Phase-II trial on observation for early rectal cancer following CTRT. Probably 1st trial for early stage tumors in rectum.

1. • Neoadjuvant Chemotherapy, Excision, and Observation for Early Rectal Cancer:
The Phase II NEO Trial Primary End Point Results
Hagen F. Kennecke et al.,
Ascopubs.org/journal/jco
August 18,2022
PRESENTER: DR ROHIT JAIN
SGE, KGMU, LUCKNOW
MODERATOR: DR PRITHEESH RAJAN

2. • 7 institutions in Canada and the United States.
• Study opened to accrual on August 22, 2017.
• Results are based on database lock from January 20, 2021
• Median follow-up of 15.4 months.

3. INTRODUCTION

4. • Organ-sparing therapy for early-stage rectal cancer may avoid -permanent ostomy or functional
disturbances(LARS).
• Current standard therapy for cT1/T2N0 rectal tumors- TME
• For cT3/N1- preoperative chemoradiation + TME
• Transanal excision surgery (TES) used for select T1/T2N0 rectal tumors

5. • Issues with TME - bowel function, incontinence, and sexual function.
• perioperative radiation - LARS in 60%, wound-healing complications,affects sphincter and sexual function
• Studies with cT1-3 - pelvic chemoradiation followed by TES reported organ preservation rate of 50%-68%
• no prospective experience of neoadjuvant chemotherapy and transanal surgery for stage I rectal tumors

6. Primary objective

7. • Determine organ preservation rate in patients with early (cT1-3a,b N0) rectal cancer treated with neoadjuvant FOLFOX or
CAPOX and TEMS or TAMIS.
• Protocol-specified organ preservation rate (psOPR): Proportion of patients with tumor downstaging to ypT0/T1,N0 and who
avoided radical surgery.
• Observed organ preservation rate (oOPR): Proportion of patients down staged to ypT0/T1 plus higher yp stage patients who
declined recommended TME surgery

8. Secondary objective

9. 1. Locoregional Relapse Rate (LRR)
2. Distant Relapse Rate (DRR)
3. Disease Free Survival (DFS)
4. Post-operative complications
5. Adverse events
6. Quality of Life (QoL)
7. Cost-effectiveness to current standard approach.

10. Inclusion Criteria

11. • Histologically confirmed invasive well-moderately differentiated rectal adenocarcinoma
• cT1-T3abN0 - Pelvic MRI
• M0 stage - CT imaging.
• Mid to low-lying tumour eligible for local tumour excision in the opinion of the treating
surgeon.
• Age >18 years.
• Adequate normal organ and marrow function
• ECOG performance status of 0, 1.

12. Exclusion Criteria

13. • High risk factors on initial/follow-up biopsy: High histologic grade, mucinous histology,
lymphatic or vascular invasion.
• H/o other malignancies
• Synchronous cancer
• Prior treatment for rectal cancer.
• Previous pelvic radiation
• Known dihydropyrimidine dehydrogenase deficiency
• Active cardiovascular disease
• Contra-indications to undergo MRI imaging.

14. Procedures

15. Treatment Schema

16. Chemotherapy regimen
• 6 cycles of mFOLFOX6 or 4 cycles of CAPOX- investigator discretion.

17. Post chemotherapy
• Pelvic MRI + proctoscopy 2-3 weeks after the last dose of chemotherapy.
• Protocol-defined evidence of response proceeded to TES.
• Progression or no response - TME surgery
• MRI with cT3ab/N1, or involved or threatened CRM -preoperative pelvic
radiation

18. Surgery plan
• Tumour excision within 2-5 weeks (FOLFOX) or 3-6 weeks (CAPOX) after first dose
of last cycle of chemotherapy.

19. Transanal excision surgery
• Surgeon preference and tumor location
• TAMIS
• TEM
• Open
• 2-6 weeks after the last cycle of chemotherapy.
• Tumor excision - minimum of 1cm gross margin.
• Trial surgeons - Min 20 previous TES
Submit an unedited video of procedure with sutured defect

20. Radiation treatment plan
• Pelvic radiation : Excisional specimen demonstrates ypT3+ / N+ disease
Radical TME surgery.
standard preoperative chemoradiation or short course pelvic radiation
 Optional preoperative pelvic radiation
1. pre-excision MRI reporting at least one of these findings:
2. cT3ab stage
3. node positive disease
4. not clear circumferential radial margin (CRM)
• Patients who cannot tolerate six cycles of FOLFOX or require dose modification

