Treatment Strategies for Biliary Tract Cancer: A Surgical Perspective from Historical Evolution to Neoadjuvant Therapy

Therapeutic Advances in Pancreatic Cancer

Multidisciplinary considerations in the treatment of triple-negative breast cancer.

Multidisciplinary management in the treatment of intrahepatic cholangiocarcinoma.

Chemotherapy + PD-1/PD-L1 Blockade Should Be the Preferred Option in the Neoadjuvant Therapy of NSCLC

The Efficacy of Neoadjuvant versus Adjuvant Therapy for Resectable Esophageal Cancer Patients: Direct and Indirect Comparisons <i>via</i> Meta-Analysis

Locally advanced rectal adenocarcinoma: Treatment sequences, intensification, and rectal organ preservation.

Current treatment recommendations for resectable or borderline pancreatic carcinoma support upfront surgery and adjuvant therapy. However, neoadjuvant therapy (NT) seems to increase prognosis of pancreatic carcinoma and come to everyone's attention gradually. Randomized controlled trials offering comparison with the NT are lacking and optimal neoadjuvant treatment regimen still remains uncertain. This study aims to compare both treatment strategies for resectable or borderline resectable pancreatic cancer. The PRISMA checklist was used as a guide to systematically review relevant peer-reviewed literature reporting primary data analysis. We searched PubMed, Medline, EMBASE, Cochrane Datebase and related reviews for randomized controlled trials comparing neoadjuvant therapy with surgery first for resectable or borderline resectable pancreatic carcinoma. We estimated relative hazard ratios (HRs) for median overall survival and ratios risks (RRs) for microscopically complete (R0) resection among different neoadjuvant regimens and major complications. We assessed the effects of neoadjuvant therapy on R0 resection rate and median overall survival with Bayesian analysis. Thirteen eligible articles were included. Eight studies performed comparison neoadjuvant therapy with surgery first, and R0 resection rate was recorded in seven studies. Compared with surgery first, neoadjuvant therapy did increase the R0 resection rate (RR = 1.53, I2 = 0%, P< 0.00001), there was a certain possibility that gemcitabine + cisplatin (Gem+Cis) + Radiotherapy was the most favorable in terms of the fact that there was no significant difference concerning the results from the individual studies. In direct comparison, four studies were included and estimated that Neoadjuvant therapy improved mOS compared with upfront surgery (HR 0.68, 95% CI 0.58-0.92; P = 0.012; I2 = 15%), after Bayesian analysis it seemed that regimen with Cisplatin/ Epirubicin then Gemcitabine/ Capecitabine (PEXG) was most likely the best with a relatively small sample size. The rate of major surgical complications was available for six studies and ranged from 11% to 56% with neoadjuvant therapy and 11% to 45% with surgery first. There was no significant difference between neoadjuvant therapy and surgery first, also with a high heterogeneity (RR = 0.96, 95%CI = 0.65-1.43; P = 0.85; I2 = 46%). In conclusion neoadjuvant therapy might offer benefit over up-front surgery. Neoadjuvant therapy increased the R0 resection rate with gemcitabine + cisplatin + Radiotherapy that was the most favorable and improved mOS with Cisplatin/ Epirubicin then Gemcitabine/ Capecitabine (PEXG) that was most likely the best.

