1 First Department of Medicine, Laiko Hospital, University of Athens; 2 Alexandra Hospital, Department of Clinical Therapeutics, University of Athens; 3 Rio Hospital, University of Patras, Patra; 4 Metaxa Cancer Hospital, Piraeaus; 5 AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki; 6 IKA, Thessaloniki; 7 Ippokration Hospital, Athens; 8 Second Department of Internal Medicine, Propaedeutic, University of Athens; 9 Henry Dunan Hospital, Athens; 10 Hygeia Hospital, Athens, Greece
Received 7 March 2002; revised 22 April 2002; accepted 16 May 2002
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Abstract |
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To determine the activity and safety of the combination of paclitaxel and pegylated liposomal doxorubicin (Caelyx®) in patients with locally advanced breast cancer.
Patients and methods:
This was a multicenter phase II study. Thirty-five newly diagnosed patients with locally advanced breast cancer were included in the study. Histological or cytological diagnosis was necessary for inclusion. Median age was 54 years (range 2673 years). Fifteen patients were premenopausal and 20 postmenopausal. Paclitaxel was administered at a dose of 175 mg/m2 and pegylated liposomal doxorubicin 35 mg/m2 every 3 weeks for six cycles.
Results:
Twenty-five patients (71%) responded. Six (17%) had a complete response, 19 (54%) had a partial response, four remained stable, two progressed and four were not evaluated for response due to discontinuation of chemotherapy. Three patients had a pathologically complete response. A total of 173 cycles were administered. The primary toxicity observed was skin toxicity. Grade 3 skin toxicity was noted in four patients (11%). Palmarplantar erythrodysesthesia (PPE) grade 3 was experienced by three (9%). Two patients presented with PPE and skin toxicity. Hematological toxicities included grade 3 leukopenia in four patients (3%). Other grade 3 toxicities were uncommon and included only alopecia in 29 patients (83%). Grade 3 or 4 neurotoxicity was not observed in any patient. Dose reduction was necessary in seven patients; in six due to skin toxicity and in one due to neutropenia. Four patients discontinued treatment due to skin toxicity. There were no treatment-related deaths.
Conclusions:
The combination of pegylated liposomal doxorubicin and paclitaxel was active in locally advanced breast cancer. The primary toxicity was cutaneous toxicity and it was manageable.
Key words: breast cancer, liposomal doxorubicin, neoadjuvant, paclitaxel
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Introduction |
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Anthracyclines such as doxorubicin are considered among the most active single agents in advanced breast cancer. However, the use of anthracyclines is limited by their acute toxicities (nausea, vomiting, alopecia, mucositis and myelosuppression) and by their potential for causing cumulative cardiac damage. An attempt to improve the therapeutic index of anthracyclines includes drug encapsulation in liposomes. With the development of stealth liposomes, the drug circulation time is prolonged and the pattern of drug distribution to tissues is altered.
Two phase I studies with stealth pegylated liposomal doxorubicin (PLD) (Caelyx®; Schering Plough, and Doxil®; Alza Corporation) initially provided anecdotal evidence of antitumor activity in breast cancer [2].
In the first reported phase II trial of PLD in metastatic breast cancer an overall response rate of 31% was achieved, with 16 patients having a partial response and four complete responders in 64 assessable cases. Dose-limiting toxicity was grade 3 at doses of 60 mg/m2 every 3 weeks. The incidence of grade
3 skin toxicity was greatly reduced at doses of 45 mg/m2 and the mild myelosuppression seen with this regimen would favor its use in combination chemotherapy [3].
The introduction of paclitaxel into metastatic breast cancer treatment has yielded encouraging results. It has a unique cytotoxic mechanism of promoting assembly and preventing disassembly of microtubules [4]. Disruption of microtubule dynamics arrests and subsequently kills cells in the G2 and M phases of the cell cycle. It has also been shown to have anti-angiogenic activity [5]. Results from many phase II trials have demonstrated that paclitaxel is effective against metastatic breast cancer as a single agent and in combination regimens. Importantly it has been shown to be partially non-cross-resistant with many other agents and is active in heavily treated patients including those who have received prior anthracycline treatment [6, 7].
