Moving Away From the "One Shoe Fits All" Strategy: The Key to Future Progress in Chemotherapy
http://www.100md.com
《临床肿瘤学》
Jules Bordet Institute, Canceropole de l'Universite Libre de Bruxelles, Brussels, Belgium
Chemotherapy has long been considered our most efficient weapon in the fight against breast cancer, particularly in the United States, where its most enthusiastic supporters explored very high doses of cytotoxic agents in the hope of eradicating metastatic disease. This dream, unfortunately, did not materialize.1 In Europe, faith in our second most powerful weapon against the disease—namely endocrine therapy—grew more rapidly and reached important milestones with the demonstration that tamoxifen and, more recently, the aromatase inhibitors, have a significant impact on the course of early endocrine-responsive breast cancer.2,3 Today, divergent opinions between the continents remain, but they are much less pronounced than a decade ago. This is well exemplified by the fact that one of the Review Articles in the chapter on chemotherapy in this issue of the Journal of Clinical Oncology was co-authored by an American-Australian medical oncology team!
The comprehensive review by Hamilton and Hortobagyi4 nicely summarizes the incremental progress made through the incorporation into the clinic of a number of new, useful cytotoxic agents that demonstrate either partial non-cross resistance with older drugs or improved toxicity profiles. It is, however, obvious that the major emphasis of the last 5 years has been on the development of new drugs, with less attention paid to four other important dimensions in the use of chemotherapy: (1) optimal drug schedule; (2) optimal timing of drug administration; (3) potential gains from a "wedding" of chemotherapy and newer endocrine agents; and (4) improved understanding of heterogeneity in the magnitude of treatment benefit. Let us briefly examine these four challenges one by one and understand why we need to address them better in the next 5 years.
OPTIMAL DRUG SCHEDULE
The fact that a single manipulation of drug scheduling, namely an every-2-week administration of chemotherapy instead of a 3-week schedule, could reduce the risk of dying from node-positive, early breast cancer by 31% came as a surprise to all of us.5 Even if there might be confounding factors accounting for the difference observed,6 Cancer and Leukemia Group B (CALGB) trial 9344 has had the merit of shifting our thinking away from drugs and of underscoring the important role of academic groups in developing innovative concepts for cancer therapy. We have also learned, through the conduct of academic-led trials, that the antitumor activity of paclitaxel in breast cancer is strongly schedule dependent, after having spent a great deal of energy in exploring different doses and different infusion times with no obvious clinical benefit identified.7,8
OPTIMAL DRUG TIMING
There is preliminary evidence that the timing of adjuvant chemotherapy in relation to surgery might be of critical importance in endocrine, nonresponsive breast cancer, with improved outcomes for women who start therapy within 2 weeks of their operation.9 Only a large, prospective, randomized academic trial can put this unsettled issue to rest.
An important US Intergroup trial (Southwestern Oncology Group 8814) has revealed key information in relation to the optimal timing of chemotherapy and tamoxifen in the adjuvant treatment of postmenopausal women with hormone receptor–positive tumors: cyclophosphamide, adriamycin, and fluorouracil (CAF) followed by tamoxifen was found to provide better disease-free survival than CAF combined with tamoxifen, and these results, recently updated at the 27th Annual San Antonio Breast Cancer Symposium, are holding up.10
POTENTIAL GAINS FROM A WEDDING OF CHEMOTHERAPY AND NEWER ENDOCRINE AGENTS
The divorce between chemotherapy and tamoxifen—in other words, the need to give these treatment modalities sequentially rather than in combination—is here to stay. The above-mentioned US Intergroup trial 0100 is the most direct proof of a negative treatment interaction.
It is also tempting to speculate that concomitant tamoxifen and chemotherapy administration might have weakened two large National Surgical Adjuvant Breast and Bowel Project (NSABP) trials investigating the merit of adriamycin and cyclophosphamide (AC) followed by paclitaxel in the adjuvant setting, and AC followed by docetaxel in the neoadjuvant setting.11,12 The former trial11 showed only a modest disease-free survival gain over AC alone, in contrast to a similar CALGB trial, which dissociated chemotherapy and tamoxifen administration and found a survival gain for AC followed by paclitaxel. The second trial12 failed to show any disease-free or overall survival gain for AC followed by docetaxel compared with AC alone, a disappointing result in view of prior reports of higher pathologic response rates with the taxane-based regimen.
