High-dose chemotherapy with peripheral blood stem cell support for stage IIIB inflammatory carcinoma of the breast

The purpose of this study was to determine outcomes for 56 patients with inflammatory breast cancer (IBC) receiving high-dose chemotherapy (HDC) with cyclophosphamide, thiotepa and carboplatin (CTCb) with peripheral blood stem cell (PBSC) support. All patients received the same total amount of chemotherapy but there were differences in the sequence of therapy: 15 received induction chemotherapy, chemotherapy mobilization of PBSC and CTCb after surgery (adjuvant group) while 41 received induction chemotherapy with (n = 17) or without (n = 24) chemotherapy for mobilization of PBSC prior to surgery and CTCb after surgery (neoadjuvant group). Median time from diagnosis to HDC was 5.5 months (range 3.5-12.5). Fifty-one patients (91%) required admission to the hospital following HDC for a median of 11 days (range 5-25). There were two (4%) infectious deaths after HDC. Twenty-four patients (43%) have relapsed at a median of 18 months (range 8-50) from diagnosis resulting in death in 34%. The probabilities of overall (OS) and event-free survival (EFS) at 3 years for all 56 patients were 0.72 and 0.53, respectively, with a median follow-up of 44 months (range 15-76) from diagnosis. There were no differences in OS, EFS or patterns of relapse between patients in the adjuvant or neoadjuvant groups. These sequences of combined modality therapy incorporating HDC are comparable or superior to other intensive approaches for the treatment of IBC. Further improvements will be necessary to decrease systemic recurrences.     

A short course of induction chemotherapy followed by two cycles of high-dose chemotherapy with stem cell rescue for chemotherapy naive metastatic breast cancer: sequential phase I/II studies

Two cycles of high-dose chemotherapy with stem cell support (HDC) may increase the total dose delivered and dose intensity. A brief induction phase and different non-cross-resistant agents for each HDC cycle were used to avoid drug resistance. Twenty-six women with metastatic BC had induction and stem cell mobilization with two cycles of doxorubicin/G-CSF given every 14 days. Patients with stable disease or better after induction received HD CTCb followed by HD melphalan and dose-escalated paclitaxel. At 475 mg/m(2) of paclitaxel by 24-h infusion, dose-limiting transient peripheral sensory neuropathy was encountered. No toxic deaths occurred. Complete and near complete response after completion of therapy was achieved in 22 (85%) of 26 patients. The median EFS was 38 months. The median OS has not yet been reached. At a median follow-up of 33 (25-43) months, actuarial EFS and OS were 54% (95% confidence interval (CI), 39-69%) and 69% (95% CI, 56-79%), respectively. This double transplant approach lasts only 14 weeks and is feasible, safe, and tolerable. Whilst selection biases may in part contribute to favorable EFS and OS, a randomized comparison of standard therapy vs double transplant in both metastatic and locally advanced breast cancer is warranted.     

Prognostic significance of the immunocytochemical detection of contaminating tumor cells (CTC) in apheresis products of patients with high-risk breast cancer treated with high-dose chemotherapy and stem cell transplantation

The aim of this study was to determine whether the detection of CTC in the apheresis product contribute significantly to treatment failure of patients with high-risk breast carcinoma treated with high-dose chemotherapy (HDC) and stem cell transplantation (SCT). Patients were with stage II and III adenocarcinoma of the breast with > or = 10 axillary lymph nodes affected after primary surgery (> or = 10 N+) who had received HDC with SCT. We analyzed retrospectively the presence of CTC as assessed by immunocytochemistry (ICC) in the apheresis products obtained after standard adjuvant chemotherapy. We compared the clinical outcome of patients who received HDC and SCT with or without CTC-positive apheresis. One hundred and twenty-seven apheresis products samples were obtained from 51 patients. Fourteen (27.4%) of these samples were CTC positive. After a median follow-up of 4.6 years, 20 patients have relapsed, 14 died from progression of their disease and 30 patients remain alive and free of progression. For the whole group of patients the 5 year probabilities of DFS and OS were 60% (IC 95%, 47-75%) and 71% (IC 95%, 55-83%), respectively. However, the 5 year probabilities of DFS were 23% (IC 95%, 0-46) and 75% (IC 95%, 60-89) for patients with CTC positive and negative, respectively. The 5 year probabilities of OS were 42% (IC 95%, 15-68) and 83% (IC 95%, 70-95) for patients with CTC positive and negative, respectively. Both univariate and multivariate analysis showed that the presence of CTC in the apheresis product was the only prognostic factor associated with a higher incidence of clinically overt disease relapse (P = 0.002) and shorter survival (P = 0.003). The presence of cytokeratin-positive metastatic cells in the apheresis product increases the risk of relapse after HDC and SCT in patients with stage II and III adenocarcinoma of the breast with > or = 10 N+.     

