Intensive dose-dense compared with high-dose adjuvant chemotherapy for high-risk operable breast cancer: Southwest Oncology Group/Intergroup study 9623.

PURPOSE: Southwest Oncology Group (SWOG)/Intergroup study 9623 was undertaken to compare treatment with an anthracycline-based adjuvant chemotherapy regimen followed by high-dose chemotherapy (HDC) with autologous hematopoietic progenitor cell support (AHPCS) with a modern dose-dense dose-escalated (nonstandard) regimen including both an anthracycline and a taxane. PATIENTS AND METHODS: Participants in this phase III randomized study had operable breast cancer involving four or more axillary lymph nodes and had completed mastectomy or breast-conserving surgery. Patients were randomly assigned to receive four cycles of doxorubicin and cyclophosphamide followed by HDC with AHPCS or to receive sequential dose-dense and dose-escalated chemotherapy with doxorubicin, paclitaxel, and cyclophosphamide. The primary end point of this study was disease-free survival (DFS). RESULTS: Among 536 eligible patients, there was no significant difference between the two arms for DFS or overall survival (OS). Estimated five-year DFS was 80% (95% CI, 76% to 85%) for dose-dense therapy and 75% (95% CI, 69% to 80%) for transplantation. Estimated 5-year OS was 88% (95% CI, 84% to 92%) for dose-dense therapy and 84% (95% CI, 79% to 88%) for transplantation. CONCLUSION: There is no evidence that transplantation was superior to dose-dense dose-escalated therapy. Transplantation was associated with an increase in toxicity and a possibly inferior outcome, although the hazard ratios were not significantly different from 1.

Tacrolimus and mycophenolate mofetil after nonmyeloablative matched-sibling donor allogeneic stem-cell transplantations conditioned with fludarabine and low-dose total body irradiation.

We evaluated tacrolimus/mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis after a nonmyeloablative stem cell transplantation (NST) from a matched sibling donor (MSD). Thirty-two patients (median age, 57 years) with advanced hematologic malignancies, who were poor candidates for a conventional myeloablative transplantation, received fludarabine (30 mg/m(2), day -4 to day -2), total-body irradiation (TBI) (200 cGy, day 0), infusion of donor peripheral blood progenitor cells (day 0), oral tacrolimus 0.06 mg/kg twice daily (from day 3), and oral MMF at 15 mg/kg twice daily (days 0-+27). Tacrolimus was tapered from day +100 to day +180 in those patients with indolent malignancies (n = 25), and from day +35 to day +56 in those with aggressive tumors (n = 7). Regimen toxicities and myelosuppression were mild, allowing 75% of patients to have entirely outpatient transplantations. One patient (3%) experienced a nonfatal graft rejection. Rates of grades II-IV and III-IV acute GVHD were 15.6% and 3%, respectively. Acute GVHD was diagnosed at median day +78 (range, days +31-+84). Extensive chronic GVHD was observed in 10 of 24 evaluable patients (41.6%) at a median onset of day +198 (range, days +128-+277), either spontaneously (n = 5) or elicited after tumor progression (n = 5). Five patients experienced transplantation-related mortality (TRM) (15.6%) from either acute GVHD-related multiorgan failure (MOF) (n = 3) or infectious complications (n = 2). At median follow-up of 19 months (range, 2-41 months), the overall survival, progression-free survival, and disease-free survival rates are 62.5%, 50%, and 40%, respectively. In conclusion, the use of tacrolimus/MMF after MSD NST is associated with encouraging rates of GVHD control.

Evaluation of the effect of age on treatment-related mortality and relapse in patients with high-risk primary breast cancer receiving high-dose chemotherapy.

There are contradictory results regarding a potential increased responsiveness of younger women with high-risk primary breast cancer to high-dose compared with standard-dose chemotherapy. Observations from some, but not all, randomized trials, suggest that the potential benefit of high-dose treatment may be limited to younger patients. We analyzed, at median follow-up of 8 years, the prognostic effect of age in 264 patients enrolled in prospective phase II and III trials of high-dose chemotherapy, using a uniform regimen. Median age was 49 (range, 36-71). Among patients < or = 49 and > 49 years of age, the relapse rates were 27% and 25%, respectively (P = 0.7). In those age groups, the transplant-related mortality rates were 6.5% and 4%, respectively (P = 0.8). No age differences were observed between patients surviving transplant (median age 49) and those who experienced transplant-related mortality (median 47.5) (P = 0.9). Event-free survival (P = 0.3) and overall survival (P = 0.4) did not differ between patients < or = 49 and > 49 years of age. In conclusion, we did not detect a detrimental effect of older age on transplant-related mortality or relapse after high-dose chemotherapy for high-risk primary breast cancer at long-term follow-up. The debate about the age effect in this population remains unsettled.

