The LUTADOSE trial: tumour dosimetry after the first administration predicts progression free survival in gastro-entero-pancreatic neuroendocrine tumours (GEP NETs) patients treated with [177Lu]Lu-DOTATATE.

PURPOSE: In Peptide Receptor Radionuclide Therapy (PRRT) with [177Lu]Lu-DOTATATE of gastro-entero-pancreatic neuroendocrine tumours (GEP NETs) a question remains open about the potential benefits of personalised dosimetry. This observational prospective study examines the association of individualized dosimetry with progression free survival (PFS) in G1-G2 GEP NETs patients following the standard [177Lu]Lu-DOTATATE therapeutic regimen. METHODS: The analysis was conducted on 42 patients administered 4 times, and on 165 lesions. Dosimetry was performed after the first and the forth cycle, with two SPECT/CT scans at day 1 and 7 after administration. Global mean Tumour absorbed Dose of each patient (GTD) was calculated after cycle 1 and 4 as the sum of lesion doses weighted by lesion mass, normalized by the global tumour mass. Cumulative GTD_TOT was calculated as the mean between cycle 1 (GTD_1) and 4 (GTD_4) multiplied by 4. Patients were followed-up for median 32.8 (range 18-45.5) months, through blood tests and contrast enhanced CT (ceCT). This study assessed the correlation between global tumour dose (GTD) and PFS longer or shorter than 24 months. After a ROC analysis, we stratified patients according to the best cut-off value for two additional statistical analyses. At last a multivariate analysis was carried out for PFS > / < 24 months. RESULTS: The median follow-up interval was 33 months, ranging from 18 to 45.5 months. The median PFS was 42 months. The progression free survival rate at 20 months was 90.5%. GTD_1 and GTD_TOT were statistically associated with PFS > / < 24 m (p = 0.026 and p = 0.03 respectively). The stratification of patients on GTD_1 lower or higher than the best cut-off value at 10.6 Gy provided significantly different median PFS of 21 months versus non reached, i.e. longer than 45.5 months (p = 0.004), with a hazard ratio of 8.6, (95% C.I.: [2 - 37]). Using GTD_TOT with the best cut-off at 43 Gy, the same PFS values were obtained as after cycle 1 (p = 0.035). At multivariate analysis, a decrease in GTD_1 and, with lower impact, a higher global tumour volume were significantly associated with PFS < 24 months. We calculated the Tumour Control Probability of obtaining PFS > 24 months as a function of GTD_1. DISCUSSION: Several statistical analyses seem to confirm that simple tumour dosimetry with 2 SPECT/CT scans after the first administration allows to predict PFS values after 4 × 7.4 GBq administrations of 177Lu[Lu]-DOTATATE in G1-G2 GEP NETs. This result qualitatively confirms recent findings by a Belgian and a French study. However, dosimetric thresholds are different. This probably comes from different cohort baseline characteristics, since the median PFS in our study (42 m) was longer than in the other studies (28 m and 31 m). CONCLUSION: Tumour dosimetry after the first administration of [177Lu]Lu-DOTATATE offers an important prognostic value in the clinical decision-making process, especially for the future as alternative emitters or administration schedule may become available.

Occurrence of breast-cancer-related lymphedema after reverse lymphatic mapping and selective axillary dissection versus standard surgical treatment of axilla: A two-arm randomized clinical trial.

BACKGROUND: The need for axillary dissection (AD) is declining, but it is still essential for many patients with nodal involvement who risk developing breast-cancer-related lymphedema (BCRL) with lifelong consequences. Previous nonrandomized studies found axillary reverse mapping and selective axillary dissection (ARM-SAD) a safe and feasible way to preserve the arm's lymphatic drainage. METHODS: The present two-arm prospective randomized clinical trial was held at a single comprehensive cancer center to ascertain whether ARM-SAD can reduce the risk of BCRL, compared with standard AD, in patients with node-positive breast cancer. Whatever the type of breast surgery or adjuvant treatments planned, 130 patients with nodal involvement met our inclusion criteria: 65 were randomized for AD and 65 for ARM-SAD. Twelve months after surgery, a physiatrist assessed patients for BCRL and calculated the excess volume of the operated arm. Lymphoscintigraphy was used to assess drainage impairment. Self-reports of any impairment were also recorded. RESULTS: The difference in the incidence of BCRL between the two groups was 21% (95% CI, 3-37; p = .03). A significantly lower rate of BCRL after ARM-SAD was confirmed by a multimodal analysis that included the physiatrist's findings, excess arm volume, and lymphoscintigraphic findings, but this was not matched by a significant difference in patients' self-reports. CONCLUSIONS: Our findings encourage a change of surgical approach when AD is still warranted. ARM-SAD may be an alternative to standard AD to reduce the treatment-related morbidity.

