Abstract
Background
The ideal adjuvant therapy for resected cholangiocarcinoma remains controversial. National guidelines stratify recommendations based on margin status, though few studies are currently available for reference.
Methods
Data was abstracted on all patients with definitive resections of cholangiocarcinoma at our institution between 2000 and 2013. Adjuvant chemoradiation consisted of 45 Gy delivered to elective nodal regions and 50.4–54 Gy to the surgical bed with concurrent fluoropyrimidine-based chemotherapy. Subgroup analyses were performed delineated by margin status.
Results
Curative resection was performed on 95 patients followed by adjuvant chemoradiation in 23/95 (24%) and observation in 72/95 (76%) with a median follow-up of 21.7 months. For those receiving adjuvant chemoradiation the median overall survival was 30.2 months compared with 26.3 months for those observed (p = 0.0695). In a multivariable model controlling for other prognostic factors, adjuvant chemoradiation was associated with improved disease-free survival (HR 0.50, p = 0.03) and overall survival (HR 0.37, p = 0.004). In multivariable models stratified by margin status, adjuvant chemoradiation was associated with improved overall survival following both margin-negative (HR 0.34, p = 0.035) and margin-positive (HR 0.15, p = 0.003) resections.
Conclusions
Overall survival was improved with adjuvant chemoradiation following either margin-negative or margin-positive resections, which is not currently reflected in national guidelines.
Introduction
For patients with clinically-localized cholangiocarcinoma (CC), local control remains a significant issue even following aggressive resection. Analogous to gallbladder and pancreatic adenocarcinomas, patients are often diagnosed late in the disease process with both nodal and distant metastases occurring early and often.1, 2, 3, 4, 5, 6, 7, 8 Among the minority of patients whose presentation is amenable to curative resection, local recurrence is the rule not the exception.1, 9, 10, 11 While the only curative treatment for CC patients remains surgical resection, post-operative outcomes have shown no significant improvements in the past several years11 with the current five-year survival rate stagnating at a mere 5% for all CC patients.12 Due to a historically low incidence in Western countries in addition to a low proportion of resectable disease at presentation, there are few established criteria for the treatment of CC in the post-operative setting.13
The high rate of local recurrence following resection suggests the need for aggressive adjuvant therapy, though few studies have addressed this issue to date. A few retrospective series have shown benefits in both local control and improved overall survival when using radiation therapy (RT) for unresectable CC,14, 15, 16, 17, 18 establishing its activity in this disease. Adjuvant chemotherapy (CT) and/or concurrent chemoradiation (CRT) for resected CC has also been associated with increased survival in pooled meta-analyses of historic international series, especially in those with involved lymph nodes or microscopic residual disease following resection.19, 20 One recent phase II trial evaluating adjuvant capecitabine and gemcitabine followed by concurrent capecitabine and RT demonstrated good tolerability and promising efficacy,21 but there remains a need for comparative studies of adjuvant therapy for CC in Western populations.
The current lack of available data examining the benefit gained with adjuvant CRT in CC across detailed clinicopathologic features can only be rectified with prospective studies or comprehensive institutional review. The goal of this retrospective study was to specifically measure the benefit of adjuvant CRT following definitive resection of CC in the context of an in-depth examination of other potentially predictive factors.
Methods
Inclusion and exclusion criteria
Data was abstracted on all patients with a pathologic diagnosis of CC at our institution between January 2000 and December 2013. All patients with non-metastatic CC who underwent curative-intent resection surviving at least eight weeks were identified. Bile duct adenocarcinomas arising from the gallbladder or ampullary regions were excluded. Patients experiencing perioperative mortality within eight weeks of surgery were excluded, as this likely would have precluded initiation of adjuvant CRT. Only four patients received chemotherapy alone and were excluded from final analysis to avoid excess heterogeneity within the adjuvant therapy cohort. Eastern Cooperative Oncology Group (ECOG) scale was used to quantify performance statuses at time of first post-operative follow-up.22
Surgical and adjuvant therapy
All tumors in an intrahepatic location were resected with partial hepatectomies, perihilar tumors with common bile duct and hepatic resections with or without cholecystectomy, and distal bile duct tumors with pancreaticoduodenectomies (Whipple procedure). Margins were considered positive (R1) if tumor cells were present on, or very close (<1 mm) to, the inked specimen margin. The decision of when to employ adjuvant CRT was commonly discussed at a multidisciplinary tumor board conference. It has been our institution's practice to consider adjuvant therapy only in the setting of positive surgical margin and/or presence of other high-risk features such as nodal disease, perineural spread (PNS), lymphovascular space invasion (LVSI) or nodal extracapsular extension (ECE).
