- Email: [email protected]
Integration of trastuzumab into adjuvant systemic therapy of breast cancer: Ongoing and planned clinical trials
Integration of Trastuzumab Into Adjuvant Systemic Therapy Breast Cancer: Ongoing and Planned Clinical Trials Gabriel Clinical HER2
trials
using
murine
have
shown
positive
the
humanized
monoclonal
activity breast
and
survival
rates
was
added
to first-line
the zumab now
with
the
have
promising in the entered
been
shown
metastatic adjuvant
United
States
and
in this
report,
Europe.
trastuzumab
as adjuvant
Semin
28
W.B.
Oncol Saunders
setting, breast
(suppl
this cancer
Five
capturing therapy 16):41-46.
SAFETY
the for
with
paclitaxel
of
of
novel
biologic
has
trials
in both
the
trials breast
trastu-
are
evolving
Copyright
role
disof
cancer. 0
2001
by
Company.
VEREXPRESSION of the human epidermal growth factor-2 gene (also known as HER2/ neu and c-erbB-2) occurs in approximately 25% of breast cancers and is associated with an aggressive form of the disease and a poor prognosis.‘-3 The HER2 gene encodes a transmembrane receptor (~185) with tyrosine kinase activity. In light of the increased understanding of the biology of HER2 and its interaction with other members of the epidermal growth factor receptor family in intracellular signaling pathways, HER2 has become a highly promising cancer target for breast cancer.4 Clinical trials using trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA), a humanized version of the antieHER2 murine monoclonal antibody 4D5, have shown antitumor activity in patients with HER2-positive metastatic breast cancer.526 Improved response and survival rates emerged when trastuzumab was added to first-line combination chemotherapy with anthracycline/cyclophosphamide or paclitaxel compared with the same chemotherapy alone.728 Because trastuzumab combined with chemotherapy results in prolongation of survival, it is important to incorporate this agent into adjuvant systemic therapy regimens for patients with primary breast cancer. However, because excessive clinical and subclinical cardiotoxicity was observed during the pivotal trial of anthracycline/cyclophosphamide delivered with concurrent weekly trastuzumab,*
0
Seminars in Oncology, Vol 28, No 5, Suppl I6 (October),
are clearly
needed
for this group of
AND EFFICACY CHEMOTHERAPY
OF ADJUVANT REGIMENS
com-
Because
profile
clinical
A. Perez
HERZ-
trastuzumab
alone.
efficacy
Edith
response
when or
and
with
and
safer regimens patients.
anti-
chemotherapy
chemotherapy
safety
cussed
trastuzumab,
Improved
combination
same
of the
4D5,
in patients
cancer.
anthracyclinelcyclophosphamide pared
version
antibody
antitumor
metastatic
N. Hortobagyi
of
200 I: pp 4 I-46
The Early Breast Cancer Trialists’ Group metaanalysis of randomized trials in the adjuvant setting showed that adjuvant chemotherapy, adjuvant tamoxifen, and adjuvant ovarian ablation produce reproducible and highly significant reductions in the odds of recurrence and death from chemotherearly breast cancer. 9-11 Combination apy was shown to be more effective than singleagent therapy, and anthracycline-containing regimens were shown to be more effective than regimens without anthracyclines. Thus, most oncologists use regimens such as 5-fluorouracil/doxorubicin/cyclophosphamidei* or doxorubicin/cyclophosphamide (AC)i3 for high-risk patients with primary breast cancer. With four to six cycles of these combinations, resulting in cumulative doxorubicin doses of 240 to 300 mg/m’ given by bolus or short intravenous infusion, the risk of cardiac toxicity is generally less than 1%. However, this risk reaches 5% at doses of 400 mg/m’ and 20% when the cumulative doxorubicin dose reaches 600 mg/m’. l4 Use of continuous-infusion doxorubicin (48 to 96 hours), epirubicin, the cardiopro-
From the Department of Breast Medical 0ncolog)i , The Uniuersity of Texas M. D. Anderson Cancer Center, Houston, TX; and the Division of Hematology/Oncology, Mayo Clinic, Jacksonville, FL. Dr Hortobagyi has received research grant support from BristolMyers Squibb and Ribozyme Pharmaceuticals. He has received honoraria from AstraZeneca, Auentis, Bristol-Myers Squibb, Genentech, Nouartis, Pharmacia, and Ribozyme Phavnaceuticals, and has served as a consuht to Agouron, Genentech, Nouartis, and Ribozyme Pharmaceuticals. Address reprint requests to Gabriel N. Hortobagyi, MD, FACE’, Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Bled, Box 424, Houston, TX 77030-4009. Copyright 0 2001 by W.B. Saunders Company 0093-7754/01/2805-I607$35.00/0 doi:l0.1053/sonc.2001.28549 41
HORTOBAGYI
tectant dexrazoxane, or liposome-encapsulated anthracyclines can lessen the risk of cardiotoxicity.15J6 Improved disease-free and overall survival rates were reported when four cycles of singleagent paclitaxel followed four cycles of AC.17 A recommended taxane combination for the treatment of breast cancer remains undetermined, awaiting results of several large trials comparing doxorubicin (or epirubicin)/paclitaxel or doxorubicin (or epirubicin)/docetaxel with doxorubicin/ cyclophosphamide or epirubicin/cyclophosphamide.18 In recent years it has become increasingly important to explore new agents, new combinations, and new ways of administering active agents. A great deal of emphasis has been placed on the study of dose escalation of selected chemotherapy drugs, which is often referred to as increased dose intensity. These manipulations are meant to circumvent resistance. However, recent trials have shown that dose escalation of cyclophosphamide to more than 600 mg/m’ does not improve diseasefree or overall survival,19 doses of doxorubicin higher than 60 mg/m’ have no clear incremental benefit,17 and high-dose chemotherapy with autologous bone marrow or stem-cell support does not clearly improve survival in preliminary analysis.20 Thus, new strategies for breast cancer treatment are needed. SAFETY THE
OF TRASTUZUMAB PIVOTAL TRIALS
-
In the first pivotal multinational trial, trastuzumab was evaluated as a single agent in women with HER2-overexpressing breast cancers that had progressed despite conventional cytotoxic chemotherapy for metastatic disease.5 A single-arm study enrolled 222 patients from seven countries over a 17-month period. The primary objective of this large phase II trial was to assessthe safety and efficacy of trastuzumab in this clinical setting. Most of the patients enrolled in this trial had been heavily pretreated. These investigators reported that nine of 213 treated patients (4%) achieved a complete response and 37 patients (17%) achieved a partial response. Median duration of response in patients achieving either a complete or partial response was 9.1 months (range, 1.6 to > 26 months), and for all treated patients the median time to disease progression was 3.1 months
AND
PEREZ
(range, 0 to > 28 months). Median survival duration for all patients was 13 months (range, 0.5 to > 30 months). Approximately 40% of patients experienced fever and/or chills during or shortly following the first infusion; however, these symptoms were rarely observed (< 3%) with subsequent infusions. Severe adverse reactions were rare. The second pivotal trial21 used similar eligibility criteria, except that patients could not have received any prior treatment for metastatic disease; however, patients could have received adjuvant chemotherapy. Eligible patients were randomized to receive either chemotherapy alone or chemotherapy plus trastuzumab as the initial treatment for metastatic breast cancer. The chemotherapy regimen consisted of AC for patients who had not received adjuvant anthracycline, and paclitaxel for those who had adjuvant therapy that included an anthracycline. This trial allowed patients who progressed while receiving chemotherapy alone to be crossed over to receive trastuzumab. The addition of trastuzumab to paclitaxel resulted in statistically significant increases in response rate and time to progression, as well as in the l-year survival rate (68% versus 79%) and median survival. These initial clinical trials of trastuzumab reported some serious adverse cardiac events, especially in patients who were receiving concomitant chemotherapy.22 This prompted a more in-depth, retrospective assessment of cardiac events across these trials to determine the incidence and severity of congestive heart failure, cardiomyopathy, and/or reduction in ejection fraction. The highest incidence was seen in patients who had also received an anthracycline simultaneously (19%) versus an overall incidence of about 3% in all other patients. In the large phase II trial, there was a 5% incidence of clinically significant cardiac toxicity; however, 96% of these patients had received prior anthracyclines. The incidence of cardiac events in patients treated with paclitaxel alone or paclitaxel plus trastuzumab was 1% and 4%, respectively (P = NS). Additionally, in the postmarketing setting, rare serious and fatal infusion-related events have occurred. Most patients who experienced the more serious and fatal infusion-related events had pre-existing pulmonary compromise and advanced malignancy.