High-dose chemotherapy as a consolidation approach in advanced ovarian cancer: long-term results.

The aim of this study was to assess the long-term impact of high-dose chemotherapy (HDC) as consolidation in a large series (n = 55) of advanced chemosensitive ovarian cancer patients who were optimally cytoreduced at time of first surgery or at interval debulking surgery (IDS). HDC consisted of carboplatin (600 mg/m(2) days 1 and 2), etoposide (450 mg/m(2) days 1 and 2) and melphalan (50 mg/m(2), days 3 and 4). The primary endpoint of the study was the assessment of time to progression (TTP) and overall survival (OS). In September 2000 the overall population had a median follow-up of 55 months (range 17--137) and a TTP of 35 months with a 5-year TTP rate of 35% (CI 95%: 21--49) whereas OS averaged 75 months with a 5-year OS of 59% (CI 95%: 45--73). In patients achieving optimal primary cytoreduction the median TTP was 44 months with a 5-year rate of 43% (CI 95%: 26--60). In the same series the 5-year OS rate was 62% (CI 95%: 45--79) (median OS = 75 months). In patients who were optimally cytoreduced at the time of IDS the median TTP was 25 months and the 5-year TTP rate was 22% (CI 95%: 3--41) and median OS was 46 months with a 5-year OS rate of 50% (CI 95%: 27--73). HDC with hematopoietic support could represent an effective approach for the treatment of advanced optimally cytoreduced ovarian cancer patients with chemosensitive disease. Patients who underwent IDS because of unresectable tumors at the time of first surgery had the greater survival benefit from HDC.     

Outcome of 67 patients with solid tumors relapsed after high-dose chemotherapy and peripheral blood stem cell transplantation

We retrospectively analyzed the outcome of 67 patients with breast (n=24), ovarian (n=11) or testicular cancer (n=32) treated for relapse after high-dose chemotherapy (HDC) and peripheral blood stem cell (PBSC) transplantation. Treatment, survival and toxicity were analyzed. Patients with breast, ovarian or testicular cancer received a mean of 5.9 (range 1-24), 5.1 (1-13) and 4.6 (1-13) regimens for relapse after HDC. Overall response at the end of the observation period was 20.8% for patients with breast cancer (three complete (CR) and two partial responses (PR)), 45.5% (one CR, four PR) for ovarian and 9.4% (three PR) for testicular cancer patients. The mean overall-survival (OAS) from first relapse was 28 (range 3-44), 17 (2-24) and 10 (1-28) months, respectively. Leukocytopenia grade 3/4 occurred in 27-63% of patients, and thrombocytopenia grade 3/4 was observed in 58-88%, respectively. Nonhematological grade 3/4 toxicities were below 20%. In conclusion, patients with relapse after HDC usually have a poor outcome but long-term survivors are observed. Hematological toxicity is common, while other severe side effects are less frequent.     

Randomized trial of low-dose interleukin-2 vs cyclosporine A and interferon-gamma after high-dose chemotherapy with peripheral blood progenitor support in women with high-risk primary breast cancer

High-risk primary breast cancer patients treated with high-dose chemotherapy (HDC) and stem cell support (SCS) have shown prolonged disease-free survival (DFS) in many studies; however, only one trial has demonstrated an overall survival benefit (OS). We hypothesize that the period following myeloablative therapy is ideal for immunologic manipulation and studied the effects of two different methods of immunotherapy following HDC with SCS aimed at the window of immune reconstitution. Seventy-two women with high-risk stage II or III breast cancer were randomized following HDC to receive either interleukin 2 (IL-2) at 1 million units/m(2) SQ daily for 28 days or combined cyclosporine A (CsA) at 1.25 mg/kg intravenously daily from day 0 to +28 and interferon gamma (IFN-gamma) 0.025 mg/m(2) SQ every 2 days from day +7 to +28. At a median follow-up of 67 months, no significant difference was observed in DFS or OS between the two treatment groups. The IL-2 arm had a 59% DFS (95% CI (0.45, 0.78)) and a 72% OS (95% CI (0.58, 0.88)) at 5 years. The CsA/INF-gamma arm had a similar outcome with a 55% DFS (95% CI (0.40, 0.76)) and a 78% OS (95% CI (0.65, 0.94)) at 5 years. Treatment was well tolerated, without increased toxicity.     

