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November 3, 1993, Vol 270, No. 17 >
ARTICLE | November 3, 1993

Dose-Intensive Therapy for Breast Cancer FREE

Joyce A. O'Shaughnessy, MD; Kenneth H. Cowan, MD, PhD
[+] Author Affiliations

Reprint requests to the Medical Breast Cancer Section, Medicine Branch, National Cancer Institute, Bldg 10, Room 12N226, National Institutes of Health, Bethesda, MD 20892 (Dr O'Shaughnessy).


JAMA. 1993;270(17):2089-2092. doi:10.1001/jama.1993.03510170079035
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Published online
Article
References

SELECTED CASE  In 1988, a 38-year-old woman noticed progressive, symmetrical hardening of both breasts. Mammograms showed dense tissue bilaterally with no discrete masses and biopsies were unfortunately not recommended. In 1989, she developed lumbar back pain, and a complete blood cell count showed a hemoglobin level of 90 mg/L, a white blood cell count of 3.4×109/L, and a platelet count of 90×109/L. Her breast examination showed bilateral, diffuse denseness without skin involvement. Breast and bone marrow biopsies showed estrogen receptor-positive infiltrating ductal breast carcinoma metastatic to the bone marrow. She was treated with dose-intensive fluorouracil, leucovorin calcium, doxorubicin, and cyclophosphamide (FLAC) in combination with the hematopoietic growth factor, granulocyte-macrophage colony-stimulating factor (GMCSF). After two cycles of therapy, her back pain had disappeared and her blood cell counts normalized. After 10 cycles, her breast examination was normal, but repeat bone marrow examination showed a residual microscopic focus

