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04 Jul 2019
Gastrointestinal cancers
Shah Zeb Khan
Shah Zeb Khan

Gastroesophageal junction (GEJ) and gastric adenocarcinoma prognosis remains poor despite of recent advancement in therapies. Multimodal approach represents the standard of care for treatment of resectable oesophageal and gastric cancer patients today, especially in the case of GEJ and cardial tumors. In fact, various trials showed an improvement in overall survival (OS) by using a perioperative treatment if compared with surgery.

MAGIC trial is the first landmark trial, which showed overall survival (OS) improvement with perioperative chemotherapy in resectable gastric (74%), GEJ junction (11-12%) and lower esophageal adenocarcinoma (14-15%) (1). Patients received 3 cycles of ECF/ECX in pre and post operative settings. The experimental arm showed significant improvement in 5 year OS (36%) with hazard ratio (HR) for death of 0.75 (95% Confidence interval (CI) 0.60-0.93, p=0.0009) as compared to surgery alone (23%). Another landmark phase III trial done was FNCLCC/FFCD (2). It has similar design to MAGIC trial and patient received 2-3 cycles of Cisplatin and 5-Flourouracil before and after surgery. Control group underwent surgery alone and there was significant improvement in OS seen in chemotherapy group (38% vs 24%) with HR for death of 0.69 (95% CI, 0.50-0.89, p= 0.02). Both MAGIC and FNCLCC/FFCD demonstrated a significant improvement in OS in pts treated with perioperative chemotherapy regardless of anatomical location of tumor (GEJ or gastric) making this strategy a new standard of care in Europe.

The role of Docetaxel has been investigated in gastric cancer in different settings and exerted significant activity in clinical trials (3). The classical DCF (taxane + platinum + fluoropyrimidine) regimen was associated with high toxicity profile with tolerability issues, failing to perform betterment than doublets, frontline. Eventually, the FLOT regimen was evaluated in phase II trial in metastatic or unresectable gastric cancer patients (4).

Significant clinical responses were seen in patients with more acceptable safety profile than classical DCF.

Recently, randomized phase II/III trial of FLOT4 for locally advanced resectable gastric (44%) or GEJ (siewert I-II-III, 56%) non-metastatic adenocarcinoma was published in Lancet Journal (5). 716 patients underwent randomization in which 360 were assigned to the standard regimen MAGIC with ECF/ECX (3 weekly cycle of Epirubicin=50mg/m2 D1, Cisplatin= 60mg/m2 D1, 5-FU= 200mg/m2 continous IV infusion D1-D21 or Oral Capecitabine= 1250mg/m2 BID D1-D21 on investigator's choice) and 356 to FLOT ( biweekly cycle of Docetaxel= 50mg/m2 D1, Oxaliplatin= 85mg/m2 D1, Leucovorin 200mg/m2 D1 and 5-FU= 2600mg/m2 24 hour infusion D1). Patient with ECOG 0-2 were included and interestingly 24% population was more than 70 years of age. Surgery was done after 4 weeks of last chemotherapy dose. The primary outcome was OS and disease free survival (DFS) with intention to treat (ITT) analysis. There were 11 progression or early deaths in ECF/ECX as compared to 6 patients in FLOT group after 4 preoperative chemotherapy. The estimated 5 year OS was 45% in FLOT group and 36% in ECF/ECX. Median OS in FLOT group was about 50 months as compared to 35 months in In the standards arm. More patients with ypN0 stage were seen in FLOT Group ( 49% vs 41% , p=0.025). Patients achieving margin negative surgery (R0) were more in FLOT group (85% vs 78%, p=0.0162). Median DFS was 30 months in FLOT group and 18 months in ECF/ECX (HR 0.75,95% CI,0.62-0.91;p=0.0036). Regarding surgical morbidity and mortality, similar outcomes were observed in both group (30 days post-op mortality = 2% in the FLOT group and 3% in the ECF/ECX group) and surgical complications (51% in the FLOT group and 50% in the ECF/ECX). The FLOT was beneficial in all the subgroups analyzed, such as proximal versus distal tumors ( including Siewert I tumors). More grade III/IV toxicities of infection (18%), neutropenia (51%), diarrhea (10%) and leukopenia(27%) were seen in FLOT group as compared to ECF/ECX. The authors concluded that FLOT can be considered as new standard of care in perioperative setting for locally advanced resectable GEJ and gastric adenocarcinomas as it showed significant OS improvement compared to conventional ECF/ECX.

It will be interesting to note that could these results be generalized globally including asian population. There exist clear differences in the both the surgical and adjuvant treatments as well as the long term outcomes in the treatment of gastric cancer between the East and the West (6). Based on this, the question is if FLOT could be effective also in the non-western population. Also previous studies have documented that Asian population have more frequency of taxane related toxicities so the dose tolerability could be an issue with FLOT (52%, grade III/IV neutropenia) seen (7).

References

  1. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastro-esophageal cancer. N Engl J Med 2006; 355: 11-20.
  2. Ychou M, Boige V, Pignon JP, et al. Perioperative chemotherapy compared with surgery alone for resectable gastro-esophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol 2011; 29: 1715-21.
  3. Van Cutsem E, Moiseyenko VM, Tjulandin S, et al. Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol 2006; 24: 4991-97.
  4. Al-Batran SE, Hartmann JT, Hofheinz R, et al. Biweekly fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) for patients with metastatic adenocarcinoma of the stomach or esophagogastric junction: a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol 2008; 19: 1882-87.
  5. Al-Batran, S.-E. 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): a randomised, phase 2/3 trial. Lancet https://doi.org/10.1016/S0140-6736(18)32557-1 (2019)
  6. Bickenbach K, Strong VE. Comparisons of Gastric Cancer Treatments: East vs. West. J Gastric Cancer. 2012 Jun;12(2):55-62. https://doi.org/10.5230/jgc.2012.12.2.55
  7. Kenmotsu H, Tanigawara Y. Pharmacokinetics, dynamics and toxicity of docetaxel: Why the Japanese dose differs from the Western dose. Cancer Sci. 2015;106(5):497-504. doi:10.1111/cas.12647

Discussion question

  1. Should FLOT be adopted as new standard of care especially for siewert I/II tumors of GEJ, where the current standard of care includes concurrent chemoradiotherapy
  2. Should the triplet with a taxane be used in adjuvant settings after upfront surgical resection?
Last update: 04 Jul 2019

Shah Zeb Khan declares no conflict of interest

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