Management of distal cholangiocarcinoma with arterial involvement: Systematic review and case series on the role of neoadjuvant therapy

Table 3 Summary of study’s findings

Ref.	Rationale	Results	Conclusions	GRADE1
McMasters et al[23], 1997	Premier paper on NAT in eCCA; Initial experience; NAT vs UR	4 dCCA received NAT for advanced disease; 100% had R0 resection; 25% had PCR; No survival difference between NAT vs UR; 100% died “within relatively short period of time”	NAT is safe; NAT is associated with a high rate of PCR; NAT may improve R0 rate; Encourages further multicentre trials	Moderate: Few patients; No definition of “locally advanced”; Specific to dCCA
Czito et al[27], 2006	Dose determination for novel CRT for resectable and unresectable UGI cancers; NAT only	3 dCCA received NAT; 1 (resectable) patient had R0 resection and PCR; 1 (unresectable) had 33% decreased in tumour size, underwent R1 resection; 1 was not resected due to metastatic disease; Survival not reported	No specific conclusion on NAT in dCCA	Very low: Few patients; No comparator group; Trial halted before completion; Offers no conclusion
Nelson et al[31], 2009	Evaluation of CRT in neoadjuvant setting for eCCA; NAT vs AC	12 eCCA received NAT (hilar and distal); 10 had NAT due to BLR or LA disease, 2 for surgeon preference; 91% had R0 resection and 25% had PCR; 5-year-OS: 53% vs 23%, despite more advanced disease in NAT cohort	NAT affords local control and enhances resectablity and survival in eCCA	Low: Few patients; Only includes resected patients; Heterogenous indication for NAT; Includes hilar and distal tumours
Kobayashi et al[33], 2015	Assessment of safety of NAT for all BTC; Assessment of pathological effect of NAT for BTC	15 dCCA received NAT (25 total); 96.0% R0 resection rate (total); 3-year-OS 75.2% for dCCA	NAT gemcitabine with RT feasible to improve survival and control regional extension	Very low: Excluded patients with major vessel involvement; Includes hilar and distal tumours
Cloyd et al[26], 2019	Pragmatic assessment of NAT use in resected dCCA; NAT vs UR	45 dCCA; 21 had NAT; 5/21 chemotherapy only, 10/21 CRT, 6/21 both; Varied indications for NAT; 95.0% had R0 resection; 1/21 had PCR; Median OS: 40.3 months UR vs 50.3 months UR; 14.3% NAT had local recurrence vs 0% UR	Does not support routine administration but beneficial in advanced disease or in patients with poor PS	Moderate: Only includes resected patients; Specific to dCCA
Oh et al[28], 2021	Demonstration of feasibility of conversion surgery after palliative chemotherapy for unresectable eCCA	12 eCCA, 4 dCCA commenced on palliative chemotherapy; 2 patients deemed unresectable due to LN enlargement, 1 due to PV/SMV invasion with SMA abutment, and one due to PV abutment; 3 received Gem-based chemo, and 1 received FOLFIRINOX, 2 also received radiotherapy; All 4 had R0 resection (100%); 2 were alive at last FU (12 and 68 months) and 2 had died (24 and 7 months); Only one patient developed recurrence, 9 months post-operatively (died at 24 months)	Conversion surgery is a feasible and effective treatment strategy in certain unresectable CCAs	Moderate: Few patients; Includes all patients with initially unresectable disease, specifying distal disease; Chemo given with palliative intent, rather than NAT
Adam et al[25], 2023	Describe pattern of NAT use in CCA; NAT vs UR	157 eCCA received NAT; 24% were T downstaged; 9% were N downstaged; 83% NAT had R0 resection vs 76% UR; OS: 38.4 (NAT) months vs 25.6 (UR) months	NAT is associated with downstaging, improved R0 resection and survival for eCCA	Very low: Excluded patients with advanced disease; Uses national database with heterogenous data; Includes hilar and distal tumours
