Complete metabolic response with [18 F]fluorodeoxyglucose-positron emission tomography/computed tomography predicts survival following induction chemotherapy and radical cystectomy in clinically lymph node positive bladder cancer.

OBJECTIVE: To determine whether repeated [18 F]fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET-CT) scans can predict increased cancer-specific survival (CSS) after induction chemotherapy followed by radical cystectomy (RC). PATIENTS AND METHODS: Between 2007 and 2018, 86 patients with clinically lymph node (LN)-positive bladder cancer (T1-T4, N1-N3, M0-M1a) were included and underwent a repeated FDG-PET-CT during cisplatin-based induction chemotherapy. The 71 patients that had a response to chemotherapy underwent RC. Response to chemotherapy was evaluated in LNs through repeated FDG-PET-CT and stratified as partial response or complete response using three different methods: maximum standardised uptake value (SUVmax ), adapted Deauville criteria, and total lesion glycolysis (TLG). Progression-free survival (PFS) and CSS were analysed for all three methods by Cox regression analysis. RESULTS: After a median follow-up of 40 months, 15 of the 71 patients who underwent RC had died from bladder cancer. Using SUVmax and the adapted Deauville criteria, multivariable Cox regression analyses adjusting for age, clinical tumour stage and LN stage showed that complete response was associated with increased PFS (hazard ratio [HR] 3.42, 95% confidence interval [CI] 1.20-9.77) and CSS (HR 3.30, 95% CI 1.02-10.65). Using TLG, a complete response was also associated with increased PFS (HR 5.17, 95% CI 1.90-14.04) and CSS (HR 6.32, 95% CI 2.06-19.41). CONCLUSIONS: Complete metabolic response with FDG-PET-CT predicts survival after induction chemotherapy followed by RC in patients with LN-positive bladder cancer and comprises a novel tool in evaluating response to chemotherapy before surgery. This strategy has the potential to tailor treatment in individual patients by identifying significant response to chemotherapy, which motivates the administration of a full course of induction chemotherapy with a higher threshold for suspending treatment due to toxicity and side-effects.

Comparison of conventional and Si-photomultiplier-based PET systems for image quality and diagnostic performance.

BACKGROUND: A new generation of positron emission tomography with computed tomography (PET-CT) was recently introduced using silicon (Si) photomultiplier (PM)-based technology. Our aim was to compare the image quality and diagnostic performance of a SiPM-based PET-CT (Discovery MI; GE Healthcare, Milwaukee, WI, USA) with a time-of-flight PET-CT scanner with a conventional PM detector (Gemini TF; Philips Healthcare, Cleveland, OH, USA), including reconstruction algorithms per vendor's recommendations. METHODS: Imaging of the National Electrical Manufacturers Association IEC body phantom and 16 patients was carried out using 1.5 min/bed for the Discovery MI PET-CT and 2 min/bed for the Gemini TF PET-CT. Images were analysed for recovery coefficients for the phantom, signal-to-noise ratio in the liver, standardized uptake values (SUV) in lesions, number of lesions and metabolic TNM classifications in patients. RESULTS: In phantom, the correct (> 90%) activity level was measured for spheres ≥17 mm for Discovery MI, whereas the Gemini TF reached a correct measured activity level for the 37-mm sphere. In patient studies, metabolic TNM classification was worse using images obtained from the Discovery MI compared those obtained from the Gemini TF in 4 of 15 patients. A trend toward more malignant, inflammatory and unclear lesions was found using images acquired with the Discovery MI compared with the Gemini TF, but this was not statistically significant. Lesion-to-blood-pool SUV ratios were significantly higher in images from the Discovery MI compared with the Gemini TF for lesions smaller than 1 cm (p < 0.001), but this was not the case for larger lesions (p = 0.053). The signal-to-noise ratio in the liver was similar between platforms (p = 0.52). Also, shorter acquisition times were possible using the Discovery MI, with preserved signal-to-noise ratio in the liver. CONCLUSIONS: Image quality was better with Discovery MI compared to conventional Gemini TF. Although no gold standard was available, the results indicate that the new PET-CT generation will provide potentially better diagnostic performance.

