Current and future therapy for mesothelioma

Dana Clement, Vlad Afrasanie

Regional Institute of Oncology Iaşi, Romania

Mesothelioma affects mostly older individuals who have been occupationally exposed to asbestos. The incidence rate of mesothelioma has decreased in Australia, in the United States, and in Western Europe, where the use of asbestos was banned or strictly regulated in the 1970s and 1980s, demonstrating the value of these preventive measures. However, in these same countries, the overall number of deaths from mesothelioma has not decreased as the size of the population and the percentage of old people have increased. Novel immunohistochemical and molecular markers have improved the accuracy of diagnosis. The discovery that germline BRCA1-associated protein 1 (BAP1) mutations cause mesothelioma and other cancers (BAP1 cancer syndrome) elucidated some of the key pathogenic mechanisms, and treatments targeting these molecular mechanisms and/or modulating the immune response are being tested. The role of surgery in pleural mesothelioma is controversial because it is difficult to predict who will benefit from aggressive management, even when local therapies are added to existing or novel systemic treatments. There are different opinions, a modest amount of data, a lack of standardization for recommendation of the best surgical approach and, most importantly, no proven survival benefit of aggressive surgical interventions. Two operations – extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D) – are performed with curative intent. By contrast, partial pleurectomy or VATS with pleurodesis are performed with palliative intent in order to manage recurrent pleural effusions or to reexpand a partially entrapped lung. Both EPP and P/D aim to achieve a macroscopic complete resection of all tumors. Multimodality therapy is often used for clinical stage I to III pleural mesothelioma. However, the optimal combination therapy remains debated. The outcomes after induction chemotherapy followed by EPP and adjuvant hemithoracic radiation have been disappointing, with median survivals ranging from 16 to 20 months in trials that included more than 40 patients. However, patients who completed adjuvant hemithoracic radiation had a median survival of 29 to 39 months and achieved excellent local control. Clinical trials using cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors failed to improve survival in mesothelioma. Subsequent trials suggested that some patients may benefit from PD-L1 inhibitors. Several trials using checkpoint inhibitors in mesothelioma have met accrual goals or are recruiting. The experimental arms of these trials include combinations of PD-L1 inhibitors with CTLA-4 inhibitors, chemotherapy, or antibody-drug conjugates. It is estimated that 20% to 25% of the patients with mesothelioma may benefit from checkpoint inhibitors. Most patients, however, do not meet the eligibility criteria to participate in phase 2 or 3 clinical trials. There are still many limitations in selecting patients for these treatments, including lack of predictive tests for benefits, absence of drugs to overcome resistance in initial responders, and therapies to convert nonresponding tumors into responsive tumors.

Dose-dense chemotherapy in early breast cancer – the experience of Emergency County Hospital of Alba Iulia

Răzvan-Ovidiu Curcă, Sorin-Cornel Hosu

Emergency County Hospital of Alba Iulia, Romania

Introduction. Increasing the dose intensity of cytotoxic therapy by shortening the intervals between cycles, or by giving individual drugs sequentially at full dose rather than in lower-dose concurrent treatment schedules, might enhance efficacy. The last publication of Cancer Research UK, released in Lancet in February 2019, supports the use of dose-dense therapy and finds a benefit by reducing the 10-year risk of recurrence and death from breast cancer with 15% without increasing mortality from other causes. Materials and method. In 2013, we started to administer dose-dense chemotherapy (DDC) at the Emergency County Hospital of Alba Iulia in early breast cancer patients. The standard inclusion criteria to treat with DDC where T3-4 or 4 N+; triple negative breast cancer or HER2-positive patients. Standard DDC protocols were used with support of peg-filgrastim 24 hours after chemotherapy. Results. Individual patient data were provided for 74 women. The median age was 54 years old (17-74). DDC was adjuvant in 28 women and in 46 patients in neoadjuvant setting. Up to 19.09.2019, there had been administered a total of 531 cycles of DDC. The median follow-up was 20 months (2-75). Prognostic factors. Primary tumor: 23 patients (30%) had T3-4 tumors; 56 patients (75.7%) were node positive, of which 33 patients (44.6%) were cN1 or pN1-3+; 18 patients (24.3%) were cN2 or pN4-9+; 5 patients (6.7%) were cN3c or pN3 (pN>10).  Molecular IHC profile:  32.4% (24 patients) – triple negative; 9.5% (7 patients) – HER2 positive; 41.9% (31 patients) – luminal B type and 16.2% (12 patients) – luminal A. Type of DDC protocol: 51.4% were four cycles of EC 100 two weekly + 12 weeks paclitaxel +/- trastuzumab; 18.9% were four cycles of EC 100 two weekly + 4 x paclitaxel two weekly +/- trastuzumab; 18.9% were four cycles of EC 100 two weekly; 10.8% were 4 cycles of EC 100 two weekly + docetaxel two weekly +/- trastuzumab. Out of 46 patients treated in neoadjuvant setting, 36 patients were evaluated after surgery. Eight patients (22.2%) obtained pCR. From the subgroup of triple negative and HER-2 positive, the rate of pCR was 33.3%. Regarding the toxicity of DDC, 38 patients (51.4%) had any toxicity other than alopecia. Hematological toxicity G3-4 was recorded in 10.8% of the patients and only one patient presented other G3-4 toxicities (infusion reaction). Conclusions. According to the 2019 EBCTC meta-analysis, dose-dense chemotherapy is for all patients with early breast cancer requiring neoadjuvant or adjuvant chemotherapy. The overall toxicity is not significantly higher compared to conventional chemotherapy, with the exception of hematological toxicity, which is significantly lower. Dose-dense chemotherapy is also feasible in Romania, and the experience of the Emergency County Hospital of Alba Iulia, extended over six years, demonstrates this, without a doubt.

Neoadjuvant clinical trials in early-stage breast cancer: is pathologic complete remission a reliable surrogate marker for overall survival?

Mircea Dediu

MD, PhD, Sanador Oncology Center, Bucharest, Romania

Many analyses on the efficacy of neoadjuvant treatment (NAT) for early breast cancer, including a meta-analysis derived from 10 randomized trials, came to the conclusion that patients who would achieve pathologic complete response (pCR) following NAT would experience significant improvement in disease-free survival and overall survival (OS). Thus, pCR was proposed as a surrogate endpoint for OS, with pCR representing a robust prognostic marker for survival at an individual level. In the current analysis, we argue that OS following NAT-induced pCR might have reflected the start-line prognosis of patients mainly defined – among other factors – by the initial pathological lymph node status while being largely independent on the type of administered treatment, thus pleading against the pCR surrogacy hypothesis. We, therefore, propose to redefine pCR as a surrogate endpoint of NAT trials by the involvement of additional biologic parameters.