Fujii et al[29], 2022	Investigate impact of NAT CRT on body composition in patients with dCCA	16 dCCA received NAT CRT, all resectable; 16 progressed to surgery, with 100% R0 rate; 6/16 had significant AEs (grade > 3); 9/16 were sarcopenic pre-NAT, 8/16 after NAT (one patient recovered during NAT); 3-year-OS without sarcopenia: 100% versus 71% with sarcopenia (NS); Patients with sarcopenia had significantly shorter DFS (P = 0.025)	NAT CRT is safe in this cohort and does not significantly affect body composition; Further studies necessary to assess impact of sarcopenia on OS in biliary tract cancer	Low: Few patients; Resectable only and no indication for NAT given
Parente et al[30], 2023	Evaluate role of NAT in each subset of CCA, specifically impact on survival; NAT vs AC vs UR	271 CCA had NAT; 81% R0 resection rate, vs 78% (UR) vs 67% (AC); Median OS 38.1% (NAT) vs 21.8% (UR) 28.0% (AC); NAT significantly improved survival vs AC; HR: 0.65 (0.53-0.78), P < 0.001	NAT + resection vs UR increased survival, regardless of nodal or margin status; Careful MDT evaluation warranted for NAT incorporation into CCA management; Multicentre trials needed	Low: Included distal tumours only but no indication for NAT given; Only includes resected patients; Uses national database with heterogenous data
Toyoda et al[32], 2023	Characterize impact of NAT on eCCA prognosis and establish trends in utilisation; NAT vs UR	70 eCCA received NAT; Over a decade, proportion of NAT use increased from 1.2%-2.1%; Median OS 26 months UR vs 23 months UR; 5-year-survival 21.5% UR vs 25.5% UR; Advanced Stage eCCA OS HR: 0.53 (0.30-0.92), P = 0.02	Use of NAT in CCA remains low but is increasing; No overall benefit, however beneficial in advanced disease	Low: Includes hilar and distal tumours; Uses national database with heterogenous data
Choi et al[24], 2023	Assessment of effectiveness of local (improved chance of surgery with curative intent) and systemic disease (reduced risk of metastasis) control using a triplet chemotherapy; Locally advanced CCA	95 eCCA had NAT; 60.0% were resectable following NAT; 91.2% had R0 resection; 24 dCCA were resected + 4 distal and hilar; 4 dCCA had PCR	Triplet chemotherapy has acceptable safety profile; Clear downstaging effect in LA disease	Low: Includes hilar and distal tumours
Silver et al[34], 2023	Characterize NAT trends over time in eCCA; Identify factors associated with NAT use; NAT impact on outcomes	417 eCCA received NAT (215 chemo only versus 202 CRT); Increase from 0.5% to 5.8% of NAT use across study time frame (2004-2017); NAT improved R0 resection rate (OR: 1.49; 95%CI: 1.10-2.02) and longer mOS (35.1 months vs 25.3 months) vs surgery alone; NAT CRT improved R0 rate (OR: 3.52, 95%CI: 2.11-5.86) and showed longest mOS of 47.8 months, with improvement in OS of HR: 0.64, 95%CI: 0.52-0.79 vs surgery alone	NAT, especially NAT CRT, is associated with improved post-operative outcomes and increased survival in eCCA	Low: Include distal and hilar tumours; No indication for NAT given; Only includes resected patients; Uses national database with heterogenous data

¹Cochrane Grade of Recommendations, Assessment, Development and Evaluation (GRADE) approach.

NAT: Neoadjuvant therapy; CRT: Chemoradiotherapy; RT: Radiotherapy; AC: Adjuvant chemotherapy; UR: Upfront resection; dCCA: Distal cholangiocarcinoma; eCCA: Extrahepatic cholangiocarcinoma; BTC: Biliary tract cancer; OS: Overall survival; PCR: Pathological complete response; HR: Hazard ration; LA: Locally advanced.