Pathological evaluation of neoadjuvant chemotherapy in advanced gastric cancer

Gastric cancer (GC) is one of the most common malignancies worldwide and ranks fifth and third with regard to the incidence and mortality, respectively, of malignant tumors [1]. A local recurrence rate as high as 50% and a long-term survival rate of less than 30% are observed among approximately 90% of patients with advanced GC, even after radical surgery [2]. Therefore, improving the efficacy of therapy for patients with advanced GC is an important aspect for overall treatment outcomes of this disease. At present, multidisciplinary treatment including neoadjuvant chemotherapy is the standard treatment for advanced GC, and many studies have shown that this approach can improve survival compared with surgery alone [3, 4]. Indeed, neoadjuvant chemotherapy can result in downstaging, reduced intraoperative dissemination, and enhanced R0 resection rates, which all improve the prognosis. Another important role of neoadjuvant chemotherapy is to evaluate the effect of the neoadjuvant chemotherapy regimen to guide the selection of the postoperative chemotherapy approach [2]. However, the current efficacy of common chemotherapy drugs is only 49–69.7% [5‐13]. Of those who undergo neoadjuvant chemotherapy, the identification of patients for whom therapy would be effective is difficult due to the lack of a uniform standard assessment, which greatly influences prognosis and the options for postoperative chemotherapy regimens. One study reported that due to their respective limitations, traditional methods of imaging assessment (e.g., computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, and endoscopy) are inaccurate for the evaluation of the efficacy of neoadjuvant treatment for GC [14], which impacts selection of the therapy regimen and indications for treatment outcomes.

At present, the common accepted standard for evaluation of therapeutic efficacy is pathological examination of tumor specimens from surgical resection following neoadjuvant chemotherapy to determine graded histological regression (GHR). As the most commonly used criteria, pathological efficacy evaluation (GHR ≥ 2/3 is effective) was proposed by Japan’s Gastric Cancer Research Association (JCGC) in 1999, and histopathological regression classification of primary tumor beds (GHR ≥ 90% is effective) was proposed by Becker et al. in 2003 [15, 16]. In Becker’s 2003 study, GHR ≥ 90% was observed in only 11.1% of patients (4/36), and in a later study with an increased sample size, the proportion of patients with GHR ≥ 90% was only 21.2% (102/480) [17]. The effective rate of GHR ≥ 2/3 reported by Kurokawa et al. was 34% [18]. Based on these standards, most patients with advanced GC who undergo neoadjuvant chemotherapy are faced with a replacement chemotherapy regimen after surgery, which is a burden to clinical practice. Whether the patients who have benefited from neoadjuvant chemotherapy can be identified only by these “rigorous” pathological criteria or if more reasonable criteria can be established for easier screening and implementation of clinical decisions remains unknown; therefore, this question warrants further research.

In this retrospective study, 87 patients with GC who met the inclusion criteria were regularly followed up to assess the association of each clinicopathological feature with overall survival (OS). This approach allowed for the determination of independent predictors of OS and the effective GHR standard for neoadjuvant chemotherapy in GC.

Many large-scale clinical trials and meta-analyses have indicated that patients with advanced GC who received perioperative chemotherapy including neoadjuvant chemotherapy had a higher rate of R0 resection and longer disease-free survival and OS than patients who underwent surgery alone [3, 4, 19, 20]. In this study, the median survival of 87 patients with advanced GC was 97.5 months, while the 5-year OS rate was 54%. Although a control group of patients who underwent surgery alone was not established in this study, the results of our study were similar to those of other analogous and comparative studies [13] and could report the value of perioperative chemotherapy to a certain degree. Ultimately, patients who directly benefit from neoadjuvant chemotherapy (chemotherapy effective) exhibit long-term survival, whereas those for whom neoadjuvant chemotherapy is ineffective have the opportunity to be treated with potentially effective drugs that will benefit their overall treatment plan and help them achieve an improved prognosis and prolonged OS [2]. Thus, methods and standards for determining the efficacy of neoadjuvant chemotherapy (namely, distinguishing between patients who respond differently to chemotherapy regimens) need to be developed to achieve the goal of an overall treatment program.

At present, two primary methods are used to judge the efficacy of neoadjuvant chemotherapy in GC: imaging and pathology. Imaging evaluations mainly refer to the solid tumor reaction standard, as achieved by spiral CT and other techniques, to determine efficacy. However, such an evaluation is associated with many issues, including high demand regarding the experience of the imaging physician and the poor correlation between results and prognosis [21, 22]. Several studies have shown that the accuracy of enhanced CT after neoadjuvant chemotherapy in T staging and N staging is only 57% and 37%, respectively, mainly because it is difficult to distinguish between tissue fibrosis after chemotherapy and the tumor itself using CT [23]. Our previous study also found that the consistency between imaging after neoadjuvant chemotherapy and postoperative pathological testing is not high, which demonstrates that the efficacy, as determined by imaging, compared with inefficacy failed to show a longer survival time (p = 0.438) [24].