Impact of acquisition time and penalizing factor in a block-sequential regularized expectation maximization reconstruction algorithm on a Si-photomultiplier-based PET-CT system for 18F-FDG.

BACKGROUND: Block-sequential regularized expectation maximization (BSREM), commercially Q. Clear (GE Healthcare, Milwaukee, WI, USA), is a reconstruction algorithm that allows for a fully convergent iterative reconstruction leading to higher image contrast compared to conventional reconstruction algorithms, while also limiting noise. The noise penalization factor ß controls the trade-off between noise level and resolution and can be adjusted by the user. The aim was to evaluate the influence of different ß values for different activity time products (ATs = administered activity × acquisition time) in whole-body 18F-fluorodeoxyglucose (FDG) positron emission tomography with computed tomography (PET-CT) regarding quantitative data, interpretation, and quality assessment of the images. Twenty-five patients with known or suspected malignancies, referred for clinical 18F-FDG PET-CT examinations acquired on a silicon photomultiplier PET-CT scanner, were included. The data were reconstructed using BSREM with ß values of 100-700 and ATs of 4-16 MBq/kg × min/bed (acquisition times of 1, 1.5, 2, 3, and 4 min/bed). Noise level, lesion SUVmax, and lesion SUVpeak were calculated. Image quality and lesion detectability were assessed by four nuclear medicine physicians for acquisition times of 1.0 and 1.5 min/bed position. RESULTS: The noise level decreased with increasing ß values and ATs. Lesion SUVmax varied considerably between different ß values and ATs, whereas SUVpeak was more stable. For an AT of 6 (in our case 1.5 min/bed), the best image quality was obtained with a ß of 600 and the best lesion detectability with a ß of 500. AT of 4 generated poor-quality images and false positive uptakes due to noise. CONCLUSIONS: For oncologic whole-body 18F-FDG examinations on a SiPM-based PET-CT, we propose using an AT of 6 (i.e., 4 MBq/kg and 1.5 min/bed) reconstructed with BSREM using a ß value of 500-600 in order to ensure image quality and lesion detection rate as well as a high patient throughput. We do not recommend using AT < 6 since the risk of false positive uptakes due to noise increases.

A Prospective Observational Study to Evaluate the Effects of Long-Acting Somatostatin Analogs on 68Ga-DOTATATE Uptake in Patients with Neuroendocrine Tumors.

Patients with neuroendocrine tumors (NETs) are often treated with somatostatin analogs (SSAs) for control of symptoms and tumor growth. Such therapy could theoretically lead to misinterpretation of somatostatin receptor imaging with 68Ga-DOTATATE PET/CT by interfering with tracer-receptor binding. Guidelines recommend an interval of 3-4 wk between the last dose and imaging. The aim of this study was to evaluate if long-acting (LA) SSA treatment changes the uptake of 68Ga-DOTATATE in patients with NETs. Methods: From 2013 to 2016, 296 patients with, or under evaluation for, NETs were included in this prospective observational study. The effect of LA SSA on tracer uptake was evaluated in 2 main patient populations: those undergoing 68Ga-DOTATATE PET/CT before starting LA SSA treatment and at least once afterward, and those receiving ongoing LA SSA therapy, in whom the effect of the interval between the last dose of LA SSA and the PET/CT exam was analyzed. A third, explorative, analysis was performed to evaluate if clinical disease progression, regression, or stable tumor status changed the uptake of 68Ga-DOTATATE. In the 3 analyses, measurements of SUVmax in normal liver and tumor lesions were compared. Results: The median SUVmax in normal liver was significantly higher before treatment (8.6; interquartile range, 7.4-10.2) than after treatment initiation (6.0; 4.7-8.0) (P < 0.001). No significant changes in SUVmax were seen in tumor lesions after treatment initiation. No significant differences in SUVmax were found in normal liver or tumor lesions dependent on the interval between last dose of LA SSA and PET/CT. Conclusion: Treatment with LA SSA does not change SUVmax in tumor lesions, whereas SUVmax in normal liver is significantly lower after treatment. The findings have implications for interpretation of 68Ga-DOTATATE PET/CT for response assessment after SSA therapy and for guidelines on discontinuation of treatment before PET/CT.

