Nikola Cihoric

Hyperthermia-related clinical trials on cancer treatment within the ClinicalTrials.gov registry.

Abstract Purpose: Hyperthermia has been shown to improve the effectiveness of chemotherapy and radiotherapy in the treatment of cancer. This paper summarises all recent clinical trials registered in the ClinicalTrials.gov registry. Materials and methods: The records of 175,538 clinical trials registered at ClinicalTrials.gov were downloaded on 29 September 2014 and a database was established. We searched this database for hyperthermia or equivalent words. Results: A total of 109 trials were identified in which hyperthermia was part of the treatment regimen. Of these, 49 trials (45%) had hyperthermic intraperitoneal chemotherapy after cytoreductive surgery (HIPEC) as the primary intervention, and 14 other trials (13%) were also testing some form of intraperitoneal hyperthermic chemoperfusion. Seven trials (6%) were testing perfusion attempts to other locations (thoracic/pleural n = 4, limb n = 2, hepatic n = 1). Sixteen trials (15%) were testing regional hyperthermia, 13 trials (12%) whole body hyperthermia, seven trials (6%) superficial hyperthermia and two trials (2%) interstitial hyperthermia. One remaining trial tested laser hyperthermia. Conclusions: In contrast to the general opinion, this analysis shows continuous interest and ongoing clinical research in the field of hyperthermia. Interestingly, the majority of trials focused on some form of intraperitoneal hyperthermic chemoperfusion. Despite the high number of active clinical studies, HIPEC is a topic with limited attention at the annual meetings of the European Society for Hyperthermic Oncology and the Society of Thermal Medicine. The registration of on-going clinical trials is of paramount importance for the achievement of a comprehensive overview of available clinical research activities involving hyperthermia.

Prognostic role of FGFR1 amplification in early-stage non-small cell lung cancer

Background:Recently, fibroblast growth factor receptor 1 (FGFR1) was discovered in squamous cell carcinomas (SCC) of the lung with FGFR1 amplification described as a promising predictive marker for anti-FGFR inhibitor treatment. Only few data are available regarding prevalence, prognostic significance and clinico-pathological characteristics of FGFR1-amplified and early-stage non-small cell lung carcinomas (NSCLC). We therefore investigated the FGFR1 gene status in a large number of well-characterised early-stage NSCLC.Methods:FGFR1 gene status was evaluated using a commercially available fluorescent in situ hybridisation (FISH) probe on a tissue microarray (TMA). This TMA harbours 329 resected, formalin-fixed and paraffin-embedded, nodal-negative NSCLC with a UICC stage I–II. The FISH results were correlated with clinico-pathological features and overall survival (OS).Results:The prevalence of an FGFR1 amplification was 12.5% (41/329) and was significantly (P<0.0001) higher in squamous cell carcinoma (SCC) (20.7%) than in adenocarcinoma (2.2%) and large cell carcinoma (13%). Multivariate analysis revealed significantly (P=0.0367) worse 5-year OS in patients with an FGFR1-amplified NSCLC.Conclusions:FGFR1 amplification is common in early-stage SCC of the lung and is an independent and adverse prognostic marker. Its potential role as a predictive marker for targeted therapies or adjuvant treatment needs further investigation.

Current status and perspectives of interventional clinical trials for glioblastoma – analysis of ClinicalTrials.gov

The records of 208.777 (100%) clinical trials registered at ClinicalTrials.gov were downloaded on the 19th of February 2016. Phase II and III trials including patients with glioblastoma were selected for further classification and analysis. Based on the disease settings, trials were classified into three groups: newly diagnosed glioblastoma, recurrent disease and trials with no differentiation according to disease setting. Furthermore, we categorized trials according to the experimental interventions, the primary sponsor, the source of financial support and trial design elements. Trends were evaluated using the autoregressive integrated moving average model. Two hundred sixteen (0.1%) trials were selected for further analysis. Academic centers (investigator initiated trials) were recorded as primary sponsors in 56.9% of trials, followed by industry 25.9%. Industry was the leading source of monetary support for the selected trials in 44.4%, followed by 25% of trials with primarily academic financial support. The number of newly initiated trials between 2005 and 2015 shows a positive trend, mainly through an increase in phase II trials, whereas phase III trials show a negative trend. The vast majority of trials evaluate forms of different systemic treatments (91.2%). In total, one hundred different molecular entities or biologicals were identified. Of those, 60% were involving drugs specifically designed for central nervous system malignancies. Trials that specifically address radiotherapy, surgery, imaging and other therapeutic or diagnostic methods appear to be rare. Current research in glioblastoma is mainly driven or sponsored by industry, academic medical oncologists and neuro-oncologists, with the majority of trials evaluating forms of systemic therapies. Few trials reach phase III. Imaging, radiation therapy and surgical procedures are underrepresented in current trials portfolios. Optimization in research portfolio for glioblastoma is needed.

