22 Advances in Oncology—From Research to Application
Introduction
The modern scientific propositions, which still seem to be valid today, go back to Galileo, Bacon, Descartes, and others (11). The validity of knowledge depended on its implementation in both material and technique. Descartes, in particular, maintained that detailed mechanistic findings regarding the pathogenesis of diseases would certainly lead to appropriate therapies. This view has been more successful than the competing theories of natural philosophers in solving the scientific problems of the seventeenth century, and the continuous successes in medicine have obviously proved that this interpretation is correct.
At first glance, this view is undergoing a revival in molecular medicine: artificial joints and cultured organs, electrically coupled pacemakers, implantable drug pumps, and gene probes-they all remind us a bit of the artistic mechanical clocks, musical boxes, and waterworks that Descartes was so enthusiastic about.
Opposed to this monocausal, mechanistic view of the world is another type of medicine that tries to understand the human being as the sum of all somatic, emotional, and social attributes. In oncology, the two different therapeutic approaches have been vigorously competing with one another, with the treatment strategies being molded by the model idea on which they are based.
The disease “cancer” is considered an accelerated proliferation of cells no longer governed by the growth controls of the organ. The development of new drugs able to interfere with this increased cellular growth was therefore a correct and consequent approach. It was successful primarily with early childhood tumors and tumors derived from the hemopoietic organs. The success rates were far lower with solid tumors, especially in adults.
The past 50 years have been the heyday of the monocausal model (7), with the anticancer strategy consisting of surgery, radiotherapy, and chemotherapy. Therapeutic approaches not directly based on cytostasis were no longer considered. The existing medicine was founded on the undisputed basic sciences of physics and chemistry and has now elevated itself to the status of an applied science.
Something has changed, however, because treatment results in oncology have stagnated and the prayer wheel-like prophecies of a therapeutic breakthrough have not materialized. It has even been demonstrated that there was a slow but steady increase in both cancer morbidity and cancer mortality between 1950 and 1982, despite all campaigns and clinical trials (2). A follow-up study for the period of 1970 to 1994 arrived at the following impressive, unambiguous, but often criticized conclusion: “The war against cancer is far from over. Observed changes in mortality due to cancer primarily reflect changing incidence or early detection. The effect of new treatments for cancer on mortality has been largely disappointing. The most prominent approach to the control of cancer is a national commitment to prevention, with a concomitant rebalancing of the focus and funding of research” (3).
A change in paradigm took place in basic research, and cellular and molecular biology replaced pure chemistry and physics as the central sciences. It was only the sum of all findings on carcinogenesis that finally triggered a shift in thinking from a single-minded view to a more complex approach (10). Tumor growth was now more than just the uncontrolled growth of neoplastic cells. The numerous sequential genetic alterations over decades, an outwitted immune system, an adequate vascularization, and a conversion of the normal process of cellular aging are just some of the factors involved in the complex code of carcinogenesis.
Now, it is important that the achievements made so far are not abandoned and that new approaches are combined with the tried and tested strategies against cancer. Effective protocols of chemotherapy and/or radiotherapy must not be questioned only because certain circles in the scientific community might have emotional or conceptual reservations. Old and new forms of therapy should be explored together for the benefit of the patient. Here, complementary oncology can make a considerable contribution, provided a well-founded theory is put forward.
New Approaches
High-Dose Chemotherapy
There is a direct relationship between the dose of chemotherapy and the extent to which tumor cells are killed, though the data given as evidence are mainly derived from experiments with cultured cells. Based on these in-vitro data, a curative reduction in tumor cells would require a five to eight times higher dose than is actually used in clinical protocols. However, such an increase in dose usually results in a complete collapse of the hematopoietic system so that particularly the defenses against infections are no longer guaranteed. In most cases, the hematopoietic system can only be reconstituted by costly autologous bone marrow transplantation. For this purpose, hematopoietic stem cells are harvested by multiple iliac crest punctures prior to chemotherapy. These cells, together with growth factors, are reinfused into the patient after chemotherapy in order to restore immunocompetence.
A less invasive procedure involves the preparation of hematopoietic progenitor cells from peripheral blood (CD34+ cells) by means of cell separators. In order to increase the number of these stem cells in the peripheral blood, mobilizing chemotherapy followed by growth factors is carried out immediately before the collection of cells. This form of high-dose chemotherapy during the reconstitution of important parts of the hematopoietic system is promising in case of the following indications:
– lymphogranulomatosis
– highly malignant non-Hodgkin lymphoma during the first chemotherapy-sensitive recurrence
– plasmacytoma with good remission after conventional chemotherapy
– small cell bronchial carcinoma (limited success)
– ovarian carcinoma (limited success).
Clinical studies still need to back up the value of this therapeutic modality for various other tumors.
