Perioperative FLOT in gastric cancer: completing the regimen

A 59-year-old woman has an adenocarcinoma of the gastric body, with wall thickening and two suspicious lymph nodes on CT. Staging laparoscopy shows no peritoneal implants. The team indicates perioperative chemotherapy with FLOT, but she has lost 9 kilos in the last three months, eats little and gets tired climbing a flight of stairs. After the second cycle, she arrives with diarrhea and neutropenia, and the oncologist wonders whether she will be able to complete the four cycles before surgery and, even more, the four after it. The scene is fictional and was written for teaching.

This text uses the case as a clinical reasoning scenario for students and health professionals. The topic is perioperative chemotherapy with FLOT in operable gastric and gastroesophageal junction cancer, based on the FLOT4 trial. The question Dr. Alexei proposed brings together two points from the list: who is a good candidate for FLOT, and how selection, nutrition and support influence the chance of finishing the full regimen? The text does not replace your country's guideline or your institution's protocol. If you play the case of the day on NEXO, you will recognize the pattern: an excellent plan on paper can fail because nobody looked at who will receive it.

Key points

• FLOT4 showed that perioperative FLOT prolongs survival compared with the epirubicin regimen, with a median of 50 versus 35 months.
• The regimen has four cycles before and four after surgery, every 2 weeks.
• Fewer than half of the patients in FLOT4 completed the entire planned treatment, and the postoperative phase is the one most often lost.
• Sarcopenia and weight loss at diagnosis are associated with early discontinuation and more complications.
• Careful selection, nutritional support and early management of toxicity increase the chance of completing the plan.
• Tumors with microsatellite instability deserve special attention before deciding on chemotherapy.

Why this is a reasoning scenario

Surgery alone cures a small share of patients with locally advanced gastric cancer. The MAGIC trial, published in 2006, showed that chemotherapy before and after surgery increased 5-year survival from 23 to 36 per 100 patients, as Geerts and colleagues summarize in the introduction to their Dutch analysis (Geerts and colleagues, 2024). FLOT4 took the next step and replaced the anthracycline regimen with a regimen containing docetaxel and oxaliplatin.

The gain was clear, but it came at a price. FLOT is intense, and the patient with gastric cancer often arrives malnourished, sometimes with partial obstruction or bleeding. The decision, therefore, is not just choosing the best regimen. It is choosing the right regimen for the right person and creating the conditions for that person to reach the end. Anyone who looks only at the trial's median survival forgets that this number was obtained in selected patients followed closely.

Clinical reasoning here has three steps. The first is to confirm that the tumor is operable and that staging is complete, including the peritoneum. The second is to assess whether the patient tolerates the regimen, looking at function, nutrition and comorbidities. The third is to plan support from day one, and not only when toxicity appears. The series has already covered staging in the post on staging failures in gastric cancer and the team's work in the post on nutrition and surgical preparation.

What makes this error easy to make

In the office, the patient often downplays weight loss and fatigue, and the doctor, eager to start, may do the same. Nutritional assessment is left for later, the CT is not read for body composition and the first appointment with the dietitian only happens when the patient has already lost more weight. Each of these delays reduces the chance of completing the postoperative phase, which is precisely the most fragile one.

What FLOT4 tested and showed

FLOT4-AIO was a German phase 2 and 3 study that compared perioperative FLOT with ECF or ECX (epirubicin, cisplatin and fluorouracil or capecitabine) in patients with locally advanced, operable gastric or gastroesophageal junction adenocarcinoma. Farrokhi and colleagues report that 356 patients were randomized to FLOT and 360 to ECF or ECX (Farrokhi and colleagues, 2022).

Median overall survival was 50 months with FLOT versus 35 months with ECF or ECX, with a hazard ratio of 0.77, according to the table of reference studies in the review by Irino and colleagues (Irino and colleagues, 2021). Median disease-free survival was 30 versus 18 months, and complete resection occurred in 85 versus 78 per 100 patients, according to Nappo and colleagues (Nappo and colleagues, 2023). The pathological complete response rate was 16 per 100 patients with FLOT versus 6 with ECF or ECX, according to Sisic and colleagues (Sisic and colleagues, 2023).

A network meta-analysis by Cai and colleagues, with 8 studies and 2,434 patients, placed perioperative FLOT as the strategy with the highest probability of survival benefit compared with surgery alone, with a hazard ratio of 0.58 (Cai and colleagues, 2018). Indirect comparisons like this have limits, but the direction of the result is consistent with the randomized study.