Single-agent paclitaxel has demonstrated activity (response rates of 5662%) in phase II studies in metastatic breast cancer [810].
The single-agent activity of paclitaxel in previously untreated and previously treated patients with metastatic cancer, and the apparent lack of cross-resistance with anthracyclines, provide the rationale for investigating paclitaxel/doxorubicin regimens in the neoadjuvant and adjuvant setting.
As neoadjuvant chemotherapy offers an important test bed for novel therapies including new drugs or new combination of drugs, we initiated a phase II trial to determine the efficacy and toxicity of the combination of paclitaxel and PLD in patients with locally advanced breast cancer.
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Patients and methods |
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Before initiation of therapy, all patients underwent staging work-up, which included: a complete history and physical examination; a complete blood count; chemistry profile; chest radiograph; liver ultrasound or computed tomography scan of the liver; and bone scan mammograms of both breast were performed. Ejection fraction assessment and electrocardiograms were obtained before study entry and 34 weeks after completion of preoperative chemotherapy.
Patients were required to have: disease measurable by physical examination or diagnostic breast imaging; age 18 years or over; Karnofsky performance status of at least 70; life expectancy of at least 12 months; adequate hematological, renal, hepatic and cardiac function; and a negative pregnancy test for all premenopausal women.
Specific criteria for exclusion were as follows: previous treatment for breast cancer, including surgery, radiation, cytotoxic and endocrine treatments (except surgical diagnostic procedures); previous malignancy except for curatively treated non-melanoma skin cancer, or carcinoma in situ of the cervix; pre-existing neurotoxicity >2; active infection or other serious underlying medical or psychiatric condition which would impair the ability of the patient to receive protocol treatment.
Treatment
Following standard premedication with glucocorticoids and H1- and H2-receptor blockers chemotherapy consisted of PLD 35 mg/m2 dissolved in 5% dextrose 250 ml administered over 60 min on day 1 and paclitaxel 175 mg/m2 in a 3-h infusion on day 1 immediately after the infusion of PLD, every 3 weeks. Patients were initially treated for a total of four cycles. Responding patients continued to receive six cycles and then a modified radical mastectomy was performed. Subsequent radiation therapy to the chest wall and supraclavicular region was employed. Hormonal therapy with tamoxifen (20 mg/day for 5 years) was provided to all patients who were hormone-receptor positive.
Following surgery, patients who had unfavorable tumor characteristics, such as positive lymph nodes, high nuclear grade or negative estrogen receptors were treated with six cycles of cyclophosphamide/methotrexate/5-fluorouracil at doses of 100 mg/m2 on days 114, 40 mg/m2 on days 1 and 8, and 600 mg/m2 on days 1 and 8, respectively, every 28 days.
After preoperative chemotherapy was administered, breast tumors were classified according to clinical response. In the absence of clinical evidence of tumor in the breast, the response to therapy was categorized as clinically complete (cCR). When the reduction in clinical size of the breast tumor was 50%, the response was judged to be partial (cPR). When there was an increase of >25% in the size of a breast tumor after a minimum of two cycles of therapy the patient was considered to have progressive disease (cPD). Patients whose breast tumor response did not meet the definition of either cCR, cPR or cPD were considered to have stable disease (cSD). Thus, patients with cSD could have a tumor response <50% or an increase in tumor size of <25%. A similar classification was used to record the response of an axillary tumor to preoperative therapy in patients who had clinically positive nodes when they received their first cycle of preoperative therapy. The overall clinical response of both breast and axillary tumors was determined by combining the sum of the product of the tumor measurements in both the breast and axilla.
Surgical specimens from patients who had either a clinically complete breast or axillary tumor response to preoperative therapy were evaluated for their pathological tumor status. A pathologically complete response (pCR) was considered to have occurred when there was no histological evidence of tumor cells.
