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68Ga-FAPI-04 positron emission tomography/CT and laparoscopy for the diagnosis of occult peritoneal metastasis in newly diagnosed locally advanced gastric cancer: study protocol of a single-centre prospective cohort study
  1. Shunyu Zhang1,2,
  2. Qiancheng Hu1,2,
  3. Xinchuan Chen3,
  4. Nan Zhou1,2,
  5. Qiyue Huang1,2,
  6. Sirui Tan1,2,
  7. Minggang Su4,
  8. Hongfeng Gou1,2
  1. 1 Department of Medical Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
  2. 2 Gastric Cancer Center, Sichuan University West China Hospital, Chengdu, Sichuan, China
  3. 3 Department of Hematology, Sichuan University, Chengdu, Sichuan, China
  4. 4 Department of Nuclear Medicine, Sichuan University, Chengdu, Sichuan, China
  1. Correspondence to Dr Hongfeng Gou; gouhongfeng1977{at}wchscu.cn; Dr Minggang Su; suminggang{at}sina.com

Abstract

Introduction Accurate baseline clinical staging is critical to inform treatment decision-making for patients with gastric cancers. Peritoneal metastasis (PM) is the most common form of metastasis in gastric cancer and mainly diagnosed by diagnostic laparoscopy and peritoneal lavage evaluation. However, diagnostic laparoscopy is invasive and less cost-effective. It is urgent to develop a safe, fast and non-invasive functional imaging method to verify the peritoneal metastasis of gastric cancer. The aim of our study was to evaluate the proportion of patients in whom 68Ga-FAPI-04 positron emission tomography/CT (PET/CT) led to a change in treatment strategy and to assess the diagnostic accuracy of 68Ga-FAPI-04 PET/CT for the detection of occult peritoneal metastasis compared with laparoscopic exploration.

Methods and analysis In this single-centre, prospective diagnostic test accuracy study, a total of 48 patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma (cT4a-b, N0-3, M0, based on CT images) who are considering radical tumour surgery will be recruited. All participants will undergo 68Ga-FAPI-04 PET/CT before the initiation of laparoscopic exploration. The primary outcome is the proportion of patients with occult peritoneal metastatic lesions detected by 68Ga-FAPI-04 PET/CT, leading to a change in therapy strategy. The secondary outcomes include the diagnostic performance of 68Ga-FAPI-04 PET/CT for occult peritoneal metastasis, including sensitivity, specificity, accuracy, positive predictive value and negative predictive value.

Ethics and dissemination The study protocol was approved by the Ethics Committee of West China Hospital, Sichuan University (2022-1484). Study results will be presented at public and scientific conferences and in peer-reviewed journals.

Trial registration number ChiCTR2300067591.

  • diagnostic imaging
  • gastrointestinal tumours
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STRENGTHS AND LIMITATIONS OF THIS STUDY

  • This is a prospective single-centre, single-arm study designed to test the diagnostic value of 68Ga-FAPI-04 positron emission tomography/CT (PET/CT) in the occult peritoneal metastasis from gastric cancer.

  • Laparoscopic exploration along with peritoneal lavage cytology is employed as controls in all 68Ga-FAPI-04 PET/CT assays performed for the diagnosis of peritoneal metastasis in patients with gastric cancer.

  • Laparoscopic exploration with ‘Huaxi four-step’ has been widely performed for the diagnosis of peritoneal metastasis in our centre, preventing a missed diagnosis by practising clinicians.

  • The diagnosis of peritoneal metastasis between nuclear medicine physicians and surgeons is conducted in a blinded fashion.

  • The potentially subjective and operator-dependent diagnoses of CT limit the initial assessment of occult peritoneal metastases.