Phase I and pharmacokinetic study of docetaxel combined with melphalan and carboplatin, with autologous hematopoietic progenitor cell support, in patients with advanced refractory malignancies.

The purpose of this study was to define the maximal tolerated dose (MTD), extramedullary toxicities, and pharmacokinetics of docetaxel combined with high-dose melphalan and carboplatin with autologous hematopoietic progenitor cell support. Fifty-nine patients with advanced refractory malignancy (32 breast cancer, 10 non-Hodgkin lymphoma, 6 germ cell tumors, 4 Hodgkin disease, 4 ovarian cancer, 2 sarcoma, and 1 unknown primary adenocarcinoma) with a median of 3 prior chemotherapy regimens and a median of 3 organs involved were enrolled. Treatment included docetaxel (150-550 mg/m2 infused over 2 hours on day -6), melphalan (150-165 mg/m2 infused over 15 minutes from day -5 to -3), and carboplatin (1000-1300 mg/m2 as a 72-hour continuous infusion from day -5). Five patients died from direct regimen-related organ toxicity (2 capillary leak syndrome, 2 enterocolitis, and 1 hepatic toxicity), and 1 additional patient died from pulmonary aspergillosis. The docetaxel MTD was defined as 400 mg/m 2 , combined with melphalan (150 mg/m2 ) and carboplatin (1000 mg/m2 ). The MTD cohort was expanded to enroll a total of 26 patients, 1 of whom died from toxic enterocolitis. The remaining 25 patients presented the following extramedullary toxicity profile, which was manageable and largely reversible: stomatitis, myoarthralgias, peripheral neuropathy, gastrointestinal and cutaneous toxicities, and syndrome of inappropriate antidiuretic hormone secretion. Docetaxel exhibited linear pharmacokinetics in the dose range tested (150-550 mg/m2 ). Pharmacodynamic correlations were noted between the docetaxel area under the curve and peripheral neuropathy or stomatitis. The response rate among 38 patients with measurable disease was 95%, with 47% complete responses. At a median follow-up of 26 months (range, 7-72 months), the 3-year event-free survival and overall survival were 26% and 36%, respectively. In conclusion, a 4-fold dose escalation of docetaxel, combined with melphalan and carboplatin, is feasible with autologous hematopoietic progenitor cell support. The notable activity of this regimen in treatment-refractory patients warrants its further evaluation.

Phase II feasibility and pharmacokinetic study of concurrent administration of trastuzumab and high-dose chemotherapy in advanced HER2+ breast cancer.

PURPOSE: To evaluate the safety of concurrent treatment with trastuzumab and high-dose chemotherapy (HDC), using cyclophosphamide, cisplatin, and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), with autologous hematopoietic progenitor cells support, in patients with HER2+ advanced breast cancer. EXPERIMENTAL DESIGN: Patients with HER2-overexpressing high-risk primary breast cancer (HRPBC; defined as > or =4 involved nodes or inflammatory disease), or metastatic breast cancer (MBC) were eligible. Treatment consisted of a loading dose of trastuzumab at 4 mg/kg (day -5), HDC (days -5 to -2), autologous hematopoietic progenitor cells infusion on day 0, and weekly maintenance trastuzumab (2 mg/kg) from day +1 (minimum of 9 doses). Cardiac monitoring included serial left ventricular ejection fraction measurements before treatment and on days +20 and +65. RESULTS: Thirty-three patients were prospectively enrolled (13 HRPBC, 20 MBC). Toxicity seemed similar to that expected with this HDC regimen alone. Neutrophils and platelets engrafted promptly. There were no cases of grade 4 or 5 toxicity. One patient experienced symptomatic grade 3 acute cardiac failure on day -4, responsive to treatment. Trastuzumab did not alter the pharmacokinetics of HDC. Eleven of twelve MBC patients with measurable disease (nine of them refractory to previous chemotherapy) experienced an objective response (9 complete and 2 partial responses). At median follow-up of 34 (13-58) months, all HRPBC patients remain alive and free of disease; the MBC group has event-free survival and overall survival rates of 45 and 70%, respectively. CONCLUSIONS: Incorporation of trastuzumab into HDC (cyclophosphamide, cisplatin, and BCNU) is feasible, with no apparent increased toxicity or pharmacokinetic interactions.

