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Abstract:
Background: From the moment of diagnosis, malignant mesothelioma (MM), decreases health-related quality-of-life (QOL) in patients and their caregivers. In addition to the symptoms of the disease itself, aggressive treatments options such as surgery, radiation, and chemotherapy can cause side effects which border on the intolerable. Specifically, chemotherapy is associated with side effects such as fatigue, nausea, vomiting, and systemic pain which has been described as unpleasant and stressful. The side effects of treatments can be burdensome enough to lead to noncompliance or outright refusal of continuation of care. Data from 13 frequently cited QOL studies conducted in the United States and Europe between 1990 and 2009 focus on chest pain and shortness of breath as the two chief symptoms of pleural mesothelioma. The largest QOL study to date, conducted across five continents, enrolled 495 patients in a multicenter study evaluating MM using the LCSS (lung cancer symptom scale). Investigators reported the most common symptoms as: fatigue (94%), dyspnea (89%), loss of appetite (86%), Chest pain (85%), cough (75%), and hemoptysis (24%). Ninety-two percent of patients experienced three or more above symptoms. Research on the psychological aspects of patients living with mesothelioma has shown their disregard for their exposure to asbestos in respect to their diagnosis. One such study investigated the reactions of 38 patients upon diagnoses with mesothelioma. Interestingly, although most patients had exposure to asbestos, only 17% of patients reported being concerned about their health prior to diagnosis, and, perhaps most interestingly, 65% of those with asbestos exposure denied anger towards the asbestos industry. Such studies’ preliminary findings suggest the need for better information about asbestos and mesothelioma, especially for high-risk individuals. Mesothelioma has a number of emotional consequences as well. A study conducted by the British Lung Foundation (BLF) reported significant impairment of emotional function and/or emotional state in patients with mesothelioma and their family members. The BLF’s study further reported a more positive response amongst patients versus caregivers in regards to supportive treatment to their emotional functioning. However, the authors did not provide a definition for significantly impaired emotional functioning, opacifying the results of such support. Recent psychological studies have demonstrated health benefits in cancer patients when sharing their illness experiences through online blogs. It has been suggested that blogging creates a survivor identity and facilitates a social support network for patients. Further, studies suggest that expressive writing increases self-management of chronic pain and lowers depressive symptoms. Methods: The platform for the support group was remote, consisting of both online and telephone domains. Each participant received an email a week prior to support sessions with an access code to the online and phone conference systems. Participants would utilize both online and phone systems during sessions, which were held once a week during evenings for a total of 6 weeks. Sessions were guided (by a team of healthcare professionals consisting of: a social worker, nurse, and community group leader) and kept closed, available only to those affected by mesothelioma – confidentiality was kept strong to encourage dialogue. The only non-patient participants were the group’s facilitators. The platform facilitated anonymity, should a patient have wished to remain so. Session summaries and follow-up information were provided online after support meetings. Conclusions: Active participation in a guided support group allowed participants to share their feelings and concerns about their diagnosis without feeling judged by their peers or healthcare providers while getting the emotional, mental, and post-active treatment support they needed facilitating the transition to follow-p care. The online portion of the platform was particularly helpful in assuaging common negative concerns like: fear of healthcare provider judgment, confidentiality, self-editing, emotional backlash from loved ones, and disapproval of lifestyle post-active treatment. Analysis of support session dialogue allowed facilitators to gauge information available to patients as well as to provide information about life after active treatment. Online space (on our blogs) gave participants a place to provide more communicative responses outside the main dialogue of support sessions.

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Abstract:
Multi-disciplinary care has become an essential part of medicine, especially in oncology. This care is not limited to the disciplines of medical, surgical and radiation oncology. We as providers must start, if we haven't already, expanding our thinking to involving other disciplines such as nutrition, social work, respiratory therapy, palliative care, physical therapy, psychiatry etc. Even though medicine is becoming more personalized with targeted therapies, we cannot allow this to narrow our focus of treating the patient as a whole. Our panel of experts from different disciplines will review and discuss lung cancer and mesothelioma cases highlighting the importance of a multi-disciplinary approach to patient care.

Abstract:
Background: The model of clinical trials in lung cancer has evolved quite dramatically over the past years. Expanded phase I trials in biomarker-driven populations are a new paradigm of accelerated drug approval. Enrolling patients in these clinical trials creates several new challenges. Clinical Research Nurses (CRNs) play an important role in recruitment, actual drug delivery, and monitoring of this whole process. Methods: Identify the different barriers to recruitment that CRNs face with these clinical trials. Barriers to participation can be patient-related, physician-related or tissue-related. Review of literature was the basis for the patient- and physician-related barriers. To identify the tissue barriers, we studied our own database. We also present practical tips to overcome these barriers out of own expertise in the field. Results: Patients’ barriers to participate in clinical trials include individual characteristics, practical issues, and attitudes. The most common barriers are the individual characteristics: cultural background, health literacy, ethnicity, and age. Lack of knowledge, insurance coverage, extra appointments, reimbursement, and patient ineligibility are typical practical barriers. Attitudinal barriers are reluctance to randomisation, fear for side effects, and efficacy concerns (e.g. allocation to placebo) (1-3). To overcome these barriers the trial should be explained clearly. Patient should be supported in what may be a difficult decision and should not be pressured to do so. Dedicated CRNs may help with monitoring the recruitment process, providing additional information, and obtaining informed consent (1). The process of informed consent is the optimal time to define clearly the terms of the clinical trial, and to explain the sometimes difficult to understand medical and legal terms in the informed consent document. Optimally, this should lead to good understanding by the patient of the potential benefits and risks (4). Main physicians’ barriers are lack of time due to competing priorities, insufficient staff and training to meet the ever increasing procedures from competent authorities or institutional review boards and finance departments, worry about the impact on the doctor-patient relation, concern for patients, and lack of reward and recognition. Lack of time is considered a major barrier. Doctors experience time pressure from their usual clinical practice and management duties. Recruitment, the consent process, and the follow up of clinical trials on top of that demand a large piece of extra time (1;4;5). Lack of support staff, for example CRNs, can also account for poor recruitment. A stable clinical research team is likely to be advantageous. CRNs should not only have expert clinical and well developed critical thinking skills, but be well acquainted with the complex scientific, regulatory, and ethical aspects of clinical research (6). Well trained and experienced CRNs truly are “PI-extensions”. By monitoring the clinical activity to find possible candidates for trials, they support the physician with recruitment, and later on with the follow-up of included patients. Over the last years, we saw a major progress in the treatment of advanced non-small cell lung cancer, largely due to new targeted agents, monoclonal antibodies, and immunomodulatory agents. Both in clinical practice, as well as in clinical trials, the availability of tissue for biomarker analysis – in order to make the best choice for the patient – is crucial. Tissue availability is a new important barrier to clinical trials, as we noted from our own experience (7). Moreover, central lab confirmation of an already known biomarker, is often requested before the patient is allowed to start therapy, leading to sometimes important delays. In our respiratory oncology trial unit, we analysed of our molecular database regarding this barrier (7). The mean waiting time between signing informed consent and receiving results of the biomarker analysis from the central laboratory turned out to be 25 calendar days! While delivering a tissue sample for central confirmation of molecular testing is crucial in biomarker-driven NSCLC trials, the mandatory waiting of patients to start therapy is to be discussed. Waiting times for central laboratory analysis not only lead to an important delay in treatment initiation, but even ineligibility for the trial(s) under consideration. Start of therapy based on a properly validated local test, with a posteriori central biomarker testing to guarantee the integrity of the trial, would be more rewarding for quite some patients (8). Conclusion: Recruitment in lung cancer clinical trials is a complex and vulnerable process with different types of barriers. Identifying such barriers can help clinical trial staff to develop strategies to optimize participation and cooperation. Well-trained CRNs have a unique knowledge and set of skills that allows them to make a significant contribution to the clinical research team. CRNs should follow the rapid change in clinical trials closely, so that they can be a guide for patients in their clinical trial journey. Moreover, they have an important role in minimising the patient barriers, give support in physician barriers, and facilitating tissue barriers. References (1) Ross S, Grant A, Counsell C et al. Barriers to participation in randomised controlled trials: A systematic review. J Clin Epidemiol 1999;52:1143-1156. (2) Manne S, Kashy D, Albrecht T et al. Attitudinal barriers to participation in oncology clinical trials: Factor analysis and correlates of barriers. Eur J Cancer Care 2015;24:28-38. (3) Kaplan CP, Napoles AM, Dohan D et al. Clinical trial discussion, referral, and recruitment: Physician, patient, and system factors. Cancer Causes Control 2013;24:979-988. (4) Mills EJ, Seely D, Rachlis B et al. Barriers to participation in clinical trials of cancer: A meta-analysis and systematic review of patient-reported factors. Lancet Oncol 2006;7:141-148. (5) Seruga B, Sadikov A, Cazap EL et al. Barriers and challenges to global clinical cancer research. Oncologist 2014;19:61-67. (6) Hastings CE, Fisher CA, McCabe MA et al. Clinical research nursing: A critical resource in the national research enterprise. Nurs Outlook 2012;60:149-156. (7) Lepers S, Ottevaere A, Oyen C et al. The challenge of molecular testing for clinical trials in advanced non-small cell lung cancer patients: analysis of a prospective database. J.Thorac.Oncol. 2015; 10 Suppl: Mini Oral presentation WCLC 2015. (8) Adam V, Dooms C, Vansteenkiste J. Lung cancer at the intensive care unit: The era of targeted therapy. Lung Cancer 2015;E-pub May 18.

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This paper discusses the prevalence of distress in the lung cancer population, reviews the benefits and barriers of screening and provides practical strategies to implement psychosocial screening. Background: Lung cancer is the leading cause of death by cancer for both men and women worldwide. Most lung cancers are diagnosed at advanced stage and approximately 15% of lung cancer patients will be alive five years post-diagnosis.[1] Psychosocial distress is common for those experiencing cancer. The National Comprehensive Cancer Network (NCCN) defines psychosocial distress as ‘an unpleasant experience of an emotional, psychological, social or spiritual nature, that interferes with the ability to cope with cancer treatment, which extends along a continuum from common normal feelings of vulnerability, sadness and fear, to problems that are disabling such as true depression, anxiety, panic and feeling isolated or in a spiritual crisis’. The NCCN considers distress to be a treatable complication of cancer.[2] Lung cancer patients’ distress levels are among the highest of all cancer types with up to 60% of lung cancer patients experiencing clinical level of psychological distress compared with approximately 35% of patients with other cancer diagnoses.[3 4] These high levels of distress have been found to continue throughout the course of the illness. Prevalence of anxiety and depression in patients with lung cancer ranges from 20% to 50% [3 5] and patients with lung cancer have been identified as having one of the highest rates of suicide within the cancer population. [6] Distress has been associated with a deterioration in quality of life, higher pain levels, increased fatigue, increased family burden and reduced adherence to medical treatments. Despite high levels of distress in this population, lung cancer patients also report experiencing a significantly higher mean number of unmet needs 15.6 (95% CI 12.1–19.1), compared to 10.9 (95% CI 10.0–11.8) in other cancer patients.[7] Psychosocial distress screening Distress screening is defined as "a brief method for prospectively identifying, triaging, and educating cancer patients and their families at risk for illness-related biopsychosocial complications that undermine the ability to fully benefit from medical care, the efficiency of the clinical encounter, patient satisfaction, and safety."[2] Practice clinical guidelines recommend that all cancer patients undergo regular screening, with the American College of Surgeons (ACoS) Commission on Cancer (CoC) requiring cancer centers to implement screening programs for psychosocial distress as a new criterion for accreditation as of 2015. Without formal screening, distress may go unrecognized, clinicians could focus on the medical aspects of the illness and consider distress as a “normal” part of cancer and patients may not be offered effective biopsychosocial treatments to address distress. Without intervention for distress, the distress of lung cancer patients has been found to remain high, post six months of medical treatment.[8] Many tools exist for the screening of distress and these tools have undergone varying degrees of validation in the lung cancer patient group. The Distress Thermometer is the most popular of these tools and has been found to be both acceptable to patients with lung cancer and clinicians. In deciding which distress screening tool to employ, it is important that effective screening takes both disease (i.e. stage of illness, prognosis, side-effects, functional impairment) and demographic risk factors (i.e. age, isolation, past mental health history) into account, is easy to administer and sensitive to the identification of distress. Screening accompanied by discussion with lung cancer patients was found to be more effective than screening alone.[8] Overall, routine screening leads to improvements in communication with patient, families and staff, enhances psychosocial referrals improves symptom management and quality of life. However, some barriers may exist to the successful implementation of routine screening, including: a lack of knowledge about screening; a lack of training about how to manage distress; limited resources and time pressure; lack of institutional support; and a concern that screening may lead to ‘false positives’.[9] Implementing screening for distress recommendation The successful implementation of routing screening needs to be considered at the institutional, multidisciplinary team and individual clinician level. At an organizational level, screening and psychosocial care needs to be valued, prioritized and embedded in policy. Organizations need to ensure adequate psychosocial resources are available, staff are adequately trained and supported and that there is an ongoing evaluation of any psychosocial screening and referral process. At a multidisciplinary team level, the team needs to view psychosocial screening and treatment as part of routine care and distress needs to be assessed across the cancer trajectory, not just at a single point.[10] Treating team members need to consistently inform patients and families that the management of distress is a central part of their medical care. Teams should use a validated and easy to use instrument to assess distress and all screening should be followed by a triage discussion to help formulate treatment plans and referrals. Treatment plans must be clearly documented and communicated to the patient, family and team.[10] At an individual level, clinician should implement policy and procedures that support routine screening and access relevant training, support and supervision. Conclusion Lung cancer patients are among the most distressed and at risk cancer population. Evidence suggests that treating teams must take a person-centred approach to treatment including consideration of patients’ psychosocial needs. Routine screening allows practitioners and treating teams to appropriately consider psychosocial care and engage patients in intervention to minimize the potential negative impacts of untreated or poorly treated distress. References 1. American Cancer Society. Cancer facts and figures 2013. Atlanta, GA: American Cancer Society, 2013. 2. Network NCC. Clinical Practice Guidelines inOncology on Distress Management: National Comprehensive Cancer Network, 2011. 3. Zabora J, BrintzenhofeSzoc K, Curbow B, et al. The prevalence of psychological distress by cancer site. . Psychooncology 2001;10(1):19-28. 4. Graves KD, Arnold SM, Love CL, et al. Distress screening in a multidisciplinary lung cancer clinic: prevalence and predictors of clinically significant distress. Lung Cancer 2007;55(2):215-24 5. Linden W, Vodermaier A, Mackenzie R, et al. Anxiety and depression after cancer diagnosis. Prevalence rates by cancer type, gender, and age. J Affect Disord 2012;;141:343–51 6. Urban D, Rao A, Bressel M, et al. Suicide in lung cancer: who is at risk? Chest 2013;144(4):1245-52 doi: 10.1378/chest.12-2986[published Online First: Epub Date]|. 7. Li J, Girgis A. Supportive care needs: are patients with lung cancer a neglected population? Psycho-Oncology 2006;15(6):509-16 8. Carlson LE, Waller A, Groff SL, et al. Screening for distress, the sixth vital sign, in lung cancer patients: effects on pain, fatigue, and common problems-secondary outcomes of a randomized controlled trial. Psycho-Oncology 2013;22(8):1880-88 doi: 10.1002/pon.3223[published Online First: Epub Date]|. 9. Ristevski E, Breen S, Regan M. Incorporating supportive care into routine cancer care: the benefits and challenges to clinicians' practice. Oncology Nursing Forum 2011;38(3):E204-E11 doi: 10.1188/11.ONF.E204-E211[published Online First: Epub Date]|. 10. Pirl W, Braun I, Deshields T, et al. Implementing Screening for Distress. The Joint Position Statement from the American Psychosocial Oncology Society, Association of Oncology Social Work and Oncology Nursing Society merican Psychosocial Oncology Society, Association of Oncology Social Work and Oncology Nursing Society, 2015.