Impact of penalizing factor in a block-sequential regularized expectation maximization reconstruction algorithm for 18F-fluorocholine PET-CT regarding image quality and interpretation.

BACKGROUND: Recently, the block-sequential regularized expectation maximization (BSREM) reconstruction algorithm was commercially introduced (Q.Clear, GE Healthcare, Milwaukee, WI, USA). However, the combination of noise-penalizing factor (ß), acquisition time, and administered activity for optimal image quality has not been established for 18F-fluorocholine (FCH). The aim was to compare image quality and diagnostic performance of different reconstruction protocols for patients with prostate cancer being examined with 18F-FCH on a silicon photomultiplier-based PET-CT. Thirteen patients were included, injected with 4 MBq/kg, and images were acquired after 1 h. Images were reconstructed with frame durations of 1.0, 1.5, and 2.0 min using ß of 150, 200, 300, 400, 500, and 550. An ordered subset expectation maximization (OSEM) reconstruction with a frame duration of 2.0 min was used for comparison. Images were quantitatively analyzed regarding standardized uptake values (SUV) in metastatic lymph nodes, local background, and muscle to obtain contrast-to-noise ratios (CNR) as well as the noise level in muscle. Images were analyzed regarding image quality and number of metastatic lymph nodes by two nuclear medicine physicians. RESULTS: The highest median CNR was found for BSREM with a ß of 300 and a frame duration of 2.0 min. The OSEM reconstruction had the lowest median CNR. Both the noise level and lesion SUVmax decreased with increasing ß. For a frame duration of 1.5 min, the median quality score was highest for ß 400-500, and for a frame duration of 2.0 min the score was highest for ß 300-500. There was no statistically significant difference in the number of suspected lymph node metastases between the different image series for one of the physicians, and for the other physician the number of lymph nodes differed only for one combination of image series. CONCLUSIONS: To achieve acceptable image quality at 4 MBq/kg 18F-FCH, we propose using a ß of 400-550 with a frame duration of 1.5 min. The lower ß should be used if a high CNR is desired and the higher if a low noise level is important.

Pre-treatment 18F-choline PET/CT is prognostic for biochemical recurrence, development of bone metastasis, and cancer specific mortality following radical local therapy of high-risk prostate cancer.

BACKGROUND: The aim of this study was to determine whether lymph node metastasis on pre-treatment 18F-choline PET/CT is an independent prognostic factor for biochemical recurrence (BCR), skeletal metastasis, and cancer specific mortality (CSM), after radical local treatment (radical prostatectomy and/or radiotherapy) in men with high-risk prostate cancer. Medical records were reviewed for men with newly diagnosed high-risk prostate cancer who had pre-treatment 18F-choline positron emission tomography fused with computed tomography (PET/CT) scan for primary metastasis staging. RESULTS: Of 174 eligible men, 124 met the criteria for inclusion. The PET/CT scan was negative for metastasis in 97 (78%) men, inconclusive in 15 (12%), and positive in 12 (10%). The men with a positive PET/CT scan had significantly shorter time to BCR (p = 0.02), time to skeletal metastasis (p = 0.002), and time to prostate cancer specific death (p < 0.001). On multivariable Cox regression analysis, including also tumour stage, Gleason score, and PSA, a non-negative PET/CT scan was the only significant covariate for time to BCR (HR 2.6, 95% CI 1.3-5.5) and time to skeletal metastasis (HR 2.7, 95% CI 1.3-5.9). CONCLUSIONS: In men with a newly diagnosed high-risk prostate cancer and a negative or inconclusive bone scan, 18F-choline uptake on PET/CT suggestive metastasis was associated with recurrence, progression to distant metastasis, and prostate cancer death. This strongly indicates that the choline uptakes represented metastasis and not false positive findings.

