H.-J. Biersack

Radioembolization of Liver Tumors With Yttrium-90 Microspheres

Radioembolization (RE), also termed selective internal radiation therapy (SIRT), has been gradually introduced to the clinical arsenal of cytoreductive modalities in recent years. There is growing evidence for efficiency in liver tumors of various entities, with the most prominent ones being hepatocellular carcinoma, colorectal cancer, and neuroendocrine tumors. Hepatic metastases of numerous other tumor entities including breast cancer, cholangiocarcinoma, and pancreatic cancer are treatment-sensitive, even when being refractory to other treatment modalities such as bland-embolization, regional, or systemic chemotherapy. The antitumor effect of SIRT is related to radiation rather than embolization, with extraordinary high local radiation doses obtained selectively at the site of viable tumor and little affection of the surrounding normal liver tissue. Morphologic changes after RE may pose difficulties for interpretation in conventional restaging with regard to tumor viability and true response to treatment. Therefore, functional imaging, that is, metabolic imaging with (18)F fluorodeoxyglucose positron emission tomography (computed tomography) in the majority of treated tumors, is regarded the gold standard in this respect and should be included for pre- and post-SIRT assessment. To prevent serious toxicity to be associated with the potent antitumor efficacy, meticulous pretreatment evaluation is of particular importance. Improvements in predicting dosimetry will help optimize treatment and patient selection. Nuclear medicine procedures are essential for planning, performing, and monitoring of RE. However, the interdisciplinary aspect of patient management has to be emphasized for this particular treatment form. As SIRT is moving forward from the salvage setting indication to the use in earlier stages of hepatic tumor disease and with the advent of new treatment protocols and targeted therapies, embedding SIRT into a multidisciplinary approach will become even more important. This article focuses on procedural and technical aspects for selection, preparation, and performance of treatment as well as post-therapeutic monitoring and response assessment.

FDG-PET in immunocompetent patients with primary central nervous system lymphoma: correlation with MRI and clinical follow-up.

PurposeThe role of FDG-PET in primary central nervous system lymphoma (PCNSL) is unclear. It was the aim of this study to investigate the role of FDG-PET in detecting PCNSL and in predicting response to chemotherapy.MethodsAn FDG-PET scan of the brain was performed in 15 patients with histologically proven PCNSL (16 PET examinations, Siemens ECAT EXACT). PET was planned to investigate patients at the time of primary diagnosis, after chemotherapy and at the time of suspected relapse in seven, five and three cases, respectively. All except two patients simultaneously underwent MRI of the brain. FDG-PET results were correlated with histological results after stereotactic biopsy (primary diagnosis group) and with clinical data and MRI during follow-up.ResultsSix of the seven patients in the primary diagnosis group demonstrated a true positive finding (86%). In one of the true positive PET patients, there were two tumour lesions, one of which was only detectable on the FLAIR MRI sequence. In five patients, FDG-PET showed no sign of PCNSL during ongoing chemotherapy. These results were confirmed by the clinical follow-up (mean 26.6 months). MRI demonstrated minimal residual disease which had disappeared on further follow-up MRI in three of these five patients at the time of PET scanning. Recurrence of disease was confirmed concordantly by FDG-PET and MRI in three different patients. The standardised uptake value of all tumours was 10.2 (4.3–13.7).ConclusionPCNSLs demonstrate high FDG uptake and can be diagnosed by FDG-PET with high sensitivity. It seems that FDG-PET is suitable for early therapeutic monitoring after chemotherapy.

Outcome of peptide receptor radionuclide therapy with 177Lu-octreotate in advanced grade 1/2 pancreatic neuroendocrine tumours.