Introduction

Gastric cancer is one of the most serious malignant tumours worldwide, ranking fifth in incidence and third in mortality.1 It is especially prevalent in China, accounting for approximately half of the global incidence.2 Surprisingly, >35% of patients are diagnosed initially with metastatic gastric cancer without the opportunity for curative surgery.3 Peritoneal metastasis (PM) is the most common form of metastasis in gastric cancer and accounts for nearly 50% of deaths in patients with gastric cancer.4

Accurate baseline clinical staging is critical to inform treatment decision-making for patients with gastric cancers. Contrast-enhanced CT, endoscopic ultrasonography and 18F-FDG positron emission tomography/CT (PET/CT) are widely used for preoperative imaging to visualise metastases. Unfortunately, both CT and 18F-FDG PET/CT are not particularly accurate, with low to moderate sensitivities for PM, which is common in gastric cancer.5 6 In the study by Smyth et al, 113 patients with locally advanced gastric or gastro-oesophageal cancer identified by CT and/or endoscopic ultrasound criteria underwent additional preoperative 18F-FDG PET/CT and laparoscopic staging. Twenty-one cases of PM were diagnosed by laparoscopic exploration, but none of these 21 cases showed lesions by 18F-FDG PET/CT.7

Diagnostic laparoscopy and peritoneal lavage evaluation can be used to confirm occult peritoneal metastatic lesions on imaging. Although the eighth edition of the TNM staging system for gastric cancer recommends performing diagnostic laparoscopy and peritoneal lavage evaluation for all patients with cT3/T4 and no distant metastasis based on imaging,8 the indications for diagnostic laparoscopy are still controversial. The relatively low positive rate and high cost make diagnostic laparoscopy less cost-effective.9 Diagnostic laparoscopy is an invasive procedure that might affect cardiopulmonary function and increase the risk of anaesthesia. There are certain limitations when exploring the posterior wall of stomach. In addition, the accuracy of exploration in patients with a history of surgery is compromised because postoperative adhesions may limit the extent of exploration. These are the reasons why laparoscopy staging is not widely used in clinical practice.

There is an urgent need to develop effective early non-invasive functional information diagnosis strategies for PM of gastric cancer, preventing futile treatment and improving the quality of life of patients and cost-effectiveness. 68Ga-labelled fibroblast activation protein inhibitor (FAPI) is a novel tumour-targeting agent, as fibroblast activation protein is overexpressed in cancer-associated fibroblasts. Recent investigations indicated that 68Ga-FAPI-04 PET/CT was able to detect more metastatic lesions in the peritoneum than 18F-FDG PET/CT (159 vs 47, p<0.001). The tracer uptake of 68Ga-FAPI-04 PET/CT was significantly higher than that of 18F-FDG PET/CT (maximum standard uptake values (SUVmax), 7.1 vs 4.5, p=0.002; target-to-background ratio (TBR) 8.1 vs 3.2, p<0.001).10 Although the evidence for performing 68Ga-FAPI-04 PET/CT is stronger than 18F-FDG PET/CT in PM, the credibility of these studies is not as high due to the lack of a gold standard (laparoscopic staging) as a control. Therefore, the aim of the present study was to evaluate the value of 68Ga-FAPI-04 PET/CT for the detection of occult PM in patients with newly diagnosed locally advanced gastric cancer.

Methods

Study design

This study is designed as a prospective observational, single-centre, single-blind, cohort study on the diagnostic value of 68Ga-FAPI-04 PET/CT in patients with locally advanced gastric cancer who were considered candidates for curative-intent treatment based on CT. The planned duration of the study was commenced in November 2022 and will be completed in July 2024. The trial schema is outlined in figure 1.

Figure 1

Flow diagram of the study protocol. Patients meeting inclusion and exclusion criteria will be recruited in our study. They will first undergo examination of 68Ga-FAPI-04 positron emission tomography/CT (PET/CT) and laparoscopic exploration with the Huaxi four-step procedure will be performed within 14 days after the 68Ga-FAPI-04 PET/CT scan. Patients without peritoneal metastases will be treated with neoadjuvant therapy while those with peritoneal metastases will receive first-line palliative care. AJCC, American Joint Committee on Cancer; FAPI, fibroblast activation protein inhibitor; TNM, tumour, node, metastases.