Abstract:
I am going to introduce the medical care for cancer and nursing for cancer in Japan. Starting from 1981, cancer claimed 1[st] place of the cause of death, and it currently account for approximately 30% of the cause of death. About 900,000 people are annually affected by the cancer. The per category death rate is in the order of lung cancer in 1[st] place, stomach cancer in 2[nd] place, and colorectal cancer in 3[rd] place. The per category affected subject rate is in the order of stomach cancer in 1[st] place, colorectal cancer in 2[nd] place, and lung cancer in 3[rd] place. As you can see from the above, cancer is a serious health problem for Japanese, and although Japan implemented countermeasure for cancer starting from the 60’s, “Cancer Control Act” was established in 2006, and “Basic Plan to Promote Cancer Control Program” was also setup to promote such Act. The purpose of the countermeasure is to do the following: 1.Reduce cancer death (Reduce age-adjusted mortality under 75 years, 2.reduction of burden and improvement of quality of life among cancer patients and their families, 3.Buliding a society in which cancer patients can live peacefully. Based on such backdrop, the role of nurses are further increased. To enhance the specialization of nursing for cancer, “Japanese Society of Cancer Nursing” was established in 1987, and it is now celebrating its 30[th] anniversary. This establishment has been supporting activities such as education and research. Nurses with certification such as “Certified Cancer Nurse Specialist” that can be obtained with completion of master’s course at graduate school, and “Certified Nurse” that can be obtained with 600 hours of education for those with over 5 years of nurse experience are taking active role in the fields of Palliative Care, Cancer Chemotherapy Nursing, Cancer Pain Management Nursing, Breast Cancer Nursing, Radiation Therapy Nursing, etc. Such active role is making positive contribution toward the enhancement of specialization in the clinical field. A variety of issues surrounds the medical care for cancer such as being able to correspond to the advancement of medical technology, increase of cancer survivor, and aging of patients. There is much anticipation for the good use of specialization in the cancer-nursing for team medicine to support the life of patient and to respect the decision-making of patient. I would like to introduce these types of initiatives that are specific to the condition surrounding the nursing for cancer and enhancement of specialized nursing in Japan.

Abstract:
Background Exercise has been introduced to improve physical capacity (VO~2peak~ and 1RM) and quality of life and to reduce symptoms and side-effects of treatment in patients with cancer, mostly investigated in patients with breast cancer (1,2). Against this background a feasibility study was developed to investigate the safety and feasibility of a preoperative and postoperative exercise program in patients undergoing surgery for lung cancer (3). The study concluded that the preoperative exercise program was not feasible. However, initiation of exercise two weeks postoperatively for patients with NSCLC was safe and feasible. A randomized clinical trial (PROLUCA) was therefore developed to investigate the efficacy of a postoperative exercise intervention in a non-hospital setting. Objectives The objective of the presented study was to explore operable lung cancer patient experiences with the postoperative exercise intervention from a longitudinal perspective according to patient motivation and patient perceived benefits and barriers of exercise. Methods This qualitative component formed part of the randomized control trial (PROLUCA) comparing the efficacy of early initiated postoperative exercise (initiated two weeks after surgery) with the effect of exercise initiated 14 weeks after surgery (usual care). NSCLC patients referred for surgery at the Department of Thoracic Surgery, Copenhagen University Hospital, were recruited for the exercise intervention. More details on the RCT study can be found in the published protocol by Sommer et al. (3). Nineteen patients enrolled in the exercise intervention two weeks post-surgery participated in qualitative interviews at three time points; the day after surgery, 7 weeks post-surgery and 4 months post-surgery. An analysis based on Ricoeur’s theory of interpretation was conducted in a phenomenological hermeneutical approach (4). Results The patient sample’s mean age was 63 years (range 48–75). Patients underwent video-assisted thoracoscopic surgery (VATS) with intent to cure. The majority (79 %) had comorbidities, including chronic obstructive pulmonary disease (26 %), cardiovascular disease (26 %) and hypertension (26%). Pre-illness physical activity levels of the patients showed that 47 % had not met the national recommendation for physical activity. Patients started exercising 15 days following surgery (median) (range 14–41 days). Delay was due to postoperative complications (pain, pneumothorax, pneumonia, atrial fibrillation, general discomfort). Eight participants dropped out of the intervention. Reasons for non-adherence included chemotherapy side effects (nausea, fatigue) (n=3), other reasons (n=1), fractured arm (n=1), work (n=1), terminally ill husband (n=1) and death (n=1). The mean attendance rate for the 11 participants who completed the intervention was 82 % (range 58–100 %). No patients experienced severe adverse events (e.g. heart- or respiration stop) during or following exercise. The interview findings are organized into three themes reflecting the timespan related to the patients’ treatment trajectory: 1) Pre-intervention motivation for participation; 2) Benefits and barriers of the intervention; 3) Overall experiences with the intervention. Motivation for participation included patients’ expectations of physical benefits and the security of having professionals present. Patients experienced physical and emotional benefits and affirmed their social identity, including improved breathing and increased well-being and energy level. Group training had social benefits and the patients experienced a sense of belonging. Exercising with others in a similar circumstance was meaningful to the patients and created a sense of community. Barriers were primarily related to side-effects of chemotherapy. The intervention put the patients on track to a healthier lifestyle regarding physical activity and smoking, and regaining vitality and energy increased the participants’ faith in the future. The patients were satisfied with the exercise intensity level, contents and variation and felt that after 12 weeks of two 60-min weekly sessions they had regained a good amount of strength and energy. Two of the eight patients who were undertaking adjuvant chemotherapy started training on completion of their treatment, while three other patients exercised while being treated. Discussion To our knowledge, this is the first study that addresses operable NSCLC patient perspectives on participating in an exercise intervention during the immediate post-surgical period and subsequent chemotherapy. The sample of the 19 patients included in the interview study appears to be a select group of operable lung cancer patients. So far it has not been possible to compare the interview sample with the larger sample of the trial and therefore not possible to discuss representativeness of the selected sample. However, when comparing the interview study sample with other operable lung cancer patients, it appears that the study patients are a little younger, better educated, have early stage disease, good performance status and are used to physical activity. Although this sample is comparable with other lung cancer exercise samples (5), this suggests social inequality related to the intervention’s design. This might also explain why the operable lung cancer patients consented to participate in the intervention and changed their behaviour—a finding that is not comparable with the general lung cancer population reported to have particularly low levels of physical activity during the post-treatment period (6) and with patients engaged in light physical activity (7). Despite the fact that the studied sample might be a select group, the diagnosis appears to represent “a teachable moment” as discussed by Demark-Wahnefried and colleagues (8), and the intervention seem to assist the patients by increasing their physical function and energy, their well-being and improve their social capital. Eleven of the patients completed the intervention with a mean attendance rate of 82 %, which is comparable with other exercise intervention studies (9). This result underscores the patients’ desire and ability to complete the intervention. Reasons for dropping out of the intervention were due to external conditions unrelated to the intervention or due to chemotherapy side effects. Conclusion This study contributes to the literature by taking into account patient perspectives of exercise interventions. The supervised intervention was undertaken safely by operable lung cancer patients initiated 2 weeks after surgery. This select group of lung cancer patients experienced physical and emotional benefits and affirmed their social identity. This qualitative study indicates that exercise is beneficial for lung cancer patients in the postsurgical trajectory and especially for those who were physically active and motivated pre-illness. References 1. Adamsen L, Quist M,Andersen C, Moller T, Herrstedt J, Kronborg D et al (2009) Effect of a multimodal high intensity exercise intervention in cancer patients undergoing chemotherapy: randomised controlled trial. BMJ 339:b3410 2. Mishra SI, Scherer RW, Snyder C, Geigle PM, Berlanstein DR, Topaloglu O (2012) Exercise interventions on health-related quality of life for people with cancer during active treatment. Clin Otolaryngol 37(5):390–392 3. Sommer MS, Trier K, Vibe-Petersen J, Missel M, Christensen M, Larsen KR et al (2014) Perioperative rehabilitation in operation for lung cancer (PROLUCA)—rationale and design. BMC Cancer 14:404-2407–14-404 4. Ricoeur P (1976) Interpretation Theory. Discource and the surplus of meaning. TCU Press, Texas 5. Jones LW, Eves ND, Spasojevic I,Wang F, Il'yasova D (2011) Effects of aerobic training on oxidative status in postsurgical non-small cell lung cancer patients: a pilot study. Lung Cancer 72(1):45–51 6. Coups EJ, Park BJ, Feinstein MB, Steingart RM, Egleston BL, Wilson DJ et al (2009) Physical activity among lung cancer survivors: changes across the cancer trajectory and associations with quality of life. Cancer Epidemiol Biomarkers Prev 18(2):664–672 7. Lin YY,Wu YC, RauKM, Lin CC (2013) Effects of physical activity on the quality of life in Taiwanese lung cancer patients receiving active treatment or off treatment. Cancer Nurs 36(4):E35–E41 8. Demark-Wahnefried W, Aziz NM, Rowland JH, Pinto BM (2005) Riding the crest of the teachable moment: promoting long-term health after the diagnosis of cancer. J Clin Oncol 23(24):5814–5830 9. Kjaer TK, Johansen C, Ibfelt E, Christensen J, Rottmann N, Hoybye MT et al (2011) Impact of symptom burden on health related quality of life of cancer survivors in a Danish cancer rehabilitation program: a longitudinal study. Acta Oncol 50(2):223–232

Abstract:
Background This paper will reflect upon some of the ethical challenges in conducting clinical research into lung cancer and mesothelioma. Lung cancer care, treatment and research operate in a complex environment. Characteristics of lung cancer that contribute to this complexity are that, in comparison to other cancer sites, it has a limited evidence base, high mortality, late presentation, diagnosis at advanced stage, few curative treatments, complex trial designs and nihilistic attitudes regarding treatment and research. As a result, people delay reporting lung cancer symptoms because of fear, fatalism and poor knowledge of treatment.[1] Such beliefs and attitudes may also influence decisions or prevent people from participating in research. When they are asked to participate, they are often in a situation of advanced illness with fear and/or fatalism in their minds. As such, they may be desperate volunteers.[ 2] Desperate Volunteers An example of a study involving desperate volunteers might be a surgical intervention for mesothelioma, such as the procedures in Mesothelioma And Radical Surgery (MARS)Trial[3] study or the new feasibility study of MARS 2. Treatment options in lung cancer and mesothelioma are increasing, but remain limited, especially regarding curative treatment. In mesothelioma, surgery will not be curative, but might be seen as the only palliative treatment that can make a substantial inroad into the disease pogression. Research treatments may therefore be seen as “the only treatment in town”. Both the multidisciplinary team and the patient may not see any other viable treatment. If the intervention is only available within research then research emerges as the only option. So what are the ethical challenges here? The ethical principle of voluntariness comes into play. Might recruitment into a trial be experienced as coercive – even if this is not the intention of the person recruiting? Is the experience of being approached about trial participation seen as coercive, or is it a decision in difficult circumstances? We need to ensure it is the later. It may be a decision taken under pressure, but needs to be made in a voluntary capacity. Other factors that will impact on levels of desperation, and the balance between coercion or decision, include whether the intervention is available outside the trial or not, and the trial design i.e. does it involve randomisation. Both these things will impact on someone’s readiness to participate in research and whether they will seek treatment outside of a trial. Finally it is necessary to consider whether the level of distress or desperation is impacting upon mental capacity.[4] Trials for all As previously stated, the evidence base for lung cancer is limited when compared to other cancer sites. There is also a drive in the UK cancer and health research community to ensure all patients have a right to access any appropriate trial. In the historical context of lung cancer being the “poor relation” in terms of research activity, caution is required to avoid being over-zealous in putting this right. People have the right to have access to appropriate trials but this does not mean every patient should be on a trial. There are many reasons why people will not want to embark on the journey of being a research participant. This should be respected. There is a theoretical argument that an over-zealous “trails for all” approach could have two other impacts. First, it may lead a desperate volunteer to misinterpret or inflate what the trial may offer in terms of treatment, cure or symptom impact; second it may change perceptions of equipoise. Equipoise Clinical equipoise provides the ethical basis and justification for medical research which involves assigning or randomising patients to different treatment arms of a trial. The term was first used by Benjamin Freedman in 1987.[5] If clinical equipoise exists there is genuine uncertainty over whether a treatment will be beneficial. It follows that it is reasonable for a clinician in equipoise to assign a patient to one arm or the other of a randomised trial. The challenge lies in deciding whether equipoise exists and whose interpretation it is based upon. Usually the decision is made according to the best evidence.[6] An ethical window of opportunity will exist within which it is justified to conduct a randomised trial. That is until evidence is generated to demonstrate whether an intervention is better than standard treatment or not. However, there is a value-based element to equipoise. As such equipoise may vary between researcher, clinician, and patient – and between different patients. For example, on the basis of best evidence it may be justified to randomise between a surgical intervention and standard care, as clinical equipoise is seen to exist. However, if standard treatment is NO treatment, will the patient view equipoise in the same way as the scientist? Implications The above challenges will apply in different ways to different patients and contexts. However This paper focuses on some key messages for clinical and research practice. These can be summarised as: · Information and consent: The process of providing participants with sufficient information, and obtaining informed consent, need to be actively managed in these complex situations. Sufficient time needs to be allowed in times of heightened emotion and a cooling off period is recommended in between information and consent. Also, consent should be approached in a staged or continuous manner, where willingness to continue participation in research is verified at different stages in the study. [· ]Research designs: Where possible, patient preference trial designs should be considered.[7,8] · Availability of research intervention outside of the trial: Consider the impact of this at the design stage. Is an agreement possible to cease delivery outside of a trial until evidence is generated? · Equipoise: Whose equipoise is the trial based on? It is necessary to consider patient/participant values as well as the judgements of the scientist and clinician. · Patient experience: It is worth including a qualitative component in trials to understand what is going on for the participants, and trial staff, in terms of decisions to participate and be randomised, response to allocation, and experience of intervention. 1. Tod AM. Allmark P. Craven J. Diagnostic delay in lung cancer: a qualitative study. Journal of Advanced Nursing. 2008. 61(3), 336-343 2. Allmark P (2006) Should desperate volunteers be included in randomised controlled trials? JMedEth 32, 548-53 3. Treasure T, et al. Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study. Lancet Oncol. 2011 Aug;12(8):763-72. doi: 10.1016/S1470-2045(11)70149-8. Epub 2011 Jun 30. 4. Mental Capacity Act Code of Practice (2005) online Chapter 11 5. Freedman B (1987) Equipoise and the ethics of clinical research NEJM 317(3), 141-5 6. Kurzrock J, Stewart D (2014) Equipoise abandoned? Randomization and clinical trials. Ann Onc 24(10), 2471-74 7. Ismalia A, Walter S 2014 Review of designs for accommodating patients' or physicians' preferences in randomized controlled trials. In Montfort K van. et al Developments in Statistical Evaluation of Clinical Trials Sedgwick P (2013) What is a patient preference trial? BMJ 347:f5970

