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Background: The value of nephrectomy in metastatic renal-cell cancer has long been debated. Several nonrandomized studies suggest a higher rate of response to systemic therapy and longer survival in patients who have undergone nephrectomy.Methods: We randomly assigned patients with metastatic renal-cell cancer who were acceptable candidates for nephrectomy to undergo radical nephrectomy followed by therapy with interferon alfa-2b or to receive interferon alfa-2b therapy alone. The primary end point was survival, and the secondary end point was a response of the tumor to treatment.Results: The median survival of 120 eligible patients assigned to surgery followed by interferon was 11.1 months, and among the 121 eligible patients assigned to interferon alone it was 8.1 months (P=0.05). The difference in median survival between the two groups was independent of performance status, metastatic site, and the presence or absence of a measurable metastatic lesion.Conclusions: Nephrectomy followed by interferon therapy results in longer survival among patients with metastatic renal-cell cancer than does interferon therapy alone. [ABSTRACT FROM AUTHOR]

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.

We report outcomes in advanced lymphoma patients (n = 32) who enrolled in a trial of prospectively planned combined autologous/reduced-intensity transplantation (RIT) (n = 25) or who received RIT shortly after prior autografting because of high relapse risk or progressive disease (n = 7). Nine patients on the autologous/RIT transplant protocol did not proceed to planned RIT because of patient choice (n = 4), disease progression (n = 3), toxicity (n = 1), or no adequate donor (n = 1). Among the 23 other patients, RIT was started a median of 59 days (range 31-123) after autologous transplant. Fifteen patients had related donors, five patients had unrelated donors, and three patients had cord blood donors. Among all patients completing RIT, the median overall survival time was 385 days (95% CI 272-792), and the median relapse-free survival time was 157 days (95% CI 119-385). At the time of reporting, six patients (26%) remain alive and three patients (13%) remain alive without relapse. The 100-day transplant-related mortality (TRM) was 9% among all patients and was 0% among matched sibling donors. Overall TRM was 43%. Tandem transplant is feasible in advanced lymphoma with low early TRM. However, practical challenges associated with the strategy were significant and high levels of late TRM due to graft-versus-host disease and infections suggest that modifications of the procedure will be needed to improve outcomes and patient retention.

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.

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.

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.

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.

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.

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.

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.

Congenital sideroblastic anemia (CSA) is a dyserythropoietic disorder that leads to transfusion dependency and subsequent iron overload. Nonmyeloablative allogeneic hematopoietic stem cell transplantation (NST) was performed for a patient with CSA, who had contraindications to conventional allografting. Conditioning was fludarabine, low-dose total body irradiation and antithymocyte globulin, followed by peripheral blood stem cell transplant. Cyclosporine and mycophenolate mofetil were used for graft-versus-host disease prophylaxis. Complete donor chimerism was observed day +131. Early after transplant, the patient became transfusion independent, allowing a regular phlebotomy program. On day +190, refractory lactic acidosis followed by fatal cardiovascular collapse developed, without evidence of infection. Data from this case demonstrates that NST may correct the erythropoietic defect of CSA.

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.

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%.

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.

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.

Ex vivo expanded peripheral blood progenitor cells (PBPCs) have been proposed as a source of hematopoietic support to decrease or eliminate the period of neutropenia after high-dose chemotherapy. CD34 cells were selected from rhG-CSF mobilized PBPCs from patients with breast cancer and were cultured for 10 days in defined media containing 100 ng/mL each of rhSCF, rhG-CSF, and PEG-rhMGDF in 1 L Teflon bags at 20 000 cells/mL. After culture the cells were washed and reinfused on day 0 of transplantation. On day +1, cohort 1 patients (n = 10) also received an unexpanded CD34-selected PBPC product. These patients engrafted neutrophils (absolute neutrophil count, >500/microL) in a median of 6 (range, 5-14) days. Cohort 2 patients (n = 11), who received expanded PBPCs only, engrafted neutrophils in a median of 8 (range, 4-16) days. In comparison, the median time to neutrophil engraftment in a historical control group of patients (n = 100) was 9 days (range, 7-30 days). All surviving patients are now past the 15-month posttransplantation stage with no evidence of late graft failure. The total number of nucleated cells harvested after expansion culture was shown to be the best predictor of time to neutrophil engraftment, with all patients receiving more than 4 x 10(7) cells/kg, engrafting neutrophils by day 8. No significant effect on platelet recovery was observed in any patient. These data demonstrate that PBPCs expanded under the conditions defined can shorten the time to engraftment of neutrophils compared with historical controls and that the rate of engraftment is related to the dose of expanded cells transplanted.