Preoperative high-dose chemotherapy with peripheral blood stem cell support as a primary management of locally advanced breast cancer

Locally advanced breast cancer (LABC) has a poor prognosis with a high risk of local recurrence and distant metastasis. Preoperative combined chemotherapy with or without granulocyte colony-stimulating factor (G-CSF) support does not improve the long-term survival rate. In our report, two patients with LABC received preoperative high-dose chemotherapy with peripheral blood stem cell support (HDC/PBSCs). Prior to high-dose chemotherapy with peripheral blood stem cell support, they both received induction chemotherapy of cyclophosphamide, epirubicin and 5-fluorouracil (FEC) for two cycles which resulted in a partial response. PBSC mobilization and collection were carried out following the second cycle of induction chemotherapy followed by G-CSF. High-dose cyclophosphamide (2500 mg/m2), carboplatin (600 mg/m2) and etoposide (600 mg/m2) were administered with PBSC support. A radical mastectomy was performed followed by adjuvant chemotherapy with FEC regimen for four cycles, followed by local irradiation, and endocrine therapy with tamoxifen. Both patients achieved a remarkable response in the primary lesion after HDC/PBSCs and tolerated the whole treatment well. Preoperative HDC/PBSCs as a new strategy in the treatment of LABC seems practical but it needs to be studied more deeply.     

High-dose chemotherapy and CD34-selected peripheral blood progenitor cell transplantation for patients with breast cancer metastatic to bone and/or bone marrow.

Fifty women with breast cancer metastatic to bone or bone marrow involvement on light microscopy at the time of initial evaluation were treated with high-dose chemotherapy (HDC) and peripheral blood progenitor cell (PBPC) transplantation with CD34(+) cell selection using the Isolex 300i system. All patients received induction chemotherapy. PBPC were mobilized with chemotherapy and granulocyte colony-stimulating factor. The median CD34(+) progenitor purity was 94.7% (range 72-98.7%) and recovery 38.4% (range 21-60%). Forty-eight hours after HDC with cyclophosphamide, cisplatin and carmustine, PBPC were reinfused. Median time to neutrophil count >0.5 x 10(9)/l was 9 (range 9-12) days and to platelet transfusion independence 11 (4-30) days. These data demonstrate that selected CD34(+) PBPCs allow rapid hematologic reconstitution after HDC. During follow-up, 23% of patients developed herpes zoster. Two patients developed cytomegalovirus infections. Three patients developed fungal infections. The development of these infections was not associated with steroid use but appeared more frequently in patients with diabetes mellitus. Seventy-four per cent of patients received steroids for pulmonary toxicity. Treatment-related mortality was 4%. Progression-free survival and overall survival at 35 months was 22.4% and 40.5%, with a median of 11.4 months and 15.4 months, respectively.     

HER2 overexpression as a prognostic factor in metastatic breast cancer patients treated with high-dose chemotherapy and autologous stem cell support

We retrospectively evaluated the predictive and prognostic role of HER2 expression in 44 metastatic breast cancer (MBC) patients treated with high-dose consolidation chemotherapy (HDCT) and autologous stem cell support after induction chemotherapy (IC) with six courses of epirubicin+paclitaxel (22 patients) or gemcitabine+epirubicin+paclitaxel (22 patients). HER2 expression was evaluated by an immunohistochemical method (Herceptest, Dako). A total of 13 patients (29.5%) showed a HER2 overexpression (score 3+). After IC, nine patients were in complete response (CR), 30 in partial response (PR), and five in stable disease (SD); after HDCT, 20 (45.5%) obtained a CR, and 23 were in PR, for a conversion rate of 48.5%. Conversion rate for HER2-positive patients was 87.5 vs 37% for HER2-negative patients (P=0.018). The median progression-free (PFS) and overall survivals (OS) were 17.6 (95% CI 13.2-22.0) and 44 (95% CI 25.9-62.3) months, respectively. Patients with HER2 overexpression experienced a significantly (P=0.0042) shorter median PFS (15.3 months, 95% CI 11.1-19.5) compared to HER2-negative patients (21.3 months, 95% CI 14.3-28.4). The median OS was 27.6 months (95% CI 4.5-50.7) in HER2-positive patients and 50.3 months (95% CI 38.7-62.0) in HER2-negative patients (P=0.345). These results indicate that HER2 overexpression predicts a worse outcome for patients with MBC treated with HDCT, despite the high CR rate obtained in this subset of patients.     

