Abstract
Background:
Nodal positivity is a predictor of poor survival following resection for intrahepatic cholangiocarcinoma (ICC). The aim of this study was to evaluate the impact of surgical resection on survival in patients with lymph node (LN) positive ICC.
Methods:
An augmented version of the Surveillance, Epidemiology, and End Results program database was utilized to identify patients with LN-positive ICC without distant metastases from 2000 to 2014. Patients were stratified by treatment: chemotherapy alone or surgical resection with/without chemotherapy. Survival was evaluated using Kapian-Meier and Cox proportional hazard models.
Results:
169 patients who underwent treatment for LN-positive ICC were identified. 88% underwent surgical resection and 12% underwent chemotherapy alone. The median survival for patients who underwent surgical resection was not different from patients treated with chemotherapy alone (19 months 95% Confidence Interval (CI) 17–33 versus 20 months CI 10–27, p = 0.323). A cox-proportional hazard ratio model demonstrated that black race was associated with worse survival (p < 0.05), while surgical resection was not Independently associated with survival.
Conclusion:
Surgical resection for patients with LN-positive ICC may not improve survival compared to chemotherapy alone. Pathologic LN evaluation should be performed prior to surgical resection, to improve patient selection and ensure receipt of optimal therapy.
Introduction
Intrahepatic cholangiocarcinoma (ICC) is increasing in incidence and represents the second most common primary liver malignancy, affecting about 1 per 100,000 people in the United States.1 While survival for ICC has improved over time, outcomes remain poor, likely due to the insidious clinical course and aggressive natural history of disease.2 Combined, these factors lend to a diagnosis when the tumor has reached an advanced stage. For patients who undergo surgical resection, the median survival is only 20–40 months, and only 15–20 months for patients not undergoing resection.3–6
Several factors, including lymph node (LN) involvement, multifocal disease, tumor size, vascular invasion, and older age are associated with worse survival in patients with ICC.7 In particular, LN positive disease is a strong negative prognostic factor. Rates of pathologic LN evaluation, either pre-operatively or at the time of surgical resection, remain highly variable.2,8 Recent data suggest that adequate lymphadenectomy (6 or more LN) is only performed in approximately 10% of patients who undergo liver resection for ICC.2 The number of patients undergoing pre-operative pathologic LN evaluation is unknown. The presence of LN metastases represents advanced disease with survival approaching that of unresectable disease.6,9 Most studies evaluating the prognostic implications of LN positivity in ICC are derived from patients undergoing surgical resection.10 Very little data exists for patients with ICC with clinically evident LN metastases prior to surgical resection. Some authors have suggested that ICC with clinically evident LN metastases should be considered a relative contraindication to resection.6,11
In 2010, Valle et al. reported results of a randomized trial comparing overall survival for patients with locally advanced or metastatic biliary tract cancers who received either gemcitabine alone or a combination of cisplatin and gemcitabine.12 This trial found a significant survival advantage to combination therapy in patients who could not undergo surgical resection.12 While it is clear that palliative chemotherapy can extend OS for patients with non-resectable disease, the impact of nodal positivity on surgical decision making is less well established. While this has yet to be evaluated specifically in ICC, Creasy et al. evaluated the treatment of patients with LN positive gallbladder carcinoma.13 Using a large single-institutional database of patients with locally advanced and LN positive gallbladder carcinoma the study concluded that while overall outcomes were extremely poor, the subset of patients who received neoadjuvant therapy with a positive response were more likely to undergo successful surgery and had improved overall survival.13 Further, preliminary results from the BilCap study, which evaluates the role of adjuvant capecitabine versus observation alone after surgery for biliary tract cancers, shows an overall survival benefit to the addition of adjuvant chemotherapy.14 However, it should be noted that ICC only represents a small proportion of patients in these studies. Thus, while it is evident that chemotherapy improves survival for patients with advanced cholangiocarcinoma, the ability to select patients who are likely to benefit from surgery has been evasive.
Given the rarity of ICC, there is little level one evidence to guide diagnosis, management and treatment. The objective of this study was to evaluate the outcomes of patients who have LN positive disease confirmed by pathology, and to assess whether the current “surgery first” treatment algorithm is appropriate for this group of patients. For that reason, patients were included only if they had pathologically proven LN positivity and treated with either chemotherapy alone or surgical resection with or without chemotherapy for ICC. The objective of this study was to evaluate if there is a survival benefit to up front surgical resection for patients with pathologically confirmed LN-positive ICC over chemotherapy alone.