Aims and end points

The primary end point of this study is the proportion of eligible patients in whom 68Ga-FAPI-04 PET/CT leads to a change in treatment strategy after diagnosis. Some patients with advanced gastric cancer can have curative-intent treatment, whereas metastatic gastric cancer have to be treated with palliative intent. Changes in treatment strategy are explained by an inability to perform curative-intent treatment due to changes in diagnosis and staging, mainly including changes from curative to palliative therapy. Signs of PM on 68Ga-FAPI-04 PET/CT are as follows: diffuse FAPI uptake in the peritoneum, intestinal wall, large omental sac and the presence of peritoneal or supratentorial nodules on CT. Secondary objectives are (1) to assess the diagnostic accuracy of 68Ga-FAPI-04 PET/CT for the detection of PM compared with laparoscopic exploration by parameters such as sensitivity, specificity, accuracy, positive predictive value, negative predictive value, positive likelihood ratio and negative likelihood ratio in newly diagnosed, advanced, untreated patients with gastric cancers; (2) to assess lesion detectability by SUVmax for primary tumours and peritoneal carcinomatosis; (3) to compare the location of PM between 68Ga-FAPI-04 PET/CT and laparoscopic staging; (4) to assess the performance of 68Ga-FAPI-04 PET/CT in diagnosing regional lymph node metastasis.

Patient enrolment

Inclusion started in November 2022, and at the end of the anticipated inclusion period in July 2024, 48 participants will be included in the primary outcome analysis. To recruit this number of patients, we have anticipated a 20-month inclusion period at the gastric cancer centres in West China Hospital because of the ongoing pandemic of COVID-19. All potentially eligible patients will be discussed in the gastric cancer multidisciplinary team (MDT) meeting. Gastrointestinal surgeons, oncologists and nuclear medicine physicians have between 5 and 20 years of experience. Within a time window of 14 days before the initiation of laparoscopic exploration, consenting patients will be examined by 68Ga-FAPI-04 PET/CT. Typical signs of PM from gastric cancer on CT include uneven thickening of the peritoneum, greater omental clumps, nodular thickening of the mesentery, massive fluid accumulation in the abdominal and pelvic cavities.6 Occult peritoneal metastases are defined as instances where PM is not initially detected on CT scans but is diagnosed during laparoscopic exploration or open surgery.11 12 Peritoneal carcinomatosis is classified into either the omental cake type (diffuse type) or the nodular type.13 CT images will be used as a reference to distinguish diffuse lesions from physiological intestinal uptake and nodular lesions from hypermetabolic lymph nodes.14 The staging and extent of peritoneal metastases will be characterised by the criteria for PM in the Japanese Guidelines for Gastric Cancer Management, which will be interpreted in detail later. The diagnostic capabilities of 68Ga-FAPI-04 PET/CT will also be assessed by comparison of imaging results to laparoscopic exploration results.

Study population

Patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma proven by histology will be recruited to the study consecutively in West China Hospital from November 2022 to July 2024. The specific inclusion and exclusion criteria are described below.

Inclusion criteria:

  • Patients aged ≥18 years.

  • Patients with Eastern Cooperative Oncology Group performance status of 0 or 1 at study entry.

  • Histologically proven gastric or gastro-oesophageal junction (Siewert type III) adenocarcinoma.

  • Patients with advanced gastric cancer (cT4a-b, N0-3, M0) on initial staging evaluation by contrast-enhanced CT of the chest, abdomen and pelvis (according to the eighth edition of the American Joint Committee on Cancer TNM staging system) without evidence of metastatic spread.

  • Patients with adequate organ function, defined as no severe dysfunction of the lungs, kidneys, heart, bone marrow and clinical laboratory test value.

Exclusion criteria:

  • Patients with allergic constitution or with drug allergy.

  • Patients with active double primary malignancies.

  • Patients with thyroid abnormalities such as hyperthyroidism and hypothyroidism who are unable to undergo general anaesthesia.

  • Patients who are possibly pregnant, pregnant, unwilling to practice contraception during the study or breast feeding.

  • Patients diagnosed with mental illness that could have difficulty in participating in the trial.

  • Patients with a history of previous abdominal inflammatory diseases (such as peritonitis, pancreatitis, cholecystitis, inflammatory bowel disease).

  • Patients with a history of abdominal trauma.

  • Patients with a history of cerebrovascular accident within the past 6 months.

  • Patients with a history of continuous systematic administration of corticosteroids within 1 month.