PurposeThe clinical benefit of peptide receptor radionuclide therapy (PRRT) in patients with pancreatic neuroendocrine tumours (pNET) has not yet been well described and defined in its full extent due to limited data in this tumour subgroup. This study was intended to obtain robust, comparative data on the outcome and toxicity of standardized PRRT with 177Lu-octreotate in a well-characterized population of patients with advanced pNET of grade 1/2 (G1/2).MethodsWe retrospectively analysed a cohort of 68 pNET patients with inoperable metastatic disease consecutively treated with 177Lu-octreotate (four intended cycles at 3-monthly intervals; mean activity per cycle 8.0xa0GBq). Of these 68 patients, 46 (67.6xa0%) had documented morphological tumour progression during the 12xa0months before initiation of treatment, and PRRT was the first-line systemic therapy in 35 patients (51.5xa0%). Response was evaluated according to modified Southwest Oncology Group (SWOG) criteria and additionally with Response Criteria in Solid Tumors (RECIST) 1.1. Survival was analysed using Kaplan-Meier curves and Cox proportional hazards model for univariate and multivariate analyses. Toxicity was assessed by standard follow-up laboratory work-up including blood count, and liver and renal function, supplemented with serial 99mTc-DTPA clearance measurements.ResultsThe median follow-up period was 58xa0months (range 4xa0–xa0112). Reversible haematotoxicity (grade 3 or more) occurred in four patients (5.9xa0%). No significant nephrotoxicity (grade 3 or more) was observed. Treatment responses (SWOG criteria) consisted of a partial response in 41 patients (60.3xa0%), a minor response in 8 (11.8xa0%), stable disease in 9 (13.2xa0%), and progressive disease in 10 (14.7xa0%). Median progression-free survival (PFS) and overall survival (OS) were 34 (95xa0% CI 26xa0–xa042) and 53xa0months (95xa0% CI 46xa0–xa060), respectively. A G1 proliferation status was associated with longer PFS (pu2009=u20090.04) and OS (pu2009=u20090.044) in the multivariate analysis. Variables linked to impaired OS, on the other hand, were a reduced performance status (Karnofsky score ≤70 %, pu2009=u20090.007), a high hepatic tumour burden (≥25xa0% liver volume, pu2009=u20090.017), and an elevated plasma level of neuron-specific enolase (NSE >15xa0ng/ml, pu2009=u20090.035).ConclusionThe outstanding response rates and survival outcomes suggest that PRRT is highly effective in advanced G1/2 pNET when compared to data of other treatment modalities. Independent predictors of survival are the tumour proliferation index, the patient’s performance status, tumour burden and baseline plasma NSE level.

Imaging of prostate cancer metastases with 18F-fluoroacetate using PET/CT.

Fluorine-18 fluoroacetate [1] appears to be an interesting alternative to 11C-acetate [2, 3] for imaging prostate cancer with PET. We acquired the first 18F-fluoroacetate PET images in a patient with prostate cancer, rising PSA (101 ng/ml) and progressive bone metastases. Scanning started 70 min after i.v. injection of 280 MBq 18F-fluoroacetate using a combined PET/CT system (Siemens Biograph). The images demonstrate moderate to intense uptake in several (thick arrows) but not all (thin arrows) metastatic bone lesions, with SUVmean of 2.82–4.10 and SUVmax of 3.36–5.11. This compared favourably to accumulation in the liver, with SUVmean of 2.35–2.71 and SUVmax of 3.0–3.58. The mode of excretion was predominantly via the bowel (arrowheads), with low activity in the urine. Compared with 11C-acetate PET, 18F-fluoroacetate offers the possibility of delayed imaging with the potential to further increase the tumour-to-background ratios. Upper row: CT image slices; middle row: combined 18F-fluoroacetate PET/CT; lower row: 18F-fluoroacetate PET References

Long-Term Hematotoxicity After Peptide Receptor Radionuclide Therapy with 177Lu-Octreotate

