Modern management of rectal cancer

 reference: Am Journal of Surgery 2024

1. Three basic approaches to TNT

a. Induction chemo for 12-16 weeks, then long ( 5.5 weeks) Concurrent chemo XRT or short ( 1 week) chemo-XRT

b. Induction chemoXRT ( short or long) followed by consolidation chemo for 12-16 weeks

c. Chemo alone 12-16 weeks and adding chemo XRT only if less than 20% tumor response.

Studies supporting TNT

a. POLISH II--> T3/T4 pt--> short course CRT followed by 3 cycles chemo--> similar OS, path CR, local control. 50% OS in 5 yr means that the survival benefit was reduced by chemo being given for only 3 cycles. So suboptimal chemo.

b. STELLAR

Non inferiority trial for locally advanced rectal ca T3/T4 or N+

The adjuvant capeox was only for 2 cycles rather than 6 in the conventional TNT arm. The conventional TNT arm consisted of only long course chemo XRT, not neoadjuvant chemo. Chemo was given adjuvantly Capeox for 2 cycles in the intervention arm and 6 cycles in the conventional arm.

3 yr DFS similar 62%.

c. RAPIDO trial- highest risk locally advanced T4, EMVI, N2+, involvement of mesorectal fascia. TNT 5 yr OS 80%.

d. OPRA: higher organ preservation with consolidation chemo following induction CRT. Superior path CR also if chemo is given as consolidation.

e. PROSPECT ( de-escalate rx in low risk pts): Omitting CRT if induction chemo FOLFOX if tumor showed a > 20% reduction. Both groups underwent TME. Highest risk pts as in the RAPIDO trial were omitted.

f. PRODIGE trial used FOLFIRINOX neoadjuvantly versus JANUS trial/ ENSEMBLE trials are testing FOLFIRINOX/CAPOXIRI versus FOLFOX

Summary of evaluation of early stage rectal cancer

• Location of tumor: Anterior/ mid rectum/ distal/ posterior/ upper rectum
• Pathology
• MMR status:
• family hx: Germline testing referral for all pt less than age 50Y
• CEA
• MRI stage: 
• High risk MRI finding:  circumferential resection margin (CRM) compromised or extramural vascular invasion (EMVI)
• EUS rectal for T1/T2
• CT chest/AP
• Full colonoscopy finding

MD Anderson Protocol: 

Reference: The panel identified the use of neoadjuvant chemoradiotherapy, followed by chemotherapy as the best treatment modality for organ preservation. FOLFIRINOX is best suited for patients who have bulky tumours and a good performance status, while the RAPIDO protocol of 5×5 Gy, followed by six cycles of CAPOX chemotherapy was believed to be the appropriate regimen for most patients. Determination of T3 subtype can also be difficult in clinical practice, and a consensus was found that small T3 tumours should receive potent, local therapy with chemoradiation. In contrast, in case of larger T3 tumours it seems best to adhere to the RAPIDO protocol.

Stage 4 lung cancer with driver mutations

 1. RET mutated: First line selpercatinib or pralesitinib based on phase III trial showing better PFS ( 24 m versus 12 m) , ORR 84 vs 64% compared to chemo+pembro. SE: LFT abnormalities, Qtc prolongation and hypertension. Diarrhea, dry mouth, fatigue, Low plt.

2. NTRK mutated: < 1% of all stage 4 lung ca.  larotrectinib typically administered at 100 mg orally twice daily for adults, and entrectinib at 600 mg daily

3. EGFR exon 19 deletion, exon 21 L858R mutation are the most common types. If T790M mutation is identified de novo without prior EGFR rx, do germline testing.

4. BRAF: dabrafenib+ trametinib or encorafenib+ binimetinib

5. cMET- capmatinib, tepotinib, crizotinib, for high CMET--> telisotuzumab ( ADC)

Six serious side effects of bevacizumab: Hypertension, arterial embolism including stroke, MI, reversible posterior leukoencephalopathy syndrome, bowel perforation, proteinuria