Ken Herrmann • Hinrich A. Wieder • Matthias P.A. Ebert • Johannes Czernin
In 2011, an estimated number of 21,520 new cases of gastric cancer and 10,340 gastric cancer related deaths were expected in the United States.1 Corresponding worldwide incidence rates were approximately 989,000 new cases of gastric cancer in 2008 and around 738,000 gastric cancer related deaths during the same year.2 Incidence rates of gastric cancer are twice as high in males as in females, and around 70% of new cases and deaths occur in developing countries with the highest rate in Eastern Asia.2 Long-term survival of gastric cancer remains poor despite a significant increase over the past years (5 years relative survival rates: 1975–1977: 16% and 1999–2006: 27%, respectively).1
In contrast to other malignancies, such as lung cancer and prostate cancer, gastric cancer rates have decreased substantially in most parts of the world.1,2 This decrease is reported to be caused by factors related to the increased use and availability of refrigeration, reductions in chronic Helicobacter pylori infection and smoking.3–5
Carcinogenesis of gastric cancer is a multistep process that involves many environmental and genetic factors. It was shown that H. pylori is implicated in more than 80% of gastric cancers.6 In contrast, most of the approximately 1 billion people infected worldwide do not develop gastric cancer demonstrating that H. pylori infection alone is not sufficient to cause the disease.7 Moreover, a number of other causes comprising levels of the hormone gastrin,8genetic and dietary factors,9,10 and other chronic gastric inflammation-causing factors11 contribute to the development of gastric cancer. Altogether, gastric cancers are complex diseases and their etiology is not fully understood at this time.
As prognosis of gastric cancer remains poor, it is crucial to identify pretherapeutic predictive marker for response and prognosis. Tumor localization, Lauren classification, tumor differentiation, mucin production, and clinical stage have all been previously shown to be prognostic factors in patients who did not undergo preoperative chemotherapy.12–14 More recently, tumor localization, Lauren classification, and tumor differentiation were reported to be positive predictive factors even in patients undergoing neoadjuvant treatment.15
Correct clinical staging is crucial to stratify risk in patients and assign the optimal treatment. In 2010, the International Union Against Cancer and the American Joint Committee on Cancer (AJCC) have revised the staging system and published the seventh edition in 2010.16 For gastric cancer, the following changes were made.17
• Gastroesophageal junction (GEJ) tumors are staged as esophageal cancers, except tumors arising in the stomach >5 cm from the GEJ.
• T classification categories have been redefined, and the T classification of stomach cancer and esophageal cancer have been harmonized.
• N categories have been modified to better represent the distribution of the number of positive lymph nodes.
• M1 category has been amended to include positive peritoneal cytology.
• Stage IV now includes only patients with M1 disease.
• New stage groups have been added to the staging system (IIB and IIIC).
In addition to staging, restaging and assessment of response to treatment are also important for the management of gastric cancer patients. To improve the outcome, combined modality treatments including perioperative chemotherapy, radiotherapy, or chemoradiotherapy in combination with surgical resection have been widely evaluated. A recently published meta-analysis comprising 17 randomized controlled trials of adjuvant and neoadjuvant chemotherapy in gastric cancer demonstrated a statistically significant overall (p < 0.001) and disease-free survival (p < 0.001) benefit for patients treated with fluorouracil-based adjuvant chemotherapy versus surgery alone.23 A trial initiated by the European Organisation for Research and Treatment of Cancer (EORTC) investigating the value of neoadjuvant treatments in gastric cancer randomized patients with tumors in the proximal third of the stomach to preoperative chemotherapy followed by surgery or to surgery alone. A significantly increased R0 resection rate (macro- and microscopically negative resection margins) was found for patients with neoadjuvant chemotherapy prior to surgery but no survival benefit was shown.24 As a consequence of the inconclusive results for survival, the currently valid German S3 guideline “Diagnosis and Treatment of Esophagogastric Cancer” lacks a clear recommendation regarding the benefit of neoadjuvant treatment.25
The aim of this chapter is to discuss the relevant clinically approved and investigational applications of nuclear medicine techniques for staging, restaging, treatment response monitoring, and radio-guided sentinel lymph node surgery in gastric cancer.
