Gastric cancer is the third leading cause of cancer death and the fifth most common cancer in the world [1]. Worldwide, approximately 1 million new cases of gastric cancer are diagnosed annually [2].
The overall 5-year survival for resectable gastric cancer is approximately 20% to 30% worldwide.
However, a 70% survival rate has been achieved in Japan and other Eastern countries, where the high incidence of the disease is managed with screening programs to find tumors at an earlier stage, and patients receive surgery. radical in centers with high volume of cases [3].
Over the past 2 decades, there have been significant changes in the management of patients with gastric cancers. Neoadjuvant treatment is increasingly used, and in some countries it is currently the gold standard for those with locally advanced disease [3,4].
Standardized surgical dissection and adherence to oncological principles, even when minimally invasive techniques are used, are important to obtain good survival rates [5-8]. There is also increasing appreciation for the improvement of the overall patient journey, involving prehabilitation before surgery, and improved recovery pathways in the immediate postoperative period [9].
Understanding the impact of the intervention and identifying areas where small progress has been made is key to determining which components of the treatment need further guidance to try to improve outcomes.
This study evaluates outcomes after gastric resection over the past 30 years in a single high-volume care center in the United Kingdom. Key changes to management strategy and their potential impact have been highlighted, along with areas where little progress has been made. The aim was to help identify which potential areas may lend themselves to further improvement, and to identify areas of research to target to help improve results.
| Methods |
> Patient population
Consecutive patients treated for adenocarcinoma of the stomach between January 1989 and December 2018, at the Northern Oesophagogastric Unite, Newcastle upon Tyne , were included . Patients were discussed in a multidisciplinary meeting and subsequently received neoadjuvant chemotherapy, followed by surgery (either total or subtotal gastrectomy), or had surgery as initial curative management. Patients were identified from a contemporaneously maintained database.
> Pretreatment staging
All patients were staged according to standardized protocols, including endoscopy with specimen biopsy and thoracoabdominal computed tomography (CT). During the time period of this study, positron emission tomography and CT evolved to be a necessary component in patients considered for radical (curative) treatment, and endoscopic ultrasound was used selectively.
Staging laparoscopy with washes for cytology was used in potential cases of locally advanced disease. In patients with histologically proven locally advanced malignancy that was resectable, without metastasis (cT1N+ or cT3+N0-3), perioperative chemotherapy followed by surgery was the primary treatment option after integration of the MAGIC (Medical Research Council Adjuvant ) study. Gastric Infusional Chemotherapy ) [10]. Patients with histology other than adenocarcinoma and those with metastatic disease at the time of operation were excluded.
> Treatment
Multiple neoadjuvant regimens were used in the present study, determined by standard of care and clinical trial recruitment at the time of treatment, with patients treated early in the study time period having single-modality surgery. However, most patients with locally advanced cancer received chemotherapy according to the MAGIC trial regimen. Total or subtotal gastrectomy with D2 lymph node dissection was performed within 4 to 8 weeks after completing neoadjuvant therapy, using an open approach.
> Surgical technique
Resections were performed using a standardized open approach with en bloc radical D2 lymphadenectomy [11]. Proximal tumors and patients diagnosed with linitis plastica were treated with total gastrectomy. Patients with a distal tumor where an adequate distance could be achieved (>5 cm) received a subtotal gastrectomy.
The standardized approach was employed throughout the time period, with a bursectomy when possible, and en bloc lymph node dissection. For total gastrectomy, an esophagojejunal anastomosis was routinely performed using a circular stapler, with a Roux-en-Y reconstruction, in a retrocolic manner. A 45 cm Roux branch was created with a jejuno-jejunal anastomosis in 2 continuous planes.
Subtotal gastrectomy with D2 lymphadenectomy was performed in a similar manner. However, the stomach was cut with a mechanical device, leaving a small remnant irrigated by 2 or 3 short vessels. The Roux branch was prepared as already mentioned and a manual end-to-side gastrojejunostomy, like a Hoffmeister valve, was performed in 2 planes.
> Pathological anatomy and staging
The histopathological report was carried out by gastrointestinal specialist pathologists, using a standardized proforma. This was in line with guidelines produced by the Royal College of Pathologists , which includes tumor type and differentiation, depth of infiltration, and tumor regression [12,13].
