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.     

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.     

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).     

Expression of C-erbB-2/HER-2 in patients with metastatic breast cancer undergoing high-dose chemotherapy and autologous blood stem cell support.

C-erbB-2/HER-2 (designated HER-2) is overexpressed in both primary and metastatic breast cancer and predicts poor prognosis. We investigated the expression of HER-2 in patients with metastatic breast cancer undergoing high-dose chemotherapy (HDCT) with autologous blood stem cell (ABSC) support and correlated the presence (positive) or absence (negative) of HER-2 overexpression in these patients with response to treatment, progression-free survival (PFS) and overall survival (OS). The level of HER-2 expression was analyzed in 57 patients with metastatic breast cancer undergoing HDCT with ABSC support. Plasma from peripheral blood was taken at three different time points during the course of treatment and was analyzed using an enzyme immunoassay (EIA) to detect circulating levels of the extracellular portion of HER-2. HER-2 levels were elevated (>0.2 U/mg protein) in 27/57 (47.4%) patients at one or more time points during treatment. The level of HER-2 varied during the course of treatment. Following induction chemotherapy (ICT), five patients who were negative initially, showed overexpression of HER-2. Three patients overexpressed HER-2 only after HDCT/ABSC. Response to treatment was similar in patients independent of plasma HER-2 levels. Overexpression of HER-2 was associated with a significantly shorter PFS (P = 0.004, log rank) and OS (P = 0.003, log rank) after HDCT/ABSC. HER-2 overexpression, patient age, estrogen receptor status, progesterone receptor status, and previous hormone treatment were assessed by univariate and multivariate analysis. Univariate analysis determined that only HER-2 overexpression correlated significantly with decreases in progression free survival (P = 0.005, Cox regression). Decreased overall survival correlated significantly with HER-2 overexpression (P = 0.004) and decreased expression of both estrogen receptor (P = 0.032) and progesterone receptor (P = 0.039). In multivariate analysis of these variables, only HER-2 expression levels proved to be of independent statistical significance in predicting outcome for both PFS (P = 0.007) and OS (P = 0.002). These results suggest that overexpression of HER-2, measured by EIA in plasma may predict a shorter PFS and OS in patients with metastatic breast cancer treated with HDCT and ABSC support.     

HER-2 expression is a prognostic factor in patients with metastatic breast cancer treated with a combination of high-dose cyclophosphamide, mitoxantrone, paclitaxel and autologous blood stem cell support

The expression levels of a circulating extracellular domain of HER-2 can be detected in the plasma and serum of patients with metastatic breast cancer using an enzyme immunoassay (ELISA) method. In this study, we evaluated the clinical significance of high and low levels of HER-2 in the plasma of 46 patients with metastatic breast cancer enrolled in a clinical trial of high-dose chemotherapy (HDCT) using cyclophosphamide, mitoxantrone, and paclitaxel with autologous stem cell transplantation (ASCT). Using 2500 U/ml as the cut-point, 20 patients (46%) had elevated HER-2 levels (HER-2 positive). Our results suggest that patients with metastatic breast cancer and high soluble plasma HER-2 have a significantly poorer overall (OS) and progression-free survival (PFS) following high-dose chemotherapy with paclitaxel and ASCT. The median OS of patients with low levels of HER-2 was significantly longer (P < 0.01) than the median OS of patients with high levels of HER-2 (29.8 months vs 15.9 months). PFS was also significantly longer (P < 0.01) for patients who were HER-2-negative, than for patients who were HER-2-positive (13.0 vs 8.6 months). Univariate analysis showed that patients with liver or lung metastases had significantly reduced OS and PFS. Patients with metastases to two or more sites also had a significantly reduced time to disease progression, but not OS. In multivariable analysis, lung metastases contributed along with HER-2-positive status to determine a group of patients with significantly poorer OS. However, HER-2-positive status remained the only independent predictor of PFS.     

Pegase 03: a prospective randomized phase III trial of FEC with or without high-dose thiotepa, cyclophosphamide and autologous stem cell transplantation in first-line treatment of metastatic breast cancer