Study procedures

Radiopharmaceutical preparation

The good manufacturing practice-grade precursor DOTA-FAPI-04 was supplied by Jiangsu Huayi Technology (Jiangsu, China). [68Ga]GaCl3 was produced from a [68Ge]/[68Ga]Ga generator (Model IGG100, Eckert & Ziegler, Germany) and eluted by an automated module (miniAllinone, Trasis, Belgium) using 10.0 mL of 0.1 M hydrochloride acid. Radiolabeling was also performed in the miniAllinone module. The radiochemical purities of the final products were both over 95%.

PET/CT imaging

The PET/CT scans were obtained 60 min after the intravenous injection of 111–185 MBq [68Ga]Ga-DOTA-FAPI-04. All PET/CT images were acquired from the head to the upper thighs. The CT scans were performed with a tube voltage of 120 kV, an effective tube current of 70–200 mAs (Dose Modulation (uMI780, United-Imaging Healthcare)), and a slice thickness of 3 mm. PET scans were immediately performed after the CT scan in 3D acquisition mode (matrix: 192×192) with 4–5 bed positions and 2 min/position. PET data were reconstructed iteratively (2 iterations and 20 subsets) with CT data for attenuation correction, and the PET/CT images were then coregistered and displayed using dedicated software (Image Fusion software, UIH).

PET/CT imaging analysis

68Ga-FAPI-04 PET/CT images will be analysed independently on a dedicated software (Image Fusion software) by two experienced nuclear medicine physician groups. Image analysis includes visual analysis and semiquantitative assessment.

1. Visual analysis: excluding the possibilities of physiological uptake, trauma, infection and inflammation, pathological uptake of FAPI is present in the primary tumour and metastatic lesions, manifesting as a focal uptake higher than that of the background.

2. Semiquantitative analysis: on transaxial images, the regions of interest are drawn along the margin of each lesion on the PET images for semiquantitative analysis. The SUVmax are automatically calculated and used to quantify tracer uptake in lesions.15 The TBR is calculated by dividing the lesion SUVmax by the SUV mean of the background.16 When performing patient-based assessments, it will take the highest uptake of the primary tumour or metastases in each region. When performing lesion-based assessments, the analysis includes the average SUVmax of all lesions (≤3) or the three lesions with the highest activity if there are multiple metastases (>3).

Staging laparoscopy and lavage cytology

The surgeon blinded to the 68Ga-FAPI-04 PET/CT results will perform laparoscopic exploration after finishing a 68Ga-FAPI-04 PET/CT scan. Laparoscopic exploration with the Huaxi four-step procedure is performed within 14 days after the 68Ga-FAPI-04 PET/CT scan. The ‘Huaxi four-step’ procedures have been described in detail in previous literature and carried out for many years in our centre.17 The ‘Huaxi four-step’ procedures are as follows:

Step 1: anterior abdominal wall and surface of abdominal viscera;

Step 2: pelvic cavity and surface of abdominal viscera;

Step 3: the mesentery and the small intestine;

Step 4: stomach and adjacent structures, omental bursa.

PM is diagnosed pathologically by histological and/or cytology findings. Approximately 500 mL of peritoneal lavage fluid is routinely retained during surgery and sent for cytology examination after laparoscopic exploration. According to the 15th edition of the Japanese Guidelines for Gastric Cancer Management, we evaluated the criteria for PM.18 The staging of PM is classified as follows: PX signifies an unclear metastatic state; P0 indicates the absence of PM; P1a denotes concentration in specific areas like the stomach, greater and lesser omentum, pancreatic capsule and spleen; P1b represents metastasis to the upper abdomen including the visceral peritoneum above the umbilicus or above the transverse colon; and P1c indicates metastasis in the peritoneum of the middle and lower abdomen.

Data collection, monitoring and follow-up

The data will be collected in this study by applying study-specific data collection forms (case report forms) starting at the time of recruitment. Additionally, the primary source of clinical data will be derived from electronic medical records during the conduction of the study. All data will be stored electronically and kept strictly confidential on a database. The clinical trial will be monitored by the Clinical Trial Centre West China Hospital. All patients will then be followed up for at least 6 months at our centre.

