• E-mail
• Print
• Comment
• Font Size
• Digg
• del.icio.us
• Discuss article

High-Dose Chemotherapy With Autologous Hematopoietic Stem-Cell Support Compared With Standard-Dose Chemotherapy in Breast Cancer Patients With 10 or More Positive Lymph Nodes: First Results of a Randomized Trial

Posted on: Friday, 5 August 2005, 09:00 CDT

Objective

To compare High Dose Chemotherapy (HDCT) with Standard Dose Chemotherapy (SD-CT) as consolidation after 4 cycles of anthracycline based adjuvant chemotherapy in patients with primary breast cancer and 10 or more involved axillary lymph nodes.

Introduction

Sequential trials of adjuvant chemotherapy have proven beyond doubt the survival advantage when primary surgery for breast cancer is followed by adjuvant anthracycline based cytotoxic chemotherapy. However, patients remain at risk of recurrence, particularly those with multiple involved axillary lymph nodes. Non randomised trials of high dose chemotherapy with bone marrow or peripheral blood stem cell rescue appeared to show an advantage compared to historical controls, prompting the need for well conducted randomised controlled trials.

Methods

1. 307 patients with 10 or more involved axillary nodes, but without distant metastases, were randomised over 7 years.

2. All patients received four cycles of Epirubicin 90 mg/m and Cyclophosphamide 600 mg/m^sup 2^.

3. This was followed by either high dose chemotherapy with Cyclophosphamide 6000 mg/m^sup 2^, Thiotepa 600 mg/m and mitoxantrone 40 mg/m^sup 2^ fractionated over 4 days or 3 cycles of a day 1&8 CMF regimen.

4. Radiotherapy treatment was not specified in the protocol until 1998 when it was recommended and similarly, Tamoxifen was not initially included in the protocol treatment, but recommended in a subsequent protocol amendment.

Results

At a median of 3.8 years follow up, the Hazard ratio for event free survival was 0.75 (95% CI 0.54-1.06, NS) in favour of HDCT. There were no differences in overall survival.

Five patients in the high-dose arm suffered serious adverse events "probably" related to treatment which were fatal in 3 cases. Toxicity related to CMF was not systematically recorded.

Conclusion

This trial did not show any statistically significant differences in outcome with HDCT compared to conventionally dosed treatment. Further follow up is required and a meta-analysis of all high dose trials is warranted.

Commentary

In the late 1980s and early 1990s, possibly due to a lack of new agents to test in the adjuvant setting in breast cancer, High Dose Chemotherapy with Stem Cell or Bone Marrow rescue was sugggested as a way to improve survival. There were several phase II trials which demonstrated impressive results from late dose intensification, at least compared to historical controls, and pressure built to offer high dose chemotherapy to women at high risk of recurrence. Several randomised trials of high dose chemotherapy have been conducted in women at high risk of relapse and so far none have been convincingly positive [4-7]. The exceptions to this were 2 trials originating from South Africa in which a double transplant was used. However, the two trials were subsequently discredited and in the late 1990s, high dose chemotherapy was effectively torpedoed with many trials closing, or their recruitment foundering.

High dose chemotherapy and trials of HDCT have a number of intrinsic weaknesses:

1. HDCT is toxic and so there is invariably a treatment related death rate which must be overcome before any treatment related advantage becomes apparent.

2. HDCT trials are almost always small due to the toxicity of the treatments used and issues around randomisation. This means many have not been adequately statistically powered to detect realistic differences in outcome

3. HDCT (because of its toxicity) has been tested in ultra high risk patients, frequently those with 10 or more involved axillary nodes. However, modelling of outcomes using computerised risk assessment tools suggests that choosing a slightly lower risk group might increase the chance of modifying the natural history of disease

4. HDCT trials have compared dose intensification with anthracycline based "standard" treatment. Combinations of anthracyclines with Taxanes are now the standard of care and so results of these trials, many of which started in the early 1990s, are not comparable with optimal contemporary regimens.

5. HDCT turns adjuvant chemotherapy for breast cancer from a generally well tolerated outpatient treatment into a more challenging inpatient experience with inevitable severe toxicity. As a result, even if found to be advantageous with respect to survival, HDCT would require a detailed risk benefit analysis before application in routine clinical practice particularly because breast cancer is so common and the technology is so resource use intense.

