Published online Jan 14, 2018. doi: 10.3748/wjg.v24.i2.274
Peer-review started: November 19, 2017
First decision: November 30, 2017
Revised: December 13, 2017
Accepted: December 20, 2017
Article in press: December 20, 2017
Published online: January 14, 2018
Actually, curative surgery with complete D2 lymph node dissection is the treatment of choice for gastric cancer (GC). In high-volume reference centers surgery alone gives excellent survival rates. Anyway, in western countries, prognosis remains poor outside reference centers even after curative resection, especially for the high rate of recurrence mainly due to incomplete nodal dissection. Many trials have investigated the impact of adjuvant treatment by comparing surgery alone with surgery followed by adjuvant chemotherapy, but there is no definitive evidence of any survival advantage.
Therefore, in the last decade, a multimodal approach of GC has been suggested with the adoption of preoperative or perioperative treatment (NAC). The problem is that NAC has been introduced in the national guidelines of many countries, especially after publication of MRC and French RCTs, without a clear and evidence-based medicine (EBM)-related demonstration of a survival benefit compared to controlled surgery with proper enlarged LN dissection in patients with only stomach tumors.
In fact, MAGIC and FNCLCC-FFCD RCTs have shown a survival advantage of NAC + surgery vs surgery alone, but surgery performed in these patients did not include a proper extended lymphadenectomy in the majority of cases, and many patients had lower esophageal or cardia cancer instead of only GC. Therefore, it is possible that a proper radical surgery (gastrectomy with D2 LN dissection) may nullify the survival benefit of NAC described after incomplete surgery and also that the location of the tumor outside the stomach (cardia and lower esophagus), may amplify the response to preoperative treatment.
To document a possible benefit of NAC after adequate D2 gastrectomy for only stomach cancer, we proceeded to review the literature on neoadjuvant treatment for resectable gastric cancer by mainly investigating these variables.
Neoadjuvant (pre- or peri-operative) chemotherapy has been recently introduced in the national guidelines of many countries mainly after publication of MRC and French RCTs, without a clear and evidence-based medicine (EBM)-related demonstration of a survival benefit compared to controlled surgery with proper enlarged LN dissection in patients with only stomach tumors. The advantage reported after NAC seems mostly related to incomplete nodal dissection performed in both arms of these trials and to heterogeneous recruitment of lower esophagus and esophago-gastric junction cancer together with proper stomach cancer. Are there any trials among RCTs available in Literature investigating the effect of NAC over an homogeneous population of patients with only-stomach cancer treated with complete D2 lymph node dissection in both arms? Otherwise we could not exclude that: 1) a proper radical surgery (gastrectomy with D2 LN dissection) may nullify the survival benefit of NAC described after incomplete surgery and 2) the location of the tumor outside the stomach (esophago-gastric junction and lower esophagus) may amplify the response to preoperative treatment. In other words, NAC could be unuseful in proper gastric cancer submitted to curative complete D2 dissection.
The main objective was to investigate whether a possible survival benefit (OS and/or DSS and/or DFS) of NAC after adequate D2 gastrectomy for only stomach cancer was documented in all RCTS available in Literature till now. Secondary outcomes included the perioperative response rates, the R0 (margin negative) resection rate, and OS or DFS or DSS according to the type of lymph node dissection performed (D1, D2, others) after neoadjuvant treatment. We realized that no RCTs available till now could document a survival benefit of NAC over surgery alone for homogeneous population of patients with tumor of the only stomach treated with complete D2 gastrectomy and that a further large volume randomized trial is needed.
We proceeded to conduct a complete review of the literature with the support of the Federate Library of Medicine of Turin. The body of evidence for this review was primarily comprised of mature randomized controlled trial (RCT) data. All published randomized trials comparing NAC-containing procedures vs no treatment before surgery in patients with gastric cancer (or gastric cancer + cardia cancer + lower-esophagus cancer) were included in our analysis. Blinding the trial conditions was not necessary. There was no language restriction. Esophagogastric junction and lower esophageal cancer patients were considered only if they were enrolled together with proper gastric cancer patients in the same study. The reason for considering also esophago-gastric junction and lower esophageal cancers in the recruitment process was that these locations represented a consistent part of the study population of the main RCTs actually claimed to be the basis for NAC treatment in gastric cancer.
