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© 1999 American Society for Clinical Oncology Vinorelbine and Paclitaxel as First-Line Chemotherapy in Metastatic Breast CancerFrom the Grupo Oncológico Cooperativo del Sur, Argentina. Address reprint requests to Dr Luis Romero Acuña, GOCS Neuquén, Rivadavia 360, 8300 Neuquén, Argentina
PURPOSE: To evaluate the efficacy and toxicity of a combination of vinorelbine (VNB) and paclitaxel (PTX) as first-line chemotherapy in metastatic breast carcinoma (MBC). PATIENTS AND METHODS: Between August 1995 and August 1997, 49 patients with untreated MBC received a regimen that consisted of VNB 30 mg/m2 in a 20-minute intravenous (IV) infusion on days 1 and 8 and PTX 135 mg/m2 in a 3-hour IV infusion (starting 1 hour after VNB) on day 1. Cycles were repeated every 28 days. The median age of the patients was 52 years, and 59% of patients were postmenopausal. Median performance status was 1. Dominant sites of disease were soft tissue in 6%, bone in 29%, and viscera in 65%. RESULTS: Objective responses were recorded in 27 of 45 assessable patients (60%; 95% confidence interval, 46% to 74%). Complete remissions occurred in three patients (7%), and partial remissions occurred in 24 patients (53%). No change was recorded in 12 patients (27%), and progressive disease occurred in six patients (13%). The median time to treatment failure was 7 months, and median survival duration was 17 months. The limiting toxicity was myelosuppression, mainly leukopenia in 49 patients (100%) (grade 1 to grade 2, four patients; grade 3, 30 patients; and grade 4, 15 patients). Neutropenia was observed in 100% of patients (grade 1 to grade 2, three patients; grade 3, 11 patients; grade 4, 35 patients). Two treatment-related deaths due to febrile neutropenia were observed in patients with massive liver involvement. Peripheral neurotoxicity developed in 33 patients (67%) (grade 1, 25 patients; grade 2, eight patients); there were no grade 3 or grade 4 episodes. CONCLUSION: The combination of VNB-PTX showed significant activity as first-line chemotherapy for patients with MBC. Myelosuppression was the dose-limiting side effect, whereas neurotoxicity was mild to moderate.
CHEMOTHERAPY PLAYS a central role in the treatment of breast cancer. Adjuvant therapy can reduce the risk of recurrence and death among women with early-stage disease.1 In stage IV breast cancer, chemotherapy offers a significant opportunity for palliation and longer survival.2 However, late recurrences may take place after adjuvant treatment,3 and chemotherapy for metastatic breast cancer (MBC) is rarely, if ever, curative.2 Although different strategies, such as high-dose or high-intensity chemotherapy, have provided new perspectives,4,5 better therapeutic options still depend on the identification of new and more active drugs or combinations to supplement those currently available. Chemotherapy for all stages of breast cancer is based on the combined use of three major classes of anticancer drugs: alkylating agents, antimetabolites, and anthracycline antibiotics. In spite of continuous research efforts, the more substantive advance since the design of the classic regimen of cyclophosphamide, methotrexate, and fluorouracil (CMF) has been the introduction of doxorubicin and epirubicin.2,6 In recent years, however, drug development has provided the field of breast cancer treatment with compounds endowed with new or more selective mechanisms of action that may improve current treatment options.7 The most promising new group of cytotoxic chemotherapy agents are drugs that poison the mitotic spindle, such as taxanes and vinca alkaloids. Paclitaxel (PTX) and docetaxel bind reversibly and specifically to the ß-subunit of tubulin, promoting its assembly and stabilizing the microtubules after spindle formation has occurred. These compounds induce the formation of stable microtubule bundles, impairing reorganization of the microtubular skeleton and blocking the cells in the G2-M phase of the cell cycle. Resistance to taxanes seems to be mediated by phosphoglycoprotein and the multidrug resistance (MDR) phenotype but may also be due to specific mutations in tubulin that interfere with the mechanism of microtubule stabilization.8 Vinorelbine (VNB), a semisynthetic vinca alkaloid, inhibits microtubule assembly, and thus its activity is cell cycle specific. This compound blocks formation of the mitotic spindle apparatus at metaphase and prevents cell division. This is in contrast to the mechanism of action of taxanes, which promote and stabilize the assembly of microtubules after spindle formation. One of the most promising aspects of vinorelbine concerns the selective nature of its effect on nonneural microtubules.9,10 Phase II studies of breast cancer have consistently demonstrated the antitumor activity of both drugs when used either alone or in combination with other agents.11-19 On the basis of this clinical experience, it seems a logical step to combine vinorelbine with paclitaxel, because of the marked antitumor activity of both agents, the relatively good tolerability of each drug when administered as a single agent, and the apparently complementary mechanism of cytotoxic action. This combination would create a total microtubule poison and could offer theoretical advantages based on potential synergy when the drugs are given together. In fact, preclinical data have shown that the combination was synergistic in vitro when the drugs were given simultaneously or VNB preceded PTX; in contrast, antagonism was observed when PTX was administered before VNB.20-22 Another interesting observation concerning this combination is that PTX could overcome resistance to VNB resulting from mutations in tubulin, and vice versa.23,24 However, because both VNB and PTX seem to be MDR substrates, the potential for cross-resistance development remains unknown.25 On this basis, the Grupo Oncológico Cooperativo del Sur (GOCS) activated the present prospective phase II study to evaluate the efficacy and toxicity of the novel combination of VNB and PTX as first-line chemotherapy for the treatment of patients with MBC.