Pathological response, mainly through GHR, is commonly used for assessment in China and elsewhere to reflect efficacy. Many studies have reported that pathological assessment provides a good indication of patient prognosis [15‐17, 24]. Currently, widely adopted GHR criteria include the JCGC pathological evaluation criteria and Becker’s histological tumor regression grade [15, 16]. However, the percentage of efficacy using the Becker criteria is low [17, 25] and was only 22.4% in our previous study [24], which is similar to the result in the present study (17.2%). Kurokawa et al. and Tsuburaya et al. used GHR criteria of the JCGC and reported efficacy rates of 34% [18] and 29% [13], respectively. In our previous study, the efficacy rate was 29.9% [24], which is similar to the findings of the current study (34.5%). For 20–30% efficacy under such criteria, researchers must consider whether the majority of patients with neoadjuvant chemotherapy need to change their postoperative chemotherapy regimen or whether the GHR evaluation criteria should be adjusted.

In this study, a univariate analysis of either all 87 patients or 85 patients after the exclusion of 2 who died of non-disease progression revealed that tumor location (p = 0.009, Fig. 4), Lauren classification (p = 0.002, Fig. 2), and ypTNM stage were highly significantly correlated with OS, which was consistent with what was reported in previous studies [24, 26, 27]. When patients were grouped according to different GHR rates, the median survival time of the effective group was significantly longer than that of the ineffective group (p = 0.028, 0.013, respectively) according to the Becker criteria and the JCGC criteria. Compared with a GHR < 50%, GHR ≥ 50% showed a significant survival benefit (no benefit vs 34.5 months, p = 0.022), which was consistent with what was shown in previous studies [15, 24, 25, 28]. In addition, Mansour et al. [29] found a significant difference in the 3-year survival between patients with a GHR ≥ 50% and a GHR < 50% (69% vs. 44%, p = 0.01). These results suggest that using a GHR ≥ 50% and more “stringent” standards, the overall median survival time and survival rate for the effective group are significantly better than those of the control group and that GHR is an indicator of survival and prognosis. It is worth noting that when a GHR ≥ 50%/< 50% is used as a pathological criterion, the efficacy rate was 50.6% (Fig. 5; in our previous study, this rate was 49.2%. The rates reported by Ferri et al. and two other studies were 49%, 45.6%, and 46.4% [17, 25, 28], which were higher than the 20–30% rate based on the Becker and JCGC criteria.

Our multivariate analysis results did not show a significant correlation between GHR and OS. In contrast, the Lauren classification and ypTNM stage were significantly associated with OS, which again verifies our previous findings [24]. Studies by Sylvie et al. and Viani et al. also showed that the Lauren classification is an independent prognostic factor that affects the survival of patients with advanced GC [26, 27]. To some degree, the Lauren classification is related to tumor biological behavior, which may explain its prognostic value [30]. Diffuse GC often occurs in younger individuals and often presents with early regional lymph node metastasis and distant metastasis [31‐33]. Both the univariate and multivariate analyses showed that ypTNM stage is an important independent prognostic factor, which again verified our previous results. Schmidt, Davies, Lowy, and others have also reached the same conclusion [22, 24, 34, 35]. In our multivariate analysis, grouping was performed using the GHR ≥ 50%/< 50% criterion or the more stringent Becker and JCGC criteria, which was followed by regression analysis to calculate the survival time. The results revealed no significant difference between the effective and ineffective groups (p values were 0.689, 0.998, 0.267; see Table 3). The studies by Fujitani and Schmidt et al. also support this finding [22, 36], which suggests that the degree of tumor necrosis after chemotherapy does not independently affect patient survival and that it only affects survival significantly when chemotherapy-induced tumor necrosis significantly induces downstaging. Thus, patients who have significant tumor necrosis confirmed by postoperative pathology and a lower ypTNM stage may directly benefit from neoadjuvant chemotherapy and achieve long-term survival.

Although GHR was not an independent prognostic factor for survival in our multivariate analysis, we recommend using a GHR ≥ 50%/< 50% as the primary pathologic criterion for patients with advanced GC after they receive neoadjuvant chemotherapy. This recommendation is in accordance with our univariate analysis and can be used to determine the appropriate postoperative adjuvant chemotherapy regimen. The reasons are described as follows: (1) According to our univariate survival analysis, the effective group showed a significantly longer survival time than the control group using the GHR ≥ 50% criterion or the more “stringent” Becker and JCGC criteria; however, the stricter criteria failed to exhibit independent effects on survival time in the multivariate analysis. In contrast, the criteria for GHR below 50% failed to show a significant effect on survival in the univariate analysis. (2) Many studies have shown that the overall clinical efficacy of common chemotherapy drugs is approximately 50%; moreover, the proportion of efficacy determined by the GHR ≥ 50%/< 50% criterion was approximately 50%. Both values are close to each other and are therefore more easily accepted and promoted clinically. (3) The nearly 70–80% of “ineffective” patients who require a change in their postoperative chemotherapy regimen will become strong clinical burdens if neoadjuvant chemotherapy is evaluated according to the currently used Becker and JCGC criteria. Therefore, we propose distinguishing GC patients after neoadjuvant chemotherapy by the GHR ≥ 50%/< 50% criterion, which is practical and feasible. For those with a GHR rate of less than 50%, continuation of the preoperative chemotherapy regimen as a postoperative adjuvant chemotherapy regimen is not recommended.

In summary, the Lauren classification and ypTNM stage after neoadjuvant chemotherapy are independent prognostic factors for advanced gastric cancer. GHR ≥ 50%/< 50% can be used as the primary criterion to evaluate the curative effects of neoadjuvant chemotherapy in advanced GC and to guide the selection of postoperative adjuvant chemotherapy regimens.

As this report describes a single-center, small-scale study without control groups, the sample size should be expanded in a future study to confirm these findings.