The Oncologist, Vol. 5, No. 6, 497-500,
December 2000
© 2000 AlphaMed Press
NCI All Ireland Cancer Conference Proceedings |
Biological Concepts of Prolonged Neoadjuvant Treatment plus GM-CSF in Locally Advanced Tumors
H.M. Pinedo,
T.D. de Gruijl,
E. van der Wall,
J. Buter
Department of Medical Oncology, University Hospital "Vrije Universiteit," Amsterdam, The Netherlands
Correspondence:
H.M. Pinedo, M.D., Ph.D., Head, Department of Medical Oncology, University Hospital "Vrije Universiteit," Postbus 1007 MB, Amsterdam, The Netherlands. Telephone: 31-20-4444300; Fax: 31-20-4444355; e-mail: hm.pinedo{at}azvu.nl
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ABSTRACT
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Local treatment with surgery and radiotherapy gives unsatisfactory results in patients with locally advanced cancer. In many cases distant metastases appear shortly after the removal of the primary tumor. Selecting breast cancer as a model for locally advanced disease, we are extrapolating our findings to other solid tumors. Neoadjuvant chemotherapy has improved survival of these patients by downstaging the primary tumors allowing local treatment and early elimination of distant micrometastases.
We recently reported in this journal on a study of 42 patients with locally advanced breast cancer (LABC) who received prolonged neoadjuvant chemotherapy of doxorubicin, cyclophosphamide, and GM-CSF prior to surgery and postoperative radiotherapy. These results were promising and prompted us to initiate an international randomized phase III study in which either six neoadjuvant cycles or three neoadjuvant cycles plus three adjuvant cycles are being compared. In LABC patients treated with six neoadjuvant chemoimmunotherapy cycles, we observed a significant rise in the dendritic cell content of the axillary tumor-draining lymph nodes after therapy, associated with an encouraging disease free survival and overall survival. We hypothesize that the prolonged presence of draining lymph nodes in combination with the repeated tumor antigen release, dendritic cell recruitment, and activation may account for the observed increased survival of LABC patients. Based on our findings and the results of preclinical studies, we hypothesize that it is more effective to administer chemotherapy in an extended neoadjuvant regimen, taking advantage of the concurrent biological and immunological processes in the primary tumor and its draining lymph nodes.
Key Words. GM-CSF • Doxorubicin • Cyclophosphamide • Antineoplastic agents • Combined breast neoplasms • Angiogenesis • Dendritic cells
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INTRODUCTION
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Local treatment with surgery and radiotherapy gives unsatisfactory results in patients with locally advanced cancer. In many cases distant metastases appear shortly after the removal of the primary tumor. This problem is known from several tumor types originating from breast, esophagus, stomach, bladder, or the head and neck region.
Apparently in many patients nondetectable micrometatastases are present at the time of diagnosis. Selecting breast cancer as a model for locally advanced disease, we are extrapolating our findings to other solid tumors. When treated with local therapy alone, patients with locally advanced or inflammatory breast cancer (LABC) have a poor prognosis with a five-year overall survival (OS) rate of only 5%-20% [1, 2]. Neoadjuvant chemotherapy has improved survival of these patients by downstaging the primary tumors allowing local treatment and by early elimination of distant micrometastases. Generally three to four preoperative chemotherapy cycles are administered followed by a number of postoperative chemotherapy cycles. The reported clinical response rates vary between 30% and 80% with 10%-30% clinical complete remissions and long-term survival in 15% of the patients [3-6]. High-dose chemotherapy with autologous stem cell support further improved disease-free survival (DFS) to a reported 64% after 30 months [7] but has yet to be shown to improve OS. We recently reported in this journal on a study of 42 patients with LABC who received prolonged neoadjuvant chemotherapy of doxorubicin, cyclophosphamide, and GM-CSF prior to surgery and postoperative radiotherapy [8]. GM-CSF was chosen instead of G-CSF because of its additional immunostimulatory and potential angiogenic effects. We hypothesized that the prolonged presence of the primary tumor and the long-term administration of GM-CSF with the primary tumor and the axillary lymph nodes in situ might give rise to tumor-specific cytotoxic T-cell responses. Furthermore, tumor-derived antiangiogenic factors might inhibit growth in micrometastases. To improve these effects, the number of neoadjuvant chemotherapy cycles was gradually extended from four to six cycles during the study whenever toxicity allowed it. A high clinical response rate of 98% with a 50% complete response rate was observed. At a median follow-up of 49 months, for a total of 42 patients the actuarial DFS and OS rates at three years are 57% and 79%, respectively. With a median follow-up of five years, the actuarial DFS and OS rates of all patients are 55% and 67%, respectively. However, in the 24 patients who received six neoadjuvant cycles, the actuarial DFS and OS at five years are 66% and 79%, respectively. These promising results have prompted us to initiate an international randomized phase III study in which either six neoadjuvant cycles or three neoadjuvant cycles plus three adjuvant cycles are being compared. Immunological and biological factors are being studied both in the primary tumor with its draining lymph nodes and the peripheral blood of all patients [9].
