Glioblastoma (No. 1)

Incidence & Overall Survival Following Conventional Treatment (revised 03.27.2024)

I have been researching glioblastoma, looking for details that may be missing from the information available to those currently receiving treatment recommendations from healthcare providers.

In this article, I offer an independent review the incidence and overall survival rate of a particular type of brain cancer called glioblastoma. I also discuss the survival associated with surgery to partially remove the tumor, and 2) additional conventional treatments of chemotherapy and radiotherapy.

Here is a sampling of the statistics offered by the National Brain Tumor Society (NBTS):¹

• “The five-year survival rate for glioblastoma patients is 6.9 percent.”

• “The average length of survival for glioblastoma patients is estimated to be eight months.”

• “Survival rates and mortality statistics have been virtually unchanged for decades.”

• “Despite first being identified in the scientific literature in the 1920’s, there have only been four drugs and one device ever approved by the FDA specifically for the treatment of glioblastoma, and none of these treatments have succeeded in significantly extending patient lives beyond a few extra months.”

Having worked at a Cancer Institute, I want to know more details of survival. Given the low overall 5-year survival rate, what percent of patients survive one, two, three and four years? What factors are related to longer survival? Does surgery improve survival? Does chemotherapy improve survival? Does radiotherapy² improve survival? These are important questions for those considering how to best approach this life-threatening condition.

The Malta Study (Grech et al., 2020)

A recent study of incidence and survival of glioblastoma was published in 2020. The investigators collected data in a European hospital on 100 patients diagnosed with glioblastoma during the time period 2008 - 2017.³

• The median survival was 10 months (half survived less than 10 months; half survived more than 10 months.) Due to the fact that the median (10 months) and average of 8 months (reported by the National Brain Tumor Society) are very similar (i.e., they differ by only 2 months) we can infer few (perhaps no) long-term survivors in the cohort. If some patients survived a long time, the average would be impacted; the average would be higher than the median. The survival is very low for this cohort of patients.

• Incidence (the rate of new cases in a year) is increasing over time. The hospital had 3 cases in 2008 and the number climbed steadily to 21 cases in 2018. [page 3] “The reasons for this increase in incidence are yet to be determined, and only possible causal factors can be postulated. Contributing factors may include an increase in diagnosis consequent to increasing ease of access to neuroimaging, an aging population, ionizing radiation, radio frequency electromagnetic fields” [pages 1-2] I will address these potentially causal factors in Part 2.

• The overall Kaplan-Meier survival curve for all 100 patients is presented in Figure 2. Two factors significantly impacted survival: age and surgery. Younger patients survived longer as did those who had Maximum Safe Resection. [pages 5-6] But, it is important to realize that being young and having surgery do not change the fatality of the condition.

• The Kaplan-Meier survival curves for both ‘resection=yes’ and ‘resection=no’ are both shown in Figure 3. Among those who had resection, slightly over 50% survived 1 year; approximately 30% survived 2 years; approximately 20% survived 3 years; approximately 18% survived 4 and 5 years. This helps to clarify the degree to which initial surgery improves survival. The exact percents are not specified; however, eyeballing the curves, surgery more than doubles the likelihood of surviving at 1, 2 and 3 years post-diagnosis. I wonder, though: what are potentially confounding factors here? Who says no to surgery? Only the oldest in the cohort? If so, then the statistic is meaningless.

• ‘Year of biopsy’ was not a significant factor, which means that recent cases did not have improved survival compared to those earlier in the cohort. [page 5]

Unfortunately (and suspiciously,) data on whether or not the patients received chemotherapy and/or radiotherapy “was not collected.” I believe this to be an egregious omission, as, patients deserve to make treatment decision based on all valid, available data. Of course, the investigators had knowledge of all treatment as they reviewed each medical record. To include age, gender and resection in the statistical model but not other major treatments is unscientific and misleading at best.⁴

I searched for an answer to this important question: What is the survival difference between those who receive chemotherapy and/or radiotherapy following surgery and those who stop conventional treatment following surgery? An answer to this question (preferably from an independent research group) is crucial, because patients want to weigh the probability of surviving a certain length of time with the quality of that survival, taking into account the impact (i.e., all treatment effects and potential complications) of each additional treatment offered.

Certainly, it is a complex question. However, solid clinical trial design and simple math should be able to tease out the effect of additional treatment. Basic epidemiology could be used to answer this question.

Has basic epidemiology been used to answer this question?

