Showing papers in "Expert Review of Anticancer Therapy in 2013"
TL;DR: Gliadel wafers may marginally increase survival and local control in newly diagnosed GBM patients but are associated with a high complication rate; therefore, it is recommended not to recommend using Gliadel wAFers in patients with GBM.
Abstract: Glioblastoma multiforme (GBM) is the most aggressive brain tumor. Standard treatment includes surgery, radiation and chemotherapy. Prognosis is dismal with an average survival of approximately 1 year. Gliadel wafers are one treatment option, working as a source for local chemotherapy delivery. Their use is controversial with questionable survival benefit and potential side effects. We reviewed the literature in an effort to clarify their role in the treatment of high-grade gliomas. A systematic PubMed search was performed using the keywords ‘Gliadel’, ‘carmustine’ or ‘BCNU wafers’ in newly diagnosed high-grade glioma patients. Treatment regimen, and median survival were analyzed. Adverse event ratio was calculated by computing the number of adverse events in a study per patient receiving carmustine wafers. Nineteen studies with 795 patients were included in our review. Survival was 8.7–22.6 months with a mean overall survival (OS) of 16.2 months (control survival is approximately 14 months with surgery an...
125 citations
TL;DR: A comprehensive review of developments in targeted therapy for advanced non-small-cell lung cancer, reviewing in detail efforts, both successful and in some cases less so, to target EGFR, VEGF and ALK.
Abstract: Therapy for advanced non-small-cell lung cancer has developed significantly with new awareness of histologic subtype as an important factor in guiding treatment and the development of targeted agents for molecular subgroups harboring critical mutations that spur on cancer growth. In this comprehensive review, we look back at developments in targeted therapy for advanced non-small-cell lung cancer, reviewing in detail efforts, both successful and in some cases less so, to target EGFR, VEGF and ALK. This review provides an overview of where the field stands at present and the areas we feel are most likely to provide challenges and potential successes in the next 5 years including immune checkpoint inhibition, epigenetic therapy and driver mutation targeting.
103 citations
TL;DR: In this article, the authors summarized current data on afatinib-associated diarrhea and provided strategies for its management, including patient education, early identification, timely management and ongoing assessment, encouraging patient compliance and allowing patients to obtain the maximum therapeutic benefit from this agent.
Abstract: Gastrointestinal (GI) adverse events (AEs) are frequently observed in patients receiving EGF receptor (EGFR; also known as HER1 or ErbB1) tyrosine kinase inhibitor therapy. GI AEs are among the most common and most impactful on a patient's quality of life. Severe diarrhea can result in fluid and electrolyte losses, leading to dehydration, electrolyte imbalances and renal insufficiency. Afatinib is an irreversible, oral, ErbB family blocker, inhibiting EGFR (ErbB1), HER2 (ErbB2) and ErbB4 receptor kinases. It also inhibits transphosphorylation of ErbB3. Similar to reversible tyrosine kinase inhibitors of EGFR, GI AEs - in particular, diarrhea - have frequently been observed in afatinib-treated patients. This article summarizes current data on afatinib-associated diarrhea and provides strategies for its management. Patient education, early identification, timely management and ongoing assessment will help to prevent aggravation, afatinib dose reductions or therapy discontinuation, encouraging patient compliance and allowing patients to obtain the maximum therapeutic benefit from this agent.
86 citations
TL;DR: Current data on the dermatologic AEs associated with afatinib treatment across the clinical trial program is summarized, and strategies for their effective management are provided.
Abstract: Dermatologic adverse events (AEs) are frequently observed in patients receiving EGF receptor (EGFR; also known as ErbB1) tyrosine kinase inhibitor therapy. The impact of these AEs goes beyond cosmesis to the discomfort from itching, pain and secondary infections, all of which may significantly impact on patient well-being, adherence and clinical outcomes. Afatinib is a potent, irreversible, oral, ErbB family blocker, inhibiting EGFR (ErbB1), HER2 (ErbB2) and ErbB4 receptor kinases. It also inhibits transphosphorylation of ErbB3. Similar to EGFR inhibitors, dermatologic AEs have been frequently observed in patients treated with afatinib. Papulopustular (acneiform) rash, pruritus, xerosis, paronychia and alopecia will require patient education and proactive treatment interventions. This article summarizes current data on the dermatologic AEs associated with afatinib treatment across the clinical trial program, and provides strategies for their effective management.