DETECTION AND STAGING OF GASTRIC CARCINOMA
State of the Art
Endoscopy has become the primary tool for detection of gastric cancer and is recommended as “good clinical practice” in numerous clinical guidelines.25,26 Endoscopic procedures allow the determination of the presence and location of gastric cancer and the biopsy of suspicious lesions. Endoscopy is a safe procedure with low complication rates (1:1000). Therefore, endoscopy should be considered the modality of choice for detection of gastric cancer.
For staging of gastric cancer, endoscopic ultrasound (EUS) and B-mode ultrasound have proven to be very accurate for T-staging and moderately accurate for N- and M-staging. These modalities are, therefore, considered the primary imaging modalities for staging. In a meta-analysis pooled sensitivities and specificities for T-staging based on these modalities were: T1: 88% and 100%, T2: 82% and 96%, T3: 90% and 95%, and T4: 99% and 97%.27,28The sensitivities and specificities for N-staging were 58% and 92% and 65% and 92% for N1 and N2, respectively.27 Whereas EUS has only a limited accuracy for M-staging, sensitivities of 77% and 81% for detection of liver metastases have been reported for B-mode ultrasound.29,30
In addition to EUS and B-mode ultrasound, a diagnostic contrast-enhanced CT of thorax and abdomen is recommended. Overall accuracy of CT for T-staging is reported to be 43% to 82% according to the NCCN guidelines, whereas the German S3 guideline reports accuracies of 77% to 89%.31,32 Corresponding sensitivity and specificity for detection of local lymph node metastases are 78% and 62%, respectively.31,33 For contrast-enhanced CT, a sensitivity of 70% and a specificity of 72% for detection of distant metastases had been reported.32 CT revealed a high sensitivity but not specificity to detect lung metastases. The use of MRI, however, is only recommended for patients who cannot undergo EUS and/or CT.9,15
FIGURE 6.1. A 61-year-old female undergoing 18F-FDG PET/CT for staging of an endoscopically detected gastric cancer. Coronal (A), sagittal (B), and transaxial (C) images display an increased 18F-FDG uptake in projection of the known primary cancer (single arrows). Moreover, 18F-FDG PET/CT also depicts increased glucose metabolism in the bone marrow and in the mesentery (double arrows, D).
Role of Nuclear Medicine
According to the most recent NCCN and German guidelines, there is no clear recommendation for the routine use of 18F-FDG PET/CT and/or bone scintigraphy in the staging of gastric cancer patients.25,31 The German S3 guideline proposes that PET/CT might provide useful additional information, especially regarding the detection of distant metastases (Fig. 6.1), in locally advanced gastric cancers of the intestinal type.25,32 The routine use of 18F-FDG PET/CT, however, is not recommended. Both NCCN and the German S3 guideline list the low tracer accumulation in diffuse and mucinous tumor types (Fig. 6.2) as a major limitation contributing to the inferior detection rate compared to diagnostic CT and EUS.25,31,34 The NCCN guideline reports a lower sensitivity (56% versus 78%) but a higher specificity (92% versus 62%) for 18F-FDG PET/CT compared with contrast-enhanced CT in detection of local lymph node involvement.31,33 However, the NCCN guideline also mentions that combined 18F-FDG PET/CT has a number of potential advantages over 18F-FDG PET alone.31 18F-FDG PET/CT was reported to be more accurate for staging (68%) than PET (47%) or CT (53%) alone. Bone scintigraphy, as part of the routine staging of gastric cancer patients, is not recommended in the absence of specific symptoms.32
FIGURE 6.2. A 62-year-old male with biopsy proven gastric signet ring cell tumor undergoing 18F-FDG PET/CT for staging (A: coronal view, B and C: transaxial views of CT, PET, and fused PET/CT of mediastinum and upper abdomen). 18F-FDG PET/CT does not show increased uptake in the primary tumor (single arrows) or in the lung lesion (histopathologically proven lung metastasis).
