Peptidradiorezeptortherapie neuroendokriner Tumoren

Therapy of neuroendocrine tumors (NET) using radiolabeled somatostatin receptors, such as ¹⁷⁷Lu-DOTATATE or ⁹⁰Y-DOTATOC is gaining more and more importance. Due to overexpression of somatostatin receptors in NET the tumor-to-background ratio is very favorable. A significant therapy response is achievable in approximately 20??6% of treated patients with a median time to progression of up to 40 months. Furthermore, this kind of therapy is very beneficial in the case of hormone-active, functional NET in terms of symptom control. Also quality of life is significantly improved after therapy, even in non-responding patients. The most common side-effects of this therapy are nausea, vomiting and transient hematologic toxicity. However, late serious side-effects, such as renal impairment or myelodysplastic syndrome are rare if renal protection is used during the course of therapy.     

Radionuclide Therapy for Neuroendocrine Tumors

Peptide receptor radionuclide therapy (PRRT) is a form of systemic radiotherapy that allows targeted delivery of radionuclides to tumor cells expressing high levels of somatostatin receptors. The two radiopeptides most commonly used for PRRT, ⁹⁰Y-DOTATOC and ¹⁷⁷Lu-DOTATATE, have been successfully employed for more than a decade for the treatment of advanced neuroendocrine tumors (NETs). Recently, the phase III, randomized NETTER-1 trial has compared ¹⁷⁷Lu-DOTATATE versus high-dose octreotide LAR in patients with progressive, metastatic midgut NETs, demonstrating exceptional tolerability and efficacy. This review summarizes recent developments in the field of radionuclide therapy for gastroenteropancreatic and lung NETs and considers possible strategies to further enhance its clinical efficacy.     

Peptide receptor radionuclide therapy for patients with advanced pancreatic neuroendocrine tumors

¹⁷⁷Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) is now approved for patients with advanced gastroenteropancreatic neuroendocrine tumors (NET), and it is therefore important to understand the efficacy and safety of PRRT in this patient population. PRRT efficacy and safety outcomes have frequently been summarized for patient populations with gastroenteropancreatic NET, but not specifically in patients with pancreatic NET (panNET). The pivotal phase 3 trial of ¹⁷⁷Lu-DOTATATE PRRT in NET was restricted to patients with a midgut primary site. No phase 3 trial data on PRRT treatment outcomes are currently available for the panNET patient population. This review presents the available evidence for panNET treatment outcomes with PRRT and demonstrates that the available data favor PRRT as a modality for this NET primary site. However, several other therapies for advanced panNET are currently available, and the sequencing and combination of PRRT with these other therapies is set to become the big challenge for the future of panNET management. Patient, tumor, and logistical factors (tumor burden, expression of somatostatin receptors, availability of PRRT, patient preferences, and concerns over long-term toxicity) need to be taken into consideration when selecting therapy.     

