To evaluate and confirm efficacy and safety of electrochemotherapy with bleomycin or cisplatin on cutaneous and subcutaneous tumour nodules of patients with malignant melanoma and other malignancies in a multicenter study. This was a two year long prospective non-randomised study on 41 patients evaluable for response to treatment and 61 evaluable for toxicity. Four cancer centers enrolled patients with progressive cutaneous and subcutaneous metastases of any histologically proven cancer. The skin lesions were treated by electrochemotherapy, using application of electric pulses to the tumours for increased bleomycin or cisplatin delivery into tumour cells. The treatment was performed using intravenous or intratumoural drug injection, followed by application of electric pulses generated by a Cliniporator™ using plate or needle electrodes. Tumour response to electrochemotherapy as well as possible side-effects with respect to the treatment approach, tumour histology and location of the tumour nodules and electrode type were evaluated. An objective response rate of 85% (73.7% complete response rate) was achieved on the electrochemotherapy treated tumour nodules, regardless of tumour histology, and drug used or route of its administration. At 150 days after the treatment (median follow up was 133 days and range 60–380 days) local tumour control rate for electrochemotherapy was 88% with bleomycin given intravenously, 73% with bleomycin given intratumourally and 75% with cisplatin given intratumourally, demonstrating that all three approaches were similarly effective in local tumour treatment. Furthermore, electrochemotherapy was equally effective regardless of the tumour type and size of the nodules treated. Side-effects of electrochemotherapy were minor and acceptable, as reported by the patients. We demonstrated that electrochemotherapy is an easy, highly effective, safe and cost-effective approach for the treatment of cutaneous and subcutaneous tumour nodules of different malignancies. Electrochemotherapy can provide immediate clinical benefit in patients with advanced cutaneous and subcutaneous metastases.
Abstract The population of cancer survivors has grown steadily over the past several decades. Surviving cancer, however, is not synonymous with a life free of problems related to the disease and its treatment. In this paper we provide a brief overview of selected physical and psychosocial health problems prevalent among cancer survivors, namely pain, fatigue, psychological distress and work participation. We also address issues surrounding self-management and e-Health interventions for cancer survivors, and programmes to encourage survivors to adopt healthier lifestyles. Finally, we discuss approaches to assessing health-related quality of life in cancer survivors, and the use of cancer registries in conducting psychosocial survivorship research. We highlight research and practice priorities in each of these areas. While the priorities vary per topic, common themes that emerged included: (1) Symptoms should not be viewed in isolation, but rather as part of a cluster of interrelated symptoms. This has implications for both understanding the aetiology of symptoms and for their treatment; (2) Psychosocial interventions need to be evidence-based, and where possible should be tailored to the needs of the individual cancer survivor. Relatively low cost interventions with self-management and e-Health elements may be appropriate for the majority of survivors, with resource intensive interventions being reserved for those most in need; (3) More effort should be devoted to disseminating and implementing interventions in practice, and to evaluating their cost-effectiveness; and (4) Greater attention should be paid to the needs of vulnerable and high-risk populations of survivors, including the socioeconomically disadvantaged and the elderly.
Abstract Improvements in treatment and earlier diagnosis have both contributed to increased survival for many cancer patients. Unfortunately, many treatments carry a risk of late effects including cardiovascular diseases (CVDs), possibly leading to significant morbidity and mortality. In this paper we describe current knowledge of the cardiotoxicity arising from cancer treatments, outline gaps in knowledge, and indicate directions for future research and guideline development, as discussed during the 2014 Cancer Survivorship Summit organised by the European Organisation for Research and Treatment of Cancer (EORTC). Better knowledge is needed of the late effects of modern systemic treatments and of radiotherapy to critical structures of the heart, including the effect of both radiation dose and volume of the heart exposed. Research elucidating the extent to which treatments interact in causing CVD, and the mechanisms involved, as well as the extent to which treatments may increase CVD indirectly by increasing cardiovascular risk factors is also important. Systematic collection of data relating treatment details to late effects is needed, and great care is needed to obtain valid and generalisable results. Better knowledge of these cardiac effects will contribute to both primary and secondary prevention of late complications where exposure to cardiotoxic treatment is unavoidable. Also surrogate markers would help to identify patients at increased risk of cardiotoxicity. Evidence-based screening guidelines for CVD following cancer are also needed. Finally, risk prediction models should be developed to guide primary treatment choice and appropriate follow up after cancer treatment.