Abstract:
An individual is considered a cancer survivor from the time of diagnosis, through the balance of his or her life (NCSI –Survivorship definitions 2004) . In the UK Lung cancer survival has improved over the past two decades .In 1990 17% of male and female lung cancer patients were alive after one year compared with 29% of men and 33% of women diagnosed with lung cancer in 2010 . (The National Cancer Intelligence Network – public health England 2013).Such noticeable improvement in survival rates illustrates the improvements in Lung cancer care from diagnostics, treatments and configuration of cancer services. However variations and gaps in the delivery of lung cancer care nationally and internationally reinforce concerns around survivorship care. Lung cancer is a diagnosis associated with heavy disease burden and survivors may experience a myriad of concerns related to diagnosis and or treatment with high levels of physical and psychological distress affecting the quality of life for both patients and carer’s. Maguire et al (2012) reported that many people with a lung cancer diagnosis feel that supportive care needs are not being met, they have significantly more unmet supportive care needs compared to other cancer types. They are also less aware of supportive care elements available and have limited information to resources. (Steele and Fitch, 2008) The American Cancer Society (ACS)’s has set one of its 2015 goals for the nation as establishing “..Measurable improvement in the quality of life from the time of diagnosis and for the balance of life for all cancer survivors” Recent years have seen the growth of a new trends in medicine that are based entirely on data obtained from patients own assessment of their symptoms and ability to function “normally” Widely known in the cancer fields as a self-evaluation of health status or outcomes assessment. Such assessments were directed primarily towards patient evaluation and came to be known as health-related quality of life (HRQOL) in order to distinguish it from the quality of life of the general population. HRQOL refers to multidimensional assessments that include physical, psychological, social domains and also include other domains such as cognitive functioning, sexuality and spirituality. While single areas such as performance status or symptoms may be components of HRQOL they are, by themselves, insufficient to constitute a complete HRQOL assessment. In addition, the assessment of HRQOL does not usually include some other patient reported assessments, such as needs assessment and satisfaction with care. Thus, patient-reported outcomes (PROs) a more inclusive term, was proposed to include any data that may be reported directly by the patient without an intermediary such as a family member or a healthcare professional (Willke et al. 2004). The process of obtaining PRO data is commonly referred to as PRO measurement (PROM)s (Osoba 2011) The National cancer survivorship Initiative, (NCSI) launched in 2007, initially had limited evidence around the needs of cancer survivors. Taking action to improve outcomes (NCSI 2013)collected information on quality of life (QoL) through the use of PROMS and identified that many cancer survivors had unmet needs. Following on from the success of this National Cancer Survivorship Initiative, The Living With and Beyond Cancer (LWBC) Programme was set up in June 2014. This two year partnership between NHS England and Macmillan Cancer Support is aimed at entrenching NCSI findings and recommendations ensuring that those living with and beyond cancer get the care and support they require to lead as healthy and active a life as possible, for as long as possible. There are a number of key recommendations, including the introduction of an integrated package of interventions, “The Recovery Package”, which includes • Structured Holistic Needs Assessment and Care Planning, • Treatment Summaries and Cancer Care reviews • Patient education and support events (Health and Wellbeing Clinic) • Advice about and access to schemes that support people to undertake physical activity and healthy weight management. The collaboration of multi-disciplinary working involved in such interventions will enable improved outcomes for cancer survivors, through creating a shared understanding between patient and professionals about the issues important to the individual patient, identifying any needs to be addressed in an appropriate and timely manner. It has been designed to complement the stratified care pathway (NHS Improvement 2012) which enables individualised follow-up care as a supported self-management programme, shared care or complex care. REFRENCES National Cancer Institute –Survivorship definitions 2004 The National Cancer Intelligence Network – public health England 2013) One-year survival for lung cancers diagnosed in England 1990-2010 Maguire,R. et al. What is the value of the routine use of patient-reported outcome measures toward improvement of patient outcomes, processes of care, and health service outcomes in cancer care? A systematic review of controlled trials. J Clin Oncol. 2014 May 10;32(14):1480-501 Steele R, Fitch MI. Why patients with lung cancer do not want help with some needs. Support 2008 Mar;16(3):251-9. The American Cancer Society 2015 Organisational outcomes Willke, R.J., Burke, L.B. and Erickson, P. (2004) Measuring treatment impact: a review of patient reported outcomes and other efficacy endpoints in approved product labels. Control Clinical Trials 25: 535_552. Osoba,D. Health-related quality of life and cancer clinical trials Advance Medical Oncology (2011) 3(2) 57_71 The National cancer survivorship Initiative Living with and beyond cancer: Taking action to improve outcomes (2013) The Recovery Package, National Cancer Survivorship Initiative, NHS Improvement 2012 Innovation to implementation: Stratified pathways of care for people living with or beyond cancer- NHS Improvement 2012

Abstract:
Chemotherapy is the bedrock of advanced SCLC management. Platinum-based chemotherapy is the most widely employed regimen in the frontline setting.[1] Systemic therapy is administered for SCLC in different settings including frontline, maintenance and salvage settings. Frontline Therapy: The clinical efficacy of frontline chemotherapy does not significantly differ based on the choice of partner chemotherapy employed along with platinum particularly in non-Japanese patients. The limited impact of the established frontline chemotherapy regimen is highlighted by the fact that lass than 25% of patients with extensive stage SCLC survive past 2 years. Nonetheless, population-based analysis of real-world patient outcome showed survival benefit of chemotherapy whereas the outcome for untreated patients has not improved in the last 20 years.[2] Attempts to improve on treatment efficacy through intensification of chemotherapy regimens have met with uniform failure with heightened toxicity and no significant survival benefit. Incorporation of targeted biologic agents showed some promise in the preclinical and clinical settings. The addition of antiangiogenic agent to standard platinum-based doublet showed a non significant but positive trend towards improved survival. The SALUTE trial enrolled and randomly assigned 52 patients to receive standard platinum-doublet along with bevacizumab or placebo.[3] The median PFS and RR were higher in the bevacizumab group (5.5 vs. 4.4 months; hazard ratio [HR], 0.53; 95% CI, 0.32 to 0.86) and 58% (95% CI, 43% to 71%) vs. 48% (95% CI, 34% to 62%). The median overall survival (OS) was no different (HR of 1.16; 95% CI, 0.66 to 2.04).[3] E3501 study also evaluated the benefit of antiangiogenic therapy in a 63-patient single arm study treated with cisplatin, etoposide and bevacizumab.[4] The response rate was 63.5%, median PFS of 4.7 months and OS was 10.9 months. Patients who had high baseline VCAM had a higher risk of progression or death compared with those who had low baseline VCAM levels. Using a different partner chemotherapy of carboplatin, irinotecan and bevacizumab, Spigel et al. reported an ORR of 84% (95% CI 71-93%), median TTP of 9.13 months (95% CI 7.36-9.46 months) and median OS of 12.1 months.[5] Identification of a reliable predictive biomarker would be critical for this management strategy to proceed beyond the completed phase II trials. Similarly, the E1508 study combined inhibitors of the hedgehog developmental pathway (vismodegib; GDC0049) and insulin-like growth factor receptor (cixutumumab; IMCA12) with platinum-doublet chemotherapy and compared the clinical outcome to platinum-doublet only. There was no improvement in median PFS (4.7, 4.4, 4.6 months) or OS (9.4, 9.8, 10.1 months).[6] The combination of ipilimumab, an immune checkpoint inhibitor targeting CTLA4, with platinum doublet chemotherapy was very promising as a frontline regimen in SCLC especially when administered in a phased schedule.[7] The study randomized 130 patients with chemotherapy-naïve SCLC-ED in a 1: 1: 1 ratio to receive paclitaxel/carboplatin with placebo (control), ipilimumab concurrent with paclitaxel/carboplatin or phased ipilimumab following induction paclitaxel/carboplatin. Phased ipilimumab improved irPFS versus control [HR =0.64; P=0.03] with median irPFS of 6.4 vs. 5.3 months and median OS of 12.9, vs. 9.9 months. This promising result provided the rationale for a phase III study of this regimen in newly diagnosed SCLC-ED. Maintenance or Consolidation Therapy: The strategy of maintenance or consolidation therapy has been systematically evaluated in SCLC-ED following completion of frontline doublet chemotherapy. Topotecan was investigated as a maintenance therapy in E7593 study, a phase III trial that randomized patients with stable or responding disease following induction doublet chemotherapy to observation or four cycles of topotecan. A total of 223 were randomized to observation (n-111) or topotecan (n = 112). The PFS associated with consolidation topotecan was 3.6 months v 2.3 months (P <.001) for observation but without any significant difference in OS between the observation and topotecan arms (8.9 months v 9.3 months; P =.43).[8] Similarly, E1500 evaluated temsirolimus as maintenance therapy following frontline therapy of SCLC-ED. The study enrolled 87 patients with either stable or responding disease following induction platinum-doublet to receive temsirolimus (25mg or 250mg) every week until disease progression. The median and 1-year PFS were 2.2 months (95% CI: 1.8, 2.9) and 4.7% (95% CI: 0.2%, 9.2%), respectively. The median OS was 8 months (95% CI: 6.5, 9.5). Both topotecan and temsirolimus failed to show clinical benefit as consolidation or maintenance therapy following frontline doublet chemotherapy.[9] However, sunitinib as a maintenance therapy was associated with improved PFS in SCLC-ED. The CALGB 30504 trial was a randomized phase II study that enrolled patients without progression to placebo or sunitinib. Ninety-five patients were randomly assigned; 10 patients did not receive maintenance therapy (five on each arm). The median PFS was 2.1 months for placebo and 3.7 months for sunitinib (HR, 1.62; 70% CI, 1.27 to 2.08; 95% CI, 1.02 to 2.60; one-sided P = .02). Median overall survival from random assignment was 6.9 months for placebo and 9.0 months for sunitinib (HR, 1.28; 95% CI, 0.79 to 2.10; P = 0.16). A phase III study to confirm this positive finding is currently in planning.[10] Salvage Therapy: The poor outcome associated with SCLC is due primarily to the refractoriness of relapsed disease to salvage therapy.[11] Although a number of agents have shown activity in relapsed SCLC including irinotecan, paclitaxel, bendamustine, etoposide and gemcitabine, topotecan remains the only approved agent for the treatment of relapsed SCLC in Western countries. Amrubicin showed positive efficacy and is an approved agent in Japan for relapsed SCLC. However, it failed to demonstrate superior efficacy over topotecan in a randomized phase III study conducted in the West. A total of 637 patients were randomized to amrubicin or topotecan. The median PFS was 4.1 vs. 3.5 months (HR, 0.802; P = .018); median OS was 7.5 months vs. 7.8 months (HR: 0.880; P = .170); with amrubicin and topotecan respectively.[12] Immune checkpoint inhibitors targeting PD-1 signaling (nivolumab; pembrolizumab) and CTLA4 pathways (ipilimumab) are currently being evaluated in relapsed SCLC. Initial reports showed encouraging activity of this class of therapeutic agents with superior efficacy noted with combination therapy over single agent and potential enrichment for patients likely to benefit with the use of PD-L1 expression as a predictive biomarker.[13][, ][14] Perspectives on the future: E2511 is an ongoing phase II study exploring whether the addition of a PARP inhibitor to platinum doublet will result in improved clinical outcome. There is preclinical support and biological rationale to expect that PARP inhibitor therapy will enhance the efficacy of DNA-damage inducing chemotherapy regimen. The study completed accrual in the 2[nd] quarter of 2015 and results are awaited. The genomics of SCLC is significantly understudied in comparison to the non-small cell lung cancer and other cancer types. Recent works using state of the art genomic assays confirmed previously known frequent alterations in RB, TP53 and Myc family genes.[15][, ][16] These works also identified hitherto unknown driver alterations in other genes such as the SOX family of genes. Advancement in the management of SCLC in the coming years is most likely to emanate from the integration of immunecheckpoint blockade into standard treatment paradigm for SCLC as well as through successful exploitation of the frequent genetic and epigenetic alterations that characterize this disease for targeted therapeutics. References: 1. Pillai RN, Owonikoko TK. Small cell lung cancer: therapies and targets. Seminars in oncology 2014;41:133-142. 2. Behera M, Ragin C, Kim S, et al. Trends in small cell lung cancer (SCLC) survival: Predictors and impact of systemic therapy. J Clin Oncol 2014;32:abstr 7599. 3. Spigel DR, Townley PM, Waterhouse DM, et al. Randomized phase II study of bevacizumab in combination with chemotherapy in previously untreated extensive-stage small-cell lung cancer: results from the SALUTE trial. J Clin Oncol 2011;29:2215-2222. 4. Horn L, Dahlberg SE, Sandler AB, et al. Phase II study of cisplatin plus etoposide and bevacizumab for previously untreated, extensive-stage small-cell lung cancer: Eastern Cooperative Oncology Group Study E3501. J Clin Oncol 2009;27:6006-6011. 5. Spigel DR, Greco FA, Zubkus JD, et al. Phase II trial of irinotecan, carboplatin, and bevacizumab in the treatment of patients with extensive-stage small-cell lung cancer. J Thorac Oncol 2009;4:1555-1560. 6. Belani CP, Dahlberg SE, Rudin CM, et al. Three-arm randomized phase II study of cisplatin and etoposide (CE) versus CE with either vismodegib (V) or cixutumumab (Cx) for patients with extensive stage-small cell lung cancer (ES-SCLC) (ECOG 1508). J Clin Oncol 2013;31:abstr 7508). 7. Reck M, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. Ann Oncol 2013;24:75-83. 8. Schiller JH, Adak S, Cella D, et al. Topotecan versus observation after cisplatin plus etoposide in extensive-stage small-cell lung cancer: E7593--a phase III trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2001;19:2114-2122. 9. Pandya KJ, Dahlberg S, Hidalgo M, et al. A randomized, phase II trial of two dose levels of temsirolimus (CCI-779) in patients with extensive-stage small-cell lung cancer who have responding or stable disease after induction chemotherapy: a trial of the Eastern Cooperative Oncology Group (E1500). J Thorac Oncol 2007;2:1036-1041. 10. Ready NE, Pang HH, Gu L, et al. Chemotherapy With or Without Maintenance Sunitinib for Untreated Extensive-Stage Small-Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Phase II Study-CALGB 30504 (Alliance). J Clin Oncol 2015;33:1660-1665. 11. Owonikoko TK, Behera M, Chen Z, et al. A systematic analysis of efficacy of second-line chemotherapy in sensitive and refractory small-cell lung cancer. J Thorac Oncol 2012;7:866-872. 12. von Pawel J, Jotte R, Spigel DR, et al. Randomized phase III trial of amrubicin versus topotecan as second-line treatment for patients with small-cell lung cancer. J Clin Oncol 2014;32:4012-4019. 13. Antonia SJ, Bendell JC, Taylor MH, et al. Phase I/II study of nivolumab with or without ipilimumab for treatment of recurrent small cell lung cancer (SCLC): CA209-032. J Clin Oncol 2015;33:suppl; abstr 7503. 14. Ott PA, Fernandez MEE, Hiret S, et al. Pembrolizumab (MK-3475) in patients (pts) with extensive-stage small cell lung cancer (SCLC): Preliminary safety and efficacy results from KEYNOTE-028. J Clin Oncol 2015;33. 15. Rudin CM, Durinck S, Stawiski EW, et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nature genetics 2012;44:1111-1116. 16. Peifer M, Fernandez-Cuesta L, Sos ML, et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nature genetics 2012;44:1104-1110.

