Methodological arguments for the necessity of randomized trials in high-dose chemotherapy for breast cancer

In the past ten years high-dose chemotherapy with autologous haematopoetic stem-cell support (HD-CT) has increasingly been used for breast cancer. But the vast majority of trials are small phase I/II studies showing until now not enough evidence that HD-CT is superior to conventional-dose chemotherapy (CD-CT). In contrast to this, the public perception of this treatment is different. Patients as well as physicians often uncritically believe in reports contrasting the positive results obtained in case series treated by HD-CT with those of historical control groups. This leads to the problem that many patients and also clinicians are not willing to participate in randomized trials on this topic.A critical assessment of current knowledge on the effectiveness of HD-CT in breast cancer is given. The problems related to the use of historical controls, in general, and especially in the setting of HD-CT are demonstrated. Using data of patients treated with CD-CT within trials of the German Breast Cancer Study Group (GBSG) it will be shown that results similarly favorable to those reported from patients treated with a high-dose regimen may be produced using quite simple selection mechanisms.Comparisons of patients treated with HD-CT with historical control groups of patients treated with CD-CT may be misleading. A valid treatment comparison is only possible by means of large randomized trials. Clinicians should participate in the ongoing trials and enter all eligible patients.     

Overview of randomized trials in high risk breast cancer patients treated with adjuvant systemic therapy with or without postmastectomy irradiation.

Postmastectomy irradiation has been analyzed in several randomized trials, usually without the presence of systemic therapy. Overview analysis of these studies has shown that, although postmastectomy irradiation generally reduces the locoregional recurrence rate by a factor of 3, this is not transferred into a general long-term survival benefit. Recently, a clinically relevant survival gain from adjuvant radiotherapy has been shown in high-risk premenopausal patients also treated with adjuvant chemotherapy. There are now 11 published trials, including more than 6000 patients, in which the effect of postmastectomy radiotherapy has been evaluated in the presence of adjuvant systemic therapy. This article reviews the available data from these trials, as well as problems in their design, sample size, inclusion criteria, quality, and extent of treatments, and length of follow-up time.     

Treatment of estrogen receptor-negative or hormonally refractory breast cancer with double high-dose chemotherapy intensification and bone marrow support

We have used high-dose therapy followed by randomization to receive or not receive autologous bone marrow infusion in 58 stage IV breast cancer patients (all were estrogen receptor-negative [ER-] or primary hormonal refractory). Patients received a median of four courses of induction chemotherapy and if stable or responding received two courses of intensive therapy with cyclophosphamide 4.5 to 5.25 g/m2, etoposide 750 to 1,200 mg/m2, and cisplatin 120 to 180 mg/m2 (CVP). The complete remission (CR) rate after completion of the induction and intensive phases was 55%. Median progression-free interval from induction is 57 weeks with a projected 2-year progression-free survival of approximately 25%. Six of seven patients followed for greater than 2 years are still progression-free. Three favorable features predicted for improved progression-free survival are the following: (1) absent liver involvement, (2) absent soft tissue involvement, and (3) less than or equal to two disease sites (P values of .001, .013, and .048, respectively). Hormonal and menopausal status did not predict for progression-free survival. Major toxicities were infectious secondary to neutropenia, with a 93% incidence of fever and a 38% incidence of sepsis. The treatment-related mortality rate was 9%, with three infectious, one coronary, and one late hemorrhage-related death of unknown cause. Longer follow-up is still needed to truly evaluate the possibility of long-term disease-free survival, but further studies of this approach to high-dose intensification in poor prognostic groups of stage IV breast cancer appear warranted.     

A critique of the eleven randomised trials of high-dose chemotherapy for breast cancer

Data from 11 randomised studies on high-dose chemotherapy for breast cancer are currently available. Most investigators, patients and insurers would agree that the two discredited South African trials are uninterpretable, and that the Scandinavian trial (which compares one very high-dose cycle versus six escalated dose cycles) does not ask the question of high-dose therapy versus conventional-dose therapy. Only two of the eight remaining studies randomised more than 200 patients (783 patients for the Cancer and Leukaemia Group B (CALGB) and 885 for the Dutch study). Both of these studies have trends in relapse-free survival favouring high-dose therapy. In a planned analysis of the first 284 patients entered into the Dutch study, with a median follow-up approximately 7 years, both disease-free and overall survival were significantly improved in the high-dose therapy arm. These and the other trials are discussed in detail below.     