In this particular trial an anthracycline containing stem has been followed by either HDCT or standard CMF chemotherapy. In design the study is very similar to the Anglo-Celtic I trial and in essence the results are very similar [I]. Three patients (2%) died from treatment related toxicity in the HDCT arm which compares favourably with other studies. A trend to improved event free survival was seen, but in common with other HDCT trials, this did not appear to translate into a survival advantage.

Translating this result into clinical practice is simple. High dose chemotherapy cannot be recommended for any patient in the adjuvant treatment of breast cancer except in the context of an appropriate randomised trial for an appropriately selected group of patients. Differences produced when comparing taxane containing adjuvant chemotherapy regimens to anthracyclines have been much more convincing and much more consistent across a number of large trials and the concept of dose intensification by increasing dose density rather than delivering a single big chemotherapy hit has been shown to be an effective strategy with improvements in toxicity compared to standard treatment [8]. We now target (postmenopausal) hormone receptor positive patients with Aromatase inhibitors and Her-2 positive patients with Trastuzumab, continually diminishing the number of candidates for a HDCT approach. In short HDCT has been, and I believe appropriately, consigned to history.

Reference

1. Leonard RCF, Lind M, Twelves C, Coleman R, van Belle S, Wilson C, et al. Conventional adjuvant chemotherapy versus single-cycle, autograft-supported, high-dose, lateintensification chemotherapy in high-risk breast cancer patients: A randomized trial. Journal of the National Cancer Institute 2004;96(14):1076-1083.

Further Reading

Bezwoda WR, Seymour L1 Dansey RD. High-dose chemotherapy with hematopoietic rescue as primary treatment for metastatic breast cancer: a randomized trial. J Clin Oncol 1995:13:2483-2489.

Weiss RB, Gill GG, Hudis CA. An on-site audit of the South African trial of high-dose chemotherapy for metastatic breast cancer and associated publications. Journal of Clinical Oncology 2001;19(ll):2771-2777.

Peters WP, Rosner G, Vredenburgh J, Shpall EJ, Crump M, Marks L, et al. Updated results of a prospective, randomized comparison of two doses of combination alkyating agents (AA) as consolidation after CAF in high-risk primary breast cancer involving ten or more axillary lymph nodes (LN): CALGB 9082/SWOG 9114/NCIC Ma-13. Proc Am Soc Clin Oncol 2001 ;Abstract No: 81.

Rodenhuis S, Richel DJ, van der Wall E, Schornagel JH, Baars JW, Koning CCE, et al. Randomised trial of high-dose chemotherapy and haemopoietic progenitor-cell support in operahle breast cancer with extensive axillary lymph-node involvement. Lancet 1998;352:515.

Bergh J, Wiklund T, Erikstein B, Lidbrink E, Lindman H, Malmstrom P, et al., for the Scandinavian Breast Group 9401 study. Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow- supported high-dose chemotherapy as adjuvant treatment for high- risk breast cancer: a randomised trial Lancet 2000;356:1384.

Roch H, Viens P, Biron P, Lotz J-P, Asselain B, for the PEGASE Group. High-dose chemotherapy for breast cancer: The French PEGASE experience. Cancer Control 2003;10(l):42-47.

Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent comhination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of intergroup trial C974I/cancer and leukemia group B trial 9741. J Clin Oncol 2003;21:1431-1439.

Zander AR, Kroger N, Schmoor C, Kruger W, Mobus V, Fnckhofen N, Metzner B, Schultze W, Berdel WE, Koenigsmann M, Thiel E, Wandt H, Possinger K, Trumper L, Kreienberg R, Carstensen M, Schmidt EH, Janicke F, Schumacher M, Jonat W. journal of Clinical Oncology 22(12);2004:2273-2283

Commentary by: Mark Verrill, MA, FRCP, Department of Medical Oncology, Northern Institute for Cancer Research, University of Newcastk, Newcastle upon Tyne, UK

Copyright CRC Press Mar 2005

Source: Women's Oncology Review

More News in this Category