Methods
Utilizing an augmented version of the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program database, which includes radiation and chemotherapy data, patients diagnosed with ICC from 2000 to 2014 were identified. The SEER database is a composite collection of cancer surveillance in 18 distinct geographical areas, representing 28% of the United States population. The database collects patient characteristics including age at diagnosis, race, and sex. Tumor characteristics in the registry include primary tumor site, histologic subtype, stage, tumor size, LN status, grade, diagnostic confirmation, type of surgery, and cause of death.
Patients aged 18 years or older who were diagnosed with ICC using the World Health Organizations’ International Classification of Disease (ICD), 3rd edition (Supplementary Table 1) were identified. Patients were included only if they had lymph node positive disease confirmed by pathology. Patients were excluded if they had distant metastatic disease. As only de-identified patient data was used, this study was exempt from review by the Institutional Review Board of the University of Minnesota.
In an effort to simulate an intention to treat analysis, patients were stratified by treatment into two groups: patients treated with chemotherapy alone and patients treated with surgical resection, with or without chemotherapy. Survival was evaluated utilizing Kaplan Meier survival curves as well as Cox proportional hazard ratio (HR) modeling. Factors utilized in the Cox proportional model were age, gender, race, grade, tumor (T) stage, and treatment type. A p-value of ≤0.05 was used to denote statistical significance. Statistical analysis was performed using SAS software, version 9.3 (SAS Institute, Cary, NC).
Results
169 patients aged 18 years or older with LN-positive ICC from 2000 to 2014 who underwent treatment with either chemotherapy, surgery, or both were identified. Patient and tumor characteristics are shown in Table 1. Of the patients who underwent surgical resection, 63 (43%) underwent surgery alone and 85 (57%) underwent surgery and received chemotherapy.
Table 1.
Patient characteristics for patients with lymph node positive intrahepatic cholangiocarcinoma from 2000 to 2014 from the SEER database
| Characteristics | Surgery ± Chemotherapy | Chemotherapy alone | p-value | ||
|---|---|---|---|---|---|
| N = 148 | % | N = 21 | % | ||
| Age | 0.544 | ||||
| 18−49 | 27 | 18 | 2 | 9 | |
| 50−59 | 32 | 22 | 9 | 43 | |
| 60−69 | 47 | 32 | 5 | 24 | |
| 70+ | 42 | 28 | 5 | 24 | |
| Sex | 0.705 | ||||
| Female | 77 | 52 | 10 | 48 | |
| Male | 71 | 48 | 11 | 52 | |
| Race | 0.256 | ||||
| White | 126 | 85 | 17 | 81 | |
| Black | 8 | 5 | 3 | 14 | |
| Other | 14 | 10 | 1 | 5 | |
| Year | 0.871 | ||||
| 2000−2008 | 59 | 40 | 10 | 48 | |
| 2009−2014 | 89 | 60 | 11 | 52 | |
| Grade | 0.774 | ||||
| I | 14 | 10 | 1 | 5 | |
| II | 79 | 53 | 12 | 57 | |
| III | 55 | 37 | 8 | 38 | |
| T Status | 0.058 | ||||
| I | 30 | 20 | 5 | 24 | |
| II | 48 | 32 | 4 | 19 | |
| III | 54 | 37 | 5 | 24 | |
| IV | 16 | 11 | 7 | 33 | |
| Size | 0.217 | ||||
| <2 cm | 9 | 6 | 1 | 5 | |
| 2−5 cm | 47 | 32 | 5 | 24 | |
| 5+ | 79 | 53 | 10 | 47 | |
| Missing | 13 | 9 | 5 | 24 | |
Overall median survival for the entire cohort was 19 months. The Kaplan Meier curve for overall survival among the two treatment arms is shown in Fig. 1a. There was an insignificant 1-month difference in survival between patients with LN-positive ICC treated with surgery, with or without chemotherapy, compared to patients treated with chemotherapy alone (19 months 95% Confidence Interval (CI) 17–33); 20 months CI 10–27, p = 0.323). We further separated patients who underwent surgery with chemotherapy from those who underwent surgery alone. Patients who underwent surgery alone had a median survival of 13 months (CI 7–22); patients who received chemotherapy alone had a median survival of 19 months (CI 17–33); and patients who underwent surgery and received chemotherapy had a median survival of 20 months (CI 10–27; p = 0.009, Fig. 1b).
Figure 1.