The total number of nodes in each location and lymph node metastases were recorded along with the presence of extracapsular, lymphatic, venous and perineural invasion. The lymph node groups were dissected from the specimen by the acting surgeon and analyzed separately by the pathologist [14]. The pathological stage was determined using the TNM staging system of the American Joint Committee on Cancer , 8th edition, which was applied retrospectively to the above specimens [15].
> Follow-up and definition of recurrence
Patients were followed until death or for 10 years. Patients were seen at 3- to 6-month intervals for the first 2 years, every 6 months for another 2 years, and then annually. Disease recurrence was based on clinical grounds and confirmed endoscopically or radiologically. The minimum follow-up used for long-term survival was 36 months.
> Complications
Complications were recorded contemporaneously. The presence of complications was defined as previously [16]. In addition to recording the occurrence of complications, they were also classified according to severity, using the Accordion [17] and Clavien-Dindo [18] scores.
Statistic analysis
Categorical variables were compared using the c2 test. Non-normally distributed data were analyzed with the Mann-Whitney U test. Survival was estimated using Kaplan-Meier curves and compared using the log-rank test. Multivariable analyzes used Cox proportional hazards models.
The comparison of the results between 5-year periods (1989-1993, 1994-1998, 1999-2003, 2004-2008, 2009-2013, and 2014-2018) was also carried out, although for prolonged survival, the patients were They analyzed only through 2017, to provide a minimum follow-up of 36 months for survivors. Data analysis was performed with the R Foundation Statistical program (R 3.2.2) with TableOne, ggplot2, Hmisc, Marchit, and survival packages (R Foundation for Statistical Computing, Vienna, Austria), as previously reported [19 ].
| Results |
> Baseline demographics
Between 1989 and 2018, 1,162 patients underwent gastrectomy for gastric cancer. The median age of the entire cohort was 71 years (interquartile range [IQR]: 63-76) and 763 patients (66%) were men. The overall median survival for the entire cohort was 32 months (IQR: 14-77). The majority of patients underwent subtotal gastrectomy (54%; n = 623 patients).
> Patient presentation
During that 30-year period, there was an increase in the number of patients undergoing gastrectomy in each 5-year period.
During the study period the presence of symptoms changed, with a significant drop in the number of patients with weight loss, from 71% initially, to 45% ( P = 0.001) in the final period; This was correlated with a small increase in body mass index (BMI), from 25 kg/m2 to 26 kg/m2 ( P < 0.001), and few patients presented with anorexia, from 42% in the baseline cohort. of the period, up to 5% ( P < 0.001).
The most common presentation for patients in the most recent cohort was epigastric discomfort, which 67% reported as a symptom, compared with 7% to 12% in the first 2 cohorts ( P < 0.001). The presentation of patients with regurgitation and odynophagia fell steadily over the years of the study, from 38% to 27% ( P = 0.002) and from 8% to 2% ( P = 0.001).
> Changes in stage at presentation and surgery.
Those who underwent surgery were increasingly at an advanced clinical stage (stage III), with 11% of patients in the earliest cohort having stage III disease, compared to 56% in the final cohort ( P < 0.001). There was a significant change in surgery performed with more than 70% of patients in the initial cohort undergoing total gastrectomy, compared to approximately 40% in recent years.
> Changes in pathological anatomy
The mean lymph node harvest was significantly lower in the first 2 cohorts (19 and 25 nodes, respectively), compared with the later cohorts (28-35; P < 0.001); Longitudinal R1 resection rates were significantly reduced from 21% to 6% ( P = 0.002).
> Patient results
Overall survival improved more than the 30 years studied. Median survival increased between each cohort from 28.3 months in the first, to 53 months in the final cohort ( P < 0.001). Overall, there was a steady improvement in survival per stage in each time period.
The overall complication rate was 42%, with a significant decrease from 54% to 35% ( P = 0.006). There was also a significant decrease in the rate of major complications, from 16% to 4% ( P < 0.001).