Radionuclide therapy in neuroendocrine tumours: a systematic review

The purpose of this systematic review was to investigate the effects of therapeutic radiopharmaceuticals in patients with different types of advanced neuroendocrine tumour (NETs). A literature search was carried out in MEDLINE and EMBASE from January 1998 to November 2010. The Cochrane Library (to Issue 10, 2010) and the Standards and Guidelines Evidence Inventory of Cancer Guidelines, including over 1100 English-language cancer guidelines from January 2003 to June 2010, were also checked. No existing systematic reviews or clinical practice guidelines based on a systematic review or randomised controlled trials focusing on this topic were found. Twenty-four fully published articles were abstracted and summarised: 16 articles focused on five peptide receptor radionuclide therapy ((111)In-DTPAOC, (90)Y-DOTALAN, (90)Y-DOTATOC, (90)Y-DOTATATE, and (177)Lu-DOTATATE) and eight focused on (131)I-MIBG treatment. Limited evidence from a historical comparison of studies in one centre supported that (177)Lu-DOTATATE might be associated with greater clinical outcomes compared with (90)Y-DOTATOC or (111)In-DTPAOC. The severe toxicities for (177)Lu-DOTATATE included hepatic insufficiency in 0.6%, myelodysplastic syndrome in 0.8% and renal insufficiency in 0.4% of patients in this study. Insufficient evidence suggested efficacy of (131)I-MIBG in adult NET patients, but the overall tumour response rate from (131)I-MIBG was 27-75% for malignant neuroblastoma, paraganglioma or pheochromocytoma. Haematological toxicities were the main severe side-effects after (131)I-MIBG and 4% of patients developed secondary malignancies in one study. To date, peptide receptor radionuclide therapy seems to be an acceptable option and is relatively safe in adult advanced NET patients with receptor uptake positive on scintigraphy, but patients' renal function must be monitored. (131)I-MIBG may be effective for malignant neuroblastoma, paraganglioma or pheochromocytoma, but its side-effects need to be considered. No strong evidence exists to support that one therapeutic radiopharmaceutical is more effective than others. Well-designed and good-quality randomised controlled trials are required on this research topic.     

The clinical value of [90Y-DOTA]-D-Phe1-Tyr3-octreotide (90Y-DOTATOC) in the treatment of neuroendocrine tumours: A clinical phase II study

Purpose:The aim of this phase II study was to evaluate the tumourresponse of neuroendocrine tumours to targeted irradiation with theradiolabelled somatostatin analogue ⁹⁰Y-DOTATOC. In addition, thepalliative effect of ⁹⁰Y-DOTATOC treatment on the malignantcarcinoid syndrome and tumour-associated pain was investigated. Patients and methods:Forty-one patients (mean age 53 years) withneuroendocrine gastroenteropancreatic and bronchial tumours were included.Eighty-two percent of the patients had therapy resistant and progressivedisease. The treatment consisted of four intravenous injections of a total of6000 MBq/m^{2 90}Y-DOTATOC, administered at intervals ofsix weeks. Results:The overall response rate was 24%. For endocrinepancreatic tumours it was 36%. Complete remissions (CR) were found in2% (1 of 41), partial remissions (PR) in 22% (9 of 41),minor response in 12% (5 of 41), stable disease (SD) in 49% (20of 41) and progressive disease (PD) in 15% (6 of 41). The median followup was 15 months (range 1 month to 36 months). The median duration of responsehas not been reached at 26 months. The two-year survival time was 76 ±16%. Eighty-three percent of the patients suffering from the malignantcarcinoid syndrome achieved a significant reduction of symptoms. The treatmentwas well tolerated. A reduction of pain score was observed in all patients (5of 41) with morphine dependent tumour-associated pain. Side effects includedgrade III (NCIGC) pancytopenia in 5%, and vomiting shortly afterinjection in 23%. No grade III–IV renal toxicity wasobserved. Conclusion:Targeted radiotherapy with ⁹⁰Y-DOTATOC isa novel, well-tolerated treatment for neuroendocrine tumours with a remarkableobjective response rate, survival time, and symptomatic response.     

Peptide Receptor Radionuclide Therapy for Patients With Advanced Lung Carcinoids

Neuroendocrine neoplasms (NEN) are a family of malignancies of diverse origin, including the lung, gastrointestinal tract, and pancreas. Lung NEN include well differentiated neuroendocrine tumors (NET) classified as typical carcinoids or atypical carcinoids, and poorly differentiated neuroendocrine carcinomas classified as small-cell lung carcinoma or large-cell neuroendocrine carcinoma. According to a recent analysis of a large, population-based registry, approximately one-third of all patients with lung typical/atypical carcinoids have distant metastases at diagnosis, and median survival for these patients is 24 months. At present, only 1 therapy is approved by the US Food and Drug Administration (FDA) for patients with advanced lung typical/atypical carcinoids, everolimus, indicating a clear need for more treatment options in this patient population. Although not yet supported by results from randomized prospective trials, somatostatin analogues are considered an acceptable treatment option for patients with lung typical/atypical carcinoids expressing somatostatin receptors. Peptide receptor radionuclide therapy (PRRT) with ¹⁷⁷Lu-DOTATATE was recently approved by the FDA for the treatment of gastroenteropancreatic NET; however, the role of PRRT in patients with lung typical/atypical carcinoids remains unclear, because they were not included in the pivotal NETTER-1 (Neuroendocrine Tumors Therapy) trial. Herein we provide a comprehensive review of the available clinical evidence for efficacy and safety of PRRT in patients with lung typical/atypical carcinoids. On the basis of the preliminary evidence of efficacy and the consistent safety profile in this patient group, we propose that experienced multidisciplinary NET teams may consider PRRT alongside everolimus as an option for patients with advanced somatostatin receptor-positive lung typical/atypical carcinoids whose disease is progressing during first-line treatment with somatostatin analogues.     

