Obesity is an independent predictor of poor survival in metastatic breast cancer: retrospective analysis of a patient cohort whose treatment included high-dose chemotherapy and autologous stem cell support.

The purpose of the study was to identify predictors of long-term survival in metastatic breast cancer (MBC). A cohort of 96 patients, who received high-dose chemotherapy with autologous stem cell support (HD-ASCT) as part of their treatment, was analyzed. Percent long-term survival at 10 years was 24.5% (CI 17.2-34.9%) when metastasis was diagnosed and 14.4% (CI 8.7-23.9%) when MBC was diagnosed. Survival was impacted significantly by body mass index (BMI). Median overall survival from initial diagnosis or from time of metastasis for patients with BMIs ≤30 and >30 (obese) was 7.1 (CI 4.4-8.7) and 3.2 years (2.41-6.75), respectively, or 3.2 or 2.3 years (all P = 0.02). Also, obesity was the only independent patient-related predictor of time to metastasis and of survival. While obesity is linked with poor outcomes in earlier stages of breast cancer, this has not been previously reported for MBC.

Optimal use of G-CSF administration after hematopoietic SCT.

After hematopoietic SCT (HSCT), G-CSF is commonly used to enhance stem cell engraftment to minimize the morbidity and mortality associated with prolonged neutropenia. However, there is no consensus on the optimal use of G-CSF after high-dose chemotherapy followed by HSCT. This review was performed to evaluate the evidence regarding the use of G-CSF after autologous and allogeneic HSCT. Studies investigating the use of G-CSF in comparison to control (observation or placebo), early vs delayed initiation of G-CSF, and other approaches driven by patient-specific parameters to identify optimal use of G-CSF have been reviewed. Various outcomes such as neutrophil and platelet engraftment, post-transplant length of hospital stay, post-transplant complications such as infection and GVHD, and survival have been assessed. Finally, we provide the level of evidence for each of the outcomes analyzed while evaluating strategies for using G-CSF in patients undergoing autologous or allogeneic HSCT.

High-dose CEB vs BEAM with autologous stem cell transplant in lymphoma.

Between January 1996 and July 2002, 72 patients with non-Hodgkin's lymphoma or Hodgkin's disease underwent high-dose chemotherapy with autologous stem cell transplant conditioned with either cyclophosphamide, etoposide, carmustine (CEB) or carmustine, etoposide, cytarabine, melphalan (BEAM) at a single institution. In all, 52 patients received CEB and 20 patients received the BEAM regimen. Patient characteristics that were significantly different between the two groups are tumor grade and extranodal involvement (P = 0.0196, 0.0341, respectively). Regimen-related toxicities examined yielded only diarrhea occurring at a higher rate in the BEAM group (81 vs 51%, P = 0.0026), although cases were milder (92 vs 57%). Patients treated with CEB developed mucositis at a slightly higher rate (79%) than patients treated with BEAM (75%), but this difference did not reach statistical significance. However, the mucositis that occurred within the BEAM group was predominately mild (67%) in contrast to the predominance of moderate to severe cases in the CEB group (74%). In addition, patients treated with CEB required growth factor support for a longer time than patients treated with BEAM (P = 0.0399). Response rates were high in both groups, with trends favoring the BEAM group. Overall survival was higher after treatment with BEAM than with CEB (84 vs 60%).

Use of capecitabine as first-line therapy in patients with metastatic breast cancer relapsing after high-dose chemotherapy and autologous stem cell support.

High-dose chemotherapy with autologous stem cell support (HDC-ASCS) can produce high complete remission rates in patients with metastatic breast cancer (MBC). However, the majority of those so treated will relapse within 3 years. The ability of such patients to tolerate further myelosuppressive chemotherapy may be limited and the best therapy is undefined. In this retrospective study we assessed the role of capecitabine as initial therapy after relapse. Ten patients (median age = 47 years; oestrogen receptor-positive, n = 4; visceral disease, n = 6; prior anthracycline, n = 8, prior taxanes, n = 10), whose disease progressed at a median of 246 days (range 69-480) after HDC-ASCS and who were treated with capecitabine (2500 mg/m2 per day for 2 weeks of a 3-week cycle) as initial therapy for relapse, were assessed retrospectively for response and toxicity. They received a median of eight cycles (range 4-24) of capecitabine. The toxicities encountered while receiving capecitabine were: hand-foot syndrome (grade 1, n = 3; grade 2, n = 4; grade 3, n = 1); diarrhoea (grade 1, n = 1; grade 2, n = 3); nausea (n = 2) and fatigue (n = 5). Haematological toxicity was seen in only one patient. No patient required hospitalization for toxicity. Three achieved a complete remission, four a partial remission and three disease stabilization. After a median follow-up of 183 days from commencing capecitabine (range 97-540), all patients were alive and five were in remission. Five progressed after remissions that lasted between 63 and 252 days. Oral capecitabine is an active and well-tolerated agent when used alone as first-line therapy in patients who have relapsed after HDC-ASCS for MBC.

