Drs. Armstrong and Davidson have nicely reviewed the use of dose-intensive chemotherapy in the treatment of metastatic and high-risk early-stage breast cancer, and we agree with the basic premise of the articlethat there are no conclusive data to support the routine use of doses beyond the standard range outside of a study setting. Bonadonna et al in 1981 demonstrated that inferior dosing of CMF chemotherapy (cyclophosphamide [Cytoxan, Neosar], methotrexate(Drug information on methotrexate), fluorouracil(Drug information on fluorouracil) [5-FU]) in node-positive breast cancer was equivalent to not receiving chemotherapy at all. Extrapolating from this information and from data from other supportive studies, a number of prospective trials of more dose-intensive regimens were undertaken in the next 2 decades.
Many trials have demonstrated that increased dose intensity could potentially result in better response rates and sometimes in prolongation of median time to progression but not in improved survival. Dose thresholds have been established for many active agentsdoxorubicin (60 mg/m2); cyclophosphamide(Drug information on cyclophosphamide) (600 mg/m2), paclitaxel(Drug information on paclitaxel) (175 mg/m2)as has the fact that adequate dosing is essential (dose threshold). Escalation beyond standard dosing remains a question for study with no convincing evidence of efficacy and some data demonstrating harm in terms of second malignancies, especially in the case of leukemogenesis with high-dose alkylating agents.
An interesting hypothesis currently being investigated in prospective trials is that of dose density. This strategy calls for decreasing time between treatments (ie, the time available for tumor regrowth is reduced) by using sequential administration of single agents in an intensive fashion rather than in combination. This concept has a theoretical appeal that it is hoped will translate into a survival benefit in prospective trials currently underway.
Metastatic Breast Cancer
There are now five reported prospective randomized trials of high-dose chemotherapy and stem cell support in advanced breast cancer. We agree with the authors that the 1995 Bezwoda trial must be discarded because of uncertain validity, especially in light of this investigator’s admittedly fraudulent data on the role of this therapy in high-risk breast cancer, presented in abstract form at the plenary session of ASCO 1999. We are thus left with four randomized trials in the metastatic setting on which to comment.
The French PEGASE 4 trial although small (61 patients randomized), did show a trend toward improvement of median overall survival for the high-dose arm, but that trend was not statistically significant. The results suggested, however, that this therapeutic approach holds promise. The Philadelphia Intergroup study, did not show any incremental benefit for high-dose chemotherapy in 3-year overall, or relapse-free survival. Criticism regarding the number of eligible patients actually randomized (199 patients in the analysis) is unwarranted. This was a study of two postremission approaches. Only 310 patients responded to induction therapy and thus were eligible for randomization; the majority were thus randomized.
We are unsure of how to interpret the prolonged median survival of the group receiving high-dose chemotherapy at second recurrence (3.2 years) rather than at first complete remission (2.3 years) in the Duke Crossover study (98 patients). The only patients randomized were those in complete remission, which represented approximately 25% of the original 400 patients entered into the study. We await final analysis and publication of the complete manuscript to interpret these data further.
Investigators at Duke also looked at high-dose chemotherapy in 69 patients with breast cancer that had metastasized to a limited number of bone sites. They again examined the role of delayed vs immediate vs high-dose chemotherapy after standard chemotherapy. The difference in progression-free survival (1.0 vs 0.91 years) has been reported as significantly favoring high-dose chemotherapy, although one could well question the clinical significance; indeed, median overall survivals were approximately the same (2.01 vs 1.8 years) at 4.9 years median follow-up.
Thus, despite more than 10 years of investigation with over 5,000 patients treated and a collective randomized trial experience in over 400 patients, there is no definitive evidence of the therapeutic efficacy of high-dose chemotherapy in metastatic breast cancer. A number of other randomized trials in metastatic breast cancer remain to be reported. We believe that until proof of principle is demonstrated in the adjuvant high-risk breast cancer setting, where treatment of micrometastatic disease is the goal, use of this modality in metastatic breast cancer should be limited to innovative clinical investigations.
High-Risk Breast Cancer
Turning to early-stage breast cancer and high-dose chemotherapy, there are six randomized published trials, one of which is the strongly positive but discredited South African study mentioned earlier. A Dutch pilot trial examined the role of high-dose chemotherapy (with cyclophosphamide, thiotepa [Thioplex], and carboplatin(Drug information on carboplatin) [Paraplatin]) in 97 patients with a positive infraclavicular lymph node biopsy who had responded to initial treatment with preoperative FEC (fluorouracil, epirubicin(Drug information on epirubicin) [Ellence], cyclophosphamide). At a median follow-up of 49 months there was no difference in progression-free or overall survival between the two arms.
The same group has now enrolled 885 patients with four or more positive axillary lymph nodes and examined the same high-dose chemotherapy regimen used in the pilot study in place of a fifth cycle of FEC. A planned subgroup analysis of the first 284 patients showed a benefit in 3-year overall and relapse-free survival. The results are promising, but the final results are not expected until 2002. Meanwhile, enthusiasm must be tempered by the other studies reported to date.
An M. D. Anderson trial in 78 patients with 10 or more positive axillary nodes showed no benefit for the high-dose arm at a median follow-up of 6.5 years. A 525-patient trial by the Scandinavian Breast Cancer Study Group reported no difference in relapse-free or overall survival at a 2-year median follow-up. A CALGB Intergroup trial in 874 women with 10 or more involved lymph nodes found similar event-free and overall survival data at a median follow-up of 37 months and, so far, does not favor high-dose therapy, although a trend toward reduced relapse-free survival is evident.
Comments and Recommendations
What can we conclude? Unfortunately, most patients with metastatic breast cancer still relapse and die within 3 years, and better therapeutic interventions are needed. High-dose chemotherapy and stem cell rescue does allow for increased dose density, intensity, and response. The morbidity, mortality, and cost of high-dose chemotherapy with stem cell rescue has decreased substantially over the past decade, and quality of life does not decline substantially after transplant. These observations support further study of this approach.
However, the incorporation of one cycle of high-dose chemotherapy and stem cell rescue into the treatment of metastatic breast cancer has so far been associated with no difference in overall or relapse-free survival. Follow-up of these studies is adequate given the short natural history of metastatic breast cancer, and these results are unlikely to change with longer observation. The design of the reported studies reflects current practice but such treatment may be suboptimal; promising designs such as double/tandem transplants, stem cell purging, immunotherapy, and so forth are worthy of active investigation.
The incorporation of high-dose chemotherapy with stem cell rescue into the treatment of high-risk breast cancer, however, has been much more successful. All studies show a greater than 60% to 70% 3-year relapse-free survival, and this is as good as the results obtained with any other treatment for high-risk breast cancer. The follow-up periods for these studies are not yet long enough to determine benefit in light of the long natural history of high-risk breast cancer. We also need to await mature results of other ongoing trials in high-risk breast cancer for final answers.
We still believe that high-dose therapy and stem cell rescue will ultimately be shown to improve outcome in breast cancer. We agree, however, that up to this point this has not been demonstrated, and use of this modality should be limited to well-designed clinical trials. These studies should be supported by physicians, patients, and third-party payers. The past history of inadequate support for these trials has led to delayed information, to the detriment of us all. That said, we hope and believe that the next generation of therapeutic interventions will be even more effective and make the entire matter of high-dose chemotherapy and stem cell transplant for breast cancer moot.