Update on radioligand therapy with 177Lu-PSMA for metastatic castration-resistant prostate cancer: clinical aspects and survival effects.

OBJECTIVE: To give an updated overview on clinical aspects and survival effects of lutetium-177-prostate-specific membrane antigen (PSMA) (177Lu-PSMA) radioligand therapy (RLT), a novel treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: PubMed/MEDLINE database was searched for relevant articles published up to March 2021. The search was restricted to English-language articles. RESULTS: Current evidence from the literature consistently demonstrated the efficacy, safety, and survival benefit of 177Lu-PSMA RLT in mCRPC. However, current data rely predominantly on retrospective analyses, showing heterogeneity of patient population and treatment protocols. More recently, results from the first randomized phase II study (TheraP) demonstrated that 177Lu-PMSA therapy significantly improved prostate-specific antigen response rate (66% vs 37%) and had fewer grade 3/4 adverse events when compared to cabazitaxel in patients with docetaxel-pretreated, progressive mCRPC. This review is intended to provide an updated overview of treatment protocols and responses, toxicity profile, and survival effects of 177Lu-PSMA RLT. CONCLUSIONS: 177Lu-PSMA RLT has emerged as a promising targeted treatment in mCRPC. It is currently applied in compassionate use programs and following exhaustion of approved therapies. Crucial for establishing this treatment in routine clinical management will be the results of the phase III VISION trial, which may confirm the encouraging patient outcomes reported to date.

Radioembolization of Hepatocellular Carcinoma with 90Y Glass Microspheres: No Advantage of Voxel Dosimetry with Respect to Mean Dose in Dose-Response Analysis with Two Radiological Methods.

In this confirmatory study, we tested if a calculation that included the non-uniformity of dose deposition through a voxel-based dosimetric variable Ψ was able to improve the dose-response agreement with respect to the mean absorbed dose D. We performed dosimetry with 99mTc-MAA SPECT/CT and 90Y-PET/CT in 86 patients treated 8 instead of 4 days after the reference date with 2.8 times more 90Y glass microspheres/GBq than in our previous study. The lesion-by-lesion response was assessed with the mRECIST method and with an experimental densitometric criterion. A total of 106 lesions were studied. Considering Ψ as a prognostic response marker, having no Ψ provided a significantly higher AUC than D. The correlation, t-test, and AUC values were statistically significant only with the densitometric method and only with post-therapy dosimetry. In comparison with our previous study, the dose-response correlation and AUC values were poorer (maximum r = 0.43, R2 = 0.14, maximal AUC = 0.71), and the efficacy at a high dose did not reach 100%. The expected advantages of voxel dosimetry were nullified by the correlation between any Ψ and D due to the limited image spatial resolution. The lower AUC and efficacy may be explained by the mega-clustering effect triggered by the higher number of microspheres/GBq injected on day 8.

Safety and activity of radium-223 in metastatic castration-resistant prostate cancer: the experience of Istituto Nazionale dei Tumori.

INTRODUCTION: Therapeutic decision-making in metastatic castration-resistant prostate cancer (mCRPC) represents an open challenge. Radium-223 is approved for patients with symptomatic bone metastases, no visceral involvement, progressing after at least 2 lines of systemic therapy, or ineligible for any other systemic treatment. METHODS: We performed a retrospective, observational study on patients with mCRPC treated with radium-223 at our institution outside of clinical trials, to assess the safety and activity in a real-world population. Data regarding baseline patient/disease characteristics and treatment outcomes (number of cycles, treatment-related adverse events [AEs], cause of discontinuation, and best response) were collected. RESULTS: Overall, 41 patients were treated from September 2015 to September 2018. Median age was 73 years; baseline Eastern Cooperative Oncology Group Performance Status (ECOG PS) was 0, 1, or 2 in 15%, 80%, and 5% of cases, respectively; and 3%, 41%, 44%, and 12% of patients had <6, 6-20, >20, and superscan bone lesions, respectively. A median number of 5 cycles (interquartile range 3-6) with median dose 19.52 MBq (interquartile range 12.87-24.83) was received. Treatment schedule was completed in 49% of cases; discontinuations due to AEs, disease-related death, or disease progression occurred in 24%, 33%, and 43% of patients, respectively. Any-grade AEs occurred in 73% and grade 3/4 treatment-related AEs occurred in 29% of patients, mainly anemia, decreased platelet count, and fatigue. No skeletal-related events or treatment-related deaths were recorded. After treatment, 66%, 2%, and 32% of patients had a stable, improved, or deteriorated ECOG PS versus baseline, respectively, and 24%, 61%, and 15% reported a stable, improved, or worsened pain symptom control. Post-treatment versus baseline alkaline phosphatase was reduced or stable in 46% and increased in 54% of patients, whereas prostate-specific antigen was decreased or stable in 83% and increased in 17% of patients. CONCLUSIONS: Our study provides clinically useful real-world data on radium-223, highlighting the importance of multidisciplinary patient management to guarantee the best continuum of care for patients with mCRPC.

