Recent advances in carcinoid pathogenesis, diagnosis and management

Carcinoid tumors usually present as diagnostic dilemmas due to obscure or nonspecific symptomatology. Advances in molecular biology are allowing the investigation of molecular markers of aggressiveness, better serum tumor markers, as well as the molecular pathogenesis of carcinoid heart disease. Somatostatin receptor scintigraphy (SRS) and whole body positron emission tomography (PET) are providing much improved sensitivity in localization of both primary and metastatic tumors. Long acting depot somatostatin analogues are combining effectiveness and ease of use for medical management of carcinoid syndrome. An additional benefit may be tumor growth suppression.     

Systemic therapy for advanced carcinoid tumors: where do we go from here?

Carcinoid tumors are relatively indolent, but the treatment of advanced disease remains a challenge. Liver-directed therapies are a consideration in patients with liver-dominant disease. Somatostatin analogs (SSTa) are routinely used to control hormone-mediated symptoms (carcinoid syndrome), but the identification of systemic agents with antitumor efficacy has proven difficult. Aside from octreotide for small bowel carcinoid (which is associated with delayed progression), no treatment has proven antitumor activity. Chemotherapy seems to be of limited value. The role of interferon is also controversial; it is typically used after failure of octreotide. Peptide receptor radionuclide therapy may have activity in patients with SST receptor-expressing tumors, but randomized controlled trials are lacking. Advances in the understanding of the mechanisms underlying tumor progression have led to the identification of several potential therapeutic targets (including the vascular endothelial growth factor [VEGF] and mammalian target of rapamycin [mTOR] signaling pathways), but none has been definitively validated in carcinoid. Everolimus is associated with a trend toward improved progression-free survival in patients with progressive carcinoid, but is not approved for this indication. Therefore, a serious unmet need remains for additional therapeutic strategies for patients with advanced disease. Several avenues are under study, including the use of novel SSTa; VEGF and mTOR inhibitors; and agents that interfere with insulin growth factor 1 receptor and AKT signaling. Moving forward, optimizing patient selection based on clinical features or biomarkers holds promise for identifying individuals most likely to benefit from therapy.     

Systemic therapy for advanced pancreatic neuroendocrine tumors: an update

Well-differentiated neuroendocrine tumors (NETs) can be subdivided into carcinoid and pancreatic NETs (pancNETs). Although these tumors share many morphologic and clinical characteristics, carcinoid tumors appear to be far less sensitive to therapeutic agents than pancNETs, and recent advances approved for pancNETs have not been submitted for FDA approval in patients with carcinoid tumors. Treatment options for patients with advanced pancNETs are multidisciplinary and include surgical resection, liver-directed therapies, and systemic therapies. Cytotoxic therapies, such as temozolomide, fluorouracil, oxaliplatin, and streptozocin-based chemotherapy regimens, are active against some pancNETs, and can play a role in the palliation of patients with advanced disease and symptoms related to tumor bulk. Two therapies were recently approved for progressive well-differentiated pancNETs: sunitinib and everolimus. Both agents showed improved progression-free survival in patients with progressive pancNETs, but can also result in nontrivial toxicities, and therefore should only be considered in patients with progressing and advanced or symptomatic disease. This article discusses these recent trials and provides an update of systemic treatment options in patients with well-differentiated pancNETs.     

Metastatic Carcinoid Tumors and the Malignant Carcinoid Syndrome

Patients with metastatic carcinoid tumors and the malignant carcinoid syndrome have benefited immensely from diagnostic and therapeutic advances during the past decade. Magnetic resonance imaging and whole body scintigraphy with radiolabeled analogues of somatostatin have improved our ability to diagnose, detect, stage and follow response to therapy. Surgical, medical, and radiation therapy may all contribute to the management of these patients. This disease is variable in its presenting symptoms and the biologic behavior of the tumor. The spectrum of clinical manifestations varies depending upon the type and quantity of polypeptide hormones or biogenic amines being produced. Although the tumors are usually indolent in their growth, the more dedifferentiated or anaplastic tumors can be quite aggressive. Thanks to new treatments that are very effective in the subgroup of anaplastic neuroendocrine carcinomas it is vital to recognize this subset. As research scientists and clinicians we must be aware of the natural history of the disease in order to optimize each patient's treatment. This highly selective review focuses on studies performed in collaboration with Dr. Charles Moertel along with other colleagues at the Mayo Clinic, have done in the past few years.     

What’s New in Imaging for Gynecologic Cancer?