Purpose: To ascertain the predictive value of Her-2/neu overexpression and p53 mutations, assessed by immunohistochemistry, in high-risk primary breast cancer (HRPBC) treated with high-dose chemotherapy (HDCT)., Patients and Methods: We obtained paraffin-embedded tumor blocks from 146 HRPBC patients previously enrolled at our program onto clinical trials of HDCT for four to nine involved axillary lymph nodes, > or = 10 involved axillary nodes, or inflammatory carcinoma. All patients received the same HDCT regimen, with cyclophosphamide, cisplatin, and carmustine (STAMP-I), followed by autologous stem-cell transplantation. Median follow-up was 42 months (range, 5 to 90 months). The same pathologist, blinded to clinical outcome, reviewed all immunostained slides., Results: Positive results for Her-2/neu and p53 were found in 44.5% and 34% of the patients, respectively. Positivity for Her-2/neu was significantly associated with increased risk of relapse and death. No correlation was found between p53 mutations and relapse-free survival (RFS) or overall survival (OS). Multivariate analyses included Her-2/neu overexpression and the following variables previously identified as independent predictors of outcome in this population: tumor size, nodal ratio (number of involved nodes/number of dissected nodes), and hormone receptor status. All four variables had independent value., Conclusion: Her-2/neu overexpression is an independent negative predictor of RFS and OS in HRPBC treated with HDCT. Its inclusion in our previously described predictive model increases the predictive capacity of this model for the low-risk subgroup. In contrast, p53 mutations lack predictive value in this setting.

The success of high-dose cytoreductive strategies depends not only on antitumor activity but also on the tolerability of treatment. Although advances in supportive care have significantly reduced mortality due to infection and hemorrhage, regimen-related toxicities remain problematic. Hepatic veno-occlusive disease (VOD) is the most serious regimen-related toxicity after high-dose cytoreductive therapy. Risk factors for VOD are well established, but the biology of the syndrome remains poorly understood. Unfortunately, no pharmacologic approaches that clearly prevent or treat VOD have been identified. A better understanding of the pathogenesis of VOD will lead to more effective prevention and treatment strategies.

The purpose of this review is to analyze the current status of high-dose chemotherapy (HDCT) with autologous stem cell transplantation for patients with breast cancer. Current results from the major prospective phase 2 and phase 3 trials in metastatic breast cancer (MBC) and high-risk primary breast cancer (HRPBC) are reviewed. Prognostic factors and future research directions are also discussed. The encouraging results of phase 2 trials suggested a benefit for HDCT in HRPBC and some categories of patients with MBC. Some investigators have argued that patient selection might have been a critical factor in those studies. Recently reported randomized trials in patients with chemosensitive MBC have included only small numbers of patients in complete remission and thus have not adequately addressed the relative value of HDCT versus maintenance standard-dose chemotherapy in this patient subset. Although initial results of 2 studies have been reported, most randomized phase 3 studies of HDCT in HRPBC require longer follow-up before definitive conclusions can be made about its efficacy in this setting. We conclude that the role of HDCT for HRPBC or MBC patients has not yet been fully defined. Longer follow-up of the ongoing randomized trials is necessary, and their mature results will help clarify this important question. In the meantime, it is imperative that research continues, to enhance the efficacy of the procedure. This may come through incorporating more active drugs into HDCT regimens and combining HDCT with novel strategies aimed at eradication of posttransplantation minimal residual disease.