A phase II study of two cycles of high-dose chemotherapy with autologous stem cell support in patients with metastatic breast cancer who meet eligibility criteria for a single cycle.

Multi-cycle high-dose chemotherapy with autologous stem cell support (HDC-ASCS) may improve the results obtained with single-cycle HDC-ASCS in metastatic breast cancer (MBC). However, the tolerability and efficacy of additional cycles of HDC-ASCS in patients selected using standard eligibility criteria for single cycle HDC-ASCS is uncertain. Twenty-nine patients with MBC and a CR or PR to induction chemotherapy were selected by standard institutional eligibility criteria for single-cycle HDC-ASCS. Cycle 1 HDC-ASCS (cyclophosphamide 6 g/m2; mitoxantrone 70 mg/m2; carboplatin 800 mg/m2) was followed by a planned second cycle (etoposide 1.6 g/m2; thiotepa 800 mg/m2; carboplatin 800 mg/m2 modulated by tamoxifen 120 mg/m2/day x 5 days) with a median interval of 3.2 months. CR rate was 20% after induction chemotherapy and 33% and 54% after HDC cycles I and II, respectively. Sixteen patients (55%) failed to complete HDC cycle II within 200 days because of disease progression, toxicity, inadequate stem cell collection, insurance denials or patient choice. Median progression-free survival (PFS) for all 29 patients entered is 301 days from date of HDC cycle I and actuarial PFS at 2 years is 35%. For the 13 patients who received the two cycles of HDC-ASCS, actuarial PFS at 2 years was 54% (P = NS compared to those receiving only one cycle). These data show that a second cycle of full-dose intensity HDC-ASCS may increase the proportion of patients with MBC that achieve CR and may increase PFS. However, a large proportion of patients that complete HDC-ASCS cycle I may fail to proceed to cycle II in a timely fashion. Bone Marrow Transplantation (2000) 25, 519-524.

Simultaneous administration of G-CSF and GM-CSF for re-mobilization in patients with inadequate initial progenitor cell collections for autologous transplantation.

BACKGROUND: A proportion of candidates for high-dose chemotherapy with autologous PBPC support (HDC-PBPCS) will not provide an adequate PBPC yield from their first mobilization. The value of re-mobilization and the best regimen for re-mobilization in these patients is unclear. METHODS: In 23 patients who failed to provide > or = 3 x 10(6) CD34+ cells/kg after their first mobilization, PBPC were re-mobilized using a regimen of simultaneous administration of G-CSF and GM-CSF (10 microg/kg/day each) with leukaphereses (LP) starting Day 4 or 5 of CSF administration. Yields of WBC/kg, MNC/kg and CD34+ cells/kg/L of processed blood were compared between the first and second mobilization in each patient. The ability of the combined yield from the two mobilizations to achieve the desired threshold PBPC yield and the tolerability of the re-mobilization were determined. RESULTS: The re-mobilization regimen was well-tolerated and no patient discontinued the regimen because of toxicity. Median collected WBC/kg/L (1.37 x 10(7) versus 2.62 x 10(7), p = 0.0065), MNC/kg/L (0.77 x 10(7) versus 1.97 x 10(7), p = 0.0003), CD34+ cells/kg/L (1.64 x 10(7) versus 4.18 x 10(7), p = 0.001) were significantly higher after the second mobilization (G-CSF/GM-CSF combination). Percentage of CD34+ cells in the leukapheresis was also significantly higher after the second mobilization (median 0.104% versus 0.195%, p = 0.036). Twelve of 22 patients achieved the target PBPC dose (> 3 x 10(6)/CD34+ cells/kg) after two mobilizations (six patients achieved the target from the second mobilization alone). A further eight underwent HDC-PBPCS without achieving the target PBPC dose. These patients experienced a significant delay in neutrophil and platelet engraftment when compared with those patients achieving the target dose. DISCUSSION: This study demonstrates that the combination of G-CSF and GM-CSF is an effective and tolerable method for re-mobilization of PBPC in patients who fail to provide an adequate yield from their first mobilization.

