18F-Fluorocholine (FCH) is a radiopharmaceutical used in positron emission tomography (PET) imaging for the evaluation of various types of cancer, particularly prostate cancer. It is a synthetic choline analog labeled with the radioactive isotope fluorine-18, which allows it to be detected and visualized in the body using PET scanning technology.
Choline is an essential nutrient that is taken up by cells for the synthesis of cell membranes and other important cellular functions. Cancer cells, including prostate cancer cells, have an increased demand for choline due to their rapid growth and proliferation. FCH PET imaging works by targeting and visualizing the increased choline uptake in cancer cells, allowing for the detection and localization of cancerous lesions.
FCH PET imaging is commonly used in the diagnosis, staging, and monitoring of prostate cancer. It can help identify primary prostate tumors, detect metastatic disease, and assess treatment response. FCH PET scans provide important information about tumor location, extent, and metabolic activity, helping guide treatment decisions and improve patient outcomes.
Overall, FCH PET imaging is a valuable tool in the management of cancer patients, offering insights into tumor biology and disease progression. It is considered safe and well-tolerated, with minimal side effects reported in patients undergoing FCH PET scans. FCH PET imaging plays a crucial role in the personalized treatment of cancer patients, providing clinicians with important information to tailor treatment plans and optimize patient care.
Description
18F-Fluorocholine (Fluorine-18 labeled choline, FCH, 18F-FCH, 18F-Fcholine, 18F-fluoromethyl-dimethyl-2-hydroxyethyl-ammonium, 18F-Fluoromethylcholine, 18F-FCho) is a generic PET radiopharmaceutical developed at the end of the 1990s (first publication in the US, Duke University 2000).
This tracer should not be confused with 18F-Fluoroethyl-choline (FECH/FEC), another generic fluorinated choline equivalent that is available at some rare places and that differs by an additional carbon atom compared to 18F-Fluorocholine. In fact, the first data collected with choline were obtained using 11C-Choline (product discovered in Japan in 1997). The labeling with Carbon-11 does not affect the molecular structure while the 18F-Fluorocholine substitutes a fluorine atom to a hydrogen atom and 18F-Fluoroethylcholine adds an F-CH2 group to the original choline. In both fluorinated tracers, these molecules can behave slightly differently from the original choline or the 11C-Choline.
Clinical applications
Beside glucose, cells have a large need for phosphatidylcholine that is an important constituent of their membrane. In tumor cells, the rate of synthesis of this phosphatidylcholine through phosphorylation of choline by the enzyme choline kinase is much higher than in normal cell. The labeled choline analogue allows the visualization of the increased rate of choline transmembrane transport and subsequent transformation.
11C as well as 18F analogues (11C-Choline, 18F-Fluoroethylcholine FECH or 18F-Fluorocholine FCH) have shown their ability to concentrate specifically in a variety of tumor including prostate cancer, brain tumors, esophageal, hepatocellular carcinoma (HCC) and lung cancer.
18F-Fluorocholine is not indicated for prostate cancer diagnosis (lower sensitivity in the case of small tumors) but is useful in staging and restaging.
Next to the main application in metastasized prostate cancer, FCH could be useful in lobular breast cancer, glioblastoma, gastric cancer. It appears that labeled choline derivatives may serve as markers of the activity of signaling through a signal transduction pathway involving Ras and the mitogen-activated protein kinase pathway.
Average patient dose for 18F-Fluorocholine is 10 mCi.
Availability
International use of FCH is unprotected, except in the US where the inventor (at a certain time the company Lucera) holds the intellectual property for the manufacture of FCH. As the rights owners have not yet found a budget to run the required phase III trial before filing an NDA, this drug is still not available in the US. In the meantime, the company Lucera has disappeared from the landscape and the right for 18F-FCH in the US are back with the Duke University, Durham NC, USA. However, all patents covering the molecule must have expired.
In Europe, Iason (distributing 18F-FCH since 2004 for clinical purpose) obtained in April 2010 the market approval for imaging of prostate cancer bone metastases and staging of HCCs (IASOcholine®). The product is sold in the areas covered by Iason including under license (AAA in France under the brand name Fluorochol™ since 2016). The product is now also available from ACOM under the name of ColinPET and from MAP Medical (Curium since 2019) in the European Nordic countries. The company IBA Molecular (Curium) completed the application and obtained its MA in 2016 under the brand name Fluorocholine CIS bio international. Cyclopharma and Siemens Healthcare obtained a MA for France in 2017 respectively under the brand names ProstaTep™ and Fluorocholine (18F) Siemens Healthcare. In all other countries FCH is available in centers that have access to an in-house cyclotron and in the frame of a patient named protocol or a clinical trial.
Note that providers of prostate imaging agents based on choline are selling this tracer under the generic name ‘fluorocholine’, usually not specifying if it is based on methyl- or ethylcholine. This lack of detailed information adds confusion when trying to analyze the market, but as both tracers are addressing the same indications and have the same potential, this makes no difference at the level of the diagnostic.
