Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer.

PURPOSE: Brain metastases develop in one third of patients with advanced HER2+ breast cancer. Effective therapy for patients with central nervous system (CNS) progression after cranial radiation is extremely limited and represents a major clinical challenge. Lapatinib, an epidermal growth factor receptor/HER2 inhibitor, was associated with regressions of CNS lesions in a small phase 2 trial. The current study was done to further evaluate the CNS activity of lapatinib. The study was later amended to allow patients who progressed on lapatinib the option of receiving lapatinib plus capecitabine. EXPERIMENTAL DESIGN: Eligible patients had HER2+ breast cancer, progressive brain metastases, prior trastuzumab, and cranial radiotherapy. The primary end point was CNS objective response, defined as >or=50% volumetric reduction of CNS lesion(s) in the absence of increasing steroid use, progressive neurologic signs and symptoms, or progressive extra-CNS disease. RESULTS: Two-hundred and forty-two patients entered the study. CNS objective responses to lapatinib were observed in 6% of patients. In an exploratory analysis, 21% of patients experienced a >or=20% volumetric reduction in their CNS lesions. An association was observed between volumetric reduction and improvement in progression-free survival and neurologic signs and symptoms. Of the 50 evaluable patients who entered the lapatinib plus capecitabine extension, 20% experienced a CNS objective response and 40% experienced a >or=20% volumetric reduction in their CNS lesions. CONCLUSIONS: This study confirms the modest CNS antitumor activity of lapatinib. Additional responses were observed with the combination of lapatinib and capecitabine. Further studies of lapatinib-based regimens for CNS metastases from HER2+ breast cancer are warranted.

Phase III study comparing oral topotecan to intravenous docetaxel in patients with pretreated advanced non-small-cell lung cancer.

PURPOSE: This open-label, randomized, multicenter, phase III study compared oral topotecan versus intravenous (IV) docetaxel in patients with previously treated non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage III or IV NSCLC, performance status < or = 2, who had received only one prior chemotherapy regimen, were randomly assigned to treatment with oral topotecan 2.3 mg/m2/d on days 1 to 5 or IV docetaxel 75 mg/m2 day 1 every 21 days. RESULTS: A total of 829 patients were randomly assigned. In intent-to-treat analysis, 1-year survival rates were 25.1% with topotecan and 28.7% with docetaxel. The difference of -3.6% (95% CI, -9.59% to 2.48%) met the predefined criteria for noninferiority of topotecan relative to docetaxel because the lower limit of the 95% CI was above -10%. Median survival was 27.9 weeks with topotecan and 30.7 weeks with docetaxel. Although not statistically significant (log-rank P = .057), the higher survival rate with docetaxel was maintained across the entire treatment period. The median time to progression was 11.3 weeks with topotecan versus 13.1 weeks with docetaxel (log-rank P = .02). The overall response rate was 5% in each group. Grade 3/4 neutropenia occurred more frequently with docetaxel (60% v 50%). Grade 3/4 anemia and thrombocytopenia occurred more frequently with topotecan (26% v 10% and 26% v 7%, respectively). CONCLUSION: Oral topotecan provides activity in the treatment of relapsed, locally advanced, unresectable NSCLC. Both regimens were well tolerated with differing safety profiles. Topotecan may provide an option for patients who desire an orally available treatment after relapse.

Unrelated donor marrow transplantation for myelodysplastic syndromes: outcome analysis in 510 transplants facilitated by the National Marrow Donor Program.

Between April 1988 and July 1998, 510 patients with myelodysplastic syndromes (MDS) underwent unrelated donor bone marrow transplantation (BMT) facilitated by the National Marrow Donor Program. Median age was 38 years (range, <1-62 years). Several conditioning regimens and graft-versus-host disease (GVHD) prophylaxis methods were used, and T-cell depletion was used in 121 patients. Donors were serologically matched for HLA-A, -B, and -DRB1 antigens for 74% of patients. Of 437 patients evaluable for engraftment, 24 (5% cumulative incidence, with 95% confidence interval [CI] of 3%-7%) failed to engraft, and an additional 33 (8% cumulative incidence; 95% CI, 6%-10%) had late graft failure. Grades II to IV GVHD developed in 47% of patients (95% CI, 43%-49%), and limited and extensive chronic GVHD developed at 2 years in 27% (95% CI, 24%-30%). The incidence of relapse at 2 years was 14% (95% CI, 11%-17%). Greater relapse was independently associated with advanced MDS subtype and no acute GVHD. The estimated probability of disease-free survival (DFS) at 2 years was 29% (95% CI, 25%-33%). Improved DFS was independently associated with less advanced MDS subtype, higher cell dose, recipient cytomegalovirus (CMV) seronegativity, shorter interval from diagnosis to transplantation, and transplantation in recent years. Common causes of death were treatment-related complications accounting for 82% of fatalities. The 2-year cumulative incidence of treatment-related mortality (TRM) was 54% (95% CI, 53%-61%). Sixty-nine percent of TRM occurred within the first 100 days, and 93% occurred within the first year of transplantation. Higher TRM was independently associated with older recipient and donor age, HLA mismatch, and recipient CMV seropositivity. This study demonstrates that unrelated donor BMT cures a significant proportion of patients with MDS. TRM is the major problem limiting the success of unrelated donor BMT in MDS. The observations made in this study should facilitate the design of prospective trials aimed at improving the results of unrelated donor stem cell transplantation for MDS.