REFERENCES

1 +
Frei EIII,Antman K, Teicher B, Eder P, Schnipper L.  Bone marrow autotransplantation for solid tumors—prospects. J Clin Oncol . 1989;;7:515-526.
2 +
Carmo-Pereira J, Costa FO, Henriques E, et al.  A comparison of two doses of Adriamycin in the primary chemotherapy of disseminated breast carcinoma. Br J Cancer . 1987;;56:471-473.
3 +
Wheeler RH, Ensminger WD, Thrall JH, et al.  High-dose doxorubicin: an exploration of the dose-response curve in human neoplasia. Cancer Treat Rep . 1982;;66:493-498.
4 +
Jones RB, Holland JF, Bhardwaj S, Norton L, Wilfinger C, Strashun A.  A phase I-II study of intensive dose Adriamycin for advanced breast cancer. J Clin Oncol . 1987;;5:172-177.
5 +
Hryniuk W, Bush H.  The importance of dose intensity in chemotherapy of metastatic breast cancer. J Clin Oncol . 1984;;2:1281-1288.
6 +
Bastholt L, Dalmark M, Gjedde S, et al.  Epirubicin at four different dose levels in metastatic breast cancer: a randomized trial. Proc Am Soc Clin Oncol . 1992;;11:A51.
7 +
Tannock IF, Boyd NF, Deboer G, et al.  A randomized trial of two dose levels of cyclophosphamide, methotrexate, and fluorouracil chemotherapy for patients with metastatic breast cancer. J Clin Oncol . 1988;;6:1377-1387.
8 +
Antman KH.  Dose-intensive therapy in breast cancer.  In: Armitage JO, Antman KH, eds. High-Dose Cancer Therapy . Baltimore, Md: Williams and Wilkins; 1992;:701-718.
9 +
Hryniuk W, Levine MN.  Analysis of dose intensity for adjuvant chemotherapy trials in stage II breast cancer. J Clin Oncol . 1986;;4:1162-1170.
10 +
Ang P-T, Buzdar AU, Smith TL, Kau S, Hortobagy GN.  Analysis of dose intensity in doxorubicincontaining adjuvant chemotherapy in stage II and III breast carcinoma. J Clin Oncol . 1989;;7:1677-1684.
11 +
Budman DR, Wood W, Henderson IC, et al.  Initial findings of CALGB 8541: a dose and dose intensity trial of cyclophosphamide (C), doxorubicin (A), and 5-fluorouracil (F) as adjuvant treatment of stage II, node + breast cancer. Proc Am Soc Clin Oncol . 1992;;11:A29.
12 +
Eddy DM.  High-dose chemotherapy with autologous bone marrow transplantation for the treatment of metastatic breast cancer. J Clin Oncol . 1992;;10:657-670.
13 +
Antman KH, Ayash L, Elias A, et al.  A phase II study of high-dose cyclophosphamide, thiotepa, and carboplatin with autologous marrow support in women with measurable advanced breast cancer responding to standard-dose therapy. J Clin Oncol . 1992;;10:102-110.
14 +
Peters WP, Shpall EJ, Jones RB, et al.  High-dose combination cyclophosphamide (CPA), cisplatin (CDDP), and carmustine (BCNU) with bone marrow support as initial treatment for metastatic breast cancer: 3- to 6-year follow-up. Proc Am Soc Clin Oncol . 1990;;9:A31.
15 +
Dunphy F, Spitzer G.  Use of very-high-dose chemotherapy with autologous bone marrow transplantation for treatment of breast cancer. J Natl Cancer Inst . 1992;;84:128-129.
16 +
Williams SF, Mick R, Desser R, et al.  High-dose consolidated therapy with autologous stem cell rescue in stage IV breast cancer. J Clin Oncol . 1989;;7:1824-1830.
17 +
Peters WP.  Use of CSF-primed peripheral blood progenitor cells in high-dose chemotherapy studies for metastatic and primary breast cancer. Ann Oncol . 1992;;3( (suppl 1) ):164.
18 +
Elias AD, Ayash L, Anderson KC, et al.  Mobilization of peripheral blood progenitor cells by chemotherapy and granulocyte-macrophage colony-stimulating factor for hematologic support after high-dose intensification for breast cancer. Blood . 1992;;79:3036-3044.
19 +
Peters WP, Ross N, Vrendenburgh J, et al.  High-dose chemotherapy and autologous bone marrow support as consolidation after standard-dose adjuvant therapy for high-risk primary breast cancer. J Clin Oncol . 1993;;11:1132-1143.
20 +
Demetri GD, Horowitz J, McGuire BW, et al.  Dose intensification of mitoxantrone with adjunctive G-CSF (r-methu-G-CSF) in patients with advanced breast cancer: a phase I trial. Proc Am Soc Clin Oncol . 1992;;11:A370.
21 +
Hudis C, Lebwohl D, Crown J, et al.  Feasibility of adjuvant dose-intensive cyclophosphamide with G-CSF after doxorubicin in women with high risk stage II/III resectable breast cancer. Proc Am Soc Clin Oncol . 1992;;11:A48.
22 +
Bronchud MH, Howell A, Crowther D, et al.  The use of granulocyte colony-stimulating factor to increase the intensity of treatment with doxorubicin in patients with advanced breast and ovarian cancer. Br J Cancer . 1989;;60:121-125.
23 +