Chemotherapy and Radiotherapy for Glioblastoma

The gold standard chemotherapy drug is Temozolide. This drug was studied in the EORTC-NCIC Trial and findings were published by Stuff et al. (2009).⁵ Temozolide was the first drug to be offered in addition to radiotherapy after statistically significant increases in median survival and 2-year survival rates were reported. It should be noted, though, that known deficiencies and valid critique of this study are also part of the record.⁶ Specifically, cases other than glioblastomas (i.e., histologies known to be associated with longer survival times) were known to be included in the treatment arm, calling into question the validity of the results. As future drug trials are compared to the gold standard, all clinical trial results compared to Temozolide (there are many) should also be critically assessed.

For example, Tumor-Treating Fields as an additional treatment to Temozolide has been studied and findings were published by in 2015.⁷ Results describe: “The interim analysis included 210 patients randomized to TTFields plus temozolomide and 105 randomized to temozolomide alone, and was conducted at a median follow-up of 38 months (range, 18-60 months). I may not have noticed several years ago, but my fraud sensitivity has increased dramatically since reviewing the Pfizer clinical trials for covid injections. Here too, ‘median follow-up’ is used, which is absurd in a trial that uses survival as the endpoint.

The most recent study I found is the analysis of the EORTC Randomized Phase III CATNON Trial published by Tesileanu et al. (2022).⁸ They report:

Of the 751 patients entered in the CATNON study, 670 had fully molecularly characterized tumors. A total of 159 of these tumors met the WHO 2021 molecular criteria for glioblastoma, IDH-wt. Of these patients, 47 received radiotherapy only and 112 received a combination of radiotherapy and temozolomide. There was no added effect of temozolomide on either overall survival [HR, 1.19; 95% confidence interval (CI), 0.82–1.71] or progression-free survival (HR, 0.87; 95% CI, 0.61–1.24). MGMT promoter methylation was prognostic for overall survival, but was not predictive for outcome to temozolomide treatment either with respect to overall survival or progression-free survival.

These investigators conclude:

In this cohort of patients with glioblastoma, IDH-wt temozolomide treatment did not add benefit beyond that observed from radiotherapy, regardless of MGMT promoter status.

I can offer no further interpretation of efficacy of treatment beyond surgery. Some trial results are considered ‘significant’ and they become part of the menu of options. Other show no effect. Either way, the word ‘significant’ in a clinical trial refers to statistical significance and not clinical significance. A difference between 13 months and 14 months can be statistically significant if there are enough subjects in the analysis. This may or not be meaningful to an individual and her/her family after taking into account changes in quality of life due to treatment.

But most concerning, I can find no clinical trial that compare surgery only to surgery + radiotherapy. I will continue to search the archives.

Lingering Questions

For each treatment offering, here is a list of things to consider:

1. Is this treatment potentially curative or is it considered management or palliative?

2. How does this treatment impact 1- and 2-year survival rates?

3. Quality of life: What are the common effects of the treatment? What are the potential serious complications, and how common are they?

4. If a combination protocol is recommended: Has this combination been studied in a placebo-controlled clinical trial (where some people did not receive the experimental treatment?) If so, what increase in survival was reported among people with the same type of tumor?

Summary

Referring back to the opening NBTS statistics on treatments for glioblastoma: “none have succeeded in significantly extending patient lives beyond a few extra months.” Any claim beyond this should be carefully evaluated. Anyone considering conventional treatment should consider all treatment effects, because quality of life can be significantly altered by both chemicals and radiation.

Patients and their families must define for themselves what increase in survival would be meaningful, taking into account the potential impact of each additional treatment offered.

1. Source: https://braintumor.org/events/glioblastoma-awareness-day/about-glioblastoma/

2. Note: I still use the word ‘radiation’ to describe the common cancer treatment, but the term ‘radiotherapy’ is used in the scientific literature.

3. Source: https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(09)70025-7/abstract

4. Note: It is difficult to assume ignorance or incompetence, since this protocol was accepted by an Institutional Review Board and also Lancet peer-review. Both should have insisted that all potentially survival-impacting treatments be included—not just surgery. In my opinion, patients are being asked to consent to one or more interventions without being fully informed of minimal (or no) scientifically demonstrated benefit to survival.

5. Source: https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(09)70025-7/abstract

6. Source: https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.24950

7. Source: https://pubmed.ncbi.nlm.nih.gov/26670971/

8. https://aacrjournals.org/clincancerres/article/28/12/2527/699284/Temozolomide-and-Radiotherapy-versus-Radiotherapy