[18F]FDG PET/CT Integration in Evaluating Immunotherapy for Lung Cancer: A Clinician's Practical Approach.

The advent of immune checkpoint inhibitors (ICIs) has revolutionized the treatment paradigm of lung cancer, resulting in notable enhancements in patient survival. Nevertheless, evaluating treatment response in patients undergoing immunotherapy poses distinct challenges due to unconventional response patterns like pseudoprogressive disease (PPD), dissociated response (DR), and hyperprogressive disease (HPD). Conventional response criteria such as the RECIST 1.1 may not adequately address these complexities. To tackle this issue, novel response criteria such as the iRECIST and imRECIST have been proposed, enabling a more comprehensive assessment of treatment response by incorporating additional scans and considering the best overall response even after radiologic progressive disease evaluation. Additionally, [18F]FDG PET/CT imaging has emerged as a valuable modality for evaluating treatment response, with various metabolic response criteria such as the PERCIMT, imPERCIST, and iPERCIST developed to overcome the limitations of traditional criteria, particularly in detecting pseudoprogression. A multidisciplinary approach involving oncologists, radiologists, and nuclear medicine specialists is crucial for effectively navigating these complexities and enhancing patient outcomes in the era of immunotherapy for lung cancer. In this review, we delineate the key components of these guidelines, summarizing essential aspects for radiologists and nuclear medicine physicians. Furthermore, we provide insights into how imaging can guide the management of individual lung cancer patients in real-world multidisciplinary settings.

Cancer imaging with fluorine-18-labeled choline derivatives.

The choline transporter and choline kinase enzyme frequently are overexpressed in malignancy. Therefore, positron-emitter-labeled compounds derived from choline have the potential to serve as oncologic probes for positron emission tomography. The fluorine-18 ((18)F)-labeled choline derivative fluorocholine (FCH) in particular has demonstrated potential utility for imaging of a variety of neoplasms, including those of the breast, prostate, liver, and brain. The pharmacokinetics of FCH and other choline tracers allow for whole-body imaging within minutes of injection while still achieving high tumor-to-background contrast in most organs, including the brain. These features, along with the possibility of imaging malignancies that have proved elusive with the use of (18)F-fluorodeoxyglucose positron emission tomography support further clinical investigations of (18)F-labeled choline tracers.

[Clinical usefulness of positron emission tomography in prostate cancer]. / Utilité clinique de la tomographie par émission de positons dans le cancer de la prostate.

In prostate cancer, use of FDG, the radiopharmaceutical currently most widely used in oncology, is limited to the most aggressive cancers and, in the absence of another tracer, to attempting to localise occult recurrences detected biochemically (elevated PSA serum levels). Four other PET tracers are currently suggested in various situations of prostate cancer development: for guiding biopsies, for diagnosis and staging of the primary cancer and of local or metastatic recurrences, especially in bone, and for localizing occult biochemical recurrence. This article is illustrated by cases summarising our experience with fluoromethylcholine-(18F) and PET/CT. They cover a wide spectrum of clinical settings: localisation of intraprostatic neoplastic lesions, initial staging, monitoring treatment by ultrasound, detection of occult recurrences and characterisation of images on conventional imaging modalities, which are questionable or difficult to interpret.

Can fluorodihydroxyphenylalanine PET replace somatostatin receptor scintigraphy in patients with digestive endocrine tumors?

UNLABELLED: The aim of this study was to evaluate whether (18)F-fluorodihydroxyphenylalanine ((18)F-FDOPA) PET is accurate for the diagnosis and follow-up of any type of well-differentiated digestive endocrine tumor and to assess its performance compared with standard somatostatin receptor scintigraphy (SRS) using (111)In-pentetreotide. METHODS: We reviewed the results of 33 evaluable (18)F-FDOPA PET and (111)In-pentetreotide SRS examinations performed between March 2002 and September 2005 in 30 patients referred for documented well-differentiated digestive endocrine tumor. RESULTS: The sensitivity and accuracy of (18)F-FDOPA PET were significantly better for carcinoid tumors (defined according to the World Health Organization 2000 classification) (n = 19) than for noncarcinoid tumors (n = 14)-that is, 93% versus 25% for sensitivity (P < 0.01) and 89% versus 36% for accuracy (P < 0.01), respectively. In contrast, the performances of (111)In-pentetreotide SRS did not differ according to the carcinoid or noncarcinoid type of the primary endocrine tumor-that is, 81% versus 75% for sensitivity and 79% versus 71% for accuracy, respectively. In carcinoid tumors, comparison between (18)F-FDOPA PET and (111)In-pentetreotide SRS showed that (18)F-FDOPA PET more accurately evaluated the extent of disease than (111)In-pentetreotide SRS. (111)In-Pentetreotide SRS did not reveal any additional lesions in any case. Conversely, in noncarcinoid tumors, the extent of the disease was more accurately evaluated in all cases by (111)In-pentetreotide SRS than by (18)F-FDOPA PET. CONCLUSION: This preliminary study emphasizes the importance of a precise histologic characterization of well-differentiated digestive endocrine tumor to select the best radiopharmaceutical. (18)F-FDOPA PET appears to be useful in carcinoid tumors and could become the first-line scintigraphic imaging modality for these tumors, but (111)In-pentetreotide SRS appeared to be a better first-line scintigraphic imaging modality for noncarcinoid digestive tumors.