The limits of the targeted treatment in NSCLC

Mircea Dediu

MD, PhD, Sanador Oncology Center, Bucharest, Romania

Currently, the targeted treatment is the standard in EGFR, ALK and ROS mutated non-small cell lung cancer (NSCLC). There is no doubt that these innovative molecules have dramatically changed the patients’ outcome in these subcategories. Following the lead of these successful achievements, intensive research activities are performed worldwide in order to increase the value of this therapeutic rationale. However, the newest data presented foresee a less enthusiastic horizon related to this subject. The current presentation will summarize the author’s perspective on which the limits of a reasonable expectation related to the targeted therapy has already been reached in NSCLC.

Isolated brain relapse after pathological complete response of HER2-positive locally advanced breast cancer

Diana Andreea Gae, Daniela Luminiţa Zob, Cristian Vasile, Gabriela Niculai, Dana Lucia Stănculeanu

“Prof. Dr. Alexandru Trestioreanu” Institute of Oncology Bucharest, Romania

The novel HER2-targeted therapies have radically changed the prognosis of HER2-positive breast cancer in both early and advanced settings. However, the resistance to these therapies, de novo or acquired, remains a challenge in the treatment of HER2-positive breast cancer patients. We report the case of a 50-year-old woman with no important risk factors for breast cancer, who presented in our clinic with inflammatory breast cancer, clinically stage IIIC. The immunohistochemical tests have shown a poorly differentiated invasive carcinoma – no special type (NST), ER-, PR-, HER2 3+, Ki67 >14%. The patient received six cycles of neoadjuvant chemotherapy containing taxan and cyclophosphamide associated with anti-HER2 therapy (only trastuzumab, as pertuzumab was not reimbursed at that time in neoadjuvant setting), and 3D conformal radiation therapy, prior to surgery. A right modified radical mastectomy was performed, the postoperative histology showing a pathological complete response. During the adjuvant treatment with trastuzumab, the patient developed brain metastases, which required whole-brain radiotherapy. The systemic treatment was changed with trastuzumab emtansine, under which the brain metastases disappeared. Unfortunatelly, after six months, a relapse of the brain lesions was described at the imaging assessment. Currently, the patient is undergoing treatment with lapatinib and capecitabine. In this case, we can discuss about the pathological complete response in an advanced stage of HER2-positive breast cancer obtained without dual anti-HER2 blockade in the neoadjuvant setting, but which had a short time until relapse and only with brain metastases. 

Tumor heterogeneity – implications in the mechanisms of resistance to targeted therapies

B. Gafton

“Grigore T. Popa” University of Medicine and Pharmacy Iaşi, Regional Institute of Oncology Iaşi, Romania

Introduction. Tumor heterogeneity is increasingly recognized as a major impact factor and one of the main mechanisms of resistance to targeted therapies. In addition, tumor heterogeneity impacts biomarker validation, and driver mutations need to be identified for better outcomes. Tumor genetic diversity provides a substrate for tumor adaptation and evolution. However, the evolutionary genomic techniques may provide new targets and new treatment options. Conclusions. We believe that clinicians need to understand the possible mechanisms of resistance in order to recommend the optimal sequence of targeted therapies.

Updates in prostate cancer therapy

Laurenţia Galeş

“Carol Davila” University of Medicine and Pharmacy, Bucharest, “Prof. Dr. Alexandru Trestioreanu” Institute of Oncology, Bucharest, Romania

The introduction of novel agents for the management of advanced prostate cancer provides a range of treatment options with significant benefits for men with metastatic castration-resistant prostate cancer, as well as metastatic hormonal-sensitive disease or in earlier stages. Currently, drugs that are effective in castrate-resistant prostate cancer (CRPC) are being moved to hormone-sensitive disease. There were at least three phase III clinical trials results in prostate cancer presented at the ASCO annual meeting this year addressing this topic. Randomized phase III trials have demonstrated superiority with the addition of docetaxel or abiraterone to standard ADT (androgen deprivation therapy) in metastatic hormone-sensitive prostate cancer (mHSPC)(1-3). In the phase III ARCHES trial, radiographic PFS (rPFS) was improved by adding enzalutamide to ADT in mHSPC, although overall survival (OS) data were still immature(4). ENZAMET was a phase III trial of standard of care (SoC) therapy with or without enzalutamide in metastatic hormone-sensitive prostate cancer. The primary endpoint of OS was significantly improved with enzalutamide versus NSAA(3,4). The second study, TITAN, was a phase III trial of apalutamide versus placebo in patients with metastatic hormone-sensitive prostate cancer receiving ADT. Apalutamide, a different androgen receptor inhibitor from enzalutamide, was approved by FDA for treating patients with non-metastatic CRPC (nmCRPC). The coprimary endpoints were OS and rPFS(5,6). Both endpoints were met. The TITAN data are very similar to those from other phase III trials in mHSPC and they should support the approval of apalutamide in this setting. Noteworthy, it is very difficult to compare data across multiple phase III studies, so we cannot conclude whether one drug is better than another in the setting of mHSPC. The third study was phase III ARAMIS: QoL outcomes with darolutamide plus ADT versus placebo plus ADT in patients with nmCRPC. The primary endpoint was metastasis-free survival (MFS) and secondary endpoints included OS, safety, and time to pain progression(7,8). Darolutamide significantly improved MFS in nmCRPC, with a favorable safety profile. The quality of life (QoL) was maintained, and worsening of certain disease-related symptoms was delayed by adding darolutamide to ADT. These results support adding darolutamide as a treatment option for patients with nmCRPC. On July 30, 2019, FDA approved darolutamide for treating nmCRPC based on the ARAMIS data, so we now have three different androgen receptor inhibitors available in this disease setting. Abiraterone acetate received licencing for use in only “high-risk” metastatic hormone-naïve prostate cancer (mHNPC) following the LATITUDE trial findings. However, a “risk-related” effect was not seen in the STAMPEDE trial. A post-hoc analysis of the STAMPEDE study, where the outcomes of metastatic hormone-sensitive prostate cancer (mHSPC) treated with androgen deprivation (ADT) or ADT + abiraterone acetate were compared by risk according to LATITUDE criteria (≥3 metastases on bone scan; Gleason score >7; visceral metastases) was published online by Alex P. Hoyle, in European Urology, at 23rd of August, 2019. No difference in effect was observed between low- and high-risk groups for overall survival or failure-free survival. These data support the treatment intensification with abiraterone acetate for all men with metastatic disease, independent of risk. There is still a great interest in treating men with intermediate-risk or high-risk prostate cancer using a multimodal therapy to improve outcomes. A randomized study published online by Pirkko-Liisa Kellokumpu-Lehtinen in European Urology, at 20th of August 2019, added docetaxel to standard therapy of external beam radiotherapy plus ADT to compare biochemical disease-free survival. Based on these data, adjuvant docetaxel did not appear to improve outcomes with ADT for patients with intermediate- or high-risk prostate cancer. Currently, novel agents, such as next-generation androgen receptor (AR) axis-targeting treatments, poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors and PD-1 inhibitors, are under clinical investigation. With increasing treatment options for mCRPC, the information on how to personalize management and how to select and sequence existing therapies is beginning to emerge, as are predictive biomarkers. Finally, the early use of active agents in the castration-sensitive state will likely also change the clinical management of the disease when it becomes castrate-resistant. The best strategies for patient selection and optimal sequential use to achieve the longest cumulative survival improvement and to prevent early resistance remain unclear(9).