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IMMUNOLOGICAL ASPECTS IN LOCALLY ADVANCED DISEASE
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In various ways tumor cells can escape recognition by the immune system as a potential threat. This enables growth of the tumor to a size too large to be handled by the immune effector cells. Dendritic cells play an important role in the initiation of an antitumor response [10]. These bone marrow-derived cells are the most professional antigen-presenting cells identified to date. In an immature state they take up tumor antigens and present these in the context of major histocompatibility complex molecules to naïve or memory T-cells. Depending on the recognition of self and nonself antigens and so-called danger signals, either tolerance or an effective cellular immune response is induced. In several tumor types, dendritic cell infiltration in the primary tumor has been associated with prolonged survival and a reduced incidence of metastatic disease [11-15].
In patients with LABC, a dysfunction of dendritic cells has been observed [16, 17]. A general immunosuppressive state with depressed T-cell reactivity is progressive and prognostically significant with increasing stages of breast cancer [18]. The immune system appears to be disabled by several tumor-derived cytokines that have been shown to inhibit dendritic cell maturation (interleukin 10 [IL-10], transforming growth factor ß [TGF-ß], IL-6, and vascular endothelial growth factor [VEGF]), and T-cell effector functions in vitro (IL-10, TGF-ß) [19-22].
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IMMUNOTHERAPEUTIC EFFECTS OF PROLONGED NEOADJUVANT CHEMOTHERAPY AND GM-CSF ADMINISTRATION
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During neoadjuvant chemotherapy combined with long-term administration of GM-CSF, several processes take place that can potentially overcome the apparent failure of the immune system to eradicate the tumor. Chemotherapy reduces the production of tumor-derived immunosuppressive factors, enabling the initiation of tumor-specific cytotoxic T-cell responses. Chemotherapy-induced tumor cell necrosis and apoptosis both cause release of antigen, which can be taken up by newly recruited immature dendritic cells. GM-CSF not only recruits dendritic cells from the bone marrow, but also stimulates their maturation and activation to acquire their maximum ability to prime cytotoxic T-cells [23]. GM-CSF-mediated recruitment of dendritic cells to the tumor site may protect tumor-infiltrating lymphocytes from an early death by Fas-mediated apoptosis [24]. In LABC patients treated with six neoadjuvant chemoimmunotherapy cycles, we observed a significant rise in the dendritic cell content of the axillary tumor-draining lymph nodes after therapy, associated with an encouraging DFS and OS. We hypothesize that the prolonged presence of draining lymph nodes in combination with the repeated tumor antigen release, dendritic cell recruitment, and activation may account for the observed increased survival of LABC patients.
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BIOLOGICAL ASPECTS OF PROLONGED PRESENCE OF THE PRIMARY TUMOR
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From the Lewis lung carcinoma (LLC) model it is known that in the presence of the primary tumor, the development of distant metastases is arrested. However, after the removal of the primary tumor, distant metastases neovascularize and start to grow rapidly within three days. A circulating angiogenesis inhibitor, angiostatin, was shown to be responsible for the dormancy of micrometastases [25]. The process of neovascularization is controlled by several pro- and antiangiogenic factors. Depending on the balance of these factors, either new vessel formation will start or metastases are kept dormant [26]. Macrophage-derived factors have shown to be responsible for the induction of angiostatin production. Furthermore, transfection of LLC cells with the GM-CSF gene inhibited tumor growth, while an increased number of tumor-infiltrating macrophages and elevated levels of circulating angiostatin were found [27]. These studies suggest a role for GM-CSF in the generation of a circulating angiogenesis inhibitor. As described in an earlier study [28], we observed an increase in macrophages in the mastectomy specimens compared with pretreatment biopsies, possibly due to the administration of GM-CSF.
These macrophages may be responsible for the generation of angiostatin or other protein fragments inhibitory for angiogenesis as has been shown in the LLC model.