76 citations
TL;DR: A comprehensive review of the key role of proteasome inhibitors in the myeloma treatment pathway is provided, and the similarities and differences in pharmacology, routes of administration, and efficacy and safety profiles between bortezomib, carfilzomib and investigational agents are highlighted.
Abstract: Proteasome inhibition has been shown to be an effective strategy for the treatment of multiple myeloma, as demonstrated by the clinical activity of the first-in-class agent bortezomib. Recently, the second-generation proteasome inhibitor carfilzomib has been approved in the USA in the relapsed and refractory setting, and several other investigational agents are in clinical development, including MLN9708, marizomib, oprozomib and delanzomib. Here, the authors provide a comprehensive review of the key role of proteasome inhibitors in the myeloma treatment pathway, and highlight the similarities and differences in pharmacology, routes of administration, and efficacy and safety profiles between bortezomib, carfilzomib and investigational agents. The authors also evaluate the potential for further improving myeloma treatment through the ongoing development of novel proteasome inhibitors.
75 citations
TL;DR: Among behavioral factors weakening the immune system, smoking appeared to strongly increase the risk of cervical cancer, while poor diet only moderately increased the risk, and it is difficult to determine whether sexually transmitted infections other than human papillomavirus infection are independent risk factors.
Abstract: A markedly increased risk of cervical cancer is known in women immunosuppressed due to AIDS or therapy following organ transplantation. The aim of this review is to determine the association between other conditions affecting the immune system and the risk of cervical cancer. Patients with end-stage renal disease seem to be at an increased risk of cervical cancer. A higher risk of cervical precancerous lesions was found in patients with some autoimmune diseases; particularly if treated with immunosuppressants. Among behavioral factors weakening the immune system, smoking appeared to strongly increase the risk of cervical cancer, while poor diet only moderately increased the risk. It is difficult to determine whether sexually transmitted infections other than human papillomavirus infection are independent risk factors. Identifying those groups of women likely to fail in clearing persistent human papillomavirus infections would help individualize screening guidelines and target immune-associated factors in the cervical cancer etiology.
72 citations
TL;DR: An update on NMSC is provided with special emphasis on dermoscopy in the diagnosis and management of basal cell carcinoma, actinic keratosis, Bowens’ disease and squamous cell carcinomas.
Abstract: Dermoscopy has become an integrative part of the clinical examination of skin tumors. This is because it significantly improves the early diagnosis of melanoma and non-melanoma skin cancer (NMSC) including basal cell carcinoma and keratinocyte skin cancer compared with the unaided eye. Besides its value in the noninvasive diagnosis of skin cancer, dermoscopy has also gained increased interest in the management of NMSC. Dermoscopy has been used in the preoperative evaluation of tumor margins, monitoring of the outcomes of topical treatments and post-treatment follow-up. This article provides an update on NMSC with special emphasis on dermoscopy in the diagnosis and management of basal cell carcinoma, actinic keratosis, Bowens' disease and squamous cell carcinoma.
72 citations
TL;DR: Two hereditary forms of RCC, succinate dehydrogenase (SDH) and hereditary leiomyomatosis and RCC (HLRCC), are characterized by mutations in Krebs cycle enzymes, rendering them dependent on glycolysis for energy requirements, which may make them vulnerable to novel metabolic strategies.
Abstract: Renal cell carcinoma (RCC) is a heterogenous group of cancers that arise from the nephron. While there are distinct histologic subtypes associated with common genetic alterations, most forms of RCC are linked by a common pathway of dysregulated metabolism. Reliance on aerobic glycolysis, a feature of cancer first hypothesized by Warburg, is a common feature in sporadic and hereditary forms of kidney cancer. Two hereditary forms of RCC, succinate dehydrogenase (SDH) and hereditary leiomyomatosis and RCC (HLRCC), are characterized by mutations in Krebs cycle enzymes, rendering them dependent on glycolysis for energy requirements. The reliance on these pathways may make them vulnerable to novel metabolic strategies, including inhibition of glycolysis, glucose uptake and macromolecule biosynthesis.