FCH will remain expensive (EUR 500 to EUR 1000/dose – US$ 550 to US$ 1,100) and in the US it could be sold above US$ 1,500 (EUR 1,300). Sales potential of 18F-FCH is estimated at about EUR 5 million (US$ 5.5 million) in Europe and as much in the US. This potential could be multiplied by ten if the price would drop below EUR 600 (US$ 660), and as long as there is no other alternative for imaging prostate cancer. However, one should keep in mind that each new manufacturing center would require a supplementary investment of at least EUR 300,000 (US$ 330,000) before getting the authorization to distribute doses. Iason is selling its license to interested parties.
The equivalent Carbon-11 labeled analogue, 11C-Choline, is available in some radiopharmacies located next to an imaging center (e.g., Zevacor). In the US, 11C-Choline obtained a MA in September 2012 (Mayo Clinic).
Competition
Prostate cancer imaging is based on conventional imaging modalities such as transrectal ultrasound (TRUS), computed tomography (CT), high-resolution magnetic resonance imaging (HR-MRI), ultrasound Doppler alone or combined with micro-bubble contrast agent, three-dimensional stereotactic US (3D-US), higher-resolution 3T MRI, endorectal coils MRI, dynamic contrast enhanced MRI (DCE-MRI), diffusion weighted MRI (DW-MRI) and MR spectroscopy (MRS). Nuclear medicine imaging physicians have access to ProstaScint (expensive) or prostate specific membrane antigen (PSMA) imaging (under development). For advanced metastasized cancer, bone scans (99mTc or 18F-sodium fluoride) are used for detecting and staging the disease. PET with FDG is not really useful as prostate cancer is a slow progressing cancer. Recently the generic 68Ga-PSMA-11 became available at some specific places that invested in 68Ge/68Ga generator, but in absence of official MA this tracer with not be reimbursed.
The area of tracers under development for imaging of prostate cancer is more crowded. The list of products under clinical development includes 11C-Choline, 11C-Methionine, 18F- Fluoroacetate, 18F-Fluoroethylcholine, 61Cu and 64Cu-ATSM, 68Ga-Bombesin (BAY86-7548), 68Ga-PSMA-11, 89Zr-Df-IAB2M, 99mTc-Bombesin, 99mTc-MIP-1404, 123I-MIP-1072, and 177Lu-TLX591 (priority given to therapy for this latter).
This tracer will now mainly have to compete against 18F-Fluciclovine which obtained MA in the US in May 2016 under the brand name Axumin.
Comments
This is a typical example of a molecule that became generic because inventors did not have the budget to complete full clinical development. Moreover, the inventor kept the IP in the North America area, blocking even further the situation in these countries. As a consequence, the industry remained uninterested. As the development costs for a molecule are about the same if the molecule is targeting one country or the entire world, it is much less rewarding to work for the US area alone. Also, with the passing of time, even in the US, the patent will expire (apparently, completely around 2022), further reducing the potential exclusivity advantage. A phase III clinical trial is needed to complete the dossier of 18F-FCH in the US. Such a trial will take about two to three years to which at least one year will have to be added before approval. So, by starting this study in 2020, the tracer could not be on the market before 2024, and implementation at the largest sites will take at least two years leaving nothing for exclusivity.
In Europe the companies that filed the NDA for the generic formulation could rely on all clinical data that were published in the past 15 years. New clinical trials were required only for indications that were not well documented. However, as it is a generic, these data will become part of the generic database as soon as published and will not be required by subsequent competitors.
If this tracer comes on the market in a competitive environment (like FDG), while keeping its generic status (so for example without an orphan tracer status), it is estimated that the dose price would be higher than FDG but probably around EUR 500–700 (US$550-800) for a market that could be higher than EUR 15 million (US$ 17 million).
18F-Fluorocholine corresponds to a real medical need as FDG is not sufficient to address the specific prostate cancer imaging issue. Over the time this tracer will extend to other centers and become available, as a generic, like FDG. Opposite to most other tracers, the US will probably be the last country where this molecule will become available. In fact, some US centers (e.g., Mayo Clinic) have already identified this disadvantage and anticipated the long time before access to 18F-FCH by filing a dossier and obtaining approval for the locally produced 11C-Choline.
The recent introduction of 18F-Fluciclovine and 68Ga-PSMA molecule creates a serious competition in the field of prostate cancer imaging despite its generic status and will of course seriously dampen interest for 18F-Fluorocholine. Recent data have shown that both 68Ga-PSMA and 18F-Fluciclovine are shown to be more accurate in the detection of recurrent disease as compared with radiolabeled 11C/18F-choline PET/CT.
The chemistry of 18F-Fluorocholine is quite difficult. It is a fragile tracer and its production can be relatively unreliable, resulting in short-term cancellations (which happened in UK during the spring 2019). Next to the price, this will be probably the other reason why the interest of this tracer will considerably fade within the next years.