Options for the treatment of Glioblastoma and other Gliomas

New year new projects. Many visitors to this site have asked me to translate Ben Williams’ guide on different options for the treatment of Glioblastoma and other gliomas into Italian. The guide is full of information on the different treatments, their effects and also contains useful references to the scientific literature. Well, Ben Williams gave me permission to do the translation of his guide. So I decided to tackle the problem by dividing it into small pieces. Starting from this article I will publish the different chapters translated into Italian one after the other and after the last chapter I will collect them in a single publication. Also here keep in mind that the Guide often refers to the context of the United States which is slightly different from what we find in Italy. In any case, I believe that the amount of practical information contained in the guide is enormous and that this information is also useful for discussing it with the doctors who follow you or follow your loved ones. However, remember to use the new chatbot that provides important information (list of clinical trials active in Italy, list of centers specialised for the treatment of glioblastoma, list of treatments in the virtual trials database, effectiveness of treatments according to the information present you virtual trials) . Among other things, I’d like to be able to create an Italian version of the virtual trial database, perhaps as a subsequent project to this one. So let’s start with the introductory chapter.

Introduction

Since my diagnosis of glioblastoma (GBM) in 1995 at the age of 50, I have spent a lot of time researching treatment options and the following discussion summarizes what I have learned. Most of the information comes from medical journals and the proceedings of major cancer conferences. Some information has been provided by others about various online support groups for brain tumor patients, which I have followed over time, and some comes from direct communications with various doctors conducting the treatments. References are presented at the end for those who wish, with the help of their doctors, to take the information contained in this document seriously. Although this discussion is intended primarily as a descriptive of the recent development of new treatment options, it is motivated by my belief that single agent treatment protocols are unlikely to be successful.

A fuller account of my treatment philosophy, and the reasons behind it, is given in my book from (2002), “Surviving Terminal Cancer: Clinical Trials, Drug Cocktails and Other Treatments Your Doctor Will Not Tell You About”. It is currently only available on Amazon.com, where book reviews are also available.

When I began my search for effective treatments, the options available offered little chance of surviving my diagnosis. Standard treatment included surgery, radiotherapy, and nitrosourea-based chemotherapy, either BCNU alone or CCNU combined with procarbazine and vincristine (known as PCV combination). Although this treatment helped a small minority of people, the 5-year survival rate was only 2-5%. Median survival was approximately one year, which is 2-3 months longer than that of patients who received only radiation without chemotherapy. Fortunately, as will be discussed in the next section, the past decade has produced a new standard of treatment for newly diagnosed patients: the combination of radiation with a new chemotherapy agent, temozolomide (trade name Temodar in the US and Temodal elsewhere in the world). Three other treatments are also now available that have FDA approval for cancers that have come back or progressed after initial treatment: Gliadel, Avastin, and an electric field therapy called Optune (formerly known as NovoTTF). All of these are considered standard of care for recurrent cancers (this information is important for insurance reasons) and are also legally used for newly diagnosed patients. Each will be discussed later in this document.

There are three general premises for the treatment approach that will be described in this document. The first premise is borrowed from the therapeutic approach that has evolved in the treatment of AIDS. Both viruses and cancer cells have unstable genetic structures that are susceptible to mutations. This implies that the dynamics of evolution will create new forms resistant to any treatment that may have been administered. However, if multiple different treatments are used at the same time (rather than sequentially, as is now the case), each mutation has less chance of being successful. A mathematical model describing these hypotheses has recently been developed and has been shown to accurately describe the melanoma growth pattern (1).

The second premise is that cancer treatments of all types are probabilistic in their effects. None of them work in all cases, partly because a given cancer diagnosis is an amalgam of different genetic defects that respond in different ways to any given treatment agent. This is particularly true for glioblastomas, which have a multiplicity of genetic aberrations that vary widely from individual to individual and sometimes even within the same tumor of a given individual. Consequently, it is common that any ‘effective’ treatment agent will only be effective in a minority of patients, often in the range of 10-35%, but will do little or nothing in the majority of other patients. The result is that the chances of finding an effective treatment increase with the number of different therapeutic agents that are used. The probabilistic effects are in fact added together.

An important implication of the genetic diversity of cancers such as GBM is that trials of individually presented treatment agents often fail, not because they lack efficacy, but because they target only one or sometimes two growth pathways, leaving the other pathways of tumor growth unattended. Therefore, even at the clinical trial level, testing of individual treatment agents in isolation can provide misleading indications. A drug that fails in isolation may indeed be effective when combined with other drugs that target other growth pathways.