A recently published prospective single center trial investigated the value of 18F-FDG PET/CT for adding relevant information to routine CT, EUS, and laparoscopic staging in 113 patients with locally advanced gastric cancer.35 In 31 patients, occult metastatic disease was discovered by either laparoscopy (n = 21) and/or 18F-FDG PET/CT (n = 11) with overlap in only one patient. 18F-FDG PET/CT provided crucial additional information in approximately 10% of the patients by describing occult metastatic lesions protecting the patients from increased morbidity by futile surgeries (Fig. 6.3). A cost-analysis reported an estimated cost saving of $13,000 per patient.35
The recent introduction of combined MR PET whole-body scanners raises the potential of a new dimension in whole-body oncology imaging.36 First results show that integrated whole-body PET/MR is feasible in a clinical setting with high quality imaging in a short examination time.37 Staging of gastric cancer might be an interesting application for MR PET but no clinical data is available.
As previously mentioned, 18F-FDG PET/CT has a limited sensitivity for the detection of diffuse and mucinous gastric tumors.25,31,34 This observation was recently confirmed when detection rates of 97% for pure intestinal subtype tumors but only 44% for diffuse tumors, respectively, were reported.35 As increased proliferative activity has been shown to be potentially more specific for malignant tumors than are alterations of glucose metabolism,38 a number of groups have investigated the in vivo proliferation tracer 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) for detection of gastric cancer and compared it to 18F-FDG PET/CT.39,40 Reported sensitivities for 18F-FLT PET were 100% and 95%, respectively with both studies comprising a significant percentage of nonintestinal tumors (67% and 43%). Interestingly, 18F-FDG PET/CT had, in the larger study population of 45 patients, only a sensitivity of 69%,39 whereas the study with 21 patients reported a sensitivity of 95%.40 This might reflect selection bias; that is, the percent of various gastric carcinoma subtypes in the group studied.
These investigational approaches are currently not part of the clinical routine yet. Randomized multicenter trials are necessary to study the impact of the new imaging approaches on patient management and outcome with special regard to potential reimbursement and/or legal approval.
Nuclear medicine techniques currently play no significant role in the clinical routine of staging gastric cancer. 18F-FDG PET/CT might provide important additional information for staging especially regarding the detection of distant metastases. To date, however, insufficient data are available to determine whether the inclusion of 18F-FDG PET/CT has a meaningful impact on the initial staging of patients with gastric cancer.
DIAGNOSIS OF RECURRENCE AND RESTAGING
State of the Art
The available guidelines only address restaging after neoadjuvant treatment.25,26,31 According to the German S3 guideline, the accuracy of EUS and CT regarding the staging of the primary tumors is low.25,41,42 Downstaging of T and N category by EUS42 or reduction of tumor thickness of more than 50% by EUS, however, were correlated with better survival.41 Moreover, if clinical symptoms indicate tumor progression during chemotherapy, a symptom-oriented restaging is recommended to consider immediate surgery.43 Interestingly, the prognostic relevance of achieving histopathologic response after neoadjuvant chemotherapy is not established as only two studies that included 36 and 30 patients have addressed this issue.44,45 In only one of these two studies was a correlation between tumor regression grade and survival reported.44
FIGURE 6.3. A patient with 18F-FDG-avid gastric cancer undergoing 18F-FDG PET/CT scan for staging. Coronal (A), transaxial (B and C), and sagittal (D) views display the increased 18F-FDG uptake in the primary tumor (single arrow). Moreover, 18F-FDG PET/CT depicted lymph node involvement and a liver metastasis (double arrows).
