Radiotherapy and the abscopal effect

Ion Christian Chiricuţă
MD PhD, AMETHYST Radiotherapy Center, Otopeni

Although radiation has generally been considered immunosuppres­sive, several recent studies have shown that radiation actually has the potential to be immunomodulatory. Radiation-induced cell death is an immunologically active process wherein dying tumor cells release tumor-associated antigens (TAAs) that can potentially be exploited to stimulate robust tumor-specific immune responses.  Cells undergoing radiation-induced cell death also develop distinctive changes on their plasma membranes. These changes act as danger signals to promote phagocytosis by antigen-presenting cells (APCs) such as macrophages and dendritic cells (DCs). Certain proteins, including heat-shock proteins, calreticulin and high-mobility group box 1 (HMGB1), have been shown to be critical danger signals. Plasma membrane expres­sion of heat-shock proteins, which occurs following radiation, helps mark damaged cells for the elimination by the immune system and facilitates antigen cross-presentation, dendritic cells (DC) matura­tion and natural killer (NK) cell activation. Calreticulin is a crucial determinant of whether dying tumor cells are phagocytosed by APCs. The nuclear nonhistone protein HMGB1 binds to toll-like receptor 4 (TLR4), thereby providing a signal to DCs to initiate TLR4-dependent antigen processing. Targeted Small Molecule Inhibitors (SMIs) can: increase the number and function of tumor antigen-specific T cells and decrease the number and function of myeloid-derived suppres­sor cells (MDSCs) and Tregs; block the tumor-cell cycle and induce apoptosis, and inhibit neoangiogenesis, modulate hypoxia, and normalize tumor vasculature. Conventional radiotherapy is characterized by:  well-established tumoricidal effects, can also activate the host immune system, modulates tumour phenotypes, enhances antigen presentation and tumour immunogenicity, increases production of cytokines and alters the tumour microenvironment, enabling destruction of the tumour by the immune system. Investigating the combination of radiotherapy with immunotherapeutic agents - which also promote the host antitumour immune response - is therefore a logical progression. The question arose as to whether the ablative radiation doses used can also stimulate immune responses and, if so, whether we can amplify these effects by combining immunotherapy and stereotactic ablative radiotherapy (SABR). Substantial preclinical evidence has revealed a synergistic relationship between radiothe­rapy and immunotherapy. Anecdotal evidence and prospective clinical data also support the efficacy of this treatment regimen. Learning how best to exploit radiation-induced immunogenic changes in cancer patients with the addition of active immunotherapy is an exciting frontier in cancer therapy research, and has the potential to greatly improve patient care in the future. Conclusions. Radiotherapy has been seen now as an immunomodulatory treatment. Radiotherapy may be an important adjunct to immunotherapies with the potential to enhance the antigenicity of tumors and promote as well as stromal targeting. Radiotherapy may activate effectors of innate immunity through TLR-dependent mechanisms.

Basic concepts of immunology and immunotherapy

Şerban Negru
Associate Professor for Medical Oncology, University of Timișoara 
Medicine faced a spectacular revolution during the last few years regardind the treatment of cancer. Immunotherapy represents a complete change in the philosophy of cancer approach. The immune system becomes the primary target of treatment, instead of the malignant cell. At the same time, new treatments are coming toghether with new mechanisms of action, new side effects and different patterns of response. Each oncologist is confronted with the dilemma of becoming more and more involved in a very complex field which requires a lot of new and different basic knowledges. Understanding fundamental immunology becomes essential. Basic concepts like antigens, antibodies, major histocompatibility complex molecules should be thoroughly reviewed, as well as the main cells involved in the immune mechanisms of action. T lymphocytes, primary effectors of anticancer immunity, are activated by various methods to eliminate the tolerance installed during disease progression. Efficient activation of the immune system is a formidable weapon capable of definitively eliminating the tumor and obtaining healing in a significant number of cases. Intravesical BCG therapy followed by systemic cytokine treatments with IL-2 or IFN-γ were the first promising results. In 2011, Sipuleucel-T, the first autologous immunotherapy for asymptomatic metastatic prostate cancer, was approved as a treatment standard in oncology. The procedure aims at ex vivo incubation of T lymphocytes obtained from patients by leukapheresis with a chimeric product. The use of anti-CTLA-4 or anti-PD-1 antibodies in metastatic malignant melanoma therapy has produced unprecedented results. Recent studies have achieved long-term survival in almost half of the cases, in a disease considered incurable and deadly. The encouraging results of melanoma were then reproduced in other locations such as lung or kidney cancer. Stimulating the immune system to get it to efficiently eliminate cancer cells is an adventure over a century that seduced, mumbled and then disappointed generations of researchers, clinicians and investors alike. In recent years, however, immunotherapy has produced so spectacular clinical results that it has become the main direction of research and the most important hope in the fight against cancer.