The story with our newer and powerful endocrine treatment modalities, namely the aromatase inhibitor family and the estrogen receptor downregulator fulvestrant, could be a different one. Trials exploring sequencing versus combined administration of these agents with chemotherapy are to be designed and accompanied by a strong translational research component.
HETEROGENEITY IN THE MAGNITUDE OF CHEMOTHERAPY BENEFIT
Here is the biggest and most exciting challenge ahead of us: Now that basic scientists are providing us with impressive tools with which to explore the complex molecular heterogeneity of the disease, there is no longer any excuse for the conduct of very large trials that restrict their primary goal to the identification of a small average treatment benefit linked to a new drug regimen.
With the "one shoe fits all" strategy, in existence for the last 20 years, our public health system is threatened in view of the exponential increase in the cost of cancer treatments. The financial "toxicity" of adjuvant chemotherapy is nicely discussed in the article by Drs Hamilton and Hortobagyi.4 The key question is, do all women need expensive boots rather than comfortable sandals There is growing evidence that marked heterogeneity exists in the magnitude of benefit associated with chemotherapy in general,10,13 as well as with some key cytotoxic agents such as the anthracyclines and the taxanes, in particular. The weakness of this evidence is its retrospective nature and its focus on just a few candidate molecular markers, evaluated according to poorly standardized assays.14
We are progressively becoming aware that hormone receptor–negative and –positive breast cancers are two markedly different diseases under the new microscope provided by gene expression analysis tools such as reverse transcriptase polymerase chain reaction or cDNA/oligonucleotide microarrays. Within these two diseases, important subgroups are being identified, further stressing the complex molecular heterogeneity of breast cancer.15 However, only the HER-2-positive subgroup is accepted today as a special entity, and this is mainly due to the discovery of trastuzumab, the anti-HER-2 monoclonal antibody that has revolutionized the standard of care for these women. Let us now start dissecting the breast cancer population into its relevant subgroups, join forces to prioritize the clinical questions for each of these subsets, and strengthen the collaboration with colleagues in the lab in order to find "molecular signatures" that will allow for marked progress in treatment tailoring in general, and chemotherapy tailoring in particular.
Author's Disclosures of Potential Conflicts of Interest
The author indicated no potential conflicts of interest.
Acknowledgment
I dedicate this editorial to Jean Klastersky, MD, PhD, who has been head of the department of medicine of the Jules Bordet Institute for 28 years. He will be retiring on April 1, 2005, just around the time of publication of this editorial. He has supported my research and professional development for the last two decades.
REFERENCES
Lake D, Hudis C: High-dose chemotherapy in breast cancer. Drugs 64:1851-1860, 2004
Early Breast Cancer Trialists' Collaborative Group: Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet 351:1451-1467, 1998
D'Hondt V, Piccart M: Controversies in the adjuvant treatment of breast cancer: New adjuvant endocrine treatment strategies. Ann Oncol 15:iv23-iv29, 2004 (suppl 4)
Hamilton A, Hortobagyi G: Chemotherapy: What progress in the last 5 years J Clin Oncol 23:1760-1775, 2005
Citron M, Berry D, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup trial C9741/Cancer and Leukemia Group B trial 9741. J Clin Oncol 21:1431-1439, 2003
Piccart-Gebhart M: Mathematics and oncology: A match for life J Clin Oncol 21:1425-1428, 2003
Green M, Buzdar A, Smith T, et al: Weekly (wkly) paclitaxel (P) followed by FAC as primary systemic chemotherapy (PSC) of operable breast cancer improves pathologic complete remission (pCR) rates when compared to every 3-week (Q 3 wk) P therapy (tx) followed by FAC- final results of a prospective phase III randomized trial. Proc Am Soc Clin Oncol 21:35a, 2002 (abstr 135)
Seidman A, Berry D, Cirrincione C, et al: CALGB 9840: Phase III study of weekly (W) paclitaxel (P) via 1-hour(h) infusion versus standard (S) 3h infusion every third week in the treatment of metastatic breast cancer (MBC), with trastuzumab (T) for HER2 positive MBC and randomized for T in HER2 normal MBC. Proc Am Soc Clin Oncol 22:14S, 2004 (abstr 512; suppl)
Colleoni M, Bonetti M, Coates AS, et al: Early start of adjuvant chemotherapy may improve treatment outcome for premenopausal breast cancer patients with tumors not expressing estrogen receptors. The International Breast Cancer Study Group. J Clin Oncol 18:584-590, 2000
