Cholangiocarcinoma (CC) is an uncommon cancer emerging from the epithelial cells of the extrahepatic, perihelia, intrahepatic bile ducts. Histopathologically, around 95% of these cases are adenocarcinomas.
Cholangiocarcinomas have a high mortality rate because most cases are diagnosed at a locally advanced stage. Intrahepatic, perihilar, and distal cholangiocarcinomas make up 10%, 40%, and 50% of cases respectively.
Epidemiology
Cholangiocarcinomas costitute roughly 3% of all gastrointestinal malignancies, and are the second most prevalent primary liver tumors, and account for 10-15% of all hepatobiliary cancers.
In recent years, patients diagnosed with intrahepatic lesions have increased while the frequency of patients with extrahepatic lesions has decreased. As with most malignancies, older individuals are more susceptible.
Men between ages 50-70 are more likely to develop choloangiocarcinoma, and men are also more susceptible to these lesions than women are. This can be attributed to men having a higher incidence of primary sclerosing cholangitis than women.
Anatomy
Pathophysiology
Cholangiocarcinoma, like many other cancers, develops from precursor lesions such as biliary intraepithelial neoplasia and intraductal papillary mucinous neoplasia. Mutations in a range of oncogenes and tumor suppressor genes causes normal epithelium to transform into one of these premalignant lesions.
Gene mutations in genes including RAS, p52, SMAD4, BRAF and others are harbored by choloangiocarcinomas. The specific molecular pathway responsible for this process has not been found.
Etiology
Numerous cases of cholangiocarcinoma are idiopathic and lack a clear risk factor, but a variety of risk factors have been found, including primary hepatobiliary illness, genetic diseases, toxic exposures, and infections.
Primary hepatobiliary disorders include chronic liver disease, primary sclerosing cholangitis, fibropolycystic liver disease, and cholelithiasis/cholecystitis. Primary Sclerosing cholangitis seems to be the greatest risk factor for developing choloangiocarcinomas, as they are responsible for almost 30% of cases.
Some other conditions which are associated with or potentially increase for developing choloangiocarcinomas are:
HIV
Helicobacter pylori
Diabetes mellitus
Liver flukes
Obesity
Metabolic syndrome
Genetic illnesses such as Cystic fibrosis, papillomatosis, BAP1 tumor predisposition syndrome
Genetics
Prognostic Factors
According to the SEER database, the combined 5-year survival rate for extrahepatic choloangiocarcinomas is just slightly higher than for intrahepatic carcinomas. Most cases of choloangiocarcinomas are fatal because this condition is generally diagnosed at a local advanced stage.
In both cases, cancer with distant spread has a mere 2% 5-year survival rate. Localized intrahepatic choloangiocarcinomas have a 24% 5-year survival rate, whereas patients with localized extrahepatic choloangiocarcinomas have a 17% 5-year survival rate.
For extrahepatic cancers, regional spread into lymph nodes or nearby structures does not change the survival rate much, but in intrahepatic cancers the 5-year survival rate drops down to 9% in case of regional spread.
Surgery is the primary treatment for all subtypes, but it’s only viable if further damage will not be caused by damaging lymph nodes and vascular structures around the cancer site. Cholangiocarcinoma patients require personalized treatment.
Indicated for Cholangiocarcinoma
21 days each cycle; 13.5 mg orally every day for 14 days after that, 7 days off therapy
It should be continued until the disease progression or the occurrence of unacceptable toxicity
It is indicated for metastatic/locally advanced cholangiocarcinoma in prior treated patients with FGFR2 rearrangement
Myeloid or Lymphoid Neoplasms
13.5 mg orally every day
It should be continued until the disease progression or the occurrence of unacceptable toxicity
It is indicated for refractory or relapsed lymphoid/myeloid neoplasms in adults with FGFR1
Dose titration for adverse reactions
Cholangiocarcinoma
1st dose diminishment: 9 mg every day for 1st 14 days of the 21-day cycle
2nd dose diminishment: 4.5 mg every day for 1st 14 days of the 21-day cycle
Permanently discontinue for patients who are unable to tolerate the 4.5 mg every day
MLNs
1st dose diminishment: 9 mg every day
2nd dose diminishment: 4.5 mg every
3rd dose diminishment: 4.5 mg every day for 1st 14 days of the 21-day cycle
Permanently discontinue for patients who are unable to tolerate the 4.5 mg every day for 1st 14 days of the 21-day cycle
Hyperphosphatemia
Serum phosphate levels (7-10 mg/dl): After starting phosphate-decreasing therapy within two weeks, withhold if the phosphate levels are >7 mg/dl
Resume when phosphate levels are <7 mg/dl
Serum phosphate levels (>10 mg/dl): After starting phosphate-decreasing therapy within one week, withhold if the phosphate levels are >10 mg/dl
Resume when phosphate levels are <7 mg/dl
If the phosphate levels are >10 mg/dl, even after two doses of diminishment, permanently discontinue
Retinal pigment epithelial detachment
Continue the treatment if asymptomatic, stable on examination
Symptomatic/worsening on examination, withhold; after examination, if the improvement is seen, resume at the lower dose
Permanently discontinue, if symptoms still persist
Coadministration with the CYP3A inhibitors
Generally, avoid coadministration
If needed, use at a reduced dose ( 13.5mg reduced to 9 mg, 9 mg reduced to 4.5 mg)
If a strong/moderate condition CYP3A inhibitor is stopped, enhance the pemigatinib dose to the dose, which is taken before starting inhibitor
20 mg orally daily
Continue till unacceptable toxicity or disease progression occurs
Dose Adjustments
Dosage Modifications
reductions of dose due to adverse effects
reduction of First dosage: 16 mg daily
reduction of Second dosage: 12 mg daily
12 mg/day not tolerated: discontinue permanently
Detachment of the Retinal pigment epithelium (RPED)
Continue at the current dosage and periodic ophthalmic testing
Continue at the current dosage if RPED resolves in less than 14 days.