Myelosuppression may be the dose-limiting toxicity in peptide receptor radionuclide therapy (PRRT). The aim of this study was to investigate the incidence, severity, and reversibility of long-term hematotoxicity in a large cohort of patient undergoing PRRT with 177Lu-octreotate for metastatic neuroendocrine tumors. The impact of potential risk factors, including initial cytopenia, advanced bone metastatic disease, previous chemotherapy, and cumulative administered activity, and the protective effects of splenectomy were of particular interest. Methods: A total of 632 PRRT courses were performed in 203 patients with metastatic neuroendocrine tumors. A mean activity of 7.9 GBq of 177Lu-octreotate was administered per treatment cycle, with a goal of 4 courses at standard intervals of 3 mo. Hematologic parameters were determined before each treatment course, at 2- to 4-wk intervals between the courses, 8–12 wk after the last course of PRRT, and at 3-month intervals for further follow-up. Toxicity was recorded with Common Terminology Criteria for Adverse Events (version 3.0). Results: Myelodysplastic syndrome as a delayed adverse event was documented in 3 patients (1.4%). Relevant but reversible hematotoxicity (grade 3 or 4) occurred in 23 patients (11.3%) and 29 administrations (4.6%), with leukopenia in 2.7% and thrombocytopenia in 1.7%. The mean time to blood count recovery was 12 mo after the termination of PRRT (range, 3–22 mo). The only preexisting factor that contributed to hematotoxicity was initial cytopenia (P < 0.001). A high level of cumulative administered activity (>29.6 GBq) was associated with relevant leukopenia (P < 0.001). None of the patients with a history of splenectomy developed grade 3 or 4 hematotoxicity, and splenectomy was inversely associated with the incidence and degree of leukopenia (P = 0.02) and thrombocytopenia (P = 0.03) Conclusion: PRRT-induced myelosuppression is almost invariably reversible and rarely requires clinical measures. Administered activity and initial cytopenia are the only factors contributing to myelosuppression, whereas splenectomy may exert a protective effect.

Predictors of Long-Term Outcome in Patients with Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors After Peptide Receptor Radionuclide Therapy with 177Lu-Octreotate

Outcome analyses for patients with gastroenteropancreatic neuroendocrine tumors (GEP NET) after peptide receptor radionuclide therapy (PRRT) are still limited, especially with regard to the impact of the Ki-67 index. Using a single-center analysis, we aimed to establish predictors of survival. Methods: We retrospectively analyzed a consecutive cohort of 74 patients who had metastatic GEP NET and underwent PRRT with 177Lu-octreotate (mean activity of 7.9 GBq per cycle, aimed at 4 treatment cycles at standard intervals of 3 mo). Patients (33 with pancreatic NET and 41 with nonpancreatic GEP NET) had unresectable metastatic disease graded as G1 or G2 (G1/G2) and documented morphologic or clinical progression within less than 12 mo or uncontrolled disease under somatostatin analog treatment. Responses were evaluated according to modified Southwest Oncology Group criteria. Potential predictors of survival were analyzed with the Kaplan–Meier curve method (log-rank test) and multivariate analysis (P < 0.05). Results: The response rates were 36.5% partial response, 17.6% minor response, 35.1% stable disease, and 10.8% progressive disease for the entire cohort; 54.5% partial response, 18.2% minor response, 18.2% stable disease, and 9.1% progressive disease for pancreatic NET; and 22.0% partial response, 17.1% minor response, 48.8% stable disease, and 12.2% progressive disease for nonpancreatic GEP NET. The median progression-free survival and overall survival were 26 mo (95% confidence interval, 18.3–33.7) and 55 mo (95% confidence interval, 48.8–61.2), respectively. Besides the Ki-67 index, a Karnofsky performance score of less than or equal to 70%, a hepatic tumor burden of greater than or equal to 25%, and a baseline plasma level of neuron-specific enolase of greater than 15 ng/mL independently predicted shorter overall survival (hazard ratio, 2.1–3.1). Patients with a Ki-67 index of greater than 10% still had median progression-free survival and overall survival of 19 and 34 mo, respectively. Conclusion: The results of this study demonstrated the favorable response and long-term outcome of patients with G1/G2 GEP NET after PRRT. Independent predictors of survival were the Ki-67 index, the patient’s performance status (Karnofsky performance scale score), the tumor burden, and the baseline neuron-specific enolase level. Even patients with a Ki-67 index of greater than 10% seemed to benefit from PRRT, with a good response and a notable long-term outcome. We present the first evidence, to our knowledge, that even in patients with metastatic disease the distinction between G1 and G2—in particular, between G1 (Ki-67 index of 1%–2%) and low-range G2 (Ki-67 index of 3%–10%)—provides prognostic stratification.

