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Postoperative recurrent patterns of gallbladder cancer: possible implications for adjuvant therapy

Postoperative recurrent patterns of gallbladder cancer: possible implications for adjuvant therapy Background: Gallbladder cancer (GBC) is an uncommon malignancy with high recurrent rate and poor prognosis. This study investigates the recurrent patterns of postoperative GBC, with the aim to guide the adjuvant treatments, including the radiotherapy. Methods: Retrospectively analyzed the 109 GBC patients who underwent surgery in our institution from January 2013 to 2018. Clinical follow-up revealed 54 recurrent cases, of which 40 had detailed locations of recurrence. The sites of recurrence were recorded and divided into the tumor bed, corresponding lymphatic drainage area, intrahepatic recurrence, and the other distant metastasis. Results: The median follow-up time is 34 months (IQR: 11–64). The median disease-free survival (DFS) and overall survival (OS) were 48.8 months and 53.7 months, respectively. Through univariate analysis, risk factors for DFS and OS include tumor markers (CA199 and CEA), hepatic invasion, perineural invasion, lymphovascular invasion, TNM staging and tumor differentiation. Through multivariate analysis, risk factors for DFS include hepatic invasion and TNM staging, and for OS is TNM staging only. Of the 40 cases with specific recurrent sites, 29 patients (29/40, 72.5%) had recurrence in the potential target volume of postoperative radiotherapy (PORT ), which include tumor bed and corresponding lymphatic drainage area. The common recurrent lymph node groups included abdominal para-aortic lymph node (No.16, 15/29), hepatoduodenal ligament lymph node (No.12, 8/29), retro-pancreatic head lymph node (No.13, 7/29) and celiac axis lymph node (No.9, 4/29). Twenty cases with recurrences inside the potential PORT target volume were accompanied by distant metastasis. Another 11 cases had distant metastasis alone, so totally 31 cases developed distant metastasis (31/40, 77.5%), including 18 cases with hepatic metastasis. Conclusion: The recurrence and metastasis rates are high in GBC and adjuvant therapy is needed. Up to 75% of the recurrent cases occurred in the potential target volume of postoperative radiotherapy, suggesting that postoperative radiotherapy has the possible value of improving local-regional control. The potential target volume of radiotherapy should include the tumor bed, No.8, No.9, No.11, No.12, No.13, No.14, No. 16a2, No. 16b1 lymph node groups. Keywords: Gallbladder cancer, Adjuvant radiotherapy, Target volume, Patterns of recurrence Introduction Gallbladder cancer (GBC) is an uncommon type of tumor [1], with the highest incidence in biliary tract tumors [2]. *Correspondence: qichun_wei@zju.edu.cn The occurrence of GBC is significantly related to chronic gallstone, and the malignancy incidence is positively cor- Department of Radiation Oncology, Ministry of Education Key Laboratory of Cancer Prevention and Intervention, The Second Affiliated Hospital, related with the size of gallstone [3]. Other risk factors Zhejiang University School of Medicine, Hangzhou, Zhejiang, China include gallbladder polyps (> 1 cm), chronic cholecystitis, © The Author(s) 2022. 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The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Yuan et al. Radiation Oncology (2022) 17:118 Page 2 of 11 porcelain gallbladder, anomalous pancreaticobiliary node-positive disease [25]. Therefore, the recurrent pat - ductal junction and chronic typhoid infection [4–7]. terns after GBC surgery may provide valuable informa- Patients with Early stage of GBC has no obvious typi- tion for adjuvant therapeutic options. cal clinical symptoms [8], and some cases are inciden- In this study, failure patterns of 109 postoperative GBC tally discovered during or after surgery [9]. At the time patients were retrospectively analyzed, with the aim to of diagnosis, most patients are with advanced diseases, explore the sites with high risk of local recurrence and only 10–30% of patients are surgically resectable [10]. metastasis. Such information would be of great value to However surgical resection is still the only way of radi- adjuvant therapy, including the design of radiotherapy cal cure for gallbladder cancer [11]. As the postoperative target volume and the application of systematic therapy. recurrence rate and metastasis rate are high, adjuvant therapeutics should should be emphasized that adjuvant Methods therapy can improve survival in GBC patients [12]. Patients The best adjuvant treatment for GBC remains contro - The study was approved by the Institutional Review versial [13]. Only a few retrospective studies and rand- Board of the Second Affiliated Hospital, Zhejiang Univer - omized phase III trials on postoperative adjuvant therapy sity School of Medicine (SAHZU). The medical records of GBC can be found through PubMed. Postoperative from January 2013 to 2018 were retrospectively analyzed, radiotherapy for GBC was proposed by Bosset et  al. for including 109 patients who were followed up for at least the first time14. Todoroki et  al. suggested that surgi - 2 months after resection. All the patients achieved histo- cal resection combined with intraoperative radiation pathology diagnosis after surgery. Patients with previous therapy with or without external radiation therapy (with or contemporaneous tumor history were excluded. The 2- and 3-year survival rate of 20.2% and 10.1%) has a bet- clinical variables collected in the retrospective analysis ter survival rate than surgical treatment alone for stage included gender, age, T stage, N stage, clinical TNM stag- IV GBC patients (1- and 2-year survival rate of 11.1% and ing, tumor differentiation, recurrence time, tumor bio - 0%) (P < 0.05) [15]. A retrospective analysis of 3187 GBC markers, history of gallstones, bile duct stones, hepatitis, patients was conducted by Mojica et  al., using the Sur- diabetes, hypertension, schistosomiasis and postopera- veillance, Epidemiology and End Results (SEER) database, tive adjuvant treatment. Tumor clinical staging was per- patients who received adjuvant radiotherapy had a bet- formed according to AJCC staging system, 8th Edition. ter median survival (14  months vs. 8  months, P < 0.001). Follow-up period ended on September 28, 2020. Among the numbers of predictors, the only favorable factors for survival were local lymph node metastasis Recurrent patterns (P = 0.0001) and liver invasion (P = 0.011) [16]. Similarly, According to the 8th edition of the AJCC staging system, Wang et  al. obtained a result that adjuvant radiotherapy inter-aortocaval lymph node and para-aortic lymph node was one of the prognostic factors [17]. Yang et al. pointed metastasis are regarded as distant metastasis. Therefore, out that the 5-year survival rate and average survival time in this study, the term “local-regional recurrence” was not of GBC patients in the stage III and IV in adjuvant radio- used. We defined “the potential target volume of postop - therapy groups were significantly better than those of the erative radiotherapy (PORT)” which include