High-dose BCNU Research Articles

A Randomized Phase II Trial Comparing BeEAM with BEAM As Conditioning Regimen for Autologous Stem Cell Transplantation in Lymphoma Patients

Introduction BCNU containing BEAM (BCNU, etoposide, cytarabine, melphalan) is one of the most commonly used conditioning regimens in lymphoma patients before autologous stem cell transplantation (ASCT). A frequently observed non-hematological complication of high-dose BCNU containing regimens is pulmonary toxicity that might lead to permanent damage with a reported incidence varying from 2% to 64%. Replacing BCNU with bendamustine in the BeEAM regimen has shown to be effective and feasible in phase II trials. So far, no randomized clinical trial has compared the established BEAM protocol with the BeEAM regimen. Here we present the results of a randomized phase II clinical trial (EudraCT2014-003629-16). Methods In this multicentre Austrian Swiss trial, 108 patients were enrolled from January 2015 to December 2018 and randomly assigned to the BeEAM (N=53) or BEAM (N=55) arm as a conditioning regimen. Patients enrolled had either mantle cell lymphoma (MCL) (N=39), diffuse large B-cell lymphoma (DLBCL) (N=57) or follicular lymphoma (FL) (N=12). The conditioning regimen was administered according to the standard BEAM protocol (BCNU: 300mg/m2) and the BeEAM regimen was given according the regimen first published by Giuseppe Visani et al. 2011 (bendamustine: 2x200mg/m2 on consecutive days). Hematological engraftment after ASCT was defined as the first day of neutrophil counts above 0.5 x 109/l, and of platelet counts above 20 x 109/l in the absence of platelet transfusion in the previous 3 days. The primary endpoint of the study was to evaluate whether replacement of BCNU by bendamustine could reduce lung toxicity defined, as a decrease of the diffusion capacity of the lung for carbon monoxide (DLCO) by at least 20%, at 3 months after ASCT. Secondary endpoints included overall survival (OS) and progression-free survival (PFS), acute toxicity, hematological recovery and engraftment, pulmonary function parameters as assessed by spiro- and ergometry from diagnosis until 1-year after ASCT and quality of life according to the EORTC-Q30 questionnaire. ResultsAge, disease status and remission status were well balanced and did not differ between the two study groups. Engraftment: Median number of infused CD34+ cells x 106/kg was 4.3 in the BeEAM vs. 4.6 in the BEAM arm. All patients engrafted and there was no difference in time to engraftment between the BeEAM and BEAM group. Respiratory function: The primary endpoint was achieved in 8/41(19.5%) in the BeEAM and in 9/43 (20.9%) in the BEAM group. There was no significant difference in DLCO and spiro- and ergometry in the BeEAM and BEAM group during the whole study period (Table 1). Although 2 patients died because of treatment related lung toxicity in the BEAM arm, we did not observe any functional detoriation in the patients who received the BCNU-containing BEAM regimen. Additionally, blood gas analysis revealed similar results in both study arms at screening, 3 months and 1-year after ASCT. Toxicity: Acute toxicity grade 3-5 according to CTCAE v4.0 was observed in 43.4% of the patients in the BeEAM arm and in 34.5% of the patients in the BEAM arm in the category any adverse event (p =0.43). Infections and infestations were observed in 9.4% of patients in the BeEAM arm and in 14.5% in the BEAM arm (p=0.56). Respiratory, thoracic and mediastinal disorders were only detected in the BEAM arm (5.5%) (p=0.24). In contrast to previous trials, grade 3-5 renal toxicity was low, both in the BeEAM and BEAM arm, respectively (1.9% vs. 1.8%) (p=1.00). Gastrointestinal toxicity occurred more frequently in the BeEAM arm (13.2%) than in the BEAM arm (5.5%) (p=0.20). Median follow-up was 369 days (15-540 days). In the BeEAM arm 4 out of 53 patients died during the observational period, 6 out of 55 in the BEAM arm (log-rank test p=0.54, Figure 1). Ten patients in each group had a progression or died during the observational period (log-rank test p=0.89). Quality of life: There was no statistical difference in the assessment of quality of life in the two study arms. Conclusion BeEAM is a feasible, well tolerated regimen resulting in similar clinical results as observed with the BEAM regimen. Interestingly we did not see any difference in impairment of pulmonary function, however 2 patients died in the BEAM arm of lung toxicity and no lung related deaths were observed in the BeEAM group. In our conclusion, BeEAM is a reasonable alternative to the BEAM regimen. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Infusion reactions are common after high-dose carmustine in BEAM chemotherapy and are not reduced by lengthening the time of administration.