At the end of the process, only RCTs were included in this review. As we wanted to include all RCTS available in Literature at the moment, any chemotherapy regimen performed before resective surgery with or without postoperative adjuvant treatment was included and located in the NAC-arm as well as in the surgery alone-arm (SA-arm) we enrolled all types of gastrectomy and lymphadenectomy that were performed (D0, D1, D1plus, D2, D3). The quality of the included RCTs was assessed usin nodified JADAD’s scoring system and Cochrane reviewers’ andbook 5.0.1 RCT criteria.
The currently available data support the adoption of NAC procedures in several national guidelines based on low-volume study populations with mixed sites of the primary disease (lower esophagus, esophago-gastric junction and stomach). Statistical tests have often shown evidence of the heterogeneity of chemotherapy effects according to the site of the primary tumor. In fact, in both Magic and FNCLCC-FFCD trials, tests for heterogeneity showed that perioperative chemotherapy effects were much more evident for esophago-gastric junction cancer and much less for stomach cancer.
Furthermore, in both these RCTs supporting the adoption of NAC, surgery provided to patients was incomplete because extended nodal dissection was performed in less than 50% of patients or not described, and no results on the LN yield were documented to warrant its adequacy. The only well-designed RCT with extended surgery performed in almost all cases was prematurely ended for poor accrual, but at the moment of its closure, it failed to demonstrate a survival benefit for NAC.
Moreover, in national reference centers for gastric cancer care and research, OS and DSS rates of subsites of patients theoretically fit for NAC submitted to surgery alone with complete D2 dissection and performed for cancers located in the stomach only, are even higher than those reported after NAC followed by incomplete surgery provided to a patient population with mixed sites of the primary tumor.
This study documented that the adoption of NAC procedures in several national guidelines is actually based on low-volume study populations with mixed sites of the primary disease (lower esophagus, esophago-gastric junction and stomach) and with inadequate surgery as concern the extent of nodal dissection (incomplete D2 dissection). In fact, statistical tests reported in these trials have shown evidence of the heterogeneity of chemotherapy effects according to the site of the primary tumor, documented a major effect mainly over esophagogastric junction cancer. Moreover, survival rates reported in Surgery-Alone arm by main RCTs claimed to be fundamental for supporting the adoption of NAC ( MRC and French trials) are really too low as compared to rates documented in reference centers study population after proper D2 gastrectomy without preoperative chemotherapy. Effectively, in these surgical series coming from high volume referral centres, survival rates after extended surgery without NAC are even higher than those reported after NAC followed by incomplete surgery.
Our hypothesis is that, with current data available it ‘s not possible to exclude that: (1) The location of the tumor outside the stomach (esophago-gastric junction and lower esophagus) may amplify the response to preoperative treatment. (2) A proper radical surgery (gastrectomy with D2 LN dissection) may nullify the survival benefit of NAC described after incomplete surgery. (3) On the contrary, NAC effect on survival is more likely to be evident after incomplete surgery. In other words, NAC could be unuseful in cancer of the only stomach submitted to curative complete D2 dissection.
We think additional high volume sample-size multicenter (and eventually multinational) RCTs comparing newer treatment regimens of neoadjuvant settings (capecitabine, oxaliplatin, docetaxel) combined with molecular therapies (epidermal growth factor receptor inhibitors or antiangiogenic agents) followed by controlled D2 surgery with controlled D2 surgery alone are necessary to investigate the survival effects of modern preoperative chemotherapy in patients with gastric cancer only who receive proper extended surgery. This is the ony way to investigate if neoadjuvant therapy can positively impact survival also in homogeneous population of gastric cancer patients without any biases related to location of the tumor and adequacy of surgery administered.