Abstract:
Lung Cancer is the leading cause of cancer-related death[1]. Small-cell lung cancer accounts for about 15-20% of lung cancer[2]. Although SCLC is chemosensitive, majority of SCLC patients develop disease progression soon after the first line therapy and need 2[nd] line therapy. However, over the past decades, most studies have failed and there is no substantial progress in second-line therapy for SCLC[3]. Topotecan remains 2[nd] line therapy for SCLC patients with sensitive relapse. 1. Targeted therapy Almost all of the studies focused on the molecular targeted therapy for second-line treatment of SCLC were failed. However, in a recent randomized phase II trial (CALGB 30504) of chemotherapy with or without maintenance sunitinib for untreated extensive-stage SCLC, the primary end point [progression-free survival (PFS)] was met for maintenance sunitinib than placebo [median PFS: 3.7 vs 2.1 months; hazard ratio (HR), 1.62; 95% confidence interval (CI), 1.02 to 2.60; P = 0.02]. Overall survival (OS) in maintenance group was also better than in placebo (median OS: 9.0 vs 6.9 months; HR, 1.28; 95% CI, 0.79 to 2.10; P = 0.16). This result suggested that maintenance sunitinib was safe and improved PFS in extensive-stage SCLC[4]. 2. Topotecan Single-agent chemotherapy such as topotecan, paclitaxel, docetaxel, irinotecan, gemcitabine, ifosfamide, vinorelbine and temozolomide have been studied in 2[nd] line therapy of SCLC. But single agent topotecan is the only second-line therapy approved by the U.S. Food and Drug Administration for the treatment of relapsed SCLC. Both oral and intravenious topotecan could significantly improve PFS and OS compared with placebo. Compared with cyclophosphamide, doxorubicin, and vincristine (CAV) regimen in relapsed SCLC patients (n = 211), topotecan produced comparable efficacy but poorer quality of life [5]. Toxicity of topotecan could not be tolerated in many patients. 3. Amrubicin Anthracyclines, including doxorubicin, liposomal doxorubicin, epirubicin, mitoxantrone, have been studied in 2[nd] line therapy of SCLC. Tumor response rate ranged from 0% to 20%. Amrubicin, a third-generation anthracycline and potent topoisomerase II inhibitor, has shown promising activity in SCLC. In ACT-1 trial, amrubicin failed to improve OS compared with topotecan but an improvement in OS was noted in patients with refractory disease treated with amrubicin[6]. 4. Immunotherapy Monoclonal antibodies again immune checkpoint inhibitors including ipilimumab, nivolumab and pembrolizumab have been approved as therapy of some solid tumors including melanoma, non-small cell lung cancer (NSCLC), and also studied in SCLC. In the phase Ib KEYNOTE-028 study, SCLC patients who were failure of or inability to receive standard therapy with PD-L1 positivity received pembrolizumab 10 mg/kg, the overall survival rate (ORR) was 35% and safety profiles were consistent with previous studies[7]. Another two trials to explore the efficacy of combination of pembrozulimab and chemotherap/ radiotherapy for extensive-stage SCLC are ongoing (NCT02359019 and NCT02402920). Ipilimumab is a fully human IgG1 cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) monoclonal antibody[8]. In the phase I/II CheckMate-032 study, SCLC patients with progressive disease after > 1 prior line of therapy received nivolumab + ipilimumab or nivolumab monotherapy. The combination or monotherapy showed activity and durable response in SCLC patients who progressed after > 1 prior line of therapy and safety profile was consistent with other tumor types. Unlike NSCLC, second-line therapy has a little progress in SCLC. Second-line treatment for SCLC should be based on the time of recurrence, the reaction and toxicity of first-line chemotherapy, and performance status (PS). A patient’s response to first-line treatment and the duration of the subsequent progression-free period influences the likelihood that a patient will respond to second-line chemotherapy[9]. Tumors that are refractory to first-line chemotherapy or relapse within 60 to 90 days are considered chemoresistant. Tumors whose response to first-line therapy exceeds 60 to 90 days are considered to be chemosensitive and the recommended second-line therapy is the single agent chemotherapy. Topotecan is the optimal choice. Patients in whom response to first-line therapy is maintained for longer than 180 days are likely to benefit from retreatment with prior etoposide/platinum chemotherapy[10]. Immunotherapy in SCLC is widely studied now. References [1] Siegel R, Ma J, Zou Z and Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014;64:9-29. [2] Arcaro A. Targeted therapies for small cell lung cancer: Where do we stand? Crit Rev Oncol Hematol 2015; [3] Spigel DR and Socinski MA. Rationale for chemotherapy, immunotherapy, and checkpoint blockade in SCLC: beyond traditional treatment approaches. J Thorac Oncol 2013;8:587-98. [4] Ready NE, Pang HH, Gu L, Otterson GA, Thomas SP, Miller AA, et al. Chemotherapy With or Without Maintenance Sunitinib for Untreated Extensive-Stage Small-Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Phase II Study-CALGB 30504 (Alliance). J Clin Oncol 2015;33:1660-5. [5] von Pawel J, Schiller JH, Shepherd FA, Fields SZ, Kleisbauer JP, Chrysson NG, et al. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 1999;17:658-67. [6] von Pawel J, Jotte R, Spigel DR, O'Brien ME, Socinski MA, Mezger J, et al. Randomized phase III trial of amrubicin versus topotecan as second-line treatment for patients with small-cell lung cancer. J Clin Oncol 2014;32:4012-9. [7] A Potential Immune Therapy for Mesothelioma. Cancer Discov 2015; [8] Sharma P and Allison JP. The future of immune checkpoint therapy. Science 2015;348:56-61. [9] Giaccone G, Donadio M, Bonardi G, Testore F and Calciati A. Teniposide in the treatment of small-cell lung cancer: the influence of prior chemotherapy. J Clin Oncol 1988;6:1264-70. [10] Metro G and Cappuzzo F. Emerging drugs for small-cell lung cancer. Expert Opin Emerg Drugs 2009;14:591-606.

Abstract:
Introduction The neuroendocrine tumours of the lung are all malignant lesions, unified by a common characteristic of neuroendocrine differentiation, but diverse in terms of histological features, clinical presentation, aetiology and biology. In the new World Health Organisation classification of lung tumours, published in 2015, the four major types of neuroendocrine tumour (small cell carcinoma, large cell neuroendocrine carcinoma, carcinoid tumour and atypical carcinoid tumour) are now included under a single heading of neuroendocrine tumours. Small cell carcinoma (SCLC) SCLC is a high-grade malignant epithelial tumour comprising relatively small cells with scanty cytoplasm, fusiform to round nuclei, finely disperse granular chromatin, inconspicuous nucleoli and prominent nuclear moulding. Mitoses, apoptosis and extensive necrosis are typical. Tumours characteristically have neuroendocrine granules visible on electron microscopy and most cases express neuroendocrine markers by immunohistochemistry. An organoid architecture with rosettes and trabeculae is uncommon, but SCLC samples are often small, precluding identification. SCLC may be seen combined with other non-small cell carcinoma (NSCLC) subtypes (Combined small cell carcinoma). Here, SCLC has priority, regardless of the relative proportion of the tumour that is SCLC. SCLC accounts for between 10-15% of cases diagnosed and is strongly associated with tobacco smoking. The typical presentation of SCLC is stage IV metastatic disease with rapid progression. Radiologically a large central mass with contiguous, bulky hilar nodes is typical and mediastinal invasion is usually evident. The vast majority of SCLC present. Production of hormonal peptides accounts for several paraneoplastic complications. Ectopic hormones (or hormone-like peptides) such as ADH or ACTH, and peptides native to the pulmonary neuroendocrine cells (calcitonin and gastrin-releasing peptide) may be produced. Large cell neuroendocrine carcinoma (LCNEC) Another high grade neuroendocrine carcinoma, characterized by morphological neuroendocrine features (rosettes, trabeculae, peripheral nuclear palisading). Cells are relatively large, cytoplasm abundant/eosinophilic, and nuclei show coarse chromatin and nucleoli. Nodular tumour, a fine vascular stroma, cribriform architecture and central comedo necrosis are common. Mitoses are abundant (always >10 per 2mm[2]: rarely <30 and averages 75). Combined tumours, with SCLC or, more often NSCLC, when adenocarcinoma is the most frequent accompaniment, are not unusual. LCNEC should demonstrate neuroendocrine differentiation by immunohistochemistry [NCAM/CD56 (~100%), Chromogranin (80-85%), synaptophysin (50-60%). At least 50% express TTF1. Usually at least two stains are positive. There is a similar, strong association between LCNEC and tobacco smoking. These are relatively rare tumours, accounting for about 4% of resected cases but true prevalence across all stages, is not clear. Presentation and radiological appearances are no different from other NSCLC cases of similar stage; the vast majority of LCNEC are diagnosed in surgical resections. They are more often peripheral than centrally located tumours. The bulky nodal/mediastinal disease common in SCLC, is uncommon in LCNEC but there may be selection and diagnostic bias driving this observation. Hormonal production and paraneoplastic syndromes are rare in LCNEC, another difference with SCLC. Carcinoid tumour Carcinoid tumours are malignant tumours, divided into typical carcinoid (TC) where there is no evidence of necrosis and mitoses number less than 2 per 2mm[2] of tumour. Atypical carcinoid tumours (AC) may show punctate necrosis and/or exhibit 2 or more, but <10 mitoses per 2mm[2]. Otherwise, the lesions are very similar histologically - small regular cells, variable cytoplasm, bland round to oval nuclei. Architecture is usually insular, trabecular but rosettes or glands occur. Spindle cell carcinoids occur mostly in thee lung periphery; insular/trabecular lesions are characteristically central. Strong neuroendocrine markers expression is expected. Proliferation markers such as Ki67 mirror, to some extent, the mitotic rate, may aid distinction from high grade neuroendocrine tumours in crushed samples but are not reliable or recommended for distinguishing TC from AC. These are rare tumours, accounting for 4-6% of primary lung ‘cancers’; atypical carcinoid account for around 10% of all lung carcinoids. Typical carcinoids may show lymph node spread in 10% cases, distant metastases are rare. In AC, distant metastases are not unusual. Syndromes related to peptides (Cushing’s, Acromegaly) or secretion of 5-HT (carcinoid syndrome) are very rare. Neuroendocrine tumour development and Genetics Precursor lesions are not described for the high grade lesions and the strong link with smoking and the common combination with NSCLC elements makes it likely that origins at least, are from the same cell populations that give rise to other NSCLC. Both central and peripheral lung epithelial compartments are capable of neuroendocrine differentiation, possibly in part driven by transcription factor ASCL1. It is also notable that a proportion of EGFR-mutated adenocarcinomas recur as SCLC after initial response to EGFR tyrosine kinase inhibitors. Carcinoid tumours probably also derive from the same epithelia, but via different mechanisms. Carcinoid and SCLC or NSCLC effectively never co-exist in the same lesion and carcinoids are not associated with tobacco smoking. Rarely carcinoids are associated with MEN type 1 syndrome, and sporadic cases may show MEN1 mutations. A rare disease called diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is associated with spindle-cell carcinoid tumours, often multiple, and is considered a rare carcinoid precursor lesion. There are evolving data which show that SCLC in particular, has patterns of very frequent mutations and epigenetic changes (gene hypermethylation) reflecting tobacco carcinogenesis. SCLC and LCNEC share many features in their genetic profile and inactivating mutations of both RB and TP53 are characteristic. SCLC shares many of the characteristic deletions or losses of tumour suppressor genes seen in squamous cell carcinoma, especially in 3p loci. SCLC and LCNEC show many alterations in genes involved in cell cycle regulation. In LCNEC, some genes such as TTF1, CDKN2, STK11 and KEAP1 may be altered, akin to that seen in some squamous cell or adenocarcinomas, again, and reminiscent of the post-EGFR TKI recurrence scenario, raising the possibility of origin through divergent differentiation within ‘NSCLC precursors’. Carcinoid tumour genomics are entirely different, less well studied, and as expected, do not show a ‘tobacco signature’. As well as MEN1 mutations, alteration of genes of the methylation complex and chromatin remodelling genes are not infrequent. Carcinoid tumours are NOT precursor lesions for, and do not evolve into, SCLC or LCNEC.

