[177Lu]Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-resistant prostate cancer (ENZA-p): an open-label, multicentre, randomised, phase 2 trial.

BACKGROUND: Enzalutamide and lutetium-177 [177Lu]Lu-prostate-specific membrane antigen (PSMA)-617 both improve overall survival in patients with metastatic castration-resistant prostate cancer. Androgen and PSMA receptors have a close intracellular relationship, with data suggesting complementary benefit if targeted concurrently. In this study, we assessed the activity and safety of enzalutamide plus adaptive-dosed [177Lu]Lu-PSMA-617 versus enzalutamide alone as first-line treatment for metastatic castration-resistant prostate cancer. METHODS: ENZA-p was an open-label, randomised, controlled phase 2 trial done at 15 hospitals in Australia. Participants were men aged 18 years or older with metastatic castration-resistant prostate cancer not previously treated with docetaxel or androgen receptor pathway inhibitors for metastatic castration-resistant prostate cancer, gallium-68 [68Ga]Ga-PSMA-PET-CT (PSMA-PET-CT) positive disease, Eastern Cooperative Oncology Group performance status of 0-2, and at least two risk factors for early progression on enzalutamide. Participants were randomly assigned (1:1) by a centralised, web-based system using minimisation with a random component to stratify for study site, disease burden, use of early docetaxel, and previous treatment with abiraterone acetate. Patients were either given oral enzalutamide 160 mg daily alone or with adaptive-dosed (two or four doses) intravenous 7·5 GBq [177Lu]Lu-PSMA-617 every 6-8 weeks dependent on an interim PSMA-PET-CT (week 12). The primary endpoint was prostate-specific antigen (PSA) progression-free survival, defined as the interval from the date of randomisation to the date of first evidence of PSA progression, commencement of non-protocol anticancer therapy, or death. The analysis was done in the intention-to-treat population, using stratified Cox proportional hazards regression. This trial is registered with ClinicalTrials.gov, NCT04419402, and participant follow-up is ongoing. FINDINGS: 162 participants were randomly assigned between Aug 17, 2020, and July 26, 2022. 83 men were assigned to the enzalutamide plus [177Lu]Lu-PSMA-617 group, and 79 were assigned to the enzalutamide group. Median follow-up in this interim analysis was 20 months (IQR 18-21), with 32 (39%) of 83 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 16 (20%) of 79 patients in the enzalutamide group remaining on treatment at the data cutoff date. Median age was 71 years (IQR 64-76). Median PSA progression-free survival was 13·0 months (95% CI 11·0-17·0) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 7·8 months (95% CI 4·3-11·0) in the enzalutamide group (hazard ratio 0·43, 95% CI 0·29-0·63, p<0·0001). The most common adverse events (all grades) were fatigue (61 [75%] of 81 patients), nausea (38 [47%]), and dry mouth (32 [40%]) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and fatigue (55 [70%] of 79), nausea (21 [27%]), and constipation (18 [23%]) in the enzalutamide group. Grade 3-5 adverse events occurred in 32 (40%) of 81 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 32 (41%) of 79 patients in the enzalutamide group. Grade 3 events that occurred only in the enzalutamide plus [177Lu]Lu-PSMA-617 group included anaemia (three [4%] of 81 participants) and decreased platelet count (one [1%] participant). No grade 4 or 5 events were attributed to treatment on central review in either group. INTERPRETATION: The addition of [177Lu]Lu-PSMA-617 to enzalutamide improved PSA progression-free survival providing evidence of enhanced anticancer activity in patients with metastatic castration-resistant prostate cancer with risk factors for early progression on enzalutamide and warrants further evaluation of the combination more broadly in metastatic prostate cancer. FUNDING: Prostate Cancer Research Alliance (Movember and Australian Federal Government), St Vincent's Clinic Foundation, GenesisCare, Roy Morgan Research, and Endocyte (a Novartis company).

Overall survival with [177Lu]Lu-PSMA-617 versus cabazitaxel in metastatic castration-resistant prostate cancer (TheraP): secondary outcomes of a randomised, open-label, phase 2 trial.