New strategies in marrow purging for breast cancer patients receiving high-dose chemotherapy with autologous bone marrow transplantation

Summary High-dose chemotherapy and autologous bone marrow transplantation (ABMT) are commonly used to treat selected patients with high-risk breast cancer. A limitation of ABMT is that clonogenic cancer cells could be collected with the bone marrow and produce a relapse of disease when reinfused into patients. Purging the marrowex vivo may eliminate the tumor cells, but it can also delay engraftment. We employed two different purging methods whereby breast cancer cells were depleted without delaying engraftment. The addition of WR-2721 (amifostine) to 4-hydroperoxycyclophosphamide (4-HC) reduced the time to engraftment by 10 days compared with marrow purged with 4-HC alone (26 versus 37 days, respectively). The positive selection of CD34+ hematopoietic progenitors produced engraftment within 21 days. The use of granulocyte colony-stimulating factor (G-CSF) accelerated the engraftment time of CD34+ hematopoietic progenitors to 11 days.Held in conjunction with the 15th Annual San Antonio Breast Cancer Symposium, December 1992, and supported by an educational grant from Lederle Oncology; editing by The Medicine Group USA, Inc.     

Survival of tumor cells in stem cell preparations and bone marrow of patients with high-risk or metastatic breast cancer after receiving dose-intensive or high-dose chemotherapy.

PURPOSE: We evaluated whether dose-intensive or high-dose chemotherapy can eliminate micrometastases in high-risk breast cancer patients. EXPERIMENTAL DESIGN: We monitored cytokeratin (CK)/17-1A positive cells in the bone marrow (BM) and peripheral blood stem cells (PBSC) and studied Her-2/neu serum levels of patients with locally advanced (n = 13; group 1) and metastatic breast cancer (n = 30; group 2) using immunomagnetic separation, immunocytochemistry, and ELISA. RESULTS: CK+ cells were found in the BM of 3 of 13 (23%) group 1 patients before but not after chemotherapy, resulting in an overall survival (OS) of 92% after a median follow-up of 33 months. Contamination of PBSC in 2 of 9 (22%) patients was not associated with decreased survival. In group 2 patients, the CK+ rate was 60% (18 of 30 patients) before and 40% (4 of 10 patients) after therapy with an OS rate of 43% after 29 months. PBSC samples were positive in 7 of 24 (29%) patients. CK+ BM and PBSC led to a rapid progress and short OS, whereas tumor cell-free BM and PBSC resulted in a mean OS of 30 months. The antigen 17-1A was detected on most CK+ cells in both patient groups before therapy, on all of CK+ PBSC, and on CK+ cells in group 2 patients after therapy. Increased Her-2/neu levels were found in group 2 patients before chemotherapy. CONCLUSION: Micrometastatic cells are present in PBSC grafts and can survive even high-dose chemotherapy. The presence of immunotherapeutic target antigens supports the idea that a combined chemoimmunotherapy might be successful in eliminating minimal residual disease.     

Role and limits of salvage chemotherapy in breast cancer patients treated with high-dose chemotherapy.

High-dose chemotherapy (HDC) with autologous peripheral bloodprogenitor cell support for breast cancer has been widely investigatedin phase III clinical trials [1]. The majority of transplantedpatients relapse, but the most appropriate treatment for themhas not yet been established. In the literature, there are fewdata regarding salvage chemotherapy after HDC. Martin et al.used a combination of methotrexate, oral tegafur     

Up-front tandem high-dose chemotherapy compared with standard chemotherapy with doxorubicin and paclitaxel in metastatic breast cancer: results of a randomized trial.