Abstract:
Introduction: Small cell lung cancer (SCLC) is the most common and most virulent neuroendocrine (NE) carcinoma. For pathological and therapeutic reasons human lung cancers are traditionally divided into non-SCLCs (NSCLCs) and SCLCs which currently account for 10 – 15% of all lung cancers. While prognosis for all lung cancers is poor, it is dismal for SCLC with less than 5% for patients surviving for five years. As molecular characterization of NSCLCs is quickly taking hold in guiding personalized care of cancer patients, the approach to SCLC is still based on principles developed decades ago. There has been practically no improvement in survival for past thirty years. Following the 2013 congressional mandate demanding concentrated research focus on such recalcitrant cancers as SCLC and pancreatic cancer it will hopefully be changing. Epidemiology and Histology: SCLC is strongly associated with smoking history and commonly found both in women and men at their sixties. It is mostly a centrally located submucosal mass in major airways although peripheral tumors have been reported. At the time of diagnosis, most SCLCs have already metastasized. There are no known premalignant lesions. Histologically the tumors are characterized by sheets of poorly differentiated cells with finely granular chromatin pattern and inconspicuous nuclei, and scanty cytoplasm among other features. Mitoses (>10 per high power field), areas of necrosis and ‘Azzopardi effect’ are consistent with aggressive nature and high DNA content of the tumor. When SCLC is associated with any of the histologic types of NSCLC, it is called combined SCLC (1). Neuroendocrine (NE) Features and the Cell of Origin: Ultrastructurally SCLC is characterized by the presence of scattered dense core vesicles, a hall mark of endocrine differentiation. Functionally the cells reveal a variety of NE properties such as uptake and synthesis of bioactive amines, hormones and neuropeptides, the presence of neural receptors such as nicotinic acetylcholine receptors, antigens and ion channels with the neuron-like ability to conduct electric currents. Consequently, SCLCs may be associated with ectopic hormone secretion or paraneoplastic syndromes. In addition, airway epithelium harbors a rare cell type with similar properties that is only visible using special techniques such as electron microscopy or immunohistochemistry and called pulmonary NE cells (2). In normal lung they occur as solitary cells or innervated clusters called neuroepithelial bodies or NEBs. It has been commonly believed that the pulmonary NE cell is the precursor of SCLC although there has been no direct evidence. Recent studies applying sophisticated tracing techniques in transgenic mice support the hypothesis while still leaving open the question what happens in human lung (3). Spectrum of Neuroendocrine (NE) Differentiation in Lung Cancers: SCLC is the prototype of pulmonary NE cancers but up a third of all lung cancers may reveal a degree of NE differentiation. They range from well differentiated carcinoids and atypical carcinoids to less well differentiated SCLCs and large cell NE carcinomas (LCNECs) and finally to 10% of NSCLCs that show focal NE differentiation (NSCLC-NEs). Notably the cancers are molecularly, histogenetically, morphologically distinct entities and should be distinguished from SCLCs. Clinically SCLCs and LCNECs are high-grade NE tumors while NSCLC-NEs appear to be a more controversial entity. Molecular Pathology: SCLC presents a complex genomic landscape with a high number of mutations due to the toxic impact of tobacco smoke. The field is rapidly evolving. However, both Rb and p53 are almost invariably inactivated in SCLCs. Rb is altered in many human NE cancers regardless of the tissue of origin, while p53 mutations are common in NSCLCs. In contrast, SCLCs lack Ras mutations which are typical of many NSCLCs. Moreover, SCLCs may show overexpression or amplification of MYC genes. In addition, achaete-scute homolog 1 (ASCL1), a transcription factor required for proper development of pulmonary NE cells (2), is pivotal for the survival of a majority of SCLCs and as well as NSCLC with NE features (4). Accordingly, ASCL1 is a lineage-specific oncogene for SCLCs. Efforts to identify relevant pathways regulated by this gene as well as others that might provide molecular targets for treatments are ongoing on several fronts. Tools for Investigation: Because SCLC is routinely diagnosed mainly using small bronchial biopsies or needle aspiration cytology specimens prior to cytotoxic chemo- and radiotherapies there has been a chronic shortage of suitable material for molecular and biological research. Fortunately, there are many well characterized human SCLC cell lines available that quite accurately recapitulate both molecular and histopathological features of the primary tumors. More recently, a range of genetically engineered mouse models have been generated based on the conditional ablation of both Rb and p53 tumor suppressor genes with select other genetic alterations (5). In vivo models provide important material to investigate sequential evolution of SCLC including metastases, molecular profiling and preclinical studies (6). Summary and Conclusions: SCLC is a neuroendocrine (NE) carcinoma with dismal prognosis and no substantial improvements in therapies for several decades. While the identification of effective therapies remains a major challenge, advances in understanding the biology, improved molecular techniques and sophisticated animal models have opened up novel avenues for the development of targeted therapies. References: 1. Travis WD et al. (2004). Pathology and genetics of tumors of the lung, pleura, thymus and heart. Lyon: IARC Press. 2. Linnoila, R.I. (2006). Lab Invest 86, 425-44 3. Sutherland, K.D., Proost, N., Brouns, I., Adriaensen, D., Song, J.-Y., and Berns, A. (2011).Cancer Cell 19, 754–764. 4. Augustyn, A., Borromeo, M., Wang, T., Fujimoto, J., Shao, C., Dospoy, P.D., Lee, V., Tan, C., Sullivan, J.P., Larsen, J.E., Girard, L., Behrens, C., Wistuba, I.I., Xie, Y., Cobb, M.H., Gazdar, A.F., Johnson, J.E., Minna, J.D. (2014). Proc Natl Acad Sci U S A. 111 ,14788-93. 5. Gazdar, A.F., Savage, T.K., Johnson, J.E., Berns, A., Sage, J., Linnoila, R.I., MacPherson, D., McFadden, D.G., Farago, A., Jacks, T., Travis, W.D., Brambilla, E. (2015). J Thorac Oncol. 10, 553-64. 6. McFadden, D.G., Papagiannakopoulos, T., Taylor-Weiner, A., Stewart, C., Carter, S.L., Cibulskis, K., Bhutkar, A., McKenna, A., Dooley, A., Vernon, A.,et al. (2014). Cell 156, 1298–1311.

Abstract:
With the adoption of reimbursement for lung cancer screening in eligible beneficiaries both by third party payers and Medicare, smoking cessation becomes a strategic partner to reduce lung cancer mortality. In the present paradigm, Medicare will require screening programs to meet criteria of the American College of Radiology (or equivalent body) for radiologists, CT scanner platforms, and facilities; to satisfy specific patient eligibility criteria and shared decision-making; and to submit all screening data to a CMS-approved registry. Among the requirements is that the imaging facility or screening program make available smoking cessation interventions for current smokers. There are two basic approaches for this: [a] partnering in a transdisciplinary program that includes primary care, subspecialty care, and imaging in which counseling, shared decision-making, and smoking cessation programs are integrated and typically provided by the clinicians; or [b] building these services into an integrated screening facility with delivery by a qualified health care provider working in concert with the imagers. Some hybrid models have been described. Ultimately, the choice of approach is largely dependent upon institutional culture, institutional resources, and degree(s) of decentralization of the screening program. This session will introduce the benefits and liabilities of each approach as well as implications for costs

Abstract:
Lung cancer screening with computed tomography has demonstrated a significant reduction in mortality (1) leading to the recommendation for annual low-dose CT (LDCT) screening for lung cancer for adults between 55 and 80 years old who are at high risk for lung cancer because of their age and extensive smoking history. In addition to lung cancer screening having public health benefit for early detection of lung cancer, lung cancer screening programs may also represent a “teachable moment” for reaching smokers and promoting cessation through the delivery of evidence-based tobacco cessation treatment (2). Since the advent of lung cancer screening programs, there has been much interest in the impact of lung cancer screening on smoking behaviors. Ostroff and colleagues (3) first published the observation that 25% of current smokers seeking lung cancer screening reported smoking cessation one-year following enrollment in a lung cancer screening program Since then, several observational studies have reported cessation rates ranging from 6.6% to 42% following enrollment in lung cancer screening programs (4-11). However, a more recent systematic review of clinical trials and cohort studies examining smoking behaviors among individuals undergoing LDCT for lung cancer screening concluded that lung cancer screening per se does not change smoking behaviors leading to the conclusion that further research is needed to develop and evaluate cost-effective models for delivery of tobacco treatment in lung cancer screening protocols (12). A recent survey of lung cancer screening sites examined the organizational priority, practice patterns and perceived barriers associated with tobacco treatment (13). To facilitate the integration of tobacco treatment within lung cancer screening programs, a greater understanding of the barriers associated with implementation is needed. Thus, the presentation objectives are to: 1) Establish the rationale for integration of tobacco dependence treatment in lung cancer screening programs; 2) Examine patterns and predictors of smoking cessation among lung cancer screening program enrollees; 3) Examine current organizational priority, practice patterns and perceived barriers associated with tobacco treatment delivery; 4) Review opportunities and challenges of integrating tobacco dependence in lung cancer screening protocols. This presentation will provide a blueprint for developing and implementing evidence-based tobacco treatment services within the context of lung cancer screening program. 1. Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, Fagerstrom RM, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. The New England journal of medicine. 2011;365(5):395-409. Epub 2011/07/01. PMID: 21714641. 2. Poghosyan H, Kennedy Sheldon L, Cooley ME. The impact of computed tomography screening for lung cancer on smoking behaviors: a teachable moment? Cancer nursing. 2012;35(6):446-75. Epub 2012/01/03. PMID: 22209869. 3. Ostroff JS, Buckshee N, Mancuso CA, Yankelevitz DF, Henschke CI. Smoking cessation following CT screening for early detection of lung cancer. Preventive medicine. 2001;33(6):613-21. Epub 2001/11/22. PMID: 11716658. 4. Ashraf H, Tonnesen P, Holst Pedersen J, Dirksen A, Thorsen H, Dossing M. Effect of CT screening on smoking habits at 1-year follow-up in the Danish Lung Cancer Screening Trial (DLCST). Thorax. 2009;64(5):388-92. Epub 2008/12/05. PMID: 19052048. 5. Clark MM, Cox LS, Jett JR, Patten CA, Schroeder DR, Nirelli LM, et al. Effectiveness of smoking cessation self-help materials in a lung cancer screening population. Lung cancer (Amsterdam, Netherlands). 2004;44(1):13-21. Epub 2004/03/12. PMID: 15013579. 6. Cox LS, Clark MM, Jett JR, Patten CA, Schroeder DR, Nirelli LM, et al. Change in smoking status after spiral chest computed tomography scan screening. Cancer. 2003;98(11):2495-501. Epub 2003/11/25. PMID: 14635086. 7. MacRedmond R, McVey G, Lee M, Costello RW, Kenny D, Foley C, et al. Screening for lung cancer using low dose CT scanning: results of 2 year follow up. Thorax. 2006;61(1):54-6. Epub 2006/01/07. PMCID: PMCPMC2080704. 8. Schnoll RA, Miller SM, Unger M, McAleer C, Halbherr T, Bradley P. Characteristics of female smokers attending a lung cancer screening program: a pilot study with implications for program development. Lung cancer (Amsterdam, Netherlands). 2002;37(3):257-65. Epub 2002/09/18. PMID: 12234693. 9. Taylor KL, Cox LS, Zincke N, Mehta L, McGuire C, Gelmann E. Lung cancer screening as a teachable moment for smoking cessation. Lung cancer (Amsterdam, Netherlands). 2007;56(1):125-34. Epub 2007/01/02. PMID: 17196298. 10. Townsend CO, Clark MM, Jett JR, Patten CA, Schroeder DR, Nirelli LM, et al. Relation between smoking cessation and receiving results from three annual spiral chest computed tomography scans for lung carcinoma screening. Cancer. 2005;103(10):2154-62. Epub 2005/04/13. PMID: 15825210. 11. van der Aalst CM, van den Bergh KA, Willemsen MC, de Koning HJ, van Klaveren RJ. Lung cancer screening and smoking abstinence: 2 year follow-up data from the Dutch-Belgian randomised controlled lung cancer screening trial. Thorax. 2010;65(7):600-5. Epub 2010/07/16. PMID: 20627916. 12. Slatore CG, Baumann C, Pappas M, Humphrey LL. Smoking behaviors among patients receiving computed tomography for lung cancer screening. Systematic review in support of the U.S. Preventive Services Task Force. Annals of the American Thoracic Society. 2014;11(4):619-27. Epub 2014/04/08. PMID: 24701999. 13. Ostroff J, Borderud S, Copeland A, editors. Readiness and capacity of US lung cancer screening sites to deliver tobacco dependence treatment. Healthography: American Public Health Association 142nd Annual Meeting & Expo; 2014; New Orleans, LA.

Background:
People living with lung cancer (LC), LC survivors and carers are impacted by LC in different ways. The Global Lung Cancer Coalition (GLCC) recognises lung cancer patients’ and carers’ isolation and the challenges they face (GLCC, 2015). However for those affected by LC, limited data exists on the priority of their challenges, their ability to cope with these challenges and if enough relevant information and support is available. Identifiable variances between patient and carer experience and how challenges differ based on gender, age and nationality are also unknown. In 2013, The GLCC and Boehringer Ingelheim collaborated to create a global survey to identify these priorities and variances.

Methods:
A unique web-based survey was designed to isolate the single greatest challenge faced by individuals affected by LC. 200 specific and globally relevant challenges were identified by LC experts from the GLCC, grouped into categories and illustrated, with a small text descriptor. At survey entry, respondents identified their greatest challenge relevant to either daily life or medical care. Via an associated illustration, respondents chose subsequent sub-categories of challenges until one specific challenge was identified as the most significant. Respondents answered 3 questions in relation to that challenge regarding 1) availability of information 2) ability to cope 3) level of support required. Screening was conducted for age, gender, treatment and nationality. Respondents were asked to identify if they were living with LC, a LC survivor or a carer. The survey was available in 11 languages and promoted through the GLCC, LC clinicians, charities and associated support groups.

Results:
2871 individuals visited the survey site. 725 (25%) completed the survey. 64% of LC patients chose a daily life challenge as their most significant, compared to a medical care challenge (36%); 55% of carers also chose a daily life challenge, compared to a medical care challenge (45%). Of all participants who chose daily life, 19.8% identified emotional and/or social needs as the most significant sub-topic, 14.8% identified survivorship/ caring for myself; 13.8% body image and 7.6% stigma. Of all participants who chose medical care, 20.5% identified diagnosis as the most significant sub-topic; 18.9% identified treatment planning & options; 14.9% receiving treatment and 10.2% end of life issues. 56.2% of individuals who chose one of the top 16 challenges (n=589, 81% of all participants) requested more information about the challenge identified.

Conclusion:
Psychosocial issues related to daily life and a lack of relevant information posed some of the greatest challenges to LC patients. LC patients were more likely to identify daily life issues such as dealing with emotional needs, self-care, body image or changing relationships as their greatest challenge rather than medical care issues such as diagnosis, treatment planning or screening. Lung cancer patients have the right to have the enormous burden of lung cancer acknowledged by professional carers, policy makers and the general public (GLCC, 2015). Daily life challenges should be identified and alleviated as part of routine LC care to ensure LC patients and carers receive the necessary spectrum of support and information.

Background:
Over the past decades, researchers have evaluated numerous treatment options for lung cancer with varying degrees of success. The stepwise nature of innovation in this process has made it difficult to assess progress across different therapeutic areas. Stakeholders therefore frequently disagree about the extent of past achievements, the current greatest unmet needs, and priorities for future efforts. In an effort to bridge this gap, Lilly Oncology’s Patient Access to Cancer care Excellence (PACE) initiative developed the Continuous Innovation Indicators[TM ](CII): a robust tool to generate consistent measures of progress in cancer treatments with flexibility to accommodate different cancer subtypes and treatment modalities.

Methods:
Trained analysts review references from the primary literature and record statistical measures of relevant outcomes in a standardized format called “Pieces of Evidence.” A Value Matrix classifies each Piece of Evidence by its therapeutic goal, creating a map of available treatments across different stages of disease. A transparent algorithm then tallies these records and generates Evidence Scores (E-Scores), a novel measure of progress over time. Analyses can be weighted by therapeutic goals or restricted to specific disease subtypes or classes of treatment. The Indicators currently contain data on non-small cell lung cancer (NSCLC) and 11 other solid tumors.

Results:
The first data release of the CII demonstrates steady progress in the development of chemotherapeutic agents against NSCLC, particularly since 1990 (Panel A). Analysis of the data by histological subtype reveals relatively greater progress against non-squamous compared to squamous NSCLC (Panel B). Data from the CII further indicate the relative contributions to progress against NSCLC from different classes of treatment (Panel C). Aligning progress curves with drug approval dates allows us to better understand how the value of new treatments evolves over time (Panel C). Importantly, the CII highlight a critical unmet need in NSCLC (Panel D): there are no curative therapies for regional or metastatic disease supported by current evidence.Figure 1



Conclusion:
Through the use of treatments in multiple classes and combinations, steady progress has been made against NSCLC. Still, pressing unmet needs remain. By offering a standardized and comprehensive approach, the Continuous Innovation Indicators[TM] can help researchers, policymakers, and advocates objectively understand past progress and current needs of NSCLC in a broader context. A link to the public interface is available on the PACE Continuous Innovation website at: https://pacenetworkusa.com/continuousinnovation.php.

Background:
LC may be associated with negative societal perceptions compared to other cancers. This study measured the explicit, conscious attitudes (EAs), implicit, unconscious attitudes (IAs) and implicit stereotypes of LC relative to breast cancer (BC), explored the demographic factors associated with the explicit and implicit biases in LC, and whether these biases affect the LC drug treatment rates.