Patient Selection The present trial was performed at GOCS member institutions in Argentina (Appendix). Women with a histologically confirmed diagnosis of breast carcinoma and evidence of metastatic disease were entered onto our protocol, 08-BR-95. Eligibility criteria included a life expectancy greater than 3 months; bidimensionally measurable lesions; performance status 0 to 2 (Eastern Cooperative Oncology Group scale); adequate bone marrow and liver function, unless inadequate because of tumor involvement (hemoglobin level  11 g/dL; leukocyte count 4,000/mL; platelet count 100,000/mL; bilirubin and transaminase levels < 1.5 times the upper limit of normal [ULN]); and adequate renal function with creatinine clearance greater than 60 mL/min. Patients with metastases confined to the skeleton had to have x-ray–assessable lytic lesions, and those who showed progressive disease (PD) during primary hormonotherapy were eligible for protocol entry 1 month after the last hormonal manipulation. A minimum interval to relapse of 4 weeks after completion of adjuvant chemotherapy was required. The protocol was approved by the ethics committee of GOCS before its activation, and written informed consent was obtained from patients, given the investigational nature of the study. Ineligibility criteria were prior systemic chemotherapy for metastatic disease; history of adjuvant chemotherapy including VNB and/or PTX; and CNS metastases, hilar enlargement, pleural effusion, or malignant ascites as the only evidence of metastatic disease. Additional ineligibility criteria included a history of alcohol abuse or peripheral neuropathy, geographic inadequacy for appropriate follow-up, myocardial infarction within 6 months before entry onto the study, active ischemic heart disease, and uncontrolled hypertension.
Pretreatment and Follow-Up Evaluation
Treatment Plan
Response Criteria
Toxicity and Dosage Modification Guidelines Both VNB and PTX doses were adjusted according to the absolute neutrophil count (ANC) observed in weekly CBCs. No dosage modifications were adopted for grade 1 hematologic toxicity. When greater than grade 1 toxicity was recorded, treatment was delayed until the ANC was at least 2,000/mL and the platelet count was at least 100,000/mL and then was restarted at 75% of the VNB and PTX doses. Dose reductions were considered definitive if greater than grade 1 toxicity was recorded in two consecutive cycles; otherwise, treatment was continued at full doses. Patients experiencing grade 4 hematologic toxicity in two consecutive cycles were removed from the protocol. The day 8 VNB dose was omitted if, after a 2-week delay from the planned date of treatment, hematologic toxicity greater than grade 1 persisted. Dosage modifications were also foreseen for the development of neurotoxicity as follows: grade 1, 100% of doses; grade 2, 75% of VNB and PTX doses; grades 3 or 4, the patient was removed from the protocol. Originally, the protocol was less stringent about liver function in patients with massive liver involvement, and women with up to 2.5 times the ULN of transaminases (with a normal bilirubin level) were admitted onto the study. However, shortly after activation, the protocol was amended. Since then, patients with massive liver metastases were required to have a normal bilirubin level and a transaminase level of 1.5 times the ULN or lower. This change was prompted by reports of severe myelotoxicity in patients with massive liver involvement (described in the Results section, under Toxicity).
Statistical Analysis
From August 1995 to July 1997, 49 women were entered onto this study. All patients were assessable for toxicity, whereas 45 patients were assessable for response. Three patients developed febrile neutropenia after the first cycle of therapy, and two of them died of sepsis. The third patient fully recovered, but she was removed from the study. Another patient refused further therapy after the first cycle of treatment and thus was considered not assessable for response. Patient characteristics are listed in Table 1. The ages of the patients ranged from 31 to 75 years (median, 52 years). Sixty-one percent were postmenopausal, and the median performance status was 1. Thirty-two patients (65%) had visceral disease as the dominant metastatic pattern. Thirteen patients (28%) had a DFI of less than 1 year. Eleven of these 13 patients (85%) had stage IV disease at initial diagnosis of breast cancer.