Sample size considerations

In view of the previous literature, the estimated proportion of cases that are expected to change treatment planning is 3% in patients with gastric cancer based on 18F-FDG PET/CT examination.19 Assuming a treatment planning change rate of 12% through 68Ga- FAPI-04 PET/CT, a total of 48 patients will be recruited in our study with an alpha value (two-sided) of 5% and a power of 80% (1−β=0.8), taking into account for a drop-out rate of approximately 5%.20–25

Statistical analysis

Statistical analyses will be performed using SPSS software (V.22.0, IBM). Continuous variables are expressed as the mean±SD. Categorical variables are expressed as numbers and percentages. The diagnostic performance of 68Ga-FAPI-04 PET/CT will be explored using sensitivity, precision, specificity,and positive and negative predictive values. Lesion detectability, such as SUVmax and TBR, will also be calculated. A p value of <0.05 is defined as statistically significant.

Patient and public involvement

There was no patient or public involvement in the design, conduct, reporting, or dissemination plans of this study.

Ethics and dissemination

This study was conducted according to the principles of the Helsinki II Declaration. The study protocol was approved by the Ethics Committee of West China Hospital and was registered in the Chinese Clinical Trial Registry (ChiCTR2300067591). All eligible participants receive both oral and written study information by the enrolling clinician and will sign a written informed consent form before study participation. Patients also have the right to withdraw from at any time of the study without giving any explanation, and their medical benefits and rights will not be affected.

The results will be reported in peer-reviewed scientific journals and public health conferences according to methodological criteria and recommendations as outlined by Standards for Reporting Diagnostic accuracy studies for diagnostic tests.26 Results will be disseminated in a variety of ways including abstracts, posters and presentations at scientific and public health conferences and published manuscripts in peer-reviewed journals.

Discussion

This study adopts functional imaging, 68Ga-FAPI-04 PET/CT, to evaluate the incidence and severity of occult peritoneal metastases in patients with localised gastric cancer before laparoscopic exploration to decrease the number of unnecessary surgical explorations.

For locally advanced gastric cancer, perioperative chemotherapy or preoperative chemoradiotherapy is currently recommended. If distant metastases are detected during the diagnostic process, treatment strategies may need to be changed from curative surgery to palliative systemic therapy. PM is one of the most common metastatic sites of gastric cancer. In recent population-based studies, the incidence of peritoneal metastases in patients with gastric cancer has been rising as high as 21%, especially tumours with serosal layer or adjacent organ infiltration (T4).27 Peritoneal metastases have poor outcomes in patients with advanced gastric cancer, with median overall survival ranging from 2 to 9 months.27–29 For patients with gastric cancer, accurate diagnosis of PM has clinical significance regarding optimal treatment options and avoiding unnecessary surgery.

CT, as a routine imaging technique for preoperative staging, has low accuracy for detecting metastatic disease, especially peritoneal metastases. 18F-FDG PET/CT provides a benefit when used in conjunction with CT in preoperative staging, but its sensitivity is still very low in detecting peritoneal carcinomatosis.30–32 FDG uptake is positively correlated with the size of the tumour.33 Small peritoneal metastatic lesions can easily lead to an insignificant uptake of FDG and false negative results. 18F-FDG PET/CT might also not be suitable for the detection and confirmation of diffuse and mucinous gastric cancer due to the relatively low expression level of glucose transporter 1. In addition, elevated blood glucose and chemotherapy possibly cause false-negative results, which may not truly reflect the growth state of cancer. These results suggest a limited additional role for 18F-FDG PET/CT in gastric and oesophagogastric junction cancer staging, especially for the diagnosis of peritoneal metastases.

An average of 25% of patients with newly diagnosed gastric adenocarcinoma have subradiological, intra-abdominal M1 disease (metastasis to peritoneum, liver or non-regional lymph nodes) that is detected at surgical staging by laparoscopy or laparotomy.19 Increasingly, laparoscopic exploration is also beginning to be used for clinical studies for precise tumour staging in patients with localised gastric cancer. Accurate diagnosis and precise staging of laparoscopic exploration are important implications for gastric cancer treatment strategies.34 Diagnostic laparoscopy is considered a necessary part of preoperative assessment in patients with gastric cancer, especially in locally advanced gastric cancer (T3/T4 and/or N+ tumours) identified by preoperative imaging. However, there is an urgent need to develop a safe, fast and non-invasive functional imaging method to verify PM of gastric cancer when compared with laparoscopic exploration.