Intra-individual comparison of sentinel lymph node scintigraphy on the day of injection and on the following day in breast cancer.

OBJECTIVES: To compare, intra-individually, the detection rates of sentinel node on lymphoscintigraphy performed on the day of injection (D0) and on the following day (D1) in breast carcinoma. We also compared 2-day and 1-day protocols in the two groups of patients. METHODS: The 2-day and 1-day protocols included 76 patients in group 1 and 23 patients in group 2. Patients from group 1 underwent lymphoscintigraphy twice--at 2 h (lymphoscintigraphy 1) and 18 h (lymphoscintigraphy 2) post-injection at four sites periareolar using 99mTc sulfur colloid. Patients from group 2 underwent lymphoscintigraphy only at 2 h post-injection. The detection rates and the number of sentinel nodes were compared in the two lymphoscintigraphy examinations for group 2. RESULTS: The detection rate on lymphoscintigraphy in group 1 was 92% at D0 and 96% at D1. The overall agreement between lymphoscintigraphy 1 and lymphoscintigraphy 2 was 69/76 (91%). In 2/76 women, the sentinel node disappeared at D1 on lymphoscintigraphy, but remained detectable during surgery, and in 5/76 women, the sentinel node appeared at D1 on lymphoscintigraphy. The mean number of sentinel nodes detected on lymphoscintigraphy was 2.05+/-0.14 at D0 and 1.76+/-0.11 at D1 (P=0.004) in group 2, the detection rate of the sentinel node was 20/23 (87%). CONCLUSION: Our study demonstrated that for patients undergoing the 2-day protocol for sentinel node procedure in early stage breast cancer, the optimal imaging time would be to perform lymphoscintigraphy 1 h after injection, with the possibility of imaging patients the following day in cases where lymphoscintigraphy was negative.

[FDG PET and its impact on patient's management in oncology]. / L'examen TEP au fluorodésoxyglucose-(18F) et son impact sur la décision thérapeutique en cancérologie.

FDG, a radioactive glucose analog for PET imaging, requires some precautions: it should be used only in patients with glycemia < 7mmol/L, fasting for at least 6 h but well hydrated, and after pregnancy is ruled out. FDG-PET has many indications in oncology. Its clinical utility has been documented in some circumstances, listed as routine indications in the European Principal Characteristics Summary and the French Standards, Options, and Recommendations. The European "Points to Consider" define as a principal criterion of clinical utility the impact of the imaging results on patient management. The original results presented here evaluate the clinical impact of FDG-PET among patients at Tenon Hospital by the rate of modifications in patient' management, determined with the same questionnaire as that used in two California studies of 2044 patients. Our response rate was lower than in our previous retrospective study in 2000 (34% versus 73%), probably because a prospective evaluation requires more work by the referring physician (who had to respond to two separate letters). On the other hand, the modification rate rose significantly (54% versus 46%, p<0.001), especially for colorectal cancer (58% versus 44%, p<0.02). The California studies had similar response rates (31%-48%, depending on the indication). Their modification rates were also similar, although higher for lymphoma (68%), colorectal (65%) and breast (58%) cancers.

[PET and malignant cerebral tumors]. / La TEP dans les tumeurs malignes cérébrales.