Carmustine (BCNU) is used in the conditioning regimens BEAM and CBV for autologous stem cell transplantation. Carmustine-related infusion reactions, while not described in the BEAM literature, occurred in 95% of patients who received CBV. The most common symptoms include flushing, facial pain, headache, and hypotension. These reactions have been attributed to the absolute ethanol that is used in the reconstitution process or alternatively by a direct effect of carmustine. It is currently recommended that carmustine 300mg/m2 be infused over at least 100min (3-5mg/m2/min). Prior to October 2014, carmustine infusions were given over 90min but were changed to 120min based on the above recommendation. We compared the two infusion rates in patients receiving BEAM to see if lengthening the infusion decreased the frequency of reactions. Overall, 100 patients received BCNU as part of BEAM or Zevalin BEAM and were equally divided between 90 and 120min infusion times. The primary outcome was the incidence of infusion-related reactions which were graded based on CTCAE 4.03 descriptions of flushing and infusion-related reactions. We also evaluated the impact of premedication as well as the efficacy of medications used to treat infusion reactions. Between the years 2013-2016, there were 50 patients who received BCNU over 90min and 50 patients over 120min. There were no significant differences observed for diagnosis, age and gender between the two groups. Twenty-eight (56%) in the 90-min and 26 (52%) in the 120-min infusion intervals developed a reaction (p = 0.6882). Of the patients that developed a reaction, 19 patients (67%) in the 90-min and all 26 patients (100%) in the 120-min infusion were given premedications predominately acetaminophen, in addition to dexamethasone. Among reacting patients, 57% of the 90-min and 65% of the 120-min groups received additional intervention (p = 0.53). Infusion reactions during high-dose BCNU are common and are not clearly reduced by modestly extending the duration of infusion or giving premedications.

AT-49 * SAFETY EVALUATION OF HIGH-DOSE BCNU-LOADED BIODEGRADABLE IMPLANTS IN CHINESE PATIENTS WITH RECURRENT MALIGNANT GLIOMAS

OBJECTIVES: Malignant gliomas are common primary brain tumors with dismal prognosis. The blood-brain barrier and unacceptable systemic toxicity limit the employment of chemotherapeutic agents. BCNU-impregnated biodegradable polymers (Gliadel®) have been demonstrated to prolong the survival of patients with malignant gliomas. Until now, no biodegradable drug delivery system has been commercially available in China. In the present study, we evaluated the safety of implants with high-dose BCNU in Chinese patients with recurrent malignant gliomas. PATIENTS AND METHODS: Adults with supratentorial recurrent malignant glioma were eligible. High-dose BCNU-loaded PLGA implants (20 mg of BCNU in each implant) were placed in the debulking cavity. The implants were investigated by a classical 3 + 3 design. Four levels of BCNU, up to 12 implants, were evaluated. Pharmacokinetic sampling was performed. The toxicity of the implants and the survival of patients were recorded. RESULTS: Fifteen recurrent patients were enrolled with 12 glioblastomas and 3 anaplastic gliomas. Among 15 patients, 3 were treated with 3 implants (60 mg of BCNU), 3 with 6 implants (120 mg), 3 with 9 implants (180 mg) and 6 with 12 implants (240 mg). No dose-limiting toxicity was observed in the cohort of patients. Subgaleal effusion was the most common adverse event, presenting in 7 patients (46.7%). The median overall survival (OS) was 322 days (95% CI, 173 - 471 days). The 6-month, 1-year and 2-year survival rates were 66.7%, 40% and 13.3%, respectively. CONCLUSIONS: The high-dose BCNU-loaded PLGA implants were safe for Chinese patients with recurrent malignant gliomas and further investigation for efficacy is warranted.

