Smaller, uncontroll trials of high-...

Smaller, uncontroll trials of high-dose adjuvant chemotherapy with autologous stem-cell redeem for node-positive breast cancer have produc inconsistent outcomes Rodenhuis and colleagues report forward the results of a large, prospective, controll multicenter trial of aggressive "transplant" treatment in women with locally metastatic breast cancer.

The research originally enrolled fewer than 300 patients moreover was expanded to a total of 885 patients when a preliminary analysis did not reveal a large enough statistical consequence difference between the transplant and the standard treatment clusters The trial enrolled women younger than 56 years who had undergone surgery for breast cancer that revealed at least four axillary lymph nodes with metastases unless no distant metastases. Chest radiography, bone scanning, liver sonography, and magnetic resonance imaging were used to reject persons with widely metastatic disease. Additional exclusion criteria included renal insufficiency (creatinine clearance rate of les than 60 mL by minute [1.0 mL per second]) hepatic insufficiency (serum bilirubin even greater than 1.46 mg through dL [24.96 [micro]mol per L]) or evidence of possible marrow disease (white children cell count less than 4000 by means of [mm.sup.3] [4.0 3 [10.sup.9] for L], platelet count less than 100000 through [mm.sup.3]).

Trial participants were randomized to receive standard chemotherapy with fluorouracil (500 mg by [m.sup.2] of body surface), epirubicin (90 mg by [m.sup.2]), and cyclophosphamide (500 mg by [m.sup.2]) every three weeks for five revolution of times Patients assigned to autologous, stem-cell transplant had four round of yearss of the same treatment, with peripheral vital fluid harvest of stem cells after the third round of years and a final high-dose round of years of cyclophosphamide (6 g by [m.sup.2]), thiotepa (480 mg by [m.sup.2]), and carboplatin (1,600 mg through [m.sup.2]). Of the 442 patients randomized to the high-dose clump 45 persons did not suffer high-dose treatment because of declined agreement medical complications, or other reasons. All patients with hormone-receptor-positive tumors received tamoxifen for three years after treatment. The median duration of follow-up after treatment was four and three fourths years.

Using an intent-to-treat analysis that included all randomized patients whether or not they complet their assigned therapy, there was no significant overall survival advantage to transplant therapy. The subgroup of women with 10 or more positive nodes did have significantly longer relapse-free survival at the [i]finale[/i] of follow-up (61 percent) than those receiving standard treatment (51 percent) Women with four to nine positive nodes and those whose tumors were positive for HER2/neu gene amplification (30 percent of cases) did not benefit in bourns of long-term survival from transplant.

High-dose therapy could not be complet in six patients because of complications (high flush cardiac arrhythmia, and possible heart failure), and four patients died because of adverse events Secondary cancers developed more many times during follow-up in patients who received high-dose chemotherapy (21 patients; 48 percent) than among those receiving standard treatment (15 patients; 34 percent)

The authors end that high-dose chemotherapy with stem-cell liberation increases relapse-free survival after five years of follow-up by means of 10 percent but does not improve overall survival. The improved relapse-free survival is limited to women with 10 or more positive nodes and HER2/neu-negative tumors.

Rodenhuis s et al. High-dose chemotherapy with hematopoietic stem-cell liberate for high-risk breast cancer. N Engl J M July 3 2003;349:7-16

EDITOR'S NOTE: A similar investigation (1) of high-dose chemotherapy and stem-cell liberate is reported in the same issue. This trial, by dint of Tallman and associates, involved 417 patients and raise no significant difference in relapse-free survival with transplant treatment. The high-dose treatment was lethal in 46 percent of cases, and secondary cancers were more usual among transplant patients (7.6 percent) than among those receiving standard chemotherapy (35 percent)

An accompanying editorial on Elfenbein (2) notes that relapse-free survival may be the better yardstick by the agency of which to measure treatment efficacy in these studies. Overall survival, the usual "gold standard," includes many nonrandomized, post-treatment "salvage" measures that affect ultimate survival, and time-to-relapse alone does not take into account patients who died early onward because of adverse effects of treatment. Whether the 10 percent advantage in relapse-free survival after five years (demonstrated in and nothing else one trial) is worth the 09 to 46 percent risk of death with transplant and a higher rate of secondary tumors is a tough call for women with high-risk breast cancer.

REFERENCES

(1) Tallman M et al. Conventional adjuvant chemotherapy with or without high-dose chemotherapy and autologous stem-cell transplantation in high-risk breast cancer. N Engl J M 2003;349:17-26