Magnetic resonance imaging (MRI) is the optimal modality for local staging of gynecological tumors. Advances in functional MRI with diffusion-weighted and dynamic contrast-enhanced sequences provide more detailed information regarding tumor cellularity, vascularity, and viability. Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) now has an established role in imaging for gynecological cancers, particularly staging of locally advanced cervical cancers and pre-salvage exenterative therapy in relapsed gynecologic tumors. Novel PET tracers, targeting other aspects of tumor biology, are being evaluated although none are currently in routine clinical use. New PET/MR scanners have the potential to combine the strengths of both modalities in one sitting. This review covers advances in gynecologic imaging concentrating on cervical, endometrial, and ovarian cancers.     

Carcinoid Tumors

Carcinoid tumors are rare, slow‐growing neuroendocrine tumors arising from the enterochromaffin cells disseminated throughout the gastrointestinal and bronchopulmonary systems. Though they have been traditionally classified based on embryologic site of origin, morphologic pattern, and silver affinity, newer classification systems have been developed to emphasize the considerable clinical and histopathologic variability of carcinoid tumors found within each embryologic site of origin. These neoplasms pose a diagnostic challenge because they are often innocuous at the time of presentation, emphasizing the need for a multidisciplinary diagnostic approach using biochemical analysis, standard cross‐sectional imaging, and newer advances in nuclear medicine. Similarly, treatment of both primary and disseminated carcinoid disease reflects the need for a multidisciplinary approach, with surgery remaining the only curative modality. The prognosis for patients with these tumors is generally favorable; however, it can be quite variable and is related to the location of the primary tumor, extent of metastatic disease at initial presentation, and time of diagnosis.     

Current perspectives in gliomas

The annual incidence of primary central nervous system tumors, including gliomas, is increasing, however, the prognosis of these tumors remains poor with a median survival of only 5 years. The imaging of tumors by computerised tomography, magnetic resonance imaging and newer methods such as positron emission tomography and proton magnetic resonance spectroscopy (¹H-MRS) is increasing our knowledge of tumor biology and extent of the disease. Advances within the field of neurosurgery have improved operative procedures reducing mortality and morbidity. Furthermore, radiotherapy planning, tumor targeting and repositioning for treatment have all improved initial tumor management The role of adjuvant chemotherapy remains controversial. Chemotherapy for advanced and recurrent disease has been extensively investigated, and although improvements in quality of life have been recorded, no prolongation of survival has been documented. With new discoveries and increasing knowledge of the physiology and molecular biology of these tumors the potential for targeting therapy at a genetic level is becoming increasingly promising. This review provides an overview of these current perspectives in glioma management.     

Recent advances in carcinoids and gastrointestinal neuroendocrine tumors

The main advances in the management of carcinoid and gastrointestinal neuroendocrine tumors have been in the areas of imaging and therapy. New techniques have been developed to detect and identify the sites of tumor so that correct therapeutic decisions can be made. Although surgery remains the mainstay of treatment of localized and some cases of advanced disease, the use of biologic agents and new drugs has proven valuable in those patients in whom surgery is not indicated. These include interferon-alpha, the somatostatin analogue octreotide, omeprazole. Different methods of delivery have been investigated with mixed success. Future progress in the understanding and management of neuroendocrine tumors is likely to be slow due to their rarity and long natural history.     

Gastric carcinoid

PURPOSE OF REVIEW: Gastric carcinoid tumors are rare lesions but have been the focus of much scientific investigation. The incidence of gastric carcinoid appears to be increasing without a corresponding increase in survival, despite utilization of the latest available therapies. Therefore, there is great interest in furthering the understanding of the biologic basis of these tumors, delineating the connection between hypergastrinemia and gastric carcinoids, and most importantly, improving upon current treatment options. RECENT FINDINGS: This review discusses the current biologic understanding of gastric carcinoid tumors, including the role of hypergastrinemia on enterochromaffin-like cell proliferation and its relation to acid-suppressive therapy. Numerous diagnostic and therapeutic modalities including endoscopic ultrasound, somatostatin receptor scintigraphy, long-acting octreotide, hepatic artery embolization, endoscopic mucosal resection, and surgical resection have also been the focus of recent investigations. SUMMARY: Despite the many advances that have been made in both the basic science and clinical arenas, the optimal treatment of gastric carcinoid tumors is still a matter of debate. As the understanding of the biologic basis of gastric carcinoid tumors increases, the treatment will likely be a multimodal approach tailored to individual tumor biology and will incorporate a variety of diagnostic and therapeutic modalities.     

