Dose-dense adjuvant chemotherapy for primary breast cancer
© BioMed Central Ltd 2005
Published: 10 February 2005
Adjuvant chemotherapy has been proven to reduce significantly the risk for relapse and death in women with operable breast cancer. Nevertheless, the prognosis for patients presenting with extensive axillary lymph node involvement remains suboptimal. In an attempt to improve on the efficacy of existing chemotherapy, a phase III intergroup trial led by the Cancer and Leukemia Group B (CALGB 97-41) was designed, which tested a mathematical model of tumor growth based on the Norton–Simon hypothesis. This hypothesis, developed about 3 decades ago, and the kinetic model derived from it, created the basis of the concepts of dose density and sequential therapy, both of which were tested in CALGB 97-41. This large prospective randomized trial demonstrated that shortening the time interval between each chemotherapy cycle while maintaining the same dose size resulted in significant improvements in disease-free and overall survival in patients with node-positive breast carcinoma. This finding is highly relevant and has immediate implications for clinical practice.
Breast cancer is the most commonly diagnosed form of cancer and is the second most common cause of cancer-related death in women, both in Europe and in the USA. It was estimated that in the year 2004 about 40,100 patients would die from metastatic breast carcinoma in the USA [1, 2]. Although increased patient awareness and improved screening techniques (including mammography, ultrasound, and breast magnetic resonance imaging) now permit early detection of localized and resectable tumors, many women still die from recurrent breast carcinoma, suggesting that a substantial number of patients already have distant micrometastasis at the time of diagnosis. With time, a significant number of patients will develop metastatic disease, even after seemingly curative surgery and radiotherapy. Systemic adjuvant chemotherapy for early-stage breast cancer is utilized to eradicate microscopic deposits of cancer cells that may have spread or metastasized from the primary breast cancer, and so it is recommended in large groups of patients to prevent or delay progression, based on risk assessment.
Impact of adjuvant chemotherapy on reducing annual odds of recurrence and death
CMF versus nil (8150)
+24 ± 3
+14 ± 4
CMF+ versus nil (3218)
+20 ± 5
+15 ± 5
Anthracyclines+ versus CMF (6950)
+12 ± 4
+11 ± 5
Longer versus shorter (6104)
+7 ± 4
-1 ± 5
The Oxford overview  confirmed that polychemotherapy (more than two agents) offers a survival advantage compared with single agents in the adjuvant setting. Four to six courses of therapy (3–6 months) appear to confer optimal benefit, with the administration of additional courses adding to toxicity without substantially improving overall benefit.
As previously mentioned, the available data indicate that adjuvant chemotherapy with an anthracycline-containing regimen results in a small but statistically significant improvement in survival compared with regimens that do not contain an anthracycline. The current standard adjuvant anthracycline-containing regimens are as follows: doxorubicin and cyclophosphamide (AC); epirubicin and cyclophosphamide (EC); cyclophosphamide, doxorubicin, and 5-fluorouracil; 5-fluorouracil, doxorubicin or epirubicin, and cyclophosphamide (FAC/FEC); AC followed by CMF; doxorubicin or epirubicin followed by CMF; AC followed by paclitaxel; and docetaxel, doxorubicin, and cyclophosphamide. Although CMF is commonly utilized for lower risk, node-negative breast carcinomas, regimens containing an anthracycline and/or taxanes are usually recommended for higher risk, node-positive breast carcinomas. Taxanes, including paclitaxel and docetaxel, were recently introduced in the adjuvant setting for breast carcinoma.
Currently available phase III data with adjuvant paclitaxel-anthracycline combinations demonstrate their significant superiority in terms of clinical outcome when compared with doxorubicin-based, non-taxane-containing combinations. The Cancer and Leukemia Group B (CALGB) 93-44 trial reported a significant improvement in disease-free survival (DFS) at 5 years (70% versus 65%) and overall survival (OS; 80% versus 77%) for the sequential addition of paclitaxel to AC . The National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B28 reported similar results . In the Breast Cancer International Research Group 001 trial  the docetaxel, doxorubicin, and 5-fluorouracil combination was significantly superior to FAC.
Dosing and dose escalation
In an attempt to improve the efficacy of chemotherapy in breast cancer, dose intensification has been evaluated extensively over the past decade. Dose intensity is calculated by dividing the total dose of drug given per surface area by the duration of treatment. It is expressed as mg/m2 per week . The most widely used method of increasing dose intensity has been dose escalation. Dose escalation is tested by comparing higher doses with lower ones. In some dose ranges escalation improves efficacy, and in some dose ranges it does not.
