RESUMO
BACKGROUND: Approximately 4-9% of patients have a tumor-positive resection margin after neoadjuvant chemoradiotherapy (nCRT) and esophagectomy. Although it is associated with decreased survival, Western guidelines do not recommend adjuvant treatment. OBJECTIVE: The aim of this study was to assess the proportion of patients who received adjuvant therapy, and to evaluate overall survival (OS) after esophagectomy in patients with a tumor-positive resection margin. METHODS: Patients diagnosed with resectable (cT2-4a/cTxN0-3/NxM0) esophageal cancer between 2015 and 2022, and treated with nCRT followed by irradical esophagectomy, were selected from the Netherlands Cancer Registry. The primary outcome was the proportion of patients with a tumor-positive resection margin who started adjuvant treatment ≤16 weeks after esophagectomy, including chemotherapy/radiotherapy, immunotherapy, or targeted therapy. OS was calculated from the date of surgery until the date of death or last day of follow-up. RESULTS: Overall, 376 patients were included in our study, of whom 357 were treated with nCRT. Of these 357 patients, 98.3% had a microscopically irradical resection and 1.7% had a macroscopically irradical resection. Approximately 72.3% of tumors showed a partial response (Mandard 2-3) and 11.8% showed little/no pathological response (Mandard 4-5) to nCRT. One of 357 patients underwent adjuvant chemoradiotherapy and 39 patients (61%) underwent adjuvant immunotherapy (nivolumab). The median and 5-year OS rate of all patients was 16.4 months (95% confidence interval 13.1-19.8) and 21%, respectively. CONCLUSION: Real-world population-level data showed that no patients with a tumor-positive resection margin underwent adjuvant therapy following nCRT and esophagectomy prior to 2021. Interestingly, 61% of patients were treated with adjuvant nivolumab in 2021-2022. OS after irradical esophagectomy is poor and long-term data will explore the added value of nivolumab.
Assuntos
Neoplasias Esofágicas , Esofagectomia , Margens de Excisão , Terapia Neoadjuvante , Humanos , Esofagectomia/mortalidade , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/mortalidade , Masculino , Feminino , Terapia Neoadjuvante/mortalidade , Idoso , Pessoa de Meia-Idade , Taxa de Sobrevida , Seguimentos , Prognóstico , Quimiorradioterapia Adjuvante/mortalidade , Quimioterapia Adjuvante , Estudos RetrospectivosRESUMO
At present, treatment of potentially curable oesophageal cancer includes neoadjuvant chemoradiotherapy followed by oesophagectomy. Alternatively, neoadjuvant chemotherapy is used. To date, strong evidence on the superiority of one modality over the other has not been provided. Currently, up to one-third of patients show a pathologically complete response after neoadjuvant chemoradiotherapy. To optimise the efficacy of neoadjuvant treatment for individual patients, prediction of response to neoadjuvant treatment is highly desired. Therefore, several clinical diagnostic modalities have been investigated for early response evaluation, of which positron emission tomography (PET) has been studied most extensively. To identify patients who might benefit from postponing or even omitting surgery, recent advances have been made in evaluating response after completion of neoadjuvant chemoradiotherapy. This review provides an overview of current evidence and recent advances in neoadjuvant chemoradiotherapy for oesophageal cancer and discusses the use of neoadjuvant chemotherapy compared to chemoradiotherapy. Moreover, clinical response evaluation to neoadjuvant chemoradiotherapy is reviewed.
Assuntos
Quimiorradioterapia/métodos , Neoplasias Esofágicas/terapia , Terapia Neoadjuvante/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
In many countries, neoadjuvant chemoradiotherapy (nCRT) plus surgery is standard treatment for resectable oesophageal cancer. After nCRT, up to 30% of all patients have no residual disease in the resection specimen. Consequently, an active surveillance approach, in which patients undergo frequent clinical investigations after nCRT instead of standard oesophagectomy, is increasingly applied in selected patients. Here, we describe outcomes for three patients who underwent active surveillance. A 63-year old woman was considered unfit for surgery after nCRT. Four years after completion of nCRT, she still had no signs of disease recurrence. The second patient, a 57-year old woman, refused surgery when no residual disease was detectable after nCRT. One year following treatment, she developed a vertebral metastasis, in the absence of locoregional disease. The third patient concerned a 66-year old man with a clinically complete response after nCRT, who also refused surgery. During active surveillance, he developed a locoregional regrowth and underwent a radical oesophagectomy.