Efficacy of 177Lu-Dotatate Induction and Maintenance Therapy of Various Types of Neuroendocrine Tumors: A Phase II Registry Study

Peptide receptor radionuclide therapy (PRRT) has been recently established as a treatment option for progressive gastro-entero-pancreatic neuroendocrine tumors (NETs) including four 200 mCi induction cycles. The purpose of this phase 2 trial is to expand use of PRRT to different types of NETs with the application of dose adjustment and evaluate value of maintenance therapy in patients who had disease control on induction therapy. Forty-seven PRRT naïve NET patients with different primary origin received ¹⁷⁷Lu-DOTATATE induction therapy, ranging from 75 to 150 mCi per cycle, based on patients’ clinical status such as liver and renal function, extent of metastases, and previous therapies. Thirty-four patients underwent additional maintenance therapy (50–100 mCi per cycle) following induction course until they developed disease progression. The estimated median progression-free survival (PFS) was 36.1 months. The median PFS in our MNET subgroup was 47.7 months, which is markedly longer than NETTER-1 trial with median PFS of 28.4 months. The median PFS was significantly longer in patients who received PRRT as first-line treatment after disease progression on somatostatin analogs compared to patients who received other therapies first (p-value = 0.04). The total disease response rate (DRR) and disease control rate (DCR) was 32% and 85% based on RECIST 1.1 and 45% and 83% based on Choi criteria. This trial demonstrates longer PFS with the addition of low dose maintenance therapy to induction therapy compared to NETTER-1 trial that only included induction therapy. Also, we observed considerable efficacy of PRRT in various types of advanced NETs.     

Peptide receptor radionuclide therapy for metastatic paragangliomas

There is little evidence to direct the management of malignant paragangliomas (mPGL) beyond initial surgical treatment. Peptide receptor radionuclide therapy (PRRT), using somatostatin analogues, is effective in other neuroendocrine tumours, but data on its efficacy in treating mPGL are scarce. We report safety and efficacy outcomes from a case series of five patients with advanced mPGLs treated with ¹⁷⁷Lu-DOTATATE PRRT. The mean age of our cohort was 34 years (range 16–47); 4 patients were male with bone disease being the most prevalent metastatic site. PRRT scheme varied between 1 and 4 cycles, with premature cessation due to suspected pneumonitis in one case and disease progression in another. Three patients with previously documented progressive disease achieved stabilization following treatment; one had partial response and one was treatment refractory. Median progression-free survival was 17 months (range 0–78 months). 177-Lu-DOTATATE is an effective therapy in mPGLs in this molecularly defined patient cohort, warranting further investigation in larger studies including hereditary and sporadic mPGL.     

