An update on clinical oncology for the non-oncologist

ABSTRACT Recent advances in the understanding of tumor driver mutations, signaling pathways that lead to tumor progression, and the better understanding of the interaction between tumor cells and the immune system are revolutionizing cancer treatment. The pace at which new treatments are approved and the prices at which they are set have made it even more difficult to offer these treatments in countries like Brazil. In this review we present for the non-oncologist these new treatments and compare their availability in Brazilian public health system and private health system with that of developed countries.


INTRODUCTION
Within the last few years, the field of systemic therapy in medical oncology has seen two dramatic changes. First, the advances in the understanding of genetic abnormalities led to the discovery of various tumor driver mutations with the consequent development of different targeted therapies. Second, the better understanding of interaction between tumor cells and immune system led to the now much broader field of immuno-oncology and the consequent development of immunotherapies, which is currently being tested for treatment of different cancer types. In addition to these advances, a few new traditional chemotherapies have been approved and some already well-known treatments have had their indication broadened. Our objective is to review, for non-oncologists, the most recent advances of modern systemic cancer treatment.

TARGETED THERAPIES
New technologies developed after the year 2000 allowed progressively more ambitious and thorough evaluation of tumors at molecular level. A major initiative has been the whole genome sequencing of various tumors, launched in 2005 as part of The Cancer Genome Atlas. (1) So far, more than 20 different tumor types have been fully sequenced. The advances in the evaluation of genetic and epigenetic abnormalities and their consequences on the transcriptome have allowed a better understanding and further mapping of an intricate signaling pathway network, which characterizes the hallmarks of cancer cells. (2,3) The identification of driver mutations have crossed histologically driven tumor classifications, leading to a new way of looking at tumors, now based on the mutations rather than histology or organ in which the tumor arises. Although the identification of targets in tumor cells led to the development of various targeted therapies, we are now confronting the fact that these treatments have unfortunately not led to cure in metastatic cancers as once expected, despite the fact that outcomes such as progression free survival and overall An update on clinical oncology for the non-oncologist Avanços em oncologia para o não oncologista Rafael Aliosha Kaliks 1 survival have improved. In addition, before choosing the therapies, it is necessary to test the target, which sometimes requires sophisticated and costly techniques. Considering that some targets may be present in less than 5 to 10% of the patient population, many of them need to be tested in order to find one eligible for the targeted treatment. Adding the costs of tests and the drugs, these therapies are almost prohibitive for the Brazilian Public Health System, which prevent a significant majority of our population from receiving such treatments. Table 1 shows selected new targeted therapies made available in the last three years. Approval in Brazil has been limited, mainly due to regulatory delays, but

IMMUNOTHERAPY
Human immune system has been known for quite some time for recognizing tumor antigens and mounting an immune response, although the actual explanation for the variability in tumor control by the immune system remains elusive. Cancer cells are capable of evading the immune surveillance by suppressing tumordirected immunity through mechanisms described over the last two decades. (24) It occurs by inhibiting helper and cytotoxic T cells while stimulating regulatory T cells instead. Inhibitory mechanisms determined by cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed death 1 (PD1) and its ligand programmed death ligand 1 (PD-L1) can currently be targeted and inhibited by new immunotherapies, which lead to unblocking the immune response. This will ultimately unleash an immune attack on cancer cells. Anti-CTLA-4 antibodies as well as PD1 and PD-L1 inhibitors are already approved and used to treat a limited number of tumor types (melanoma and lung cancer), and promising preliminary results indicate potential future use in a large variety of cancers. Table 2 outlines the new immunotherapies, its approved indications, mechanism of action and main results in clinical trials.
The successful combination of two immunotherapies was already reported. Combined nivolumab and ipilimumab had better results than either drug alone to treat metastatic melanoma. (32,33) Both nivolumab and pembrolizumab, as well as other anti-PD1, anti PD-L1 and combinations with anti-CTLA-4, are under test for a variety of tumors, with some extraordinary preliminary results. Positive results with these immunotherapies have been reported in kidney, bladder, pancreatic, metastatic colorectal cancer related to Lynch syndrome, gastroesophageal cancer and glioblastoma, among others. Of note, although, is that for most diseases exist a clear correlation of benefit with the higher expression of PD-L1 on tumor cells, (34,35) and there is still no standardized evaluation for the expression of PD1 or PD-L1. An unique aspect related to immunotherapies is sometimes the significant delayed response, which has been reported both with anti-CTLA-4 as well as anti--PD1 inhibitors. (36,37) This highlights the need for careful consideration before deeming these drugs ineffective, and it has led to the establishment of a different set of response criteria, known as immune-related response criteria (irRC). (38) Immune related adverse events derive from the activation of autoimmune-mediated diseases in the skin, gastrointestinal tract, liver and endocrine system. The most clinically relevant adverse

OTHER NEW SYSTEMIC TREATMENTS
In addition to the new targeted therapies and immunotherapies, few other new treatments (with various mechanisms of action) with significant clinical impact have emerged and been approved for clinical use in recent years. Table 3 describes new systemic treatments, its indications, mechanisms of action and main results in clinical trials.  There is currently a very vivid discussion around the world about the significant costs associated with new cancer therapy in general, and specifically about anticancer drugs. Immunotherapies, which seem to be on their way to become indicated for a large proportion of cancer patients, and some of the newer targeted therapies can cost hundreds of thousands of dollars per patient annually. (45) Cost is certainly a significant limiting factor for these drugs becomes available in Brazil.
Some good cancer treatments are still under registration process in Brazil, highlighting the gap between what is practice here in comparison with developed countries. No less important is the significant difference between what is registered and used in the private health system and what is available and used in the Brazilian public health system. Unless pricing of drugs becomes more reasonable in the near future, and unless health technology evaluation for the public health system starts to be dictated by well-established standards and pre-specified cost-effectiveness limits, new cancer therapies will be ever more limited in developing countries like Brazil, and as a consequence the difference between what is practiced internationally and in our country will widen significantly.