Breast Cancer

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

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Abstract

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/m2 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. Bone Marrow Transplantation (2001) 28, 447–454.

Main

Patients with metastatic breast cancer (BC) are considered incurable with conventional therapy. Palliation is achieved in that combination chemotherapy regimens, especially those containing doxorubicin and/or taxanes, result in response rates of 50–80% and complete response rates of 4–27% in previously untreated patients. Median response duration is generally less than 1 year. In a recent randomized study reported by Sledge et al,1 the median time to failure was 6 months for single agent doxorubicin and paclitaxel, and 8 months for the combination. Overall median survivals were 19 to 22 months, with estrogen receptor negativity, visceral dominant disease, three or more sites of metastatic disease, and a short disease-free interval or prior adjuvant therapy being factors indicating poor prognosis.1

High-dose therapy with hematopoietic stem cell support shows promise in enlarging the fraction of patients who achieve complete response (CR) and in increasing the proportion of patients who achieve relatively durable event-free survival (EFS). Following a single high-dose cycle, approximately 50% of women with metastatic breast cancer responding to induction chemotherapy achieve a CR and approximately 15–20% remain in continuous CR at 5 years.2,3 This approach is limited by the fact that most patients still relapse within 2 years. These results are remarkably consistent across many single and multi-institutional trials. Given the acknowledged selection biases inherent in transplant studies, it remains a matter of debate whether a single high-dose cycle is better than conventional therapy. Nonetheless, the strong scientific pharmacologic basis for dose, the observed high complete response rates, and the frequent association in cancer treatment between the development of high rates of CR and subsequent development of curative therapy, supports further investigation in this arena. One such direction, rendered potentially feasible by the increasing safety of high-dose therapy, is to deliver multiple cycles of high-dose chemotherapy. Multiple cycles may enhance first order cytotoxicity particularly for breast cancer with its lower growth fraction. Moreover, more agents and higher cumulative doses may be delivered potentially to overcome drug resistant subpopulations.4,5

Multiple cycles create the clinical variables of sequence and interval.6,7 Evidence from double transplant models in mice indicates that tandem transplants are more effective than a single transplant.4 However, initial treatment with melphalan may increase broad-spectrum drug resistance acutely, whereas use of melphalan later in therapy may result in collateral sensitivity against tumor cells.6,8,9 The development of acute drug resistance is typically transient, and may have separate mechanisms from those operative after chronic selection.

Based upon these considerations and our prior experience using short initial therapy, the design of this trial incorporated a short induction/mobilization phase followed by the double transplant, but reversed the sequence of the two transplant regimens.5,6,10 The major objective of this phase I trial was to define the maximum tolerated dose (MTD) of paclitaxel when combined with high-dose melphalan in the context of a short induction followed by double high-dose combination chemotherapy. Other objectives were to explore the impact of regimen sequence on the complete and near-complete response (CR/nCR) rates, and the event-free and overall survivals of women with metastatic breast cancer treated in such a fashion.

Methods

Eligibility

Women with histologically documented metastatic breast cancer were eligible. Patients with CNS or marrow involvement were excluded. The patients were under age 60 years with a Zubrod performance status 0–1. Prior adjuvant therapy with up to 320 mg/m2 cumulative doxorubicin was allowed. A disease-free interval (DFI) from completion of adjuvant chemotherapy to diagnosis of metastases or recurrence of at least 6 months was required. No prior chemotherapy for metastatic disease was permitted. Required laboratory results included leukocytes 3.0 × 109/l, platelets 100 × 109/l, creatinine 159 μmol/l (1.8 mg/dl), serum aspartate aminotransferase (AST) 2.5 × normal and bilirubin 1.5 × normal, and a cardiac ejection fraction 50% by radionuclide ventriculogram. The study was conducted according to the guidelines of the Dana-Farber Cancer Institute and Beth Israel Hospital institutional review boards. Signed informed consent was obtained.

Eligibility to proceed with first intensification

Patients could proceed with intensification if there was no evidence of disease progression after doxorubicin and they had insurance approval or financial capability. Adequate hematopoietic stem cell collections to support both high-dose cycles (defined below) were required. Cardiac ejection fraction had to be 45%.