FDG-PET in monitoring therapy of breast cancer

Fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) has been used successfully for the staging and re-staging of breast cancer. Another significant indication is the evaluation of therapy response. Only limited data are available on the use of FDG-PET in breast cancer after radiation therapy. The same holds true for chemotherapy. Only the therapy response in locally advanced breast cancer after chemotherapy has been investigated thoroughly. Histopathological response could be predicted with an accuracy of 88–91% after the first and second courses of therapy. A quantitative evaluation is, of course, a prerequisite when FDG-PET is used for therapy monitoring. Only a small number of studies have focussed on hormone therapy. In this context, a flare phenomenon with increasing standardised uptake values after initiation of tamoxifen therapy has been observed. More prospective multicentre trials will be needed to make FDG-PET a powerful tool in monitoring chemotherapy in breast cancer.

Accurate assessment of long-term nephrotoxicity after peptide receptor radionuclide therapy with 177 Lu-octreotate

PurposeRenal radiation during peptide receptor radionuclide therapy (PRRT) may result in glomerular damage, a potential reduction of glomerular filtration rate (GFR) and ultimately lead to renal failure. While reported PRRT nephrotoxicity is limited to data derived from serum creatinine—allowing only approximate estimates of GFR—the aim of this study is to accurately determine PRRT-induced long-term changes of renal function and associated risk factors according to state-of-the-art GFR measurement.MethodsNephrotoxicity was analysed using 99mTc-diethylenetriaminepentaacetic acid (DTPA) clearance data of 74 consecutive patients with gastroenteropancreatic neuroendocrine tumours (GEP NET) undergoing PRRT with 177Lu-octreotate. The mean follow-up period was 21xa0months (range 12–50) with a median of five GFR measurements per patient. The change of GFR was analysed by linear curve fit. Potential risk factors including diabetes mellitus, arterial hypertension, previous chemotherapy, renal impairment at baseline and cumulative administered activity were analysed regarding potential impact on renal function loss. In addition, Common Terminology Criteria for Adverse Events (CTCAE) v3.0 were used to compare nephrotoxicity determined by 99mTc-DTPA clearance versus serum creatinine.ResultsThe alteration in GFR differed widely among the patients (mean −2.1u2009±u200913.1xa0ml/min/m2 per year, relative yearly reduction −1.8u2009±u200918.9xa0%). Fifteen patients (21xa0%) experienced a mild (2–10xa0ml/min/m2 per year) and 16 patients (22xa0%) a significant (>10xa0ml/min/m2 per year) decline of GFR following PRRT. However, 11 patients (15xa0%) showed an increase of >10xa0ml/min/m2 per year. Relevant nephrotoxicity according to CTCAE (grade ≥3) was observed in one patient (1.3xa0%) with arterial hypertension and history of chemotherapy. Nephrotoxicity according to serum creatinine was discordant to that defined by GFR in 15xa0% of the assessments and led to underestimation in 12xa0% of patients. None of the investigated factors including cumulative administered activity contributed to the decline of renal function.ConclusionSerious nephrotoxicity after PRRT with 177Lu-octreotate is rare (1.3xa0%). However, slight renal impairment (GFR loss >2xa0ml/min/m2 per year) can frequently (43xa0%) be detected by 99mTc-DTPA clearance assessments. Cumulative administered activity of 177Lu-octreotate is not a major determinant of renal impairment in our study.