4008 Background: Radical surgical resection represents the only potentially curative treatment option for Biliary Tract Cancer (BTC) and (incidental) Gallbladder Carcinoma ((I)GBC). Nevertheless, 5-year OS is only 20–40% after curatively intended resection and data regarding pure adjuvant chemotherapy in BTCs are currently conflicting. Encouraging results of neoadjuvant/perioperative concepts in other malignancies provide a rationale to use this treatment in the early phase management of GBC and intrahepatic as well extrahepatic cholangiocarcinoma (ICC/ECC). Methods: GAIN is a multicenter, randomized, controlled, open-label phase III trial, including patients (pts) with localized or locally advanced resectable non metastatic biliary tract cancer (intra-/extrahepatic cholangiocarcinoma ICC/ECC; GBC in front of radical liver resection). Pts were randomized to either neoadjuvant (perioperative) systemic chemotherapy (Gemcitabine + Cisplatin 3 cycles pre- and post-surgery) followed by radical surgery (Arm A) or to direct surgery followed by adjuvant treatment (Arm B) according to investigators choice. Primary endpoint was OS; secondary endpoints were PFS/EFS, R0-resection rate, toxicity, perioperative morbidity, mortality and QoL. Recruitment was stopped after enrollment of 68 pts due to a slow enrollment rate. Results: Between Dec 2019 and Feb 2024, 68 pts were randomized and the ITT comprised 32 pts in Arm A and 30 pts in Arm B. Baseline characteristics were similar between arms (overall, male 55%; median age 66.0; cT3/T4 29.0%; cN+ 30.6%; 37.1% ICC, 30.6% ECC and 32.3% GBC). 90.6% of pts in Arm A completed all 3 pre-operative cycles. 43.8% in Arm A completed adjuvant treatment and 23.3% in Arm B received adjuvant treatment. Median follow-up was 11.8 months. Neoadjuvant treatment improved OS (mOS, Arm A 27.8 vs. 14.6 months Arm B; HR 0.46 [0.22 - 0.96]; p = 0.04) and R0 resection rate (62.5% vs 33.3%). This effect was also seen in event-free survival. Postoperative morbidity rates were similar in both arms (33.3% (A) vs. 32% (B)) and the 30- and 90-days mortality rates were lower for Arm A (30-days: 4.2% vs. 24%; 90-days: 4.2% vs. 28%). No new safety/toxicity signals were observed. In Arm A, 12 pts (38.7%) had at least one treatment related adverse event (TRAE) with grade 3 and 1 pt (3.2%) with grade 4. No fatal TRAEs were observed. Conclusions: Neoadjuvant / perioperative gem/cis clearly improved OS and R0 resection rate in pts with biliary tract cancer compared to direct surgery and was able to nearly double mOS while not increasing the morbidity rate and even decreasing mortality rates. Clinical trial information: NCT03673072 .

4157 Background: The use of neoadjuvant chemotherapy (NAC) for pancreatic ductal adenocarcinoma (PDAC) has shown clear advantages in locally advanced and borderline resectable disease. The benefit in upfront resectable PDAC is debated. Moreover, in early clinical stages IA/IB, potential benefits including improved R0 resection rate, decreased tumor upstaging, and survival, are not clear. We hypothesize that NAC will be associated with improved outcomes and survival compared to adjuvant therapy in patients with clinical stage IA/IB PDAC. Methods: The National Cancer Database (NCDB) PUFs (2004-2017) were used to perform a retrospective review of patients with clinical stage IA or IB PDAC undergoing surgery. Treatment groups were selected based on timing of chemotherapy. Patients receiving chemotherapy or surgery alone were excluded. Results: We identified 6,613 patients with clinical stage IA or IB PDAC who underwent surgery. The neoadjuvant therapy group (NAT) included 1,533 patients who received neoadjuvant or perioperative chemotherapy, and the adjuvant therapy group (AT) contained 5080 patients who received chemotherapy after surgery. Patients in the NAT had higher rates of T1 and T2 disease and lower rates of T3 pathology compared to the AT (pT1: 18.7% vs 7.8%; pT2: 20.1 vs 18.6%; pT3: 59.3% vs 72.1%, p&lt;0.0001). Additionally, the NAT had significantly higher rates of N0 disease and less N1 pathology (pN0: 54.6% vs 37.5%; pN1: 45.4% vs 62.5%, p&lt;0.0001). The R0 resection rate was higher in the NAT (83.2% vs 62.3%, p=0.0197) and there was less lymphovascular invasion (LVI) compared to the AT (34.8% vs 48.1%, p&lt;0.0001). Using Kaplan Meier estimates, the NAT was associated with improved overall survival (OS) compared to the AT (median OS: 33.4 vs 27.5 months, p&lt;0.0001). On multivariable analysis, R0 resection (HR=0.715, CI: 0.619-0.825, p&lt;0.0001), LVI (HR=1.126, 95% CI: 1.038-1.222, p=0.0043) but not receipt of NAC (HR=0.94, 95% CI: 0.852-1.038, p=0.2229) were independent risk factors for OS. Conclusions: NAC is beneficial in patients with stage IA/IB PDAC undergoing surgical resection as it is associated with improved oncologic outcomes including increased R0 resection rate, decreased tumor upstaging, lymph node metastasis, and LVI. Furthermore, patients receiving NAC were found to have improved survival over those getting adjuvant therapy. Based on these results, we recommend all patients diagnosed with PDAC be considered for NAC prior to surgery. [Table: see text]