Intracranial Ependymomas: A Review

Ependymomas are rare neuroectodermal tumors arising from ependymal cells of the ventricular system, choroid plexus, filum terminale, and central canal of the spinal cord (1,2). This review focuses on intracranial ependymomas with special emphasis on pathology, etiology, cytogenetic characteristics, and adjuvant radiation therapy. Recent advances in neurosurgical technique, radiation therapy, and molecular biology have affected management of these tumors and have the potential to increase long-term cure rates. The role of highly advanced radiation therapy techniques such as stereotactic radiosurgery will need to be better defined.     

A phase II study of docetaxel in patients with metastatic carcinoid tumors

Twenty-one patients with metastatic carcinoid tumors were treated with docetaxel. Although the treatment was well tolerated, no objective radiologic responses were observed. Novel, more effective agents are needed for this disease. Background. Traditional combination chemotherapy regimens containing streptozocin, doxorubicin, and 5-fluorouracil have yielded disappointing results in patients with metastatic carcinoid tumors. The lack of efficacy of these combinations, together with their toxicity, has led to efforts to investigate therapeutic agents that are potentially more active and tolerable. We, therefore, assessed the efficacy of docetaxel in the treatment of patients with metastatic carcinoid tumors. Methods. Twenty-one patients with metastatic carcinoid tumors were treated with docetaxel, administered at a dose of 75 mg/m² every three weeks. Patients were followed for evidence of toxicity, response, and survival. Results. Docetaxel was well tolerated in this patient population. However, no objective radiologic responses were noted in any of the 21 patients. Of the 13 patients who were evaluable for biochemical responses to therapy, four (31%) experienced decreases in 24-hour urinary 5-hydroxyindole acetic acid (5HIAA) excretion of greater than 50%. The clinical course of the patients enrolled in this study was marked by a high incidence of radiologically stable disease (81%), a median progression-free survival time of 10 months, and a median overall survival time of 24 months. Conclusion. Although treatment with docetaxel results in biochemical responses in patients with metastatic carcinoid tumors, the lack of more significant antitumor activity demonstrates the need for novel, more effective agents in this disease.     

Cytotoxic Treatment in Patients with Malignant Carcinoid Tumors: Response to streptozocin—alone or in combination with 5-FU

Thirty-one patients with malignant carcinoid tumors were treated with streptozocin—alone (n=7) or in combination with FU (n=24). The responses to treatment were followed by the determination of tumor markers, urinary 5-HIAA, serum PP, HCG-a and -β subunits, as well as determination of the size of liver metastases on computerized tomography or ultrasonography. Three patients (9.7%) showed objective responses with a mean remission time of 2.7 months. Eighteen patients (58%) showed stable disease, whereas ten patients (32.3%) showed progressive disease directly from the start of therapy. A good correlation was found between the changes in tumor markers and tumor size, although the changes occurred earlier in the markers than in the size. Estimated median survival from the time of histologically verified carcinoid tumor was 41 months and from start of therapy 22 months. Our data indicate that combination treatment with streptozocin and 5-fluorouracil is of little value for patients with malignant carcinoid tumors.     

The impact of recent data on the optimization of standards of care in newly diagnosed glioblastoma

Glioblastoma is an aggressive form of brain cancer with a poor long-term prognosis. Treatment regimens for newly diagnosed disease range from surgical resection alone to surgery followed by radiotherapy with concurrent and adjuvant chemotherapy. Ongoing investigations are focused on optimization of chemotherapy by improving dosing and duration schedules and utilization of biomarkers for patient selection. Our understanding of glioblastoma tumor biology, the role of molecular signaling pathways, cellular repair mechanisms, and angiogenesis has increased greatly over the past few years, leading to the investigation of a variety of targeted therapies. In addition, advances in radiographic assessment have significantly impacted not only improvement in diagnosis, but interpretation of response to therapy. In order to effectively evaluate the clinical utility of new agents, as well as incorporate advances in radiographic assessment, changes to current clinical trial design need to be considered. This article reviews the care for newly diagnosed glioblastoma, as well as how recent findings might be incorporated into patient care.     