Savarese DM, Denicoff AM, Berg SL, et al.  A phase I and pharmacokinetic study of high-dose piroxantrone along with granulocyte colony-stimulating factor (G-CSF). J Clin Oncol . 1993;;11:1795-1803.
24 +
Swain S, Honig S, Egan E, et al.  A phase I, dose-intensity trial for node-positive breast cancer patients using adjuvant cyclophosphamide (C), doxorubicin (A), and granulocyte colony-stimulating factor (G-CSF). Proc Am Assoc Cancer Res . 1992;;33: A1533.
25 +
Demetri GD, Younger J, Shapiro C, et al.  A phase I study of dose-intensified CAF chemotherapy with adjunctive r-met(hu)G-CSF(G-CSF) in patients with advanced breast cancer. Proc Am Soc Clin Oncol . 1992;;11:A255.
26 +
Lind MJ, Cantwell B, Millward MJ, et al.  The use of rhGCSF to accelerate the delivery of ifosfamide and epirubicin in women with locally advanced or metastatic carcinoma of the breast. Proc Am Assoc Cancer Res . 1992;;33:A1447.
27 +
Watanake T, Miya T, Fukutomi T, et al.  Phase I study of high-dose epirubicin (EPI) and cyclophosphamide (CPA) with rG-CSF for metastatic breast cancer. Proc Am Soc Clin Oncol . 1992;;11: A178.
28 +
Hoekman K, Wagstaff J, van Groeningen CJ, et al.  Effects of recombinant human granulocyte-macrophage colony-stimulating factor on myelosuppression induced by multiple cycles of high-dose chemotherapy in patients with advanced breast cancer. J Natl Cancer Inst . 1991;;83:1546-1559.
29 +
Sunderland M, Abeloff M, Neidhart J, et al.  Continuous GM-CSF failed to ameliorate neutropenia and worsened thrombocytopenia in a dose-intensive regimen for breast cancer. Breast Cancer Res Treat . 1991;;19:158.
30 +
Neidhart JA.  Dose-intensive treatment of breast cancer supported by granulocyte-macrophage colony-stimulating factor (GM-CSF). Breast Cancer Res Treat . 1991;;20( (suppl) ):515-523.
31 +
Luikart SD, MacDonald M, Herzan D, et al.  Ability of daily or twice daily granulocyte-macrophage colony-stimulating factor (GM-CSF) to support dose escalation of etoposide (VP-16) and carboplatin (CBDCA) in extensive small cell lung cancer (SCLC). Proc Am Soc Clin Oncol . 1991;;10:242.
32 +
Steward WP, Verweij J, Somers R, et al.  Granulocyte-macrophage colony-stimulating factor allows safe escalation of dose intensity of chemotherapy in metastatic adult soft tissue sarcomas: a study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol . 1993;;11:15-21.
33 +
Abrams J, Parkes H, Pearl P, et al.  Phase I dose escalation trial of cytoxan (C), Adriamycin (A), leucovorin (L) and fluorouracil (F) plus granulocyte-macrophage colony-stimulating factor (GM-CSF). Proc Am Soc Clin Oncol . 1991;;10:A3247.
34 +
Tjulandin S, Lichinicer J, Glaspy M, et al.  Granulocyte colony-stimulating factor (G-CSF) as an adjunct to doxorubicin (DOX) and thiotepa (TPA) therapy for advanced breast cancer. Proc Am Soc Clin Oncol . 1992;;11:A125.
35 +
Carmo-Pereira J, Henriques E, Costa FO.  FEC (5-fluorouracil, epirubicin, and cyclophosphamide) as first-line chemotherapy in disseminated breast carcinoma, with or without granulocyte colony-stimulating factor (G-CSF): preliminary results. Proc Am Soc Clin Oncol . 1992;;11:A121.
36 +
Venkurin M, Sertoli MR, Ardozzoni A, et al.  Prospective randomized trial of accelerated FEC chemotherapy (CT) with or without GM-CSF in advanced breast cancer. Proc Am Soc Clin Oncol . 1992;;11:A36.
37 +
Gordon MS, Hoffman R.  Growth factors affecting human thrombopoiesis: potential agents for the treatment of thrombocytopenia. Blood . 1992;;80:302-307.
38 +
Chaudhary PM, Roninson IB.  Expression and activity of P-glycoprotein, a multidrug efflux pump in human hematopoietic stem cells. Cell . 1991;;66: 85-94.
39 +
Galski H, Sullivan M, Willingham MC, et al.  Expression of a human multidrug resistance cDNA (MDRl) in the bone marrow of transgenic mice: resistance to daunomycin-induced leukopenia. Mol Cell Biol . 1989;;9:4357-4363.
40 +
Sorrentino BP, Brandt SJ, Bodine D, et al.  Selection of drug-resistant bone marrow cells in vivo after retroviral transfer of human MDR1. Science . 1992;;257:99-102.
41 +
Verfaille C, Blakolmer K, McGlave P.  Purified primitive human hematopoietic progenitor cells with long-term in vitro repopulating capacity adhere selectively to irradiated bone marrow stroma. J Exp Med . 1990;;172:509-520.
42 +
Wilson WH, Jain V, Bryant G, et al.  Phase I and II study of high-dose ifosfamide, carboplatin, and etoposide with autologous bone marrow rescue in lymphomas and solid tumors. J Clin Oncol . 1992;; 10:1712-1722.

