Whither high-dose chemotherapy in breast cancer?
© BioMed Central Ltd on behalf of the copyright holders 2000
Received: 4 November 2000
Accepted: 8 November 2000
Published: 1 December 2000
Four trials of high-dose chemotherapy with stem cell support in breast cancer in the adjuvant and metastatic settings have shown no long-term disease-free or overall survival gain. This relative failure of a single high-dose therapy we believe opens up the development of a dose-dense approach with block scheduling as the most promising way forward. This intensive chemotherapy can be more easily combined with the newer biological therapies and our prediction is that this will prove to be the most effective treatment in the future for women with poor risk breast cancer.
Keywordsbreast cancer high-dose chemotherapy
Our intended pun implies that we have reached a crossroads in high-dose chemotherapy for breast cancer. Is high-dose chemotherapy going anywhere, or should we allow it to wither on the vine? The conclusion of this commentary is that, in its present form, high-dose treatment has not been found to be superior to conventional-dose treatment in either the metastatic or adjuvant setting. However, we should be careful not to 'throw the baby out with the bath water'. Rather, we should look seriously at intensifying chemotherapy with more active drugs, given in different schedules. Our judgement is that using conventional cytotoxic chemotherapy, the approach pioneered by the Memorial Sloan-Kettering Hospital, New York, USA, with 'dose-dense' chemotherapy given in a 'block schedule', is likely to produce the best results . However, there is also now much to be gained from looking at biological agents in combination with conventional chemotherapy, particularly with the recent encouraging results with the use of trastuzumab (Herceptin, Genentech, San Francisco, CA, USA) .
High-dose chemotherapy in breast cancer has been a controversial issue for some time. Several phase 2 trials showed promising results in patients with chemotherapy-responsive metastatic disease, when the data were compared with the outcome in historical control individuals [3,4]. However, most recently published randomized trials demonstrate a lack of effectiveness in both the adjuvant and metastatic settings [5,6,7,8]. The trials of Bezwoda and coworkers from South Africa [9,10,11,12] remained the only important positive evidence for high-dose chemotherapy, until the publication of the onsite review of the Bezwoda studies  and the investigator's admission of serious scientific misconduct. Although international commentators [14,15] have suggested that further trials of high-dose chemotherapy should be carried out, our view is that such studies will have to be innovative enough to persuade oncological clinical investigators worldwide that this approach is worth investigating further.
The concept of dose intensity is based on the hypothesis that a single or tandem exposure to very high doses of chemotherapy will eliminate any remaining tumour cells, and thereby result in a cure. High-dose treatment is based on escalating the dose of chemotherapeutic agents, in particular alkylating agents, which will result in severe bone marrow depression. The technique of autologous bone marrow transplantation and more recently the use of peripheral blood stem cells to restore marrow function have made this approach possible.
There is considerable in vivo evidence that dose intensification can improve responses in breast cancer. One of the first studies was performed by Bonadonna et al . Those investigators analyzed two of their clinical trials retrospectively, and reported that patients who received a higher percentage of the intended dose of chemotherapy had a significantly longer disease-free survival. Review of patients in adjuvant and palliative breast cancer trials [17,18] suggested a linear dose-response relationship for patients receiving conventional doses of chemotherapy. This was particularly steep once the threshold intensity had been surpassed. A prospective study by the Cancer and Leukemia Group B  confirmed that both pre-menopausal and postmenopausal women receiving high or moderate doses of cyclophosphamide, doxorubicin and fluorouracil had significantly better disease-free and overall survival than those receiving low doses. A meta-analysis of 14 studies with higher doses without bone marrow support in metastatic breast cancer showed a survival advantage, although this was modest .
In the 1980s, high-dose treatment with bone marrow support was introduced into breast cancer treatment after it had proven successful in more chemosensitive diseases such as leukaemia and lymphoma. Disappointingly, four studies [5,6,7,8], including more than 1400 patients receiving adjuvant treatment, failed to prove an advantage in the adjuvant setting. Similarly, there was no survival benefit in patients with metastatic disease, although a higher response rate was reported [21,22].
A variety of reasons potentially account for this. One hypothesis is that the dose-response curve usually has a sigmoid shape with a threshold, a lag phase, a linear phase and a plateau phase . The dose-response curve is steep in the linear phase. Reduction of dose intensity in the linear phase results in a marked decrease in cure rates before a significant reduction in the complete remission rate. On average, a dose reduction of 20% leads to a loss of 50% in the cure rate. Increasing the dose intensity can therefore be a useful way to increase the effect of certain drugs. This potentially explains the benefit of more dose intense, conventional regimens, as found by Bonadonna et al  and Wood et al . In contrast to other malignancies such as lymphoma, the dose-response curve for breast cancer seems to be shifted to the left, and escalating doses to the levels used for the high-dose treatment may reach the plateau phase.