The most common complications were pulmonary complications, followed by cardiac complications, surgical site infections, and anastomotic leaks. There was a significant decrease in pulmonary and cardiac complications. This was accompanied by a drop in mortality during hospitalization and within 30 days, from 8% to 1% between the first and last cohort ( P < 0.001).
| Discussion |
This study provides a unique insight into changes in the presentation, treatment and outcomes of gastric cancer over a 30-year period. Likewise, it provides a 10-year follow-up, which has not been previously reported in the field of gastric cancer in the Western population.
The results presented demonstrate a significant increase in 5-year survival over the study time period.
Overall, the median survival was 32 months; However, well over 50% of patients were alive at 5 years in the last cohort, compared with less than 25% in the first 2 cohorts.
Additionally, there has been an improvement in short-term outcomes, with a significant drop in patient length of stay, with the median length of stay in the latest cohort being 8 days, which corresponds with the institution of the improved recovery pathway, and a drop in mortality during hospitalization, from 4% to 1% in the last time period.
Additionally, there was a drop in the complication rate that may have contributed to the length of stay. Overall complications fell from 42% to 35%, but more importantly, the rate of “significant” complications (Clavien-Dindo grade 3 or higher) fell from 16% to 4% in the latest cohort, which compares favorably with a recent large national study in the Netherlands [20,21]. These more serious complications are more likely to impact patient length of stay and potentially affect postoperative quality of life.
There are several factors that could have contributed to the improved results, although it is impossible to establish a direct cause-effect relationship.
The integration of a standardized enhanced recovery pathway may have served to ensure uniform care for patients, with a standardized analgesic regimen (which has dispensed with epidurals and now favors rectal sheath catheters and patient-controlled analgesia, as well as intrathecal diamorphine in induction) [22,23], early mobilization, and uniform approach to nutrition. This multimodal analgesic regimen, without an epidural, reduces the incidence of hypotension, which can limit patients’ ability to mobilize, and may have contributed to the reduction of pulmonary complications.
Despite the drop in complications, there was an increase in the treatment of patients with worse initial physical status, as indicated by the American Society of Anesthesiologist (ASA), which was used as a surrogate for that measurement. Other patient parameters that may have contributed to short-term outcomes include BMI, smoking status, and alcohol intake.
Regarding BMI, there has been a minimal increase in patients’ median BMI over the study period, from 25 to 26. Perhaps more notable was the proportion of current smokers (defined as smokers within 6 weeks of their surgery). It fell dramatically from 38% to 20%, and even the proportion of never smokers increased similarly. That could have been a major contribution in improving the postoperative recovery of patients.
The improved survival may not be unexpected, given that perioperative chemotherapy has become the standard of care for patients with locally advanced disease since the MAGIC study was published [10].
Although that study demonstrated a 13% improvement in 5-year survival associated with the perioperative use of chemotherapy, the results in the present study have nearly doubled survival in the era of perioperative treatment.
However, perioperative chemotherapy is likely to only account for a small proportion of the improved outcomes seen, with lower mortality (from 8% to 1% in recent cohorts) and lower morbidity, although it has been shown to lead to worse outcomes. long-term. [24,25].
Additionally, improvements in patient staging, with improved cross-sectional imaging and laparoscopy to diagnose occult metastatic disease, may have contributed to improved patient selection and treatment optimization.
It is not possible to identify the impact of individual changes on the improvement of these outcomes, but it is likely to be multifactorial, with a standardized surgical technique used by all surgeons [11], an experienced team involved in the staging and postoperative management of the patients and, more recently, a multi-faceted enhanced recovery pathway, which takes a holistic approach to patient care.
This study also demonstrated a change in the presence of symptoms over 30 years. There was a continuing trend towards fewer patients presenting with weight loss and anorexia, and more with abdominal discomfort and pain. These changes may correspond to greater access to endoscopy, allowing the investigation of symptoms that may have been previously ignored [26].
In fact, there were more patients with stage 0 and 1 disease in the later cohorts, although some of that may be due to the impact of neoadjuvant treatment downstaging on patients, some of this could be due to primary care referrals based on symptoms that may have been previously ignored.
It is also notable that there was a significant change in the operations performed, with total gastrectomy being approximately 70% of the earliest operations, which fell to around 40% in the later cohorts. This contrasts with what has been previously documented, with a trend towards more proximal and junctional cancers [27].
