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treatment for glioblastomas, but its use has never been shown to produce a better | treatment for glioblastomas, but its use has never been shown to produce a better | ||
outcome than treatment with BCNU as a single agent. Nevertheless, there is now a large | outcome than treatment with BCNU as a single agent. Nevertheless, there is now a large | ||
amount of research studying the effects of combining temozolomide with other therapies, | amount of research studying the effects of combining temozolomide with other therapies, | ||
most of which supports the view that such combinations improve treatment outcome, | most of which supports the view that such combinations improve treatment outcome, | ||
Revision as of 05:31, 29 March 2024
Welcome
Since my own diagnosis of glioblastoma (GBM) in 1995 at age 50, I have spent considerable time researching treatment options, and the following discussion summarizes what I have learned. Most of the information is from medical journals and the proceedings of major cancer conferences. Some information has been contributed by others to various online brain tumor patient support groups, which I have followed up on, and some is from direct communications with various physicians conducting the treatments that are described. References are presented at the end for those who would like their physicians to take this information seriously. Although this discussion is intended to be primarily 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, and patients are best served if they utilize multiple treatment modalities, and go beyond the “certified” treatments that too often are the only treatment options offered.
Amore extensive account of my philosophy of treatment, and the reasons for it, are provided in my (2002) book, Surviving "Terminal" Cancer: Clinical Trials, Drug Cocktails, and Other Treatments Your Doctor Won't Tell You About. Currently, it is available only at Amazon.com, where reviews of the book also are available.
When I began my search for effective treatments, the available options offered little chance for surviving my diagnosis. The standard treatment included surgery, radiation, and nitrosourea-based chemotherapy, either BCNU alone or CCNU combined with procarbazine and vincristine (known as the PCV combination). While this treatment has helped a small minority of people, its 5-year survival rate has been only 2-5%. Median survival has been about a year, which is 2-3 months longer than for patients receiving radiation alone without chemotherapy. Fortunately, as will be discussed in the next section, the past ten years has produced a new “gold standard” of treatment for newly diagnosed patients: the combination of radiation with a new chemotherapy agent, temozolomide (trade name Temodar in the USA and Temodal elsewhere in the world). While this new standard appears to produce a notable improvement over previous treatments, it still falls far short of being effective for the great majority of patients.
Also available now are three other treatments that have FDA approval for tumors that have recurred or have progressed after initial treatment: Gliadel, Avastin, and an electrical field therapy named Optune (formerly known as NovoTTF). All of these are considered standard of care for recurrent tumors (which is important for insurance reasons), and can legally also be used for newly diagnosed patients as well. Each will be discussed later in this article. �There are three general premises to the approach to treatment that will be described. The first is borrowed from the treatment approach that has evolved in the treatment of AIDS. Both viruses and cancer cells have unstable genetic structures susceptible to mutations. This implies that the dynamics of evolution will create new forms that are resistant to whatever the treatment may be. However, if several different treatments are used simultaneously (instead of sequentially, which is typically the case), any given mutation has a smaller chance of being successful. A mathematical model instantiating these assumptions has recently been developed and has been shown to describe the pattern of tumor growth for melanoma (1).
The second premise is that cancer treatments of all sorts are probabilistic in their effects. None work for everyone, in part because any given cancer diagnosis is an amalgam of different genetic defects that respond in different ways to any given treatment agent. This is especially true for glioblastomas, which have a multiplicity of genetic aberrations that vary widely across individuals and sometimes even within the same tumor of a given individual. As a result it is common that any given "effective" treatment agent will
benefit only a minority of patients, often in the range of 10-35%, but do little if anything for the majority. The result is that the chances of finding an effective treatment increase the more different treatment agents that are utilized. Probabilistic effects can and do summate.
An important implication of the genetic diversity of GBM tumors is that tests of treatment agents presented individually will often fail, not because they lack effectiveness, but because they target only one or sometimes two growth pathways, leaving other growth pathways to be upregulated to maintain the growth of the tumor. Thus, even at the level of clinical trials, tests of individual treatment agents in isolation may be a misguided strategy. A drug that fails in isolation might in fact be effective when combined with other drugs that target the additional alternative growth pathways.
