Total Neoadjuvant Therapy (TNT)

in Rectal Cancer, the Rapido trial

Daniel Gan
 Outline

• Rapido trial
– Design
– Survival Data
– Toxicity
– Surgical and Pathological Outcome
 Problem

• Unmet need to improve overall survival

– Low compliance rates for postoperative treatment in
rectal cancer (43–74%), while colon cancer is 70–86%
(Cavalho et al, Lancet Oncol 2014)
– Delay of systemic therapy diminish effect of systemic
therapy (Biagi et al, JAMA 2011)

Chemo-RT is the current SOC, issue is:

• Sub-optimal chemo delivery pre-op
• Total > 4 months till patient gets optimal chemo
– 5 wk CRT + 8 wk to op + 4 wk to recover
Inclusion criteria:
• cT4a/b
• Extramural vascular invasion
• cN2
• Involved mesorectal fascia
• Enlarged lateral lymph nodes
Primary End Point: time to
disease related treatment
failure (DrTF)
• Locoregional failure
• Distant metastasis
• New colon primary tumor
• Treatment-related death
Inclusion criteria:
• cT4a/b
• Extramural vascular invasion
• cN2
• Involved mesorectal fascia
• Enlarged lateral lymph nodes
Secondary endpoint:
• Overall survival
• CRM -ve (margin > 1 mm) rate
• pCR rate
• Short and long-term toxicity
• Surgical complications
• Quality of life
 RAPIDO POLISH II

Design

MRI Yes No
assessment
Concurrent Capecitabine Bolus FU + Oxaliplatin
chemo
Consolidation 18 weeks CAPOX/FOLFOX 6 weeks FOLFOX
chemo

Duration to 23-25 weeks 12-13 weeks

surgery
 Design - RAPIDO
Fairly balanced between experimental and standard arms

Intermediate risk (ESMO) low cT3a/b, N1, MRF clear, EMVI- is

not included

Primary End Point? DFS vs tDrTF (Time to Disease related

Treatment Failure)
• Protocol amended once
• DFS not suitable in neoadjuvant setting as all patients had
disease at randomisation, some will never be disease free
 Design
18 weeks (4.5 months) pre-op chemotherapy
• Reasoning was that adjuvant colon trials show that 3 months
CAPOX was non-inferior to 6 months CAPOX
• However, non-inferiority applies only to low risk stage III
 Design
Duration from start of treatment to surgery: 23-25 weeks (6m)
• Longer period in experimental group may lead to increased
downstaging
- pCR 28% vs 14%, p<0.0001, (OR 2.40 [1.70– 3.39]; p < 0.001)

• In the Stockholm III trial, the downstaging effect was more

pronounced after 5x5Gy with delayed surgery (4-8 weeks)
than after long-course radiotherapy (25x2Gy)
-pCR 10.4% vs 2.2% (p<0.0001)
-Superior OS: 0.51 (0.26–0.99) p = 0.046 and TTR: 0.27 (0.09–
0.86) p = 0.027 with pCR
-But no concurrent chemo for long course
 Design
Duration from start of treatment to surgery: 23-25 weeks
• Small proportion of non-responding tumors may progress
during pre-op treatment

• Higher rate of ypT4 in experimental than the standard group

(9% vs 6%)

• In patients with little or no response to therapy, extended

interval to surgery may be disadvantageous

• Early response imaging may be advocated

 Results - Disease Related TF

Sensitivity analysis done for time related bias.

Restaging and surgery 10 weeks earlier in standard arm.
-Difference still significant but magnitude reduced (p=0.019 to p=0.048)
 Results – Distant Metastases

Cumulative probability of distant metastases was 20.0% vs 26.8%

(HR 0.69 [95% CI 0.54–0.90]; p=0.0048
Results – OS, DFS, LRR

OS P=0.59, Post-op DFS P=0.13

LRR P=0.12, HR 1.42

Cumulative probability of
locoregional failure at 3 years was
8.3% in the experimental arm and
6.0% in the standard arm (HR 1.42
[95% CI 0.91–2.21]; p=0.12
 Results – Adjuvant Chemotherapy
• Adjuvant chemotherapy did not affect the probability of
disease-related treatment failure at 3 years (HR 1.18 [95% CI
0.85–1.64]; p=0.32)