BACKGROUND: The TheraP study reported improved prostate-specific antigen responses with lutetium-177 [177Lu]Lu-PSMA-617 versus cabazitaxel in men with metastatic castration-resistant prostate cancer progressing after docetaxel. In this Article, we report the secondary outcome of overall survival with mature follow-up, and an updated imaging biomarker analysis. We also report the outcomes of participants excluded due to ineligibility on gallium-68 [68Ga]Ga-PSMA-11 and 2-[18F]fluoro-2-deoxy-D-glucose (2-[18F]FDG) PET-CT. METHODS: TheraP was an open-label, randomised phase 2 trial at 11 centres in Australia. Eligible participants had metastatic castration-resistant prostate cancer progressing after docetaxel, and PET imaging with [68Ga]Ga-PSMA-11 and 2-[18F]FDG that showed prostate-specific membrane antigen (PSMA)-positive disease and no sites of metastatic disease with discordant 2-[18F]FDG-positive and PSMA-negative findings. Participants were randomly assigned (1:1) to treatment with [177Lu]Lu-PSMA-617 (every 6 weeks for a maximum of six cycles; starting at 8·5 GBq, decreasing by 0.5 GBq to 6·0 GBq for the sixth cycle) versus cabazitaxel (20 mg/m2 every 3 weeks, maximum of ten cycles). Overall survival was analysed by intention-to-treat and summarised as restricted mean survival time (RMST) to account for non-proportional hazards, with a 36-month restriction time corresponding to median follow-up. This trial is registered with ClinicalTrials.gov, NCT03392428, and is complete. FINDINGS: 291 men were registered from Feb 6, 2018, to Sept 3, 2019; after study imaging, 200 were eligible and randomly assigned to treatment with [177Lu]Lu-PSMA-617 (n=99) or cabazitaxel (n=101). After completing study treatment, 20 (20%) participants assigned to cabazitaxel and 32 (32%) assigned to [177Lu]Lu-PSMA-617 were subsequently treated with the alternative regimen. After a median follow-up of 35·7 months (IQR 31·1 to 39·2), 77 (78%) participants had died in the [177Lu]Lu-PSMA-617 group and 70 (69%) participants had died in the cabazitaxel group. Overall survival was similar among those assigned to [177Lu]Lu-PSMA-617 versus those assigned to cabazitaxel (RMST 19·1 months [95% CI 16·9 to 21·4] vs 19·6 months [17·4 to 21·8]; difference -0·5 months [95% CI -3·7 to 2·7]; p=0·77). No additional safety signals were identified with the longer follow-up in this analysis. 80 (27%) of 291 men who were registered after initial eligibility screening were excluded after [68Ga]Ga-PSMA-11 and 2-[18F]FDG PET. In the 61 of these men with follow-up available, RMST was 11·0 months (95% CI 9·0 to 13·1). INTERPRETATION: These results support the use of [177Lu]Lu-PSMA-617 as an alternative to cabazitaxel for PSMA-positive metastatic castration-resistant prostate cancer progressing after docetaxel. We did not find evidence that overall survival differed between the randomised groups. Median overall survival was shorter for men who were excluded because of low PSMA expression or 2-[18F]FDG-discordant disease. FUNDING: Australian and New Zealand Urogenital and Prostate Cancer Trials Group, Prostate Cancer Foundation of Australia, Endocyte (a Novartis company), Australian Nuclear Science and Technology Organization, Movember, It's a Bloke Thing, CAN4CANCER, and The Distinguished Gentleman's Ride.

Can 68 Ga-PSMA positron emission tomography and multiparametric MRI guide treatment for biochemical recurrence after radical prostatectomy?