Pegase 03 is a multicenter prospective randomized phase III trial evaluating the impact of first-line high-dose chemotherapy (HDC) with stem cell support on overall survival (OS), disease-free survival (DFS) and response rate in 308 patients with histologically proven metastatic breast cancer responding to induction therapy. Eligible patients received four induction cycles with FEC 100 (5-fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2), cyclophosphamide 500 mg/m(2)). Patients with objective response (N=179) were randomized to one cycle of HDC (cyclophosphamide 6000 mg/m(2) and thiotepa 800 mg/m(2) (CHUT)) and stem cell support (N=88), or no further treatment (N=91). All patients were observed until disease progression or death. One toxic death occurred after CHUT. Other toxicities were manageable. The response rate at 3 months was higher in the intensification arm: 82.7% (25.3% complete response (CR)) versus 59.2% (14.1% CR) (P=0.0002). Median follow-up was 48 months. Median DFS was 11 and 6.6 months in the intensification and the observation arms, respectively (P=0.0001). There was no survival difference: 33.6 versus 27.3% OS at 3 years (P=0.8) and 22.9 versus 22.3 months median time to relapse in the intensification and observation arms, respectively. In this randomized trial, HDC with CHUT improved DFS but not OS, corroborating findings from earlier trials.     

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.     

Irreversible electroporation after induction chemotherapy versus chemotherapy alone for patients with locally advanced pancreatic cancer: A propensity score matching analysis

BackgroundLocally advanced pancreatic cancer (LAPC) is a devastating disease and irreversible electroporation (IRE) is a non-thermal ablation method that is especially suitable for the treatment of LAPC. This study aimed to compare the long-term survival of LAPC patients after induction chemotherapy followed by IRE and chemotherapy alone.MethodsFrom August 2015 to August 2017, a total of 132 patients with LAPC were identified. The oncological outcomes of these two treatments were analyzed by propensity score matching (PSM) analysis.ResultsBefore PSM analysis, patients with LAPC had better overall survival (OS) and progression-free survival (PFS) after induction chemotherapy followed by IRE than those who received chemotherapy alone (2-year OS rates, 57.9% vs 19.8%, P < 0.001; 2-year PFS rates, 31.4% vs 9.3%, P < 0.001). The baseline clinicopathological factors were balanced between the 2 groups through PSM analysis. Even after PSM, the OS and PFS rates of patients after induction chemotherapy followed by IRE treatment were superior to those of patients who received chemotherapy treatment alone (2-year OS rates, 57.9% vs 18.1%, P < 0.001; 2-year PFS rates, 31.4% vs 7.1%, P < 0.001). Multivariate Cox regression analysis indicated that chemotherapy plus IRE was a significant prognostic factor for both OS and PFS in patients of both the whole cohort and the matched cohort.ConclusionsInduction chemotherapy followed by IRE provided better OS and PFS than chemotherapy alone for patients with LAPC. This combination method may be a more suitable treatment for patients with LAPC.     

联合化疗方案治疗老年晚期胃癌的临床疗效和安全性分析

目的探讨临床常用晚期胃癌联合化疗方案治疗老年胃癌的临床疗效和安全性。方法回顾性研究2010年1月至2012年12月期间一线接受联合化疗的老年（年龄≥65岁）晚期胃癌患者20例。化疗2月后评价疗效,化疗期间监测药物毒性反应,对无进展生存时间（PFS）和总生存期（OS）进行随访。结果接受联合化疗的老年胃癌患者客观缓解率为15%,疾病控制率为90%,中位PFS和OS分别为6月和20.1月;分层分析显示仅肿瘤分期与患者PFS（P〈0.01）和OS（P〈0.01）显著相关,与年龄（≤75岁vs〉75岁）或化疗方案无关;化疗期间全部Ⅲ~Ⅳ度药物毒性反应的发生率为35%。结论采用联合化疗方案治疗晚期老年胃癌患者毒性反应在可耐受范围内,并可带来生存获益,方案和剂量的选择值得进一步临床研究。     

Autologous hematopoietic stem cell transplantation for breast cancer in Europe: critical evaluation of data from the European Group for Blood and Marrow Transplantation (EBMT) Registry 1990-1999

The aim of this study was to identify trends in high-dose chemotherapy (HDC) with autologous hematopoietic stem cell transplantation (ASCT) and to assess survival in a large cohort of breast cancer (BC) patients receiving this therapy in Europe from 1990 to 1999. A total of 7471 patients who received HDC with ASCT between January 1, 1990 and December 31, 1999 were reported to the European Group for Blood and Marrow Transplantation Registry. Data required for demographics and survival analysis were available for 2679 patients with high-risk primary BC; 921 patients with inflammatory BC (IBC), and 2295 patients with metastatic disease. The main evaluation parameters were progression-free survival (PFS) and overall survival (OS). Between 1990 and 1998, autotransplants for BC increased 30-fold. Significant trends included use of blood-derived rather than marrow-derived stem cells, increment of reporting centers and decrease of mortality within 100 days from transplantation. The 5-year PFS and OS probabilities were 53 and 68% for high-risk disease and 42 and 53% for IBC, respectively. For metastatic disease 5-year PFS and OS probabilities in the whole cohort were 18 and 27%, respectively, while for women transplanted in complete remission the 5-year PFS was 29%. In conclusion, HDC with ASCT has been increasingly used until 1998 and the 100-day mortality rate has been constantly less than 2% from 1995 to date. The 5-year survival of high-risk BC is related to the number of axillary nodes involved at surgery. Outcome of patients with IBC is encouraging, suggesting the need for randomized trials. Patients with metastatic disease responding to pretransplant chemotherapy and harboring ER+ tumors have a better outcome.     