Dosimetry in myeloablative (90)Y-labeled ibritumomab tiuxetan therapy: possibility of increasing administered activity on the base of biological effective dose evaluation. Preliminary results.

AIM: In our multicentric ongoing phase I activity escalation study, (90)Y-labeled ibritumomab tiuxetan (Ze-valin was administered in activity per kilo twice- and three times the maximum tolerable dose of 15 MBq/kg suggested for nonmyeloablative treatments by the U.S. registration study. The radioinduced myelodepression was overcome by stem cell autografting. The dosimetric aim was to correlate possible extramedullary toxicities to the organ-absorbed doses or to the biologic effective dose (BED). This is a conceptually more suitable parameter, as it takes into account not only the absorbed dose, but also the influence of the dose rate and of the tissue repair mechanism. METHODS: Pretreatment planar dosimetry was performed on 16 patients with a median 200 MBq of (111)In-Zevalin. Conjugate view technique, background, attenuation, and partial scatter correction were adopted. Blood samples and a planar whole body scintigram were collected at least at 0.5, 48, 96, and 120 hours. Individual organ mass correction was based on a computed tomography scan. Internal dose calculation was performed by the OLINDA/EXM software. One (1) week after dosimetry, 12 patients were treated with 30 MBq/kg and 4 patients with 45 MBq/kg of (90)Y-Zevalin. RESULTS: The absorbed dose per unit activity (Gy/GBq) were (median and range of 16 dosimetric studies): heart wall 3.8 [0.5, 9.7]; kidneys 4.9 [2.8, 10.5]; liver 5.5 [3.9, 8.9]; lungs 2.8 [0.4, 6.8]; red marrow 1.1 [0.8, 2.1]; spleen 6.3 [1.5, 10.9]; and testes 4.6 [3.0, 16.7]. The absorbed dose (Gy) for the 4 patients administered with 45 MBq/kg were (median and range): heart wall 17.6 [9.4, 25.1]; kidneys 16.3 [7.9, 20.3]; liver 20.9 [15.4, 24.3]; lungs 7.7 [5.6, 11.4]; red marrow 3.0 [2.4, 3.3]; spleen 28.4 [18.9, 30.8]; and testes 16.5 [12.2, 17.3]. No extramedullary toxicity was observed. CONCLUSIONS: The administration of 45 MBq/kg of (90)Y ibritumomab tiuxetan to 4 patients with stem cell autografting was free from extramedullary toxicity. This is in agreement with both organ doses and BEDs below the corresponding toxicity thresholds. For these clinical and dosimetric reasons, a further increase in injectable activity could have been conceivable. If the more appropriate BED parameter were chosen for toxicity limit calculations, a wider margin of increase would have been possible. Our theoretical investigation demonstrates that, in this particular case of (90)Y Zevalin therapy, the uncertainty about radiobiological parameters was not a limiting factor for a BED-based calculation of the maximum injectable activity.

Pitfalls in oncology: a unique case of thoracic splenosis mimicking malignancy in a patient with resected breast cancer.

Thoracic splenosis (TS) is a condition of autotransplantation of splenic tissue into the pleural cavity after thoraco-abdominal trauma, with diaphragmatic and spleen injury. It is usually asymptomatic and discovered as an incidental finding at imaging performed for other reasons. Its differential diagnosis regards different benign and malignant conditions and should be discerned avoiding invasive procedures. We report a case of thoracic mass associated with pleural nodules mimicking malignancy in a patient with resected breast cancer for whom a diagnosis of TS was made early by using non-invasive methods. Briefly, we review the literature data on TS, comment concisely the possible implications of using invasive procedures and describe the current non-invasive techniques available. Furthermore, we highlight the importance of an accurate medical history collection, the role of the multidisciplinary board and their impact on treatment decision making. Finally, we conclude that clinical information and imaging would be the discriminating factors to avoid unnecessary invasive procedures.

Feasibility of somatostatin receptor scintigraphy in the detection of occult primary gastro-entero-pancreatic (GEP) neuroendocrine tumours.