OBJECTIVE: To evaluate the role of multiparametric magnetic resonance imaging (mpMRI) and Gallium-68 (68 Ga)-prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) in guiding salvage therapy for patients with biochemical recurrence (BCR) post-radical prostatectomy. PATIENTS AND METHODS: Patients were evaluated with paired mpMRI and 68 Ga-PSMA PET/CT scans for BCR (prostate-specific antigen [PSA] >0.2 ng/mL). Patient, tumour, PSA and imaging characteristics were analysed with descriptive statistics. RESULTS: A total of 117 patients underwent paired scans to investigate BCR, of whom 53.0% (62/117) had detectable lesions on initial scans and 47.0% (55/117) did not. Of those without detectable lesions, 8/55 patients proceeded to immediate salvage radiotherapy (sRT) and 47/55 were observed. Of patients with negative imaging who were initially observed, 46.8% (22/47) did not reach threshold for repeat imaging, while 53.2% were rescanned due to rising PSA levels. Of these rescanned patients, 31.9% (15/47) were spared sRT due to proven distant disease, or due to absence of disease on repeat imaging. Of the original 117 patients, 53 (45.3%) were spared early sRT due to absence of disease on imaging or presence of distant disease, while those undergoing delayed sRT still maintained good PSA responses. Of note, patients with high-risk features who underwent sRT despite negative imaging demonstrated satisfactory PSA responses to sRT. Study limitations include the observational design and absence of cause-specific or overall survival data. CONCLUSION: Our findings support the use of mpMRI and 68 Ga-PSMA PET/CT in guiding timing and necessity of salvage therapy tailored to detected lesions, with potential to reduce unnecessary sRT-related morbidity. Larger or randomized trials are warranted to validate this.

Combined Utility of 68Ga-Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography and Multiparametric Magnetic Resonance Imaging in Predicting Prostate Biopsy Pathology.

BACKGROUND: 68Gallium-labelled prostate-specific membrane antigen positron emission tomography (68Ga-PSMA-11 PET) is a valuable staging tool, but its utility in characterising primary prostate cancer remains unclear. The maximum standardised uptake value (SUVmax) is a quantification measure of highest radiotracer uptake within PET-avid lesions. OBJECTIVE: To assess the utility of SUVmax in detecting clinically significant prostate cancer (csPCa) on biopsy alone and in combination with multiparametric magnetic resonance imaging (mpMRI). DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective analysis of 200 men who underwent 68Ga-PSMA-11 PET/CT, mpMRI, and transperineal template prostate biopsy between 2016 and 2018. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary and secondary outcomes were detection of grade group (GG) 3-5 and GG 2-5 prostate cancer, respectively. We used the Mann-Whitney U test to compare SUVmax by GG, and calculated sensitivity and specificity for csPCa detection via 68Ga-PSMA-11 PET/CT, mpMRI, and both. Multivariable logistic regression analyses were used to identify predictors of csPCa on biopsy. RESULTS AND LIMITATIONS: The median SUVmax was greater for GG 3-5 tumours (6.40, interquartile range [IQR] 4.47-11.0) than for benign and GG 1-2 tumours (3.14, IQR 2.55-3.91; p < 0.001). The median SUVmax was greater for GG 3 (5.70, IQR 3.68-8.67) than for GG 2 (3.47, IQR 2.70-4.74; p < 0.001). For GG 3-5 disease, sensitivity was 86.5%, 95.9%, and 98.6%, and the negative predictive value (NPV) was 88.4%, 88.5%, and 93.3% using SUVmax ≥4, a Prostate Imaging-Reporting and Data System (PI-RADS) score of 3-5, and both, respectively. This combined model detected more GG 3-5 disease than mpMRI alone (98.6% vs 95.9%; p = 0.04). SUVmax was an independent predictor of csPCa for GG 3-5 disease only (odds ratio 1.27 per unit, 95% confidence interval 1.13-1.45). Our results are limited by the retrospective study design. CONCLUSIONS: Greater SUVmax on 68Ga-PSMA-11 PET/CT is associated with detection of GG 3-5 cancer on biopsy. The combination of PI-RADS score and SUVmax provides higher sensitivity and NPV than either alone. 68Ga-PSMA-11 PET/CT may be useful alongside mpMRI in improving risk stratification for localised disease. PATIENT SUMMARY: The amount of a radioactive tracer taken up in the prostate during a type of scan called PET (positron emission tomography) can predict whether aggressive prostate cancer is likely to be found on biopsy. This may complement the more usual type of scan, MRI (magnetic resonance imaging), used to detect prostate cancer.

68Ga-Prostate-Specific Membrane Antigen Positron Emission Tomography Maximum Standardized Uptake Value as a Predictor of Gleason Pattern 4 and Pathological Upgrading in Intermediate-Risk Prostate Cancer.