Prognostic analysis of early lymphocyte recovery in patients with advanced breast cancer receiving high-dose chemotherapy with an autologous hematopoietic progenitor cell transplant.

PURPOSE: The purpose of this study was to evaluate the prognostic effect of early posttransplant lymphocyte recovery in patients with advanced breast cancer receiving high-dose chemotherapy with autologous hematopoietic progenitor cell transplantation. EXPERIMENTAL DESIGN: We analyzed the effect of the absolute lymphocyte count on day +15 posttransplant on freedom from relapse and overall survival in patients with high-risk primary breast cancer or metastatic breast cancer, enrolled between 1990 and 2001 in prospective high-dose chemotherapy trials, using a uniform regimen of cyclophosphamide, cisplatin, and 1,3-bis(2-chloroethyl)-1-nitrosourea. RESULTS: Four hundred and seventy-six patients (264 high-risk primary breast cancer and 212 metastatic breast cancer patients) were evaluated at median follow-up of 8 years (range, 1.5-11 years). The disease-free survival and overall survival rates in the high-risk primary breast cancer group were 67% and 70%, respectively. Patients with metastatic breast cancer patients had 21.8% disease-free survival and 31.5% overall survival rates. Day +15 absolute lymphocyte count correlated with freedom from relapse (P = 0.007) and overall survival (P = 0.04) in the metastatic breast cancer group, but not in the high-risk primary breast cancer group (P = 0.5 and 0.8, respectively). The prognostic effect of absolute lymphocyte count in metastatic breast cancer was restricted to those patients receiving unmanipulated peripheral blood progenitor cells (P = 0.04). In contrast, absolute lymphocyte count had no significant effect in those metastatic breast cancer patients receiving bone marrow or a CD34-selected product. In multivariate analyses, the prognostic effect of day +15 absolute lymphocyte count in metastatic breast cancer was independent of other predictors, such as disease status, pre-high-dose chemotherapy treatment, number of tumor sites, or HER2. CONCLUSIONS: Early lymphocyte recovery is an independent outcome predictor in metastatic breast cancer patients receiving high-dose chemotherapy and an autologous peripheral blood progenitor cell transplant. These observations suggest that immune strategies targeting minimal posttransplant residual disease may prove worthwhile.

Long-term analysis and prospective validation of a prognostic model for patients with high-risk primary breast cancer receiving high-dose chemotherapy.

PURPOSE: We described previously a prognostic model for high-risk primary breast cancer patients receiving high-dose chemotherapy (HDC). Such model included nodal ratio (no. involved nodes:no. dissected nodes), tumor size, hormone receptors, and HER2. In the present study we intended to test this model prospectively in a second patient cohort. In addition, we analyzed the long-term overall outcome of our HDC trials. EXPERIMENTAL DESIGN: We analyzed all 264 patients enrolled since 1990 in our prospective trials for 4-9+, > or = 10+ nodes, or inflammatory disease. Patients of the second cohort (treated since 1997) had their prognostic score estimated prospectively before receiving HDC. RESULTS: Fourteen patients (5.3%) died from HDC-related complications. At median follow-up of 7.1 years, relapse-free survival and overall survival of the whole group were 69.8% and 73%, respectively. Median time to relapse was 14 months (63.5% relapses within the first 2 years, 6.7% after year 5). The model was validated in the second cohort, establishing the following pretransplant risk categories: low risk (low score, HER2-), 44% patients, 87% freedom from relapse (FFR); intermediate risk (low score, HER2+), 29% patients, 68% FFR; and high risk (high score, any HER2), 27% patients, 49% FFR. CONCLUSIONS: Few relapses are seen after year 5 of follow-up, which indicates the need for mature results of the randomized trials before their final interpretation or meta-analysis. Our prospectively validated prognostic model, if additionally confirmed in the randomized trial populations, may provide an insight into the relative benefit of HDC in different risk patient subsets.

Reduced-intensity allogeneic stem cell transplantation.