We retrospectively evaluated 443 breast cancer patients treated with high-dose cyclophosphamide, cisplatin, and BCNU (STAMP-I) with autologous stem cell support to characterize the cardiac toxicity of this regimen. Patients had stage II-III (n = 243) or stage IV (n = 200) breast cancer. We observed an overall 5.1% incidence of cardiac complications, both clinical and subclinical, in the whole group: 4.9% in stage II-III and 5.5% in stage IV patients. Clinical cardiomyopathy (CMP) was observed in 1.6% of stage II-III patients (1 case of fatal grade 5 toxicity and 3 cases of grade 3 CMP) and in 3.5% of patients with stage IV disease (1 case of grade 4 and 6 cases of grade 3). The incidence of cardiac toxicity did not differ significantly between the groups. Prior radiation therapy to the mediastinum or left chest wall (P = .001) and advanced age (P = .01) were independent predictors of an increased risk of the appearance of this complication. No pharmacodynamic correlation was observed between any of the 3 drugs and cardiac toxicity.

High-dose chemotherapy (HDCT) is currently under evaluation for high-risk primary breast cancer (HRPBC), defined by extensive axillary nodal involvement or inflammatory breast carcinoma. Phase II studies of HDCT for HRPBC show that 30-40% of patients eventually relapse. We retrospectively reviewed 176 patients enrolled in clinical trials of HDCT for HRPBC at the University of Colorado and analyzed 23 potential predictive variables for relapse. All of the patients received the same regimen, with cyclophosphamide, cisplatin, and BCNU. Nine patients who experienced a toxic death were excluded from this analysis. The resulting predictive model was subsequently tested in an independent patient set treated at Duke University with the same HDCT regimen. Nodal ratio (number of involved nodes:number of sampled nodes), tumor size, grade, stage, estrogen receptor, progesterone receptor, and clinical inflammatory breast carcinoma correlated with risk of relapse. Nodal ratio, tumor size, and the combined estrogen receptor/progesterone receptor status were independent predictors. A scoring system using those three variables determines the risk of relapse, with a sensitivity and specificity of 60 and 90%, respectively, and a positive and negative predictive value of 65 and 88%, respectively. The differences in relapse-free survival and overall survival between high- and low-score patients were highly significant (P<0.000001). This model was subsequently validated in the Duke patient set. This model can identify two subgroups of HRPBC patients with low (12%) and high (65%) risk for recurrence after HDCT. Future research that tests new therapies will focus on those patients with a high score.

The purpose of this study was to assess the efficacy of high-dose chemotherapy (HDC) with autologous stem cell transplant in stage IV breast cancer patients with minimal metastases. Eligible patients had (a) disease that could be resected en bloc and/or irradiated with curative intent using a single field and could, thus, be rendered as having no evidence of disease (NED); and/or (b) <5% bone marrow involvement. From September 1991 to August 1997, 40 consecutive patients were prospectively entered on the study. Pre-HDC local treatment consisted of surgery (n = 31) and radiotherapy (XRT; n = 3). All patients received HDC with cyclophosphamide, cisplatin, and 1,3-bis(2-chloroethyl)-1-nitrosourea and autologous stem cell transplant, with or without CD34 selection. Following HDC, 22 patients received XRT. Four patients died of treatment-related complications. Eighteen patients developed grade 3 nonhematological toxicities (15 lung, 2 cardiomyopathy, and 1 optic neuritis), which resolved with therapy. Within a median follow-up of 49 (15-91) months, 14 patients had relapsed. Twenty-five patients (62.5%) were alive, and 22 patients (55%) were alive and free of disease. Median event-free and overall survivals were 43 and 77 months, respectively. In the subset of patients with one metastatic site, 17 of 24 (68%) remained relapse free. Grade 2 tumors, a single metastatic site, and delivery of XRT were favorable predictors of relapse-free survival in univariate but not multivariate analyses. Inclusion of HDC, as described, in the multimodal treatment of stage IV breast cancer patients with minimal metastases is promising. These results warrant prospective randomized trials with a HDC-containing arm in this patient population.