Safety evaluation of high-dose BCNU-loaded biodegradable implants in Chinese patients with recurrent malignant gliomas

ObjectivesMalignant gliomas are common primary brain tumors with dismal prognosis. The blood–brain barrier and unacceptable systemic toxicity limit the employment of chemotherapeutic agents. BCNU-impregnated biodegradable polymers (Gliadel®) have been demonstrated to prolong the survival of patients with malignant gliomas. Until now, no biodegradable drug delivery system has been commercially available in China. In the present study, we evaluated the safety of implants with high-dose BCNU in Chinese patients with recurrent malignant gliomas. Patients and methodsAdults with supratentorial recurrent malignant glioma were eligible. High-dose BCNU-loaded PLGA implants (20mg of BCNU in each implant) were placed in the debulking cavity. The implants were investigated by a classical 3+3 design. Four levels of BCNU, up to 12 implants, were evaluated. Pharmacokinetic sampling was performed. The toxicity of the implants and the survival of patients were recorded. ResultsFifteen recurrent patients were enrolled with 12 glioblastomas and 3 anaplastic gliomas. Among 15 patients, 3 were treated with 3 implants (60mg of BCNU), 3 with 6 implants (120mg), 3 with 9 implants (180mg) and 6 with 12 implants (240mg). No dose-limiting toxicity was observed in the cohort of patients. Subgaleal effusion was the most common adverse event, presenting in 7 patients (46.7%). The median overall survival (OS) was 322days (95% CI, 173–471days). The 6-month, 1-year and 2-year survival rates were 66.7%, 40% and 13.3%, respectively. ConclusionsThe high-dose BCNU-loaded PLGA implants were safe for Chinese patients with recurrent malignant gliomas and further investigation for efficacy is warranted.

Beyond Nausea & Vomiting: Monitoring Less Common Reactions To High Dose BCNU

High dose carmustine (BCNU) is the first chemotherapy agent administered as part of the conditioning regimen BEAM +/- R for autologous blood and marrow transplantation (BMT) for lymphoma. Nausea and vomiting are common adverse drug reactions (ADR) to high dose BCNU and can be effectively controlled by administration of anti-emetics. Less common ADRs such as headache, facial flushing, oral tingling, eye problems, dizziness and allergic reaction have been reported but standard methods of prevention and/or treatment are not known.

Phase II trial of intratumoral BCNU injection and radiotherapy on untreated adult malignant glioma

DTI-015 (BCNU dissolved in ethanol) utilizes solvent facilitated perfusion (SFP) for intratumoral drug delivery. A phase II clinical trial of DTI-015 and fractionated external beam radiotherapy on newly diagnosed, malignant gliomas investigated early changes in tumour physiology and metabolism, clinical outcome and safety. Pre- and post DTI-015 injection neuro-imaging included computed tomography (CT) cerebral blood flow and volume, glucose and thallium single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). Clinical status was determined before and after DTI-015, prior to radiotherapy and 3 monthly thereafter until progression (defined by Macdonald criteria). Primary endpoint was radiographic response. Secondary endpoints were progression free (PFS) and overall survival (OS). Twelve patients were enrolled; eight glioblastoma multiforme (GBM), four anaplastic astrocytoma (AA). Three days after DTI-015 injection, mean tumour blood flow (Paired t-test; P < 0.001) and blood volume (Paired t-test; P = 0.001) were significantly reduced. There was a significant decrease in glucose utilization (Paired t-test; P < 0.001) and thallium uptake (Paired t-test; P < 0.001) at 6 days. Tumour blood volume had a sustained reduction (Paired t-test; P = 0.001) at 26 days after DTI-015. There were two serious adverse events. Two patients with AA achieved a partial response. Median PFS was 39 weeks for AA and 27 weeks for GBM; median OS for GBM was 47 weeks and 132 weeks for AA. The imaging data forms a biological basis for understanding the effects of high dose BCNU delivered intratumorally by SFP, and suggests early effects on tumour vasculature and metabolism.

Incidence and risk factors of central nervous system recurrence in aggressive lymphoma—a survey of 1693 patients treated in protocols of the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL)