Assuntos
Quimiorradioterapia Adjuvante , Neoplasias Esofágicas/terapia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Recidiva Local de Neoplasia , Resultado do TratamentoRESUMO
Neoadjuvant chemoradiotherapy (nCRT) followed by surgery is standard of care for locally advanced esophageal cancer in many countries. After nCRT up to one third of all patients have a pathologically complete response in the resection specimen, posing an ethical imperative to reconsider the necessity of standard surgery in all operable patients after nCRT. An active surveillance strategy following nCRT, in which patients are subjected to frequent clinical investigations after the completion of neoadjuvant therapy, has been evaluated in other types of cancer with promising results. In esophageal cancer, both patients who are cured by neoadjuvant therapy alone as well as patients with subclinical disseminated disease at the time of completion of neoadjuvant therapy may benefit from such an organ sparing approach. Active surveillance is currently applied in selected patients with esophageal cancer who refuse surgery or are medically unfit for major surgery after completion of nCRT, but this strategy is not (yet) adopted as an alternative to standard surgery or definitive chemoradiation. The available literature is scarce, but suggests that long-term oncological outcomes after active surveillance are noninferior compared to standard surgical resection, providing justification for comparison of both treatments in a phase III trial. This review gives an overview of the current knowledge regarding active surveillance after completion of nCRT in esophageal cancer and outlines future research perspectives.
Assuntos
Neoplasias Esofágicas/terapia , Junção Esofagogástrica , Conduta Expectante , Quimiorradioterapia Adjuvante , Esofagectomia , Humanos , Terapia Neoadjuvante , Resultado do TratamentoRESUMO
INTRODUCTION: Pancreatic cancer is among the five most lethal malignancies in the world. Unfortunately, many malignant tumors go undetected by the current primary diagnostic tools. (18)FDG-PET and (18)FDG-PET/CT might be useful to confirm suspected pancreatic cancer. METHODS: A meta-analysis was performed using all major search engines. Methodological quality of included studies was assessed as well as quality of the PET-protocol. The following pooled estimates served as primary outcome measures: sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy. RESULTS: Thirty-five studies were included. Pooled estimates for (18)FDG-PET were: sensitivity 90%, specificity 76%, PPV 90%, NPV 76% and accuracy 86%. Pooled estimates for (18)FDG-PET/CT were: sensitivity 90%, specificity 76%, PPV 89%, NPV 78% and accuracy 86%. The pooled sensitivity and specificity for (18)FDG-PET to differentiate between pancreatic cancer and chronic pancreatitis were 90% and 84%, respectively. CONCLUSION: Both (18)FDG-PET and (18)FDG-PET/CT offer no benefit over the current primary diagnostic tools in diagnosing pancreatic cancer. However, the (18)FDG-PET/CT systems are still improving. We should investigate the sensitivity and specificity of these new systems while reevaluating the tradeoff between false positive and false negative results. Yet, (18)FDG-PET/CT may have a role in the staging of pancreatic cancer, in survival prediction, and may add to other diagnostic information, like histology.
Assuntos
Fluordesoxiglucose F18 , Neoplasias Pancreáticas/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Tomografia Computadorizada por Raios X/métodos , Feminino , Humanos , Masculino , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Neoplasias Pancreáticas/patologia , Compostos Radiofarmacêuticos , Sensibilidade e EspecificidadeRESUMO
Nuclear medicine plays a pivotal role in the imaging and treatment of neuroendocrine tumours (NETs). Somatostatin receptor scintigraphy (SRS) with [(111)In-DTPA(0)]octreotide has proven its role in the diagnosis and staging of gastroenteropancreatic NETs (GEP-NETs). New techniques in somatostatin receptor imaging include the use of different radiolabelled somatostatin analogues with higher affinity and different affinity profiles to the somatostatin receptor subtypes. Most of these analogues can also be labelled with positron-emitting radionuclides that are being used in positron emission tomography imaging. The latter imaging modality, especially in the combination with computed tomography, is of interest because of encouraging results in terms of improved imaging quality and detection capabilities. Considerable advances have been made in the imaging of NETs, but to find the ideal imaging method with increased sensitivity and better topographic localisation of the primary and metastatic disease remains the ultimate goal of research. This review provides an overview of the currently used imaging modalities and ongoing developments in the imaging of NETs, with the emphasis on nuclear medicine and puts them in perspective of clinical practice. The advantage of SRS over other imaging modalities in GEP-NETs is that it can be used to select patients with sufficient uptake for treatment with radiolabelled somatostatin analogues. Peptide receptor radionuclide therapy (PRRT) is a promising new tool in the management of patients with inoperable or metastasised NETs as it can induce symptomatic improvement with all Indium-111, Yttrium-90 or Lutetium-177-labelled somatostatin analogues. The results that were obtained with [(90)Y-DOTA(0),Tyr(3)]octreotide and [(177)Lu-DOTA(0),Tyr(3)]octreotate are even more encouraging in terms of objective tumour responses with tumour regression and documented prolonged time to progression. In the largest group of patients receiving PRRT, treated with [(177)Lu-DOTA(0),Tyr(3)]octreotate, a survival benefit of several years compared with historical controls has been reported.