(a) Kaplan Meier curves of overall survival for patients with lymph node positive intrahepatic cholangiocarcinoma as stratified by surgery with or without chemotherapy and chemotherapy alone. And (b) surgery alone, surgery with chemotherapy, and chemotherapy alone
A Cox proportional hazards model was performed to evaluate independent factors related to survival (Table 2). In this cohort of patients with LN positive ICC, age 60–69 was associated with an increased hazard ratio (HR) of death when compared to patients aged 18–49. Black race was also associated with an increased HR of death when compared to Non-Hispanic white race. There was a trend toward increased HR of death for T3 and T4 disease when compared to T1 disease. Surgery with or without chemotherapy was not independently associated with a decrease HR of death in this cohort of patients with LN-positive ICC.
Table 2.
Cox proportional hazard model for survival of patients with lymph node positive intrahepatic cholangiocarcinoma
| Hazard Ratio [95% Confidence Interval] | p-value | |
|---|---|---|
| Age | ||
| 18−49 | REF | |
| 50−59 | 1.126 [0.602−2.105] | 0.709 |
| 60−69 | 1.879 [1.049 = 3.363] | 0.033 |
| 70+ | 1.444 [0.793 = 2.631] | 0.229 |
| Gender | ||
| Female | REF | |
| Male | 0.938 [0.645−1.364] | 0.737 |
| Race | ||
| Non-Hispanic White | REF | |
| Black | 2.106 [1.012−4.384] | 0.046 |
| Other | 1.122 [0.584−2.154] | 0.730 |
| Grade | ||
| I | REF | |
| II | 1.054 [0.528−2.103] | 0.881 |
| III | 1.270 [0.624−2.586] | 0.509 |
| T stage | ||
| 1 | REF | |
| 2 | 1.473 [0.817−2.654] | 0.198 |
| 3 and 4 | 1.755 [0.986−3.124] | 0.055 |
| Missing | 1.874 [0.970−3.610] | 0.061 |
| Treatment | ||
| Surg. ± Chemo | REF | |
| Chemo Alone | 1.227 [0.715−2.106] | 0.457 |
Bold type Indicates statistical significance. Abbreviation: REF: Referent.
Discussion
Based on this retrospective review of the SEER program database, surgical resection with or without chemotherapy for patients with LN-positive ICC did not provide a significant improvement in overall survival when compared to treatment with chemotherapy alone. Surgical resection was not independently associated with a decreased HR of death. The median survival for patients who had surgical resection alone was significantly less than those who received chemotherapy with or without surgery, highlighting the importance of systemic therapy in this patient population.
Current national guidelines suggest that all patients with LN positive ICC should receive systemic therapy as part of their treatment strategy.15 Despite these recommendations, in the current study only 57% of patients who underwent surgery also received chemotherapy. These selected patients who received surgery and chemotherapy did have a slightly improved survival compared to chemotherapy alone (19 months compared to 20 months, p = 0.323). Although the increase in median survival is only one month, the survival curves remain divergent at 5-year follow up, suggesting that surgery may add a durable survival benefit (Fig. 1b). However, as seen in the present study, a significant number of patients do not receive adjuvant treatment after major cancer surgery. Sadly, even in the subset of patients who received optimal treatment with resection plus chemotherapy, the median overall survival was only marginally improved.
Treatment of ICC represents a clinical challenge given a lack of prospective randomized data to guide management. Consequently, the treatment strategies recommended for ICC are based largely on retrospective reviews of large databases, or clinical trials which include a mix of patients with biliary tract cancers. For patients with LN-positive ICC, level one evidence is even more limited. Several retrospective studies evaluating adjuvant therapy in ICC have found that patients with LN-positive disease benefit most from post-operative chemotherapy.16–18 One retrospective study of the National Cancer Database compared overall survival between patients treated with surgery plus adjuvant therapy, surgery without adjuvant therapy, non-operative treatment (chemotherapy with or without radiation), and no treatment in patients with LN-positive ICC.9 Patients who underwent non-operative treatment (chemotherapy with or without radiation) had the lowest median survival at 13 months, patients who underwent surgery alone had a median survival of 16 months, and patients who were treated with surgery plus adjuvant chemotherapy had a median survival of 23 months.9 Surgery was independently associated with a decreased HR of death on multivariable analysis. However, the NCDB study included patients who did not have pathologic confirmation of LN metastasis, which may have overestimated the number of patients with true LN-positivity and thus altered survival.9 In addition to lack of pathologic LN confirmation, the study excluded patients with T4 disease. Taken together, these differences may explain some of the discordance between the present study of the SEER database and the previous NCDB evaluation. Regardless of differences in study protocol, it is striking that a “surgery first” approach does not have a clear and substantial survival advantage compared to chemotherapy alone in both this present study and the previous NCDB study.9
Patients with LN-positive ICC do derive a survival benefit from adjuvant chemotherapy.3,16 Several retrospective reviews of large databases have found that chemotherapy is beneficial for patients with high-risk ICC, including patients with R1/2 resections and those with LN-positivity. These studies demonstrate that for patients with high risk of systemic disease progression, including those with T3/T4 tumors and LN positivity, receipt of chemotherapy improves median survival after surgical resection.16–18 The present data suggests that surgical resection may not add any significant survival benefit compared to chemotherapy alone for patients who are found to be LN positive. Given that a significant number of patients do not receive adjuvant chemotherapy following major cancer surgery, it may be that these patients would be best treated with up front chemotherapy followed by surgical resection only in patients who do not demonstrate signs of progression, or who have a clinical response to treatment.