Our objective was to assess whether the total area under the curve (AUC) of high-dose cyclophosphamide (CPA), combined with cisplatin and 1,3-bis(2-chloroethyl)-1-nitrosourea, could be predicted from its AUC on the first day of treatment. We reviewed the AUC of CPA in 470 patients who underwent pharmacokinetic monitoring of the drug. All patients received the same high-dose regimen of CPA, cisplatin, and 1,3-bis(2-chloroethyl)-1-nitrosourea (STAMP-I) with identical antiemetic support. Subsequently, patients who experienced a toxic death, relapsed after high-dose chemotherapy, or remained relapse-free at a minimum follow-up of 1 year after high-dose chemotherapy were analyzed for a correlation between the total AUC of CPA and both relapse-free survival and toxic death. The AUC of CPA decreased from day 1 to day 2 in most patients. However, its changes from day 2 to day 3 varied significantly. Neither the value of AUC on day 1 nor its decreasing trend from day 2 to day 3 could predict the AUC on day 3 and the total AUC. Our pharmacodynamic analysis in 335 patients failed to show a correlation between the total AUC of CPA and either toxic death or relapse-free survival. The significant intersubject variability in the AUC of CPA makes the final AUC of the drug unpredictable from an initial measurement on day 1. Thus, in this combination, measurement of levels of parent CPA, with the objective of real-time therapeutic monitoring of this drug, is not informative.

The purpose of this study was to describe acute encephalopathy as a new toxicity associated with paclitaxel, when it is delivered at high doses (> or =600 mg/m2) with stem cell support. A total of 129 patients, included in clinical trials of paclitaxel-containing high-dose chemotherapy, were analyzed. A total of 114 patients received paclitaxel at a dose of > or =600 mg/m2. Six patients presented acute encephalopathy starting between 7 and 23 days after paclitaxel treatment; two of them had received prior whole-brain irradiation. Paclitaxel was given alone (one patient), with cyclophosphamide and cisplatin (two patients), and with cyclophosphamide and cisplatin plus 1,3-bis(2-chloroethyl)-1-nitrosourea (three patients). Central nervous system toxicity consisted of rapid obtundation and coma (five patients) and severe confusional picture with paranoid ideations (one patient). Brain magnetic resonance imaging showed diffuse white matter atrophy (one patient) or multiple small infarcts (one patient), or it was normal (four patients). Other complementary tests, including cerebrospinal fluid analysis and electroencephalography, were nondiagnostic. An effect from concomitant psychotropic medications or from other organ toxicities was excluded in all patients. Three patients recovered after 8-15 days, either spontaneously (two patients) or after high-dose steroids (one patient). Three patients died of irreversible coma. Necropsy, performed in two patients, showed generalized white matter atrophy and multiple brain parenchymal infarcts, respectively. No pharmacodynamic correlation between the occurrence of encephalopathy and a pharmacokinetic parameter of paclitaxel could be identified. Paclitaxel-containing high-dose chemotherapy can cause severe acute encephalopathy. An aggravating effect from prior brain irradiation or concurrent 1,3-bis(2-chloroethyl)-1-nitrosourea seems possible.

Over the past decade, peripheral blood progenitor cells (PBPCs) have replaced bone marrow as the major source of haematopoietic support. This transition from marrow to PBPCs is due to the fact that, for many clinical studies, a significantly faster rate of engraftment, particularly for platelets, has been demonstrated for patients who receive PBPC support when compared to similarly treated patients who are transplanted with bone marrow. The leukapheresis procedure itself, quality of PBPC graft, methods of PBPC mobilization, purging, and ex vivo expansion will be discussed in detail.