Assuntos
Neoplasias Gastrointestinais/diagnóstico por imagem , Tumores Neuroendócrinos/diagnóstico por imagem , Neoplasias Pancreáticas/diagnóstico por imagem , 3-Iodobenzilguanidina/análogos & derivados , 3-Iodobenzilguanidina/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Gastrointestinais/radioterapia , Humanos , Ligantes , Imageamento por Ressonância Magnética , Tumores Neuroendócrinos/radioterapia , Octreotida/análogos & derivados , Neoplasias Pancreáticas/radioterapia , Radioisótopos/uso terapêutico , Cintilografia , Receptores de Somatostatina/metabolismo , Tomografia Computadorizada por Raios XRESUMO
CONTEXT: Insulinomas are relatively rare neuroendocrine tumors of the pancreas. Only 10% are considered malignant. Control of insulin hypersecretion and hypoglycemia in patients with malignant insulinomas may be extremely difficult. Different medications and chemotherapy schedules have been used. PATIENTS: Five patients with metastatic insulinomas and severe, poorly controllable, hypoglycemia are described. These patients required continuous glucose infusion to control severe hypoglycemia, which were induced by the high levels of insulin secretion. Conventional medications, such as diazoxide, or streptozotocin-based chemotherapies had been used to control hypoglycemia but were ineffective and/or produced adverse effects. All patients were treated with sc octreotide. INTERVENTION: Peptide receptor radionuclide therapy with radiolabeled-somatostatin analogs was used. RESULTS: After the start of radiolabeled somatostatin analog therapy, the five patients with metastatic insulinomas had stable disease for a mean period of 27 months. During these months, the patients were without any hypoglycemic episodes. Finally, three of five patients died because of progressive disease. CONCLUSIONS: Radiolabeled somatostatin analog therapy can stabilize tumor growth and can be very successful in further controlling severe hypoglycemia in malignant insulinomas. In our series, this eventually resulted in improved survival outside the hospital setting.
Assuntos
Hipoglicemia/tratamento farmacológico , Insulinoma/complicações , Lutécio/uso terapêutico , Octreotida/uso terapêutico , Neoplasias Pancreáticas/complicações , Radioisótopos/uso terapêutico , Adulto , Feminino , Humanos , Hipoglicemia/etiologia , Radioisótopos de Índio/uso terapêutico , Masculino , Pessoa de Meia-Idade , Somatostatina/análogos & derivados , Resultado do TratamentoRESUMO
Tumors and metastases bearing the somatostatin receptor subtypes 2 (SSTR2) or SSTR5 can be visualized in vivo after injection of radiolabeled octapeptide somatostatin analogs like 111In-pentetreotide. The sensitivity of 111In-pentetreotide scintigraphy for the detection of carcinoid tumors is 86-95%. The sensitivity of 111In-pentetreotide scintigraphy for the detection of gastrinomas, vasoactive intestinal polypeptide-secreting tumors, and glucagonomas as well as clinically non-functioning lesions is 75-100%. However, for insulinoma this is 50-60%. 111In-pentetreotide scintigraphy generally has a lower detection rate for benign pheochromocytomas than 123I-MIBG scintigraphy, but it can have a complementary role for the staging of malignant pheochromocytomas. It can also be used for the detection of extra-adrenal pheochromocytomas and paragangliomas. Most GH- and TSH-secreting pituitary adenomas can be visualized using 111In-pentetreotide. 111In-pentetreotide scintigraphy is negative in microprolactinomas and ACTH-secreting pituitary microadenomas. 111In-pentetreotide scintigraphy has been successful for the localization of extra-pituitary ACTH-secreting tumors and their metastases, and especially for occult tumors. A large variety of lesions in and around the pituitary region express somatostatin receptors and, therefore, can be visualized by 111In-pentetreotide scintigraphy.
Assuntos
Tumores Neuroendócrinos/diagnóstico por imagem , Somatostatina , Tumor Carcinoide/diagnóstico por imagem , Neoplasias Gastrointestinais/diagnóstico por imagem , Humanos , Radioisótopos de Índio , Tumores Neuroendócrinos/química , Paraganglioma/diagnóstico por imagem , Feocromocitoma/diagnóstico por imagem , Neoplasias Hipofisárias/diagnóstico por imagem , Cintilografia , Receptores de Somatostatina/análise , Somatostatina/análogos & derivadosRESUMO
Peptide receptor radionuclide therapy (PRRT) holds great promise for the future regarding the treatment of various cancers. With the use of radiolabelled peptides, which bind with high affinity to their receptors on cancer cells, it is possible to target the cancer efficiently. In gastroenteropancreatic tumors, radiolabelled somatostatin analog therapy has proven to be effective. Dose-limiting organs are the bone marrow and the kidneys. With the currently used dose schemes and kidney protection, PRRT is relatively safe and serious side-effecs are rare. Which radiolabelled somatostatin analog can be regarded as the most effective therapy cannot be concluded from the available literature. Also, the development of therapy strategies with combinations of different radionuclides and or peptides is of interest as these strategies may provide an increase in therapeutic efficacy in the future.