Intrinsic resistance to the available chemotherapeutic drugs and the development of resistant clones during chemotherapy are also likely to be partly responsible for the failure of high-dose chemotherapy to impact on the survival of breast cancer patients. Some years ago Goldie and Coldman developed a mathematical model that predicted that mutations causing drug resistance occur in tumours of 103-106 tumour cells , which is much lower than the clinically detectable level (ie a tumour at detectable level would be almost certain to have at least one drug-resistant clone, if not more).
Another reason for the failure of high-dose treatment in breast cancer is the choice of drugs available for dose escalation. The drug combinations used include mostly alkylating agents and platinum. Unfortunately, some of the most effective drugs in breast cancer, namely anthracyclines and taxanes, are not suitable for dose escalation to the same extent because of the cardiotoxicity of anthracyclines and neurotoxicity of taxanes.
Perhaps with the resounding failure of conventional high-dose chemotherapy approaches in breast cancer, we should turn our attention to the 'dose-dense' approach with the block scheduling suggested by the mathematical models of Day , and developed clinically by Norton and Day . Our expectation of high-dose treatment with bone marrow support has thus far not been fulfilled either in the adjuvant or in the metastatic setting. A dose-intense conventional approach remains the 'gold standard'. Although there is a variety of treatment options available, further research is needed to explore different ways to find improved treatment strategies. The recent introduction of Herceptin, a cerbB2 antibody, into the clinic, which has been shown to improve survival in patients with metastatic disease, is one step in that direction.
- Norton L, Day R: Potential innovations in scheduling cancer chemotherapy. In: Important Advances in Oncology. Edited by deVita V, Hellman S, Rosenberg S. Philadelphia: JB Lippincott Company;. 1991, 57-72.Google Scholar
- Barnes DM, Miles DW: Response of metastatic breast cancer to trastuzumab?. Lancet. 2000, 355: 160-161. 10.1016/S0140-6736(99)00430-4.View ArticlePubMedGoogle Scholar
- Peters WP, Shpall EJ, Jones RB, Olsen GA, Bast RC, Gockerman JP, Moor JO: High-dose combination alkylating agents with bone marrow support as initial treatment for metastatic breast cancer. J Clin Oncol. 1988, 6: 1368-1376.PubMedGoogle Scholar
- Peters WP, Ross M, Vredenburgh JJ, Meisenberg B, Marks LB, Winer E, Kurtzberg J, Bast RC, Jones R, Shpall E: High dose chemotherapy and autologous bone marrow support as consolidation after standard dose adjuvant chemotherapy for high-risk primary breast cancer. J Clin Oncol. 1993, 11: 1132-1143.PubMedGoogle Scholar
- Rodenhuis S, Richel DJ, van der Wall E, Schornagel JH, Baars JW, Koning CCE, Peterse J, Borger JH, Nooijen WJ, Dalesio O, Rutgers E: Randomised trial of high-dose chemotherapy and haemopoietic progenitor-cell support in operable breast cancer with extensive axillary lymph node involvement. Lancet. 1998, 352: 515-572. 10.1016/S0140-6736(98)01350-6.View ArticlePubMedGoogle Scholar
- Hortobagyi GN, Buzdar AU, Theriault RL, Valero V, Frye D, Booser DH, Holmes FA, Giralt S, Khouri I, Andersson B, Gajewski JL, Rondon G, Smith TL, Singletary SE, Ames FC, Sneige N, Strom EA, McNeese MD, Deisseroth AB, Champlin RE: Randomized trial of high-dose chemotherapy and blood cell autografts for high-risk primary breast carcinoma. J Natl Cancer Inst. 2000, 92: 225-233. 10.1093/jnci/92.3.225.View ArticlePubMedGoogle Scholar
- Peters W, Rosner G, Vredenburgh J, Shpall E, Crump M, Richardson P, Marks L, Cirrincione C, Wood W, Henderson I, Hurd D, Norton L: A prospective, randomised comparison of two doses of combination alkylating agents as consolidation after CAF in high-risk primary breast cancer involving ten or more axillary lymph nodes (LN): Preliminary results of CALBG9082/SWOG 9114/NCIC MA-13 [abstract]. Proc Am Soc Clin Oncol. 1999, 18: 2-Google Scholar
