Mathematical optimisation of the cisplatin plus etoposide combination for managing extensive-stage small-cell lung cancer patients

Abstract

Background:Small-cell lung cancer (SCLC) represents one of the most aggressive forms of lung cancer. Despite the fair sensitivity of SCLC to chemotherapy and radiotherapy, the current standard treatment regimens have modest survival rates and are associated with potential life-threatening adverse events. Therefore, research into new optimised regimens that increase drug efficacy while respecting toxicity constraints is of primary importance.Methods:A PK/PD model for the combination of cisplatin and etoposide to treat extensive-stage SCLC patients was generated. The model takes into consideration both the efficacy of the drugs and their haematological toxicity. Using optimisation techniques, the model can be used to propose new regimens.Results:Three new regimens with varying timing for combining cisplatin and etoposide have been generated that respect haematological toxicity constraints and achieve better or similar tumour regression. The proposed regimens are: (1) Protocol OP1: etoposide 80 mg m−2 over 1 h D1, followed by a long infusion 12 h later (over 3 days) of 160 mg m−2 plus cisplatin 80 mg m−2 over 1 h D1, D1–D1 21 days; (2) Protocol OP2: etoposide 80 mg m−2 over 1 h D1, followed by a long infusion 12 h later (over 4 days) of 300 mg m−2 plus cisplatin 100 mg m−2 over 1 h D1, D1–D1 21 days; and (3) Protocol OP3: etoposide 40 mg m−2 over 1 h, followed by a long infusion 6 h later (3 days) of 105 mg m−2 plus cisplatin 50 mg m−2 over 1 h, D1–D1 14 days.Conclusions:Mathematical modelling can help optimise the design of new cisplatin plus etoposide regimens for managing extensive-stage SCLC patients.

The prognostic value of the serum neuron specific enolase and lactate dehydrogenase in small cell lung cancer patients receiving first-line platinum-based chemotherapy

“…[ 3 , 5 ] About two-third SCLC patients present with metastasis in regional lymph nodes or distant organs at the time of diagnosis, which dramatically declines remission rate of this extremely aggressive malignancy. [ 6 , 7 ] Despite SCLC is highly sensitive to chemotherapy and radiotherapy, with initial response rates from 60% to 80%, [ 8 ] relapses still exist in patients. [ 3 , 5 ] Median survival (MS) for SCLC patients with limited disease (LD) is currently 14 to 20 months, with 20% to 40% surviving to 2 years, and for those with extensive disease (ED), the values are 7 to 13 months and 5%, respectively.…”

“…Combination chemotherapy, generally 4 to 6 cycles of platinum-based and etoposide or irinotecan, is the cornerstone treatment in both LD and ED SCLC patients, especially for patients with metastatic disease. [ 3 , 8 ] A phase III randomized trial revealed that patients receiving platinum-based chemotherapy had better clinical response and longer survival duration than patients treated with anthracycline-based chemotherapy. [ 10 ] Regardless of these improvements in SLCL treatments, 19% to 43% patients still do not response well to platinum-based chemotherapy, [ 10 , 11 ] thus identification of convincing biomarkers for prognosis is deadly needed.…”

Dose- and time-dependence of the host-mediated response to paclitaxel therapy: a mathematical modeling approach

“…Methods employed for modeling the efficacy of cytotoxic drugs have linked the effect to the drug concentration by means of well-established differential equations for description of tumor growth [ 18 ]. Apart from the classical log-kill Skipper-Schabel-Wilcox [ 41 ] and Norton-Simon [ 42 ] models, more recent works include: transit compartments modeling damaged cancer cells [ 43 , 44 ], an interface effect compartment [ 45 ] or models specific to metronomic chemotherapy based on the assumption of an anti-angiogenic action of the cytotoxic drug [ 20 , 21 , 46 ]. Counterintuitively however, when concurrently modeling the time-course of the effect and the dose dependence for the invasion assays, a model based on this approach was unable to adequately reproduce the data.…”

Circular RNA in Lung Cancer Research: Biogenesis, Functions, and Roles

“…In 2018, 2.1 million new LC cases and 1.8 million deaths were reported worldwide, making LC the leading form of cancer in terms of both morbidity and mortality [1,2]. Lung cancer has been pathologically classified into two main subsets: small cell lung cancer (SCLC), comprising 15% of the total cases [3], and the rest 85% non-small cell lung cancer (NSCLC) [4]. The NSCLC is classified into three subtypes; large cell lung carcinoma (LCLC; 10%), lung squamous cell carcinoma (LUSC; 25%), and lung adenocarcinoma (LUAD; 40%).…”