21. • Adverse events - measured using CTCAE V5.0
• Perioperative and operative details collected prospectively.
• QoL & rectal function - European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–C30
Fecal Incontinence Quality of Life (FIQL)
LARS surveys
• Questionnaires : Baseline, pre-excision (postchemotherapy), and 6, 12, 24, and 36 months after surgery.
• Molecular profiling : formalin fixed, paraffin-embedded diagnostic biopsies if sufficient.
If inadequate tumor - resection specimens used.
Next-generation sequencing (NGS) :Foundation One CDx assay at Foundation Medicine (Cambridge, MA)

22. Statistics

23. • H0 : No interest if psOPR <50%
• H1: Promising if psOPR > 65%

24. • 2 stage minimax design: Stop the trial at the end of first stage if <10 of the first 22 patients accrued met psOPR
Promising if, out of the total patients accrued, > 30 met psOPR
• Minimum and maximum sample sizes: 22 and 50
• Type-I error rate & power of this design: 0.1 & 0.8
• High proportion of patients declined protocol recommended surgery, oOPR was defined at the time of data analysis
• Exact Clopper-Pearson confidence intervals : for both psOPR and oOPR.
• Kaplan-Meier method: 1- and 2-year locoregional relapse-free survival

25. Results

27. Summary of Chemotherapy Adverse Events
• mfolfox6 =32, CAPOX =26
• 91% and 89%, respectively , completed all planned cycles.
• No unexpected toxicities

28. Surgical Therapy
No response->pelvic chemoradiation->TES
• n=56 , 10 TME - residual ypT21 and/or R1/2 tumor in the excision specimen
n=58
56
TES
3= OPEN
53=TAMIS/TEM
R0 -52 (93%)
R1 – 3 (3.5%)
R2: 2 (3.5%)
n=2
No Sx
progression to cT3b -> TME
(ypT2N0 with -ve crm)

29. Organ Preservation
• psOPR of 57% (90% CI, 45 to 68)
• psOPR similar among T stage subgroups
• 63% (n=8), 54% (n=37),62% (n=13)
cT1, T2, T3ab respectively
n=58
n=33
TES SPECIMEN
n=23
n=10
Tumor downstage
ypT0/1, NO/X Recommended TME
TME
n=13
Declined TME
Observation
oOPR of 46/58 (79% with 90% CI, 69 to
88)
yp
stage
1 high risk T1
11 T2
1 T3

30. Tumor Genotyping
• 53/58 patients with sufficient tissue
• RAS Mutation : 16/33 (49%) of RAS-mutant tumors downstaged vs 12/20 (60%) in the RAS wild-type
• BRAF V600E: No mutations noted
• MMR status(55/58) : by IHC or NGS
55/55 (100%) were pMMR
• ERBB2 amplification:3/53 (5.7%), all had downstaging and psOPR of 67%.
• QoL and rectal function: Compliance- 100% at baseline, 89% pre-excision, 85% 6 months, 86% 12 months
• Major LARS: Baseline- 10%
pre-excision: 0
6 months: 22%
12 months: 14%

31. DISCUSSION

32. • >50 % experienced complete or near complete pathologic downstaging and met psOPR
• Significant patients chose to defer recommended TME in favor of close observation on study.
• No unexpected toxicities
• oOPR - 79%, including who declined recommended surgery
• 13 who declined recommended TME, 85% -ypT2N0, 1 –> LRR-> TME.

33. • 13/56 (23%)->TES->ypT1-> removed microscopic residual disease that may otherwise have been difficult to
differentiate from a clinical complete response on proctoscopy and MRI
• Few postoperative complications, no patients required readmission after TES
• Early QoL suggest only minor effects on bowel function, which subsequently improved
• Mean LARS score increased to minor LARS 6 months after excision and improved by the 12-month time point to
no LARS, similar to baseline.

34. • 10 who had TME surgery, only 2 had pathologically N1 tumors similar to expected node-positive rate
• Minimal change in fecal incontinence scores.
• RAS mutation, was not associated with response to chemotherapy.
• Tumors had preserved mismatch repair, a low mutation burden, and no BRAF V600E mutations, characteristic of
the majority of left sided colorectal tumors

35. Limitations
• MRI-staged early rectal cancer with no unfavorable histologic characteristics
• Smaller number
• Expertise for TES
• All are Pmmr
• ERBB2 gene amplification in 6% (3) is small number difficult to make any predictive efficacy

36. Conclusion
• Demonstrates important role by TES in documenting the residual tumor burden , thereby
informing provider and patient decision making about the need of subsequent therapy
• 3 months of induction chemotherapy may successfully downstage a significant proportion of
patients with favorable-risk, early-stage rectal cancer, allowing well-tolerated organ-preserving
surgical therapy with minimal effect on organ function.