the tumor control group (P < 0.05), but patients in stage II have no bed (surgical margin) and high-risk lymphatic drainage significant difference between two groups [18]. In sev - area. Long term follow-up was performed by specialist eral postoperative chemoradiotherapy studies of GBC, physicians. The initial recurrent sites were classified to Jeong et  al. suggested that adjuvant radiotherapy might the potential target volume of PORT recurrence, intra- have benefit in local control of GBC [19] and most of the hepatic recurrence, and other distant recurrence. Tumor studies revealed that adjuvant chemoradiotherapy can recurrences were detected by imagiological  examination achieve a good long-term survival rate [20, 21], especially (most cases will be monitored by continuous postopera- it may be useful for the tumor patients undergoing R0 tive evaluation). For recurrent local lymph nodes, it can resection without lymph node dissection. However, some have the features of greater or equal to 10  mm in short studies have shown that adjuvant therapy has no signifi - diameter, obvious necrosis, obvious enhancement, and cant effect on improving disease-free survival (DFS) [22]. eccentric calcification. If possible, PET/CT can assist Due to the lack of phase III randomized controlled trials in diagnosis, and the presence of distant metastasis can (RCT) data, the role of postoperative adjuvant radiother- be determined at the same time. There are only 2 cases apy remains unclear [23, 24]. According to the National were diagnosed as tumor recurrence by biopsy, though Comprehensive Cancer Network (NCCN) Guidelines, we encouraged to get definite pathological diagnosis. The postoperative chemoradiotherapy or chemotherapy initial recurrent pattern, DFS and OS will be analyzed. is feasible for GBC, especially in patients with lymph DFS was from the day of operation to the time of first Y uan et al. Radiation Oncology (2022) 17:118 Page 3 of 11 tumor recurrence, OS was from the day of operation to the P value < 0.05. IBM SPSS Statistics 23.0 and Graphpad the death or the last follow-up time. Prism 5.0 was used for statistical analyses. Statistical analysis Results The correlation of patients’ characteristics with DFS Patient characteristics and OS were analyzed by Kaplan Meier analysis. Sig- The characteristic statistics of 109 patients are shown nificance was evaluated with the log-rank test. Cox pro - in Table  1. There were 37 males (33.9%) and 72 females portional hazards models was applied for multivariate (66.1%). The mean age was 64.5  years, and the median survival analysis. Statistical significance was defined as age was 65  years (IQR: 56–73). Preoperative CA-199 Table 1 Gallbladder cancer patient characteristics Characteristics No Percentage (%) Gender Male 37 33.9 Female 72 66.1 Age (yrs) Median 65 Range 37–89 CA199 (107 cases) > 37 U/ml 52 48.6 CEA (105 cases) > 5 ng/ml 26 24.8 Gallstone 61 56.0 Bile duct stone 20 18.3 Hepatitis 5 4.6 Hypertension 37 33.9 Diabetes 7 6.4 History of schistosomiasis 5 4.6 Jaundice Serum bilirubin > 17.1 μmol/L 29 26.6 Serum bilirubin > 34.2 μmol/L 16 14.7 T stage Tis 6 5.5 T1 10 9.2 T2 50 45.9 T3 35 32.1 T4 8 7.3 N stage N0 67 61.5 N1 26 23.9 N2 16 14.7 Distant metastasis 9 8.3 AJCC 8th Staging System 0 6 5.5 I 10 9.2 II 31 28.4 III 36 33.0 IV 26 23.9 Liver invasion 30 27.5 Perineural invasion 33 30.3 Lymphovascular invasion 36 33.0 Tumor differentiation Well differentiated 20 18.3 Moderate differentiated 35 32.1 Poor differentiated 45 41.3 Undifferentiated 1 0.9 Unknown 8 7.3 Adjuvant chemotherapy 8 7.3 Adjuvant chemoradiotherapy 5 4.6 Yuan et al. Radiation Oncology (2022) 17:118 Page 4 of 11 and CEA elevation were found in 48.6% (52/107 cases) significant difference in the prognosis of GBC patients and 24.8% (26/105 cases) of the cases. Among the 109 with gender, age, preoperative jaundice and previous patients, 61 patients (56.0%) had gallstones. As to the medical history. The postoperative survival status of pathological differentiation of GBC, 20 cases (18.3%) patients was related to the elevation of CA199 (DFS, were well differentiated, 35 cases (32.1%) were moder - P = 0.0002; OS, P = 0.0029) and CEA (DFS, P = 0.0009; ately differentiated, 45 cases (41.3%) were poorly dif - OS, P = 0.0064) (Fig . 1). The other factors included liver ferentiated, 1 case (0.9%) was undifferentiated, and the invasion (DFS, P < 0.0001; OS, P < 0.0001), perineural differentiation of the other 8 cases (7.3%) were unknown. invasion (DFS, P = 0.0412; OS, P = 0.0169), lymphovas- According to the 8th edition of AJCC Staging System, the cular invasion (DFS, P = 0.0004; OS, P = 0.0003), tumor tumor T stage was as follows: Tis, 6 cases (5.5%); T1, 10 differentiation (well vs moderate vs poor and undif - cases (9.2%); T2, 50 cases (45.9%); T3, 35 cases (32.1%); ferentiated, DFS, P = 0.0006; OS, P = 0.0002) (Fig .  2), T4, 8 cases (7.3%). N stage: N0, 67 cases (61.5%); N1, 26 tumor T stage (Tis and T1 vs. T2 vs. T3 vs. T4, DFS, cases (23.9%); N2, 16 cases (14.7%). Distant metastasis P < 0.0001; OS, P < 0.0001), lymph node metastasis N occurred in 9 cases (8.3%). In TNM staging, there were stage (N0 vs. N1 vs. N2, DFS, P < 0.0001; OS, P < 0.0001) 6 (5.5%), 10 (9.2%), 31 (28.4%), 36 (33%) and 26 cases and the tumor TNM staging (I vs. II vs. III vs. IV, DFS, (23.9%) with stage 0, I, II, III and VI respectively. Post- P < 0.0001; OS, P < 0.0001) (Fig .  3). The results of all operative pathology showed liver invasion in 30 cases univariate analysis are shown in Table  2. In multivari- (27.5%), perineural invasion in 33 cases (30.3%), lympho- ate analysis, both liver invasion (RR: 2.308; 95% confi - vascular invasion in 36 cases (33%). dence interval [CI]: 1.045–5.097; p = 0.038) and TNM staging of tumor (RR: 3.135; 95% confidence interval Follow‑up and survival [CI]: 1.432–6.863; p = 0.004) are important to PFS. But The median follow-up time was 34  months (IQR: for OS, only TNM staging (RR: 2.676; 95% confidence 11–64) in 109 patients. The median disease free sur - interval [CI]: 1.396–5.132; p = 0.003) is statistically vival (DFS) and overall survival (OS) were 48.8 months significant. and 53.7  months. In univariate analysis, there was no Fig. 1 Survival outcomes of baseline data. (A) Kaplan–Meier curves of DFS and OS in group with CA-199 elevated or normal. (B) Kaplan–Meier curves of DFS and OS in group with CEA elevated or normal Y uan et al. Radiation Oncology (2022) 17:118 Page 5 of 11 Fig. 2 Survival outcomes of pathological factors. (A) Kaplan–Meier curves of DFS and OS in group with liver invasion positive or negative. (B) Kaplan–Meier curves of DFS and OS in group with perineural invasion positive or negative. (C) Kaplan–Meier curves of DFS and OS in group with lymphovascular invasion positive or negative. (D) Kaplan–Meier curves of DFS and OS in group of tumor differentiation Yuan et al. Radiation Oncology (2022) 17:118 Page 6 of 11 Fig. 3 Survival outcomes of tumor staging. (A) Kaplan–Meier curves of DFS and OS in group of T stage. (B) Kaplan–Meier curves of DFS and OS in group of N stage. (C) Kaplan–Meier curves of DFS and OS in group of TNM staging Recurrence rate and 80.8% (21/26 cases). The