A third general principle is that any successful treatment needs to be systemic in nature because it is impossible to identify all of the extensions of the tumor into normal tissue. Moreover, cancer cells are typically evident in locations in the brain distant from the main tumor, indicating that metastases within the brain can occur, although the great majority of tumor recurrences are within or proximal to the original tumor site. Localized treatments such as radiosurgery may be beneficial in terms of buying time, but they are unlikely to provide a cure, except in cases when the tumor is detected early and is very small. Even if the 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 immunological treatments in just the last few years, which will be discussed in a later section, the only systemic treatment available has been cytotoxic chemotherapy, which historically has been ineffective except for a small percentage of patients. An important issue, therefore, is whether chemotherapy can be made to work substantially better than it typically does. Agents that facilitate or augment its effects are critically important. As will be seen, a number of 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 can be packaged that provide effective treatment based on several different independent principles. Thus, the AIDS-type of combination approach is now a genuine possibility whereas it would not have been fifteen years ago. Because many of these relatively nontoxic new agents were developed for purposes other than cancer, or for different kinds of cancer, their utilization in the treatment of glioblastomas is "off-label", with the result that many oncologists have been hesitant to prescribe them. Thus, patients themselves need to become familiar with these new agents and the evidence available regarding their clinical effectiveness. It is possible, although by no means proven, that some combination of these newly repurposed agents offers the best possibility for survival.
Patients may or may not learn about the treatments that will be described from their physicians. To appreciate why, it is important to understand how American medicine has been institutionalized. 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 been studied only in nonrandomized 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 an individual patient. Thus, even though a given trial for a new treatment may seem very promising, patients can participate only if that trial is offered by their medical facility. Yet 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 prognoses. For newly diagnosed patients this is at best a last resort. What is needed instead is access to the most promising new treatments, in the optimum combinations, at the time of initial diagnosis.
In the discussion to follow, it is important to distinguish between treatment options at the time of initial diagnosis versus those when the tumor either did not respond to the initial treatment or responded for a period of time and then recurred. Different measures of treatment efficacy are often used for the two situations, which sometimes makes treatment information obtained in one setting difficult to apply to the other. The recurrent tumor situation is also complicated by the fact that resistance to the initial treatment may or may not generalize to new treatments given at recurrence. �The Importance of Brain Tumor Centers
When someone is diagnosed with a brain tumor they are faced with a situation about which they know very little, but nevertheless must develop a treatment plan very quickly, because GBMs grow very rapidly if left untreated. The first step, if possible, is to have as much of the tumor removed as possible, because various data show substantially increased survival times for those with complete resections, relative to those who have incomplete resections or only biopsies. Accordingly, it is best that patients seek treatment at a major brain tumor center because neurosurgeons there will have performed many more tumor removals than general neurosurgeons that typically work in the community setting. This is especially important in recent times, as surgical techniques have become increasingly more sophisticated and utilize procedures that community treatment centers do not have the resources to perform. I know of numerous cases in which a local neurosurgeon has told the patient the tumor is inoperable, only to have the same tumor completely removed at a major brain tumor center.
An additional advantage of utilizing a major brain tumor center is that they are better equipped to do genetic analyses of tumor tissue, which are increasingly important in guiding treatment decisions. Moreover, they provide a gateway into clinical trials.
The Importance of Brain Tumor Centers
When someone is diagnosed with a brain tumor they are faced with a situation about which they know very little, but nevertheless must develop a treatment plan very quickly, because GBMs grow very rapidly if left untreated. The first step, if possible, is to have as much of the tumor removed as possible, because various data show substantially increased survival times for those with complete resections, relative to those who have incomplete resections or only biopsies. Accordingly, it is best that patients seek treatment at a major brain tumor center because neurosurgeons there will have performed many more tumor removals than general neurosurgeons that typically work in the community setting. This is especially important in recent times, as surgical techniques have become increasingly more sophisticated and utilize procedures that community treatment centers do not have the resources to perform. I know of numerous cases in which a local neurosurgeon has told the patient the tumor is inoperable, only to have the same tumor completely removed at a major brain tumor center.
An additional advantage of utilizing a major brain tumor center is that they are better equipped to do genetic analyses of tumor tissue, which are increasingly important in guiding treatment decisions. Moreover, they provide a gateway into clinical trials.