Androgen receptor status is highly conserved during tumor progression of breast cancer

BackgroundWith the advent of new and more efficient anti-androgen drugs targeting androgen receptor (AR) in breast cancer (BC) is becoming an increasingly important area of investigation. This would potentially be most useful in triple negative BC (TNBC), where better therapies are still needed. The assessment of AR status is generally performed on the primary tumor even if the tumor has already metastasized. Very little is known regarding discrepancies of AR status during tumor progression. To determine the prevalence of AR positivity, with emphasis on TNBCs, and to investigate AR status during tumor progression, we evaluated a large series of primary BCs and matching metastases and recurrences.MethodsAR status was performed on 356 primary BCs, 135 matching metastases, and 12 recurrences using a next-generation Tissue Microarray (ngTMA). A commercially available AR antibody was used to determine AR-status by immunohistochemistry. AR positivity was defined as any nuclear staining in tumor cells ≥1 %. AR expression was correlated with pathological tumor features of the primary tumor. Additionally, the concordance rate of AR expression between the different tumor sites was determined.ResultsAR status was positive in: 87 % (307/353) of primary tumors, 86.1 % (105/122) of metastases, and in 66.7 % (8/12) of recurrences. TNBC tested positive in 11.4 %, (4/35) of BCs. A discrepant result was seen in 4.3 % (5/117) of primary BC and matching lymph node (LN) metastases. Three AR negative primary BCs were positive in the matching LN metastasis, representing 17.6 % of all negative BCs with lymph node metastases (3/17). Two AR positive primary BCs were negative in the matching LN metastasis, representing 2.0 % of all AR positive BCs with LN metastases (2/100). No discrepancies were seen between primary BC and distant metastases or recurrence (n = 17).ConclusionsMost primary (87 %) and metastasized (86.1 %) BCs are AR positive including a significant fraction of TNBCs (11.4 %). Further, AR status is highly conserved during tumor progression and a change only occurs in a small fraction (4.1 %). Our study supports the notion that targeting AR could be effective for many BC patients and that re-testing of AR status in formerly negative or mixed type BC’s is recommended.

Surgery for Stage IIIA Non-Small-cell Lung Cancer: Lack of Predictive and Prognostic Factors Identifying Any Subgroup of Patients Benefiting From It.

Although a trimodality regimen for patients with stage IIIA/pN2 non-small-cell lung cancer (NSCLC) has been variably used owing to limited evidence for its benefits, it remains unknown whether any patient subgroup actually receives benefit from such an approach. To explore this question, the published data were reviewed from 1990 to 2015 to identify the possible predictors and prognosticators in this setting. Overall survival was the endpoint of our study. Of 27 identified studies, none had studied the predictors of improved outcomes with trimodality treatment. Of the potential patient- and tumor-related prognosticators, age, gender, and histologic type were the most frequently formally explored. However, none of the 3 was found to influence overall survival. The most prominent finding of the present review was the substantial lack of data supporting a trimodality treatment approach in any patient subgroup. As demonstrated in completed prospective randomized studies, the use of surgery for stage IIIA NSCLC should be limited to well-defined clinical trials.

