Yttrium-labelled peptides for therapy of NET.

Peptide receptor radionuclide therapy (PRRT) consists in the systemic administration of a synthetic peptide, labelled with a suitable beta-emitting radionuclide, able to irradiate tumours and their metastases via the internalization through a specific receptor, overexpressed on the cell membrane. After 15 years of experience, we can state that PRRT with (90)Y-labelled peptides is generally well tolerated. Acute side effects are usually mild, some of which are related to the co-administration of amino acids, such as nausea. Others are related to the radiopeptide, such as fatigue or the exacerbation of an endocrine syndrome, which rarely occurs in functioning tumours. Chronic and permanent effects on target organs, particularly the kidneys and the bone marrow, are generally mild if the necessary precautions are taken. Currently, the potential risk to kidney and red marrow limits the amount of radioactivity that may be administered. However, when tumour masses are irradiated with adequate doses, volume reduction may be observed. (90)Y-octreotide has been the most widely used radiopeptide in the first 8-10 years of experience. Unfortunately, all of the published results derive from different and inhomogeneous phase I/II studies. Hence, a direct comparison is virtually impossible to date. Nevertheless, even with these limitations, objective responses are registered in 10-34% of patients. The optimal timing of (90)Y-DOTATOC in the management of somatostatin receptor (SSTR)-positive tumours and the way in which it should be integrated with other treatments have yet to be defined, and prospective phase II/III trials comparing the efficacy and toxicity of different schemes of (90)Y-DOTATOC administration are still warranted.

Peptide receptor radionuclide therapy with ¹77Lu-DOTATATE: the IEO phase I-II study.

PURPOSE: Peptide receptor radionuclide therapy (PRRT) is used in tumours expressing type 2 somatostatin receptors (sst(2)), mainly neuroendocrine. The aim of this prospective phase I-II study was to evaluate the toxicity and efficacy of (177)Lu-DOTATATE in multiple cycles. METHODS: Fifty-one consecutive patients with unresectable/metastatic sst(2)-positive tumours, divided into two groups, received escalating activities (3.7-5.18 GBq/cycle, group 1; 5.18-7.4 GBq/cycle, group 2) of (177)Lu-DOTATATE. Cumulative activities ranged from 3.7 to 29.2 GBq (median 26.4 GBq in median 6 cycles, group 1, 21 patients) and 5.55 to 28.9 GBq (median 25.2 GBq in 4 cycles, group 2, 30 patients), based on dosimetry. RESULTS: No major acute or delayed renal or haematological toxicity occurred (one grade 3 leukopenia and thrombocytopenia). Cumulative renal absorbed doses were 8-37 Gy (9-41 Gy bioeffective doses). A median decrease of creatinine clearance of 21.7% 6 months after PRRT, 23.9% after 1 year and 27.6% after 2 years was observed. Higher losses (>20%) occurred in patients with risk factors for renal toxicity, particularly hypertension and diabetes. Cumulative bone marrow doses were <1.5 Gy. Blood elements showed a progressive mild drop during cycles and recovered during follow-up (median 30 months). Thirty-nine patients were progressive at enrolment. Partial and complete responses occurred in 15 of 46 (32.6%) assessable patients. The median time to progression was 36 months. Overall survival was 68% at 36 months. Non-responders and patients with extensive tumour involvement had lower survival. CONCLUSION: (177)Lu-DOTATATE was well tolerated up to 29 GBq cumulative activity (up to 7.4 GBq/cycle). The maximum tolerated dose/cycle was not reached. However, considering the individual bone marrow function and the presence of risk factors for kidney toxicity, it seems safer to divide cumulative activities into lower activity cycles.

Sentinel node biopsy in male breast cancer.

