Multimodality therapy for locoregional extrahepatic cholangiocarcinoma

A population-based analysis

Abstract

BACKGROUND:

Although surgical resection is the mainstay of treatment for extrahepatic cholangiocarcinoma, the majority of patients present with advanced disease. Due in part to numeric rarity, the optimum role of radiotherapy (RT) for extrahepatic cholangiocarcinoma, as well as its relative benefit, is an area of debate. The specific aim of this series was to estimate survival for extrahepatic cholangiocarcinoma patients receiving surgery and adjuvant RT using a robust population-based data set.

METHODS:

Data were extracted from the Surveillance, Epidemiology, and End Results (SEER) limited-use data set for selected extrahepatic cholangiocarcinoma cases. Lognormal multivariate survival analysis was implemented to estimate survival for patients for treatment cohorts based on extent of surgical intervention and RT.

RESULTS:

Parametric estimated median survival for patients receiving total/radical resection + RT was 26 months; it was 25 months for total/radical resection alone, 25 months for subtotal/debulking resection + RT, 21 months for subtotal/debulking resection, 12 months for RT alone, and 9 months for those not receiving surgery or RT. Parametric multivariate analysis revealed age, American Joint Committee on Cancer Stage, grade, and surgical/radiation regimen as statistically significant covariates with survival. Surgery alone and adjuvant RT cohorts demonstrated evidence of improved survival compared with no treatment; comparatively, RT alone was associated with survival decrement. Early improvement in survival in adjuvant cohorts was not observed at later time points.

CONCLUSIONS:

Survival estimates using SEER data suggest an early survival advantage for adjuvant RT for patients with locoregional extrahepatic cholangiocarcinoma. Although future prospective series are needed to confirm these observations, SEER data represent the largest domestic population-based extrahepatic cholangiocarcinoma cohort, and may provide useful baseline survival estimates for future studies. Cancer 2009. Published 2009 by the American Cancer Society.

Primary cancers of the bile ducts, known as cholangiocarcinomas, are rare tumors, with an annual incidence of 0.6 to 1 of 100,000 persons in the United States.1, 2 Despite their rarity, cholangiocarcinomas are highly lethal.3 Therapeutic interventions for cholangiocarcinomas are predicated on the distinction between intrahepatic and extrahepatic cholangiocarcinomas,1, 4 as well as the resectability of disease. At present, surgical resection is the preferred therapy for extrahepatic disease.5 Unfortunately, the vast majority of patients present with locally advanced or metastatic disease, which is not amenable to definitive resection, with reported 5-year overall survival rates of 0% to 39%.6 Although definitive and adjuvant radiotherapy (RT) techniques have been investigated, typically via retrospective data from single institutions, outcomes remain suboptimal.7-15 At present, the utility of incorporating RT, as well its impact on disease outcome, is an area of debate,13, 14 due in part to the numeric rarity of these tumors.16

The purpose of the current study was to use multivariate regression analysis to evaluate survival differences between extrahepatic cholangiocarcinoma patients treated with multimodality therapy, specifically investigating the impact of RT and extent of surgical intervention.

Specific aims of this study were: 1) determination of observed mortality differentials, if any, for patients receiving combined surgical/RT treatment compared with surgery only, RT only, or nonsurgery/non-RT cohorts; and 2) generation of potential population-based survival benchmarks and hypotheses for institutional and cooperative group trials.

