Economists, physicists and engineers use mathematical models extensively in their respective industries.
Now, French researchers are using mathematical modeling as a tool to optimize cancer treatments for mesothelioma patients.
In a small phase I clinical trial, researchers at Aix-Marseille University in Marseille, France, determined the approach was a better way to assess the safety and efficacy of dosage levels for chemotherapy drug vinorelbine (Navelbine).
The model is based on two principles:
The study included patients with progressing mesothelioma and non-small cell lung cancer (NSCLC) following standard treatments.
Researchers found the most responsive vinorelbine regimen was three oral doses — 60 mg, 30 mg and 60 mg — weekly until progression. The median length of treatment was 6.5 weeks.
Lead researcher Fabrice Barlesi believes mathematical modeling “may help to rationally decide the better regimen to be clinically tested across infinite possibilities.”
“This is the first step, with some encouraging results and a next cohort which is already ongoing,” Barlesi told Asbestos.com. “It may be a new option for the future.”
Perfecting the Treatment Plan Process
Treatment options are often limited with rare and aggressive cancers such as mesothelioma. The standard of care for the disease is a multimodal approach consisting of surgery, chemotherapy and possibly radiation therapy.
Chemotherapy has been a standard treatment option for most cancers for decades, but its importance for mesothelioma patients continues to be recognized.
A 2016 study showed the median survival of patients who received chemotherapy was three times longer compared to patients who did not. Patients who underwent a combination of surgery and chemotherapy lived even longer.
Deciding which chemotherapy drugs to use, along with the optimal dosage and scheduling regimen, remains a challenge. Metronomic chemotherapy usually refers to the continuous use of low-dose oral chemotherapy drugs.
Barlesi notes that “outdated and underpowered strategies” in metronomics lead to conflicting results of how to administer the drugs.
“Several regimens have been tested, mostly designed on a trial-and-error mode,” Barlesi wrote in the study. “Of note, the vinorelbine regimens substantially vary across previous studies with, doses ranging from 30 to up to 70 mg, administration ranging from continuous to weekly schedules, and a wide range for durations of treatment.”
By using a computational metronomic model, Barlesi and his team determined a more effective and tolerable vinorelbine regimen. The schedule consists of:
This regimen showed a reduced toxicity and fewer side effects compared to previously reported schedules. The most common adverse effect was anemia, which occurred in 10 of 12 patients.
“So far to our knowledge, this study provides the first example of the assessment of a computational metronomic schedule, presently for oral vinorelbine,” Barlesi wrote. “This study demonstrates the feasibility of this approach since both preliminary encouraging signs of activity and no unexpected toxicities were observed, in this heavily pre-treated patients’ population.”
Study Size and Rarity of Mesothelioma Present Challenges
As a phase I clinical trial, it is a novel approach at this point but a promising step for future chemotherapy treatment plan protocols.
The limited number of patients in the study — nine NSCLC and three mesothelioma — is also problematic, but the planned second phase of the study will include the new model’s effect on the immune system as well as additional data from other vinorelbine clinical trials.
Barlesi said any possible differences in chemotherapy schedules between mesothelioma and NSCLC patients is “too difficult to say” at this point given the low number of mesothelioma patients in the phase I study.
“At this time, we are focusing on tolerance, [pharmacokinetic] data and inter or intrapatients variability,” Barlesi said. “We’ll study preliminary efficacy and then decide if we should go to specific cohorts especially in mesothelioma patients.”