A third premise which is a general principle is that any successful treatment must be systemic in nature because it is impossible to identify all tumor extensions in normal tissue. Furthermore, cancer cells are typically present in locations in the brain distant from the main tumor, indicating that metastases may occur within the brain, although the vast majority of tumor recurrences are within or proximal to the site of the original tumor. Localized treatments such as radiosurgery can be beneficial in terms of acquired time, but are unlikely to provide a cure, except in cases where the tumor is detected early and is very small. Even if localized treatment eradicates 99% of the tumor, the small amount of residual tumor will expand geometrically, eventually causing significant clinical problems.

Until the development of immunotherapeutic treatments in recent years, which we will discuss in a dedicated section, the only systemic treatment available was cytotoxic chemotherapy, which has historically been ineffective except for a small percentage of patients. An important question, then, is whether chemotherapy can be made to work substantially better than it does today. Agents that facilitate or enhance its effects are of paramount importance. As will be seen, some older drugs developed for other purposes have been shown in laboratory studies to be effective against cancer, often with minimal toxicity. The availability of these treatments raises the possibility that some combination of these new agents could be tailored to provide effective treatment based on several independent principles. Therefore, the combined AIDS-like approach is now a real possibility, whereas it would not have been fifteen years ago. Because many of these relatively non-toxic new agents have been developed for purposes other than cancer or for different types of cancer, their use in the treatment of glioblastomas is off-label, resulting in many oncologists hesitating to prescribe them. Therefore, patients themselves should become familiar with these new agents and the available evidence regarding their clinical efficacy. It is possible, although not proven in any way, that a combination of these newly designated agents offers the best chance of survival.

Patients may or may not understand the treatments that will be described by their doctors. To appreciate why, it is important to understand how the medical system works. For most medical problems there is an accepted standard of what is the best available treatment. Ideally, such treatments are based on phase III clinical trials in which patients are randomly assigned to receive the new treatment or some type of control condition. Treatments that have only been studied in non-randomized phase II trials will rarely be offered as a treatment option, even if the accepted “best available treatment” is generally ineffective. What happens instead is that patients are encouraged to participate in clinical trials. The problem with this approach is that most medical centers offer few options for a single patient. Therefore, even though a given trial for a new treatment may look very promising, patients can only participate if that trial is offered by their medical center. Even more problematic is that clinical trials with new treatment agents almost always initially study that agent in isolation, usually with patients with recurrent tumors who have the worst prognosis. For newly diagnosed patients this is the last chance at best. Instead, what is needed is access to the most promising new treatments, in the optimal combinations, at the time of initial diagnosis and not with patients with recurrent tumors who have the worst prognosis.

In the discussion that follows, it is important to distinguish between treatment options at the time of initial diagnosis and those in which the tumor did not respond to initial treatment or only responded for a period of time but then came back. In these two situations, different measures of treatment effectiveness are often used, which sometimes makes the comparison difficult. The presence of a recurrent tumor is also complicated by the fact that the resistance to the initial treatment may or may not generalize to new treatments administered after the recurrence.

The importance of specialized centers for the treatment of brain tumors

When someone is diagnosed with a brain tumor, they are faced with a situation they know very little about, however they have to develop a treatment plan very quickly, because GBMs grow very fast if left untreated. The first step, if possible, is to remove as much of the tumor as possible, because various data show substantially longer survival times for those who get complete resections, compared to those who get only incomplete resections or worse only biopsies. As a result, it is best for patients to seek treatment at a major brain tumor treatment center because neurosurgeons will have performed far more operations than general neurosurgeons who typically work in non-specialist hospitals. This is particularly important in recent times, as surgical techniques have become increasingly sophisticated and use procedures that are not available in non-specialized treatment centers. I know of numerous cases in which a neurosurgeon from the local hospital told the patient that the tumor was inoperable, while the tumor was then completely removed in a specialized center for the treatment of brain tumors. The centres specialised in the treatment of brain tumors are better equipped to perform genetic analyzes of tumor tissue, which are increasingly important in guiding treatment decisions. In addition, they provide access to clinical trials.

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(1) Bozic.I., Reiter, JG, Allen, B., et al. Evolutionary dynamics of cancer in response to targeted combination therapy. Elife, 2013, 2 e00747

Good! I hope you enjoyed reading, I have been as faithful as possible. A new chapter very soon!