Normal biodistribution of FDG includes intense physiologic uptake in the brain, which consumes glucose. The high background therefore makes it difficult to detect the foci taking up glucose, which correspond to malignant lesions. FDG PET is nevertheless clinically useful for detecting high-grade gliomas, cerebral lymphomas and, in some cases, unexpected brain metastases in whole-body PET examinations. As an adjunct to CT and MRI, FDG-PET can make stereotactic radiosurgery more precise in targeting primary or secondary brain cancers and can differentiate necrotic fibrosis from viable cancer tissue during follow-up in cases of abnormal or equivocal MRI results. When available, methionine-(11C) PET delineates low grade gliomas accurately. Several fluorine (18F)-labeled radiopharmaceuticals have been proposed in this setting, with FET and FDOPA apparently the most effective. Four original clinical cases illustrating performances of FET and FDOPA PET in this setting are presented.

[PET in head and neck cancers]. / La TEP dans les cancers des voies aérodigestives supérieures.

FDG PET is useful when cancer in the head or neck (except for tumors of the salivary glands, which cannot be characterized accurately) is diagnosed or suspected but not confirmed by biopsy. It can, for example, find evidence of suspicious lymph nodes in clinically N0 necks, detect foci suggestive of distant metastases or second cancers, and provide useful prognostic information. Because it can be very difficult to identify anatomical structures and landmarks on PET images in the head and neck region, PET/CT fusion is very helpful in this area. In early assessment of chemotherapy, the absence of a significant reduction in FDG uptake after one or two cycles predicts lack of efficacy and thus indicates the need to modify the regimen. Conversely, the disappearance of FDG foci indicates effective treatment and good prognosis but cannot rule out the persistence of any malignant tissue at the end of treatment, especially neoadjuvant. Diagnostic impact is probably greatest in monitoring for recurrence and restaging known recurrence: FDG PET should be performed - perhaps routinely - early enough that curative options are still open, but long enough after the end of treatment to avoid false positive results from inflammation. The strategy and timing of FDG PET during follow-up should be determined in more detail in the future, as should the role (if any) of fluorotyrosine (FET) PET in squamous cell carcinoma.

[FDG-PET in localization of cancers of unknown primary origin]. / Place de la TEP au FDG dans la localisation des cancers de primitif inconnu.

FDG-PET can be successful in localizing the primary cancer when a metastasis is discovered but no primary tumor can be identified (cancer of unknown primary, or CUP) by physical examination, laboratory testing (for tumor markers, for example) or conventional imaging. The greatest number of PET studies in CUP concern secondary lesions in cervical lymph nodes, and PET is an established clinical use (highest ranking, 1A) according to the 3rd German Consensus Conference and an "option" in the French Standards, Options, and Recommendations. Success rates range from 30% to 50% in most studies using PET; a higher rate was reported recently with PET/CT. FDG-PET should be performed sufficiently early in cases of neurological paraneoplastic syndrome, because established lesions become irreversible. Identification of the antibody present helps to specify the organ and FDG-PET can then localize the lesion; together these techniques make it possible to perform curative surgery even when the primary tumor is not visible. The success rate is somewhat lower than in cases of metastasis, around 35%. The clinical utility of PET in other paraneoplastic syndromes has not yet been sufficiently studied, but these conditions are rare. It is precisely in cases with a kind of 'orphan' indication that FDG PET should be considered, as an effective "problem solver".

[PET in primary pulmonary or pleural cancer]. / La TEP dans les cancers bronchopulmonaires ou pleuraux primitifs.

In our hospital as in many others, primary lung cancer is the most frequent indication for FDG PET. Studies have assessed the clinical utility of this imaging modality in characterizing solitary pulmonary nodules or masses, initial staging, defining tumor volume in radiotherapy and searching for recurrence of or restaging non-small cell carcinoma; studies are currently underway to evaluate its use in early assessment of chemotherapy response. Small cell lung cancer has a high FDG uptake and PET/CT can be useful for rapid staging. False negative results may be due to pure bronchioloalveolar carcinomas and endocrine tumors. FDG-PET will certainly play a more important role in the diagnosis and follow-up of pleural cancers in the future. An unexpected positive FDG PET focus should be considered as a warning, but histological proof should precede any irrevocable decisions.

[PET in thyroid cancers]. / La TEP dans le cancer de la glande thyroïde.