Prognostic value of CD57<Superscript>+</Superscript> T lymphocytes in the peripheral blood of patients with advanced gastric cancer

Background  Natural killer (NK)-like T cells comprising CD56⁺ T cells and CD57⁺ T cells belong to a subset of CD1d-independent NKT cells playing an important role in regulating immune responses. Although NK-like T cells are reported to increase in patients with advanced gastric carcinomas, it remains unknown how NK-like T cells are involved in disease progression in gastric cancer patients. Methods  The proportions of Th1 cells (interferon [IFN]-γ-producing CD4⁺ T cells), Th2 cells (IL-4-producing CD4⁺ T cells), and NK-like T cells (CD56⁺ T cells and CD57⁺ T cells) in the peripheral blood of 48 gastric cancer patients and 20 healthy controls were measured by two-color flow cytometry analysis and by intracellular cytokine analysis to investigate an association of these immune cells with the survival rate of gastric cancer patients. Results  Univariate analysis showed that Th1 cells and CD57⁺ T cells, as well as some clinicopathological factors, significantly influenced the survival rate. CD57-high (≧18%) patients survived for a significantly shorter period after surgery compared to CD57-low patients (P = 0.046; Kaplan-Meier, log-rank test) in the stage III–IV patients, but not in the stage I–II patients. Further, multivariate analysis showed that lymphatic invasion was a statistically significant independent risk factor in all the gastric cancer patients, but the proportion of CD57⁺ T cells as well as depth of tumor were statistically significant independent risk factors in patients with advanced carcinomas (stage III–IV). Conclusion  An increased proportion (≧18%) of CD57⁺ T cells in the peripheral blood of patients with advanced gastric carcinomas could indicate a poor prognosis.     

Somatostatin Receptor Theranostics for Refractory Meningiomas

Somatostatin receptor (SSTR)-targeted peptide receptor radionuclide therapy (PRRT) represents a promising approach for treatment-refractory meningiomas progressing after surgery and radiotherapy. The aim of this study was to provide outcomes of patients harboring refractory meningiomas treated by 177Lu-DOTATATE and an overall analysis of progression-free survival at 6 months (PFS-6) of the same relevant studies in the literature. Eight patients with recurrent and progressive WHO grade II meningiomas were treated after multimodal pretreatment with 177Lu-DOTATATE between 2019 and 2022. Primary and secondarily endpoints were progression-free survival at 6-months (PFS-6) and toxicity, respectively. PFS-6 analysis of our case series was compared with other similar relevant studies that included 86 patients treated with either 177Lu-DOTATATE or 90Y-DOTATOC. Our retrospective study showed a PFS-6 of 85.7% for WHO grade II progressive refractory meningiomas. Treatment was clinically and biologically well tolerated. The overall analysis of the previous relevant studies showed a PFS-6 of 89.7% for WHO grade I meningiomas (n = 29); 57.1% for WHO grade II (n = 21); and 0 % for WHO grade III (n = 12). For all grades (n = 86), including unknown grades, PFS-6 was 58.1%. SSTR-targeted PRRT allowed us to achieve prolonged PFS-6 in patients with WHO grade I and II progressive refractory meningiomas, except the most aggressive WHO grade II tumors. Large scale randomized trials are warranted for the better integration of PRRT in the treatment of refractory meningioma into clinical practice guidelines.     

68Ga‐DOTATATE Positron Emission Tomography‐Computed Tomography Quantification Predicts Response to Somatostatin Analog Therapy in Gastroenteropancreatic Neuroendocrine Tumors