Those receiving RT were prescribed 45 Gy directed to the tumor bed and at-risk nodal stations with an additional sequential boost dose of 5.4–9 Gy to the pre-surgical tumor volume delivered in 1.8 Gy daily fractions employing intensity-modulated radiation therapy (IMRT) planning techniques (see eFig. 1 in the supplement). All patients received concurrent 5-fluorourocil or capecitabine during the course of RT. Toxicities of adjuvant CRT were characterized according to common terminology criteria for adverse events (CTCAE) version 4.03.23
Statistical analysis
As measured from time of diagnosis, the primary outcomes were disease-free survival (DFS) with an endpoint of recurrence, or death from any cause in the instance of no recurrence, and overall survival (OS) with an endpoint of death from any cause. If endpoints for DFS and OS were not noted, patients were censored at date of last follow-up. The independent samples t-test was used to compare means and the χ2 test, or Fisher's exact test when the assumptions of the χ2 test were not tenable, was used to compare proportions for categorical variables. TNM classification and group staging was recorded as described by the American Joint Committee on Cancer (AJCC) Staging Manual, 7th ed.24
The Kaplan–Meier method was used to estimate DFS and OS. Survival curves were compared using the log-rank test. Univariate Cox proportional hazards models were initially used to assess the relationships of study variables with OS and DFS. Variables having a univariate significance of p < 0.2 were included in a multivariable model. Since surgical margin status has previously been used to guide treatment recommendations,13 we repeated the univariate and multivariate analyses within two subgroups defined by margin status. All p-values were two-sided and all statistical analyses were conducted using SAS, version 9.4.25
Results
Patient demographics and tumor characteristics
Of 103 patients treated surgically for CC at our institution between 2000 and 2013, 95 underwent resections with curative-intent and met the inclusion criteria for this analysis (Fig. 1) with a median follow-up of 21.7 months. An R0 resection was achieved in 67 (71%) cases. Of the 28 (29%) R1 resections, 18 specimens revealed tumor present at the margin and 10 harbored tumor within 1 mm. Patient demographic, pathologic, and treatment characteristics are presented in Table 1. Patients who received adjuvant CRT were more likely to have undergone R1 resection (p = 0.006) and have nodal involvement with extracapsular extension (p = 0.003) than patients who were observed; otherwise, the two groups were well-matched. Of note, 21/23 patients in the adjuvant CRT cohort had at least one of the risk factors described in the methods section above (positive margin, nodal positivity, PNS, LVSI, or ECE). Of the other two patients, one received adjuvant CRT following a second surgery for residual disease and the other upon patient request.
Figure 1.
Study schema
Table 1.