The Standard of Care for Initial Treatment
Glioblastoma
Although chemotherapy has a long history of being ineffective as a treatment for glioblastoma, a large randomized European-Canadian clinical trial (EORTC trial 26981/22981) has shown clear benefits of adding the new chemotherapy agent, temozolomide (trade name Temodar in the USA, Temodal elsewhere in the world) to the standard radiation treatment (2). This treatment, followed by 6 or more monthly cycles of temozolomide, has become known as the “Stupp protocol” after Roger Stupp, the Swiss oncologist who led the trial. In this trial, one group of patients received radiation alone; the other group received radiation plus Temodar, first at low daily dosages during the six weeks of radiation, followed by the standard schedule of higher-dose Temodar for days 1-5 out of every 28-day cycle. Median survival was 14.6 months, compared to a median survival of 12 months for patients receiving radiation only, a difference that was statistically significant. More impressive was the difference in two-year survival rate, which was 27% for the patients receiving temodar but 10% for those receiving only radiation. Longer-term follow-up has indicated that the benefit of temozolomide (TMZ) persists at least up to five years: The difference in survival rates between the two treatment conditions was 16.4% vs. 4.4% after three years, 12.1% vs. 3.0% after four years, and 9.8% vs. 1.9% after five years (3). As a result of these findings, the protocol of TMZ presented during radiation is now recognized as the "gold standard" of treatment. Note, however, that all of these numbers are somewhat inflated because patients over the age of 70 were excluded from the trial.
In July of 2016, the National Comprehensive Cancer Network (NCCN) recommended Optune as a category 2A treatment for newly diagnosed glioblastoma in combination with the standard temozolomide-based chemotherapy (see press release here). This rating indicates a uniform consensus by the NCCN that this treatment is appropriate. As the NCCN is recognized as setting the standards for cancer treatment in the USA and in other countries abroad which follow its guidelines, Optune in combination with standard chemotherapy following radiation could now be considered to be a new standard of care for newly diagnosed glioblastoma. See more detailed information on Optune in Chapter 3.
Anaplastic astrocytoma
Though the “Stupp protocol” of combined temoradiation (concomitant radiation and temozolomide chemotherapy) followed by monthly cycles of temozolomide has been routinely applied to anaplastic astrocytoma patients, prospective confirmation of this use in this patient population has awaited results of the “CATNON” randomized phase 3 trial for 1p/19q non-codeleted grade 3 gliomas. Results of the interim analysis for this trial were first released for the ASCO 2016 annual meeting. Between 2007 and 2015, 748 patients were randomized to receive either i) radiation alone, ii) radiation with concomitant temozolomide, iii) radiation followed by 12 adjuvant monthly cycles of temozolomide, or iv) radiation with temozolomide both concurrently and with follow-up monthly cycles. At the time of the interim analysis (October 2015), significant progression-free and overall survival benefit was found with adjuvant temozolomide treatment (arms iii and iv). Median progression-free survival was 19 months in arms i and ii (not receiving adjuvant temozolomide) versus 42.8 months (receiving adjuvant temozolomide). 5-year survival rate was 44.1% and 55.9% in arms i and ii versus iii and iv. Median survival was not yet reached for arms iii and iv.
This analysis did not address the benefit of temozolomide concurrent with radiation, a question that will be answered with further follow-up, and studies assessing the impact of IDH1 mutation and MGMT methylation were still ongoing.
Determining who will benefit
A two-year survival rate of less than 30% obviously cannot be considered an effective treatment, as the great majority of patients receiving the treatment obtain at best a minor benefit, accompanied with significant side effects (although Temodar is much better tolerated than previous chemotherapy treatments, especially with respect to the cumulative toxicity to the bone marrow). This raises the issues of how to determine who will benefit from the treatment, and, most importantly, how to improve the treatment outcomes.
One approach to determining whether an individual patient will benefit from chemotherapy is simply to try 1-2 rounds to see if there is any tumor regression. The debilitating effects of chemotherapy typically occur in later rounds, at which point there is a cumulative decline in blood counts. The extreme nausea and vomiting associated with chemotherapy in the mind of the lay public is now almost completely preventable by anti-nausea agents, including Zofran (ondansetron), Kytril (granisetron) and Emend. (aprepitant). Marijuana also can be very effective in controlling such effects, and recent research has suggested that it has anti-cancer properties in its own right. Thus, for those patients who are relatively robust after surgery and radiation, some amount of chemotherapy experimentation should be possible without major difficulties.
