Search

Background: VEGF, HER2 and EGFR targeted agents are currently used in gastric, esophageal and colorectal cancers. However, treatment outcomes are still poor in most gastrointestinal (GI) cancers. Immune checkpoints are one of the most promising immunotherapy approaches. In this review article, we aim to discuss the efficacy and safety of anti-PD-1/PD-L1 therapies in GI cancers, including gastric, esophageal and colorectal cancer in published or reported recent studies., Scope: A literature search was made from PubMed and ASCO Annual Meeting abstracts by using the following search keywords: "nivolumab", "pembrolizumab", "avelumab", "GI cancers" "anti-PD1 therapy" and "anti-PD-L1 therapy". The last search was on 2 November 2016. The most important limitation of our review is that most of the data on anti-PD-1/PD-L1 therapies in GI cancers relies on phase 1 and 2 trials., Findings: Currently, there are two anti-PD-1 (nivolumab and pembrolizumab) and one anti-PDL1 (atezolizumab) agents approved by FDA. After the treatment efficacy of immune checkpoint blockade was shown in melanoma, renal cell cancer and non-squamous lung cancer, trials which evaluate immune checkpoint blockade in GI cancers are ongoing. Early results of trials have been promising and encouraging for patients with advanced stage gastroesophageal cancer. According to early results of published trials, response to anti-PD1/PD-L1 agents appears to be associated with tumor PD-L1 levels. According to two recently published phase 2 trials, the clinical benefits of immune checkpoint blockade with both nivolumab and pembrolizumab were limited in patients with microsatellite instability (MSI) positive advanced colorectal cancer. However, several phase 2/3 trials are still ongoing., Conclusion: Both pembrolizumab and nivolumab show promising efficacy with acceptable safety data in published trials in GI cancers, especially in refractory MSI positive metastatic colorectal cancer.

Background: Denosumab is fully human monoclonal antibody that specifically binds and inactivates receptor activator of NF-kB ligand (RANKL), an important ligand that regulates bone remodeling. In this review, we aimed to show the clinical data about denosumab treatment and discuss its advantages for the management of patients with solid tumors and bone metastasis., Scope: Denosumab showed positive results in clinical studies of solid tumors with bone metastasis. PubMed database and ASCO Symposium Meeting abstracts were searched until August 2015 by using the terms 'denosumab', 'RANKL inhibitor' and 'bone metastasis'. The last search was on 21 August 2015. All resulting studies were retrieved and were also checked for related publications. Clinical trials in this review fulfilled the following criterion: inclusion of sufficient data to allow estimation of the efficacy and safety of denosumab., Findings: The effects of denosumab on skeletal-related events (SREs) were investigated in three large randomized trials: one in patients with breast cancer, one in patients with prostate cancer, and one in patients with multiple myeloma or solid tumors other than breast or prostate cancer. In the breast cancer and prostate cancer studies denosumab was non-inferior and also superior to zoledronic acid in terms of the primary outcome time to first on-study SRE. In the third study denosumab was non-inferior to zoledronic acid but was not superior to zoledronic acid in solid tumors excluding breast and prostate cancer with bone metastases. In the three studies median overall survival and disease progression rates were similar between zoledronic acid and denosumab. Denosumab has also been studied in bone loss associated with hormonal therapy in both breast and prostate cancer. Adjuvant denosumab significantly reduced the risk of clinical fracture risk by 50% in breast cancer patients and by 62% in non-metastatic prostate cancer patients treated with adjuvant aromatase inhibitors or androgen deprivation therapy. In addition, biochemical markers of bone turnover and fractures were significantly reduced in patients under denosumab treatment., Conclusion: The promising outcomes in the initial trials with denosumab have shown clinical activity and a favorable safety profile in patients with solid tumors and bone metastasis. Denosumab significantly reduced treatment-related osteoporosis associated with breast and prostate cancer and was superior to zoledronic acid in prevention or delaying of SRE.

