Sometimes – in most cases – it’s just a stomach ache or general malaise that causes nausea, abdominal pain and weight loss. Symptoms that we can all really experience without giving too much weight. And it is precisely the generic nature of these symptoms that makes cholangiocarcinoma so insidious and difficult to diagnose. In fact, 70% of patients present at diagnosis with a disease already in an advanced stage, with few options for treatment. To raise the level of attention and knowledge of this neoplasm a little, World Cholangiocarcinoma Day is celebrated tomorrow, the World Day to inform about symptoms, risk factors and opportunities for treatment of cholangiocarcinoma.
A growing tumor
Unfortunately, even if still little known, the disease is constantly growing. As emerged during a virtual press conference, supported by Incyt, and dedicated to the topic, new cases in Italy have increased by 14% in 5 years. “Cholangiocarcinoma is a type of primary liver cancer that originates from cholangiocytes, the cells that line the bile ducts, responsible for transporting bile from the liver to the intestine,” he says. Filippo de Braud, professor of Medical Oncology at the University of Milan and director of the Department and Division of Medical Oncology of the Irccs National Cancer Institute Foundation of Milan. “It is distinguished on the basis of the site of onset in intrahepatic, if it develops within the liver, and extrahepatic, if it arises from the extrahepatic biliary tract”.
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The risk factors
What makes a person more susceptible to developing this type of cancer? “Gallstones and primary sclerosing cholangitis, a severe chronic inflammatory disease of the liver, are powerful risk factors for intrahepatic forms,” replies de Braud. “In addition, obesity, cigarette smoking, chronic inflammatory bowel diseases, excessive alcohol consumption and exposure to carcinogenic chemicals, toxins and various environmental agents (dioxins, nitrosamines, radon and asbestos) increase the risk of developing cancer “.
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The difficulty of making early diagnoses
Precisely due to the generic nature of the symptoms and the fact that the disease is usually asymptomatic for a long time. “There are no screening tests or routine diagnostic tests that can identify it at an early stage, when surgical removal is still possible”, clarifies Nicola Silvestris, member of the national board of Aiom (Italian Association of Medical Oncology) and associate professor of Medical Oncology at the IRCCS Istituto Tumori ‘Giovanni Paolo II’ in Bari. More defined symptoms appear if the neoplasm is advanced. “In intrahepatic cholangiocarcinoma – continues Silvestris – non-specific disorders can be felt, such as abdominal pain, weight loss, nausea, malaise: for this reason, the diagnosis is accidental in 20-25% of cases”. In the extrahepatic form, 90% of patients present to the specialist with jaundice (yellow color of the skin and sclerae, due to the accumulation of bile in the blood) with dark urine, whitish stools and itching (due to increased levels of salts in the blood) without pain, and symptoms referable to cholangitis, such as pain and fever, are observed only in 10% of cases.
Raise awareness among family doctors
Raising awareness of this type of tumor and its risk factors is certainly the first step to improve the situation and the Cholangiocarcinoma Patients Association, founded in 2019, is also working in this direction precisely to help patients access correct information and to promote research on this little-known tumor. “The path leading to diagnosis is very complex for extrahepatic cholangiocarcinomas, but it is often late also for intrahepatic cholangiocarcinomas, where the diagnostic path would be easier if the signs / symptoms of suspicion were detected early”, he notes Giovanni Brandi, director of the Specialization School of Medical Oncology at the University of Bologna, founder of the Italian Cholangiocarcinoma Patients Association (APiC) and of the Italian Cholangiocarcinoma Group (GICO). “For this reason, even family doctors must be sensitized, so that they are able to detect the first suspicious symptoms. Sometimes a simple laboratory alteration, such as an increase in alkaline phosphatase, is enough to induce suspicion to be investigated. In addition, it is essential that patients are referred early to referral centers where complete care is possible by a dedicated multidisciplinary team, consisting of the medical oncologist, the hepatobiliary surgeon, the diagnostic radiologist and interventionist, hepatologist, endoscopist and radiotherapist, able to better define the diagnostic and therapeutic path “.
The role of asbestos
But why, despite not detecting any known risk factor in more than half of cholangiocarcinoma cases, in Western countries and, therefore, also in Italy, the diagnoses of the intrahepatic form continue to increase? “Clinical studies – replies Brandi – have focused on widespread environmental factors, identifying in the previous exposure to asbestos a potential responsible for the surge in cases of intrahepatic cholangiocarcinomas, which can only be explained by the descent into the field of a risk factor of environmental nature. This mineral is a well-defined risk factor for malignancies such as mesothelioma and cancers of the lung, ovary and larynx. To date, epidemiological, genomic and pathological data are accumulating which indicate the role of asbestos as an additional risk factor for the development of intrahepatic cholangiocarcinomas ”. Indeed, some retrospective and prospective case-control studies (the latter being published in 2022) suggest that the risk of developing intrahepatic cholangiocarcinomas increases at least 5 times in the exposed. All this has already led to definitive sentences by Italian courts that have accepted the correlation between asbestos and the development of intrahepatic cholangiocarcinomas.
Surgery and chemotherapy to cure
About 12,700 people live in Italy after the diagnosis of cholangiocarcinoma. How is this type of cancer treated? “Only 25% of patients are candidates for surgery, but the operation, if performed in the early stage of the disease, can have a resolutive outcome,” says Silvestris. In many cases, precautionary chemotherapy is indicated after surgery. Nonetheless, even after radical and potentially curative surgical resection, recurrence occurs in 60% of cases within two years. In patients who cannot be operated on or in whom the disease has come back, the first choice treatment is chemotherapy, which can help control the evolution of the tumor, albeit with limited efficacy. In fact, most patients at some point no longer respond to first-line chemotherapy ”.
Molecularly targeted drugs
Currently, 5-year survival is 17% in men and 15% in women. “This is why new weapons are needed – underlines de Braud. “In recent years, much attention has been paid to the molecular characterization of the disease through gene sequencing techniques, which have made it possible to identify alterations targeted by specific drugs. And there are numerous studies aimed at understanding the role of targeted therapies in advanced or metastatic cholangiocarcinoma, in particular in tumors with intrahepatic genesis. Overall, about half of cholangiocarcinomas have one or more mutations potentially treatable with molecularly targeted drugs “. In particular, translocations of FGFR2 (fibroblast growth factor receptor 2) are present in approximately 7% of intrahepatic cholangiocarcinomas in Europe.
A new targeted therapy
This includes the new targeted therapy pemigatinib which in the multicentre phase II clinical trial FIGHT-202 demonstrated an overall response rate of 37% and a median duration of response in patients with FGFR2 fusions or rearrangements. 8 months. “Pemigatinib – continues de Braud – has a higher activity than that of other molecules used in second or subsequent lines of treatment. The results are important and, in a small percentage of patients, complete responses were even observed, so the disease disappeared ”. Based on the results of the FIGHT-202 study, last year the European Commission approved pemigatinib in locally advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements and with disease progression after at least one previous line of systemic therapy.
“Pemigatinib is the first target therapy approved in Europe for this indication and its approval by the European Commission – concludes Onofrio Mastandrea, Executive Director, General Manager, Incyte Biosciences Italia – it is an important result for the entire scientific community, but above all for patients, considering the important unmet therapeutic need linked to cholangiocarcinoma “.