Four-step high-dose sequential chemotherapy with double hematopoietic progenitor-cell rescue for metastatic breast cancer.

Patrone, Franco; Ballestrero, Alberto; Ferrando, Fabio; Brema, Fulvio; Moraglio, L.; Valbonesi, M; Basta, Palmina; Ghio, Riccardo; Gobbi, Marco; Sessarego, Mario

doi:10.1200/jco.1995.13.4.840

Cited by 38 publications

(14 citation statements)

References 23 publications

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“…Mucositis is a frequent and important complication of high-dose NOV and L-PAM (Mulder et al, 1989;Ellis et al, 1990;Wallerstein et al, 1990;Bowers et al, 1993;Attal et al, 1994;Stiff et al, 1994;Patrone et al, 1995). Nonhaematological toxicity was observed in 76% of patients in our series, and in a third (33%) of them it was of intermediate-high grade requiring parenteral nutrition and some analgesic treatment.…”

Section: Discussionmentioning

confidence: 60%

“…Breast cancer patients received a four-step high-dose treatment as previously reported (Patrone et al, 1995), including: first, cyclophosphamide (CY) 6 g m-2; second, NOV 60-90 mg m-2 plus L-PAM 140-180 mg m-2 and PBPC rescue; third, methotrexate 8 g m-2 plus vincristine 1.4 mg in-2; and fourth, etoposide 1.5 g m-2 plus carboplatin 1.5 g m-2 and PBPC rescue. NHL patients received similar treatment except for the metothrexate plus vincristine step which was omitted.…”

Section: High-dose Chemotherapymentioning

confidence: 99%

“…In fact, NOV has haematological dose-limiting toxicity with reportedly limited cardiotoxicity compared with other anthracyclines, can be escalated at least five times above the conventional dose and clearly exhibits a steep dose-response curve in vitro (Von Hoff et al, 1986). Thus, it has been included in several high-dose regimens delivered with haematopoietic rescue (Mulder et al, 1989;Ellis et al, 1990;Wallerstein et al, 1990;Bowers et al, 1993;Attal et al, 1994;Stiff et al, 1994;Patrone et al, 1995). However, it has been claimed that very high dosages imply haematological toxicity that cannot be adequately rescued even by haematopoietic progenitor cell reinfusion (Attal et al, 1994).…”

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confidence: 99%

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High-dose mitoxantrone with peripheral blood progenitor cell rescue: toxicity, pharmacokinetics and implications for dosage and schedule

Ballestrero

Ferrando²,

Garuti³

et al. 1997

Br J Cancer

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Summary The optimal use of mitoxantrone (NOV) in the high-dose range requires elucidation of its maximum tolerated dose with peripheral blood progenitor cell (PBPC) support and the time interval needed between drug administration and PBPC reinfusion in order to avoid graft toxicity. The aims of this study were: (1) to verify the feasibility and haematological toxicity of escalating NOV up to 90 mg m-2 with PBPC support; and (2) to verify the safeness of a short (96 h) interval between NOV administration and PBPC reinfusion. Three cohorts of ten patients with breast cancer (BC) or non-Hodgkin's lymphoma (NHL) received escalating doses of NOV, 60, 75 and 90 mg m-2 plus melphalan (L-PAM), 140-180 mg m-2, with PBPC rescue 96 h after NOV. Haematological toxicity was evaluated daily (WHO criteria). NOV plasma pharmacokinetics was also evaluated, as well as NOV cytotoxicity against PBPCs. Haematological recovery was rapid and complete at each NOV dose level without statistically significant differences, and there were no major toxicities. NOV plasma concentrations at the time of PBPC reinfusion were below the toxicity threshold against haemopoietic progenitors. It is concluded that, when adequately supported with PBPCs, NOV can be escalated up to 90 mg m-2 with acceptable haematological toxicity. PBPCs can be safely reinfused as early as 96 h after NOV administration.Keywords: high-dose chemotherapy; mitoxantrone; peripheral blood progenitor cells High-dose chemotherapy is commonly based on alkylating agents, mainly because of the myeloid dose-limiting toxicity, the steep dose-response curve in vitro and the favourable dose ratio (with a four-to tenfold escalation with respect to conventional doses) of these drugs (Frei and Canellos, 1980;Frei, 1995). However, the growing extension of high-dose chemotherapy to solid tumours and the development of multistep high-dose programmes have led to a broader use of drugs belonging to different classes and acting by different mechanisms (Gianni and Bonadonna, 1989).Among the non-alkylating agents, mitoxantrone (NOV), an anthraquinone compound that is active against a variety of haematological and solid tumours, has received considerable attention. In fact, NOV has haematological dose-limiting toxicity with reportedly limited cardiotoxicity compared with other anthracyclines, can be escalated at least five times above the conventional dose and clearly exhibits a steep dose-response curve in vitro (Von Hoff et al, 1986). Thus, it has been included in several high-dose regimens delivered with haematopoietic rescue (Mulder et al, 1989;Ellis et al, 1990;Wallerstein et al, 1990;Bowers et al, 1993;Attal et al, 1994;Stiff et al, 1994;Patrone et al, 1995). However, it has been claimed that very high dosages imply haematological toxicity that cannot be adequately rescued even by haematopoietic progenitor cell reinfusion (Attal et al, 1994). A special matter of concern arises from its Received 10 December 1996 Revised 5 March 1997 Accepted 11 March 1997 Correspondence to: F Patrone, DIMI...