Eligibility to proceed with second intensification

Patients must have recovered performance and clinical status to near pre-transplant levels. The absolute neutrophil count must have recovered to 1.0 × 109/l and patients must not be refractory to platelet transfusion. The serum AST and bilirubin must be within 2.5 × and 1.5 × normal, respectively.

Treatment

The treatment schema is outlined in Figure 1.

Figure 1
figure1

Schema of trial.

Induction therapy (days 1–35):

Two cycles of bolus doxorubicin at 30 mg/m2/day on days 1, 2, and 3 were given 14 days apart. G-CSF at 5 μg/kg s.c. daily began on day 4 of each cycle and ended upon completion of PBPC collection.

Hematopoietic stem cell collection:

PBPCs were collected by two-volume leukapheresis when the WBC was at least 3.0 × 109/l and rising, and cryopreserved according to standard methods.11 Two phereses were planned during the first cycle and up to five phereses for the second cycle to reach a target of 2 × 106 CD34+ cells/kg to support each intensification (total of 4 × 106 CD34+ cells/kg).

Intensification 1: CTCb with PBPC (days 36–49):

CTCb consists of cyclophosphamide 1500 mg/m2/day × 4 days (total dose 6000 mg/m2), thiotepa 125 mg/m2/day × 4 days (total dose 500 mg/m2), and carboplatin 200 mg/m2/day × 4 days (total dose 800 mg/m2). All chemotherapy drugs were given by 96-h continuous infusion beginning day −7. Mesna at 1500 mg/m2/day (total dose 7500 mg/m2) was mixed with cyclophosphamide and continued for an additional 24 h after cyclophosphamide was completed (120-h continuous infusion beginning on day −7). Half of the PBPCs collected were reinfused (2 × 106 CD34+ cells/kg) approximately 72 h after the completion of chemotherapy (day 0). G-CSF 5 μg/kg/day s.c. once a day began on day 0 and continued until ANC 1.0 × 109/l. Glutathione 10 g and ursodiol 300 mg were given orally three times a day starting day 0 until recovery as hepatic protection.12,13

Intensification 2: melphalan, dose-escalated paclitaxel with PBPC (days 71–84):

Dexamethasone 20 mg was given orally as premedication at approximately 12 and 6 h prior to paclitaxel. Thirty minutes before and then every 6 h for 16 doses, decadron 4 mg i.v., benadryl 50 mg i.v. and ranitidine 50 mg i.v. were given. Paclitaxel was given by 24-h infusion beginning with a dose of 250 mg/m2 on day −3. Doses were escalated by increments of 75 mg/m2 in cohorts of three patients until dose-limiting toxicity (DLT) occurred in two or more of the first 3–6 patients. The prior dose level would then be defined as the MTD. Ten additional patients were accrued to the MTD dose level to confirm its safety.

Melphalan was given as a 1-h i.v. infusion twice at 90 mg/m2 each (total dose of 180 mg/m2) approximately 6–12 h apart on day −1 (approximately 12–24 h after completion of paclitaxel). Melphalan was administered with at least two liters hydration.

Half of the PBPCs collected were reinfused (2 × 106 CD34+ cells/kg) 18–48 (typically 24) h after the completion of chemotherapy (day 0). G-CSF at 5 μg/kg/day s.c. daily would begin on day 0 and continue until ANC 1.0 × 109/l. According to patient and physician discretion, patients could be discharged from hospital on day +1 and managed as outpatients with daily clinic visits as appropriate.

Post-intensification therapy:

Surgery or radiation therapy to accessible sites of prior bulk disease (generally three or fewer), and/or hormonal therapy in patients with estrogen or progesterone receptor positive disease, were encouraged after intensification. Bisphosphonate therapy was given for 24 months to patients with bony metastases. Herceptin was not available for use. Follow-up consisted of clinic visits every 3 months for 2 years, then every 6 months to 5 years, then yearly. Clinic visits included a CBC with differential, liver function tests, and tumor markers (if originally elevated), a chest radiograph, and radiographic imaging, including CT scans, of involved sites. Routine surveillance of uninvolved sites was not performed unless suggested by signs or symptoms.