Bi-weekly vincristine, epirubicin and methylprednisolone in alkylator-refractory multiple myeloma.

Nine patients with poor-prognosis, alkylator-refractory stage III multiple myeloma (MM) were treated with a 23-h continuous infusion (CI) of a compatible mixture of vincristine (VCR) and epirubicin (EPI) daily for 4 days along with a daily 1-h infusion of high-dose methyl prednisolone (MP) to total of 5 days (VEMP); cycles were repeated every 2 weeks when possible, usually on an outpatient basis. WHO grade 3 or 4 neutropenia and infection were the predominant toxicities encountered, necessitating some treatment delays and dose reductions. Two patients died during treatment. Peripheral neuropathy necessitated discontinuation of the VCR in six patients without obvious loss of efficacy of the regimen. Skeletal muscle dysfunction and cardiomyopathy did not occur; trivial ECG abnormalities occurred during a minority of infusions but were of indeterminate relationship to the chemotherapy. Confusion occurred in two patients; alopecia was frequent but reversible, and mild/moderate dyspepsia and stomatitis were common but easily managed. Eight patients achieved a partial response (PR); another patient experienced early death during his second cycle before response assessment. The median survival from the first VEMP administration was 9 months (range, 1-64 + months), the median response duration was 7 months (range, 1-64 + months). Two patients experienced responses too short to be clinically relevant (< or = 2 months). An analysis of weekly paraprotein estimations suggests that the intended bi-weekly cycle length may be optimal. Six of these nine patients derived major benefit from this bi-weekly regimen, which deserves further exploration.

Combination chemotherapy with teniposide (VM26) and carboplatin in small cell lung cancer.

Seventy patients with previously untreated histologically proven small cell lung cancer (SCLC) were treated with a combination of teniposide 60 mg/m2 intravenously (i.v.) on days 1 through 5 and carboplatin 400 mg/m2 i.v. on day 1 every 28 days for six courses. Patients with limited stage disease, (LD) who achieved a response, subsequently received 2,000 cGy prophylactic cranial and 3,000 cGy involved field thoracic radiotherapy. Of the 70 patients, 62 were evaluable for response: 47 patients (76%) achieved an objective response; 14 of 29 patients (48%) with LD had a complete response (CR), with a partial response (PR) plus CR rate of 76%. Seven of 33 patients (21%) with extensive disease (ED) achieved a CR, with a combined PR and CR rate of 76%. Median time to progression (TTP) for all responders was 292 days (42 weeks). Median duration of survival for all LD patients was 415 days (59 weeks). Survival for LD patients was 88% at 6 months, 61% at 12 months, and 29% at 18 months. Median survival duration for all patients in the study was 311 days (44 weeks), with a survival of 79% at 6 months, 44% at 1 year, and 16% at 18 months. Myelosuppression was the main toxicity, with World Health Organization (WHO) grade 3 or 4 infection occurring in 33% of patients. Two patients died of pneumonia, one complicated by renal failure, and another suffered cardiac arrest related to treatment. The high activity of this drug combination justifies its use as a first-line treatment of previously untreated SCLC.

Teniposide (VM-26) and carboplatin as initial therapy for small cell lung cancer.

Forty-four patients with previously untreated histologically proven small cell lung cancer (SCLC) were treated with a combination of teniposide 60 mg/m2 intravenously (IV) on days 1 through 5 and carboplatin 400 mg/m2 IV on day 1 every 28 days for six courses. Patients with limited disease (LD) subsequently received prophylactic cranial and thoracic radiotherapy. Of the 44 patients, 40 were evaluable for response: 31 (78%) achieved an objective response; 9 of 18 patients (50%) with LD had a complete response (CR), with a partial response (PR) plus CR rate of 78%. Two of 22 patients (9%) with extensive disease achieved a CR, with a combined PR and CR rate of 77%. Median duration of response for all evaluable patients was 253 days (36 weeks). Median duration of survival for LD patients was 368 days (52 weeks). Survival of LD patients was 86% at 6 months, 52% at 12 months, and 26% at 18 months. Median duration of survival for all patients in the study was 275 days, with a survival of 79% at 6 months, 36% at 1 year, and 12% at 18 months. Myelosuppression was the main toxicity, with World Health Organization (WHO) grade 3 or 4 infection occurring in 38% of patients. However, no patient died of sepsis or hemorrhage. Treatment was otherwise well tolerated, with no neurotoxicity or nephrotoxicity documented. The high activity of this drug combination justifies its use as first-line treatment of previously untreated SCLC.