Outcome and toxicity of salvage therapy with 177Lu-octreotate in patients with metastatic gastroenteropancreatic neuroendocrine tumours.

PurposeWe assessed the outcome and toxicity of salvage therapy (repeat treatment) with 177Lu-octreotate and high cumulative activities in patients with metastatic gastroenteropancreatic neuroendocrine tumours (GEP-NET).MethodsWe retrospectively analysed a consecutive cohort of 33 patients with metastatic GEP-NET who underwent salvage peptide receptor radionuclide therapy (PRRT) in our institution. All patients had progressive NET prior to salvage treatment and had shown an initial response to PRRT. The mean cumulative activity was 44.3xa0GBq (30.0–83.7xa0GBq). Radiographic response was assessed using CT and/or MRI according to modified SWOG criteria. Toxicity was evaluated using laboratory data, including complete blood counts and renal function tests using CTCAE 3.0. Survival analysis was performed with the Kaplan-Meier curve method and a significance level at pu2009<u20090.05.ResultsRadiographic responses consisted of complete response in 1 patient (3.0xa0%), partial response in 6 patients (18.2xa0%), minor response in 1 patient (3.0xa0%), stable disease in 14 patients (42.4xa0%), and progressive disease in 11 patients (33.3xa0%). Median progression-free survival (PFS) from the start of salvage therapy was 13xa0months (95xa0% CI 9–18) and patients with a history of a durable PFS after initial PRRT tended to have long-lasting PFS after salvage treatment (pu2009=u20090.04). None of the patients developed severe nephrotoxicity (grade 3/4) or a myelodysplastic syndrome during follow-up. Relevant albeit reversible haematotoxicity (grade 3/4) occurred in 7 patients (21.2xa0%). The cumulative administered activity was not associated with an increased incidence of haematotoxicity.ConclusionPRRT with 177Lu-octreotate in the re-treatment setting is safe and effective in patients with metastatic GEP-NET.

The significance of bremsstrahlung SPECT/CT after yttrium-90 radioembolization treatment in the prediction of extrahepatic side effects

PurposeUnwanted deposition of 90Y microspheres in organs other than the liver during radioembolization of liver tumours may cause severe side effects such as duodenal ulcer. The aim of this study was to evaluate the significance of posttherapy bremsstrahlung (BS) SPECT/CT images of the liver in comparison to planar and SPECT images in the prediction of radioembolization-induced extrahepatic side effects.MethodsA total of 188 radioembolization procedures were performed in 123 patients (50 women, 73 men) over a 2-year period. Planar, whole-body and BS SPECT/CT imaging were performed 24xa0h after treatment as a part of therapy work-up. Any focally increased extrahepatic accumulation was evaluated as suspicious. Clinical follow-up and gastroduodenoscopy served as reference standards. The studies were reviewed to evaluate whether BS SPECT/CT imaging was of benefit.ResultsIn the light of anatomic data obtained from SPECT/CT, apparent extrahepatic BS in 43% of planar and in 52% of SPECT images proved to be in the liver and hence false-positive. The results of planar scintigraphy could not be analysed further since 12 images were not assessable due to high scatter artefacts. On the basis of the gastrointestinal (GI) complications and the results of gastroduodenoscopy, true-positive, true-negative, false-positive and false-negative results of BS SPECT and SPECT/CT imaging in the prediction of GI ulcers were determined. The sensitivity, specificity, positive and negative predictive values and the accuracy of SPECT and SPECT/CT in the prediction of GI ulcers were 13%, 88%, 8%, 92% and 82%, and 87%, 100%, 100%, 99% and 99%, respectively.ConclusionDespite the low quality of BS images, BS SPECT/CT can be used as a reliable method to confirm the safe distribution of 90Y microspheres and in the prediction of GI side effects.