The aim of this study was to assess the feasibility of somatostatin receptor scintigraphy (SRS) for the detection of the site of unknown primary neuroendocrine neoplasms in patients in whom clinical examination and conventional radiological imaging had failed to do so. From 1996 to 2000, 36 patients were referred with gastro-entero-pancreatic (GEP) neuroendocrine tumours. In these patients, no clinical, radiological or endoscopic diagnostic modalities had been able to identify the primary tumour. Twenty-nine patients had liver metastases. Of the others, one had skin and one had lymph node metastases, three had diffuse metastatic involvement and two had carcinoid syndrome. SRS was carried out with both whole-body and single-photon emission tomography (SPET) acquisition, 24 and 48 h after the intravenous administration of In-pentetreotide. SRS findings were suggestive of the possible site of the primary lesion in 14 patients (39%). Six patients underwent surgery on the basis of the SRS findings and, therefore, the final, i.e. pathological, diagnosis was reached. In two patients, the final diagnosis was obtained within 6 months of SRS by means of a follow-up computed tomography (CT) scan. In the remaining six patients, the final diagnosis was reached after at least 2 years of follow-up by means of clinical, radiological and/or nuclear medicine findings. In all eight patients, the primary site identified during follow-up was consistent with the SRS findings. It can be concluded that SRS modified management in the six patients who had surgery. However, the most important finding was that SRS prompted surgical management in 17% of cases.

Recombinant human thyrotropin (rhTSH) in the follow-up and treatment of patients with thyroid cancer.

The follow-up of thyroid cancer is based on the detection of residual and recurrent thyroid carcinoma. This is traditionally done by means of measurements of serum thyroglobulin (Tg) combined with various imaging techniques (131I-whole body scan, ultrasound and other modalities). Tg serum levels and the uptake of 131I on a whole body scan (WBS) depend on TSH stimulation, which in thyroidectomized patients can be obtained either by withdrawal of thyroid hormone treatment (thyroxine) or by administration of exogenous TSH. At present exogenous human TSH is obtained by means of recombinant DNA technology, (recombinant human TSH (rhTSH), Thyrogen). Even if the administration of rhTSH and withdrawal of thyroid hormone are not completely equivalent, the use of rhTSH has already entered the clinical routine (rhTSH Tg test and rhTSH WBS) because with rhTSH the morbidity and discomfort associated with the withdrawal of thyroid hormone can be avoided. At a recent International Consensus Conference on the follow-up of differentiated thyroid carcinoma it was proposed to carry out only Tg measurement after rhTSH stimulation; moreover, it was stated that 131I whole body scan has to be discouraged in patients submitted to radical surgery and radioiodine ablation with no clinical evidence of residual tumor and with undetectable levels of Tg during hormonal suppression of TSH. Similar strategies in this respect tend to eliminate the 131I WBS and propose only the rhTSH Tg test combined with head and neck ultrasound (US). This is still a matter of debate, also because it is not valid for all risk groups and not all patients undergo the same clinical management (radical surgery or not, thyroid ablation with 131I or not). However, the availability of rhTSH will definitely change the management of papillary and follicular thyroid carcinoma, also with regard to iodine treatment. In fact, rhTSH can be used during radioiodine treatment to enhance the 131I uptake by the cancer cells in particular groups of patients. Patients who could benefit from this approach can be divided into three subgroups: 1) patients in whom thyroxine withdrawal may be dangerous because of the effects of long-term TSH stimulation on the tumor mass (brain metastases, vertebral metastases, presence of neurological signs, heart diseases); 2) patients affected by tumors with marked biological aggressiveness and a low iodine uptake (variants of follicular carcinoma, insular carcinoma, tall and columnar cell variants of papillary thyroid carcinoma, Hürthle cell carcinoma); 3) patients with hypothalamic-pituitary alterations. The potential efficiency of rhTSH in radiometabolic treatment is an important issue that has been studied in a limited number of patients, but is worthy of further investigations in large perspective. A recent clinical prospective trial has been proposed by the Thyroid Cancer Study Group of the Istituto Nazionale Tumori and is now ongoing.

Evaluation of circulating calcitonin: analytical aspects.

