Mandard Regression : How to interpret after neoadjuvant chemotherapy and surgery ? A meta-analysis
- Mandard/TRG
after neoadjuvant FLOT is both strongly prognostic and predictive
of who benefits from adjuvant FLOT in oesophageal/gastro‑oesophageal
adenocarcinoma.pmc.ncbi.nlm.nih+1
- In
the SPACE‑FLOT cohort (n=1,887), survival benefit from adjuvant FLOT was
essentially confined to partial responders (intermediate TRG).academic.oup
- Partial
responders (≈64% of patients) had significantly improved DFS (HR ≈0.68)
and OS (HR ≈0.55) with adjuvant FLOT versus no adjuvant therapy, even
after multivariable adjustment.pmc.ncbi.nlm.nih+1
- Complete
responders (pCR, ≈12%) had excellent outcomes (2‑year DFS ≈87%) and no
significant additional benefit from adjuvant FLOT, supporting
consideration of omitting postoperative FLOT in this group.academic.oup
- Minimal
responders (worst TRG tier, ≈24%) showed no clear benefit from
adjuvant FLOT in SPACE‑FLOT, but a smaller homogeneous cohort (Heckl et
al.) suggested substantial benefit when all neoadjuvant cycles were
completed, indicating residual uncertainty.pmc.ncbi.nlm.nih+1
- Meta‑analytic
data across neoadjuvant chemotherapy series show that better TRG (lower
Mandard/Becker score) consistently correlates with longer DFS and OS,
confirming TRG as an independent prognostic factor.nature+2
- TRG
is prognostic after neoadjuvant chemotherapy (e.g. FLOT) but much
less so after chemoradiotherapy (e.g. CROSS), so TRG‑guided adjuvant
decisions are more reliable in perioperative‑chemotherapy pathways.esmo+1
- Primary‑tumor
TRG can be discordant from nodal response; some patients with poor Mandard
scores still achieve ypN0 and have good survival, so nodal status and TRG
should be interpreted together when planning adjuvant therapy.pmc.ncbi.nlm.nih+1
- Operationally,
a response‑adapted strategy emerges: give adjuvant FLOT to partial
responders, consider omitting it in complete responders, and individualize
decisions in minimal responders (taking into account tolerance, ypTNM, and
emerging biomarkers such as ctDNA).ascopubs+2
- Future
refinement will likely combine TRG with molecular and liquid‑biopsy
markers to better select who truly needs adjuvant FLOT, aiming to preserve
the survival gains of perioperative FLOT (as shown in ESOPEC) while
reducing unnecessary toxicity.ascopubs+2
The SPACE-FLOT study represents the most definitive evidence
to date on the relationship between Mandard regression grade and adjuvant FLOT
benefit, analyzing 1,887 patients with gastro-oesophageal adenocarcinoma who
received neoadjuvant FLOT and underwent curative-intent surgery across 43
hospitals in 12 countries. With a median follow-up of 25.5 months, the study
demonstrated that pathological response to neoadjuvant FLOT significantly
predicts which patients derive survival benefit from adjuvant FLOT chemotherapy.academic.oup
Partial Responders: Clear Benefit from Adjuvant FLOT
Partial responders, representing 64% of the study population
(1,207 patients), demonstrated significant and substantial benefit from
adjuvant FLOT chemotherapy. Among PR patients who received adjuvant FLOT
versus those who did not, the 2-year disease-free survival (DFS) was 74.5%
versus 61.9%, with an unadjusted hazard ratio of 0.68 (95% CI 0.55-0.86,
p<0.001). This benefit persisted after adjusting for baseline differences
using Cox regression analysis (HR 0.73, 95% CI 0.58-0.92, p=0.007) and
propensity score matching (HR 0.72, 95% CI 0.58-0.88, p=0.002). The overall
survival benefit was even more pronounced, with an adjusted hazard ratio of
0.63 (95% CI 0.50-0.79, p<0.001), translating to a 37% reduction in
mortality risk with adjuvant FLOT. Furthermore, patients who did not receive
adjuvant treatment had significantly higher rates of peritoneal, nodal, bone,
central nervous system, and chest wall recurrence compared to those who
