Chemoradiotherapy for patients with locally advanced or unresectable extra-hepatic biliary cancer

Introduction

The most well-established curative-intent therapy for patients with extra-hepatic biliary cancer (EBC), including extra-hepatic cholangiocarcinoma or gallbladder cancer, is radical, margin-negative, surgical resection with the consideration for post-operative chemotherapy with or without RT, depending upon risk factors (1-4). However, the prognosis for patients with locally advanced, unresectable EBC remains poor with the primary treatment consisting of multi-agent chemotherapy (5).

A number of series have reported outcomes of radiotherapy (RT) or chemoradiotherapy (CRT) for patients with unresectable EBC (6-30). These series report local control (LC) of approximately 50–70%, median survival of 10–24 months, and 3-year overall survival (OS) of 10–20%, with survival limited by competing risks of local and distant disease relapse and underlying medical comorbidities and complications. RT has also demonstrated a palliative role in preventing or alleviating biliary obstruction (20-23). Unfortunately, patients are at a high risk of both disease and treatment-related morbidity with grade 3 or higher acute adverse events (AEs) of 20–30% and potential late complications including gastroduodenal ulceration or bleeding in 10–20% (6-30). Biliary and liver infection is tumor-related and fairly ubiquitous in this cohort with reported rates of severe infection as high as 60% (31).

Interestingly, many of the aforementioned series demonstrate long-term survival in a subset of patients, indicative of a potentially select subgroup for whom disease biology or treatment-related factors may be associated with sustained disease control and long-term survival. However, the role of RT for patients with unresectable EBC remains inconclusive. The purpose of this series is to report the therapeutic efficacy, AEs, and disease and treatment-related associates with outcomes for a cohort of patients with unresectable EBC treated with RT. We present the following article in accordance with the STROBE reporting checklist (available at http://dx.doi.org/10.21037/jgo-20-245).

Methods

Patient population

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by our institutional review board of the Mayo Clinic in Rochester, Minnesota (No. 18-003400) as a retrospective study deemed as minimal risk and exempt of the need for informed consent for individual participants included in the study.

We performed a single institution retrospective cohort study of patients with histologically or cytologically confirmed EBC, including extra-hepatic cholangiocarcinoma or gallbladder cancer, who received RT between 1998 and 2018. Patients were excluded if they were less than 18 years of age, had distant metastatic disease, were initially deemed suitable for any form of curative-intent surgical resection including radical resection or radical resection followed by liver transplantation (32), had prior abdominal RT, or did not provide research consent.

Pre-treatment evaluation

All patients underwent pre-treatment evaluation within a specialized multi-disciplinary practice including gastroenterology, surgical oncology, medical oncology, and radiation oncology. Assessments included history and physical examinations, diagnostic evaluation including CA 19-9 (94%), and computed tomography (CT) of the abdomen and pelvis (100%). Magnetic resonance imaging (MRI) abdomen was obtained in 58% of patients. Systemic imaging assessments included evaluation of the chest with chest X-ray alone (54%) or CT chest (42%), and positron emission tomography-computed tomography (PET-CT) was performed in 13% of patients. Patients underwent endoscopic retrograde cholangiopancreatography (ERCP) for local disease characterization with the addition of internal biliary stent placement (90%) or percutaneous biliary drainage (4%) for those with clinically significant biliary obstruction.

Treatment techniques

All patients underwent CT-based simulation with immobilization devices and optional respiratory motion-management strategies as deemed appropriate by the treating physician. When indicated, additional diagnostic studies such as MRI abdomen, contrast-enhanced CT, or PET-CT were registered to the planning CT to assist with target delineation.

Target volumes included the internal gross tumor volume (iGTV), which consisted of the gross primary tumor and clinically involved regional lymph nodes accounting for respiratory motion on a 4-dimensional CT scan, when indicated. The clinical target volume (CTV) consisted of a 5–10 mm expansion upon the iGTV to encompass microscopic disease extension and most patients had elective inclusion of regional lymph nodes, such as the porta hepatis and celiac lymph nodes. A 5–10 mm margin was added to the CTV to generate the planning target-volume (PTV).