We thus hypothesize that the primary tumor and its stroma can generate antiangiogenic peptides that may keep micrometastases dormant.
A considerable interplay between the immunomodulating and antiangiogenic effects of the proposed neoadjuvant treatment exists. VEGF, a proangiogenic factor, has been shown to inhibit dendritic cell maturation in vitro [20], which may be overcome by GM-CSF. Furthermore, angiogenesis inhibitors can upregulate adhesion molecules that are important for leucocyte-endothelial cell interactions [29]. Finally, the recruitment and maturation of dendritic cells induced by GM-CSF may lead to increased levels of intratumoral IL-12. This cytokine has previously been shown both to direct the initiation of effective cell-mediated antitumor immune responses and exhibit considerable antiangiogenic effects [30, 31].
To study these proposed hypotheses we have initiated the Spinoza trial, an international multi-center phase III study in patients with LABC, comparing the conventional approach of applying three preoperative and three postoperative cycles of chemoimmunotherapy and the extended chemoimmunotherapy approach.
Patients with stage IIB (with a primary tumor >5 cm), IIIA, and IIIB breast cancer according to the American Joint Committee on Cancer criteria are included. Primary objectives of the study are to increase the three-year DFS and OS. A second randomization takes place to study the effects of GM-CSF on OS and DFS in comparison with G-CSF in both treatment arms. We are collecting peripheral blood, tumor, and axillary lymph node samples to study the immunomodulating effects of GM-CSF or G-CSF on dendritic cells and tumor-specific T-lymphocytes.
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CONCLUSION
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Based on our findings and the results of preclinical studies, we hypothesize that it is more effective to administer chemotherapy in an extended neoadjuvant regimen, taking advantage of the concurrent biological and immunological processes in the primary tumor and its draining lymph nodes. The initiated international randomized Spinoza trial will allow, by its bifactorial design, testing of the effect of prolonged neoadjuvant treatment as well as the effect of GM-CSF compared with G-CSF on the DFS and OS of patients with LABC. These results may be expanded to the treatment of other locally advanced solid tumors.
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REFERENCES
|
|---|
-
Booser DJ, Hortobagyi GN. Treatment of locally advanced breast cancer. Semin Oncol 1992;19:278-285.[Medline]
-
Jaiyesimi IA, Buzdar AU, Hortobagyi G. Inflammatory breast cancer: a review. J Clin Oncol 1992;10:1014-1024.[Abstract]
-
Rouesse J, Friedman S, Sarrazin D et al. Primary chemotherapy in the treatment of inflammatory breast carcinoma: a study of 230 cases from the Institut Gustave-Roussy. J Clin Oncol 1986;4:1765-1771.[Abstract]
-
Attia-Sobol J, Ferriere JP, Cure H et al. Treatment results, survival and prognostic factors in 109 inflammatory breast cancers: univariate and multivariate analysis. Eur J Cancer 1993;29:1081a-1088a.[CrossRef]
-
Chevallier B, Bastit P, Graic Y et al. The Centre H. Becquerel studies in inflammatory non metastatic breast cancer. Combined modality approach in 178 patients. Br J Cancer 1993;67:594-601.[Medline]
-
Karlsson YA, Malmstrom PO, Hatschek T et al. Multimodality treatment of 128 patients with locally advanced breast carcinoma in the era of mammography screening using standard polychemotherapy with 5-fluorouracil, epirubicin, and cyclophosphamide: prognostic and therapeutic implications. Cancer 1998;83:936-947.[CrossRef][Medline]
-
Ayash LJ, Elias A, Ibrahim J et al. High-dose multimodality therapy with autologous stem-cell support for stage IIIB breast carcinoma. J Clin Oncol 1998;16:1000-1007.[Abstract]
-
Honkoop AH, Luykx-de Bakker SA, Hoekman K et al. Prolonged neoadjuvant chemotherapy with GM-CSF in locally advanced breast cancer. The Oncologist 1999;4:106-111.[Abstract/Free Full Text]
-
Luykx-de Bakker SA, Verheul HM, de Gruijl TD et al. Prolonged neoadjuvant treatment in locally advanced tumours: a novel concept based on biological considerations. Ann Oncol 1999;10:155-160.[Abstract/Free Full Text]
