Breast cancer and other solid tumors: Lecture Prof. Pinedo about dealing with it dated April 20, 2001
Below the full text of the lecture by Prof. Pinedo held at the University of Utrecht on Friday, April 20, 2001. If there are medical terms are not clear you can probably find an explanation on our page medical terms . Try your search through the list by word, although we realize that not everything there is to be found. "Primary tumor, friend or foe?"Prof. Dr. HM Pinedo
David de Wied Lecture 2001
April 20, 2001
The primary tumor: friend or foe?
Receptiveness to new ideas
In the second half of the 19th century, the pathologist Virchow established the importance of lymph node drainage station and affected organs. Lymph nodes play an important role in cancer. At the end of the 19th century, the famous surgeon William Halsted refined the technique of mastectomy and suggested the need for removal of all axillary nodes with metastases at issue therein (Fig. 1). You must realize that this work dates from a time when cancer treatment consisted of surgery only. At that time, the radical excision of the breast and lymph nodes without question the only way to a survival of the patient.
In the first half of the 20th century made its appearance radiotherapy, while the hormone therapy and chemotherapy are now more than 50 years. Shortly after the second world war Farber suggested the beneficial effect of methotrexate in leukemia patients already fixed. This folic acid antagonist turned out to be effective in breast cancer and other tumor types.
Moreover, progress in the understanding of the biology and immunology of the tumor in the past 20 years dizzying proportions.
The concept of Halsted was, unfortunately, despite all these developments, more than a century stand. The established order has trouble integrating the new disciplines and knowledge of tumor immunology in the modern multidisciplinary policy. They can these developments are not fully follow rapidly, causing unnecessary delays. The breast-conserving surgery had a much earlier example can be introduced, but the step was too large for a long time.
Another example is the introduction of the sentinel node procedure. Here, the first node in the discharge area of a body at a microscopic metastasis studied. In the absence of cancer, all other nodes unchanged. Even this intervention came too late. Incidentally, this procedure is still too limited application. Main goal of surgery is the restriction of the mutilation. The patient is spared a swollen arm, but I am of the opinion that the preservation of the glands also prove a beneficial effect on survival of patients with breast cancer (Fig. 2).
Why, man, in this case the oncologist that hard old habits overboard and quickly deploy new knowledge? Circumstances have since changed dramatically. David de Wied In this lecture I would like an advocate for new research on the treatment of locally advanced cancers (LUK). I also want a plea for research into the possibility of benefiting from the biological processes in the tumor and draining lymph nodes in the fight against metastases. This can be done by in situ leaving the primary tumor for a long time while using the knowledge of tumor biology and chemo-immunotherapy. For now I suggest this only for the treatment of locally advanced tumors, irrespective of the conventional treatments have a very poor prognosis. Many clinical studies and numerous clinical experiences, which over the past 30 years I have gained as oncologist, have this vision with me only reinforced. Let the primary tumor and draining lymph nodes, which took many immune responses against the tumor has deployed assisted us before we remove the tumor and glands. In quick and hasty removal of a large tumor in most patients die within a few years anyway with their metastases. The step seems huge, but it's certainly worth a try. We throw the baby out with the bathwater by the tumor and the draining lymph nodes immediately after diagnosis to remove?
Locally advanced tumors
The treatment of patients with locally advanced cancer (LUK) is a complex clinical problem. Although surgical removal of the tumor and radiation usually local control can be achieved, we often see a short time after treatment metastases appear. These metastasessizeable influence on the disease course and prognosis or the survival of these patients. This applies to virtually all tumor types, including breast cancer, esophagus cancer, stomach cancer, tumors of the head and neck, etc. These tumors have in making the diagnosis is usually micrometastases (by spreading caused small tumors at a distance) with standard diagnostic not be detectable. After treatment of the primary tumor, they grow rapidly into visible metastases. In popular parlance, this phenomenon for years interpreted as a result of exposure to tumor cells 'oxygen' during surgery. With advanced techniques in these patients and even patients with small tumors at an early stage of the disease cancer cells in blood and bone marrow demonstrated. A multidisciplinary approach, starting with some chemotherapy treatments to kill the most sensitive cells, the treatment outcomes for these patients improved. These are usually three courses of chemotherapy with the aim to reduce the primary tumor and micrometastases at an early elimination. Then usually follows a local treatment with surgery, radiotherapy and often, then again three cycles of chemotherapy used. This is called the 'sandwich therapy'.