Resuming at the prior or lower dose, once resolved; delay if f the condition does not resolve in less than 14 days Hyperphosphatemia
Above 5.5 to below 7 mg/dL of Serum phosphate: Continue the existing dosage while beginning phosphate-lowering medication; monitor serum phosphate on a weekly basis.
Serum phosphate Above 7 to below 10 mg/dL
start or adjust the phosphate-lowering treatment; monitor the serum phosphate on a weekly basis
Reduce dosage to the next level
Continue at this lowered dose if the serum phosphate is below 7 mg/dL within two weeks of the dose reduction.
Reduce the dose even more to the next reduced level if the serum phosphate level is more than 7 mg/dL within two weeks.
If the serum phosphate is greater than 7 mg/dL within two weeks of the second dosage reduction, delay till serum phosphate is less than 7 mg/dL and then restart the prescribed dose.
serum phosphate above 10 mg/dL
Start or modify phosphate-reducing treatment and monitor the serum phosphate on weekly basis.
Restart at the next lower dose once the phosphate level is below 7 mg/dL.
If the serum phosphate is above 7 mg/dL in two weeks after 2 dosage interruptions and reductions, discontinue permanently.
Other adverse effects
Grade 3: delay till toxicity gets resolves to Grade 1 or to baseline
Before suspending, resume the hematologic toxicities that resolves less than a week.
resume for more adverse effects at the next reduced dosage
Grade 4: Discontinue permanently Renal impairment
Mild and moderate (CrCl 30 to 89 mL/min): dosage adjustment is not necessary
Severe (CrCl 15 to 29 mL/min), renal dialysis in ESRD (CrCl below 15 mL/min): Not known Hepatic impairment
Mild: dosage adjustment is not necessary
Moderate to severe: Not known
Cholangiocarcinoma (CC) is an uncommon cancer emerging from the epithelial cells of the extrahepatic, perihelia, intrahepatic bile ducts. Histopathologically, around 95% of these cases are adenocarcinomas.
Cholangiocarcinomas have a high mortality rate because most cases are diagnosed at a locally advanced stage. Intrahepatic, perihilar, and distal cholangiocarcinomas make up 10%, 40%, and 50% of cases respectively.
Cholangiocarcinomas costitute roughly 3% of all gastrointestinal malignancies, and are the second most prevalent primary liver tumors, and account for 10-15% of all hepatobiliary cancers.
In recent years, patients diagnosed with intrahepatic lesions have increased while the frequency of patients with extrahepatic lesions has decreased. As with most malignancies, older individuals are more susceptible.
Men between ages 50-70 are more likely to develop choloangiocarcinoma, and men are also more susceptible to these lesions than women are. This can be attributed to men having a higher incidence of primary sclerosing cholangitis than women.
Cholangiocarcinoma, like many other cancers, develops from precursor lesions such as biliary intraepithelial neoplasia and intraductal papillary mucinous neoplasia. Mutations in a range of oncogenes and tumor suppressor genes causes normal epithelium to transform into one of these premalignant lesions.
Gene mutations in genes including RAS, p52, SMAD4, BRAF and others are harbored by choloangiocarcinomas. The specific molecular pathway responsible for this process has not been found.