Clinicopathologic factors in resected cholangiocarcinoma patients
| Total (n = 95) | aCRT (n = 23) | OBS (n = 72) | p-Value | |
|---|---|---|---|---|
| Median age | 64 (38–86) | 62 (38–80) | 65 (39–86) | 0.09 |
| Sex | 0.70 | |||
| Male | 57 (60%) | 13 (57%) | 44 (61%) | |
| Female | 38 (40%) | 10 (43%) | 28 (39%) | |
| Race | 0.11 | |||
| White | 85 (89%) | 23 (100%) | 62 (86%) | |
| Other | 10 (11%) | 0 (0%) | 10 (14%) | |
| ECOGa | 0.92 | |||
| 0–1 | 69 (78%) | 18 (78%) | 51 (77%) | |
| 2 | 20 (22%) | 5 (22%) | 15 (23%) | |
| Location | 0.29 | |||
| Intrahepatic | 33 (35%) | 6 (26%) | 27 (38%) | |
| Perihilar | 22 (23%) | 8 (35%) | 14 (19%) | |
| Distal | 40 (42%) | 9 (39%) | 31 (43%) | |
| LVSI | 12 (13%) | 4 (17%) | 8 (11%) | 0.48 |
| PNS | 31 (33%) | 9 (39%) | 22 (31%) | 0.44 |
| ECE | 4 (4%) | 4 (17%) | 0 (0%) | 0.003 |
| Margin status | 0.006 | |||
| R1 | 28 (29%) | 12 (52%) | 16 (22%) | |
| R0 | 67 (71%) | 11 (48%) | 56 (78%) | |
| Tumor stage | 0.10 | |||
| 1 | 29 (31%) | 3 (13%) | 26 (36%) | |
| 2 | 29 (31%) | 8 (35%) | 21 (29%) | |
| ≥3 | 37 (39%) | 12 (52%) | 25 (35%) | |
| Nodal status | 0.20 | |||
| 0 | 64 (67%) | 13 (57%) | 51 (71%) | |
| ≥1 | 31 (33%) | 10 (43%) | 21 (29%) | |
| Group stage | 0.18 | |||
| I | 35 (37%) | 5 (22%) | 30 (42%) | |
| II | 37 (39%) | 10 (43%) | 27 (38%) | |
| III/IV | 23 (24%) | 8 (35%) | 15 (21%) |
aCRT, adjuvant chemoradiation; OBS, observation; LVSI, lymphovascular space invasion; PNS, perineural spread; ECE, extracapsular extension; R1, positive margin; R0, negative margin; ECOG, Eastern Cooperative Oncology Group performance status.
Six patients were lost to post-operative follow-up.
Survival outcomes
The median DFS of the entire cohort was 18.7 (13.9–22.8) months. Survival outcomes are demonstrated in Fig. 2. The median DFS of patients who received adjuvant CRT was 21.6 (13.6–79.6) months versus 17.3 (CI 12.2–22.8) months for those who were observed (p = 0.15). Median OS of the entire surgical cohort was 28.6 (20.8–39.2) months. The median OS of patients who received adjuvant CRT was 30.2 (CI 21.6–114.3) months versus 26.3 (CI 15.0–39.2) months for those who were observed (p = 0.07). The crude rates of patterns of first failure are presented eTable 1 in the supplement.
Figure 2.
Survival outcomes with adjuvant CRT versus observation
The results of the univariate and multivariate analyses of potential prognostic factors across the entire cohort are shown in Table 2a. In the multivariable models, group stage (p = 0.004) and use of adjuvant CRT (HR = 0.50, p = 0.03) were statistically significant predictors of DFS. Similarly, group stage (p = 0.01) and use of adjuvant CRT (HR = 0.37, p = 0.004) were statistically significant predictors of OS.
Table 2.
Potential prognostic clinicopathologic factors for DFS and OS for (a) entire cohort and (b) cohort stratified by margin status
| (a) | ||||||||
|---|---|---|---|---|---|---|---|---|
| UVA |
MVA |
UVA |
MVA |
|||||
| Factors | HR (DFS) | p-Value | HR (DFS) | p-Value | HR (OS) | p-Value | HR (OS) | p-Value |
| Age | 1.01 (0.99–1.03) | 0.41 | 1.02 (0.99–1.04) | 0.21 | ||||
| Female | 1.14 (0.70–1.85) | 0.59 | 0.88 (0.52–1.49) | 0.62 | ||||