Assuntos
Tumores Neuroendócrinos/radioterapia , Somatostatina/análogos & derivados , Humanos , Radioisótopos de Índio/uso terapêutico , Marcação por Isótopo , Lutécio , Radioisótopos , Receptores de Somatostatina/metabolismo , Radioisótopos de Ítrio/uso terapêuticoRESUMO
BACKGROUND/AIMS: We prospectively evaluated whether fluorine-18 deoxyglucose (FDG) positron coincidence detection (PCD) or FDG single-photon emission computed tomography (SPECT) provides additional benefits to our conventional preoperative evaluation of lesion detection in patients suspected to have hepatocellular carcinoma (HCC). METHODS: Thirteen consecutive patients with a suspected HCC underwent conventional preoperative evaluation with ultrasonography (US), triple-phase helical computed tomography (CT), superparamagnetic iron oxides (SPIO) enhanced magnetic resonance imaging (MRI) and serum alpha-fetoprotein (AFP) level. All 13 patients had an FDG-PCD and SPECT. These results were evaluated to assess the value of FDG-PCD and SPECT in addition to US, SPIO-enhanced MRI and triple-phase helical CT. RESULTS: Ten of the 13 (77%) patients had at least one histologically confirmed HCC without extrahepatic abdominal spread. The tumors ranged in size from 1 to 8 cm and the serum AFP ranged from 3 to 30 000 microg/l. Of these 10 patients, two patients had an increased tumor F-FDG uptake (sensitivity of 20%); one patient with an AFP of 5 microg/l and a tumor size of maximum 4.5 cm and one patient with an AFP of 249 microg/l and a tumor size of maximum 2 cm. In three patients with a benign liver mass, FDG imaging with either PCD or SPECT was negative. There was no false positive finding. CONCLUSIONS: We found poor sensitivity of FDG-PCD and FDG-SPECT for the detection of HCC. There were no clear relations between AFP or tumor size and FDG uptake. Therefore, we conclude that FDG imaging with PCD or SPECT has no value in the preoperative work-up for HCC in patients with cirrhosis.
Assuntos
Carcinoma Hepatocelular/diagnóstico por imagem , Fluordesoxiglucose F18 , Neoplasias Hepáticas/diagnóstico por imagem , Compostos Radiofarmacêuticos , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Tomografia Computadorizada de Emissão/métodos , Adulto , Idoso , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/patologia , Feminino , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/patologia , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Sensibilidade e EspecificidadeRESUMO
In vivo somatostatin receptor-mediated scintigraphy has proven to be a valuable method for the visualisation of neuroendocrine tumours and their metastases. A new application is the use of radiolabelled analogues for somatostatin receptor-mediated therapy. This paper presents a review on the basic science, historical background and current knowledge of somatostatin receptor subtypes and their expression in neuroendocrine tumours. New somatostatin analogues, new chelators, "new" radionuclides and combinations thereof are also discussed. Due attention is given to limitations and future perspectives of somatostatin receptor-mediated imaging and therapy.
Assuntos
Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/radioterapia , Compostos Radiofarmacêuticos/uso terapêutico , Receptores de Somatostatina/análise , Somatostatina/análogos & derivados , Humanos , Radioisótopos de Índio/uso terapêutico , Lutécio , Tumores Neuroendócrinos/química , Octreotida/análogos & derivados , Octreotida/uso terapêutico , Cintilografia , Receptores de Somatostatina/classificação , Somatostatina/uso terapêutico , Radioisótopos de Ítrio/uso terapêuticoRESUMO
Somatostatin receptor (SS-R) scintigraphy successfully shows primary cancers and metastases in patients with a variety of SS-R-positive tumours. In vitro studies have shown that SS-Rs are present in lymph nodes from patients with Hodgkin's disease (HD). We performed a prospective study in 126 newly diagnosed patients with HD and compared the results of SS-R scintigraphy with conventional staging procedures, i.e. physical examination, computerized tomography (CT) scanning and other imaging techniques. We report positive scintigraphy in all patients. The lesion-related sensitivity was 94% and varied from 98% for supradiaphragmatic lesions to 67% for infradiaphragmatic lesions. In comparison with CT scanning and ultrasonography, SS-R scintigraphy provided superior results for the detection of Hodgkin's localizations above the diaphragm. In the intra-abdominal region, the CT scan was more sensitive than the SS-R scan. A false-positive scan was rarely seen. In stages I and II supradiaphragmatic HD patients, SS-R scintigraphy detected more advanced disease in 18% (15 out of 83) of patients, resulting in an upstaging to stage III or IV, thus directly influencing patient management. Our data would support the validity of SS-R scanning as a powerful imaging technique for the staging of patients with HD.