Central nervous system (CNS) relapse is a devastating and usually fatal complication of aggressive lymphoma. The extent of the disease, the proliferation rate and the sites of extranodal involvement have been discussed as risk factors. We analyzed the patients treated on protocols of the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL) between 1990 and 2000, evaluated the rate and prognostic factors for CNS recurrence and developed a risk model trying to identify subsets of patients suitable for future prophylactic strategies. From 1993 to 2000, 1399 patients [<or=60 years with normal lactate dehydrogenase (LDH) and >60 years irrespective of LDH] were randomized to receive six cycles of combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP)-21, CHOP-14 or six cycles of CHOP+etoposide (CHOEP)-21, CHOEP-14 in a 2x2 factorial study design in the NHL-B1/B2 studies. From 1990 to 1997, 312 patients<or=60 years with an elevated LDH were randomized to five cycles CHOEP+involved field (IF) radiotherapy or three cycles CHOEP followed by high-dose BCNU, etoposide, cytarabine and melphalan (BEAM) and autologous stem-cell transplantation (NHL-A study). A total number of 1711 patients were initially eligible for this study, of whom 18 patients had to be excluded due to primary CNS involvement. In the remaining 1693 assessable patients, 37 cases of relapse or progression to the CNS (2.2%) were observed. The protocol asked for an intrathecal (i.th.) prophylaxis in patients with lymphoblastic lymphoma only (n=17), but overall 71 patients (71 of 1693=4.2%) received prophylaxis by decision of the treating physicians. Multivariate Cox regression analysis identified increased LDH (P<0.001) and involvement of more than one extranodal site (P=0.002) as independent predictors of CNS recurrence in the NHL-B1/B2 study population. Treatment with etoposide also evolved as a prognostic factor because the risk of CNS failure was significantly reduced after CHOEP (P=0.017). Elderly patients presenting with both an elevated LDH and lymphoma involvement in liver, bladder or adrenals had an up to 15-fold risk of spread of the disease to the CNS. The incidence of CNS relapse in 1693 patients treated for aggressive lymphomas on DSHNHL protocols from 1990 to 2000 was low (2.2%), although CNS prophylaxis was administered to <5% of patients. Thus, a general prophylaxis for all patients is not warranted, the less so since the effectiveness of i.th. prophylaxis itself is judged controversially. Increased LDH and involvement of more than one extranodal site were confirmed as independent risk factors. A cumulative 20% incidence of CNS disease in certain prognostic subgroups of elderly patients may render these candidates for i.th. prophylaxis; however, this approach would imply a potential overtreatment of approximately 80% of these patients deemed at high risk.

Morbidity and transplant-related mortality of CBV and BEAM preparative regimens for patients with lymphoid malignancies undergoing autologous stem-cell transplantation

CBV and BEAM are the two most frequently used regimens for patients with lymphoma undergoing autologous hematopoietic stem-cell transplantation (ASCT). This study compared their morbidity and transplant-related mortality (TRM) in 113 patients with non-Hodgkin's lymphoma (69) and Hodgkin's disease (44) undergoing ASCT between 1990 – 2004. CBV (cyclophosphamide, 6000 mg m−2; VP-16, 750 mg m−2; and high-dose BCNU, 800 mg m−2) was administered to 75 patients and 38 received BEAM (BCNU, 300 mg m−2; VP-16, 800 mg m−2; cytarabine, 800 mg m−2; melphalan, 140 mg m−2). Patients in the BEAM group had a significantly higher median age (p = 0.002) and were more heavily treated before ASCT (p = 0.003). More patients showed active disease at transplant in the BEAM group (p = 0.04). Sinusoidal obstruction syndrome (SOS) was more frequent in the CBV group (11% vs 0%, p = 0.048). There were 20 (18%) transplant-related deaths, 18 in the CBV and two in the BEAM group. Infectious complications (12 patients, seven with pneumonia) and SOS (four) were the most frequent causes of death. The cumulative incidences of TRM were 25% in the CBV and 7% in the BEAM group (p = 0.02). CBV thus produced a higher incidence of SOS and TRM than BEAM in this series.

A phase I trial with extended cohort of gemcitabine and vinorelbine followed by autologous peripheral blood stem cell transplantation for recurrent or refractory Hodgkin’s lymphoma

