# Gastric Cancer: Adjuvant and Neoadjuvant Radiation Approaches

## Overview

Gastric cancer remains a major cause of cancer-related mortality worldwide, with notable geographic variation in incidence rates. The highest rates are observed in East Asia, South America, and Eastern Europe. The role of radiation therapy in the management of gastric cancer is controversial and varies significantly between Western and Asian treatment centers. In Western practice, the historical standard was based on the INT-0116 trial, which supported adjuvant chemoradiotherapy (CRT) following surgery. However, there has been a shift toward perioperative chemotherapy regimens such as MAGIC and FLOT4, which do not include radiation. Conversely, Asian centers emphasize radical D2 lymph node dissection followed by adjuvant chemotherapy alone, typically using S-1 or CAPOX, without routine radiation. The declining role of adjuvant radiation therapy reflects improvements in surgical techniques, particularly the widespread adoption of D2 dissection, and the availability of more effective systemic therapies.

## Landmark Clinical Trials

The INT-0116 or MacDonald trial was a pivotal phase III study comparing surgery alone to surgery followed by adjuvant chemoradiotherapy consisting of 45 Gy in 25 fractions combined with 5-FU and leucovorin. This trial enrolled 556 patients with stage IB to IV (M0) gastric or gastroesophageal junction (GEJ) adenocarcinoma. The results demonstrated a significant improvement in 3-year overall survival (OS) of 50% in the CRT arm versus 41% in the surgery-alone arm, with a hazard ratio (HR) of 1.35 (p=0.005). Relapse-free survival at 3 years was also improved (48% vs. 31%). The OS benefit persisted in a 10-year update. However, a major criticism of INT-0116 was that only 10% of patients underwent a D2 lymphadenectomy, while 54% had less than a D1 dissection (D0). This raised the possibility that the benefit of CRT was compensating for inadequate lymph node dissection rather than providing an independent therapeutic advantage.

The MAGIC trial, conducted by Cunningham and colleagues, was a phase III study comparing perioperative chemotherapy with surgery alone in 503 patients with resectable gastric, GEJ, or lower esophageal adenocarcinoma. Patients received three cycles of ECF (epirubicin, cisplatin, and 5-FU) before and after surgery. The trial showed a 5-year OS of 36% with chemotherapy versus 23% with surgery alone (HR 0.75), establishing perioperative chemotherapy as a standard in Europe. Notably, this regimen did not include radiation. A limitation was that only 42% of patients completed postoperative chemotherapy, highlighting compliance challenges.

The FLOT4 trial compared perioperative FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) to perioperative ECF or ECX. FLOT demonstrated superiority with a median OS of 50 months versus 35 months and a pathological complete response (pCR) rate of 16% compared to 6%. This established FLOT as the preferred perioperative chemotherapy regimen in Western practice. Like MAGIC, FLOT did not incorporate radiation, further reducing the role of adjuvant radiotherapy.

In the Asian context, the ARTIST trial from South Korea compared adjuvant chemotherapy with capecitabine and cisplatin (XP) alone versus XP combined with radiation therapy (45 Gy) after D2 gastrectomy. Overall, there was no significant difference in disease-free survival (DFS) at 3 years (78.2% vs. 74.2%). However, subgroup analyses suggested a potential benefit of chemoradiotherapy in node-positive patients and those with intestinal-type histology. Despite this, ARTIST did not support routine use of adjuvant CRT after D2 dissection.

The ARTIST-II trial further evaluated adjuvant S-1 and oxaliplatin (SOX) chemotherapy with or without radiation in node-positive gastric cancer after D2 gastrectomy. The 3-year DFS was 78% with SOX plus radiation versus 73% with SOX alone, a difference that was not statistically significant. This trial again failed to demonstrate a clear benefit of adding radiation after adequate surgery combined with modern chemotherapy.

The CRITICS trial compared perioperative chemotherapy alone (ECC or ECX) to perioperative chemotherapy followed by postoperative chemoradiotherapy (45 Gy with cisplatin and capecitabine). There was no difference in 5-year OS (43% vs. 40%). Compliance with postoperative treatment was poor in both arms. CRITICS did not support replacing postoperative chemotherapy with chemoradiotherapy.