What FLOT4 did not answer

The study was conducted at European centers, with high-volume surgery and patients in good functional status. It did not compare FLOT with the adjuvant regimens used in Asia, such as S-1 or capecitabine with oxaliplatin after surgery, which remain the standard in several countries. The review by Irino and colleagues notes that FLOT4 changed practice in Europe, while Japan and Korea kept the adjuvant strategy based on their own studies (Irino and colleagues, 2021).

The regimen and the schedule

The protocol described by Glatz and colleagues, identical to that of FLOT4, uses four 2-week cycles before and four after surgery, with docetaxel 50 mg/m², folinic acid 200 mg/m², fluorouracil 2,600 mg/m² as a 24-hour infusion and oxaliplatin 85 mg/m², all on day 1 (Glatz and colleagues, 2020). Surgery usually takes place 4 to 6 weeks after the last preoperative cycle, and the postoperative phase begins 4 to 8 weeks after the operation in the same paper. Check the package insert and your service protocol before prescribing.

• Preoperative phase: four cycles, about 8 weeks.
• Interval until surgery: about 4 to 6 weeks, with restaging.
• Surgery: gastrectomy with D2 lymphadenectomy at an experienced center.
• Recovery: 4 to 8 weeks, with attention to eating after gastrectomy.
• Postoperative phase: four more cycles, if conditions allow.

The schedule shows why treatment is long. From the first cycle to the last, the patient spends about 6 months in treatment. Any surgical complication, weight loss or infection can delay or cancel the final phase.

Who is a good candidate

The typical candidate has locally advanced gastric or gastroesophageal junction adenocarcinoma, without distant metastasis, with a tumor that can be removed. Real-world registries tend to use criteria similar to those of the study: the Dutch analysis by Geerts and colleagues included resectable tumors classified as cT2 to cT4a, with any lymph node status and no metastasis (Geerts and colleagues, 2024). Glatz and colleagues treated patients with cT3 or cT4 tumors and/or clinically involved lymph nodes (Glatz and colleagues, 2020).

Functional status weighs as much as the stage. Patients with good performance, adequate renal and liver function and no major neuropathy tolerate the regimen better. Advanced age, cardiac comorbidities and severe malnutrition are not automatic contraindications, but they require discussion about dose adjustment or two-drug regimens.

Before starting

• Confirm staging with computed tomography and, when indicated, laparoscopy with peritoneal lavage cytology.
• Request microsatellite instability or mismatch repair proteins on the biopsy.
• Assess weight, recent loss, intake and muscle strength.
• Review renal function, liver function and blood count.
• Assess dysphagia, obstruction and bleeding, which may require an alternative route for nutrition.
• Agree with the surgery team on the likely date of the operation.

The weight of microsatellite instability

Nappo and colleagues analyzed 265 patients treated with FLOT at Italian centers and found high instability in about 10 in every 100 tumors (Nappo and colleagues, 2023). These tumors appeared more often in women, in people over 70 and in the antrum, and had better survival than the stable ones. The authors note that earlier studies suggested little benefit from fluoropyrimidine chemotherapy in this group. The test result should therefore be available before defining the strategy, and the discussion may include studies with immunotherapy.

When to choose another path

Not every patient with an operable tumor should receive FLOT. People who are very frail, with significant functional loss, renal failure or severe heart disease, may benefit more from a two-drug regimen or from surgery followed by adjusted adjuvant treatment. The Asian studies with S-1 or with capecitabine and oxaliplatin after gastrectomy offer another reference, cited by Irino and colleagues. The choice must be recorded with the reason, so that the team and the patient understand what was changed and why. Consciously choosing a less intensive regimen is different from giving up on curative treatment.

Nutrition and body composition

Malnutrition is common in gastric cancer and often goes unnoticed in patients with overweight. Staging CT allows muscle mass to be measured at the level of the third lumbar vertebra, with no extra exam. Rinninella and colleagues studied patients before and after preoperative FLOT and found sarcopenia in about 73 in every 100 at diagnosis (Rinninella and colleagues, 2021). During chemotherapy, body mass index, skeletal muscle index and visceral fat fell significantly in the same group.