PURPOSE: The role of high-dose chemotherapy (HDCT) in metastatic breast cancer remains controversial. Trials with late intensification HDCT have failed to show an advantage in overall survival. This study was initiated to compare up-front tandem HDCT and standard combination therapy in patients with metastatic breast cancer. PATIENTS AND METHODS: Patients without prior chemotherapy for metastatic disease were randomly assigned to standard combination therapy with doxorubicin and paclitaxel (AT) or double HDCT with cyclophosphamide, mitoxantrone, and etoposide followed by peripheral-blood stem-cell transplantation. HDCT was repeated after 6 weeks. Patients were stratified by menopausal and hormone-receptor status. The primary objective was to compare complete response (CR) rates. RESULTS: A total of 93 patients were enrolled onto the trial. Intent-to-treat CR rates for patients randomized to HDCT and AT were 12.5% and 11.1%, respectively (P = .84). Objective response rates were 66.7% for patients in the high-dose group and 64.4% for patients in the AT arm (P = .82). In an intent-to-treat analysis, there were no significant differences between the two treatments in median time to progression (HDCT, 11.1 months; AT, 10.6 months; P = .67), duration of response (HDCT, 13.9 months; AT, 14.3 months; P = .98), and overall survival (HDCT, 26.9 months; AT, 23.4 months; P = .60). HDCT was associated with significantly more myelosuppression, infection, diarrhea, stomatitis, and nausea and vomiting, whereas patients treated with AT developed more neurotoxicity. CONCLUSION: This trial failed to show a benefit for up-front tandem HDCT compared with standard combination therapy. HDCT was associated with more acute adverse effects.     

Importance of radiation therapy for breast cancer patients treated with high-dose chemotherapy and stem cell transplant

PURPOSE: To determine local-regional failure rates in breast cancer patients treated with surgery and high-dose chemotherapy with stem cell transplant and to relate local-regional failure to the use and timing of radiation treatment. METHODS AND MATERIALS: We retrospectively reviewed the records of 165 breast cancer patients treated on institutional protocols with surgery and high-dose chemotherapy with stem cell transplant. All patients had either Stage III disease, 10 or more positive axillary lymph nodes, or 4 or more positive axillary lymph nodes following neoadjuvant chemotherapy. Twelve patients had inflammatory breast cancer. Thirteen patients treated with breast preservation and 5 patients who died from toxicity within 30 days of transplant were excluded from the analyses of local-regional recurrences. In the remaining 147 patients, 108 were treated with adjuvant radiation and 39 were not. The disease stage distribution for these two groups was comparable. The median follow-up for surviving patients was 35 months. RESULTS: The 3- and 5-year actuarial disease-free survival (DFS) for the entire group was 60% and 51%, respectively. The 5-year rates of freedom from isolated local-regional recurrence were 95% in the patients treated with adjuvant radiation and 86% in the patients who did not receive radiation (p = 0.014, log rank comparison). The 5-year rates of any local-regional recurrence as a first event (isolated recurrences plus those with simultaneous local-regional and distant recurrences) were 92% versus 82%, respectively for patients whose treatment did and did not include radiation (p = 0.038). We could not demonstrate a correlation of the timing of radiation with the risk of local-regional recurrence. CONCLUSIONS: These data indicate that high-dose chemotherapy does not negate the importance of radiation in optimizing local-regional control in patients with high-risk breast cancer. Given the results of recent randomized trials studying postmastectomy radiation, which show that improving local-regional control improves overall survival (OS), we believe that all breast cancer patients with high-risk primary breast cancer who are treated with high-dose chemotherapy with stem cell transplant should receive radiation as a component of their treatment.     

Impact of consolidation radiotherapy in patients with advanced breast cancer treated with high-dose chemotherapy and autologous bone marrow rescue.