BACKGROUND AND AIM: Calcitonin (hCT) is a useful serum marker for the diagnosis and monitoring of medullary thyroid carcinoma (MTC). However, hCT values provided by different methods may differ, leading to difficulties in the interpretation of hCT results. In this study we compared four immunoradiometric (IRMA) and radioimmunometric (RIA) assays for hCT determination. MATERIAL AND METHODS: hCT was measured in 35 patients by means of the following commercially available IRMA or RIA kits: CT US (Biosource), IRMA hCT (Schering-CIS bio international), ultra-sensitive calcitonin (DSL), and calcitonin assay (Scantibodies). A comparison of the distribution of the hCT values measured by the tested IRMA-RIAs and a correlation analysis were performed. RESULTS: The hCT values were widely dispersed and the classification of the patients according to the hCT cutoff value varied depending on the assay used. CONCLUSION: Despite efforts to develop new, highly specific antibodies, the evaluation of this marker is still flawed by analytical inaccuracy. hCT values are widely dispersed depending on the method used for marker measurement; as a consequence, patient classification according to the hCT cutoff value is still dependent on the assay used.

Critical aspects of immunoradiometric thyroglobulin assays.

BACKGROUND AND AIM OF THE STUDY: Thyroglobulin (Tg) evaluation is currently used in the follow-up of patients with differentiated thyroid carcinoma (DTC), but the measurement methods are flawed by analytical inaccuracy. In this paper we describe the results of a comparison between seven different immunoradiometric assays (IRMAs) for Tg determination. MATERIAL AND METHODS: Tg was measured in 50 patients with DTC by means of the following commercially available IRMA kits: HTGK-2 (DiaSorin), Tg IRMA (Schering-CIS bio international), ELSA-hTG (Schering-CIS bio international), Tg IRMA C.T. (ICN Pharmaceuticals), SELco Tg (Medipan Diagnostica), Tg Bridge IRMA (Adaltis) and IRMA-mat Tg (BYK-Sangtec Diagnostica). The distribution of the Tg values measured by the different IRMAs was compared and a correlation analysis was performed. RESULTS: The Tg values were widely dispersed and the classification of patients according to Tg concentrations of clinical relevance varied depending on the IRMA used. CONCLUSION: Despite efforts to develop standardized Tg assays, the measurement of this biomarker is still affected by a considerable degree of analytical inaccuracy. Tg values vary widely between assays and the classification of patients according to Tg values with clinical relevance is still dependent on the assay used.

Diagnostic procedures in the follow-up of patients affected by MEN type 2.

Multiple endocrine neoplasia type 2 (MEN 2) is an inherited disease caused by germline mutations in the RET proto-oncogene. The most distinctive MEN 2 variants are MEN 2A, MEN 2B and familial medullary thyroid cancer (FMTC). The hallmark of these syndromes is the development of medullary thyroid carcinoma (MTC), which occurs in almost all patients with MEN 2 syndromes. Other endocrinopathies are variably expressed. Pheochromocytoma and hyperparathyroidism occur in patients with MEN 2A with a frequency of about 50% and 30%, respectively. In this paper we summarize the most relevant diagnostic methods to detect and monitor MTC, pheochromocytoma and hyperparathyroidism.

Sentinel lymph node detection following the hysteroscopic peritumoural injection of 99mTc-labelled albumin nanocolloid in endometrial cancer.

PURPOSE: The purpose of this study was to assess the feasibility of sentinel lymph node (SLN) detection in endometrial cancer patients with a dual-tracer procedure after hysteroscopic peritumoural injection. METHODS: Twenty-six women with previously untreated endometrial adenocarcinoma underwent the hysteroscopic injection of 111 MBq 99mTc-Nanocoll and blue dye administered subendometrially around the lesion. On the same day, all 26 patients underwent lymphoscintigraphy, followed 3-4 h later by hysterotomy with bilateral salpingo-oophorectomy and pelvic lymphadenectomy. Para-aortic lymphadenectomy was also performed in cases of either serous or papillary carcinoma (n=7/26). All SLNs were removed and examined with haematoxylin and eosin staining and immunohistochemical techniques. RESULTS: The procedure was well tolerated by patients, only two experiencing transient vagal symptoms. The sensitivity of this technique for correct identification of SLNs was 100%. Lymph node metastases were found in 4 out of the 26 patients (15%), bilaterally in the external iliac region (n=1), unilaterally in the external iliac region (n=1), unilaterally in the common iliac region (n=1) and unilaterally in the para-aortic region (n=1). In all four cases, nodal metastases were located within SLNs detected by lymphoscintigraphy. Only 10 of the 26 patients (38%) had significant blue dye staining. All blue-stained SLNs were radioactive. CONCLUSION: In patients with endometrial cancer, it is feasible to use lymphatic mapping and SLN biopsy to define the topographic distribution of the lymphatic network and also to accurately detect lumbo-aortic and pelvic metastases within SLNs. In the majority of patients with early stage endometrial cancer, this procedure may avoid unnecessary radical pelvic lymphadenectomy. It may also guide para-aortic lymph node dissection on the basis of the SLN status.