New potent and specific radiotracers consisting of FAP-specific small molecule inhibitors (FAPIs) have been rapidly developed for tumour imaging and quantification, and their application has been investigated for imaging various malignancies according to the characteristics of cancer-associated fibroblasts in gastric cancer.35 36 Published results of a retrospective observational study that examined 46 patients with paired imaging data suggested that 68Ga-FAPI-04 PET/CT demonstrated superior sensitivity and a higher PCI score than 18F-FDG PET/CT for the detection of peritoneal metastases in patients with various types of cancer.14 Only 13 patients with gastric cancer were enrolled in their study, which may overestimate the capability of 68Ga-FAPI-04 PET/CT for detecting peritoneal metastases. A prospective head-to-head comparison showed that 68Ga-FAPI-04 PET/CT had superior detection capabilities for both primary gastric adenocarcinoma and peritoneal metastases in patients with gastric cancer compared with 18F-FDG PET/CT.36 The gold standard test for the diagnosis of peritoneal metastases, laparoscopy exploration with histological confirmation, was not performed in their study, and thus peritoneal metastases were underestimated in patients with gastric cancer. Further prospective observational studies are needed to evaluate the detection capabilities of peritoneal metastases using 68Ga-FAPI-04 PET/CT in patients with gastric cancer based on laparoscopic exploration with histological confirmation.

Early and accurate diagnosis of PM is essential to enhance the prognosis of patients with gastric cancer.37 Currently, preoperative diagnosis of peritoneal metastases has remained unsatisfactory. This study was designed to explore an effective non-invasive strategy for the preoperative diagnosis of peritoneal metastases from gastric cancer. It offers the following advantages. First, 68Ga-FAPI-04 PET/CT might detect earlier and more peritoneal metastases of gastric cancer that are not found during initial staging with CT. Therefore, restaging and changing the planned treatment strategy occur at a relatively early stage once 68Ga-FAPI-04 PET/CT is performed. It also helps to avoid unnecessary radical gastrectomy, improve quality of life and decrease medical costs. Second, traditional diagnostic tests are usually focused on sensitivity and specificity. In this study, the primary outcome was the rate of changing the planned treatment strategy after 68Ga-FAPI-04 PET/CT. This factor is favourable for greater 68Ga-FAPI-04 PET/CT use in the daily clinical routine because early diagnosis is reflected in an improved overall survival ratio. Last, laparoscopic exploration and laparotomy lavage cytology indicated that PM served as controls, and the diagnostic performance of 68Ga-FAPI-04 PET/CT will be very convincing in the future.

In conclusion, this study represents the most comprehensive analysis of 68Ga-FAPI-04 PET/CT in gastric cancer with PM. We describe the development of functional imaging for detecting PM of gastric cancer. We believe that the results of this trial could have a certain impact on the imaging stage diagnosis in gastric cancer. High-quality and well-designed multicentre studies are required to help us better understand 68Ga-FAPI-04 PET/CT in the future.

Ethics statements

Patient consent for publication

Acknowledgments

We express our gratitude to all the patients who will participate in this study. In addition, we acknowledge the support of our institution.

References

Footnotes

  • SZ and QH contributed equally.

  • Contributors HG and MS were the principal investigators who were responsible for the study design and procedures. QH and SZ drafted the manuscript under HG supervision. MS, QH and XC were responsible for imaging expertise. SZ, NZ, ST and QH participated in the execution and collection of the data. XC and SZ contributed to applying for and receiving funding. All authors contributed to providing significant comments on the implementation of the protocol and approved the final manuscript.

  • Funding The work was supported by Resident/Specialist Research Fund of West China Hospital, Sichuan University. This work was financially supported by Sichuan Science and Technology Programme (no. 2020YFS0256 China).

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.