External beam RT (EBRT) was delivered with three-dimensional conformal radiotherapy (3DCRT) or intensity modulated radiotherapy (IMRT) most commonly to a dose of 50.4 Gy in 28, once-daily fractions, or 45 Gy in 30, twice daily, fractions. Concurrent chemotherapy was delivered in 94% of patients and included either 5-flourouracil or capecitabine. Eight patients received intraluminal biliary low-dose rate (LDR) or high-dose rate (HDR) brachytherapy prescribed to a dose of 20–25 Gy (LDR) or 9.3 Gy (HDR) at 1-cm depth.

Patient assessments

Patients underwent oncologic surveillance at 3 to 6-month intervals as part of routine clinical care with history and physical examination, laboratory evaluation, and diagnostic imaging. Local progression (LP) was defined as progression at the primary tumor site; regional progression was defined as recurrence or progression within non-metastatic regional lymph nodes; distant metastasis (DM) sites were defined as non-regional lymph nodes or distant organs. Disease recurrence was diagnosed histologically, or when unavailable, clinically per radiographic findings. AEs of treatment were assessed and attributed per Common Terminology Criteria for AEs version 4.0 (CTCAE). Acute AEs were defined as those occurring during RT or within 3 months of RT completion. Late AEs were defined as any complication which occurred greater than 3 months following completion of RT.

Statistical analysis

Statistical analysis was performed using SAS version 9.4 (SAS Institute Inc., Cary, NC). OS and progression-free survival (PFS) from the start of RT were estimated using the Kaplan-Meier method. The cumulative incidences of LP, locoregional progression (LRP), DM, and late AEs were reported using the competing risk model, with death as a competing risk. Baseline patient, tumor, and treatment characteristics associated with OS and PFS were assessed using a univariate Cox proportional hazards regression model. EBRT biologically effective dose (BED) was calculated using the linear-quadratic model assuming an α/β of 10 Gy. Associations between BED and outcomes were assessed by stratifying by the median BED of 59.5 Gy₁₀ (equivalent to 50.4 Gy in 28 fractions). Multivariate Cox proportional hazards regression models were examined for the outcomes of OS and PFS, including as candidate variables those with a univariate significance of P<0.15. A backward selection method was used to identify a parsimonious model. The alpha-level was set at 0.05 for statistical significance. Significance tests (P values) were not adjusted for multiple testing. Patterns of disease progression were reported descriptively. Patients dependent upon biliary stenting prior to RT were assessed for the ability to transition to stent-free, defined as being stent-free for at least a 3-month period following RT.

Results

A total of 48 patients met study inclusion criteria and were included for analysis. Patient and treatment characteristics are demonstrated in Tables 1,2. No patient underwent surgical resection or resection with liver transplantation following RT.

Table 1 Baseline patient characteristics
Full table

Table 2 Treatment characteristics
Full table

Survival and disease control

The median patient follow-up duration was 13 months [interquartile range (IQR): 6–29]. The median OS was 12.0 months [95% confidence interval (CI): 2.3–73.2 months]. The 2-, 3-, and 5-year OS were 33% (95% CI: 22–50%), 20% (95% CI: 11–36%), and 7% (95% CI: 2–20%), respectively. The median and 2-year PFS were 9.0 months (95% CI: 1.7–73.2 months) and 21% (95% CI: 12–36%) (demonstrated in Table 3 and Figure 1), respectively. The cause of death was cancer-related in 38 (79%) patients, non-cancer-related in 9 (19%) patients-most commonly due to liver or biliary infection (56%), and was unknown in 1 patient (2%).

Table 3 Oncologic efficacy
Full table

Figure 1 Estimated OS (A), PFS (B), LP (C), LRP (D) and DM (E).