received adjuvant FLOT.academic.oup
Complete Responders: No Significant Benefit from Adjuvant
FLOT
Complete responders, comprising 11.7% of patients (221
patients) who achieved pathological complete response (pCR) to neoadjuvant
FLOT, showed no significant survival benefit from adjuvant FLOT. Among
CR patients, 61.5% received adjuvant FLOT while 38.5% did not. The 2-year DFS
was remarkably similar: 87.9% with adjuvant FLOT versus 86.2% without adjuvant
therapy. After adjusting for baseline characteristics including age, ASA grade,
and surgical complications, the DFS hazard ratio was 0.79 (95% CI 0.35-1.79,
p=0.575) and the overall survival hazard ratio was 0.69 (95% CI 0.29-1.68,
p=0.417). These non-significant findings persisted across multiple analytical
approaches including propensity score matching. The high baseline prognosis in
this group (~87% 2-year DFS) suggests that neoadjuvant FLOT plus surgery may be
sufficient for achieving cure in complete responders, rendering additional
adjuvant chemotherapy of limited value.academic.oup
Minimal Responders: Conflicting Evidence
Minimal responders, representing 24.3% of patients (459
patients) with the worst TRG tier, present a more complex picture with conflicting
evidence regarding adjuvant FLOT benefit. In the SPACE-FLOT study, after
adjustment for baseline characteristics, there was no significant DFS benefit
(HR 1.21, 95% CI 0.89-1.64, p=0.218) or OS benefit (HR 0.96, 95% CI 0.70-1.30,
p=0.801) from adjuvant FLOT in minimal responders. However, a German real-world
cohort study by Heckl et al. (2025) found that patients with minimal/no
histopathologic response (Becker TRG 3) who received adjuvant chemotherapy had
significantly longer survival (OS: 22.3±2.6 months versus 8.7±2.4 months,
p=0.005; tumor-specific survival: 22.3±4.5 months versus 8.7±2.4 months,
p=0.016).pmc.ncbi.nlm.nih+1
The discrepancy between these findings may be explained by
differences in neoadjuvant treatment completion rates. In the SPACE-FLOT
minimal responder cohort, 87.9% of patients who received adjuvant FLOT had
completed all four neoadjuvant cycles, compared to only 66.8% of those who did
not receive adjuvant therapy. This suggests that patients who did not receive
adjuvant therapy were already compromised by poor tolerance to neoadjuvant
treatment, introducing significant selection bias. In contrast, the Heckl study
specifically analyzed only patients who had received at least all four
neoadjuvant FLOT cycles, providing a more homogeneous comparison group and
potentially explaining why adjuvant benefit was observed. These findings
suggest that in minimal responders who tolerate optimal neoadjuvant therapy,
adjuvant FLOT may still provide survival benefit, particularly for controlling
micrometastatic disease that has demonstrated chemoresistance at the primary
tumor site.pmc.ncbi.nlm.nih+1
Prognostic Value of Mandard TRG in Neoadjuvant
FLOT-Treated Patients
Beyond its predictive value for adjuvant therapy benefit,
Mandard TRG serves as a powerful independent prognostic factor in patients with
oesophageal adenocarcinoma treated with neoadjuvant chemotherapy. A recent
meta-analysis by Wu et al. (2025) including 11 studies with 2,733 patients with
locally advanced gastric cancer receiving neoadjuvant chemotherapy demonstrated
that lower TRG scores (better pathological response) were associated with
prolonged disease-free survival (HR 0.53, 95% CI 0.32-0.88) and overall
survival (HR 0.59, 95% CI 0.39-0.87). Sensitivity analysis confirmed the
robustness of these findings, although publication bias was detected for
overall survival outcomes.pmc.ncbi.nlm.nih+2
Studies specifically examining gastric and
gastro-oesophageal junction adenocarcinoma have consistently shown that
patients with Mandard TRG 1-2 (complete or near-complete response) have
superior survival outcomes compared to TRG 3-5 (minimal or no response).