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Section: Discussionmentioning

confidence: 60%

Section: High-dose Chemotherapymentioning

confidence: 99%

mentioning

confidence: 99%

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High-dose mitoxantrone with peripheral blood progenitor cell rescue: toxicity, pharmacokinetics and implications for dosage and schedule

Ballestrero

Ferrando²,

Garuti³

et al. 1997

Br J Cancer

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“…Of note, eight of the 18 patients (44%) remained alive Nine patients had developed chest wall involvement and progression-free 10-18 months post-transplant, a figure prior to the transplant but had not developed distant metawhich compares favorably with other recently reported stases and were considered to have non-metastatic disease trials of high-dose therapy for metastatic disease. [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][28][29][30][31][32][33] for the purposes of this study. The median progression-free More recently, Broun et al 15 reported treating 28 women survival among these nine patients was 2.09 years.…”

Section: Engraftment and Transfusion Supportmentioning

confidence: 99%

Phase II study of high-dose cyclophosphamide, etoposide, and carboplatin (CEC) followed by autologous hematopoietic stem cell rescue in women with metastatic or high-risk non-metastatic breast cancer: multivariate analysis of factors affecting survival and engraftment

Goldberg

Magdalinski

et al. 1997

Bone Marrow Transplant

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Summary:Seventy women with high-risk stage II (n = 10), IIIA Breast cancer remains an important source of morbidity and mortality among women, with an estimated 46 000 deaths annually in the United States alone. 1 Despite extensive (n = 12), IIIB (n = 11), or IV (n = 37) breast cancer research, recently published studies continue to report zero received cyclophosphamide 6000 mg/m 2 , etoposide or near-zero long-term progression-free survival rates 2400 mg/m 2 , and carboplatin 1200 mg/m 2 followed by among women with metastatic disease 2-7 and less than 50% infusion of autologous hematopoietic stem cells (AHSC).long-term survival among women with locoregional disWomen with high-risk stage II disease had eight or ease. 8,9 For example, a recently published 20-year followmore involved axillary lymph nodes (n = 9) or axillary up analysis 8 of a major adjuvant chemotherapy trial and breast relapse following lumpectomy, chemoreported 37% long-term progression-free survival among therapy, and radiation therapy (n = 1). Women with women with one to three involved axillary lymph nodes, measurable stage III or stage IV disease were required 26% progression-free survival among women with four to to demonstrate complete or partial response to conven-10 axillary nodes involved, and no long-term progressiontional-dose chemotherapy prior to transplant. The overfree survivors among women with more than 10 involved all (complete plus partial) response rate for the 31 nodes. Similarly, a recently reported large chemotherapy patients not in complete remission at the time of transtrial in women with previously untreated metastatic disease plant was 55%. With a median follow-up of 545 days, reported a 0% survival rate at less than 5 years. 7 the 2-year actuarial progression-free survival rates forDisappointing long-term results with conventional-dose patients with stage II, IIIA, IIIB and IV are 86, 75, 42 therapy, as well as both controlled and uncontrolled studies and 13%, respectively. Factors independently predictive suggesting a chemotherapeutic dose-response relationship of longer progression-free survival by multivariate for breast cancer within conventional dose ranges 7-9 have analysis included lower stage disease, status of disease led to the introduction of high-dose therapy (HDC) folat transplant (in CR vs not in CR), and positive estrogen lowed by rescue with autologous blood or marrow-derived receptor status. Factors predictive of more rapid neuhematopoietic stem cells (AHSC) in women with metastatic trophil engraftment by multivariate analysis included or high-risk non-metastatic breast cancer. 10-33 post-transplant administration of hematopoietic growthWe elected to study the combination of high-dose cyclofactors, greater number of infused CFU-GM, mobilizphosphamide, etoposide, and carboplatin (CEC) for a phase ation with G-CSF or cyclophosphamide/G-CSF (vs II study in this patient population for several reasons: (1) mobilization with GM-CSF or no mobilization), andThe efficacy of high-dose alkylating agent-based c...

