In the Journals

New treatment approaches induce responses in unresectable intrahepatic cholangiocarcinoma

Chemotherapy combined with hepatic arterial infusion of floxuridine or with selective internal radiotherapy induced antitumor activity among patients with unresectable intrahepatic cholangiocarcinoma, according to results of separate phase 2 studies published in JAMA Oncology.

Both regimens appeared safe. Additionally, a high proportion of patients who underwent selective internal radiotherapy and chemotherapy as first-line treatment were downstaged to surgical intervention, with favorable outcomes.

“Intrahepatic cholangiocarcinoma is an uncommon disease in the United States and has a poor prognosis,” William Jarnagin, MD, chief of the hepatopancreatobiliary service and Leslie Blumgart chair in surgery at Memorial Sloan Kettering Cancer Center, told HemOnc Today. “It has not [historically] received the attention of investigators or drug companies because they won’t recover their investments on drug production. It’s now getting more attention because it is becoming more common in the Western Hemisphere, probably due to fatty liver disease, which is an epidemic and a major risk factor for intrahepatic cholangiocarcinoma.”

The standard treatment for intrahepatic cholangiocarcinoma (ICC) is resection, but risk for recurrence remains high. Also, many patients present with unresectable advanced disease, Jarnagin said. These patients generally receive doublet gemcitabine and cisplatin chemotherapy, but response rates are low.

Hepatic arterial infusion

Jarnagin and colleagues evaluated hepatic arterial infusion of floxuridine, a precursor of fluorouracil, for the treatment of ICC in two previous trials. The first involved patients with no disease outside the liver, among whom the pump chemotherapy alone showed promise. Researchers halted a subsequent trial combining the liver-directed therapy with bevacizumab (Avastin, Genentech) because of toxicity.

In the current single-arm, phase 2 study, Jarnagin and colleagues evaluated hepatic arterial infusion of floxuridine with the addition of systemic gemcitabine and oxaliplatin among 38 patients (median age at diagnosis, 64 years; range, 39-81; 34% men) with unresectable ICC.

PFS of 80% at 6 months served as the primary endpoint.

Median follow-up was 30.5 months.

Results showed 22 patients (58%) achieved partial radiographic response and 32 (84%) demonstrated disease control by 6 months. Four patients responded sufficiently enough to undergo resection. One patient had a complete pathologic response.

Median PFS was 11.8 months (one-sided 90% CI, 11.1), with a 6-month PFS rate of 84.1% (90% CI, 74.8-infinity).

Median OS was 25 months (95% CI, 20.6-not reached), with a 1-year OS rate of 89.5% (95% CI, 80.2-99.8).

Researchers observed no significant difference in 24-month OS between patients with lymph node-positive disease (n = 18; 50%; 95% CI, 30-83) and those with lymph node-negative disease (n = 16; 60%; 95% CI, 40-91).

Four patients (11%) withdrew from the study because of grade 4 adverse events. These events included portal hypertension (n = 1), gastroduodenal artery aneurysms (n = 2) and infection in the pump pocket (n = 1).

A subgroup analysis showed significant 2-year OS improvement among patients with IDH1/2-mutated vs. wild-type tumors (90% vs. 33%; P = .01).

Ninety percent of patients (n = 9) in a confirmatory cohort achieved disease control by 6 months, with median PFS of 12.8 months (one-sided; 90% CI, 6.4).

“I believe we will continue to see positive results,” Jarnagin told HemOnc Today. “We have a phase 3 trial in the advanced planning stages that will test systemic chemotherapy alone vs. systemic and pump chemotherapy. We’ve applied for NCI funding and are in a position to get this done. We hope to open it sometime in the spring.”

Selective internal radiotherapy

In a separate single-arm, phase 2 trial, Julien Edeline, MD, PhD, clinical oncologist at Centre Eugène Marquis in France, and colleagues evaluated the safety and effectiveness of selective internal radiotherapy combined with chemotherapy for 41 patients (mean age, 64 years; standard deviation, 10.7 years; 63% men) with unresectable ICC.