Immunophenotypic profile of tumor buds in breast cancer

Background: Tumor buds are associated with lympho-vascular invasion and lymph node metastases leading to the assumption that they are involved in the early metastatic process. Hence, it would be important to know if tumor buds can be targeted with the most widely used targeted therapies in breast cancer (BC) and if changes in hormone and Her2 status occur. The aim of this study was to answer these questions by determining whether hormone receptor (HR) and Her2 status are expressed in the tumor buds of a large cohort of BCs. Design: We constructed a tumor bud next-generation tissue microarray (ngTMA) consisting of n = 199 BCs of non-special type. Generally, two 1 mm punches were taken from the tumor bud areas in the periphery (PTB) and within the tumor center (ITB). HR and Her2 status was assessed using immunohistochemistry and fluorescence in situ hybridization, respectively. HR status was positive if ≥1% of tumor bud cells were positive. Her2 status was considered positive if bud cells showed strong complete membranous Her2 over-expression or Her2 amplification. Results: Most tumor buds were positive for estrogen (ER) (PTB: 86%; ITB: 88.3) and progesterone receptor (PgR) (PTB: 72%; ITB: 72.8%) and Her2 was positive in: PTB 11.5% and ITB 11%. A difference between the main tumor mass and tumor buds (PTB and ITB) was seen for PgR in 3.5% of cases (n = 7). No differences were seen for ER and Her2 between tumor buds and main tumor mass. Conclusion: Most tumor buds (96.5%) share the same HR and Her2 expression profile of the main tumor mass, implying that tumor buds relay on the same pathways as the main tumor mass and might be equally responsive to targeted therapies.

No Role For Trimodality Therapy and Consolidation Chemotherapy Compared With Concurrent Radiochemotherapy Alone in Stage III Non-Small-Cell Lung Cancer

TO THE EDITOR: We read the joint American Society for Radiation Oncology (ASTRO)/American Society of Clinical Oncology (ASCO) clinical practice guideline endorsement by Bezjak et al that focused on the place and role of radiotherapy (RT) alone or in combination with chemotherapy (CT) and/or surgery in stage II to III non–small-cell lung cancer. Although we agree with most of their statements, we believe that two of these statements should be considered from an additional standpoint, to bring more clarity to the readership of the Journal of Clinical Oncology and to the membership of both the ASTRO and ASCO societies. The considerations are the following. First, the authors claim that, despite total failure of consolidation CT, it can be considered in patients who may have received suboptimal CT administered concurrently with RT. We are not aware of any evidence in the form of a prospective phase III trial or meta-analysis or of any other high-level evidence that has addressed this question and that would support this statement. We believe that this approach should not be considered in everyday practice and, instead, that investigators and practicing clinicians should focus their investigations on the issue of which patients should receive consolidation drug treatment and which should not. Despite our attempt to emphasize that, after concurrent RT-CT, several subgroups of patient responses exist (ie, complete response, partial response [PR], stable disease, progressive disease), the investigators of the trials published so far never provided complete patterns of treatment failure after the end of the consolidation CT and followup, and related the response after consolidation CT to that achieved after concurrent RT-CT (and before consolidation). It is unlikely that patients who experienced progressive disease, stable disease, or even some weak PR would benefit from any additional or consolidation CT administered, for example, after 60 Gy of RT with either full or attenuated doses of CT. Why, then, administer more CT (as consolidation) to a patient whose disease is already progressing quickly and who will die? Why not identify the best candidates (eg, patients who experience complete response and good PR) for whom, regardless of their status before the start of RT-CT, such consolidation CT would have the greater likelihood of acting on microscopic intrathoracic and/or extrathoracic disease that, presumably, remains present? Current evidence speaks against compensation for suboptimal CT administered concurrently with RT. Rather, it calls for more insight into who would benefit from it. More intensive treatment does not mean better outcomes, as we have recently seen in the RTOG 0617 trial. Second, regarding the suggested trimodality therapy, the authors claim that it should be done according to best surgical judgment, and that the best candidates would include those who have a planned lobectomy, had no weight loss, were women, and had only one nodal station. We believe that existing evidence should be preferred to best specialist judgment; that is, we prefer evidence-based oncology versus expert-based opinion, which should be avoided by all means. Avoidance is especially important, because the evidence to support such expert-based claims is extremely weak and is based on, as the authors clearly admit, only one post hoc analysis that is rather unrated in evidence-based principles. In addition, these best candidates were identified only from INT 0139 results, but other prospective studies did not identify these factors or candidates. Furthermore, claims that no weight loss, female sex, or only one nodal station should be used to choose the best potential candidates for the success of trimodality therapy do not reflect the existing evidence. To be used in a process of choice of appropriate patients, various factors should have been investigated as predictors of superiority of trimodality treatment over exclusive RTCT, but these factors have never been investigated. In addition, they have not even been consistently identified—not only in existing phase III studies but also in available phase II studies, or even in retrospective studies—as important prognostic factors. Unfortunately, the investigators placed little emphasis, so far, on these issues and precluded identification of such factors. Therefore, no solid evidence exists for such claims, as they are based only on one post hoc subgroup study and have an unfortunate lack of identified predictors and prognosticators in this setting. We are not against use of either consolidation CT or trimodality therapy. Rather, we question expert-based opinion that, although is a best intention, does not always take into account existing evidence, or the lack of it, to lead to a best judgment. Ultimately, this correspondence should be seen as a call for more clinical research in the field of locally advanced non—small-cell lung cancer, preferably through well-designed clinical trials that should, we hope, provide enough high-quality evidence to guide daily practice outside a trial setting.

