Recently, we reported preliminary data on our experience with sequential
doxorubicin (Adriamycin) followed by paclitaxel (Taxol) in the treatment
of advanced breast cancer that was either untreated or had relapsed after
adjuvant therapy.[1-3] These phase I/II trials, carried out at the Medical
Oncology Departments of hospitals in Forlì, Ravenna, and Rimini,
Italy, were based on data from our previous experimental studies of primary
human breast cancer cultures and two established cancer cell lines (MCF-
7 and our anthracycline-resistant cell line BRC-230).We
compared the in vitro activity of three different modalities for administering
combination doxorubicin and paclitaxel:
- Simultaneous exposure of the cells to both drugs
- Sequential cell exposure of paclitaxel followed by doxorubicin
- Doxorubicin followed by paclitaxel.
The sequence in which doxorubicin was followed by paclitaxel produced
the best results, showing a clearcut synergistic effect in the BRC-230
cell line and an additive effect in MCF-7.
This effect was confirmed in 11 cultures of human breast cancer (synergistic
and additive effects were observed in four and six cases, respectively).
On the basis of these preclinical data, we designed a clinical trial to
evaluate the efficacy of a sequential regimen in which doxorubicin was
followed by paclitaxel.
In the phase I study, patients with advanced breast cancer were treated
with a fixed dose of doxorubicin (50 mg/m²) by intravenous bolus,
16 hours before receiving a three-hour infusion of paclitaxel (in escalating
doses from 130 mg/m² to 250 mg/m²). The phase I study was planned
as an open-label, dose-finding trial. The goals of the study were to define
the maximum tolerated dose (MTD) of paclitaxel given in combination with
fixed-dose doxorubicin in treating patients with breast cancer that had
relapsed after adjuvant therapy or had not been treated previously with
chemotherapy, and to evaluate the efficacy and tolerability of a short
(three hours) paclitaxel infusion.
From April 1994 to February 1995, 19 patients received 128 cycles of
the sequential doxorubicin/ paclitaxel combination. The dose of paclitaxel
was escalated by 30 mg/m² per dose level group, starting at 130 mg/m²
and increasing to 250 mg/m². Three patients were treated at the first
dose level (130 mg/m²), and four patients were treated at each of
the other dose levels. Even with escalation of paclitaxel to 250 mg/m²,
the MTD of paclitaxel was not reached. The treatment was well tolerated
at each paclitaxel dose level. According to protocol criteria, three patients
received granulocyte colony-stimulating factor at the hematologic nadir.
Fatigue, peripheral neurotoxicity, myalgia, and arthralgia were the
predominant nonhematologic side effects encountered. A grade 4 neutropenia
occurred in 20% of the cycles, but treatment generally was not associated
with severe clinical events. Only one patient, treated for multiple bone
lesions with concomitant chemoradiotherapy and paclitaxel 190 mg/m²,
developed a severe febrile neutropenia that required hospitalization. As
shown in Table 1, no cases of grade 3
or 4 nonhematologic toxicity were reported.
To confirm the efficacy and toxicity results of phase I, the doxorubicin/paclitaxel
sequence also was evaluated in a subsequent phase II study in which paclitaxel
was to be given in a fixed dose, established as that immediately below
the MTD defined in phase I of the trial. Since no clear MTD was reached
during the phase I study, and because it was feared that the risks of severe
neutropenia and severe peripheral neurotoxicities would increase with further
escalation of the paclitaxel dose, phase I was closed and phase II started
with fixed doses of the two drugs.
Thus, from April 1995 to January 1996, 13 patients with the same eligibility
criteria as established for phase I were treated with fixed doses of doxorubicin
(50 mg/m²) and paclitaxel (220 mg/m²) in
hopes of confirming the positive results of the phase I study, both in
terms of toxicity (particularly cardiac toxicity) and response rates. Patients
received a total of 95 cycles of therapy and results showed the same toxicity
trend as was seen in phase I, apart from an increase in peripheral neurotoxicity
and grade 4 neutropenia. Moreover, as shown in Table
2, severe febrile neutropenia occurred in only eight cycles (8%), in
Although the phase I study end point was not therapeutic efficacy, clinical
responses were analyzed. Table 3 summarizes
the results observed in the phase I and phase II studies, both individually
and combined. Phase II results confirmed the high response rate obtained
in phase I. For all 32 patients in phases I and II together, the overall
response rate was 78.1%, with 31.3% complete remissions (CRs) and 46.9%
partial remissions (PRs). At 16 months' median overall follow-up for the
two phases, the median time to progression for all patients is nine months
(median duration of objective response, nine months; median duration of
complete remission, seven months). As of November 1996, six patients with
complete remissions have relapsed (five from phase I and one from phase
II) and disease has progressed in 12 with partial remissions (eight from
phase I and four from phase II).
Phase I of this study demonstrated good tolerability and high efficacy
for sequential doxorubicin followed by paclitaxel in patients relapsed
after prior adjuvant therapy or as first-line therapy in previously
untreated patients, with paclitaxel given by three-hour infusion in escalating
doses of 130 to 250 mg/m². Treatment was well tolerated at all dose
levels and the MTD was not reached at paclitaxel 250 mg/m².