Total follow-up time was 53 patient-years, with an average of 13 months (range, 1 to 27 months) and a failure rate (deaths) of 0.51 failures per year. Responses to treatment were reviewed independently by two or more investigators. Objective regression was recorded in 27 of 45 fully assessable patients (60%) (95% confidence interval, 46% to 74%). Three patients (7%) achieved a CR, and 24 patients (53%) achieved a PR. No change was observed in 12 patients (27%), and PD was seen in six patients (13%). The three complete responders had a visceral metastatic pattern (two patients with lung and liver metastases, and one with lung involvement only). Responses in these patients were confirmed by computed tomographic scans. All patients with bone metastases achieving objective responses showed recalcification of lytic lesions and confirmed improvement on bone scans. In no patient was objective response in bone recorded, as judged by radiographic stabilization of disease with symptomatic improvement. Additionally, three patients showed rapid complete recalcification (as assessed after the second and third cycle of therapy) of extensive lytic lesions and normalization of previously elevated levels of alkaline phosphatase. However, uptake areas persisted on the bone scans, so these responses were considered partial remissions. Sixty-three percent of patients with dominant bone disease and 88% of those with dominant visceral disease maintained their original metastatic pattern at the moment of the first progression to treatment. The CNS was the first site of relapse in five patients (10%) and the only site observed in four of them. Most patients who achieved OR did so at the end of the third course of therapy (24 of 27 patients [89%]). The median time to treatment failure for the whole group was 7 months, whereas the median survival duration was 17 months. Analysis of subgroups showed that similar ORs were obtained in patients with either a dominant bone metastatic pattern or dominant visceral disease. However, significant differences were observed when response to treatment was correlated with menopausal status, DFI, and number of metastatic sites. Postmenopausal status, longer DFI, and low number of metastatic sites were associated with a better chance of achieving OR (Table 2).
Regarding prior adjuvant chemotherapy, the combination of VNB and PTX induced responses in 10 of 22 patients (45%) who had received prior doxorubicin, cyclophosphamide, and 5-fluorouracil chemotherapy and in five of seven patients (71%) who had been treated with the CMF combination. Similarly, OR was recorded in five of nine patients (55%) who had received adjuvant hormonotherapy and in three of three patients (100%) who had progressed to hormonotherapy for treatment of metastatic disease.
Dose-Intensity
Toxicity
Myelosuppression was the major dose-limiting toxicity. Leukopenia occurred in all patients and was grade 3 or 4 in 45 patients (93%). Grade 4 neutropenia was recorded in 71% of patients in at least one cycle. The median nadir of WBC counts was 1,500/mL (range, 200 to 3,700/mL), and the median time to WBC count recovery to more than 3,000/mL was 7 days. The median nadir of ANC was 416/mL (range, 0 to 1,900/mL). Grade 4 thrombocytopenia was documented in two patients, but there were no bleeding complications. The median nadir of platelet counts was 210,000/mL (range, 10,000 to 320,000/mL). Anemia was observed in 32 patients (65%); six patients (12%) experienced grade 3 anemia requiring packed RBC transfusions. The median nadir of hemoglobin was 11.3 g/dL (range, 6.6 to 12.4 g/dL). No patient entered onto this trial received prophylactic therapy with antibiotics or colony-stimulating factors. At the beginning of the study, three patients with normal bilirubin levels but transaminase levels of up to 2.5 times the ULN due to massive liver involvement were included. These patients developed febrile neutropenia after the first cycle of therapy, and two died of sepsis. The third patient recovered after intensive treatment with antibiotics and colony-stimulating factors but was removed from the study, and an amendment to protocol was introduced, as described under Patients and Methods. Among the remaining patients, five episodes of febrile neutropenia requiring hospitalization were observed. Three of these patients had liver metastases with normal bilirubin levels and transaminase levels of 1.5 times the ULN or lower. Positive blood cultures were obtained in two cases. All patients recovered after appropriate treatment. Although nonhematologic toxicity was frequently observed, it was rarely dose limiting. Myalgias, which usually started on day 3 after administration of both drugs and lasted for approximately 4 days, occurred in 31 patients (63%) and were registered in 44% of cycles; no patient required opioid analgesics. Peripheral neuropathy was observed in 33 patients (67%) and was predominantly sensorial in character. Mild paresthesias in hands and/or feet were observed in 46% of cycles, usually associated with myalgias and generally lasting no more than 7 days. Attenuation or loss of deep tendon reflexes was observed in 20 patients (41%). In 79% of patients experiencing neurotoxicity, the onset of symptoms was recorded after the first cycle of therapy. Even when the incidence of neurotoxicity seemed to be cumulative, no grade 3 or 4 episodes were recorded. Constipation was observed in 14 patients (20%); one of them developed paralytic ileus after the sixth cycle of treatment and recovered with specific therapy. Emesis was not relevant, and mucositis was seen in 18 patients (37%), mainly grade 1. Phlebitis was observed in seven (41%) of 17 patients who did not have a central venous access. Two of them (12%) developed severe local reactions. Other toxicities included asthenia in 16 patients (33%) and grade 3 alopecia in 42 patients (86%). No patient developed pulmonary or cardiac toxicity, and no hypersensitivity reaction was observed.