The most recent TOPGEAR trial compared perioperative ECF or FLOT chemotherapy alone to the same chemotherapy combined with preoperative chemoradiotherapy (45 Gy with 5-FU). While preoperative CRT increased the pathological complete response rate (17% vs. 8%), it did not improve overall survival. Therefore, routine addition of preoperative radiation to perioperative chemotherapy is not supported.

| Trial | Design | RT Included | D2 Rate | Key Result | Conclusion |
|---|---|---|---|---|---|
| INT-0116 | Adj CRT vs. surgery alone | Yes (45 Gy) | 10% | 3-yr OS 50% vs. 41% (p=0.005) | CRT benefit; but inadequate surgery |
| MAGIC | Periop ECF vs. surgery alone | No | Variable | 5-yr OS 36% vs. 23% | Periop chemo standard |
| FLOT4 | Periop FLOT vs. ECF/ECX | No | Variable | Median OS 50 vs. 35 mo | FLOT preferred regimen |
| ARTIST | Adj XP vs. XP + CRT (post-D2) | Yes (45 Gy) | 100% | No DFS difference | No RT benefit after D2 |
| ARTIST-II | Adj SOX vs. SOX + RT (post-D2) | Yes | 100% | No DFS difference | No RT benefit after D2 |
| CRITICS | Periop chemo vs. chemo + postop CRT | Yes (45 Gy) | ~80% | No OS difference | No CRT benefit |
| TOPGEAR | Periop chemo vs. chemo + preop CRT | Yes (45 Gy) | Variable | Higher pCR, no OS benefit | Preop RT not supported |

## When Radiation May Still Be Considered

Radiation therapy may still be appropriate in certain clinical scenarios. After surgeries with inadequate lymphadenectomy (D0 or D1), particularly when fewer than 15 lymph nodes are examined, the INT-0116 data remain most applicable. In such cases, chemoradiotherapy may compensate for suboptimal surgical staging and treatment. If a D2 dissection was not performed and the patient is not a candidate for re-resection, adjuvant CRT should be considered.

Following D2 surgery, radiation may be reasonable for patients with high-risk features such as positive surgical margins (R1 or R2), where adjuvant radiation to the surgical bed can reduce locoregional recurrence. Extensive nodal involvement despite D2 dissection, such as N3 disease, has some retrospective data suggesting benefit from CRT. Similarly, T4 tumors with serosal invasion carry a higher risk of locoregional recurrence and may warrant radiation.

In the palliative setting, radiation therapy can be used to control bleeding from unresectable gastric tumors, with doses such as 30 Gy in 10 fractions or 20 Gy in 5 fractions achieving hemostasis in 50-80% of cases. Radiation may also provide partial relief of gastric outlet obstruction, although endoscopic stenting is generally preferred.

## Radiation Therapy Technique

The gross tumor volume (GTV) for radiation planning includes the residual tumor or tumor bed, guided by preoperative imaging, surgical clips, and pathology reports. The clinical target volume (CTV) encompasses the tumor bed plus regional lymph node stations at risk. These include perigastric nodes (stations 1-6 for distal tumors and 1-4 for proximal tumors), the celiac axis (station 9), the splenic hilum (stations 10-11) for proximal tumors, and the hepatoduodenal ligament (station 12). Para-aortic nodes are generally excluded unless involved. For postgastrectomy patients, the anastomotic site is also included. The planning target volume (PTV) is defined as the CTV plus a margin of 5-10 mm to account for respiratory motion, which is assessed using 4D-CT.

The standard adjuvant radiation dose is 45 Gy delivered in 25 fractions of 1.8 Gy each, as established by INT-0116. A boost up to 50.4-54 Gy may be given to residual disease or positive margins.