PURPOSE: To examine the impact of consolidation radiotherapy (RT) after high-dose chemotherapy with autologous bone marrow rescue (HDC) in patients with advanced breast cancer. PATIENTS AND METHODS: Between 1988 and 1994,425 patients with metastatic or recurrent breast cancer received doxorubicin, fluorouracil, and methotrexate (AFM) induction chemotherapy in a single-institution prospective trial. One hundred patients who achieved a complete response were randomized to receive HDC (cyclophosphamide, cisplatin, carmustine), with autologous bone marrow rescue immediately after AFM, or to observation, with HDC to be administered at next relapse. Seventy-four of the 100 became eligible for RT; 53 received consolidation RT (HDC RT+ and 21 did not (HDC RT-). The assignment of RT was not randomized. The RT+ and RT- groups were similar with regard to number of involved sites, the fraction of patients with only local-regional disease, age, and interval since initial diagnosis. Local control at previously involved sites and distant sites was assessed with extensive radiologic and clinical evaluations at the time of first failure or most recent follow-up. The impact of RT on failure patterns, event-free survival, and overall survival was evaluated. RESULTS: Sites of first failure were located exclusively at previously involved sites in 28% of RT+ patients versus 62% of RT- patients (P < .01). Event-free survival at 4 years was 31% and 21% in the RT+ and RT-groups, respectively (P = .02). Overall survival at 4 years was 30% and 16% in the RT+ and RT- groups, respectively (P = .20). CONCLUSION: Patients with advanced breast cancer who were treated with HDC without RT failed predominantly at the initial sites of disease. The addition of RT appeared to reduce the failure rate at initial disease sites and may improve event-free and overall survival. Our observations await verification in a trial in which assignment to RT is randomized.     

The status of high-dose chemotherapy in breast cancer

High-dose chemotherapy in breast cancer is a subject of considerable controversy. Preliminary results from several randomized trials have shown that it is certainly not the breakthrough hoped for in the early 1990s. The available data are, however, compatible with a modest but potentially important effect on relapse-free survival in the adjuvant treatment of high-risk breast cancer. To prove such an effect, several more years of maturation are required for a number of randomized studies. At this point in time, there is no justification for the use of high-dose chemotherapy in breast cancer outside clinical studies.     

Monitoring of disseminated tumor cells in bone marrow in high-risk breast cancer patients treated with high-dose chemotherapy

The present study aimed to investigate the clinical relevance of disseminated tumor cells (DTC) in breast cancer patients before and after high-dose adjuvant chemotherapy with or without progenitor stem-cell support. One hundred and eighteen high-risk stage II breast cancer patients entering the Scandinavian Study Group multicenter trial were randomized to 9 cycles of tailored and dose-escalated FEC (5-fluorouracil, epirubicin, cyclophosphamide) or 3 cycles of standard FEC followed by high-dose chemotherapy. Bone marrow (BM) samples at diagnosis and 6 months after completion of chemotherapy were assessed for the presence of cytokeratin positive (CK+) cells. Before treatment, 29% of the patients were CK+ (21% in the dose-escalated group and 36% in the high-dose-group). Six months after treatment, 17% of the patients were CK+ (17 and 16% respectively). Of the 95 patients who were evaluated 6 months after treatment, 60% were consistently CK-. CK+ cells in BM was evaluated as a prognostic and predictive marker and compared to other defined prognostic factors of the primary tumor. Monitoring BM changes at the time of diagnosis and 6 months posttreatment is an independent predictive factor for breast-cancer-specific survival (BCS) (p = 0.001). Those who have consistent CK negative (-) BM findings constitute a group of patients with good prognosis. Our results suggest that changes in CK+ cells in BM before and after chemotherapy can be used clinically as a surrogate maker to predict outcome in breast cancer patients.     

Paclitaxel-containing high-dose chemotherapy in high-risk breast cancer patients

Despite standard-dose adjuvant chemotherapy, the prognosis for patients with breast cancer and extensive axillary lymph node involvement at diagnosis is poor. The efficacy of a paclitaxel-containing, high-dose chemotherapy protocol in 21 high-risk breast cancer patients is assessed. After standard-dose chemotherapy followed by peripheral blood stem cell (PBSC) mobilization, high-dose therapy with paclitaxel, carboplatin, and cyclophosphamide and CD34-selected PBSC rescue was given. Hematologic reconstitution after high-dose therapy was rapid. Main toxicity included diarrhea grade I or II in about half of the patients and infections were observed in 19%. Five-year probabilities for relapse and failure-free survival were 32% and 62%, respectively. High-dose consolidation with paclitaxel, carboplatin, and cyclophosphamide achieves a high failure-free survival in patients with high-risk breast cancer with acceptable toxicities and stable, long-term hematopoietic reconstitution. Evaluation of the benefit of high-dose therapy in these patients in larger prospective, randomized trials is warranted and currently under way.     

A predictive model for relapse in high-risk primary breast cancer patients treated with high-dose chemotherapy and autologous stem-cell transplant.