The appropriate management of patients developing new disease manifestations after adjuvant systemic therapy for breast carcinoma represents a therapeutic problem. With the increasing use of anthracycline-based combinations in the adjuvant setting, more patients with metastatic disease have a prior history of anthracycline exposure, thus limiting the use of this relatively effective group of drugs for palliation. There is a need, therefore, for the development of non–anthracycline-based combinations for the treatment of patients with metastatic breast cancer. In recent years, the suggestion that women without impending organ failure can be treated initially with phase II agents without compromising ultimate survival has improved the outlook for new drug or drug combination development.33 The activity of PTX against MBC has prompted a growing number of studies using this drug in combination with several anticancer agents. Because of the high therapeutic potential of PTX and doxorubicin, this combination emerged as one of the most promising. Initial studies in previously untreated patients resulted in high response rates but showed a disturbing incidence of cardiotoxicity. Alterations in the sequence and time of delivery of both drugs could ameliorate this side effect.34 Similarly, encouraging results were reported in initial experiences with the association of PTX and cisplatin.35-37 However, more recent studies have shown poorer results in terms of antitumor efficacy and have consistently observed a high incidence of neurologic toxicity, with asthenia and fatigue often regarded as dose limiting.34 Combinations of PTX with cyclophosphamide, ifosfamide, and mitoxantrone are at a more preliminary stage.34 The present study is the first to report on the efficacy of an association of PTX plus VNB administered as first-line chemotherapy for patients with disseminated breast cancer. Considerations relative to sequence-dependent synergistic interactions between VNB and PTX were taken into account in the schedule design. In fact, preclinical in vivo data suggested that both the sequence of administration and the ratio of the two drugs were important predictors of the efficacy of treatment. Simultaneous administration of the two drugs or administration of VNB followed shortly by PTX was found to be more successful (in vitro) than PTX followed by VNB.20-22 Doses of VNB and PTX selected were the lowest showing antitumor activity against breast cancer when used as single agents. Our results suggest that, in this setting, the VNB and PTX combination has a high antitumoral activity, as indicated by the OR rate, median time to treatment failure, and overall survival. Although we were unable to deliver consistently the full planned dose on schedule in all patients, the activity of this combination was significant. Patients entered onto the study were in good general condition and had not received previous treatment for metastatic disease. However, these favorable characteristics for response to therapy were counterbalanced by the unfavorable prevalence of visceral metastases and short disease-free interval in the majority. The 60% response rate recorded in this trial, which included a 7% CR rate, is in the range of those reported for standard combinations such as CMF- or doxorubicin-containing regimens commonly used against MBC.38 This finding seems significant, as our patient population differs from those of other current studies of PTX associations, most of which include chemotherapy-naive patients or patients not previously exposed to anthracyclines.34 Although high response rates after exposure to anthracyclines are rarely reported, the VNB plus PTX combination showed an interesting activity in this group of patients, inducing OR in 10 (45%) of 22 women who had received prior doxorubicin, cyclophosphamide, and 5-fluorouracil chemotherapy as adjuvant treatment. With the doses and schedule used in this study, hematologic toxicity was severe and was the dose-limiting side effect. Leukopenia occurred in all patients and was grade 3 or 4 in 45 patients (93%). Grade 4 neutropenia was recorded in at least one cycle in 71% of patients. A similar pattern of hematologic toxicity was observed by other authors using this combination in pilot studies in patients with lung and breast carcinoma.39-44 The liver plays a prominent role in the metabolism and elimination of VNB and PTX, and liver function alterations cause persistence of elevated blood concentrations of both drugs.45,46 At the time of activation of this trial (1995), there was a lack of information regarding dosage adjustments for VNB and PTX in patients with liver involvement. Two phase I studies suggested that patients with up to 5 times the upper limit of the normal levels of transaminases could be treated, provided