Muscle mass is not just a number. Koch and colleagues showed that sarcopenic patients treated with perioperative chemotherapy and surgery stopped chemotherapy earlier (50 versus about 23 in every 100) and had more severe complications after the operation (about 43 versus 17 in every 100) (Koch and colleagues, 2019). Survival was also lower in this group.

Huemer and colleagues, at an Austrian center, found a significant drop in skeletal muscle index during preoperative FLOT and an association between sarcopenia before treatment and worse progression-free survival, with a hazard ratio of 5.08 (Huemer and colleagues, 2023). The number of patients was small, and the confidence interval is wide, but the direction repeats across studies.

What to do with this information

The first step is to measure. Current weight, loss in recent months, intake and muscle mass must be in the medical record before the first cycle. The second is to act: nutritional counseling, oral supplements, treatment of dysphagia and, when necessary, enteral nutrition by tube or jejunostomy. The third is to reassess at every cycle, because the loss continues during treatment. Supervised exercise and control of symptoms such as nausea, mucositis and diarrhea help maintain intake.

After gastrectomy

Eating changes a great deal after total or partial removal of the stomach. Early satiety, dumping syndrome, diarrhea and intolerance to some foods are common in the first months, and the patient may lose weight even when eating regularly. This is exactly the period when the postoperative phase of FLOT should begin. Small, frequent meals, high-calorie-density supplements, vitamin B12 and iron replacement when indicated, and guidance on separating liquids from solids are part of the care. In patients who reached surgery already malnourished, a feeding jejunostomy performed during the same operation can ensure intake while the oral route adjusts.

Finishing the regimen: where patients get lost

The preoperative phase is usually completed by most patients. At the Heidelberg center, Sisic and colleagues report that about 94 in every 100 patients treated with FLOT completed all planned cycles before surgery (Sisic and colleagues, 2023). The problem comes after the operation.

Yang and colleagues note that only about 46 in every 100 FLOT4 patients completed all planned treatment, partly because of postoperative complications and intolerance (Yang and colleagues, 2023). At the authors' own center, 24 in every 100 patients in the perioperative group did not receive the planned adjuvant phase. This loss drove interest in total neoadjuvant chemotherapy, in which all cycles are given before surgery. In Yang's study, patients on this strategy received more cycles with all drugs, with no difference in surgical complications, but the comparison was retrospective and the choice depended on the initial response.

Toxicities that interrupt treatment most

• Neutropenia: was the most common serious event in RealFLOT, in about 20 in every 100 patients in the preoperative phase.
• Diarrhea and mucositis: reduce intake and speed up weight loss.
• Oxaliplatin neuropathy: builds up over the cycles and may require stopping the drug.
• Fatigue and functional loss: weigh more after gastrectomy.
• Surgical complications: fistula and infection delay or cancel the final phase.

Colony-stimulating factor use, early dose adjustment and prompt treatment of diarrhea are measures that help keep to schedule. Frank conversation with the patient about what to expect also matters.

How the team increases the chance of completing treatment

Completing the regimen does not depend on the oncologist alone. The nurse who advises the patient about fever and diarrhea, the dietitian who tracks weight at every cycle, the surgeon who respects the agreed interval and the pharmacist who reviews interactions form the network that keeps to schedule. When each works in isolation, small delays add up. A cycle postponed for neutropenia pushes back surgery, delayed surgery pushes back recovery, and slow recovery makes the decision about the postoperative phase hard.

A few simple measures usually help. Setting all dates at the start, with surgery already scheduled, reduces improvisation. Having a direct channel for the patient to report symptoms keeps a two-day bout of diarrhea from becoming a hospital admission. Reviewing weight and intake at every visit allows action before major loss. And discussing the case again at a multidisciplinary meeting after surgery, with the specimen and the recovery in hand, helps decide honestly whether the final phase is worth the risk. This reassessment is different from giving up: it means adjusting the plan to the person who came out of surgery, who is not always the same one who went in.

What real-world data show

Studies outside the clinical trial show similar results, but with nuances. RealFLOT, an Italian prospective study with 206 patients at 15 centers, reports that about 60 in every 100 received at least 4 cycles at full dose, 92 in every 100 underwent surgery and about 69 in every 100 started the postoperative phase (Giommoni and colleagues, 2021). Of these, some received de-intensified regimens according to clinical condition. Complete pathological response occurred in about 7 in every 100 patients, and 30-day mortality after surgery was 1 in every 100.