Abboretti et al. (2024) reported that TRG 1-2 patients had significantly better
3-year DFS (81% versus 47%, p=0.041) and a trend toward better 3-year OS (92%
versus 55%, p=0.054) compared to TRG 3-5 patients. Similarly, Athauda et al.
(2023) found in a cohort of 788 patients that those with lower TRG scores had
markedly better survival, with 5-year overall survival of 77% for TRG 1-2
versus 41% for TRG 4-5.nature+3
Importantly, TRG also correlates with other prognostic
factors including ypT stage, ypN stage, and resection margin status. Patients
with better pathological response (lower TRG) are more likely to have lower ypT
and ypN stages, less lymphovascular invasion, and higher R0 resection rates.
However, multivariate Cox regression analyses have demonstrated that TRG
remains an independent predictor of survival even after adjusting for these
pathological features in many studies.pmc.ncbi.nlm.nih+4
Treatment Modality Effects: Neoadjuvant Chemotherapy
versus Chemoradiotherapy
A critical and often overlooked finding is that the
prognostic significance of Mandard TRG differs substantially between
neoadjuvant chemotherapy and neoadjuvant chemoradiotherapy. Capovilla et
al. (2025) analyzed 563 patients with oesophageal adenocarcinoma, comparing 278
patients who received neoadjuvant chemotherapy (NACT; predominantly FLOT
regimen) with 285 patients who received neoadjuvant chemoradiotherapy (NACRT;
predominantly CROSS regimen). The results demonstrated that TRG was
significantly associated with both overall survival (p<0.0001) and
disease-free survival (p<0.0001) after NACT, with distinct separation of
survival curves across TRG categories. However, in the NACRT group, different
TRG subgroups showed comparable survival outcomes, with no significant
correlation between TRG and survival.pmc.ncbi.nlm.nih
This differential effect is hypothesized to result from the
distinct cytotoxic and fibrotic effects induced by chemotherapy versus
chemoradiotherapy on neoplastic tissue. Radiation therapy can induce extensive
fibrosis and cellular changes that may not accurately reflect chemosensitivity,
whereas chemotherapy-induced regression more directly indicates tumor biology
and systemic treatment responsiveness. Consequently, TRG derived from
FLOT-treated specimens appears to be a more reliable biomarker for guiding
adjuvant chemotherapy decisions than TRG from chemoradiotherapy-treated
specimens.pmc.ncbi.nlm.nih
Furthermore, despite higher rates of pathological complete
response after neoadjuvant chemoradiotherapy (19.51% in CROSS) compared to
neoadjuvant chemotherapy (11.54% in FLOT, p=0.06 in one study), this did not
translate into superior long-term survival. The recently published ESOPEC trial
demonstrated that perioperative FLOT resulted in superior 3-year overall
survival (57.4% versus 50.7%, HR 0.70, 95% CI 0.53-0.92, p=0.01) and
progression-free survival (51.6% versus 35.0%, HR 0.66, 95% CI 0.51-0.85) compared
to preoperative CROSS chemoradiotherapy in resectable oesophageal
adenocarcinoma. These findings underscore that pathological response rates
alone do not serve as reliable surrogate endpoints for survival, and that TRG
must be interpreted in the context of the specific neoadjuvant treatment
regimen employed.nature+2
Discordance Between Primary Tumor Regression and Nodal
Response
An important clinical observation is that Mandard TRG at the
primary tumor site does not always correlate with lymph node response to
neoadjuvant chemotherapy. Knight et al. (2021) analyzed 555 patients with
oesophageal adenocarcinoma who received neoadjuvant chemotherapy and found that
27.75% achieved complete nodal response (cN+ to ypN0), yet 61 of 154 complete
nodal responders (39.6%) had high Mandard scores (TRG 4-5) indicating poor
primary tumor response. Conversely, among 332 patients with Mandard 4-5 scores,
61 (18.4%) achieved complete nodal response.pmc.ncbi.nlm.nih+1
Similarly, Kang et al. (2022) reported that among patients
with high Mandard scores (4-5), 49.4% demonstrated tumor regression on imaging
evaluation and 19.0% achieved ypN0 stage despite poor primary tumor response.