Statistical methods

Toxicities were assessed on a daily basis during hospitalization, then weekly during recovery using the NCI Common Toxicity Scale. Transient mucositis, febrile neutropenia, emesis, acute diarrhea, or hematopoietic toxicities were not considered to contribute to dose-limiting toxicity. Other grade 4 reversible, grade 3 neurotoxicity, or grade 3 chronic toxicities were considered dose-limiting.

All patients entered on the trial are included in the outcome analysis whether or not they underwent transplant. Standard response criteria for complete (CR), partial (PR), stable (SD), and progression (DP) were used, but with addition of the near-CR category.10 Near-CR included VGPR (>90% reduction with persistent radiographic abnormalities felt to represent scar), PR* (resolution of all soft tissue disease, but with residual abnormal bone scan with sclerotic lesions documented by radiograph or CT), and NMD (all metastatic sites of disease were surgically resected or irradiated prior to induction chemotherapy) for at least 4 weeks. Response designations to induction chemotherapy did not include duration requirements. Time to failure was calculated from day on-study to the documentation of progression or death from any cause. Survival was calculated from day on-study to the documentation of death from any cause. Time to failure and survival were estimated by the Kaplan–Meier method.14 Confidence intervals (CI) were constructed around the Kaplan–Meier estimates using Greenwood's variance formula.15 Univariate comparisons of these endpoints between patient groups based on pre-transplant characteristics, such as induction response, were made using the logrank test.16 Multiple factors were simultaneously assessed using proportional hazards regression.17 However, due to small sample sizes, a lack of significance has a relatively low power to exclude a true association.

Results

Patient characteristics

Between November 1996 and April 1998, 26 women aged 31–55 years (median 43) with newly diagnosed metastatic disease were enrolled. Their characteristics at presentation with breast cancer are presented in Table 1. Eighteen (69%) had received prior adjuvant chemotherapy. Sixteen (62%) women had received prior hormone therapy (adjuvant setting in six and metastatic setting in 15). Thirteen patients overall (50%) had presented with estrogen receptor-positive disease of whom 77% had received prior hormonal therapy. The median disease-free interval from initial presentation to onset of metastatic disease was 27 months. The median number of organs involved was two (range 1–5). Sites of disease included 12 (46%) with visceral disease with or without bone or soft tissue disease, 11 (42%) with bone disease (eight with bony-only disease), and the remainder (12%) with soft tissue disease only (Table 2). Characteristics of these 26 patients at enrolment on study, and those remaining alive and/or progression-free at the time of this report (median follow-up of 33 months) are summarized in Table 2.

Table 1 Patient characteristics at presentation with breast cancer
Table 2 Patient characteristics at time of on-study

Treatment

All 26 received two cycles of doxorubicin. One had disease progression and was removed from study. Of the remaining 25 patients, all received both transplant cycles. No toxic deaths occurred. The median time from day 1 CTCb to day 1 TxM was 40 (34–74) days. The median hospitalization from CTCb was 19 days (range 14–28), and from TxM was 15 days (range 9–24).

Toxicity to intensification 1 (CTCb) (Table 3)

Table 3 Grade 2/3/4 toxicities of melphalan/paclitaxel regimen and of the CTCb regimen

No unexpected toxicities were encountered during the first intensification. Gastrointestinal toxicities were dominant. Of 25 patients, grade 3 toxicities included diarrhea in two, mucositis in 14, nausea and vomiting in nine (one grade 4), skin rashes in four, and hypocalcemia in four. All were transient. Eight patients had line infections.

Toxicity to intensification 2 (melphalan and paclitaxel (TxM))

The grade 3 and 4 toxicity of melphalan and dose-escalated paclitaxel is summarized in Table 3. No unexpected toxicities were encountered. Dose-limiting peripheral sensory toxicity occurred in four of six at the 475 mg/m2 paclitaxel dose level. Five other patients had transient grade 3 sensory neuropathy, frequently associated with debilitating arthralgias and myalgias. Neuropathic symptoms peaked about day +10, then gradually faded over several months, typical of the time course described with paclitaxel neuropathy.18 Grade 3 or worse nausea and vomiting occurred in six, diarrhea in four, mucositis in 20 (grade 4 in six), and skin rashes in three. Occasional hypocalcemia requiring repletion was noted. A total of eight patients had received adjuvant doxorubicin with doses of 240 mg/m2 in four, 300 mg/m2 in one, and 320 mg/m2 in two. No cardioprotectants were administered. One patient developed congestive heart failure responsive to medication with later full recovery off medication. She had received a cumulative dose of 420 mg/m2 of doxorubicin. One patient with a remote history of syncopal episodes developed symptomatic ventricular arrhythmias about 1 year post double transplant treated successfully with an atrial pacemaker. Her doxorubicin exposure was limited to 180 mg/m2. All patients completed both transplant cycles without mortality or need for ICU care.