Unfortunately, high-dose chemotherapy is also an example of how complex developments toward efficiency control can escape supervision by the scientific community. A South African clinical study claimed to have demonstrated surprisingly good results in case of advanced mammary carcinoma. However, the results of this study could not be reproduced at the international level. During an international investigation of the data, it became conspicuous that many data were not correctly collected, negative findings were suppressed, and patient protocols were even faked. This deliberate deception of oncological experts must be regarded as a very serious violation of scientific rules, because the women received a therapy that had no life-prolonging advantage but brought on considerable side effects and, hence, treatment-induced suffering.
Treatment Optimization Studies
The therapeutic results achieved by chemotherapy and/or radiotherapy must not be given up. However, the clinical efficacy of these protocols needs to be improved in so-called treatment optimization studies. For this purpose, existing protocols of proved efficacy are complemented by substances that may help with:
– overcoming chemoresistance
– enhancing the effect of cytostatic agents
– increasing the response rate
– prolonging the survival time
– reducing side effects.
Substances used in addition to the established protocols must not interfere in terms of pharmacokinetics and pharmacodynamics with the chemotherapeutic agents and should have no, or only minor, side effects of their own.
Third generation modulators that help overcome chemoresistance are already available. These are modified calcium antagonists of the verapamil type. In general, however, we still have to be content with keeping the ability of tumor cells to detoxify and repair during chemotherapy as low as possible. It is therefore a doubtful practice—because undocumented—to administer cell-protecting preparations of high antioxidant potential simultaneously with chemotherapy and/or radiotherapy, for many cytostatic agents as well as radiation act by producing highly reactive radicals that destroy cellular DNA.
Another way of optimizing conventional therapies is the targeted administration of food supplements. In a prospective clinical study, women with mammary carcinoma consumed every day a mixture of soy bean, honey, and low-fat milk in addition to receiving treatment according to a chemotherapy/radiation protocol involving anthracycline. This adjuvant treatment significantly improved the quality of life parameters (nausea, vomiting) as well as functional parameters (lowest point of leukocytes and thrombocytes).
Cancer Treatment Based on Target Structures
The idea of attacking cancer selectively was first conceived by two scientists, von Behring and Ehrlich. Their description of cancer was based mainly on the specific differences between tumor cells and normal body cells. Today, we can indeed identify distinctive molecular features of the cell surface that represent tumor-specific or tumor-associated markers. It is possible to produce monoclonal antibodies that recognize and block these surface molecules. The specific binding of antibodies then interrupts the signal transduction cascade leading to cell proliferation, migration, and metastasis.
Rituximab—An Antibody to CD20
CD20 is a transmembrane protein of normal and malignant B lymphocytes. It is required for B-cell differentiation and is expressed on over 90 % of B-cell non-Hodgkin lymphoma. The chimeric monoclonal antibody to CD20, rituximab (Rituxan), contains some mouse but mostly human amino acid sequences. The variable part of the antibody binds to the CD20 antigen, and the Fc fragment initiates complement-mediated and antibody-dependent cellular cytotoxicity (6).
Patients with indolent non-Hodgkin lymphoma that relapsed after initial chemotherapy received monotherapy with rituximab. The remission rate was almost 50 % and the duration of remission was 13 months on average. A second cycle of therapy after renewed progression was similarly effective (8).
Trastuzumab—An Antibody to ErbB-2
Trastuzumab (Herceptin) is a humanized monoclonal antibody directed against erbB-2 (also called HER-2/neu, HER2), a member of the family of epithelial growth factor receptors (EGFR). ErbB-2 is a heterodimerization partner of EGFR and, as such, a receptor for the EGF/TGF-α family of mitogens and involved in ligand-mediated signal transduction. The intracellular domain of this transmembrane protein exhibits tyrosine kinase activity, which triggers the signal transduction cascade for proliferation and migration once the ligand binds to the cell surface (4).
Trastuzumab recognizes and binds to the erbB-2 antigen, which is overexpressed on mammary carcinoma cells by up to 30 %. The mechanism of cytotoxicity is still unclear, but antibody-dependent cellular cytotoxicity is suspected.
In women with erbB-2-overexpressing mammary carcinoma, monotherapy at the metastatic state after pretreatment with chemotherapy resulted in a remission rate of 15 %. The remission rate increased to 25 % if no chemotherapy had been carried out before. In combination with paclitaxel (Taxol), a response rate of 42 % was achieved in patients with recurrent breast cancer after adjuvant chemotherapy with anthracycline, as compared with 17 % for paclitaxel alone. Prolongation of the progression-free period from three months to almost seven months and improvement of the quality of life has been documented (6).
Imatinib—An Inhibitor of Abl Tyrosine Kinase
Imatinib mesylate (Glivec/Gleevec) is a 2-phenylamino-pyridine derivative that selectively inhibits the Abl tyrosine kinase (14). It has been approved in both Europe and the United States for patients with interferon-resistant chronic myeloid leukemia (CML). Its mechanism of action is based on the fact that malignant cell clones of CML, which express the Brc/Abl oncogene, are constitutively dependent on the activity of the Abl enzyme, whereas normal myeloid cells are only facultatively dependent. This explains why this drug is well tolerated clinically. In one study, almost all patients (up to 100 %) responded with a reduction in the number of tumor cells when they were in a blast crisis (14).
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