that patients had a normal level of bilirubin.47,48 Thus, we initially admitted onto the study patients with these characteristics due to tumor involvement of the liver. Two consecutive women developed severe neutropenia and sepsis, and they died despite intensive treatment with antibiotics and colony-stimulating factors. This observation prompted an amendment to the protocol, and since then, only patients with normal bilirubin levels and transaminase levels not greater than 1.5 times the ULN were included. However, to date, a definite set of guidelines for dose modifications of both drugs in the presence of altered liver function tests has not yet been defined and validated. From our experience, we believe that extreme caution should be observed in patients with massive liver involvement. We suggest that the VNB-PTX combination, at the dose and schedule used in this study, should be administered only to patients with a normal bilirubin level and transaminase levels not greater than 1.5 times the ULN. Neurologic toxicity was generally mild. Even when two thirds of patients demonstrated peripheral neuropathy, no grade 3 or 4 episodes were registered, and signs and symptoms reverted in all cases after treatment discontinuation. Another side effect frequently encountered was myalgia, but this symptom did not interfere with the treatment program, and all cases were controlled with nonopioid analgesics. Other toxic effects were mostly mild and tolerable. The association of VNB and PTX has attracted the interest of several investigators, who have conducted encouraging studies of this combination. The extent and the content of previous treatment influenced the results obtained, and the dose-limiting toxicity in all experiences was mainly myelosuppression.39-44 More recent studies in heavily pretreated patients (most of them with prior exposure to anthracyclines) confirmed the efficacy and toxicity profile of VNB plus PTX.49-51 These observations are relevant because, to date, only one type of organ toxicity caused by chemotherapy, bone marrow suppression, can be effectively dealt with by addition of colony-stimulating factors. Even when used as single agents, the best dose and schedule of administration of VNB and PTX to maximize antitumoral activity and minimize toxicity remain to be established. From this perspective, the observation by Martin et al50 that VNB 30 mg/m2 and PTX 135 mg/m2, administered on day 1 every 3 weeks, could be safely given and resulted in a high response rate in pretreated patients, is relevant. A new treatment option that is currently being investigated is known as dose-dense therapy. In this approach, active drugs are delivered sequentially at their ideal dose level separated by short intertreatment intervals. Thus, dose intensification is achieved by means of rapidly recycled treatment. The identification of new agents holds great promise, and the assessment of VNB and PTX in this treatment modality should be considered. In summary, according to our results and those of other authors, further studies of the VNB-PTX combination are warranted. In our opinion, three potential strategies deserve particular attention: (1) addition of hematopoietic growth factors to our therapeutic program to attenuate hematotoxicity and increase dose intensity, allowing evaluation of the impact of this variable upon the efficacy of the combination and the eventual appearance of dose-limiting nonhematologic toxicities; (2) omission of day 8 VNB dose with cycles repeated every 3 weeks; and (3) assessment of a sequential dose-dense program of VNB followed by PTX, or vice versa.
The member institutions of the Grupo Oncológico Cooperativo del Sur are as follows: Centro Radioterapeutico de Excelencia Oncologica, Bahía Blanca; Centro de Salud "Dr. Leonidas Lucero," Bahía Blanca; Hospital Interzonal General "Dr. José Penna," Bahía Blanca; Hospital Italiano Regional del Sur, Bahía Blanca; Policlínica Privada Instituto de Medicina Nuclear, Bahía Blanca; Clinica Pueyrredon, Mar del Plata; Hospital Provincial Neuquen, Neuquén; Policlinico de la Asociación de Obras Sociales, Neuquén; Unidad Oncologica del Comahue, Neuquén; Centro Oncologico del Litoral, Santa Fe; Centro de Oncología y Terapia Radiante, Santa Rosa-La Pampa; Hospital Lucio Molas, Santa Rosa-La Pampa; and Sanatorio Santa Rosa S.R.L., Santa Rosa-La Pampa, Argentina.
Supported in part by Laboratorios Rontag, Buenos Aires, Argentina We thank Silvia Albornoz and Ricardo Gonzalez for skillful data management of this study.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test or Fisher's exact test when appropriate. Disease-free interval (DFI), duration of response, and duration of survival were considered from the beginning of therapy and assessed by means of the product-limit method of Kaplan and Meier.
