With an estimated annual incidence of 3,000 cases annually in the United States, EHCC remains a rare but aggressive neoplasm8
. While complete surgical resection remains the foundation of curative intent therapy for EHCC, owing to its anatomical location and natural history, the majority of patients present with locally advanced disease at diagnosis. The rarity of EHCC has precluded mounting of large-scale randomized controlled trials. Thus, at present, the role of adjuvant therapy for EHCC remains controversial, despite promising institutional data23-25
. Consequently, while imperfect, the utilization of large-scale population-based datasets, such as SEER, represent a useful mechanism for mortality risk estimation. Such data may be especially useful for tumors such as cholangiocarcinoma, where single institutions have difficulty accruing sufficient numbers to afford appropriately statistically powered analyses.
The data presented herein suggest that the addition of radiotherapy to therapeutic intent surgical interventions was associated with improved median survival compared to either surgery alone, radiotherapy alone or nonsurgery/nonradiotherapy cohorts in a multifactorial model. However, it should be noted that, with sufficient follow-up (i.e. >5 years), in univariate survival analysis, the mortality curves for the surgical and combined modality cohorts converge, and, as shown in Figures and , adjuvant radiotherapy may be associated with long-term (>5 years) survival decrement
. Long-term outcomes were uniformly dismal with 5-year survival rates of 18% for surgery alone, 16% for surgery+RT, and under 3% for those receiving radiotherapy alone or no recorded therapy. The majority of detected survival benefit from the addition of radiotherapy to surgical intervention appears to be had within the initial 1-2 years following therapy (Figures and ). Post-hoc
graphical analysis of the individual cumulative hazard rates of treatment cohorts over time revealed that the survival probability after total resection+RT was greater than total resection alone for 14 months; after 14 months of follow-up total resection alone exhibited lower cumulative hazard rates. The addition of radiotherapy was associated with improved survival probability for subtotal resection patients up to 21 months of follow-up, with a higher cumulative hazard rate thereafter compared to subtotal resection alone. EBRT alone was associated with improved hazard rates compared to no treatment only before 65 months of follow-up. Why the benefit for adjuvant radiotherapy dissipates over time is unclear. This observation may be due to delayed local recurrence in those patients receiving surgical resection and radiotherapy; alternately, it may be attributable to treatment-related factors unaccounted for in SEER (e.g. chemotherapeutic regimens not recorded in SEER, performance status differentials, variant radiotherapy techniques and/or fractionation/dose schedules, post-therapy complication rates, delay in distant metastatic progression due to improved local control26
). Alternatively, prognostic variables not recorded in SEER might lead to negative selection bias for definitive or adjuvant radiotherapy (e.g. positive margins after resection, advanced pathologic features). The surgical margin status issue is of special significance, and unfortunately, is not a recorded variable within the SEER dataset. It is possible that the adjuvant radiotherapy cohort includes many patients who received radiotherapy secondary to suboptimal resection. If true, radiotherapy might confer some deferral of disease progression, but would be inadequate for eradiacating bulk disease. If many suboptimally resected cholangiocarcinomas are de facto
, it becomes apparent, as Crane et al
. have noted previously, that conventional radiation-only regimens are insufficient to ensure local control10
, and may only be able to defer disease progression temporarily. However, such explanations are purely conjecture in the absence of prospective clinical trial data.