Assuntos
Doença de Hodgkin/diagnóstico por imagem , Linfonodos/diagnóstico por imagem , Receptores de Somatostatina/análise , Somatostatina/análogos & derivados , Adolescente , Adulto , Idoso , Feminino , Humanos , Pulmão/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Prospectivos , Cintilografia , Sensibilidade e Especificidade , Baço/diagnóstico por imagem , Tomografia Computadorizada por Raios XRESUMO
UNLABELLED: In this prospective study, somatostatin receptor (SS-R) scintigraphy was compared with conventional staging procedures for the initial staging of patients with low-grade non-Hodgkin's lymphoma (NHL). METHODS: Fifty consecutive untreated patients with low-grade NHL underwent SS-R scintigraphy as part of their initial staging. Planar images were obtained 24 and 48 h after intravenous injection of 220 MBq (111)In-pentetreotide. SPECT images of the upper abdomen were obtained from all patients. SS-R scans were evaluated blindly without knowledge of the results of the conventional staging methods. SS-R scintigraphy findings were compared with the results of physical and radiologic examinations. RESULTS: SS-R scintigraphy findings were positive in 42 of 50 patients (84%). In 10 patients (20%), the SS-R scan revealed new lesions that had not been revealed by conventional staging procedures. These 10 patients were all upgraded to a higher stage. Consequently, the treatment plan would have been altered in 5 patients (10%). However, in 19 patients (38%), lesions apparent after conventional staging methods were missed by SS-R scintigraphy. The sensitivity of SS-R scintigraphy varied from 62% for supradiaphragmatic lesions to 44% for infradiaphragmatic lesions. The specificity of SS-R scintigraphy was high (98%-100%). In comparison with CT scanning and sonography, SS-R scintigraphy is inferior for the visualization of NHL lesions in the thorax and abdomen. CONCLUSION: Although SS-R scintigraphy findings are positive in a large proportion of patients with low-grade NHL, in most patients only part of the lesions can be visualized. Because of the limited sensitivity, we recommend SS-R scintigraphy for initial staging of patients with low-grade NHL only in selected conditions and not for the general work-up.
Assuntos
Linfoma não Hodgkin/diagnóstico por imagem , Receptores de Somatostatina/análise , Somatostatina/análogos & derivados , Tomografia Computadorizada de Emissão de Fóton Único , Feminino , Humanos , Radioisótopos de Índio , Linfonodos/diagnóstico por imagem , Masculino , Estadiamento de Neoplasias , Estudos Prospectivos , Compostos Radiofarmacêuticos , Sensibilidade e Especificidade , Tomografia Computadorizada por Raios XRESUMO
OctreoTher ((90)Y-DOTA-D-Phe(1)-Tyr(3)-octreotide, a.k.a. (90)Y-SMT 487) consists of a somatostatin peptide analogue (Tyr(3)-octreotide), coupled with a complexing moiety (DOTA), and labeled with a tightly bound beta-emitter (yttrium-90). By targeting somatostatin receptor-positive tumors (as imaged by OctreaScan it may deliver a tumoricidal dose of radiation. Phase I clinical trials, conducted in patients with neuroendocrine tumors, established the safety and tolerability of the dose selected for further study and demonstrated the capacity of OctreoTher to deliver radiation doses to tumors that resulted in significant neuroendocrine tumor shrinkage. Novartis-sponsored phase II studies will soon begin to test the efficacy of OctreoTher in breast and small cell lung cancer. A fixed-dose regimen of 120 mCi/cycle x 3 cycles administered with concomitant amino acid infusion has been chosen for the study. Phase I data and published literature support that this fixed dose regimen will be safely tolerated.
Assuntos
Radioisótopos de Índio/uso terapêutico , Neoplasias/radioterapia , Octreotida/análogos & derivados , Compostos Radiofarmacêuticos/uso terapêutico , Radioisótopos de Ítrio/uso terapêutico , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/radioterapia , Carcinoma de Células Pequenas/metabolismo , Carcinoma de Células Pequenas/radioterapia , Relação Dose-Resposta à Radiação , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/radioterapia , Masculino , Camundongos , Camundongos Nus , Neoplasias/metabolismo , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/radioterapia , Octreotida/uso terapêutico , Receptores de Somatostatina/metabolismo , Somatostatina/análogos & derivadosRESUMO
Peptide receptor scintigraphy with the radioactive somatostatin analogue [111In-DTPA-D-Phe1]octreotide is a sensitive and specific technique to show in vivo the presence and abundance of somatostatin receptors on various tumors. With this technique primary tumors and metastases of neuroendocrine cancers as well as of many other cancer types can be localized. This technique is currently used to assess the possibility of peptide receptor radionuclide therapy with repeated administration of high doses of [111In-DTPA-D-Phe1]octreotide. 111In emits Auger and conversion electrons, having a tissue penetration of 0.02-10 microns and 200-500 microns, respectively. Thirty end-stage patients with mostly neuroendocrine progressing tumors were treated with [111In-DTPA-D-Phe1]octreotide, up to a maximal cumulative patient dose of about 74 GBq, in a phase-I trial. There were no major clinical side effects after up to 2 years of treatment, except that in a few patients a transient decline in platelet counts and lymphocyte subsets occurred. Promising beneficial effects on clinical symptoms, hormone production, and tumor proliferation were found. Of the 21 patients who received a cumulative dose of more than 20 GBq, eight showed stabilization of disease and six others a reduction in tumor size. There is a tendency towards better results in patients whose tumors have a higher accumulation of the radioligand. Peptide receptor radionuclide therapy is also feasible with 111In as the radionuclide. Theoretically, depending on the homogeneity of distribution of tumor cells expressing peptide receptors and the size of the tumor, beta-emitting radionuclides, e.g., 90Y, labeled to DOTA-chelated peptides may be more effective than 111In for peptide receptor radionuclide therapy. The first peptide receptor radionuclide therapy trials with [90Y-DOTA-Tyr3]octreotide started recently.
