High-dose chemotherapy with autologous stem cell rescue in breast cancer

SummaryBackground Because metastatic breast cancer is a lethal disease despite some responsiveness to systemic chemotherapy, high-dose chemotherapy with autologous stem cell rescue is being utilized with increasing frequency. This analysis was undertaken to determine the outcome for such patients treated with intensive chemotherapy between 1989–1994, at the Hoag Cancer Center in Newport Beach, CA.Methods During 1989, only patients with metastatic disease who had failed more than two standard breast cancer chemotherapy regimens were considered eligible for such treatment. They received high-dose BCNU/ cyclophosphamide/cisplatinum chemotherapy with autologous bone marrow rescue. After January 1990, patients with metastatic disease were eligible only if they had received limited prior chemotherapy and demonstrated responsiveness to induction chemotherapy. Beginning June 1990, patients with metastatic disease were to receive mitoxantrone and thiotepa (MiTepa) followed by peripheral blood stem cell rescue, then ifosfamide, carboplatin and etoposide (ICE) chemotherapy followed by peripheral blood stem cell rescue. High-risk adjuvant patients were to receive one course of ICE followed by rescue.Results Between 1/89–12/94, 48 breast cancer patients underwent 65 intensive chemotherapy treatments followed by autologous stem cell rescue. During 1989, three of the eight patients with metastatic disease died within 60 days because of therapy-related complications. The longest failure-free survival (FFS) of these eight was 12.2 months, and the longest overall survival (OS) 20.5 months. Since 1/90, one physician has treated 24 patients with metastatic breast cancer, 17 of whom actually underwent two successive transplants with MiTepa/ICE. For the latter group, median FFS is 23.2 months; median OS is 39.7 months. There were no acute deaths, but two patients died > 60 days after initial transplant from therapy-related complications, venoocclusive disease (5.2 months) and myelodysplastic syndrome (30.5 months), while five died of progressive disease at 22.5, 32.8, 39.4, 46.3, and 51.3 months. For the 24 metastatic patients treated 1990–1994, 1-, 2-, and 3-year FFS rates are 86%, 40%, and 17%, respectively, while OS rates are 91%, 80%, and 65%. Of 11 patients treated in the adjuvant setting, only one has relapsed (9.8 months) with follow-up from 3–61 months.Conclusions Modifications made in the program, including selection of patients responsive to induction chemotherapy, transfusion of peripheral blood stem cells, implementation of hematopoietic colony stimulating factors, and use of tandem intensive treatments has been associated with a low rate of acute morbidity and encouraging survival rates.Presented in part at the 16th Annual San Antonio Breast Cancer Symposium, November 5, 1993     

High-dose chemotherapy and autologous stem cell transplant in women with de novo chemosensitive metastatic breast cancer

The prognosis of patients with de novo stage IV breast cancer seems to be similar to that of patients with metastatic disease. Because these patients have not been exposed to prior therapy, the use of high dose chemotherapy (HDCT) may be beneficial. Twenty-four newly diagnosed (median age 42) responding metastatic breast cancer patients underwent HDCT (Stamp V) and stem cell support as their initial treatment. The predominant sites of metastatic disease were bone (12), lung (5), liver (2), lymph nodes (6), marrow (4), and soft-tissue (1). Estrogen/progesterone receptors were positive in 35%, negative in 45%, and unknown in 20%. Before transplantation, 10 patients were in complete remission (CR), 6 were in partial remission (PR), and 8 were inevaluable. Radiotherapy was administered to sites of documented metastatic disease. Tamoxifen was given to patients with receptor positive and unknown tumor status. After a median follow-up of 60 months from diagnosis (range 42 to 96 months), 15 patients have relapsed and 10 died. Mean and median progression free survival from transplant are 53 (SE 6.6, CI 40-66) and 60 (SE 18, CI 25-96) months, respectively. The median survival has not yet been achieved (>6 years). There was no treatment-related mortality. The use of HDCT in patients with chemosensitive, de novo metastatic breast cancer is safe and well tolerated. Overall clinical outcome is good; however, this study cannot determine whether this was due to treatment or selection bias.     