- The Scandinavian Breast Cancer Study 9401: Results from a randomised adjuvant breast cancer study with high dose chemotherapy with CTCb, supported by autologous bone marrow stem cells versus dose escalated and tailored FEC therapy [abstract]. Proc Am Soc Clin Oncol. 1999, 18: 2a-Google Scholar
- Bezwoda WR, Seymour L, Dansey R: High-dose chemotherapy with haematopoietic rescue as primary treatment for metastatic breast cancer: a randomised trial. J Clin Oncol. 1995, 13: 2483-2489.PubMedGoogle Scholar
- Bezwoda WR: Primary and high dose chemotherapy for metastatic breast cancer: update and analysis of prognostic features [abstract]. Proc Am Soc Clin Oncol. 1998, 17: 115-Google Scholar
- Bezwoda WR: Randomised controlled trial of high-dose chemotherapy (HD-CNVp) versus standard dose (CAF) chemotherapy for high risk, surgically treated, primary breast cancer [abstract]. Eur J Cancer. 1999, 35(suppl 4): 230-10.1016/S0959-8049(99)81322-7.View ArticleGoogle Scholar
- Bezwoda WR: Randomised controlled trial of high-dose chemotherapy (HD-CNVp) versus standard (CAF) chemotherapy for high-risk, surgically treated, primary breast cancer [abstract]. Proc Am Soc Clin Oncol. 1999, 18: 2a-Google Scholar
- Weiss RB, Rifkin RM, Stewart FM, Theriault RL, Williams LA, Herman AA, Beveridge RA: High dose chemotherapy for high risk primary breast cancer: an on-site review of the Bezwoda study. Lancet. 2000, 355: 999-1003. 10.1016/S0140-6736(00)90024-2.View ArticlePubMedGoogle Scholar
- Bergh J: Where next with stem-cell-supported high-dose therapy for breast cancer?. Lancet. 2000, 355: 944-945. 10.1016/S0140-6736(00)90007-2.View ArticlePubMedGoogle Scholar
- Lippman ME: High-dose chemotherapy plus autologous bone marrow transplantation for metastatic breast cancer. N Engl J Med. 2000, 342: 1119-1120. 10.1056/NEJM200004133421508.View ArticlePubMedGoogle Scholar
- Bonadonna G, Valagussa P, Moliterni A, Zambetti M, Brambilla C: Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node positive breast cancer: the results of 20 years of follow-up. N Engl J Med. 1995, 332: 901-906. 10.1056/NEJM199504063321401.View ArticlePubMedGoogle Scholar
- Hryniuk W, Bush H: The importance of high dose intensity in chemotherapy of metastatic breast cancer. J Clin Oncol. 1984, 2: 1281-1287.PubMedGoogle Scholar
- Hrynuik W, Levine MN: Analysis of dose intensity for adjuvant chemotherapy trials in stage II breast cancer. J Clin Oncol. 1986, 4: 1162-1170.Google Scholar
- Wood WC, Budman DR, Korzun H, Robert Cooper, Younger J, Hart RD, Moore A, Ellerton JA, Norton L, Ferree CR, Ballow AC, Frei E, Craig Henderson I: Dose and dose intensity of adjuvant chemotherapy for stage II, node positive breast carcinoma. N Engl J Med. 1994, 330: 1253-1259. 10.1056/NEJM199405053301801.View ArticlePubMedGoogle Scholar
- Fossati R, Confalonieri C, Torri V, Ghislandi E, Penna A, Pistotti V, Tinazzi A, Liberati A: Cytotoxic and hormonal treatment for metastatic breast cancer a systematic review of published randomised trials involving 31,510 women. J Clin Oncol. 1998, 16: 3439-3460.PubMedGoogle Scholar
- Stadtmauer EA, O'Neill A, Goldstein LJ, Crilley PA, Mangan KF, Ingle JN, Brodsky I, Martino S, Lazarus HM, Erban JK, Sickles C, Glick JH: Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous haematopoietic stem cell transplant group. N Engl J Med. 2000, 342: 1069-1076. 10.1056/NEJM200004133421501.View ArticlePubMedGoogle Scholar
- Lotz JP, Cure H, Janvier M, Morvan F, Asselain B, Guillemot M, Laadem A, Maraninchi D, Gisselbrecht C, Roche H: High-dose chemotherapy (HD-CT) with haemopoietic stem cell transplantation (HSCT) for metastatic breast cancer (MBC): results of the French Protocol PEGASE 04 [abstract]. Proc Am Soc Clin Oncol. 1999, 18: 43a-Google Scholar
- Day R: Treatment sequencing, asymmetry, and uncertainty: protocol strategies for combination chemotherapy. Cancer Res. 1986, 46: 3876-3885.PubMedGoogle Scholar
- Goldie JH, Coldman AJ: A mathematical model for relating the drug sensitivity of tumours to their spontaneous mutation rate. Cancer Treatment Reports. 1979, 63: 1727-1733.PubMedGoogle Scholar