70 citations
TL;DR: There is sufficient data now to suggest that SLNM with 99mTc plus blue dye in the hands of a surgeon with extensive experience should prove to be an important part of individualized cervical cancer surgery and increase the safety of less radical or fertility-sparing surgery.
Abstract: The prognosis of endometrial cancer (EC) is generally favorable, while lymph node status remains the most important prognostic factor. Sentinel lymph node mapping (SLNM) could help to find women in whom adjuvant therapy could be omitted. This review analyzes different techniques of injection and histopathologic elaboration of SLNM in EC. Results of studies on SLNM in ECs seem to be promising, but only a small series have been published so far. The studies are subdivided into three groups by the technique of injection (hysteroscopic, subserosal and cervical). Range of detection rate for SLNM varies from 45 to 100%. Hysteroscopic injection is not easy to learn; moreover, exact peritumoral injection in large tumors is often impossible. Subserosal administration of tracer is difficult during laparoscopic or robotic surgery. Cervical injection is quite a controversial technique because distribution of SLNs in ECs is different from cervical cancer; moreover, there is no large study using cervical injection with systematic pelvic and para-aortic lymphadenectomy.
68 citations
TL;DR: The prognostic and predictive impact of HER2 deregulation and the clinical implications of anti-HER2 strategies in NSCLC are discussed.
Abstract: In non-small-cell lung cancer (NSCLC), the identification of oncogenic driver mutations led to the definition of different clinical entities with different therapeutic opportunities, as demonstrated in patients harboring EGF receptor (EGFR) mutations or anaplastic lymphoma kinase translocations. Human EGFR2 (or HER2) has an established role as a prognostic and predictive factor in breast cancer. Although HER2 deregulation, including overexpression, amplification and mutation, has been described in NSCLC, its role as a therapy biomarker remains undefined. In the last few years, there has been a growing interest on HER2 mutation, with few anecdotal or retrospective studies suggesting a relevant role for this biomarker. This review discusses the prognostic and predictive impact of HER2 deregulation and the clinical implications of anti-HER2 strategies in NSCLC.
61 citations
TL;DR: In breast cancer, RANK ligand appears to play an important role in the process of chemotaxis between circulating tumor cells and the bone microenvironment, which enables RANK-expressing breast cancer cells to migrate into the bone.
Abstract: In breast cancer, RANK ligand (RANKL) appears to play an important role in the process of chemotaxis between circulating tumor cells and the bone microenvironment, which enables RANK-expressing breast cancer cells to migrate into the bone. Mounting clinical evidence has further demonstrated that the anti-RANKL monoclonal antibody; denosumab is the most effective approach in the prevention of skeletal-related events. On the other hand, inhibiting RANKL in preclinical models, not only reduced breast cancer formation but also decreased the development of lung metastases, suggesting RANKL as a novel target for breast cancer chemoprevention. In addition, recent data have pointed to a potential role of RANKL in the biology of breast cancer arising at a young age. Hence, RANKL emerges as a key molecule, not only in the field of breast cancer bone metastasis but also in the biology of breast cancer as a whole.
TL;DR: It is anticipated that proteasome inhibitors may prove to be of added value in therapeutic interventions for acute leukemia, particularly when combined with conventional chemotherapeutics.
Abstract: Proteasome inhibition has been recognized as a novel treatment modality in hematologic malignancies. Initially, the reversible proteasome inhibitor bortezomib demonstrated efficacy in multiple myeloma (MM), which supported its approval for relapsed and refractory MM in 2003. Later on, carfilzomib, a next-generation irreversible proteasome inhibitor was approved by the US FDA in July 2012 for relapsed/refractory MM. Currently, several other proteasome inhibitors are undergoing preclinical and clinical evaluation. The successes of proteasome inhibitors in MM are now being translated to other hematologic malignancies, including acute leukemia. The first clinical studies with bortezomib in leukemia revealed promising clinical activity, particularly when combined with conventional chemotherapeutics. In this review the position of proteasome inhibitors in acute leukemia treatment is summarized and discussed. Special focus is also attributed to immunoproteasome inhibitors. As a future perspective, it is anticipated that proteasome inhibitors may prove to be of added value in therapeutic interventions for acute leukemia.
TL;DR: This review will critically assess the evidence forming the basis of current understanding of the precise pH conditions in the extracellular tumor matrix, its regulation by cancer cells and relationship with hypoxia, its relevance to malignant progression and its exploitation for therapeutic advantage.