Lognormal fit of survival all patients with EHCC surviving > 2 months, stratified by therapy cohort
Since SEER represents the largest domestic cholangiocarcinoma dataset, the observed phenomena whereby early survival is improved by the addition of radiotherapy, while late survival is either unaltered or decreased, may explain the relatively contradictory findings in smaller institutional series. Some posit minimal utility for adjuvant therapy27
, while others suggest an appreciable survival benefit7, 12, 15, 16, 23, 28-33
. Consequently, our findings may demonstrate both opinions to be correct, with early survival improvement noted despite minimal benefit in the long-term (see Figures and ). Some authors have observed series where suboptimal resections (R1) may derive minimal gain from the addition of surgery to radiotherapy7
. While not directly explained in this series, owing to the unavailability of margin status and other relevant pathologic (lymphovascular or perineural invasion) and clinical (performance status, comorbid conditions) confounders in SEER, the significantly poorer outcomes observed for the radiotherapy only cohort should give pause to implementation of radiation monotherapy for patients with potentially difficult resections, and should spur aggressive surgery whenever indicated clinically. n
While SEER represents an exceedingly robust dataset, several limitations should be assiduously noted. SEER data does not afford analysis of chemotherapy regimen utilization, and thus it is impossible to impute what role, if any, the addition of chemotherapy to any treatment cohort may have on survival patterns. Furthermore, relevant specific information regarding surgical and radiotherapy treatment techniques (e.g. margin status, dose/fractionation, time between surgery and radiotherapy) are not captured within the SEER dataset. The SEER Historic Staging system, while affording ready comparison between distinct eras, is inherently imprecise in order to collapse patients based on extent of disease. Additionally, no EHCC patients diagnosed 1973-1998 received formal AJCC staging within SEER, making the logic-statement/scripting stage conversion by the authors necessary, based on available extent of disease data. While some information regarding the anatomic location may be gleaned from the SEER topography codes, insufficient information is available for rigorous definition of tumor location34
or resectability, major prognostic factors in many series5, 8, 13, 15, 29, 35, 36
. For example, Welzel et al. demonstrated that discrimination of Klatskin's tumors from other extrahepatic cholangiocarcinomas is unreliable using SEER1
; consequently, the inclusion of Klatskin's tumors within this series should be noted, and might skew results. Forty-five tumors (0.97% of all patients) were coded 8162/3 (Klatskin tumor); of these 20 received no treatment, 9 received external beam radiation monotherapy, 7 received total resection alone, 5 had total resection and radiation, and 2 each received subtotal resection or subtotal resection with radiotherapy. SEER, like most registry data, has multiple “catch-all” identifiers (e.g. “Surgery NOS”, “Unknown Grade”) which may obfuscate careful definition of categorical cohorts. SEER data is limited geographically, as not all U.S. cancer registries contribute to SEER, and temporally limited, as not all registries have contributed data for the same span of time. Though we utilized year of diagnosis as a surrogate for evolving radiotherapy, surgery, or chemotherapy practice, SEER variables does not directly account for technological improvement or changes in either surgical35, 37
or radiation technique over time11
. Finally, SEER data collection is dependent upon the quality of decentralized local registrars for completeness and accuracy of data entry, with limited direct quality control.
Nonetheless, SEER provides the largest domestic population-based estimation of EHCC, with case numbers several-fold greater than available in single-institutional series. The value of such numerical power should not be underestimated. In addition, population-based datasets such as SEER may more accurately reflect the true expected survival of EHCC patients in the community medical milieu, rather than only at specific academic centers. These may explain why, in comparison to several retrospective series reported in the literature, survival results from the present analysis show comparatively worse survival for adjuvant radiotherapy patients than the markedly smaller, albeit more detailed, retrospective series available in extant literature7, 9, 10, 12, 13, 15, 16, 36, 38
. Likewise, differentials in the clinical outcomes associated with tertiary centers (e.g. improved late survival at high volume centers39
, or increased utilization of adjuvant radiotherapy in institutions with on-site radiotherapy facilities40
) may be obscured in pooled registry data.
This dataset represents, to our knowledge, the first to characterize the effect of multimodality therapy as a using parametric survival analysis in cholangiocarcinoma. The nonproportionality of the hazard functions observed in this series with regard to therapeutic cohort necessitate a historically underutilized, but increasingly implemented statistical comparison41-43
. Ahmed et al
. have recently described several distinct methodologies for accounting for nonproportionality in survival series19
. We have chosen lognormal survival fitting, which has a long history within cancer survival analysis44
, as it is robust45, 46
, applicable in cases of non-proportionality47
, statistically succinct18
, and broadly interpretable as a mechanism for defining survival event estimates46
. While more elegant corrections for nonproprtionality are available, none are widely implemented19
. Additionally, parametric analyses have the added benefit of the capacity to generate, given specific multivariate input parameters, an estimation of the survival at any given time point in follow-up. We hope to eventually transform this dataset into a risk-profiling tool, as has previously been performed using SEER data regarding gallbladder carcinomas48
Our data support recent work by Shinohara et al.49
, who showed a beneficial effect of adjuvant radiotherapy for intrahepatic cholangiocarcinomas. As in that series, long-term survival was poor despite the addition of radiotherapy. Nonetheless, demonstrated early survival improvement alone may serve as a justification for adjuvant radiotherapy, even though 5-year mortality is unimproved. This early survival benefit, coupled with available data detailing patterns of failure for cholangiocarcinoma15, 50-56
, lend credence to the position that adding radiation post-operatively when possible for local/regional disease is a reasonable first-line therapeutic approach for EHCC, in the absence of more definitive data from randomized controlled trials.