No grade 3 or 4 nonhematologic toxicity was reported, and only one patient
treated with concomitant chemoradiotherapy and paclitaxel 190 mg/m²
had treatment suspended due to severe febrile neutropenia. No significant
cardiotoxicity was observed in this group. All patients were evaluated
by echocardiogram every two cycles; left ventricular ejection fraction
values never fell below normal limits in any phase I patient.
The objective response rate for 19 phase I patients assessable for response
was 78.9%, with 47.3% PRs and 31.6% CRs. A dose-response relationship was
observed: All patients treated with higher paclitaxel dose levels (from
190 mg/m² to 250 mg/m²) achieved objective responses (six CRs
and six PRs). At lower paclitaxel dose levels, no CRs were observed. The
high response rate in the phase I trial and the absence of severe toxicityin
particular, the lack of congestive heart failurewhich was observed in
some other studies,[5-6] required further confirmation in a phase II trial
using fixed doses of doxorubicin and paclitaxel. In 10 of 95 cycles, the
paclitaxel dose was reduced: In eight cycles (two patients), the dose was
reduced by one dose level (-30 mg/m²) because of grade 4 febrile neutropenia
plus grade 2 neurotoxicity, and in two cycles (one patient) the dose was
reduced by two levels (-60 mg/m²) because of grade 4 febrile neutropenia
complicated by grade 3 mucositis and diarrhea. At a median follow-up of
14 months for patients included in the phase II trial, we have confirmed
that no significant cardiac toxicity was reported in 12 of 13 patients
in this phase. However, in one patient, who received a cumulative doxorubicin
dose of 400 mg/m², the left ventricular ejection fraction decreased
from 60% to 43% without clinical symptoms. The patient, who completed the
full therapeutic program (eight cycles) was entered into follow-up and
her ejection fraction values returned to normal limits within two months.
As of November 1996, after progression of her neoplastic disease, the patient
is being treated with second-line chemotherapy.
The 32 patients who took part in phase I/II of this study received 133
cycles of chemotherapy: 22 patients (68.7%) received a cumulative doxorubicin
dose of 400 mg/m², seven patients (21.9%) received a cumulative doxorubicin
dose of 300 to 350 mg/m², while only three patients (9.4%) were treated
with cumulative doxorubicin doses ranging from 150 to 250 mg/m².
At a median follow-up of 16 months for the entire study population,
no patient has developed clinical signs or symptoms of significant cardiotoxicity.
Although the doxorubicin dose per cycle was lower than that studied by
Dombernowsky and Gianni (50 mg/m² vs 60 mg/m²), we believe that
this different pattern of toxicity might have been influenced mainly by
the different timing of the schedule (the 16-hour interval between the
two drug infusions). In any event, further clinical trials that include
pharmacokinetic evaluations are required to confirm these observations.
To date, two further phase II trials are ongoing in our institutions.
In the first, the goal is to confirm, in anthracycline-pretreated patients,
the efficacy and tolerability reported in this phase I/II trial. In the
second, we are hoping to verify, in untreated patients, a possible difference
in the occurrence of cardiotoxicity when the same schedule and timing used
in this phase I/II trial are repeated but a higher doxorubicin dose (60
vs 50 mg/m²) is used. Currently, the 10 patients enrolled in this
last trial are receiving fixed doxorubicin doses (60 mg/m²) followed
by paclitaxel 220 mg/m². No severe cardiotoxicity has been observed
and no patients have discontinued treatment because of toxicity.
1. Amadori D, Frassineti GL, Zoli W, et al: A phase I/II study of paclitaxel
and doxorubicin in the treatment of advanced breast cancer. Semin Oncol
23(suppl 1):19-23, 1996.
2. Amadori D, Frassineti GL, Zoli W, et al: A phase I/II study of sequential
doxorubicin and paclitaxel in the treatment of advanced breast cancer.
Semin Oncol 23(suppl 11):16-22, 1996.
3. Frassineti GL, Zoli W, Tienghi A, et al: The sequential administration
of combined doxorubicin and paclitaxel in the treatment of advanced breast
cancer. Semin Oncol 23(suppl 12):22-28, 1996.
4. Zoli W, Flamigni A, Frassineti GL, et al: In vitro activity of Taxol
and Taxotere in comparison with doxorubicin and cisplatin on primary cell
cultures of human breast cancers. Breast Cancer Res Treat 34:63-69,
5. Gianni L, Munzone E, Capri G, et al: Paclitaxel by three hour infusion
in combination with bolus doxorubicin in women with untreated metastatic
breast cancer: High antitumor efficacy and cardiac effect in a dose-finding
and sequence-finding study. J Clin Oncol 13:2688-2699, 1995.
6. Dombernowsky P, Gehl J, Boesgaard M, et al: Paclitaxel and doxorubicin,
a highly active combination in the treatment of metastatic breast cancer.
Semin Oncol 23(suppl 1):13-18, 1996.