Lung cancer treatment in 2017: NCCN guidelines and clinical practice in USA

Doru Paul
MD, PhD Assistant, Professor of Medicine, Hofstra Northwell Health School of Medicine, Hematology-Oncology Attending, Monter Cancer Center, New York, USA

As estimated by the American Cancer Society (ACS) in 2017, 222,500 new cases of lung cancer will be diagnosed in the United States of America. With 155,080 deaths expected in 2017, lung cancer represents the deadliest form of cancer in US. Although the cure for this disease is still an unmet goal, in the last five years lung cancer field has seen impressing progress. Because of the rapidly evolving treatment and screening options, it is challenging for clinicians to remain up-to-date on new recommendations and guidelines. National Comprehensive Cancer Network (NCCN) was created in January 31, 1995, as a national alliance with the purpose of creating standards of care for the treatment of cancer and performing outcomes research. The role of NCCN is to develop and communicate scientific information related to cancer management in order to better inform the decision-making process between patients and physicians, ultimately improving patient outcomes and delivering high-quality, cost-effective services to people with cancer across the US. In November 1996, the first NCCN Practice Guidelines in Oncology were published for several disease types including lung cancer, and in March 1998, (the NCCN website for clinicians) was launched. In May 1998, the first NCCN guidelines for patients were published, and in April 2009 the first NCCN website for patients was launched. Currently, NCCN is an alliance of 27 of the US leading cancer centers. Recent Non-Small Cell Lung Cancer (NSCLC) and Small Cell Lung Cancer (SCLC) updates to the NCCN Clinical Practice Guidelines in Oncology and NCCN Guidelines for Lung Cancer Screening provide recommendations that can assist clinicians in managing their patients with lung cancer. It is important to understand that the guidelines provide recommendations that need to be individualized by the treating physicians for every individual patient. Also, the field of lung cancer is evolving very fast and the guidelines are continuously updated frequently, sometimes several times a year. Often, the information included in the NCCN Guidelines is lagging behind clinical practice. For example, although the 8th edition of TNM staging for lung cancer has been already published in 2016 and represents the new world standard since January 2017(1,2), the current August 2017 NCCN guidelines refer to the previous, 7th edition of TNM staging. Finally, it is important to distinguish the FDA approval of a drug that determines reimbursement of a drug by insurance companies and clinical guidelines. The emergence of new genetic biomarkers, advances in screening and the availability of new classes of systemic treatments have changed the landscape of lung cancer and we will highlight some of the key changes. Several classes of targeted agents (e.g., EGFR mutations inhibitors, ALK translocations inhibitors, ROS-1 translocations inhibitors, B-RAF mutations inhibitors etc.) are now standard of care in the treatment of advanced lung adenocarcinoma both in front line and after progression. In November 2015, necitumumab (a recombinant human IgG1 monoclonal antibody designed to block the ligand binding site of epidermal growth factor receptor - EGFR) in combination with gemcitabine and cisplatin has been approved in the frontline treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC). Arguably, the most important recent advance in the field of lung cancer is the FDA approval of immune checkpoint inhibitors both in front line and in second line. In comparison with chemotherapy, immunotherapy demonstrated better progression free survival (PFS), overall survival (OS) and toxicity profile. The role of immune checkpoint inhibitors is to restore and augment the antitumor immune action of cytotoxic T cells by blocking immune checkpoint molecules on T cells or their ligands on antigen presenting cells and tumor cells. The first in class approved im­mune checkpoint inhibitor has been ipilimumab, an anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) monoclonal antibody. The second class of immune check point inhibitors are the PD-1 and PD-L1 inhibitors. The most significant results in 2016 regarding the treatment of lung cancer have been the validation of the use of pembrolizumab, a PD-1 inhibitor, alone, as  first line treatment in both adenocarcinoma and squamous cell cancers of the lung with strong PD-L1 expres­sion (>50%). Also, in May 2017, pembrolizumab in combination with pemetrexed and carboplatin received FDA accelerated approval for use in treatment-naïve stage IV non-squamous lung cancer without EGFR mutations or ALK translocations. Since 2015, in USA, nivolumab and pembrolizumab have replaced docetaxel for the second-line treatment of advanced NSCLC and, in 2016, atezolizumab, a PD-L1 inhibitor, has been also FDA approved in the second-line treatment of advanced lung cancer regardless of the PD-L1 expression. In May 2017, durvalumab, another PD-L1 inhibitor, received FDA accelerated approval for use in patients with locally advanced lung cancer that had stable disease after platinum-based chemotherapy and radio­therapy. Unfortunately, overall, the response rate in NSCLC to check point inhibitors is only approximately 25%. The lack of response in the remaining 75% of the patients may be related, among other factors, to “immune ignorance” - i.e., a combination of absence of PD-L1 expression on the surface of tumor cells and absence of tumor infiltrating lymphocytes (TIL). Recently, the “cancer immunogram”(3) has been proposed by a group of researchers, as a seven-factor model for describing the different interactions between cancer and the immune system, with the aim of focusing biomarker research and to help guide treatment choice for each individual patient. Also, for the first time, immunotherapy has been shown promising efficacy in the treatment of small cell lung cancer. The combination of ipilimumab and nivolumab is currently endorsed by the NCCN Guidelines for use in second-line treatment of patients with advanced small cell lung cancer that failed front line platinum-based chemotherapy. It is worth mentioning that for lung cancer screening, in order to improve the accuracy of cancer detection, new recommendations have been recently added to the NCCN Clinical Practice Guidelines. Finally, plasma genotyping (also known as liquid biopsy) is a new tool that has expanded the options for assessing molecular markers for patients with NSCLC, and is recommended by NCCN for patients with cancers bearing mutations of the epidermal growth factor (EGFR) gene that progressed after responding to an EGFR directed tyrosine kinase inhibitor.