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.     

A short course of induction chemotherapy followed by two cycles of high-dose chemotherapy with stem cell rescue for chemotherapy naive metastatic breast cancer

A single cycle of high-dose chemotherapy with stem cell support (HDC) in women with responsive metastatic breast cancer (BC) consistently achieves over 50% complete and near complete response (CR/nCR). This significant cytoreduction results in a median event-free survival (EFS) of 8 months, and approximately 20% 3-year and 16% 5-year EFS in selected patients. To improve long-term outcomes, new strategies to treat minimal residual tumor burden are needed. Increased total dose delivered can be achieved with two cycles of HDC. Critical design issues include shortening induction chemotherapy to avoid development of drug resistance and the use of different agents for each HDC cycle. We have determined the maximum tolerated dose (MTD) for paclitaxel combined with high-dose melphalan in the context of a double transplant and explored the impact of a short induction phase. Between June 1994 and August 1996, we enrolled 32 women with metastatic BC on to this phase I double transplant trial. Induction consisted of doxorubicin 30 mg/m2/day days 1-3 given for 2 cycles every 14 days with G-CSF 5 microg/kg s.c. days 4-12. Stem cell collection was performed by leukapheresis in each cycle when the WBC recovered to above 1000/microl. Patients with stable disease or better response to induction were eligible to proceed with HDC. HDC regimen I (TxM) included paclitaxel with dose escalation from 0 to 300 mg/m2 given on day 1 and melphalan 180 mg/m2 in two divided doses given on day 3. HDC regimen II was CTCb (cyclophosphamide 6 g/m2, thiotepa 500 mg/m2, and carboplatin 800 mg/m2 total doses) delivered by 96-h continuous infusion. At the first dose level of 150 mg/m2 paclitaxel by 3 h infusion, four of five patients developed dose-limiting toxicity consisting of diffuse skin erythema and capillary leak syndrome. Only two of these five completed the second transplant. Subsequently, paclitaxel was delivered by 24-h continuous infusion together with 96 h of dexamethasone and histamine receptor blockade. This particular toxicity was not observed again. No toxic deaths occurred and dose-limiting toxicity was not encountered. Three patients were removed from study prior to transplant: one for insurance refusal and two for disease progression. All others completed both cycles of transplant. Complete and near complete response (CR/nCR) after completion of therapy was achieved in 23 (72%) of 32 patients. The median EFS is 26 months. The median overall survival has not yet been reached. At a median follow-up of 58 months, EFS and overall survival are 41% and 53%, respectively. This double transplant approach is feasible, safe, and tolerable. Treatment duration is only 14 weeks and eliminates lengthy induction chemotherapy. The observed event-free and overall survivals are promising and are better than expected following a single transplant. Whilst selection biases may in part contribute to this effect, a much larger phase II double transplant trial is warranted in preparation for a potential randomized comparison of standard therapy vs single vs double transplant.     

High-dose melphalan-based chemotherapy and autologous stem cell transplantation after second look laparotomy in patients with chemosensitive advanced ovarian carcinoma: long-term results

The importance of dose intensity has been suggested in ovarian carcinoma. We retrospectively evaluated the long-term results of melphalan-based high-dose chemotherapy (HDC) with hematopoietic rescue in a unicentric series of 33 patients with advanced ovarian cancer sensitive to first-line chemotherapy. Before HDC, treatment with debulking surgery and platinum-based chemotherapy was followed by second-look operation (SLO). HDC consisted of melphalan (n = 8), melphalan and cyclophosphamide (n = 9), or melphalan, etoposide and carboplatinum (n = 16). Toxicity was mainly hematological. One death occurred from infection during aplasia. With a median follow-up of 60 months after intensification, the 5-year progression-free survival (PFS) rate was 29% and the 5-year overall survival (OS) rate was 45%. Survival differed significantly according to tumor status at SLO. Women with microscopic or macroscopic disease at SLO, ie with a pathological partial response to first-line therapy (PPR), had survivals of 7% at 5 years, similar to other salvage therapies. Better results were obtained in the 20 women with a complete pathological response (PCR) at SLO with 43% 5-year PFS (median, 51 months) and 75% 5-year OS (median not reached). In conclusion, melphalan-based HDC with hematopoietic rescue had an acceptable toxicity in patients with chemosensitive advanced ovarian cancer. In situations of salvage therapy for patients in PPR, this treatment was not effective in long-term analysis. On the contrary, long-term results were favorable in patients with PCR, suggesting further prospective randomized studies comparing HDC and other consolidation treatments should be undertaken in this particular situation.     