Numerous cases of cholangiocarcinoma are idiopathic and lack a clear risk factor, but a variety of risk factors have been found, including primary hepatobiliary illness, genetic diseases, toxic exposures, and infections.
Primary hepatobiliary disorders include chronic liver disease, primary sclerosing cholangitis, fibropolycystic liver disease, and cholelithiasis/cholecystitis. Primary Sclerosing cholangitis seems to be the greatest risk factor for developing choloangiocarcinomas, as they are responsible for almost 30% of cases.
Some other conditions which are associated with or potentially increase for developing choloangiocarcinomas are:
HIV
Helicobacter pylori
Diabetes mellitus
Liver flukes
Obesity
Metabolic syndrome
Genetic illnesses such as Cystic fibrosis, papillomatosis, BAP1 tumor predisposition syndrome
According to the SEER database, the combined 5-year survival rate for extrahepatic choloangiocarcinomas is just slightly higher than for intrahepatic carcinomas. Most cases of choloangiocarcinomas are fatal because this condition is generally diagnosed at a local advanced stage.
In both cases, cancer with distant spread has a mere 2% 5-year survival rate. Localized intrahepatic choloangiocarcinomas have a 24% 5-year survival rate, whereas patients with localized extrahepatic choloangiocarcinomas have a 17% 5-year survival rate.
For extrahepatic cancers, regional spread into lymph nodes or nearby structures does not change the survival rate much, but in intrahepatic cancers the 5-year survival rate drops down to 9% in case of regional spread.
Surgery is the primary treatment for all subtypes, but it’s only viable if further damage will not be caused by damaging lymph nodes and vascular structures around the cancer site. Cholangiocarcinoma patients require personalized treatment.
Indicated for Cholangiocarcinoma
21 days each cycle; 13.5 mg orally every day for 14 days after that, 7 days off therapy
It should be continued until the disease progression or the occurrence of unacceptable toxicity
It is indicated for metastatic/locally advanced cholangiocarcinoma in prior treated patients with FGFR2 rearrangement
Myeloid or Lymphoid Neoplasms
13.5 mg orally every day
It should be continued until the disease progression or the occurrence of unacceptable toxicity
It is indicated for refractory or relapsed lymphoid/myeloid neoplasms in adults with FGFR1
Dose titration for adverse reactions
Cholangiocarcinoma
1st dose diminishment: 9 mg every day for 1st 14 days of the 21-day cycle
2nd dose diminishment: 4.5 mg every day for 1st 14 days of the 21-day cycle
Permanently discontinue for patients who are unable to tolerate the 4.5 mg every day
MLNs
1st dose diminishment: 9 mg every day
2nd dose diminishment: 4.5 mg every
3rd dose diminishment: 4.5 mg every day for 1st 14 days of the 21-day cycle
Permanently discontinue for patients who are unable to tolerate the 4.5 mg every day for 1st 14 days of the 21-day cycle
Hyperphosphatemia
Serum phosphate levels (7-10 mg/dl): After starting phosphate-decreasing therapy within two weeks, withhold if the phosphate levels are >7 mg/dl
Resume when phosphate levels are <7 mg/dl
Serum phosphate levels (>10 mg/dl): After starting phosphate-decreasing therapy within one week, withhold if the phosphate levels are >10 mg/dl
Resume when phosphate levels are <7 mg/dl
If the phosphate levels are >10 mg/dl, even after two doses of diminishment, permanently discontinue
Retinal pigment epithelial detachment
Continue the treatment if asymptomatic, stable on examination
Symptomatic/worsening on examination, withhold; after examination, if the improvement is seen, resume at the lower dose
Permanently discontinue, if symptoms still persist
Coadministration with the CYP3A inhibitors
Generally, avoid coadministration
If needed, use at a reduced dose ( 13.5mg reduced to 9 mg, 9 mg reduced to 4.5 mg)
If a strong/moderate condition CYP3A inhibitor is stopped, enhance the pemigatinib dose to the dose, which is taken before starting inhibitor
20 mg orally daily
Continue till unacceptable toxicity or disease progression occurs
Dose Adjustments
Dosage Modifications
reductions of dose due to adverse effects
reduction of First dosage: 16 mg daily
reduction of Second dosage: 12 mg daily
12 mg/day not tolerated: discontinue permanently
Detachment of the Retinal pigment epithelium (RPED)
Continue at the current dosage and periodic ophthalmic testing
Continue at the current dosage if RPED resolves in less than 14 days.
Resuming at the prior or lower dose, once resolved; delay if f the condition does not resolve in less than 14 days Hyperphosphatemia
Above 5.5 to below 7 mg/dL of Serum phosphate: Continue the existing dosage while beginning phosphate-lowering medication; monitor serum phosphate on a weekly basis.