Abstract: Rapid malignant proliferation, prior to effective tumor neoangiogenesis, creates a microenvironment around solid cancers, which is predominantly hypoxic and characterized by a high interstitial fluid pressure. Presumably as an adaptive response, tumor cells favor metabolic activity with apparently inefficient energy output, and production of intermediates that promote cellular replication, preferentially through anaerobic glycolysis, a phenomenon that persists even in re-established normoxic conditions (anomalously referred to as 'aerobic glycolysis'). Extrusion of the consequently excessive accumulation of lactate and protons decreases extracellular pH, leading to a microenvironment considered conducive to promotion of tumor motility, invasion and metastasis, and one that will invariably influence response to drug treatment. This review will critically assess the evidence forming the basis of current understanding of the precise pH conditions in the extracellular tumor matrix, its regulation by cancer cells and relationship with hypoxia, its relevance to malignant progression and its exploitation for therapeutic advantage.
TL;DR: A review of the literature of SSE in melanoma detection finds that visual aids such as total body photography and dermoscopy, which have improved physician exams, are becoming elements accessible to patients for augmentation of self-exam.
Abstract: Early detection of cutaneous melanoma results in reduced morbidity and mortality. Although screening by physicians has been shown effective, the role of skin self-examination (SSE) in melanoma secondary prevention is less well studied. Various methods and educational strategies have been implemented to empower patients to perform efficacious SSEs. Patient demographics play an important role in their likelihood to examine their own skin and ability to detect melanoma. Visual aids such as total body photography and dermoscopy, which have improved physician exams, are becoming elements accessible to patients for augmentation of self-exam. This review examines the literature of SSE in melanoma detection.
TL;DR: Increased knowledge on boswellic acids and cyclooxygenase-2 inhibitors which are available for clinical application may help to exploit their anti-edema activity more efficiently in the future.
Abstract: The long-term treatment of peritumoral edema remains a major challenge in clinical neuro-oncology. Steroids have been and will remain the backbone of any anti-edematous therapy because of their striking activity, convenient oral administration and also because of their cost-effectiveness. Their side effects, however, can compromise quality of life, particularly upon continuous administration. Therapeutic alternatives which may replace or - at least - help to reduce the steroid dose are limited. However, with the development of new agents such as corticorelin acetate, there is a hope that steroid-induced side effects can be delayed and reduced. The administration of anti-angiogenic agents with steroid-sparing effects, for example, bevacizumab, is limited due to their costs. Increased knowledge on boswellic acids and cyclooxygenase-2 inhibitors which are available for clinical application may help to exploit their anti-edema activity more efficiently in the future.
TL;DR: Anatomical and histopathological aspects and the probability of lactation and breast feeding after breast irradiation are reviewed and lactation is possible after radiotherapy, present in at least 50% of the patients, but in reduced volume.
Abstract: The incidence of breast cancer in premenopausal women is increasing and many of them still remain fertile after treatment. Allied to the current tendency to postpone pregnancy, it is expected that an increasing number of patients undergoing conservative treatment for breast cancer will get pregnant. Anatomical and histopathological aspects and the probability of lactation and breast feeding after breast irradiation are reviewed in this article. Lactation is possible after radiotherapy, present in at least 50% of the patients, but in reduced volume. This perspective is more correlated to the type of surgery and radiation dose used. Biochemical changes were observed in irradiated breast milk. Breastfeeding in the contralateral breast is not affected.
TL;DR: Oncotype DX is a multigene assay that provides prognostic information in terms of 10-year distant recurrence and predicts the likelihood of adjuvant chemotherapy benefit in estrogen receptor positive breast cancer patients, based on the expression of a panel of 21 genes from a tumor specimen.
Abstract: Oncotype DX® is a multigene assay that provides prognostic information in terms of 10-year distant recurrence and predicts the likelihood of adjuvant chemotherapy benefit in estrogen receptor positive breast cancer patients, based on the expression of a panel of 21 genes (16 cancer-related and five reference genes) from a tumor specimen (core biopsy or surgical resection). It has been validated using multiple prospectively designed studies of archived tumor specimens from well-controlled clinical studies. In different countries with varying therapeutic approaches, using Oncotype DX has consistently resulted in a significant reduction in the number of patients who are prescribed chemotherapy, and in addition, it can identify a smaller subset of patients who would benefit from chemotherapy among patients who would otherwise receive endocrine therapy alone.