MATERIALS AND METHODS

Patient data from cases diagnosed from 1973 to 2005 were obtained from the April 2008 (based on the November 2007 submission) version of the Surveillance, Epidemiology, and End Results (SEER) limited-use data set.17 Included cases of extrahepatic cholangiocarcinoma were identified by topography codes representing extrahepatic bile ducts (C24.0) and histology codes representative of cholangiocarcinoma (histology codes 8010, 8020, 8041, 8070, 8140, 8144, 8160, 8162, 8260, 8310, 8490, and 8560). Perihilar cholangiocarcinomas, or Klatskin tumors, were specifically identified by topography code C24.0 and specific histology code 8162/3; because these tumors cannot be reliably differentiated from extrahepatic cholangiocarcinoma, in accordance with previously described identification analysis of cases in SEER data sets1; they therefore were included in this analysis. Case data with malignant primary indicator status denoting second (or greater) primary tumor(s) and those cases not specifically denoting local or regional disease (eg, SEER historic stage A indicating distant/unknown extent of disease) were excluded from analysis. Cases were included if a positive microscopic confirmation, exfoliative cytology, or positive laboratory test/marker study was specified. SEER variable data were derived from direct accession via SEER*Stat,17 and extracted as tab-delimited data into commercial statistical analysis software (StatView and JMP [version 6.0]; SAS Institute Inc, Cary, NC). The following variables were extracted from SEER data: age, RT, surgery of primary tumor site, site-specific surgery, lymph node surgery, histologic grade, sex, extent of disease, and cause of death. Specific nominal variables were created using SEER data, and software-scripted logic statements were used to create composite variables for analysis. Because American Joint Committee on Cancer (AJCC) staging was unavailable directly from SEER data for all patients, for those patients for whom the extent of local/regional involvement and lymph node status could be ascertained, AJCC stage (6th edition) was assigned by the authors using custom scripting of logic statements to pool available case data. Cases without sufficient information for AJCC grouping via custom scripting (eg, primary tumor cannot be assessed, regional lymph nodes cannot be assessed, presence of distant metastasis cannot be assessed, or “unknown” extent of disease values) were excluded. Cases were coded by therapeutic modalities received as a logic statement using the RT and surgery of primary site/site-specific surgery variables derived from SEER*Stat, matching the therapeutic data to the appropriate SEER documentation. Cases with denotation of either external beam RT (EBRT), or no RT in the radiation variable of SEER*Stat were included; other radiation modalities (eg, brachytherapy) were excluded. Site-specific surgery variables were used to exclude nontherapeutic intent procedures (ie, biopsy only, or exploratory surgical procedures). Those cases with site-specific surgery codes indicating potential therapeutic intent resection were included. Cases with site-specific surgery variables denoting “radical” or “total” resection were grouped; all other cases indicating “debulking” or “subtotal” resection were pooled.

Patients receiving RT without indication of surgical intervention were coded as EBRT alone. All cases with SEER-extracted notation of therapeutic surgical resection without indication of RT were categorically coded as either “subtotal resection alone” or “total/radical resection alone.” Those with notation indicating potentially therapeutic surgical intervention and RT were denoted as combined modality therapy recipients, “subtotal resection + RT” or “total/radical resection + RT,” depending on the extent of surgical resection recorded. Any case not demonstrating evidence of either potentially therapeutic surgical resection or RT was classified as nontreatment. To account for perioperative mortality as a potential confounding factor, statistical analyses were performed only on patients who had survived >2 months from diagnosis.

The main variable of interest, therapeutic regimen, was evaluated using univariate parametric lognormal survival analysis,18 after visual inspection revealed crossing of survival curves with graphic representation of product-limit survival curves.19, 20 Because the proportional hazard assumption could not be met for the variable of interest,21 as determined by Schoenfeld residual calculation,22 for multifactorial/multivariate analysis, a parametric lognormal analysis was performed, obviating the need to hazard proportionality throughout follow-up. A parametric lognormal18 full-factorial model, which included the following variables (derived from literature review to impact survival with extrahepatic cholangiocarcinoma), was used: age (as a continuous measure), year of diagnosis (as a continuous measure), therapy cohort (no treatment, EBRT alone, subtotal resection, subtotal resection + RT, total resection, total resection + RT), grade (well differentiated/grade I, moderately differentiated/grade II, poorly differentiated/grade III, undifferentiated/grade IV, unknown/not specified), and derived AJCC 6th edition stage (IA, IB, IIA, IIB, III). Survival estimation was performed using lognormal parametric survival regression with a maximum likelihood approach to calculate β, the factor effect of the aforementioned variables, as well as the 95% confidence interval (95% CI) of β, assuming an approximation of a normal distribution. For categorical variables, β values >0 indicate a positive association with regard to survival; β < 0 suggests an association with survival decrement. For continuous variables (age, year of diagnosis), positive β values indicate increasing probability of survival with increasing numeric value of the variable in question. Statistical significance for each variable was evaluated using a chi-square approximation set at a α = .05, with n − 1 degrees of freedom, in which n is the number of subvariables within a categoric variable of interest, and was uncorrected for multiple comparisons.