| Location | Reference: Intrahepatic | 0.93 | Reference: Intrahepatic | 0.51 | ||||
| Perihilar | 1.00 (0.55–1.83) | 1.15 (0.59–2.23) | ||||||
| Distal | 1.10 (0.64–1.90) | 1.41 (0.79–2.53) | ||||||
| Tumor stagea | Reference: T1 | 0.003 | Reference: T1 | 0.005 | ||||
| T2 | 1.67 (0.89–3.15) | 1.81 (0.91–3.63) | ||||||
| T3–4 | 2.81 (1.55–5.07) | 2.96 (1.54–5.67) | ||||||
| ≥1 nodea | 2.03 (1.23–3.36) | 0.006 | 2.55 (1.49–4.37) | <0.001 | ||||
| Group stage | Reference: I | 0.003 | 0.002 | Reference: I | 0.010 | 0.003 | ||
| II | 1.21 (1.02–3.23) | 2.08 (1.14–3.77) | 2.21 (1.19–4.11) | 2.74 (1.44–5.20) | ||||
| III/IV | 2.92 (1.59–5.35) | 2.96 (1.61–5.44) | 2.61 (1.33–5.10) | 2.79 (1.41–5.52) | ||||
| R1 vs R0 | 1.61 (0.98–2.65) | 0.06 | 1.90 (1.13–3.22) | 0.01 | 1.63 (0.96–2.75) | 0.07 | 2.00 (1.14–3.51) | 0.01 |
| ECE | 1.63 (0.59–4.55) | 0.35 | 1.06 (0.33–3.42) | 0.95 | ||||
| LVSI | 1.43 (0.71–2.89) | 0.32 | 1.58 (0.77–3.26) | 0.21 | ||||
| PNS | 1.16 (0.70–1.92) | 0.56 | 1.34 (0.79–2.27) | 0.27 | ||||
| DF vs LF | 1.21 (0.58–2.50) | 0.62 | ||||||
| aCRT | 0.66 (0.38–1.16) | 0.13 | 0.47 (0.26–0.87) | 0.01 | 0.56 (0.30–1.06) | 0.07 | 0.33 (0.17–0.66) | 0.002 |
| (b) | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Factors | UVA |
MVA |
UVA |
MVA |
|||||
| HR (DFS) | p-Value | HR (DFS) | p-Value | HR (OS) | p-Value | HR (OS) | p-Value | ||
| R0 | Age | 1.01 (0.98–1.04) | 0.59 | 1.02 (0.99–1.05) | 0.26 | ||||
| Female | 1.16 (0.63–2.11) | 0.63 | 0.82 (0.42–1.61) | 0.57 | |||||
| ECOG 2 vs ≤1 | 1.07 (0.45–2.58) | 0.88 | 1.37 (0.56–3.33) | 0.49 | |||||
| Location | Reference: Intrahepatic | 0.78 | Reference: Intrahepatic | 0.50 | |||||
| Perihilar | 1.19 (0.54–2.62) | 1.40 (0.59–3.35) | |||||||
| Distal | 1.27 (0.65–2.47) | 1.54 (0.74–3.22) | |||||||
| Tumor stagea | Reference: T1 | 0.030 | Reference: T1 | 0.013 | |||||
| T2 | 1.62 (0.74–3.56) | 1.78 (0.75–4.25) | |||||||
| T3–4 | 2.69 (1.30–5.58) | 3.37 (1.48–7.64) | |||||||
| ≥1 nodea | 2.13 (1.14–3.98) | 0.018 | 2.51 (1.27–4.97) | 0.008 | |||||
| Group stage | Reference: I | 0.06 | 0.01 | Reference: I | 0.029 | 0.009 | |||
| II | 1.99 (1.00–3.96) | 2.62 (1.26–5.44) | 2.64 (1.26–5.52) | 3.25 (1.48–7.13) | |||||
| III–IV | 2.32 (1.07–5.04) | 2.68 (1.21–5.93) | 2.40 (0.98–5.85) | 2.93 (1.17–7.33) | |||||
| ECE | 1.61 (0.38–6.80) | 0.51 | 0.92 (0.13–6.83) | 0.94 | |||||
| LVSI | 2.06 (0.73–5.88) | 0.17 | 2.40 (0.81–7.12) | 0.11 | 3.01 (1.03–8.83) | 0.045 | 3.10 (1.01–9.52) | 0.05 | |
| PNS | 1.63 (0.84–3.17) | 0.15 | 1.60 (0.81–3.18) | 0.18 | 2.17 (1.09–4.34) | 0.028 | 2.03 (0.98–4.18) | 0.06 | |
| DF vs LF | 0.81 (0.30–2.22) | 0.69 | |||||||
| aCRT | 0.52 (0.22–1.23) | 0.13 | 0.34 (0.13–0.85) | 0.020 | 0.56 (0.22–1.44) | 0.23 | 0.34 (0.13–0.93) | 0.04 | |
| R1 | Age | 1.01 (0.97–1.05) | 0.68 | 1.00 (0.96–1.04) | 0.96 | ||||
| Female | 1.15 (0.51–2.60) | 0.74 | 0.82 (0.34–1.96) | 0.65 | |||||
| ECOG 2 vs ≤1 | 2.63 (1.10–6.30) | 0.03 | 7.22 (2.35–22.20) | <0.001 | 2.35 (0.96–5.74) | 0.06 | 4.85 (1.59–14.84) | 0.006 | |
| Location | Reference: Intrahepatic | 0.72 | Reference: Intrahepatic | 0.90 | |||||
