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© 1999 American Society for Clinical Oncology Infusional Paclitaxel and Weekly Vinorelbine Chemotherapy With Concurrent Filgrastim for Metastatic Breast Cancer: High Complete Response Rate in a Phase I-II Study of Doxorubicin-Treated PatientsFrom the Division of Oncology, University of Washington, Seattle, and Puget Sound Oncology Consortium, Puget Sound, WA; Amgen, Inc, Thousand Oaks, CA; Glaxo Wellcome Inc, Research Triangle Park, NC; and Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ. Address reprint requests to Georgiana K. Ellis, MD, University of Washington, Division of Oncology, Box 356043, Seattle, WA 98195-6043; email gellis{at}u.washington.edu
PURPOSE: We investigated 96-hour paclitaxel infusion combined with weekly (days eight and 15) vinorelbine as salvage therapy for metastatic breast cancer in anthracycline-exposed patients. All patients received scheduled support with granulocyte colony-stimulating factor (G-CSF; filgrastim). Tumor response, toxicity, time to progression (TTP), and survival were assessed. PATIENTS AND METHODS: This single-center nonrandomized trial enrolled 32 patients. Anthracycline exposure and subsequent progression were common to all patients. Paclitaxel and vinorelbine were escalated over three dosing levels, stratified by liver function. RESULTS: Seven patients (22%) achieved a complete response and nine patients achieved a partial response for an overall response rate of 50%. The median TTP was 6.1 months, and median survival time was 14.1 months. Dose-limiting toxicity was neutropenia, with dose delay or reduction in seven of 32 patients. Febrile neutropenia requiring hospitalization was uncommon (three of 32 patients; 9%). There were no treatment-related deaths. Grade 3/4 thrombocytopenia occurred in two patients (6%), and 13 patients (41%) required RBC transfusions for anemia. Grade 3 nausea and vomiting was seen in one patient, who was found to be Addisonian. Despite potentially overlapping neurologic toxicities of the two agents, only two patients (6%) were removed from the study because of progressive peripheral neuropathy. CONCLUSION: Administration of 96-hour paclitaxel infusion and subsequent weekly vinorelbine with G-CSF support is well tolerated. The response rate, TTP, and survival data are encouraging for therapy given to anthracycline pretreated patients with metastatic breast cancer. If these results can be verified in multi-institution trials, this or a similar combination of drugs would merit investigation as first-line therapy in this patient population.
STAGE IV BREAST CANCER remains a difficult disease to treat. Treatment is made more problematic with increased exposure to chemotherapy in the adjuvant setting.1 Paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ) is an agent with significant activity against anthracycline-refractory breast cancer. Data from Wilson et al2 indicate that it may be more effective when given as a prolonged infusion, with a response rate of 48% compared with an expected response rate of approximately 25% for 3- or 24-hour infusions, after progression on an anthracycline.3,4 Seidman et al5 administered the drug as a 96-hour continuous infusion and observed a 28% response rate in 25 patients whose disease was refractory to administration of paclitaxel by 3-hour infusion. Hypersensitivity reactions were not seen with this prolonged infusion schedule, despite the omission of standard premedications. Both groups of investigators noted increased toxicity among patients with even mild transaminase elevation, reflecting liver dysfunction: Wilson et al have recommended dose reduction in such patients from 140 mg/m2 to 105 mg/m2 (75% dose); and Seidman et al observed steady-state drug concentrations more than twice as high in patients with an elevated AST level. Vinorelbine (Navelbine; Glaxo Wellcome, Inc, Research Triangle Park, NC) is also an agent with significant activity in the treatment of relapsed or refractory breast cancer. In a randomized trial reported by Jones et al6 in 1994, vinorelbine produced a higher response rate (46.5% v 28.2% with objective response or stabilization of disease) and longer time to disease progression (median, 12 v 8 weeks) when compared with melphalan as a single agent in the anthracycline-refractory (third-line) setting. There may be a dose-response to this agent. Livingston et al7 investigated a dose-intensive regimen of weekly vinorelbine with continuous granulocyte colony-stimulating factor (G-CSF; filgrastim [Neupogen; Amgen, Inc, Thousand Oaks, CA) support and reported a response rate of 25% in 40 patients, all of whom were refractory to prior anthracyclines and most of whom (38 of 40; 95%), were refractory to paclitaxel as well (fourth-line). The median delivered dose-intensity (DDI) for this trial (a phase I-II study) was 27.7 mg/m2/wk compared with a reported median of 15.7 mg/m2/wk in another series with less-heavily pretreated patients.8 This