Own observations
In our institution we have locally advanced breast cancer (Lübke), esophageal cancer and recently also selected as a model for a new approach in the context of a trial. Our strategy is based on assumptions of immunology and angiogenesis (blood vessel growth) research. Lübke It consists of a heterogeneous group of breast tumors with different biological and clinical characteristics. This group includes tumors larger than 5 cm, which often have spread to locoregional lymph nodes, whereas with conventional research methods no detectable distant metastases. Moreover, even the skin of the chest become affected, the most malignant form of Lübke. Patients with a Lübke have a small chance of recovery when they are alone with surgery and radiotherapy treatment. Less than 20% of these patients survive five years after this treatment continues. Also in this tumor type has preoperative (neoadjuvant) chemotherapy, consisting of three treatments, the survival of the patients improved. Most patients receive treatment than after local chemotherapy again, the sandwich approach (Fig. 3).
In our study, 42 patients treated with more than three Lübke preoperative regimens consisting of a relatively high dose of doxorubicin, cyclophosphamide and granulocyte-macrophage colony stimulating factor (GM-CSF). GM-CSF is a growth factor that the precursors of white blood cell in the bone marrow division and maturation. This diminishes the risk of infection after chemotherapy and reduced any further course administered without delay. In addition, GM-CSF with characteristics that lead to stimulation of the immune system. Our goal was the treatment after three courses to pursue. Initially, some patients treated with four courses. But in the course of the study, if the side effects so permitted, five and finally six courses for the operation.
We saw 98% of patients with significant tumor shrinkage (Fig. 4). Only one patient remained unchanged in tumor size during the neo-adjuvant chemotherapy. None of the patients the tumor grew during this treatment. Side effects were moderate to severe and mainly involved a temporary decrease in white blood cells and platelets. With each new course was the blood picture is restored. Other side effects were anemia (anemia) in need of blood transfusions, and transient inflammation of the mucous membranes. Clinical heart failure due to doxorubicin was never observed. Regular examination of the heart function was the cause in some patients neo-adjuvant therapy to five treatments to reduce and proceed to mastectomy. There were no fatal complications, even in the longer term. The six patients who received preoperative courses have a disease-free (without metastases) five-year survival of 66% (Fig. 5) and a five-year survival of 79% (Fig. 6).
Six of the 11 patients with skin infiltration, the subgroup with by far the worst prognosis are disease free. The observation period after treatment of 42 patients has been at least 5 years! In some cases we found a very strong overgrowth of the connective tissue in the removed breast, which many macrophages as the only remnant of the Lübke.
These promising results in patients, this new, long-term preoperative treatment including GM-CSF underwent ledto a major research program. In an international, randomized study, these findings widely tested. It is to save the time of surgical intervention also randomized to GM-CSF and G-CSF. G-CSF stimulates only prolifisatie and differentiation of the precursors of white blood cell. With this second ballot, the immunological effect of GM-CSF tested as G-CSF immunological effect of GM-CSF fog (Fig. 7).
Immunological effects of GM-CSF
Immunological studies and clinical trials are for the benefit of vaccination in cancer have focused attention on new immunotherapeutic strategies in the treatment of cancer. The latest protocols use the unique features of the recently discovered dendritic cells. Dendritic cells are
from stem cells in bone marrow. After differentiation, they are professional antigen (immune activating protein on the cell membrane) presenting cells. They are fully equipped to tumor-specific antigens present on naive, memory T cells. The membrane of the cancer multiple immune activating proteins expressed. Obviously there are many antigens will be discovered. These antigens are potential targets for cell killing T cells. These are white blood cells that are capable of certain surface proteins to recognize and kill. Assuming that these dendritic cells in vivo cytotoxic T-cells can activate, our treatment regimen for patients with Lübke modified and extended. Example of this process than the time to develop.