EU cancer plan: data, technologies and human touch

Marius Geantă

President of The Center for Innovation in Medicine, Bucharest, Romania

The Center for Innovation in Medicine proposed a visionary EU plan on cancer based on human touch, data, technology and modelling approach that empowers citizens. At the center of our vision, there are the citizen/patient and the need for a true personalised approach for prevention, early detection, diagnosis and treatment of cancer. Every citizen/patient is unique and deserves the best possible healthcare, but this is not always possible due to the heterogeneity of the disease (every cancer is unique) and the heterogeneity of the health systems. New technologies require new skills which are closely linked to the concept of health literacy, as recognised in the Council conclusions of the Luxembourg EU Presidency. New technologies allow a prognosis of risk that was unthinkable a few years ago and lead to new levels of health-related and health policy related decision-making for the individual, but also health systems which directly touch on the concept of health literacy. Personalised, digital health approaches are the single most effective means to revolutionise healthcare, as they amplify the potential of value-based medicine and reduce healthcare costs, while providing better and safer treatment, prevention and well-being options on an individual basis. Digital twins, accurate data-driven computer models based on the key biological processes that keep us healthy or lead to disease are essential for predictive personalised medicine approaches in cancer. Using these models, better therapies, preventive or lifestyle measures can be identified, without exposing individuals to unnecessary risk and the healthcare system to unnecessary costs. Individual predictive models of patients and citizens will, however, not only provide powerful tools to select the optimal therapy prevention measure or measures to enhance the well-being of healthy individuals. They can also be used to explore the effects of potential changes in healthcare policies and reimbursement strategies on the local, national, European and ultimately worldwide level (diseases travel quickly in todays highly interconnected world). Such DigiTwin could, however, also be used to improve a major limitation we are facing – there is still very expensive and takes much too long to develop the new drugs we need in the future to help increasingly small groups of patients. Models of individual patients, but also the any experimental models used in preclinical research in drug development could, in principle, significantly decrease risks, cost and the time needed to develop any new drugs – e.g., by low cost (possibly quite large) in silico clinical trials on virtual patient populations to identify if a drug candidate is likely to address the medical needs of a group of patients up to then not adequately covered before entering preclinical development. The resulting savings on all levels can be redistributed, reinforcing the positive effects on health maintenance and well-being: Europe’s citizens will live healthier for longer. At the same time, these new opportunities have also some ethical implications which require the “buy-in” of its “users”. Health literacy may be a catalyst as it ensures that health policies are not developed “on behalf of” but “with” and “through” people who are in turn able to participate more fully and exert a higher degree of control over their health and well-being. For health systems, we have to be able to make the transition from the current model (the scientific foundation of healthcare systems from EU member states dates back one century) to learning health systems capable of continuous improvement in the way that care is delivered. A healthcare system integrating continuous improvement will only work based on the ability to track what is happening in the health system, and also be able to analyze it. For the moment, even though we had “a perfect dataset on cancer”, we will not be able to take all the advantages due to the fragmentation and the way health systems are organised and conducted. At the core of the learning healthcare systems is the opportunity to collect and analyze at individual level (citizen/patient) real world data and systematic, large-scale and routine use of outcomes measurement – this could enable the transition to outcomes-based system, but also to new regulatory and reimbursement pathways. Last but not least, such “learning health systems” will only work if they also become “health literate systems” which ensures navigation support and are readable for community members, the consumers.

Immune-related adverse events – retrospective analysis of 22 patients from the Bucharest Institute of Oncology

Adelina Silvana Gheorghe, Isabela Anda Komporaly, Andreea Mihaela Stoica, Bogdan Georgescu, Raluca Ioana Mihăilă, Dana Lucia Stănculeanu

“Prof. Dr. Alexandru Trestioreanu” Institute of Oncology, Bucharest, Romania

Introduction. Immune checkpoint inhibitors are becoming increasingly used for various tumor types, with outstanding oncological outcomes. However, blocking PD-1/PD-L1 and CTLA-4 pathways result in a variety of immune-related adverse events, which should be noticed on time by the physicians, in order to take appropriate measures. Materials and method. We performed a retrospective analysis of the immune-related adverse events in 22 patients treated at the “Prof. Dr. Alexandru Trestioreanu” Institute of Oncology, Bucharest, with nivolumab (13 patients, out of which six had renal neo­plasm, six had melanoma and one had lung cancer), ipilimumab (one patient with melanoma), combination of nivolumab and ipilimumab (five patients with melanoma), pembrolizumab (two patients with lung cancer) and avelumab (one patient with Merkel cell carcinoma). Results. The patients included in the study were between 21 and 75 years old, with a median age of 61 years old and a sex ratio of 27% females and 73% males. The most common immune-related adverse event was the alteration of hepatic function in 54.54% of the cases (elevated transaminases, gamma-glutamyltransferase, alkaline phosphatase, lactate dehydrogenase and choles­tasis syndrome), while the pancreatic function was less affected, with rises of lipase and amylase in only 13.63% of the patients. Pneumonitis and renal injury were equally present in 22.72% of the cases. Another common adverse event observed was the hematological toxicity, manifested as anemia or leucopenia in almost half of the patients (40.90%). Endocrine disorders (hypothyroidism and hyperthyroidism) were noticed in about one-third of the cases (27.27%). Less frequent events (9.09%) included neurological and skin toxicities (vitiligo or rash). There was only one case of cardiac toxicity to nivolumab, manifested as life-threatening arrhythmia. Except this severe cardiac adverse event, all the others were low-grade, thus allowing the continuation of immunotherapy and being manageable with specific treatment. Conclusions. Immunotherapy-related toxi­cities may be more common than reported in literature and a special focus should be placed on managing them correctly, preferably using interdisciplinary references from specialists (gastroenterologists, endocrinologists, dermatologists etc.). 

Primary gastric squamous cell carcinoma – a rare entity

Andreea-Daniela Gheorghe1, Gabriela Fricăţel2, Traian Tache2, Andra-Iulia Suceveanu3, Luminiţa Micu4, Laura Mazilu1

1. Oncology Department, “St. Andrew the Apostle” Clinical Emergency Hospital of Constanţa; Faculty of Medicine, “Ovidius” University of Constanţa, Romania

2. Oncology Department, “St. Andrew the Apostle” Clinical Emergency Hospital of Constanţa, Romania

3. Gastroenterology Department, “St. Andrew the Apostle” Clinical Emergency Hospital of Constanţa; Faculty of Medicine, “Ovidius”  University of Constanţa, Romania

4. Pathology Department, “St. Andrew the Apostle” Clinical Emergency Hospital of Constanţa, Romania

Primary gastric squamous cell carcinoma (SCC) is a rare form of gastric cancer, with fewer than 100 cases reported in literature and first described in 1895. We present the case of a 65-year-old woman with no significant medical history. The onset of disease was insidious, the patient complaining of epigastric pain and weight loss. An upper digestive endoscopy was performed and showed a large tumor with a central ulcer in gastric fornix, with normal esophagus and cardia. Biopsies performed were negative for malignancy. The patient underwent surgery with total gastrectomy, splenectomy and epiploectomy. The histopatological and imunohistochemical results showed a primary gastric squamous cell carcinoma. The patient was referred to the oncology department for treatment. An MRI of abdomen and pelvis showed liver metastasis. The patient started palliative chemotherapy. We present this case to highlight that squamous cell carcinoma is a cause of primary gastric cancer, and even though it is a rare entity with few cases of primary SCC of the stomach published in literature, the specialists should be aware of its existence.