Combined modality therapy in Stage IIIA non-small cell lung cancer: Clarity or confusion despite the highest level of evidence?

Abstract Recent years have witnessed a number of clinical trials in Stage IIIA non–small cell lung cancer (NSCLC) comparing (A) induction chemotherapy (CHT) with induction CHT and radiotherapy (RT), each followed by surgery; (B) either induction CHT or induction RT-CHT, each followed by surgery, with definitive RT-CHT (no surgery). Due to the heterogeneity of patient, tumor and treatment characteristics across these trials, various meta-analyses (MAs) have been performed to define the optimal treatment approach in this setting for this clinical presentation. Six such MAs exist. In spite of the differences between MAs, it appears that RT does not add extra benefit to induction CHT administered before surgery, and that a trimodality (i.e. including surgery) regimen is not superior to definitive concurrent RT-CHT. While one can consider both induction CHT followed by surgery and exclusive concurrent RT-CHT as feasible in this setting, lack of pre-treatment predictive factors identifying patients who might preferentially benefit from a surgical approach limits its use to well-planned clinical trials.

Adjuvant immunotherapy in resected early non-small cell lung cancer-battle lost, hopefully not the war!

Lung cancer is major cancer killer in both sexes (1). In spite of improvements in diagnostic and therapeutic efforts in recent decades, still only a vast minority of patients with non-small cell lung cancer (NSCLC) undergo surgery. In these patients, additional chemotherapy (CHT) is considered a standard of care worldwide (2). Unfortunately, in spite of the lowest possible T and/or N burden of the disease, many people experience relapse, leading to a 5-year survival rates which range from more than 70% for stage IA to less than 25% in stage IIIA NSCLC (3). It is, therefore, not surprising that many efforts have been attempted to improve these figures. Building on recent success of drug therapy in advanced disease, usually labeled as targeted agents, some studies investigated adjuvant use of drugs such as erlotinib or gefitinib, but failed to demonstrate superiority over existing standards of care (4,5). Besides studies which showed the failure of tyrosine kinase inhibitors (TKIs), there were studies investigating the use of the DNA repair marker ERCC1 in adjuvant setting of NSCLC. While initial results were optimistic (6), more recent results were disappointing, leading to suggestion to abandon this research pathway (7-10).

Clinical trials involving positron emission tomography and prostate cancer: an analysis of the ClinicalTrials.gov database

BackgroundThe goal of this study is to evaluate the status and future perspectives of clinical trials on positron emission tomography in prostate cancer for diagnostic or therapeutic as well as for surveillance purposes.MethodsThe www.ClinicalTrials.gov database was searched on the 20th of January 2017 for all trials containing terms describing “prostate cancer” (prostate, prostatic, malignant, malignancy, cancer, tumor) and “positron emission tomography”. In total 167 trials were identified. Trials that included diseases other than PCa were excluded (n = 27; 16%). Furthermore, we excluded trials (n = 4, 2%) withdrawn prior to first patient enrollment. The remaining trials (n = 137, 82%) were selected for further manual classification analysis.ResultsOne hundred thirty-seven trials were detected and analyzed. Majority of trials were in “active” recruitment status (n = 46, 34%) followed by trials that had been “completed” - (n = 34, 25%) and trials with “closed recruitment but active follow-up” (n = 23, 17%). Phase 1 and 2 comprised 46% of the complete trial portfolio. Locally confined disease was of major interest (n = 46, 34%), followed by metastatic disease – not otherwise specified (n = 43, 13%). Evaluation of PET was the primary goal of the trial in 114 (83%) cases. Most of the trials evaluated only one agent (n = 122, 89%). Choline and PSMA represented two major groups (total 50%) and they were equally distributed across trial portfolio with 25% (n = 34) each. PSMA trials showed the highest average annual growth rate of 56%. The trials were conducted in 17 countries.ConclusionThe scientific community is showing a strong and ever-growing interest in the field and we expect that in the coming years, more phase III trials will be initiated ultimately delivering the required Level 1 evidence.