High-dose chemotherapy with mitoxantrone + melphalan and autologous stem cell rescue in metastatic breast cancer patients: a study of feasibility and tolerability

Hematological and extra-hematological toxicity of mitoxantrone-containing regimens with autologous stem cell rescue was evaluated in 32 metastatic breast cancer patients. The schedule was the final part of two high-dose chemotherapy programs, including an induction phase with three courses of conventional chemotherapy with epirubicin (120 mg/m2) and cyclophosphamide (600 mg/m2) plus three courses of docetaxel (100 mg/m2) and a first high-dose chemotherapy consisting of cyclophosphamide (6000 mg/m2), thiotepa (500 mg/m2) and carboplatin (800 mg/m2) or melphalan (160 mg/m2) plus thiotepa (600 mg/m2). The final second autograft phase included mitoxantrone (60 mg/m2) associated with melphalan (160 mg/m2) and autologous stem cell rescue infusion. The median duration of severe neutropenia and thrombocytopenia was 9 (range, 7-13) and 11.5 (range, 9-29) days. The median number of units of erythrocytes and platelets transfused was 1 (0-11) and 4 (1-9), respectively. Fever for a median of 2 (0-8) days developed in 71.8% of the patients. Mucositis was observed in 81.2% (WHO grade 3-4 in 25%). No acute or late cardiac toxicity was observed. One patient died because of a transplant-unrelated cause. The response according to the program phase showed an increased rate of complete response, from 12.5% at the end of conventional chemotherapy to 21.9% after the first high-dose chemotherapy course, to increase to 43.9% after the treatment with mitoxantrone-melphalan. We conclude that a conditioning regimen with high dose mitoxantrone-melphalan fits well within the high-dose chemotherapy program.     

High-dose consolidation therapy with autologous stem cell rescue in stage IV breast cancer

We designed a phase II study to determine whether induction chemotherapy (CT) consisting of leucovorin, vincristine, methotrexate, doxorubicin, and cyclophosphamide (LOMAC) followed by high-dose intensification chemotherapy (ICT) with cyclophosphamide, thiotepa, and autologous stem cell rescue (ASCR) could increase the complete response (CR) rate and survival in women with stage IV breast cancer. Twenty-nine women were enrolled on study; 16 patients had received prior adjuvant chemotherapy and no patient had received chemotherapy for stage IV disease. Two patients were found to be ineligible and excluded from further analysis. Of the 27 patients treated, four (15%) obtained a CR and 15 (56%) a partial response (PR) after LOMAC induction, for an overall response rate of 70%. Of the 22 patients treated with ICT, 12 patients had a CR, and nine were in PR after induction and converted to CR after ICT. The toxicities included nausea/vomiting, mucositis, diarrhea, dermatitis, alopecia, and infections secondary to neutropenia. The 1-year survival is 60%; the median has not yet been reached. The time to treatment failure for patients on study is 10 months. The treatment approach of ICT and ASCR following induction chemotherapy can lead to an improved CR rate in stage IV breast cancer. How this increased CR rate leads to a prolonged disease-free survival requires further follow-up.     

High-dose chemotherapy with autologous stem cell rescue in the outpatient setting

Intensive outpatient care is rapidly becoming the primary mode of care for selected patients undergoing high-dose chemotherapy with autologous peripheral blood stem cell (PBSC) transplantation. Although the traditional inpatient model of care may still be necessary for high-risk patients, published data suggest that outpatient care is safe and feasible during or after administration of high-dose chemotherapy and autologous PBSC transplant. Blood and marrow transplant (BMT) centers have developed programs to provide more outpatient care under three basic models: an early discharge model, a delayed admission model, and a comprehensive, or total, outpatient model. This review will describe these models of care and address the elements necessary for the development of an outpatient BMT program, including patient selection, staff development, and patient and caregiver education. Available supportive care strategies to facilitate outpatient care will also be highlighted. Clinical outcome data and pharmacoeconomic analyses evaluating various outpatient BMT programs, as well as limited quality-of-life evaluations, will be reviewed.     

High-dose chemotherapy with autologous stem cell rescue for children with recurrent malignant brain tumors