Central polyuria-polydipsia syndrome in a patient with non-small cell lung cancer

Andreea-Daniela Gheorghe1, Gabriela Fricăţel2, Traian Tache2, Liliana Mocanu3, Laura Mazilu1

1. Oncology Department, “St. Andrew the Apostle” Clinical Emergency Hospital of Constanţa; Faculty of Medicine, “Ovidius” University of Constanţa, Romania

2. Oncology Department, “St. Andrew the Apostle” Clinical Emergency Hospital of Constanţa, Romania

3. Pathology Department, “St. Andrew the Apostle” Clinical Emergency Hospital of Constanţa, Romania

Metastases to the pituitary gland are not frequently reported, probably due to the fact that most of the patients are asymptomatic, only 6.8% of cases being symptomatic. The common clinical manifestations are diabetes insipidus, visual disturbances, headache and fatigue. We present the case of a 60-year-old man diagnosed with stage IV lung adenocarcinoma (EGFR negative, ALK negative, and PD-L1 negative). CT scan of the brain prior to chemotherapy showed no evidence of brain metastasis. The patient received four cycles of chemotherapy with partial response and continued the maintenance treatment with pemetrexed. Two weeks after the first administration of pemetrexed, the patient presented polydipsia and polyuria. The nephrologic examination excluded a renal cause of the syndrome. The endocrinologic examination established the diagnosis of central polyuric – polydipsic syndrome, and the patient started the treatment with desmopresine. An MRI of the pituitary gland showed a nodular adenohypophysis, with a hypovascular lesion probably secondary to lung cancer. Because of the incert aspect of the MRI, our patient did not have indication for radiotherapy. We report the case because this is a rare manifestation of lung cancer and because the differential diagnosis between pituitary metastasis and adenoma is often very difficult.

Anthracyclines – the development of modern pharmaceutical forms

Mihaela Itul-Toderesc, Khaled Al Ghieb, Bianca Gălăţeanu, Octav Ginghină, Carolina Negrei

Fundeni Clinical Institute, Bucharest, Romania

Cancer has become one of the most difficult challenges on healthcare worldwide. Systemic chemotherapy is the most frequently used therapeutic strategy. However, there are considerable limitations because of the toxicity over disease-free tissues and of the low medicine concentrations reached at the tumor inherently level. Anthracyclines, the antineoplastic medicines from the antimetabolites antibiotics class, have a wide spectrum of action, with an important role in the treatment of leukemia, lymphomas and of many solid tumours. Their usage is rather limited, especially because of the cardiac toxicity. In this respect, there have been studied and achieved different modern pharmaceutical forms reducing the toxicity of these molecules. Different pharmaceutical forms have been studied and formulated aiming to deliver the substance at the level of the tumor cells, limiting its deliverance at the level of healthy tissues. One example in this respect is represented by liposomes which are delivered in a limited way to the level of the organs and tissues, as it follows: cord, kidneys, and nervous system. Nanotechnology offers unique approaches for the studying and control of a variety of biological processes. Many types of nanoparticles with biomedical relevance are available (polymeric nanoparticles, metallic nanoparticles, liposomes, micelles, quantum dots, dendritic polymers etc.). Regarding the use of nanoparticles, it is important that the materials are biocompatible, hemocompatible, immunocompatible and capable of recognizing the target situs specific from the body after the systemic administration. Biodegradation is also taken into consideration, since the degradation products of these nanoparticles may generate immune, allergic or toxic responses. Both natural and synthetic biodegradable polymers are studied, to reveal the advantages, disadvantages, and their clinical potential.

Reenactment of the chemo dilutions – legality or necessity

Mihaela Itul-Toderesc, Khaled Al Ghieb, Bianca Gălăţeanu, Octav Ginghină, Roxana Stroe, Carolina Negrei

Fundeni Clinical Institute, Bucharest, Romania

The cytotoxic medicines are therapeutic agents intended for anticancer therapy. These medicines are very toxic at the cell’s level, mainly through their action within the cells division. Many anticancer substances proved to have a carcinogenic, mutagenic, and teratogenic character. Thus, side effects come over the healthy persons which get into contact with the sick ones, especially the nursing staff. The contamination with these substances may be realized by means of skin contact, inhalation or through ingestion. The handling of anticancer medicines may determine different disorders, as follows: skin eruption, infertility, abortion and even the appearance of leukemia and other forms of cancer. For the safe usage of these medicines, at the European Union level, norms have been imposed for the centralized reenactment of the chemo dilutions. Therefore, the imperious reenactment of these medical solutions within specially arranged spaces, with hoods and protection equipment that should fulfil certain standards for protecting the nursery staff who handle them. The legislation in our country is somehow limited; the few regulations are established by Law no. 319/2006, regarding the security and health legislation, updated. Once our country has adhered to the European Union, Romania obeys the directives, norms and European recommendations, undergoing the implementation of ISOPP. There are also two main directives regarding the individual equipment of protection (EIP): Directive no. 89/686/EEC for the harmonization of the EIP legislation; Directive no. 89/656/EEC, regarding the usage of the protection equipment at the working place. Taking into the consideration the increasing number of dilutions which are realized within our sanitary units in Romania, a firm legislation should be thought and implemented, in order to protect the healthcare professionals.

Adjuvant therapy for malignant melanoma of the skin

M.V. Marinca

Department of Medical Oncology, “Grigore T. Popa” University of Medicine and Pharmacy, Iaşi, Romania

Cutaneous malignant melanoma (cMM) is one of the most aggressive human cancers. Despite a marked increase in prevention and early detection efforts, and although most patients undergoing a definitive resection of a localized tumor generally will not have relapses, the mortality rates of high-risk cMM (tumor thickness >4 mm, high mitotic rate, ulceration, nodal involvement) remain unchanged. In these subsets of patients, the use of postoperative treatment is warranted to reduce the risk of recurrence. In this review, we outline the timeline and the recent breakthroughs of adjuvant systemic therapy in stage III cMM. Historically, interferon-alpha has been the only treatment to achieve significant (while inconsistent) improvements in overall survival (OS). Currently, its role remains confined to some patients with ulcerated tumors. Since the advent of immunotherapy in 2011, impressive results have pushed its use from the palliative setting to the first line in metastatic disease, and recently to the postoperative stage. The first of these agents to be studied in clinical trials was a monoclonal antibody against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), ipilimumab. In the adjuvant setting, ipilimumab has shown significant improvements in relapse free survival (RFS) and OS, but at the cost of significant immune-related adverse events. Newer agents (specifically PD-1 inhibitors) have outperformed ipilimumab in terms of both efficacy and safety. For patients with tumors expressing BRAF V600 mutations, another currently approved option is the postoperative use of BRAF/MEK inhibitors. As these approaches have not been compared head-to-head, the choice of treatment in these patients should be based on tolerability profile and patient preference. While the novel drugs are definitely increasing the chance of cure, and promising data are emerging for other potentially curative approaches (such as radiation therapy or neoadjuvant treatments), the main challenge remains the lack of prognostic and predictive markers to ensure the optimal selection of patients who will need (and benefit from) adjuvant therapy. Whenever possible, patients should be enrolled in formal clinical trials, preferably with a translational component.