6651 Background: High dose chemotherapy and autologous stem cell transplantation (ASCT) is the most effective treatment for recurrent or refractory Hodgkin’s lymphoma (HL). Disease recurrence is still a major cause of treatment failure. Augmented BCNU-regimens are reported to have good outcomes but greater pulmonary toxicity. A novel transplant regimen incorporating gemcitabine and vinorelbine, active drugs in HL different from alkylating agents, was tested to establish MTD of gemcitabine and to assess safety at the MTD. Methods: In this phase I extended cohort study, dose escalation with gemcitabine in combination with vinorelbine followed by high dose BCNU, etoposide (VP-16), and cyclophosphamide (CY) and ASCT. 18 patients with recurrent or refractory HL were enrolled. 7 patients had dose escalation before determining the MTD of gemcitabine at 1250 mg/m2 on the basis of elevated liver transaminases and a symptom complex of fever, HA, and skin toxicity. 11 additional patients were studied at the MTD to establish safety. The regimen consisted of gemcitabine 1250 mg/m2 CI and vinorelbine 30 mg/m2 on day-13 and day-8, BCNU 10 mg/kg on day-6, VP-16 60 mg/kg on day-4, CY 100 mg/kg on day-2. Regimen-related toxicity was the primary endpoint. FFP and EFS were secondary endpoints. Results: 5 patients had no risk features; 13 had high risk features (stage IV disease at relapse, failure to achieve min disease, or B sxs at relapse). Median f/u time was 231 days (44 to 791d). Gr 1–2 skin rash was seen but with complete resolution. Transient fever and liver transaminase elevations also fully recovered. All patients engrafted. Remarkable was reduction in BCNU-induced pneumonitis in only 2 of 18 patients (11%), as compared to our standard regimen incidence rate of 35%. Est FFP and EFS at 1 year in low risk patients was 100% and for high risk patients, 73%(CI:47–99%) Conclusions: This novel transplant regimen has decreased incidence of pulmonary toxicity compared with augmented BCNU-regimens and provides a reduced toxicity platform for further development of post-transplant immunotherapy to improve transplant outcome. No significant financial relationships to disclose.

Time-Dependent Effect of Non-Hodgkin's Lymphoma Grade on Disease Free Survival (DSF) of Relapsed/Refractory Patients Treated with High-Dose Chemotherapy (HDC) Plus Autologous Hematopoietic Stem Cell Transplant (AHSCT).

HDC and AHSCT is an effective treatment option for patients with relapsed or refractory NHL. The outcome of this treatment depends on the histological grade (indolent versus aggressive) with a well documented time dependent difference in temporal relapse pattern. We developed statistical models to describe the time dependent outcome after AHSCT based on histologic grade and other variables. During January 1993 to December 2003, 114 relapsed or refractory NHL patients were treated at single institution using high-dose BCNU 600 mg/m2, etoposide 2400 mg/m2, and cisplatin 200 mg/m2 IV over 5 days and AHSCT. Median age was 53.5 (range: 25–70) years, 78 patients had aggressive NHL and 36 indolent NHL. Immediately before transplant, 75 patients received involved-field radiotherapy (IFR) to sites of prior bulky (> 5 cm) disease. Twenty-seven patients had mobilized stem cell transplant (13 with in vivo purging and 14 with ex-vivo purging). At a median follow up of 33 (range: 3 to 118) months, the estimated 5 year Kaplan-Meier probabilities of overall survival (OS) and DSF were 61% and 51%, respectively. DFS was similar up to about 1.2 years between indolent and aggressive NHL (Figure 1). DFS of the group who had purged stem cells was improved marginally over non-purged group. Cox proportional hazards model was used to adjust for differences in baseline characteristics between grades that might affect DFS. The proportionality assumption of Cox model was tested by adding a time-dependent covariate for each variable. This showed that the proportionality did not hold for lymphoma grade, indicating the relationship between the grade and DFS differed over time. The results of piece-wise Cox model after controlling age, IFR, purging status indicate there was no difference of DFS between the grade groups up to 1.2 years (optimal cut-off point) post-transplantation (p = 0.748). However, the relative risk for experiencing relapse after 1.2 year in patients with indolent compared with patients with aggressive NHL was 4.22 (p = 0.006) with 95% confidence interval (1.5, 11.9). Our results statistically prove the previously described biological differences in outcomes of patients with indolent and aggressive NHL following HDC. The time-dependent effect of lymphoma grade on DFS indicates the need for early (within first year) incorporation of novel therapeutic approaches, such as post-transplant immunotherapy, tandem high-dose therapy and, allogeneic transplant to generate graft-versus-lymphoma effect, in management of patients with indolent NHL undergoing autologous transplantation. [Display omitted]

High-dose BCNU followed by autologous hematopoietic stem cell transplantation in supratentorial high-grade malignant gliomas: a retrospective analysis of 114 patients.