PURPOSE: Accurate risk stratification remains a barrier for the safety of active surveillance in patients with intermediate-risk prostate cancer. [68Ga]Ga-PSMA-11 prostate-specific membrane antigen positron emission tomography/computerized tomography (68Ga-PSMA PET/CT) and the maximum standardized uptake value (SUVmax) may improve risk stratification within this population. MATERIALS AND METHODS: We reviewed men with International Society for Urological Pathology Grade Group (GG) 2-3 disease on transperineal template biopsy undergoing 68Ga-PSMA PET/CT from November 2015 to January 2021. Primary outcome was the presence of high percentage Gleason pattern 4 (GP4) disease per segment at surgery at 3 thresholds: >/<50% GP4, >/<20% GP4, and >/<10% GP4. SUVmax was compared by GP4, and multivariable logistic regression examined the relationship between SUVmax and GP4. Secondary outcome was association between SUVmax and pathological upgrading (GG 1/2 to GG ≥3 from biopsy to surgery). RESULTS: Of 220 men who underwent biopsy, 135 men underwent surgery. SUVmax was higher in high GP4 groups: 5.51 (IQR 4.19-8.49) vs 3.31 (2.64-4.41) >/<50% GP4 (p <0.001); 4.77 (3.31-7.00) vs 3.13 (2.64-4.41) >/<20% GP4 (p <0.001); and 4.54 (6.10-3.13) vs 3.03 (2.45-3.70) >/<10% GP4 (p <0.001). SUVmax remained an independent predictor of >50% (OR=1.39 [95%CI 1.18-1.65], p <0.001) and >20% (OR=1.24 [1.04-1.47], p=0.015) GP4 disease per-segment, and of pathological upgrading (OR=1.22 [1.01-1.48], p=0.036). SUVmax threshold 4.5 predicted >20% GP4 with 58% specificity, 85% sensitivity, positive predictive value 75% and negative predictive value 72%. Threshold 5.4 predicted pathological upgrading with 91% specificity and negative predictive value 94%. CONCLUSIONS: SUVmax on 68Ga-PSMA PET/CT is associated with GP4. SUVmax may improve risk stratification for men with intermediate-risk prostate cancer.

68 Ga-prostate-specific membrane antigen (PSMA) PET/CT as a clinical decision-making tool in biochemically recurrent prostate cancer.

OBJECTIVE: PSMA PET/CT has demonstrated superior sensitivity over conventional imaging in the detection of local and distant recurrence in biochemically relapsed (BCR) prostate cancer. We prospectively investigated the management impact of 68 Ga-PSMA PET/CT imaging in men with BCR, with the aim of identifying baseline clinicopathological predictors for management change. PATIENTS AND METHODS: Men with BCR who met eligibility criteria underwent 68 Ga-PSMA-11 PET/CT at Monash Health (Melbourne, Australia). Intended management plans were prospectively documented before and after 68 Ga-PSMA PET/CT imaging. Binary logistic regression analysis was performed to identify potential clinicopathological predictors of management change. Descriptive statistics were used to characterize the nature of these changes. RESULTS: Seventy men underwent 68 Ga-PSMA-11 PET/CT imaging. Median age was 67 years (IQR 63-72) and median PSA was 0.48 ng/ml (IQR 0.21-1.9). PSMA-avid disease was observed in 56% (39/70) of patients. Pre-scan management plan was altered following scanning in 43% (30/70) of patients. Management changes were significantly more common in patients with higher baseline PSA levels (PSA≥2 ng/ml, p = 0.01). 18/36 (50%) of the patients initially planned for watchful waiting had their management changed, including the use of salvage pelvic radiotherapy (n = 7) and stereotactic ablative body radiotherapy to oligometastatic disease (n = 6). CONCLUSION: Management change after 68 Ga-PSMA PET/CT for BCR is common and typically resulted in treatment intensification strategies in those planned for a watchful waiting approach. This study adds to the growing pool of evidence supporting the clinical utility of PSMA PET/CT imaging in the care of patients with BCR after definitive therapy.

[177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial.

