What is it about?
The medical manuscript describes a novel and safest treatment for advanced stage IV pancreatic, colon, and bile duct cancers. Four clinical objectives are achieved. A total of 205 patients with these notoriously difficult and resistant cancers were treated with this new chemotherapy, and the findings are summarized below. The first objective was to prolong overall survival. The treatment achieved this milestone at greater than 12 and 24 months. Each disease series confirmed the survival for the second and third time. The second objective was to analyze the prognostic blood test (PBTs) as a method to evaluate the treatment. The results showed that the majority of patients added 9 to 24 months to their survival compared to historical groups with the same disease, advanced stage, and PBT profile. These PBTs are routine blood tests that are immediately available. The third objective was to safely expand eligibility criteria to include patients aged 70s and 80s, heavily treated resistant tumors, prior severe side effects due to standard treatments, and frailty. These are factors that often disqualify patients from standard chemotherapy treatment. The new chemotherapy produced the same safety, reversal of resistance, and prolonged survival for both high-risk and ideal patients when PBTs had the same favorable profiles. The fourth objective was to evaluate the survival of the worst quartile of patients using objective PBTs. These patients now have a 40-60% milestone, greater than 12 through 16-month median survival, and 20% rates of 24-month survivors. All 205 patients had a predictable poor prognosis with standard treatment, but based on PBTs, both ideal and high-risk patients have a best new overall survival. The treatment integrates and expands on these four modifications of standard combination chemotherapy. The drugs used are gemcitabine, fluorouracil, irinotecan, and a platinum, with, as needed, an added Taxane ± Mitomycin C and added inhibitors or angiogenic or epidermal growth factors. The blood tests used are the A.L.A.N. model, serum albumin, and platelet counts. Abnormal tests that lose some of much of their prognostic impact due to the chemotherapy include absolute neutrophil and lymphocyte counts, and the neutrophil-lymphocyte ratio. The dosages, however, may not be applicable to other combinations, drugs, or to treat with curative intent. Therefore, caution is advised. Each disease and specific combination was chosen for clinical development based on ex vivo human resistant laboratory tests, dose-response drug interactions, and reversal of resistance that were reproducible in dozens of tumors, and as reported, are applied without individual tests.
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Why is it important?
PBTs reflect mechanisms of lethality. The findings support the evaluation of this chemotherapy to complement immunotherapy, anti-inflammatory, and anti-growth factor “target drugs”. With PBTs, the benefits of chemotherapy are now testable and applicable to individual pathophysiology and mechanisms of lethality, offering direction for personalized treatment. The findings encourage testing of the axiomatic unchallenged standard chemotherapy treatment and development practices for difficult-to-treat diseases and poorly tolerated drugs. The manuscript suggests four modifications of standard combination therapy: lowest dosages tested to date, 1/4 – 1/2 of the standard vs. maximum tolerated dosages may safely expand development with added drugs; four through six simultaneous drugs vs. one to two drugs utilized; recombination of failed drugs vs. abandonment of failed drugs; re-challenge use of the same drugs a second and third time, with or without new partner drugs, which are largely ineffective when used alone. Each modification has independent laboratory and clinical supporting evidence.
Perspectives
These findings take my career motive and primary investigational model to the next level because their implications apply to a broad spectrum of difficult diseases and drugs. The motive is to support the development of further improvements in safety, eligibility, indications, and efficacy for many approved drugs. We aim to treat all patients “with the perspective that their safety and value both clinically and financially can be improved.” The career theme is to apply models in order to investigate specific limitations, including the use of important drugs. The models examine the boundaries of clinical progress and failed trials, with the emphasis on integration and interactions of additional options. They evolved from successes with single drugs, platins, and fluorouracil. The findings described in PLOS ONE identify four modifications of general standard practices for approved drugs. New feasible objectives may reduce rates of consequential adverse events to less than 5% and provide additional lines of therapy for more than half of identifiable patients with some of the top five causes of death due to cancer.
Dr. Howard Bruckner
Read the Original
This page is a summary of: Actionable tests and treatments for patients with gastrointestinal cancers and historically short median survival times, PLoS ONE, November 2022, PLOS,
DOI: 10.1371/journal.pone.0276492.
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