Hematologic toxicity

Patients received half of their stem cells for the first and the other half for the second. The duration of myelosuppression was remarkably consistent comparing the hematopoietic recovery from the first and the second intensifications, which suggested no evident cumulative stromal damage (Table 4). Fever during neutropenia occurred in all patients in each cycle.

Table 4 Hematologic events for patients receiving both cycles

Response to therapy

Of 26 patients, one (4%) achieved a CR, 11 near-CR (42%), 10 (38%) PR, three (12%) SD, and one (4%) PD to induction therapy (Table 5). All but the one patient with PD were eligible and proceeded with transplant. The best overall response upon completion of therapy including high-dose therapy was CR in four (15%) and near-CR in 18 (69%) for an overall CR/near-CR rate of 85% (Table 5).

Table 5 Response to induction and to intensifications

Post-transplant therapy

Eleven patients received hormonal therapy (first-line tamoxifen in five (three ER+, two ER−), the rest second to fourth line) until progression. Four received surgery for locally advanced disease in two and isolated metastatic sites in two. Nineteen received radiation therapy to bone, distant nodal, chest wall, or local-regional sites.

Time to failure and relapse (Figure 2)

Figure 2
figure2

Overall and event-free survival (all patients enrolled on study).

With a median follow-up time of 33 (25–43) months, the median time to failure from initiation of induction was 38 months. The actuarial 3 year EFS is 54% (95% confidence intervals, 39%-69%). Of patients achieving CR/nCR, PR, or < PR in response to doxorubicin, eight of 12, five of 10, and one of four remain event-free, respectively. Seven of eight patients with bony-only disease remain event-free. Characteristics of those patients remaining event-free at the time of writing are described in Table 2. By 6 months after the HDC, performance status was 0 in eight, one in four due to peripheral neuropathy, and two in one patient due to depression. Of the two patients with visceral disease remaining free from progression, one had pleural and lung metastases and one had lung and liver metastases.

Survival (Figure 2)

With a median follow-up time of 33 months, the median survival from initiation of induction has not been reached. The actuarial 3-year overall survival is 69% (95% confidence intervals, 56%–79%). Of the 19 patients alive, 13 remain event-free.

Neither age, disease-free interval, estrogen receptor status, tumor grade, prior chemotherapy, sites of disease, nor response to doxorubicin were associated with EFS or overall survival, but the trial was limited in power to detect only large clinical effects.

Discussion

Double transplant intensifies therapy by combining active agents in a dose intensive way which otherwise could not be given all at once. Multicycle therapy may be more effective in tumors with low growth fractions and important host–tumor environmental interactions. In our experience, double transplant is safe and feasible. Dose-limiting peripheral sensory neuropathy was encountered at the 475 mg/m2 dose level of paclitaxel. The MTD was therefore reached at a paclitaxel dose of 400 mg/m2, a dose associated with moderate, but largely reversible, peripheral sensory neuropathy. Dose-escalation of paclitaxel resulted in a modest increase in mucositis. Treatment could be delivered within 14–16 weeks. Full recovery of performance status occurred within the first 4 months for 90% of patients, similar to the distribution observed after single transplant. All eligible patients completed both cycles of transplant without mortality or need for intensive care.

Toxicity of the double intensification regimen appears unrelated to the sequence of the two intensification components, as non-hematologic toxicities of CTCb were similar whether or not TxM preceded it (Ref. 10 and this trial). Since the doses of paclitaxel changed during this extended phase I/II trial, toxicities specific to paclitaxel such as peripheral neuropathy and mucositis were affected by dose escalation. However, the general time-course of toxicities of TxM appeared unaffected by the change of sequence. Interestingly, the recovery of hematopoietic function from each regimen for a particular patient was highly predictable and similar between the two intensifications. This was also independent of sequence, suggesting that there is no apparent additive stromal cell damage from high-dose melphalan, which might otherwise affect repopulation of marrow with sequential autografts.