| Perihilar | 0.71 (0.27–1.87) | 1.10 (0.39–3.12) | |||||||
| Distal | 0.72 (0.27–1.90) | 1.27 (0.47–3.43) | |||||||
| Tumor stagea | Reference: T1 | 0.090 | Reference: T1 | 0.29 | |||||
| T2 | 1.45 (0.49–4.35) | 2.11 (0.67–6.70) | |||||||
| T3–4 | 2.95 (1.06–8.21) | 2.32 (0.78–6.91) | |||||||
| ≥1 nodea | 1.63 (0.70–3.80) | 0.26 | 2.34 (0.98–5.60) | 0.056 | |||||
| Group stage | Reference: I | 0.006 | 0.002 | Reference: I | 0.26 | 0.09 | |||
| II | 1.32 (0.44–3.94) | 2.09 (0.63–6.97) | 1.69 (0.52–5.37) | 2.93 (0.83–10.39) | |||||
| III/IV | 5.09 (1.70–15.29) | 10.56 (2.68–41.61) | 2.47 (0.83–7.31) | 4.06 (1.14–14.41) | |||||
| ECE | 1.57 (0.35–7.06) | 0.55 | 0.80 (0.18–3.53) | 0.77 | |||||
| LVSI | 0.87 (0.29–2.58) | 0.80 | 0.81 (0.27–2.41) | 0.71 | |||||
| PNSb | 0.39 (0.17–0.89) | 0.03 | 0.24 (0.09–0.67) | 0.01 | 0.31 (0.13–0.76) | 0.011 | 0.09 (0.03–0.39) | 0.001 | |
| DF vs LF | 3.89 (0.89–16.97) | 0.071 | |||||||
| aCRT | 0.55 (0.23–1.28) | 0.17 | 0.69 (0.27–1.79) | 0.45 | 0.38 (0.15–0.94) | 0.036 | 0.15 (0.05–0.53) | 0.003 | |
UVA, univariable analyses; MVA, multivariable analyses; HR, hazard ratio; ECE, extracapsular extension; LVSI, lymphovascular space invasion; PNS, perineural spread; R1, positive margin; R0, negative margin; aCRT, adjuvant chemoradiation; DF, distant failure; LF, local failure; ECOG, Eastern Cooperative Oncology Group performance status.
Not included in MVA to avoid co-linearity with group staging.
aCRT was employed on 6/12 (50%) with PNS as opposed to 6/16 (37.5%) without PNS.
Subgroup analyses stratified by margin status
Table 2b presents the results of the subgroup analyses of potential prognostic factors stratified by margin status. In multivariable models of the patients who achieved R0 resections, group stage (p = 0.01) and use of adjuvant CRT (HR = 0.34, 0.02) were significant predictors of DFS. Group stage (p = 0.009), presence of LVSI (HR = 3.10, p = 0.05), and adjuvant CRT (HR = 0.34, p = 0.04) were significantly associated with OS following R0 resections, with PNS closely approaching significance (HR 2.03, p = 0.06).
In multivariable analyses of the patients who underwent R1 resections, ECOG performance status >1 (HR = 7.22, p < 0.001), group stage (p = 0.002), and PNS (HR = 0.24, p = 0.006) were significant predictors of DFS. Following R1 resections, ECOG performance status >1 (HR = 4.85, p = 0.006), the use of adjuvant CRT (HR = 0.15, p = 0.003), and the presence of PNS (HR 0.17, p = 0.003) were significantly associated with OS. Fig. 3 demonstrates survival outcomes stratified by margin status.
Figure 3.
Survival outcomes stratified by margin status
Radiation toxicity
Five patients in the adjuvant CRT cohort experienced grade 3–4 toxicities potentially attributable to CRT. One patient experienced a gastrointestinal stricture requiring distal gastrectomy. Another suffered severe dehydration resulting in brief hospitalization and failure to complete her boost phase, though this proved to be a transient issue. Three patients exhibited signs of worsening clinically decompensated liver failure following completion of CRT due to radiation-induced biliary strictures or disease progression or both.