FDG PET can detect thyroid cancer in patients referred for exploration of a different cancer. Because of its lack of specificity, however, this modality is not indicated for examination of thyroid nodules: ultrasonography and fine needle biopsy with cytology allow histological diagnosis, which can be completed by iodine-123 scintigraphy when an autonomous nodule is suspected. No information is currently available about the utility of FDG PET in preoperative staging. In follow-up of patients undergoing thyroidectomy for adenocarcinoma, FDG PET is useful for detecting recurrence in cases where serum thyroglobulin levels rise and iodine-131 scintigraphy is negative: surgical resection may be appropriate. Nonetheless FDG PET should be performed more widely and earlier: the initial presence of foci positive for FDG is a major predictor of shorter survival, and most cancer lesions take up either iodine or FDG. In follow-up of medullary carcinoma, FDG PET detects residual tissue better than any other scintigraphic procedures, especially when serum levels of CEA (carcinoembryonic antigen) are rising rapidly. FDOPA PET seems to have better sensitivity than FDG-PET and may be useful in occult recurrence, as three case reports indicate.

[FDG (18 fluorodeoxyglucose) positron emission tomography and breast cancer]. / Tomographie par emission de positons (TEP) au FDG et cancer du sein.

Positron emission tomography (PET) is a metabolic radionuclide imaging method in which a tracer labeled with a positron emitter is detected with a dedicated system. 18F-fluorodeoxyglucose (FDG) accumulates in tumor cells because of their increased glycolytic activity, and is thus widely used as a tracer in oncology. This increased metabolic activity precedes morphologic modifications, making FDG-PET a very useful tool for detecting and staging cancer. It can also be used to characterize morphologic changes, differentiating not only between benign and malignant lesions, but also between viable tumor cells and areas of necrosis and/or fibrosis induced by treatments. Being a whole-body examination, it allows malignancies to be staged in a single procedure. Systems combining PET and CT (computed tomography) offer improved performance, providing both metabolic and anatomical data. This technique appears to be useful for initial breast cancer staging, especially of locally advanced forms and suspected recurrences (increase of isolated tumor marker). Early studies of PET evaluation of responses to hormonal and/or cytotoxic therapies have also given very promising results. However, this technique does not seem sufficiently sensitive to be included in the initial screening or diagnosis of primary tumors, owing to its limited resolution (about 5 mm) and its restricted availability. This approach is poorly sensitive when used for axillary assessment, but offers good specificity.

Detection of hepatocellular carcinoma with PET/CT: a prospective comparison of 18F-fluorocholine and 18F-FDG in patients with cirrhosis or chronic liver disease.

UNLABELLED: This prospective study aimed to compare the diagnostic performance of (18)F-fluorocholine and (18)F-FDG for detecting and staging hepatocellular carcinoma (HCC) in patients with chronic liver disease and suspected liver nodules. METHODS: Whole-body PET/CT was performed in a random order at 10 min after injection of 4 MBq of (18)F-fluorocholine per kilogram and at 1 h after injection of 5 MBq of (18)F-FDG per kilogram. PET/CT results were read in a masked manner by 2 specialists, and diagnostic performance was assessed from the results of consensus masked reading. Those focal lesions appearing with increased or decreased activity, compared with background, on (18)F-fluorocholine PET/CT were considered positive for malignancy. The standard of truth was determined on a per-site basis using data from a histologic examination and a follow-up period of more than 6 mo; on a per-patient basis, the Barcelona criteria were also accepted as a proof of HCC in 5 patients. RESULTS: Eighty-one patients were recruited; standard of truth was determined in 59 cases. HCC was diagnosed in 34 patients. Therefore, sensitivity was 88% for (18)F-fluorocholine and 68% for (18)F-FDG (P = 0.07), and in 70 sites, sensitivity was 84% for (18)F-fluorocholine, significantly better than the 67% for (18)F-FDG (P = 0.01). Of the 11 patients with well-differentiated HCC, 6 had a positive result with (18)F-fluorocholine alone, whereas (18)F-FDG was never positive alone; corresponding site-based sensitivity was 94% for (18)F-fluorocholine and 59% for (18)F-FDG (P = 0.001). The detection rate of 18 sites corresponding to other malignancies was 78% for (18)F-fluorocholine and 89% for (18)F-FDG. In nonmalignant sites, (18)F-fluorocholine appeared less specific than (18)F-FDG (62% vs. 91% P < 0.01) because of uptake by focal nodular hyperplasia. CONCLUSION: (18)F-fluorocholine was significantly more sensitive than (18)F-FDG at detecting HCC, in particular in well-differentiated forms. In contrast, (18)F-FDG appeared somewhat more sensitive at detecting other malignancies and was negative in focal nodular hyperplasia. Thus (18)F-fluorocholine appears to be a useful PET/CT tracer for the detection and surveillance of HCC; however, performing PET/CT with both radiopharmaceuticals seems to be the best option.