TRASTUZUMAB
IN ADJUVANT
THERAPY
43
OF BREAST CANCER
STRATEGIES TO DEVELOP A SAFE AND EFFECTIVE TRASTUZUMAB-CONTAINING ADJUVANT SYSTEMIC THERAPY REGIMEN In view of the existing information about the cardiotoxic potential of trastuzumab, several strategies might be pursued to develop a safe and effective adjuvant regimen that targets HER2-overexpressing breast cancer cells. The first would be to develop a chemotherapy regimen that does not contain an anthracycline; in this manner, the adverse interaction between trastuzumab and the anthracycline would be avoided. An example of this approach is the development of clinical trials with a taxane (paclitaxel or docetaxel) and a platinum salt (carboplatin or cisplatin) in association with trastuzumab. Recent data have suggested that the antitumor activity of such combinations would approximate that achieved with other leading combinations in the metastatic breast cancer setting.*sJ+ An example of this strategy is the Breast Cancer International Research Group protocol BCIRG 006. Multiple retrospective analyses have suggested that HER2overexpressing tumors respond better to an anthracycline-containing regimen than to other treatments.2s-27 Therefore, while this is an interesting hypothesis, other approaches that include anthracyclines also should be investigated. A second strategy would be to avoid the anthracycline-trastuzumab interaction by administering these two agents sequentially and without overlap. In view of the prolonged half-life of trastuzumab (about 25 days), th ese sequential programs must be designed with great care to reduce the risk of cardiac toxicity to a minimum. Examples of this approach include the National Surgical Breast and Bowel Project clinical trial B-31, the North Central Cancer Treatment Group adjuvant trial 983 1, and the Eastern Cooperative Oncology Group (ECOG) trial 2198. A criticism of this approach would be that the simultaneous use of cytotoxic agents and trastuzumab seems to be optimal, at least on the basis of preclinical studies.28 The sequential combination of cytotoxic agents and trastuzumab might be less effective than the simultaneous combination. A third approach is to substitute an anthracycline with lower cardiotoxic potential (liposomeencapsulated anthracyclines, epirubicin, doxorubitin with dexrazoxane) or the use of continuous-
infusion schedules known to be less cardiotoxic. Several phase II studies have this approach under evaluation. While epirubicin and doxorubicin by continuous-infusion schedules appear equivalent in efficacy to bolus doxorubicin, there is insufficient evidence about the therapeutic efficacy of some of the other novel anthracyclines compared with bolus doxorubicin.z9 We will review the ongoing major clinical trials in patients with primary breast cancer that evaluate the role of trastuzumab in the adjuvant setting. ONGOING AND PLANNED CLINICAL TRIALS OF TRASTUZUMAB ADJUVANT THERAPY There are two new large adjuvant clinical trials planned by different cooperative groups in the United States incorporating HER2 status into the decision-making process. These trials will evaluate the tolerability and efficacy of trastuzumab and chemotherapy for patients diagnosed with HER2, overexpressing, node-positive primary breast cancer. On the basis of favorable results from the Cancer and Leukemia Group B study 9344 testing four cycles of paclitaxel after four cycles of AC, this sequence is serving as the platform for incorporating trastuzumab into several studies.30 The National Surgical Adjuvant Breast and Bowel Program B-31 trial, led by Drs Edward Romond and Elizabeth Tan Chiu, is a phase III randomized multicenter trial that will compare AC followed by paclitaxel + trastuzumab in patients with node-positive, HERZ-positive breast cancer.31 Patients are randomized to one of the two treatment arms. This study opened in February 2000 and has accrued over 350 patients. The target accrual is 2,700 patients. B-31 has a stringent prospective cardiac evaluation and monitoring system built into the protocol. Interim analysis of cardiac toxicity is scheduled after 200 patients have been followed for at least 6 months beyond initiation of trastuzumab. Similar analysis is planned after 600 patients and after 1,000 patients. All patients initially receive AC chemotherapy alone administered every 3 weeks four times. Patients are then randomized to either paclitaxel alone at a dose and schedule of 175 mg/m2 intravenously every 3 weeks for four doses, or paclitaxel at the same dose and schedule in combination with trastuzumab at a loading dose of 4 mg/kg/wk followed by trastuzumab 2 mg/kg/wk
44
Fig I. Schema for the National Surgical Project B-3 I adjuvant trial. A, doxorubicin; mide; P, paclitaxel; T, trastuzumab.