Improved outcomes of high-risk relapsed Hodgkin lymphoma patients after high-dose chemotherapy: a 15-year analysis

High-dose chemotherapy and autologous stem-cell transplant (HDC/ASCT) is standard treatment for chemosensitive relapsed classical Hodgkin lymphoma, although outcomes of high-risk relapse (HRR) patients remain suboptimal. We retrospectively analyzed all HRR classical Hodgkin lymphoma patients treated with HDC/ASCT at our institution between 01/01/2005 and 12/31/2019. HRR criteria included primary refractory disease/relapse within 1 year, extranodal extension, B symptoms, requiring more than one salvage line, or positron emission tomography (PET)-positive disease at ASCT. All patients met the same ASCT eligibility criteria. We treated 501 patients with BEAM (n=146), busulphan/melphalan (BuMel) (n=38), gemcitabine (Gem)/BuMel (n=189) and vorinostat/Gem/BuMel (n=128). The Gem/BuMel and vorinostat/Gem/BuMel cohorts had more HRR criteria and more patients with PET-positive disease at ASCT. Treatment with brentuximab vedotin (BV) or anti-PD1 prior to ASCT, PET-negative disease at ASCT, and maintenance BV increased over time. BEAM and BuMel predominated in earlier years (2005-2007), GemBuMel and BEAM in middle years (2008-2015), and vorinostat/GemBuMel and BEAM in later years (2016-2019). The median follow-up is 50 months (range, 6-186). Outcomes improved over time, with 2-year progressionfree survival (PFS)/overall survival (OS) rates of 58%/82% (2005-2007), 59%/83% (2008-2011), 71%/94% (2012-2015) and 86%/99% (2016-2019) (P<0.0001). Five-year PFS/OS rates were 72%/87% after vorinostat/ GemBuMel, 55%/75% after GemBuMel, 45%/61% after BEAM, and 39%/57% after BuMel (PFS: P=0.0003; OS: P<0.0001). These differences persisted within the PET-negative and PET-positive subgroups. Prior BV and vorinostat/GemBuMel were independent predictors of more favorable outcome, whereas primary refractory disease, ≥2 salvage lines, bulky relapse, B symptoms and PET-positivity at ASCT correlated independently with unfavorable outcomes. In conclusion, post-HDC/ASCT outcomes of patients with HRR classic Hodgkin lymphoma have improved over the last 15 years. Pre-ASCT BV treatment and optimized synergistic HDC (vorinostat/GemBuMel) were associated with this improvement.     

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.     

Should we continue to study high-dose chemotherapy in metastatic breast cancer patients? A critical review of the published data

Data from eight randomised trials on high-dose chemotherapy (HDC) for metastatic breast cancer (MBC) have been published, but only seven studies are evaluable after the Bezwoda trial was discredited. Moreover, overall survival (OS) has been evaluated in only four out of seven studies since three had a crossover design. OS was similar for the HDC and standard-dose chemotherapy (SDC) group in the four evaluable trials, while disease-free survival (DFS) was improved in the HDC group in six of the seven trials. The delay in relapse for patients with metastatic disease represents an important clinical outcome; furthermore, since none of the reported studies randomised more than 220 patients, their statistical power may have been too limited to detect meaningful survival differences. Finally, preliminary experiences have shown that HDC seems to be the ideal platform upon which to build novel therapies. In conclusion, HDC remains an important field of clinical research for breast cancer patients with stage IV disease and, from the studies reported in this article, there is some evidence for offering this therapeutic modality to selected patients who are interested in a medically aggressive approach.     