Advances in molecular imaging for breast cancer detection and characterization

Advances in our ability to assay molecular processes, including gene expression, protein expression, and molecular and cellular biochemistry, have fueled advances in our understanding of breast cancer biology and have led to the identification of new treatments for patients with breast cancer. The ability to measure biologic processes without perturbing them in vivo allows the opportunity to better characterize tumor biology and to assess how biologic and cytotoxic therapies alter critical pathways of tumor response and resistance. By accurately characterizing tumor properties and biologic processes, molecular imaging plays an increasing role in breast cancer science, clinical care in diagnosis and staging, assessment of therapeutic targets, and evaluation of responses to therapies. This review describes the current role and potential of molecular imaging modalities for detection and characterization of breast cancer and focuses primarily on radionuclide-based methods.     

A clinical overview of carcinoid tumors: perspectives for improvement in treatment using peptide analogs (review)

Carcinoid tumors were first described more than a century ago, but the treatment of patients with advanced disease remains a challenge to physicians. The etiology of carcinoid tumors, the biologic determinants of the growth of these malignancies, as well as the high frequency of multiple carcinoid and/or non-carcinoid tumors in patients with this disease also remain to be elucidated. A 5-decade analysis of 13,715 carcinoid tumors in the USA showed that distant metastases were demonstrated at the time of diagnosis in 12.9% of patients with this neoplasia. The overall 5-year survival rate for all patients with carcinoids regardless of the site, was reported to be 67.2%. The prognosis of patients with early stage disease is good and surgical resection is the standard form of treatment. The resection of local or regional metastases can result in cure for some cases. However, patients with metastatic dissemination have poor outcomes since chemotherapy is generally ineffective. Surgical resection of isolated hepatic metastases, surgical hepatic artery ligation or embolization produce responses in selected patients. Radiation therapy may ease the pain of bone metastases. The administration of long acting analogs of somatostatin can control the symptoms of diarrhea and flushing in patients with the malignant carcinoid syndrome. However, a complete regression of metastatic carcinoid tumors following the administration of somatostatin analog octreotide has been reported so far in only 3 cases. Other modalities of treatment, including liver transplantation and the administration of radiolabeled somatostatin analogs have likewise been applied in patients with advanced disease. It is expected that advances in proteomics research will contribute to our understanding of the mechanisms of diseases and aid in designing new drugs.     

Primary carcinoid tumor of the ovary: report of an unusual case

Carcinoid tumors are endocrine malignancies that are often associated with a characteristic syndrome, the malignant carcinoid syndrome, which is most common in patients with small bowel tumors and liver metastases. In the rare instances when the syndrome is present without liver metastases the primary tumor is usually localized to the bronchus or ovary and secretes hormones directly into the systemic circulation. About two thirds of patients with carcinoid syndrome have evidence of carcinoid heart disease. We report on a case of a primary ovarian carcinoid tumor with an unusual clinical presentation.     

Is there evidence-based benefit of autologous stem cell transplantation in children with solid tumors?

Multidisciplinary care, a better understanding of tumor biology, and advances in chemotherapy have dramatically improved the prognosis of solid tumors in children.The diseasefree survival (DFS) has increased over the last three decades from <20 to 30% in the early 1970s to now 70% after 5-10 years of follow-up [1]. This progress has been limited to patients with localized tumors. However, a subset of children with advanced, therapy-resistant or relapsed disease has not derived any benefit from these advances. Despite multimodal conventional therapy, for example in newly diagnosed highrisk neuroblastomas, Ewing family tumors, metastatic rhabdomyosarcomas, or high-grade gliomas, the probability of long-term survival has remained poor, with less than 30%. After tumor progression or recurrence following adequate initial treatment, even less than 10% of patients with solid tumors survived [2].     

Bevacizumab for the treatment of advanced non-small-cell lung cancer

Until recently, advances in non-small-cell lung cancer (NSCLC) care have been limited; new chemotherapy regimens have not significantly impacted patient survival. With our improved understanding of tumor biology, novel biological therapies targeting key tumorigenic processes targeting factors essential for tumor growth, such as angiogenesis, have been developed that improve patient outcomes beyond those achieved with chemotherapy alone. One of these, bevacizumab (Avastin), specifically targets VEGF, which is key to the malignant growth and progression of solid tumors. Bevacizumab-based therapy until progression significantly delays disease progression, has a well-characterized and acceptable safety profile in bevacizumab-eligible patients and was the first treatment to improve the overall survival of patients with advanced NSCLC beyond 1 year, a significant breakthrough in advanced NSCLC care. Furthermore, bevacizumab-based therapy significantly delays disease progression and has a well-characterized and acceptable safety profile. Based on these data, bevacizumab has received approval for the first-line treatment of NSCLC in the USA and Europe. A number of ongoing trials will potentially expand the eligible patient population for bevacizumab and further define its role in NSCLC treatment.