An alternative way to ascertain the value of chemotherapy for an individual patient is the use of chemosensitivity testing for the various drugs that are possible treatments. Such testing typically requires a live sample of the tumor and thus must be planned in advance of surgery. Culturing the live cells is often problematic, but a number of private companies across the country offer this service. Costs range from $1000-$2500, depending on the scope of drugs that are tested. Such testing is controversial, in part because the cell population evolves during the process of culturing, which results in cells possibly different in important ways from the original tumor sample. Nevertheless, recent evidence has shown that chemosensitivity testing can enhance treatment effectiveness for a variety of different types of cancer, including a recent Japanese study using chemosensitivity testing with glioblastoma patients (4). However, this study did not involve cell culturing but direct tests of chemosensitivity for cells harvested at the time of surgery. In general, when chemosensitivity testing indicates an agent has no effect on a patient's tumor the drug is unlikely to have any clinical benefit. On the other hand, tests indicating that a tumor culture is sensitive to a particular agent do not guarantee clinical effectiveness, but increase the likelihood that the agent will be beneficial.
The Role of MGMT
A significant advance in determining which patients will benefit from Temodar was reported by the same research group that reported the definitive trial combining Temodar with radiation. Tumor specimens from the patients in that trial were tested for the level of activation of a specific gene involved in resistance to alkylating chemotherapy (which includes temozolomide and the nitrosoureas, BCNU, CCNU, and ACNU). full text
Dexamethasone
Most glioma patients will be exposed to dexamethasone (Decadron) at some point, as this corticosteroid is the first-line treatment to control cerebral edema caused by the leaky tumor blood vessels. Many also require dexamethasone during radiotherapy, and perhaps beyond this time if substantial tumor remains post-resection. Dexamethasone is an analog to the body’s own cortisol, but is about 25 times more potent. Though often necessary, dexamethasone comes with a long list of adverse potential side effects with prolonged use, including muscle weakness, bone loss, steroid-induced diabetes, immunosuppression, weight gain, and psychological effects.
New evidence also shows an association between dexamethasone use and reduced survival time in glioblastoma. This evidence has to be weighed against the fact that uncontrolled cerebral edema can be fatal in itself, and that dexamethasone is often required for its control. However, the attempt should always be made to use dexamethasone at the lowest effective dose, and to taper its use after control of edema is achieved, under a physician’s guidance.
In a retrospective study of 622 glioblastoma patients treated at Memorial Sloan Kettering Cancer Center, multivariate regression analysis showed an independent negative association of steroid use at the start of radiotherapy with survival (324). A similar negative association with survival outcomes was found in patients in the pivotal phase 3 trial that led to temozolomide being approved for glioblastoma in 2005, and for a cohort of 832 glioblastoma patients enrolled in the German Glioma Network.
Follow up studies in mice helped elucidate these retrospective clinical observations. In a genetically engineered PDGFB-driven glioblastoma mouse model, dexamethasone alone had no effect on survival, but pretreatment with dexamethasone for 3 days prior to a single dose of 10 Gy radiation negatively impacted the efficacy of radiation. This negative impact of dexamethasone on radiation efficacy was even more dramatic with multiple doses of dexamethasone given before 5 treatments with 2 Gy radiation, which more closely mimics what GBM patients are exposed to. In contrast, an antibody against VEGF, which could be considered a murine surrogate for Avastin, did not interfere with the efficacy of radiation.
In vivo mechanistic examination revealed that dexamethasone may interfere with radiation by slowing proliferation, leading to a higher number of cells in the more radioresistant G1 phase of the cell cycle, and fewer cells in the more radiosensitive G2/M phase. This finding has far-reaching implications about the potential interference by drugs with cytostatic mechanisms of action on the efficacy of radiation therapy.
The authors conclude by suggesting that antibodies against VEGF, most notably bevacizumab (Avastin), could be used as an alternative anti-edema drug during radiation in place of steroids. However, this use has to be weighed in importance against the exclusion from certain promising clinical trials due to prior use of Avastin being an exclusion criteria in some of these trials.