Associates with outcomes

On univariate analysis (demonstrated in Table 4), EBRT BED >59.5 Gy₁₀ was associated with improved OS (HR: 0.40, 95% CI: 0.18–0.92, P=0.03) and PFS (HR: 0.37, 95% CI: 0.16–0.84, P=0.02) (demonstrated in Figure 2), and increasing tumor size per 1 cm was associated with poorer PFS (HR: 1.29, 95% CI: 1.02–1.63). When RT regimens were assessed as an EBRT BED ≤59.5 Gy₁₀vs. EBRT BED ≤59.5 Gy₁₀ + brachytherapy boost vs. EBRT BED >59.5 Gy₁₀ to compare techniques of local dose escalation, EBRT BED >59.5 Gy₁₀ remained associated with improved OS (HR: 0.41, 95% CI: 0.18–0.94, P=0.04), and PFS (HR: 0.34, 95% CI: 0.15–0.78, P=0.01) but the addition of brachytherapy did not. On multivariate analysis, EBRT BED >59.5 Gy₁₀ was associated with improved PFS (HR: 0.34, 95% CI: 0.15–0.78, P=0.01). No variable was associated with OS on multivariate analysis.

Table 4 Univariate associates with overall survival and progression-free survival
Full table

Figure 2 Survival estimates following RT for patients with EBC stratified by radiation dose. RT, radiotherapy; EBC, extra-hepatic biliary cancer.

Patterns of disease progression

Twenty-five (52%) patients were identified with disease progression by last radiographic follow-up. The 2-year cumulative incidences of LP, LRP, and DM were 27% (95% CI: 17–44%), 31% (95% CI: 20–48%), and 33% (95% CI: 22–50%), respectively (demonstrated in Table 3 and Figure 1C,D,E). Patterns of first progression included: DM (n=8, 17%), local only (n=7, 15%), local + DM (n=4, 8%), local + regional + DM (n=3, 6%), regional + DM (n=2, 4%), or local + regional (n=1, 2%). Isolated locoregional first-progression occurred in 8 (32%) patients. An equal number of patients experienced locoregional first-progression (n=17, 35%) as DM first-progression (n=17, 35%). The majority of patients (92%) received elective regional lymph node irradiation and no patient experienced an isolated regional-only first-progression.

AEs

Of the 48 total patients, 1 (2%) patient discontinued treatment early after having received 43.2 Gy of a planned 50.4 Gy, 3 (6%) patients required an unintended mid-treatment break, and 9 (19%) patients were hospitalized during RT. Of these, 2 patients were hospitalized due to RT-related toxicities, including one patient with severe nausea and vomiting and another patient with severe abdominal pain, 4 patients were hospitalized due to liver or biliary infection, and 2 patients were hospitalized due to medical complications unrelated to RT (one who required monitoring due to supratherapeutic anti-coagulation and a second patient who experienced a mid-treatment cerebrovascular accident). Acute grade 3 or higher treatment-related gastrointestinal (GI) AEs occurred in 13% of patients. The 2-year cumulative incidence of late grade 3 or higher GI complications was 27% (95% CI: 13–36%), with 17% (95% CI: 5–27%) attributable to RT (demonstrated in Table 5). Treatment-related AEs included: stomach or small bowel ulceration (2%, 95% CI: 0–6%), small bowel obstruction (2%, 95% CI: 0–6%), or GI bleed (15%, 95% CI: 4–24%). No patient experienced treatment-related bowel perforation or fistula, and no patient experienced a grade 5 toxicity. No differences in acute (P=0.27) or late (P=0.59) GI AEs were identified amongst patients treated with EBRT BED ≤59.5 Gy₁₀, EBRT BED >59.5 Gy₁₀, or EBRT BED ≤59.5 Gy₁₀ plus brachytherapy.