Tandem and triple high-dose chemotherapy with autologous stem cell rescue in metastatic breast cancer

The purpose of this phase II study was to evaluate the therapeutic efficacy and toxicity of a tandem or triple high-dose chemotherapy (HDC) with autologous peripheral blood stem cell transplantation (PBSCT) in patients with metastatic breast cancer (MBC) as first line chemotherapy. Conventional chemotherapy consisted of two cycles of epirubicin 120 mg/m² and ifosfamide 7500 mg/m² in the case of tandem HDC and one cycle of paclitaxel 135 mg/m², epirubicin 90 mg/m² and ifosfamide 6000 mg/m² in the case of triple HDC. Tandem HDC was composed of two cycles of epirubicin 180 mg/m², ifosfamide 12000 mg/m² and carboplatin 900 mg/m². In the case of triple HDC, paclitaxel 180 mg/m², etoposide 1500 mg/m² and thiotepa 600 mg/m² was added as the third cycle. Patients with tandem HDC (n = 20) were evaluable for both survival and toxicity, and patients with triple HDC (n = 21) only for toxicity because of short-term follow-up. Both tandem and triple HDC were well tolerated and could be safely administered. Non-hematological WHO grade 3 or 4 toxicities were mucositis (8), temporary renal insufficiency (1), myocardial infarction (1), and neuropathy (1). No toxic death occurred. The Kaplan-Meier estimates for 44-months without progression and the overall survival were 12% and 38% respectively. The median survival was 22 months (95% CI: 7.4–51.7 months) and the median progression-free interval 14 months (95% CI: 5.1–43.7 months). In a population with an unfavorable prognosis, tandem HDC showed similar efficacy as to that described in other phase II studies. Triple HDC seems not to improve patient outcome compared to tandem HDC, but a long-term follow up is required. Received: 20 April 1998 / Accepted: 6 August 1998     

Effect of induction chemotherapy and tandem cycles of high-dose chemotherapy on outcomes in autologous stem cell transplant for metastatic breast cancer

We assessed the effect standard-dose induction chemotherapy and tandem cycles of high-dose chemotherapy (HDC) have on outcomes in metastatic breast cancer. One hundred and one women with metastatic breast cancer were enrolled in two non-randomized phase II studies. The first group of 64 patients (induction group) received four cycles of docetaxel 75 mg/m2 and doxorubicin 50 mg/m2. The next 37 patients did not receive induction (no induction group). Both groups received two (tandem) cycles of HDC. Blood-derived stem cells were collected after the first HDC cycle, processed using CD34+ cell selection and then reinfused after the second HDC cycle. Outcomes were compared between the two groups and also to patients participating in the Philadelphia (inter-group) randomized metastatic breast cancer transplant trial (PBT-01). Intent-to-treat analysis revealed no significant differences in complete response rates (37.5% vs 27%; P = 0.20), overall response (75% vs 71%), median progression free survival (PFS) (11.9 vs 8 months; P = 0.24) and overall survival (OS) (>36 vs 25 months; P = 0.16), in the induction vs no induction groups, respectively. Adjusting for differences in known baseline characteristics, induction group patients were found to have significantly longer PFS (P = 0.002), OS (P = 0.01) and more frequent conversion from a partial to complete response (58% vs < or = 13%, P < or = 0.0002) when compared with PBT-01 patients. Induction chemotherapy administered prior to tandem cycles of HDC does not appear to adversely affect outcomes in metastatic breast cancer patients. Outcomes in our induction group also compare favorably with those observed in PBT-01 and warrant further clinical investigation.     