specific recurrence rates Fifty-four patients (54/109, 49.5%) developed post- are shown in Table 3. operative recurrence at the time of last follow-up. No recurrence was found in patients with Tis and T1. The recurrence rates of patients with T2, T3, T4 were 42.0% Initial disease recurrence (21/50 cases), 71.4% (25/35 cases), 100% (8/8 cases), Among the 54 cases, the imaging of 40 cases were able respectively. The recurrence rates of patients with N0, to identify the sites of initial recurrence. The other 14 N1, N2 were 35.8% (24/67 cases), 69.2% (18/26 cases), cases had follow-up imaging in local hospital and came 75% (12/16 cases). As to TNM staging, the recurrence to our institution with hardcopy diagnostic report rates of those with staging 0 & I, II, III, and IV were 0% only, so the exact locations of tumor recurrences were (0/16 cases), 32.3% (10/31 cases), 63.9% (23/36 cases) unavailable. Only 2 recurrent cases were diagnosed Y uan et al. Radiation Oncology (2022) 17:118 Page 7 of 11 Table 2 Univariate analysis of PFS and OS in gallbladder cancer Characteristics No Percentage (%) Median DFS P value Median OS P value Gender Male 37 33.9 Not reached 0.5023 Not reached 0.396 Female 72 66.1 36 41 Age (yrs) < 65 years old 53 48.6 Not reached 0.6539 Not reached 0.0707 ≥ 65 years old 56 51.4 24 32 CA199 (107 cases) > 37 U/ml 52 48.6 8 0.0002 22 0.0029 Normal 55 51.4 Not reached Not reached CEA (105 cases) > 5 ng/ml 26 24.8 10 0.0009 20.5 0.0064 Normal 79 75.2 Not reached Not reached Gallstone Positive 61 56.0 64 0.6478 37 0.5273 Negative 48 44.0 39.5 Not reached Bile duct stone Positive 20 18.3 Not reached 0.0778 Not reached 0.3589 Negative 89 81.7 30 42 Hepatitis Positive 5 4.6 5 0.5023 15 0.3835 Negative 104 95.4 64 Not reached Hypertension Positive 37 33.9 42 0.8149 44 0.6685 Negative 72 66.1 64 Not reached Diabetes Positive 7 6.4 Not reached 0.7271 Not reached 0.3616 Negative 102 93.6 48 42 Schistosomiasis Positive 5 4.6 Not reached 0.3306 Not reached 0.7756 Negative 104 95.4 48 44 Jaundice Serum bilirubin > 17.1 μmol/L 29 26.6 Not reached 0.5973 32 0.3446 Normal 80 73.4 48 Not reached T stage Tis + T1 16 14.7 Not reached < 0.0001 Not reached < 0.0001 T2 50 45.9 Not reached Not reached T3 35 32.1 6 18 T4 8 7.3 3 11 N stage N0 67 61.5 Not reached < 0.0001 Not reached < 0.0001 N1 26 23.9 12 18 N2 16 14.7 5 11 TNM Staging II 31 28.4 Not reached < 0.0001 Not reached < 0.0001 III 36 33.0 22 24 IV 26 23.9 4 13 Liver invasion Positive 30 27.5 3 < 0.0001 11 < 0.0001 Negative 79 72.5 Not reached Not reached Perineural invasion Positive 33 30.3 15 0.0412 24 0.0169 Negative 76 69.7 Not reached Not reached Lymphovascular invasion Positive 36 33.0 9 0.0004 20 0.0003 Negative 73 67.0 Not reached Not reached Tumor differentiation Well 20 18.3 Not reached 0.0006 Not reached 0.0002 Moderate 35 32.1 64 Not reached Poor + Undifferentiated 46 42.2 6 15 The bold figures in the table are the data with P < 0.05 by biopsy, and the remaining cases were diagnosed as (29/40, 72.5%), 18 (18/40, 45.0%) and 21 (21/40, 52.5%), tumor recurrence by serial follow-up imaging. respectively. Among them, 23 cases had multiple sites Initial recurrences occurred in the potential PORT of initial disease recurrence (Fig. 4). volume, remnant liver and the other distant sits were 29 Yuan et al. Radiation Oncology (2022) 17:118 Page 8 of 11 Table 3 Recurrent pattern of gallbladder cancer (40 cases in total) Staging No Tumor bed (10 cases) Lymphatic drainage area (23 Remnant liver (18 cases) Other distant cases) metastases (21 cases) T0 &T1 16 0 (0%) 0 (0%) 0 (0%) 0 (0%) T2 50 5 (10%) 10 (20%) 3 (6%) 8 (16%) T3 35 5 (14.3%) 10 (28.6%) 11 (31.4%) 8 (22.9%) T4 8 0 (0%) 3 (37.5%) 4 (50%) 5 (62.5%) N0 67 5 (7.5%) 9 (13.4%) 10 (14.9%) 9 (13.4%) N1 26 5 (19.2) 6 (23.1%) 5 (19.2%) 7 (26.9%) N2 16 0 (0%) 8 (50%) 3 (18.8%) 5 (31.3%) TNM 0 & I 16 0 (0%) 0 (0%) 0 (0%) 0 (0%) II 31 2 (6.5%) 3 (9.7%) 3 (9.7%) 3 (9.7%) III 36 8 (22.2%) 8 (22.2%) 8 (22.2%) 10 (27.8%) IV 26 0 (0%) 12 (46.2%) 7 (26.9%) 8 (30.8%) Of the 29 patients whose initial recurrence inside the potential PORT volume, 9 (9/40, 22.5%) developed recur- rence only inside the potential PORT volume, includ- ing 2 tumor bed recurrences, 7 lymph node metastases, and none had recurrence in both sites simultaneously (Table  4). Twenty had synchronous distant metastasis, including 9 in remnant liver, 16 in other distant sites, and of these, 5 had synchronous recurrences at remnant liver and other distant sites. Among the 31 patients with distant metastasis, 11 Fig. 4 Initial recurrent pattern of GBC. Initial recurrent pattern of 40 patients did not develop recurrence in the potential cases occurred in the potential PORT volume, remnant liver and the PORT volume, including 6 hepatic metastasis, 1 abdom- other distant sits inal wall metastasis, 1 multiple pelvic implantation Table 4 The characteristics of 9 patients with isolated PORT volume recurrences Postoperative pathological stage Postoperative pathologically Detailed recurrence sites positive lymph nodes Case 1 T3N2M0 12, 13 12 (12a), 7, 16 (16a2) Case 2 T2N0M0 12 (12b) Case 3 T2N0M0 Tumor bed Case 4 T2N0M1 (Hepatic metastasis) 13 Case 5 T2N1M0 9, 13 16 (16b1) Case 6 T3N2M0 12, 13 3, 6, 13, 17, 7, 8, 9,12, 14, 16 (16a1, 16a2, 16b2) Case 7 T2N1M1 (Metastatic lymph nodes invade surrounding tissue) 13 16 (16b1, 16b2) Case 8 T2N1M0 8、9、12 Tumor bed Case 9 T3N1M1 (Metastatic lymph nodes invade surrounding tissue) 13 13, 15, 16 (16a2, 16b1) Y uan et al. Radiation Oncology (2022) 17:118 Page 9 of 11 metastasis and 3 multiple metastasis in remnent liver and nodes (No.16), hepatoduodenal ligament lymph nodes abdominal wall. The other 20 patients had distant metas - (No.12), retro-pancreatic head lymph node (No.13), tasis and recurrence in the potential PORT volume at the celiac axis lymph node (No.9), right lymph node of cardia same time. (No.1), lesser curvature lymph node (No.3), splenic artery In the 23 cases of lymph node recurrence, the com- lymph node (No.11) and superior mesenteric artery and mon sites of lymph node metastases were para aortic vein lymph node (No.14). According to Uesaka and Ito’s lymph nodes (station No.16, n = 15), hepatoduodenal anatomical description of gallbladder lymphatic drainage, ligament lymph nodes (No.12, n = 8), retro-pancreatic there were four routes of gallbladder lymphatic drainage: head lymph nodes (No.13, n = 7), celiac axis lymph nodes gallbladder pancreaticoduodenal route (mainly), gallblad- (No.9, n = 4). In addition, 3 cases had recurrence in the der hepatoduodenal ligament route, gallbladder mesen- right lymph nodes of cardia (No.1), lesser curvature teric route and porta hepatis route [31, 32]. Finally, the lymph nodes (No.3), splenic artery lymph nodes (No.11) first three pathways converged at the level of the left renal and superior mesenteric artery and vein lymph nodes vein in the para aortic lymph nodes. The porta hepatis (No.14). There were 2 cases in superior pyloric lymph pathway may be related to liver metastasis. The left renal nodes (No.5), left gastric artery lymph nodes (No.7), vein is the dividing line between No.16a2 and No.16b1, middle colon vascular lymph nodes (No.15) and anterior which is consistent