Albain K, Barlow W, O'Malley F, et al: Concurrent (CAFT) versus sequential (CAF-T) chemohormonal therapy (cyclophosphamide, doxorubicin, 5-fluorouracil, tamoxifen) versus T alone for postmenopausal, node-positive, estrogen (ER) and/or progesterone (PgR) receptor-positive breast cancer: Mature outcomes and new biologic correlates on phase III Intergroup trial 0100 (SWOG-8814). San Antonio Breast Cancer Symposium, 2004, December 8-11, (abstr 37)
Mamounas E, Bryant J, Lembersky B, et al: Paclitaxel (T) following doxorubicin/cyclophosphamide (AC) as adjuvant chemotherapy for node-positive breast cancer: Results from NSABP B-28. Proc Am Soc Clin Oncol 22:4, 2003 (abstr 12)
Bear H, Anderson S, Smith R, et al: A randomized trial comparing preoperative (preop) doxorubicin/cyclophosphamide (AC) to preop AC followed by preop docetaxel (T) and to preop AC followed by postoperative (postop) T in patients (pts) with operable carcinoma of the breast: Results of NSABP B-27. Breast Cancer Res Treat 88:S16, 2004 (abstr 26)
Buzdar A, Valero V, Theriault R, et al: Pathological complete response to chemotherapy is related to hormone receptor status. San Antonio Breast Cancer Symposium 2003. Breast Cancer Res Treat 82:S1, 2003 (abstr 302)
Di Leo A, Cardoso F, Scohy S, et al: Predictive molecular markers: A new window of opportunity in the adjuvant setting, in Nabholtz JM (ed): Breast cancer management—Application of Clinical and Translational Evidence to Patient Care, Part II, Section 2. Philadelphia, PA, Lippincott Williams Wilkins, 2003, pp 367-380
Sotiriou C, Desmedt C, Durbecq V, et al: Genomic and molecular classification of breast Cancer, in Ross JS, Hortobagyi G (eds): Molecular Oncology of Breast Cancer. Sudbury, MA, Jones and Bartlett Publishers, 2005, pp 81-95(Martine J. Piccart-Gebhar)
Chemotherapy has long been considered our most efficient weapon in the fight against breast cancer, particularly in the United States, where its most enthusiastic supporters explored very high doses of cytotoxic agents in the hope of eradicating metastatic disease. This dream, unfortunately, did not materialize.1 In Europe, faith in our second most powerful weapon against the disease—namely endocrine therapy—grew more rapidly and reached important milestones with the demonstration that tamoxifen and, more recently, the aromatase inhibitors, have a significant impact on the course of early endocrine-responsive breast cancer.2,3 Today, divergent opinions between the continents remain, but they are much less pronounced than a decade ago. This is well exemplified by the fact that one of the Review Articles in the chapter on chemotherapy in this issue of the Journal of Clinical Oncology was co-authored by an American-Australian medical oncology team!
The comprehensive review by Hamilton and Hortobagyi4 nicely summarizes the incremental progress made through the incorporation into the clinic of a number of new, useful cytotoxic agents that demonstrate either partial non-cross resistance with older drugs or improved toxicity profiles. It is, however, obvious that the major emphasis of the last 5 years has been on the development of new drugs, with less attention paid to four other important dimensions in the use of chemotherapy: (1) optimal drug schedule; (2) optimal timing of drug administration; (3) potential gains from a "wedding" of chemotherapy and newer endocrine agents; and (4) improved understanding of heterogeneity in the magnitude of treatment benefit. Let us briefly examine these four challenges one by one and understand why we need to address them better in the next 5 years.
OPTIMAL DRUG SCHEDULE
The fact that a single manipulation of drug scheduling, namely an every-2-week administration of chemotherapy instead of a 3-week schedule, could reduce the risk of dying from node-positive, early breast cancer by 31% came as a surprise to all of us.5 Even if there might be confounding factors accounting for the difference observed,6 Cancer and Leukemia Group B (CALGB) trial 9344 has had the merit of shifting our thinking away from drugs and of underscoring the important role of academic groups in developing innovative concepts for cancer therapy. We have also learned, through the conduct of academic-led trials, that the antitumor activity of paclitaxel in breast cancer is strongly schedule dependent, after having spent a great deal of energy in exploring different doses and different infusion times with no obvious clinical benefit identified.7,8
OPTIMAL DRUG TIMING
There is preliminary evidence that the timing of adjuvant chemotherapy in relation to surgery might be of critical importance in endocrine, nonresponsive breast cancer, with improved outcomes for women who start therapy within 2 weeks of their operation.9 Only a large, prospective, randomized academic trial can put this unsettled issue to rest.
