Treatment and long term safety outcomes of Peptide Receptor Radionuclide Therapy for metastatic neuroendocrine tumours: an Asian experience.

Peptide-receptor radionuclide therapy (PRRT) is a targeted molecular therapy used to treat neuroendocrine tumours (NET). It has been shown to be effective and well-tolerated in patients with metastatic neuroendocrine tumours in several centres in United States (US), Europe and Australia. Tolerability and efficacy data emerging from Asian centres remain few. Epidemiological evidence suggests that there are differences in neuroendocrine neoplasms between the population groups. We aim to describe the treatment and safety outcomes of PRRT in the Asian population. Methods One hundred and seven (107) patients with metastatic neuroendocrine tumour who had undergone PRRT treatment from January 2012 to March 2019 were included in this retrospective study. The response rates using RECIST1.1 and qualitative analysis were examined. The overall and progression free survival curves were also evaluated. Results The median progression free survival was 49 months. Response assessment after completion of treatment showed that 33(37.9%) of 87 patients had partial or complete response. Subgroup analysis comparing high- and low-grade NET showed that there was a significant difference in the time to progression curves. Comparison of the number of cycles and progression free and overall survival also showed a significant difference. Ten patients (9%) had grade 3 or more haematological toxicities. Four patients (4%) had grade 3/4 hepatobiliary toxicities, although the presence of extensive liver metastases was a confounding factor. None of the patients had grade 3/4 acute kidney injury. Conclusion Our results show that PRRT is safe and effective in the treatment of metastatic neuroendocrine tumour in the Asian population. There was a significant difference in the progression free survival curves between low-grade and high-grade NET, and in the progression free and overall survival comparing the number of cycles received.

Clinical and demographic pattern of chronic granulomatous disease (CGD) from a multicenter perspective: Malaysia's experience over 26 years.

BACKGROUND: A retrospective review of clinical manifestations and demographic pattern of patients diagnosed as chronic granulomatous disease (CGD) from 7 hospitals in Malaysia. An analysis of the available database would establish clinical characteristics, diagnoses and outcome including microbiologic pattern. Studying the demography allows us to document the occurrence of CGD amongst multiethnic groups and its geographical distribution for Malaysia. METHODS: Data from the Malaysia Primary Immunodeficiency Network (MyPIN) with cases of CGD diagnosed from 1991 until 2016 were collated and analysed. RESULTS: Twenty patients were diagnosed as CGD. Males (N = 13, 65%) outnumber females (N = 7, 35%). CGD is commonest amongst the Malays (65%) followed by the Chinese (15.0%), Indians (10.0%) and natives of Borneo (10.0%), reflecting the ethnic composition of the country. The mean age of diagnosis was 3.7 years. There was a positive family history in 40% of the cases. Abscess was the main presenting feature in 16 patients (80%) with one involving the brain. Pneumonia occurred in 10 (50%) and one with complicated bronchiectasis. Catalase-positive bacteria were the most commonly isolated pathogen with Chromobacterium violaceum predominating (N = 5, 25%) with consequent high mortality (N = 4, 80%). All CGD patients with C. violaceum infection displayed CD4 + (T helper cells) lymphopenia. CONCLUSION: This study has shown CGD occurs in the major ethnic groups of Malaysia. To the best of our knowledge, this is the first and the largest series of chronic granulomatous disease in South East Asia which may be reflective of similar clinical pattern in the region. C. violaceum infection is associated with a higher mortality in CGD patients in Malaysia. All the CGD patients with C. violaceum infection in this patient series displayed CD4 + (T helper) lymphopenia. We recorded rare clinical manifestation of CGD viz. brain abscess and bronchiectasis.

International recommendations for personalised selective internal radiation therapy of primary and metastatic liver diseases with yttrium-90 resin microspheres.