The probability that these effects are actually realized in this way increasing (Fig. 8).
These immunological hypothesis is one of the two hypotheses of our strategy. The hypothesis that combination of chemotherapy, GM-CSF and the prolonged presence of the primary tumor and the draining lymph nodes, leading to optimal mobilization and differentiation of dendritic cells. In this way the tumor-specific T-cell killing cells in the axillary lymph nodes activated. The cytotoxic T-cells, which find their way into the blood, would then have to contribute to a reduction of the tumor and eradication of micrometastases.
Potentially relevant processes
In recent years, research has increased understanding of the interaction between tumor and immune system. I will be a number of immunological processes, that our strategy Lübke could be relevant, briefly.
1) Decrease production immunosuppressive factors. Reduction of the primary tumor under the influence of chemotherapy, the amount of immunosuppressive factors from the tumor cells decrease. Tumors produce a protein that the activation of T cells and can inhibit the growth and maturation of dendritic cells brakes. Destruction of tumor cells, the production of these immunosuppressive cytokines and reducing the induction of cell killing T cells easier.
2) Improved mobilization and differentiation of dendritic cells.
In patients with locally advanced breast cancer is a disturbed differentiation or maturation of dendritic cells is described. Treatment with GM-CSF not only enhances the mobilization of the precursors of the dendritic cell, but is also capable of their maturation and activation, respectively, to improve and strengthen. This allows an efficient presentation of tumor antigens and activation of tumor-specific cell killing T cells occur.
3) stimulated by GM-CSF mobilization of dendritic cells to the tumor and thereby improved survival of tumor-infiltrating lymphocytes.
Treatment with GM-CSF results in a greater number of dendritic cells at the site of the tumor and axillary lymph nodes. In previous studies, a better prognosis observed in patients with a large number of dendritic cells in the tumor. This phenomenon can be explained by protection by dendritic cells called lymphocytes in the tumor from tumor-induced apoptosis. Tumors that express Fas ligand may via this protein programmed cell death (apoptosis) of T-cells trigger. Dendritic cells has been reported that T cells can protect against the premature programmed death.
4) Apoptosis of tumor cells and dendritic cell cross-dependent activation of cytotoxic T cells.
Dendritic cells can easily record and then apoptotic cell fragments of these apoptotic cells present antigens to cytotoxic T cells. Chemotherapyinduced apoptosis of tumor cells, the availability of tumor antigens via this process easier.
5) 'Priming' (tame) of tumor-specific cytotoxic T cells in the draining lymph nodes.
Lymph nodes are the natural venue for circulating dendritic cells and T cells. They are the optimal microenvironment for providing necessary cytokines and co-stimulatory signals to the "priming" of T cells. Maintaining the lymph nodes during the neo-adjuvant chemotherapy which ensures optimal conditions with tumor antigen-loaded dendritic cells, T cells can take to bind and activate.
The prolonged presence of tumor-draining lymph nodes, the continuous supply of antigen, the dendritic celmobilisatie and their activation by the large number of cycles of chemotherapy with GM-CSF, could be an explanation for the prolonged survival of our patients with locally advanced breast cancer.
Anti-angiogenic properties of the primary tumor
The second hypothesis, which our strategy is applied, is based on the production of anti-angiogenic proteins by the primary tumor through the blood micrometastases dormant account. The formation of new blood vessels from existing vessels, called angiogenesis, is a prerequisite for the growth of primary tumor and its metastases.