An important US Intergroup trial (Southwestern Oncology Group 8814) has revealed key information in relation to the optimal timing of chemotherapy and tamoxifen in the adjuvant treatment of postmenopausal women with hormone receptor–positive tumors: cyclophosphamide, adriamycin, and fluorouracil (CAF) followed by tamoxifen was found to provide better disease-free survival than CAF combined with tamoxifen, and these results, recently updated at the 27th Annual San Antonio Breast Cancer Symposium, are holding up.10
POTENTIAL GAINS FROM A WEDDING OF CHEMOTHERAPY AND NEWER ENDOCRINE AGENTS
The divorce between chemotherapy and tamoxifen—in other words, the need to give these treatment modalities sequentially rather than in combination—is here to stay. The above-mentioned US Intergroup trial 0100 is the most direct proof of a negative treatment interaction.
It is also tempting to speculate that concomitant tamoxifen and chemotherapy administration might have weakened two large National Surgical Adjuvant Breast and Bowel Project (NSABP) trials investigating the merit of adriamycin and cyclophosphamide (AC) followed by paclitaxel in the adjuvant setting, and AC followed by docetaxel in the neoadjuvant setting.11,12 The former trial11 showed only a modest disease-free survival gain over AC alone, in contrast to a similar CALGB trial, which dissociated chemotherapy and tamoxifen administration and found a survival gain for AC followed by paclitaxel. The second trial12 failed to show any disease-free or overall survival gain for AC followed by docetaxel compared with AC alone, a disappointing result in view of prior reports of higher pathologic response rates with the taxane-based regimen.
The story with our newer and powerful endocrine treatment modalities, namely the aromatase inhibitor family and the estrogen receptor downregulator fulvestrant, could be a different one. Trials exploring sequencing versus combined administration of these agents with chemotherapy are to be designed and accompanied by a strong translational research component.
HETEROGENEITY IN THE MAGNITUDE OF CHEMOTHERAPY BENEFIT
Here is the biggest and most exciting challenge ahead of us: Now that basic scientists are providing us with impressive tools with which to explore the complex molecular heterogeneity of the disease, there is no longer any excuse for the conduct of very large trials that restrict their primary goal to the identification of a small average treatment benefit linked to a new drug regimen.
With the "one shoe fits all" strategy, in existence for the last 20 years, our public health system is threatened in view of the exponential increase in the cost of cancer treatments. The financial "toxicity" of adjuvant chemotherapy is nicely discussed in the article by Drs Hamilton and Hortobagyi.4 The key question is, do all women need expensive boots rather than comfortable sandals There is growing evidence that marked heterogeneity exists in the magnitude of benefit associated with chemotherapy in general,10,13 as well as with some key cytotoxic agents such as the anthracyclines and the taxanes, in particular. The weakness of this evidence is its retrospective nature and its focus on just a few candidate molecular markers, evaluated according to poorly standardized assays.14
We are progressively becoming aware that hormone receptor–negative and –positive breast cancers are two markedly different diseases under the new microscope provided by gene expression analysis tools such as reverse transcriptase polymerase chain reaction or cDNA/oligonucleotide microarrays. Within these two diseases, important subgroups are being identified, further stressing the complex molecular heterogeneity of breast cancer.15 However, only the HER-2-positive subgroup is accepted today as a special entity, and this is mainly due to the discovery of trastuzumab, the anti-HER-2 monoclonal antibody that has revolutionized the standard of care for these women. Let us now start dissecting the breast cancer population into its relevant subgroups, join forces to prioritize the clinical questions for each of these subsets, and strengthen the collaboration with colleagues in the lab in order to find "molecular signatures" that will allow for marked progress in treatment tailoring in general, and chemotherapy tailoring in particular.
Author's Disclosures of Potential Conflicts of Interest
The author indicated no potential conflicts of interest.
