Prolonged survival with first-line chemotherapy in advanced extrahepatic cholangiocarcinoma

Abstract

Biliary tract cancer accounts for roughly 3% of adult malignancies of the gastrointestinal system. First-line treatment with gemcitabine–cisplatin chemotherapy is the standard for the management of metastatic biliary tract cancers. We present the case of a man who presented with abdominal pain, decreased appetite and weight loss for 6 months. Baseline evaluation revealed a liver hilar mass with ascites. Imaging, tumour markers, histopathology and immunohistochemistry revealed the diagnosis of metastatic extrahepatic cholangiocarcinoma. He was treated with gemcitabine–cisplatin chemotherapy followed by maintenance chemotherapy with gemcitabine and demonstrated an exceptionally good response and tolerance to chemotherapy with no long-term toxicity so far on maintenance therapy and progression-free survival exceeding 2.5 years after diagnosis. The rarity of this case is the exhibition of prolonged clinical response with maintenance chemotherapy for an aggressive cancer, thus needing further research into duration and outcomes of maintenance chemotherapy.

Background

Biliary tract cancer (BTC) accounts for roughly 3% of adult malignancies of the gastrointestinal system and is the second most frequent hepatobiliary tumour following hepatocellular carcinoma.¹ BTC encompasses a mixed group of aggressive malignancies, including intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma (eCCA), ampulla of Vater cancer and gallbladder cancer (GBC). The iCCAs comprise 10%–20% of all cholangiocarcinomas with a median age of 70 years and 5-year survival rates of 8%. eCCAs occur at a median age of 72 years and consist of perihilar eCCAs that make up for 50%–60% of all cholangiocarcinomas with a 5-year survival rate of 10% and distal eCCAs that constitute 20%–30% of all cholangiocarcinomas with a 5-year survival of 10%.^2–4 There are multiple risk factors for eCCA such as choledochal cysts, cholangitis, biliary cirrhosis, choledocholithiasis, cholecystitis, cholecystectomy, Clonorchis sinensis infection, inflammatory bowel disease, alcohol liver disease, chronic pancreatitis, duodenal ulcer and type II diabetes mellitus.⁵ The increased incidence of cholangiocarcinomas in Asian countries is being particularly attributed to hepatitis B infections and liver fluke infections.⁶ Prolonged survival is best offered by surgical resection. Distant and locoregional recurrences remain high even after surgery with negative tumour margins. Patients with metastatic disease need systemic therapy as a therapeutic option. Gemcitabine–cisplatin (GemCis) combination chemotherapy remains the first-line treatment for BTC.⁷ Here, we present a rare case of a man with metastatic eCCA with exceptionally good response and tolerance to chemotherapy with no long-term toxicities with maintenance therapy and having progression-free survival (PFS) of over 2.5 years since diagnosis.

Case presentation

A man in his 60s with a history of type II diabetes mellitus on treatment with oral hypoglycaemic agents and with no addictions presented to the hospital. He reported gradually increasing abdominal distension, dyspepsia, abdominal pain and decreased appetite for 6 months associated with weight loss of about 10 kg since 3 months. His Eastern Cooperative Oncology Group Scale of Performance Status was 2 on presentation. His examination revealed pallor, abdominal distension and ascites. Blood tests revealed haemoglobin of 89 g/L and normal renal and liver function tests. Baseline evaluation with ultrasonography of the abdomen revealed a liver hilar mass with ascites. Serum CA 19-9 value was 8591 U/mL (normal: <30 U/mL) and serum alpha-fetoprotein was within normal limits. Positron emission tomography (PET)-CT (figure 1A) revealed enhancing mass lesion of 3.5×1.9 cm at the liver hilum, extending to the left lobe and encasing the main portal vein with moderate intrahepatic biliary radical dilatation (IHBRD). There was a presence of enhancing omental nodularity with moderate ascites. A laparoscopic peritoneal biopsy was done. Histopathology of the peritoneal biopsy tissue suggested adenocarcinoma. Immunohistochemistry was positive for cytokeratin (CK) 7, CK 19 and carcinoembryogenic antigen, while negative for CK 20, calretinin and thyroid transcription factor 1, establishing the diagnosis of metastatic cholangiocarcinoma. He was initiated on GemCis chemotherapy and had symptomatic relief within 3 weeks. PET-CT was done about 3 months later (figure 1B) and revealed 24×14 mm mass lesion at the liver hilum and mild IHBRD with no ascites or omental disease, suggestive of partial response as per Response Evaluation Criteria in Solid Tumours (RECIST) criteria. CA 19-9 was 937 U/mL. After six cycles of GemCis, PET-CT was repeated and was suggestive of partial response as per RECIST criteria. Hence, the patient was started on gemcitabine maintenance of 1000 mg/m² therapy two times per week. He underwent 38 cycles of maintenance chemotherapy without any Common Terminology Criteria for Adverse Events (CTCAE) grade II or above toxicities. CA 19-9 was noted to be 73 U/mL in his latest blood tests. His disease is in complete remission as per his latest PET-CT taken 2.5 years after initiating chemotherapy (figure 1C).