Serum phosphate Above 7 to below 10 mg/dL
start or adjust the phosphate-lowering treatment; monitor the serum phosphate on a weekly basis
Reduce dosage to the next level
Continue at this lowered dose if the serum phosphate is below 7 mg/dL within two weeks of the dose reduction.
Reduce the dose even more to the next reduced level if the serum phosphate level is more than 7 mg/dL within two weeks.
If the serum phosphate is greater than 7 mg/dL within two weeks of the second dosage reduction, delay till serum phosphate is less than 7 mg/dL and then restart the prescribed dose.
serum phosphate above 10 mg/dL
Start or modify phosphate-reducing treatment and monitor the serum phosphate on weekly basis.
Restart at the next lower dose once the phosphate level is below 7 mg/dL.
If the serum phosphate is above 7 mg/dL in two weeks after 2 dosage interruptions and reductions, discontinue permanently.
Other adverse effects
Grade 3: delay till toxicity gets resolves to Grade 1 or to baseline
Before suspending, resume the hematologic toxicities that resolves less than a week.
resume for more adverse effects at the next reduced dosage
Grade 4: Discontinue permanently Renal impairment
Mild and moderate (CrCl 30 to 89 mL/min): dosage adjustment is not necessary
Severe (CrCl 15 to 29 mL/min), renal dialysis in ESRD (CrCl below 15 mL/min): Not known Hepatic impairment
Mild: dosage adjustment is not necessary
Moderate to severe: Not known
Cholangiocarcinoma (CC) is an uncommon cancer emerging from the epithelial cells of the extrahepatic, perihelia, intrahepatic bile ducts. Histopathologically, around 95% of these cases are adenocarcinomas.
Cholangiocarcinomas have a high mortality rate because most cases are diagnosed at a locally advanced stage. Intrahepatic, perihilar, and distal cholangiocarcinomas make up 10%, 40%, and 50% of cases respectively.
Cholangiocarcinomas costitute roughly 3% of all gastrointestinal malignancies, and are the second most prevalent primary liver tumors, and account for 10-15% of all hepatobiliary cancers.
In recent years, patients diagnosed with intrahepatic lesions have increased while the frequency of patients with extrahepatic lesions has decreased. As with most malignancies, older individuals are more susceptible.
Men between ages 50-70 are more likely to develop choloangiocarcinoma, and men are also more susceptible to these lesions than women are. This can be attributed to men having a higher incidence of primary sclerosing cholangitis than women.
Cholangiocarcinoma, like many other cancers, develops from precursor lesions such as biliary intraepithelial neoplasia and intraductal papillary mucinous neoplasia. Mutations in a range of oncogenes and tumor suppressor genes causes normal epithelium to transform into one of these premalignant lesions.
Gene mutations in genes including RAS, p52, SMAD4, BRAF and others are harbored by choloangiocarcinomas. The specific molecular pathway responsible for this process has not been found.
Numerous cases of cholangiocarcinoma are idiopathic and lack a clear risk factor, but a variety of risk factors have been found, including primary hepatobiliary illness, genetic diseases, toxic exposures, and infections.
Primary hepatobiliary disorders include chronic liver disease, primary sclerosing cholangitis, fibropolycystic liver disease, and cholelithiasis/cholecystitis. Primary Sclerosing cholangitis seems to be the greatest risk factor for developing choloangiocarcinomas, as they are responsible for almost 30% of cases.
Some other conditions which are associated with or potentially increase for developing choloangiocarcinomas are:
HIV
Helicobacter pylori
Diabetes mellitus
Liver flukes
Obesity
Metabolic syndrome
Genetic illnesses such as Cystic fibrosis, papillomatosis, BAP1 tumor predisposition syndrome
According to the SEER database, the combined 5-year survival rate for extrahepatic choloangiocarcinomas is just slightly higher than for intrahepatic carcinomas. Most cases of choloangiocarcinomas are fatal because this condition is generally diagnosed at a local advanced stage.
In both cases, cancer with distant spread has a mere 2% 5-year survival rate. Localized intrahepatic choloangiocarcinomas have a 24% 5-year survival rate, whereas patients with localized extrahepatic choloangiocarcinomas have a 17% 5-year survival rate.
For extrahepatic cancers, regional spread into lymph nodes or nearby structures does not change the survival rate much, but in intrahepatic cancers the 5-year survival rate drops down to 9% in case of regional spread.
Surgery is the primary treatment for all subtypes, but it’s only viable if further damage will not be caused by damaging lymph nodes and vascular structures around the cancer site. Cholangiocarcinoma patients require personalized treatment.
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