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Commentary on “Paclitaxel, 5-Fluorouracil, and Leucovorin (TFL) in the Treatment of Metastatic Breast Cancer”
Commentary on "Paclitaxel, 5-Fluorouracil, and Leucovorin (TFL) in the Treatment of Metastatic Breast Cancer" Andrew Seidman
Breast Cancer Medicine Service Memorial Sloan-Kettering Cancer Center New York, NY
Nicholson and colleagues offer a straightforward report of a phase II trial combining paclitaxel with 5fluorouracil and leucovorin for the treatment of metastatic breast cancer. As such, they present at first glance a reasonable, well-tolerated and active regimen, consistent with prior reports of similar combinations. Particularly relevant is the preserved activity of this regimen following anthracyclines. Should we care about this data enough to consider incorporating this, or similar regimens, into our clinical practices? Are phase III trials necessary to demonstrate a "palpable" advantage (eg, time to progression, overall survival, or quality of life) for such combinations over paclitaxel-based monotherapy? To be sure, the only randomized trial to date comparing paclitaxel monotherapy to paclitaxel-containing combination chemotherapy (ECOG #1193) failed to show a survival or quality of life advantage for the paclitaxel/doxorubicin doublet as compared to the use
144 • Clinical Breast Cancer July 2000
of either single agent sequentially. Do we then expect a survival benefit from a paclitaxel/fluorouracil combination? Why do we pursue the alphabet soup of innumerable iterations, taxane, fluorouracil, vinorelbine, gemcitabine, anthracycline, etc. combinations year after year after year? Is it because of the demonstration that combination chemotherapy can cure patients with advanced stages of other chemosensitive malignancies such as lymphomas and germ-cell tumors? After over two decades of preclinical and clinical research exploring countless combinations of cytotoxic chemotherapy for metastatic breast cancer, we cannot yet consider metastatic disease a curable entity. Is it the lack of other questions to ask or perhaps an "emperor’s new clothes phenomenon" (ie, follow the leader, despite all evidence to the contrary) that drives us in our pursuit of combination after combination after combination? In fairness, there is a combination of paclitaxel and another agent that has recently been demonstrated to confer a survival benefit – the combination of paclitaxel and trastuzumab, the humanized mon-
oclonal antibody targeting the HER2/ neu receptor for women whose tumors overexpress that receptor. An updated analysis of the pivotal trial data indicates an even greater magnitude of benefit for the paclitaxel/ trastuzumab doublet when patients are selected on the basis of HER2 gene amplification (fluorescent in situ hybridization) as compared to immunohistochemistry (Dr. Robert Mass, personal communication, May 2000). Perhaps applied pharmacogenomics will allow us to better select patients who truly might derive a meaningful gain from combinations of cytotoxic chemotherapy (and not merely moderately higher response proportions often with accompanying additive toxicity). Until that time, before we combine cytotoxic agents with palliative intent in the management of metastatic breast cancer, it behooves us all to question the conventional wisdom of combination chemotherapy in this setting.
Breast Cancer Medicine Service Memorial Sloan-Kettering Cancer Center New York, NY
Nicholson and colleagues offer a straightforward report of a phase II trial combining paclitaxel with 5fluorouracil and leucovorin for the treatment of metastatic breast cancer. As such, they present at first glance a reasonable, well-tolerated and active regimen, consistent with prior reports of similar combinations. Particularly relevant is the preserved activity of this regimen following anthracyclines. Should we care about this data enough to consider incorporating this, or similar regimens, into our clinical practices? Are phase III trials necessary to demonstrate a "palpable" advantage (eg, time to progression, overall survival, or quality of life) for such combinations over paclitaxel-based monotherapy? To be sure, the only randomized trial to date comparing paclitaxel monotherapy to paclitaxel-containing combination chemotherapy (ECOG #1193) failed to show a survival or quality of life advantage for the paclitaxel/doxorubicin doublet as compared to the use
144 • Clinical Breast Cancer July 2000
of either single agent sequentially. Do we then expect a survival benefit from a paclitaxel/fluorouracil combination? Why do we pursue the alphabet soup of innumerable iterations, taxane, fluorouracil, vinorelbine, gemcitabine, anthracycline, etc. combinations year after year after year? Is it because of the demonstration that combination chemotherapy can cure patients with advanced stages of other chemosensitive malignancies such as lymphomas and germ-cell tumors? After over two decades of preclinical and clinical research exploring countless combinations of cytotoxic chemotherapy for metastatic breast cancer, we cannot yet consider metastatic disease a curable entity. Is it the lack of other questions to ask or perhaps an "emperor’s new clothes phenomenon" (ie, follow the leader, despite all evidence to the contrary) that drives us in our pursuit of combination after combination after combination? In fairness, there is a combination of paclitaxel and another agent that has recently been demonstrated to confer a survival benefit – the combination of paclitaxel and trastuzumab, the humanized mon-
oclonal antibody targeting the HER2/ neu receptor for women whose tumors overexpress that receptor. An updated analysis of the pivotal trial data indicates an even greater magnitude of benefit for the paclitaxel/ trastuzumab doublet when patients are selected on the basis of HER2 gene amplification (fluorescent in situ hybridization) as compared to immunohistochemistry (Dr. Robert Mass, personal communication, May 2000). Perhaps applied pharmacogenomics will allow us to better select patients who truly might derive a meaningful gain from combinations of cytotoxic chemotherapy (and not merely moderately higher response proportions often with accompanying additive toxicity). Until that time, before we combine cytotoxic agents with palliative intent in the management of metastatic breast cancer, it behooves us all to question the conventional wisdom of combination chemotherapy in this setting.