TL;DR: Evidence to date suggests potentially distinct roles for bevacizumab and EGF receptor-targeted biological agents (cetuximab and panitumumab) in the treatment of metastatic CRC.
Abstract: The medical treatment of colorectal cancer (CRC) has evolved greatly in the last 10 years, involving complex combined chemotherapy protocols and, in more recent times, new biologic agents. Advances in adjuvant therapy have been limited to the addition of oxaliplatin and the substitution of oral fluoropyrimidine (e.g., capecitabine) for intravenous 5-fluorouracil with no evidence for improved outcome with biological agents. Clinical benefit from the use of the targeted monoclonal antibodies, bevacizumab, cetuximab and panitumumab, in the treatment of metastatic CRC is now well established, but the optimal timing of their use requires careful consideration to derive the maximal benefit. Evidence to date suggests potentially distinct roles for bevacizumab and EGF receptor-targeted biological agents (cetuximab and panitumumab) in the treatment of metastatic CRC. This article reviews the evidence in support of modern treatments for CRC and the decision-making behind the treatment choices, their benefits and toxicities.
TL;DR: The preface to the recently published book on ‘Rare Tumors in Children and Adolescents’, edited by some of the authors of this manuscript, begins with this evocative sentence: “If you work on frequent cancers, do randomized trials! If youWork on rare cancers – FIND FRIENDS!”
Abstract: The preface to the recently published book on ‘Rare Tumors in Children and Adolescents’, edited by some of the authors of this manuscript, begins with this evocative sentence: “If you work on frequent cancers, do randomized trials! If you work on rare cancers – FIND FRIENDS!” [1]. This is exactly the spirit that led to the foundation of the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT), the first seeds of which were sown in 2008. National groups working in Italy, France, the UK, Poland and Germany join forces in EXPeRT in the conviction that children with very rare tumors may benefit from a closer-knit, stronger international network, and the project is now officially supported by the International Society of Paediatric Oncology [2].
TL;DR: The molecular mechanism of necroptosis is described and how it could be manipulated in the treatment of cancer is summarized.
Abstract: Programmed cell death plays an important role in animal development, tissue homeostasis and eliminating harmful or virally infected cells. Necroptosis, a novel form of programmed cell death, is caspase independent but RIPK and RIPK3 dependent. Moreover, it is suggested that necroptosis can be specifically inhibited by small molecular inhibitors such as necrostatin-1. Its signaling pathways have something in common with apoptosis, although the molecular mechanisms of necroptosis need to be further elucidated. Previous evidences suggest that necroptosis has significant effects in regulating various physiological processes and disease, such as ischemic brain injury, immune system disorders and cancer. In this review, the molecular mechanism of necroptosis is described and how it could be manipulated in the treatment of cancer is summarized.
TL;DR: Sinonasal undifferentiated carcinoma is a highly aggressive lesion arising in the superior nasal cavity and paranasal sinuses and recurrence with metastasis to lymph nodes and distant sites is frequent.
Abstract: Sinonasal undifferentiated carcinoma is a highly aggressive lesion arising in the superior nasal cavity and paranasal sinuses. Differential diagnosis is wide because a range of similar lesions can present at this site. There is increasing evidence that sinonasal undifferentiated carcinoma is a surface (Schneiderian) epithelial-derived malignancy, with or without concurrent neuroendocrine differentiation. Prognosis is poor; recurrence with metastasis to lymph nodes and distant sites is frequent. A combination of radical surgery, chemotherapy and radiotherapy appears to provide the best chance of survival.
TL;DR: The aim of the present study was to analyze predictors of outcome in patients with recurrent glioblastoma and to make a critical of review of data in literature with a view to comparing the effect on outcome of second surgery against well-known prognostic determinants.
Abstract: Deciding upon the therapeutic approach for patients with recurrent glioblastoma is a challenge. Although second surgery may provide effective palliation, it has yet to be established whether it prolongs survival and/or improves quality of life; nor have data been reported in literature to demonstrate that repeat surgery is indicated for patients with recurrence. The few studies investigating this issue are retrospective and have been conducted on small series, and their data sets are not homogeneous. The aim of the present study was, therefore, to analyze predictors of outcome in patients with recurrent glioblastoma and to make a critical of review of data in literature with a view to comparing the effect on outcome of second surgery against well-known prognostic determinants.