The dose escalation concept was based on the Skipper–Schabel–Wilcox model, also termed the log-kill model – the first significant proliferation model in clinical oncology . According to this model, enough cycles of enough drugs at high enough doses should be able to kill a high percentage, if not all, of the cells. Unfortunately, this has not been clinically proven to be true for breast carcinoma. Dose escalation randomized trials have demonstrated a threshold effect for the AC combination, with doses of 60 mg/m2 doxorubicin and 600 mg/m2 cyclophosphamide appearing optimal. Moderate to marked dose escalation of cyclophosphamide did not prove beneficial in two NSABP trials, and, disturbingly, there was a report of 21 cases of myeloproliferative disorders in the NSABP B25 trial [9, 10]. Similar results were suggested for doxorubicin in the report of the CALGB 93-44 trial . Here, a 50% increase (60 mg/m2, 75 mg/m2, and 90 mg/m2) in doxorubicin dose and dose intensity (administered every 21 days) did not improve outcome.
There is currently no convincing evidence demonstrating that that more dose escalated treatment regimens (e.g. high-dose chemotherapy with peripheral stem cell support) result in overall improved outcomes compared with the administration of polychemotherapy programs at standard dose levels .
Tumor cell growth kinetics show that human solid tumors do not exhibit an exponential growth pattern, but rather are better fit by a sigmoid growth pattern, for which the Gompertzian equation is the most commonly used. In the Gompertzian equation, the doubling time is not constant but rather increases with increasing tumor size, up to a certain mass/volume .
The randomized trial of doxorubicin and CMF from the National Cancer Institute of Milan  can be interpreted as a 'proof of principle' of the dose dense hypothesis. In that study, adjuvant sequential chemotherapy with doxorubicin for four cycles followed by CMF was compared with the same regimen delivered in an alternating manner. Interestingly, the authors expected the alternating regimen to prove superior, based on the Goldie–Coldman hypothesis . Instead, the sequential (more dose dense) plan was associated with significantly improved DFS and OS. Bonadonna and coworkers  concluded that, although in the alternating plan the four cycles of doxorubicin were spread over 27 weeks, in the sequential plan they were administered within 9 weeks, and therefore the increased dose intensity of doxorubicin could account for the superiority of the latter plan. Functionally, the intensity of the treatment was increased by shortening the intervals without increasing dose levels of doxorubicin, providing clinical support for exploration of the hypothesis that more dose dense chemotherapy can improve outcomes.
Evidence from other trials
Other trials have tested the dose dense hypothesis, with positive results; however, not all of them are 'clean' tests of the dose density concept. In fact, the interpretability of studies may often be confounded by the design, in that the two arms are not equal in terms of the number of cycles or total drug dose, or even different drugs are delivered .
There were, however, several important differences between the Venturini and CALGB 97-41 trials, including the sample size (1214 versus 2005 patients, respectively), selection criteria (34% of patients in the Venturini trial had node-negative disease), and the chemotherapy regimens utilized. The Venturini trial was also relatively under-powered. Furthermore, it is preferable to use the sequential AC followed by paclitaxel therapy, as used in the CALGB 97-41 study, rather than FEC14, as utilized in the Venturini trial. In fact, previous studies have demonstrated that the FEC100 regimen (containing 100 mg/m2 epirubicin) is more effective than FEC50 (containing 50 mg/m2 epirubicin) when given every 3 weeks in early-stage breast cancer . The assumption could be made that the use of the FEC100 regimen given every 2 weeks with granulocyte CSF may provide benefit. However, in a pilot trial  we recently reported that FEC100 regimen delivered every 2 weeks was not feasible because of nonhematologic toxicity, suggesting that caution should be exercised in adopting this approach for different regimens.