Intensity-modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT) is recommended to minimize dose to critical organs such as the left kidney, liver, and small bowel. Historical anterior-posterior/posterior-anterior (AP/PA) fields were associated with high renal and hepatic toxicity. IMRT significantly reduces the volume of the left kidney receiving 20 Gy (V20) and lowers the mean liver dose. Respiratory motion management with 4D-CT is particularly important for proximal tumors near the diaphragm.

Organ-at-risk (OAR) constraints include limiting the left kidney V20 to less than 30% or mean dose below 18 Gy to preserve bilateral renal function. The right kidney V20 should also be under 30%. The liver mean dose should be below 30 Gy with V30 under 30%. Small bowel volume receiving 45 Gy should be less than 195 cc. The spinal cord maximum dose should not exceed 45 Gy, and for proximal or cardia tumors, the heart mean dose should be kept below 26 Gy.

<image>A flowchart illustrating the evolving treatment paradigm for gastric cancer. Branch 1 (Western approach): perioperative FLOT (current standard) with surgery; adjuvant CRT reserved for inadequate lymphadenectomy or positive margins. Branch 2 (Asian approach): D2 gastrectomy followed by adjuvant S-1 or CAPOX; no RT. Key trials are annotated at each decision point: INT-0116, MAGIC, FLOT4, ARTIST, ARTIST-II, CRITICS, TOPGEAR. The overall trend toward decreasing use of radiation in gastric cancer is highlighted.</image>

<image>An axial CT planning image showing IMRT dose distribution for adjuvant postoperative gastric cancer radiation. The CTV (blue contour) encompasses the tumor bed (Billroth II anastomosis), celiac axis, perigastric nodal stations, and hepatoduodenal ligament. The 95% isodose line (green) covers the CTV to 45 Gy. The left kidney (orange), liver (brown), and small bowel loops (yellow) are contoured with dose-volume histogram inset showing compliance with OAR constraints.</image>

<image>A comparison table of the major adjuvant and perioperative trials in gastric cancer. Columns: INT-0116, MAGIC, FLOT4, ARTIST, ARTIST-II, CRITICS, TOPGEAR. Rows include: treatment approach, lymphadenectomy extent, radiation (yes/no), chemotherapy regimen, pCR rate, 5-year OS, and key conclusion. The table highlights the diminishing role of radiation across successive trials.</image>

## Key Clinical Pearls

The role of radiation therapy in gastric cancer has diminished significantly over time. While the INT-0116 trial established adjuvant chemoradiotherapy as a standard, this was in an era when most patients underwent inadequate lymphadenectomy, with 90% having less than a D2 dissection. More recent trials conducted in the context of D2 surgery, such as ARTIST, ARTIST-II, and CRITICS, have failed to demonstrate a benefit from adding radiation. Currently, perioperative FLOT chemotherapy is the Western standard of care for resectable gastric cancer, and radiation is not included as it has not shown an overall survival benefit in this setting. Radiation should still be considered after surgeries with inadequate lymphadenectomy (D0 or D1), for patients with positive surgical margins, or for palliative indications such as tumor bleeding or pain. When planning adjuvant radiation, IMRT is essential to spare critical organs like the left kidney and liver, as historical AP/PA techniques are associated with unacceptable renal toxicity. The divergence between Western and Asian gastric cancer practices reflects fundamental differences in surgical technique—D1 versus D2 lymphadenectomy—as well as biological differences, including varying proportions of intestinal versus diffuse histology and differences in Helicobacter pylori subtypes.

## References

- Macdonald JS et al. "Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction." *N Engl J Med*. 2001;345(10):725-730.  
- Cunningham D et al. "Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer." *N Engl J Med*. 2006;355(1):11-20.  
- Al-Batran SE et al. "Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4)." *Lancet*. 2019;393(10184):1948-1957.  
- Lee J et al. "Phase III trial comparing capecitabine plus cisplatin versus capecitabine plus cisplatin with concurrent capecitabine radiotherapy in completely resected gastric cancer with D2 lymph node dissection: the ARTIST trial." *J Clin Oncol*. 2012;30(3):268-273.  
- Cats A et al. "Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial." *Lancet Oncol*. 2018;19(5):616-628.