Inconclusive results are available as to whether chemo/radiotherapy should be administered to resectable esophageal cancer patients before surgery (neoadjuvant therapy) or after surgery (adjuvant therapy). The paper, via a meta-analysis of effects of treatment modalities when administering chemo/radiotherapy, aims to systematically evaluate the effect of timing of chemo/radiotherapy and surgery. We performed a systematic literature search for clinical trials of neoadjuvant and adjuvant therapy for patients with esophageal cancer. Using meta-analysis, we conducted direct and adjusted indirect comparisons of overall survival, complete resection rate (R0 resection), perioperative mortality, leakage rate and local recurrence in patients with resectable esophageal cancer. A total of 32 studies involving 7985 patients with esophageal cancer were included in the meta-analysis. Twenty-five randomized controlled studies indirectly compared neoadjuvant/adjuvant therapy with surgery alone, while five non-randomized controlled studies and two randomized controlled studies directly compared neoadjuvant with adjuvant therapy. Neoadjuvant therapy followed by surgery, compared with surgery along with adjuvant therapy, showed a significant overall survival advantage in our pooled analysis (HR 0.88; 95% CI 0.79-0.98). Directly compared with adjuvant therapy, neoadjuvant therapy demonstrated a lower local recurrence rate (OR 0.56; 95% CI 0.43-0.74) with low heterogeneity (I2 = 1%). Neoadjuvant therapy, comparing to surgery with or without adjuvant therapy, showed a significantly higher R0 resection rate (OR 2.86; 95% CI 2.02-4.04) with moderate heterogeneity (I2 = 38%) and no significant differences in postoperative anastomotic leakage (P = 0.50). However, neoadjuvant therapy, compared with surgery adjuvant therapy, significantly increased perioperative mortality in both direct and indirect comparisons (P < 0.01). We found that neoadjuvant therapy was associated with higher overall survival and R0 resection rate without increasing postoperative anastomotic leakage for patients with resectable esophageal cancer, whereas neoadjuvant therapy was associated with higher perioperative mortality after esophagectomy.

TPS4653 Background: Currently, complete surgical resection represents the only potentially curative treatment option for Biliary Tract Cancer (BTC) including Gallbladder Cancer (GBC). Even after curative resection, 5-year OS is only 20–40%. GBC is relatively rare, but still the fifth most common neoplasm of the digestive tract and even the most frequent cancer of the biliary system. Gallbladder carcinoma is suspected preoperatively in only 30% of all pts, while the majority of cases are discovered incidentally by the pathologist after cholecystectomy for a benign indication. For improving curative rates in BTC and GBC, early systemic therapy combined with radical resection seems to be a promising approach. The earliest moment to apply chemotherapy would be in front of radical surgery. Encouraging results of neoadjuvant/perioperative concepts in other malignancies provide an additional rationale to use this treatment in the early phase of GBC management and even in intrahepatic and extrahepatic cholangiocarcinoma. Especially because data regarding pure adjuvant chemotherapy in BTC`s are conflicting. Methods: This is a multicenter, randomized, controlled, open-label phase III study including pts with incidentally discovered GBCs after simple cholecystectomy in front of radical liver resection and pts with resectable/borderline resectable cholangiocarcinomas (ICC/ECC) scheduled to receive perioperative chemotherapy (Gemcitabine + Cisplatin 3 cycles pre- and post-surgery) or surgery alone followed by a therapy of investigator’s choice. Primary endpoint is OS; secondary endpoints are PFS, R0-resection rate, toxicity, perioperative morbidity, mortality and QoL. A total of N=333 patients with GBC or BTC will be included. Recruitment has just started; first patient in was on December 6, 2020. EudraCT number: 2017-004444-38. Clinical trial information: NCT03673072 .