represents an increase in DDI of 75%, made possible by the concurrent administration of G-CSF. Seven patients (18%) had reversible grade 3/4 nonhematologic complications, primarily related to neurotoxicity. Dose-limiting toxicity was neutropenia, with an uncommon occurrence of febrile neutropenia requiring hospitalization (three of 40 patients; 8%). Preclinical data suggest that there may be synergism between the vinca alkaloids and the taxane compounds. Whereas the vinca alkaloids, like vinorelbine, induce net disassembly of microtubules, the taxanes promote microtubule polymerization.9 The polymerized microtubules are quite stable, which inhibits the normal reorganization of the microtubule network. Some drug-resistant cell lines, produced by prolonged exposure to paclitaxel in vitro, have tubulin-mutant subunits that have an inherently slow rate of microtubule assembly when grown in the absence of drug.10 This mechanism of resistance imparts increased sensitivity to the vincas in human cell lines.11 Bissery et al,12 studying mice bearing a variety of solid tumors in vivo, have observed synergism of the taxane compound, docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA) when given with vinorelbine. In this system, it was possible to administer full doses of both agents, which was not the case for the combination of docetaxel with agents from other classes. Both clinical observations13-18 and preclinical data suggest paclitaxel by 96-hour infusion combined with weekly vinorelbine may be optimal. Dose-limiting toxicity for both drugs and schedules, in patients with normal liver function, is neutropenia. For vinorelbine alone, this can be greatly reduced by concurrent administration of G-CSF.19 We therefore initiated a study of these agents in combination.
Thirty-two patients with metastatic breast cancer were enrolled onto the study. All had metastatic breast cancer known to be either estrogen receptor–negative or clinically hormone-refractory. Patients were eligible for the study if they had received previous anthracycline chemotherapy or had a contraindication to such an agent. Documented informed consent was obtained from all patients according to institutional guidelines.
Treatment Evaluation Staging evaluations were conducted within 2 weeks of initiation of chemotherapy and consisted of a physical examination and a medical history including all previous cancer therapy, Karnofsky performance status assessment, baseline laboratory values, and diagnostic imaging to evaluate all metastatic sites (bone scan and computed tomography of chest and abdomen in all patients, with additional imaging studies as indicated). Patients with untreated CNS disease were not eligible. Symptoms, toxicities, and adverse events were recorded at weekly visits thereafter, with repeat imaging of assessable disease at 6-week (2-cycle) intervals.
Complete (clinical) response was defined as the complete disappearance of all objective disease; partial response was defined as a reduction of at least 50% from baseline of the biperpendicular diameters of all measurable lesions without the appearance of new lesions. Bone disease was categorized as responding by calcification of previously lytic disease, improvement or resolution of bone pain, and reduction and/or normalization of tumor markers, if previously elevated. Responses were confirmed by second evaluation at least 4 weeks later. Lesser responses were viewed as stable disease. Progression was defined as an increase of
Experimental Design and Statistical Considerations Treatment consisted of paclitaxel by 96-hour infusion, followed by vinorelbine administration on days 8 and 15. Both drugs were initially administered at 75% of the full dose (105 mg/m2/96 hours, and 22.5 mg/m2/wk, respectively), with G-CSF at 5µg/kg subcutaneously administered on all days except those of paclitaxel infusion; this cycle was repeated every 3 weeks. Dose escalation was planned as shown in Table 1.
Patient characteristics are listed in Table 2. All patients had either hormone (estrogen ± progesterone) receptor–negative disease or were hormone-refractory. All patients had received prior doxorubicin; 12 (38%) developed metastatic disease, failed to respond, or showed disease progression while receiving doxorubicin; 12 (38%) relapsed within 12 months of adjuvant doxorubicin; eight (25%) had disease that was not formally refractory but had received their maximum cumulative dose (  450 mg/m2) of this anthracycline. Five patients (16%) had received previous paclitaxel by shorter (1-hour or 3-hour) infusions; all experienced disease progression on this therapy. The median age of the patients was 47 years (range, 30 to 70 years). The median number of disease sites was two (range, one to four sites); 72% of patients had visceral sites of disease, and 9% of patients had bone-only disease. The mean number of previous chemotherapeutic regimens was 1.6 (range, one to three regimens; both as adjuvant therapy and for advanced disease).