Non-responders (stable or progressive disease) were referred for radiotherapy.
Dose reduction
Blood counts were performed on the day of treatment. In the case of granulocytopenia or thrombocytopenia on the first day of the cycle, treatment was delayed until the absolute neutrophil count (ANC) was 1500/µl and platelets
100 000/µl, respectively. In the case of grade 3 or 4 granulocytopenia and/or thrombocytopenia the dose of PLD and paclitaxel was reduced by 25% in all subsequent cycles. If the ANC was between 1000/µl and 1499/µl on day 1, then treatment with granulocyte colony-stimulating factor (G-CSF) could be administered. If ANC was <1000/µl then treatment was postponed for 1 week and treatment with growth factor was initiated. In this case the growth factor was given prophylactically in all subsequent cycles. If hematological recovery was not achieved by day 42 of the cycle, the patient would be taken off study. In the case of grade 2 neurological toxicity the dose of paclitaxel was reduced by 25%. Treatment was interrupted permanently in the case of any grade 4 non-hematological toxicity (except nausea/vomiting and alopecia) and the patient taken off study. In the case of erythrodysesthesia a stepwise approach to modify PLD treatment was adopted [11]. Toxicity criteria were those adopted by WHO.
Statistical design
The size of the study was based on response rate after neoadjuvant therapy. Using Simons two-stage minimax design a sample of 37 patients has an 80% power at the 5% level of significance to reject the hypothesis that the true response rate is <70%, if at least 23 responses occur. At the first stage, if <13 responses occur out of the first 23 patients, the study will conclude that the anticipated response rate is <5% and be terminated.
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Results |
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Disease was stable in four patients (11%) (95% CI 3.20% to 26.74%) and progressed in two (6%) (95% CI 0.70% to 19.26%). Of the six patients with cCR, three patients were actually confirmed to have achieved a pCR at the time of surgery (Table 2).
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Two patients exhibited allergic reactions that consisted of flushing with an onset early during the first infusion of PLD. Discontinuation of PLD and the administration of antihistamines and corticosteroids led to prompt and full recovery. The infusion was reconstituted at a slower rate and no further allergic responses recurred with subsequent cycles of treatment. One patient refused surgery after undergoing six cycles of chemotherapy and having achieved a cPR.
All patients were evaluated for toxicity and efficacy based on intention-to-treat analysis. The overall response rate was assessed by physical evaluation. Responders were referred for surgery.
Six patients had no palpable tumor before surgery. Two patients had minimal residual disease (one 0.5 cm and negative axillary lymph nodes and the other 0.6 cm and micrometastasis in one axillary lymph node).
With a median follow-up of 16 months there have been eight recurrences (one lymph nodes, two skin, one liver, one lung, one bone, one meningitis carcinomatosus, and one developed a second primary breast cancer) and three deaths. The median time to progression has not yet been reached.
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Discussion |
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To the best of our knowledge this is the first study reporting on the efficacy and toxicity of the combination of paclitaxel and PLD in locally advanced breast cancer. This regimen has only been tested in metastatic breast cancer and the response rate was 69%, similar to the overall response rate observed in our group [12]. The doses of the two drugs used in combination were identified in a phase I/II trial performed in advanced head and neck cancer by the Hellenic Cooperative Oncology Group (J. Janninis, personal communication). Additionally, the efficacy seen in our study is similar to that reported in other recently completed trials in locally advanced breast cancer. In a pilot study where 32 patients with locally advanced breast cancer were treated with doxorubicin 60 mg/m2 and paclitaxel 200 mg/m2 overall response rate was 88% and cCR was achieved by 31% of patients. Findings at pathological examination indicated a gross complete response in 15% of patients and a pCR in 7% of patients [13]. In another phase III study, the arm that received a combination of doxorubicin (60 mg/m2) and paclitaxel (200 mg/m2) achieved a clinical response rate of 85%, which included a complete remission rate of 14% [14]. The combination of paclitaxel and doxorubicin was further evaluated in a randomized phase III trial comparing four with six cycles of preoperative chemotherapy. Overall response rates were 20% and 32% and the rates of pCRs were 5% and 10% in the four-cycle and six-cycle arms, respectively [15]. The complete response rate in our study was 17% and the pCR rate was 8%, which is somewhat lower than those reported in these trials [1315], but questions concerning equivalence of efficacy can only be answered in large prospective randomized phase III trials.