The switch from an avascular to a little tumor vascular tumor is determined by pro-and anti-angiogenic factors. An excess of pro-angiogenic factors, new vessels are formed, whereas angiogenesis inhibitors in tumor dormant state managed to keep (Fig. 9). The apoptosis in dormant metastases is significantly increased compared to that in growing tumors, whereas the proliferation in both situations is identical. Different normal cell types can angiogenic / anti-angiogenic balance control such as fibroblasts, macrophages and endothelial cells. Recently I discovered my PhD Henk Verheul that the platelet transport is in our blood "Vascular Endothelial Growth Factor (VEGF). The platelet transports except this very potent angiogenic factor, other angiogenic and anti-angiogenic agents in special compartments. Due to the continuous crashing of platelets in solid tumors (trapping) is a constant outpouring of these factors place in the solid tumor, regardless of tumor type. A relationship between the poor prognosis of cancer patients and a high number of circulating platelets is not out of place.
The anti-angiogenic factors
We have in recent years by the work of Judah Folkman and his group learned more about anti-angiogenic factors. In their animal model is a peptide shown to angiostatin, which is issued by the primary tumor. The substance is an anti-angiogenic site of micrometastases (Fig. 10).
After removal of the primary tumor manifested rapidly growing metastases in their animal model. Even in patients with breast cancer are circulating angiogenic and anti-angiogenic factors has been demonstrated. In some patients the serum stimulates endothelial cells in vitro, while the blood of others a Inhibition of vascular cells. This inhibition could be eliminated by using an antibody against the anti-angiogenic thrombospondin substance, which indicates a possible anti-angiogenic role for this protein. It therefore appears that the primary tumor responsible for the release of various pro-and anti-angiogenic factors in the blood. The exact source of these factors is still unclear. Remarkably, like angiostatin, various fragments of larger extracellular matrix and plasma proteins, an anti-angiogenic effect. Several of these substances are now in early clinical study.
End hear fragments of fibronectin, collagen XVIII, plasminogen and prothrombin, all released during construction and destruction of tumor tissue with its extracellular matrix.
It was probably made that a metallo-elastase from macrophages, the urokinase and matrix metalloproteinase-3 are responsible for the production of angiostatin. It is also known that the introduction (transfection) of the GM-CSF gene in cancer cells of their development into an in vivo inhibits tumor. This effect goes hand in hand with an increased number of macrophages in these tumors and an increase in blood levels of angiostatin in the experimental animal. These observations suggest that the production of angiogenesis inhibitor (s) a role for GM-CSF. It is not inconceivable that other anti-angiogenic fragments of large proteins similarly produced. We found in our patients afterchemo-immunotherapy is also a strong increase in the number of macrophages in the tumor. This is probably a result of the GM-CSF. By analogy with the animal model, these macrophages may be responsible for the production of angiostatin and other angiogenesis-inhibiting protein fragments.
The second hypothesis is that the prolonged presence of the primary tumor during treatment leads to a continuous release of anti-angiogenic peptides in the blood. The production of these factors would take place in both the cancer and the intervening stroma (eg infiltrating macrophages). This anti-angiogenic factors may micrometastases in a dormant state of cleanliness and show synergy with chemotherapy. Upon purchase of the primary tumor before the end of the systemic (medicated) treatment, a local inflammatory reaction at the site of the original tumor persisted. Tissue Converting will, as in the tumor, leading to degradation of the extracellular matrix by proteases and enzymatic cleavage of extracellular and plasma proteins stimulate. The fragments from these proteins were, as in the animal, angiostatin may contain. Issue of these factors to the blood will inhibit the growth of micrometastases and synergistically with chemotherapy, which will continue. Currently we are exploring, before, during and after neo-adjuvant therapy, the effect of plasma and serum of patients with locally advanced tumors on the proliferation of endothelial cells. We are also looking for angiogenesis-inhibiting fragments of extracellular matrix proteins.