Femoral head necrosis in three patients with relapsed ovarian cancer receiving high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation

We report three patients with relapsed ovarian cancer who developed femoral head necrosis requiring endoprosthetic hip surgery 16-35 months after high-dose chemotherapy (HDC) with treosulfan (47 and 56 g/m(2) body-surface area (BSA)) given as 3-25 h infusions and followed by autologous peripheral blood stem cell (PBSC) transplantation. One woman received two courses of single agent treosulfan while the other two patients received one course of high-dose treosulfan either preceded or followed by high-dose carboplatin, etoposide and cyclophosphamide. A total of 30 women with ovarian cancer were treated with HDC at our unit and 21 of them received treosulfan-containing regimens. Femoral head necrosis was not observed in patients either receiving conditioning regimens without treosulfan (n=9) or when the total treosulfan dose was given over 3 consecutive days (n=3) or in patients with a diagnosis other than ovarian cancer and treated with high-dose treosulfan (n=10). We conclude that women with relapsed ovarian cancer receiving HDC with excessive single-dose treosulfan might be at an increased risk of developing bone necrosis.     

吉非替尼单药治疗晚期非小细胞肺癌的疗效与安全性

目的 探讨吉非替尼治疗晚期非小细胞肺癌(NSCLC)的疗效与安全性.方法 分析2002年10月-2006年4月在北京协和医院呼吸科接受吉非替尼(250 mg/d)治疗的晚期NSCLC患者的临床资料,用Kaplan-Meier方法 计算中位生存期,用多因素Cox回归法分析不同因素对生存期的影响.结果 (1)共入选204例患者,中位生存期为16.3个月(95% CI 14.5～18.2个月).1年生存率为57%.疾病客观有效率、稳定率分别为31.4%、41.7%.(2)未接受过化疗的26例患者的中位生存期16.0个月(95% CI 13.7～18.3个月),接受过化疗的人群中位生存期16.5个月(95% CI 14.2～18.8个月),差异无统计学意义(P=0.758).(3)204例患者中142例患者疾病进展,进展后58例停止服药,84例继续服药至死亡或仍在服药,2组的生存期分别为19.9个月(95% CI 13.1～26.7个月)、16.4个月(95% CI 14.2～18.6个月),差异无统计学意义(P=0.534).(4)多因素Cox回归分析显示,ECOG体能评分、病理类型、吉非替尼的客观疗效、化疗后复发、呼吸困难的变化与生存期明显相关.客观有效率与患者年龄、吸烟状况、病理类型、呼吸困难变化、皮疹显著相关.(5)不良反应一般较轻(1度或2度),停药后可逆.最常见的不良反应为皮疹72.6%(138/190)、腹泻33.7%(64/190).结论 晚期NSCLC患者接受吉非替尼治疗的耐受性好,对化疗失败的患者可明显延长生存时间.     

Multivariate analysis of survival in inflammatory breast cancer: impact of intensity of chemotherapy in multimodality treatment

The prognosis of inflammatory breast cancer (IBC) is poor. We evaluated clinical and biopathological characteristics that could affect survival in 74 women with nonmetastatic IBC consecutively treated in our institution between 1976 and 2000. Patients received primary anthracycline-based chemotherapy at conventional doses (n=20) or high-dose chemotherapy (HDC) with haematopoietic stem cell support (HSCS) (n=54). After chemotherapy, 84% of patients underwent mastectomy, 95% were given radiotherapy and 55% tamoxifen. Immunohistochemistry data (ER, PR, ERBB2, P53) on pre-chemotherapy specimens suggested strong differences between IBC and non-IBC. The rate of pathological complete response to chemotherapy was 26% (27% with HDC and 17% with conventional doses, not significant). No single factor was found predictive of response. With a median follow-up of 48 months after diagnosis, the 5-year projected disease-free survival (DFS) was 24% and overall survival (OS) 41%. In multivariate analysis, the strongest independent prognostic factor was the delivery of HDC. The 5-year DFS and OS of patients were respectively 28 and 50% with HDC and 15 and 18% with conventional chemotherapy. These results and comparisons with other series of patients suggest a role for HDC with HSCS as part of the therapeutic approach in IBC. Further prospective studies are required to confirm it.     