Background: Basal cell carcinoma (BCC) is the most common cancer. Most cases of BCCs are treated with only optimal surgical resection. However, unresectable, locally advanced or metastatic tumors might have potential to progress. In this patient group, there is no standardized treatment approach. Vismodegib is a new selective inhibitor of the hedgehog (Hh) pathway. This manuscript is aimed to review the efficacy of the Hh pathway inhibitor vismodegib in BCC patients with locally advanced or metastatic disease., Scope: Vismodegib showed positive results in clinical studies. A computerized search of the PubMed and American Society of Clinical Oncology Meeting abstracts was performed, by searching for the following keywords: 'vismodegib', 'pathway', 'inhibitor', and 'targeted therapies for BCC'. The last search was done on 1 September 2014. Most of the vismodegib data depend on phase I and II trials., Findings: Preclinical and clinical studies have shown that Hh pathway activation occurs in BCC. In BCC patients the role of chemotherapy is not completely known. Although conventional chemotherapies like cisplatins increase the response rate in BCC, improvement in overall survival and progression free survival were not demonstrated. Results of both phase I and phase II studies have shown that vismodegib is a potential new treatment strategy for patients with locally advanced and metastatic BCC. As in previously published phase I trials, in the ERIVANCE BCC study the primary endpoint, objective response rate, significantly increased by 43% and 30% in patients with locally advanced and metastatic BCC, respectively. Because of the promising results in phase I and II trials, vismodegib was approved by the Food and Drug Administration (FDA) in the treatment of patients with BCC who are not suitable for surgery or radiotherapy or with relapsed locally advanced disease following surgery or metastatic disease., Conclusion: Recent trials have shown that vismodegib has produced promising activity in patients with locally advanced and metastatic BCC. The ongoing studies with vismodegib in other solid tumors and BCC will shed light on more certain treatment pathways.

Introduction: Trastuzumab is the first anti-HER-2 humanized monoclonal antibody. The benefit of adjuvant trastuzumab has been shown in randomized phase III trials. Despite trastuzumab being recommended for 52 weeks in the adjuvant treatment of HER-2 positive breast cancer according to the current breast cancer guidelines, there is still no consensus on the optimal duration of adjuvant trastuzumab. The aim of our study is to investigate the efficacy and safety of adjuvant trastuzumab for 9 weeks and 52 weeks in axillary lymph node positive HER-2 positive breast cancer patients., Patients and Methods: A total of 271 HER-2 and axillary node positive breast cancer patients who received trastuzumab in adjuvant treatment between the years 2005 and 2013 were retrospectively analyzed. Patients with axillary node positive HER-2 positive breast cancer who were non-metastatic were enrolled to the study. Patients were allocated to the 9 week trastuzumab group (n = 155) or the 52 week trastuzumab group (n = 116). Kaplan-Meier survival analysis was carried out for disease free survival (DFS) and overall survival (OS). Two-sided p values of <0.05 were considered statistically significant. The most important limitation of our manuscript is the retrospective design., Results: The median follow-up time for this analysis was 34 (4-95) months. Patients' clinical and pathological characteristics were well balanced between the two treatment arms. In the 9 week trastuzumab treatment group, the DFS rate was 96.7%, 84.8% and 74.9% in the first, third and fifth years respectively, whereas in the 52 week trastuzumab treatment group it was 94.3%, 80.0% and 80.0% (P = 0.76). In the 9 week trastuzumab treatment group, the OS rate was 99.3%, 92.2% and 88.3% in the first, third and fifth years respectively, whereas in the 52 week trastuzumab treatment group it was 99.0%, 94.7% and 78.6% (P = 0.99). In both groups, symptomatic heart failure was not reported but asymptomatic left ventricular ejection fraction (LVEF) decline was observed 3 (1.9%) and 18 (15.5%) patients in the 9 week and 52 week trastuzumab treatment groups, respectively (P < 0.001)., Conclusion: In our study, the efficacy of trastuzumab for 52 weeks and 9 weeks was similar in node-positive HER-2 positive breast cancer. Cardiotoxicity was significantly increased in the 52 week trastuzumab arm compared to the 9 week trastuzumab arm.

Background: Small cell lung cancer (SCLC) patients, who have achieved complete or partial response after chemotherapy, should be followed with prophylactic cranial irradiation (PCI). PCI for extrapulmonary small cell carcinoma (EPSCC) is not routinely recommended. The purpose of this review is to discuss all aspects of PCI in management of EPSCC., Scope: The PubMed database and the database of online abstracts of the American Society of Oncology (ASCO), ASCO Genitourinary (GU) Cancers meetings and clinical trials were searched up to 15 October 2013 using the following search keywords: 'SCC or EPSCC of each organ site and prophylactic cranial radiotherapy'. The language of screened abstracts and manuscripts was limited to English. The papers which included the largest case series and data of cases about prophylactic cranial radiotherapy and/or were published in the last 10 years were selected., Findings: Many single center studies showed low incidence of brain metastasis in patients with esophageal small cell carcinoma (SCC). Due to the low incidence of brain metastasis, PCI is not recommended for esophageal SCC. Genitourinary, colorectal, small bowel and appendix cranial metastatic SCCs are extremely rare. Therefore, PCI is not recommended. The frequency of brain metastasis of prostate small cell carcinoma is much higher (16-19%) compared to other counterparts of EPSCC. PCI can be performed in selected cases of prostate SCC. High rates (41%) of brain metastasis develop in head and neck SCC. PCI should be considered for patients with head neck SCC., Conclusion: In the literature, the brain metastasis incidence of EPSCC might vary from 1.7% up to 40%. In many patients with ESPCC, PCI is not recommended. However, we have to keep in mind that primary head and neck and prostate SCC are exceptions due to the high incidence of cranial metastasis; PCI should be recommended for these patients on an individual basis.