Conventional treatment of high-grade glioma includes maximal surgical resection followed by external radiation therapy. Despite this treatment, the prognosis for patients is poor. High doses of chemotherapy might be another way to increase the response rate and median survival. Increasing doses of BCNU might be more effective, but also provokes unacceptable myelotoxicity. This dose-limiting toxicity can be circumvented by using autologous blood stem cell rescue. We report our experience of high-dose BCNU followed by transplantation of autologous hematopoietic stem cells in 114 patients with high-grade gliomas. Of the 114 gliomas, 78 were glioblastoma multiforme (GM) (68%), 24 anaplastic astrocytomas (AA) (21%), and 12 anaplastic oligodendrogliomas (OD) (11%). Complete surgical resection was performed for 22 patients (18 GM and 4 AA). The median age was 44 years (range 17-65). A total of 84 patients received autologous hematopoietic stem cells from bone marrow harvest, while 30 patients received granulocyte colony-stimulating factor followed by apheresis and received peripheral blood progenitor cells (PBPC). High dose of BCNU (800 mg/m(2)) was given at least 1 month after neurosurgery. Bone marrow or PBPC was transplanted 48-72 h after chemotherapy. Radiotherapy was started approximately 40 days after transplantation to a total of 60 Gy. Median follow-up was 89 months (19-163). The overall survival (OS) was, respectively, 12 months for GM, 37 months for OD and 81 months for AA. Histological type appeared to be the main discriminating factor, with a worse prognosis for GM. Within the GM population, age, completeness of surgery, and response appeared to be one important prognostic factors. The AA and OD populations were small to reliably assess prognostic factors. On multivariate analysis, the main prognostic factors were histologic type, quality of surgery, and age (P<0.005). Five of 114 patients had lethal complications from the procedure. Four of these patients had a Karnovsky performance score (KPS) of 60%. The protocol thus appears to be feasible but patients should be selected for KPS more than 70%. We observed long-term survivors, although the OS and the time to treatment failure seem to be comparable to that described for other treatment. Additional pilot studies are unlikely to reveal more than a modest benefit from this procedure and therefore a randomized study should be performed.

High-dose carmustine, thiotepa and etoposide followed by autologous bone marrow rescue for the treatment of high risk central nervous system tumors.

Forty-two patients (29 newly diagnosed) with high grade gliomas (n = 37), medulloblastoma (n = 2) or non-biopsied tumors (n = 3) with supratentorial (n = 24), brain stem (n = 11), posterior fossa (n = 5) or spinal (n = 2) location were eligible for this study with adequate organ function and no bone marrow tumor infiltration. Median patient age was 12.2 years (range, 0.7-46.8). A total of 600 mg/m2 BCNU, 900 mg/m2 thiotepa and 1500 or 750 mg/m2 etoposide (VP-16) was administered followed by autologous bone marrow reinfusion (ABMR). Twenty-one newly diagnosed patients received local irradiation (RT) post ABMR. Nine early deaths were observed (21%), as well as one secondary graft failure. Half of the patients aged 18 years or older experienced toxic deaths, whereas only 15% of patients younger than 18 years experienced toxic death (P = 0.05). Of 25 evaluable newly diagnosed patients, 20% achieved complete remission (CR) and 4% partial remission (PR), while 28% remained in continuing complete remission (CCR) and 44% remained with stable disease prior to RT. Of eight evaluable patients with recurrent disease, one achieved CR and two PR, while one remained in CCR and four with stable disease for 1 to 110.2 months. Overall survival was 36%, 24% and 17% at 1, 2 and 3 years following ABMR, with three newly diagnosed patients and one patient treated for recurrent disease being alive, without disease progression 64.4, 67.0, 86.3 and 110.2 months after ABMR, respectively. The combination of high-dose BCNU/ thiotepa/VP-16 has substantial toxicity but definite activity for high risk CNS tumors. Similar protocols with lower toxicity merit further evaluation in both newly diagnosed and recurrent CNS tumors.

Cardiac toxicity following high-dose cyclophosphamide, cisplatin, and BCNU (STAMP-I) for breast cancer

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. Biol Blood Marrow Transplant 2000;6(2A):198-203.

Optic disc and retinal microvasculopathy after high-dose chemotherapy and autologous hematopoietic progenitor cell support.

