The progression of any kind of cancer often informs the type of therapeutics used to fight it. For example, cancers that progress rapidly require more aggressive treatment; cancers that have a slower disease progression usually require a more nuanced therapeutic approach.

As published in Liver International, Tovoli and colleagues conducted a study on the pattern of progression in one specific type of cancer—intrahepatic cholangiocarcinoma. This is important because we do not currently possess an accurate picture of the prognosis of intrahepatic cholangiocarcinoma.

The Implications of Disease Progression Patterns

In particular, post-progression survival (PPS) after the administration of frontline therapy for intrahepatic cholangiocarcinoma has been “scantly investigated,” according to Tovoli et al. 

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The implications of this are obvious: if we do not know how current therapies affect the prognosis of patients with intrahepatic cholangiocarcinoma, the oncological community is handicapped when it comes to determining the best course of treatment for its patients. To optimize treatment strategy, physicians need to understand the disease progression of intrahepatic cholangiocarcinoma, both with and without the administration of treatment.

Read more about cholangiocarcinoma etiology 

Tovoli and colleagues had access to a database of 332 patients with intrahepatic cholangiocarcinoma, 241 of whom had received first-line systemic therapy. A total of 206 patients were included in this study. The first-line therapies in use were gemcitabine combined with cisplatin, gemcitabine combined with oxaliplatin, and gemcitabine alone. The researchers performed a multivariable Cox analysis of the patients’ overall survival along with radiological assessments of disease progression. 

They hypothesized that the pattern of progression of intrahepatic cholangiocarcinoma can drive patients’ PPS, and the results of the study largely validated their hypothesis. Among the 206 patients under investigation, their median overall survival was 14.1 months. Independent predictors of overall survival included previous surgery, permanent first-line discontinuation, and disease progression. 

The most important findings of the study were: 

  • The pattern of disease progression independently predicted PPS in patients eligible for clinical trials. This is regardless of the enrollment criteria; even patients who had metastasis upon enrollment had different PPS according to their pattern of disease progression.
  • The radiological pattern of progression in cases of intrahepatic cholangiocarcinoma influences post-progression outcomes, including determining candidates suitable for second-line trials. 

The results also demonstrated that the appearance of new extrahepatic lesions independently predicted overall survival in patients who exhibited radiological progression. Disease progression due to the presence of new extrahepatic lesions was also found to be an independent predictor of PPS; other independent predictors included performance status, bilirubin >3 mg/dL, ascites, and time to progression to the frontline treatment. A total of 138 patients were eligible for second-line treatment, with the PPS for patients without new extrahepatic lesions being 16.8 months and the PPS for those with new extrahepatic lesions being 5.9 months. 

This study demonstrates that the disease progression of intrahepatic cholangiocarcinoma has a profound implication on the prognosis of these patients. 

Many Factors Influence Recurrence-Free Survival 

In JAMA Surgery, Mavros and colleagues conducted a systematic review and meta-analysis on the treatment and prognosis of patients diagnosed with intrahepatic cholangiocarcinoma. The team analyzed only studies that assessed predictors of survival or recurrence in patients undergoing curative-intent surgery. The final total of studies analyzed was 57, comprising 4756 patients. 

Among the factors that predicted a shorter recurrence-free interval in their study were: 

  • Younger age 
  • Larger tumor size 
  • Presence of multiple tumors 
  • Presence of satellite nodules 
  • Microvascular invasion 
  • Major vascular invasion 
  • Perineural invasion 
  • Positive surgical margin 
  • Lymph node metastases 
  • Poor tumor differentiation
  • History of a major hepatectomy 
  • Administration of multiple blood transfusions 
  • Receipt of preoperative chemotherapy.

Factors not associated with recurrence-free survival length included sex, presence of concurrent chronic hepatitis infection, cirrhosis, concomitant resection of extrahepatic bile ducts, and administration of postoperative chemotherapy.

Read more about cholangiocarcinoma treatment 

“The prognosis of [intrahepatic cholangiocarcinoma] remains grave, with less than one-third of the patients who undergo curative-intent surgical treatment surviving beyond 5 years after resection,” Mavros and colleagues wrote. ”Prognosis is dictated primarily by tumor factors, such as tumor size, lymph node invasion, and vascular invasion, which underlines the necessity for earlier diagnosis.”

Implications for Treatment Approach and Clinical Trials

The study conducted by Tovoli and colleagues demonstrated that disease progression has a major impact on the prognosis of patients with intrahepatic cholangiocarcinoma, while the study done by Mavros and colleagues showed that, should surgical resection be needed, the prognosis of patients with intrahepatic cholangiocarcinoma remains poor. 

The conclusion we can draw from these trials is that patients should be started on first-line therapies when indicated. There should be a close observation by both physician and patient on the progression of the disease, which can be tracked more accurately via radiological imaging. If second-line therapies are warranted, they should be prescribed. If surgical resection is indicated and carried out, patients should be made aware that the recurrence-free survival post-resection remains poor. 

Perhaps the biggest implication of these studies relates to how clinical researchers choose to structure their trials in the future. They should choose to design trials with experimental drugs with the goal of improving the prognosis seen with existing treatment options. Only then can we slowly but surely move away from the current treatment paradigm for intrahepatic cholangiocarcinoma into a more hopeful phase with better outcomes. 


Tovoli F, Garajová I, Gelsomino F, et al. Pattern of progression of intrahepatic cholangiocarcinoma: implications for second-line clinical trialsLiver Int. 2022;42(2):458-467. doi:10.1111/liv.15117

Mavros MN, Economopoulos KP, Alexiou VG, Pawlik TM. Treatment and prognosis for patients with intrahepatic cholangiocarcinoma: systematic review and meta-analysisJAMA Surg. 2014;149(6):565-574. doi:10.1001/jamasurg.2013.5137