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Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
Frei EIII,Antman K, Teicher B, Eder P, Schnipper L.  Bone marrow autotransplantation for solid tumors—prospects. J Clin Oncol . 1989;;7:515-526.
2 +
Carmo-Pereira J, Costa FO, Henriques E, et al.  A comparison of two doses of Adriamycin in the primary chemotherapy of disseminated breast carcinoma. Br J Cancer . 1987;;56:471-473.
3 +
Wheeler RH, Ensminger WD, Thrall JH, et al.  High-dose doxorubicin: an exploration of the dose-response curve in human neoplasia. Cancer Treat Rep . 1982;;66:493-498.
4 +
Jones RB, Holland JF, Bhardwaj S, Norton L, Wilfinger C, Strashun A.  A phase I-II study of intensive dose Adriamycin for advanced breast cancer. J Clin Oncol . 1987;;5:172-177.
5 +
Hryniuk W, Bush H.  The importance of dose intensity in chemotherapy of metastatic breast cancer. J Clin Oncol . 1984;;2:1281-1288.
6 +
Bastholt L, Dalmark M, Gjedde S, et al.  Epirubicin at four different dose levels in metastatic breast cancer: a randomized trial. Proc Am Soc Clin Oncol . 1992;;11:A51.
7 +
Tannock IF, Boyd NF, Deboer G, et al.  A randomized trial of two dose levels of cyclophosphamide, methotrexate, and fluorouracil chemotherapy for patients with metastatic breast cancer. J Clin Oncol . 1988;;6:1377-1387.
8 +
Antman KH.  Dose-intensive therapy in breast cancer.  In: Armitage JO, Antman KH, eds. High-Dose Cancer Therapy . Baltimore, Md: Williams and Wilkins; 1992;:701-718.
9 +
Hryniuk W, Levine MN.  Analysis of dose intensity for adjuvant chemotherapy trials in stage II breast cancer. J Clin Oncol . 1986;;4:1162-1170.
10 +
Ang P-T, Buzdar AU, Smith TL, Kau S, Hortobagy GN.  Analysis of dose intensity in doxorubicincontaining adjuvant chemotherapy in stage II and III breast carcinoma. J Clin Oncol . 1989;;7:1677-1684.
11 +
Budman DR, Wood W, Henderson IC, et al.  Initial findings of CALGB 8541: a dose and dose intensity trial of cyclophosphamide (C), doxorubicin (A), and 5-fluorouracil (F) as adjuvant treatment of stage II, node + breast cancer. Proc Am Soc Clin Oncol . 1992;;11:A29.
12 +
Eddy DM.  High-dose chemotherapy with autologous bone marrow transplantation for the treatment of metastatic breast cancer. J Clin Oncol . 1992;;10:657-670.
13 +
Antman KH, Ayash L, Elias A, et al.  A phase II study of high-dose cyclophosphamide, thiotepa, and carboplatin with autologous marrow support in women with measurable advanced breast cancer responding to standard-dose therapy. J Clin Oncol . 1992;;10:102-110.
14 +
Peters WP, Shpall EJ, Jones RB, et al.  High-dose combination cyclophosphamide (CPA), cisplatin (CDDP), and carmustine (BCNU) with bone marrow support as initial treatment for metastatic breast cancer: 3- to 6-year follow-up. Proc Am Soc Clin Oncol . 1990;;9:A31.
15 +
Dunphy F, Spitzer G.  Use of very-high-dose chemotherapy with autologous bone marrow transplantation for treatment of breast cancer. J Natl Cancer Inst . 1992;;84:128-129.
16 +
Williams SF, Mick R, Desser R, et al.  High-dose consolidated therapy with autologous stem cell rescue in stage IV breast cancer. J Clin Oncol . 1989;;7:1824-1830.
17 +
Peters WP.  Use of CSF-primed peripheral blood progenitor cells in high-dose chemotherapy studies for metastatic and primary breast cancer. Ann Oncol . 1992;;3( (suppl 1) ):164.
18 +
Elias AD, Ayash L, Anderson KC, et al.  Mobilization of peripheral blood progenitor cells by chemotherapy and granulocyte-macrophage colony-stimulating factor for hematologic support after high-dose intensification for breast cancer. Blood . 1992;;79:3036-3044.
19 +
Peters WP, Ross N, Vrendenburgh J, et al.  High-dose chemotherapy and autologous bone marrow support as consolidation after standard-dose adjuvant therapy for high-risk primary breast cancer. J Clin Oncol . 1993;;11:1132-1143.
20 +
Demetri GD, Horowitz J, McGuire BW, et al.  Dose intensification of mitoxantrone with adjunctive G-CSF (r-methu-G-CSF) in patients with advanced breast cancer: a phase I trial. Proc Am Soc Clin Oncol . 1992;;11:A370.
21 +
Hudis C, Lebwohl D, Crown J, et al.  Feasibility of adjuvant dose-intensive cyclophosphamide with G-CSF after doxorubicin in women with high risk stage II/III resectable breast cancer. Proc Am Soc Clin Oncol . 1992;;11:A48.
22 +
Bronchud MH, Howell A, Crowther D, et al.  The use of granulocyte colony-stimulating factor to increase the intensity of treatment with doxorubicin in patients with advanced breast and ovarian cancer. Br J Cancer . 1989;;60:121-125.
23 +
