Introduction

Gastric cancer (GC) is the fifth most common malignant tumor and the fourth leading cause of cancer death worldwide. In Colombia. 8214 new cases of GC and 6491 deaths from this disease were recorded in 2020. becoming the neoplasm with the highest mortality rate. accounting for 11.7% of all cancer deaths in the country¹. Most patients with GC have symptoms of an advanced stage at the time of presentation. and 34% have distant metastases at the initial presentation². Systemic therapy and palliative care are the mainstays of treatment for patients with locally advanced GC who are not candidates for surgery or have distant metastases (also known as incurable GC³). These patients typically have a median overall survival (OS) of no more than 16 months⁴. However. in recent years conversion therapy (CT). defined as a surgical treatment aimed at achieving R0 resection after a favorable response to induction chemotherapy. has been gaining acceptance as a novel strategy for improving the oncologic outcomes of patients for tumors that were originally considered unresectable for technical and/or oncological reasons4. In this context. the concept of adjuvant surgery arises. defined as resective surgery performed after systemic chemotherapy and that is expected to be curative⁵.

The biology of gastric carcinomas varies depending on the site of metastasis and the specific presentation and behavior of the metastatic disease. Nowadays. there is no agreement on the criteria for selecting patients eligible for CT. nor on the ideal chemotherapy regimen or the optimal time interval between chemotherapy and surgery⁶.

Although CT looks promising. it has not been proven in controlled clinical trials probably due to its complicated nature. still under development. and the fact that the number of candidate patients is too small to carry out a randomized control trial⁷. The information about the efficacy of CT for the management of patients with advanced GC comes from retrospective singlecenter studies involving patients with a variety of noncurative factors. and from multicenter prospective or retrospective cohort studies focused on patients with one non-curative factor⁴.

The aim of the present study was to estimate the results of CT in a series of patients with advanced and incurable gastric cancer treated at the Department of Gastrointestinal Surgery of Instituto Nacional de Cancerología de Colombia (INC). over a 12-year period.

As far as we know. this would be the first cohort of CT in GC reported in Colombia.

Material and methods

Patients who underwent induction chemotherapy and subsequent intended curative surgery between January 1. 2010. and December 31. 2021. were included in the study. The study included patients who met the following eligibility criteria: 1) histologically confirmed primary gastric adenocarcinoma. and 2) stage T4b tumor. i.e.. a tumor considered incurable due to invasion of adjacent structures or organs. extra-regional lymph node involvement. or distant metastasis documented by staging investigations.

We included only patients with unresectable tumors that were locally advanced or had lymph node involvement or hematogenous metastasis and excluded those with peritoneal dissemination because they express a different tumor biology and are managed by a specific team in our institution.

Contrast-enhanced computed tomography scan of the chest and abdomen and laparoscopy were the only methods used for patient staging. Patients with Siewert type I and II gastroesophageal junction cancer were excluded. because neoadjuvant therapy is the standard of care in this setting. Additionally. patients in whom an R0 resection was not achieved were excluded from the survival analyses. as they did not receive curative surgeries. constituting a failure of CT.

We reviewed the electronic medical records of our institution from the platform SAP® and retrieved the patients’ demographic and clinical characteristics. The Eastern Cooperative Oncology Group (ECOG)⁸ score was used to assess patients’ performance status. The following variables were included: induction chemotherapy. type of surgery. lymph node clearance. pathology findings obtained from the surgical specimen. complications and postoperative mortality at 30 and 90 days using the Clavien-Dindo⁹ classification. adjuvant chemotherapy. OS rate at 3 and 5 years. and tumor recurrence.

Normality of distribution of variables was assessed using the Shapiro-Wilk test. Quantitative variables with normal distribution were expressed as mean ± standard deviation and those with non-normal distribution as median and interquartile range. and 95% confidence intervals were determined. Categorical variables were expressed as absolute and relative frequencies.

Overall survival was calculated from the time of initiation of chemotherapy until the date of death from any cause. Patients lost to follow-up or those who did not experience the event before the study ended were right censored. Survival functions were estimated using the life table and Kaplan-Meier methods. and survival curves at 3 and 5 years were constructed. All the statistical calculations were performed using Stata 16 software package. The study protocol was approved by the institutional review board o the INC.

Results

Twenty-three patients with incurable advanced GC due to invasion of adjacent organs. extra-regional lymph node involvement or hematogenous metastases were managed with CT during the study period. The response to CT was evaluated in all the patients using contrast-enhanced computed tomography before surgery. As 2 cases were excluded from the survival analyses because they did not achieve R0 resections. the final cohort was made of 21 patients. Mean age at the moment of diagnosis was 56 years (range 42-72). 74% were men and 20 patients (96%) had an ECOG score⁸ of 0 or 1. One-third of cases had a distal tumor. Loss of MMR proteins on immunohistochemical testing. as a surrogate marker for microsatellite instability. was found in 13% of tumors.

The most common criterion indicating unresectability was a T4b tumor. which was present in 56.5% of cases. Imaging tests confirmed unresectability in 39.1% of patients. while laparoscopy/laparotomy confirmed it in the remaining 60.9%. In 10 (43.5%) patients. surgical staging was performed at the INC.