TL;DR: The quality of reporting in RCTs on acupuncture for cancer pain was poor and indicates that RCTS on acupunctureFor cancer pain need substantial improvement.
Abstract: This study aims to analyze the quality of reporting and its correlates in randomized controlled trials (RCTs) on acupuncture for cancer pain. Quality of reporting for included papers was assessed against a subset of criteria adapted from the CONSORT 2010 statement and STRICTA. An overall quality score (OQS) and a combined key methodologic index score (MIS) was calculated for each trial. Factors associated with OQS and MIS were then identified. A total of 32 RCTs were included in the full text. The median OQS based on the CONSORT Statement and STRICTA was 4.0 and 0, respectively. The significant predictors for CONSORT OQS were year of publication and nationality of authors, for STRICTA it was nationality of authors and for MIS it was publication language. The quality of reporting in RCTs on acupuncture for cancer pain was poor. This indicates that RCTs on acupuncture for cancer pain need substantial improvement.
TL;DR: Thanks to novel advancements in knowledge of molecular pathogenesis of this tumor, many new systemic agents and locoregional treatments are in different stages of clinical development and they represent an important promise of further improvements in patients’ survival.
Abstract: Hepatocellular carcinoma is a major health problem. It is the sixth most common cancer worldwide and the third most common cause of cancer-related death. Despite the availability of several treatment opportunities, diagnosis is still made in an advanced phase, limiting application of most therapeutic choices that currently are based on the Barcelona Clinic Cancer Liver Classification and include surgical resection, orthotopic liver transplantation and ablative methods for very early and early disease, arterial chemoembolization for intermediate stages and systemic therapy with sorafenib for advanced hepatocellular carcinoma. Thanks to novel advancements in knowledge of molecular pathogenesis of this tumor, many new systemic agents and locoregional treatments are in different stages of clinical development and they represent an important promise of further improvements in patients' survival.
TL;DR: Clinical assessment of radiolabeled trastuzumab and anti-HER2 affibody molecule demonstrated potential to identify new lesions but both agents lacked sensitivity and highlighted the need for improved pharmacokinetics.
Abstract: Molecular imagings of hEGF receptor 2 (HER2) using radiolabeled tracers has the potential to determine the extent of HER2-positive disease and could be of great clinical value. HER2 overexpression affects 20-25% of breast cancer patients, conferring a worse prognosis. HER2 status determines choice and response to therapy but can change in response to treatment and during disease progression. Anti-HER2 agents in development for molecular imaging include immunoglobulins (trastuzumab and pertuzumab), immunoglobulin fragments, F(ab´)2, diabodies, nanobodies and nonimmunoglobulin scaffolds, affibody and designed ankyrin-repeat proteins. Clinical assessment of radiolabeled trastuzumab and anti-HER2 affibody molecule demonstrated potential to identify new lesions but both agents lacked sensitivity and highlighted the need for improved pharmacokinetics. New tracers in the pipeline showed preclinical promise and could potentially improve sensitivity.
TL;DR: Some histological subtypes of sarcoma are resistant to conventional chemotherapy and patients with these diseases should be offered participation in early phase clinical trials of novel drugs.
Abstract: Approximately 50% of patients with localized soft tissue sarcomas will develop recurrent disease after complete surgical resection, requiring alternative means of treatment. Conventional chemotherapy comprising of doxorubicin and ifosfamide has shown benefit in advanced disease, however, there remains a clear need for more effective, less toxic, therapies for the treatment of this heterogeneous group of mesenchymal malignancies. Recently, greater emphasis has been placed on the underlying biology of individual sarcoma subtypes, with the development and evaluation of novel therapies both in common and in rare subtypes. In addition, there is a greater specificity in the selection of chemotherapy agents based on activity in individual histological subtypes. Despite these advances the management of sarcoma, and in particular of rare subtypes, remains a major challenge. Some histological subtypes are resistant to conventional chemotherapy and patients with these diseases should be offered participation in early phase clinical trials of novel drugs.