HORTOBAGYI
Breast and Bowel C, cyclophospha-
for a total of 52 weeks. The effect of the addition of trastuzumab on overall survival and disease-free survival will be determined. Cardiotoxicity on each treatment arm will be compared. The dosing schedule and schema for this trial are depicted in Fig 1. The North Central Cancer Treatment Group is coordinating a prospective Breast Intergroup trial (N983 1) under the direction of Dr Edith A. Perez. This trial is designed to test the incremental benefit and toxicity of trastuzumab added to standard adjuvant chemotherapy in patients with node-positive, HER2-positive breast cancer.32 In addition, this trial will test the relative benefits of simultaneous versus sequential use of paclitaxel and trastuzumab. Participating groups include the North Central Cancer Treatment Group, the ECOG, the Cancer and Leukemia Group B, and the Southwest Oncology Group. The primary endpoints of the study are disease-free survival and cardiac tolerability. The secondary goals include overall survival, evaluation of HER2 status as a prognostic indicator for disease*free survival and overall survival, and evaluation of concordance of immunohistochemistry (by HercepTest; Dako, Carpenteria, CA) and fluorescence in situ hybridization (by PathVysion Kit; Vysis, Downers Grove, IL) and their correlation with disease-free survival and overall survival. The accrual goal is for 3,000 patients to be enrolled over a 4-year period. Thorough, noninvasive cardiac monitoring will be included. Formal interim analyses and coordination with the National Surgical Breast Adjuvant and Bowel Project, the National Cancer Institute, and
Fig 3. Schema for zumab; A, doxorubicin;
AND
ECOG 2198. P, paclitaxel; C, cyclophosphamide.
PEREZ
T, trastu-
the Breast Intergroup are integral to the conduct of this pivotal study. The dosing schedule and schema for this trial are depicted in Fig 2. Three additional trials involving adjuvant trastuzumab therapy in breast cancer are planned or in progress. The ECOG has completed accrual to a limited (234 patients) pilot adjuvant study (ECOG 2198) evaluating the cardiac tolerability of paclitaxel 175 mg/m2 once every 3 weeks for four doses (with weekly trastuzumab) followed by AC once every 3 weeks for four doses, with randomization to either no further trastuzumab or 40 weekly doses of the monoclonal antibody treatment (Fig 3). An international group of investigators, The Breast Cancer International Research Group, will conduct a multicenter, randomized clinical trial (BCIRG 006) comparing the adjuvant regimen of AC for four doses followed by docetaxel for four doses with four cycles of the docetaxel/carboplatin combination, with or without weekly trastuzumab, under the direction of Dr Jean-Marc Nabholtz. In a previous large phase II trial, Perez et a133 showed a high response rate with the paclitaxel/carboplatin combination in patients with metastatic breast cancer. The three-arm trial activated in February 2001 is a logical extension of that work to determine the relative efficacy and safety of the docetaxel/carboplatin combination with or without trastuzumab, and to compare it with the AC combination followed by docetaxel (Fig 4). Finally, a phase III study of neoadjuvant AC 2 dexrazoxane and paclitaxel rt rrastuzumab
Node + or -
ACx4
___,
Docx4
ACx4
-
Docx4+TXx52wk
HER2 + Car or+Docx6+T*x52wk
Cis Fig Fig 2. Schema for the North Central Cancer Treatment Group adjuvant trial N983 I. A, doxorubicin; C, cyclophosphamide; P, paclitaxel; T, trastuzumab. *Schedule will be modified to once every 3 weeks.
4.
Schema
search Group phosphamide; T, trastuzumab. weeks.
for
the
Breast
protocol BCIRG Car, carboplatin; * Schedule
may
Cancer
International
006. A, doxorubicin; Cis, cisplatin; Doe, be modified
Re-
C, cyclodocetaxel;
to once
every
3
TRASTUZUMAB
IN ADJUVANT
THERAPY
45
OF BREAST CANCER
Fig 5. Schema for National Cancer Institutes study NCICOO- 1836. A, doxorubicin; C, cyclophosphamide; Dex, dexrazoxane, P, paclitaxel; T, trasturumab; XRT, radiation therapy.
followed by local surgery t adjuvant trastuzumab in women with stage IIB, IIIA, or BIB breast cancer is being sponsored by the Cancer and Leukemia Group B and the National Cancer Institute (Cancer and Leukemia Group B q-9808). Primary objectives of this trial, which has recently been activated, include assessment of the safety and efficacy of AC alone or with dexrazoxane, with and without trastuzumab, and determination of whether the initial pathologic response in patients receiving neoadjuvant therapy correlates with eventual 5-year disease-free and overall survival (Fig 5). Consideration also is being given to modifying the maintenance schedule of trastuzumab to administer this agent once every 3 weeks at a dose of 6 mg/kg instead of weekly at a dose of 2 mg/kg. The rationale for this modification is based on a pharmacokinetic safety and efficacy study, led by Dr Brian Leyland-Jones, evaluating paclitaxel 175 mg/m’ plus trastuzumab 6 mg/kg administered together every 3 weeks (after a loading dose of trastuzumab 8 mg/kg) f or eight cycles, followed by the once-every-3-week schedule of trastuzumab alone. Preliminary results were presented at the American Society of Clinical Oncology meeting in May 2001, showing fairly similar pharmacokinetics and toxicities between the every-3-week regimen and the weekly trastuzumab schedule that is standard in clinical practice. Thus, trastuzumab and paclitaxel given every 3 weeks has potential applications to adjuvant and metastatic breast cancer studies.34 SUMMARY The results of the initial trastuzumab trials have clearly shown that this agent is active in patients with advanced HER2-positive breast cancer, alone or in combination with anthracyclineor taxanebased chemotherapy. Substantial efforts are now being directed toward studying promising schedules and combinations in the adjuvant setting by cooperative groups in both the United States and
Europe. In addition, new strategies to decrease the cardiac toxicity observed with the combination of anthracyclines and trastuzumab will be tested by prospective cardiac monitoring. Novel antitumor agents, other than antibodies, that selectively target HER2 and other signaling proteins are under intense preclinical testing and could emerge as potentially important adjuvant agents in years to come. Trials evaluating newer, more selective antiestrogens and antitumor vaccines are being designed and will add another aspect to the adjuvant treatment of cancer. Thus, safer and more effective therapies for this group of patients should soon be available. For now, trastuzumab is the first targeted monoclonal antibody therapy that has passed the rigors of preclinical testing and clinical trials in patients with advanced breast cancer, and has now entered evaluation as adjuvant therapy for breast cancer. The results of these carefully planned and scientifically rigorous studies have the potential to significantly alter the standard of care for breast cancer management and improve cure rates for this disease. Completion of these ongoing trials through collaborative efforts between