High-dose chemotherapy (HDCT) is currently under evaluation for high-risk primary breast cancer (HRPBC), defined by extensive axillary nodal involvement or inflammatory breast carcinoma. Phase II studies of HDCT for HRPBC show that 30-40% of patients eventually relapse. We retrospectively reviewed 176 patients enrolled in clinical trials of HDCT for HRPBC at the University of Colorado and analyzed 23 potential predictive variables for relapse. All of the patients received the same regimen, with cyclophosphamide, cisplatin, and BCNU. Nine patients who experienced a toxic death were excluded from this analysis. The resulting predictive model was subsequently tested in an independent patient set treated at Duke University with the same HDCT regimen. Nodal ratio (number of involved nodes:number of sampled nodes), tumor size, grade, stage, estrogen receptor, progesterone receptor, and clinical inflammatory breast carcinoma correlated with risk of relapse. Nodal ratio, tumor size, and the combined estrogen receptor/progesterone receptor status were independent predictors. A scoring system using those three variables determines the risk of relapse, with a sensitivity and specificity of 60 and 90%, respectively, and a positive and negative predictive value of 65 and 88%, respectively. The differences in relapse-free survival and overall survival between high- and low-score patients were highly significant (P<0.000001). This model was subsequently validated in the Duke patient set. This model can identify two subgroups of HRPBC patients with low (12%) and high (65%) risk for recurrence after HDCT. Future research that tests new therapies will focus on those patients with a high score.     

Results of two randomized trials evaluating adjuvant anthracycline-based chemotherapy in 1146 patients with early breast cancer

Two randomized trials evaluated the effect of 6 courses of anthracycline-based chemotherapy in early breast cancer. A total of 1 146 patients were included: 311 high-risk node-negative premenopausal patients and 835 high-risk node-negative or node-positive postmenopausal patients. Patients were randomized after surgery to receive either no chemotherapy (control group) or 6 courses of anthracycline-based chemotherapy (CT group). Postmenopausal patients received adjuvant tamoxifen for at least two years. Radiotherapy was delivered after completion of chemotherapy in the CT group. The 10-year disease-free survival (DFS) rates were 60% in the control group and 65% in the CT group (log-rank test, p = 0.01). The 10-year distant metastasis rates were 28% and 23% (p = 0.02), and the 10-year local recurrence rates were 12% and 10%, respectively (p = 0.24). Chemotherapy was significantly less effective in post-menopausal patients with estrogen receptor-positive tumors. Adjuvant anthracyclin-based chemotherapy yielded a significant benefit for DFS by lowering the risk of distant metastases. After up to 10 years of follow-up, deferring radiotherapy after chemotherapy did not compromise local control.     

Phase II trial of high-dose chemotherapy with autologous stem cell transplant for stage IV breast cancer with minimal metastatic disease.

The purpose of this study was to assess the efficacy of high-dose chemotherapy (HDC) with autologous stem cell transplant in stage IV breast cancer patients with minimal metastases. Eligible patients had (a) disease that could be resected en bloc and/or irradiated with curative intent using a single field and could, thus, be rendered as having no evidence of disease (NED); and/or (b) <5% bone marrow involvement. From September 1991 to August 1997, 40 consecutive patients were prospectively entered on the study. Pre-HDC local treatment consisted of surgery (n = 31) and radiotherapy (XRT; n = 3). All patients received HDC with cyclophosphamide, cisplatin, and 1,3-bis(2-chloroethyl)-1-nitrosourea and autologous stem cell transplant, with or without CD34 selection. Following HDC, 22 patients received XRT. Four patients died of treatment-related complications. Eighteen patients developed grade 3 nonhematological toxicities (15 lung, 2 cardiomyopathy, and 1 optic neuritis), which resolved with therapy. Within a median follow-up of 49 (15-91) months, 14 patients had relapsed. Twenty-five patients (62.5%) were alive, and 22 patients (55%) were alive and free of disease. Median event-free and overall survivals were 43 and 77 months, respectively. In the subset of patients with one metastatic site, 17 of 24 (68%) remained relapse free. Grade 2 tumors, a single metastatic site, and delivery of XRT were favorable predictors of relapse-free survival in univariate but not multivariate analyses. Inclusion of HDC, as described, in the multimodal treatment of stage IV breast cancer patients with minimal metastases is promising. These results warrant prospective randomized trials with a HDC-containing arm in this patient population.     