Over 50 patients with metastatic breast cancer have been treated with this double transplant regimen, 26 in the current report and 32 with the opposite sequence.10 Although the intent-to-treat outcomes reported in the present study remain early, the event-free and overall survivals to the current level of follow-up mirror the results of the previously reported trial of the reverse sequence (Figure 3). While not absolutely definitive, no clear outcome differences have yet emerged to suggest any substantive effect of the sequence of regimens when they are separated by 5 weeks. It seems unlikely that it will be worthwhile addressing this question in a phase III trial, although there is no evidence to suggest that the current sequence with melphalan/paclitaxel second is inferior to the reverse. Although a myriad of possibilities exist, the most likely explanation for the effect seen in preclinical models and our clinical experience is the uncertainty how to extrapolate the timing for the off-rate of acute drug-induced resistance between mouse and woman.

Figure 3
figure3

Overall and event-free survival of short induction/double transplant: effect of sequence: (curves extending beyond 5 years represent the sequence Ax2 → TxM → CTCb (Ref. 10); curves extending to 40 months represent the current study Ax2 → CTCb → TxM).

We are tremendously encouraged, however, by the favorable outcomes described in our two double transplant studies. We recognize that selection biases, overt or not, can influence the interpretation of outcomes, particularly in small trials with short follow-up. Not only were the participants in these trials selected for high-dose therapy, but they were enrolled in cohorts of three patients every 2 months due to the phase I aspect of the trial. We know that patients receiving conventional doxorubicin-containing chemotherapy, but selected for candidacy for high-dose therapy, generally have a better prognosis.19,20,21 For example, the median progression-free and overall survivals for this group of patients with metastatic disease receiving FAC chemotherapy was 16 and 30 months, and the 3- and 5-year progression-free survivals were 10% and 7% in the MD Anderson experience.19 Those who achieved CR enjoyed a median time to progression of 22 months, 3- and 5-year progression-free survivals of 30% and 20%, and a median survival of 40 months. These patients had not received prior adjuvant chemotherapy, but had received local-regional measures to treat sites of metastatic disease. In our own experience of single transplant for metastatic breast cancer in response to induction therapy, the median EFS and overall survivals were 8 and 24 months, and 16% remain progression-free a median of 7 years later.3,22 These latter results are similar to those published by the ABMTR.2 Two randomized trials reported have evaluated the role of high-dose therapy in metastatic breast cancer as either primary therapy or as consolidation after induction therapy,23,24 and a third has been discredited.25 One small study suggested that an improvement in both disease-free and overall survival could be achieved with the use of high-dose therapy compared to conventional-dose therapy, although it did not reach statistical significance.23 Stadtmauer et al24 showed no benefit for transplant compared with 18 months of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) chemotherapy following six cycles of induction chemotherapy, although this trial was also small, and was only powered to be able to demonstrate a doubling of survival. Only 5% converted from PR to CR with HDC, potential evidence that the use of multiple cycles of low-dose cyclophosphamide-containing therapy during the induction phase may have contributed to drug resistance. Historical comparisons, particularly in individual phase I/II studies, must always be viewed with reservation, given the possibility of selection bias.

We believe the favorable outcomes reported in both our double transplant trials suggest that double intensification with short induction is an important concept to test in phase III trials in metastatic breast cancer, and in earlier stage breast cancer in comparison to standard-dose therapy or single intensification. In addition, further phase I efforts to add new novel agents to this double transplant regimen are warranted given the favorable toxicity profile and feasibility of this approach. Increases in rates of complete and near complete response may have additional merit if new therapies emerge to treat residual tumor. This would be particularly effective in the setting of minimal tumor burden.

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Acknowledgements

This work was supported in part by a grant from the Public Health Service Grant CA13849 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.

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Correspondence to AD Elias.

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Elias, A., Richardson, P., Avigan, D. et al. 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. Bone Marrow Transplant 28, 447–454 (2001) doi:10.1038/sj.bmt.1703148

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Keywords

  • metastatic breast cancer
  • hematopoietic stem cell support
  • double transplant

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