New and emerging information, technologies, and analytic capacity mean that the time is now right to re-examine the decisions made in prior decades which have had a profound impact on how common diseases are treated today. Most of these decisions were made based on the results of randomized clinical trials (RCT’s). 30 years ago, the RCT was the “gold standard” but by today’s standard the RCT seems quite archaic, was enormously time and work intensive, measured only a limited number of criteria and the results were indiscriminately applied to the general population, many of whom would never have been eligible to participate in the trial.
As a start, we present an analysis of RTOG 88-08, a RCT that changed the management of Locally Advanced Non-Small Cell Lung Cancer for millions of patients.
Review of RTOG 88-08 Randomized Clinical Trial
The following represents a critical review of Clinical trial 8808. The backdrop of this critique is not to criticize the methodologies, findings or reputations of the excellent science and scientists who conducted the trial. Rather it is a critique of the continuation of the findings from the early 1990s into the late 2010s still driving clinical practice.
At the time the methodologies, understandings and findings were appropriate for the day. By the standards of the last quarter of the 20th Century the work met all “gold standard” criteria and was multi-institutional and international. Indeed the work was superb, fast and comprehensive.
Summary of findings
1. The median survival rate in the Combined Chemo/RT was 13.2 months compared to 11.4 months in the Radiation alone (an improvement of 1.8 months).
2. The 2-year survival rate increase from 19% to 27% with the addition of chemotherapy. (approximately a 50% increase). This increase was reported as statistically significant and prompted clinical practice to change globally.
3. The clinical treatment changed based on these two findings, such that the standard of care remains to treat with chemotherapy plus radiation for regionally advanced non-small cell lung cancer.
1. The median survival rate is marginal at best.
2. The 2-year survival rate, stated another way, indicates that 2 years following treatment:
a. 73% of all patients are dead
b. 73% received no benefit
3. Using the standards of 2016, the parameters of the clinical study are remarkably limited being:
d. Performance Status
e. Hematologic and Biochemical Lab work being within normal range
f. Pulmonary function
4. There are many more criteria by which studies such as this need to be evaluated. The lack of inclusion of genomic, proteomic and other data means that most patients received wholly unnecessary and ineffective treatment. As such the SOC needs to be seriously interrogated and replaced with new clinically efficacious approaches.
Recommendations and Alternative Clinical Treatments
1. Much has changed since 1992. The continued use of toxic therapies which fail to benefit the majority of patients cannot withstand the new lens of longitudinal efficacy, new understandings and new technologies that can both invalidate and propose new clinical research and approaches, increasing clinical efficacy (5-year survival and full remission).
2. The use of chemotherapy and radiation therapy may indeed be efficacious with further study, but new therapies, including neoadjuvant therapy alone may be more appropriate for large numbers of patients, saving them unnecessary, non-beneficial and potentially harmful interventions.
3. In fact, the statement in the conclusion that the findings being statistically small is mediated and offset by the high frequency of the disease. This thinking justifies research, but does not justify clinical practice.
4. The dataset of the time is now woefully and demonstrably deficient. It can no longer drive clinical conclusions and it is time to use today’s standards to drive what will undoubtedly be several SOC appropriate for given sub-populations. Fortunately this can be done quickly using new techniques, cutting down trial time and increasing trial bandwidth. This means many more treatment regimens faster for appropriate sub-population use.
5. Appropriate interrogation of all relevant patient data under such clinical treatment to determine:
a. Who they are.
b. What existing and new targets can be identified.
c. What new treatments can be designed (even predicted using sophisticated AI compound-target matching techniques)
6. The continuation of clinical treatment as-is is not the best use of money, expertise and clinical efficacy. On all of these counts, the prudent approach is to find and fund new approaches, quickly, that have better clinical efficacy that can save / not harm people today.
It is important to address the financial impact of the existing protocols versus a targeted protocol that combines the good science and authentic clinical efficacy of the preceding. This is best done with some elementary to take his two main criticisms and address the
1. Costs of current patient treatment is highly conservative at $25,000 for a gold standard treatment of both. This also does not include failed lines of therapy prior to and after CT+RT.. If a more realistic cost is considered and the costs of failed lines of therapy are also considered the actual costs are likely $75000-100,000.
2. Costs of current patient treatment do not include ethical considerations of treating a high proportion of patients without benefit or the re-allocation of costs elsewhere where benefits can be achieved.
The second issue is the analysis. It is possible for a reasonably large team of 25-30 individuals with world-class expertise in genomic treatment, longitudinal data, pharmacogenomics and pharmacokinetics to determine highly effective targeted therapies on a per patient basis. It is not possible, nor is it economically feasible to scale that either in terms of team or in terms of patient access. It is only possible to develop targeted therapies for a wide number of patients and align that to such expertise using computational means, in particular certain AI technologies. These technologies will be imminently widely available, exceptionally advanced and rapidly getting better. They will consistently perform at a 5σ level, far above teams of humans who cannot juggle the parameters. While criticism of this will only come from those who do not understand the nature of 21st century computing, the truth is existing clinical behaviors, existing financial incentives and indiscriminate health policy can be ameliorated, if not eliminated entirely when such computational tools are permitted to drive both precision medicine and, in the case of the patient, personal medicine.