Discussion
In this study we investigated the role of adjuvant CRT after curative-intent resection for CC. In a multivariable model controlling for other prognostic factors, the use of adjuvant CRT was associated with improved DFS and OS. Given the current emphasis on surgical margin status with regard to recommendations for adjuvant therapy, we performed subgroup analyses of R0 and R1 resections as separate cohorts. Interestingly, we found a significant benefit in OS with adjuvant CRT regardless of margin status.
The survival benefit observed in this study with adjuvant CRT following R0 resections may be explained by the presence of occult nodal and distant disease at time of surgery, supported by similar rates of recurrences in the observed cohorts following either R0 or R1 resections: 43 versus 37%, respectively (see eTable 1 in the supplement). That a benefit in OS but not DFS was measured with adjuvant CRT following R1 resections could possibly be explained by observed R1 patients failing to live long enough to establish gross recurrent disease. It is curious that PNS was associated with improved survival outcomes in the R1 cohort. Additional analyses were performed and did not show it to be a surrogate for other factors recorded. We can only speculate the potential for earlier and more consistent adjuvant CRT in patients with both positive margins and presence of PNS.
To our knowledge, this study is the largest single-institution retrospective Western series of the use of adjuvant CRT following definitive resection of CC. These results corroborate another recent retrospective experience reported from Shanghai of resected intrahepatic CC and concurrent lymph node involvement showing an almost 10-month OS benefit with adjuvant RT (n = 24) as compared to surgery alone (n = 66).26 Our results are further in line with two large database studies: Abott et al. recently analyzed a national cancer database (n = 8741) demonstrating a benefit in OS with adjuvant CRT after surgical resection of extrahepatic CC regardless of margin status,27 and a retrospective SEER analysis of patients with intrahepatic CC (n = 3839) showed an OS benefit of five months with adjuvant RT (n = 269) as compared to surgery alone (n = 960).15 As opposed these large national database inquiries which lack not only specifics of therapy but also in-depth demographic and tumor detail, our results provide an inclusive analysis of a number of clinicopathologic factors potentially at play.
The benefit of any therapy must be weighed against expected toxicity. As with most hepatobiliary cancers, liver failure as a result of poorly-characterized disease progression as opposed to radiation-induced hepatocyte or biliary tree damage was hard to tease out. In our review, up to three patients experienced worsening liver failure potentially related to adjuvant CRT, though true treatment-related toxicity is difficult for us to clearly quantify.
The survival advantage gained with the use of adjuvant CRT in this study is also modest at approximately four months. Many surgical failures are a result of poor disease characterization prior to resection. Better identification of surgical candidates employing innovative prognostic indicators is also a crucial component to better tailoring CC therapies moving forward.2 In addition, novel approaches such as neoadjuvant CRT for marginally-resectable primaries seem to be promising and warrant further investigation.28, 29, 30, 31
Though there are limitations with any retrospective study, well-defined and broad inclusion criteria were employed to minimize inherent biases associated with such a design. We included a detailed examination of potential prognostic factors, but we recognize the possibility of biases which were not captured in our statistical models. This study also included tumors of heterogeneous locations within the bile duct which require different surgical managements; however, no differences in failure rates or survival outcomes were observed across the different primary sites.
Notwithstanding these limitations, the use of adjuvant CRT in this study was associated with improved OS across all margin statuses, which is not currently reflected in our national guidelines. How CRT compares to chemotherapy alone remains an important unanswered question, but given the rate of local failures in the observed cohort of our study we feel RT should remain a component of any adjuvant therapy until proven otherwise. While controversy continues to surround the optimal choice of treatment in the post-operative setting for localized CC, this study adds to a growing body of literature that supports a survival benefit from adjuvant therapy, particularly concurrent CRT.
Disclosures
The preliminary findings from this study have previously been presented in abstract form at the 2014 ASCO Gastrointestinal Cancers Symposium in San Francisco, CA.
Financial disclosures and/or conflicts of interest
None declared.
Footnotes
Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.hpb.2016.07.008.
Appendix A. Supplementary data
The following is the supplementary data related to this article:
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