Strategies for improving the Standard of Care
Combatting chemoresistance
There are several ways that cancer cells evade being killed by cytotoxic chemotherapy. Already mentioned is that the damage inflicted by the chemotherapy is quickly repaired before actually killing the cell (due to the activity of the MGMT repair enzyme). A second source of resistance is that the chemo agent is extruded from the cancer before the next cell division (chemotherapy typically affects only those cells in the process of dividing). A third way is that the chemo agent doesn’t penetrate the blood-brain barrier. While Temodar is generally believed to cross the blood-brain-barrier effectively, empirical studies of its concentration within the tumor tissue have shown that its penetration is incomplete.
A major source of chemo-resistance for many types of cancer comes from glycoprotein transport systems (technically called ABC transporters) that extrude the chemotherapy agent before it has the chance to kill the cell. This is important because chemotherapy is effective only when cells are dividing, and only a fraction of the cell population is dividing at any given time. The longer the chemotherapy remains in the cell, the more likely it will be there at the time of cell division. If extrusion of the chemotherapy drug could be inhibited, chemotherapy should in principle become more effective. Calcium channel blockers, which include commonly used medications for hypertension such as verapamil, have thus been studied for that purpose (11).
Unfortunately, these agents have potent effects on the cardiovascular system, so that dosages sufficiently high to produce clinical benefits usually have not been achievable. However, a recent study (12) did report a substantial clinical benefit for patients with breast cancer with a relatively low dosage (240 mg/day). An earlier randomized trial with advanced lung cancer (13) also demonstrated a significant benefit of verapamil, using a dose of 480 mg/day, both in terms of frequency of tumor regression and survival time. In addition, the combination of verapamil with tamoxifen (which itself blocks the extrusion by a somewhat different mechanism) may possibly increase the clinical benefit (14). In laboratory studies, the calcium channel blockers nicardipine and nimodipine (15, 16) have also been shown to effectively increase chemotherapy effectiveness, and may have direct effects on tumor growth themselves. Quinine derivatives such as quinidine and chloroquine also inhibit the extrusion pump. Among the strongest inhibitors of the extrusion pump is a common drug used in the treatment of alcoholism, Antabuse, also known as disulfiram (17,18). Yet another class of drugs that keep the chemo inside for longer time periods are proton pump inhibitors used for acid reflux (e.g., Prilosec) (19). One approach to blocking the glycoprotein pump without the high toxic doses is to combine several agents together, using lower doses of each individual agent, as combining different agents has been shown to be synergistic in laboratory studies (20).
The most promising clinical results for combatting chemo-resistance has come from the addition of chloroquine, an old anti-malaria drug, to the traditional chemotherapy agent, BCNU. See Chapter 5, Chloroquine section for further details.
Disruption of the blood-brain-barrier (BBB) is also potentially very important and has been extensively investigated. The issue is complicated by the fact that tumor tissue already has a substantially disrupted BBB (which is the basis of using contrast agents to identify the tumor). However, this disruption is incomplete, so any chemotherapy agent that does not cross the intact BBB will not contact all portions of the tumor. Various ways of disrupting the BBB have been studied, but none has been generally successful, primarily because of their systemic side effects. Recently, however, the common erectile dysfunction drugs (Viagra, Levitra, Cialis) have been discovered to disrupt the BBB in laboratory animals. In a rat brain tumor model, the addition of Viagra or Levitra to a common chemotherapy agent, Adriamycin, substantially improved survival time (26).
Optimizing the Schedule of Chemotherapy
The standard schedule for using full-dose Temodar is days 1-5 out of every 28-day cycle. The large phase 3 EORTC-NCIC study (2005) also added daily Temodar during radiation at a lower dosage, followed by the standard five-day schedule after radiation was completed. But there has never been a persuasive rationale for why this standard schedule should be preferred over various alternatives.