1. UICC. TNM Classification of Malignant Tumours. 8th ed., Hoboken, NJ: Wiley-Blackwell; 2016.
2. Frank C. Detterbeck, Daniel J. Boffa, Anthony W. Kim and Lynn T. Tanoue. The Eighth Edition Lung Cancer Stage Classification. Chest 2017; 151(1):193-203.
3. Christian U. Blank, John B. Haanen, Antoni Ribas, Ton N. Schumacher. The “cancer immunogram”. Science May 6, 2016. 658-60.

Circulating tumor cell and cell-free circulating tumor DNA in lung cancer – review of recent advances with focus on technical aspects and their potential in clinical management of lung cancer

Florinel Pop 
Associate Professor, “Carol Davila” University of Medicine București 
Circulating tumor cells (CTCs) are tumor cells that are separated from the primary site or metastatic lesion and disseminate in blood circulation. CTCs are considered to be part of a long process of cancer metastasis. Liquid biopsy is dependent on a series of methods of isolation and quantification of the number of CTC and tumoral cfDNA, with a direct impact on cell fenotyping and genomic profile. The current techniques enable genomics analysis of a single tumor cell or very small quantities of tumoral cfDNA. This review shows the technical aspects related to the identification and isolation of CTCs, the methods of molecular analysis including techniques of amplification of the entire whole genome from a single cell (WGA - whole genome amplification), and the main sequencing methods of isolated nucleic acids from CTCs or blood. The results acquired using these methods have an impact on the analysis of the neoplastic heterogeneity, on the evaluation of the processes of epithelial – stromal transition, early detection of circulant tumoral embolism, in the appreciation of prognostic biomarkers and the response to therapy, allowing thus personalized therapies.