BACKGROUND: Lutetium-177 [177Lu]Lu-PSMA-617 is a radiolabelled small molecule that delivers ß radiation to cells expressing prostate-specific membrane antigen (PSMA), with activity and safety in patients with metastatic castration-resistant prostate cancer. We aimed to compare [177Lu]Lu-PSMA-617 with cabazitaxel in patients with metastatic castration-resistant prostate cancer. METHODS: We did this multicentre, unblinded, randomised phase 2 trial at 11 centres in Australia. We recruited men with metastatic castration-resistant prostate cancer for whom cabazitaxel was considered the next appropriate standard treatment. Participants were required to have adequate renal, haematological, and liver function, and an Eastern Cooperative Oncology Group performance status of 0-2. Previous treatment with androgen receptor-directed therapy was allowed. Men underwent gallium-68 [68Ga]Ga-PSMA-11 and 2-flourine-18[18F]fluoro-2-deoxy-D-glucose (FDG) PET-CT scans. PET eligibility criteria for the trial were PSMA-positive disease, and no sites of metastatic disease with discordant FDG-positive and PSMA-negative findings. Men were randomly assigned (1:1) to [177Lu]Lu-PSMA-617 (6·0-8·5 GBq intravenously every 6 weeks for up to six cycles) or cabazitaxel (20 mg/m2 intravenously every 3 weeks for up to ten cycles). The primary endpoint was prostate-specific antigen (PSA) response defined by a reduction of at least 50% from baseline. This trial is registered with ClinicalTrials.gov, NCT03392428. FINDINGS: Between Feb 6, 2018, and Sept 3, 2019, we screened 291 men, of whom 200 were eligible on PET imaging. Study treatment was received by 98 (99%) of 99 men randomly assigned to [177Lu]Lu-PSMA-617 versus 85 (84%) of 101 randomly assigned to cabazitaxel. PSA responses were more frequent among men in the [177Lu]Lu-PSMA-617 group than in the cabazitaxel group (65 vs 37 PSA responses; 66% vs 37% by intention to treat; difference 29% (95% CI 16-42; p<0·0001; and 66% vs 44% by treatment received; difference 23% [9-37]; p=0·0016). Grade 3-4 adverse events occurred in 32 (33%) of 98 men in the [177Lu]Lu-PSMA-617 group versus 45 (53%) of 85 men in the cabazitaxel group. No deaths were attributed to [177Lu]Lu-PSMA-617. INTERPRETATION: [177Lu]Lu-PSMA-617 compared with cabazitaxel in men with metastatic castration-resistant prostate cancer led to a higher PSA response and fewer grade 3 or 4 adverse events. [177Lu]Lu-PSMA-617 is a new effective class of therapy and a potential alternative to cabazitaxel. FUNDING: Prostate Cancer Foundation of Australia, Endocyte (a Novartis company), Australian Nuclear Science and Technology Organization, Movember, The Distinguished Gentleman's Ride, It's a Bloke Thing, and CAN4CANCER.

No needle to fear: An approach to needle phobic patients.

18F-FDG is the most commonly used radioisotope in PET scanning and is administered intravenously. When patients cannot cannulated, there are limited options available for functional tumour assessment. A fifty year old male presented for investigation of a suspected lung carcinoma identified during investigation of pneumonia. The patient had a severe needle phobia, intellectual disabilities and multiple co-morbidities which made cannulation impossible. An alternative administration method was sought, with successful oral administration occurring in both staging and restaging scans. The scans demonstrated resolution of a suspected lung cancer indicating it was an inflammatory/infective process, preventing the need for more invasive investigative approaches. A non-invasive and positive experience allowed for accurate diagnosis and repeat imaging for this patient, enabling follow up imaging to occur. It is reported that oral administration of 18F-FDG may be useful for assessment of suspected cancers for patients where cannulation isn't possible, when limitations are taken into consideration.

Detection and localisation of primary prostate cancer using 68 gallium prostate-specific membrane antigen positron emission tomography/computed tomography compared with multiparametric magnetic resonance imaging and radical prostatectomy specimen pathology.

