Total neoadjuvant therapy using short course radiation with or without SIB to lateral pelvic lymph nodes in locally advanced ugly rectal cancer.
Authors: KRISHNATRY RAHUL , Jain Aditi , Kazi Mufaddal Khuzema , Gudi Shivakumar , Rane Devankshi , Pawar Purva , Ramaswamy Anant , Bhargava Prabhat Ghanshyam , Haria Purvi , Kumar Suman , Ramadvar Mukta , Ostwal Vikas S. , Saklani Avanish , Engineer Reena 
Published: January 2024

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Background: Optimal management for lateral pelvic lymph nodes (LPLN) in Ugly locally advanced rectal cancer (LARC) is unknown & is associated with worse outcomes. We hypothesise that total neo-adjuvant (TNT) using Short-course radiotherapy (SCRT) with SIB to lateral pelvic lymph nodes would improve outcomes. Methods: All consecutive patients of LARC with LPLN treated with SCRT-based TNT from Jan 2021 – Dec 2022 were reviewed (IEC No: 4116). The LPLN (external, internal, common iliac or obturator) was considered radiologically significant based on joint clinic review with classical criteria. They were divided into two groups (SIB-IMRT: up to 30Gy/5#; or not). The chemotherapy schedule was similar to RAPIDO study, followed by TME +/- LPLN dissection based on radiological response assessed in joint clinic. Two groups were compared for baseline features using Fisher’s exact/Chi-Square tests as appropriate. Outcomes were reviewed for overall response in LPLN (radiological or pathological), disease outcomes & toxicity (acute radiotherapy CTCAE v5, 30-day Clavien Dindo post-surgical, & HRQL EOTRC QLQ-C30). Results: From 398 patients, 83 (20.8%) were identified with LPLN receiving SCRT with TNT, of which 44 (53.01%) received a SIB boost. Overall, 40% were aged ≤ 45 years, 50% had poor histology (signet, PDAC, Mucinous), 35% had EMVI, and 83% were N2+. The two groups had a similar distribution of baseline features (p>0.05) & were matched for poor prognostic factors. The patients who received a boost were 20% more likely to complete TNT and undergo TME than patients who did not (81.8% vs 61.5%; p=0.0099), mainly due to a significantly lesser event of disease progression before surgery, rendering them inoperable (25% vs 33.3%; p=0.024). Boost was associated with an increased overall response at LPLN by 20% (84.1% vs 64.1%; p=0.011) & decreased need for PLND by 15% in patients considered for surgery (15.9% vs 30.56%; p=0.072). At a median follow-up of 18 months, 26 patients (31.33%) identified with disease progression were similarly distributed in two groups with similar patterns (all but one had distant metastasis, of which 6 had loco-regional failures). A total of 17 deaths with a non-significant trend of higher 18-month OS observed (boost: 83.4+6.3 vs 75.6+7.8%; HR:2.29(CI:0.85 - 6.19; p=0.09). None of the patients had acute > grade 3 CTCAE v5 toxicity within 4 weeks of radiotherapy completion. Four (4.8%) deaths were chemotherapy-related, & one post-surgery toxicity with similar > grade 3 Clavien Dindo complications in two arms. EORTC QLQ C-30 PROM scores were similar in two groups. Conclusions: In ugly, poor biology LARC, TNT with SCRT-SIB to LPLN seem safe & feasible with improved response, treatment completion & operability without significantly increase in toxicity rates. Long-term prospective studies are warranted to identify significant survival impact.