RESULTS

A total of 1569 cases of primary locoregional extrahepatic cholangiocarcinoma met inclusion criteria. The median age at diagnosis was 68 years (mean, 66.9 years; standard deviation, 12.4 years [range, 25-97 years]). Six hundred sixty (42% of patients) were women, and 909 (58%) were men. Of the patients included, 1220 (78%) were white, 109 (7%) were black, and 240 were American Indian/Asian/Pacific Islander/other/unknown. Stage and pathologic grade demographics are described in Table 1 for the study population, stratified by treatment cohort. Overall product limit and lognormal fit of survival are shown in Figure 1 for the study population.

Figure 1. Product-limit survival (in red) with superimposition of lognormal fitted survival (in blue) for included patients is shown.

Table 1. Selected Demographic Features of Included Cases, Stratified by Treatment Cohort

	AJCC Stage, No. (%)					Pathologic Grade, No. (%)
	IA	IB	IIA	IIB	III	Grade I	Grade II	Grade III	Grade IV	Unknown
AJCC indicates American Joint Committee on Cancer; RT, radiotherapy, EBRT, external beam radiotherapy.
Subtotal resection + RT	12 (0.76)	24 (1.53)	30 (1.91)	36 (2.29)	2 (0.13)	17 (1.08)	43 (2.74)	31 (1.98)	1 (0.06)	12 (0.76)
Subtotal resection alone	45 (2.87)	29 (1.85)	59 (3.76)	51 (3.25)	3 (0.19)	29 (1.85)	67 (4.27)	59 (3.76)	2 (0.13)	30 (1.91)
Total resection + RT	15 (0.96)	46 (2.93)	73 (4.65)	132 (8.41)	9 (0.57)	37 (2.36)	135 (8.60)	78 (4.97)	5 (0.32)	20 (1.27)
Total resection alone	79 (5.04)	56 (3.57)	161 (10.26)	156 (9.94)	12 (0.76)	84 (5.35)	206 (13.13)	118 (7.52)	2 (0.13)	54 (3.44)
EBRT alone	24 (1.53)	11 (0.70)	70 (4.46)	32 (2.04)	9 (0.57)	19 (1.21)	26 (1.66)	19 (1.21)	1 (0.06)	81 (5.16)
No treatment	127 (8.09)	20 (1.27)	161 (10.26)	67 (4.27)	18 (1.15)	32 (2.04)	66 (4.21)	56 (3.57)	2 (0.13)	237 (15.11)
All patients	302 (19.25)	186 (11.85)	554 (35.31)	474 (30.21)	53 (3.38)	218 (13.89)	543 (34.61)	361 (23.01)	13 (0.83)	434 (27.66)

Kaplan-Meier plots by treatment cohort are shown in Figure 2, with comparison with lognormal fit event curves in Figure 3; the median survival was 17 months (95% CI, 16-18 months) for all patients with a survival of >2 months (Fig. 1). On univariate analysis, patients receiving surgery and RT exhibited superior median estimated survival times compared with those receiving either RT or surgical intervention alone, and all combined modality groups had outcomes superior to patients for whom no therapy was described (Table 2). RT alone was associated with decreased survival compared with no treatment (Table 2), whereas subtotal resection alone was not associated with either improved or decreased probability of survival.

Figure 2. Product-limit survival for all patients with extrahepatic cholangiocarcinoma surviving >2 months, stratified by therapy cohort, is shown. Tx indicates treatment; EBRT, external beam radiotherapy; RT, radiotherapy.

Table 2. Lognormal Parametric Survival Regression Results by Therapeutic Cohort (Univariate)

Cohort	No. of Events	No. of Censored	β	SE	95% CI	Estimated Median Survival, mo	95% CI, mo	Whole Model Effect Likelihood
SE indicates standard error; 95% CI, 95% confidence interval; RT, radiotherapy; EBRT, external beam radiotherapy.
Subtotal resection + RT	75	28	0.30	0.10	0.10-0.49	24.46	19.56-30.57
Subtotal resection alone	120	42	0.13	0.08	−0.03-0.29	20.70	17.38-24.66
Total resection + RT	173	95	0.36	0.07	0.23-0.50	26.12	22.66-30.09	<.001
Total resection alone	267	132	0.32	0.06	0.20-0.43	24.96	22.26-27.99
EBRT alone	121	23	−0.40	0.08	−0.56-−0.24	12.18	10.13-14.64
No treatment	245	46	0.00	—	—	8.97	7.88-10.20

Results from multivariate lognormal parametric survival analysis revealed a whole model log likelihood >χ2 probability of <.001, and are presented graphically in Figure 4. Age (as a continuous variable), grade, therapy cohort, and AJCC grouping were observed to have a statistically significant association with alteration in survival in multivariate analysis (all P < .001); year of diagnosis was not (P = .88). As in the univariate analysis, total resection, total resection + RT, and subtotal resection were associated with improved survival, subtotal resection provided no evidence of either survival improvement or decrement, and RT alone was associated with decreased survival compared with patients receiving no treatment.