Figure 1.

(A) Positron emission tomography (PET)-CT scan at the time of diagnosis. (B) PET-CT scan 3 months after initiating chemotherapy. (C) PET-CT scan 2.5 years after initiating chemotherapy.

Outcome and follow-up

The patient’s latest PET-CT showed that the disease is in complete remission. His last follow-up showed that he was clinically stable and had tolerated the treatment well.

Discussion

In the early stages of cholangiocarcinoma, even following curative surgery, there is an extremely high recurrence rate, with a median 5-year survival of less than 50%.^{8 9} During diagnosis, patients usually present with non-resectable disease, thus having a poor prognosis with a median survival of 3–6 months.¹⁰ Landmark trials such as the phase III ABC-02 and the randomised phase II BT22 trials established GemCis as the new standard of care for treatment and extending survival for advanced BTC.^{7 11} A meta-analysis done by Valle et al further supported this treatment strategy.¹² In a recent large retrospective study on cholangiocarcinomas to evaluate outcomes with first-line chemotherapy by Bhargava et al, the median PFS was 7.56 months and overall survival (OS) was 12.16 months with GemCis regimen being used in 63.5% of patients.¹³ These findings are very similar to those seen in the seminal ABC-02 (median PFS—8 months; median OS—11.7 months) and BT22 (median PFS—5.8 months; median OS—11.2 months) Studies. In a retrospective study of patients with advanced BTC receiving GemCis as first-line treatment, it was found that male gender, baseline high CA 19-9 levels, initial metastatic disease and poor performance status were significantly associated with poor outcome.¹⁴ To the best of our knowledge, there are no individual case reports depicting PFS of eCCAs to first-line chemotherapy for more than 2 years. Our patient showed good clinical response within 3 weeks of initiating chemotherapy and was having continuing good response with treatment. He experienced only CTCAE grade I fatigue and grade I neutropenia with no long-term toxicities. This suggests an excellent tolerance of chemotherapy regimen compared with 18.7% of patients who had grade III and IV fatigue and 25.3% of patients who had grade III and IV neutropenia as per the ABC-02 Study.⁷ In the ABC-02 trial, which compared GemCis regimen with gemcitabine alone in patients with locally advanced or metastatic BTC, patients received first-line GemCis up to a maximum of eight cycles and then their treatment was discontinued irrespective of their response; whereas in BT22 trial, which had similar treatment arms, treatment with GemCis was continued to a maximum of 16 cycles (48 weeks). Maintenance chemotherapy has been found to prolong survival in lung cancer and has been recommended to improve the outcome in colon and pancreatic cancers, but there is a lack of data in this regard for BTC.^{15 16} A retrospective study by Hyung et al aimed to see the clinical benefit of maintenance therapy for patients with advanced BTC showing no progression after six to eight cycles of first-line GemCis chemotherapy. Among the 740 patients with BTC in the initial screen, 231 cases (31.2%) were eligible for analysis (111 in the observation group and 120 in the maintenance group). A median of 14 cycles of GemCis was administered in the maintenance phase (range 9–42), with gemcitabine monotherapy in 42.5% of patients from the ninth cycle.¹⁷ The median OS from the GemCis initiation was 20.5 months and 22.4 months in the observation and maintenance groups, respectively (p=0.162). The median PFS was 10.4 months and 13.2 months, respectively (p=0.320). There was no significant difference in the proportion of patients receiving second-line chemotherapy after progression on GemCis between two groups. They concluded that maintenance chemotherapy with GemCis for advanced BTC in whom disease control has been achieved after six to eight cycles may not produce a survival benefit due to cumulative toxicities and impact on quality of life from the sustained administration of chemotherapeutic drugs.¹⁷