Salvage treatment with epirubicin and/or paclitaxel in metastatic breast cancer patients relapsed after high-dose chemotherapy with peripheral blood progenitor cells

AIMS AND BACKGROUND: To evaluate feasibility and efficacy of paclitaxel as a single agent or in combination with epirubicin in breast cancer taxane-naive patients who have failed previous high-dose chemotherapy. METHODS: Since February 1995, we have treated 32 patients in first relapse or progression after high-dose chemotherapy. Nineteen patients had metastatic breast cancer, 12 more than 3 involved axillary lymph nodes, and 1 inflammatory breast cancer at inclusion to the program. The median time to relapse after high-dose chemotherapy was 12 months (range, 2-43). At relapse, 12 patients were treated with epirubicin (90 mg/m2) plus paclitaxel (175 mg/m2) administered on day 1 every 21 days. In 20 patients who had previously received more than 350 mg/m2 of a cumulative dose of epirubicin and in one patient pretreated with chemotherapy containing mitoxantrone, we employed paclitaxel (175 mg/m2) alone. A median number of five courses was administered (range, 2-10). RESULTS: The overall response rate after 3 courses (29 of 32 patients were assessable) was 55% and after 6 courses (21 of 32 patients were assessable) was 57%. The median time to progression was 7 months (95% CI, 5.7-9.2), and median survival was 27.5 months (95% CI, 17.8-37.0). Toxicity was recorded for 180 cycles (epirubicin + paclitaxel for 62 cycles and paclitaxel alone for 118 cycles). The main toxicity in both regimens was hematologic. We observed WHO grade 3-4 neutropenia (in 8 patients, 25%), for which G-CSF (5 microg/kg/day s.c.) was employed. WHO grade 3-4 thrombocytopenia occurred in 2 patients (6%) and WHO grade 3 anemia in 1 patient (3%). CONCLUSIONS: Our study showed that paclitaxel (alone or in combination with epirubicin) is feasible as salvage treatment in heavily pretreated patients.     

Taxanes as primary chemotherapy for early breast cancer: meta-analysis of randomized trials

BACKGROUND: In patients with locally advanced and operable breast cancer, neoadjuvant chemotherapy has been demonstrated to increase the chance of breast-conserving surgery (BCS) when compared with adjuvant treatment; moreover, patients who achieve a pathologic complete response (pCR) have a better outcome. A literature-based meta-analysis of randomized clinical trials (RCTs) to 'weigh' how much taxanes add to anthracyclines as primary treatment over standard chemotherapy was conducted. METHODS: Event-based relative risk ratios (RR) with 95% confidence intervals (95% CI) were derived through both a fixed-effect and a random-effect model; a heterogeneity test was applied as well. Absolute differences (AD) and the number (of patients) needed to treat (NNT) were calculated. Primary endpoints were: 1) pCR rate and 2) BCS rate. A sensitivity analysis of 3 subgroups according to taxane strategies was conducted. RESULTS: Data for primary endpoints were available for 7 RCTs (2455 patients). The rate of BCS was significantly higher for patients receiving taxanes, with an AD of 3.4% (P = .012), which translates into 29 patients NNT, without significant heterogeneity. The rate of pCR was higher for patients receiving taxanes, although not statistically significant. In the sensitivity analysis, patients receiving taxanes as a sequential schedule had a significant higher probability to achieve pCR, with an AD of 2.4% (P = .013), which translates into 41 patients NNT, without significant heterogeneity. Patients receiving taxanes as a concomitant schedule had a significantly higher probability to achieve BCS, with an AD of 5.3% (P = .027), which translates into 19 patients NNT, without significant heterogeneity. The complete response rate was significantly higher in the taxane arms, regardless of the adopted strategy, with an AD ranging from 6.7% to 15.5%. CONCLUSIONS: The combination of taxanes and anthracyclines as neoadjuvant chemotherapy for early breast cancer improves the chance of achieving both higher BCS and pCR rates.