Abstract Breast cancer deaths in western countries are falling due to screening and adjuvant therapy, but the treatment of metastatic breast cancer (MBC) has not shown comparable advances. The most active single agents are taxanes, which extend both disease-free and overall survival. However, opportunities remain for improving outcome. Nanoparticle technology is proving a valuable addition to the pharmaceutical armamentarium, particularly in oncology. Its use to bind paclitaxel to human albumin (nanoparticle albumin-bound paclitaxel; nab -paclitaxel; Abraxane®) ensures solubility of the taxane without the use of solvents and minimizes the risk of hypersensitivity reactions without premedication. The homogeneous colloidal suspension created allows rapid dispersal of unbound drug and linear pharmacokinetics. Albumin-mediated transport of paclitaxel across the endothelium facilitates uptake of drug, and a degree of tumour selectivity is achieved by the albumin-binding propensity of SPARC (Secreted Protein Acidic Rich in Cysteine), a substance expressed on and around many breast tumours. Clinical trials in first- and second-line MBC show that nab -paclitaxel is both more effective than solvent-based taxanes and associated with less severe neutropenia. Sensory neuropathy occurs but improves rapidly when compared with that caused by conventional taxanes. A clinical development programme is investigating nab -paclitaxel in the adjuvant and neoadjuvant settings. The low incidence of neutropenia makes nab -paclitaxel a good candidate for combination with other cytotoxics. It is also being assessed when given with biologic agents such as trastuzumab and bevacizumab.
Abstract Sexual dysfunction is a common consequence of cancer treatment, affecting at least half of men and women treated for pelvic malignancies and over a quarter of people with other types of cancer. Problems are usually linked to damage to nerves, blood vessels, and hormones that underlie normal sexual function. Sexual dysfunction also may be associated with depression, anxiety, relationship conflict, and loss of self-esteem. Innovations in cancer treatment such as robotic surgery or more targeted radiation therapy have not had the anticipated result of reducing sexual dysfunction. Some new and effective cancer treatments, including aromatase inhibitors for breast cancer or chemoradiation for anal cancer also have very severe sexual morbidity. Cancer-related infertility is an issue for younger patients, who comprise a much smaller percentage of total cancer survivors. However, the long-term emotional impact of being unable to have a child after cancer can be extremely distressing. Advances in knowledge about how cancer treatments may damage fertility, as well as newer techniques to preserve fertility, offer hope to patients who have not completed their childbearing at cancer diagnosis. Unfortunately, surveys in industrialised nations confirm that many cancer patients are still not informed about potential changes to their sexual function or fertility, and all modalities of fertility preservation remain underutilised. After cancer treatment, many patients continue to have unmet needs for information about restoring sexual function or becoming a parent. Although more research is needed on optimal clinical practice, current studies suggest a multidisciplinary approach, including both medical and psychosocial treatment options.
Abstract The potentially detrimental effects of cancer and related treatments on cognitive functioning are emerging as a key focus of cancer survivorship research. Many patients with central nervous system (CNS) or non-CNS tumours develop cognitive problems during the course of their disease that can result in diminished functional independence. We review the state of knowledge on the cognitive functioning of patients with primary and secondary brain tumours at diagnosis, during and after therapy, and discuss current initiatives to diminish cognitive decline in these patients. Similarly, attention is paid to the cognitive sequelae of cancer and cancer therapies in patients without CNS disease. Disease and treatment effects on cognition are discussed, as well as current insights into the neural substrates and the mechanisms underlying cognitive dysfunction in these patients. In addition, rehabilitation strategies for patients with non-CNS disease confronted with cognitive dysfunction are described. Special attention is given to knowledge gaps in the area of cancer and cognition, in CNS and non-CNS diseases. Finally, we point to the important role for cooperative groups to include cognitive endpoints in clinical trials in order to accelerate our understanding and treatment of cognitive dysfunction related to cancer and cancer therapies.
