Prolonged Survival Shown With SIRT and Y90 Plus Chemotherapy in Intrahepatic Cholangiocarcinoma

Stephen L. Chan, MBB

A phase 2 study has shown that adding selective internal radiation therapy (SIRT) with Y90 resin microspheres to gemcitabine/cisplatin can extend overall survival in patients with inoperable intrahepatic cholangiocarcinoma (ICC), according to a poster presented during the 2021 International Liver Cancer Association (ILCA) Conference.¹

The median overall survival (OS) observed was 21.6 months (95% CI, 7.3-25.2) for patients with ICC.

Results of the trial (NCT02167711), which involved 3 Asian centers, also showed that the median progression-free survival (PFS) was 9 months (95% CI, 3.2-13.1).

For patients treated with SIRT-Y90 who did not receive chemotherapy, the median PFS was 6.6 months (95% CI, 2.5-9.8) and the median OS was 13.6 months (95% CI, 5.4-21.6).

“Our data was comparable to the Western data [NCT01912053], and we consider further clinical development to be warranted,” said lead author Stephen L. Chan, MBBS, an associate clinical professor of the Department of Clinical Oncology at the Chinese University of Hong Kong, China, in a virtual presentation during the meeting.

In the phase 2 Yttrium-90 Microspheres in Cholangiocarcinoma (MISPHEC trial), which is the Western study that Chan referenced, 41 patients with unresectable inoperable intrahepatic cholangiocarcinoma who had not received chemotherapy or intra-arterial therapy were treated at 7 centers in France from November 2013 through June 2016.²

Patients were assigned to 8 cycles of concomitant first-line chemotherapy with 25 mg/m2 cisplatin and 1000 mg/m2 gemcitabine; that was reduced to 300 mg/m2 for the cycles just prior to and after SIRT, on days 1 and 8 of a 21-day cycle. Investigators administered SIRT during cycle 1 for those with 1 hemiliver disease or cycles 1 and 3 for disease involving both hemilivers.

After a median follow-up of 36 months (95% CI, 26-52), the median PFS was 14 months (95% CI, 8-17) and the median OS was 22 months (95% CI, 14-52). The 1- and 2-year OS rates were 75% and 45%, respectively; the 1- and 2-year PFS rates were 55% and 30%.

Similarly, the randomized, phase 3 ABC-02 trial (NCT00262769) established gemcitabine plus cisplatin as the standard of care in locally advanced or metastatic biliary tract cancer.³ In those results, the median OS was 11.7 months for the combination compared with 8.1 months for gemcitabine monotherapy (HR, 0.64; 95% CI, 0.52-0.80; P <.001). The median PFS was 8.0 months vs 5.0 months, in favor of the combination (P <.001).

In the single-arm findings reported at the 2021 ILCA Conference, 24 patients with intrahepatic cholangiocarcinoma were assigned to 1 course of SIRT-Y90 administered via the hepatic artery at a dose of at least 120 Gy to the intrahepatic tumor. Patients then received a maximum 8 cycles of chemotherapy with cisplatin at a dosage of 25 mg/m2 on days 1 and 8, followed by gemcitabine at a dosage of 1000 mg/m2 on days 1 and 8 every 3 weeks

Investigators assessed patients for acute toxicity related to SIRT-Y90 1 week after the treatment. Patients with grade 1 or lower treatment-related toxicities and adequate hematological, renal, and hepatic functions then proceeded to gemcitabine/cisplatin chemotherapy.

Investigators performed CT scans every 6 weeks until progressive disease according to RECIST criteria. For patients who stopped chemotherapy for any reason other than withdrawal of consent, investigators continued regular follow-up to watch for delayed toxicity until 9 months following SIRT-Y90, death, or the patient was lost to follow-up.

The primary end point was OS. Secondary endpoints included PFS, response rate, disease control rate (DCR), toxicity, and time from Y90 to commencement of chemotherapy.

Patients were treated at participating centers in Hong Kong (28.2%), Singapore (25.0%), and Thailand (45.8%). All patients had an ECOG score of 0 or 1. Most patients were diagnosed with stage IVA (50.0%) or stage IVB (25%) stage disease. The remainder were diagnosed with stage III (16.6%), stage II (4.2%), or stage I (4.2%) disease.

The median age was 62 years (range, 35-79), and men to female ratio was 15:9.

All patients received SIRT-Y90 according to the protocol. Sixteen (67%) proceeded to chemotherapy and received a median of 4.5 cycles (range, 1-8). The median time from completion of SIRT-Y90 to start of gemcitabine/cisplatin treatment was 29 days (range, 7-42).

The overall response rate (ORR) was 25% (95% CI, 3.8%-46.2%) among the 16 patients who received at least 1 cycle of chemotherapy following SIRT-Y90 with a DCR of 75% (95% CI, 53.8% -96.2%). In the intent-to-treat (ITT) population, the ORR was 16.7% (95% CI, 1.8%-31.6%) with a DCR of 58.3% (95% CI, 38.6%-78.1%) following administration of SIRT-Y90.

Among the 8 patients who were unable to receive subsequent chemotherapy, 12.5% experienced disease progression. The others had poor underlying conditions such as presence of liver and splenic abscess and inadequate renal function before commencement of chemotherapy (8%), abdominal pain after SIRT-Y90 (4%), consent withdrawal (4%), or death (4%).

At a median follow-up of 8.5 months (range, 1.1-30), 19 patients died, 17 of whom had disease progression.

The rate of grade 3/4 toxicities was less than 10% in the ITT population. During the SIRT portion, the most common grade 3/4 toxicities included abdominal pain (4%), vomiting (4%), ascites (4%), elevated aspartate aminotransferase (AST; 4%), increased blood bilirubin (4%) and hypercalcemia (4%).

During the chemotherapy phase, common grade 3/4 treatment-induced toxicities included grade 3 elevated alanine aminotransferase (4%) grade 3 elevated AST (8%), grade 4 elevated alkaline phosphatase (4%) and grade 3/4 increased bilirubin (8%).

Among other grade 3/4 toxicities, investigators observed leukopenia in 1 (4%) patient, neutropenia in 4 (17%), anemia in 2 (8%) and thrombocytopenia in 2 patients (8%). Investigators also recorded 1 (4%) case of grade 4 hypercalcemia.

_References:

_{1. Chan SL, Chotipanich C, Choo SP, et al. Selective internal radiation therapy with Yttrium-90 resin microspheres followed by gemcitabine plus cisplatin for treatment of intra-hepatic cholangiocarcinoma: a phase 2 single-arm multicenter clinical trial. Presented at: 2021 International Liver Cancer Association Conference; September 2-5, 2021; virtual Abstract P-42.}

_{2. Edeline J, Touchefeu Y, Guiu B, et al. Radioembolization plus chemotherapy for first-line treatment of locally advanced intrahepatic cholangiocarcinoma: a phase 2 clinical trial. JAMA Oncol. 2020;6(1):51-59. doi:10.1001/jamaoncol.2019.3702}

_{3. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362(14):1273-1281. doi:10.1056/NEJMoa0908721}