Assuntos
Radioisótopos de Índio/uso terapêutico , Tumores Neuroendócrinos/radioterapia , Octreotida/análogos & derivados , Ácido Pentético/análogos & derivados , Compostos Radiofarmacêuticos/uso terapêutico , Divisão Celular/efeitos da radiação , Relação Dose-Resposta à Radiação , Feminino , Humanos , Radioisótopos de Índio/efeitos adversos , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Octreotida/efeitos adversos , Octreotida/farmacocinética , Octreotida/uso terapêutico , Compostos Radiofarmacêuticos/efeitos adversos , Compostos Radiofarmacêuticos/farmacocinética , Dosagem RadioterapêuticaRESUMO
Peptide receptor scintigraphy with [111In-DTPA-D-Phe1]-octreotide is a sensitive and specific technique to show in vivo the presence and abundance of somatostatin receptors on various tumours. With this technique primary tumours and metastases of neuroendocrine cancers as well as of many other cancer types can be localised. This technique is currently used to assess the possibility of peptide receptor radionuclide therapy with repeated administrations of high doses of [111In-DTPA-D-Phe1]-octreotide. 111In emits Auger and conversion electrons having a tissue penetration of 0.02 to 10 microns and 200 to 500 microns, respectively. Twenty end-stage patients, mostly with neuroendocrine progressing tumours, were treated with [111In-DTPA-D-Phe1]-octreotide, up to a maximal cumulative patient dose of about 74 GBq, in a phase I trial. Results showed there were no major clinical side-effects after up to 2 years treatment, except that in a few patients a transient decline in platelet counts and lymphocyte subsets occurred. Promising beneficial effects on clinical symptoms, hormone production and tumour proliferation were found. Of the 16 patients who received a cumulative dose of more than 20 GBq, 5 patients showed stabilisation of disease and 5 other patients a reduction in size of tumours. There is a tendency towards better results in patients whose tumours have a higher accumulation of the radioligand. In conclusion, peptide receptor radionuclide therapy is feasible, also with 111In as radionuclide. Theoretically, depending on the homogeneity of distribution of tumour cells expressing peptide receptors, beta-emitting radionuclides, e.g. 90Y, labelled to DOTA-chelated peptides may be more effective than 111In for peptide receptor radionuclide therapy. The first peptide receptor radionuclide therapy trials with [90Y-DOTA-Tyr3]-octreotide started recently.
Assuntos
Antineoplásicos Hormonais/administração & dosagem , Neoplasias do Sistema Digestório/radioterapia , Tumores Neuroendócrinos/radioterapia , Octreotida/uso terapêutico , Neoplasias do Sistema Digestório/diagnóstico por imagem , Neoplasias do Sistema Digestório/mortalidade , Feminino , Humanos , Masculino , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/mortalidade , Prognóstico , Cintilografia , Dosagem Radioterapêutica , Índice de Gravidade de Doença , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Peptide receptor scintigraphy with the radioactive somatostatin analogue, [111In-DTPA0]octreotide, is a sensitive and specific technique to show in vivo the presence and abundance of somatostatin receptors on various tumours. AIM: With this technique primary tumours and metastases of neuroendocrine cancers as well as of many other cancer-types can be localised. This technique is currently used to assess the possibility of peptide receptor radionuclide therapy (PRRT) with repeated administrations of high doses of [111In-DTPA0)octreotide. 111In emits Auger and conversion electrons having a tissue penetration of 0.02-10 microns and 200 to 500 microns, respectively. PATIENTS AND METHODS: Thirty end-stage patients with mostly neuroendocrine progressing tumours were treated with [111In-DTPA0]octreotide, up to a maximal cumulative patient dose of about 74 GBq, in a phase I trial. RESULTS: There were no major clinical side effects after up to two years treatment, except that in a few patients a transient decline in platelets counts and lymphocyte subsets occurred. Promising beneficial effects on clinical symptoms, hormone production and tumour proliferation were found. Of the 21 patients who received a cumulative dose of more than 20 GBq, eight patients showed stabilisation of disease and six other patients a reduction in size of tumours. There is a tendency towards better results in patients whose tumours have a higher accumulation of the radioligand. CONCLUSIONS: PRRT is feasible, also with 111In as radionuclide. Depending on the homogeneity of distribution of tumour cells expressing peptide receptors and the size of the tumour, beta-emitting radionuclides, e.g., 90Y, labelled to DOTA-chelated peptides, are also attractive candidates for PRRT. The first PRRT trials with [90Y-DOTA0,Tyr3]octreotide started recently.
