Reviews on Recent Clinical Trials - Volume 12, Issue 2, 2017

Primary endocrine therapy is an option in cases of hormone receptor positive and HER2 negative non-metastatic breast cancer. Aromatase inhibitors are considered the therapy of choice in postmenopausal patients. In premenopausal patients aromatase inhibitors in combination with LHRHanalogues are regarded superior to tamoxifen. Three different settings have to be discriminated: Patients too frail for surgery are candidates for primary endocrine therapy in order to control the disease. Treatment duration is determined by the course of the disease. Patients with tumors not operable in general or not operable by breast conserving therapy but not fit for or with relative contraindications to chemotherapy either are candidates for neoadjuvant endocrine therapy in order to achieve downstaging. Treatment duration should be at least 6 months and probably not longer than 12 months with the individual duration depending on the experience and skills of the breast surgeon. Patients in whom the indication for chemotherapy is uncertain due to an intermediate risk neoadjuvant endocrine therapy may undergo endocrine therapy in order to perform in vivo sensitivity testing. Treatment duration should be at least 3 months up to 6 months according to current data. Data from retrospective analyses show that short-term on-treatment assessment of Ki67 by rebiopsy or postoperative assessment of the PEPI score may identify low risk groups with no meaningful expected benefit from additional chemotherapy. In order to retrieve more detailed recommendations, results of ongoing prospective trials have to be awaited. Data regarding on-treatment genomic testing are promising but immature for clinical practice as of yet.

Background: Patients with triple negative breast cancer (TNBC) are characterized by an unfavorable prognosis particularly when not responding well to anthracycline-taxane chemotherapy. This is due to a more aggressive biology in some cases but most importantly to a lack of agents other than conventional chemotherapy. Hence, there is an urgent need to optimize therapy of patients with TNBC in order to improve prognosis. Objective: The objective of this review is to present the current understanding of TNBC biology and give an insight of current therapeutic concepts in the neoadjuvant treatment setting. Method: Current literature has been selected based on a literature search and current therapeutic concepts are explained and commented on. Results: Novel therapeutic concepts for patients with TNBC focus on a) chemotherapy optimization through alternate scheduling, dosing or alternative/additional chemotherapeutic agents, b) evaluation of novel targeted agents and c) identification of clinically relevant patient subgroups through prognostic/ predictive biomarkers to enable a more personalized treatment approach. Potential novel therapeutic targets include inhibition of Poly-A-Ribose-Polymerase (PARP), checkpoint inhibition and antiandrogenic agents. Conclusion: Treatment of TNBC is currently been optimized both through optimization of chemotherapy and introduction of novel targeted agents which should enhance treatment response rates in the future.

In HER2-positive early breast cancer, neoadjuvant treatment with a combination of sequential chemotherapy and HER2-targeted therapy is currently the standard of care. This is followed by breast surgery, radiotherapy (if indicated), completion of 12 months of HER2-directed therapy, and - depending on the tumor biology - endocrine adjuvant therapy, and ultimately follow up. 10-year survival rates in the HER2-positive subgroup of breast cancer do reach now more than 75% with the introduction of first adjvuant and later neoadjuvant HER2-targeted therapies over the last 15 years. The neoadjvuant setting helps to downstage locally advanced tumors, to provide early information of tumor response, to assess the efficacy of new therapies in vivo, to reduce treatment duration, and to introduce new targeted therapies into the clinical routine. It also allows enrolling fewer patients into clinical trials in order to reach adequate effects in clinical outcome. The neoadjuvant approach and our interest in this setting are based on pCR (pathological complete response) and its translation into better long-term outcome. In recent trials, we have reached more than 60% pCR with a subsequent improvement of DFS and hopefully OS. Therefore, chemotherapy schedules and new HER2-targeted agents such as lapatinib, pertuzumab, and T-DM1 have been introduced into the neoadjuvant setting. To balance over- and undertreatment, current trials include personalized concepts and assess new biomarkers and tumorbiological factors. We have learned for example to differentiate between HR (hormone receptor)-positive and -negative tumors in the HER2-positive population. Depending on pCR or non-pCR after neoadjuvant treatment, the adjuvant therapy may be adjusted. This concept of post-neo-adjuvant trials is now entering the field of strategies in the neoadjuvant setting for HER2-positive non-metastatic primary breast cancer. The 2017 standard of care in the neoadjuvant setting according to national and international guidelines combines a taxane-containing chemotherapy with a dual blockade of trastuzumab and pertuzumab. This review will point out current trials and their strategies to continue improving outcome and reduce morbidity as well as mortality in HER2-positive early breast cancer.