High-dose cyclophosphamide + carboplatin and interleukin-2 (IL-2) activated autologous stem cell transplantation followed by maintenance IL-2 therapy in metastatic breast carcinoma - a phase II study

While high-dose chemotherapy and stem cell transplantation is associated with higher complete response rates than conventional chemotherapy in patients with metastatic breast cancer (MBC), its role in conferring a survival advantage is unproven. We report the results of a prospective phase II trial of 33 patients accrued between 1996 to 1998 with chemosensitive MBC, who received cyclophosphamide (Cy) 2000 mg/m2/day and carboplatin (Cb) 600 mg/m2/day for 3 consecutive days, followed by infusion of peripheral blood stem cells cultured in IL-2 for 24 h on day 0 as adoptive immunotherapy. Low-dose interleukin-2 (IL-2) was administered from day 0 to +4 and/or +7 to +11, +14 to +18, +21 to +25, then 5 days per month for 11 months to augment a graft-versus-tumor effect. The results of this study were compared to those of a historical control group treated with an identical high-dose Cb + Cy regimen with SCT but without IL-2 treatment. Only gastrointestinal (GI) toxicity was more frequent in the IL-2 cohort (P = 0.0031). At a median follow-up of 18.6 months, the median progression-free survival (PFS) is 9 months (2.4-40) and the median OS has not been reached yet. The Kaplan-Meier estimated 2 year PFS is 35%, compared with 17% in the control arm (P = 0.73), and the estimated 2 year OS is 78%, compared with 61% in the control arm (P = 0.22). Multivariate analysis showed that ER status was an independent predictor for OS and PFS, and less chemotherapy prior to HDCSCT predicted for a better PFS. These results show that augmenting HDC with IL-2 activated SCT is well-tolerated. Whether a therapeutic advantage is achievable in patients with MBC remains to be determined. Bone Marrow Transplantation (2000) 25, 19-24.     

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+.     

Pulmonary toxicity of induction chemotherapy prior to standard or high-dose chemotherapy with autologous hematopoietic support

We closely followed the pulmonary function of 150 consecutive high-risk breast cancer patients who underwent standard induction CAF (cyclophosphamide, doxorubicin, 5-fluorouracil) chemotherapy, followed by randomization to either standard-dose CPB (cyclophosphamide, cisplatin, bischloroethylnitrosourea [BCNU]) chemotherapy (SDC) or to high-dose CPB chemotherapy (HDC) with autologous bone marrow transplantation (ABMT) and peripheral blood progenitor cell support (PBPCS). Previously, we have described a delayed pulmonary toxicity syndrome (DPTS) which characterizes the pulmonary dysfunction after HDC and ABMT in this patient population. However, little is known concerning the role induction chemotherapy plays in its development. We found that after three cycles of induction CAF, the mean diffusing capacity of the lungs for carbon monoxide (DL(CO)) significantly decreased by 12.6%. Additionally, in patients receiving HDC, the mean DL(CO) further decreased to a nadir of 55.2 +/- 14.1% which was significantly lower than those receiving SDC (nadir: 80.7 +/- 12.3%). DPTS occurred in 72% of patients receiving HDC as compared with only 4% of patients receiving SDC. All individuals diagnosed with DPTS were treated with prednisone and the 2-yr follow-up of pulmonary function revealed a gradual improvement in mean DL(CO) such that there were no differences between HDC and SDC groups at the end of the study. No mortality was attributable to pulmonary toxicity in either group. After induction chemotherapy, but before HDC, bronchoalveolar lavage (BAL) demonstrated significant elevations in interleukin-6 (IL-6), IL-8, neutrophils, and lymphocytes. We conclude that induction CAF produces asymptomatic pulmonary dysfunction and inflammation which may prime the lungs for further injury by HDC and predispose to the development of DPTS. Fortunately, in this specific ABMT patient population, the early and judicious use of prednisone appears to improve pulmonary function in patients who develop DPTS.     

High-dose therapy followed by autologous purged stem cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by the GOELAMS with final results after a median follow-up of 9 years

Autologous stem cell transplantation (ASCT) as first-line therapy for follicular lymphoma (FL) remains controversial. The multicenter study randomized 172 patients with untreated FL for either immunochemotherapy or high-dose therapy (HDT) followed by purged ASCT. Conditioning was performed with total body irradiation (TBI) and cyclophosphamide. The 9-year overall survival (OS) was similar in the HDT and conventional chemotherapy groups (76% and 80%, respectively). The 9-year progression-free survival (PFS) was higher in the ASCT than the chemotherapy group (64% vs 39%; P = .004). A PFS plateau was observed in the HDT group after 7 years. On multivariate analysis, OS and PFS were independently affected by the per-formance status score, the number of nodal areas involved, and the treatment group. Secondary malignancies were more frequent in the HDT than in the chemotherapy group (6 secondary myelodysplastic syndrome/acute myeloid leukemia and 6 second solid tumor cancers vs 1 acute myeloid leukemia, P = .01). The occurrence of a PFS plateau suggests that a subgroup of patients might have their FL cured by ASCT. However, the increased rate of secondary malignancies may discourage the use of purged ASCT in combination with TBI as first-line treatment for FL. This trial has been registered with ClinicalTrials.gov under identifier NCT00696735.