BackgroundSomatostatin analogs (SSAs) are the frontline antitumor therapy in advanced well‐differentiated gastroenteropancreatic neuroendocrine tumors (GEP‐NETs). A subset of patients demonstrate early disease progression on SSA therapy, yet the currently known predictors for treatment failure lack specificity to affect therapeutic decision. SSAs target tumor somatostatin receptors, the level of which can be quantitatively assessed with ⁶⁸Ga‐DOTATATE positron emission tomography‐computed tomography (PET/CT). We investigated the ability of ⁶⁸Ga‐DOTATATE PET/CT to predict response to SSA therapy.Materials and MethodsThe records of 108 consecutive patients with well‐differentiated grade 1–2 GEP‐NETs on SSA monotherapy who received ⁶⁸Ga‐DOTATATE PET/CT scans were retrospectively reviewed to obtain baseline characteristics, ⁶⁸Ga‐DOTATATE maximum standardized uptake value (SUVmax), and progression‐free survival (PFS) data. The optimal SUVmax cutoff for patient stratification was obtained with receiver operating characteristic curve analysis. PFS in the high versus low SUVmax groups was compared with Kaplan‐Meier survival analysis. The effects of baseline characteristics and SUVmax on PFS were examined with univariate and multivariate Cox regression.Results ⁶⁸Ga‐DOTATATE SUVmax predicted therapeutic failure with sensitivity and specificity of 39% and 98%, respectively. SUVmax of <18.35 was associated with shorter PFS, which was reproduced in the subgroup analysis of SSA‐naïve patients. Low SUVmax was the only predictor of early treatment failure (hazard ratio, 6.85) in multivariate analysis, as well as in the subgroup analysis of grade 2 GEP‐NETs.ConclusionLow SUVmax on ⁶⁸Ga‐DOTATATE PET/CT independently predicts early failure on SSA monotherapy in patients with well‐differentiated grade 1–2 GEP‐NET. Patients with lack of expected benefit from SSA therapy can be readily identified using routine ⁶⁸Ga‐DOTATATE PET/CT with very high specificity.Implications for PracticeBased on ⁶⁸Ga‐DOTATATE positron emission tomography‐computed tomography imaging, clinicians can better inform patients on the expected benefit of somatostatin analog therapy for gastroenteropancreatic neuroendocrine tumors, especially when access to the therapy is difficult, and offer proactive discussion on alternative management options.     

Mobilized CD34+ cells as a biomarker candidate for the efficacy of combined maximal tolerance dose and continuous infusional chemotherapy and G-CSF surge in gastric cancer

We investigated whether the level of bone marrow-derived progenitor cells and mature endothelial cells could be used as predictors of clinical outcome in patients receiving taxotere-based chemotherapy for advanced gastric cancer. Peripheral blood mononuclear cells were obtained from 49 gastric cancer patients who received taxotere combined with 5-FU and leucovorin and prophylactic G-CSF treatment. To categorize the cells, the cell markers CD34, vWF, P1H12, and CD31 were stained. Changes in these cells were examined before and after chemotherapy, and the clinical significance of these changes to response prediction and prognosis were investigated. Before the second cycle of chemotherapy, the number of CD34⁺/vWF⁺ and CD34⁺ cells was higher in non-responders as compared to the responders. Patients with 6.2 CD34⁺/vWF⁺ cells/ml had a shorter progression free survival (3.7 months) as against patients with <6.2 CD34⁺/vWF⁺/ml (6.0 months, p = 0.076). Patients with 5.8 CD34⁺ cells/ml had shorter progression free survival (4.0 months) than patients with <5.8 CD34⁺ cells/ml (6.1 months, p = 0.046). In an ex vivo pharmacokinetic study, the maximum inhibition (I_max) for HUVEC and YCC3 cells was 13.0 ± 6.6% and 74.0 ± 2.0%, respectively. The time to reach I_max (T_max) was 72 h in all HUVEC cells and 0.5 hours in YCC3 cells. We suggested that CD34⁺/vWF⁺ and CD34⁺ cells can be used as a biomarker for prediction and CD34⁺ cells for prognosis.     

Repurposed Effect of 177Lu-DOTATATE in the Treatment of Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is an uncommon subcategory of non-Hodgkin lymphoma (NHL). Pathogenesis primarily includes overexpression of CCND1 and SOX11 along with other molecular aberrations. Lutetium ¹⁷⁷Lu-DOTATATE is a radiolabeled somatostatin analogue used for the treatment of gastrointestinal neuroendocrine tumors. There are no clinical data supporting the use of Lutetium ¹⁷⁷Lu-DOTATATE in the treatment of lymphoma. We describe the case of an 84-year-old man with a history of MCL and carcinoid tumor of the lung. Following progression of the carcinoid malignancy, the patient was treated with Lutetium ¹⁷⁷Lu-DOTATATE. After treatment, there was an overall improvement of the patient’s MCL that was demonstrated by stable lymphadenopathy on serial CT scans and down-trend of the absolute lymphocyte count. Therefore, we hypothesize that ¹⁷⁷Lu-DOTATATE might have a role and can be repurposed for treating MCL.     

