The prognosis for women with primary breast cancer involving multiple axillary nodes remains poor. High-dose chemotherapy with stem-cell support produced promising results in initial clinical trials ...conducted at single institutions.
Seven hundred eighty-five women aged 22 to 66 years with stage IIA, IIB, or IIIA breast cancer involving 10 or more axillary lymph nodes were randomized after surgery and standard adjuvant chemotherapy to either high-dose cyclophosphamide, cisplatin, and carmustine (HD-CPB) with stem-cell support or intermediate-dose cyclophosphamide, cisplatin, and carmustine (ID-CPB) with G-CSF support but without stem cells. Planned treatment for all patients included locoregional radiation therapy. Hormone-receptor-positive patients were to receive 5 years of tamoxifen. Event-free survival (EFS) was the primary end point.
Median follow-up was 7.3 years. Event-free survival was not significantly different between the two treatment groups (P = .24). The probability of being free of an event at 5 years with HD-CPB was 61% (95% CI, 56% to 65%), and was 58% (95% CI, 53% to 63%) for ID-CPB. Thirty-three patients died of causes attributed to HD-CPB, compared with no therapy-related deaths among women treated with ID-CPB. Overall survival for the two arms was identical at 71% at 5 years (P = .75).
HD-CPB with stem-cell support was not superior to ID-CPB for event-free or overall survival among all randomized women with high-risk primary breast cancer.
Abstract
Based on clinical activity in phase 2 studies, lenalidomide was evaluated in a phase 2/3 study in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Following tumor lysis ...syndrome (TLS) complications, the protocol was amended to a phase 1 study to identify the maximum tolerated dose-escalation level (MTDEL). Fifty-two heavily pretreated patients, 69% with bulky disease and 48% with high-risk genomic abnormalities, initiated lenalidomide at 2.5 mg/day, with dose escalation until the MTDEL or the maximum assigned dose was attained. Lenalidomide was safely titrated to 20 mg/day; the MTDEL was not reached. Most common grade 3-4 adverse events were neutropenia and thrombocytopenia; TLS was mild and rare. The low starting dose and conservative dose escalation strategy resulted in six partial responders and 30 patients obtaining stable disease. In summary, lenalidomide 2.5 mg/day is a safe starting dose that can be titrated up to 20 mg/day in patients with CLL.
The array of options for the initial management of follicular small cleaved lymphoma (FSCL) and follicular mixed lymphoma (FML) ranges from little or no therapy to the use of intensive combinations ...of drugs. The Cancer and Leukemia Group B (CALGB) compared two contrasting approaches: a single agent, and combination chemotherapy capable of curing diffuse aggressive lymphomas.
A total of 228 patients with stage III or IV FSCL or FML were randomized to cyclophosphamide or the combination of cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin (CHOP-B). Treatment was continued in responders for 2 years beyond maximal response. The primary end point was survival in the most common subtype, FSCL.
Ninety-one percent of all patients responded; complete responses were seen in 66% of those treated with cyclophosphamide and in 60% treated with CHOP-B (P =.36). At 10 years with either cyclophosphamide or CHOP-B, respectively, overall time to failure (25% failure free v 33%; P =.107) and survival (44% alive v 46%; P =.79) were similar by treatment. Outcomes in FSCL also were similar. In 46 patients with FML, at 10 years the combination was associated with better failure-free (9% v 48%; P =.005) and overall (25% v 61%; P =.024) survival. Acute toxic effects were more common with combination chemotherapy. Second malignancies, which might be attributed to treatment, were seen with both approaches.
There is no advantage to the initial use of the relatively intensive combination, CHOP-B, for patients with FSCL compared with the less toxic single agent, cyclophosphamide. However, in an unplanned subgroup analysis, patients with FML who received the combination experienced improved disease control and survival.
To determine the impact of fiberoptic bronchoscopy (FOB), including quantitative bacterial cultures obtained by BAL and protected specimen brushing on therapeutic decisions and outcome in bone marrow ...transplant (BMT) patients.
Retrospective review of all BMT patients undergoing FOB during a 4-year period. Setting: A tertiary care university hospital.
Three hundred five patients underwent BMT; 71 (23%) had FOB to assess pulmonary infiltrates. Allogeneic BMT recipients underwent FOB 3.37 times more often than autologous recipients (p<0.001). Pathogens were identified in 31 (46%) patients undergoing FOB; bacteria were most commonly isolated although 86% of patients had received broad-spectrum empiric antibiotics. Therapy was changed in 20 (65%) patients when a microorganism was identified and in 9 (22%) with nondiagnostic results (p=0.0026), but isolation of a presumed pathogen had no apparent effect on survival. There were 19 (27%) FOB complications, including bleeding in 8 (11%) patients and death in 2 (3%). Major complications were associated with prolonged prothrombin time (p=0.006) and were more common (36% vs 14%; p<0.05) in patients who had protected specimen brushing vs BAL alone. Mortality at 40 months in BMT patients not requiring FOB was 33% compared with 61% mortality in those undergoing FOB (p<0.001); mortality was 96% in patients with respiratory failure requiring mechanical ventilation.
FOB is diagnostically useful in the evaluation of some BMT patients with pulmonary complications and often influences therapy, although no impact on survival was clearly demonstrated. FOB should be performed only after benefits of the procedure are weighed carefully against its increased risk in this select population.
Summary
Background
: Angiogenesis is implicated in the pathophysiology and progression of myelodysplastic syndromes (MDS). Vatalanib (PTK787/ZK222584; Novartis and Schering AG) inhibits receptor ...tyrosine kinases of vascular endothelial growth factor, platelet derived growth factor and c-Kit. We examined whether vatalanib induces hematological responses in MDS and/or delays progression to acute myeloid leukemia (AML) or death.