BACKGROUND: High-dose chemotherapy (HDCT) with autologous stem cell rescue (ASCR) has been reported to be effective in treating children with recurrent central nervous system (CNS) malignancies. METHODS: To evaluate the efficacy and toxicities of HDCT and ASCR, the medical records of 27 children with recurrent CNS malignancies who received such therapy at St. Jude Children's Research Hospital between 1989 and 2004 were reviewed. RESULTS: The median age at diagnosis was 4.5 years (range, 0.4-16.6 years) and that at ASCR was 6.7 years (range, 1.1-18.5 years). Diagnoses included medulloblastoma (13 patients), primitive neuroectodermal tumor (3 patients), pineoblastoma (2 patients), atypical teratoid rhabdoid tumor (2 patients), ependymoma (3 patients), anaplastic astrocytoma (2 patients), and glioblastoma multiforme (2 patients). The 5-year overall and progression-free survival (PFS) rates were 28.2% and 18.5%, respectively. The 5-year PFS rate for patients aged<3 years at diagnosis (57.1%) was significantly better than older patients (5.0%) (P=.019). Among the 6 long-term survivors (5 with M0 disease and 1 with M3 disease at diagnosis), 5 received both radiotherapy and HDCT as part of their salvage regimen; 4 were aged<3 years at diagnosis and had received chemotherapy only as part of frontline therapy. Two patients died of transplant-related toxicities; 44% experienced grade 3 or 4 transplant-related toxicities (toxicities were graded according to the National Cancer Institute Common Toxicity Criteria). CONCLUSIONS: HDCT with ASCR is not an effective salvage strategy for older children with recurrent CNS malignancies. The significantly better outcome in the younger cohort was most likely related to the use of radiotherapy as part of the salvage strategy.     

High-dose tri-alkylator chemotherapy with autologous stem cell rescue in patients with refractory malignancies

Forty patients with refractory solid tumors or non-Hodgkin's lymphoma were treated with high-dose cyclophosphamide, thiotepa, and carmustine (BCNU), followed by autologous stem cell rescue, in a phase I dose escalation study. The dose-limiting toxic effect was delayed drug-induced pulmonary disease, seen in three patients who received 660-750 mg of BCNU/m2 in combination with cyclophosphamide and thiotepa. The early death rate due to toxic effects was 20%; all deaths were attributed to sepsis or respiratory failure. The overall response rate was 63%. The median time to disease progression was 14 weeks. Although this regimen provided effective cytoreduction, its use in heavily pretreated patients with bulky disease is of limited value.     

High-dose therapy with autologous stem cell rescue for pediatric sarcomas

PURPOSE OF REVIEW: The principal pediatric sarcomas are Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma. While the prognosis for these diseases is generally favorable, it is possible to identify groups of patients with each diagnosis whose prognosis remains unacceptably poor. Based on the chemotherapy sensitivity of these tumors, many investigators have suggested that consolidation with high dose chemotherapy with or without radiation therapy followed by stem cell rescue could improve the prognosis for these high risk patients. This review evaluates the results of high dose therapy with stem cell reconstitution used to consolidate treatment of high risk patients with sarcomas. RECENT FINDINGS: The majority of the trials which have been conducted to assess this hypothesis have treated relatively small numbers of patients. They do not use consistent definitions of high risk. They have used different regimens for cytoreduction. They have used a variety of sources for stem cells. In many series, the consolidation therapy is applied only to patients who have achieved a significant response to prior therapy and the results have then been compared to a cohort of patients with similar presenting features, not all of whom responded to initial therapy. SUMMARY: The published results do not demonstrate an unequivocal benefit for consolidation with high-dose therapy. Future trials of high-dose therapy must define rigorous eligibility criteria, must have an appropriate, preferably randomized, control group, and must be designed with sufficient power to evaluate the hypothesis.     

High-dose chemotherapy with heamatopoietic rescue: application to primary management of metastatic breast cancer

The development of more effective treatment strategies currently provides the only realistic hope of reducing breast cancer mortality. Among such treatments, the use of high-dose chemotherapy (HDC) has been proposed as a potentially curative strategy. Consideration of the factors involved in the successful treatment of human tumours suggests that HDC is rationally planned with regard to tumour kinetics as well as chemotherapy sensitivity and resistance patterns. Ideally HDC should include dose escalation of at least 5–10-fold of drugs shown to have a steep dose-response curve and that have been effective in first-line treatment of breast cancer. Many current chemotherapy regimens lack one or the other of these attributes. Two randomized studies of HDC in breast cancer have been recently published. In the first study, HDC using a combination of cyclophosphamide, mitoxantrone and VP-16 as initial treatment was compared with a conventional-dose regimen consisting of cyclophosphamide, mitoxantrone and vincristine. The second study compared the effects of early or delayed HDC in patients who had achieved an optimal response to conventional-dose ‘induction’chemotherapy. Both studies showed HDC to be more effective than conventional-dose treatment in delaying time to progression but only the study that used HDC as initial treatment showed an effect of HDC on survival. The differences between these two investigations can probably be explained on the basis of the different effects on tumour kinetics and the efficiency of HDC when used as salvage therapy in the delayed HDC group. The finding that 20–25% of patients receiving HDC for metastatic breast cancer show prolonged disease-free survival suggest that HDC has an established role in the treatment of breast cancer. Attention now needs to turn to methods of optimizing this treatment strategy.     