Table 5 Late adverse events
Full table

The 2-year cumulative incidence of biliary infection following RT was 46% (95% CI: 30–58%). Of the 45 (94%) patients dependent upon biliary decompression or stenting prior to RT, 1 was able to become stent-free after completion of RT and remained stent-free for 7 months until death from non-cancer causes. The 3 patients who did not require pre-treatment biliary stenting all remained stent-free following RT.

Discussion

We report our institutional experience of RT for patients with locally advanced EBC who were deemed inoperable by conventional surgical techniques and not suitable for radical resection with liver transplantation. We identified 3- and 5-year survival in a subset of patients and that BED >59.5 Gy₁₀ (equivalent to a dose of 50.4 Gy in 28 fractions) was associated with improved OS on univariate analysis and improved PFS on both univariate and multivariate analyses. Despite this, patients are at considerable risk of tumor- and treatment-related morbidities, thus suggesting that improvements in patient selection and medical, supportive, and cancer-directed care are needed to further maximize the therapeutic gains of local RT for patients with 
unresectable EBC.

The majority of data describing RT for patients with EBC are limited to relatively small, single institution series (demonstrated in Table S1) (6-30). Foo et al. reported on 24 patients treated between 1980-1991 with EBRT to a median dose of 50.4 Gy in 28 fractions plus biliary brachytherapy with concurrent 5-FU chemotherapy in 38% of patients (6). They demonstrated 5-year OS of 14% with a trend towards improved OS for patients who received concurrent chemotherapy. Late toxicities of gastroduodenal ulceration and bleeding or cholangitis occurred in 42% and 50% of patients, respectively. Crane et al. reported on 52 patients treated between 1957 and 2000 with EBRT doses ranging between 30 and 85 Gy with concurrent 5-FU chemotherapy in 73% of patients (7). They demonstrated a median OS of 10 months and 2-year OS of 13%. Grade 3 or higher AEs occurred in approximately 21% of patients. Bisello et al. reported on 76 patients with unresectable biliary cancer (4% intrahepatic cholangiocarcinoma; 96% EBC) treated between 1991 and 2017 with a median EBRT dose of 50 Gy, biliary brachytherapy in 51%, and concurrent 5-FU or gemcitabine-based chemotherapy in 78% of patients (8). They demonstrated a median OS of 13.5 months, 2-year OS of 26%, and 3-year OS of 11%. Acute grade 3 GI AEs occurred in 13% of patients. Yoshioka reported on 209 patients treated between 2000 and 2011 with EBRT to 50 Gy with concurrent chemotherapy in 78% of patients plus biliary brachytherapy in 27% (9). Two-year OS was approximately 30%. LC in these series ranged from 59–67%. These outcomes compare similarly to our series with a median OS of 12.0 months, 2-year OS of 33%, 3-year OS of 20%, and acute and late treatment-related GI AEs of 13% and 17%. In summary, these retrospective data suggest that RT is associated with sustained survival in approximately 10–20% of patients and that these outcomes have been replicable amongst many institutions internationally, consistent across time, and reproducible despite substantial heterogeneity in patient, disease, and treatment characteristics.

Despite these findings, the question still remains whether the addition of RT improves outcomes compared to chemotherapy alone. The Advanced Biliary Cancer Trial-02 (ABC-02) randomized 410 patients with metastatic (76%) or locally advanced and unresectable (24%) biliary tract cancer to receive chemotherapy with gemcitabine or gemcitabine plus cisplatin and demonstrated an improvement in PFS and OS with the addition of cisplatin, thereby establishing the current standard of care chemotherapy regimen for this cohort (5). The median OS was 11.7 months and only 5 (1%) patients were alive and disease-free at 2 years suggesting that despite improved median OS with combination chemotherapy, chemotherapy alone offers limited chance of long-term survival and disease control. To assess the potential benefit of the addition of RT, Torgeson et al. performed a propensity score-matched National Cancer Database analysis of 2996 patients with an unresectable EBC (73%) or cancer of the Ampulla of Vater (27%) treated with chemotherapy alone vs. CRT (15). CRT was associated with improved median OS (14.5 vs. 12.6 months, HR: 0.84, p<0.001). Similarly, Shinohara et al. performed a propensity-score matched analysis using the Surveillance, Epidemiology, and End Results database and demonstrated a median OS of 9 vs. 4 months (HR: 0.61, 95% CI, 0.54–0.70, P<0.0001) in favor of palliative RT vs. no RT or surgery (28).

