Dataset Information

Neoadjuvant therapy for locally advanced gastric cancer patients. A population pharmacodynamic modeling.

ABSTRACT:

Background

Perioperative chemotherapy (CT) or neoadjuvant chemoradiotherapy (CRT) in patients with locally advanced gastric (GC) or gastroesophageal junction cancer (GEJC) has been shown to improve survival compared to an exclusive surgical approach. However, most patients retain a poor prognosis due to important relapse rates. Population pharmacokinetic-pharmacodynamic (PK/PD) modeling may allow identifying at risk-patients. We aimed to develop a mechanistic PK/PD model to characterize the relationship between the type of neoadjuvant therapy, histopathologic response and survival times in locally advanced GC and GEJC patients.

Methods

Patients with locally advanced GC and GEJC treated with neoadjuvant CT with or without preoperative CRT were analyzed. Clinical response was assessed by CT-scan and EUS. Pathologic response was defined as a reduction on pTNM stage compared to baseline cTNM. Metastasis development risk and overall survival (OS) were described using the population approach with NONMEM 7.3. Model evaluation was performed through predictive checks.

Results

A low correlation was observed between clinical and pathologic TNM stage for both T (R = 0.32) and N (R = 0.19) categories. A low correlation between clinical and pathologic response was noticed (R = -0.29). The OS model adequately described the observed survival rates. Disease recurrence, cTNM stage ?3 and linitis plastica absence, were correlated to a higher risk of death.

Conclusion

Our model adequately described clinical response profiles, though pathologic response could not be predicted. Although the risk of disease recurrence and survival were linked, the identification of alternative approaches aimed to tailor therapeutic strategies to the individual patient risk warrants further research.

SUBMITTER: Martin-Romano P

PROVIDER: S-EPMC6508715 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

Neoadjuvant therapy for locally advanced gastric cancer patients. A population pharmacodynamic modeling.

Martin-Romano Patricia P Solans Belén P BP Cano David D Subtil Jose Carlos JC Chopitea Ana A Arbea Leire L Lozano Maria Dolores MD Castanon Eduardo E Baraibar Iosune I Salas Diego D Hernandez-Lizoain Jose Luis JL Trocóniz Iñaki F IF Rodriguez Javier J

PloS one 20190509 5

<h4>Background</h4>Perioperative chemotherapy (CT) or neoadjuvant chemoradiotherapy (CRT) in patients with locally advanced gastric (GC) or gastroesophageal junction cancer (GEJC) has been shown to improve survival compared to an exclusive surgical approach. However, most patients retain a poor prognosis due to important relapse rates. Population pharmacokinetic-pharmacodynamic (PK/PD) modeling may allow identifying at risk-patients. We aimed to develop a mechanistic PK/PD model to characterize ...[more]

PMID: 31071108

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Project description:Background:There is recent interest in treating locally advanced rectal cancer (LARC) patients with total neoadjuvant therapy (TNT). However, whether TNT is associated with improved overall survival (OS) remains unknown. This study compares outcomes following TNT and following neoadjuvant chemoradiation therapy (nCRT) in patients with LARC, clinically defined cT3/4 or node positive disease, using the National Cancer Database. Methods:LARC patients diagnosed between 2004-2015 were included. TNT was defined as multi-agent chemotherapy given at least 2 months before RT followed by pre-operative chemoradiation therapy and definitive surgery without adjuvant chemotherapy. nCRT was defined as pre-operative RT and chemotherapy started within 2 weeks from each other followed by definitive surgery with or without adjuvant chemotherapy. Kaplan-Meier curve with logrank test and multivariable Cox proportional hazards regression modelling were used to analyse the primary endpoint of overall survival (OS). Multivariable logistic regression modelling was used for secondary outcomes to determine if TNT is associated with pathological complete response (pCR), defined as ypT0N0, and negative circumferential resection margin (CRM). Findings:Data from 372 TNT patients and 707 nCRT patients were analysed after a 2:1 propensity matching with replacement. Kaplan-Meier curve showed that OS with TNT was comparable to that with nCRT (p = 0•16). The 5-year OS rates for TNT and nCRT were 73•6% vs. 78•5% (p = 0•20). Multivariable Cox proportional hazards regression modelling confirmed no difference in OS between TNT and nCRT (HR = 1•21, p = 0•25). With TNT, 16•9% patients achieved pCR, whereas 13•1% patients achieved pCR with nCRT (p = 0•12). TNT was not found to be significantly associated with pCR (OR = 1•36, p = 0•13) or negative CRM (OR = 1•77, p = 0•19) in multivariable logistic regression modelling. Interpretation:With results from current clinical trials pending, our data suggested that TNT and nCRT resulted in similar survival, while TNT led to higher pCR and CRM negative rate, albeit not statistically significant.

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Dataset Information

Neoadjuvant therapy for locally advanced gastric cancer patients. A population pharmacodynamic modeling.

Background

Methods

Results

Conclusion

Publications

Neoadjuvant therapy for locally advanced gastric cancer patients. A population pharmacodynamic modeling.

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