Methods:
EAs were derived from participants (Ps) [cancer patients (n = 493), caregivers (n = 1332), healthcare providers (HCPs, n = 623), and the general public (n = 1356)] ratings about how patients with LC and BC “do feel” (descriptive attitudes) or “ought to feel” (normative attitudes) about their disease. IAs and implicit stereotypes were measured with the Implicit Association Test (IAT). Analysis of covariance (ANCOVA) was used to assess the demographic factors associated with bias toward LC. Linear regressions were performed to analyze the association between the biases against LC and LC treatment rates across different states in the United States.

Results:
Females (p < 0.001), higher income (p = 0.015), and people reporting themselves with more knowledge about cancer disease (p < 0.001), caregivers (p = 0.008), and whites (p < 0.001) expressed stronger negative descriptive attitudes toward LC. Males (p = 0.007), and higher income (p = 0.010) expressed less-positive normative attitudes toward LC. Females (p < 0.001), higher education (p = 0.003), non-cancer patient participants (p = 0.019), and whites (p = 0.031) had stronger negative IAs about LC. State-level analysis showed that the lower drug treatment rates for LC patients are significantly associated with older patients population (p = 0.011) and higher percentage of government as payer (p = 0.023). State-level analysis shows no significant association between IAT scores and LC treatment rates.

Conclusion:
Explicit and implicit bias against LC compared to BC was associated with gender, education, income levels and cancer knowledge, but not treatment rates.

Abstract not provided

Background:
Survival of incurable cancer patients is improving gradually. Several hundred new therapies are under development. However, internationally, regulatory complexity slows progress by increasing drug development costs (hence, fewer drugs can be assessed with available resources) and by producing numerous speed bumps that delay approval of useful drugs and that increase resources required to document that other agents are ineffective.

Methods:
We assessed cancer therapies undergoing phase III trials between 2001 and 2015. To be included, trials had to document statistically significant improvement in overall survival. We excluded adjuvant trials and trials in uncommon malignancies. To determine the number of life-years potentially lost per year required for drug approval, we multiplied the improvement in median survival in years by the estimated number of patients (North American and worldwide) dying annually from the relevant malignancy.

Results:
In the Table, we present the life-years lost per year required for approval for 21 therapies in 10 malignancies. When the combined impact of all tumor sites and drugs are considered together, there were 29 life-years lost in North America per hour of delay in therapy approval (1 for every 2 minutes of delay) and 260 life-years lost worldwide per hour of delay (1 for every 14 seconds of delay). These numbers do not take into account impact of drugs non-evaluable due to cross-over or missing survival data, drugs that were prematurely abandoned, drugs still undergoing investigation, or approaches for non-malignant lethal diseases. Figure 1



Conclusion:
Clearly, the survival gains associated with the foregoing drugs are only modest. Despite this, there would be a large negative impact associated with approval delays even if factors such as co-morbidities, performance status, ability to pay, etc, limit the number of patients treated to a fraction of the total dying from a specific malignancy. There are numerous opportunities to improve efficiency of cancer drug approval without sacrificing safety or data integrity. This requires urgent attention.

Background:
Participation in oncology clinical trials has historically been low compared to the number of individuals diagnosed with cancer each year. It has been reported that between 3% and 5% of adults with cancer participate in clinical trials. However, research into this statistic usually focuses on the reasons why patients choose not to participate, rather than whether or not clinical trials are designed adequately to capture a proper patient sample truly representative of the population being studied. This study explored a sample of lung cancer patients who received treatment with proton therapy and compared the group to the eligibility requirements of two lung cancer trials. We hypothesized that most patients treated with proton therapy would not be eligible to participate in the currently accruing cooperative group studies.

Methods:
The Proton Collaborative Group’s (PCG) prospective registry was mined for information on all lung cancer patients who received proton therapy between the years of 2010 and 2015. These patients were then evaluated to determine if they would have been eligible to participate in either of the two active cooperative group clinical trials for proton therapy currently enrolling patients with inoperable stage II-IIIB non-small cell lung cancer (NSCLC): PCG LUN005 (phase I/II trial of hypofractionated proton therapy) and RTOG 1308 (phase III trial randomizing to protons versus photons).

Results:
A total of 244 consecutive patients with lung cancer were available in the registry for evaluation. Patients were ineligible for LUN005 and RTOG 1308 due to exclusionary stage (n=77), histology (n=37), performance status (n=66), prior surgery for lung cancer (n=53), and/or prior radiation therapy (RT) for lung cancer (n=53). Of the remaining 55 patients, 27 were enrolled in the PCG registry prior to LUN005 or RTOG 1308 opening for accrual. This left 28 patients. Those patients were ineligible for the following reasons: prior chemotherapy (n=3), prior RT within the treatment field (n=3), prior cancer (n=6), weight loss (n=2), outdated procedures (n=2), oxygen dependence (n=1), disease progression prior to RT start (n=2), or not felt to be an upfront candidate for concurrent chemotherapy and RT (n=2). This left 7 patients who were ultimately eligible for enrollment, one of which refused trial participation and one of which the reason for not participating was unknown. Reasons for lack of enrollment of the 5 remaining patients on LUN005 were due to administrative issues (ex: protocol enrollment on hold pending interim review), whereas RTOG 1308 was unavailable for those patients at their treating center.

Conclusion:
The vast majority of patients treated with proton therapy for lung cancer on PCG’s prospective registry were not eligible for participation cooperative group trials. Given the high ineligibility rate among patients found in this study, pragmatic trials with more inclusive eligibility criteria are needed to better mirror the general population of patients with newly diagnosed, locally advanced NSCLC. More inclusive trials may allow for increased rates of trial participation and further advances and improvements in survival.

Background:
Twitter is a social media platform that may improve clinical trial awareness and enrollment. Little is known about current communication on Twitter regarding clinical trials.

Methods:
We searched the keyword “lung cancer” in Twitter messages from January 5 - 21, 2015. Duplicate and non-English tweets were excluded. Randomly selected tweets were independently evaluated for content and user type by two coders (kappa=0.71). An exploratory analysis was conducted on tweets regarding lung cancer clinical trials. Differences in user type by content were evaluated by Pearson’s chi square test.

Results:
We found 26,059 tweets with the keyword “lung cancer” from 10,039 unique users with 72,239,356 followers, including 15,346 unique tweets. We randomly selected 1,516 (10%) as the study cohort. Table 1 summarizes tweet categories and Table 2 shows tweet content by user type. Most of the dialogues focused on support and prevention. 221 (15%) of tweets were about clinical trials. 92 (42%) were from individuals, such as patients, health advocates, health providers and non-health users (p-value < 0.001). Of clinical trial tweets, 183 (83%) concerned therapeutic trials, 28 (13%) non-therapeutic, and 10 (4.5%) basic research. 144 (65%) of the therapeutic clinical trial tweets concerned immunotherapy. Most of the 183 therapeutic clinical trial tweets, 158 (86%), had embedded-links directing users to news articles. Only 1 tweet linked to a recruitment website with patient enrollment information.

Table 1. Lung cancer tweets by content type

Tweet categories	Frequency, N (%)
Support	358 (24)
Prevention	357 (24)
Miscellaneous (non-health related)	256 (17)
Clinical Trials	221 (15)
Treatment	86 (6)
Diagnosis	78 (5)
General Information	69 (4)
Screening	53 (3)
Symptoms	38 (2)

Table 2. Lung cancer tweets by user type

Tweet categories	Individual	Organization	News Media
Support	258	28	42
Prevention	210	50	74
Miscellaneous	221	6	11
Clinical Trials	92	48	71
Treatment	48	13	17
Diagnosis	35	15	26
General Information	23	33	8
Screening	19	23	9
Symptoms	26	1	7

Conclusion:
A significant proportion (15%) of lung cancer tweets concern clinical trials and are from individuals. Most of these tweets focus on immunotherapy. Our data suggest that Twitter represents a contemporary medium that could connect patients and other interested individuals with information about clinical trials, including links on screening and enrollment. The ubiquity of current social media use and our findings suggest that tailored messages about clinical trials on Twitter could have utility, improve awareness, trial referral and perhaps enrollment.

Abstract not provided

Background:
The prevailing patient care model for lung cancer involves serial referrals among multiple clinical specialists. This practice may cause delays in diagnosis and treatment, patient/caregiver confusion and anxiety, poor communication among physicians, and diminished opportunities for patients to receive evidence-based care. The multidisciplinary care model may rectify these problems with the serial model, and thereby improve the quality and outcomes of care. However, the value of the multidisciplinary care model has not been objectively established. We collected the perspectives of key stakeholders on the 2 models of care. We sought to: examine the perceived strengths and weaknesses of each model; uncover potential barriers to establishing an effective multidisciplinary care program; and establish meaningful benchmarks with which to measure care delivery in both models. This work preceded a prospective comparative effectiveness study of the 2 models of care.

Methods:
We conducted 21 focus groups, involving 106 subjects (22 patients, 24 caregivers, 9 nurses, 8 hospital administrators, 4 executives of health insurance companies, and 39 physicians). The physicians included groups of medical and radiation oncologists, hospitalists, pulmonologists, thoracic surgeons, and primary care physicians. Patients had received care for a confirmed or suspected lung cancer in the Baptist Memorial Health Care System within the preceding 6 months. Disease stage ranged from early, with curative-intent treatment, to advanced-stage with palliative-intent care. Providers may or may not have had personal experience of the multidisciplinary model. We used verbatim transcripts of the audio recordings and field notes to analyze the content of each focus group session using Dedoose Software. We identified recurring themes and variants within and across the various stakeholder groups.

Results:
Several overlapping themes emerged. There was a perception that the multidisciplinary care improved physician collaboration, care coordination, accuracy of diagnosis, concordance with treatment recommendations, timeliness of care, efficiency of care-delivery, and patient satisfaction. Potential obstacles to successful implementation of the multidisciplinary care model included problems with physician reimbursement, the duration of the patient-physician interaction, and acceptability/integration of the model within the current health care infrastructure. These concerns were especially prevalent among physicians. Overcoming these barriers would require physician and patient education, efficient use of electronic medical records, and improving general awareness about the multidisciplinary care model. Identified evaluative benchmarks included measures of patient/caregiver experience and satisfaction, survival rates, timeliness of care, the quality of patient-physician communication, consistency of recommendations among physicians, and the adequacy of consultation times.

Conclusion:
The stakeholders in lung cancer care had broadly overlapping beliefs about optimal care delivery for lung cancer. However, they also had different expectations, and motivations. These competing factors have the potential to influence perceptions about the quality, efficiency, and effectiveness of lung cancer care delivery. Patients, caregivers, clinicians, administrators, and third-party payers were in favor of the multidisciplinary model for lung cancer care. However, key barriers must be addressed for optimal implementation. Meaningful stakeholder input is essential to improving the quality of lung cancer care.

Background:
Pemetrexed maintenance therapy (MT) after induction with platinum-based chemotherapy plus pemetrexed has recently become a concrete strategy of treatment for advanced non-squamous NSCLC patients, by extending survival, delaying disease progression, and maintaining quality of life. However, the benefit of the MT has to be weighed against the potential burden of a long-term treatment, and thus patients’ perception and preferences should be taken into account in the definition of the strategy of treatment.

Methods:
After conducting a focus group with 8 physicians dealing with NSCLC and concerning their opinions about the MT from a clinical and emotional point of view, a 12 questions-anonymous survey has been carried out in 13 Italian Oncologic Institutions and supported by WALCE (Women Against Lung Cancer in Europe), with the aim to evaluate patients' attitude toward the MT, the benefit they expected and to provide data about physicians awareness about patients’ inclinations. The Distress Thermometer Questionnaire has also been employed to perform a bio-psycho-social-spiritual assessment of the evaluated patients. Patients' evaluations have been performed at the beginning of chemotherapy (T0) and at the beginning of MT (T1), while physicians fill the survey only once during the study.

Results:
The survey has been prospectively (1st of December 2014-28th of February-2015) administered to 92 newly diagnosed advanced non-squamous NSCLC patients (58,7% male, median age 63,9 years), EGFR wilde-type, consecutively enrolled and suitable for first-line platinum/pemetrexed-based chemotherapy, and to 37 referring physicians (equally distributed per gender, with median age 41 years). To date, after platinum-based induction chemotherapy (median number of cycles 3,3, equally distributed between cisplatin and carboplatin), 24 of 92 patients enrolled (26,1%) have already started the pemetrexed MT. Main results are shown in Table 1. Most of the patients (73,9%) are in favor of MT. Until life expectation is over 3 months, data show agreement between patients' and physicians' perceptions of patients. When OS benefit drops at 1 month the two perceptions split: a lower percentage of patients (44,5%) would perform MT. By contrast, even without OS benefit, 71,3% of patients accept MT if it can increase symptom control. Figure 1



Conclusion:
Study is ongoing and data about T1 evaluations are still immature. Our preliminary data suggest the importance, when MT communication is done by the referral physician, to stress more symptoms control rather than survival rates.

Background:
Despite lung cancer being the leading cause of cancer death in developed countries, there is surprisingly little qualitative research that documents lung cancer patients’ diagnostic pathway and beyond. Recent evidence from the UK highlighted that people diagnosed with the disease will have had three or more consultations with their family physician (general practitioner, GP) before referral to a lung cancer specialist. This study aimed to document the diagnostic pathway from the patient perspective through qualitative interviews and process mapping. The study is one component of a lung cancer implementation research program in the Australian setting.

Methods:
We developed a qualitative interview schedule to conduct with patients and their caregivers. We recruited participants via treating clinician (respiratory physician/pulmonologist or medical oncologist) by sending a personal invitation letter. All patients were at least six months post-diagnosis at the time of first invitation and we obtained human ethics committee approvals. Interviews were conducted by telephone or face-to-face, according to the participant’s preference. All interviews were recorded, transcribed and coded using a coding framework developed by four members of the investigator team (SY, NR, ML, PB). The transcripts were coded in NVIVO 10 software. We interpreted the transcripts with two specific purposes in mind: first, to draw detailed maps of their journey, documenting the key points about which participants spoke about. Secondly, we conducted a content analysis and developed qualitative themes to understand and interpret patient journeys.

Results:
Twenty lung cancer patients participated in the qualitative interviews. Interviews took about one hour to complete. The patient journey maps provided rich data to understand the complexity of pathways that patients experience in the lead up to their lung cancer diagnosis, their subsequent treatment through to survivorship or palliation phase. A number of patients recalled very precise information about their journey and had recorded diary entries of key dates or times in their diagnostic pathway. We examined all the maps to identify common elements in the pathways. We used the qualitative material to understand how patient care was coordinated across the journey and will report on specific themes. In particular, we will highlight the theme of advocacy. It was evident that hospital-based clinicians were frequently perceived as the coordinator of their patient’s care. We will discuss their role in advocating for urgent patient diagnostic investigations when these were necessary. These clinicians were frequently perceived by patients as their advocates beyond diagnosis, as were GPs where the patient had an established relationship with this physician. We will also address the themes of patient anxiety and self-advocacy, and provide specific examples of how patients self-managed their care.

Conclusion:
The patient journey through lung cancer diagnosis is complex and qualitative interviews provide a rich source of information to better understand how clinicians and family physicians advocate for patients, and how some patients self-advocate in their care. The resulting patient maps and qualitative material will inform lung cancer implementation research projects to address the diagnostic pathway and improving patient care.