Introduction: Targeted intraoperative radiotherapy (TARGIT - IORT) as a tumour bed boost after breast conserving surgery is well established for women with early breast cancer. A previous study from our group shows a beneficial effect of TARGIT-IORT on overall survival (OS) but not disease-free survival (DFS) after neoadjuvant chemotherapy compared to an external boost suggesting a potential non-inferiority of TARGIT-IORT. In this study, we present results regarding the high-risk subset of patients (i.e. with triple negative (TN) and HER2 positive tumours) from this cohort. Method: In this non-randomized cohort study involving patients with HER2 positive (n= 28) and triple negative (n=42) tumours after NACT we compared outcomes of 40 patients with tumour bed boost applied with TARGIT IORT during lumpectomy versus 30 patients treated in the previous 13 months with external (EBRT) boost. All patients received whole breast radiotherapy. Rates of DFS and OS were compared. Results: Median follow up was 49 months. In comparison of TARGIT-IORT vs. EBRT 5-year Kaplan- Meier estimates of OS showed no significant difference among patients with HER2 positive tumours (100% vs. 91.7%, log rank p = 0.22). The same was seen for DFS (83.3% vs. 77.0%, log rank p=0.38). The results for TN cases were similar (OS : 87.5% vs. 74.1%, log rank p=0.488; DFS 87.5% vs. 60%, log rank p=0.22). Conclusion: Although survival estimates trended towards favouring TARGIT-IORT, no significant differences could be observed and the significantly positive result for OS favoring TARGIT-IORT in the whole cohort of 116 patients could not be reproduced in this subset analysis of patients with TN and HER2 positive tumours. This may be contributable to the limited number of patients but may also indicate that effects seen in the whole cohort were mainly driven by ER and/or PR positive and HER2 negative tumours. Most importantly, non-inferiority of TARGIT-IORT as an intraoperative boost could be reproduced in these high-risk patients.

Background: Last two to three decades, this world witnesses a rapid progress of biomarkers and bioinformatics technologies. Cancer bioinformatics is one of such important omics branches for experimental/clinical studies and applications. Methods: Same as other biological techniques or systems, bioinformatics techniques will be widely used. But they are presently not omni-potent. Despite great popularity and improvements, cancer bioinformatics has its own limitations and shortcomings at this stage of technical advancements. Results: This article will offer a panorama of bioinformatics in cancer researches and clinical therapeutic applications-possible advantages and limitations relating to cancer therapeutics. A lot of beneficial capabilities and outcomes have been described. As a result, a successful new era for cancer bioinformatics is waiting for us if we can adhere on scientific studies of cancer bioinformatics in malignant- origin mining, medical verifications and clinical diagnostic applications. Conclusion: Cancer bioinformatics gave a great significance in disease diagnosis and therapeutic predictions. Many creative ideas and future perspectives are highlighted.

Background: As we move away from the traditional chemotherapy era to targeted therapy, the validity of old assessment paradigms associated with therapeutics are being raised in the context of immunotherapy. The old paradigm required elaborating on the toxicity assessment, with no expectation of efficacy in early phase trials. Safety data from Phase 1 and 2 studies with many immunotherapeutics show limited toxicities and draw attention to the need to demonstrate efficacy in the early evaluation of new agents. Methods: Literature searches indicate that molecular oncology mechanistic-based agents are being linked with molecular disease status and clinical benefit. Biomarkers and other endpoints are being employed to accomplish this. Perspectives for a meaningful context of integrating biomarkers and clinical trial design are reviewed. Results: The design and conduct of clinical trials have not been fully adjusted to the new era of personalized oncology, and so we are in transition. A part of this transition is the management of expectations and trial designs that need to be considered relative to preclinical experience in the development of therapeutics. For example, pathological complete response is now considered a surrogate marker for favorable prognosis in breast cancer patients who are treated in the neoadjuvant setting. This surrogate marker is tied to novel agents’ mechanistic characteristics with no preclinical counterpart. Conclusion: The old paradigm considers patients equal with similar chances to respond to treatments, but the new paradigm considers patient’s heterogeneity, a major fact that informs the design of clinical trials. By linking every treatment to a mechanism of action and to the presence of a specific biomarker, new trials are going to have more subjects who are likely to respond to the treatment.

Background: Since more than 50 years glucocorticoids represent the milestone in the treatment of inflammatory diseases, including rheumatoid arthritis (RA). However, many patients with RA present a circadian rhythm in symptoms severity with a significant worsening in the morning, that correlates with cyclic changes in circulating hormones and cytokines. Classical steroid therapy given in the morning fails to intercept this pathophysiological phenomenon. In the last years, a novel formulation of prednisone has been developed in order to better fit these variations, improve efficacy and minimize adverse events (chronotherapy). This modified-release (MR) prednisone is administered in the evening at 10.00 p.m. and absorbed after about 4 hours. Methods: In this article, we reviewed the recent clinical trials evaluating the efficacy of MR prednisone in RA patients, including two randomized controlled double-blind clinical trials Circadian Administration of Prednisone in Rheumatoid Arthritis – 1 (CAPRA-1) and CAPRA-2 and other nonrandomized observational studies. Results: According to the available evidence, MR prednisone seems effective in ameliorating morning stiffness in RA patients. Conclusion: In conclusion, the use of MR prednisone in the treatment regimen could be a costeffective choice in a significant proportion of RA patients, particularly in those with a clinical phenotype characterized by morning stiffness or morning recrudescence of pain. With regards to the safety, MR prednisone adverse events profile does not differ from that of IR glucocorticoids.