with the recurrent pattern of para pancreatic lymph nodes (No.17). And 1 case occurred in aortic lymph nodes in 15 cases. Lymph nodes recurred gastric omental lymph nodes (No.4), subpyloric lymph at the level of left renal vein in every case. In addition, a nodes (No.6), common hepatic artery lymph nodes small number of No.16a1 and No.16b2 recurrences were (No.8) and splenic hilum lymph nodes (No.10). In 15 considered as secondary lymph node metastasis. cases of para aortic lymph node recurrence, there were 2 J Socha et  al. performed systematic review and meta- cases in 16a2, 3 cases in 16b1, 7 cases in 16a2 and 16b1, 1 analysis of lymph node metastases in biliary tumors of case in 16b1 and 16b2, 1 case in 16a1, 16a2 and 16b2, and different T stages [33]. It is suggested that the adjuvant 1 case in 16a2, 16b1 and 16b2 at the same time. radiotherapy target volume of T3-4 GBC should include No.8, No.9, No.12, No.13, No.14, No.16 lymph node Discussion groups. In our retrospective study, only 1 case of recur- The study showed the factors affecting the survival sta - rent metastatic lymph node was located at No.8. For tus of patients with gallbladder cancer after resection cross-regional lymph nodes, the center of lymph node and the recurrence mode after operation. According to was used as the localization marker for statistical analysis the research results, 49.5% of the patients had recurrence during imaging review. The No.9, No.12 and No.13 were after surgery, which is consistent with the recurrence rate all distributed around No.8, and each landmark tissues of some previous studies [26, 27]. and organs were close to each other. Therefore, combined In this study, postoperative recurrence rate varied with with the literature, No.8 should be included in the post- different stages. Postoperative recurrence mainly occurs operative radiotherapy target volume. Combined with in the middle and advanced stages of gallbladder cancer. other research reports and structural relationships, No.1 For early gallbladder cancer (TNM stage 0&I), the post- and No.3 have a small probability of metastasis, and the operative recurrence rate is 0%, and the five-year survival greater toxic side effects of PORT can be predicted. So rate is 100%. This result was the same as that of lee et al. the inclusion of the above two groups of lymph nodes in [28]. Of the 40 cases with detail follow-up records of the PORT target volume is not considered in this study. recurrence, there was no significant difference between No.14 metastases of locally advanced gallbladder cancer relapsing in radiotherapy potential volume only (9 cases, have also been observed in other studies, and the same 22.5%) and distant metastasis only (11 cases, 27.5%). number of No.11 metastases occurred in our study. Ana- According to the different recurrent patterns of previ - tomically, we considered that the PORT target volume ous trials, this result is consistent with the fact [22, 26, should include No.11 (corresponds to the lymphatic 29, 30]. Although there is no plentiful enough large-scale region of the proximal splenic artery) and No.14, which phase III clinical trial, many previous trials and this study may improve local control of the disease. At the same suggested that specific adjuvant therapy should be taken time, attention should be paid to patients’ radiotherapy for GBC with high recurrence rate. tolerance, and appropriate adjustments can be made for Postoperative radiotherapy is recommended to com- different patients and different stages. Therefore, after bine with chemotherapy in all feasible patients with comprehensive consideration, the target volume of adju- locally advanced gallbladder cancer. According to the vant radiotherapy should include the tumor bed, No.8, analysis of the initiate recurrent pattern of 29 cases, the No.9, No.11, No.12, No.13, No.14, No.16a2 and No.16b1 common recurrent lymph nodes were para aortic lymph lymph node groups. Yuan et al. Radiation Oncology (2022) 17:118 Page 10 of 11 Among the GBC patients with TNM stage II-IV (93 cancer may need multicenter prospective trials to prove cases, 54 cases of recurrence, recurrence rate: 58%), its effectiveness. the recurrence rate in the potential target volume of radiotherapy is almost the same as the rate of distant Abbreviations metastasis. Therefore, adjuvant chemotherapy is also GBC: Gallbladder cancer; PET/CT: Positron emission tomography/computed important. In this study, OS and DFS of adjuvant radio- tomography; DFS: Disease-free survival; OS: Overall survival; PORT: Postopera- tive radiotherapy; SEER: Surveillance, epidemiology and end results; NTRK: therapy, adjuvant chemotherapy and adjuvant chemo- Neurotrophic tryrosine receptor kinase; MSI-H: Microsatellite instability-high; radiotherapy were not statistically significant. The same dMMR: Deficient mismatch repair. results were also found in other trials [34, 35]. This Acknowledgements result may be caused by the small sample size. In two This work was supported by National Natural Science Foundation of China phase III clinical trials, capecitabine monotherapy and (No.82073332). adjuvant chemotherapy with fluorouracil and mito - Author contributions mycin C, respectively, showed significant improve - ZY analyzed data and wrote the article. YS and ZY were responsible for image ments in PFS and OS [35, 36]. For the high recurrence evaluation and clinical data analysis. LL and YG analyzed data and statistics. rate of GBC, as well as the high incidence of distant QW designed, revised, and supervised the writing and concept of the article. All authors read and approved the final manuscript. metastasis and local recurrence, postoperative adju- vant chemoradiotherapy is a better choice, especially Availability of data and materials for the relatively advanced GBC. The phase II SWOG Datasets can be retrieved from authors by formal request from interested readers. Datasets will not be directly shared on public link as the national S0809 trial included patients with extrahepatic chol- personal data protection act. angiocarcinoma or gallbladder cancer (N = 79), pro- viding prospective data for adjuvant chemotherapy/ Declarations chemoradiotherapy (concurrent chemoradiotherapy with capecitabine after capecitabine/gemcitabine Ethics approval and consent to participate This study was approved by Institutional Review Board of SAHZU. chemotherapy). The 2-year survival rate was 65%, and the median survival time was 35  months. Most of the Consent for publication patients (86%) who participated in the trial completed Not applicable. the treatment, indicating that the regimen was gen- Competing interests erally tolerable [37, 38]. But gemcitabine concurrent The authors declare that the research was conducted in the absence of any chemoradiotherapy is not recommended because of its commercial or financial relationships that could be construed as a potential conflict of interest. limited experience and side effects [39]. According to the National Comprehensive Cancer Received: 17 January 2022 Accepted: 27 June 2022 Network (NCCN) Guidelines, in addition to gemcit- abine + cisplatin and other chemotherapy regimens, tar- geted therapy or immunotherapy can be combined for postoperative recurrence of gallbladder cancer in special References 1. Levy AD, Murakata LA, Rohrmann CJ. Gallbladder carcinoma: radiologic- circumstances. For NTRK gene fusion-positive tumors, pathologic correlation. Radiographics. 2001;21(2):295–314. Entrectinib, Larotrectinib can be used. For MSI-H/ 2. Sheth S, Bedford A, Chopra S. 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Postoperative recurrent patterns of gallbladder cancer: possible implications for adjuvant therapy