The purpose of this study was to prospectively evaluate the retinal and optic nerve changes in patients undergoing high-dose chemotherapy (HDC) followed by autologous hematopoietic progenitor cell support (AHPCS). One hundred and forty patients undergoing HDC and AHPCS underwent extensive pre- and post-transplant ophthalmologic evaluations for development of retinal microvascular complications. One hundred and ten patients received high-dose cyclophosphamide, cisplatin and BCNU; thirty received identical doses of cyclophosphamide and cisplatin, but received paclitaxel instead of BCNU. Thirty-four patients (24%) had retinal findings of either cotton wool spots (CWS) (n = 20) or retinal hemorrhages (n = 18) during follow-up, which ranged from 1 to 12 months. Ten (7%) of these patients, all of whom received BCNU, showed ocular toxicity characterized by CWS 1 to 4 months post transplant (n = 10); optic disc edema (n = 3); and variable vision loss associated with the onset of BCNU-induced pulmonary toxicity. Retinal and optic disc microvascular complications may occur after high-dose chemotherapy followed by AHPCS. The association of ischemic retinal lesions and/or optic disc edema with BCNU-induced pulmonary toxicity and the lack of ocular toxicity in patients that did not receive BCNU may suggest that BCNU is the etiologic agent.

Effect of hypertonic glucose in thermotolerant rat BT4An gliomas treated with combined hyperthermia and BCNU in vivo.

The influence of hypertonic glucose i.p. on development of thermotolerance and thermochemosensitivity with BCNU in thermotolerant tumours, and on intratumoural pH alterations in previously unheated and thermotolerant tumours, was investigated in BT4An tumours grown on the hind foot of BD IX rats. Thermotolerance was induced with local waterbath hyperthermia (44 degrees C/45 min) 24 h before start of test treatment. Hypertonic glucose immediately after priming hyperthermia did not inhibit development of thermotolerance, despite a significant reduction of pH by glucose. The pH reduction was less in thermotolerant tumours. Glucose administered before treatment of thermotolerant tumours did not change the growth rate of tumours treated with hyperthermia (44 degrees C/45 min), BCNU (20 or 25 mg/kg i.p.) or thermochemotherapy with a low or high dose BCNU (10 or 20 mg/kg), in contrast to previous results, where glucose enhanced thermochemosensitivity of non-thermotolerant tumours.

Involved field radiation therapy for Hodgkin's disease autologous bone marrow transplantation regimens

From 1986 through 1992, involved-field radiation therapy (IF-RT) was administered to 29 of 86 patients with recurrent Hodgkin’s disease (HD) who received a high-dose cyclophosphamide/etoposide regimen with autologous bone marrow transplantation (A-BMT). Patients without a significant history of prior RT received total body irradiation (TBI), initially as a single dose S-7.5 Gy, and subsequently with fractionated TBI (F-TBI) delivering 12 Gy. Previously irradiated patients received a high-dose BCNU regimen instead of TBI. IF-RT was employed selectively, usually for sites of bulky disease (> 5 cm). IF-RT doses were typically 20 Gy at 2 Gy per fraction for TBI patients and 30-40 Gy at l-8-2.0 Gy per fraction for non-TBI Patients. Fatal complications developed in four patients while second malignancies have developed in two. The region which received IF-RT was the site of first recurrence in only two cases (7%). With a median follow-up of 28 months, the two-year disease-free survival rate was 44%. For the 22 patients treated by either F-TBI or high-dose BCNU, the 2-year disease-free survival rate was 50% with a median follow up of 29 months. Selective use of IF-RT may increase the chances of complete remission and disease free survival in HD patients with a history of bulky disease.

Involved field radiation therapy for Hodgkin's disease autologous bone marrow transplantation regimens

From 1986 through 1992, involved-field radiation therapy (IF-RT) was administered to 29 of 86 patients with recurrent Hodgkin's disease (HD) who received a high-dose cyclophosphamide/etoposide regimen with autologous bone marrow transplantation (A-BMT). Patients without a significant history of prior RT received total body irradiation (TBI), initially as a single dose 5–7.5 Gy, and subsequently with fractionated TBI (F-TBI) delivering 12 Gy. Previously irradiated patients received a high-dose BCNU regimen instead of TBI. IF-RT was employed selectively, usually for sites of bulky disease (>5 cm). IF-RT doses were typically 20 Gy at 2 Gy per fraction for TBI patients and 30–40 Gy at 1.8-2.0 Gy per fraction for non-TBI Patients. Fatal complications developed in four patients while second malignancies have developed in two. The region which received IF-RT was the site of first recurrence in only two cases (7%). With a median follow-up of 28 months, the two-year disease-free survival rate was 44%. For the 22 patients treated by either F-TBI or high-dose BCNU, the 2-year disease-free survival rate was 50% with a median follow up of 29 months. Selective use of IF-RT may increase the chances of complete remission and disease free survival in HD patients with a history of bulky disease.