Breast cancer remains a worldwide public health concern, despite the fact that mortality rates have been declining in the USA, Canada, and Europe  Advances in detection, diagnosis, and treatment of breast cancer have certainly contributed to this decline, but the search for optimal regimens and their applications is still ongoing. Results with dose-dense chemotherapy in CALGB 97-41 are exciting, showing improved DFS and OS and less grade 4 neutropenia. The findings of that study suggest that dose dense scheduling with appropriate chemotherapy regimens and CSF support is 'ready for prime time' and can replace conventional dosing as the new standard of care in primary breast cancer. On the basis of current data, practicing oncologists should consider treating patients with breast cancer in this dose dense manner. However, extrapolating these data to all regimens outside a clinical trial setting should be done with caution, because unexpected toxicities may emerge. These findings suggest important avenues for future research in both breast cancer and other chemosensitive tumors, and confirmatory studies are encouraged; in this regard, it is of paramount importance to continue to support clinical trials.
doxorubicin and cyclophosphamide
Cancer and Leukemia Group B
- CMF = cyclophosphamide:
methotrexate, and 5-fluorouracil
epirubicin and cyclophosphamide
- ETC = epirubicin:
paclitaxel, and cyclophosphamide
- FAC/FEC = 5-fluorouracil:
doxorubicin or epirubicin, and cyclophosphamide
National Surgical Adjuvant Breast and Bowel Project
- Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E, Feuer EJ, Thun MJ, American Cancer Society: Cancer Statistics 2004. CA Cancer J Clin. 2004, 54: 8-29.View ArticlePubMedGoogle Scholar
- Levi F, Lucchini F, Negri E, Zatonski W, Boyle P, La Vecchia C: Trends in cancer mortality in the European Union and accession countries, 1980–2000. Ann Oncol. 2004, 15: 1425-1431. 10.1093/annonc/mdh346.View ArticlePubMedGoogle Scholar
- Early Breast Cancer Trialists' Collaborative Group: Polychemotherapy for early breast cancer: an overview of the randomized trials. Lancet. 1998, 352: 930-942. 10.1016/S0140-6736(98)03301-7.View ArticleGoogle Scholar
- Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S, Ingle JN, Cooper MR, Hayes DF, Tkaczuk KH, et al: Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol. 2003, 21: 976-983. 10.1200/JCO.2003.02.063.View ArticlePubMedGoogle Scholar
- Mamounas EP, Bryant J, Lembersky BC, Fisher B, Atkins JN, Fehrenbacher L, Raich PC, Yothers G, Soran A, Wolmark N: Paclitaxel following doxorubicin/cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer [abstract 12]. Proc Am Soc Clin Oncol. 2003, 22: 4-View ArticleGoogle Scholar
- Nabholtz JM, Pienkowski T, Mackey J, et al: Phase III trial comparing TAC (docetaxel, doxorubicin, cyclophosphamide) with FAC (5-fluorouracil, doxorubicin, cyclophosphamide) in the adjuvant treatment of node positive breast cancer patients: interim analysis of the BCIRG 001 study [abstract 141]. Proc Am Soc Clin Oncol. 2002, 21: 36a-Google Scholar
- Hryniuk W, Levine MN: Analysis of dose intensity for adjuvant chemotherapy trials in stage II breast cancer [abstract]. J Clin Oncol. 1986, 4: 1162-1170.PubMedGoogle Scholar
- Skipper HE: Laboratory models: some historical perspective. Cancer Treat Rep. 1986, 70: 3-7.PubMedGoogle Scholar
- Fisher B, Anderson S, Wickerham DL, DeCillis A, Dimitrov N, Mamounas E, Wolmark N, Pugh R, Atkins JN, Meyers FJ, et al: Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B22. J Clin Oncol. 1997, 15: 1858-1869.PubMedGoogle Scholar
- Fisher B, Anderson S, DeCillis A, Dimitrov N, Atkins JN, Fehrenbacher L, Henry PH, Romond EH, Lanier KS, Davila E, 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. 1999, 17: 3374-3388.PubMedGoogle Scholar
- Rodenhuis S, Bontenbal M, Beex LV, Wagstaff J, Richel DJ, Nooij MA, Voest EE, Hupperets P, van Tinteren H, Peterse HL, et al: High-dose chemotherapy with hematopoietic stem-cell rescue for high-risk breast cancer. N Engl J Med. 2003, 349: 7-16. 10.1056/NEJMoa022794.View ArticlePubMedGoogle Scholar