Purpose: Prior studies show that increased levels of the DNA repair protein O6 methylguanine-DNA methyltransferase (MGMT), also referred to as O6-alkylguanine-DNA alkyltransferase (AGT) correlate with the resistance of glioma cell lines to nitrosoureas. The observed nitrosourea sensitivity of MGMT-deficient lines (methyl excision repair negative [MER-]) and those repair-proficient lines pretreated with MGMT-specific inhibitors (eg, O6 benzylguanine) has raised the possibility that tumor MGMT levels may be an important predictor of survival in patients with gliomas., Patients and Methods: We correlated the MGMT level in malignant astrocytoma tissues, obtained from patients treated with radiotherapy and bis-chloroethylnitrosourea (BCNU) on a prior prospective trial (Southwest Oncology Group [SWOG] 8737), with overall and failure-free survival., Results: Of 64 assessable patients with malignant astrocytoma (63% glioblastoma, 37% anaplastic astrocytoma), 64% had high (> 60,000 molecules/nucleus) MGMT levels. The overall median survival for patients with high versus low MGMT levels was 8 and 29 months, respectively (P=.0002), and median failure-free survival 3 and 6 months, respectively (P=.008). Subset analysis by histology (high v low MGMT levels) for anaplastic astrocytoma was 14 versus 62 months (n=24) and for glioblastoma was 7 versus 12 months (n=40). The overall hazards ratio (risk for death) for high versus low MGMT levels was 3.41; in young patients, the hazards ratio was higher (age 18 to 40 years, 4.19; age 41 to 60 years, 3.08) but became equal by MGMT level at age older than 60 years (1.11). Multivariate analysis showed that MGMT was independent of other known prognostic factors (age, performance status, histology)., Conclusion: The MGMT level in tumor tissue specimens may be a predictive marker of survival in patients with malignant astrocytoma that is independent of other previously described prognostic variables.

Venocclusive disease of the liver (VOD) is one of the most common and serious complications following stem cell transplantation. High-dose chemotherapy or chemoradiotherapy injures the structures of Zone 3 of the liver acinus and produces the clinical syndrome of hepatomegaly or right upper quadrant pain, jaundice, and fluid retention. VOD occurs in up to 54% of stem cell transplant recipients and is fatal in 25-50% of them. While the clinical signs of VOD usually manifest during the first post-transplant week, late presentation can occur. The purpose of this review is to discuss the manifestations and pathophysiology of VOD and the options for prevention and treatment.

Hepatic veno-occlusive disease (VOD) is the most common of the regimen-related toxicities accompanying stem cell transplantation (SCT). Despite aggressive therapies, including the combination of tissue plasminogen activator (t-PA) and heparin, severe VOD is almost uniformly fatal. Defibrotide (DF) is a polydeoxyribonucleotide with activity in several vascular disorders and, unlike t-PA and heparin, produces no systemic anticoagulant effects. Nineteen patients who developed severe VOD after SCT were treated with DF on a compassionate-use basis. Patients had clinically established VOD and met risk criteria predicting progression and fatality. At the initiation of DF, all 19 patients had evidence of multiorgan dysfunction; median bilirubin was 22.3 mg/dL, 12 patients had renal insufficiency (5 dialysis dependent), 14 required oxygen supplementation, and encephalopathy was present in 8 patients. Beginning a median of 6 days after diagnosis of VOD, DF was administered intravenously in doses ranging from 5 to 60 mg/kg/d for a planned minimum course of 14 days. In no case was DF discontinued for attributable toxicity. No severe hemorrhage related to DF administration was observed. Resolution of VOD (bilirubin <2 mg/dL with improvement in other symptoms and signs) was seen in 8 patients (42%). Six of 8 responders survived past day +100, contrasted with the 2% predicted survival reported in comparable patients. The observed response rate, survival to day +100, and absence of significant DF treatment-associated toxicity are compelling and warrant further evaluation., (Copyright 1998 by The American Society of Hematology.)