Optimal therapy in breast cancer HR-positive and Her-2 negative

Dana Grecea
“Prof. Dr. I. Chiricuţă” Institute of Oncology, Cluj-Napoca
Molecular studies have shown that breast cancer includes a large number of subgroups defined by the presence of a specific genomic or protein alteration. Estrogen receptor (ER) expression was the first validated target in breast cancer, leading to the optimal development of endocrine therapy. Estrogen receptor-positive (ER+)/ human epidermal growth factor receptor 2 (HER-2)-negative breast cancer accounts for 60-70% of all breast cancers. The standard of care treatment for patients with ER+ breast cancer takes several factors into consideration, including the stage of disease and recurrence score. Not all ER+ breast cancers respond optimally to endocrine therapy. The mechanisms that can lead to primary and/or secondary hormonal resistance in ER+ breast cancer include a decrease or loss of ER expression or an up-regulation of growth factor signaling pathways, such as the epidermal  growth factor receptor (EGFR) or HER2, the mitogen-activated protein kinase (MAPK) or the PI3K/AKT/mTOR pathways. Up to 70% of breast cancers can have some form of PI3K/AKT/mTOR pathway. Hyperactivation of the PI3K/AKT/mTOR signaling pathway was proven to promote both de novo and acquired resistance to hormone therapy. Increased understanding of endocrine resistance mechanisms has led to the development of targeted agents. Three CDK4/6 inhibitors (palbociclib, ribociclib and abemaciclib) are in advanced clinical testing. In PALOMA-1, progression-free survival (PFS) with combination therapy (letrozole with palbociclib) was 20.2 months vs. 10.2 months in the control arm (HR 0.49; 95% CI: 0.319-0.748; p=0.0004). Ribociclib is being studied in the metastatic and neoadjuvant settings in the ongoing MONALEESA trials. In MONALEESA-2 the PFS was significantly longer in the ribociclib group than in the placebo group. After 18 months, the PFS rate was 63% versus 42.2% in the placebo group. MONARCH trials are evaluating abemaciclib in the neoadjuvant setting, in metastatic disease, in combination with fulvestrant or nonsteroidal Als. In PALOMA-2, first-line palbociclib with letrozole significantly improved median PFS versus letrozole (24.8 months vs. 4.5 months; HR: 0.58, 95% CI: 0.46-0.72; p<.0001). Neutropenia and leukopenia were the most frequently reported adverse reactions. Toxicities of targeted therapies and impact on quality of life must be taken into account when treating patients. Ongoing trials are evaluating inhibitors of the PI3K pathway, CDK4/6 and HDAC in combination with hormone therapy in the metastatic, adjuvant and neoadjuvant settings.

Treatment of psychiatric comorbidities in patients with cancer

Robert G. Bota
MD, MSG, DFAPA, Department of Psychiatry and Human Behavior, University of California, Irvine