-
Luykx-de Bakker SA, de Gruijl TD, Scheper RJ et al. Dendritic cells: a novel therapeutic modality. Ann Oncol 1999;10:21-27.[Free Full Text]
-
Coppola D, Fu L, Nicosia SV et al. Prognostic significance of p53, bcl-2, vimentin, and S100 protein-positive Langerhans cells in endometrial carcinoma. Hum Pathol 1998;29:455-462.[CrossRef][Medline]
-
Gallo O, Bianchi S, Giannini A et al. Correlations between histopathological and biological findings in nasopharyngeal carcinoma and its prognostic significance. Laryngoscope 1991;101:487-493.[Medline]
-
Ikeguchi M, Ikeda M, Tatebe S et al. Clinical significance of dendritic cell infiltration in esophageal squamous cell carcinoma. Oncol Rep 1998;5:1185-1189.[Medline]
-
Ishigami S, Aikou T, Natsugoe S et al. Prognostic value of HLA-DR expression and dendritic cell infiltration in gastric cancer. Oncology 1998;55:65-69.[CrossRef][Medline]
-
Saito H, Tsujitani S, Ikeguchi M et al. Relationship between the expression of vascular endothelial growth factor and the density of dendritic cells in gastric adenocarcinoma tissue. Br J Cancer 1998;78:1573-1577.[Medline]
-
Lespagnard L, Gancberg D, Rouas G et al. Tumor-infiltrating dendritic cells in adenocarcinomas of the breast: a study of 143 neoplasms with a correlation to usual prognostic factors and to clinical outcome. Int J Cancer 1999;84:309-314.[CrossRef][Medline]
-
Gabrilovich DI, Corak J, Ciernik IF et al. Decreased antigen presentation by dendritic cells in patients with breast cancer. Clin Cancer Res 1997;3:483-490.[Abstract]
-
Marrogi AJ, Munshi A, Merogi AJ et al. Study of tumor infiltrating lymphocytes and transforming growth factor-beta as prognostic factors in breast carcinoma. Int J Cancer 1997;74:492-501.[CrossRef][Medline]
-
Gabrilovich DI, Chen HL, Girgis KR et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells [published erratum appears in Nat Med 1996;2:1267]. Nat Med 1996;2:1096-1103.[CrossRef][Medline]
-
Gabrilovich D, Ishida T, Oyama T et al. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 1998;92:4150-4166.[Abstract/Free Full Text]
-
Buelens C, Verhasselt V, De Groote D et al. Interleukin-10 prevents the generation of dendritic cells from human peripheral blood mononuclear cells cultured with interleukin-4 and granulocyte/macrophage-colony-stimulating factor. Eur J Immunol 1997;27:756-762.[Medline]
-
Morel AS, Quaratino S, Douek DC et al. Split activity of interleukin-10 on antigen capture and antigen presentation by human dendritic cells: definition of a maturative step. Eur J Immunol 1997;27:26-34.[Medline]
-
Albert ML, Sauter B, Bhardwaj N. Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature 1998;392:86-89.[CrossRef][Medline]
-
Lu L, Qian S, Hershberger PA et al. Fas ligand (CD95L) and B7 expression on dendritic cells provide counter-regulatory signals for T cell survival and proliferation. J Immunol 1997;158:5676-5684.[Abstract]
-
O'Reilly MS, Holmgren L, Shing Y et al. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 1994;79:315-328.[CrossRef][Medline]
-
Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996;86:353-364.[CrossRef][Medline]
-
Dong Z, Yoneda J, Kumar R et al. Angiostatin-mediated suppression of cancer metastases by primary neoplasms engineered to produce granulocyte/macrophage colony- stimulating factor. J Exp Med 1998;188:755-763.[Abstract/Free Full Text]
-
Honkoop AH, Pinedo HM, de Jong JS et al. Effects of chemotherapy on pathologic and biologic characteristics of locally advanced breast cancer. Am J Clin Pathol 1997;107:211-218.[Medline]
-
Griffioen AW, Damen CA, Mayo KH et al. Angiogenesis inhibitors overcome tumor induced endothelial cell anergy. Int J Cancer 1999;80:315-319.[CrossRef][Medline]
-
Cavallo F, Di Carlo E, Butera M et al. Immune events associated with the cure of established tumors and spontaneous metastases by local and systemic interleukin 12. Cancer Res 1999;59:414-421.[Abstract/Free Full Text]
-
Duda DG, Sunamura M, Lozonschi L et al. Direct in vitro evidence and in vivo analysis of the antiangiogenesis effects of interleukin 12. Cancer Res 2000;60:1111-1116.[Abstract/Free Full Text]
Received August 15, 2000;
accepted for publication August 15, 2000.
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Abstract
Introduction