Chemotherapy consisted of concomitant first-line cisplatin, dosed at 25 mg/m2, and gemcitabine — dosed at 1000 mg/m2 but reduced to 300 mg/m2 in cycles just before and after selective internal radiotherapy — on days 1 and 8 of eight 21-day cycles.

Patients received selective internal radiotherapy, administered using glass yttrium-90 microspheres, during the first cycle if they had one hemiliver disease or during the first and third cycles if they had disease involving both hemilivers.

Response rate at 3 months according to RECIST 1.1 served as the primary endpoint. Secondary endpoints included toxicity, PFS, OS, disease control rate and response rate based on Choi criteria.

Median follow-up was 36 months (95% CI, 26-52).

Researchers reported a response rate of 39% (95% CI, 26-53) at 3 months and a disease control rate of 98% (95% CI, 89-99). Central review confirmed the results, with a best response rate of 41% (95% CI, 28-55) and a response rate according to Choi criteria of 93% (95% CI, 82-98).

Median PFS was 14 months (95% CI, 8-17). Researchers observed PFS rates of 55% at 12 months and 30% at 24 months.

Median OS was 22 months (95% CI, 14-52), with OS rates of 75% at 12 months and 45% at 24 months.

Twenty-nine patients (71%) experienced grade 3 or grade 4 toxicities, including neutropenia, thrombocytopenia, anemia and asthenia. Eight of nine patients downstaged to surgical intervention achieved microscopic-free margins after resection.

Median RFS among patients who underwent resection could not be determined after median follow-up of 46 months (range, 31-not reached).

“The responses seem similar between both studies, but it’s always risky to compare two studies because patients might have different baseline characteristics,” Edeline told HemOnc Today.
selective internal radiotherapy, we were able to downstage more patients to resection, but again this is difficult to compare. Taken together, both studies showed encouraging results for locoregional treatment of ICC, and phase 3 [studies] should be conducted.”

Optimism with caution

The results of each of the studies reflect momentum in treating unresectable ICC, Aaron J. Scott, MD, clinical oncologist in the division of hematology and oncology at University of Arizona Cancer Center, and Rachna T. Shroff, MD, associate professor of medicine, director of the clinical trials office and chief of the section of GI medical oncology at University of Arizona Cancer Center, wrote in a related editorial.

The promising results, however, should be considered with caution until they are confirmed in larger cohorts, they noted.

“As the efforts from those such as [the researchers and colleagues] shed more light on methods for locoregional treatment in patients with unresectable disease, the ability to integrate clinical and prognostic factors, biomarker data, chemotherapy, locoregional treatment and surgical management is paramount to the ongoing improvement in care for patients with ICC,” Scott and Shroff wrote. “Priority should be placed on enrolling patients with unresectable ICC into clinical trials to better understand the true benefit of locoregional therapy in these patients.” – by John DeRosier

For more information:

Julien Edeline, MD, PhD , can be reached at Centre Eugène Marquis, Rue de la Bataille, Flandres Dunkerque, CS 44229, 35042 Rennes Cedex; email: j.edeline@rennes.unicancer.fr.

William Jarnagin, MD, can be reached at Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065; email: jarnagiw@mskcc.org.

Disclosures: Edeline reports consultant roles with and research funding from BTG International, as well as personal fees from AstraZeneca, Bristol-Myers Squibb, Eisai, Ipsen and Merck Sharp & Dohme. Jarnagin reports no relevant financial disclosures. Please see the studies for all other researchers’ relevant financial disclosures. Scott reports personal fees and research funding from Exelixis Pharmaceuticals, FivePrime Therapeutics and Incyte; an advisory role with Genentech; and research funding from Merck. Shroff reports research grants and personal fees from and/or advisory roles with from Exelixis Pharmaceuticals, Merck, QED Therapeutics and Seattle Genetics, and personal fees from Agios and Seattle Genetics.