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Abstract

Background: Gallbladder cancer (GBC) is an uncommon malignancy with high recurrent rate and poor prognosis. This study investigates the recurrent patterns of postoperative GBC, with the aim to guide the adjuvant treatments, including the radiotherapy. Methods: Retrospectively analyzed the 109 GBC patients who underwent surgery in our institution from January 2013 to 2018. Clinical follow-up revealed 54 recurrent cases, of which 40 had detailed locations of recurrence. The sites of recurrence were recorded and divided into the tumor bed, corresponding lymphatic drainage area, intrahepatic recurrence, and the other distant metastasis. Results: The median follow-up time is 34 months (IQR: 11–64). The median disease-free survival (DFS) and overall survival (OS) were 48.8 months and 53.7 months, respectively. Through univariate analysis, risk factors for DFS and OS include tumor markers (CA199 and CEA), hepatic invasion, perineural invasion, lymphovascular invasion, TNM staging and tumor differentiation. Through multivariate analysis, risk factors for DFS include hepatic invasion and TNM staging, and for OS is TNM staging only. Of the 40 cases with specific recurrent sites, 29 patients (29/40, 72.5%) had recurrence in the potential target volume of postoperative radiotherapy (PORT ), which include tumor bed and corresponding lymphatic drainage area. The common recurrent lymph node groups included abdominal para-aortic lymph node (No.16, 15/29), hepatoduodenal ligament lymph node (No.12, 8/29), retro-pancreatic head lymph node (No.13, 7/29) and celiac axis lymph node (No.9, 4/29). Twenty cases with recurrences inside the potential PORT target volume were accompanied by distant metastasis. Another 11 cases had distant metastasis alone, so totally 31 cases developed distant metastasis (31/40, 77.5%), including 18 cases with hepatic metastasis. Conclusion: The recurrence and metastasis rates are high in GBC and adjuvant therapy is needed. Up to 75% of the recurrent cases occurred in the potential target volume of postoperative radiotherapy, suggesting that postoperative radiotherapy has the possible value of improving local-regional control. The potential target volume of radiotherapy should include the tumor bed, No.8, No.9, No.11, No.12, No.13, No.14, No. 16a2, No. 16b1 lymph node groups. Keywords: Gallbladder cancer, Adjuvant radiotherapy, Target volume, Patterns of recurrence Introduction Gallbladder cancer (GBC) is an uncommon type of tumor [1], with the highest incidence in biliary tract tumors [2]. *Correspondence: qichun_wei@zju.edu.cn The occurrence of GBC is significantly related to chronic gallstone, and the malignancy incidence is positively cor- Department of Radiation Oncology, Ministry of Education Key Laboratory of Cancer Prevention and Intervention, The Second Affiliated Hospital, related with the size of gallstone [3]. Other risk factors Zhejiang University School of Medicine, Hangzhou, Zhejiang, China include gallbladder polyps (> 1 cm), chronic cholecystitis, © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Yuan et al. Radiation Oncology (2022) 17:118 Page 2 of 11 porcelain gallbladder, anomalous pancreaticobiliary node-positive disease [25]. Therefore, the recurrent pat - ductal junction and chronic typhoid infection [4–7]. terns after GBC surgery may provide valuable informa- Patients with Early stage of GBC has no obvious typi- tion for adjuvant therapeutic options. cal clinical symptoms [8], and some cases are inciden- In this study, failure patterns of 109 postoperative GBC tally discovered during or after surgery [9]. At the time patients were retrospectively analyzed, with the aim to of diagnosis, most patients are with advanced diseases, explore the sites with high risk of local recurrence and only 10–30% of patients are surgically resectable [10]. metastasis. Such information would be of great value to However surgical resection is still the only way of radi- adjuvant therapy, including the design of radiotherapy cal cure for gallbladder cancer [11]. As the postoperative target volume and the application of systematic therapy. recurrence rate and metastasis rate are high, adjuvant therapeutics should should be emphasized that adjuvant Methods therapy can improve survival in GBC patients [12]. Patients The best adjuvant treatment for GBC remains contro - The study was approved by the Institutional Review versial [13]. Only a few retrospective studies and rand- Board of the Second Affiliated Hospital, Zhejiang Univer - omized phase III trials on postoperative adjuvant therapy sity School of Medicine (SAHZU). The medical records of GBC can be found through PubMed. Postoperative from January 2013 to 2018 were retrospectively analyzed, radiotherapy for GBC was proposed by Bosset et  al. for including 109 patients who were followed up for at least the first time14. Todoroki et  al. suggested that surgi - 2 months after resection. All the patients achieved histo- cal resection combined with intraoperative radiation pathology diagnosis after surgery. Patients with previous therapy with or without external radiation therapy (with or contemporaneous tumor history were excluded. The 2- and 3-year survival rate of 20.2% and 10.1%) has a bet- clinical variables collected in the retrospective analysis ter survival rate than surgical treatment alone for stage included gender, age, T stage, N stage, clinical TNM stag- IV GBC patients (1- and 2-year survival rate of 11.1% and ing, tumor differentiation, recurrence time, tumor bio - 0%) (P < 0.05) [15]. A retrospective analysis of 3187 GBC markers, history of gallstones, bile duct stones, hepatitis, patients was conducted by Mojica et  al., using the Sur- diabetes, hypertension, schistosomiasis and postopera- veillance, Epidemiology and End Results (SEER) database, tive adjuvant treatment. Tumor clinical staging was per- patients who received adjuvant radiotherapy had a bet- formed according to AJCC staging system, 8th Edition. ter median survival (14  months vs. 8  months, P < 0.001). Follow-up period ended on September 28, 2020. Among the numbers of predictors, the only favorable factors for survival were local lymph node metastasis Recurrent patterns (P = 0.0001) and liver invasion (P = 0.011) [16]. Similarly, According to the 8th edition of the AJCC staging system, Wang et  al. obtained a result that adjuvant radiotherapy inter-aortocaval lymph node and para-aortic lymph node was one of the prognostic factors [17]. Yang et al. pointed metastasis are regarded as distant metastasis. Therefore, out that the 5-year survival rate and average survival time in this study, the term “local-regional recurrence” was not of GBC patients in the stage III and IV in adjuvant radio- used. We defined “the potential target volume of postop - therapy groups were significantly better than those of the erative radiotherapy (PORT)” which include the tumor control group (P < 0.05), but patients in stage II have no bed (surgical margin) and high-risk lymphatic drainage significant difference between two groups [18]. In sev - area. Long term follow-up was performed by specialist eral postoperative chemoradiotherapy studies of GBC, physicians. The initial recurrent sites were classified to Jeong et  al. suggested that adjuvant radiotherapy might the potential target volume of PORT recurrence, intra- have benefit in local control of GBC [19] and most of the hepatic recurrence, and other distant recurrence. Tumor studies revealed that adjuvant chemoradiotherapy can recurrences were detected by imagiological  examination achieve a good long-term survival rate [20, 21], especially (most cases will be monitored by continuous postopera- it may be useful for the tumor patients undergoing R0 tive evaluation). For recurrent local lymph nodes, it can resection without lymph node dissection. However, some have the features of greater or equal to 10  mm in short studies have shown that adjuvant therapy has no signifi - diameter, obvious necrosis, obvious enhancement, and cant effect on improving disease-free survival (DFS) [22]. eccentric calcification. If possible, PET/CT can assist Due to the lack of phase III randomized controlled trials in diagnosis, and the presence of distant metastasis can (RCT) data, the role of postoperative adjuvant radiother- be determined at the same time. There are only 2 cases apy remains unclear [23, 24]. According to the National were diagnosed as tumor recurrence by biopsy, though Comprehensive Cancer Network (NCCN) Guidelines, we encouraged to get definite pathological diagnosis. The postoperative chemoradiotherapy or chemotherapy initial recurrent pattern, DFS and OS will be analyzed. is feasible for GBC, especially in patients with lymph DFS was from the day of operation to the time of first Y uan et al. Radiation Oncology (2022) 17:118 Page 3 of 11 tumor recurrence, OS was from the day of operation to the P value < 0.05. IBM SPSS Statistics 23.0 and Graphpad the death or the last follow-up time. Prism 5.0 was used for statistical analyses. Statistical analysis Results The correlation of patients’ characteristics with DFS Patient characteristics and OS were analyzed by Kaplan Meier analysis. Sig- The characteristic statistics of 109 patients are shown nificance was evaluated with the log-rank test. Cox pro - in Table  1. There were 37 males (33.9%) and 72 females portional hazards models was applied for multivariate (66.1%). The mean age was 64.5  years, and the median survival analysis. Statistical significance was defined as age was 65  years (IQR: 56–73). Preoperative CA-199 Table 1 Gallbladder cancer patient characteristics Characteristics No Percentage (%) Gender Male 37 33.9 Female 72 66.1 Age (yrs) Median 65 Range 37–89 CA199 (107 cases) > 37 U/ml 52 48.6 CEA (105 cases) > 5 ng/ml 26 24.8 Gallstone 61 56.0 Bile duct stone 20 18.3 Hepatitis 5 4.6 Hypertension 37 33.9 Diabetes 7 6.4 History of schistosomiasis 5 4.6 Jaundice Serum bilirubin > 17.1 μmol/L 29 26.6 Serum bilirubin > 34.2 μmol/L 16 14.7 T stage Tis 6 5.5 T1 10 9.2 T2 50 45.9 T3 35 32.1 T4 8 7.3 N stage N0 67 61.5 N1 26 23.9 N2 16 14.7 Distant metastasis 9 8.3 AJCC 8th Staging System 0 6 5.5 I 10 9.2 II 31 28.4 III 36 33.0 IV 26 23.9 Liver invasion 30 27.5 Perineural invasion 33 30.3 Lymphovascular invasion 36 33.0 Tumor differentiation Well differentiated 20 18.3 Moderate differentiated 35 32.1 Poor differentiated 45 41.3 Undifferentiated 1 0.9 Unknown 8 7.3 Adjuvant chemotherapy 8 7.3 Adjuvant chemoradiotherapy 5 4.6 Yuan et al. Radiation Oncology (2022) 17:118 Page 4 of 11 and CEA elevation were found in 48.6% (52/107 cases) significant difference in the prognosis of GBC patients and 24.8% (26/105 cases) of the cases. Among the 109 with gender, age, preoperative jaundice and previous patients, 61 patients (56.0%) had gallstones. As to the medical history. The postoperative survival status of pathological differentiation of GBC, 20 cases (18.3%) patients was related to the elevation of CA199 (DFS, were well differentiated, 35 cases (32.1%) were moder - P = 0.0002; OS, P = 0.0029) and CEA (DFS, P = 0.0009; ately differentiated, 45 cases (41.3%) were poorly dif - OS, P = 0.0064) (Fig . 1). The other factors included liver ferentiated, 1 case (0.9%) was undifferentiated, and the invasion (DFS, P < 0.0001; OS, P < 0.0001), perineural differentiation of the other 8 cases (7.3%) were unknown. invasion (DFS, P = 0.0412; OS, P = 0.0169), lymphovas- According to the 8th edition of AJCC Staging System, the cular invasion (DFS, P = 0.0004; OS, P = 0.0003), tumor tumor T stage was as follows: Tis, 6 cases (5.5%); T1, 10 differentiation (well vs moderate vs poor and undif - cases (9.2%); T2, 50 cases (45.9%); T3, 35 cases (32.1%); ferentiated, DFS, P = 0.0006; OS, P = 0.0002) (Fig .  2), T4, 8 cases (7.3%). N stage: N0, 67 cases (61.5%); N1, 26 tumor T stage (Tis and T1 vs. T2 vs. T3 vs. T4, DFS, cases (23.9%); N2, 16 cases (14.7%). Distant metastasis P < 0.0001; OS, P < 0.0001), lymph node metastasis N occurred in 9 cases (8.3%). In TNM staging, there were stage (N0 vs. N1 vs. N2, DFS, P < 0.0001; OS, P < 0.0001) 6 (5.5%), 10 (9.2%), 31 (28.4%), 36 (33%) and 26 cases and the tumor TNM staging (I vs. II vs. III vs. IV, DFS, (23.9%) with stage 0, I, II, III and VI respectively. Post- P < 0.0001; OS, P < 0.0001) (Fig .  3). The results of all operative pathology showed liver invasion in 30 cases univariate analysis are shown in Table  2. In multivari- (27.5%), perineural invasion in 33 cases (30.3%), lympho- ate analysis, both liver invasion (RR: 2.308; 95% confi - vascular invasion in 36 cases (33%). dence interval [CI]: 1.045–5.097; p = 0.038) and TNM staging of tumor (RR: 3.135; 95% confidence interval Follow‑up and survival [CI]: 1.432–6.863; p = 0.004) are important to PFS. But The median follow-up time was 34  months (IQR: for OS, only TNM staging (RR: 2.676; 95% confidence 11–64) in 109 patients. The median disease free sur - interval [CI]: 1.396–5.132; p = 0.003) is statistically vival (DFS) and overall survival (OS) were 48.8 months significant. and 53.7  months. In univariate analysis, there was no Fig. 1 Survival outcomes of baseline data. (A) Kaplan–Meier curves of DFS and OS in group with CA-199 elevated or normal. (B) Kaplan–Meier curves of DFS and OS in group with CEA elevated or normal Y uan et al. Radiation Oncology (2022) 17:118 Page 5 of 11 Fig. 2 Survival outcomes of pathological factors. (A) Kaplan–Meier curves of DFS and OS in group with liver invasion positive or negative. (B) Kaplan–Meier curves of DFS and OS in group with perineural invasion positive or negative. (C) Kaplan–Meier curves of DFS and OS in group with lymphovascular invasion positive or negative. (D) Kaplan–Meier curves of DFS and OS in group of tumor differentiation Yuan et al. Radiation Oncology (2022) 17:118 Page 6 of 11 Fig. 3 Survival