Although some proximal tumors are associated with obesity, which did not change significantly over the time period, and with higher sociodemographic indices, that trend is perhaps more likely due to an inherent ethos in the department to treat proximal tumors. union by esophagectomy, which were not included in this study.
The greatest deficiency of this study is that the data derive from a single healthcare center, so the question remains whether these findings are transferable to broader populations. Surgical procedures were performed by a small cohort of 12 surgeons, with a standardized approach, during the 30 years of the study. In addition, the patients were treated in a room specialized in esophagogastric pathology. All of this helps demonstrate the excellent results that can be achieved.
Furthermore, the surgical technique did not change throughout the period, which helps demonstrate the impact of the other interventions that have occurred over time, and the need to constantly reflect on how patient management can be improved.
The most recent intervention has been the implementation of a prehabilitation program for all patients undergoing esophagogastric surgery, allowing them to remain fit while receiving neoadjuvant chemotherapy [28]. Prehabilitation has been shown to help patients stay fit [29], and a pragmatic approach has been instituted that is accessible to all patients.
Additional upcoming research includes studies evaluating avenues to assist patient rehabilitation with some evidence that a multidisciplinary program can improve cardiopulmonary fitness after surgery [30]. Additionally, this study does not include data on patient comorbidities, which may have changed over time.
The ASA score was used as a surrogate marker of physical fitness and results indicated a greater proportion with higher ASA grades in recent years. That could suggest a worse general physical condition in these patients; However, other factors, such as being a current smoker at the time of surgery, have decreased significantly and may contribute to the decrease in pulmonary complications. Likewise, there is no information on the quality of life of patients after surgery. That is an important factor given the improved survival and should be the focus of future research.
Additional work to aid patient prognosis to aid management is an important consideration. TNM classification can potentially include histopathological markers, such as perineural and lymphovascular invasion, which can provide greater prognostic accuracy and guide clinicians on how the patient should be followed [31-33].
The ability to identify biomarkers, which assist with prognosis and help guide decisions regarding the use of neoadjuvant treatment, needs further investigation, given the known deleterious effect of neoadjuvant treatment on fitness [34], and the routine use of biomarkers. , such as the presence of microsatellite instability, may influence the patient pathway, particularly the use of perioperative chemotherapy [35].
More research on nutritional support of gastrectomy patients needs to be evaluated. Although a previous randomized controlled trial from the same healthcare center did not show any benefit with omega-3 fatty acid supplementation on clinical outcomes [36], a more recent meta-analysis has shown that preoperative immunomodulatory nutrition can shorten hospital stay and reduce complications [37].
Careful consideration of nutrition in such patients may also contribute towards improved long-term outcomes, particularly with the associated risk of pancreatic insufficiency and long-term poor nutrition [38,39].
In conclusion, there has been considerable progress in the last 30 years in relation to both perioperative outcomes and long-term survival in patients with gastric cancer. This study does not examine patients’ quality of life, which needs to be addressed.
All patients had open surgery and it may be that a move towards laparoscopic surgery could improve these outcomes, with several recent studies suggesting comparable long-term outcomes [40-42], and the possibility that robotic surgery may have an oncological profile. equally effective [43]. Although laparoscopic surgery has not been adopted at the authors’ center, a robotic program has recently been initiated.
The surgeons involved have considered that this may confer advantages with excellent visualization and improved surgical skill. This can potentially provide long-term improvements in quality of life, and even increase surgeon longevity. However, care must be taken not to compromise oncological outcomes in an attempt to perform minimally invasive procedures.
Shifts in the management of early gastric cancers toward organ-sparing endoscopic therapy may also require further investigation, to establish whether endoscopic submucosal dissection has any advantage over endoscopic mucosal resection, and to determine whether treatment with Organ preservation is achievable in more advanced cancers [44].
This study highlights that continuous improvement in outcomes can be achieved by making changes to the patient pathway. There are a number of areas for additional research, identification of those who will benefit most from neoadjuvant treatment, the impact of prehabilitation, and a rehabilitation pathway for patients after improved recovery, which may contribute to further improving outcomes. results.