Chemotherapy combined with hepatic arterial infusion of floxuridine or with selective internal radiotherapy induced antitumor activity among patients with unresectable intrahepatic cholangiocarcinoma, according to results of separate phase 2 studies published in JAMA Oncology.

Both regimens appeared safe. Additionally, a high proportion of patients who underwent selective internal radiotherapy and chemotherapy as first-line treatment were downstaged to surgical intervention, with favorable outcomes.

“Intrahepatic cholangiocarcinoma is an uncommon disease in the United States and has a poor prognosis,” William Jarnagin, MD, chief of the hepatopancreatobiliary service and Leslie Blumgart chair in surgery at Memorial Sloan Kettering Cancer Center, told HemOnc Today. “It has not [historically] received the attention of investigators or drug companies because they won’t recover their investments on drug production. It’s now getting more attention because it is becoming more common in the Western Hemisphere, probably due to fatty liver disease, which is an epidemic and a major risk factor for intrahepatic cholangiocarcinoma.”

The standard treatment for intrahepatic cholangiocarcinoma (ICC) is resection, but risk for recurrence remains high. Also, many patients present with unresectable advanced disease, Jarnagin said. These patients generally receive doublet gemcitabine and cisplatin chemotherapy, but response rates are low.

Hepatic arterial infusion

Jarnagin and colleagues evaluated hepatic arterial infusion of floxuridine, a precursor of fluorouracil, for the treatment of ICC in two previous trials. The first involved patients with no disease outside the liver, among whom the pump chemotherapy alone showed promise. Researchers halted a subsequent trial combining the liver-directed therapy with bevacizumab (Avastin, Genentech) because of toxicity.

In the current single-arm, phase 2 study, Jarnagin and colleagues evaluated hepatic arterial infusion of floxuridine with the addition of systemic gemcitabine and oxaliplatin among 38 patients (median age at diagnosis, 64 years; range, 39-81; 34% men) with unresectable ICC.

PFS of 80% at 6 months served as the primary endpoint.

Median follow-up was 30.5 months.

Results showed 22 patients (58%) achieved partial radiographic response and 32 (84%) demonstrated disease control by 6 months. Four patients responded sufficiently enough to undergo resection. One patient had a complete pathologic response.

Median PFS was 11.8 months (one-sided 90% CI, 11.1), with a 6-month PFS rate of 84.1% (90% CI, 74.8-infinity).

Median OS was 25 months (95% CI, 20.6-not reached), with a 1-year OS rate of 89.5% (95% CI, 80.2-99.8).

Researchers observed no significant difference in 24-month OS between patients with lymph node-positive disease (n = 18; 50%; 95% CI, 30-83) and those with lymph node-negative disease (n = 16; 60%; 95% CI, 40-91).

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Four patients (11%) withdrew from the study because of grade 4 adverse events. These events included portal hypertension (n = 1), gastroduodenal artery aneurysms (n = 2) and infection in the pump pocket (n = 1).

A subgroup analysis showed significant 2-year OS improvement among patients with IDH1/2-mutated vs. wild-type tumors (90% vs. 33%; P = .01).

Ninety percent of patients (n = 9) in a confirmatory cohort achieved disease control by 6 months, with median PFS of 12.8 months (one-sided; 90% CI, 6.4).

“I believe we will continue to see positive results,” Jarnagin told HemOnc Today. “We have a phase 3 trial in the advanced planning stages that will test systemic chemotherapy alone vs. systemic and pump chemotherapy. We’ve applied for NCI funding and are in a position to get this done. We hope to open it sometime in the spring.”

Selective internal radiotherapy

In a separate single-arm, phase 2 trial, Julien Edeline, MD, PhD, clinical oncologist at Centre Eugène Marquis in France, and colleagues evaluated the safety and effectiveness of selective internal radiotherapy combined with chemotherapy for 41 patients (mean age, 64 years; standard deviation, 10.7 years; 63% men) with unresectable ICC.

