Based on preclinical data, we designed a phase I/II clinical trial to determine the efficacy and toxicity of doxorubicin followed by paclitaxel in the treatment of advanced breast cancer (either untreated or relapsed after
ABSTRACT: Based on preclinical data, we designeda phase I/II clinical trial to determine the efficacy and toxicity of doxorubicinfollowed by paclitaxel in the treatment of advanced breast cancer (eitheruntreated or relapsed after adjuvant therapy). In the phase I dose-findingstudy, 19 enrolled patients received bolus doxorubicin (50 mg/m²)and, after a 16-hour interval, a three-hour infusion of paclitaxel in escalatingdoses from 130 to 250 mg/m², increased by 30-mg/m² incrementsfor each dose-level group. The first dose level group (paclitaxel 130 mg/m²)included three patients. The other dose level groups included four patients.Treatment was repeated every three weeks for a maximum of eight cycles.The paclitaxel dose was escalated to 250 mg/m² without reaching themaximum tolerated dose. In the 128 cycles assessable for toxicity, therewere no relevant clinical signs or symptoms of cardiotoxicity. This absenceof significant cardiotoxicity required confirmation in a phase II trial.Since a maximum tolerated dose of paclitaxel had not been reached duringthe first study and an increasing risk of neutropenia and peripheral neurotoxicitywas feared if doses continued to escalate, a phase II confirmatory studywas begun to evaluate treatment with fixed doses of doxorubicin (50 mg/m²)and paclitaxel (220 mg/m²), using the same schedule and interval asin phase I. The 13 patients enrolled in phase II received a total of 95cycles of therapy; in 10 cycles (three patients) dose reductions were necessarybecause of toxicity. However, no significant clinical cardiotoxicity wasobserved in 12 of the 13 patients. One patient experienced an asymptomatic,transient decrease in left ventricular ejection fraction at a cumulativedoxorubicin dose of 400 mg/m². Overall clinical responses included10 complete remissions (31.3%) and 15 partial remissions (46.9%) for anobjective response rate of 78.1%. At 16 months' median follow-up, the mediantime to progression for all patients is nine months. The high responserate obtained in the phase I/II studies and, in particular, the absenceof significant cardiotoxicity require confirmation in further clinicaltrials. To date, two confirmatory phase II trials are ongoing in our institutions. [ONCOLOGY 11(Suppl):30-33,1997]
Recently, we reported preliminary data on our experience with sequentialdoxorubicin (Adriamycin) followed by paclitaxel (Taxol) in the treatmentof advanced breast cancer that was either untreated or had relapsed afteradjuvant therapy.[1-3] These phase I/II trials, carried out at the MedicalOncology Departments of hospitals in Forlì, Ravenna, and Rimini,Italy, were based on data from our previous experimental studies of primaryhuman breast cancer cultures and two established cancer cell lines (MCF-7 and our anthracycline-resistant cell line BRC-230).Wecompared the in vitro activity of three different modalities for administeringcombination doxorubicin and paclitaxel:
The sequence in which doxorubicin was followed by paclitaxel producedthe best results, showing a clearcut synergistic effect in the BRC-230cell line and an additive effect in MCF-7.
This effect was confirmed in 11 cultures of human breast cancer (synergisticand additive effects were observed in four and six cases, respectively).On the basis of these preclinical data, we designed a clinical trial toevaluate the efficacy of a sequential regimen in which doxorubicin wasfollowed by paclitaxel.
In the phase I study, patients with advanced breast cancer were treatedwith a fixed dose of doxorubicin (50 mg/m²) by intravenous bolus,16 hours before receiving a three-hour infusion of paclitaxel (in escalatingdoses from 130 mg/m² to 250 mg/m²). The phase I study was plannedas an open-label, dose-finding trial. The goals of the study were to definethe maximum tolerated dose (MTD) of paclitaxel given in combination withfixed-dose doxorubicin in treating patients with breast cancer that hadrelapsed after adjuvant therapy or had not been treated previously withchemotherapy, 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 ofthe sequential doxorubicin/ paclitaxel combination. The dose of paclitaxelwas escalated by 30 mg/m² per dose level group, starting at 130 mg/m²and increasing to 250 mg/m². Three patients were treated at the firstdose level (130 mg/m²), and four patients were treated at each ofthe other dose levels. Even with escalation of paclitaxel to 250 mg/m²,the MTD of paclitaxel was not reached. The treatment was well toleratedat each paclitaxel dose level. According to protocol criteria, three patientsreceived granulocyte colony-stimulating factor at the hematologic nadir.
Fatigue, peripheral neurotoxicity, myalgia, and arthralgia were thepredominant nonhematologic side effects encountered. A grade 4 neutropeniaoccurred in 20% of the cycles, but treatment generally was not associatedwith severe clinical events. Only one patient, treated for multiple bonelesions with concomitant chemoradiotherapy and paclitaxel 190 mg/m²,developed a severe febrile neutropenia that required hospitalization. Asshown in Table 1, no cases of grade 3or 4 nonhematologic toxicity were reported.
To confirm the efficacy and toxicity results of phase I, the doxorubicin/paclitaxelsequence also was evaluated in a subsequent phase II study in which paclitaxelwas to be given in a fixed dose, established as that immediately belowthe MTD defined in phase I of the trial. Since no clear MTD was reachedduring the phase I study, and because it was feared that the risks of severeneutropenia and severe peripheral neurotoxicities would increase with furtherescalation of the paclitaxel dose, phase I was closed and phase II startedwith fixed doses of the two drugs.