In addition to the standard schedule, three other schedules have been studied: (1) a “metronomic” low-dose daily schedule; (2) an alternating week schedule; (3) a “dose- intense” schedule in which Temodar is used on days 1-21 of every 28-day cycle. While it is possible to compare the outcomes of these different studies across different clinical trials, only a few studies have compared the different schedules within the same clinical trial. �In one single-center randomized trial with newly diagnosed patients, the alternating week schedule of 150 mg/m2 on days 1-7 and 15-21 was compared with the metronomic schedule of 50 mg/m2 daily (29). Patients completing 6 cycles of adjuvant Temodar were switched to maintenace therapy with 13-cis retinoic acid (aka Accutane). One-year survival rates were 80% vs. 69%, and two-year survival rates 35% vs. 28%, both favoring the alternating week schedule. However, neither difference was statistically significant. Median survival times for the alternating week and metronomic schedules were 17.1 vs. 15.1 months.
A second very large randomized trial compared the standard 5-day schedule with a dose- intense schedule (75-100 mg/mz2 on days 1-21). The rationale of the dose-intense schedule was that it would better deplete the MGMT enzyme (30). Median PFS favored the dose-dense arm (6.7 months vs. 5.5 months from the time of study randomization, p=0.06), while median overall survival favored the standard schedule (16.6 vs. 14.9 months from randomization). While neither difference was considered statistically significant, the dose-intense schedule had substantially more toxicity and hence cannot be recommended.
In a more recent retrospective study (313), 40 patients undergoing the standard 5-day temozolomide schedule and 30 patients undergoing a metronomic schedule (75 mg/m2) were included in the final analysis. The metronomic temozolomide schedule led to statistically significant increases in both progression-free survival and overall survival, and in both univariate and multivariate analysis. Even more importantly, this study found that the benefit of the metronomic schedule mainly occurs for those patients with EGFR overexpression (EGFR protein expression in over 30% of tumor cells), or EGFR gene amplification. Median overall survival for patients with EGFR overexpression treated with metronomic temozolomide was 34 months, compared to 12 months with standard schedule. EGFR overexpressing patients treated with metronomic temozolomide had highly statistically significantly improved progression-free survival and overall survival compared to all other groups (the other groups being EGFR overexpressing treated with standard schedule, and EGFR non-overexpressing treated with either schedule).
The investigators furthermore analysed tumor tissue samples from patients who underwent repeat resection at the time of recurrence. Interestingly, they found that samples from EGFR overexpressing tumors treated with metronomic temozolomide had significantly fewer cells positive for NF-kB/p65 (a promoter of cell proliferation and survival) compared with untreated tumors from the same patients at the time of diagnosis. No such change was observed between the primary and recurrent EGFR overexpressing tumors from patients treated with the standard schedule. Recurrent EGFR amplified tumors treated with the metronomic schedule showed fewer EGFR amplified cells and weaker EGFR staining at the time of recurrence compared with the primary tumor. No such difference was observed in EGFR amplified tumors treated with �the standard schedule. The authors draw the conclusion that this metronomic schedule impairs survival of EGFR expressing GBM cells more effectively than the standard schedule. These findings will hopefully lead to testing in prospective clinical trials. A major caveat when reviewing this study is that there is no explanation for why some of the patients were selected for the higher dose metronomic schedule rather than the standard schedule and it’s possible that these patients were healthier at baseline and that selection bias contributed to the different outcomes.
The lowest Temodar dose in metronomic chemotherapy reported to date was presented to newly diagnosed glioblastoma patients (44). After completion of standard radiation treatment, continuous daily doses of temozolomide approximately 1/10 of the typically used full dose were used in combination with Vioxx (aka rofecoxib, a discontinued COX-2 inhibitor which was later replaced by celecoxib in studies by this group). Median progression-free survival was 8 months and overall survival for 13 patients was 16 months, with minimal toxicity. A second retrospective study (45) from the same medical group compared the very low-dose schedule (20 mg/m2) with a more typical metronomic dosage (50 mg/meter-squared), although only 17 patients and six patients were included in the former and latter groups. Also included were patients who received only radiation. Median survival was 17 months and 21 months, respectively, for the two metronomic chemotherapy groups vs. 9 months for the radiation-only patients.
Although clinicians will likely resist any alternative to the standard temozolomide schedule for newly diagnosed patients outside of clinical trials, a medium-dose metronomic schedule is worthy of consideration for patients with unmethylated MGMT status, and especially for those patients with unmethylated MGMT status and amplified EGFR. For patients unfit to receive the standard high dose temozolomide schedule, a very low dose metronomic schedule of TMZ may provide some benefit, perhaps through selective toxicity to immune suppressor cells, and in combination with COX-2 inhibition as in the German studies above.