Background: Breast cancer cells can develop resistance to standard hormonal treatment and chemotherapy with the activation of the mTOR pathway; this is supported by results of preclinical and clinical studies. In clinical trials, the addition of everolimus to hormonal treatment or anti-HER2 treatment improved the outcomes of breast cancer patients. The aim of this review is to discuss the efficacy and safety data of everolimus in all categories of breast cancer in recent published studies., Scope: Everolimus showed positive results in clinical studies. A literature search was made from PubMed, ASCO and San Antonio Breast Cancer Symposium Meeting abstracts by using the following search key words: 'everolimus', 'RAD001', 'mTOR inhibitor', 'breast cancer' 'endocrine therapy resistance' and 'HER-2 targeted therapies'. The last search was on June 10, 2013. The most important limitation of our review is that most of the data on everolimus rely on phase I and II trials., Findings: Preclinical studies showed that mTOR activation can be the responsible mechanism in all subgroups of breast cancer. Results of both the TAMRAD and BOLERO-2 studies have showed that mTOR inhibition in combination with endocrine therapy can be a new treatment strategy for MBC patients who are resistant to aromatase inhibitors. In the BOLERO-2 study, time to deterioration in health-related quality of life was also significantly higher in the everolimus and exemestane arm compared to the exemestane plus placebo arm. The recently completed BOLERO-3 study showed that mTOR inhibition in combination with trastuzumab plus vinorelbine treatment significantly improved PFS compared to trastuzumab plus vinorelbine alone in trastuzumab-resistant MBC patients., Conclusion: Recent trials have shown that everolimus has produced promising anti-tumor activity in combination with trastuzumab in HER2-positive metastatic breast cancer and in combination with exemestane in patients with hormone-receptor-positive metastatic breast cancer who had recurrence or progression while receiving a nonsteroidal aromatase inhibitor. Results of ongoing studies with everolimus show evidence that using everolimus in earlier stages of the disease, namely in the adjuvant and neoadjuvant settings, could be benefical.

Background: Trastuzumab, an anti-HER2 humanized monoclonal antibody, is the standard treatment for both early and metastatic HER2-positive breast cancer. In addition to other chemotherapeutic agents, trastuzumab significantly improves response rate and survival in HER2-positive early and metastatic breast cancer. Although it is well known that trastuzumab therapy is closely associated with both symptomatic and asymptomatic cardiotoxicity, less is known about novel HER2-targeted therapies. The aim of this review is to discuss the cardiac safety data from recent studies of novel anti-HER2 drugs other than trastuzumab., Scope: Novel HER2-targeted therapies showed favorable results in HER2 positive metastatic breast cancer patients. Pubmed database, ASCO and San Antonio Breast Cancer Symposium Meeting abstracts were searched until January 2013 using the following search keywords; 'trastuzumab, trastuzumab cardiotoxicity, HER-2 targeted therapies, lapatinib, pertuzumab, trastuzumab emtansine, afatinib and neratinib'; papers which were considered relevant for the aim of this review were selected by the authors. Lapatinib, pertuzumab, T-DM1, neratinib and afatinib molecules are evaluated in the study., Findings: In a comprehensive analysis, 3689 lapatinib treated patients enrolled in 49 trials; asymptomatic cardiac events were reported in 53 patients (1.4%) and symptomatic grade III and IV systolic dysfunction was observed only in 7 patients (0.2%) treated with lapatinib. In phase I-III trials of pertuzumab, cardiac dysfunction was seen in 4.5-14.5% of patients with pertuzumab treatment and cardiac dysfunction was usually grade I and II. Cardiotoxicity of pertuzumab was usually reported with the trastuzumab combination and no additive cardiotoxicity was reported with addition of pertuzumab to trastuzumab. T-DM1 had a better safety profile compared to trastuzumab, no significant cardiotoxicity was observed with T-DM1 in heavily pre-treated patients. In the EMILIA study, only in 1.7% of patients in the T-DM1 group experienced reduction of left ventricular ejection fraction (LVEF) and grade III LVEF reduction developed only in one patient (0.2%) in the T-DM1 group compared to the lapatinib plus capacitabine group. In phase I-II trials with neratinib no cardiotoxicity was reported whereas cardiotoxicity was seen between 0-5.3% with afatinib treatment., Conclusion: Although cardiac toxicity has been reported as an adverse event for novel HER2-targeted therapies, cardiac dysfunction rate of the novel HER2-targeted therapies is significantly lower than the trastuzumab and combination of these agents with trastuzumab did not significantly increase the cardiac adverse events.