High-dose combination alkylating agent chemotherapy with autologous bone marrow support for metastatic breast cancer

Seventeen patients with metastatic breast cancer were treated with a high-dose combination chemotherapy regimen and autologous bone marrow support. Thirteen patients had prior combination chemotherapy. Fifteen patients were treated with a phase II regimen of cyclophosphamide (5.625 g/m2), cisplatin (165 mg/m2), and BCNU (600 mg/m2). Bone marrow harvest and reconstitution were uncomplicated. All patients became profoundly myelosuppressed. Fourteen of 16 evaluable patients (88%) responded, including six complete responses (CRs) (38%). The median time to tumor progression was 5 months. The median survival was 8 months. CRs occurred more frequently in patients with no prior chemotherapy for metastatic disease, inflammatory breast cancer; and patients treated within 3 months of first recurrence. The rate of tumor regression was rapid, with a median of 11 days to partial response (PR) and 12 days to CR. Those patients achieving a PR by day 7 had a greater likelihood (P = .03) of attaining a CR than those patients whose PR occurred later. Three deaths (18%) occurred, all in women with inflammatory breast cancer treated with prior chemotherapy. High-dose combined alkylating agent therapy produced high PR and CR rates in metastatic breast cancer patients, most of whom had failed prior chemotherapy. The rate of tumor regression was rapid. Current efforts are directed at developing a regimen using drugs specifically active in breast cancer, with an intent of combining an effective high-dose regimen with additional modalities of therapy in the treatment of breast cancer.     

High-dose chemotherapy with autologous bone marrow transplantation for the treatment of metastatic breast cancer.

PURPOSE: This review was undertaken to examine the evidence of effectiveness of high-dose chemotherapy and autologous bone marrow transplantation (HDC/ABMT) for the treatment of metastatic breast cancer and to compare the magnitudes of the benefits and harms of HDC/ABMT with those of conventional doses of chemotherapy. DESIGN: Published studies were reviewed and analyzed. RESULTS: No randomized controlled trials have been published that evaluate HDC/ABMT. Only one internally controlled study has been conducted; it demonstrated that HDC/ABMT and conventional treatment have virtually identical outcomes. Comparisons of uncontrolled clinical series are confounded by patient selection and other biases. Gross comparisons indicate that, compared with conventional-dose chemotherapy, HDC/ABMT achieves (1) higher complete response rates (36% v 8%), (2) higher overall response rates (70% v 39%), (3) similar median response durations (8 months v 9.6 months), (4) similar median survival durations (16 months v 16.6 months), and (5) similar overall survival rates (eg, 43% 2-year survival v 39%). Observations of cases with longer-term disease-free survival are promising but not conclusive. High-dose chemotherapy with ABMT has a higher treatment-related mortality rate (5% to 15% v 1%), a high rate of nonmortal toxicity (approximately 30%), and a high rate of side effects (approaching 100%). CONCLUSIONS: Firm conclusions are not possible because of the lack of controlled studies and the presence of numerous biases. However, the existing evidence does not demonstrate that HDC/ABMT is superior to conventional-dose chemotherapy for the treatment of metastatic breast cancer. Randomized controlled trials are needed.     

High-dose chemotherapy with autologous stem cell rescue for children with high risk and recurrent medulloblastoma and supratentorial primitive neuroectodermal tumors