How many cycles of TMZ?
An important question is how long the use of TMZ should be continued. The Stupp clinical trial continued it for only six cycles after radiation, but many patients have continued that protocol for longer period of times.
In what is perhaps the only randomized, prospective trial comparing different numbers of cycles of adjuvant temozolomide, 20 newly diagnosed glioblastoma patients were assigned to six cycles and another 20 patients were assigned to 12 cycles (355). Median progression-free survival outcomes were 12.8 months in the 6-month group and 16.8 months in the 12-month group, which was borderline statistically significant (p=0.069). Median overall survival was 15.4 versus 23.8 months, and achieved statistical significance despite the low numbers of patients included in the trial (p=0.044). A serious limitation of this study is that no information on MGMT status of the patients was collected, and therefore it’s possible that the proportion of patients with MGMT promoter methylated tumors was not equal in the two arms.
A retrospective study done in Canada (51) compared patients who received the standard six cycles of temozolomide with those who had more than six cycles (up to 12) Patients receiving six cycles had a median survival of 16.5 months, while those receiving more than six cycles had a median survival of 24.6 months.
The latest attempts to define the optimal length of monthly temozolomide (TMZ) therapy were published as abstracts for the SNO 2015 annual meeting. In the first of these studies (reference 325, abstract ATCT-08), a large team of investigators retrospectively analyzed data from four large randomized trials with the aim of comparing 6 cycles of monthly TMZ to >6 cycles. Only patients who had completed 6 cycles of TMZ and had not progressed within 28 days of completing cycle 6 were included. Important prognostic factors such as age, performance status, extent of resection and MGMT status were incorporated into the analysis. For these patients, treatment with more than 6 cycles of TMZ was associated with significantly improved progression-free survival [HR=0.77, p=0.03] independently of the examined prognostic factors, and was particularly beneficial for those with methylated MGMT status. Surprisingly, overall survival was not significantly different between the two groups (p=0.99).
In the second abstract (reference 326, abstract ATPS-38), a Japanese group attempted to clarify whether more than 12 cycles of TMZ was beneficial in terms of increased survival. Patients in this study were divided into four groups: a) 12 cycles, b) 24 cycles, c) more than 24 cycles until relapse, and d) beyond 12 cycles (this group includes the b) and c) groups). 12, 14, 12, and 40 patients were included in each of these groups. No significant progression-free survival difference was detected between groups a) and b), implying a lack of benefit of 24 versus 12 cycles. Importantly, patients who were able to continue TMZ treatment for at least 12 cycles (all the patients in this study) had a median progression-free survival of 4.3 years and median overall survival of 6.3 years. This study failed to show a benefit of continuing TMZ cycles beyond 12.
Combining the Standard Treatment with Additional Agents
Few oncologists believe that single-agent treatments are likely to be curative. The issue is finding the optimal combinations, based on toxicities and differences in the mechanisms of actions. Prior to the introduction of temozolomide, the PCV combination of procarbazine, CCNU, and vincristine had been the most widely used combination treatment for glioblastomas, but its use has never been shown to produce a better outcome than treatment with BCNU as a single agent. Nevertheless, there is now a large amount of research studying the effects of combining temozolomide with other therapies, most of which supports the view that such combinations improve treatment outcome, sometimes substantially. A variety of additional therapies are discussed in the following chapters.
Optune (formerly NovoTTF-100A) by Novocure
In the spring of 2011, the FDA approved the fourth treatment ever for glioblastoma. Unlike the previous three (gliadel, temozolomide, and Avastin), the new treatment involves no drugs or surgery, but instead uses a “helmet” of electrodes that generates a low level of alternating electrical current. A biotech company called Novocure has developed the device, called Optune, based on experimental findings that electro- magnetic fields disrupt tumor growth by interfering with the mitosis stage of cell division, causing the cancer cells to die instead of proliferating (138). Healthy brain cells rarely divide and thus are unaffected. The treatment involves wearing a collection of electrodes for 18 or more hours per day, which allows the patient to live otherwise normally. This approval in 2011 was the outcome of a randomized phase 3 trial for recurrent glioblastoma, in which Novo-TTF (now called Optune) treatment was equally effective as physician’s choice chemotherapy, but with reduced toxicity and better quality of life (139, 140).