[18F]Fluorodeoxyglucose-positron emission tomography/computed tomography response evaluation can predict histological response at surgery after induction chemotherapy for oligometastatic bladder cancer.

OBJECTIVE: Patients with limited metastatic and locally advanced bladder cancer have a poor prognosis, and no definite treatment recommendations exist. However, long-term survival is possible for selected patients if surgery is combined with multiple courses of chemotherapy (i.e. induction chemotherapy). Patients with tumours that are insensitive to chemotherapy probably have little to gain from subsequent extensive surgery. The aim of this study was to evaluate sequential FDG-PET/CT examinations as an indicator of chemotherapy response. MATERIALS AND METHODS: Between 2007 and 2015, 50 patients with oligometastatic invasive bladder cancer selected for induction chemotherapy underwent two FDG-PET/CT examinations: the first before the start of chemotherapy and the second after three courses of cisplatinum-based combination chemotherapy. Responders were given up to six courses of chemotherapy. FDG-PET/CT response was correlated with histological response in excised lymph-node metastases. RESULTS: Three patients showed progression to incurable disease during chemotherapy and another two patients did not undergo surgery, for medical reasons. Lymphadenectomy was performed in the remaining 45 patients, of whom 43 had lymph-node metastasis. FDG-PET/CT prediction of the histological nodal chemotherapy response was correct in 37 (86%) of those 43. The second FDG-PET/CT examination identified four out of nine non-responders. For response, the sensitivity, specificity, and positive and negative predictive values for FDG-PET/CT accuracy were 37 out of 37 (100%), one out of six (17%), 37 out of 42 (88%) and one out of one (100%), respectively. CONCLUSIONS: Repeated FDG-PET/CT seems to predict histological response. However, with the histological response criteria used in this study, five non-responders were not identified by the second FDG-PET/CT investigation.

PET-CT for staging and early response: results from the Response-Adapted Therapy in Advanced Hodgkin Lymphoma study.

International guidelines recommend that positron emission tomography-computed tomography (PET-CT) should replace CT in Hodgkin lymphoma (HL). The aims of this study were to compare PET-CT with CT for staging and measure agreement between expert and local readers, using a 5-point scale (Deauville criteria), to adapt treatment in a clinical trial: Response-Adapted Therapy in Advanced Hodgkin Lymphoma (RATHL). Patients were staged using clinical assessment, CT, and bone marrow biopsy (RATHL stage). PET-CT was performed at baseline (PET0) and after 2 chemotherapy cycles (PET2) in a response-adapted design. PET-CT was reported centrally by experts at 5 national core laboratories. Local readers optionally scored PET2 scans. The RATHL and PET-CT stages were compared. Agreement among experts and between expert and local readers was measured. RATHL and PET0 stage were concordant in 938 (80%) patients. PET-CT upstaged 159 (14%) and downstaged 74 (6%) patients. Upstaging by extranodal disease in bone marrow (92), lung (11), or multiple sites (12) on PET-CT accounted for most discrepancies. Follow-up of discrepant findings confirmed the PET characterization of lesions in the vast majority. Five patients were upstaged by marrow biopsy and 7 by contrast-enhanced CT in the bowel and/or liver or spleen. PET2 agreement among experts (140 scans) with a κ (95% confidence interval) of 0.84 (0.76-0.91) was very good and between experts and local readers (300 scans) at 0.77 (0.68-0.86) was good. These results confirm PET-CT as the modern standard for staging HL and that response assessment using Deauville criteria is robust, enabling translation of RATHL results into clinical practice.

A prospective study of positron emission tomography for evaluation of neck node response 6 weeks after radiotherapy in patients with head and neck squamous cell carcinoma.