Patients received a median of 14 weeks of treatment (range, 6 to 99 weeks). Dose-limiting toxicity was neutropenia, and doses were not escalated beyond level 3. Five patients were treated at level 1, five at level 2, and the remaining 22 patients at level 3. DDI for all patients was 35 mg/m2/wk for paclitaxel, and 13.5 mg/m2/wk for vinorelbine. Toxicity was largely hematopoietic. Three patients were admitted for febrile neutropenia (five events). A total of seven patients (22%) required dose delay or reduction secondary to grade 4 neutropenia, five (16%) for thrombocytopenia (two grade 4 and three grade 2; no transfusions required) and one (3%) for anemia (six with grade 3; 18%). Seventy-five percent of patients experienced significant anemia: 11 patients (34%) were treated with erythropoietin, and 13 patients (41%) received a total of 21 RBC transfusions. One patient had grade 3 nausea and vomiting and was found to be Addisonian. Two patients (6%) were removed from the study because of grade 3 neurotoxicity. Grade 3 stomatitis, requiring dose delay, was seen in two patients (6%). Nine patients achieved a partial response (28%), and seven achieved a complete response (22%), for a total of 16 responses (50%) from 32 patients. Two of 23 patients with visceral sites of disease achieved a complete response, one with nodular lung disease and one with liver disease. Details of previous doxorubicin (Adriamycin; Pharmacia & Upjohn, Bridgewater, NJ) administration and response are listed in Table 3. In patients whose disease was strictly defined as anthracycline-resistant (developing metastatic disease on adjuvant anthracycline, failing primary anthracycline therapy, or progressing while receiving anthracycline therapy), the complete response rate was 3 (25%) of 12, with an overall response rate of 5 (42%) of 12. Three of the seven patients who achieved a complete response had received prior paclitaxel by a shorter infusion time. Seven of the 32 patients proceeded to a high-dose consolidation regimen with or without peripheral-blood stem-cell support. Median time to progression was 6.1 months; the median survival time was 14.1 months. Progression and survival curves are shown in Fig 1.
With increasing doxorubicin exposure in primary breast cancer populations, administration of this useful drug in the advanced disease setting is often problematic. The taxanes have proven quite useful in this setting, with single-agent response rates as high as 47% for paclitaxel (15 patients, single institution),20 generally in the 20% to 30% range, and 41% for docetaxel (134 patients, three multicenter trials).21 Single-agent vinorelbine in anthracycline-exposed patients has been reported as having a response rate of 15%6; our previous dose-intensity (DI) study of this drug with G-CSF support as fourth-line therapy resulted in a response rate of 25%.7 Ibrahim et al13 have reported preliminary results of an ongoing phase I-II trial with the combination of paclitaxel and vinorelbine, each given by 3-hour infusion every 3 weeks. They observed a 41% response rate among 22 assessable patients with metastatic breast cancer, most of whom were receiving it as first-line therapy for stage IV disease but in a setting of prior anthracycline exposure as adjuvant therapy. Without growth factor support, the dose-limiting toxicity in this trial was neutropenia; grade 3 paresthesias occurred in five patients (4%). The authors defined their maximum-tolerated dose without growth factor support as paclitaxel 150 mg/m2 and vinorelbine 25 mg/m2, which would be a DI of 50 mg/m2/wk for paclitaxel but only 8.3 mg/m2/wk for vinorelbine. More recently, Martin et al14 have reported on the combination as first-line therapy for metastatic breast cancer in 33 patients. Paclitaxel was given at 135 mg/m2 over 1 hour followed by vinorelbine at 30 mg/m2 on day 1, repeated every 21 days, with an overall response rate of 48% (9% complete responses). These results were updated in abstract form to include 46 assessable patients, with a complete response rate of 13% and an overall response rate of 54%.15 Several other preliminary reports using this combination have been published.16-18 Long infusions of paclitaxel result in a