Biosimilar agents are approximate copies of branded biologic therapies. Since the first biosimilar was authorized in the European Union in 2006, fifteen additional agents have been approved by the European Medicines Agency, including two biosimilar monoclonal antibodies (mAbs). Biosimilar mAbs represent a distinct class given their large molecular size, complex protein structure, and post-translational modifications. While guidelines have been established for the development, approval, and use of biosimilars, further scrutiny and discussion is necessary to fully understand their potential impact on clinical outcomes. This review takes a critical look at the structural complexity of biosimilar mABs, the feasibility of indication extrapolation, the impact of product variability on immunogenicity, the importance of comprehensive pharmacovigilance, and the potential for ongoing pharmacoeconomic impact.
Abstract The impact of cancer on patients' lives can be measured using self-reported questionnaires, known as Health-Related Quality of Life (HRQOL) measures. HRQOL is defined as a multi-dimensional construct covering disease and treatment-related symptoms, physical, psychological, and social functioning. The EORTC Quality of Life Group (QLG) was created in 1984 with the mission to develop measures of HRQOL and to promote and coordinate clinical studies concerning the quality of life of cancer patients. The EORTC Quality of Life Department (QL Department) was founded in 1993 with the support of an EU grant to provide administrative, practical and scientific support to co-operative groups conducting clinical trials with HRQOL outcomes. We are proud to report significant scientific achievements that have made us international leaders in HRQOL research and have led to real changes to cancer patient treatments. We developed a modular system for HRQOL measurement consisting of the EORTC QLQ-C30, a core cancer quality of life questionnaire and supplementary questionnaire modules. The EORTC-QLQ-C30 has been one of the most widely used cancer questionnaires in randomized trials in oncology as demonstrated by systematic reviews. To date, the EORTC QLQ-C30 has been translated and linguistically validated into more than 60 languages. HRQOL outcome measures have been an integral part of EORTC clinical trials for the last 30 years. We present examples of significant, practice-changing clinical trials evaluating HRQOL in several cancer sites, such as brain tumors, breast and ovarian cancers, and malignant melanoma. In a series of systematic reviews, we examined the quality of reporting HRQOL in international cancer clinical trials, and the impact of the results on oncology practice that led to a recommendation to improve CONSORT (Consolidated Standards of Reporting Trials) with regard to reporting of HRQOL. The QLG is an international leader in methodological research in the measurement of HRQOL in oncology and pursues research in several key areas, such as cross-cultural differences between populations in HRQOL assessment, Computer-Adaptive Testing, electronic administration of EORTC QLQ-C30, and summary scores for EORTC QLQ-C30. In summary, the QLG and QL Department have been international leaders in the field. Our questionnaires have brought HRQOL assessment to the fore in many international trials that have changed oncology practice and brought the patient's perspective into cancer research.