• Similar non-significant findings with distant metastases (28.5%

[95% CI 23.1–34.0] vs 24.4% [18.2–30.6]; p=0.34) and
locoregional failure
(7.2% [4.1–10.4] vs 4.3% [1.7–7.3]; p=0.20)
Results - Tolerability
•84% get ≥75% of the prescribed
consolidation chemo
•67% completed 100%

•Compliance for CRT was 94%

•58% (108/187) ≥75% of the
protocolled adjuvant chemo
 Results - Tolerability
More patients able to complete consolidation chemo as
compared to adjuvant chemo

More patients able to complete neoadjuvant CCRT compared to

SCRT + consolidation chemo
• Diarrhoea was the most common pre-op AE in both groups.
• Pre-op, grade 3-4 AE occurred in 48% of patients in the experimental arm, 25% of the standard arm
• With postoperative chemotherapy 35% had grade 3-4 AE
 Results – Surgical Procedures

Slightly more blood loss 300cc vs 250cc (p=0.007)

Lower rate of intact mesorectum 78 vs 85% (p=0.032), missing data 12% in
experimental arm
Results – Surgical Complications

No significant difference in terms of

surgical complications
 Case – IBCM (35706400)
64y,M, underlying DM and HPT
• Presented with PR bleed and altered bowel habits
• Colonoscope 5/20: low rectal tumour 2cm FAV, HPE: HG dysplasia
• Repeat scope 6/20: tumor 7cm FAV, HPE: adenocarcinoma
• CT 6/20: lower to mid rectal thickening 4.3cm length, suspicious
lung nodules
• Loop ileostomy 7/7/20 for impending IO
• MRI pelvis 14/7/20: low to mid rectal ca, extra-mesorectal LN+,
cT3cN2Mx, MRF+
• Clinically: PS 3, subsequently improved to 2 post stoma formation
A: mesorectal LN
B: mid-rectal wall thickening
C: right upper lobe nodule
A: Extramural DOI 8mm, T3c

B: Shortest distance tumor border to

MRF 2mm at 12 oc

C: tumor node/deposit invading MRF

SCRT 25Gy/5F/1 week
10/8/20-14/8/20

C1 CAPOX 4/9/20 – Oxali 50%

DR, Cape 25% DR
(delay due to welfare issues)

C2 CAPOX – both 25% DR

C3 CAPOX – Oxali 50% DR

-admitted for G3 diarrhea

C4-6 17/12/20- Cape alone

25% DR, omit oxali
Case – IBCM (35706400)

CT TAP 23/12/20
• Smaller primary tumor, resolved
mesorectal LN
• Non-specific tiny lung nodule

MRI 29/12/20
• Tumor regression seen, smaller
extra-mesorectal node
• yT3b N0 MRF negative

For Laparoscopic ULAR 19/1/21

 2 Other Cases…
HBLY (35896976), 69y, F
• Low rectal adenoca cT3N1M0, MRF+
• CCRT 45Gy/25F + Cape, CAPOX x2, stopped as platelet 40 twice
• MRI post C2: cT3N0, MRF+
• For op by 9/2/21 (12 weeks post CCRT)

SPLW (01632051), 49y, F, under MyBRCA, RAS/RAF/MMR neg

L ovarian immature teratoma 2000, op and BEP
L breast ca pT2N1M0, HR-/HER2+ 2011, op, FEC-TH, RT
• Mid rectal adenoca cT3N1M0, MRF+
• Lap colostomy, CCRT 50.4Gy/28F + Cape, CAPOX x4, platelet 50+
• MRI interim Nov 20: smaller rectal tumor, still cT3N1, MRF+
• For op in 4 weeks
My take
-Need longer follow up to assess impact on long term survival
and local control
-Good to know subgroup analysis on association of pCR with
survival given high rates of pCR
-Optimal duration of consolidation chemo still uncertain (RAPIDO
- 18 weeks, POLISH II - 6 weeks, Stockholm 4-8 weeks delay,
STELLAR - 12 weeks pending)

-Caution to delay surgery in patient who may potentially fail

locally
-Caution in patients who may not be able to complete full course
chemo due to co-morbids ie IHD
-Role of remaining cycles of chemo should patient fail to
complete and shifted to surgery?