Follow-up after initial treatment is recommended to be adapted to the needs of the patient as well as the recurrence rates of the diagnosed tumor.25,26 The Belgian guideline recommends physical examination and blood work every 3 months as well as CT every 6 months during the first year, and subsequently only annually.26 The NCCN guidelines suggest that patients should be followed systemically including physical examination every 3 to 6 months in the first 2 years, then every 6 to 12 months during years 3 to 5 and annually thereafter. Complete blood count, imaging studies and endoscopies should be done if clinically indicated.31
In summary, restaging of the primary tumor after neoadjuvant therapy is not recommended but distant metastases should be ruled out prior to surgery.25 Surveillance protocols recommend regular physical examination; whereas the Belgian guidelines recommend routine CT scans, the NCCN deems imaging only necessary if clinically indicated.
Role of Nuclear Medicine
According to the most recent guidelines, there is no clear recommendation for the routine use of 18F-FDG PET/CT and/or bone scintigraphy for restaging, surveillance, or diagnosis of recurrence. However, as distant metastases should be ruled out prior to surgery, 18F-FDG PET/CT might add relevant information for M-staging. The NCCN guideline also states that 18F-FDG PET/CT is useful for evaluation of recurrent gastric cancer.31,46,47
The data addressing a potential role of 18F-FDG PET and 18F-FDG PET/CT for detecting gastric cancer recurrence are sparse (Table 6.1).48 In one study, 33 patients underwent an 18F-FDG PET/CT scan for suspected recurrence after surgical resection with curative intent.18 Recurrence was confirmed or ruled out histologically or by radiologic and clinical follow-up (prevalence of recurrence 61%). 18F-FDG PET correctly detected recurrence in 70% (14/20) and was false positive in four patients (specificity: 69%; 9/13). Corresponding positive and negative predictive values were 78% (14/18) and 60% (9/15), respectively. All of the six false-negative cases had intra-abdominal lesions (three had generalized abdominal metastases, one liver metastasis, one local recurrence, and one ovarian metastasis). In patients with signet-cell differentiation of the primary tumor (n = 13, disease prevalence 62% (8/13)), 18F-FDG PET had a sensitivity of 63% (5/8) and a specificity of 60% (3/5), respectively. The authors concluded that because of its poor sensitivity and low-negative predictive value 18F-FDG PET is not well suited for the follow-up of treated gastric cancer patients. 18F-FDG avidity of recurrent lesions, however, was a predictor of poor outcome (mean survival 6.9 versus 18.5; p = 0.05).
In a more recent study, 18F-FDG PET/CT was evaluated in 105 patients with clinical or radiologic suspicion of gastric cancer recurrence. Follow-up revealed 108 recurrence sites in 75 patients.19 Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 18F-FDG PET/CT for diagnosing true recurrence on a per patient basis were 75%, 77%, 89%, 55%, and 75%, respectively. On a per-lesion basis, 75 (69%) of 108 true recurrences showed positive 18F-FDG uptake, whereas 75 (89%) of 84 positive 18F-FDG uptake were confirmed to have true recurrence. The authors concluded that PET-CT might be helpful particularly in patients with a high pre-PET suspicion for recurrence.
18F-FDG PET AND 18F-FDG PET/CT FOR DETECTION OF RECURRENCE OF GASTRIC CANCER
Recent developments, such as hybrid PET/CT gastrography or combined MR PET whole-body scanners, might improve the performance of nuclear medicine techniques for restaging and recurrence detection in gastric cancer but these techniques have not yet entered the clinical routine.
Nuclear medicine techniques currently play no major role in restaging and detection of recurrence in gastric cancer patients. In the case of presurgical restaging after neoadjuvant treatment, 18F-FDG PET/CT may provide additional information to detect or rule out distant metastases. Furthermore, it is unknown whether 18F-FDG PET/CT has a meaningful impact on the management and outcome of patients who are re-evaluated for gastric cancer.