OBJECTIVE: Male breast cancer is a rare disease and axillary status is the most important prognostic indicator. Lymphoscintigraphy associated with gamma-probe guided surgery has been proved to reliably detect sentinel nodes in female patients with breast cancer. This study evaluates the feasibility of the surgical identification of sentinel node by using lymphoscintigraphy and a gamma-detecting probe in male patients, in order to select subjects who would be suitable for complete axillary lymphadenectomy. METHODS: Colloid human albumin labelled with 99Tc was administered to 18 male patients with breast cancer and clinically negative axillary lymph nodes. Lymphoscintigraphy was performed the day before surgery. An intraoperative gamma-detecting probe was used to identify sentinel nodes during surgery. RESULTS: Lymphoscintigraphy and biopsy of the sentinel node were successful in all cases. A total of 20 sentinel nodes were removed. Pathological examinations showed 11 infiltrating ductal carcinomas, two intraductal carcinomas and five intracystic papillary carcinomas. Six patients (33%) had positive sentinel node (micrometastases were found in three patients). These patients underwent axillary dissection; in five of them (83%) the sentinel node was the only positive node. Twelve patients (67%) showed negative sentinel nodes; in all of them no further surgical treatments were planned. CONCLUSIONS: As in women, lymphoscintigraphy and sentinel node biopsy under the guidance of a gamma-detecting probe proved to be an easy method for the detection of sentinel nodes in male breast carcinoma. In male patients with early stage cancer, sentinel node biopsy might represent the standard surgical procedure in order to avoid unnecessary morbidity after surgery, preserving accurate staging of the disease in the axilla.

Long-term evaluation of renal toxicity after peptide receptor radionuclide therapy with 90Y-DOTATOC and 177Lu-DOTATATE: the role of associated risk factors.

PURPOSE: Peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumours with (90)Y-DOTATOC and (177)Lu-DOTATATE is promising. The kidney is the critical organ and despite renal protection, function loss may become evident years later. The aim of this study was to analyse renal parameters in patients who had undergone dosimetry before PRRT. METHODS: Among those in protocols at our institution, 28 patients were considered: 23 received (90)Y-DOTATOC (3.8-29.2 GBq, median 12.2) and five received (177)Lu-DOTATATE (20.7-29.2 GBq, median 23.2). Patients were followed up after therapy for creatinine and creatinine clearance loss (CCL) for 3-97 months (median 30). Renal doses and bio-effective doses (BED) were calculated (MIRD, LQ model). RESULTS: After (90)Y-DOTATOC toxicity on creatinine according to NCI criteria occurred in nine cases (seven grade 1, one grade 2, one grade 3), CCL at 1 year was >5% in 12 cases and >10% in eight. A 28-Gy BED threshold was observed in patients with risk factors (mainly hypertension and diabetes), while it was 40 Gy in patients without risk factors. Probably due to the low number of patients, despite the absence of severe toxicity after hyper-fractionated PRRT, clear correlations between fractionation and toxicity could not be found. After (177)Lu-DOTATATE, no toxicity occurred in 1-2 year follow-up; CCL at 1 year >5% occurred in three patients and >10% in two. CONCLUSIONS: Our results indicate the importance of clinical screening for risk factors: In this case, a BED <28 Gy is recommended. Fractionation of therapy is important in order to decrease toxicity, and further studies are needed to evaluate its clinical impact.

Pretargeted antibody-guided radioimmunotherapy in a child affected by resistant anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL) is characterized by preferential paracortical and intrasinusoidal lymph node involvement by large anaplastic tumor cells expressing the CD30 antigen. Up to 80% of pediatric patients with ALCL can be cured with multi-agent chemotherapeutic regimens. Patients resistant to chemotherapy or suffering from early relapse have a poor prognosis and a poor chance of survival. In these cases, the highly aggressive clinical course of ALCL, associated with systemic symptoms and extranodal involvement, has been treated with different approaches in various cooperative trials, including conventional chemotherapy and human stem cell transplantation (HSCT). However, the optimal treatment has not yet been defined, in particular in cases of relapse. More recently, radioimmunotherapy has been studied with encouraging results in cancer patients, including non-Hodgkin's lymphoma. Here we describe the case of a pediatric ALCL, relapsing after HSCT, treated with pretargeted antibody-guided radioimmunotherapy, obtaining a complete remission, with excellent quality of life over the past 10 months.