advocates, patients, and the scientific community will allow us to obtain the results we so eagerly await. REFERENCES 1. Slamon DJ, Clark GM, Wang SG, et al: Human breast cancer: Correlation of relapse and survival with amplification of the HER-Z/neu oncogene. Science 235:177x182, 1987 2. Slamon DJ, Godolphin W, Jones LA, et al: Studies of HER-Z/new proto-oncogene in human breast and ovarian can, cer. Science 244:707-712, 1989 3. Hynes NE, Stem DF: The biology of e&B-Z/neu/HER-2 and its role in cancer. Biochem Biophys Acta 1198:165-184, 1994 4. Disis ML, Chewer MA: HER-2/neu protein: A target for antigen-specific immunotherapy of human cancer. Adv Cancer Res 71:343-371, 1997 5. Cobleigh MA, Vogel CL, Tripathy D, et al: Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER?,-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 17:2639-2648, 1999 6. Vogel C, Cobleigh M, Tripathy D, et al: First-line nonhormonal treatment of women with HER2 overexpressing metastatic breast cancer with Herceptin (trastuzumab, humanized anti-HER2 antibody). Proc Am Sot Clin Oncol 19:71a, 2000 (abstr 275) 7. Slamon D, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HERZ. N Engl J Med 344~783-792, 2001
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8. Norton L, Slamon D, Leyland-Jones B, et al: Overall survival advantage to simultaneous chemotherapy plus the hu, manized anti-HER2 monoclonal antibody Herceptin in HERZoverexpressing metastatic breast cancer. Proc Am Sot Clin Oncol 18:127a, 1999 (abstr 483) 9. Early Breast Cancer Trialists’ Collaborative Group: Poly chemotherapy for early breast cancer: An overview of the randomised trials. Lancet 352:930x942, 1998 10. Early Breast Cancer Trialists’ Collaborative Group: Tamoxifen for early breast cancer: An overview of the randomized trials. Lancet 351:1451-1467, 1998 11. Early Breast Cancer Trialists’ Collaborative Group: Ovarian ablation in early breast cancer: Overview of the randomised trials. Lancet 348:1189-l 196, 1996 12. Buzdar AU, Gutterman JU, Blumenschein CR, et al: Intensive postoperative chemoimmunotherapy for patients with stage II and stage III breast cancer. Cancer 41:1064-1075, 1978 13. Fisher B, Brown AM, Dimitrov NV, et al: Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen non-responsive tumors: Results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 8:1483-1496, 1990 14. van Hoff DD, Layard MW, Basa P, et al: Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 91:710-717, 1979 15. Hortobagyi GN, Frye D, Buzdar AU, et al: Decreased cardiac toxicity of doxorubicin administered by continuous intravenous infusion in combination chemotherapy for metastatic breast carcinoma. Cancer 63:37-45, 1989 16. Swain SM, Whaley FS, Gerber MC, et al: Delayed administration of dexrazoxane provides cardioprotection for patients with advanced breast cancer treated with doxorubicincontaining therapy. J Clin Oncol 15:1333-1340, 1997 17. Henderson IC, Berry D, Demetri G, et al: Improved disease-free (DFS) and overall survival (OS) from the addition of sequential paclitaxel (T) but not from the escalation of doxorubicin (A) dose level in the adjuvant chemotherapy of patients (PTS) with node-positive primary breast cancer (BC). Proc Am Sot Clin Oncol 17:101a, 1998 (abstr 390a) 18. Biganzoli L, Cufer T, Bruning P, et al: Doxorubicin/ Taxol versus doxorubicin/cyclophosphamide as first line chemotherapy in metastatic breast cancer: A phase III study. Proc Am Sot Clin Oncol 19:73a, 2000 (abstr 262) 19. Fisher B, Anderson S, DeCillis A, et al: Further evaluation of intensified and increased total dose of cyclophosphamide for the treatment of primary breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-25. J Clin Oncol 17:3374-3388, 1999 20. Peters WI’, Rosner G, Vredenburgh J, et al: A prospective, randomized comparison of two doses of combination alkylating agents (AA) as consolidation after CAF in high-risk primary breast cancer involving ten or more axillary lymph nodes (LN): Preliminary results of CALGB 9082/SWOG 9114/ NCIC MA-13. Proc Am Sot Clin Oncol lS:la, 1999 (abstr 2)
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21. Shak S: Overview of the trastuzumab (Herceptin) antiHER2 monoclonal antibody clinical program in HER&overexpressing metastatic breast cancer. Semin Oncol26:71-77, 1999 (SUPPI 12) 22. Ewer MS, Gibbs HR, Swafford J, et al: Cardiotoxicity in patients receiving trastuzumab: Primary toxicity, synergistic or sequential stress or surveillance artifact? Semin Oncol 26:96101, 1999 (suppl 12) 23. North Central Cancer Treatment Group 983252 protocol. Available at: http://cancernet.nci.nih.gov. (Accessed May 21, 2001) 24. Slamon DJ, Pate1 R, Nortfelt M, et al: Phase II pilot study of Herceptin combined with taxotere and carboplatin (TCH) in metastatic breast cancer (MBC) patients overexpressing the HER2-neu proto-oncogene. A pilot study of the UCLA Network. Proc Am Sot Oncol20:49a, 2001 (abstr 193) 25. Molitemi A, Menard S, Valagussa P, et al: HER2 overexpression and doxorubicin in the adjuvant chemotherapy of resectable breast cancer. Proc Am Sot Clin Oncol20:23a, 2001 (abstr 89) 26. De Laurentiis M, Caputo F, Massarelli E, et al: HER2 expression and anthracycline effect: Results from the Naples GUN3 randomized trial. Proc Am Sot Clin Oncol 20:34a, 2000 (abstr 133) 27. Paik S, Bryant J, Park C, et al: erbB-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone receptor-negative breast cancer. J Nat1 Cancer Inst 16: 1320-1321, 1998 28. Pietras RJ, Pegram MD, Finn RS, et al: Remission of human breast cancer xenografts on therapy with humanized monoclonal antibody to HER,2 receptor and DNA-reactive drugs. Oncogene 17:2235-2249, 1998 29. Shapiro CL, Ervin T, Welles L, et al: Phase II trial of high-dose liposome-encapsulated doxorubicin with granulocyte colony-stimulating factor in metastatic breast cancer. TLC D-99 Study Group. J Clin Oncol 17:1435-1441, 1999 30. Henderson IC, Berry D, Demetri G, et al: Adjuvant chemotherapy: Taxanes-The “Pro” position. Program and Abstracts of Adjuvant Therapy for Breast Cancer. National Institute of Health Consensus Development Conference, November 1-3, 2000. National Institutes of Health, Bethesda, MD, pp 75-78 31. National Surgical Breast and Bowel Project B-31 protocol. Available at: http://cancernet.nci/nih.gov. (Accessed May 21, 2001) 32. North Central Cancer Treatment Group N983 1 protocol. Available at: http://cancernet.nci/nih.gov. (Accessed May 21, 2001) 33. Perez EA, Hillman DW, Stella PJ, et al: A phase II study of paclitaxel plus carboplatin as first-line chemotherapy for women with metastatic breast carcinoma. Cancer 88:124-131, 2000 34. Gelmon K, Arnold A, Verma S, et al: Pharmacokinetics (PK) and safety of trastuzumab (Herceptin) when administered every three weeks to women with metastatic breast cancer. Proc Am Sot Clin Oncol 20:69a, 2001 (abstr 271)
trials
using
murine
have
shown
positive
the
humanized
monoclonal
activity breast
and
survival
rates
was
added
to first-line
the zumab now
with
the
have
promising in the entered
been
shown
metastatic adjuvant
United
States
and
in this
report,
Europe.
trastuzumab
as adjuvant
Semin
28
W.B.