Assuntos
Radioisótopos de Índio/uso terapêutico , Tumores Neuroendócrinos/radioterapia , Octreotida/análogos & derivados , Ácido Pentético/análogos & derivados , Compostos Radiofarmacêuticos/uso terapêutico , Receptores de Peptídeos/análise , Animais , Humanos , Radioisótopos de Índio/farmacocinética , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/secundário , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Octreotida/efeitos adversos , Octreotida/farmacocinética , Octreotida/uso terapêutico , Ácido Pentético/efeitos adversos , Ácido Pentético/farmacocinética , Ácido Pentético/uso terapêutico , Compostos Radiofarmacêuticos/efeitos adversos , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Receptores de Peptídeos/metabolismo , Receptores de Somatostatina/análise , Receptores de Somatostatina/metabolismoRESUMO
UNLABELLED: The presence of cholecystokinin (CCK)-B (gastrin) receptors has been shown in more than 90% of medullary thyroid cancers (MTCs) and in a high percentage of small cell lung cancers, stromal ovarium cancers and several other tumor types. METHODS: The aim of this study was to evaluate in vitro and in vivo whether 111In-labeled CCK-B receptor-specific CCK8 analog [D-Asp26,Nle28,31]CCK26-33 (D-Asp-Tyr-Nle-Gly-Trp-Nle-Asp-Phe-NH2) is suitable for CCK-B receptor scintigraphy based on the finding that unlabeled nonsulfated diethylenetriamine pentaacidic acid [DTPA0]CCK8 and tetraazacyclododecanetetraacetic acid [DOTA0]CCK8 analogs show high and specific binding for CCK-B receptors in human tumors. Fifty percent inhibitory concentrations were in the low nanomolar range. RESULTS: In vitro, [111In-DOTA0]CCK8 showed specific internalization in CCK-B receptor-positive rat pancreatic tumor cells AR42J. Internalization of the analog appeared to be time and temperature dependent and receptor specific. From the data obtained with [111In-DOTA0]CCK8 and (125I)I-gastrin, the latter being a specific ligand for the CCK-B receptor, the rat pancreatic cell line CA20948 also appeared to be CCK-B receptor positive. This provides an in vitro and in vivo rat tumor model because this cell line can be grown to solid tumors in Lewis rats. In vivo biodistribution experiments in CA20948 tumor-bearing Lewis rats showed rapid clearance of [111In-DOTA0]CCK8, and specific uptake was found in the CCK-B receptor-expressing stomach and tumor. Furthermore, comparing [111In-DOTA0]CCK8 with the radioiodinated nonsulfated CCK10 analog (D-Tyr-Gly-Asp-Tyr-Nle-Gly-Trp-Nle-Asp-Phe-NH2), both ligands having high affinity for the CCK-B receptor, tumor-to-blood ratios were significantly higher for [111In-DOTA0]CCK8 than for 125I-CCK10, analogous to the findings with radioiodinated and 111In-labeled octreotide. The study in humans with [111In-DTPA0]CCK8 showed receptor-specific uptake in the CCK-B receptor-positive stomach and in metastases in the neck region up to 48 h after injection. CONCLUSION: [111In-DOTA0]CCK8 is most promising for scintigraphy and, after coupling to therapeutic radionuclides, for radionuclide therapy of human CCK-B receptor-positive tumors such as MTC and small cell lung cancer.