Detection of bronchioloalveolar cancer by means of PET/CT and 18F-fluorocholine, and comparison with 18F-fluorodeoxyglucose.

AIM: Bronchioloalveolar (BAC) cancer is a source of false-negative F-fluorodeoxyglucose (FDG) PET/computed tomography (CT) results. A few studies reported better diagnostic performances with PET tracers of lipid metabolism, C-choline, or C-acetate, for the detection of well-differentiated adenocarcinoma or BAC. F-fluorocholine (FCH) is a lipid analogue for PET imaging, with advantages in terms of logistics and image resolution. We carried out this prospective pilot study to evaluate whether FCH PET/CT could detect lung cancer with a BAC component and could be more sensitive than FDG in this aim. METHODS: Fifteen patients with a lung nodule or lesion suspected for BAC on CT and/or with a history of BAC had PET/CT 60-90 min after 5 MBq FDG/kg body mass and, on a separate day, 10-20 min after 4 MBq FCH/kg body mass. The standard of truth was histology and a 6-month follow-up. RESULTS: Nine patients (12 lesions) presented BAC or adenocarcinoma with BAC features, two patients presented adenocarcinoma without BAC features (five lesions) and four patients presented benign lesions (15 non-malignant sites). For both FCH and FDG, patient-based sensitivity was 78% for detecting cancer with a BAC component and 82% for detecting malignancy. Site-based sensitivity for detecting malignancy was 76 and 75% for detecting cancer with BAC features, for both radiopharmaceuticals. Specificity was similar for FCH and FDG (site-based 93 vs. 81%, NS). In these early-stage cancers, only one adrenal metastasis was observed that took up FCH and FDG. CONCLUSION: In this population of patients with ground-glass opacities selected on CT suggestive of BAC or with a history of BAC and a recent lung anomaly on CT, FCH detected all malignant lesions with at least a 2.0 cm short axis. However, FDG had similar performance.

[PET and digestive cancers]. / Tomographie par émission de positons et cancers digestifs.

In digestive oncology, the most frequent indication for FDG PET, in our experience and as reported in the literature, is the localisation of recurrent colorectal cancer. This molecular imaging method has also been shown to be clinically useful in various other settings, especially for preoperative staging, for colorectal, esophageal, gastric, pancreatic, hepatic and biliary cancers. We also report on current PET practice in two particular cancers: hepatocellular carcinoma, for which other tracers, including fluoromethylcholine-(18F), are being currently evaluated, and gastrointestinal endocrine tumours, which are included in the recent French marketing authorisation of fluoroDOPA-(18F) and which are also potential targets for radiolabelled somatostatin analogues for PET imaging.

PET/CT in patients with hepatocellular carcinoma using [(18)F]fluorocholine: preliminary comparison with [(18)F]FDG PET/CT.

PURPOSE: The diagnostic accuracy of [(18)F]fluorodeoxyglucose (FDG) PET is insufficient to characterise hepatocellular carcinoma (HCC) in liver masses and to diagnose all cases of recurrent HCC. HCC has been reported to take up [(11)C]acetate, but routine use of this tracer is difficult. Choline is another tracer of lipid metabolism, present in large amounts in HCC. In a proof-of-concept study, we evaluated [(18)F]fluorocholine (FCH) uptake by HCC and compared FCH PET/CT with FDG PET/CT. METHODS: Twelve patients with newly diagnosed (n=8) or recurrent HCC (n=4) were prospectively enrolled. HCC was assessed by histology in eight cases and by American Association for the Study of Liver Diseases (AASLD) criteria in four cases. All patients underwent whole-body PET/CT 10 min after injection of 4 MBq/kg FCH. Within 1 week, 9 of the 12 patients also underwent whole-body FDG PET/CT 1 h after injection of 5 MBq/kg FDG. RESULTS: The per-patient analysis showed a detection rate of 12/12 using FCH PET/CT for both newly diagnosed and recurrent HCC. The median signal to noise ratio was 1.5+/-0.38. There was a trend towards a higher FCH SUV(max) in well-differentiated HCC (15.6+/-7.9 vs 11.9+/-0.9, NS). Of the nine patients who underwent FCH and FDG PET/CT, all nine were positive with FCH whereas only five were positive with FDG. CONCLUSION: FCH provides a high detection rate for HCC, making it potentially useful in the initial evaluation of HCC or in the detection of recurrent disease. The favourable result of this proof-of-concept study opens the way to a phase III prospective study.