BACKGROUND: The purpose of this study was to evaluate if a positron emission tomography (PET) scan, 6 weeks after radiotherapy (RT), adequately selects patients in whom a neck node dissection can be omitted. Primary endpoints were isolated neck recurrences and overall survival (OS). METHODS: One hundred five patients, mainly with oropharyngeal human papillomavirus (HPV)-positive tumors, with a positive PET scan before treatment, were evaluated regarding the neck response 6 weeks post-RT. The PET results determined the management of the neck: observation versus neck dissection. RESULTS: Median follow-up was 25 months. Positive predictive value (PPV) and negative predictive value (NPV) were 56% and 94%, respectively. Four isolated neck recurrences occurred. The 2-year OS rate was 86.3%. CONCLUSION: PET scans performed 6 weeks after RT have a high NPV and can obviate neck dissections but the PPV is insufficient. A later scheduled scan is recommended. © 2015 Wiley Periodicals © 2015 Wiley Periodicals, Inc. Head Neck 38: E473-E479, 2016.

(18)F-choline PET/CT for early detection of metastases in biochemical recurrence following radical prostatectomy.

PURPOSE: Salvage radiotherapy (SRT) for biochemical recurrence (BCR) following radical prostatectomy (RP) should if possible be added at a prostate-specific antigen (PSA) level of <1-2 ng/mL. The value of positron emission tomography combined with computed tomography (PET/CT) at such low PSA values is not defined. The purpose was to determine what proportion of a well-defined cohort of hormone-naïve patients who were candidates for early salvage radiotherapy had (18)F-choline PET/CT findings suggesting metastases. MATERIALS AND METHODS: Patients with untreated BCR following RP, PSA <2 ng/mL, and Gleason score ≥7 or PSA doubling time ≤6 months underwent (18)F-choline PET/CT. Focal choline uptake in lymph nodes or skeletal sites was recorded. RESULTS: PET/CT indicated metastases in 16 (28 %) of 58 patients. In five (9 %) patients, the scans suggested bone metastases, and in 11 (19 %) patients, the scans suggested regional lymph node metastases only. For patients with PSA levels <1.0 ng/mL, the PET/CT scans indicated metastatic recurrence in 25 %. CONCLUSIONS: (18)F-choline PET/CT may be valuable for selecting patients with BCR following RP for SRT or experimental treatment of oligometastases, even at low PSA values.

[(18)F]Fluorodeoxyglucose - positron emission tomography/computed tomography improves staging in patients with high-risk muscle-invasive bladder cancer scheduled for radical cystectomy.

OBJECTIVE: The aim of this study was to evaluate the clinical use of [(18)F]fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) in addition to conventional preoperative radiological investigations in a defined group of patients with high-risk muscle-invasive bladder cancer. MATERIALS AND METHODS: In total, 103 patients with high-risk muscle-invasive bladder cancer defined as stage T3/T4 disease or as stage T2 with hydronephrosis or high-risk histological features, who were provisionally scheduled to undergo cystectomy, were prospectively recruited to the study. The patients were referred to FDG-PET/CT in addition to standard preoperative investigation with computed tomography (CT). The final treatment decision was reached at a multidisciplinary conference based on all available information including the FDG-PET/CT findings. RESULTS: Compared to CT alone, FDG-PET/CT provided more supplemental findings suggesting malignant manifestations in 48 (47%) of the 103 patients. The additional FDG-PET/CT findings led to an altered provisional treatment plan in 28 out of 103 patients (27%), detection of disseminated bladder cancer and subsequent cancellation of the initially intended cystectomy in 16 patients, and identification of disseminated disease and treatment with induction chemotherapy before radical cystectomy in 12 patients. CONCLUSIONS: Preoperative FDG-PET/CT changed the treatment plan for a considerable proportion (27%) of the present patients. Accordingly, such examination can potentially improve the preoperative staging of cystectomy patients with high-risk features, and may also reduce the number of futile operations in patients with advanced disease who are beyond cure.

Radiotherapy response in head and neck cancer - evaluation of the primary tumour site.