Other locally advanced tumors
It is high time that similar research is set up with other locally advanced tumors. In our institute we have started to esophageal carcinoma. Also in this tumor type, one is not further than the sandwich treatment. This tumor is locally advanced breast cancer and the Lübke a very poor prognosis by the presence of micrometastases. With three courses of chemotherapy to local treatment and three after this, the results remain highly unsatisfactory. As with the long Lübke we compare chemo-immunotherapy with the standard sandwich approach. Other locally advanced tumors for this type of study are eligible to gastric cancer, bladder cancer and tumors in the head and neck.
Relationship between two hypotheses
It is obvious that the two hypotheses discussed where the strategy rests with one another. There is a substantial interaction between the immune and anti-angiogenic effects of our treatment strategy for these locally advanced tumors. Pro-angiogenic factors such as vascular endothelial growth factor (VEGF) in the laboratory to patients and inhibit the function of dendritic cells. The platelets could play a role in this process. It is likely that inhibitors of angiogenesis will have an opposite effect. Adhesion molecules, which are essential for the interaction between endothelium and lymphocytes, are suppressed by pro-angiogenic factors, while returning from exposure to angiogenesis inhibitors such as thrombospondin and platelet factor 4.
Conclusion
Prolonged neo-adjuvant chemotherapy combined with GM-CSF appears to yield favorable results in patients with locally advanced breast cancer. The assumptions behind this strategy assume that biological processes in the primary tumor can be exploited by the oncologist. In our patients the effect was most pronounced in those six courses of chemotherapy. We also preserve the primary tumor and draining lymph nodes so months left untouched by a surgeon and / or radiation oncologist. During this period he never progression of the primary tumor. Metastases did not occur during neo-adjuvant therapy. This is true even for tumors with skin infiltration. The data suggest that these lymph nodes is an important 'life line' for these patients at high risk.
Our findings and those of recent preclinical study justify a fresh new perspective on the treatment of (locally advanced) primary tumors. Further research on the value of long-term neo-adjuvant therapy, using biological properties of the primary tumor and its draining lymph nodes, in my view very urgent. We have launched an international randomized trial, the Spinoza trial, the conventional sandwich therapy and prolonged preoperative chemo-immunotherapeutic approach to breast cancer patients comparing this group.
It is time that weentrenched principles overboard and even more and especially better use of new disciplines and certainly the overwhelming enrichment of our knowledge of tumor biology.
Halsted carried out his important work in the nineteenth century. Our work in the 21st century should not delay the same result, which we in the last century in the development of techniques such as breast-conserving surgery and sentinel node procedure have experienced. Fixed ideas make way for the sake of a quick implementation of new principles. New ideas should not be dismissed a priori.
Curriculum Vitae
Michael Herbert (Bob) Pinedo (1943) studied medicine in Leiden. After his medical degree in 1967, his PhD in 1972 and its registration as an internist, he became chef de clinique of the Department of Internal Medicine at the Academic Hospital in Utrecht.
From 1974 to 1976 he was a guest lecturer at the National Cancer Institute in the United States, where he trained pharmacy students. In 1976 he became head of the oncology group of the AZU. The Vrije Universiteit in Amsterdam in 1979, then appointed him professor and head of Medical Oncology. In between Pinedo was associated with a number of years the Dutch Cancer Institute / Antoni van Leewenhoekziekenhuis. First as Head of Pharmacology Laboratory and later as Director of Clinical Research.
Bob Pinedo is regarded as an internationally renowned researcher. Throughout his academic career is marked by the mechanism of anti-cancer agents. The emphasis is on clinical and experimental research. Within his department he developed immunotherapy, angiogenesis and gene therapy research. Appreciation of his work was reflected in different prices: the Bristol-Myers Squibb Foundation Cancer Grant Award (1992), the International Chiron Award for Bioclinical Research and Training (1993), the Josef Steiner Award (1995) and the Spinoza Award (1997). Bob Pinedo is a member of the Royal Dutch Academy of Sciences and was appointed Knight of the Dutch Lion.
Copyright of this lecture held by Prof.. Pinedo and we made available by the University of Utrecht, whichthanks.