Sequelae and survivorship in patients treated with 131I-MIBG therapy

Background:

¹³¹I-meta-iodobenzylguanidine (¹³¹I-MIBG) has been in therapeutic use since 1980s. Newer treatment modalities are emerging for neuroendocrine tumours (NETs) and chromaffin cell tumours (CCTs), but many of these do not yet have adequate long-term follow-up to determine their longer term efficacy and sequelae.

Methods:

Fifty-eight patients with metastatic NETs and CCTs who had received ¹³¹I-MIBG therapy between 2000 and 2011 were analysed. Survival and any long-term haematological or renal sequelae were investigated.

Results:

In the NET group, the overall median survival and median survival following the diagnosis of metastatic disease was 124 months. The median survival following the commencement of ¹³¹I-MIBG was 66 months. For the CCT group, median survival had not been reached. The 5-year survival from diagnosis and following the diagnosis of metastatic disease was 67% and 67.5% for NETs and CCTs, respectively. The 5-year survival following the commencement of ¹³¹I-MIBG therapy was 68%. Thirty-two patients had long-term haematological sequelae: 5 of these 32 patients developed haematological malignancies. Two patients developed a mild deterioration in renal function.

Conclusion:

Long follow up of ¹³¹I-MIBG therapy reveals a noteable rate of bone marrow toxicities and malignancy and long term review of all patients receiving radionuclide therapies is recommended.     

Capecitabine and streptozocin ± cisplatin in advanced gastroenteropancreatic neuroendocrine tumours

BackgroundCytotoxic chemotherapy is widely used for advanced, unresectable pancreatic and other gastrointestinal foregut neuroendocrine tumours (NETs) and the most commonly used regimen combines 5-fluorouracil with streptozocin. The NET01 trial was designed to investigate whether capecitabine combined with streptozocin was an acceptable regimen with or without adding cisplatin.MethodsPatients with advanced, unresectable NETs of pancreatic, gastrointestinal foregut or unknown primary site were randomised to receive three-weekly capecitabine (Cap) 625 mg/m² twice daily orally, streptozocin (Strep) 1.0 g/m² intravenously on day 1, with or without cisplatin (Cis) 70 mg/m² intravenously on day 1. The primary outcome measure was objective response. Secondary outcome measures included progression-free and overall survival, quality of life, toxicity and biochemical response.Results86 (44 CapStrep, 42 CapStrepCis) patients were randomised. Best objective response rate was 12% (95% confidence interval (CI) = 2–22%) with CapStrep and 16% (95% CI = 4–27.4%) with CapStrepCis. Disease-control rate was 80% with CapStrep and 74% with CapStrepCis. The estimated median progression-free and overall survival were 10.2 and 26.7 months for CapStrep and 9.7 and 27.5 months for CapStrepCis. 44% of CapStrep and 68% of CapStrepCis patients experienced grade ⩾3 adverse events.InterpretationThe efficacies of the novel CapStrep ± Cis regimens were very similar. CapStrep was better tolerated than CapStrepCis.The trial was registered as EudraCT: 2004-005202-71 and ISRCTN: 35124268.     

