Treatment Sequence for Gastric Adenocarcinoma
For resectable stage II and III gastric adenocarcinoma, chemotherapy should come first as part of a perioperative approach, with neoadjuvant chemotherapy administered before surgery followed by postoperative chemotherapy. This represents the standard of care in Europe and the UK, based on landmark trials demonstrating significant survival improvements. 1
Evidence-Based Treatment Algorithm
For Resectable Stage II-III Disease (Standard Approach)
Perioperative chemotherapy is the established standard of care:
The MAGIC trial demonstrated that perioperative chemotherapy (3 cycles preoperatively + 3 cycles postoperatively) improved 5-year survival from 23% to 36% compared to surgery alone in resectable stage II and III gastric cancers. 1
The FNCLCC/FFCD trial confirmed similar results, with 5-year survival improving from 24% to 38% with perioperative chemotherapy. 1
The FLOT regimen (docetaxel, oxaliplatin, leucovorin, and fluorouracil) is now recognized as the standard of care for perioperative chemotherapy, with 4 preoperative cycles followed by surgery and 4 postoperative cycles. 2
FLOT demonstrated superior overall survival compared to ECX (50 months vs 35 months, HR 0.77, p=0.012). 2
Specific Regimen Recommendations
First-line perioperative chemotherapy options:
FLOT is preferred when available: 4 cycles preoperatively (8 weeks total), then surgery, then 4 additional postoperative cycles. 2
Alternative platinum/fluoropyrimidine doublets include ECX (epirubicin, cisplatin, capecitabine) or cisplatin plus 5-fluorouracil if FLOT is not feasible. 1, 2
For Patients Who Undergo Surgery Without Neoadjuvant Therapy
If surgery is performed first (not recommended for stage II-III), adjuvant treatment is mandatory:
Adjuvant chemoradiotherapy (North American Intergroup-0116 approach) improved 5-year overall survival compared to surgery alone, with a hazard ratio of 1.32 favoring adjuvant treatment after 10 years of follow-up. 1
This approach is standard in the United States but less accepted in Europe due to concerns about compensating for suboptimal surgery (54% of patients had less than D1 lymphadenectomy in the trial). 1
Adjuvant chemotherapy alone has survival benefits in non-Western populations and should be considered in high-risk patients who did not receive neoadjuvant therapy. 1
For cT4 Disease (Locally Advanced)
Preoperative chemotherapy is superior to upfront surgery:
Recent evidence demonstrates that multimodal treatment with chemotherapy (pre- or postoperative) is essential for cT4 gastric cancer, with median overall survival of 58.5 months for chemotherapy + surgery versus 32 months for upfront surgery (p=0.04). 3
Since tolerance to adjuvant treatment is reduced postoperatively, preoperative chemotherapy is the better strategy for cT4 disease. 3
For Early Stage Disease (T1a)
Surgery alone may be appropriate:
Early gastric cancers (T1a) that are well-differentiated, ≤2 cm, confined to mucosa, and not ulcerated may undergo endoscopic resection without chemotherapy (lymph node metastatic risk is virtually zero). 1
Stage IB disease without high-risk features may be considered for surgery alone, though most guidelines recommend adjunctive therapy for ≥T2 tumors. 1
For Stage IV/Metastatic Disease
Palliative chemotherapy is indicated:
Palliative chemotherapy improves survival compared to best supportive care alone. 1
Surgery is not generally recommended in the palliative setting, though select patients with good response to systemic therapy may be considered for resection. 1
Critical Implementation Points
Postoperative compliance is a major limitation:
The CRITICS trial revealed that only 59% of patients in the chemotherapy group and 62% in the chemoradiotherapy group actually started postoperative treatment after surgery. 4
This poor postoperative compliance strongly supports giving chemotherapy first (neoadjuvant approach) to ensure patients receive systemic therapy while they are still fit enough to tolerate it. 4
Surgical quality matters:
Adequate surgery should include clear surgical margins and adequate nodal dissection with a goal of obtaining at least 16-18 and preferably 20 lymph nodes. 2
D2 lymphadenectomy is preferred; chemoradiotherapy may compensate for suboptimal D1 resection but provides less benefit after optimal D2 resection. 1
Common Pitfalls to Avoid
Do not proceed directly to surgery for stage II-III disease without considering neoadjuvant chemotherapy, as this misses the opportunity to deliver systemic therapy when patients are most fit. 1, 3
Do not assume postoperative chemotherapy will be completed—nearly half of patients cannot complete adjuvant therapy due to surgical complications, poor performance status, or patient refusal. 4
Do not use surgery alone for cT4 disease—these patients have significantly worse outcomes without multimodal therapy. 3