CONCLUSION: PET-CT scans seem to be sufficient to rule out residual tumour at the primary site. Patients with positive or equivocal PET findings should be scheduled for endoscopy with biopsy or a second PET-CT scan. OBJECTIVES: Assessment of remission at the primary site, in patients treated with organ preservation therapy with curative intent, is important to identify residual tumours requiring treatment with salvage surgery. The aim of this study was to evaluate the diagnostic accuracy of fluorodeoxyglucose positron emission tomography (FDG-PET) after radiotherapy with or without chemotherapy in assessing primary site response in patients with head and neck cancer. METHODS: A total of 82 patients, with a positive baseline PET-CT scan before start of treatment, were evaluated with a PET-CT scan 6-7 weeks post-radiotherapy and with a clinical examination/endoscopy with or without biopsy 1-2 weeks later. The majority of patients had p16-positive oropharyngeal tumours. RESULTS: Post-treatment, 77% of the patients had no visible hypermetabolism. If equivocal PET scans are regarded as positive, the sensitivity, specificity, negative (NPV) and positive predictive value (PPV) and accuracy were 100%, 78%, 100%, 6% and 78%, respectively. Eight patients suffered from relapses involving the primary site during the 9-month follow-up.

Combined 18F-fluorocholine and 18F-fluoride positron emission tomography/computed tomography imaging for staging of high-risk prostate cancer.

OBJECTIVE: To investigate how often positron emission tomography/computed tomography (PET/CT) scans, with both (18)F-fluorocholine and (18)F-fluoride as markers, add clinically relevant information for patients with prostate cancer who have high-risk tumours and a normal or inconclusive planar bone scan. PATIENTS AND METHODS: Patients with prostate cancer with prostate specific antigen (PSA) levels between 20 and 99 ng/mL and/or Gleason score 8-10 tumours, planned for treatment with curative intent based on routine staging with a negative or inconclusive bone scan, were further investigated with a (18)F-fluorocholine and a (18)F-fluoride PET/CT. None of the patients received hormonal therapy before the staging procedures were completed. RESULTS: For 50 of the 90 included patients (56%) one or both PET/CT scans indicated metastases. (18)F-fluorocholine PET/CT indicated lymph node metastases and/or bone metastases in 35 patients (39%). (18)F-fluoride PET/CT was suggestive for bone metastases in 37 patients (41%). In 18 patients (20%) the PET/CT scans indicated widespread metastases, leading to a change in therapy intent from curative to non-curative. Of the patients with positive scans, 74% had Gleason score 8-10 tumours. Of the patients with Gleason score 8-10 tumours, 64% had positive scans. CONCLUSIONS: PET/CT scans with (18)F-fluorocholine and (18)F-fluoride commonly detect metastases in patients with high-risk prostate cancer and a negative or inconclusive bone scan. For 20% of the patients the results of the PET/CT scans changed the treatment plan.

Concordance between four European centres of PET reporting criteria designed for use in multicentre trials in Hodgkin lymphoma.

PURPOSE: To determine if PET reporting criteria for the Response Adapted Treatment in Hodgkin Lymphoma (RATHL) trial could enable satisfactory agreement to be reached between 'core' laboratories operating in different countries. METHODS: Four centres reported scans from 50 patients with stage II-IV HL, acquired before and after two cycles of Adriamycin/bleomycin/vinblastine/dacarbazine. A five-point scale was used to score response scans using 'normal' mediastinum and liver as reference levels. Centres read scans independently of each other. The level of agreement between centres was determined assuming (1) that uptake in sites involved at diagnosis that was higher than liver uptake represented disease (conservative reading), and (2) that uptake in sites involved at diagnosis that was higher than mediastinal uptake represented disease (sensitive reading). RESULTS: There was agreement that the response scan was 'positive' or 'negative' for lymphoma in 44 patients with a conservative reading and in 41 patients with a sensitive reading. Kappa was 0.85 (95% CI 0.74-0.96) for conservative reading and 0.79 (95% CI 0.67-0.90) for sensitive reading. Agreement was reached in 46 and 44 patients after discussion for the conservative and sensitive readings, respectively. CONCLUSION: The criteria developed for reporting in the RATHL trial are sufficiently robust to be used in a multicentre setting.