In the Netherlands, Geerts and colleagues compared FLOT with anthracycline regimens in registry data and found no significant difference in adjusted survival, although the median was numerically higher with FLOT (48.1 versus 39.9 months) (Geerts and colleagues, 2024). Patients on FLOT completed the preoperative phase more often, moved on to the adjuvant phase more often and had more complete pathological responses.

In Heidelberg, after 10 years of use, Sisic and colleagues report complete resection in 93 versus 79 in every 100 patients with FLOT and with the previous regimen, with no difference in perioperative morbidity and mortality (Sisic and colleagues, 2023). A retrospective Iranian study by Farrokhi and colleagues also favored FLOT over DCF, FOLFOX and ECF, but with a small number of patients (Farrokhi and colleagues, 2022).

Source	Type	Main finding	Lesson for practice
FLOT4 (summarized by Irino and Nappo)	Randomized	Median of 50 versus 35 months; hazard ratio 0.77	FLOT is the perioperative standard in the West for fit patients
Yang and colleagues	Retrospective	Only about 46 in every 100 completed everything in FLOT4	Plan the postoperative phase from the start
RealFLOT	Prospective observational	About 69 in every 100 started the postoperative phase	Real life loses patients after surgery
Koch and colleagues	Cohort	Sarcopenia linked to early discontinuation and complications	Measure muscle mass on the staging CT scan
Geerts and colleagues	National registry	No significant difference in adjusted survival	Results outside the trial depend on selection and support

Pathological response, recurrence and follow-up

The surgical specimen carries important prognostic information. Schirren and colleagues analyzed 702 patients treated with chemotherapy before surgery and showed that histopathological tumor regression was a strong predictor of survival (Schirren and colleagues, 2020). FLOT had the highest regression rate among the regimens evaluated, about 37.5 in every 100 patients.

Recurrence is usually early. Glatz and colleagues report that the median time to recurrence was 9 months and that 89 in every 100 recurrences occurred in the first 24 months (Glatz and colleagues, 2020). After surgery for gastric cancer, the main site was the peritoneum, in 56 in every 100 recurrences. Follow-up should be closer in the first two years and alert to signs of carcinomatosis, such as ascites, early satiety and obstruction.

The adjuvant phase after a poor response

When the pathologist shows little regression, the question arises of whether to keep the same regimen in the postoperative phase. There is no definitive answer. In the study by Glatz and colleagues, adjuvant chemotherapy was an independent predictor of recurrence-free survival, but not of overall survival (Glatz and colleagues, 2020). The decision should consider tolerance, recovery and the patient's wishes. The post on diagnostic uncertainty offers strategies for this conversation.

How NEXO helps train this reasoning

In NEXO, the case of the day is fictional, with a real clinical presentation and up to six progressive clues, and you propose the diagnosis by looking for the ICD-10 code. FLOT is a good exercise because the decisive question is not which regimen to choose, but whether that patient will be able to receive it in full. The post on differential diagnosis shows how to organize the clues, and the post on clinical decision-making helps you think about what to measure before starting.

Three exercises with cases

Change the age. Say how you would adjust the plan for a 78-year-old patient, active, with the same tumor.

Change the nutrition. Say what you would do if the CT scan showed severe sarcopenia and the patient had dysphagia for solids.

Change the report. Say how you would talk with the patient if the biopsy showed high microsatellite instability.

The post on diagnostic pause reminds you to stop before starting a long treatment. The limits on using the game are described on the NEXO economy page. If you research the teaching of clinical reasoning, the page for researchers explains how to get in touch. Professionals who write or review cases find information under curation and creators, and institutions can learn about the proposal on the partnerships page.

Frequently asked questions

How much does FLOT increase survival?

In FLOT4, the median was 50 months with FLOT versus 35 months with ECF or ECX, with a hazard ratio of 0.77 (Irino and colleagues, 2021).

What are the FLOT doses?

Docetaxel 50 mg/m², folinic acid 200 mg/m², fluorouracil 2,600 mg/m² over 24 hours and oxaliplatin 85 mg/m², on day 1, every 2 weeks, four cycles before and four after surgery (Glatz and colleagues, 2020). Check the package insert and the local protocol.

How many patients complete the treatment?

In FLOT4, about 46 in every 100 completed the entire planned treatment (Yang and colleagues, 2023). The biggest loss happens in the postoperative phase.

