The Effect of [18F] F-FAPI PET-CT on Management in Patients With Proximal Cholangiocarcinoma

Rationale

Bile duct cancer (cholangiocarcinoma) represents the second most common type of hepatobiliary cancer worldwide with an incidence of 0.35 to 2 per 100.000 annually. Currently, surgical resection is the only curative option. However, patients are not eligible for surgery if vascular invasion, distant tumor positive lymph nodes, peritoneal metastases or organ metastases are found on preoperative imaging. For this group of patients, palliative chemotherapy is the most suited treatment option. The preoperative imaging currently includes CT, MRI and FDG PET-CT. In around 29 % of potentially resectable tumors (based on preoperative imaging) metastases are found during subsequent surgery. These explorations could be avoided by implementing a diagnostic tool with significantly higher accuracy than those currently used. Single center studies have shown that fibroblast activation protein inhibitor (FAPI) PET-CT is a very promising technique for determining metastases in tumors with prominent desmoplastic reactions, like cholangiocarcinoma. Our systematic review has shown it is superior to the commonly used FDG PET-CT for this indication. The investigators predict that implementation of preoperative FAPI PET-CT could alter treatment course for at least half (13%) of patients in whom intra-operative metastasized disease is found using the current work-up.

Objective

The primary aim of this study is to assess whether preoperative \[18F\]F-FAPI PET-CT in addition to standard preoperative imaging can successfully identify metastasized disease and change treatment plan in patients with potentially resectable proximal bile duct cancer (intrahepatic, perihilar and gall bladder cholangiocarcinoma). This study also aims to evaluate if adding \[18F\]F-FAPI PET-CT to preoperative imaging is cost-effective.

Main trial endpoints

The main endpoint is the diagnostic accuracy (sensitivity, specificity, positive predictive value, negative predictive value) of \[18F\]F-FAPI PET-CT.

Secondary trial endpoints

* Diagnostic accuracy of \[18F\]F-FAPI PET-CT per abdominal region and per lesion * The number of additional significant findings on \[18F\]F-FAPI PET-CT * Change of treatment: true change and virtual change * The number of times readers' conclusions differed and why * Cost-effectiveness analysis, budget impact analysis (BIA), sector costs, societal costs, health-related quality of life (HRQoL) * The number of additional significant findings on \[18F\]F-FAPI PET-CT * Number of days between date of first imaging (CT/MRI) and starting date of chemotherapy, palliative therapy or surgical resection * The incidence and severity of AEs and SAEs according to CTCAEv5 * VOI, TTP, K1 and k2, SUV and TBR (in a subgroup of patients)

Trial design

Prospective multicenter observational cohort study, expected total duration 4 years. Participants will be participating for at least six months.

Trial population

Patients ≥18 years with potentially curable proximal cholangiocarcinoma (perihilar, intrahepatic and gall bladder cholangiocarcinoma) who are planned to undergo surgery based on imaging using CT thorax/abdomen and MRI of the upper abdomen. Exclusion criteria are previous abdominal surgery or chemotherapy, known pregnancy or lactation and indication for FDG PET-CT.

Interventions

If patients are deemed eligible for surgery (laparoscopy or laparotomy) by the weekly organ-specific multidisciplinary team (MDT) including an abdominal nuclear medicine specialist, radiologist, surgeon, gastroenterologist/hepatologist, oncologist and, optionally, pathologist, patients will be asked to participate in the study. After inclusion, patients will receive additional \[18F\]F-FAPI PET-CT. Patients who underwent \[18F\]F-FAPI PET-CT will undergo follow-up for at least six months, if clinically advisable. Follow-up includes information regarding additional imaging, surgery or complications. To determine cost-effectiveness, patients' medical consumption will be elicited using two questionnaires. Patients will be asked to fill out the 'institute for Medical Technology Assessment (iMTA) Medical Consumption Questionnaire (iMCQ)' at three and six months after their initial CT/MRI imaging (before \[18F\]F-FAPI PET-CT or surgery). Patients will also be asked to fill out the European Organisation for Research and Treatment of Cancer (EORTC) group's QLQ-C30 and QLQ-BIL21 questionnaires and the EuroQol (EQ) Group's EQ-5D-5L questionnaire once every two weeks during the first two months after \[18F\]F-FAPI PET-CT and then once every four weeks until six months follow-up.

Risks and benefits

Patients may benefit directly from \[18F\]F-FAPI PET-CT by allowing for more targeted treatment, possibly avoiding futile surgery and receiving chemotherapy or best clinical support instead, minimizing treatment delay. Avoiding futile surgery will also prevent patients from being exposed to the risks and discomfort associated with surgery: hospital stay, possibility of intraoperative or postoperative complications, postoperative pain and recovery, and mortality.

Potential risks and burdens associated with this study are an extra site visit and a time burden of approximately half a day. Risks associated with vena puncture are (re)bleed and infection. Both risks have a minimal probability of onset, and when anticipated upon, are not expected to have significant clinical consequences. Risks associated with the administration of the study agent are allergic reactions and radiation burden. \[18F\]F-FAPI is a sub-pharmacologically micro-dosed diagnostic tracer, which is why the risk of allergic reactions is expected to be minimal and no tissue damage is expected. The burden associated with undergoing a PET-CT may be laying still for a certain time, and possible experience of claustrophobia. Metastases will have to be confirmed when suspicious findings are seen on \[18F\]F-FAPI PET-CT. This could mean subjects will have to undergo additional testing such as imaging (CT or MRI) or biopsy. If these additional tests are negative for metastases, the subject's exploratory surgery will have been needlessly delayed. Having to undergo \[18F\]F-FAPI PET-CT prior to surgery will also result in a surgical delay when compared with the current clinical practice. The investigators do not expect this delay to influence the subject's prognosis. Follow-up will result in a time burden for patients to answer questionnaires on a two-weekly or monthly basis.

• Change of treatment [Time frame: Within one month following PET-CT]
• Cost-effectiveness [Time frame: Six months following PET-CT]
• Number of additional significant findings using [18F]F-FAPI PET-CT [Time frame: Within one week after PET-CT]
• Number of times nuclear medicine specialists' [18F]F-FAPI PET-CT conclusions differed from one another [Time frame: Within one week after PET-CT]
• Number of lesions found on [18F]F-FAPI PET-CT [Time frame: Within one week after PET-CT]
• Number of days between [18F]F-FAPI PET-CT and exploratory surgery [Time frame: Six months following PET-CT]
• Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 [Time frame: Six months following PET-CT]
• Number of participants in which dynamic [18F]F-FAPI PET-CT followed by conventional [18F]F-FAPI PET-CT was able to distinguish benign lesions from malignant lesions [Time frame: Six months following PET-CT]
• Change in volume of interest (cm3) using dynamic [18F]F-FAPI PET-CT [Time frame: Within one week after PET-CT]
• Difference in SUVmax between dynamic and conventional [18F]F-FAPI PET-CT [Time frame: Within one week after PET-CT]
• Difference in SUVmean between dynamic and conventional [18F]F-FAPI PET-CT [Time frame: Within one week after PET-CT]
• Difference in transport rate (k1 to k2) on dynamic [18F]F-FAPI PET-CT between participants with malignant lesions and particpants with benign lesions [Time frame: Six months following PET-CT]