Abstract not provided

Background:
In health care several indicators are developed for measuring the quality of care. Many of these indicators address the process and structure of health care, rather than the outcome of treatment and aspects which are valuable for patients. Porter (N Engl J Med 2010 363;26) described a method concentrating on achieving high value for patients by identifying and prioritizing outcome measurements. In the project “Care for Outcome” of Santeon (a cooperation of six leading, top clinical hospitals in the Netherlands) we identified outcome indicators in lung cancer which are relevant for the patient and focus on treatment outcome, like survival and quality of life.

Methods:
The project was performed in two large, non-university teaching hospitals in the Netherlands. Our objective was to develop outcome indicators which are relevant for both patients and physicians. We evaluated patients with all stages and types of lung cancer. Using a “Care delivery value chain” (CDVC) scheme as developed by Porter, we identified determinants which are important for patients. Quality of life was evaluated by Patient Reported Outcome Measures (PROMs) at different times. Around 80 outcome indicators were found by literature research. These were classified by using the Outcome Measure Hierarchy and prioritized based on: impact on patient, influence of CDVC and statistical power. A first selection of 25 outcome indicators were then evaluated by an International Academic Council on lung cancer, a Methodological Advisory Council and representatives of the government, health insurance companies and patient federations. A final set of six indicators was selected based on quality of definition and feasibility of collection. A set of appropriate patient initial conditions was identified to be used for casemix correction.

Results:
The indicators which were formed in the “Care for Outcome” project were divided in three categories. The first category was survival: 1 and 2 year mortality after diagnosis, mortality 90 days after resection and 5-year survival using Kaplan-Meier curves and Cox-survival curves. The second category was recovery: the percentage of patients with positive resection margins and quality of life after 0, 3, 6, 12 months were evaluated. The third category concerned complications and adverse events: the percentage of patients with rethoracotomy, complications after resection and toxicity after (chemo)radiation were retrospectively measured over the years 2008-2011. Multivariate regression analysis showed that, in order of impact, tumor stage, performance status and age were the strongest predictors of outcome. Next to those, comorbidity (Charlson score) and pulmonary functioning (%FEV1 and %DLCO as a proxy of smoking history) were also relevant.

Conclusion:
In the “Care for Outcome” project we systematically developed a compact set of outcome indicators for patients with lung cancer focusing on the value of treatment for these patients. We started a retrospective data analysis, looking back four years, using these outcome indicators. These reports help us to better understand our quality of care and to improve our processes. In the near future these indicators will be collected prospectively and are feasible to be used to compare different treatment modalities and hospitals across the country.

Background:
Reducing health inequalities in oncology is a major public health priority in France, particularly in terms of social and geographic exclusion and equity of access to health care services. However, no specific registry currently exists for patients with lung cancer allowing description and comparison of local situations. Our aim was to use available National medico-administrative databases to constitute a nationwide population-based cohort study to analyze disparities among French areas (the TERRITOIRE study).

Methods:
We included all patients who had a first diagnosis of lung cancer between January 1rst and December 31th 2011 in the National hospitals databases (PMSI, Programme de Médicalisation des Systèmes d'Information). Patients’ data were linked to create a retrospective cohort study with a two-year follow-up period. The 22 administrative regions were considered in this analysis. In addition of demographic characteristics, metastatic status, comorbidities and treatment procedures, we assigned each patient to socioeconomic deprivation and urbanization scores based on their postcode of residence.

Results:
We identified 41,715 patients newly diagnosed for lung cancer. Mean age at diagnosis was 66.4(±11.9) years and most of patients were men (71.8%). Patients from socioeconomic deprived areas represented 27.5% of the whole lung cancer population, ranging from 9.6% to 55.2% according to the region. Incidences of lung cancer were 35.1 per 100,000 in women and 95.3 per 100,000 in men. Age-standardized incidences showed important disparities between French regions ranging from 27.5 to 55.0 and from 82.4 to 118.2 per 100,000 in women and men, respectively. Higher incidences were found in the northern and eastern regions for men and in the southern and eastern regions for women. Although patients living in rural areas were the larger group (34.5%), Age-standardized incidence significantly increased with urbanization: from 61.8 per 100.000 in rural areas to 73.9 per 100.000 in urban areas. A majority of patients was diagnosed at a metastatic stage (52.7%) and regional disparities were important ranging from 45.0% to 58.1%. This rate also appeared higher in patients diagnosed in public hospitals compared to private ones (56.1% vs 42.9%, p<0.0001) and in local hospitals compared to university ones (60.2% vs 49.6%, p<0.0001). Adjusted comparisons showed significantly higher incidences of stage IV patients at the time of diagnosis in five regions for men and two regions for women. A majority of patients (N=23,842; 57.2%) died in the hospital during the 2-year follow-up, including 15,642 patients (71.2%) having metastasis at the time diagnosis.

Conclusion:
We have demonstrated that a comprehensive population-based cohort using medico-administrative data is a suitable approach to illustrate disparities in lung cancer incidence, management care and outcomes in France. Data from this study should help local clinical teams and health stakeholders to better understand inequality issues in their areas.

Background:
Strict legislation and regulatory standards for the approval of drugs represent a safety guarantee for the population of any country. However, inappropriate delays in the process of evaluation of new medications have potentially serious consequences that can be measured. The objective of this analysis is to estimate the impact of the delay in the registration of medicines by the Brazilian regulatory agency, ANVISA, on the life span and life with symptoms related to the disease of patients who might potentially benefit from treatment. We use the example of crizotinib (Xalcori® Pfizer, NY, USA), which had its registration refused by the agency in 2014.

Methods:
We arbitrarily selected the 3-year period from August 2011 (FDA approval) to June 2014 (refusal by ANVISA) for this analysis. The number and prevalence of NSCLC cases eligible for treatment were estimated according to data from the Brazilian National Cancer Institue (INCA). The percentage of patients with ALK-positive tumors was inferred from the literature. We assumed that every ALK-positive NSCLC patient in Brazil would have access to the drug regardless if seeking treatment through the private or public health systems. The benefits from treatment with crizotinib were considered according to the published literature available at the time of regulatory assessment.

Results:
We estimated 24.460 new cases of NSCLC/year in Brazil (INCA), 70,6% (17.269) of which are diagnosed as advanced disease. Approximately 4,3% (743) would qualify as ALK positive. In a phase III crossover trial, crizotinib treatment ensued an improved PFS (3.0 vs. 7.7 mo; HR 0.49, p<0.001) and a significant extension in the median time to deterioration of symptoms (1.4 vs. 5.6 mo; p<0.001) when compared to standard second line chemotherapy. Survival estimates were obtained from a retrospective analysis (Shaw et al. Lancet 2011) as follows: chemotherapy 6.0 vs. crizotinib 20.3 months. We estimated 707 prevalent cases of ALK+ NSCLC in Brazil at the start of our analysis and 62 new cases per month during the 3-year analysis period were projected. Applying the premises above we calculated 1.367 years of life lost, and 772 additional patients who would remain alive after the selected period between August 2011 and July 2014. Furthermore, a total of 846 years of life free of symptoms’ deterioration are lost with the associated human suffering during the same period of time.

Conclusion:
The delay in the analysis, approval and registration process of new medications in Brazil and other developing or developed countries has an important impact in terms of human lives that can be potentially measured or estimated. While this kind of scrutiny has clear methodological limitations to consider, our main objective in this analysis is to raise the issue of the urgent need for a detailed and transparent evaluation of all the steps involved in the evaluation and registration process to stall this unnecessary suffering and loss of human life.

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Background:
Cachexia is a debilitating condition often observed in patients with advanced non-small cell lung cancer (NSCLC). A decrease in body weight (BW), in particular loss of lean body mass (LBM), is a primary characteristic, and is associated with worsening functional status, quality of life, and survival. Despite the high prevalence and substantial clinical impact of cachexia in patients with advanced cancer, limited therapeutic options exist. Anamorelin is a novel, orally active, selective ghrelin receptor agonist that mimics the appetite-enhancing and anabolic effects of ghrelin. ROMANA 1 and 2 are two randomized, double-blind, Phase III trials evaluating the efficacy and safety of anamorelin in patients with advanced NSCLC and cachexia.

Methods:
In ROMANA 1 (NCT01387269; N=484) and ROMANA 2 (NCT01387282; N=495), patients with unresectable stage III/IV NSCLC and cachexia (≥5% weight loss during prior 6 months or body mass index <20kg/m[2]) were randomized (2:1) to anamorelin 100 mg daily or placebo, for 12 weeks. Co-primary endpoints were change in LBM and handgrip strength (HGS) over 12 weeks. Secondary endpoints included change in BW and in the anorexia/cachexia domain of the Functional Assessment of Anorexia/Cachexia Therapy questionnaire over 12 weeks, and pooled 1-year overall survival (OS) from both studies. Exploratory endpoints included summarizing the incidence of patients who maintained/gained LBM from baseline during 12 weeks by treatment group. Post-hoc analysis compared OS data in patients who had decrease in LBM during 12 weeks versus those who maintained/gained LBM. Safety and tolerability of anamorelin were also evaluated.

Results:
Over 12 weeks, anamorelin significantly increased median LBM versus placebo in ROMANA 1 (1.10 vs –0.44 kg; p<0.001) and ROMANA 2 (0.75 vs –0.96 kg; p<0.001); in both studies there was no difference in HGS changes between treatment arms. A significantly greater proportion of patients in the anamorelin arm versus the placebo arm maintained/gained LBM in both ROMANA 1 (58.1% vs 36.9%; p<0.001) and ROMANA 2 (51.5% vs 26.5%; p<0.001). Post-hoc analysis showed that OS was improved for patients who maintained/gained LBM versus patients who lost LBM (HR, 0.53 [95% CI, 0.42, 0.68]; p<0.001). Anamorelin-treated patients also significantly gained BW (2.20 vs 0.14 kg; p<0.001, and 0.95 vs –0.57 kg; p<0.001), and had significantly improved anorexia-cachexia symptoms and concerns (4.12 vs 1.92; <0.001, and 3.48 vs 1.34; p=0.002), compared with placebo-treated patients, in ROMANA 1 and 2, respectively. The most frequent drug-related adverse event (AE) in the anamorelin arm in both ROMANA 1 and 2 was hyperglycemia (5.3% and 4.2%); there were few drug-related grade ≥3 AEs in the anamorelin arm versus the placebo arm (0.9% vs 1.2% and 2.7% vs 2.5%).

Conclusion:
Anamorelin significantly increased LBM and BW, and improved anorexia-cachexia symptoms and concerns, compared with placebo, in patients with advanced NSCLC and cachexia. Change from baseline in HGS was similar in both treatment arms. A significantly greater proportion of patients maintained/gained LBM in the anamorelin arm versus the placebo arm. When LBM was stable or increased, OS was significantly improved. Anamorelin treatment over 12 weeks was also well tolerated.

Background:
Cancer cachexia is characterized by decreased body weight (BW), mainly lean body mass (LBM) and negatively impacts quality of life (QOL) and prognosis. ONO-7643/anamorelin (ANAM) is a novel selective ghrelin receptor agonist with appetite-enhancing and anabolic activity.

Methods:
ONO-7643-03 was a double-blind, exploratory Phase 2 trial assessing ANAM efficacy and safety in Japanese non-small cell lung cancer (NSCLC) patients with unresectable stage III/IV NSCLC, ECOG performance status (ECOG PS) 1-2 and cachexia (main criteria: ≥5% weight loss within prior 6 months). Patients were randomized to ANAM at 100 or 50 mg, or placebo, given daily orally for 12 weeks. Co-primary endpoints were change from baseline over 12 weeks in LBM (measured by DXA) and handgrip strength (HGS). Secondary endpoints included change in BW, ECOG PS, Karnofsky performance scale (KPS) and QOL assessment (QOL-ACD).

Results:
Demographics were balanced (N=180); median age=66 yr, male (68.9%), ECOG PS=1 (77.5%) and stage IV (76.1%). Treatment effects: the change in LBM over 12 weeks was 0.55 kg in the placebo arm and 1.15 kg in the ANAM 100 mg arm, and the change in LBM at both Weeks 8 and 12 showed significant differences between ANAM 100 mg and placebo (p<0.05). However, the change in HGS was similar between arms at both time points. The change in BW to Weeks 12 was -0.93 kg in the placebo arm vs +0.54 kg in the 50 mg arm and +1.77 kg in the 100 mg arm, and was significantly different between the 100 or 50 mg arms and the placebo arm at all time points (p<0.05). The cumulative rate of deterioration of ECOG PS was lowest in the 100 mg arm, and ANAM 100mg significantly improved KPS and QOL-ACD compared to placebo at Weeks 4 and 12 (p<0.05). Regarding safety, ANAM treatment for 12 weeks was well tolerated. While median survival time (MST) was not significantly different between active treatment arms and placebo, MST of patients with BW loss was significantly shorter than those without (215 vs 327 days; p=0.0055).

Conclusion:
This phase 2 study demonstrated that ANAM has promising potential in improving body composition, performance status and QOL in patients with cancer cachexia.

Background:
Lung cancer is the most common cancer worldwide with first-line chemotherapy treatments consisting predominantly of emetogenic platinum agents. Chemotherapy-induced nausea and vomiting (CINV) can be prevented in most patients with appropriate combination antiemetic regimens. The antiemetic standard-of-care for patients receiving cisplatin consists of a combination of a NK~1~ receptor antagonist (NK~1~RA), a 5-HT~3~ RA, and dexamethasone (DEX). Adherence to antiemetic guidelines is unacceptably low with patients frequently not receiving recommended antiemetic combinations. NEPA has been developed as the first oral antiemetic combination; it delivers guideline-consistent prophylaxis with its combination of a highly selective NK~1~ RA (netupitant [NETU] 300 mg) and the pharmacologically/clinically distinct 5-HT~3~ RA, palonosetron (PALO 0.50 mg). NEPA has demonstrated superior prevention of CINV compared with oral PALO. The intent of this retrospective analysis was to evaluate the efficacy of NEPA in a subset of lung cancer patients from two of the pivotal trials.

Methods:
Patients in two randomized, double-blind trials received a single dose of NEPA on Day 1 prior to cisplatin- or carboplatin-based chemotherapy. Three dose groups (NETU 100/200/300 mg + PALO 0.50 mg) showing similar efficacy were pooled in Study 1, while all patients in Study 2 received NETU 300mg/PALO 0.50 mg. All patients also received oral DEX on Day 1 (carboplatin) or Days 1-4 (cisplatin). Study 1 was single cycle, while Study 2 included evaluation over multiple chemotherapy cycles. The focus of this analysis was on the efficacy of NEPA only, as a PALO comparator group was included in only one of these studies. Endpoints were complete response (CR: no emesis, no rescue) and no significant nausea (max <25 mm on 100 mm visual analog scale) during the acute (0-24h), delayed (25-120h), and overall (0-120h) phases.

