Dose-escalation of filgrastim does not improve efficacy: Clinical tolerability and long-term follow-up on CALGB study 9141 adjuvant chemotherapy for node-positive breast cancer patients using dose-intensified doxorubicin plus cyclophosphamide followed by paclitaxel Journal Article
| Authors: | Liu, M. C.; Demetri, G. D.; Berry, D. A.; Norton, L.; Broadwater, G.; Robert, N. J.; Duggan, D.; Hayes, D. F.; Henderson, I. C.; Lyss, A.; Hopkins, J.; Kaufman, P. A.; Marcom, P. K.; Younger, J.; Lin, N.; Tkaczuk, K.; Winer, E. P.; Hudis, C. A. |
| Article Title: | Dose-escalation of filgrastim does not improve efficacy: Clinical tolerability and long-term follow-up on CALGB study 9141 adjuvant chemotherapy for node-positive breast cancer patients using dose-intensified doxorubicin plus cyclophosphamide followed by paclitaxel |
| Abstract: | Purpose: To assess the safety, tolerability, and clinical outcomes of an adjuvant chemotherapy regimen designed to incorporate a non-cross-resistant agent (paclitaxel, T) with a maximally dose-intensified regimen of doxorubicin and cyclophosphamide (AC) in conjunction with hematopoietic growth factor support (recombinant human granulocyte-colony stimulating factor; G-CSF; Filgrastim). A secondary aim was to assess if a higher dose (10 mcg/kg/day) of G-CSF is more efficacious than the conventional dose (5 mcg/kg/day) in this setting. Patients and Methods: Female patients with early-stage, node-positive invasive breast cancer were eligible for this multicenter, cooperative group feasibility trial that was designed as the pilot study for a larger randomized clinical trial. The protocol treatment comprised five cycles of dose-intensified AC (75 and 2000 mg/m2/cycle, respectively, intravenously every three weeks) with G-CSF support, followed by an additional four cycles of T (175 mg/m2 by 3 h intravenous infusion, every three weeks). Patients were randomized to receive one of two dose levels of G-CSF (5 vs. 10 mcg/kg/day) during AC chemotherapy. Data on both short-term toxicity and long-term survival were collected. Results: One hundred and seventy two node-positive patients with operable primary breast cancer were accrued to this trial between February 1993 and April 1994. 130 of the 172 patients (76%) completed all protocol-specified therapy. Of the 42 early study withdrawals, 23 were due to unacceptable acute treatment-related toxicity. No differences in toxicities or clinical outcomes were noted between the two different dose levels of G-CSF support. At 6.8 years median follow-up, relapse-free survival (RFS) and overall survival (OS) rates for all patients are 70% and 78%, respectively. Ten patients developed second malignancies during follow-up, including three cases with a hematologic malignancy (2% incidence). Conclusion: The delivery of dose-intensified AC followed by T was feasible in this large-scale pilot trial, although significant acute toxicities were commonly encountered. The data confirmed the acceptable tolerability of T after aggressive myelotoxic therapy in the adjuvant setting, leading to a larger randomized clinical trial comparing three dose levels of doxorubicin in AC with or without the addition of T (CALGB 9344). Supportive care using twice the conventional dose of G-CSF did not significantly improve the tolerability or change the toxicities of this regimen, and the occurrence of secondary malignancies is consistent with the emerging risk profile of dose-intensive regimens with growth factor support. With long-term follow-up, the clinical outcomes remain relatively favorable and correlate with such expected prognostic factors as the number of involved nodes and hormone receptor status. © 2007 Elsevier Ltd. All rights reserved. |
| Keywords: | adult; cancer survival; controlled study; treatment outcome; aged; disease-free survival; middle aged; survival rate; major clinical study; clinical trial; drug tolerability; fatigue; neutropenia; review; doxorubicin; dose response; drug dose comparison; drug dose reduction; drug efficacy; drug safety; drug withdrawal; unspecified side effect; paclitaxel; cancer adjuvant therapy; chemotherapy, adjuvant; follow up; follow-up studies; lymph node metastasis; lymphatic metastasis; anorexia; controlled clinical trial; multiple cycle treatment; pain; breast cancer; erythropoietin; anemia; blood toxicity; esophagitis; leukopenia; nausea; randomized controlled trial; stomatitis; thrombocytopenia; vomiting; antineoplastic combined chemotherapy protocols; myalgia; cyclophosphamide; breast neoplasms; information processing; arthralgia; drug dose escalation; dyspnea; febrile neutropenia; hyperglycemia; drug induced headache; malaise; feasibility study; pilot study; pilot projects; multicenter study; adjuvant chemotherapy; cardiotoxicity; ciprofloxacin; tamoxifen; cancer relapse; sensory dysfunction; heart arrhythmia; recombinant granulocyte colony stimulating factor; hormone receptor; erythrocyte transfusion; heart muscle ischemia; thrombocyte transfusion; filgrastim; pericardial disease; dose-escalation; dose-intensification; doxorubicin/cyclophosphamide; node-positive |
| Journal Title: | Cancer Treatment Reviews |
| Volume: | 34 |
| Issue: | 3 |
| ISSN: | 0305-7372 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2008-05-01 |
| Start Page: | 223 |
| End Page: | 230 |
| Language: | English |
| DOI: | 10.1016/j.ctrv.2007.11.004 |
| PUBMED: | 18234424 |
| PROVIDER: | scopus |
| PMCID: | PMC2651678 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 7" - "Export Date: 17 November 2011" - "CODEN: CTRED" - "Source: Scopus" |
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