Flt3 ligand and thrombopoietin serum levels during peripheral blood stem cell mobilization with chemotherapy and recombinant human glycosylated granulocyte colony-stimulating factor (rhu-G-CSF,lenograstim) and after high-dose chemotherapy

The purpose of this investigation was to study thrombopoietin (TPO) and Flt3 ligand (FL) serum levels in the course of peripheral blood stem cell (PBSC) mobilization and high-dose chemotherapy (HDC) and to correlate the values with stem cell yield and engraftment. Thirty-nine patients were included. PBSC were mobilized by chemotherapy followed by two body surface area-dependent doses of glycosylated recombinant human granulocyte colony-stimulating factor (rhu-G-CSF, lenograstim). PBSC could be harvested in 35 patients and 30 received a total of 62 courses of HDC (1-3 per patient). Fifty-six were analyzed and TPO and FL serum levels were measured at the start of PBSC mobilization, at the first PBSC collection, on the day of PBSC infusion, and until engraftment. Mean baseline TPO and FL serum levels were 173 pg/ml and 192 pg/ml and increased to 493 and 323 pg/ml at the start of PBSC collection. Maximum values were 2279 pg/ml TPO after HDC 1 and 2375 pg/ml after HDC 2, while the mean maximum serum levels for FL were 1181 and 1236 pg/ml after HDC 1 and 2 and PBSC transfusion, respectively. FL serum levels at the start of PBSC mobilization correlated with the total yield of CD34+ cells (17.61+/-18.8x10(6)/kg body weight, r=0.81), while TPO serum levels on days 11-13 after PBSC infusion were inversely correlated with the amount of transfused CD34+61+62+ cells (r=-0.88 and -0.79 for HDC 1 and 2). There was no strong correlation between TPO or FL serum levels and WBC and platelet engraftment. In conclusion, chemotherapy followed by glycosylated rhu-G-CSF induced elevated serum levels of TPO and to a lower degree of FL at the start of PBSC collection. The maximum increase was 13.7-fold for TPO and 6.4-fold for FL after PBSC infusion indicating endogenous release which should be considered if the clinical use of these cytokines is intended in this setting.     

Cardiac sequelae of doxorubicin and paclitaxel as induction chemotherapy prior to high-dose chemotherapy and peripheral blood progenitor cell transplantation in women with high-risk primary or metastatic breast cancer

Doxorubicin plus paclitaxel has been shown to be an active regimen for metastatic breast cancer and is now frequently used as adjuvant therapy for high-risk primary breast cancer. Initial studies reported a higher than expected rate of cardiac toxicity with this regimen. We studied 105 patients with either high-risk primary breast cancer or metastatic breast cancer who were treated with doxorubicin (60 mg/m2) and 3-h infusions of paclitaxel (175 mg/m2) cycled every 3 weeks. Patients received three cycles of chemotherapy for high-risk primary or four cycles for metastatic disease. Patients then proceeded to high-dose chemotherapy (HDC) (STAMP I cyclophosphamide, cisplatin and carmustine) and peripheral blood progenitor cell transplantation (PBPCT). Patients underwent radionuclide multi-gated angiograms (MUGA) before and following induction chemotherapy and following HDC. During induction chemotherapy 40 (38%) of the patients had a reduction in left ventricular ejection fraction (LVEF). Fourteen had a decrease of 20% or greater and two were mildly symptomatic from CHF. There was additional reduction in the LVEF after HDC with a median value for LVEF of 59% (range, 20-78%). During HDC 10 patients developed clinical signs of congestive heart failure (CHF). Five patients responded to diuretic therapy and did not require any additional treatment. Four patients responded to vasodilation and/or digoxin with improvement in cardiac function. A clinically significant decrease in cardiac function was found in a small number of patients after induction chemotherapy and HDC with PBPCT. The majority of the patients tolerated this regimen without problems. Although there was a decline in LVEF as measured by radionuclide MUGA this did not prevent the majority of patients from proceeding with HDC. Bone Marrow Transplantation (2000).     

High-dose chemotherapy with autologous haemopoietic support for advanced ovarian cancer in first complete remission: retrospective analysis from the Solid Tumour Registry of the European Group for Blood and Marrow Transplantation (EBMT)