Redrawing treatment landscape for hormone-receptor positive, HER2-negative metastatic breast cancer

Laura Mazilu1, Daniela Zob2

1. Oncology Department, “St. Andrew the Apostle” Clinical Emergency Hospital of Constanţa; Faculty of Medicine, “Ovidius” University of Constanţa, Romania

2. Department of Medical Oncology I, “Prof. Dr. Alexandru Trestioreanu” Institute of Oncology, Bucharest, Romania

Endocrine therapy (ET) remains the backbone of treatment for metastatic hormone receptor positive breast cancer, but clinical decision-making to determine the best sequence of treatments for an individual patient is challenging due to disease heterogeneity and expanding knowledge about molecular profiles, disease behavior, and resistance mechanisms to endocrine therapy(1). The analysis of resistance mechanisms to endocrine therapy has led to the development of a new generation of targeted therapies for metastatic hormone receptor positive breast cancer – anti-estrogen therapy with selective estrogen receptor modulators, aromatase inhibitors, and/or selective estrogen receptor degraders, combinations with cyclin dependent kinase (CDK) 4/6 inhibitors. All these therapies have led to significant improvements in progression-free survival (PFS) in the first and second line(2). There are multiple studies of the use of P13K inhibitors and mTOR inhibitors for the use as subsequent lines of therapy, particularly for endocrine resistance. The optimal sequencing of therapy should be based on medical comorbidities, prior adjuvant therapies, quality of life, side-effect profile, and disease-free interval(3). The mTOR inhibitor everolimus significantly improves the progression-free survival when added to endocrine therapy, but while these combination targeted therapies improve outcomes and often delay initiation of chemotherapy, the long-term overall survival data and data for the ideal strategy for sequencing these agents are lacking(1). Ongoing research evaluating potential biomarkers and mechanisms of resistance is anticipated to continue to improve outcomes for patients with HR-positive metastatic breast cancer(1).

Ovarian cancers – looking over the fence

D. Median1, G. Iancu1,2, A. Corha1

1. Filantropia Clinical Hospital of Obstetrics and Gynecology, Bucharest, Romania

2. “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania

Representing more than 65% of all ovarian cancers, the high-grade serous ovarian carcinoma (HGSOC) tends to absorb all the interest of clinicians, researchers, trialists, or pharma industry. Most of scientific meetings are focused on progresses made in understanding the mechanisms of HGSOC and their treatment, paying less attention to other forms of (non)-epithelial ovarian cancers. Even the comprehensive guidelines offer a limited amount of data on others than non-HGSOC. In this context, in daily practice, any new patient with non-HGSOC causes distress to physicians because of the paucity of data or clear management algorithms. We review the most recent data on mucinous carcinoma, low-grade serous carcinoma and non-epithelial cancers, in order to provide some practical hints and cover this gap.

What we can and what we may in HER2-positive breast cancer

D. Median

Filantropia Clinical Hospital of Obstetrics and Gynecology, Bucharest, Romania

Considered for a long time the most high-risk targetable breast cancer (BC), HER2-positive subtype became an area of tremendous progresses in oncology. At present, we know how to identify patients who need treatment escalation or the opposite, how to translate a pathologic feature like the presence of tumor-infiltrating lymphocytes (TILs) into clinical practice, how to understand the pathologic complete remission (pCR) in terms of tailoring the treatment, and how to improve the survival of patients with this condition. However, which of these great achievements can really be implemented in our current activities, considering the national reimbursement system, is still a debatable issue. We try to harmonize the current knowledge with the Romanian realities for better outcomes in our daily practice.

Noutăţi în cancerul de vezică urinară

Raluca Mihăilă2, Dana Lucia Stănculeanu1,2

1. Departamentul Oncologie Medicală, Universitatea de Medicină şi Farmacie „Carol Davila”, Bucureşti, România

2. Secţia Clinică Oncologie Medicală I, Institutul de Oncologie „Prof. Dr. Alexandru Trestioreanu”, Bucureşti, România

Deşi reprezintă o cauză importantă de mortalitate datorată cancerului, progresele terapeutice în cancerul vezicii urinare au fost limitate în ultimii 25 de ani. Identificarea biomarkerilor predictibili pentru răspunsul terapeutic este necesară, mai ales în contextul unei neoplazii heterogene, pentru a evita costurile adiacente şi toxicităţile legate de tratamentul ce nu ar aduce niciun beneficiu. În funcţie de stadializare, se poate indica tratament local, chirurgical sau radiochimioterapie. Este important de subliniat că decizia terapeutică trebuie luată în echipă multidisciplinară (urolog, oncolog, radioterapeut). Societatea Europeană de Oncologie (ESMO) şi Societatea Europeană de Urologie (EAU), alături ce cele americane, au dezvoltat ghiduri utile pentru tratamentul personalizat al pacienţilor cu neoplasm urotelial. Cu peste 170.000 de noi cazuri diagnosticate anual în Europa, cancerul vezicii urinare ocupă locul al şaselea privind incidenţa cancerelor din România, conform datelor GLOBOCAN publicate în 2018 (3924 de cazuri noi), şi este a doua cea mai frecventă localizare în tumorile tractului urinar (după cancerul prostatic). Cancerul vezicii urinare este de trei ori mai frecvent diagnosticat la sexul masculin, iar incidenţa creşte odată cu vârstă (se dublează la vârste de peste 75 de ani). Având în vedere că vârsta medie la diagnostic este între 60 şi 70 de ani, comorbidităţile medicale ridică probleme în managementul pacienţilor. Deşi supravieţuirea acestor pacienţi a crescut datorită progreselor terapeutice, mortalitatea este în continuare crescută. În România, decesele datorate cancerului vezicii urinare ocupă locul al zecelea (1587 de decese), după cancerul pulmonar, colorectal, mamar, hepatic şi cel gastric. Din punct de vedere istoric, nu au existat tratamente standard globale pentru pacienţii care progresează după chimioterapia de primă linie în cancerul vezicii urinare, iar în ultimii 30 de ani progresele au fost minore. Însă dezvoltarea inhibitorilor checkpoint a schimbat toate acestea, iar acum cinci inhibitori de PD-1 şi PD-L1 sunt aprobaţi pentru tratamentul de linia a doua în boala metastatică. Chimioterapia pe bază de platină rămâne standardul de tratament pentru pacienţii diagnosticaţi cu cancer de vezică metastatic (mBC), cu supravieţuire redusă. În 2014, atezolizumab a fost primul agent imunoterapic aprobat de FDA, pe baza rezultatelor promiţătoare ale studiului preliminar. Ulterior, au primit aprobare nivolumab, durvalumab, avelumab şi pembrolizumab. Ca terapie de prima linie, atezolizumab a demonstrat o supravieţuire globală (overall survival; OS) mediană de 15,9 luni şi o rată de răspuns obiectiv (ORR) de 23,5%, cu un CR de 9%. În prima linie, pembrolizumab (KEYNOTE 052) a avut activitate antitumorală eficientă (ORR 29%; CR 7%), cu tolerabilitate acceptabilă la vârstnici şi la pacienţii cu factori prognostici nefavorabili, neeligibili pentru terapia bazată pe platină. În ambele studii de aprobare, tratamentul în prima linie şi-a dovedit eficacitatea în cazul tumorilor cu expresie PD-L1 ridicată, astfel încât FDA a restrâns indicaţia la pacienţii neeligibili pentru tratamentul cu cisplatin, cu tumori pozitive pentru PD-L1. Bazându-se pe aceste date, studiile recente de fază II relevă rate patologice semnificative de răspuns complet atât pentru atezolizumab, cât şi pentru pembrolizumab înainte de cistectomie la pacienţii diagnosticaţi cu carcinom urotelial invaziv muscular, PD-L1 pozitivi, cisplatin-neeligibili. Mai mulţi agenţi noi – în special inhibitorul FGFR erdafitinib – au date care susţin răspunsuri favorabile comparativ cu terapiile standard pentru carcinomul urotelial metastatic. Pe baza aprobării erdafitinibului de către FDA, testarea moleculară ar trebui să includă analiza modificărilor FGFR3 sau FGFR2 genetice. Setul Therascreen FGFR RGQ RT-PCR a fost aprobat ca metodă diagnostică pentru eligibilitatea tratamentului. Noi studii sunt în derulare, vizând ţinte precum CTLA-4 şi NKTR-214, cu rezultate în aşteptare.