The median survival for high-Mandard-score patients who achieved ypN0 was 76.7
months compared to 14.5 months for low-Mandard-score (1-2) patients with ypN3a
stage. These findings suggest that neoadjuvant chemotherapy can produce
beneficial effects on lymph node metastases and overall tumor burden even when
primary tumor regression is limited, and that both primary tumor TRG and nodal
response should be considered when evaluating treatment efficacy and planning
adjuvant therapy.pmc.ncbi.nlm.nih
Implications for Clinical Practice and Personalized
Treatment
The accumulated evidence supports a response-adapted
approach to adjuvant FLOT therapy based on Mandard tumor regression grade
following neoadjuvant FLOT chemotherapy. Specifically:pmc.ncbi.nlm.nih+1
For partial responders (Mandard TRG 2-3 or intermediate
Becker grades): Strong evidence supports administration of four cycles of
adjuvant FLOT post-surgery. These patients, representing the majority (~64%) of
those treated with neoadjuvant FLOT, derive substantial survival benefit with
hazard ratios of 0.68 for disease-free survival and 0.55 for overall survival.
Adjuvant therapy completion rates in this group are reasonably high (~77%), and
the number needed to treat to prevent one recurrence or death is favorable.academic.oup
For complete responders (Mandard TRG 1 or Becker TRG 1a):
Adjuvant FLOT can potentially be omitted given the lack of survival benefit and
excellent baseline prognosis (2-year DFS ~87%). This approach would spare
approximately 12% of patients from unnecessary chemotherapy toxicity while
maintaining excellent oncological outcomes. However, emerging data on
circulating tumor DNA (ctDNA) monitoring suggests that even among complete
responders, some patients harbor minimal residual disease detectable by liquid
biopsy, and these ctDNA-positive patients may benefit from adjuvant therapy.
Therefore, in the future, integration of ctDNA testing with TRG assessment may
further refine patient selection for adjuvant therapy in complete responders.ascopubs+1
For minimal responders (Mandard TRG 4-5 or Becker TRG 3):
The decision regarding adjuvant FLOT requires individualized assessment.
Patients who tolerated all four neoadjuvant FLOT cycles and achieved R0
resection may derive survival benefit from adjuvant therapy despite poor
primary tumor response, as adjuvant treatment targets micrometastatic disease
with potentially different biology than the primary tumor. However, patients
who experienced significant toxicity during neoadjuvant treatment or have
compromised performance status post-surgery are unlikely to benefit and should
be considered for alternative approaches including enrollment in clinical
trials evaluating novel targeted agents or immunotherapy based on molecular
profiling. Notably, targetable biomarkers including PD-L1 (53.4%), Claudin 18.2
(26.2%), and HER2 (7.8%) are commonly detected in the TRG 2-3 minimal/partial
responder subset, offering opportunities for precision oncology approaches.pmc.ncbi.nlm.nih
Comparison with Other Tumor Regression Grading Systems
While the Mandard system remains the most widely used TRG
classification for oesophageal cancer, the Becker system has demonstrated
superior inter-observer reproducibility. Mirza et al. (2012) compared Mandard,
Becker, and Japanese Society for Esophageal Disease (JSED) TRG systems in
gastric and gastro-oesophageal junction adenocarcinoma and found that while all
three systems correlated with patient prognosis, the Becker system showed the
highest reproducibility because assessment based on percentage of viable tumor
cells is more objective than evaluation of the degree of fibrosis. Similarly,
Wu et al. (2020) concluded that percentage of residual tumor is more easily and
reproducibly identifiable than fibrosis extent.frontiersin+2
Despite these advantages, the Mandard system continues to be
preferred in many institutions due to its established validation in oesophageal
cancer and familiarity among pathologists. The SPACE-FLOT approach of
trichotomizing multiple TRG systems into minimal, partial, and complete
responder categories offers a pragmatic solution that leverages the prognostic
information from TRG while accounting for inter-institutional variability in
TRG system preference. This approach has immediate clinical applicability and
has been validated across diverse healthcare systems.iccr-cancer+2
Limitations and Future Directions
Several limitations in the current evidence base warrant
acknowledgment. First, most studies examining the relationship between Mandard
TRG and adjuvant FLOT outcomes are retrospective cohort analyses subject to
selection bias, particularly regarding which patients receive adjuvant therapy.