lower DI than can be achieved with short infusions: a full DI for 96-hour infusion is 46.7 mg/m2/wk, whereas a full DI for the drug given by 3-hour infusion is approximately 83 mg/m2/wk. Our DDI for the 96-hour infusion schedule in this study was 35 mg/m2/wk or approximately 75% of the full intended DI for the drug as a single agent.2 The vinorelbine DDI of 13 mg/m2/wk is approximately 65% of that reported by Jones et al6 for single-agent therapy. Because grade 4 neutropenia occurred in 22% of our patients, we believe that the use of G-CSF was necessary to achieve the DDI that was obtained. We recognize that the concept of DI in breast cancer therapeutics remains controversial, in general, and may not pertain to these two agents specifically. However, only a randomized trial could determine whether the level of DI thus achieved, as conventionally calculated, contributes importantly to the therapeutic effects seen in this study. The response rates seen in the present study compare favorably to those seen with paclitaxel as a single agent in this patient population and are similar to those of other paclitaxel/vinorelbine phase II studies, listed in Table 4. The relatively comparable, albeit early, results suggest that there may be no relationship between dose or schedule for this two-drug chemotherapy combination, despite in vivo and in vitro data suggesting that there may be schedule dependency for the taxanes. The increased complete response rate seen in the present study is unusual and may be a function of patient selection; complete responses were seen largely in patients with soft tissue and bone disease. Best disease response to previous anthracyclines may also vary from study to study. In addition, all of the reported studies using this two-drug combination are small and preliminary in nature. Of equal or greater interest than response rates is the median time to progression of 6.1 months in the present study, which is double that observed for paclitaxel alone in a recent randomized trial and almost equivalent to that seen for the combination of paclitaxel and trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA) in the same trial.22 In that study, although all paclitaxel-treated patients had prior anthracycline exposure, none had received doxorubicin for metastatic disease, whereas 22 (69%) of 32 patients in our trial had received an anthracycline for metastatic disease.
The combination of a taxane with vinorelbine may be the treatment of choice for patients after maximum anthracycline exposure and/or resistance precludes further treatment. Given its evidence for non–cross-resistance shown here and in the other clinical trials cited, and preclinical data indicating that both groups of agents act through p53-independent mechanisms,23 we believe that this combination warrants investigation as part of an initial or first-line therapy for metastatic breast cancer. Because 96-hour paclitaxel is inconvenient, the appropriate combination for further study may be with standard paclitaxel or substitution of docetaxel. Our current institutional study uses the latter approach, combined with vinorelbine on the same dose/schedule and G-CSF support.
Supported by Wellcome Oncology, Glaxo Wellcome Inc, Research Triangle Park, NC, and Amgen Inc, Thousand Oaks, CA.
1. Berruti A, Zola P, Buniva T, et al: Prognostic factors in metastatic breast cancer patients obtaining objective response or disease stabilization after first-line chemotherapy with epirubicin: Evidence for a positive effect of maintenance hormonal therapy on overall survival. Anticancer Res 17:2763-2768, 1997[Medline]
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Wilson WH, Berg SL, Bryant G, et al: Paclitaxel in doxorubicin-refractory or mitoxantrone-refractory breast cancer: A phase I/II trial of 96-hour infusion. J Clin Oncol 12:1621-1629, 1994 3. Seidman AD, Norton L, Reichman BS, et al: Preliminary experience with paclitaxel (Taxol) plus recombinant human granulocyte colony-stimulating factor in the treatment of breast cancer. Semin Oncol 20:40-45, 1993 4. Spielmann M: Taxol (paclitaxel) in patients with metastatic breast carcinoma who have failed prior chemotherapy: Interim results of a multinational study. Oncology 51:25-28, 1994
