Cholangiocarcinoma is a rare but constantly growing disease, and around 5400 new cases are estimated every year in Italy. It is not a single form of cancer, and often presents with vague symptoms, making it difficult to diagnose in time. In fact, 70 percent of diagnoses occur at an advanced stage, and the possibilities for treatment are very limited: to date, 5-year survival is only 17% in men and 15% in women. Now a new targeted therapy, available a few months ago in Italy, has proven to be effective in the treatment of cancers with particular genetic alterations, and allows to improve the chances of survival, guaranteeing a good quality of life during treatment.
The difficulties from diagnosis to treatment
The age of onset of the disease, in parallel with the increase in its incidence, is changing. Historically, most diagnoses concerned people 60 to 70 years of age, on average, while today it is falling. In patients with genetic tumor mutations, in particular, diagnoses often involve young people, 40 to 50 years of age. One of the complexities of cholangiocarcinoma, we said, is that it includes a spectrum of different tumors. In general, however, the scarcity of symptoms and their non-specificity do not allow to discover it in time and the diagnoses take place when the disease is no longer curable and it is not possible to intervene surgically.
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The two main types of cancer
Cholangiocarcinoma is a type of primary liver cancer that originates from cholangiocytes, the cells that line the bile ducts, the channels that carry bile from the liver to the intestine. It is distinguished, based on the site of onset, into intrahepatic, if it develops within the liver, and extrahepatic, if it arises from the extrahepatic biliary tract. The first, intrahepatic, is also the most difficult to diagnose. Inside the liver, in fact, there is no innervation, and until the tumor reaches the capsule that surrounds the organ – and is highly innervated – or grows to the point of compromising the functionality of the liver itself, it is difficult to experience alarming symptoms. or clear. On the other hand, some initial nonspecific symptoms such as abdominal pain, weight loss, digestive difficulties and nausea may occur. In the case of external cholangiocarcinoma, however, this often ends up occluding the biliary tract and causing jaundice, dark urine, whitish stools and itching (due to increased levels of bile salts in the blood).
Risk factors and red flags
The risk factors are also still poorly understood. In recent years, however, the occurrence in the Western world has been increasing, and doctors have noted a correlation with some diseases of the modern lifestyle, such as metabolic syndrome. “The disease certainly correlates with chronic non-alcoholic liver disease, which appears to be a risk factor for intrahepatic cholangiocarcinoma,” says Lorenza Rimassa, Associate Professor of Medical Oncology at Humanitas University, IRCCS Humanitas Research Hospital in Rozzano (Milan). “Risk factors include metabolic syndrome, obesity, fatty liver and cirrhosis, chronic liver disease, alcohol abuse and cigarette smoking. But, in most cases it is difficult to identify a specific cause, and there is still not enough knowledge to implement screening programs ”.
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When is it possible to have a suspicion? “If they persist, if the weight loss continues, and with it the difficulty in digesting, the abdominal pain – Rimassa suggests – it is certainly advisable to have a blood test and an abdominal ultrasound. If jaundice appears it is easier for the patient to notice that something is wrong, while as regards the appearance of intrahepatic forms with non-specific and vague symptoms, the role of the family doctor is very important “.
The role of surgery
All cancers that go by the name of cholangiocarcinomas are infrequent and usually have a poor prognosis. The treatment of first choice is chemotherapy, in some cases associated with immunotherapy, which is not resolutive but helps to control the evolution of the tumor, even if the disease recurs in most patients. But there is another possibility, much rarer and much more effective, that of surgery. “Surgery, if performed on the disease in its initial stage, can have a decisive outcome”, explains Alfredo Guglielmi, Full Professor of General and Hepatobiliary Surgery at the University of Verona. “Unfortunately, only 25% of patients are candidates for surgery, which is particularly difficult because it requires the use of advanced techniques, surgeons with specific training, multidisciplinary teams and highly specialized centers”. With the refinement of surgical techniques, these interventions have become increasingly safer and can guarantee good long-term results. “We proceed with liver resection for cholangiocarcinoma that grows inside the liver – continues the expert – and with pancreatic resection for the tumor that develops outside the liver or inside the head of the pancreas. Surgical treatment is aimed at the complete removal of the neoplasm. In many cases, precautionary chemotherapy is indicated after surgery ”.
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Patients who are candidates for surgery, explains Guglielmi, must be carefully selected. The tumor, in fact, must have net negative margins, that is, it must be able to be removed completely and, to its removal, the removal of the lymph nodes must also be associated to avoid metastases. These patients have a survival of up to five years, which is a very long period, considering that the average survival data is about one year. It is essential, however, to build a multidisciplinary team, consisting of a radiologist, endoscopist, gastroenterologist, oncologist and radiotherapist, in order to choose the most appropriate therapy for the patient and also to establish the treatment before and after surgery.
Genetic mutations
“About half of intrahepatic cholangiocarcinomas have one or more gene mutations, some of which can be treated with molecularly targeted drugs”, explains Giancarlo Pruneri, Professor of Pathological Anatomy at the University of Milan and Director of the Foundation’s Department of Pathology and Laboratory Medicine IRCCS National Cancer Institute of Milan. “The pathological analysis and tumor staging must always be accompanied by the search for mutations, to be performed through new gene sequencing techniques”. Today, in particular, starting from a small sample it is possible to simultaneously identify the mutations of hundreds of genes. The NGS (Next Generation Sequencing) test is one example: it is able to analyze over 300 gene mutations and can detect molecular alterations from minimal amounts of tissue. One of the most common mutations, present in 10 percent of intrahepatic cholangiocarcinomas, is that of the FGFR2 gene (fusion or rearrangement of the fibroblast growth factor receptor 2) (FGFR2). According to recent statistics, it occurs predominantly in young women.
The new drug
Before today, we said, all forms of cholangiocarcinoma were treated in the same way with chemotherapy and immunotherapy. However, in the presence of molecular genetic alterations, specific drugs may exist that directly target these alterations. This is the case with the new drug pemigatinib, an FGFR2 inhibitor. Last June Aifa approved the reimbursement of the new targeted therapy for the treatment of locally advanced or metastatic disease.
“This drug really seems to make a difference,” says Onofrio Mastandrea, Associate Vice President and General Manager of Incyte Biosciences Italia, the company that developed the drug. “With normal therapy, the median survival of patients is around one year. Pemigatinib has so far enabled a disease control rate of 82 percent, a median survival time of treated patients of 17.5 months and disease progression free time of seven months ”. The drug has also been shown to offer an important benefit in terms of tumor size reduction in 37% of patients. It is a much better tolerated treatment than chemotherapy, and the quality of life also improves a lot compared to traditional treatments, and remains stable for the duration of the treatment.