The SPACE-FLOT investigators attempted to mitigate this through propensity
score matching and multivariate adjustment, but residual confounding cannot be
entirely excluded. Prospective randomized controlled trials specifically
designed to test TRG-guided adjuvant therapy decisions would provide definitive
evidence but face practical and ethical challenges given existing data
suggesting benefit in partial responders.academic.oup+1
Second, the optimal definition of "partial
response" remains somewhat arbitrary. The SPACE-FLOT trichotomization
approach groups all intermediate TRG tiers together, but this heterogeneous
category may contain patients with substantially different prognoses and
treatment sensitivities. More granular risk stratification incorporating TRG,
ypTNM stage, lymphovascular invasion, perineural invasion, and molecular
biomarkers may further refine patient selection for adjuvant therapy.academic.oup
Third, the follow-up duration in many studies (median 25.5
months in SPACE-FLOT) remains relatively short for definitive assessment of
overall survival, as oesophageal adenocarcinoma can demonstrate late
recurrences. Longer follow-up data will be essential to confirm that TRG-guided
adjuvant therapy decisions do not compromise long-term oncological outcomes,
particularly in complete responders who may be spared adjuvant treatment.academic.oup
Fourth, most published evidence derives from Western
populations where perioperative chemotherapy predominates, and applicability to
Asian populations where different chemotherapy regimens and treatment
philosophies prevail requires validation. The MATTERHORN study demonstrated
that German patients achieved higher pathological complete response rates with
durvalumab plus FLOT compared to non-German patients, suggesting potential
ethnic or geographic differences in treatment response.pmc.ncbi.nlm.nih
Future research directions should focus on integrating
multiple biomarkers—including TRG, circulating tumor DNA, tumor mutational
burden, PD-L1 expression, HER2 status, and microsatellite instability—into
comprehensive predictive models for adjuvant therapy benefit. The combination
of pathological response assessment with liquid biopsy-based minimal residual
disease detection represents a particularly promising approach for identifying
the subset of apparent complete responders who harbor occult micrometastatic
disease and may benefit from adjuvant therapy or surveillance intensification.
Additionally, investigation of adjuvant treatment de-escalation strategies
(e.g., reduced number of cycles) in partial responders who are at lower risk
based on favorable ypTNM stage could optimize the balance between efficacy and
toxicity.ascopubs+1
Conclusion
Current evidence demonstrates that Mandard tumor regression
grade following neoadjuvant FLOT chemotherapy serves as both a powerful
prognostic indicator and a predictive biomarker for adjuvant FLOT benefit in
oesophageal adenocarcinoma. The landmark SPACE-FLOT international cohort study
conclusively established that partial responders derive substantial survival
benefit from adjuvant FLOT (DFS HR 0.68, OS HR 0.55), while complete responders
and minimal responders do not demonstrate significant benefit after adjustment
for baseline characteristics. This finding supports a personalized,
response-adapted approach to perioperative FLOT therapy, wherein adjuvant
treatment is prioritized for the majority of patients who achieve partial
response, potentially omitted in complete responders with excellent prognosis,
and individualized in minimal responders based on treatment tolerance and
molecular profiling. Implementation of TRG-guided adjuvant therapy decisions
has the potential to optimize treatment efficacy while minimizing toxicity and
healthcare costs in the management of locally advanced oesophageal
adenocarcinoma. As perioperative FLOT becomes increasingly established as
standard of care based on the ESOPEC trial results, integration of pathological
response assessment into routine clinical practice will be essential for
maximizing the therapeutic index of this intensive chemotherapy regimen.esmo+3