Background: Trastuzumab emtansine (T-DM1), a novel drug developed for the treatment of HER2-positive breast cancer, is a human epidermal growth factor receptor (HER2) targeted antibody drug conjugate, composed of trastuzumab, a stable thioether linker, and the potent cytotoxic agent DM1 (derivative of maytansine). It has been shown that, in preclinical studies, it has anti-tumor activity in trastuzumab refractory cancer cells. In this review, we aim to show the clinical data about trastuzumab-DM1 (T-DM1) therapy and to discuss the therapy advantages for the management of patients with HER2-positive breast cancer., Scope: T-DM1 showed positive results in clinical studies of HER2-positive metastatic breast cancer. PubMed database, ASCO and San Antonio Breast Cancer Symposium Meeting abstracts were searched up to September 2012 by using the terms 'trastuzumab emtansine (T-DM1) and anti-HER2 treatment'; papers which were considered relevant for the aim of this review were selected by the authors., Findings: The phase III randomized trial EMILIA has shown that T-DM1 provided objective tumor responses and significantly improved progression free survival and overall survival compared to lapatinib and capacitabine combination in HER2-positive metastatic breast cancer patients treated with a prior taxane and trastuzumab regimen. It is believed that T-DM1 will play a role in the management of patients with advanced and early stage HER2-positive breast cancer, but this awaits further study. In particular, the ongoing phase III trials MARIANNE and TH3RESA will further give information about the place of T-DM1 in the treatment algorithms for HER2-positive disease., Conclusion: The trials of T-DM1 as a single agent and in combination with other chemotherapies have shown clinical activity and a favorable safety profile in patients with HER2-positive metastatic breast cancer. There are ongoing studies of T-DM1 showing an increasing tendency towards moving the study of these agents to earlier stages of HER2-positive breast cancer.

Background: Lack of response in some patients and relapse during the course of therapy in the treatment of HER2-positive early breast cancer and metastatic breast cancer continue to challenge researchers and clinicians towards a better understanding of the fundamental mechanisms of trastuzumab action and new therapies for HER2. The aim of this review is to discuss current and future treatment options with pertuzumab in the light of new insights into HER2-positive breast cancer., Scope: Pertuzumab showed positive results in clinical studies and agents in routine clinical usage are updated. The PubMed database, ASCO and San Antonio Breast Cancer Symposium Meeting abstracts were searched up to June 2012 by using the terms 'pertuzumab' and 'anti-HER2 treatment'; papers which were considered relevant for the aim of this review were selected by the authors., Findings: The presented trials of phase II and phase III randomized trials of CLEOPATRA, NEOSPHERE and TRYPHAENA have showed pertuzumab action to be complementary to trastuzumab without increasing adverse events. Adding pertuzumab to trastuzumab in the first line of HER2-positive metastatic breast cancer and in the neoadjuvant treatment of locally advanced HER2-positive breast cancer is usually well tolerated. The evaluation of health-related quality of life showed that combining pertuzumab with docetaxel and trastuzumab compared to placebo have no detrimental effect with adding pertuzumab., Conclusion: Pertuzumab is the first HER dimerization inhibitor with a mechanism of action complementary to trastuzumab. Studies with anti-HER2 combination treatments indicate that the use of more than one HER2-targeted therapy was superior to one of these agents alone. Pertuzumab has produced impressive anti-tumor activity in combination with trastuzumab. There are ongoing studies with pertuzumab with an increasing tendency towards moving the study of these agents to earlier stages of the disease, namely in the adjuvant and neoadjuvant setting.