PURPOSE: A multidisciplinary expert panel convened to formulate state-of-the-art recommendations for optimisation of selective internal radiation therapy (SIRT) with yttrium-90 (90Y)-resin microspheres. METHODS: A steering committee of 23 international experts representing all participating specialties formulated recommendations for SIRT with 90Y-resin microspheres activity prescription and post-treatment dosimetry, based on literature searches and the responses to a 61-question survey that was completed by 43 leading experts (including the steering committee members). The survey was validated by the steering committee and completed anonymously. In a face-to-face meeting, the results of the survey were presented and discussed. Recommendations were derived and level of agreement defined (strong agreement ≥ 80%, moderate agreement 50%-79%, no agreement ≤ 49%). RESULTS: Forty-seven recommendations were established, including guidance such as a multidisciplinary team should define treatment strategy and therapeutic intent (strong agreement); 3D imaging with CT and an angiography with cone-beam-CT, if available, and 99mTc-MAA SPECT/CT are recommended for extrahepatic/intrahepatic deposition assessment, treatment field definition and calculation of the 90Y-resin microspheres activity needed (moderate/strong agreement). A personalised approach, using dosimetry (partition model and/or voxel-based) is recommended for activity prescription, when either whole liver or selective, non-ablative or ablative SIRT is planned (strong agreement). A mean absorbed dose to non-tumoural liver of 40 Gy or less is considered safe (strong agreement). A minimum mean target-absorbed dose to tumour of 100-120 Gy is recommended for hepatocellular carcinoma, liver metastatic colorectal cancer and cholangiocarcinoma (moderate/strong agreement). Post-SIRT imaging for treatment verification with 90Y-PET/CT is recommended (strong agreement). Post-SIRT dosimetry is also recommended (strong agreement). CONCLUSION: Practitioners are encouraged to work towards adoption of these recommendations.

SIRveNIB: Selective Internal Radiation Therapy Versus Sorafenib in Asia-Pacific Patients With Hepatocellular Carcinoma.

Purpose Selective internal radiation therapy or radioembolization (RE) shows efficacy in unresectable hepatocellular carcinoma (HCC) limited to the liver. This study compared the safety and efficacy of RE and sorafenib in patients with locally advanced HCC. Patients and Methods SIRveNIB (selective internal radiation therapy v sorafenib), an open-label, investigator-initiated, phase III trial, compared yttrium-90 (90Y) resin microspheres RE with sorafenib 800 mg/d in patients with locally advanced HCC in a two-tailed study designed for superiority/detriment. Patients were randomly assigned 1:1 and stratified by center and presence of portal vein thrombosis. Primary end point was overall survival (OS). Efficacy analyses were performed in the intention-to-treat population and safety analyses in the treated population. Results A total of 360 patients were randomly assigned (RE, 182; sorafenib, 178) from 11 countries in the Asia-Pacific region. In the RE and sorafenib groups, 28.6% and 9.0%, respectively, failed to receive assigned therapy without significant cross-over to either group. Median OS was 8.8 and 10.0 months with RE and sorafenib, respectively (hazard ratio, 1.1; 95% CI, 0.9 to 1.4; P = .36). A total of 1,468 treatment-emergent adverse events (AEs) were reported (RE, 437; sorafenib, 1,031). Significantly fewer patients in the RE than sorafenib group had grade ≥ 3 AEs (36 of 130 [27.7%]) v 82 of 162 [50.6%]; P < .001). The most common grade ≥ 3 AEs were ascites (five of 130 [3.8%] v four of 162 [2.5%] patients), abdominal pain (three [2.3%] v two [1.2%] patients), anemia (zero v four [2.5%] patients), and radiation hepatitis (two [1.5%] v zero [0%] patients). Fewer patients in the RE group (27 of 130 [20.8%]) than in the sorafenib group (57 of 162 [35.2%]) had serious AEs. Conclusion In patients with locally advanced HCC, OS did not differ significantly between RE and sorafenib. The improved toxicity profile of RE may inform treatment choice in selected patients.

National Cancer Centre Singapore Consensus Guidelines for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the 6th most common cancer in the world, but the second most common cause of cancer death. There is no universally accepted consensus practice guidelines for HCC owing to rapid developments in new treatment modalities, the heterogeneous epidemiology and clinical presentation of HCC worldwide. However, a number of regional and national guidelines currently exist which reflect practice relevant to the epidemiology and collective experience of the consensus group. In 2014, clinicians at the multidisciplinary Comprehensive Liver Cancer Clinic (CLCC) at the National Cancer Centre Singapore (NCCS) reviewed the latest published scientific data and existing international and regional practice guidelines, such as those of the National Comprehensive Cancer Network, American Association for the Study of Liver Diseases and the Asian Pacific Association for the Study of the Liver, and modified them to reflect local practice. These would serve as a template by which treatment outcomes can be collated and benchmarked against international data. The NCCS Consensus Guidelines for HCC have been successfully implemented in the CLCC since their publication online on 26(th) September 2014, and the guidelines allow outcomes of treatment to be compared to international data. These guidelines will be reviewed periodically to incorporate new data.