Melanoma is considered one of the immunogenic – if not the most immunogenic – malignancies. This is based on several observations. 1. Spontaneous remissions occur occasionally. 2. In about 5% of melanomas no primary tumour is found. The genetic aberrations of these tumours closely resemble those of cutaneous melanomas, and therefore are suggestive of spontaneous regressions of the primary tumours. 3. Both primary tumours and metastases often have brisk lymphocytic infiltrates, a phenomenon that is correlated with better outcome. 4. Studies of isolates of these tumour-infiltrating T lymphocytes have revealed that a proportion of these cells recognise melanoma antigens. 5. Melanomas respond to immunotherapy. These observations have led to over 30 years of research on immunotherapy for melanoma; many of these efforts have failed, with only a few exceptions: interleukin-2 (IL-2) and to a lesser degree interferon-a (IFN-〈). Recently, new developments in immunotherapy have revolutionised this treatment modality. Anti-CTLA4 has received approval from the Food and Drugs Administration (FDA) and the European Medicines Agency (EMA) for the treatment of stage IV melanomas based on the improvement in overall survival in phase III trials, and more recently blockade of PD1/PDL1 interactions has shown objective clinical responses in a stage IV melanoma in early-phase clinical trials. In addition, several independent single-institution phase I/II trials using adoptive cell therapy have shown a consistently high response rate, including durable complete remissions in a substantial percentage of treated patients. Now, for the first time, immunotherapy has moved beyond the treatment of melanoma as both CTLA4 and PD1 blockade have been shown to induce objective responses in other tumour types as well. This chapter will discuss the mechanism of action, clinical efficacy and side effects of IL-2, the novel treatments consisting of the immune checkpoint blockade drugs anti-CTLA4 and anti-PD1 and adoptive cell therapy.
Electrochemotherapy (ECT) is a non-thermal tumour ablation modality, safe and effective on any type of solid tumour. Its use is presently standardized to skin and subcutaneous localisations. ECT is based on the use of non-permeant drugs possessing high intrinsic cytotoxicity (such as bleomycin), or low-permeant drugs with known efficacy (such as cisplatin), which act directly on the cellular DNA. ECT is also based on the achievement of in vivo tumor cell electropermeabilization by means of electric pulses locally delivered to the tumors after bleomycin or cisplatin injection. Cell electropermeabilisation, a physical procedure that affects all tumor cell types, allows these anticancer drugs to enter the cells, thus magnifying their cytotoxicity by orders of magnitude. Efficacy is also sustained by a response of the host immune system, probably due to the type of cell death caused by the ECT. At least for the bleomycin injected intravenously, treatment causes a mitotic cell death that rapidly kills the dividing tumor cells and spares the neighboring non-dividing normal cells, explaining selectivity towards the dividing tumour cells and safety of the procedure. Safety is also due to the vascular effects of the electric pulses: ECT provokes a transient vascular lock which prevents further bleeding, and even stops previous bleeding in the case of hemorrhagic nodules. These bases explain why ECT is safe and very well tolerated by the patients, and why its efficacy is very high on the treated nodules, whatever the tumour histological origin.
Abstract Currently, 17–19% of all new primary malignancies occur in survivors of cancer, causing substantial morbidity and mortality. Research has shown that cancer treatments are important contributors to second malignant neoplasm (SMN) risk. In this paper we summarise current knowledge with regard to treatment-related SMNs and provide recommendations for future research. We address the risks associated with radiotherapy and systemic treatments, modifying factors of treatment-related risks (genetic susceptibility, lifestyle) and the potential benefits of screening and interventions. Research priorities were identified during a workshop at the 2014 Cancer Survivorship Summit organised by the European Organisation for Research and Treatment of Cancer. Recently, both systemic cancer treatments and radiotherapy approaches have evolved rapidly, with the carcinogenic potential of new treatments being unknown. Also, little knowledge is available about modifying factors of treatment-associated risk, such as genetic variants and lifestyle. Therefore, large prospective studies with biobanking, high quality treatment data (radiation dose–volume, cumulative drug doses), and data on other cancer risk factors are needed. International collaboration will be essential to have adequate statistical power for such investigations. While screening for SMNs is included in several follow-up guidelines for cancer survivors, its effectiveness in this special population has not been demonstrated. Research into the pathogenesis, tumour characteristics and survival of SMNs is essential, as well as the development of interventions to reduce SMN-related morbidity and mortality. Prediction models for SMN risk are needed to inform initial treatment decisions, balancing chances of cure and SMNs and to identify high-risk subgroups of survivors eligible for screening.