OBJECTIVE: To compare the accuracy of 68 gallium prostate-specific membrane antigen positron emission tomography/computed tomography (68 Ga-PSMA PET/CT) with multiparametric MRI (mpMRI) in detecting and localising primary prostate cancer when compared with radical prostatectomy (RP) specimen pathology. PATIENTS AND METHODS: Retrospective review of men who underwent 68 Ga-PSMA PET/CT and mpMRI for primary prostate cancer before RP across four centres between 2015 and 2018. Patients undergoing imaging for recurrent disease or before non-surgical treatment were excluded. We defined pathological index tumour as the lesion with highest International Society of Urological Pathology Grade Group (GG) on RP specimen pathology. Our primary outcomes were rates of accurate detection and localisation of RP specimen pathology index tumour using 68 Ga-PSMA PET/CT or mpMRI. We defined tumour detection as imaging lesion corresponding with RP specimen tumour on any imaging plane, and localisation as imaging lesion matching RP specimen index tumour in all sagittal, axial, and coronal planes. Secondary outcomes included localisation of clinically significant and transition zone (TZ) index tumours. We defined clinically significant disease as GG 3-5. We used descriptive statistics and the Mann-Whitney U-test to define and compare demographic and pathological characteristics between detected, missed and localised tumours using either imaging modality. We used the McNemar test to compare detection and localisation rates using 68 Ga-PSMA PET/CT and mpMRI. RESULTS: In all, 205 men were included in our analysis, including 133 with clinically significant disease. There was no significant difference between 68 Ga-PSMA PET/CT and mpMRI in the detection of any tumour (94% vs 95%, P > 0.9). There was also no significant difference between localisation of all index tumours (91% vs 89%, P = 0.47), clinically significant index tumours (96% vs 91%, P = 0.15) or TZ tumours (85% vs 80%, P > 0.9) using 68 Ga-PSMA PET/CT and mpMRI. Limitations include retrospective study design and non-central review of imaging and pathology. CONCLUSION: We found no significant difference in the detection or localisation of primary prostate cancer between 68 Ga-PSMA PET/CT and mpMRI. Further prospective studies are required to evaluate a combined PET/MRI model in minimising tumours missed by either modality.

Utility of SUVmax on 18 F-FDG PET in detecting cervical nodal metastases.

BACKGROUND: The presence of cervical lymph node metastasis is an important prognostic factor for patients with head and neck squamous cell carcinomas (HNSCC). Accurate assessment of lymph node metastasis in these patients is essential for appropriate prognostic and management purposes. Here, we evaluated the effectiveness of the maximum standardized uptake value (SUVmax) on positron emission tomography (PET) in assessing lymph node metastasis in HNSCC prior to surgery. METHODS: A retrospective review of 74 patients with HNSCC who underwent PET/CT prior to neck dissection were examined. Pre-operative PET/CT scans were reviewed by two experienced nuclear medicine physicians and SUVmax of the largest node in each nodal basin documented. These were compared with the histology results of the neck dissection. RESULTS: A total of 359 nodal basins including 86 basins with metastatic nodes were evaluated. A nodal SUVmax ≥3.16 yielded a sensitivity of 74.4 % and specificity of 84.9 % in detecting metastatic nodes. The nodal SUVmax/Liver SUVmax ratio was found on receiver operating characteristic (ROC) to be effective in detecting metastatic nodes with an area under ROC curve of 0.90. A nodal SUVmax/Liver SUVmax ratio ≥0.90 yielded a sensitivity of 74.1 % and specificity of 93.4 %. By comparison, visual inspection yielded sensitivities of 66.3 and 61.6 % in observers 1 and 2 respectively. The corresponding specificities were 77.7 and 86.5 %. CONCLUSIONS: Nodal SUVmax and nodal SUVmax/liver SUVmax are both useful in the pre-operative detection of metastatic nodes with the latter being superior to visual inspection. The ratio is likely to be more useful as it corrects for inter-scanner variability.

Neuraxial Anesthesia Reduces Lymphatic Flow: Proof-of-Concept in First In-Human Study.

Dilation of lymphatic vessels may contribute to iatrogenic dissemination of cancer cells during surgery. We sought to determine whether neuraxial anesthesia reduces regional lymphatic flow. Using nuclear lymphoscintigraphy, 5 participants receiving spinal anesthesia for brachytherapy had lower extremity lymph flow at rest compared with flow under conditions of spinal anesthesia. Six limbs were analyzed. Four limbs were excluded because of failure to demonstrate lymph flow (1 patient, 2 limbs), colloid injection error (1 limb), and undiagnosed deep vein thrombosis (1 limb). All analyzed limbs showed reduced lymph flow washout from the pedal injection site (range 62%-100%) due to neuraxial anesthesia. Lymph flow was abolished in 3 limbs. We report proof-of-concept that neuraxial anesthesia reduces lymphatic flow through a likely mechanism of sympathectomy.