TREATMENT RESPONSE MONITORING
State of the Art
The available oncologic guidelines do not suggest which imaging method should be used for treatment response assessments.25,26,31 However, endoscopy, EUS, and CT are the most commonly used. CT imaging as well as changes in serum levels of tumor markers have recently been used to assess treatment responses.49,50 According to the NCCN guidelines, 18F-FDG PET/CT scans are useful to predict response to preoperative (neoadjuvant) chemotherapy.20,21,31,46
Role of Nuclear Medicine
The currently available guidelines for the treatment of gastric cancer do not provide recommendations for the role of nuclear medicine techniques in treatment monitoring. Whereas the NCCN guidelines state that 18F-FDG PET/CT scans are useful to predict response to preoperative chemotherapy,20,21,31,46 the German S3 guidelines propose using 18F-FDG PET/CT only in the context of clinical research.25
The usefulness of preoperative treatment is still under debate and only few studies investigated the role of F-18F-FDG PET/CT for response assessment in gastric cancer (Table 6.2). As recently summarized by Ott et al.,51 current imaging modalities or in vitro biomarkers cannot reliably predict the treatment responses in patients with gastric cancer. Such assessments would be critically important to avoid unnecessary side effects of ineffective therapies and to provide patients with alternative treatment approaches.52
The effects of neoadjuvant chemotherapy were first studied with 18F-FDG PET in 44 patients with locally advanced gastric cancer. Thirty-five of these had tumors with visible 18F-FDG uptake at baseline and were, therefore, assessable.20 Using a response threshold of 35% SUVmean reduction in tracer uptake (as applied by Weber et al.53 for patients with adenocarcinomas of the gastroesophageal junction) 2 weeks after the start of neoadjuvant treatment, histopathologic response was predicted with sensitivities and specificities of 77% and 86%, respectively (Fig. 6.4). Metabolic responders had a better median survival (not reached versus 18.9 months; p = 0.02) and a higher 2-year survival rate (90% versus 25%; p = 0.002) than metabolic nonresponders.
Recently published long-term results have revealed that in locally advanced gastric cancer, three different response patterns exist for early response assessment after 2 weeks of neoadjuvant chemotherapy.21 Metabolic responders had a higher histopathologic response rate (69%) than metabolic nonresponders (17%) and initially 18F-FDG-negative patients (24%). Interestingly, survival of 18F-FDG-avid nonresponders and 18F-FDG-negative patients did not differ significantly (24.1 months versus 36.7 months; p = 0.46), whereas for 18F-FDG-avid responders median overall survival had not yet been reached after a median follow-up of 56 months. The authors suggest, therefore, that although metabolic response assessment is not possible in 18F-FDG-negative tumors, a therapy modification (e.g., change of chemotherapy or immediate surgery) might be considered in this patient subgroup.
18F-FDG PET AND 18F-FDG PET/CT IN EARLY ASSESSMENT OF RESPONSE TO THERAPY FOR GASTRIC CANCER
In a retrospective study of 42 patients, 18F-FDG PET responses were assessed 35 days after the start of treatment.22 A decrease in SUVmax of more than 45% provided the best prediction of histopathologic response and outcome. Metabolic response was significantly correlated with histopathologic response (less than 50% residual tumor; p = 0.007) and disease-free survival (p = 0.03). Despite these encouraging results both groups suggested that prior to applying these parameters clinically, standardization of the imaging procedure and a prospective evaluation in a multicenter trial should be performed.
FIGURE 6.4. A patient with biopsy-proven gastric cancer undergoing neoadjuvant chemotherapy prior to surgery. 18F-FDG PET/CT scans were performed prior to start of chemotherapy (A), and 14 days after start (B). The primary tumor was 18F-FDG avid in both scans (arrows) but showed semiquantitatively a decrease from SUVmean 7.3 to 3.1 (SUVmean-decrease: 58%). Histopathology after surgery confirmed histopathologic response.