PLD has a toxicity profile distinctly different from conventional doxorubicin. It rarely produces nausea and vomiting, and can usually be given without prophylactic antiemetic therapy or significant alopecia. It generally produces mild myelosuppression. Epithelial toxicities are the most significant side-effects encountered.
The combination of paclitaxel and PLD generally exhibited a similar toxicity profile. Grade 3 and 4 nausea and vomiting were not seen in our cohort of patients. Only one patient presented with grade 3 leukopenia.
Skin toxicity was marked in 14% of patients (grade 3). As it has been described previously, it occurred in the palms of hands and soles of the feet and other areas of skin such as the axillae, perineum (flexure areas) and pressure areas. In all cases, skin toxicity was reversible. In a phase II study, where single-agent PLD was administered in advanced breast cancer, repeated doses of 60 mg/m2 every 3 weeks were associated with marked skin toxicity in approximately half of the patients, whereas skin changes were typically absent or mild with doses of 45 mg/m2 every 28 days [3].
In another study where the toxicity profile and pharmacokinetics of various dose schedules of PLD were examined in a group of patients with metastatic breast carcinoma, mucositis was the main dose-limiting toxicity for high doses, whereas PPE was the predominant form of toxicity for patients treated at short dose intervals of 3 weeks [16].
As in both studies, skin changes were rarely seen following the first cycle of treatment, which implies that they occur as a result of a cumulative effect of PLD, and that repeated administration of PLD at relatively short intervals leads to toxicity when drug levels persist for a long period. Even though the dose of PLD was much lower, co-administration with paclitaxel might enhance this effect. This combination with different doses of PLD 30 mg/m2 and paclitaxel 200 mg/m2 every 21 days was administered as initial treatment for metastatic breast cancer in 13 patients and again significant handfoot syndrome was reported in nine of 13 patients [12]. In addition, even though PLD causes significantly less alopecia than doxorubicin, this was not seen in our study due to alopecia caused by paclitaxel.
Cardiac evaluation did not reveal any significant alteration during chemotherapy or follow-up. This is in contrast with the high incidence (20%) of clinical cardiac toxicity manifested by symptomatic congestive heart failure originally reported [17], which had raised concerns over potential drugdrug enhancement of toxicity. These concerns prompted a reduction of the total dose of doxorubicin to 360 mg/m2 for administration in combination with paclitaxel [18]. This measure was effective in reducing the risk of cardiac events, and in a pilot study of primary chemotherapy with doxorubicin plus paclitaxel in women with locally advanced or operable breast cancer cardiac toxicity evaluated by left ventricular ejection fraction (LVEF) was not an issue [13].
However, grade 3 cardiotoxicity was again reported in 18% of patients even though the total dose of doxorubicin was 240 mg/m2 [14]. In a subsequent trial by the same investigators no congestive heart failure was reported but a decline of LVEF 20% was seen in 19% and 22% of the four-cycle and six-cycle arms, respectively [15].
As far as the pharmacoeconomic aspects of the schedule proposed are concerned the cost of the study drugs might be outweighed by the cost of managing adverse events or the cost of drug administration. It is an outpatient regimen. No hospitalization for febrile neutropenia, no antibiotics and no red cell or platelet transfusions were required. No patients were admitted to intensive care and the number of cycles administered with G-CSF support was small (11%).
In summary, the present study indicates that PLD plus paclitaxel is effective in reducing the size of the primary tumor in women with locally advanced breast cancer. As concern about skin toxicity has arisen, administration of the combination every 4 weeks should be evaluated.
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Footnotes |
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References |
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