Optune plus chemoradiation, the next standard of care?
EF-14 is a phase 3 randomized clinical trial for newly diagnosed glioblastoma which compared standard of care chemoradiation followed by Optune (NovoTTF) and monthly cycles of Temodar, versus chemoradiation followed by monthly cycles of Temodar alone.
In November 2014, at the annual SNO meeting in Miami Beach, Roger Stupp made a “late-breaking” presentation before a packed audience, describing interim survival outcomes from the EF-14 trial, essentially ushering in what may become the new standard of care for newly diagnosed glioblastoma. This trial is the first major phase 3 trial since the “Stupp protocol” was established in 2005 to report a positive, statistically significant survival benefit for newly diagnosed glioblastoma. In fact, the trial was so successful that it was terminated early and on December 2, Novocure announced that the FDA had approved an investigational device exemption (IDE) supplement allowing all the control patients in the EF-14 trial to begin receiving therapy with Optune tumor treating fields. �The interim results presented in Miami were based on the first 315 patients enrolled in the trial, who had at least 18 months of follow-up. Of these, 105 were randomized into the control arm and 210 were randomized to receive tumor treating fields. Survival and progression-free survival were measured from the time of randomization, which was a median of 3.8 months after diagnosis. Median progression-free survival was 7.1 months in the Optune arm versus 4 months in the control arm (hazard ratio 0.63, with a high degree of statistical significance, p=0.001). Median overall survival from randomization was 19.6 months in the Optune arm versus 16.6 months in the control arm (hazard ratio 0.75, statistically significant, p=0.034). 2-year survival was 43% in the Optune arm versus 29% in the control arm. It must be kept in mind that all these statistics are measured from randomization, roughly 4 months from diagnosis, meaning that median overall survival in the Optune arm approaches 24 months from diagnosis. The statistics above are for the intention-to-treat (ITT) population, which includes all patients randomized, as opposed to the as-treated (per-protocol) population, which excludes patients who did not start their second course of temozolomide or had major protocol violations.
An October 5, 2015 press release announced that the FDA had approved Optune in combination with temozolomide for newly diagnosed glioblastoma, not quite a year after the first survival data from the trial was publicized. This is the first approval of a therapy for newly diagnosed glioblastoma since temozolomide was approved for this indication in March 2005. Two months later, in December 2015, the preliminary results of the EF-14 trial were published in the Journal of the American Medical Association (327). This publication detailed results for the first 315 patients enrolled, the same patients reported upon at the SNO 2015 annual meeting. Additional survival analysis on the per-protocol population (as opposed to the intention-to-treat population) gave an overall survival from randomization of 20.5 months in the Optune group and 15.6 months for the control group (that is, about 24.3 months and 19.3 months from diagnosis) (HR=0.64, p=0.004).
Outcomes for the entire trial population of 695 patients were published for the 2016 SNO conference, with an updated press release from Novocure coming in April 2017. Confirming the results of the interim analysis, median progression-free survival was significantly improved in the Optune group by just under 3 months (6.7 versus 4 months from randomization). Median overall survival from randomization was improved by neatly five months (20.8 versus 16 months). Survival rate at 2 years from randomization was 42.5% in the Optune group versus 30% in the control group. The April 2017 update also reported on 5 year survival rate, which was 13% in the Optune arm versus 5% in the control arm.
As of July 2016, the National Comprehensive Cancer Network (NCCN) had given Optune a 2A listing for newly diagnosed glioblastoma, indicating uniform consensus amongst the NCCN panel that this treatment is appropriate. As the NCCN is known as setting the standard treatment guidelines for cancer in the USA, this formalizes the concept of Optune as part of a new standard of care for newly diagnosed glioblastoma. Although its �status as part of a new standard of care may still be disputed by some, Novocure has announced that Optune is now available at over 600 treatment centers in the USA (click here for a list of these US centers), as well as 350 additional institutions internationally, including locations in Germany, Switzerland, Austria, and Japan.
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