Fast Facts. The most common psychiatric disorders observed in cancer patients are adjustment disorders with depression, anxiety or both. Patients with cancer have a high rate of psychiatric comorbidity; approximately one-half exhibit emotional difficulties. Cancer and cancer treatment might impede brain,s cognitive abilities as blood brain barrier is breached. Some of the most significative biologic mechanisms include cytokine suppressions and decreased BDNF levels in the hippocampal structures. Overview. Psycho-oncology is a complex discipline that addresses the psychological, behavioral and ethical aspects of cancer. In major cancer programs, the psychiatrists involved in the psycho-oncology practice address two major dimensions of cancer: (1) the psychological responses of patients to cancer at all stages of the disease, including the treatment of psychiatric morbidities such as depression and anxiety, and (2) the psychological and behavioral factors that may influence patient adherence to treatment, as well as the patient’s response to treatment. The practice of psycho-oncology has changed greatly in the last twenty years, as more children and adults have earned the title of cancer survivor. However, the quality of their survival is greatly affected by a myriad of neurological and cognitive impairments. Many cancer patients remain out of sight of the health services due to societal stigma and a lack of resources to diagnose, treat and support these cases. Regardless of the prognosis, cancer is associated with anxiety and depression in more than one-third of cancer patients. Furthermore, depression causes reduced immune responses, and the presence of untreated depression directly correlates with poor prognosis. Treatment of depression in cancer patients is very intricate, as many antidepressants can lower the efficacy of cancer drugs by interfering with their metabolism. Psycho-oncology is a highly multidisciplinary effort, and as such it requires a multidisciplinary team approach and the ability to speak a common language with the major oncological specialties (such as hematology-oncology, neurological oncology, oncological surgery and radiation oncology). Psycho-oncology research interacts with cancer epidemiology, immunology, endocrinology, cancer biology, pathology, bioethics, palliative care, rehabilitation medicine, clinical trials research, experimental design, clinical decision making, and, of course, psychiatry and psychology. Cancer is, after all, a disease of both the body and the mind - a concept which will be extensively explored in this presentation. Challenge. Physicians need to be aware of how to diagnose and treat psychiatric conditions in patients with cancer, as the risk of having a psychiatric diagnosis is 30 to 40 percent and untreated, those conditions will both decrease the quality of life and reduce the survival rate from the cancer. Learning objectives. Evaluate psychiatric diagnosis in patients with cancer. 
Recognize how psychiatric manifestations are different in patients with cancer. Discuss treatment algorithms for common psychiatric conditions in patients with cancer.


Updates in neurological oncology: ASCO 2017 and beyond

Daniela A. Bota
Associate Professor and Vice Chair for Academic Affairs, Neurology; Clinical Director, Sue and Bill Gross Stem Cell Research Center; Medical Director, Neuro-oncology Program; 
Fellowship Director, Neuro-oncology Program, UC Irvine Medical Center Manchester

New discoveries in the field of cancer genetics have greatly expanded the therapeutic options available to patients with primary and metastatic brain tumors. Even the diagnosis of a brain tumor is no longer based on simple microscopic features, but on the complicated classification of an ever expanding number of mutations. Oncologists no longer recommend the same regimen for all patients, but instead can design personalized therapies based on molecular pro­file and imaging features. Moreover, the roles of each modality such as radiation, classical chemotherapy, targeted agents and immunotherapy in treatment plans must be reviewed in light of current evidence. This year, the ASCO presentations focused extensively not only on the treatment of glioblastoma (the most common primary brain cancer), but also on the treatment of other neurologic malignancies. Noticeable advances were reported in the treatment of refractory and progressive meningioma (the CEVOREM study). Final results of the TAVAREC trial of temozolomide with or without bevacizumab in 1st recurrence grade II/III glioma without 1p/19q co-dele­tion further confirm the lack of activity of bevacizumab in this patient popula­tion. New concepts for the treatment of brain metastasis are advancing patient’s survival, while maintaining their quality of life and avoiding/delaying whole brain radiation. The AURA 3 study confirmed the high rate of CNS response in patients with T790M-positive advanced NSCLC. For melanoma brain metastasis, early treatment with novel combinations (nivolumab combined with ipilimumab) is superior to late treatment, even in patients with BRAFv600 muta­tions. Finally, the combination of neratinib+capecitabine brings new hope for patients with human epidermal growth factor receptor 2 (HER2+) breast cancer brain metastases. New research from different laboratories - including my personal research groups - is making strides in bringing new molecules and immunotherapy approaches into the clinical arena. This presentation will therefore allow for both a review of the relevant information in our field and for an introduction to what the future might bring to our reality in the challenging yet very promising field of neurological oncology.