Acknowledgment
I dedicate this editorial to Jean Klastersky, MD, PhD, who has been head of the department of medicine of the Jules Bordet Institute for 28 years. He will be retiring on April 1, 2005, just around the time of publication of this editorial. He has supported my research and professional development for the last two decades.
REFERENCES
Lake D, Hudis C: High-dose chemotherapy in breast cancer. Drugs 64:1851-1860, 2004
Early Breast Cancer Trialists' Collaborative Group: Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet 351:1451-1467, 1998
D'Hondt V, Piccart M: Controversies in the adjuvant treatment of breast cancer: New adjuvant endocrine treatment strategies. Ann Oncol 15:iv23-iv29, 2004 (suppl 4)
Hamilton A, Hortobagyi G: Chemotherapy: What progress in the last 5 years J Clin Oncol 23:1760-1775, 2005
Citron M, Berry D, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup trial C9741/Cancer and Leukemia Group B trial 9741. J Clin Oncol 21:1431-1439, 2003
Piccart-Gebhart M: Mathematics and oncology: A match for life J Clin Oncol 21:1425-1428, 2003
Green M, Buzdar A, Smith T, et al: Weekly (wkly) paclitaxel (P) followed by FAC as primary systemic chemotherapy (PSC) of operable breast cancer improves pathologic complete remission (pCR) rates when compared to every 3-week (Q 3 wk) P therapy (tx) followed by FAC- final results of a prospective phase III randomized trial. Proc Am Soc Clin Oncol 21:35a, 2002 (abstr 135)
Seidman A, Berry D, Cirrincione C, et al: CALGB 9840: Phase III study of weekly (W) paclitaxel (P) via 1-hour(h) infusion versus standard (S) 3h infusion every third week in the treatment of metastatic breast cancer (MBC), with trastuzumab (T) for HER2 positive MBC and randomized for T in HER2 normal MBC. Proc Am Soc Clin Oncol 22:14S, 2004 (abstr 512; suppl)
Colleoni M, Bonetti M, Coates AS, et al: Early start of adjuvant chemotherapy may improve treatment outcome for premenopausal breast cancer patients with tumors not expressing estrogen receptors. The International Breast Cancer Study Group. J Clin Oncol 18:584-590, 2000
Albain K, Barlow W, O'Malley F, et al: Concurrent (CAFT) versus sequential (CAF-T) chemohormonal therapy (cyclophosphamide, doxorubicin, 5-fluorouracil, tamoxifen) versus T alone for postmenopausal, node-positive, estrogen (ER) and/or progesterone (PgR) receptor-positive breast cancer: Mature outcomes and new biologic correlates on phase III Intergroup trial 0100 (SWOG-8814). San Antonio Breast Cancer Symposium, 2004, December 8-11, (abstr 37)
Mamounas E, Bryant J, Lembersky B, et al: Paclitaxel (T) following doxorubicin/cyclophosphamide (AC) as adjuvant chemotherapy for node-positive breast cancer: Results from NSABP B-28. Proc Am Soc Clin Oncol 22:4, 2003 (abstr 12)
Bear H, Anderson S, Smith R, et al: A randomized trial comparing preoperative (preop) doxorubicin/cyclophosphamide (AC) to preop AC followed by preop docetaxel (T) and to preop AC followed by postoperative (postop) T in patients (pts) with operable carcinoma of the breast: Results of NSABP B-27. Breast Cancer Res Treat 88:S16, 2004 (abstr 26)
Buzdar A, Valero V, Theriault R, et al: Pathological complete response to chemotherapy is related to hormone receptor status. San Antonio Breast Cancer Symposium 2003. Breast Cancer Res Treat 82:S1, 2003 (abstr 302)
Di Leo A, Cardoso F, Scohy S, et al: Predictive molecular markers: A new window of opportunity in the adjuvant setting, in Nabholtz JM (ed): Breast cancer management—Application of Clinical and Translational Evidence to Patient Care, Part II, Section 2. Philadelphia, PA, Lippincott Williams Wilkins, 2003, pp 367-380
Sotiriou C, Desmedt C, Durbecq V, et al: Genomic and molecular classification of breast Cancer, in Ross JS, Hortobagyi G (eds): Molecular Oncology of Breast Cancer. Sudbury, MA, Jones and Bartlett Publishers, 2005, pp 81-95(Martine J. Piccart-Gebhar)