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Seidman AD, Hochhauser D, Gollub M, et al: Ninety-six-hour paclitaxel infusion after progression during short taxane exposure: A phase II pharmacokinetic and pharmacodynamic study in metastatic breast cancer. J Clin Oncol 14:1877-1884, 1996 6. Jones S, Winer E, Vogel C, et al: Randomized comparison of vinorelbine and melphalan in anthracycline-refractory advanced breast cancer. J Clin Oncol 13:2567-2574, 1995[Abstract] 7. Livingston RB, Ellis GK, Gralow JR, et al: Dose-intensive vinorelbine with concurrent granulocyte colony-stimulating factor support in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 15:1395-1400, 1997[Abstract]
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Gasparini G, Caffo O, Barni S, et al: Vinorelbine is an active antiproliferative agent in pretreated advanced breast cancer patients: A phase II study. J Clin Oncol 12:2094-2101, 1994 9. Schiff PB, Horwitz SB: Taxol stabilizes microtubules in mouse fibroblast cells. Proc Natl Acad Sci U[00a6]S[00a6]A 77:1561-1565, 1980
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Cabral F, Wible L, Brenner S, et al: Taxol-requiring mutant of Chinese hamster ovary cells with impaired mitotic spindle activity. J Cell Biol 97:30-39, 1983 11. Zhan Z, Kang Y-K, Giannakakou P, et al: Tubulin expression and polymeization in normal tissues, human tumors and paclitaxel selected ovarian and breast cancer carcinoma cell lines. Proc Am Assoc Cancer Res 35:390, 1994 (abstr) 12. Bissery MC, Vrignaud P, Bayssas M, et al: Preclinical profile of docetaxel (Taxotere): Efficacy as a single agent and in combination. Semin Oncol 22:3-16, 1995[Medline] 13. Ibrahim N, Hortobagyi GN, Valero V, et al: Phase I study of vinorelbine (Navelbine) and paclitaxel by simultaneous 3-hour infusion for untreated metastatic breast cancer. Proc Am Assoc Cancer Res 36:242, 1995 (abstr) 14. Martin M, Casado A, Perez Segura P, et al: Paclitaxel plus vinorelbine in metastatic breast cancer patients with contraindications to receive anthracyclines. Oncology 12:28-30, 1998[Medline] 15. Martin M, Garcia Carbonero I, Lluch A, et al: Paclitaxel plus vinorelbine: An active regimen in metastatic breast cancer patients with prior anthracycline exposure. Proc Am Soc Clin Oncol 17:158a, 1998 (abstr 604) 16. Cocconi G, Mambrini A, Vasini G, et al: Vinorelbine (VI) combined with paclitaxel (TA), administered in a continuous 96-hour IV infusion (96H-CI) (VI-TA-96), in pretreated advanced breast cancer (ABC) patients (PTS). Proc Am Soc Clin Oncol 17:208a, 1998 (abstr 800) 17. Gardin G, Pronzato P, Tognoni A, et al: A phase II trial of vinorelbine (V) and paclitaxel (P) in patients with metastatic breast cancer (MBC) who have failed prior anthracycline containing chemotherapy. Proc Am Soc Clin Oncol 17:142a, 1998 (abstr 542) 18. Romero Acuña L, Langhi M, Pérez J, et al: Vinorelbine (WB) and paclitaxel (PTX) as first-line chemotherapy (FLC) in metastatic breast cancer (MBC): Final results. Proc Am Soc Clin Oncol 17:171a, 1998 (abstr 658) 19. Livingston RB, Ellis GK, Williams MA: Weekly vinorelbine (Navelbine + GCSF in Taxol-refractory metastatic breast cancer: A phase I-II study. Proc Am Soc Clin Oncol 14:110a, 1995 (abstr) 20. Gianni L, Capri G, Munzone E, et al: Paclitaxel (Taxol) efficacy in patients with advanced breast cancer resistant to anthracyclines. Semin Oncol 21:29-33, 1994 21. Ravdin PM: Treatment of patients resistant to anthracycline therapy. Anticancer Drugs 7:13-16, 1996 22. Slamon D, Leyland-Jones B, Shak S, et al: Addition of Herceptin( (humanized anti-HER2 antibody) to first line chemotherapy for HER2 overexpressing metastatic breast cancer (HER2+/MBC) markedly increases anticancer activity: A randomized multinational controlled phase III trial. Proc Am Soc Clin Oncol 17:98a, 1998 (abstr 377) 23. Zhang CC, Yang JM, White E, et al: The role of MAP4 expression in the sensitivity to paclitaxel and resistance to vinca alkaloids in p53 mutant cells. Oncogene 16:1617-1624, 1998[Medline] Submitted September 8, 1998; accepted January 25, 1999.
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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