BackgroundCurrently, complete surgical resection represents the only potentially curative treatment option for Biliary Tract Cancer (BTC) including Gallbladder Cancer (GBC). Even after curative resection, 5-year OS is only 20–40%. Gallbladder carcinoma is relatively rare, but still the fifth most common neoplasm of the digestive tract and even the most frequent cancer of the biliary system. Gallbladder carcinoma is suspected preoperatively in only 30% of all pts., while the majority of cases are discovered incidentally by the pathologist after cholecystectomy for a benign indication. For improving curative rates in BTC and GBC, early systemic therapy combined with radical resection seems to be a promising approach. The earliest moment to apply chemotherapy would be in front of radical surgery. The encouraging results of neoadjuvant/perioperative concepts in other malignancies provide an additional rationale to use this treatment in the early phase of GBC management and even ICC/ECC. Especially because data regarding pure adjuvant chemotherapy in BTC’s are conflicting.MethodsThis is a multicenter, randomized, controlled, open-label phase III study including pts. with incidentally discovered GBCs after simple cholecystectomy in front of radical liver resection and pts. with resectable/ borderline resectable cholangiocarcinomas (ICC/ ECC) scheduled to receive perioperative chemotherapy (Gemcitabine + Cisplatin 3 cycles pre- and post-surgery) or surgery alone followed by a therapy of investigator’s choice. Primary endpoint is OS; secondary endpoints are PFS, R0-resection rate, toxicity, perioperative morbidity, mortality and QoL. A total of N = 333 patients with GBC or BTC will be included. Recruitment has started in August 2019.DiscussionThe current proposed phase III GAIN study investigates whether induction chemotherapy followed by radical resection in ICC/ECC and re-resection in IGBC (and – if possible – postoperative chemotherapy) prolongs overall survival compared to radical surgery alone for incidental gallbladder carcinoma and primary resectable or borderline resectable cholangiocarcinoma. Utilizing a neoadjuvant approach including a second radical surgery will help to raise awareness for the necessity of radical surgery, especially second radical completion surgery in IGBC and improve the adherence to the guidelines.Trial registrationClinicalTrials.gov ID: NCT03673072 from 17.09.2018. EudraCT number: 2017–004444-38 from 02.11.2017.

429 Background: Esophagogastric junction (EGJ) cancer is difficult to cure with surgery alone, necessitating adjuvant chemotherapy. However, administering aggressive adjuvant chemotherapy after invasive surgery is difficult. Neoadjuvant chemotherapy, on the other hand, is expected to enhance compliance, increase the rate of curative resection, and reduce recurrence. Methods: We conducted a single center Phase I/II study to evaluate the safety and efficacy of neoadjuvant chemotherapy using docetaxel, oxaliplatin, and S-1 (DOS), followed by adjuvant chemotherapy with S-1 in patients with cT3-4aN0-3M0 adenocarcinoma of the EGJ. In Phase I, we estimated the maximum tolerated dose and dose-limiting toxicity of neoadjuvant DOS therapy and determined the recommended dose (RD). In Phase II, we assessed the safety and efficacy of the RD established in Phase I. The primary endpoint was the curative resection rate, with secondary endpoints including the 3-year overall survival rate, 3-year recurrence-free survival rate, treatment completion rate, response rate to neoadjuvant chemotherapy, pathological response, and adverse events. Neoadjuvant DOS chemotherapy was administered in three 3-week cycles. The starting dose of docetaxel was 50 mg/m², with plans to escalate it to 60 mg/m². Docetaxel and oxaliplatin (100 mg/m²) were administered on day 1, while S-1 (120 mg/body) was given orally on days 1-14. Postoperative adjuvant chemotherapy consisted of S-1 (120 mg/body), administered for 4 weeks followed by a 2-week rest period, repeated for 8 cycles. Results: Based on the 6 patients enrolled in Phase I, the RD of docetaxel was determined to be 60 mg/m². A total of 40 eligible patients, including 3 from Phase I, were enrolled in the study. Two patients discontinued protocol treatment during neoadjuvant chemotherapy due to adverse events and 1 patient discontinued due to positive peritoneal cytology. The R0 resection rate was 87.5% (35/40). Surgical procedures included esophagectomy in 18 patients, total gastrectomy in 15, and proximal gastrectomy in 4. Postoperative complications of Grade III or higher, as per the Clavien-Dindo classification, occurred in 15.0% of patients, with no surgery-related deaths. The response rates to neoadjuvant chemotherapy were 12.5% for PR, 2.5% for PD, and 85.0% for non-CR/non-PD. Pathological response rates were: Grade III in 8.1%, Grade II in 35.1% and Grade I in 56.8%. During neoadjuvant chemotherapy, Grade 3 or higher adverse events were observed, including neutropenia (82.5%), nausea (5%) and diarrhea (5%). The neoadjuvant chemotherapy completion rate was 92.5%, although 59.5% of patients required dose reductions. Conclusions: Neoadjuvant DOS therapy for esophagogastric junction cancer shows promise, achieving a high R0 resection rate and substantial pathological efficacy, with acceptable levels of adverse events. Clinical trial information: UMIN000022210.