Assuntos
Colecistocinina , Radioisótopos de Índio , Neoplasias Pancreáticas/diagnóstico por imagem , Fragmentos de Peptídeos , Receptores da Colecistocinina/análise , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Animais , Colecistocinina/farmacocinética , Colecistocinina/uso terapêutico , Colecistocinina/toxicidade , Avaliação de Medicamentos , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Neoplasias Pancreáticas/química , Fragmentos de Peptídeos/farmacocinética , Fragmentos de Peptídeos/uso terapêutico , Fragmentos de Peptídeos/toxicidade , Cintilografia , Ratos , Ratos Endogâmicos Lew , Ratos Wistar , Receptor de Colecistocinina B , Neoplasias da Glândula Tireoide/química , Distribuição Tecidual , Células Tumorais CultivadasRESUMO
UNLABELLED: Peptide receptor scintigraphy with the radioactive somatostatin-analogue [111In-DTPA0]octreotide (DTPA = diethylenetriaminepentaacetic acid) is a sensitive and specific technique to show in vivo the presence and abundance of somatostatin receptors on various tumors. With this technique primary tumors and metastases of neuroendocrine cancers as well as of many other cancer types can be localised. A new application is the use of peptide receptor radionuclide therapy, administrating high doses of 111In- or 90Y-labeled octreotide-analogues. PRECLINICAL: We investigated the radiotherapeutic effect of 90Y- and 111In-labeled [DOTA0,Tyr3]octreotide (DOTA = tetraazacyclododecanetetraacetic acid) or [111In-DTPA0]octreotide in Lewis rats bearing the somatostatin receptor-positive rat pancreatic tumor CA20948 in A) the flank or B) in the liver. PATIENTS: Thirty end-stage patients with mostly neuroendocrine progressing tumors were treated with [111In-DTPA0]octreotide, up to a maximal cumulative patient dose of about 74 GBq, in a phase 1 trial. PRECLINICAL RESULTS: A) Flank model: at least two 111MBq injections of [111In-DOTA0,Tyr3]octreotide were needed to reach tumor response, in 40% of the animals complete tumor remission was found after a follow-up period of 10 months. One or two injections of [90Y-DOTA0,Tyr3] octreotide yielded transient stable disease. B) Liver model: we found that peptide receptor radionuclide therapy is only effective if somatostatin receptors are present on the tumors, and is therefore receptor-mediated. High radioactive doses of 370 MBq [111In-DTPA0]octreotide or 93 MBq [90Y-DOTA0,Tyr3]octreotide can inhibit the growth of somatostatin receptor-positive metastases. CLINICAL RESULTS: There were no major clinical side effects after up to 2 years treatment, except that a transient decline in platelet counts and lymphocyte subsets can occur. Promising beneficial effects on clinical symptoms, hormone production and tumor proliferation were found. Of the 21 patients with progressive disease at baseline and who received a cumulative dose of more than 20 GBq [111In-DTPA0]octreotide, 8 patients showed stabilisation of disease and 6 other patients a reduction in size of tumors. There is a tendency towards better results in patients whose tumors have a higher accumulation of the radioligand. CONCLUSION: Radionuclide therapy with octreotide-derivatives is feasible, both with 111In and 90Y as radionuclides.
Assuntos
Radioisótopos de Índio/uso terapêutico , Tumores Neuroendócrinos/radioterapia , Octreotida/análogos & derivados , Radioisótopos de Ítrio/uso terapêutico , Animais , Relação Dose-Resposta à Radiação , Humanos , Octreotida/uso terapêutico , Neoplasias Pancreáticas/radioterapia , Ratos , Ratos Endogâmicos LewRESUMO
OBJECTIVE: To assess the accuracy of dobutamine stress myocardial perfusion single photon emission computed tomographic imaging (SPECT) for the diagnosis of vascular stenosis after coronary artery bypass grafting (CABG). BACKGROUND: Exercise thallium scintigraphy is a clinically useful method for the diagnosis of graft stenosis after CABG. Although dobutamine perfusion scintigraphy is an alternative method for the evaluation of patients with limited exercise capacity, its value in the diagnosis of vascular stenosis after CABG has not been studied. METHODS: Dobutamine (up to 40 lg/kg/min)-atropine (up to 1 mg) stress test in conjunction with myocardial perfusion SPECT imaging (201T1 or 99m technetium sestamibi [MIBII) was performed in 71 patients (mean age 58 9 years, 57 men) with limited exercise capacity referred for evaluation of myocardial ischemia 3.7 3.5 years after CABG. Significant vascular stenosis was defined as >50% luminal diameter stenosis of a graft or a native nongrafted coronary artery and was predicted on the basis of reversible perfusion abnormalities. RESULTS: Significant vascular stenosis was detected in 52 patients. Sensitivity, specificity, and accuracy of reversible perfusion defects at dobutamine SPECT for the overall diagnosis of vascular stenosis were 81%, confidence interval (CI) 72 to 90, 79%, CI 69 to 88, and 80%, CI 71 to 90, respectively. Significant vascular stenosis was detected in 73 arterial regions. Sensitivity, specificity, and accuracy of dobutamine SPECT for the diagnosis of regional vascular stenosis were 66%, CI 58 to 74, 83%, CI 76 to 89, and 74%, CI 67 to 81, respectively. Patients with multivessel stenosis had a higher number of ischemic segments (1.6 + 1.3 vs 1 + 1, P < .05) and ischemic perfusion score (3.2 2.7 vs 2.2 + 2.3, P < .05) than patients with single-vessel stenosis, respectively. Significant graft stenosis was detected in 67 graft regions. Sensitivity, specificity, and accuracy of dobutamine SPECT for the diagnosis of regional graft stenosis were 64%, CI 56 to 73, 85%, CI 78 to 91, and 74%, CI 66 to 82, respectively. CONCLUSION: Dobutamine stress myocardial perfusion SPECT imaging is a useful method for the diagnosis of significant vascular stenosis after CABG in patients with limited exercise capacity.