Racial and ethnic composition of volunteer cord blood donors: comparison with volunteer unrelated marrow donors.

BACKGROUND: Umbilical cord blood is an alternative peripheral blood progenitor cell source for patients who need transplantation. A presumed advantage of cord blood is the ability to increase minority recruitment. STUDY DESIGN AND METHODS: The racial composition of five member cord blood banks of the National Marrow Donor Program (NMDP) was compared, representing 9020 cord blood donors with NMDP marrow donors from comparable geographic areas, representing 417,676 donors. Cord blood and marrow donors self-reported racial designations on questionnaires. Donor statistics were compared with baseline racial data of deliveries from participating hospitals for cord blood donors and with geographic census data for marrow donors. RESULTS: The California, Florida, and Massachusetts cord blood banks recruited a lower percentage of minorities than the corresponding marrow donor centers. In New York and Colorado, minority recruitment was equivalent. In California, Florida, Massachusetts, and New York, the cord blood banks recruited a lower percentage of minorities than those delivering at the respective hospitals. The cord blood banks in California, Colorado, Florida, and Massachusetts recruited a lower percentage of minorities compared with delivery data than the corresponding marrow donor centers compared with census population (p < 0.001). In New York, the percentages were similar. CONCLUSION: The problem of insufficient minority recruitment of cord blood has not yet been solved. Better strategies are needed to recruit minority donors.

Autologous versus allogeneic unrelated donor transplantation for acute lymphoblastic leukemia: comparative toxicity and outcomes.

For patients with high-risk or relapsed acute lymphoblastic leukemia (ALL) lacking a related histocompatible donor, autologous (Auto) and unrelated donor (URD) transplantation are available options. We compared outcomes and toxicities in 712 patients with ALL (517 URD, 195 Auto) in first complete remission (CR1) or second complete remission (CR2) who underwent transplantation. All patients were <50 years old, although URD patientswere younger (median age, 14 versus 18 years, P < .002). The proportion of patients in CR1 versus CR2 was similar (36% versus 38%, P = .57), but more URD recipients than Auto recipients had high-risk karyotypes (25% versus 13%, P = .003) and white blood cell (WBC) counts > or =50 x 10(9)/L (33% versus 14%, P < .001). Engraftment was similar in URD and Auto recipients. Ex vivo purging delayed but did not prevent engraftment after Auto transplantation. Transplantation-related mortality was higher after URD transplantation (42%+/-8%) than after Auto transplantation (20%+/-12%) in CR1 (P = .004) and also in CR2. Conversely, relapse was more frequent after Auto transplantation in CR1 (Auto, 49%+/-12% versus URD, 14%+/-5%) and CR2 (64%+/-8% versus 25%+/-5%) (P < .0001). These findings showed net similar outcomes for these 2 transplantation choices. Transplantation in CR1 yielded similar 3-year survival rates for URD (51%+/-7%) and Auto (44%+/-12%), as did transplantation in CR2 (40%+/-6% versus 32%+/-9%, respectively). Multivariate regression analysis identified significantly better disease-free survival after the first 6 months in matched URD versus Auto in younger patients, in those in CR2 with CR1 >1year, WBC <50 x 10(9)/L, performance status > or =90%, and in those who have undergone transplantation since 1995. These comparative data suggest that both matched URD and Auto transplantation can yield extended survival. Although URD transplantation offers substantially better protection against leukemic relapse, improvements in allotransplantation safety and refinements in patient selection are required to better aid treatment decision making for the best overall survival.