Thus, from April 1995 to January 1996, 13 patients with the same eligibilitycriteria as established for phase I were treated with fixed doses of doxorubicin(50 mg/m²) and paclitaxel (220 mg/m²) inhopes of confirming the positive results of the phase I study, both interms of toxicity (particularly cardiac toxicity) and response rates. Patientsreceived a total of 95 cycles of therapy and results showed the same toxicitytrend as was seen in phase I, apart from an increase in peripheral neurotoxicityand grade 4 neutropenia. Moreover, as shown in Table2, severe febrile neutropenia occurred in only eight cycles (8%), infive patients.
Although the phase I study end point was not therapeutic efficacy, clinicalresponses were analyzed. Table 3 summarizesthe results observed in the phase I and phase II studies, both individuallyand combined. Phase II results confirmed the high response rate obtainedin phase I. For all 32 patients in phases I and II together, the overallresponse rate was 78.1%, with 31.3% complete remissions (CRs) and 46.9%partial remissions (PRs). At 16 months' median overall follow-up for thetwo phases, the median time to progression for all patients is nine months(median duration of objective response, nine months; median duration ofcomplete remission, seven months). As of November 1996, six patients withcomplete remissions have relapsed (five from phase I and one from phaseII) and disease has progressed in 12 with partial remissions (eight fromphase I and four from phase II).
Phase I of this study demonstrated good tolerability and high efficacyfor sequential doxorubicin followed by paclitaxel in patients relapsedafter prior adjuvant therapy or as first-line therapy in previouslyuntreated patients, with paclitaxel given by three-hour infusion in escalatingdoses of 130 to 250 mg/m². Treatment was well tolerated at all doselevels and the MTD was not reached at paclitaxel 250 mg/m².
No grade 3 or 4 nonhematologic toxicity was reported, and only one patienttreated with concomitant chemoradiotherapy and paclitaxel 190 mg/m²had treatment suspended due to severe febrile neutropenia. No significantcardiotoxicity was observed in this group. All patients were evaluatedby echocardiogram every two cycles; left ventricular ejection fractionvalues never fell below normal limits in any phase I patient.
The objective response rate for 19 phase I patients assessable for responsewas 78.9%, with 47.3% PRs and 31.6% CRs. A dose-response relationship wasobserved: All patients treated with higher paclitaxel dose levels (from190 mg/m² to 250 mg/m²) achieved objective responses (six CRsand six PRs). At lower paclitaxel dose levels, no CRs were observed. Thehigh response rate in the phase I trial and the absence of severe toxicityinparticular, the lack of congestive heart failurewhich was observed insome other studies,[5-6] required further confirmation in a phase II trialusing fixed doses of doxorubicin and paclitaxel. In 10 of 95 cycles, thepaclitaxel dose was reduced: In eight cycles (two patients), the dose wasreduced by one dose level (-30 mg/m²) because of grade 4 febrile neutropeniaplus grade 2 neurotoxicity, and in two cycles (one patient) the dose wasreduced by two levels (-60 mg/m²) because of grade 4 febrile neutropeniacomplicated by grade 3 mucositis and diarrhea. At a median follow-up of14 months for patients included in the phase II trial, we have confirmedthat no significant cardiac toxicity was reported in 12 of 13 patientsin this phase. However, in one patient, who received a cumulative doxorubicindose of 400 mg/m², the left ventricular ejection fraction decreasedfrom 60% to 43% without clinical symptoms. The patient, who completed thefull therapeutic program (eight cycles) was entered into follow-up andher ejection fraction values returned to normal limits within two months.As of November 1996, after progression of her neoplastic disease, the patientis being treated with second-line chemotherapy.
The 32 patients who took part in phase I/II of this study received 133cycles of chemotherapy: 22 patients (68.7%) received a cumulative doxorubicindose of 400 mg/m², seven patients (21.9%) received a cumulative doxorubicindose of 300 to 350 mg/m², while only three patients (9.4%) were treatedwith 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 byDombernowsky and Gianni (50 mg/m² vs 60 mg/m²), we believe thatthis different pattern of toxicity might have been influenced mainly bythe different timing of the schedule (the 16-hour interval between thetwo drug infusions). In any event, further clinical trials that includepharmacokinetic 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 thesecond, we are hoping to verify, in untreated patients, a possible differencein the occurrence of cardiotoxicity when the same schedule and timing usedin this phase I/II trial are repeated but a higher doxorubicin dose (60vs 50 mg/m²) is used. Currently, the 10 patients enrolled in thislast trial are receiving fixed doxorubicin doses (60 mg/m²) followedby paclitaxel 220 mg/m². No severe cardiotoxicity has been observedand no patients have discontinued treatment because of toxicity.
1. Amadori D, Frassineti GL, Zoli W, et al: A phase I/II study of paclitaxeland doxorubicin in the treatment of advanced breast cancer. Semin Oncol23(suppl 1):19-23, 1996.
2. Amadori D, Frassineti GL, Zoli W, et al: A phase I/II study of sequentialdoxorubicin 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 administrationof combined doxorubicin and paclitaxel in the treatment of advanced breastcancer. Semin Oncol 23(suppl 12):22-28, 1996.
4. Zoli W, Flamigni A, Frassineti GL, et al: In vitro activity of Taxoland Taxotere in comparison with doxorubicin and cisplatin on primary cellcultures of human breast cancers. Breast Cancer Res Treat 34:63-69,1995.
5. Gianni L, Munzone E, Capri G, et al: Paclitaxel by three hour infusionin combination with bolus doxorubicin in women with untreated metastaticbreast cancer: High antitumor efficacy and cardiac effect in a dose-findingand 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.