As up to a third of gastric carcinomas are initially 18F-FDG negative and, therefore, not suitable for response monitoring using 18F-FDG PET,54 18F-FLT PET has also been assessed for its ability to detect locally advanced gastric cancer39,40 and subsequently for treatment response monitoring.55 18F-FDG PET and 18F-FLT PET were performed at baseline, 14 days after the start of treatment and then again prior to surgery in 45 patients with gastric cancer. No significant association between any of the PET measurements and clinical or histopathologic response was found. Univariate Cox regression analysis for Ki67 and metabolic parameters revealed significant prognostic impact for survival only for 18F-FLT SUV(mean) measurements on day 14 (p = 0.048) and Ki67 (p = 0.006). Multivariate Cox regression analysis (including clinical response, Lauren type, ypN category, and 18F-FLT SUV(mean) day 14) revealed Lauren type and 18F-FLT SUV(mean) day 14 as the only significant prognostic factors (p = 0.006, p = 0.002). Thus, 18F-FLT uptake 2 weeks after initiation of therapy was the only imaging parameter with significant prognostic impact. However, these results must be interpreted with caution as a number of limitations have to be kept in mind such as the single-center trial study design, a relatively short follow-up, poor overall response rates, and an unfavorable prognosis of this study population.
Nuclear medicine techniques may be useful to predict response to preoperative chemotherapy. Even though the NCCN guideline supports the usefulness of 18F-FDG PET/CT, available data regarding quantitative assessment of early response to chemotherapy is from single-center studies only. Prior to routine use of 18F-FDG PET/CT guided response assessment, standardization of the imaging procedure and a prospective evaluation in a multicenter trial should be performed.
The currently available NCCN guideline states the usefulness of 18F-FDG PET/CT for predicting response to preoperative chemotherapy. As the only available comes from single-center studies only, standardization of the imaging procedure and a prospective evaluation in a multicenter trial have to be performed before 18F-FDG PET/CT guided response assessment can be routinely used.
In clinical routine of staging, restaging, and detection of recurrence in gastric cancer nuclear medicine techniques play currently no significant role. However, 18F-FDG PET/CT might provide important additional information for staging as well as presurgical restaging after neoadjuvant treatment especially regarding the detection/exclusion of distant metastases. Future studies have to address whether the inclusion of 18F-FDG PET/CT has a meaningful impact on the initial staging, restaging, and detection of recurrence of patients with gastric cancer. Also alternative PET tracers such as 18F-FLT PET need despite initially promising results further evaluation before being implemented into clinical routine.
Nuclear medicine techniques will continue to evolve with the introduction and evaluation of combined MR PET scanners, development of new PET- and SPECT-tracers and techniques beyond current PET- and SPECT-imaging such as radio-guided surgical techniques.
Potential high impact of nuclear medicine modalities on the management of gastric cancer patients can be expected in the field of treatment monitoring and response assessment. If the standardization of PET imaging can be achieved and prospective multicenter trials confirm the impact of 18F-FDG PET/CT guided response assessment on patient survival then 18F-FDG PET/CT will become a component in the clinical routine. Even though alternative tracers such as 18F-FLT might provide relevant additional information, we believe that 18F-FDG will continue to be the most frequently used tracer for routine clinical use.
First results of combined MR PET whole-body scanners showed that integrated whole-body PET/MR is feasible in a clinical setting with high quality imaging in a short examination time.37 In the near future, whole-body MR PET will be evaluated for staging and restaging of gastric cancer. However, we believe that regarding the T- and N-staging it will be difficult to prove superiority over the currently established state-of-the-art modalities endoscopy, endoscopic ultrasound and CT, especially with regard to cost-effectiveness. A more promising area appears to be M-staging but again, it will be challenging to prove superiority compared to 18F-FDG PET/CT.
Recently, the concept of sentinel lymph node biopsy for gastric cancer has been reviewed.56 Despite not being established clinically, a total of 12 studies using the radiocolloid method were available. The overall false-negative rate was 18.5% (95% CI 9.1, 28.0) compared to a false-negative rate for dye only of 34.7% (95% CI 21.2, 48.1). The combination of both methods was investigated in five studies with a pooled false-negative rate of 13.1% (95% CI –0.9, 27.2). The false-negative rate of radiocolloid alone might be even further reduced by improving SLN detection through 3D tomographic imaging modalities as has been reported in breast cancer patients.57
In summary, the field of nuclear medicine is rapidly evolving. The introduction of new diagnostic methods as well as therapies might impact the future management of gastric cancer patients.
We appreciate the excellent contributions made by our colleagues PD Dr. Ambros Beer and Mrs. Christine Praus.
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