Savarese DM, Denicoff AM, Berg SL, et al.  A phase I and pharmacokinetic study of high-dose piroxantrone along with granulocyte colony-stimulating factor (G-CSF). J Clin Oncol . 1993;;11:1795-1803.
24 +
Swain S, Honig S, Egan E, et al.  A phase I, dose-intensity trial for node-positive breast cancer patients using adjuvant cyclophosphamide (C), doxorubicin (A), and granulocyte colony-stimulating factor (G-CSF). Proc Am Assoc Cancer Res . 1992;;33: A1533.
25 +
Demetri GD, Younger J, Shapiro C, et al.  A phase I study of dose-intensified CAF chemotherapy with adjunctive r-met(hu)G-CSF(G-CSF) in patients with advanced breast cancer. Proc Am Soc Clin Oncol . 1992;;11:A255.
26 +
Lind MJ, Cantwell B, Millward MJ, et al.  The use of rhGCSF to accelerate the delivery of ifosfamide and epirubicin in women with locally advanced or metastatic carcinoma of the breast. Proc Am Assoc Cancer Res . 1992;;33:A1447.
27 +
Watanake T, Miya T, Fukutomi T, et al.  Phase I study of high-dose epirubicin (EPI) and cyclophosphamide (CPA) with rG-CSF for metastatic breast cancer. Proc Am Soc Clin Oncol . 1992;;11: A178.
28 +
Hoekman K, Wagstaff J, van Groeningen CJ, et al.  Effects of recombinant human granulocyte-macrophage colony-stimulating factor on myelosuppression induced by multiple cycles of high-dose chemotherapy in patients with advanced breast cancer. J Natl Cancer Inst . 1991;;83:1546-1559.
29 +
Sunderland M, Abeloff M, Neidhart J, et al.  Continuous GM-CSF failed to ameliorate neutropenia and worsened thrombocytopenia in a dose-intensive regimen for breast cancer. Breast Cancer Res Treat . 1991;;19:158.
30 +
Neidhart JA.  Dose-intensive treatment of breast cancer supported by granulocyte-macrophage colony-stimulating factor (GM-CSF). Breast Cancer Res Treat . 1991;;20( (suppl) ):515-523.
31 +
Luikart SD, MacDonald M, Herzan D, et al.  Ability of daily or twice daily granulocyte-macrophage colony-stimulating factor (GM-CSF) to support dose escalation of etoposide (VP-16) and carboplatin (CBDCA) in extensive small cell lung cancer (SCLC). Proc Am Soc Clin Oncol . 1991;;10:242.
32 +
Steward WP, Verweij J, Somers R, et al.  Granulocyte-macrophage colony-stimulating factor allows safe escalation of dose intensity of chemotherapy in metastatic adult soft tissue sarcomas: a study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol . 1993;;11:15-21.
33 +
Abrams J, Parkes H, Pearl P, et al.  Phase I dose escalation trial of cytoxan (C), Adriamycin (A), leucovorin (L) and fluorouracil (F) plus granulocyte-macrophage colony-stimulating factor (GM-CSF). Proc Am Soc Clin Oncol . 1991;;10:A3247.
34 +
Tjulandin S, Lichinicer J, Glaspy M, et al.  Granulocyte colony-stimulating factor (G-CSF) as an adjunct to doxorubicin (DOX) and thiotepa (TPA) therapy for advanced breast cancer. Proc Am Soc Clin Oncol . 1992;;11:A125.
35 +
Carmo-Pereira J, Henriques E, Costa FO.  FEC (5-fluorouracil, epirubicin, and cyclophosphamide) as first-line chemotherapy in disseminated breast carcinoma, with or without granulocyte colony-stimulating factor (G-CSF): preliminary results. Proc Am Soc Clin Oncol . 1992;;11:A121.
36 +
Venkurin M, Sertoli MR, Ardozzoni A, et al.  Prospective randomized trial of accelerated FEC chemotherapy (CT) with or without GM-CSF in advanced breast cancer. Proc Am Soc Clin Oncol . 1992;;11:A36.
37 +
Gordon MS, Hoffman R.  Growth factors affecting human thrombopoiesis: potential agents for the treatment of thrombocytopenia. Blood . 1992;;80:302-307.
38 +
Chaudhary PM, Roninson IB.  Expression and activity of P-glycoprotein, a multidrug efflux pump in human hematopoietic stem cells. Cell . 1991;;66: 85-94.
39 +
Galski H, Sullivan M, Willingham MC, et al.  Expression of a human multidrug resistance cDNA (MDRl) in the bone marrow of transgenic mice: resistance to daunomycin-induced leukopenia. Mol Cell Biol . 1989;;9:4357-4363.
40 +
Sorrentino BP, Brandt SJ, Bodine D, et al.  Selection of drug-resistant bone marrow cells in vivo after retroviral transfer of human MDR1. Science . 1992;;257:99-102.
41 +
Verfaille C, Blakolmer K, McGlave P.  Purified primitive human hematopoietic progenitor cells with long-term in vitro repopulating capacity adhere selectively to irradiated bone marrow stroma. J Exp Med . 1990;;172:509-520.
42 +
Wilson WH, Jain V, Bryant G, et al.  Phase I and II study of high-dose ifosfamide, carboplatin, and etoposide with autologous bone marrow rescue in lymphomas and solid tumors. J Clin Oncol . 1992;; 10:1712-1722.

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