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

Table 1 National Comprehensive Cancer Network Criteria defining resectablity at diagnosis for pancreatic ductal adenocarcinoma

Resectability status	Arterial	Venous
Resectable	No arterial tumour contact (CA, SMA, or CHA)	No tumour contacts with the SMV or PV or ≤ 180° contact without vein contour irregularity
Borderline resectable	Pancreatic head/uncinate process: (1) Solid tumour contact with CHA without extension to the CA or hepatic artery bifurcation allowing for safe and complete resection and reconstruction; (2) Solid tumour contact with the SMA of ≤ 180°; and (3) Solid tumour contact with variant arterial anatomy, and the presence and degree of tumour contact should be noted if present, as it may affect surgical planning. Pancreatic body/tail: Solid tumour contact with the CA of ≤ 180°	Solid tumour contact with the SMV or PV of > 180°, contact of ≤ 180° with contour irregularity of the vein or thrombosis of the vein but with suitable vessel proximal and distal to the site of involvement allowing for safe and complete resection and vein reconstruction: Solid tumour contact with the IVC
Locally advanced	Pancreatic head/uncinate process: Solid tumour with > 180° degrees contact with SMA or CA. Pancreatic body/tail: (1) Solid tumour contact > 180° with the SMA or CA; and (2) Solid tumour contact with CA and aortic involvement	Unreconstructible SMV or PV due to tumour involvement or occlusion (thrombus tumour)

CA: Coeliac axis; SMA: Superior mesenteric artery; CHA: Common hepatic artery; SMV: Superior mesenteric vein; PV: Portal vein; IVC: Inferior vena cava.

Table 2 Characteristics of included studies

Ref.	Country	Study type	NAT type	n (total)	n (distal)	n (NAT, distal)	n (unresectable, distal, NAT)	n (advanced vascular involvement, distal, NAT)	n (unresectable, distal, NAT, resected)
McMasters et al[23], 1997	United States	Prospective	5-FU CRT	91	28	4	4	4	4
Czito et al[27], 2006	United States	Prospective (Phase I)	Eniluracil/5-FU CRT	3	3	3	2	2	1
Nelson et al[31], 2009	United States	Retrospective	Fluoropyrimidine-based CRT	45	NR	NR	NR	NR	NR
Kobayashi et al[33], 2015	Japan	Prospective (Phase I)	Gem CRT	25	25	15	NR	NR	NR
Cloyd et al[26], 2019	United States	Retrospective	Gem or 5-FU Chemotherapy or 5-FU, cap or Gem CRT	45	45	21	9	1	9
Oh et al[28], 2021	South Korea	Retrospective	Gem-based	12	4	4	4	2	4
Adam et al[25], 2023	United States	Retrospective	NR	2514	25141	157	NR	NR	NR
Fujii et al[29], 2022	Japan	Retrospective	Gem CRT	16	16	16	NR	NR	NR
Parente et al[30], 2023	United States	Retrospective	NR	9411	1953	271	NR	NR	NR
Toyoda et al[32], 2023	United States	Retrospective	NR	6582	NR	NR	NR	NR	NR
Choi et al[24], 2023	South Korea	Retrospective	Gem/Cis/nab-P chemotherapy	129	NR	NR	NR	NR	24 (+4)2
Silver et al[34], 2023	United States	Retrospective	NR	8040	NR	NR	NR	NR	NR

¹Adam et al[25] report on extrahepatic cholangiocarcinoma, in the context of peri-ampullary malignancy, without explicitly defining distal cholangiocarcinoma.

²Choi et al[24] give a total number of patients with distal (24) and distal + hilar (4) patients who had locally advanced disease, who received NAT, and were then resected, but without giving the individual numbers of each.

NAT: Neoadjuvant therapy; CRT: Chemoradiotherapy; FU: Fluorouracil; Gem: Gemcitabine; Cap: Capecitabine; nab-P: Nab-paclitaxel; NR: Not reported.

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.