Novelties in bladder cancer

Raluca Mihăilă2, Dana Lucia Stănculeanu1,2

1. Department of Oncology, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania

2. Department of Medical Oncology I, “Prof. Dr. Alexandru Trestioreanu” Institute of Oncology, Bucharest, Romania

Although a major cause of cancer mortality, the therapeutic advances in bladder cancer have been limited for the past 25 years. The identification of predictable biomarkers for the therapeutic response is necessary, especially in the context of a heterogeneous neoplasm, in order to avoid the adjacent costs and the toxicities related to the treatment that would not benefit. Depending on the staging, local, surgical or radio-chemotherapy treatment may be indicated. It is important to emphasize that the therapeutic decision must be made in the multidisciplinary team (urologist, oncologist, and radiotherapist). European Society of Oncology (ESMO), European Society of Urology (UAE), as well as the American ones have developed useful guides for the personalized treatment of patients with urothelial neoplasm. Bladder cancer, with more than 170,000 new cases diagnosed annually in Europe, ranks sixth in the incidence of cancer in Romania, according to GLOBOCAN data published in 2018 (3,924 new cases), and is the second most frequent localization in urinary tract tumors (after prostate cancer). It is three times more commonly diagnosed in men, and the incidence increases with age (it doubles above 75 years old). Given that the average age at diagnosis is between 60 and 70 years old, medical comorbidities raises problems in patient management. Although the survival of these patients has increased due to therapeutic advances, the mortality is still increasing. In Romania, deaths due to bladder cancer occupy the tenth place (1,587 deaths), after lung, colorectal, breast, liver and gastric cancer. Historically, there have been no global standard treatments for patients progressing after first-line chemotherapy in bladder cancer, and progress has been minor over the last 30 years. But the development of checkpoint inhibitors has changed all of these, and now five PD-1 and PD-L1 inhibitors are approved for second-line treatment for metastatic disease. Platinum-based chemotherapy remains the standard of treatment for patients diagnosed with metastatic bladder cancer (mBC), with reduced survival. In 2014, atezolizumab was the first FDA-approved immunotherapy agent based on promising results from the preliminary study. Subsequently, nivolumab, durvalumab, avelumab and pembrolizumab were approved. As a first-line therapy, atezolizumab demonstrated a median overall survival (OS) of 15.9 months, an objective response rate (ORR) of 23.5%, with a CR of 9%. In the first line, pembrolizumab (KEYNOTE 052) had efficient antitumor activity (ORR 29%; CR 7%), with acceptable tolerability in the elderly and in patients with unfavorable prognostic factors, ineligible for platinum-based therapy. In both approval studies, first-line treatment has been shown effective in tumors with high PD-L1 expression, so FDA restricted the indication to patients ineligible for cisplatin treatment with PD-L1-positive tumors. Based on these data, recent phase II studies show significant pathological complete response rates for both atezolizumab and pembrolizumab prior to cystectomy in patients diagnosed with invasive urothelial carcinoma, PD-L1 positive, cisplatin-ineligible. Several novel agents – especially the FGFR inhibitor erdafitinib – have data that support favorable responses compared to standard therapies for metastatic urothelial carcinoma. Based on FDA approval of erdafitinib, molecular testing should include analysis of genetic FGFR3 or FGFR2 modifications. The Therascreen FGFR RGQ RT-PCR kit was approved as a diagnostic method for treatment eligibility. New studies are underway, with targets such as CTLA-4 and NKTR-214, with pending results.

Non-small cell lung cancer – case report

Gabriela Niculai, Daniela Zob, Diana Gae, Dana Lucia Stănculeanu

“Prof. Dr. Alexandru Trestioreanu” Institute of Oncology, Bucharest, Romania

Introduction. Lung cancer is the most common cause of death by cancer worldwide. Smoking causes the majority of lung cancer – both in smokers and in people exposed to secondhand smoke. But lung cancer also occurs in people who have never smoked and in those who never had prolonged exposure to secondhand smoke. Case presentation. We present the case of a 54-year-old smoker who came to the hospital with dry cough, dyspnea, thoracic pain and supraclavicular lymphadenopathy, being diagnosed with adenocarcinoma with lymph metastasis from primary tumor lung cancer – no additional mutations. The patient received bevacizumab, paclitaxel and carboplatin, with complete remission as best response. He developed pulmonary thromboembolism, which required urgent initiation of anticoagulant treatment and the definitive interruption of bevacizumab. Eighteen months after stopping the chemotherapy, the control CT revealed progressive disease. The patient started nivolumab as second-line treatment for metastatic disease. Currently, the patient is in complete remission. Conclusion. This is a case of stage IV lung adenocarcinoma, no ALK, EGFR- mutations, PD-L1 negative, with two CR at two lines of therapy.