outcomes of tumor staging. (A) Kaplan–Meier curves of DFS and OS in group of T stage. (B) Kaplan–Meier curves of DFS and OS in group of N stage. (C) Kaplan–Meier curves of DFS and OS in group of TNM staging Recurrence rate and 80.8% (21/26 cases). The specific recurrence rates Fifty-four patients (54/109, 49.5%) developed post- are shown in Table 3. operative recurrence at the time of last follow-up. No recurrence was found in patients with Tis and T1. The recurrence rates of patients with T2, T3, T4 were 42.0% Initial disease recurrence (21/50 cases), 71.4% (25/35 cases), 100% (8/8 cases), Among the 54 cases, the imaging of 40 cases were able respectively. The recurrence rates of patients with N0, to identify the sites of initial recurrence. The other 14 N1, N2 were 35.8% (24/67 cases), 69.2% (18/26 cases), cases had follow-up imaging in local hospital and came 75% (12/16 cases). As to TNM staging, the recurrence to our institution with hardcopy diagnostic report rates of those with staging 0 & I, II, III, and IV were 0% only, so the exact locations of tumor recurrences were (0/16 cases), 32.3% (10/31 cases), 63.9% (23/36 cases) unavailable. Only 2 recurrent cases were diagnosed Y uan et al. Radiation Oncology (2022) 17:118 Page 7 of 11 Table 2 Univariate analysis of PFS and OS in gallbladder cancer Characteristics No Percentage (%) Median DFS P value Median OS P value Gender Male 37 33.9 Not reached 0.5023 Not reached 0.396 Female 72 66.1 36 41 Age (yrs) < 65 years old 53 48.6 Not reached 0.6539 Not reached 0.0707 ≥ 65 years old 56 51.4 24 32 CA199 (107 cases) > 37 U/ml 52 48.6 8 0.0002 22 0.0029 Normal 55 51.4 Not reached Not reached CEA (105 cases) > 5 ng/ml 26 24.8 10 0.0009 20.5 0.0064 Normal 79 75.2 Not reached Not reached Gallstone Positive 61 56.0 64 0.6478 37 0.5273 Negative 48 44.0 39.5 Not reached Bile duct stone Positive 20 18.3 Not reached 0.0778 Not reached 0.3589 Negative 89 81.7 30 42 Hepatitis Positive 5 4.6 5 0.5023 15 0.3835 Negative 104 95.4 64 Not reached Hypertension Positive 37 33.9 42 0.8149 44 0.6685 Negative 72 66.1 64 Not reached Diabetes Positive 7 6.4 Not reached 0.7271 Not reached 0.3616 Negative 102 93.6 48 42 Schistosomiasis Positive 5 4.6 Not reached 0.3306 Not reached 0.7756 Negative 104 95.4 48 44 Jaundice Serum bilirubin > 17.1 μmol/L 29 26.6 Not reached 0.5973 32 0.3446 Normal 80 73.4 48 Not reached T stage Tis + T1 16 14.7 Not reached < 0.0001 Not reached < 0.0001 T2 50 45.9 Not reached Not reached T3 35 32.1 6 18 T4 8 7.3 3 11 N stage N0 67 61.5 Not reached < 0.0001 Not reached < 0.0001 N1 26 23.9 12 18 N2 16 14.7 5 11 TNM Staging II 31 28.4 Not reached < 0.0001 Not reached < 0.0001 III 36 33.0 22 24 IV 26 23.9 4 13 Liver invasion Positive 30 27.5 3 < 0.0001 11 < 0.0001 Negative 79 72.5 Not reached Not reached Perineural invasion Positive 33 30.3 15 0.0412 24 0.0169 Negative 76 69.7 Not reached Not reached Lymphovascular invasion Positive 36 33.0 9 0.0004 20 0.0003 Negative 73 67.0 Not reached Not reached Tumor differentiation Well 20 18.3 Not reached 0.0006 Not reached 0.0002 Moderate 35 32.1 64 Not reached Poor + Undifferentiated 46 42.2 6 15 The bold figures in the table are the data with P < 0.05 by biopsy, and the remaining cases were diagnosed as (29/40, 72.5%), 18 (18/40, 45.0%) and 21 (21/40, 52.5%), tumor recurrence by serial follow-up imaging. respectively. Among them, 23 cases had multiple sites Initial recurrences occurred in the potential PORT of initial disease recurrence (Fig. 4). volume, remnant liver and the other distant sits were 29 Yuan et al. Radiation Oncology (2022) 17:118 Page 8 of 11 Table 3 Recurrent pattern of gallbladder cancer (40 cases in total) Staging No Tumor bed (10 cases) Lymphatic drainage area (23 Remnant liver (18 cases) Other distant cases) metastases (21 cases) T0 &T1 16 0 (0%) 0 (0%) 0 (0%) 0 (0%) T2 50 5 (10%) 10 (20%) 3 (6%) 8 (16%) T3 35 5 (14.3%) 10 (28.6%) 11 (31.4%) 8 (22.9%) T4 8 0 (0%) 3 (37.5%) 4 (50%) 5 (62.5%) N0 67 5 (7.5%) 9 (13.4%) 10 (14.9%) 9 (13.4%) N1 26 5 (19.2) 6 (23.1%) 5 (19.2%) 7 (26.9%) N2 16 0 (0%) 8 (50%) 3 (18.8%) 5 (31.3%) TNM 0 & I 16 0 (0%) 0 (0%) 0 (0%) 0 (0%) II 31 2 (6.5%) 3 (9.7%) 3 (9.7%) 3 (9.7%) III 36 8 (22.2%) 8 (22.2%) 8 (22.2%) 10 (27.8%) IV 26 0 (0%) 12 (46.2%) 7 (26.9%) 8 (30.8%) Of the 29 patients whose initial recurrence inside the potential PORT volume, 9 (9/40, 22.5%) developed recur- rence only inside the potential PORT volume, includ- ing 2 tumor bed recurrences, 7 lymph node metastases, and none had recurrence in both sites simultaneously (Table  4). Twenty had synchronous distant metastasis, including 9 in remnant liver, 16 in other distant sites, and of these, 5 had synchronous recurrences at remnant liver and other distant sites. Among the 31 patients with distant metastasis, 11 Fig. 4 Initial recurrent pattern of GBC. Initial recurrent pattern of 40 patients did not develop recurrence in the potential cases occurred in the potential PORT volume, remnant liver and the PORT volume, including 6 hepatic metastasis, 1 abdom- other distant sits inal wall metastasis, 1 multiple pelvic implantation Table 4 The characteristics of 9 patients with isolated PORT volume recurrences Postoperative pathological stage Postoperative pathologically Detailed recurrence sites positive lymph nodes Case 1 T3N2M0 12, 13 12 (12a), 7, 16 (16a2) Case 2 T2N0M0 12 (12b) Case 3 T2N0M0 Tumor bed Case 4 T2N0M1 (Hepatic metastasis) 13 Case 5 T2N1M0 9, 13 16 (16b1) Case 6 T3N2M0 12, 13 3, 6, 13, 17, 7, 8, 9,12, 14, 16 (16a1, 16a2, 16b2) Case 7 T2N1M1 (Metastatic lymph nodes invade surrounding tissue) 13 16 (16b1, 16b2) Case 8 T2N1M0 8、9、12 Tumor bed Case 9 T3N1M1 (Metastatic lymph nodes invade surrounding tissue) 13 13, 15, 16 (16a2, 16b1) Y uan et al. Radiation Oncology (2022) 17:118 Page 9 of 11 metastasis and 3 multiple metastasis in remnent liver and nodes (No.16), hepatoduodenal ligament lymph nodes abdominal wall. The other 20 patients had distant metas - (No.12), retro-pancreatic head lymph node (No.13), tasis and recurrence in the potential PORT volume at the celiac axis lymph node (No.9), right lymph node of cardia same time. (No.1), lesser curvature lymph node (No.3), splenic artery In the 23 cases of lymph node recurrence, the com- lymph node (No.11) and superior mesenteric artery and mon sites of lymph node metastases were para aortic vein lymph node (No.14). According to Uesaka and Ito’s lymph nodes (station No.16, n = 15), hepatoduodenal anatomical description of gallbladder lymphatic drainage, ligament lymph nodes (No.12, n = 8), retro-pancreatic there were four routes of gallbladder lymphatic drainage: head lymph nodes (No.13, n = 7), celiac axis lymph nodes gallbladder pancreaticoduodenal route (mainly), gallblad- (No.9, n = 4). In addition, 3 cases had recurrence in the der hepatoduodenal ligament route, gallbladder mesen- right lymph nodes of cardia (No.1), lesser curvature teric route and porta hepatis route [31, 32]. Finally, the lymph nodes (No.3), splenic artery lymph nodes (No.11) first three pathways converged at the level of the left renal and superior mesenteric artery and vein lymph nodes vein in the para aortic lymph nodes. The porta hepatis (No.14). There were 2 cases in superior