Methods
: Two cohorts were studied. Vatalanib 1250 mg orally was given once daily (cohort 1) or 750–1250 mg once daily in an intra-patient dose escalating schedule (cohort 2) in 28-day cycles to 155 patients with MDS; 142 patients were evaluable for response and 153 for toxicity.
Results
: The median age was 70.5 years; 51 % had low risk (International Prognostic Scoring System {IPSS} Low/Intermediate-1) and 32 % had high risk (IPSS Intermediate-2/High) MDS. Hematological improvement was achieved in 7/142 (5 %) patients; all 7 were among the 47 patients able to remain on vatalanib for at least 3 months (hematological improvement achieved in 15 % of these 47 patients). For patients with low risk and high risk MDS, respectively, median progression-free survivals were 15 and 6 months, median times to transformation to AML were 28 and 6 months, and median overall survivals were 36 and 10 months. The most frequent non-hematological adverse events grade ≥2 were fatigue, nausea or vomiting, dizziness, anorexia, ataxia, diarrhea, and pain. Two deaths (one intra-cerebral hemorrhage and one sudden death) were possibly related to vatalanib.
Conclusions
: Vatalanib induces improvement in blood counts in a small proportion of MDS patients. Clinical applicability is limited by side effects.
BACKGROUND: A new cryopreservation bag for hematopoietic cell transplantation requires validation as a safe alternative to the bag currently being used in the laboratory.
STUDY DESIGN AND METHODS: ...The new bag was validated using both laboratory and clinical criteria. Laboratory validation proceeded using paired samples of mononuclear cells processed using standard procedures. Cells cryopreserved in the new and old bags were compared for viability, cell counts, CD34 enumeration, colony‐forming unit assays, and bag integrity. After completion of laboratory investigations, engraftment with the new bags was followed and compared to historical engraftment using the old bags.
RESULTS: There were no significant differences between the old and new bags detected using laboratory studies. Bag integrity was equivalent. The validation data suggested impaired cell function after cryopreservation in the new bags, but there were no significant differences in engraftment potential using either material. Days to engraftment was longer using the new bags, but statistical analysis revealed an association with CD34 dose and not with cryopreservation bag type.
CONCLUSION: The new bags were noninferior to the old bags. A change in cryopreservation bag type may appear to affect cell function and potentially affect engraftment. Multiple analyses may be needed to understand the effect of cell processing changes.
To report, from Cancer and Leukemia Group B Protocol 9082, the impact of high-dose cyclophosphamide, cisplatin, and BCNU (HD-CPB) vs. intermediate-dose CPB (ID-CPB) on the ability to start and ...complete the planned course of local-regional radiotherapy (RT) for women with breast cancer involving >or=10 axillary nodes.
From 1991 to 1998, 785 patients were randomized. The HD-CPB and ID-CPB arms were balanced regarding patient characteristics. The HD-CPB and ID-CPB arms were compared on the probability of RT initiation, interruption, modification, or incompleteness. The impact of clinical variables and interactions between variables were also assessed.
Radiotherapy was initiated in 82% (325 of 394) of HD-CPB vs. 92% (360 of 391) of ID-CPB patients (p = 0.001). On multivariate analyses, RT was less likely given to patients who were randomized to HD treatment (odds ratio OR = 0 .38, p < 0.001), older (p = 0.005), African American (p = 0.003), postmastectomy (p = 0.02), or estrogen receptor positive (p = 0.03). High-dose treatment had a higher rate of RT interruption (21% vs. 12%, p = 0.001, OR = 2.05), modification (29% vs. 14%, p = 0.001, OR = 2.46), and early termination of RT (9% vs. 2%, p = 0.0001, OR = 5.35), compared with ID.
Treatment arm significantly related to initiation, interruption, modification, and early termination of RT. Patients randomized to HD-CPB were less likely to initiate RT, and of those who did, they were more likely to have RT interrupted, modified, and terminated earlier than those randomized to ID-CPB. The observed lower incidence of RT usage in African Americans vs. non-African Americans warrants further study.
Hematopoietic stem cell transplantation (HCT) is associated with a high risk of morbidity, making advance care planning (ACP) essential. The purpose of this study was to assess and compare proxy and ...HCT candidate distress levels (Distress Thermometer) before (T1) and after (T2) ACP question completion. 79 participants (40 HCT candidates, 39 proxies) rated their distress. The T1, T2 mean distress scores (SD) for HCT candidates were 3.13(2.27), 2.96(2.10); 43% and 38% endorsed clinically significant distress (≥4). Proxies reported 4.21(2.48), 4.33 (2.46); 62% endorsed significant distress at T1, T2. The majority of proxies endorsed distress levels that were clinically significant and comparatively higher (T1 (p = 0.047) and T2 (p = 0.009)) than their paired HCT recipients. Responding to questions about ACP did not increase overall distress ratings.
Anti-B4-blocked ricin (anti-B4-bR) is a potent immunotoxin directed against the CD19 antigen. Previous phase I and II studies suggested a possible role for anti-B4-bR as consolidation after high-dose ...chemotherapy and autologous stem cell transplant. Cancer and Leukemia Group B (CALGB) 9254 is a phase III study which randomized 157 patients with B-cell lymphoma in complete remission following autologous transplant to treatment with anti-B4-bR or observation. With a median follow-up time for patients of 5.8 years, the median event-free survival for protocol treatment and observation are 2.1 and 2.9 years, respectively (p = 0.275). The median overall survival for treatment and observation are 6.1 years and not reached, respectively (p = 0.063). Therefore, no differences were found in event-free survival and overall survival between protocol treatment and observation, although there was a trend toward improved survival with observation. These data fail to support a role for anti-B4-bR as consolidative therapy after bone marrow transplant in patients with B-cell lymphoma.
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