Is There a Role for Dose-Intensive Chemotherapy With Stem Cell Rescue in Breast Cancer?

During the 1990s, perhaps noother therapy for women withbreast cancer was more controversial than high-dose chemotherapy with autologousbone marrow and/or peripheral stem cell support. With encouraging results fromlate phase I and early phase II trials in the early to mid-1990s, high-dosechemotherapy was promoted by its many enthusiastic proponents as a potentiallygreat leap forward for women with high-risk, node-positive or metastaticdisease.

In the absence of controlled randomized phase III clinical trial data, asnoted by Williams in this excellent review, breast cancer became the leadingindication for autologous stem cell transplant in North America in the 1990s.Most of these stem cell transplants occurred outside of a clinical trial, whichled to many heated and publicized battles between insurers and women for accessto these therapies. Indeed, the battle became so heated, and positions soingrained, that one investigator resorted to outright research fraud to make thecase for high-dose therapy.[1]

At the plenary session of the American Society of Clinical Oncology in 1999,investigators presented several abstracts detailing preliminary results fromphase III randomized studies of high-dose therapy vs the more"standard" chemotherapy regimens for both high-risk node-positivebreast cancer and metastatic breast cancer. After these studies demonstratedlittle or no apparent benefit for high-dose chemotherapy over the standardregimens, interest in high-dose therapy, both inside and outside the context ofclinical trials, waned. After 3 years of reflection, is there currently a rolefor high-dose chemotherapy in the management of breast cancer?

Rational Basis,Disappointing Results

Williams correctly notes that high-dose therapy has a reasonable experimentaland perhaps reasonable clinical rationale. Alkylating agents demonstrated asteep dose-response curve in experimental systems,[2] and an early phase IIclinical trial demonstrated high overall and complete response rates inmetastatic breast cancer.[3]

The data from randomized clinical trials presented to date, however, havebeen mixed. As noted, one randomized trial in metastatic disease wasfraudulent.[1] One trial enrolled women with metastatic disease and a completeresponse to initial standard-dose induction therapy to immediate or delayedhigh-dose therapy at progression.[4] Immediate consolidation with high-dosetherapy produced a better disease-free survival than delayed consolidation but apoorer over- all survival. Another study randomized women with metastatic breastcancer and a response to induction therapy to high-dose or standardchemotherapy.[5] This trial demonstrated no difference in disease-free oroverall survival between the arms.

Randomized trials of high-dose chemotherapy as adjuvant therapy for high-risknode-positive breast cancer have fared no better. To date, although there havebeen encouraging signs of a trend toward improved disease-free survival in onestudy,[6] no trial randomizing women to high-dose vs standard-dose regimens hasdemonstrated a significant disease-free or overall survival benefit.

Looking Ahead

Williams correctly points out that more long-term follow-up is needed beforedefinitive results can be determined, perhaps through a meta-analysis ofcompleted trials. However, it is likely that the benefit, if any, from high-dosechemotherapy in these studies will be small. In addition, newer agents for thetreatment of both metastatic and early-stage disease, such as the aromataseinhibitors, taxanes, and trastuzumab (Herceptin), are gaining widespreadclinical acceptance. High-dose chemotherapy would likely have to prove superiorto these newer, less toxic agents to gain acceptance in the therapeuticarmentarium.

Williams suggests that the failure of high-dose chemotherapy to improve theoutcome of women with breast cancer may be due to residual minimal diseaseand/or autograft contamination by tumor. These are reasonable hypotheses thatdeserve clinical investigation. Proof-of-principle trials exploring, forexample, high-dose chemotherapy in combination with immunomodulatorystrategies[7] such as tumor antigen vaccination or dendritic cell vaccination,are also reasonable and will likely teach us much about the host immune responseto minimal residual breast cancer. Whether such studies can be translated intolarge clinical trials with the potential for altering clinical care remains anopen question.

Conclusions

In summary, Williams has provided an excellent brief review of the currentstate of high-dose chemotherapy for breast cancer. As we await updated analysesof multiple randomized clinical trials, it is clear that high-dose chemotherapyremains an experimental therapy that should be performed only in the context ofwell-designed clinical trials. While the era of dose intensity (higher dosing)may be closing, randomized trials testing the concept of dose density (morefrequent dosing) will soon be presented at national clinical meetings. If suchtrials prove promising, physicians involved in the treatment of breast cancermay be asking not "how much," but rather, "how fast."

References:

1. Weiss RB, Gill GG, Hudis CA: An on-site audit of the South African trialof high-dose chemotherapy for metastatic breast cancer and associatedpublications. J Clin Oncol 19:2771-2777, 2001.

2. Teicher BA, Cucchi CA, Lee JB, et al: Alkylating agents: in vitro studiesof cross-resistance patterns in human cell lines. Cancer Res 46:4379-4383, 1986.

3. Peters WP, Shpall EJ, Jones RB, et al: High-dose combination alkylatingagents with bone marrow support as initial treatment for metastatic breastcancer. J Clin Oncol 6:1368-1376, 1988.

4. Peters WP, Jones RB, Vrendenburgh J, et al: A large prospective randomizedtrial of high-dose combination alkylating agents with autologous cellularsupport as consolidation for patients with metastatic breast cancer achievingcomplete remission after intensive doxorubicin based induction therapy (abstract). Proc Am Soc Clin Oncol15:121, 1996.

5. Stadtmauer EA, O’Neill A, Goldstein LJ, et al: Conventional-dosechemotherapy compared with high-dose chemotherapy plus autologous hematopoieticstem-cell transplantation for metastatic breast cancer. Philadelphia Bone MarrowTransplant Group. N Engl J Med 342:1069-1076, 2000.

6. Rodenhuis S, Bontenbal M, Beex L, et al: Randomized phase III study ofhigh-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin inoperable breast cancer with 4 or more axillary lymph nodes (abstract). Proc AmSoc Clin Oncol 19:74, 2000.

7. deMagalhaes-Silverman M, Donnenberg A, Lembersky B, et al: Posttransplantadoptive immunotherapy with activated natural killer cells in patients withmetastatic breast cancer. J Immunother 23:154-160, 2000.