The aim of reduced-intensity allogeneic stem cell transplantation is to exploit the graft-versus-tumor effect and reduce the toxicity associated with traditional ablative preparative regimens. Reduced-intensity regimens often use a purine analog with chemotherapeutic agents or low-dose total body irradiation. Postgrafting immunosuppression is variable and often consists of cyclosporine or tacrolimus plus methotrexate or mycophenolate mofetil. Regimen-related toxicity may be reduced using this approach, with a reduction in early mortality. Acute and chronic graft-versus-host disease continue to be problematic and are the primary causes of treatment-related mortality. The degree of myelosuppression is dependent on the regimen and the postgrafting immunosuppression. Myelosuppression is modest after 200 cGy of total body irradiation (with or without fludarabine), but it is more significant after regimens that use a purine analog with robust doses of chemotherapy. Stable mixed or full donor chimerism occurs with most regimens and graft rejection is more common in recipients of unrelated grafts. Reduced-intensity regimens are active in most hematologic malignancies and in some solid tumors, although the data in solid tumors are limited. Data suggest that rapidly growing malignancies require a more intensive regimen than indolent malignancies or those in remission. Reduced-intensity approaches have an appeal for nonmalignant diseases treated by allotransplantation. No prospective randomized trials have compared reduced-intensity approaches with conventional allotransplant preparation or postgrafting immunosuppression after reduced-intensity allografting. However, the strategy holds great promise and offers the possibility of curative therapy for patients who are ineligible for an ablative transplant.

Dose-intense chemotherapy every 2 weeks with dose-intense cyclophosphamide, doxorubicin, vincristine, and prednisone may improve survival in intermediate- and high-grade lymphoma: a phase II study of the Southwest Oncology Group (SWOG 9349).

PURPOSE: To test the hypothesis that therapy of intermediate- and high-grade (excluding Burkitt lymphoblastic) lymphoma with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) could be safely dose-intensified with routine filgrastim support. PATIENTS AND METHODS: Eligible patients were those who were previously untreated and who had either bulky stage II, or stage III or IV lymphoma with working formulation histology D, E, F, G, H, or J; performance status < or = 2; and acceptable end organ function. No upper age limit was specified. Therapy was dose-intensified CHOP (CHOP-DI) with filgrastim support. Each course was repeated every 14 days for six planned courses. RESULTS: Eighty-eight eligible patients were treated with CHOP-DI and had a median follow-up of 5.1 years on this phase II study, designated Southwest Oncology Group (SWOG) 9349. The progression-free survival was 51% at 2 years and 41% at 5 years. The overall survival was 60% at 5 years. Three fatal treatment-related events occurred. One patient with myelodysplastic syndrome was reported. CONCLUSION: Treatment with CHOP-DI can be safely administered in the cooperative group setting and results in improved survival. Estimated overall survival at 5 years was 14% better than that of patients treated with standard-dose CHOP in an earlier SWOG study, although progression-free survival of 60% at 2 years-the prespecified end point-was not achieved. CHOP-DI, given every 2 weeks at escalated doses, is a strategy that should be tested in a future randomized clinical trial in lymphoma.

Multi-institutional use of defibrotide in 88 patients after stem cell transplantation with severe veno-occlusive disease and multisystem organ failure: response without significant toxicity in a high-risk population and factors predictive of outcome.

Veno-occlusive disease (VOD) is the most common regimen-related toxicity accompanying stem cell transplantation (SCT). Severe VOD complicated by multisystem organ failure (MOF) remains almost uniformly fatal. Preliminary experience with defibrotide (DF), a single-stranded polydeoxyribonucleotide with fibrinolytic, antithrombotic, and anti-ischemic properties, in the treatment for severe VOD has suggested safety and activity. Eighty-eight patients who developed severe VOD after SCT were treated with DF under a defined treatment plan. At diagnosis, median bilirubin was 76.95 microM (4.5 mg/dL), median weight gain was 7%, ascites was present in 84%, and abnormal hepatic portal venous flow was present in 35%. At DF initiation, median bilirubin had increased to 215.46 microM (12.6 mg/dL), and MOF was present in 97%. DF was administered intravenously in doses ranging from 5 to 60 mg/kg per day for a median of 15 days. No severe hemorrhage or other serious toxicity related to DF was reported. Complete resolution of VOD was seen in 36%, with 35% survival at day +100. Predictors of survival included younger age, autologous SCT, and abnormal portal flow, whereas busulfan-based conditioning and encephalopathy predicted worse outcome. Decreases in mean creatinine and plasminogen activator inhibitor 1(PAI-1) levels during DF therapy predicted better survival. The complete response rate, survival to day +100, and absence of significant DF-associated toxicity in this largest patient cohort reported to date confirm the results of earlier studies. Certain features associated with successful outcome may correlate with DF-related treatment effects, and prospective evaluation of DF therapy for severe VOD should allow better definition of predictors of response or failure.

Transplantation of ex vivo expanded cord blood.