Purpose: To evaluate the feasibility of high-dose chemotherapy (HDC) with autologous hematopoietic progenitor-cell support (AHPCS) as part of combined modality therapy (CMT) in patients with inflammatory breast cancer (IBC)., Patients and Methods: From April 1993 to March 1997, 30 patients with IBC were treated at our program. Twenty-three patients received neoadjuvant chemotherapy (NAC) before HDC; 18 patients also received adjuvant chemotherapy following surgery, but before HDC. All patients received HDC with high-dose cyclophosphamide, cisplatin, and carmustine (BCNU) with AHPCS. Every patient underwent surgery either before (27 patients) or after (three patients) HDC. Patients received radiotherapy after HDC in addition to tamoxifen if their tumors were estrogen receptor-positive., Results: Thirteen patients experienced grade 3 or 4 nonhematologic noninfectious toxicities. In 12 patients (40%), this represented drug-induced lung injury, which in all cases responded to a 10-week course of corticosteroids. The only treatment-related death was secondary to hemolytic-uremic syndrome (HUS). Another patient suffered grade 4 CNS toxicity, which was completely reversible. All patients engrafted promptly. Eight patients relapsed, five of whom had a poor pathologic response to NAC. Relapses were local (five patients), local plus systemic (one), or systemic only (two). Median follow-up time from diagnosis and HDC is 23.5 (range, 7 to 49) and 19 (range, 4 to 44) months, respectively. Twenty-one patients (70%; 95% confidence interval [CI], 51% to 86%) remain alive and free of disease 4 to 44 months after HDC. Median disease-free survival (DFS) and overall survival have not yet been reached., Conclusion: HDC as part of CMT is feasible in patients with IBC. The toxicity of this treatment program is significant, but tolerable. Despite the short follow-up duration, the promising DFS observed in this group of patients warrants randomized studies that include a HDC-containing arm in patients with IBC.

Stem cell factor (SCF) is a multipotent growth factor that plays a role in the growth and development of hematopoietic cells, spermatocytes, melanocytes, and mast cells. SCF alone has little direct stimulatory activity on hematopoietic progenitors but acts synergistically with other colony-stimulating factors to potentiate their effects on colony growth. SCF also potentiates the mobilization of hematopoietic progenitor cells into the peripheral blood in response to granulocyte colony-stimulating factor (G-CSF), with or without chemotherapy. The combination of SCF plus G-CSF appears to be a particularly effective mobilization regimen for patients who have been heavily pretreated. Whether engraftment of peripheral blood progenitor cells mobilized by SCF plus G-CSF is superior to that of cells mobilized by G-CSF alone remains unclear. SCF appears to be a necessary requirement for ex vivo expansion of hematopoietic progenitors in both liquid and bioreactor culture systems and will be an important component of future cellular therapies, such as expansion of placental cord blood progenitors and retroviral-mediated gene transfer into hematopoietic target cells.

The purpose of this report is to review the Fred Hutchinson Cancer Research Center experience of treating patients with venocclusive disease of the liver (VOD) after marrow transplantation using recombinant human tissue plasminogen activator (rh-tPA) and heparin. The charts of 42 patients who had received rh-tPA and heparin for the treatment of VOD between February 1991 and December 1995 were reviewed. Response to rh-tPA and heparin was defined as a reduction in total serum bilirubin by 50% within 10 days of starting treatment. Total serum bilirubin, percent weight gain, and serum creatinine before, after, and at the start of rh-tPA and heparin were examined to determine whether these laboratory values distinguished patients who responded to treatment from those who did not. We also evaluated whether evidence of multiorgan failure (requirement for supplemental oxygen, requirement for hemodialysis, requirement for mechanical ventilation) or whether the calculated probability of a fatal outcome from VOD could discriminate responders from nonresponders. In addition, the incidence and outcome of bleeding as a major complication of thrombolytic therapy was examined. Twelve patients responded to rh-tPA and heparin and 30 patients did not. There were no statistically significant differences between responders and nonresponders in the day treatment was started, dose of rh-tPA, total serum billirubin, and percent weight gain before, after, or at the start of treatment, or the calculated probability of dying from VOD on the day treatment with rh-tPA and heparin was begun. More nonresponding patients required dialysis or mechanical ventilation (11 of 30) before or at the start of rh-tPA and heparin than responding patients (0 of 12), P = .0183. Serum creatinine was greater at the start of treatment in nonresponding patients (1.9 +/- 1.3 mg/dL) than in responding patients (1.1 +/- 0.4 mg/dL), P = .0794. Ten patients had severe bleeding episodes, which resulted in death in three patients and may have contributed to death in an additional three patients. Treatment for VOD using rh-tPA and heparin was successful in 29% of patients but was associated with a significant risk of life-threatening hemorrhage. Requirement for supplemental oxygen, dialysis, or mechanical ventilation before the start of treatment were prognostic indicators of no response to thrombolytic therapy. We do not recommend treatment using tPA and heparin in patients with severe VOD who have already developed multiorgan dysfunction.