- Norton L: A Gompertzian model of human breast cancer growth. Cancer Res. 1988, 48: 7067-7071.PubMedGoogle Scholar
- Surbone A, Gilewski T, Dang CT, Norton L: Cytokinetics. Cancer Medicine. Edited by: Holland JF, Frei E, Bast RC. 2000, Baltimore, MD: Williams and Wilkins, 491-519. 5Google Scholar
- Bonadonna G, Zambetti M, Valagussa P: Sequential or alternating doxorubicin and CMF regimens in breast cancer with more tan three positive nodes. JAMA. 1995, 273: 542-547. 10.1001/jama.273.7.542.View ArticlePubMedGoogle Scholar
- Goldie JH, Coldman JA: A mathematical model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep. 1979, 63: 1727-1733.PubMedGoogle Scholar
- Hudis C, Seidman A, Baselga J, Raptis G, Lebwohl D, Gilewski T, Moynahan M, Sklarin N, Fennelly D, Crown JP, et al: Sequential dose-dense doxorubicin, paclitaxel, and cyclophosphamide for respectable high-risk breast cancer: feasibility and efficacy. J Clin Oncol. 1999, 17: 93-100.PubMedGoogle Scholar
- Hudis C, Fornier M, Riccio L, Lebwohl D, Crown J, Gilewski T, Surbone A, Currie V, Seidman A, Reichman B, et al: 5-year result of dose-intensive sequential adjuvant chemotherapy for women with high-risk node-positive breast cancer: a phase II study. J Clin Oncol. 1999, 17: 1118-PubMedGoogle Scholar
- Fornier MN, Seidman AD, Theodoulou M, Moynahan ME, Currie V, Moasser M, Sklarin N, Gilewski T, D'Andrea G, Salvaggio R, et al: Doxorubicin followed by sequential paclitaxel and cyclophosphamide vs. concurrent paclitaxel and cyclophosphamide: 5-year results of a phase II randomized trial of adjuvant dose-dense chemotherapy for women with node-positive breast carcinoma. Clin Cancer Res. 2001, 7: 3934-3941.PubMedGoogle Scholar
- Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, Davidson NE, Martino S, Livingston R, Ingle JN, 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. 2003, 21: 1431-1439. 10.1200/JCO.2003.09.081.View ArticlePubMedGoogle Scholar
- Therasse P, Mauriac L, Welnicka-Jaskiewicz M, Bruning P, Cufer T, Bonnefoi H, Tomiak E, Pritchard KI, Hamilton A, Piccart MJ, EORTC: Final results of a randomized phase III trial comparing cyclophosphamide, epirubicin, and fluorouracil with a dose-intensified epirubicin and cyclophosphamide + filgrastim as neoadjuvant treatment in locally advanced breast cancer: an EORTC-NCIC-SAKK multicenter study. J Clin Oncol. 2003, 21: 843-850. 10.1200/JCO.2003.05.135.View ArticlePubMedGoogle Scholar
- Möbus VJ, Untch M, Du Bois A, Lueck H-J, Thomssen C, Kuhn W, Kurbacher C, Nitz U, Kreienberg R, Jackisch C: Dose-dense sequential chemotherapy with epirubicin(E), paclitaxel (T) and cyclophosphamide (C) (ETC) is superior to conventional dosed chemotherapy in high-risk breast cancer patients (≥ 4 +LN). First results of an AGO-trial [abstract 513]. Proc Am Soc Clin Oncol. 2004Google Scholar
- Venturini M, Aitini E, Del Mastro L, Sertoli MR, Conte P, Olmeo N, Mammoliti S, Cavazzini G, Pastorino S, Bruzzi P, Rosso R: Phase II adjuvant trial comparing standard versus accelerated FEC regimen I early breast cancer patients. Results from GONO-MIG1 study [abstract 12]. Breast Cancer Res Treat. 2003, S9-Suppl 1
- French Epirubicin Study Group: Benefit of a high-dose epirubicin regimen in adjuvant chemotherapy for node-positive breast cancer patients with poor prognostic factors: 5-year follow-up results of French Adjuvant Study Group 05 randomized trial. J Clin Oncol. 2001, 19: 602-611.Google Scholar
- Dang CT, D'Andrea GM, Moynahan ME, Dickler MN, Seidman AD, Fornier M, Robson ME, Theodoulou M, Lake D, Currie VE, et al: Phase II study of feasibility of dose-dense FEC followed by alternating weekly taxanes in high-risk, four or more node-positive breast cancer. Clin Cancer Res. 2004, 10: 5754-5761.View ArticlePubMedGoogle Scholar
- Ries LAG, Eisner MP, Kosary CL, Hankey BF, Miller BA, Clegg L, Mariotto A, Feuer EJ, Edwards BK, eds: SEER Cancer Statistics Review, 1975–2001. 2004, Bethesda, MD: National Cancer Institute, [http://seer.cancer.gov/csr/1975_2001/]Google Scholar