Does sarcopenia contraindicate FLOT?

Not necessarily, but it is associated with early discontinuation and more complications (Koch et al., 2019). It calls for nutritional support and closer follow-up.

Why test for microsatellite instability beforehand?

Because these tumors behave differently and may benefit less from chemotherapy with fluoropyrimidine, according to the data cited by Nappo et al. (Nappo et al., 2023).

Final checklist

• I confirmed the staging, including the peritoneum when indicated.
• I requested microsatellite instability or repair proteins.
• I recorded weight, recent loss, intake and muscle mass.
• I referred the patient to nutrition before the first cycle.
• I checked doses, renal and liver function.
• I agreed on the likely date of surgery.
• I explained the full schedule, including the postoperative phase.
• I planned closer follow-up in the first two years.

Want to practice your reasoning with progressive clues? Play the case of the day.

References

1. Cai Z, Yin Y, Zhao Z, et al. Comparative Effectiveness of Neoadjuvant Treatments for Resectable Gastroesophageal Cancer: A Network Meta-Analysis. Front Pharmacol. 2018. PMID 30127746.
2. Farrokhi P, Sadeghi A, Sharifi M, et al. Efficacy and safety of FLOT regimen vs DCF, FOLFOX, and ECF regimens as perioperative chemotherapy treatments for resectable gastric cancer patients; a report from the middle east. Res Pharm Sci. 2022. PMID 36704436.
3. Geerts JFM, van der Zijden CJ, van der Sluis PC, et al. Perioperative Chemotherapy for Gastro-Esophageal or Gastric Cancer: Anthracyclin Triplets versus FLOT. Cancers (Basel). 2024. PMID 38610969.
4. Giommoni E, Lavacchi D, Tirino G, et al. Results of the observational prospective RealFLOT study. BMC Cancer. 2021. PMID 34625033.
5. Glatz T, Verst R, Kuvendjiska J, et al. Pattern of Recurrence and Patient Survival after Perioperative Chemotherapy with 5-FU, Leucovorin, Oxaliplatin and Docetaxel (FLOT) for Locally Advanced Esophagogastric Adenocarcinoma in Patients Treated Outside Clinical Trials. J Clin Med. 2020. PMID 32824326.
6. Huemer F, Hecht S, Scharinger B, et al. Body composition dynamics and impact on clinical outcome in gastric and gastro-esophageal junction cancer patients undergoing perioperative chemotherapy with the FLOT protocol. J Cancer Res Clin Oncol. 2023. PMID 35864270.
7. Irino T, Matsuda S, Wada N, et al. Essential updates 2019/2020: Perioperative and surgical management of gastric cancer. Ann Gastroenterol Surg. 2021. PMID 33860136.
8. Koch C, Reitz C, Schreckenbach T, et al. Sarcopenia as a prognostic factor for survival in patients with locally advanced gastroesophageal adenocarcinoma. PLoS One. 2019. PMID 31639132.
9. Nappo F, Fornaro L, Pompella L, et al. Pattern of recurrence and overall survival in esophagogastric cancer after perioperative FLOT and clinical outcomes in MSI-H population: the PROSECCO Study. J Cancer Res Clin Oncol. 2023. PMID 36795195.
10. Rinninella E, Strippoli A, Cintoni M, et al. Body Composition Changes in Gastric Cancer Patients during Preoperative FLOT Therapy: Preliminary Results of an Italian Cohort Study. Nutrients. 2021. PMID 33809587.
11. Schirren R, Novotny A, Friess H, et al. Histopathologic Response Is a Positive Predictor of Overall Survival in Patients Undergoing Neoadjuvant/Perioperative Chemotherapy for Locally Advanced Gastric or Gastroesophageal Junction Cancers-Analysis from a Large Single Center Cohort in Germany. Cancers (Basel). 2020. PMID 32796715.
12. Sisic L, Crnovrsanin N, Nienhueser H, et al. Perioperative chemotherapy with 5-FU, leucovorin, oxaliplatin, and docetaxel (FLOT) for esophagogastric adenocarcinoma: ten years real-life experience from a surgical perspective. Langenbecks Arch Surg. 2023. PMID 36763220.
13. Yang J, Greally M, Strong VE, et al. Perioperative versus total neoadjuvant chemotherapy in gastric cancer. J Gastrointest Oncol. 2023. PMID 37435205.