CD8+ T cell response to human papillomavirus 16 E7 is able to predict survival outcome in oropharyngeal cancer

IntroductionImmunological response to human papillomavirus (HPV) in the development and progression of HPV16+ oropharyngeal squamous cell carcinoma (OPSCC) (accounting for the majority of viral associated cases) is largely unknown and may provide important insights for new therapeutic strategies.MethodsIn this prospective clinical trial (UKCRN11945), we examined cell-mediated immune responses to HPV16 E2, E6 and E7 in peripheral blood using IFN-γ enzyme-linked immunosorbent spot assay. CD56⁺, CD4⁺, CD8⁺ and regulatory T cell frequencies were also discerned by flow cytometry. Fifty-one study participants with oropharyngeal carcinoma were recruited. Control subjects were those undergoing tonsillectomy for benign disease. All patients were treated with curative intent by radiotherapy ± chemotherapy. Disease-specific survival was investigated by multivariate analysis.ResultsHPV16 DNA was detected in 41/51 of the OPSCC participants. T cell responses against HPV16 E6 or E7 peptides were detected in 33/51 evaluable patients, respectively and correlated with HPV status. Matched pre- and post-treatment T cell responses were available for 39/51 OPSCC cases. Within the whole cohort, elevated post-treatment CD8⁺ response to HPV16 E7 correlated with longer disease free survival (multivariate DFS p < 0.03). Within the HPV + OPSCC cohort, a significant increase in regulatory T cells (p < 0.02) was noted after treatment.ConclusionsThis is the first study to provide survival data in OPSCC stratified by cell-mediated immune response to HPV16 peptides. Within the HPV16+ OPSCC cohort, enhanced immunoreactivity to antigen E7 was linked to improved survival. An increase in regulatory T cell frequencies after treatment may suggest that immunosuppression can contribute to a reduced HPV-specific cell-mediated response.     

High 2-[F]fluoro-2-deoxy-d-glucose (FDG) uptake measured by positron emission tomography is associated with reduced overall survival in patients with oral squamous cell carcinoma

Patients with oral squamous cell carcinoma (OSCC) and poor prognosis may benefit from an intensification of the initial therapy scheme. To improve the clinical management of these patients, there is a strong requirement for an accurate assessment of the malignant properties of the individual lesion. The objective of the present analysis was to define the potential value of 2-[¹⁸F]fluoro-2-deoxy-d-glucose (¹⁸FDG) uptake in the tumor measured by positron emission tomography (PET) in predicting patients’ outcome in the clinical course of OSCC. In this respect, a clinically well-defined cohort of 79 patients with primary OSCC was retrospectively evaluated. ¹⁸FDG uptake in the primary tumor site was quantified by calculation of the maximum standardized uptake values (SUV_max). Subsequent statistical analyses found, that ¹⁸FDG uptake of the primary tumor was significantly higher in stage T3/T4 vs. T1/T2 (p < 0.001), in UICC stage IV vs. stage I–III (p = 0.01), and in N1–3 vs. N0 tumors (p < 0.001), respectively. To define SUV_max cut-off values for survival analyses, receiver operating curves (ROC) were calculated for overall and disease-free survival after 36 and 60 months, respectively. Univariate survival analysis showed that high SUV_max was significantly associated with shortened overall survival after 36 (p = 0.026) and 60 months (p = 0.02). Subsequent multi-variate Cox regression analysis including SUV_max, age, gender and UICC stage as co-variables determined that, high SUV_max was the only predictor of inferior overall survival after 60 months (p = 0.035) in this model. In conclusion, ¹⁸FDG uptake detected by PET predicts adverse outcome of patients with OSCC in this retrospective analysis. ¹⁸FDG–PET might be a promising tool to contribute to therapeutic decisions and should be evaluated in future prospective studies.     

Targeted radiotherapy for small cell lung cancer using 90Yttrium-DOTATOC, an Yttrium-labelled somatostatin analogue: a pilot trial