However, patients in the maintenance group showed higher objective response rates (27.5% vs 14.4%, p=0.015).

In yet another retrospective study by Ostwal et al, which included 396 patients with advanced GBC, the role of continuation chemotherapy was evaluated in advanced GBC. In this study, 70 out of 120 patients who did not progress after six to eight cycles of first-line treatment received maintenance chemotherapy. A median of four cycles (range of 2–15) was administered, with GemCis regimen in 48.6% of patients.¹⁸ A statistically significant improvement in median OS was seen in patients receiving continuation chemotherapy (14.8 months vs 11.9 months; p=0.033) compared with all other patient cohorts. On multivariate analysis, statistically significant factors affecting OS were a single site of metastasis, administration of continuation chemotherapy and exposure to second-line chemotherapy.¹⁸ In a retrospective study by Doherty et al on patients with advanced BTC, who received palliative chemotherapy, patients were divided into two groups for analysis: long-term responders (LTRs) who received nine or more cycles, and the controls who received two to eight cycles. Among 382 patients, 123 met the criteria for LTRs and 259 included as controls. In the LTR group, the median number of chemotherapy cycles was 12 (range 9–47) with GemCis being used in 42% of patients. A significantly longer PFS (median 13.3 vs 4.1 months, p<0.001) and a longer OS than controls (median 22.1 vs 9.2 months, p<0.001) were observed in LTR patients. The LTR patients more frequently went on to receive second-line chemotherapy (47% vs 33%, p=0.007).¹⁹

Our patient has been having ongoing treatment for almost 2.5 years with the completion of 38 cycles of gemcitabine maintenance and did not have any long-term toxicities to date. His disease has shown good response clinically, biochemically and radiologically until the time of this publication. This clinical scenario exemplifies the unmet need for guidelines on the duration and role of maintenance chemotherapy in this subgroup of patients. But there are strengths and limitations of this approach. Even though there is a paucity of the randomised trial data for maintenance chemotherapy, the above retrospective trial data suggest the benefits of this strategy which include higher objective response rates with better PFS and OS and manageable toxicities.^17–19 Well-designed randomised controlled trials need to be done in this regard before using this strategy in routine clinical practice. The recently published ABC-06 trial showed that second-line FOLFOX (Folinic Acid, Fluorouracil and Oxaliplatin) chemotherapy can improve OS in patients with advanced BTC who have had disease progression on GemCis regimen and that the survival benefit was independent of platinum sensitivity.²⁰ The drawback of maintenance chemotherapy would be that it has the potential for cumulative toxicities, which may impair the quality of life.

Learning points.

• A subset of patients with metastatic cholangiocarcinoma have good response to first-line palliative chemotherapy thereby leading to prolonged survival as depicted in this case report.

• Clinicians must give consideration to the strategy of maintenance chemotherapy after six to eight cycles of first-line chemotherapy.

• Maintenance chemotherapy after completion of standard palliative chemotherapy can be offered to a subset of patients leading to better outcomes without impairing quality of life.

• The preferred regimen and duration of maintenance chemotherapy after completion of standard palliative chemotherapy and its precise role need to be ascertained with randomised trials in future.

Ethics statements

Patient consent for publication

Obtained.