Study Raises Questions on Transplant Timing

June 1, 1996

ASCO--Immediate high-dose consolidation chemotherapy supported by transplant significantly improved disease-free survival in metastatic breast cancer patients who were in complete remission after induction therapy.

ASCO--Immediate high-dose consolidation chemotherapy supportedby transplant significantly improved disease-free survival inmetastatic breast cancer patients who were in complete remissionafter induction therapy.

However, overall survival was significantly better in the completeresponders who received transplant only at the time of relapse,suggesting that the timing of transplant in these patients maybe important, William P. Peters, MD, PhD, said at an ASCO scientificsession.

The results represent an 8-year effort by a group at Duke Universityled by Dr. Peters who is now chief and CEO of the Karmanos CancerInstitute, Detroit.

This trial enrolled 423 patients with hormone-insensitive metastaticbreast cancer who were treated with up to four cycles of an intensivedoxorubicin-based regimen. Patients who achieved complete remissionwere randomized to immediate consolidation with high-dose cyclophosphamide/platinum/carmustineand transplant or to observation. Patients in the observationarm who relapsed were given the same high-dose regimen with transplant.Partial responders were treated with immediate transplant.

The patients tended to be young, with a median age of 42 years.No prior chemotherapy for metastatic disease was allowed, althoughadjuvant chemotherapy was permitted. Patients could have no morethan three involved sites on bone scan.

Dr. Peters noted that the data are mature, with a median follow-upof 4.7 years for the complete remission patients and 3.5 yearsfor the partial responders.

Of the 105 patients who achieved a complete remission, seven werenot randomized, in four cases because the insurance company refusedto pay, he said.

Relapse-free survival was significantly longer in patients receivingimmediate transplant: 14 months vs 4 months for observation, with22% alive and disease free at 5 years vs 8% for observation.

However, median overall survival for the patients randomized tothe delayed transplant strategy was 3.6 years vs 2.3 years forthe immediate transplant group; 45% of the delayed transplantpatients are alive at 5 years vs 20% in the immediate transplantgroup. Overall survival among the transplanted partial responderswas similar to that of the immediate transplant complete responders.

"This result is at first counterintui-tive," Dr. Peterssaid, offering three possible explanations:

1. Intensive induction therapy may produce immediate resistancethat re-verses at a later date.

2. Immediate transplant might be more immunosuppressive or producemore prolonged adverse effects.

3. The high-dose regimen achieves similar tumor cell kill regardlessof the timing, and the observed result is the effect of addingthe conventional-dose remission time and the transplant time.

Dr. Peter's group at Detroit is now undertaking a trial in whichpatients will receive doxorubicin/paclitaxel-based induction therapywith transplant at different schedules: a fixed interval to transplantafter induction; induction alone with transplant at relapse; andtransplant first followed by induction at relapse.

The discussant, Larry Norton, MD, of Memorial Sloan-Kettering,hypothesized that a single cycle of cytotoxic chemotherapy canreduce the number of tumor cells to a base level but no lower."Then it doesn't make all that much difference where youstart," Dr. Norton said.

The fact that the partial responders did as well as the completeresponders indicates that high-dose therapy brings the tumor cellcount down to the same base level in both situations, he said.

Dr. Norton suggested that trials should now be performed attemptingto eradicate the remaining cancer cell population after high-dosetherapy by the addition of biologically based therapies.