Early autologous bone marrow transplantation (ABMT) in the treatment of Hodgkin's disease.

The use of ABMT "early" in Hodgkin's disease (HD) could refer to its to its application at diagnosis, as part of primary therapy or even at the first evidence of disease progression after primary therapy. We have recommended intensive therapy and ABMT to HD patients at the time of first relapse after a complete remission induced by primary chemotherapy. Among the 58 patients entering transplant protocols at the time of first relapse, the majority first received several cycles of conventional chemotherapy and/or local radiotherapy prior to hospitalization for conditioning and autotransplantation. However, all 58 were subsequently conditioned with high-dose cyclophosphamide, BCNU and VP 16-213 +/- cisplatin (CBV +/- P) and autologous transplantation. The progression free survival (PFS) after transplantation was 61% (95% confidence intervals [C.I.] 43%-74%) at a median follow-up of 3.6 (range 1.6-8.2) years. Two patients died of toxicity within the first 5 months of ABMT, while 3 late deaths occurred > 1 year post-transplant. The probability of progression was 28% (95% C.I. 17%-43%). Multivariate analysis identified 3 adverse risk factors for PFS-B symptoms at relapse, initial remission duration < 1 year and extranodal disease at relapse. PFS was significantly correlated with the number of adverse factors. Patients with 2 or 3 risk factors are candidates for more intensive or innovative measures due to the high relapse rate seen in these subgroups. Patients with 0 or 1 risk factors have a < 15% probability of relapse post-transplant, and are arguably candidates for less aggressive regimens.

Low-dose chemotherapy delays relapse of a dominated and resistant sub-population in a heterogeneous human SCLC xenograft in nude mice.

We investigated the influence of cellular heterogeneity on the response to low-dose BCNU chemotherapy of an artificially mixed human small-cell lung cancer (SCLC) xenograft in nude mice containing a BCNU-sensitive and dominating sub-population and a BCNU-resistant and undetectable (dominated) sub-population. The cell lines differed in DNA content, making them distinguishable by DNA flow cytometry (FCM). After 3 weeks of tumor growth, the mice were stratified according to tumor size and randomized to 2 different low-dose treatments with BCNU or no treatment. After a further 3 to 4 weeks, a high-dose treatment (LD10) was given to both groups of treated tumors. Changes in the relative proportions of and cell lines in the tumors were measured by FCM on fine-needle tumor aspirates. At the time of low-dose treatment, all the tumors were totally dominated by the sensitive cells. A temporary response was seen after low-dose treatment. After the high-dose treatment, a similar short response was seen. In the non-treated group, the sensitive cells continued to dominate. At the time of tumor regrowth after the low-dose treatment, most of the tumors continued to be dominated by the sensitive population. At the time of progression after the response to the high-dose treatment, the resistant cell line was the predominant population. If compared with a single high-dose BCNU treatment, the response of tumors treated with a low dose was superior, indicating that the presence of a dominating and slower growing sub-population influenced the outcome of the treatment.

High-Dose Cyclophosphamide, Etoposide and BCNU with Non-Cryopreserved Autologous Bone Marrow Transplantation for Poor Prognosis Malignant Lymphoma

20 patients with poor prognosis malignant lymphoma (Hodgkin's disease 8, high grade non-Hodgkin's lymphoma 12) were treated with high-dose cyclophosphamide (120 mg/kg), etoposide (2100 mg/m2) and BCNU (400mg/m2) followed by reinfusion of autologous non-frozen bone marrow, which had been stored for 72 hours at 4°C. All evaluable patients (19/20) had a full haematopoietic reconstitution. Median time to achieve neutrophils > 500 μl was 26 days (range 15–39) and median time to achieve an unsupported platelet count >20000/μl was 29 days (range 12–55). During a median follow-up of 10.5 months (range 2–36) 2 of 8 patients with Hodgkin's disease and 3/12 patients with non-Hodgkin's lymphoma relapsed after a median of 4.5 months (range 1–6). The projected event-free survival at 24 months was 61% and 70% for patients with non-Hodgkin's lymphoma and Hodgkin's disease respectively. We conclude that high-dose chemotherapy with non-frozen autologous bone marrow transplantation is safe in terms of haematopoietic reconst...