We read with great interest the phase 2 randomized trial FLOT4-AIO. Al-Batran et al. have published the results of the phase 2 part of this phase 2/3 randomized controlled trial (RCT). They have compared FLOT (Docetaxel, Oxaliplatin, 5FU and leucovorin) regimen to the standard neoadjuvant regimen [ECX/epirubicin, cisplatin and 5-flourouracil (ECF)] (1). The primary end point for this trial was tumour regression grade (TRG1a as per Becker’s criteria) of primary tumor. All age group of patients with non-metastatic gastric and esophagogastric junction adenocarcinoma (GaCaGEJ), > cT2 and/or N+ve, were included and patients with adjacent organ invasion were excluded. The groups compared included 137 patients in ECX/ECF vs. 128 in FLOT group in a modified intention to treat analysis. The significant findings included an improved resectability rate, favorable pT stage and R0 resection rate with the use of FLOT. FLOT also resulted in an improved overall TRG1a and TRG1a + 1b and an improved TRG1a + 1b in the intestinal histology, without any increase in perioperative outcomes and non-surgical adverse events (1).
The level I evidence favoring the use of neoadjuvant chemotherapy (NAC) for GaCaGEJ was generated following the publication of landmark MAGIC trial in 2006 (2). This landmark phase III RCT compared six cycles of ECF administered peri-operatively to surgery alone for treatment of non-metastatic ≥ stage II GaCaGEJ cancers. The salient findings in favor of NAC were a significant T and N downstaging, improvement in R0 resection, disease free survival (DFS) and overall survival (OS), without any added morbidity and mortality (2). Subsequently, French FNLCC ACCORD 07 trial, which used the doublet of cisplatin and 5-flourouracil (CF) echoed the results of the MAGIC trial (3). In the real world-setting, a study has also shown that it is possible to replace cisplatin and 5-fluorouracil with oxaliplatin and capecitabine (EOX) without compromising delivery of care and efficacy (4).
Subsequently, EORTC 40954 was stopped due to poor accrual, but showed a significantly higher R0 resection rate with NAC without an associated improvement in survival (5). Another phase III trial, which was also closed early, compared NAC to NAC followed by chemoradiotherapy (CRT) (6). Addition of CRT resulted in a significantly higher percentage of pathological complete response rate (pCR) and node negativity but non-significant improvement in survival (6). These two phase III trials failed to show survival advantage, but showed that neoadjuvant therapy improves R0 resection and pCR rate for GaCaGEJ (5,6). The CROSS trial, has shown that preoperative CRT is associated with significantly higher R0 resection, pCR rate and OS as compared to surgery alone (7). However, despite the use of neoadjuvant treatment options the 5-year OS as per these RCTs for GaCaGEJ has still not improved markedly.
Docetaxel, platinum (cisplatin/oxaliplatin) and 5-Flourouracil (5-FU) has been used as the regimen of choice for metastatic GaCaGEJ and the use of taxanes has been shown to be an independent prognostic factor if used in first-line setting (8) though DCF has been shown to be associated with substantial toxicity (9). FLOT (Docetaxel, Oxaliplatin, 5-Flourouracil and Leucovorin) has been evaluated in a phase II trial and has been found to be safe and efficacious for metastatic GaCaGEJ (9). FLO (Oxaliplatin, 5-Flourouracil and Leucovorin) was compared to FLP (Cisplatin, 5-Flourouracil and Leucovorin) in a phase III RCT and the former was associated with favorable toxicity profile in all age groups and significantly better response rate, PFS and OS in elderly (>65 years) patients (10). FLOT has been compared to FLO in a phase III RCT in elderly (>65 years) metastatic and locally advanced GaCaGEJ (11). FLOT was associated with significantly higher grade 3/4 adverse events and worse EORTC QOL score (11). However, FLOT significantly improved the response rate and PFS in subgroup of locally advanced and 65–70 years age group (11). The authors have included all age groups in FLOT4, despite a higher toxicity seen in the elderly population. The reason might be that this higher treatment toxicity did not translate into treatment discontinuations and deaths in this study (11).
Neoadjuvant docetaxel, cisplatin and 5-FU (DCF) regimen has been shown to be associated with 5-year OS of 54% in a retrospective study (12). Preoperative DCF has been compared to postoperative DCF for locally advanced gastric adenocarcinoma in a recently published phase III RCT. The trial was closed due to poor accrual, but showed a pCR of 12% with DCF (13). FLOT regimen has been studied in neoadjuvant setting in a multicenter phase II trial (14). Six cycles of this regimen resulted in a R0 resection of 86%, TRG1a rate of 20% and TRG1a + 1b rate of 40% (14). Majority (85%) of these excellent responders in this study were intestinal type (14). The pCR rate following FLOT regimen and better pCR rates for intestinal histology are similar to those observed in FLOT4 trial and are therefore not new findings. However, comparison of FLOT to epirubicin triplet regimen has never been attempted prior to this study in a randomized setting.
The pathological response of various neoadjuvant therapies has varied, based on the type of regimen and incorporation of radiation. The pCR rate with the use of epirubicin based chemotherapy have ranged from 6–8% (15,16). The use of docetaxel based chemotherapy has increased the pCR rate upto 20% as seen in Neo-FLOT (14). However, CRT has improved pCR rates even further, upto 29% in CROSS trial (7). The findings of FLOT-4 therefore confirm that docetaxel based regimen improved pCR rates.
Pathological tumor regression following chemotherapy has been found to be associated with pT, pN, R0 rate and is an independent predictor of survival in a clinic-pathological study of 480 resected GaCaGEJ (17). Major tumor regression was also less frequent in the non-intestinal variants and distal stomach primary (17). In FLOT 4 trial, the FLOT regimen resulted in a higher proportion of patients with TRG1a and 1b (1). Similarly this group has a more favorable pT stage and R0 resection rates, but not pN stage (1). TRG1a + 1b rates are better in the intestinal variant, however do not vary as per the tumor location (1). A large multi-institutional retrospective German study has also shown that pathological response rate is associated with a better survival and taxane based triplet regimen showed a trend towards OS (18). It would be interesting to see if the better TRG seen with in FLOT-4, mainly in the intestinal histology, will translate to an improvement in survival.
The authors have used Becker’s grading in FLOT 4 (1). A recent study has compared various tumor regression grading criteria—Mandard, the Japanese Gastric Cancer Association, College of American Pathologists, China and Becker-TRG systems (19). TRG was not found to be an independent predictor of survival, however Mandard system was recommended due to its better prediction of prognosis (19). The RCTs should adopt a single TRG-system for uniform reporting of results.
The drawbacks of this trial are low compliance rates seen with both the chemotherapy regimens, exclusion of patients with adjacent organ invasion (cT4b) which in our opinion could have been included. Taxane—based regimens increase pCR rates and can form an important component for neoadjuvant treatment strategies in patients with resectable gastric or esophagogastric adenocarcinoma.
Conflicts of Interest: The authors have no conflicts of interest to declare.
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Cite this article as: Mitra A, Shrikhande SV, Sirohi B. Histopathological regression after taxane based neoadjuvant chemotherapy in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma. Transl Gastroenterol Hepatol 2017;2:46.