BACKGROUND: Some small cell lung carcinomas (SCLC) express neuro-endocrine markers, such as somatostatin receptors. Therefore, somatostatin analogues can be radio-labelled with 111Indium (Octreoscan) for diagnostic scintigraphy, or with 90Y-DOTATOC for therapeutic use. This is the first trial to assess the toxicity and efficacy of treatment with 90Y-DOTATOC in patients with Octreoscan positive SCLC. METHODS: Patients with SCLC after > or =first line chemotherapy received an Octreoscan scintigraphy and results were compared to CT scans. Patients with strong somatostatin-receptor expression were treated with 60 mCi/m2 90Y-DOTATOC i.v. every 3 weeks, for a total of three cycles. Major inclusion criteria were measurable tumour lesions, disease progression, normal creatinine clearance, PS < or = 2. RESULTS: Octreoscan scintigraphy identified 70% of all primary tumours, 87% of all mediastinal lesions, but only 26% of all extrathoracic tumour manifestations. Six patients were treated. Median number of 90Y-DOTATOC cycles was 2 (1-3). The only grade 3 toxicity was fatigue (n = 2) and dyspnea (n = 1). There were no severe renal or haematological toxicities. All six patients had tumour progression, median progression free survival (PFS) was 37.5 days (28-52) and median overall (OS) was 103.5 days (28-269). CONCLUSION: This is the first report of somatostatin-receptor targeted radiotherapy for SCLC in the literature. In contrast to well differentiated neuro-endocrine tumours, 90Y-DOTATOC seems to be inactive in SCLC.     

Receptor-mediated radionuclide therapy with 90Y-DOTA-D-Phe1-Tyr3-Octreotide: preliminary report in cancer patients

Recent advances in receptor mediated tumor imaging led to the development of a new somatostatin analogue DOTA-D-Phe1-Tyr3-Octreotide. This new compound, named DOTATOC, has shown high affinity for somatostatin receptors, stable labeling with yttrium-90 (90Y) and favourable biodistribution in patients. The aim of this work was to evaluate acute and late toxicity and the response rate in cancer patients administered 90Y-DOTATOC. Twenty patients received three equal i.v. injections of 90Y-DOTATOC. Cohorts of 5 patients were treated starting with 1.1 GBq per cycle in escalating dosage (0.4 GBq increments) in subsequent groups. No patients showed acute or delayed major adverse reactions up to the dose of 2.2 GBq of 90Y-DOTATOC per cycle (6.6 GBq total). Maximum tolerated dose has not been determined yet. One patient, after 4.4 GBq total dose, developed delayed kidney grade II toxicity. Complete and partial tumor mass reduction (CR and PR) was measured in 25% of patients along with 55% showing stable disease (SD) and 20% progressive disease (PD). These results indicate that high activities of 90Y-DOTATOC can be administered with low risk of myelotoxicity, although the radiation doses to the kidneys require careful consideration. Tumor doses were high enough in most cases to obtain objective therapeutic responses.     

Radioimmunotherapy (RIT) in non-Hodgkin lymphoma

Radio-labeled anti-CD20 antibodies are a relatively novel technique that uses monoclonal antibodies to target CD20-positive cells and administer complex antibody-mediated and/or complement-dependant cytotoxicity in combination with systemic radiotherapy to targeted cells and adjacent cells via the “crossfire” effect. There are currently two main agents in clinical practice—yttrium-90 (⁹⁰Y) ibritumomab tiuxetan (Zevalin) and iodine-131 (¹³¹I) tositumomab (Bexxar)—with other agents in clinical development. Studies have been performed looking into the use of radioimmunotherapy (RIT) in indolent non-Hodgkin lymphoma (NHL), initially in patients with relapsed, treatment-refractory and transformed disease (overall response rates [ORR] 74–92% with complete response [CR] 15–51%), and also in patients not suitable for transplant (i.e., the elderly population [CR 23%]) and in isolation in the first-line setting (comparable response rates to RCHOP) and combination with chemotherapy in the first-line setting (ORR 90–100%). The use of RIT in diffuse large B cell aggressive (DLBC) NHL has been assessed initially in patients with relapsed disease, both rituximab naïve (ORR 44%) and refractory (ORR 19%), and more recently as consolidative treatment following primary chemotherapy (early results 5-year overall survival 60% vs 37%), or in combination with primary chemotherapy. The main side effects are infusion related and hematological with a delayed nadir (4–6 weeks in DLBC NHL, 6–8 weeks in indolent disease) and correlate with bone marrow reserve.