pyloric lymph pathway may be related to liver metastasis. The left renal nodes (No.5), left gastric artery lymph nodes (No.7), vein is the dividing line between No.16a2 and No.16b1, middle colon vascular lymph nodes (No.15) and anterior which is consistent with the recurrent pattern of para pancreatic lymph nodes (No.17). And 1 case occurred in aortic lymph nodes in 15 cases. Lymph nodes recurred gastric omental lymph nodes (No.4), subpyloric lymph at the level of left renal vein in every case. In addition, a nodes (No.6), common hepatic artery lymph nodes small number of No.16a1 and No.16b2 recurrences were (No.8) and splenic hilum lymph nodes (No.10). In 15 considered as secondary lymph node metastasis. cases of para aortic lymph node recurrence, there were 2 J Socha et  al. performed systematic review and meta- cases in 16a2, 3 cases in 16b1, 7 cases in 16a2 and 16b1, 1 analysis of lymph node metastases in biliary tumors of case in 16b1 and 16b2, 1 case in 16a1, 16a2 and 16b2, and different T stages [33]. It is suggested that the adjuvant 1 case in 16a2, 16b1 and 16b2 at the same time. radiotherapy target volume of T3-4 GBC should include No.8, No.9, No.12, No.13, No.14, No.16 lymph node Discussion groups. In our retrospective study, only 1 case of recur- The study showed the factors affecting the survival sta - rent metastatic lymph node was located at No.8. For tus of patients with gallbladder cancer after resection cross-regional lymph nodes, the center of lymph node and the recurrence mode after operation. According to was used as the localization marker for statistical analysis the research results, 49.5% of the patients had recurrence during imaging review. The No.9, No.12 and No.13 were after surgery, which is consistent with the recurrence rate all distributed around No.8, and each landmark tissues of some previous studies [26, 27]. and organs were close to each other. Therefore, combined In this study, postoperative recurrence rate varied with with the literature, No.8 should be included in the post- different stages. Postoperative recurrence mainly occurs operative radiotherapy target volume. Combined with in the middle and advanced stages of gallbladder cancer. other research reports and structural relationships, No.1 For early gallbladder cancer (TNM stage 0&I), the post- and No.3 have a small probability of metastasis, and the operative recurrence rate is 0%, and the five-year survival greater toxic side effects of PORT can be predicted. So rate is 100%. This result was the same as that of lee et al. the inclusion of the above two groups of lymph nodes in [28]. Of the 40 cases with detail follow-up records of the PORT target volume is not considered in this study. recurrence, there was no significant difference between No.14 metastases of locally advanced gallbladder cancer relapsing in radiotherapy potential volume only (9 cases, have also been observed in other studies, and the same 22.5%) and distant metastasis only (11 cases, 27.5%). number of No.11 metastases occurred in our study. Ana- According to the different recurrent patterns of previ - tomically, we considered that the PORT target volume ous trials, this result is consistent with the fact [22, 26, should include No.11 (corresponds to the lymphatic 29, 30]. Although there is no plentiful enough large-scale region of the proximal splenic artery) and No.14, which phase III clinical trial, many previous trials and this study may improve local control of the disease. At the same suggested that specific adjuvant therapy should be taken time, attention should be paid to patients’ radiotherapy for GBC with high recurrence rate. tolerance, and appropriate adjustments can be made for Postoperative radiotherapy is recommended to com- different patients and different stages. Therefore, after bine with chemotherapy in all feasible patients with comprehensive consideration, the target volume of adju- locally advanced gallbladder cancer. According to the vant radiotherapy should include the tumor bed, No.8, analysis of the initiate recurrent pattern of 29 cases, the No.9, No.11, No.12, No.13, No.14, No.16a2 and No.16b1 common recurrent lymph nodes were para aortic lymph lymph node groups. Yuan et al. Radiation Oncology (2022) 17:118 Page 10 of 11 Among the GBC patients with TNM stage II-IV (93 cancer may need multicenter prospective trials to prove cases, 54 cases of recurrence, recurrence rate: 58%), its effectiveness. the recurrence rate in the potential target volume of radiotherapy is almost the same as the rate of distant Abbreviations metastasis. Therefore, adjuvant chemotherapy is also GBC: Gallbladder cancer; PET/CT: Positron emission tomography/computed important. In this study, OS and DFS of adjuvant radio- tomography; DFS: Disease-free survival; OS: Overall survival; PORT: Postopera- tive radiotherapy; SEER: Surveillance, epidemiology and end results; NTRK: therapy, adjuvant chemotherapy and adjuvant chemo- Neurotrophic tryrosine receptor kinase; MSI-H: Microsatellite instability-high; radiotherapy were not statistically significant. The same dMMR: Deficient mismatch repair. results were also found in other trials [34, 35]. This Acknowledgements result may be caused by the small sample size. In two This work was supported by National Natural Science Foundation of China phase III clinical trials, capecitabine monotherapy and (No.82073332). adjuvant chemotherapy with fluorouracil and mito - Author contributions mycin C, respectively, showed significant improve - ZY analyzed data and wrote the article. YS and ZY were responsible for image ments in PFS and OS [35, 36]. For the high recurrence evaluation and clinical data analysis. LL and YG analyzed data and statistics. rate of GBC, as well as the high incidence of distant QW designed, revised, and supervised the writing and concept of the article. All authors read and approved the final manuscript. metastasis and local recurrence, postoperative adju- vant chemoradiotherapy is a better choice, especially Availability of data and materials for the relatively advanced GBC. The phase II SWOG Datasets can be retrieved from authors by formal request from interested readers. Datasets will not be directly shared on public link as the national S0809 trial included patients with extrahepatic chol- personal data protection act. angiocarcinoma or gallbladder cancer (N = 79), pro- viding prospective data for adjuvant chemotherapy/ Declarations chemoradiotherapy (concurrent chemoradiotherapy with capecitabine after capecitabine/gemcitabine Ethics approval and consent to participate This study was approved by Institutional Review Board of SAHZU. chemotherapy). The 2-year survival rate was 65%, and the median survival time was 35  months. Most of the Consent for publication patients (86%) who participated in the trial completed Not applicable. the treatment, indicating that the regimen was gen- Competing interests erally tolerable [37, 38]. 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Journal

Radiation Oncology – Springer Journals

Published: Jul 7, 2022

Keywords: Gallbladder cancer; Adjuvant radiotherapy; Target volume; Patterns of recurrence

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