Date Published: May 9, 2019
Publisher: Public Library of Science
Author(s): Patricia Martin-Romano, Belén P. Solans, David Cano, Jose Carlos Subtil, Ana Chopitea, Leire Arbea, Maria Dolores Lozano, Eduardo Castanon, Iosune Baraibar, Diego Salas, Jose Luis Hernandez-Lizoain, Iñaki F. Trocóniz, Javier Rodriguez, Aamir Ahmad.
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.
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.
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.
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.
Upper gastrointestinal tumors, including gastric cancer (GC) and gastroesophageal cancer junction (GEJC) remain a therapeutic challenge. Most patients are diagnosed with a locally advanced stage, defined as tumor growing through the gastric wall and/or regional lymph node involvement. To date, surgery with an extended lymphadenectomy and microscopically negative margins (R0) is the only potentially curative treatment [1, 2]. However, long-term survival of patients with a surgical exclusive approach remains low . Multimodal strategies (MMS), including adjuvant chemotherapy (ChT) or chemoradiotherapy (CRT), perioperative chemotherapy and neoadjuvant chemo-radiation have been correlated with improved survival times when compared to surgery alone [4–9].
In recent years, several neoadjuvant strategies in patients with locally advanced gastric and gastroesophageal adenocarcinoma have gained acceptance, due to promising data in terms of R0 resection rates, histopathological responses, therapy compliance and early treatment of micrometastatic disease [4–9]. Nevertheless, up to 15–20% of the patients develop interval progression during the preoperative therapy, thus precluding a potentially curative surgery [4, 7]. In addition, the toxicity profile is an important issue especially with the use of preoperative CRT, with up to 30% of patients requiring hospital admission due to grade 3–4 toxicity . Even in patients undergoing a complete neoadjuvant program, relapse rate is as high as 50% [4–8]. Finally, the subset of patients more likely to benefit from a more intensive approach, in terms of increasing the number of chemotherapy cycles or incorporating the use of preoperative radiation remains undetermined. Pathologic response and tumor downstaging are usually considered as surrogate markers of individual efficacy of neoadjuvant therapies. Several studies have suggested that pathologic stage (ypTNM) and especially nodal status (ypN0) strongly dictate prognosis, rather than clinical stage at diagnosis (cTNM) [16–18]. However, ypTNM stage is only available once the patient has undergone surgery and therefore cannot be employed as a baseline predictive marker. In addition, although several molecular biomarkers and CTCs dynamic changes have been associated with therapeutic response in this disease, none of them has so far been prospectively validated [18–22]. Early identification of the degree of response in an individual patient would lead to either an intensification of the neoadjuvant strategy in responding patients or to consider an early surgical approach in the absence of clinical benefit.
In conclusion, we aimed to develop a mechanistic PK/PD model able to predict response to a neoadjuvant approach including chemo and radiotherapy. The current model does not allow predicting the pattern of response in this subset of patients. The low correlation between clinical and pathologic stages, the inaccuracy of imaging techniques to properly evaluate response to neoadjuvant therapies and the lack of reliable serum tumor markers in this disease make this model unlikely to be a useful tool for precision medicine.