Adjuvant Therapy for Completely Resected Gastric Cancer with D2 LN Dissection

Konstantinos Kamposioras

Gastric cancer is the second most common cause of cancer-related death worldwide. Even in potentially curative resections 50% to 90% of patients will die of locoregional or distant recurrence. Although randomized controlled trials have shown survival benefit associated with adjuvant chemotherapy (both peri- and post-operative) and chemoradiotherapy (CRT) there is lack of consensus regarding the best adjuvant treatment approach. Results are even more inconclusive in D2 resected gastric cancer considering that in the INT-0116 trial (the largest CRT trial) only 10% of patients were treated with D2 lymph node dissection, while the benefit observed with S-1 administration as adjuvant chemotherapy in Japanese patients has not been confirmed in non-Asian population. Moreover, the benefit of adjuvant RT has long been debated in D2 resected gastric cancer based on the hypothesis that D2 resection alone may be sufficient to control locoregional recurrence.
In the ARTIST (Adjuvant Chemoradiation Therapy in Stomach Cancer) trial, the role of postoperative chemoradiotherapy in patients with curatively resected gastric cancer with D2 lymph node dissection was studied. In this study postoperative treatment with capecitabine plus cisplatin (XP) versus XP plus radiotherapy with capecitabine (XP/XRT/XP) was compared. The primary endpoint of the study was disease-free survival (DFS), with overall survival, recurrence rate, and toxicity as key secondary end points.

In total 458 patients (228 in XP and 230 in the CRT) were recruited in the study. Both treatment arms were well tolerated with high rates of compliance (treatment was completed in 75% of patients in the XP arm and 82% in CRT arm). The most common grade 3 to 4 adverse events were neutropenia, nausea, vomiting, stomatitis, HFS, and diarrhoea. Overall, there was no significant difference in DFS with the addition of XRT to XP chemotherapy (the estimated 3-year DFS rates were 78.2% in the XP/XRT/XP arm and 74.2% in the XP arm; P=.0862). Nevertheless,  in the subgroup of patients with pathologic lymph node metastasis at the time of surgery  patients assigned to the XP/XRT/XP arm experienced superior DFS when compared with those who received XP alone (P= .0365), and the statistical significance was retained at multivariate analysis (P=.0471).
The results of this study are very interesting but there are certain limitations to be discussed. Survival analysis could not be performed since the planned events were not reached due to the high rate of early stage disease in each arm (IB and II). It is suggested that lymph node positive patients may get benefit from CRT but this was derived from subgroup analysis and a future randomized control trial has been already planned to confirm this result (ARTIST-II). It is also questionable that there was no difference in locoregional recurrence in either arm while toxicity seemed not to be higher in the CRT arm. Finally, it would be quite challenging to have a third arm in such trials with Surgery alone.
It seems that there is still long way to go for the optimal adjuvant therapy in gastric cancer. The results of ongoing randomized trials will be anticipated to give more answers for the treatment of this highly fatal disease.

Adjuvant Therapy for Completely Resected Gastric Cancer with D2 LN Dissection
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