Median time between the end of induction chemotherapy and surgery was 48 days. Total gastrectomy was performed in 52.2% of the patients. and 87% underwent D2 lymphadenectomy. with a mean of 34.3 resected nodes.

The pathology examination revealed that only 2 (8.7%) patients achieved a pathologic complete response (pCR) after induction chemotherapy. One of these patients also received preoperative radiotherapy (50 Gy). The two patients with R1 resections (8.7%) were: 1) a 42-year-old man with total gastrectomy and en bloc central pancreatectomy with positive esophageal margin. who died on postoperative day 23. and 2) a 70-year-old man with total gastrectomy plus cholecystectomy with positive gallbladder margin. who was still alive at the time the study ended (23 months). Other surgical and pathological aspects are detailed in Table 1.

Platinum- and fluoropyrimidine-based chemotherapy were the most used induction regimens (Table 2).

Regarding postoperative outcomes. 10 (43.5%) patients experienced complications within 90 days after surgery: two patients died and 4 patients presented complications grade IIIb or greater according to the Clavien-Dindo classification⁹.

In our series. 18 patients (78.2%) received postoperative chemotherapy. During follow-up. tumor recurrence was documented in 11 cases. with 6 of them occurring within 6 months of surgical resection.

Recurrences were identified in the liver. bones. peritoneum. lymph nodes and soft tissues.

After a median follow-up of 28 months (range 9-115 months). 52.2% (12) of the patients were alive. 10 had died (43.5%) and one was lost to follow-up (4.3%). Median survival in this series was 41.2 months. and 3- and 5-year OS was 57.7% and 38.5%. respectively (Fig. 1).

FIGURE 1 Survival curves 

Discussion

This paper shows the results of CT for the treatment of unresectable GC in a series of patients in a Latin American cancer center. Considering that these patients would typically receive palliative chemotherapy or best supportive care. this therapeutic approach allows for curative treatment and improves the prognosis of a very select group of cases. Median survival in this series was 41.2 months. higher than that reported by the two Latin American series available in the literature published by Ramos et al.10 with 11.3 months and by Gallardo-Rincón et al.¹¹ with 13 months. Overall survival at 3 and 5 years is lower when we compare it with the majority of Asian series. as the one by Sato et al.¹² (75.4% at 3 years). but higher than that reported in the Italian series by Morgagni et al.¹³ (39.4%). However. it is difficult to compare the results. as not all the studies provide the same data (Table 3)^10-40.

In their paper. Yoshida et al. propose a widely accepted comprehensive classification for CT that focuses on the biology and heterogeneous characteristics of stage IV GC. This classification has helped to establish a common language in this regard⁵. In these categories the major division is between patients with and without macroscopically detectable peritoneal dissemination. This study focused on patients with locally advanced tumors. with resectable metastases or extra-regional lymph nodes. which can be included in categories 1 and 2. With respect to lymph node involvement. Yoshida establishes a clear difference between involvement of para-aortic lymph node station N° 16a2 (between the celiac artery and the left renal vein) and 16b1 (between the left renal vein and the inferior mesenteric artery). which correspond to category 1. and involvement of other para-aortic lymph nodes. including stations N° 16a1 (aortic hiatus). 16b2 (between the inferior mesenteric artery and the aortic bifurcation) (Fig. 2) and extra-abdominal lymph nodes. which correspond to category 2. However. the CONVO GC-1³⁹ study found that survival of patients with para-aortic lymph node metastases in stations N° 16a1/b2 was not inferior to those with metastases in stations N°16a2/b1. This probably supports the growing evidence that tumor biology is similar among cases with hematogenous and lymph node metastases. even with extra-regional involvement. but different from those with peritoneal dissemination.

FIGURE 2 Lymph node station N° 16 (paraaoric) and its sub-divisions. TC: celiac artery. AMS: superior mesenteric artery. LRV: left renal vein. AMI: inferior mesenteric artery 

Recurrence of GC is considered early if it occurs within two years after curative resection. Numerous studies have investigated predictive factors of recurrence⁴². It is unclear if this concept is applicable in the CT setting. where a significant percentage of patients experience early recurrence despite R0 resections. Standardization of extended D2+ lymphadenectomy. included in the Japanese Gastric Cancer Treatment Guidelines. 6^th edition. after neoadjuvant chemotherapy with extensive lymph node involvement documented on imaging tests prior to systemic therapy. may provide evidence in this regard.

This study has important limitations due to its retrospective nature. the use of multiple treatment schemes in CT. and the fact that it deals with patients from a single center. Further multicenter studies are needed to better characterize this group of patients and their particular aspects in the region.

The ongoing RENAISSANCE and SURGIGAST studies are expected to provide valuable information for optimizing patient selection for CT. standardizing treatment regimens. and better defining the role of surgery in this context.

It is difficult to uniformly categorize and treat all patients with stage IV GC or locally advanced tumors. Since not all cases are eligible for CT. it is necessary to optimize patient selection to maximize efficacy. It is important to consider the risks of this strategy. such as the potential for a decline in postoperative quality of life. limited survival. and early tumor recurrence. We consider that these patients should always be treated by multidisciplinary teams and in reference oncology centers.

In conclusion. CT was an option for rescuing adequately selected patients with advanced GC and returning them to curative treatment. thereby improving the OS rate of this highly lethal condition.