Oncol Saunders
setting, breast
(suppl
this cancer
Five
capturing therapy 16):41-46.
SAFETY
the for
with
paclitaxel
of
of
novel
biologic
has
trials
in both
the
trials breast
trastu-
are
evolving
Copyright
role
disof
cancer. 0
2001
by
Company.
VEREXPRESSION of the human epidermal growth factor-2 gene (also known as HER2/ neu and c-erbB-2) occurs in approximately 25% of breast cancers and is associated with an aggressive form of the disease and a poor prognosis.‘-3 The HER2 gene encodes a transmembrane receptor (~185) with tyrosine kinase activity. In light of the increased understanding of the biology of HER2 and its interaction with other members of the epidermal growth factor receptor family in intracellular signaling pathways, HER2 has become a highly promising cancer target for breast cancer.4 Clinical trials using trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA), a humanized version of the antieHER2 murine monoclonal antibody 4D5, have shown antitumor activity in patients with HER2-positive metastatic breast cancer.526 Improved response and survival rates emerged when trastuzumab was added to first-line combination chemotherapy with anthracycline/cyclophosphamide or paclitaxel compared with the same chemotherapy alone.728 Because trastuzumab combined with chemotherapy results in prolongation of survival, it is important to incorporate this agent into adjuvant systemic therapy regimens for patients with primary breast cancer. However, because excessive clinical and subclinical cardiotoxicity was observed during the pivotal trial of anthracycline/cyclophosphamide delivered with concurrent weekly trastuzumab,*
0
Seminars in Oncology, Vol 28, No 5, Suppl I6 (October),
are clearly
needed
for this group of
AND EFFICACY CHEMOTHERAPY
OF ADJUVANT REGIMENS
com-
Because
profile
clinical
A. Perez
HERZ-
trastuzumab
alone.
efficacy
Edith
response
when or
and
with
and
safer regimens patients.
anti-
chemotherapy
chemotherapy
safety
cussed
trastuzumab,
Improved
combination
same
of the
4D5,
in patients
cancer.
anthracyclinelcyclophosphamide pared
version
antibody
antitumor
metastatic
N. Hortobagyi
of
200 I: pp 4 I-46
The Early Breast Cancer Trialists’ Group metaanalysis of randomized trials in the adjuvant setting showed that adjuvant chemotherapy, adjuvant tamoxifen, and adjuvant ovarian ablation produce reproducible and highly significant reductions in the odds of recurrence and death from chemotherearly breast cancer. 9-11 Combination apy was shown to be more effective than singleagent therapy, and anthracycline-containing regimens were shown to be more effective than regimens without anthracyclines. Thus, most oncologists use regimens such as 5-fluorouracil/doxorubicin/cyclophosphamidei* or doxorubicin/cyclophosphamide (AC)i3 for high-risk patients with primary breast cancer. With four to six cycles of these combinations, resulting in cumulative doxorubicin doses of 240 to 300 mg/m’ given by bolus or short intravenous infusion, the risk of cardiac toxicity is generally less than 1%. However, this risk reaches 5% at doses of 400 mg/m’ and 20% when the cumulative doxorubicin dose reaches 600 mg/m’. l4 Use of continuous-infusion doxorubicin (48 to 96 hours), epirubicin, the cardiopro-
From the Department of Breast Medical 0ncolog)i , The Uniuersity of Texas M. D. Anderson Cancer Center, Houston, TX; and the Division of Hematology/Oncology, Mayo Clinic, Jacksonville, FL. Dr Hortobagyi has received research grant support from BristolMyers Squibb and Ribozyme Pharmaceuticals. He has received honoraria from AstraZeneca, Auentis, Bristol-Myers Squibb, Genentech, Nouartis, Pharmacia, and Ribozyme Phavnaceuticals, and has served as a consuht to Agouron, Genentech, Nouartis, and Ribozyme Pharmaceuticals. Address reprint requests to Gabriel N. Hortobagyi, MD, FACE’, Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Bled, Box 424, Houston, TX 77030-4009. Copyright 0 2001 by W.B. Saunders Company 0093-7754/01/2805-I607$35.00/0 doi:l0.1053/sonc.2001.28549 41
HORTOBAGYI
tectant dexrazoxane, or liposome-encapsulated anthracyclines can lessen the risk of cardiotoxicity.15J6 Improved disease-free and overall survival rates were reported when four cycles of singleagent paclitaxel followed four cycles of AC.17 A recommended taxane combination for the treatment of breast cancer remains undetermined, awaiting results of several large trials comparing doxorubicin (or epirubicin)/paclitaxel or doxorubicin (or epirubicin)/docetaxel with doxorubicin/ cyclophosphamide or epirubicin/cyclophosphamide.18 In recent years it has become increasingly important to explore new agents, new combinations, and new ways of administering active agents. A great deal of emphasis has been placed on the study of dose escalation of selected chemotherapy drugs, which is often referred to as increased dose intensity. These manipulations are meant to circumvent resistance. However, recent trials have shown that dose escalation of cyclophosphamide to more than 600 mg/m’ does not improve diseasefree or overall survival,19 doses of doxorubicin higher than 60 mg/m’ have no clear incremental benefit,17 and high-dose chemotherapy with autologous bone marrow or stem-cell support does not clearly improve survival in preliminary analysis.20 Thus, new strategies for breast cancer treatment are needed. SAFETY THE
OF TRASTUZUMAB PIVOTAL TRIALS
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In the first pivotal multinational trial, trastuzumab was evaluated as a single agent in women with HER2-overexpressing breast cancers that had progressed despite conventional cytotoxic chemotherapy for metastatic disease.5 A single-arm study enrolled 222 patients from seven countries over a 17-month period. The primary objective of this large phase II trial was to assessthe safety and efficacy of trastuzumab in this clinical setting. Most of the patients enrolled in this trial had been heavily pretreated. These investigators reported that nine of 213 treated patients (4%) achieved a complete response and 37 patients (17%) achieved a partial response. Median duration of response in patients achieving either a complete or partial response was 9.1 months (range, 1.6 to > 26 months), and for all treated patients the median time to disease progression was 3.1 months
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(range, 0 to > 28 months). Median survival duration for all patients was 13 months (range, 0.5 to > 30 months). Approximately 40% of patients experienced fever and/or chills during or shortly following the first infusion; however, these symptoms were rarely observed (< 3%) with subsequent infusions. Severe adverse reactions were rare. The second pivotal trial21 used similar eligibility criteria, except that patients could not have received any prior treatment for metastatic disease; however, patients could have received adjuvant chemotherapy. Eligible patients were randomized to receive either chemotherapy alone or chemotherapy plus trastuzumab as the initial treatment for metastatic breast cancer. The chemotherapy regimen consisted of AC for patients who had not received adjuvant anthracycline, and paclitaxel for those who had adjuvant therapy that included an anthracycline. This trial allowed patients who progressed while receiving chemotherapy alone to be crossed over to receive trastuzumab. The addition of trastuzumab to paclitaxel resulted in statistically significant increases in response rate and time to progression, as well as in the l-year survival rate (68% versus 79%) and median survival. These initial clinical trials of trastuzumab reported some serious adverse cardiac events, especially in patients who were receiving concomitant chemotherapy.22 This prompted a more in-depth, retrospective assessment of cardiac events across these trials to determine the incidence and severity of congestive heart failure, cardiomyopathy, and/or reduction in ejection fraction. The highest incidence was seen in patients who had also received an anthracycline simultaneously (19%) versus an overall incidence of about 3% in all other patients. In the large phase II trial, there was a 5% incidence of clinically significant cardiac toxicity; however, 96% of these patients had received prior anthracyclines. The incidence of cardiac events in patients treated with paclitaxel alone or paclitaxel plus trastuzumab was 1% and 4%, respectively (P = NS). Additionally, in the postmarketing setting, rare serious and fatal infusion-related events have occurred. Most patients who experienced the more serious and fatal infusion-related events had pre-existing pulmonary compromise and advanced malignancy.