Building upon these data, the Fédération Francophone de Cancérologie Digestive (FFCD) 9902 phase II randomized study compared treatment with 6 months of gemcitabine plus oxaliplatin vs. 5-FU and cisplatin-based CRT to a dose of 50 Gy (20). The study closed early due to slow accrual, but amongst the 36 accrued patients (anticipated accrual of 72 patients), there was no difference in median PFS (5.8 vs. 11.0 months, HR: 0.65, 95% CI: 0.32–1.33) or median OS (13.5 vs. 19.9 months, HR: 0.69, 95% CI: 0.31–1.55) and acute grade 3–4 toxicity (47% vs. 75%) for the CRT vs. chemotherapy alone cohorts, respectively. Hence, the role of RT for patients with unresectable EBC remains of debate but it is a treatment strategy supported per National Comprehensive Cancer Network guidelines (33). Our data do support the utility of RT, with a suggestion for 3- and 5-year survival in a small subset, but we acknowledge these data are hypothesis generating, may be limited to highly select subsets of patients, and should be verified in the context of a prospective trial.

As suggested in other series comparing biliary stenting vs. biliary stenting plus RT (21-23), the FFCD 9902 trial also suggested a potentially meaningful palliative role for RT with a lower rate of biliary complications (28% vs. 44%), such as obstruction with cholangitis, in the cohort receiving CRT compared with chemotherapy alone (20). In our series, the 2-year incidence of biliary infection was 46%, 1 patient was able to become stent-free following RT, and all 3 patients who did not require pre-treatment biliary stenting remained stent-free following RT. Considering our cohort selection with very advanced disease not amenable to any form of surgical resection and correlating our findings with the aforementioned studies, we propose that RT may serve a palliative cytoreductive role to improve biliary obstruction for patients with more limited volume disease, delay biliary obstruction in patients not currently obstructed, and help prevent biliary stent tumor overgrowth, but has limited capacity in reversing biliary obstruction in patients with an extensive disease burden.

Interestingly, we identified an association between improved OS and PFS with an EBRT BED >59.5 Gy₁₀ and no significant increase in AEs for dose-escalated regimens. These findings have been more strongly demonstrated in cohorts of patients with intrahepatic cholangiocarcinoma (I-CCA) for which dose escalation to a dose ≥60 Gy (34) or a BED >80.5 Gy₁₀ (35) has been associated with improved LC and OS. A challenge with EBC is the anatomical location and close proximity to highly sensitive organs, such as the duodenum which has limited capacity to tolerate RT doses above 55 Gy, without potentially life-threatening toxicity (36-38). Crane et al. evaluated the association between EBRT doses of 30 Gy, 36–50.4 Gy, and 54–85 Gy with outcomes for patients with EBC (7). They identified a prolonged median time to LP of 9 vs. 11 vs. 15 months and no significant increase in toxicity, suggesting a potential benefit of dose-escalation. Tsujino et al. demonstrated an association between improved OS and an EBRT dose of ≥45 Gy (28) and Alden et al. demonstrated improved OS with EBRT dose >55 Gy (25). More recently however, Elganainy et al. compared patients treated with non-uniform dose escalation to a BED >59.5 Gy₁₀ to segments of tumor away from small bowel vs. conventional EBRT to a BED ≤59.5 Gy₁₀ and did not demonstrate any significant differences in OS or freedom from LP (18). Despite the suggestion of improved outcomes with dose-escalation seen in some series, there is a high likelihood of patient selection bias with tumors situated away from small bowel being more likely to receive dose escalation. Therefore, if considering dose escalation, each patient should be critically assessed for the feasibility and optimal technique based upon individual patient anatomy. If deemed suitable for dose escalation, priority should still be given to meeting acceptable RT doses to adjacent organs at risk.