Desensitization for allergic reactions to chemotherapy. A single center experience

Cornelia Niţipir1,2, Cristina Orlov-Slavu1

1. “Elias” University Emergency Hospital, Bucharest, Romania

2. “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania

Introduction. Anaphylactic events after exposure to certain drugs are life-threatening events that usually lead to a permanent discontinuation of the implied substance. In most situations, similar alternatives exist, but this is not the case for some chemotherapy agents, like carboplatin, paclitaxel and oxaliplatin. The present paper summarizes the experience one clinic has with desensitization to these drugs. Materials and method. The present retrospective paper reports data on three subgroups of patients, each group with 15 subjects, who received desensitizing regimens for carbo­pla­tin, paclitaxel or oxaliplatin. The patients were treated between 2016 and 2019 at the oncology clinic of the “Elias” University Emergency Hospital, Bucharest. The initial administration was done under intensive care unit supervision, taking place in the oncology clinic. The median number of courses until the hypersensitivity reaction appeared was as follows: 8 (4-22) – carboplatin; 2 (1-5) – paclitaxel; 4 – oxaliplatin (2-6). A total of 213 courses with the desensitizing regimens were administered. Results. The number of patients with success in re-challenge with these regimens were: 14 (93.3%) with carboplatin; 12 (80%) with paclitaxel; 11 (73,3%) with oxaliplatin. Some patients had recurrent hypersensitivity reactions that mandated treatment cessation. No adrenaline administration was considered necessary for any of the reactions. The rate of response in the treated patients was 66.6% for carboplatin, 80% for paclitaxel, and 53% for oxaliplatin. Conclusions. To sum up, the proposed desensitization regimens for these chemotherapy agents are safe and effective. Personalized decisions regarding the timing and the duration of the administration are sometimes necessary.

Tolerability of dose dense regimens in breast and ovarin cancer – a single institution experience

Cornelia Niţipir1,2, Ana Maria Popa1, Maria Alecsandra Barbu1, Mihaela Olaru1

1. “Elias” University Emergency Hospital, Bucharest, Romania

2. “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania

Introduction. Dose-dense chemotherapy is the preferred treatment option in neoadjuvant and adjuvant setting for patients with breast cancer and a valid option for first-line therapy in patients with ovarian carcinoma. Studies showed contradictory data regarding toxicities when compared to standard administration. The present paper summarizes the experience our institution has with these regimens. Materials and method. We conducted a retrospective observational study on breast and ovarian cancer patients treated between 2017 and 2019 in our institution in adjuvant and neoadjuvant setting, using dose-dense regimens. The regimens used for breast cancer patients were dose-dense doxorubicin + cyclophosphamide with dose-dense sequential paclitaxel with pegfilgrastim support or weekly paclitaxel, and for ovarian cancer patients, carboplatin and weekly paclitaxel were used, with filgrastim support after day 1 of every cycle. In HER2-positive breast cancer patients, trastuzumab was initiated during taxane regimens. Results. A total of 27 breast cancer and 5 ovarian cancer patients were treated during the aforementioned period. The median age was 46 years old (interval: 28-68). The frequent adverse events were fatigue, alopecia, myalgia, grade 2 mucositis, and grade 2 hematologic toxicities. In the breast cancer group, no dose delay or dose reduction was necessary. In the ovarian cancer group, grade 3 hematologic toxicities were more frequent, resulting in treatment delays. No grade 4 or cardiac toxicities occurred during treatment. All ovarian patients had a partial response after nine weeks of treatment. Data regarding PFS is pending. Conclusions. From our experience, dose-dense regimens are safe and mostly well tolerated. The selection of patients fit for these courses is necessary, in order to avoid treatment delays.

Challenging cases in head and neck cancer

Doru Paul1, Horia Vulpe2

1. MD, PhD, Assistant Professor of Clinical Medicine, Weill Cornell Medical Center, New York, USA

2. MD, CM, Assistant Professor of Radiation Oncology, Columbia University, New York, USA

The management of head and neck cancer is rapidly evolving. In this session, Dr. Paul and Dr. Vulpe will consider the multidisciplinary management of challenging cases in head and neck cancer, focusing on the interplay between chemotherapy and radiotherapy. The session will discuss treatment approaches to locally advanced malignancies such as nasopharyngeal, oropharyngeal, and anaplastic thyroid cancer. The attendee will gain a better understanding of the role of neoadjuvant chemotherapy and how this affects subsequent radiotherapy treatment planning, as well as familiarize themselves with recent literature for each disease site.

Recurrent/metastatic head and neck cancers

The most significant result of the last year regarding the treatment of head and neck cancers for the medical oncologists have been the validation of the use of pembrolizumab in the front-line treatment of recurrent/metastatic squamous cell cancers of head and neck (R/M HNSCC). The KEYNOTE -048 study, presented at ASCO in 2019, established the efficacy of pembrolizu­mab and pembroluzimab plus chemotherapy in the first-line treatment of head and neck cancer. At the second interim analysis, pembrolizumab significantly improved overall survival in the PD-L1 combined positive score (CPS) ≥20 and ≥1 populations and had non-inferior OS in the total population with favorable safety; pembrolizumab in combination with chemotherapy significantly improved OS in the total population with comparable safety. A number of 882 patients with locally incurable R/M HNSCC and no prior systemic therapy were randomized in this phase 3 study to pembrolizumab (P) 200 mg Q3W for 24 mo (n=301), pembrolizumb for 24 months + 6 cycles of chemotherapy (PC) (cisplatin 100 mg/m2 or carboplatin AUC 5 Q3W + 5-FU 1000 mg/m2/d for 4 d Q3W) (n=281), or the standard of care chemotherapy Extreme regimen (E) (cetuximab 400 mg/m2 loading/250 mg/m2 QW + 6 cycles of chemo) (n=300). P+C significantly improved OS versus E in the CPS ≥20 (HR 0.60; 95% CI; 0.45-0.82; p=0.0004; median: 14.7 versus 11 months) and CPS ≥1 (HR 0.65; 95% CI; 0.53-0.80; p<0.0001; median: 13.6 versus 10.4 months) populations. HR (95% CI) for PFS was 0.76 (0.58-1.01) for CPS ≥20 and 0.84 (0.69-1.02) for CPS ≥1. ORR (P+C versus E) was 42.9% versus 38.2% for CPS ≥20 and 36.4% versus 35.7% for CPS ≥1. The median duration of response (DOR) was 7.1 versus 4.2 months and 6.7 versus 4.3 months, respectively. P did not significantly improve OS versus E in the total population (HR 0.83; 95% CI; 0.70-0.99; p=0.0199; median: 11.5 versus 10.7 months). HR (95% CI) for PFS was 1.29 (1.09-1.53). ORR (P versus E) was 16.9% versus 36.0%. Median DOR was 22.6 versus 4.5 months. The adverse events (AE) were inferior in the P arm and comparable with the standard of care E in the P+ C arm. All-cause grade 3-5 AE rates were 54.7% for P, 85.1% for P+C, and 83.3% for E.