TL;DR: Given the observed clinical benefit and relatively high cost of crizotinib therapy, companion diagnostics should be evaluated relative to response to therapy versus correlation alone whenever possible, and both high inter-rater reliability and external quality assessment programs are warranted.
Abstract: Crizotinib is a first-in-class oral anaplastic lymphoma kinase (ALK) inhibitor targeting ALK-rearranged non-small-cell lung cancer. The therapy was approved by the US FDA in August 2011 and received conditional marketing approval by the European Commission in October 2012 for advanced non-small-cell lung cancer. A break-apart FISH-based assay was jointly approved with crizotinib by the FDA. This assay and an immunohistochemistry assay that uses a D5F3 rabbit monoclonal primary antibody were also approved for marketing in Europe in October 2012. While ALK rearrangement has relatively low prevalence, a clinical benefit is exhibited in more than 85% of patients with median progression-free survival of 8-10 months. In this article, the authors summarize the therapy and alternative test strategies for identifying patients who are likely to respond to therapy, including key issues for effective and efficient testing. The key economic considerations regarding the joint companion diagnostic and therapy are also presented. Given the observed clinical benefit and relatively high cost of crizotinib therapy, companion diagnostics should be evaluated relative to response to therapy versus correlation alone whenever possible, and both high inter-rater reliability and external quality assessment programs are warranted.
TL;DR: An elderly man with metastatic insulinoma and severe hypoglycemia who was treated with repeated 6-week cycles of oral sunitinib malate was able to tolerate the treatment well and have a good quality of life with no evidence of tumor progression based on PET/CT findings.
Abstract: Standard cytotoxic chemotherapy has limited efficacy in advanced insulinomas, and control of blood glucose concentrations in these patients may be difficult. This article describes an elderly (74-year-old) man with metastatic insulinoma and severe hypoglycemia who was treated with repeated 6-week cycles of oral sunitinib malate (25 mg/day for 4 weeks, followed by 2 weeks off treatment). After treatment for more than 2 years, his condition improved and he continued to have a good quality of life with no evidence of tumor progression based on PET/CT findings. Although sunitinib treatment lowered the patient's blood glucose concentrations further and induced repeated symptomatic hypoglycemic episodes, he was able to tolerate the treatment well after changing the timing of sunitinib dosing and adjusting his diet.
TL;DR: In the present review, indications of WBRT will be outlined with emphasis on consolidation therapy, treatment-related neurotoxicity and efforts aimed at reducing toxicity.
Abstract: High-dose methotrexate (HD-MTX)-based chemotherapy is the current first-line therapy for primary CNS lymphoma. Whole-brain radiotherapy (WBRT) plays an important role in the management of primary CNS lymphoma and is indicated in patients with contraindication to chemotherapy, in patients with unusual histologic subtypes as curative treatment, as complementary therapy for patients failing to achieve complete remission after systemic chemotherapy and as salvage therapy for refractory or relapsing patients when systemic chemotherapy is no longer advisable. The two major pitfalls in WBRT use are transitory efficacy and neurotoxicity with deterioration of quality of life. Accordingly, WBRT administration as consolidation therapy in complete remission patients after first-line chemotherapy is controversial. In the present review, indications of WBRT will be outlined with emphasis on consolidation therapy, treatment-related neurotoxicity and efforts aimed at reducing toxicity.
TL;DR: Strategies to target the alternative NF-κB pathway include not only the use of small molecule inhibitors for NIK and IκB kinase α (IKKα), but also broad spectrum approaches such as using proteasome inhibitors or combinatorial approaches targeting both alternative and canonical pathways.
Abstract: Pancreatic cancer, due to its late diagnosis, is difficult to treat. In addition, current therapy options are insufficient and new approaches for combination treatment are required. Recent demonstration of the importance of constitutive signaling of NF-κB-inducing kinase (NIK, also named MAP3K14) in maintaining the high basal activity of the alternative NF-κB pathway in pancreatic cancer suggests novel possibilities for therapeutic intervention. Strategies to target the alternative NF-κB pathway include not only the use of small molecule inhibitors for NIK and IκB kinase α (IKKα), but also broad spectrum approaches such as using proteasome inhibitors or combinatorial approaches targeting both alternative and canonical pathways. These may also act synergistically with currently used drugs.