New drugs in sarcoma

Lucian Miron
“Grigore T. Popa” University of Medicine and Pharmacy, Discipline of Oncology and Radiotherapy, Iaşi, Regional Institute of Oncology, Iaşi
Sarcoma is the term used for cancers of connective tissue. Soft tissue sarcomas (STS) in adult  are a complex group of neoplasms. The STS biology has made major advancements in understanding of the biology and drivers of several sarcomas. Doxorubicin and ifosfamide are the most effective single drugs for metastatic non-GIST adult soft tissue sarcomas. As single drugs or in combination, anthracyclines yeld the best response rates for metastatic sarcomas (rates of 10% to 25% for each drug in various studies). Ifosfamide is particularly active in synovial sarcoma, and myxoid liposarcoma appears to be less active in leiomyosarcomas. Dacarbazine has modest activity against leiomyosarcoma, paclitaxel is active against angiosarcomas and desmoid tumors, and sunitinib and cediranib against alveolar soft part sarcoma. The combination of temozololamid and bevacizumab has activity in solitary fibrous tumors. The recently impoved understanding of biology of certain connective tissue tumors has led to clinical introduction of new molecules in the management of disease. Pazopanib is an oral multikinase inhibitor that was approved for the treatment of patients with locally advanced or metastatic STS after treatment with standard chemotherapy. Pazopanib is approved for the treatment of advanced or metastatic non-GIST soft tissue sarcoma (excluding liposarcoma) after the treatment with chemotherapy. Trabectidin is a citotoxic agent that binds to the minor grove in DNA and affects DNA, RNA and pro­tein synthesis. Trabectedin was approved for the use in patients with unresectable or metastatic leiomyosarcoma or liposarcoma after prior treatment with anthracycline-containing regimens. Eribulin is an antimitotic agent that inhibits microtubule function and demonstrated improvement in overall survival compared to dacarbazine in patients pretreated, with locally advanced or metastaic leiomyosarcoma or liposarcoma. Olaratumab (Lartruvo) is a monoclonal antibody developed for the treatment of solid tumors. It is directed against the platelet-derived growth factor receptor alpha (PDGF). Olaratumab is used in combination with doxorubicin for the treatment of adults with advanced soft-tissue sarcoma (STS) who cannot be cured by cancer surgery or radiation therapy, and who have not been previously treated with doxorubicin. In a randomised controlled trial with 133 STS patients, olaratumab plus doxorubicin improved the median of progression-free survival from 4.1 to 6.6 months as compared to doxorubicin alone (p=0.0615, narrowly missing statistical significance), and overall survival from 14.7 to 26.5 months (p=0.0003, highly significant). On October 19, 2016, the U.S. Food and Drug Administration granted accelerated approval to olaratumab for the treatment of patients with STS not amenable to curative treatment with radio­therapy or surgery, and with a histologic subtype for which an anthracycline-containing regimen is appropriate. The mTOR inhibitors have been studied in several sarcoma studies, with relatively limited success, with the exception of perivascular epitheloid cell tumors, wich are rare malignancies characterized by the activation of the mTOR pathway. Everolimus is an inhibitor of mTOR with indication in the treatment of patients with angiomyolipomas, resulted in an objective tumor response rate of 42% using 10 mg everolimus daily, compared to 0% using placebo. There are a number of ongoing trials in sarcomas investigating immunoterapy, including checkpoint inhibitors, as well as T-cell therapy. Tyrosine kinase inhibitors, including imatinib, pexidarartinib, pazopanib and axitinib, have been shown to impact the immune microenvironment within tumors. Subsets of sarcomas overexpress Her2, which has been targeted using chimeric antigen receptor (CAR) T cell. In the last years, there have been seen remarcable growth in the novel treatment strategies for sarcomas, with an increased emphasis on understanding genetic and molcular biology of various sarcoma subtypes to guide the design of clinical trials for new targeted therapies. Histologic-specific treatment of soft tissue sarcomas based on defined molecular changes continues to evolve.