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STRATEGIES TO DEVELOP A SAFE AND EFFECTIVE TRASTUZUMAB-CONTAINING ADJUVANT SYSTEMIC THERAPY REGIMEN In view of the existing information about the cardiotoxic potential of trastuzumab, several strategies might be pursued to develop a safe and effective adjuvant regimen that targets HER2-overexpressing breast cancer cells. The first would be to develop a chemotherapy regimen that does not contain an anthracycline; in this manner, the adverse interaction between trastuzumab and the anthracycline would be avoided. An example of this approach is the development of clinical trials with a taxane (paclitaxel or docetaxel) and a platinum salt (carboplatin or cisplatin) in association with trastuzumab. Recent data have suggested that the antitumor activity of such combinations would approximate that achieved with other leading combinations in the metastatic breast cancer setting.*sJ+ An example of this strategy is the Breast Cancer International Research Group protocol BCIRG 006. Multiple retrospective analyses have suggested that HER2overexpressing tumors respond better to an anthracycline-containing regimen than to other treatments.2s-27 Therefore, while this is an interesting hypothesis, other approaches that include anthracyclines also should be investigated. A second strategy would be to avoid the anthracycline-trastuzumab interaction by administering these two agents sequentially and without overlap. In view of the prolonged half-life of trastuzumab (about 25 days), th ese sequential programs must be designed with great care to reduce the risk of cardiac toxicity to a minimum. Examples of this approach include the National Surgical Breast and Bowel Project clinical trial B-31, the North Central Cancer Treatment Group adjuvant trial 983 1, and the Eastern Cooperative Oncology Group (ECOG) trial 2198. A criticism of this approach would be that the simultaneous use of cytotoxic agents and trastuzumab seems to be optimal, at least on the basis of preclinical studies.28 The sequential combination of cytotoxic agents and trastuzumab might be less effective than the simultaneous combination. A third approach is to substitute an anthracycline with lower cardiotoxic potential (liposomeencapsulated anthracyclines, epirubicin, doxorubitin with dexrazoxane) or the use of continuous-
infusion schedules known to be less cardiotoxic. Several phase II studies have this approach under evaluation. While epirubicin and doxorubicin by continuous-infusion schedules appear equivalent in efficacy to bolus doxorubicin, there is insufficient evidence about the therapeutic efficacy of some of the other novel anthracyclines compared with bolus doxorubicin.z9 We will review the ongoing major clinical trials in patients with primary breast cancer that evaluate the role of trastuzumab in the adjuvant setting. ONGOING AND PLANNED CLINICAL TRIALS OF TRASTUZUMAB ADJUVANT THERAPY There are two new large adjuvant clinical trials planned by different cooperative groups in the United States incorporating HER2 status into the decision-making process. These trials will evaluate the tolerability and efficacy of trastuzumab and chemotherapy for patients diagnosed with HER2, overexpressing, node-positive primary breast cancer. On the basis of favorable results from the Cancer and Leukemia Group B study 9344 testing four cycles of paclitaxel after four cycles of AC, this sequence is serving as the platform for incorporating trastuzumab into several studies.30 The National Surgical Adjuvant Breast and Bowel Program B-31 trial, led by Drs Edward Romond and Elizabeth Tan Chiu, is a phase III randomized multicenter trial that will compare AC followed by paclitaxel + trastuzumab in patients with node-positive, HERZ-positive breast cancer.31 Patients are randomized to one of the two treatment arms. This study opened in February 2000 and has accrued over 350 patients. The target accrual is 2,700 patients. B-31 has a stringent prospective cardiac evaluation and monitoring system built into the protocol. Interim analysis of cardiac toxicity is scheduled after 200 patients have been followed for at least 6 months beyond initiation of trastuzumab. Similar analysis is planned after 600 patients and after 1,000 patients. All patients initially receive AC chemotherapy alone administered every 3 weeks four times. Patients are then randomized to either paclitaxel alone at a dose and schedule of 175 mg/m2 intravenously every 3 weeks for four doses, or paclitaxel at the same dose and schedule in combination with trastuzumab at a loading dose of 4 mg/kg/wk followed by trastuzumab 2 mg/kg/wk
44
Fig I. Schema for the National Surgical Project B-3 I adjuvant trial. A, doxorubicin; mide; P, paclitaxel; T, trastuzumab.