Whether neoadjuvant chemotherapy (NAT) is beneficial for resectable and locally advanced intrahepatic cholangiocarcinoma (ICC) is still controversial. This study aimed to compare the efficacy of NAT followed by surgery and upfront surgery for ICC treatment. Embase, Pubmed, Web of Science and Cochrane library databases were searched to obtain comparative studies. The non-randomized interventions (ROBINS-I) was used to assess the methodological quality of included studies. The primary outcomes included 1-year, 3-year and 5-year overall survival (OS). The secondary outcomes were R0 resection, 1-year and 3-year recurrence-free survival (RFS). Nine retrospective studies were included in the meta-analysis. A total of 8211 patients were included in the study, of whom 1836 patients received NAT followed by surgery and 6375 patients received upfront surgery. Compared with upfront surgery, NAT group had a significantly better 1-year OS (relative risk (RR) 1.09; 95%CI 1.06, 1.12. p = 0.449) and 3-year OS (RR 1.15; 95%CI 1.06, 1.24. p = 0.386). NAT group had similar results compared with upfront surgery group in 5-year OS (RR 1.16; 95%CI 0.94, 1.44. p < 0.05), 1-year RFS (RR 1.05; 95%CI 0.90, 1.23. p = 0.481), 3-year RFS (RR 1.03; 95%CI 0.82, 1.30. p = 0.969) and R0 resection rate (RR 0.94; 95%CI 0.82, 1.08. p < 0.05). Compared with upfront surgery, NAT followed by surgery had better results for resectable and locally advanced ICC. Considering the patients in NAT followed by surgery group had more advanced ICC cases, NAT followed by surgery might be a rationale choice for ICC treatment. Further studies about effective downstage treatments for locally advantage ICC are needed in future.

Background and aimsCurrently, surgical resection is the most commonly performed and effective treatment for intrahepatic cholangiocarcinoma (ICC) worldwide. However, the prognosis of ICC is unsatisfactory. This study aimed to compare the efficacy and safety of neoadjuvant chemotherapy followed by surgery and upfront surgery in treating intrahepatic cholangiocarcinoma (ICC). The study also intends to explore whether chemotherapy should be introduced before surgery and which populations should be considered for neoadjuvant chemotherapy.MethodFour databases, including PubMed, EMBASE, Cochrane Library, and Web of Science, were searched from their inception dates to January 2022 for relevant articles. The statistical analysis was performed using the Review Manager Software (version5.3). The non-randomized interventions (ROBINS-I) was used to assess the methodological quality of included studies and the overall quality of evidence was assessed through the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool. Moreover, the primary outcomes included 1-year, 3-year and 5-year overall survival (OS), while the secondary outcomes were R0 resection, 1-year, 3-year and 5-year recurrence-free survival (RFS), postoperative complications and ninety-day postoperative mortality.ResultsFive studies involving 2412 patients were included in this meta-analysis. There was no significant difference in 1-year OS, 3-year OS, 1-year, 3-year and 5-year RFS, postoperative complications and ninety-day postoperative mortality between the two groups. However, the meta-analysis showed that the neoadjuvant chemotherapy group had a better 5-year OS benefit in ICC patients than the upfront surgery group (OR = 1.27, 95% CI: 1.02–1.58), while the R0 resection rate was lower in neoadjuvant chemotherapy group than that in the upfront surgery group (OR = 0.49, 95% CI: 0.26–0.91).ConclusionCompared with the upfront surgery, neoadjuvant chemotherapy followed by surgery could prolong the 5-year OS without increasing the risk of postoperative complications in ICC patients. Considering that the patients in the neoadjuvant chemotherapy followed by surgery group had more advanced ICC cases, the benefits of neoadjuvant chemotherapy may be more significant in patients with more advanced ICC.