Current practice patterns vary widely regarding LN evaluation in patients with ICC.2 While LN-positivity has repeatedly been demonstrated to be a strong negative prognostic factor for patients, operative LN evaluation remains somewhat controversial.19–21 Even with the adoption of new American Joint Commission on Cancer (AJCC) staging system22 which recommends lymphadenectomy as a component of surgical resection and defined an adequate lymphadenectomy as ≥6 nodes removed, any extent of lymphadenectomy is performed in less than 50% of patients, and only 10% of patients receive an adequate lymphadenectomy.2
In the pre-operative setting, LN evaluation is even more variable. Endoscopic ultrasound (EUS) with nodal biopsy is an effective pre-operative modality to diagnose LN-positivity in patients with ICC.23,24 While lymph node size has been used to identify patients who may have lymph node metastases, a study from Japan demonstrated a sensitivity of only 50% for identifying LN-positivity.25 Additionally, positron emission tomography, which has also been used to identify LN metastasis, may have a sensitivity as low as 31% 25 Using tumor-specific markers, such as CA 19–9, has been suggested to diagnose LN metastasis; however, the exact cutoff criterion, sensitivity, and specificity is unknown.26,27 The most appropriate pre-operative work-up for patients with suspected LN-metastasis has not yet been determined.
A number of limitations of this study must be discussed. This study is a review of a large population-based database and thus is subject to significant selection bias. In addition, even as a large population-based database was utilized, the final cohorts consisted of a small number of patients, due to the rarity of the disease and the overall lack of appropriate LN evaluation by surgeons in the United States. Despite the small sample size, it is important to note that the benefit of surgery may not be significant in LN positive patients. Therefore, more research is needed in this area with larger cohorts. Lastly, the SEER database collects whether a patient receives chemotherapy or not, but does not provide details of chemotherapy regimens, therefore limiting the ability to identify the exact agents utilized, timing of chemotherapy administration, and if patients completed treatment. Despite these limitations, this study does represent a robust population-based analysis of clinical practice patterns and the role of surgery in the management of LN positive ICC in the United States.
In this study, patients with LN-positive ICC who undergo up front surgical resection with or without chemotherapy have a comparable survival to patients treated with chemotherapy alone. Further, surgery was not independently associated with an improvement in survival. Consequently, since LN positivity is a strong prognostic factor and there is a questionable benefit to resection in LN positive patients, a thorough radiologic LN evaluation should be performed with pathologic determination of suspicious LNs prior to surgical intervention. Given the finding that surgery may add a durable, albeit small, improvement in 5-year survival in patients who also receive chemotherapy (Fig. 1) consideration should be given to a neoadjuvant chemotherapy approach for any patient known to be LN positive prior to surgical intervention.
It is clear that more investigation is necessary to identify the optimal management of patients with LN-positive ICC. However, based on the current study and others, it is the authors interpretation that thorough radiographic LN evaluation should be performed prior to surgical resection for patients with ICC.12,13 Any suspicion of LN involvement should be pathologically confirmed with EUS and FNA. Patients with ICC who are found to be LN positive prior to surgery should be considered for systemic chemotherapy prior to surgical resection in an effort to ensure that all patients receive systemic therapy, and to better select those patients who are likely to gain benefit from resection. Patients who have a response to systemic therapy, or who do not show signs of progression, may then be considered for resection. This would allow for better patient selection and ensure that all patients receive systemic therapy as part of their treatment. It would also avoid the dismal survival results seen in patients with node positive disease who are treated with surgery alone.
Supplementary Material
Funding
This research was in part funded by the University of Minnesota Department of Surgery Cancer Fund.
Footnotes
Conflict of Interest
None declared.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.org/10.1016/j.hpb.2018.08.006.
This data was presented at the annual Americas Hepato-Pancreato-Biliary Association meeting, Miami, FL, and at the International Hepato-Pancreato-Biliary Association meeting in Geneva, Switzerland, 2018.
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