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Breast and Bowel C, cyclophospha-
for a total of 52 weeks. The effect of the addition of trastuzumab on overall survival and disease-free survival will be determined. Cardiotoxicity on each treatment arm will be compared. The dosing schedule and schema for this trial are depicted in Fig 1. The North Central Cancer Treatment Group is coordinating a prospective Breast Intergroup trial (N983 1) under the direction of Dr Edith A. Perez. This trial is designed to test the incremental benefit and toxicity of trastuzumab added to standard adjuvant chemotherapy in patients with node-positive, HER2-positive breast cancer.32 In addition, this trial will test the relative benefits of simultaneous versus sequential use of paclitaxel and trastuzumab. Participating groups include the North Central Cancer Treatment Group, the ECOG, the Cancer and Leukemia Group B, and the Southwest Oncology Group. The primary endpoints of the study are disease-free survival and cardiac tolerability. The secondary goals include overall survival, evaluation of HER2 status as a prognostic indicator for disease*free survival and overall survival, and evaluation of concordance of immunohistochemistry (by HercepTest; Dako, Carpenteria, CA) and fluorescence in situ hybridization (by PathVysion Kit; Vysis, Downers Grove, IL) and their correlation with disease-free survival and overall survival. The accrual goal is for 3,000 patients to be enrolled over a 4-year period. Thorough, noninvasive cardiac monitoring will be included. Formal interim analyses and coordination with the National Surgical Breast Adjuvant and Bowel Project, the National Cancer Institute, and
Fig 3. Schema for zumab; A, doxorubicin;
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ECOG 2198. P, paclitaxel; C, cyclophosphamide.
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T, trastu-
the Breast Intergroup are integral to the conduct of this pivotal study. The dosing schedule and schema for this trial are depicted in Fig 2. Three additional trials involving adjuvant trastuzumab therapy in breast cancer are planned or in progress. The ECOG has completed accrual to a limited (234 patients) pilot adjuvant study (ECOG 2198) evaluating the cardiac tolerability of paclitaxel 175 mg/m2 once every 3 weeks for four doses (with weekly trastuzumab) followed by AC once every 3 weeks for four doses, with randomization to either no further trastuzumab or 40 weekly doses of the monoclonal antibody treatment (Fig 3). An international group of investigators, The Breast Cancer International Research Group, will conduct a multicenter, randomized clinical trial (BCIRG 006) comparing the adjuvant regimen of AC for four doses followed by docetaxel for four doses with four cycles of the docetaxel/carboplatin combination, with or without weekly trastuzumab, under the direction of Dr Jean-Marc Nabholtz. In a previous large phase II trial, Perez et a133 showed a high response rate with the paclitaxel/carboplatin combination in patients with metastatic breast cancer. The three-arm trial activated in February 2001 is a logical extension of that work to determine the relative efficacy and safety of the docetaxel/carboplatin combination with or without trastuzumab, and to compare it with the AC combination followed by docetaxel (Fig 4). Finally, a phase III study of neoadjuvant AC 2 dexrazoxane and paclitaxel rt rrastuzumab
Node + or -
ACx4
___,
Docx4
ACx4
-
Docx4+TXx52wk
HER2 + Car or+Docx6+T*x52wk
Cis Fig Fig 2. Schema for the North Central Cancer Treatment Group adjuvant trial N983 I. A, doxorubicin; C, cyclophosphamide; P, paclitaxel; T, trastuzumab. *Schedule will be modified to once every 3 weeks.
4.
Schema
search Group phosphamide; T, trastuzumab. weeks.
for
the
Breast
protocol BCIRG Car, carboplatin; * Schedule
may
Cancer
International
006. A, doxorubicin; Cis, cisplatin; Doe, be modified
Re-
C, cyclodocetaxel;
to once
every
3
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OF BREAST CANCER
Fig 5. Schema for National Cancer Institutes study NCICOO- 1836. A, doxorubicin; C, cyclophosphamide; Dex, dexrazoxane, P, paclitaxel; T, trasturumab; XRT, radiation therapy.
followed by local surgery t adjuvant trastuzumab in women with stage IIB, IIIA, or BIB breast cancer is being sponsored by the Cancer and Leukemia Group B and the National Cancer Institute (Cancer and Leukemia Group B q-9808). Primary objectives of this trial, which has recently been activated, include assessment of the safety and efficacy of AC alone or with dexrazoxane, with and without trastuzumab, and determination of whether the initial pathologic response in patients receiving neoadjuvant therapy correlates with eventual 5-year disease-free and overall survival (Fig 5). Consideration also is being given to modifying the maintenance schedule of trastuzumab to administer this agent once every 3 weeks at a dose of 6 mg/kg instead of weekly at a dose of 2 mg/kg. The rationale for this modification is based on a pharmacokinetic safety and efficacy study, led by Dr Brian Leyland-Jones, evaluating paclitaxel 175 mg/m’ plus trastuzumab 6 mg/kg administered together every 3 weeks (after a loading dose of trastuzumab 8 mg/kg) f or eight cycles, followed by the once-every-3-week schedule of trastuzumab alone. Preliminary results were presented at the American Society of Clinical Oncology meeting in May 2001, showing fairly similar pharmacokinetics and toxicities between the every-3-week regimen and the weekly trastuzumab schedule that is standard in clinical practice. Thus, trastuzumab and paclitaxel given every 3 weeks has potential applications to adjuvant and metastatic breast cancer studies.34 SUMMARY The results of the initial trastuzumab trials have clearly shown that this agent is active in patients with advanced HER2-positive breast cancer, alone or in combination with anthracyclineor taxanebased chemotherapy. Substantial efforts are now being directed toward studying promising schedules and combinations in the adjuvant setting by cooperative groups in both the United States and
