Adjuvant chemoradiotherapy after complete resection for gastric cancer was associated with an improvement in overall and disease-free survival
 and has been adopted in many Western centers since
. Some issues should be addressed though, surgical control being the major one. In the INT0116, D2-lymphadenectomy was recommended as part of the surgical treatment. However, it was performed in only 10% of the patients, who had a median survival of 48 months and no improvement with adjuvant treatment, whereas the whole study population had median survival of 36 months
. The use of this treatment in patients who had D2-lymphadenectomy was first reported in a nonrandomized Korean study with 890 patients, in which adjuvant treatment was associated with an improvement in survival (57% vs. 51%). This same group led the just published ARTIST Trial, a phase III study that compared the adjuvant treatment with chemotherapy (6 cycles of XP - Capecitabine and Cisplatin) vs. the association of chemotherapy and radiotherapy (2 cycles of XP + XP and Radiotherapy + 2 more cycles of XP) after D2-lymphadenectomy. The addition of radiotherapy provided an improvement in disease-free survival for node-positive patients
Patterns of relapse are another point of concern. In the INT 0116 trial, adjuvant chemoradiotherapy was associated with a decrease in local recurrence (29% vs. 19%), but not in systemic/peritoneal relapse. A large Eastern series with 2328 patients described loco-regional relapse to be around 20% with surgery only
. Even Western studies demonstrate that when D2-lymphadenectomy is performed less than 20% of the patients develop loco-regional recurrence
Debates remain among some Western authors regarding the extent of lymphadenectomy for gastric cancer. They are based in the negative results of two randomized trials published in 1999. Their results should be interpreted with caution, mainly due to the adverse effect of D2-related pancreatic and splenic resections in postoperative mortality. A recent update in the results of one of these trials should put an end to this controversy, as D2-lymphadenectomy was associated with a significant improvement in cancer-related mortality and in loco-regional recurrence
The present study included 90.8% of patients who were treated with D2 dissection. Severe postoperative morbidity was low and postoperative deaths were excluded, which suggests that the number of patients who were programmed to have adjuvant chemoradiotherapy and did not receive it was very low. The treatment was not associated with significant improvement in overall and disease-free survival. Some limitations about this finding should be discussed. The first one regards the two differences between the group of patients treated with resection, and the ones treated with adjuvant chemoradiotherapy, who were younger and had higher frequency of node-positive tumors. In this case, treatment could offset a worse result in patients with node-positive disease. Another limitation of the study resides in the fact that this is a retrospective cohort of consecutive cases and the more recently treated individuals were the ones who had adjuvant chemoradiotherapy and, therefore, have a shorter follow-up. The use of a historic control may represent another bias, albeit the low morbidity and mortality of patients throughout the study and the fact that all the patients were operated by the same group of surgeons.
Based on the conflicting results in the literature on the subject of chemoradiotherapy in patients treated with D2-lymphadenectomy, the toxicity it is associated with, and this own series numbers, which showed better but not significant results with adjuvant treatment, the goal was to try to identify prognostic factors that could establish which individuals would benefit from adjuvant treatment.
Besides extended resections, perineural invasion was also an independent prognostic factor associated with worse survival, as has been shown in the literature, especially if associated with lymphatic vessel invasion and early tumors
However, the most important prognostic factor for overall and disease-free survival was the interaction between N-category and N-ratio. It has been shown that this interaction individualizes groups of patients with distinguished survival numbers within the same N-category in TNM staging 6th edition
, confirming the finding in other studies that N-ratio could determine different outcomes in patients with N1 and N2 tumors
[13, 21]. The role of this interaction was now investigated in the new TNM staging system 7th edition
 and again different survival outcomes were identified in patients with N1 and N2 tumors (N2-NR2 and NR3 tumors – HR 2.02 for death and 2.26 for recurrence).
When analyzing the role of adjuvant chemoradiotherapy for each variable category, an improvement in overall survival among patients with node-positive disease was observed. However, by studying the distribution of these patients in different N-category N-ratio categories, individuals with N1 and N2 lesions and higher N-ratio seemed to have better survival with adjuvant chemoradiotherapy. By grouping these patients, this difference in outcomes was more easily identified, with a significant improvement in overall and better numbers albeit not statistically significant in disease-free survival. Those who had D2-lymphadenectomy with higher N-ratio had the worse outcomes, possibly because residual node disease was left behind. To measure the likelihood of disease in undisected regional nodes, the use of the Maruyama index (MI) has already been described. An MI < 5 was an independent survival prognostic factor among the INT0116 patients and it proved to be a valuable surgical undertreatment detection tool
The most important limitation in our study refers to the small number of patients, especially in the subgroups of N1/N2 tumors, with 65 in total. This may provide a low statistical power for the results. However, even in this small subset, very different numbers were observed and a statistically significant result was obtained, which favored the rationale of using N-ratio associated with N-category to help identify patients who supposedly had a D2-lymphadenectomy and would benefit from adjuvant chemoradiotherapy. This interaction worked as a numeric criterion that might represent, after further studies, an absolute, reproducible factor that could help select patients for this treatment could have been established.
In conclusion, in this single center series, adjuvant chemoradiotherapy was not a prognostic factor for overall and disease-free survival in gastric cancer patients treated with D2-lymphadenectomy. Patients with N1 and N2 tumors and higher N-ratios could benefit from this multidisciplinary treatment.