Stereotactic body radiotherapy (SBRT) has also been explored as a potentially curative RT strategy for patients with biliary cancer. Sandler et al. reported on a cohort of 31 patients with either intra-hepatic cholangiocarcinoma (19%) or extra-hepatic cholangiocarcinoma (81%) who received SBRT to a median dose of 40 Gy in 5 fractions (39). The median OS was 15.7 months, 2-year OS was 33%, and 2-year LC was 47%. Severe late AEs occurred in 16% of patients, including 9% with grade 3–4 duodenal ulceration or bleeding. Kozak et al. reported on a similar cohort of 40 patients (62% intra-hepatic cholangiocarcinoma; 38% extra-hepatic cholangiocarcinoma) treated with SBRT to a median dose of 40 Gy in 5 fractions (40). Amongst those with extra-hepatic cholangiocarcinoma, the median OS was 10 months, LP occurred in 30%, and acute and late hepatobiliary AEs occurred in 40% and 43%-most commonly disease-related biliary infection. Regional recurrences occurred in 24% of patients, which is consistent with patterns of recurrence following curative-intent surgery which were identified most commonly within lymph nodes along the hepatoduodenal ligament, celiac artery, superior mesenteric artery, or retroperitoneal/para-aortic (41-44). In our series, 92% of patients received elective regional lymph node irradiation and no patient experienced an isolated regional-only first-progression. Therefore, while SBRT may offer comparable LC and toxicity, more comprehensive regional lymph node coverage may be considered when offering RT to help prevent regional recurrence and perhaps could be included in future SBRT strategies which simultaneously treat elective lymph node regions to a lower RT dose.

Limitations of our study include the retrospective design, likely selection biases for RT, and small patient numbers. Conclusions regarding the role of RT would be strengthened if compared against a reference group receiving chemotherapy alone. There was potential underestimation of acute and late treatment-related AEs due to the retrospective nature of data collection for some patients. The addition of patient-reported outcomes would have strengthened this report, but unfortunately, were unavailable for most patients. Assessments of tumor and treatment characteristics associated with outcomes were limited by patient numbers, and therefore should be considered hypothesis-generating.

Further investigations are needed to optimize supportive and medical management, patient selection with radiographic response assessments and potential molecular or biological stratification, including isocitrate dehydrogenase-1 or fibroblast growth factor receptor mutational status, and incorporation of advanced RT technologies to help mitigate toxicities of treatment (24,29). Few patients in our series received initial multi-agent systemic therapy before CRT. This multi-modality treatment sequencing strategy, similar to the approach taken with locally advanced pancreas cancer and that attempted with the NRG-GI001 trial (45,46), is now more commonly utilized and may serve as a patient selection tool prior to aggressive local therapy. While not demonstrated in our series of patients with highly advanced disease deemed unsuitable for surgery, pre-operative CRT may also be explored for patients with “borderline resectable” EBC to maximize the opportunity for margin negative, potentially curative resection (47).

Conclusions

RT is associated with 3- and 5-year survival in a subset of patients with unresectable EBC although patients remain at significant risk of both tumor- and treatment-related morbidity. Further exploration of the role of RT as part of a multi-modality curative treatment strategy is warranted.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at http://dx.doi.org/10.21037/jgo-20-245

Data Sharing Statement: Available at http://dx.doi.org/10.21037/jgo-20-245

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jgo-20-245). KRJ reports that he receives honoraria from RadOncQuestions.com, LLC. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by our institutional review board of the Mayo Clinic in Rochester, Minnesota (No. 18-003400) as a retrospective study deemed as minimal risk and exempt of the need for informed consent for individual participants included in the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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