Figure 3. Graphic representation of the parameter estimate of effect (β), with 95% confidence interval, is shown. AJCC indicates American Joint Committee on Cancer; RT, radiotherapy, EBRT, external beam radiotherapy.

DISCUSSION

With an estimated annual incidence of 3000 cases annually in the United States, extrahepatic cholangiocarcinoma remains a rare but aggressive neoplasm.8 Although complete surgical resection remains the foundation of curative intent therapy for patients with extrahepatic cholangiocarcinoma, due to its anatomic location and natural history, the majority of patients present with locally advanced disease at the time of diagnosis. The rarity of extrahepatic cholangiocarcinoma has precluded mounting large-scale, randomized controlled trials. Thus, at present, the role of adjuvant therapy for extrahepatic cholangiocarcinoma remains controversial, despite promising institutional data.23-25 Consequently, although imperfect, the utilization of large-scale population-based data sets, such as SEER, represents a useful mechanism for mortality risk estimation. Such data may be especially useful for tumors such as cholangiocarcinoma, in which single institutions have difficulty accruing sufficient numbers to afford appropriately statistically powered analyses.

The data presented herein suggest that the addition of RT to therapeutic intent surgical interventions was associated with improved median survival compared with surgery alone, RT alone, or nonsurgery/non-RT cohorts in a multifactorial model. However, it should be noted that, with sufficient follow-up (ie, >5 years), in univariate survival analysis, the mortality curves for the surgical and combined modality cohorts converge, and as shown in Figures 2 through 4, adjuvant RT 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 <3% for those receiving RT alone or no recorded therapy. The majority of detected survival benefit from the addition of RT to surgical intervention appears to be had within the initial 1 to 2 years after therapy (Figs. 2 and 3). Post hoc graphic 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 RT 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 with subtotal resection alone. EBRT alone was associated with improved hazard rates compared with no treatment only before 65 months of follow-up. Why the benefit for adjuvant RT dissipates over time is unclear. This observation may be because of delayed local recurrence in those patients receiving surgical resection and RT; alternately, it may be attributable to treatment-related factors unaccounted for in SEER (eg, chemotherapeutic regimens not recorded in SEER, performance status differentials, variant RT techniques and/or fractionation/dose schedules, post-therapy complication rates, delay in distant metastatic progression because of improved local control26). Alternatively, prognostic variables not recorded in SEER might lead to negative selection bias for definitive or adjuvant RT (eg, 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 data set. It is possible that the adjuvant RT cohort includes many patients who received RT secondary to suboptimal resection. If true, RT might confer some deferral of disease progression, but would be inadequate for eradicating bulk disease. If many suboptimally resected cholangiocarcinomas are de facto unresectable tumors,7 it becomes apparent, as Crane et al have noted previously, that conventional radiation-only regimens are insufficient to ensure local control,10 and may only be able to defer disease progression temporarily. However, such explanations are purely conjecture in the absence of prospective clinical trial data.

Figure 4. Multivariate lognormal model of survival for all patients with extrahepatic cholangiocarcinoma surviving >2 months, stratified by therapy cohort, is shown. Tx indicates treatment; EBRT, external beam radiotherapy; RT, radiotherapy.

Because SEER represents the largest domestic cholangiocarcinoma data set, the observed phenomena whereby early survival is improved by the addition of RT, whereas late survival is either unaltered or decreased, may explain the relatively contradictory findings in smaller institutional series. Some posit minimal utility for adjuvant therapy,27 whereas others suggest an appreciable survival benefit.7, 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 (Figs. 2 and 4). Some authors have observed series in which suboptimal resections (R1) may derive minimal gain from the addition of surgery to RT.7 Although not directly explained in this series, owing to the unavailability of surgical 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 RT only cohort should give pause to implementation of radiation monotherapy for patients with potentially difficult resections, and should spur aggressive surgery whenever indicated clinically.