Background: The association of migraine with intracardiac communications and a resultant improvement with their closure has been a matter of controversy. Mostly observational and retrospective studies indicate a significant improvement in migraine attacks in patients undergoing percutaneous closure procedures. However, there is a paucity of randomized trials on this topic and prospective data provide little evidence that the device closure approach has any significant effect on migrainous attacks. Objective: The aim of this study is to further examine this important controversial topic by presenting our own prospective findings from a single-operator series of 110 patients with patent foramen ovale (PFO) or atrial septal defect (ASD) undergoing percutaneous device closure and also by conducting an in-depth literature review, amply discussing the data on this topic and finally proposing a practical strategy for migraineurs. Methods: A prospective analysis of our own data was conducted among 110 patients undergoing percutaneous closure of either a patent foramen ovale (PFO) (n=75) or an atrial septal defect (ASD) (n=35), investigating the impact of PFO/ASD closure on migraine symptoms. Closure was effected with use of an Amplatzer occluder in a simplified procedure, performed under local anesthesia with use of plain fluoroscopy alone without intra-procedural echocardiographic guidance. Complete sealing was obtained in 98.7% of PFO patients and 94.3% of ASD patients. All patients were questioned about migraine symptomatology and were followed-up long-term for their clinical outcome. They all received dual antiplatelet therapy for 6 months. Results: Great improvement in migraine symptomatology was observed after the closure procedures. Specifically, 54 (49%) patients suffered from migraine before the procedures, 45 PFO and 9 ASD patients. Improvement (50%) or abolition (33.3%) of migraine symptoms occurred in 45 patients, 37 (82.2%) PFO and 8 (88.9%) ASD patients, yielding an overall favorable effect of 83.3%. An atrial septal aneurysm was present in 44 (58.7%) PFO patients, which has recently been considered an important predictor of the occurrence of migraine in PFO patients. Importantly, the favorable effect extended beyond the 6-month period when dual antiplatelet therapy was discontinued. A recent comprehensive meta-analysis of 20 studies, comprising patients with unexplained stroke and migraine undergoing transcatheter PFO closure, showed that resolution of migraine occurred in a majority of patients with aura and for a smaller proportion of patients without aura. On the other hand, another recent review maintains that closure of PFO for migraine prevention does not significantly reduce the intensity and severity of migraine. Conclusion: A high percentage (49%) of PFO/ASD patients in this series were also migraine sufferers. Percutaneous closure offered migraine relief in 83% of patients, 82% in PFO patients and 89% in ASD patients. Thus, based on this experience and on literature review, a strategic approach for device closure is proposed for migraineurs with a PFO or ASD.

Background: Studies have shown that the quality of elderly care is substantially influenced by the attitudes of healthcare staff. The present study aimed to assess the attitude of rural community health workers towards elderly people. Methods: A cross-sectional design was employed in this study, which was conducted among all health workers of Harsin city (province of Kermanshah - Iran). The Kogan's Attitudes towards Older People Scale (KOPS) was used to measure data. The statistical program SPSS, version 22 was used to perform the data analysis. Results: The mean age of the participated health workers was 37.59 ± 4.48, about 85% were married and 76% were diploma holders. The average score of attitude was 150.60 ±15.31. About 15% of rural community health workers had negative attitude towards older adults. No significant relationships were observed between age, gender, marital status, work experience and educational status with attitudes toward aging. Conclusion: The findings of this study showed that rural community health workers do not have strong positive attitude towards the elderly. Therefore, it is imperative to develop efforts to improve positive attitudes of rural community health workers towards older adults and aging process.

Purpose: To evaluate the feasibility of using Helical Tomotherapy (HT) for post mastectomy left-sided breast cancer. Methods and Materials: Treatment plans were generated for 5 post mastectomy left sided breast cancer patients treated at king Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia, comparing three-dimensional technique with the HT planning. The prescribed dose was 50 Gy in 25 fractions; the planning target volume (chest wall and nodal volumes) was contoured according to RTOG atlas and the heart, lungs, spinal cord and contralateral breast were contoured as Organs at Risks (OARs). Results: Both plans achieved the planning criteria, however the HT plan increased the minimal dose to the PTV (78% vs. 45.4%, p=0.043), improving the dose conformity (0.76 vs. 0.38, p=0.034) and dose homogeneity (1.05 vs. 1.2, p=0.08), while a three-dimensional technique has better V20 of lung (15.8% vs. 22.6%, p=0.04), Mean Lung Dose (7.6Gy vs. 13.8Gy, p=0.043), contralateral breast dose (0.1 vs. 12.7, p=0.043) and comparable Mean Heart Dose (4.4Gy vs. 5.3Gy, p=0.136). Conclusion: Both plans achieved comparable target coverage and OARs sparing, however HT plans provided better dose conformity and homogeneity than did the three-dimensional plans at the cost of less sparing of the heart, left lung and contralateral breast for treatment of left-sided post mastectomy breast cancer.