Results:
231 patients (78% males, 22% females) with lung cancer received NEPA; 152 patients received cisplatin and 79 received carboplatin as initial chemotherapy. CR rates in Cycle 1 exceeded 90% in Study 1 and 80% in Study 2 (Table). As expected, overall nausea rates were somewhat lower than CR rates (87% Study 1, 80% Study 2). Overall CR rates were maintained over subsequent cycles in Study 2 (87%, 95% and 94% in Cycles 2-4, respectively). Figure 1



Conclusion:
As a combination antiemetic agent targeting two critical pathways associated with emesis, NEPA offers a convenient and highly effective option for prevention of CINV in lung cancer patients receiving platinum-based emetogenic chemotherapy.

Background:
Despite several improvements in surgical techniques and postoperative management, tissue healing and infection related complications comprise substantial amount of morbidity associated with major lung resections. Perioperative use of immunomodulating diets in order to decrease the risk of acquired infections and wound complications remains controversial. This study aims to investigate the impact of perioperative immunonutrition over a standard regimen in decreasing tissue healing and infection related morbidity and if any, its relation to immune cell function in patients undergoing major lung resection for NSCLC.

Methods:
Seventy-eight patients undergoing a major lung resection for NSCLC were randomized into two groups to receive either study formula enriched with L-arginine, nucleotides and ω-3 polyunsaturated long-chain fatty acids (Group S; n=39) or isocaloric and isonitrogenous standard formula (Group C; n=39) starting at least 4 days prior to scheduled operation and discontinued on the 8th postoperative days at the earliest. At least half of the required daily calorie intake of each patient was supplied with their assigned nutrition formula. Primary outcome of the study was incidence of tissue healing and infection related morbidity, including prolonged air leak, bronchopleural fistula, wound infection, empyema, pneumonia and sepsis leading to prolonged hospital stay and/or both ICU and hospital readmissions. Leukocyte (WBC) and Lymphocyte counts, CRP, and ratio of CD4/CD8 were also obtained as secondary outcomes at 4 different time points (t1=Randomization; t2= 1st postoperative day; t3= Prior to discharge or 7th postoperative day; t4= 1st outpatient visit following discharge).

Results:
Demographic and preoperative clinical characteristics were comparable between the groups. All patients achieved targeted nutritional support during the study period. Incidence of tissue healing and infection related morbidity was significantly higher in Group C than in Group S [20 (51%) vs. 9 (23%); p=0.02)]. Cumulative rate of both ICU and hospital readmissions were also higher in Group C than in Group S [12 (31%) vs. 4 (10%), respectively; p=0.049], although this difference was not reflected to the median length of hospital stay [5 (4-7) vs. 5.5 (4-9) days, respectively; p=0.12]. Compared to randomization, WBC was significantly higher in Group C than in Group S throughout the postoperative period (8.0x10[3] vs. 8.1x10[3], 14.0x10[3] vs. 12.1x10[3], 12.2x10[3] vs. 10.4x10[3] and 11.8x10[3] vs. 9.8x10[3] for t1, t2, t3 and t4, respectively; p=0.01). Lymphocyte counts as percentages of total WBC declined considerably during the postoperative period in both groups; however this drop was significantly more evident in Group C than in Group S (22.7% vs. 23.5%, 10.2% vs. 16.7%, 14.8% vs. 18.9% and 16.8% vs. 18.7% for t1, t2, t3 and t4, respectively; p=0.01). Confirming the favorable effect on immunity, CD4/CD8 ratio was significantly higher in Group S during postoperative period, reaching its maximum value at t3 (1.6 vs. 1.5, 1.8 vs. 1.3, 2.2 vs. 1.5 and 2.0 vs. 1.4 for t1, t2, t3 and t4, respectively; p=0.02).

Conclusion:
This study suggests that supplementary immunonutrition enriched with L-arginine, nucleotides and ω-3 polyunsaturated long-chain fatty acids may help reducing the incidence of tissue healing and infection related complications in patients undergoing lung resection for NSCLC.

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Background:
Irreversible tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR) such as afatinib have shown clinical benefits and prolonged survival in patients with NSCLC. Weight loss and sarcopenia are common in NSCLC patients and have been recognized as important prognostic factors of toxicity and survival. The aim of this study was to assess the impact of muscle and

Methods:
Patients diagnosed with NSCLC, who progressed to prior chemotherapy, received 40 mg of afatinib. Skeletal muscle (SM) was quantified by computed tomography scan analysis using pre-established Hounsfield (HU) unit threshold and lean body mass (LBM) was calculated with the following formula: LBM (kg)=(0.30 × (skeletal muscle area at L3 using CT (cm[2]))+6.06). These variables were estimated at baseline (T0) and after four months of treatment with afatinib (T1).

Results:
Eighty-four patients were assessed at baseline. 70.2% were female, mean age was 59.3±1.6 years, 94% had adenocarcinoma, 53.6% received afatinib as 2nd line of treatment, and 91.7% had a good performance status (ECOG 0-1). Patients included were both EGFR+ (23.8%) and EGFR- (76%). Body composition evaluation was obtained at T0 and T1 in 46 patients, median differences (∆) between T0 and T1 for SM, LBM and weight were -1.4(-56.8, +27.9 cm[2]), -0.42(-17,-8 kg) and -0.1(-12,+6), respectively, and were not statistically significant. Median OS and PFS were 23.8(17.9-29.7) months and 8.9(5.5-12.4) months, respectively (including EGFR+ and EGFR-). Weight loss was not statistically associated with poorer OS or PFS. However, SM and LBM loss greater that the median had a negative impact on PFS and OS. Figure 1(Figure1).



Conclusion:
SM and LBM changes throughout treatment with EGFR TKIs should be evaluated. Nutritional interventions should be focused on the maintenance of SM and LBM. Further clinical trials should focus on interventions improving these body composition variables since they are associated with better OS and PFS in patients with NSCLC treated with afatinib.

Background:
The systemic immunonutritional status has been postulated as related to the long-term prognosis in various cancer types. However, no studies have assessed the prognostic role of prognostic nutritional index (PNI) on the survival of patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)-activating mutations and receiving tyrosine kinase inhibitors (TKIs).

Methods:
Advanced NSCLC patients with sensitive EGFR mutations (19 deletion or L858R in exon 21) were retrospectively screened. The PNI was calculated as 10 x serum albumin value (g/dl) + 0.005 x peripheral lymphocyte count (per mm3). Univariate and multivariate analysis were performed to assess the prognostic value of relevant parameters.

Results:
144 cases were included for analysis after eligibility review. The optimal cut-off value of PNI for OS stratification was determined as 48.78 according to a R software-engineered, web-based system. Low PNI was significantly associated with elevated CRP level (p<0.0001) and non-response to TKIs (p=0.002). High PNI (high vs low, 35.10 vs 25.67 months; HR, 0.44; 95 % CI, 0.25–0.77; p = 0.004) correlated to superior OS. Survival analysis identified PNI as an independent prognostic factor(p=0.012). Subgroup analysis revealed that PNI was generally a significant prognostic factor in different clinical situations.

Conclusion:
Low PNI correlates with worse survival in patients with advanced NSCLC harboring EGFR sensitive mutations and treated with EGFR-TKIs. The assessment of PNI could assist the identification of patients following EGFR-TKIs treatment with poor prognosis and has implications for the routine monitoring and treatment.

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Abstract:
Background Brain metastases are an important clinical problem in patients with small cell lung cancer (SCLC), with 20% of patients having them at diagnosis and about 80% at autopsy. In patients with LS-SCLC, prophylactic cranial irradiation (PCI) significantly reduces the risk of brain metastases, and it improves survival [1]. A meta-analysis showed a survival benefit of almost 6% at 3 years with PCI (21 vs 15%). A subsequent international multi-center study comparing higher and lower dose PCI found no improvement in outcomes with higher doses [2]. Consequently, a dose of 25 Gy in 10 fractions remains the standard dose for PCI. Since the risk of brain metastases is even higher in patients with ES-SCLC, PCI has also been investigated in these patients.A randomized EORTC study showed that PCI both reduced the risk of brain metastases and improved overall survival [3]. Survival at 1 year was 27% for the patients who received PCI compared to 13% for the controls. Interestingly, patients who received PCI were more likely to receive 2[nd] or 3[rd] line chemotherapy with subsequent disease progression (68 vs45%), presumably because they remained fitter without brain metastases. PCI was well tolerated in the effect on quality of life was small and transient [4]. The beneficial effect of of PCI was underscored in the recent CREST trial, where the risk of brain metastases was less than 5% [5]. Controversies surrounding the use of PCI Firstly, PCI can have a negative effect on cognition [6], with important risk factors being advanced age, pre-existing cerebrovascular problems, diabetes and the use of anti-epileptics. It should however be appreciated that brain metastases by themselves also have an important negative effect on cognition and quality of life. Moreover, SCLC patients may have impaired cognitive functioning in comparison with healthy controls, independent of the use of chemotherapy or radiotherapy. Another point to consider is that metastases in SCLC, often are multiple with limited options for high dose (stereotactic) radiotherapy, in contrast to NSCLC. Use of radiotherapy techniques that reduce doses to the hippocampus [7], as well as the use of Alzheimer drugs drugs such as memantine and donezepil [8] may further mitigate the effect of PCI. The effectiveness and safety of these approaches remains to be be evaluated in prospective clinical trials. Second, it has been questioned whether PCI will continue to show a beneficial effect if a brain MRI is repeated after completion of chemotherapy, in order to eliminate some subclinical metastases. This is discussion intensified after the presentation of a Japanese study in 2014 [9]. In the study, MRI brain was not only performed after chemotherapy, but also at regular intervals during the follow-up. Any brain metastases detected were treated with radiotherapy or radiosurgery. The study was designed as a superiority study for PCI, with overall survival as primary endpoint, but closed early due to futility. The likelihood of finding a survival benefit of PCI was less than 0,1%, but the discussion was fueled by the incorrect and misleading title using the word ‘detrimental’. Due to slow accrual, the Japanese study enrolled 160 patients entered from 40 centers in 4 years, thereby suggesting that patient selection may have played a roll. The publication of this analysis is awaited with interest. In order to address this topic from another angle, we have re-analyzed the effect of PCI on brain metastases and survival in a previous EORTC PCI study, after excluding patients who either died or developed brain metastases in the first 8 weeks after randomization, as such patients may have had asymptomatic brain metastases, visible if an MRI would have been performed. Even after exclusion of these patients, the EORTC PCI trial found a significant effect on brain metastases (HR 0.40; p<0.001) and overall survival (HR0.74; p=0.035) [unpublished data]. Conclusion In conclusion, PCI should remain standard of care in SCLC patients who have responded to chemotherapy. The pros and cons of PCI should be individually weighted and discussed with the patient. Some promising new techniques undergoing evaluation now may reduce the side-effects of PCI. References 1. Aupérin A, Arriagada R, Pignon JP, et al.. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med. 1999 Aug 12;341(7):476-84. 2. Le Péchoux C, Dunant A, Senan S, et al. Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised clinical trial. Lancet Oncol. 2009 May;10(5):467-74. 3. Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med. 2007 Aug 16;357(7):664-72. 4. Slotman BJ, Mauer ME, Bottomley A, et al. Prophylactic cranial irradiation in extensive disease small-cell lung cancer: short-term health-related quality of life and patient reported symptoms: results of an international Phase III randomized controlled trial by the EORTC Radiation Oncology and Lung Cancer Groups. J Clin Oncol. 2009 Jan 1;27(1):78-84. 5. Slotman BJ, van Tinteren H, Praag JO, et al. Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet. 2015 Jan 3;385(9962):36-42. 6. Gondi V, Paulus R, Bruner DW, et al. Decline in tested and self-reported cognitive functioning after prophylactic cranial irradiation for lung cancer: pooled secondary analysis of Radiation Therapy Oncology Group randomized trials 0212 and 0214. Int J Radiat Oncol Biol Phys. 2013 Jul 15;86(4):656-64. 7. Kundapur V, Ellchuk T, Ahmed S, Gondi V. Risk of hippocampal metastases in small cell lung cancer patients at presentation and after cranial irradiation: a safety profile study for hippocampal sparing during prophylactic or therapeutic cranial irradiation. Int J Radiat Oncol Biol Phys. 2015 Mar 15;91(4):781-6 8. Day J, Zienius K, Gehring K, et al. Interventions for preventing and ameliorating cognitive deficits in adults treated with cranial irradiation. Cochrane Database Syst Rev. 2014 Dec 18;12:CD011335. 9. Seto T, Takahashi T, Yamanaka T, et al. Prophylactic cranial irradiation (PCI) has a detrimental effect on the overall survival (OS) of patients (pts) with extensive disease small cell lung cancer (ED-SCLC): Results of a Japanese randomized phase III trial. J Clin Oncol 32 (Suppl) Jun 11, 2014, abstract 7503

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Abstract:
Fewer than 20% of all lung cancers are small cell lung carcinomas (SCLCs). As SCLC is an aggressive tumor because of its high and early risk of dissemination, most patients (60-70%) have metastatic disease at diagnosis. Given the high propensity of SCLC for early metastatic dissemination, chemotherapy has been and still is the cornerstone of treatment based on etoposide and platinum, but SCLC is also very sensitive to radiotherapy. Median survival for patients with non-metastatic disease for whom the standard treatment is combined chemotherapy and thoracic radiotherapy, as well as prophylactic cranial irradiation (PCI), is currently 15–20 months, with 20–40% surviving to 2 years, and 25% surviving at 5 years in the best series. For metastatic patients, median survival is 8–13 months and 2 year survival is around 5%. Recent advances in SCLC management derive mostly from a better integration of chemotherapy and radiotherapy. So patients with a limited number of metastases in number and location may have an intermediate outcome; and local treatment of both the primary tumor as well as oligometastatic disease could be discussed. Such an approach is supported by the fact that many patients in early studies that established the role of thoracic radiation therapy in limited disease would now be considered as having metastatic disease. The percentage of such metastatic patients seems to have increased partly because of stage migration with the more frequent use of PET scan and brain MRI. Thus there is a category of patients with oligometastatic disease for whom local treatment may be envisaged. The oligometastatic status was first described by Hellman and Weichselbaum as an intermediate clinical state between locoregionally confined and widespread cancer in 1995. There has been strong interest lately in this subgroup of non-small cell lung cancer oligometastatic patients, with the development of stereotactic ablative radiotherapy. Until recently, there were few data supporting the role of radiation therapy in metastatic small cell lung cancer, except PCI. As there are few therapeutic options in second line, local treatment approaches have been evaluated in extensive disease. Prophylactic cranial irradiation is now part of the standard treatment in responders and more recently a phase III trial has shown that consolidation thoracic radiotherapy could improve outcome. The 2-year survival rate was 13% in the investigational arm versus 3% in the control arm where patients had 4-6 cycles of chemotherapy and PCI [Auperin, 1999; Slotman 2007; Slotman, 2015]. A randomized phase II trial (RTOG 0937) went further in the local approach of metastatic disease after systemic chemotherapy and really addressed the issue of oligometastatic disease [Gore, RTOG 0937]. It compared PCI to PCI and consolidative radiation therapy not only to the primary intrathoracic disease but also to residual extracranial metastatic lesions (1-4 extracranial metastases who achieve a CR/PR following chemotherapy). The trial has included 96 patients and has closed recently after a planned protocol interim analysis. Results are eagerly awaited. Even if there are studies supporting the role of radiotherapy in metastatic SCLC, new strategies are needed for this category of patients. There are promising preclinical data showing a strong synergy between radiotherapy and immune treatments. Such approaches are starting to be explored in SCLC in prospective studies.

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