Locoregionally advanced nasopharyngeal carcinoma

Another significant result was presented aslo at ASCO 2019 in the treatment of nasopharynx cancer. A phase 3 Chinese study, from Sun-Yat Sen University Cancer Center, published in The New England Journal of Medicine on May 31st, 2019, demonstrated that induction chemotherapy added to chemoradiotherapy significantly improved recurrence-free survival and overall survival, as compared with chemoradiotherapy alone, among patients with locoregionally advanced nasopharyngeal carcinoma.

Anaplastic thyroid cancer

The efficacy of dabrafenib and trametinib in treating anaplastic thyroid cancer was demonstrated in an open-label clinical trial of patients with rare cancers with BRAF V600E mutation. The open-label trial measured the number of patients with a complete or partial reduction in tumor size. Of the 23 evaluable patients, 57% experienced a partial response (PR) and 4% experienced a complete response (CR). Among the 14 patients with responses, 9 (64%) had no significant tumor growth for six months or longer. Common side effects included pyrexia, rash, chills, headache, arthralgia, cough, fatigue, nausea, vomiting, diarrhea, myalgia, dry skin, decreased appetite, edema, hemorrhage, hypertension, and dyspnea.

Actualities in epithelial ovarian cancer

Dana Stănculeanu, Raluca Mihăilă, Isabela Komporaly, Oana Toma, Lidia Kajanto, Adelina Silvana Gheorghe, Alina Bodilcu,Bogdan Georgescu, Daniela Zob

“Prof. Dr. Alexandru Trestioreanu” Institute of Oncology, Bucharest, Romania

Despite the undeniable progress achieved in cancer treatment, the median progression-free survival in high-grade epithelial ovarian cancer, after surgery and platinum-based chemotherapy, is still low (10-18 months), with a 38% five-year survival rate and a median overall survival of 30-75 months for patients with advanced disease. The most recent integrated treatment paradigm for use in ovarian cancer is based on carboplatin, paclitaxel and bevacizumab, followed by maintenance treatment with bevacizumab or olaparib until progression. Maintenance duration in the first-line treatment with bevacizumab has not been defined yet. Progression-free survival improves with three years in front-line olaparib maintenance for BRCA mutated (germ line or somatic) patients, whereas overall survival gains eight months for unresectable or suboptimal resected stage III or IV patients with front-line bevacizumab maintenance. Also, it has been reported a 28-month progression-free survival for optimally resected patients who received dose-dense intravenous or intraperitoneal chemotherapy plus bevacizumab, followed by maintenance bevacizumab. After progression, another chemotherapy regimen with platinum doublet is recommended, with PARP inhibitors maintenance. The use of PARP inhibitors in first line regardless of BRCA status is still in study, for example the use of niraparib in HRD (homologous recombination deficiency) tumors. Compared to niraparib alone, niraparib + bevacizumab in the treatment of ovarian cancer significantly improve PFS, regardless of HRD status or chemotherapy-free interval. Neoadjuvant chemotherapy was studied as an alternative approach and it was proved that it does not worsen survival, remaining a decision highly surgeon-dependent, according to the tumor characteristics and the risk of perioperative morbidity. Hyperthermic intraperitoneal chemotherapy (HIPEC) had shown potential biological and clinical benefits, but has not entered in the current practice, being still an experimental treatment in clinical studies. The poor prognosis of advanced epithelial ovarian cancer demonstrates the need for new and more effective treatments, possibly with less toxicity. Further trials are ongoing, with promising results for future treatment strategies, including immune checkpoint inhibitors, such as anti-PD-1 (nivolumab) and anti PD-L1 (avelumab) antibodies, alone or in combination with PARP inhibitors or anti-VEGF drugs. After recurrence, second-line treatment options for maintenance have been studied, with bevacizumab and PARP inhibitors (olaparib, niraparib and rucaparib) proving to be beneficial in platinum-sensitive disease. Regarding the low-grade serous ovarian cancer, there are already hormonal approaches recommended after the chemotherapy regimen, also being under investigation novel hormonal therapies (onapristone) in patients with positive progesterone receptors or combination therapy (ribociclib + letrozole). MEK inhibitors (selumetinib, trametinib) show promising results, as well as targeting angiogenesis. Moreover, in the era of personalized medicine, the development of effective screening biomarkers and algorithms for early disease detection would increase both survival and quality of life, thus decreasing the need for advanced-stage treatments and cumulated toxicities.

New world order – PD-L2 takes over PD-L1

Andrei Ungureanu

Amethyst Cluj-Napoca, Romania

Since the introduction of PD-L1 inhibitors in clinical practice, little light has been shed on PD-L2 inhibition. Presumably, PD-L1 inhibition is supposed to be associated with fewer side effects. The results from clinical trials using PD-L1 inhibition were unable to prove this hypothesis. The use of PD-L1 inhibition in the absence of PD-L1 testing might have no effect on PD-L1 non-expressing tumors. On the other hand, PD-1inhibition might be more efficient even in PD-L1 non-expressing tumors due to PD-L2 inhibition. The PD-L2 has six times more affinity for PD-1, but due to the low levels of expression it is outcompeted by PD-L1. But there are some tumoral types, like colorectal cancer and head and neck squamous cancers, where the expression of PD-L2 is far more important than the expression of PD-L1. The present paper tries to make justice to an underestimated potential immune target.

SBRT treatment of oligometastatic disease

Horia Vulpe

MD, CM, Assistant Professor of Radiation Oncology, Columbia University, New York, USA

Oligometastatic disease is believed to represent an intermediary state between localized and diffusely metastatic malignancy. In the last two years, no fewer than seven phase-two randomized trials have been published on the role of stereotactic body radiotherapy (SBRT) for the treatment of oligometastatic disease. More trials are underway exploring the combination between SBRT and immunotherapy. This session will review the principles behind SBRT, recent trials supporting its applications for oligometastatic disease, and the biological basis and early clinical data supporting the promising interplay between immunotherapy and high-dose radiotherapy.

Luminal breast cancer – updates in neoadjuvant and adjuvant treatment

Daniela Zob, Laura Mazilu, Dana Lucia Stănculeanu

“Prof. Dr. Alexandru Trestioreanu” Institute of Oncology, Bucharest, Romania

Estrogen receptor (ER)-positive tumors count almost two-thirds of breast cancers. ER-positive breast cancer is a heterogeneous disease with diverse histologies, gene-expression profiles and mutational patterns, with different clinical outcomes and responses to systemic treatment. Despite chemotherapy and adjuvant hormonal therapy given to patients according to the risk of relapse, these still occur. The appearance of relapses and distant metastases count for an unmet medical need of these patients. To avoid overtreatment and late adverse events such as secondary malignancies, research aims to identify those patients who can be spared adjuvant chemotherapy.  We should recognize patients with high risk of relapse for whom extended adjuvant hormone therapy is better. This presentation wants to explore new agents for targeting minimal residual disease, for overcoming endocrine resistance and to highlight patient’s tailored treatment. Data obtained from next-generation sequencing trials revealed new insight into the biology of luminal breast cancer. We will present new data from neoadjuvant and adjuvant clinical trials and new directions of research.