The majority of advanced ovarian cancer patients achieve an objective response following chemotherapy; however, only 20-30% are in remission after 5 years. Intraperitoneal or high-dose chemotherapy (HDC) may prolong disease-free and overall survival (OS) in patients with platinum-sensitive, small volume disease. To better define the subsets of patients who might benefit from HDC, we performed a retrospective analysis on 91 patients in 1st complete remission (CR) treated from 21 centres of the EBMT group. At a median follow-up of 48 months, median time-to-progression (TTP) and OS were 21.2 and 44.4 months, respectively. Tumour grade, stage, residual disease, disease status before HDC, type and year of transplant, source of haemopoietic progenitors and use of haemopoietic growth factors (HGF) after transplant were analysed for TTP and OS. The only significant parameter was the use of HGF: median OS for patients receiving or not receiving HGF was 46.2 vs 17.8 months, respectively (P: 0.035); this difference was maintained after multivariate analysis (P: 0.02). Our analysis does not identify any subgroup of patients in 1st CR who can benefit from HDC; however, median survival of patient with no residual disease has not been reached. The role of HGF after HDC deserves further investigation.     

Chronic graft-versus-host disease after allogeneic blood stem cell transplantation: long-term results of a randomized study

The use of peripheral blood stem cells (PBSCs) is rapidly growing in the allogeneic transplantation setting as an alternative to bone marrow (BM). We previously reported a higher incidence of chronic graft-versus-host disease (cGVHD) associated with allogeneic PBSC transplantation in a randomized trial. In this follow-up report, we analyzed the evolution of cGVHD in the patients (n = 101) enrolled on this study. At a median follow-up of 45 months (range, 31-57 months), we found that the 3-year cumulative incidence of cGVHD was 65% (95% confidence interval [CI] 51%-78%) in the PBSC group and 36% (95% CI 23%-49%) in the BM group (P =.004). We also found that extensive cGVHD was more frequent in the PBSC group (44% [95% CI 30%-58%] vs 17% [95% CI 7%-27%]; P =.004). The prevalence of cGVHD was always higher in the PBSC arm. Ocular involvement was more frequent in PBSC recipients (P =.02). Cutaneous and liver involvement was similar among BM and PBSC recipients. Chronic GVHD required multiple courses of immunosuppressive therapy in addition to cyclosporine and corticosteroids during longer periods (P =.03). Altogether, this translated into longer periods of hospitalization after transplantation in the PBSC group (P =.04). Finally, we also confirm that cGVHD after PBSC transplantation is associated with an antileukemic effect that is at least as potent as after BM. However, to date, this has not translated into a survival difference, possibly due to the early-stage leukemic status of these patients or to the relatively small size of the study population.     

Bone Marrow Transplantation: Prognostic Factors of Peripheral Blood Stem Cell Mobilization with Cyclophosphamide and Filgrastim (r-metHuG-CSF): The CD34+ Cell Dose Positively Affects the Time to Hematopoietic Recovery and Supportive Requirements after High-Dose Chemotherapy

To prospectively analyze factors that influence peripheral blood stem cell (PBSC) collection and hematopoietic recovery after high-dose chemotherapy (HDC), 39 patients received cyclophosphamide 4 g/m(2) and rHuG-CSF (Filgrastim) 5 &mgr;g/kg/day. Leukapheresis was started when CD34(+) cells/mL were > 5 x 10(3). A minimum of 2 x 10(6) CD34(+) cells/kg was collected. Median steady-state bone marrow CD34(+) cell percentage was 0.8% (range, 0.1 to 6). Thirty-two patients received HDC with autologous PBSC transplantation plus Filgrastim. A median of 2 (range, 0 to 6) leukapheresis per patient were performed and a median of 6.3 x 10(6) CD34(+) cells/kg (range, 0 to 44.4) collected; four patients failed to mobilize CD34(+) cells. The number of cycles of prior chemotherapy had an inverse correlation with the number CD34(+) cells/kg collected (r = -0.38; p < 0.005). Patients with <7 cycles had a higher predictability for onset of leukapheresis than patients with (3) 7 (93% versus 50%; p < 0.005). The four patients who failed to mobilize had received >/=7 cycles. The number of CD34(+) cells/kg infused after HDC had an inverse correlation with days to recovery to 0.5 x 10(9) neutrophils/L and 20 x 10(9) platelets/L (r = -0.68 and -0.56; p < 0.005). The effect of these factors on mobilization and hematopoietic recovery were confirmed by multivariate analysis. Requirements for supportive measures were significantly lower in patients given a higher dose of CD34(+) cells/kg. Therefore, PBSC collection should be planned early in the course of chemotherapy. Larger number of CD34(+) cells/kg determined a more rapid hematopoietic recovery and a decrease of required supportive measures.     

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.