Recently, we reported preliminary data on our experience with sequential doxorubicin(Drug information on doxorubicin) (Adriamycin) followed by paclitaxel(Drug information on 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 five patients.
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.