Dynamic four-dimensional computed tomography for preoperative assessment of lung cancer invasion into adjacent structures†.

OBJECTIVES: The 320-slice computed tomography (CT) provides three-dimensional and dynamic imaging resulting in the ability to assess motion analysis between two adjacent structures (the fourth dimension). Differential movements between two adjacent structures would indicate that there is no fixation between the two structures. METHODS: Eight patients with non-small-cell lung cancers located adjacent to vital structures (e.g. the great vessels) (n = 4), mediastinum (n = 1) or chest wall (n = 3) where conventional CT was unable to exclude local invasion underwent dynamic four-dimensional (4D) CT assessment. In 3 patients, the lung tumour was abutting the chest wall and 1 patient had tumour abutting the mediastinum. The remaining patients included a patient with a large 14-cm left lower lobe cancer abutting the descending thoracic aorta who had previous pleurodesis; a patient with an apical right upper lobe 6-cm cancer with static imaging appearances suggestive of tumour invasion into the apex, the mediastinal surface and superior vena cava (SVC); a patient with a 3.5-cm cancer which had a broad 2.5-cm base abutting the distal aortic arch and a patient with a 14-cm left upper lobe cancer abutting the aortic arch, descending thoracic aorta and chest wall. Differential movements between the tumour and adjacent structure on 4D CT were considered indicative of the absence of frank invasion. RESULTS: Dynamic 4D imaging revealed differential movements between the tumour and the adjacent structures in 7 cases, suggesting the absence of overt malignant invasion. Intraoperative assessments confirmed the findings. In 1 case, a small area of fixation seen on dynamic CT corresponded intraoperatively to superficial invasion of the adventitia of the SVC. CONCLUSIONS: Dynamic 4D 320-slice CT is useful in the preoperative assessment of the direct invasion of lung cancer into adjacent structures and hence its resectability.

Intravascular small cell neuroendocrine tumor in the neck.

A 40-year-old man presented with a painless enlarging right neck mass over several weeks without a history of trauma or infection. Ultrasound, contrast-enhanced CT, and MRI showed a mass in an expanded vein extending into the parotid gland. Blood-stained fine-needle aspiration biopsy demonstrated atypical lymphoid cells, but there was insufficient material for a diagnosis. The mass was intensely avid on 18F-FDG PET/CT and was suggestive of a neoplasm. Excision confirmed a mass within the external jugular vein with areas of invasion through the vessel wall. A diagnosis of small cell neuroendocrine carcinoma was made on histology.

177Lu-octreotate, alone or with radiosensitising chemotherapy, is safe in neuroendocrine tumour patients previously treated with high-activity 111In-octreotide.

PURPOSE: The aim of this retrospective study was to determine whether patients with previous peptide receptor radionuclide therapy using high-activity (111)In-pentetreotide can be safely treated with (177)Lu-octreotate and whether addition of radiosensitising chemotherapy increases the toxicity of this agent. METHODS: Records of 27 patients (aged 17-75) who received 69 (median 3 per patient) (177)Lu-octreotate administrations, including 29 in conjunction with radiosensitising infusional 5-fluorouracil (5-FU) (n = 27), or capecitabine (n = 2), between October 2005 and July 2007 subsequent to 1-8 prior cycles of (111)In-pentetreotide therapy were analysed. Toxicity was assessed during and at 8-12 weeks post-treatment, with further long-term assessments including survival status reviewed till death or study close-out date of 1 November 2009. RESULTS: Reduction in blood counts was most marked following the first dose of (177)Lu-octreotate but at early follow-up the only major haematological toxicity was a single case of grade 4 lymphopaenia. Both the presence of bone metastases and the administration of chemotherapy tended to result in greater reduction in blood counts, but these differences did not reach statistical significance. On long-term follow-up, 16 patients (59%) are alive with median overall survival of 36 months (32-44 months from first (177)Lu-octreotate therapy). None of the recorded deaths was directly related to treatment toxicity. One patient had late grade 4 anaemia and thrombocytopaenia secondary to bone marrow failure from progressive infiltration by tumour. No other significant long-term haematological toxicities were recorded and no leukaemia was observed. No renal toxicity was observed on serial serum creatinine or radionuclide glomerular filtration rate (GFR) determination on initial or long-term follow-up. CONCLUSION: (177)Lu-octreotate is a safe and well-tolerated therapy for patients who have previously been treated with (111)In-pentetreotide and can be safely combined with radiosensitising chemotherapy. However, caution is recommended in patients with bone metastases. Significant late toxicities including bone marrow or renal failure, or leukaemia directly related to radionuclide therapy, did not occur in our series.