Melanoma today is considered as a spectrum of melanocytic malignancies characterised by clinical and molecular features, including targetable mutations in several kinases such as BRAF or c-KIT. The successful development of therapies targeting these mutations has resulted in new specific treatment options. These include vemurafenib, dabrafenib, trametinib, imatinib and other kinase inhibitors that are selected when the respective mutation is present. The BRAF inhibitor vemurafenib has resulted in improved survival in patients with BRAF-mutated advanced melanoma. Dabrafenib has shown similar efficacy. The MEK inhibitor trametinib also improved overall survival. In addition, the MEK inhibitor MEK 162 was investigated in a phase II clinical trial and showed promising efficacy in terms of response rate and progression-free survival (PFS) in NRAS-mutated melanomas. After this first success in the treatment of advanced melanoma, there is expectation that combinations of kinase inhibitors will additionally improve overall survival rates and PFS in advanced melanoma.
Electrochemotherapy provides effective local control of cutaneous and subcutaneous tumour nodules of different malignancies. High objective response rate of ∼80% treated nodules was reported in the majority of clinical studies, with 30–100% long lasting complete responses. This high level of local tumour control was obtained with either systemic drug injection (bleomycin) or local drug injection (cisplatin or bleomycin) with subsequent application of electric pulses to the tumour nodules. The treatment is mostly used for palliation and has in case of in transit metastases of melanoma significant clinical benefit and impact on the quality of life. Furthermore, other clinical uses of electrochemotherapy are: neoadjuvant treatment in form of cytoreductive treatment before conventional treatments, organ and function sparing treatment and treatment of choice of painful and haemorrhagic nodules. Intraoperative treatment of tumours and development of endoluminal electrodes will bring new indications for electrochemotherapy.
Electrochemotherapy is an effective local treatment of solid tumours which combines delivery of chemotherapeutic drug and electric pulses. Electric pulses increase permeability of plasma membrane transiently and reversibly, leading to increased transport of the drug into the cell. As all clonogenic cells in the tumour need to be eradicated for effective treatment, all cells have to be permeabilised, i.e. all cells in the tumour have to be exposed to appropriate electric pulses. Electric pulses are delivered to tissue by electric pulses generator via electrodes. In general there are two types of electrodes, plate electrodes and needle electrodes. The target tissue, i.e. tumour, is to be positioned well in-between the electrodes. The electrodes should thus fit the size of the tumour for good electric field distribution. Plate electrodes which are noninvasive are better suited for tumours on the surface on the skin, whereas needle electrodes which are used invasively with appropriate and sufficient depth of their insertion are more appropriate for treating tumours seeded deeper in the skin.
Abstract Ovarian cancer is the 5th most common cancer found in women in the UK. It is the leading cause of death from gynaecological cancer, and is the 4th most common cause of cancer death among UK women. Similar to the majority of other cancers, relative survival rates for ovarian cancer are improving, although 5-year mortality rates remain stubbornly low. The stage of the disease at diagnosis is the single most important determinant of ovarian cancer survival, as many patients first present with advanced disease. Treatment of ovarian cancer involves a combination of ‘upfront’ primary surgery followed by chemotherapy. Platinum/taxane-based chemotherapy is the recommended standard-of-care first-line chemotherapy, but the majority of patients will relapse with drug-resistant disease within 3-5 years. However, not all patients can continue with platinum combination therapies due to loss of activity or toxicity-related issues, including hypersensitivity, neurotoxicity, alopecia and ototoxicity. Therefore the choice of second-line chemotherapy must take into account factors such as platinum-free treatment interval (PFI); patient's performance status; current symptoms; history of and likely future toxicities while on chemotherapy; dosing schedule requirement; and cost of treatment. A consensus in 2010 established 4 distinct subgroups within the ROC patient population based on the PFI: (platinum sensitive <12 months, partially platinum sensitive 6-12 months, platinum resistant <6 months, and refractory disease ≤4 weeks). Within patients with platinum sensitive disease, those with partially platinum sensitive disease remain the most clinically challenging to manage effectively. Non-platinum based combination therapies, in particular trabectedin with pegylated liposomal doxorubicin (PLD), offers new options together with a significant survival advantage relative to PLD alone for these patients.