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“…In an attempt to overcome this problem, Gianni et al (1992) devised innovative regimens which sequentially delivered high doses of different single agents that were putatively susceptible to different drug-resistance mechanisms (Patrone et al, 1995). Both the 'induction-consolidation' and the 'high-dose sequential models' are, however, based on the premise that populations of cells that are sensitive to a treatment can be efficiently eradicated by a single application of that treatment -a hypothesis which is not entirely consistent with classical chemotherapy theory and practice .…”

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confidence: 99%

High-dose chemotherapy of metastatic breast cancer: the end of the beginning?

Crown¹

1997

Br J Cancer

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Despite a diverse armamentarium of active drugs and response rates that now exceed 70%, the survival impact of chemotherapy in metastatic breast cancer is limited, and the disease remains essentially incurable (Cold et al, 1992). This frustrating, partial chemosensitivity prompted investigators to explore potential clinical applications of the relationship that had been demonstrated in laboratory models between drug dose and anti-cancer effect (Teicher et al, 1988). Random assignment trials, in which variations in dose within the 'standard' range (i.e. doses that could be administered without specialized haematopoietic support) were studied, yielded modest and inconsistent results; however the degree of dose escalation that had been attempted in these trials was relatively minor in comparison with that achieved in the laboratory (Hortobagyi et al, 1987; Bastholt et al, 1996).The development of marrow autografting facilitated the study of very high doses of some drugs, prominently the alkylating agents, and allowed clinical investigators to mimic the levels of drug exposure that had been assayed in the preclinical systems. The first trials of high-dose chemotherapy with autograft support in breast cancer were performed in patients with disease that had failed conventional treatment. While high rates of response were achieved, indicating that dose escalation could indeed partly overcome drug resistance, these responses were of brief duration. In addition treatment-related mortality occurred in up to 20% of patients (Eder et al, 1986). In subsequent studies in patients without prior chemotherapy for metastases, approximately 50% achieved remission and, provocatively, a minority of these remained durable (Peters et al, 1988;Ghallie et al, 1994).Investigators next turned to a strategy based on an interpretation of the work of Norton and Simon (1986). According to their kinetic model, cancer cells grew and regressed -not in the strictly exponential fashion that had previously been proposed (Skipper and Schabel, 1982) but in a Gompertzian manner. The essential feature of Gompertzian kinetics is that the growth fraction of the tumour is not constant, as would be predicted by the exponential model, but rather varies with the size of the tumour. As tumours grow larger, their growth rate decreases. They further hypothesized that the rate of regression of a cancer was related to the dose of chemotherapy administered and to the growth rate of the unperturbed tumour at

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Four-step high-dose sequential chemotherapy with double hematopoietic progenitor-cell rescue for metastatic breast cancer.

Abstract: This regimen is feasible, with acceptable toxicity. GM-CSF and PBPCs have a pivotal role, as they hasten hematologic reconstitution, abate toxicity, and allow rapid recycling.

Cited by 38 publications

References 23 publications

High-dose mitoxantrone with peripheral blood progenitor cell rescue: toxicity, pharmacokinetics and implications for dosage and schedule

High-dose mitoxantrone with peripheral blood progenitor cell rescue: toxicity, pharmacokinetics and implications for dosage and schedule

Phase II study of high-dose cyclophosphamide, etoposide, and carboplatin (CEC) followed by autologous hematopoietic stem cell rescue in women with metastatic or high-risk non-metastatic breast cancer: multivariate analysis of factors affecting survival and engraftment

High-dose chemotherapy of metastatic breast cancer: the end of the beginning?

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