Yttrium-90 hepatic radioembolization: clinical review and current techniques in interventional radiology and personalized dosimetry.

In recent years, yttrium-90 ((90)Y) microsphere radioembolization has been establishing itself as a safe and efficacious treatment for both primary and metastatic liver cancers. This extends to both first-line therapies as well as in the salvage setting. In addition, radioembolization appears efficacious for patients with portal vein thrombosis, which is currently a contraindication for surgery, transplantation and transarterial chemoembolization. This article reviews the efficacy and expanding use of (90)Y microsphere radioembolization with an added emphasis on recent advances in personalized dosimetry and interventional radiology techniques. Directions for future research into combination therapies with radioembolization and expansion into sites other than the liver are also explored.

Gender, Race, and Age at Diagnosis as Risk Factors for Metastasis or Recurrence among 1,657 Thyroid Cancer Patients Treated with Radioiodine across 40 Years in Singapore.

BACKGROUND: To obtain descriptive data on Singaporean thyroid cancer patients treated with radioiodine and to assess gender, race, and age at diagnosis as risk factors for metastasis or recurrence. METHODS: This is a retrospective study of all thyroid cancer patients treated with radioiodine of any prescribed activity at our institution. Data collected included: age at diagnosis, gender, race, histopathological type, duration of follow-up, and metastasis at diagnosis (locoregional or distant) or recurrence at any time. Gender, race, and age at diagnosis were analyzed for possible associations with metastasis or recurrence. RESULTS: A total of 1,657 thyroid cancer patients were treated with radioiodine across a 40-year period; mean follow-up 6.4 ± 6.9 years (median 4.2 years). 656 (39.6%) patients had metastasis or recurrence over the duration of their follow-up. Male gender (odds ratio (OR) 1.38; p = 0.006), Malay race (OR 1.71; p < 0.0001), and age at diagnosis of > 46 years (OR 1.31; p = 0.007) were significantly associated with metastasis or recurrence. CONCLUSION: Male gender, Malay race, and age at diagnosis of > 46 years were significant risk factors for metastasis or recurrence in Singaporean thyroid cancer patients treated with radioiodine.

Non-Target Activity Detection by Post-Radioembolization Yttrium-90 PET/CT: Image Assessment Technique and Case Examples.

High resolution yttrium-90 ((90)Y) imaging of post-radioembolization microsphere biodistribution may be achieved by conventional positron emission tomography with integrated computed tomography (PET/CT) scanners that have time-of-flight capability. However, reconstructed (90)Y PET/CT images have high background noise, making non-target activity detection technically challenging. This educational article describes our image assessment technique for non-target activity detection by (90)Y PET/CT, which qualitatively overcomes the problem of background noise. We present selected case examples of non-target activity in untargeted liver, stomach, gallbladder, chest wall, and kidney, supported by angiography and (90)Y bremsstrahlung single-photon emission computed tomography with integrated computed tomography (SPECT/CT) or technetium-99m macroaggregated albumin SPECT/CT.

The potential of hybrid SPECT/CT fusion imaging to improve diagnostic accuracy in the scintigraphic quantitative functional assessment of suspected unilateral mandibular hyperactivity.

BACKGROUND: Mandibular asymmetry is commonly caused by disproportionate mandibular growth due to unilateral condylar hyperactivity. The current standard for mandibular condyle bone scintigraphy uses single photon emission computed tomography (SPECT) imaging after intravenous administration of technetium-99m-labeled diphosphates. To our knowledge, the use of hybrid SPECT integrated with multidetector computed tomography (SPECT/CT) imaging in the scintigraphic quantitative functional assessment of mandibular condyle growth has not yet been described. CASE REPORT: A 22-year-old male with mandibular asymmetry due to suspected unilateral condylar hyperactivity underwent SPECT/CT imaging of the skull and facial bones after intravenous administration of technetium-99m methylene diphosphonate. Using CT to guide anatomical contouring, precise regions of interest were drawn over the mandibular condyles and clivus in adjacent SPECT/CT transaxial slices to calculate the mean radiotracer count ratios. For comparison of quantitative results, conventional SPECT images were obtained from the SPECT/CT data and processed according to conventional methods. Planar images were also obtained for visual assessment of mandibular condyle activity. All three methods, SPECT/CT, conventional SPECT, and planar imaging, found unilateral condylar hyperactivity of the left mandibular condyle. The condyles and clivus were easily and confidently identified on SPECT/CT images. DISCUSSION: We speculate that SPECT/CT imaging will improve the diagnostic accuracy of unilateral condylar hyperactivity. More studies are necessary to further define its role, obtain baseline reference values, and establish analysis protocols.