Umbilical cord blood (CB) from unrelated donors is increasingly used to restore hematopoiesis after myeloablative therapy. CB transplants are associated with higher rates of delayed and failed engraftment than are bone marrow transplants, particularly for adult patients. We studied the ex vivo expansion of CB in an attempt to improve time to engraftment and reduce the graft failure rate in the recipients. In this feasibility study, 37 patients (25 adults, 12 children) with hematologic malignancies (n = 34) or breast cancer (n = 3) received high-dose therapy followed by unrelated allogeneic CB transplantation. A fraction of each patient's CB allograft was CD34-selected and cultured ex vivo for 10 days prior to transplantation in defined media with stem cell factor, granulocyte colony-stimulating factor, and megakaryocyte growth and differentiation factor. The remainder of the CB graft was infused without further manipulation. Two sequential cohorts of patients were accrued to the study. The first cohort had 40% and the second cohort had 60% of their CB graft expanded. Patients received a median of 0.99 x 10(7) total nucleated cells (expanded plus unexpanded) per kilogram. The median time to engraftment of neutrophils was 28 days (range, 15-49 days) and of platelets was 106 days (range, 38-345 days). All evaluable patients who were followed for 28 days or longer achieved engraftment of neutrophils. Grade III/IV acute GVHD was documented in 40% and extensive chronic GVHD in 63% of patients. At a median follow-up of 30 months, 13 (35%) of 37 of patients survived. This study demonstrates that the CD34 selection and ex vivo expansion of CB prior to transplantation of CB is feasible. Additional accrual will be required to assess the clinical efficacy of expanded CB progenitors.

Renal dysfunction in allogeneic hematopoietic cell transplantation.

BACKGROUND: Allogeneic hematopoietic cell transplantation (HCT), formerly called bone marrow transplantation, can potentially cure various malignant and non-malignant diseases, but it is associated with a high risk of toxicity. We have previously shown an overall 21% incidence of severe acute renal failure in patients undergoing autologous HCT. The present study evaluated renal dysfunction in patients undergoing allogeneic HCT. METHODS: The clinical course of 88 adult patients who received allogeneic HCT at the University of Colorado Health Science Center was analyzed. Renal dysfunction was classified as follows: Grade 0 = normal renal function; Grade 1 =>25% decrement in GFR but twofold increase in serum creatinine; Grade 3 =>twofold increase in serum creatinine and need for dialysis. RESULTS: Of the 88 patients, 81 (92%) patients had some degree of renal dysfunction (Grade 1, 20 patients; Grade 2, 32 patients; Grade 3, 29 patients). Severe nephrotoxicity (Grade 2 and Grade 3 renal dysfunction) was associated with significantly higher frequencies of sepsis, hepatic toxicity and hepatic veno-occlusive disease (VOD), and lung toxicity. The overall mortality rate at the end of 6 months was 58%. Grade 3 renal dysfunction was associated with a significantly increased risk of mortality (82.6%). CONCLUSION: A 92% incidence of renal dysfunction in allogeneic HCT patients was found. Lung and liver toxicities were significantly correlated with developing renal dysfunction, and the mortality rates for patients with Grade 3 renal failure exceeded 80%.

Prognostic model for relapse after high-dose chemotherapy with autologous stem-cell transplantation for stage IV oligometastatic breast cancer.

PURPOSE: To study prognostic factors after high-dose chemotherapy (HDC) for patients with stage IV oligometastatic breast cancer. PATIENTS AND METHODS: Sixty patients with minimal metastatic disease amenable to local therapy enrolled onto a prospective HDC trial were analyzed for potential prognostic factors. Tumor blocks were retrospectively collected from referring institutions. RESULTS: Median follow-up was 62 months (range, 4 to 120 months). Median relapse-free survival (RFS) and overall survival (OS) times were 52 and 80 months, respectively. Five-year RFS and OS rates were 52% (95% confidence interval [CI], 39% to 64%) and 62% (95% CI, 49% to 74%), respectively. HER-2 expression, number of tumor sites, primary axillary nodal ratio (number of positive nodes divided by number of sampled nodes), number of positive axillary nodes, and delivery or omission of radiotherapy to metastases correlated with RFS. HER-2 overexpression and more than one site were independent adverse risk factors for RFS. HER-2 and the axillary nodal ratio were independent predictors of OS. The following prognostic categories for RFS were established (RFS rate, median RFS): good risk, no factors (77%, 80 months); intermediate risk, one factor (41%, 28 months); and poor risk, both factors (10%, 10 months). CONCLUSION: Long-term results in patients with oligometastatic breast cancer are encouraging but need validation in prospective randomized studies. HER-2 expression, number of sites, and primary nodal ratio are independent outcome predictors. Confirmation of these observations in this selected population would imply the need for reevaluation of the current tenet that early detection of metastatic breast cancer recurrence is of no benefit.