Chemotherapy consisted of concomitant first-line cisplatin, dosed at 25 mg/m2, and gemcitabine — dosed at 1000 mg/m2 but reduced to 300 mg/m2 in cycles just before and after selective internal radiotherapy — on days 1 and 8 of eight 21-day cycles.

Patients received selective internal radiotherapy, administered using glass yttrium-90 microspheres, during the first cycle if they had one hemiliver disease or during the first and third cycles if they had disease involving both hemilivers.

Response rate at 3 months according to RECIST 1.1 served as the primary endpoint. Secondary endpoints included toxicity, PFS, OS, disease control rate and response rate based on Choi criteria.

Median follow-up was 36 months (95% CI, 26-52).

Researchers reported a response rate of 39% (95% CI, 26-53) at 3 months and a disease control rate of 98% (95% CI, 89-99). Central review confirmed the results, with a best response rate of 41% (95% CI, 28-55) and a response rate according to Choi criteria of 93% (95% CI, 82-98).

Median PFS was 14 months (95% CI, 8-17). Researchers observed PFS rates of 55% at 12 months and 30% at 24 months.

Median OS was 22 months (95% CI, 14-52), with OS rates of 75% at 12 months and 45% at 24 months.

PAGE BREAK

Twenty-nine patients (71%) experienced grade 3 or grade 4 toxicities, including neutropenia, thrombocytopenia, anemia and asthenia. Eight of nine patients downstaged to surgical intervention achieved microscopic-free margins after resection.

Median RFS among patients who underwent resection could not be determined after median follow-up of 46 months (range, 31-not reached).

“The responses seem similar between both studies, but it’s always risky to compare two studies because patients might have different baseline characteristics,” Edeline told HemOnc Today.
selective internal radiotherapy, we were able to downstage more patients to resection, but again this is difficult to compare. Taken together, both studies showed encouraging results for locoregional treatment of ICC, and phase 3 [studies] should be conducted.”

Optimism with caution

The results of each of the studies reflect momentum in treating unresectable ICC, Aaron J. Scott, MD, clinical oncologist in the division of hematology and oncology at University of Arizona Cancer Center, and Rachna T. Shroff, MD, associate professor of medicine, director of the clinical trials office and chief of the section of GI medical oncology at University of Arizona Cancer Center, wrote in a related editorial.

The promising results, however, should be considered with caution until they are confirmed in larger cohorts, they noted.

“As the efforts from those such as [the researchers and colleagues] shed more light on methods for locoregional treatment in patients with unresectable disease, the ability to integrate clinical and prognostic factors, biomarker data, chemotherapy, locoregional treatment and surgical management is paramount to the ongoing improvement in care for patients with ICC,” Scott and Shroff wrote. “Priority should be placed on enrolling patients with unresectable ICC into clinical trials to better understand the true benefit of locoregional therapy in these patients.” – by John DeRosier

For more information:

Julien Edeline, MD, PhD , can be reached at Centre Eugène Marquis, Rue de la Bataille, Flandres Dunkerque, CS 44229, 35042 Rennes Cedex; email: j.edeline@rennes.unicancer.fr.

William Jarnagin, MD, can be reached at Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065; email: jarnagiw@mskcc.org.

Disclosures: Edeline reports consultant roles with and research funding from BTG International, as well as personal fees from AstraZeneca, Bristol-Myers Squibb, Eisai, Ipsen and Merck Sharp & Dohme. Jarnagin reports no relevant financial disclosures. Please see the studies for all other researchers’ relevant financial disclosures. Scott reports personal fees and research funding from Exelixis Pharmaceuticals, FivePrime Therapeutics and Incyte; an advisory role with Genentech; and research funding from Merck. Shroff reports research grants and personal fees from and/or advisory roles with from Exelixis Pharmaceuticals, Merck, QED Therapeutics and Seattle Genetics, and personal fees from Agios and Seattle Genetics.