Although SEER represents an exceedingly robust data set, several limitations should be assiduously noted. SEER data do 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 RT treatment techniques (eg, surgical margin status, dose/fractionation, time between surgery and RT) are not captured within the SEER data set. The SEER historic staging system, although affording ready comparison between distinct eras, is inherently imprecise to collapse patients based on extent of disease. In addition, no extrahepatic cholangiocarcinoma patients diagnosed from 1973 to 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. Although 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, which are major prognostic factors in many series.5, 8, 13, 15, 29, 35, 36 For example, Welzel et al demonstrated that discrimination of Klatskin tumors from other extrahepatic cholangiocarcinomas is unreliable using SEER1; consequently, the inclusion of Klatskin 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 patients received no treatment, 9 received EBRT monotherapy, 7 received total resection alone, 5 had total resection and RT, and 2 each received subtotal resection or subtotal resection with RT. Similar to most registry data, SEER data have multiple “catch-all” identifiers (eg, “Surgery NOS,” “Unknown Grade”) that may obfuscate careful definition of categoric cohorts. SEER data are limited geographically, as not all US cancer registries contribute to SEER, and temporally limited, as not all registries have contributed data for the same span of time. Although we used year of diagnosis as a surrogate for evolving RT, surgery, or chemotherapy practice, SEER variables do not directly account for technological improvement or changes in either surgical35, 37 or radiation technique over time.11 Finally, SEER data collection depends on 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 extrahepatic cholangiocarcinoma, with case numbers several-fold greater than available in single-institutional series. The value of such numeric power should not be underestimated. In addition, population-based data sets such as SEER may more accurately reflect the true expected survival of extrahepatic cholangiocarcinoma patients in the community medical milieu, rather than only at specific academic centers. This may explain why, in comparison with several retrospective series reported in the literature, survival results from the current analysis indicate comparatively worse survival for adjuvant RT patients than the markedly smaller, albeit more detailed, retrospective series available in extant literature.7, 9, 10, 12, 13, 15, 16, 36, 38 Likewise, differentials in the clinical outcomes associated with tertiary centers (eg, improved late survival at high volume centers,39 or increased utilization of adjuvant RT in institutions with on-site RT facilities40) may be obscured in pooled registry data.

This data set represents, to our knowledge, the first to characterize the effect of multimodality therapy using parametric survival analysis in cholangiocarcinoma. The nonproportionality of the hazard functions observed in this series with regard to therapeutic cohort necessitate a historically underused, but increasingly implemented statistical comparison.41-43 Ahmed et al have recently described several distinct methodologies for accounting for nonproportionality in survival series.19 We have chosen lognormal survival fitting, which has a long history within cancer survival analysis,44 as it is robust,45, 46 applicable in cases of nonproportionality,47 statistically succinct,18 and broadly interpretable as a mechanism for defining survival event estimates.46 Although more elegant corrections for nonproportionality are available, none is widely implemented.19 In addition, 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 data set into a risk-profiling tool, as has previously been performed using SEER data regarding gallbladder carcinomas.48

Our data support recent work by Shinohara et al,49, 50 who demonstrated a beneficial effect of adjuvant RT for intrahepatic and extrahepatic cholangiocarcinomas using SEER data. As in those analyses, long-term survival was poor despite the addition of RT. Nonetheless, demonstrated early survival improvement alone may serve as a justification for adjuvant RT, although 5-year mortality is unimproved. This early survival benefit, coupled with available data detailing patterns of failure for cholangiocarcinoma,15, 51-57 lends credence to the position that adding radiation postoperatively when possible for local/regional disease is a reasonable first-line therapeutic approach for extrahepatic cholangiocarcinoma, in the absence of more definitive data from randomized controlled trials.

Conclusions

Baseline data from SEER indicate an improved early survival profile for patients receiving multimodality therapy; however, a long-term survival advantage was not demonstrated.

Conflict of Interest Disclosures

Dr. Fuller received funding support from the National Institutes of Health/National Institute of Biomedical Imaging and BioEngineering/UTHSCSA Graduate Division of Radiological Sciences Multidisciplinary Training Grant in Human Imaging (5T32EB000817-04).