Current treatment for high risk and recurrent medulloblastoma (MB) and supratentorial primitive neuroectodermal tumors (stPNET) has a very poor prognosis in children. High dose chemotherapy (HDCT) and autologous stem cell rescue have improved survival rates. We present 19 patients (thirteen classified in the high risk group and six patients with recurrent disease) that received HDCT and autologous stem cell rescue.In the high risk group [Med Pediatr Oncol 38 (2002) 83], all patients underwent neurosurgical debulking. Standard chemotherapy was prescribed in 10 patients. Radiotherapy was given to 4 patients (all older than 4years old). In the recurrence disease group [Childs Nerv Syst 15 (1999) 498], five patients underwent surgery. Radiotherapy was given to those who were not previously irradiated. The HDCT in twelve patients consisted of busulfan 4mg/kg/day, orally over 4days in 6-hourly divided doses and melphalan at a dose of 140mg/m²/day by intravenous infusion over 5min on day –1. Three patients additionally received thiotepa 250mg/m²/day intravenously over 2days and four patients additionally received topotecan 2mg/m²/day over 5days by intravenous infusion over 30min. The other seven patients received busulfan and thiotepa at the same doses.Patients stem cells were mobilized with granulocyte colony-stimulating factor at a dose of 12g/kg twice daily subcutaneously for four consecutive days. Cryopreserved peripheral blood progenitor cells were re-infused 48h after completion of chemotherapy. With a median follow-up of 34months (range 5–93) eight complete responses and one partial response were observed. Three patients died of treatment-related toxicities (15%). The 2 year event-free survival was 37.67±14% in all patients and 57±15% for the high risk group.Therefore we conclude that HDCT may improve survival rates in patients with high risk/recurrent MB and stPNET despite treatment toxicity.     

High-dose chemotherapy with autologous stem cell rescue followed by posterior fossa irradiation for local medulloblastoma recurrence or progression after conventional chemotherapy

BACKGROUND: The objective of the current study was to determine the outcome of children with local recurrence or progression of medulloblastoma in patients who received high-dose chemotherapy (HDC) and posterior fossa (PF) irradiation. METHODS: HDC consisted in busulfan at a dose of 600 mg/m(2) and thiotepa at a dose of 900 mg/m(2) followed by autologous stem cells transplantation (ASCT). PF radiotherapy was delivered at doses from 50 grays (Gy) to 55 Gy on Day +70 after ASCT. Twenty-seven patients developed local recurrence of an initially completely resected medulloblastoma. Twelve patients had local residual disease after surgery and were enrolled into the salvage protocol at the time of local disease progression under conventional chemotherapy. RESULTS: Acute toxicity consisted mainly in hepatic veno-occlusive disease (33% of patients) and bone marrow aplasia. Two toxic deaths (5%) from infections were reported. The 5-year overall survival rate after this salvage treatment (OS(5y)) for the 39 children who were treated was 68.8% (95% confidence interval [95% CI], 53-81.2%). In the group of patients who were treated for local recurrence, the OS(5y) was 77.2% (95% CI, 58.3-89.1%). Patients with local residual disease who were treated at the time of disease progression had an OS(5y) after salvage treatment of only 50% (95% CI, 25.4-74.6%; P = .09). CONCLUSIONS: The treatment strategy that was used in this study had manageable immediate toxicity and resulted in a high overall survival rate in the setting of young children with medulloblastoma who developed local recurrence or disease progression.     

High dose chemotherapy with autologous stem cell rescue for patients with medulloblastoma

Summary High-dose chemotherapy with autologous stem cell rescue (ASCR) is a promising strategy for patients with poor prognosis cerebellar medulloblastoma. For this strategy to be effective, it must be shown that the medulloblastoma tumor cells are sensitive to the chemotherapeutic agents whose dose-limiting toxicity is hematopoietic, and stem cells must be available that are free of contaminating tumor. Several protocols for high-dose chemotherapy followed by ASCR are presented in this chapter. Initial encouraging evaluations of this technique in patients with recurrent disease has prompted testing of its feasibility in infants and young children. In a reasonably short time, the role of high-dose chemotherapy with ASCR will be determined for subgroups of patients with medulloblastoma.     

High-dose chemotherapy and autologous stem cell rescue for atypical teratoid/rhabdoid tumor of the central nervous system

Atypical Teratoid/Rhabdoid tumors (AT/RT) of the central nervous system are rare but aggressive tumors of childhood. Median survival with surgery and standard chemotherapy is less than 12 months. In an attempt to improve outcome, patients were treated with aggressive surgical resection and multi-agent chemotherapy, followed by high dose chemotherapy with autologous stem cell rescue. Nine consecutive children (median age 21 months) were diagnosed with AT/RT at the University of California San Francisco Childrens Hospital from 1997 to 2007 and treated with this aggressive approach. Diagnosis was confirmed using molecular markers. There are two long-term survivors (78 and 98 months from diagnosis). One additional patient is alive with disease. Three patients died of disease during therapy. Three patients died of disease after therapy was complete. There were no toxic deaths. Two of nine patients treated for AT/RT at our institution with high dose chemotherapy and autologous bone marrow transplant are long-term survivors, suggesting that a subset of patients can be cured with this approach.