1) Total neoadjuvant therapy (TNT) involves chemotherapy before and after chemoradiotherapy for locally advanced rectal cancer, aiming to increase downstaging and improve outcomes. 2) A review found TNT achieved a 22% pathological complete response rate compared to 13% for chemoradiotherapy alone, with possibly improved survival. 3) However, most evidence comes from observational studies. Two randomized controlled trials found TNT reduced distant metastases and improved disease-free survival compared to chemoradiotherapy alone.

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TOTAL NEOADJUVANT THERAPY
IN LOCALLY ADVANCED
CARCINOMA RECTUM
Department of Surgical Oncology
Centre for Oncology
GRH,Royapettah

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Locally advanced rectal cancer
• Involvement of perirectal tissue
• T4 primary tumor
• N2 nodal status
• Enlarged lateral lymphnodes

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Definition of TNT
• Defined as chemotherapy using cycles of induction
and /or consolidation in conjunction with standard
chemoradiotherapy prior to surgery in locally
advanced rectal cancers.

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TNT sequencing
• INDUCTION CHEMOTHERAPY
systemic chemotherapy – chemoradiotherapy – surgery
systemic chemotherapy – short course RT – surgery
• CONSOLIDATION CHEMOTHERAPY
chemoradiotherapy – systemic chemotherapy – surgery
short course RT - systemic chemotherapy – surgery

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Main Aim
• To increase pathological down staging to allow local
control and increase likely hood of sphincter
preservation and R0 resection
• To act on occult micro metastatic disease
• Increase rate of relapse free survival.

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• Intensification of neoadjuvant treatment with standard dose of
polychemotherapy added before chemo radiotherapy may help
1) To decrease distant failure
2) increase conservative surgeries
3) increase chance of resectability
4) pathologically complete response ( 22%)
5) Option to study tumor and its response to treatment

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• No substantial body of evidence on use of adjuvant chemotherapy
after chemoradiotherapy and surgery.
• Greater compliance with neoadjuvant chemotherapy compared to
adjuvant counterpart, and weak evidence in favor of adjuvant chemo

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• Slow recovery from surgery leading to delayed or non
application of chemotherapy
• Poor tolerance of chemotherapy after a major surgery

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• Patients with clinically complete response after TNT ,
a wait and see option can be considered prior to
proceeding with surgery

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• Total 28 studies ( 2003 – 2019)
• 2688 patients treated with TNT and 891 patients with standard
Neoadjuvant chemoradiotherapy
• 3 retrospective and others were prospective studies
• All except 5 are multiagent oxaliplatin based studies, remaining 5
are 5FU folinic acid based studies

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• Pooled rate of pCR was 22.4% (95% CI, P<0.001)
• Patients who received TNT has better disease free survival and
overall survival than those who receive chemoradiotherapy alone
• Nodal down staging to pN0 ranged from 30-91.6%
• Radical surgeries R0 resection ranged from 71-100%

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• Compliance was excellent ( 81.9 to 100%)
• The toxicity profile of TNT regimens was comparable
to that of standard chemoradiotherapy
• Locoregional failures and distant metastatis were
reduced by about 30%

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Subgroup analysis
• The pCR comparisons were similar in prospective and
retrospective series
• pCR rates are higher in non randomized studies than in
randomized studies
• DFS and OS analysis – even if a larger benefit was calculated
in retrospective and/or non randomized studies, the
difference among subgroups was not significant

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• Further the risk of local and distant metastases are
potentially few and this may reduce relapse and mortality
• Avrage pCR is 22%
• Patients with pCR had fewer metastasis and and a better
outcome compared with non-pCR patients. 75% reduced risk
of distant and local relapse, long term OS and DFS were
approximately 90%

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Limitations
• Majority of the studies are prospective observational type
• Of these most of them are non randomized comparative
studies
• In quantitative metaanalysis the benefit observed in non
randomized studies was not significantly larger

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•TNT is relatively a younger treatment strategy
with median follow up of 43months, it is
reasonably a short time to capture late response
and more mature data on survival

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• Even though a 22% pCR rate in the whole population
of TNT studies , in studies in which direct comparison
was possible this rate was 19%. Control arm has pCR
of 13%

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• The quality of sources are low, strong evidence based
recommendations cannot be made on this data, which
were largely produced from single institution case
series and small randomized trails

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Recent trails
The rectal cancer and preoperative induction
therapy followed by dedicated operation
(RAPIDO) trail:

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• It is a multicenter trial (54 centers)
• It’s a phase 3 randomized trail
• 920 patients
• Median follow up of 4.6yrs
• Standard vs experimental ( SCRT – Chemo – surgery )

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• Primary end point – disease related treatment failure
• At 3yrs - 30.4 % vs 23.7%
• P = 0.019
• Distant metastasis at 3 yrs 26.8% vs 20%
• Over all survival 88.8% vs 89.1%
• pCR is 14.3% vs 28.4%
• Ro resection rates are similar

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• Surgical complications are similar ( anastomotic leaks
more in experimental arm but not statistically
significant)
• Quality of life is similar

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PRODIGE 23 – A French trail
• Phase 3 RCT
• N= 461
• Standard vs experimental mFOLFIRINOX – CRT -
surgery – Adjuvant chemo
• Median follow up of 46months

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• Primary end point – 3yr DFS
• 68.5 vs 75.7%
• P=0.019

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•pCR – 11.7 vs 27.5%
• 3 yr Metastasis free survival 71.7 vs 78.8%
•3 yr OS 87.8 vs 90.8%

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• With further research and defining the optimal
sequence , type and duration of induction
chemotherapy and the ideal timings and dosage of
Radiotherapy , TNT can be considered as a new
standard of care in locally advanced rectal cancers

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