic resonance imaging and lumbar puncture). An-
other patient treated at 690 mg/rn2 developed a peroneal nerve
palsy 3 months after completing paclitaxel. This patient entered
the program with a left peroneal nerve palsy attributed to a
decompression injury. She completed the first intensification
Table 4 Hemat obogical and toxicity data
Variable Paclitaxel Melphalan CTCb
No. of patients 34 34 31
Hematological parametersCD34 + cells/kg infused
Median 1.06 1.13 1.69Range 0.45-1.86 0.78-2.08 0.67-3.06
Days to:
ANC � 500//p.l
Median 6 10 10Range 0-9 9-13 8-11
pbts � 20kJ/�b
Median 0 13 13Range 0-7 0-17 9-20
Units transfused
PRBC”
Median 0b 1 3
Range 0-I 0-8 1-6Platelets
Median 0� 12 36Range 0-6 0-30 6-66
Grade III or IV toxicitiesStomatitis/esophagitis 10 5 20
Nausea/vomiting 4/4 4/2 13/6
Diarrhea 0 1 10
LiverVOD 0 0 0Elevated bilirubin 14 5 12
Bacteremia 2 2 6
C. difficile 0 0 4Cardiac
Arrhythmia 2 0 0
Myocarditis 0 0 1
Mortality 0 0 0
a PRBC, packed red blood cells; VOD, veno-occlusive disease.b Three patients were transfused with one unit of PRBC each.C One patient received a platelet transfusion.
with a maximal sensory neurotoxicity of 3 + , which resolved by
the end of the third intensification. One month later, she devel-
oped a right peroneal nerve palsy which has not changed at 11
months of follow-up.
Other. Myalgias requiring varying types of analgesia
(acetaminophen to morphine sulfate) were observed in all pa-
tients. Obstipation lasting up to I week was observed in patients
treated at dose levels �725 mg/rn2; however, no bowel obstruc-
tion was observed and this problem resolved with the use of
laxatives.
Intensification 2: Melphalan with Peripheral Blood Stem
Cell Support
Thirty-four patients received the second intensification a
median of 22 days (range, 15-77) after the first intensification.
Sixteen patients were initially treated as inpatients and, once
deemed feasible, the remainder received melphalan as outpa-
tients.
The median time to ANC �500/p.l was 10 days (range,
9-13) and platelets to >20,000/p.l was 13 days (range 0-17;
Table 4). Twenty-one of 34 patients were readmitted with neu-
tropenia/fever (18), or severe mucositis (3). Two patients were
bacteremic with Escherichia coli and Streptococcus sanguis,
(stage IV with no evidence of disease) are disease-free (Fig. 1).
With the exception of the contralateral breast cancer, all failures
occurred at sites of prior bulk disease.
DISCUSSION
Multiple single institution studies and Autologous Blood
and Marrow Transplant Registry data identify CR as the most
significant factor associated with prolonged disease-free sur-
vival after high-dose therapy. Strategies used to increase the CR
rate include the incorporation of new drugs or new schedules of
established drugs into accepted chemotherapy treatment regi-
mens, use of repetitive cycles of high-dose chemotherapy, and
novel post-transplant consolidation strategies with various types
of immune modulation (13-15).
This study has adopted the strategies of repetitive dosing
and of incorporation of new active agents. Several institutions
have piloted sequential cycles of high-dose chemotherapy for
patients with breast cancer as long as a decade ago, although the
testing of this strategy only really became feasible with the
advent of hematopoietic growth factors and mobilization of
large numbers of blood derived stem cells which tended to result
in more rapid marrow recovery (5, 16-19; Table 6).
Paclitaxel, one of the most active drugs to emerge in the
last 20 years, has been escalated in combination with other
agents by several other investigators (10, 20-22) who have
reported coma and a dose-limiting adult respiratory distress
syndrome-like capillary leak syndrome at doses of 825 mg/rn2
leading to the death of one patient.
We have administered this dose of paclitaxel as a single
agent with only moderate and largely reversible toxicity. All,
intensifications but two were given on time, and these delays
were due to iatrogenic polymicrobial sepsis and a patient who
was considering whether to forgo further high-dose therapy and
not due directly to toxicity of therapy.
Conventional dose paclitaxel has been associated previ-
ously with a diffuse sensory polyneuropathy. With higher doses,
the sensory neuropathy seemed to be most evident within the
first week after paclitaxel and then rapidly improved before the
second intensification, resolving completely as long as 9 or 10
months later. We observed motor weakness in 5 of the 18
patients treated at the 725 and 775 mg/rn2 dose levels, although
none was observed in the 3 patients treated at the 825 mg/rn2
dose level. Whether the development of a grade IV peroneal
nerve palsy at 3 months after the completion of therapy was a
delayed toxicity of high-dose paclitaxel therapy remains un-
known. Although Yubero et al. (23) reported that neurotoxicity
of high-dose paclitaxel correlated with prior neurotoxic chem-
otherapy, no correlation between dose or number of prior cycles
of paclitaxel, prior neuropathy, or presence of liver metastases
was observed in our study.
Several issues remain to be addressed including whether
paclitaxel represents the best agent to incorporate into this
high-dose regimen, its optimum schedule, and whether pacli-
taxel is best administered as a single agent or in combination
with other active agents. Because of the small numbers of
patients treated at each dose level and the substantial concurrent
therapy, an analysis of dose response would be unreliable. Other
issues relate to the sequence of the high-dose regimens and the
potential induction or loss of drug resistance (24). Finally, the
pattern of myelosuppression and hematological recovery sug-
gests that peripheral blood progenitor support may not be re-
quired at these doses of paclitaxel.
This study demonstrates that three sequential cycles of
high-dose chemotherapy are feasible and can be safely admin-
istered without mortality. In addition, single agent paclitaxel at
doses up to 825 mg/rn2 is well-tolerated with moderate revers-
ible toxicity. The observation of transient muscle weakness
observed at the higher dose levels suggested that further dose
escalations would be hazardous, and thus we proceeded with the
Phase II trial using 825 mg/m2. The sequence of high-dose
paclitaxel, melphalan, and cyclophospharnide, thiotepa, and car-
boplatin resulted in a high complete remission rate. Whether this
alone is sufficient to extend disease-free survival requires fur-
ther follow-up.
ACKNOWLEDGMENTSWe thank the nursing and house staff for the excellent care ren-
dered our patients, and Dr. Phyllis Della LaUa and Tom Fisher for
assistance with collection of the microbiology data.
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