High-administered activity In-111 octreotide therapy with concomitant radiosensitizing 5FU chemotherapy for treatment of neuroendocrine tumors: preliminary experience.

INTRODUCTION: High-administered activity In-111 octreotide (HA-Oc) therapy has been used for patients with disseminated neuroendocrine tumors (NET) with high somatostatin receptor (SSR) expression. Combining HA-Oc with radiosensitizing 5-fluorouracil (5FU) chemotherapy could enhance efficacy. Our other aim was to assess whether concomitant 5FU would contribute to significant additional toxicity. METHODS: Fifteen (15) consecutive patients who received 3 cycles of HA-Oc+5FU were evaluated. Symptomatic, octreoscan, computed tomography (CT), hormonal responses, and toxicity were reviewed at 3 months post-last treatment. Long-term follow-up was performed to death or April 2008 to assess late toxicity and time to progression requiring retreatment. RESULTS: At 3 months post-treatment, 67% of patients had symptomatic improvement, with 20% experiencing a complete resolution of symptoms. Overall, 90% achieved stabilization or a decrease in hormone levels. Octreoscan improvement/stabilization occurred in 95% and CT stabilization in 80% of patients with previously progressive disease, but no partial or complete regression by Response Evaluation Criteria in Solid Tumors criteria. Transient lymphopenia and nausea were the most common side-effects, and there was no significant renal or grade 4 hematologic toxicity. Subacute side-effects included a peripherally inserted central catheter line thrombosis (1 patient), discomfort/pain associated with lesion necrosis, and 1 lymph node swelling. Median time to retreatment was 23 months (range, 6-34) for 10 patients. Six (6) patients deceased (no deaths directly related to 5FU); 9 patients (60%) are alive at 36-139 months. CONCLUSIONS: HA-Oc+5FU achieve a high rate of symptomatic response associated with stabilization/improvement in hormonal and functional scan abnormalities. Combination treatment achieved disease stabilization in the majority of patients with previously progressive disease. There was no significant observed increase in toxicity with additional 5FU, making it a promising adjunct to radiopeptide receptor therapy for progressive NET.

Atypical brown fat distribution in young males demonstrated on PET/CT.

The development of PET/CT has led to the recognition that metabolically active fat, referred to as "brown fat," can accumulate FDG and represents a possible source of false-positive scans in oncology patients. Numerous reports have described the typical appearance of brown fat, which most commonly presents as neck and paravertebral uptake in young female patients. Other described sites of uptake include the mediastinum and retroperitoneum. We present examples of 2 cases of atypical diffuse brown fat uptake seen in the subcutaneous fat of the thighs, abdomen, and pelvis. Both of these patients were young men and did not show uptake in the typical supraclavicular and neck fat. Although rare in our experience, knowledge of this condition may prevent misinterpretation of this finding as an infiltrative condition of the skin, such as lymphoma.

Clinical experience with the first combined positron emission tomography/computed tomography scanner in Australia.

Metabolic imaging with fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) is increasing rapidly worldwide because of superior accuracy compared with conventional non-invasive techniques used for evaluating cancer. Limited anatomical information from FDG-PET images alone dictates that complementary use with structural imaging is required to optimise benefit. Recently, combined positron emission tomography/computed tomography (PET/CT) scanners have overtaken standalone PET scanners as the most commonly purchased PET devices. We describe our experience of over 5500 scans performed since the first PET/CT scanner in Australia was commissioned at the Peter MacCallum Cancer Centre (PMCC), Melbourne, in January 2002. Clinical indications for PET/CT scans performed at PMCC largely reflect current Medicare reimbursement policy. Advantages of PET/CT include greater patient comfort and higher throughput, greater diagnostic certainty and accuracy, improved biopsy methods, and better treatment planning. We believe PET/CT will underpin more effective and efficient imaging paradigms for many common tumours, and lead to a decrease in imaging costs.