Europe. In addition, new strategies to decrease the cardiac toxicity observed with the combination of anthracyclines and trastuzumab will be tested by prospective cardiac monitoring. Novel antitumor agents, other than antibodies, that selectively target HER2 and other signaling proteins are under intense preclinical testing and could emerge as potentially important adjuvant agents in years to come. Trials evaluating newer, more selective antiestrogens and antitumor vaccines are being designed and will add another aspect to the adjuvant treatment of cancer. Thus, safer and more effective therapies for this group of patients should soon be available. For now, trastuzumab is the first targeted monoclonal antibody therapy that has passed the rigors of preclinical testing and clinical trials in patients with advanced breast cancer, and has now entered evaluation as adjuvant therapy for breast cancer. The results of these carefully planned and scientifically rigorous studies have the potential to significantly alter the standard of care for breast cancer management and improve cure rates for this disease. Completion of these ongoing trials through collaborative efforts between advocates, patients, and the scientific community will allow us to obtain the results we so eagerly await. REFERENCES 1. Slamon DJ, Clark GM, Wang SG, et al: Human breast cancer: Correlation of relapse and survival with amplification of the HER-Z/neu oncogene. Science 235:177x182, 1987 2. Slamon DJ, Godolphin W, Jones LA, et al: Studies of HER-Z/new proto-oncogene in human breast and ovarian can, cer. Science 244:707-712, 1989 3. Hynes NE, Stem DF: The biology of e&B-Z/neu/HER-2 and its role in cancer. Biochem Biophys Acta 1198:165-184, 1994 4. Disis ML, Chewer MA: HER-2/neu protein: A target for antigen-specific immunotherapy of human cancer. Adv Cancer Res 71:343-371, 1997 5. Cobleigh MA, Vogel CL, Tripathy D, et al: Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER?,-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 17:2639-2648, 1999 6. Vogel C, Cobleigh M, Tripathy D, et al: First-line nonhormonal treatment of women with HER2 overexpressing metastatic breast cancer with Herceptin (trastuzumab, humanized anti-HER2 antibody). Proc Am Sot Clin Oncol 19:71a, 2000 (abstr 275) 7. Slamon D, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HERZ. N Engl J Med 344~783-792, 2001
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8. Norton L, Slamon D, Leyland-Jones B, et al: Overall survival advantage to simultaneous chemotherapy plus the hu, manized anti-HER2 monoclonal antibody Herceptin in HERZoverexpressing metastatic breast cancer. Proc Am Sot Clin Oncol 18:127a, 1999 (abstr 483) 9. Early Breast Cancer Trialists’ Collaborative Group: Poly chemotherapy for early breast cancer: An overview of the randomised trials. Lancet 352:930x942, 1998 10. Early Breast Cancer Trialists’ Collaborative Group: Tamoxifen for early breast cancer: An overview of the randomized trials. Lancet 351:1451-1467, 1998 11. Early Breast Cancer Trialists’ Collaborative Group: Ovarian ablation in early breast cancer: Overview of the randomised trials. Lancet 348:1189-l 196, 1996 12. Buzdar AU, Gutterman JU, Blumenschein CR, et al: Intensive postoperative chemoimmunotherapy for patients with stage II and stage III breast cancer. Cancer 41:1064-1075, 1978 13. Fisher B, Brown AM, Dimitrov NV, et al: Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen non-responsive tumors: Results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 8:1483-1496, 1990 14. van Hoff DD, Layard MW, Basa P, et al: Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 91:710-717, 1979 15. Hortobagyi GN, Frye D, Buzdar AU, et al: Decreased cardiac toxicity of doxorubicin administered by continuous intravenous infusion in combination chemotherapy for metastatic breast carcinoma. Cancer 63:37-45, 1989 16. Swain SM, Whaley FS, Gerber MC, et al: Delayed administration of dexrazoxane provides cardioprotection for patients with advanced breast cancer treated with doxorubicincontaining therapy. J Clin Oncol 15:1333-1340, 1997 17. Henderson IC, Berry D, Demetri G, et al: Improved disease-free (DFS) and overall survival (OS) from the addition of sequential paclitaxel (T) but not from the escalation of doxorubicin (A) dose level in the adjuvant chemotherapy of patients (PTS) with node-positive primary breast cancer (BC). Proc Am Sot Clin Oncol 17:101a, 1998 (abstr 390a) 18. Biganzoli L, Cufer T, Bruning P, et al: Doxorubicin/ Taxol versus doxorubicin/cyclophosphamide as first line chemotherapy in metastatic breast cancer: A phase III study. Proc Am Sot Clin Oncol 19:73a, 2000 (abstr 262) 19. Fisher B, Anderson S, DeCillis A, et al: Further evaluation of intensified and increased total dose of cyclophosphamide for the treatment of primary breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-25. J Clin Oncol 17:3374-3388, 1999 20. Peters WI’, Rosner G, Vredenburgh J, et al: A prospective, randomized comparison of two doses of combination alkylating agents (AA) as consolidation after CAF in high-risk primary breast cancer involving ten or more axillary lymph nodes (LN): Preliminary results of CALGB 9082/SWOG 9114/ NCIC MA-13. Proc Am Sot Clin Oncol lS:la, 1999 (abstr 2)
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21. Shak S: Overview of the trastuzumab (Herceptin) antiHER2 monoclonal antibody clinical program in HER&overexpressing metastatic breast cancer. Semin Oncol26:71-77, 1999 (SUPPI 12) 22. Ewer MS, Gibbs HR, Swafford J, et al: Cardiotoxicity in patients receiving trastuzumab: Primary toxicity, synergistic or sequential stress or surveillance artifact? Semin Oncol 26:96101, 1999 (suppl 12) 23. North Central Cancer Treatment Group 983252 protocol. Available at: http://cancernet.nci.nih.gov. (Accessed May 21, 2001) 24. Slamon DJ, Pate1 R, Nortfelt M, et al: Phase II pilot study of Herceptin combined with taxotere and carboplatin (TCH) in metastatic breast cancer (MBC) patients overexpressing the HER2-neu proto-oncogene. A pilot study of the UCLA Network. Proc Am Sot Oncol20:49a, 2001 (abstr 193) 25. Molitemi A, Menard S, Valagussa P, et al: HER2 overexpression and doxorubicin in the adjuvant chemotherapy of resectable breast cancer. Proc Am Sot Clin Oncol20:23a, 2001 (abstr 89) 26. De Laurentiis M, Caputo F, Massarelli E, et al: HER2 expression and anthracycline effect: Results from the Naples GUN3 randomized trial. Proc Am Sot Clin Oncol 20:34a, 2000 (abstr 133) 27. Paik S, Bryant J, Park C, et al: erbB-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone receptor-negative breast cancer. J Nat1 Cancer Inst 16: 1320-1321, 1998 28. Pietras RJ, Pegram MD, Finn RS, et al: Remission of human breast cancer xenografts on therapy with humanized monoclonal antibody to HER,2 receptor and DNA-reactive drugs. Oncogene 17:2235-2249, 1998 29. Shapiro CL, Ervin T, Welles L, et al: Phase II trial of high-dose liposome-encapsulated doxorubicin with granulocyte colony-stimulating factor in metastatic breast cancer. TLC D-99 Study Group. J Clin Oncol 17:1435-1441, 1999 30. Henderson IC, Berry D, Demetri G, et al: Adjuvant chemotherapy: Taxanes-The “Pro” position. Program and Abstracts of Adjuvant Therapy for Breast Cancer. National Institute of Health Consensus Development Conference, November 1-3, 2000. National Institutes of Health, Bethesda, MD, pp 75-78 31. National Surgical Breast and Bowel Project B-31 protocol. Available at: http://cancernet.nci/nih.gov. (Accessed May 21, 2001) 32. North Central Cancer Treatment Group N983 1 protocol. Available at: http://cancernet.nci/nih.gov. (Accessed May 21, 2001) 33. Perez EA, Hillman DW, Stella PJ, et al: A phase II study of paclitaxel plus carboplatin as first-line chemotherapy for women with metastatic breast carcinoma. Cancer 88:124-131, 2000 34. Gelmon K, Arnold A, Verma S, et al: Pharmacokinetics (PK) and safety of trastuzumab (Herceptin) when administered every three weeks to women with metastatic breast cancer. Proc Am Sot Clin Oncol 20:69a, 2001 (abstr 271)