Dosimetric considerations in radioimmunotherapy and systemic radionuclide therapies: a review.

Radiopharmaceutical therapy, once touted as the "magic bullet" in radiation oncology, is increasingly being used in the treatment of a variety of malignancies; albeit in later disease stages. With ever-increasing public and medical awareness of radiation effects, radiation dosimetry is becoming more important. Dosimetry allows administration of the maximum tolerated radiation dose to the tumor/organ to be treated but limiting radiation to critical organs. Traditional tumor dosimetry involved acquiring pretherapy planar scans and plasma estimates with a diagnostic dose of intended radiopharmaceuticals. New advancements in single photon emission computed tomography and positron emission tomography systems allow semi-quantitative measurements of radiation dosimetry thus allowing treatments tailored to each individual patient.

Positron emission tomography with 2-deoxy-2-[18f] fluoro-D-glucose in the detection of malignancy in intraductal papillary mucinous neoplasms of the pancreas.

A 79-year-old Indian male was admitted with upper abdominal discomfort of 1-year duration which was associated with loss of weight and appetite. Serum tumor markers, including carcinoembryonic antigen and carbohydrate antigen 19-9, were within normal limits. A computed tomographic scan demonstrated a cystically dilated and tortuous pancreatic duct measuring 1.9 cm, suggestive of an intraductal papillary mucinous neoplasm. Fusion positron emission tomography/computed tomography with 2-deoxy-2-[18F] fluoro-D-glucose positron emission tomography (FDG-PET/CT) which was subsequently performed confirmed a metabolically active focus within the pancreatic head mass with a standard uptake value (SUVmax) of 3.5 compatible with carcinoma. A total pancreatectomy was performed and the final histology demonstrated a main-duct type intraductal papillary mucinous neoplasm with a focus of high-grade dysplasia compatible with carcinoma-in-situ. These images illustrate the emerging utility of FDG-PET/CT in the preoperative detection of malignancy in intraductal papillary mucinous neoplasm.

Positron emission tomography with CT in the evaluation of non-small cell lung cancer in populations with a high prevalence of tuberculosis.

OBJECTIVE AND BACKGROUND: To determine the utility of positron emission tomography with CT (PET-CT) in the evaluation of non-small cell lung cancer (NSCLC) in an Asian context where tuberculosis rates are moderately high. METHODS: Case records of consecutive patients with NSCLC undergoing PET-CT at the Singapore General Hospital over a 1-year period were retrospectively reviewed. The authors evaluated the sensitivity and specificity of PET-CT at their institution using surgical pathology or the tincture of time as the gold standard. RESULTS: A total of 54 patients underwent PET-CT during this period. Seven patients were evaluated for solitary pulmonary nodule, for which PET-CT gave a sensitivity of 100% and specificity of 75%. There was one patient with false positive PET-CT due to active tuberculosis. In total, 41 patients underwent PET-CT for staging of NSCLC. There was one false positive (patient was found to have active tuberculous lymphadenitis) and one false negative for NSCLC. This gave a sensitivity of 92.3% and a specificity of 95%. Histology from the adrenal glands was available in two patients with PET-CT that was positive for adrenal metastases. One proved to be benign whereas the other was consistent with metastasis. Two patients had PET-CT positive for liver metastases, which was verified by histology. Two patients with positive PET-CT for lesions in the colon turned out to be benign histologically. CONCLUSIONS: Positron emission tomography with CT for the evaluation and follow-up of solitary pulmonary nodule and NSCLC can provide additional useful information to conventional radiology for treatment planning and a non-invasive determination of prognosis. However, physicians need to be aware of the limitations of this imaging modality, particularly when tuberculosis has a high prevalence in the population.