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Abstract
Symptom clusters is a relatively new field of study, recognizing that patients are often experience multiple concurrent symptoms and some of them may be interlinked. Understanding these clusters may improve the management of unrelieved symptoms in patients with lung cancer. A symptom cluster is defined as two or more symptoms that are related to each other and that occur together (Kim et al, 2005; Molassiotis et al, 2010). A small amount of research has highlighted over the past decade the different symptom clusters that are reported by patients with lung cancer. Brown et al (2011) have shown a five-symptom cluster that includes fatigue, breathlessness, cough, pain and anorexia, present in 64% of women with lung cancer. Henoch et al (2009) identified three clusters, including a pain cluster (pain, nausea, bowel issues, appetite loss, fatigue); a mood cluster (mood, outlook, concentration, insomnia), and a respiratory cluster (breathing, cough). The latter respiratory cluster has also been shown with our own work and it was stable at various assessments over the first 12 months from diagnosis (Molassiotis et al, 2010). Depression, fatigue and pain is another one (Fox & Lyon, 2006) as is pain, fatigue and insomnia (Hoffman et al, 2007). On the clinical level, it is suggested that physicians and oncology nurses should think in terms of these naturally clustering symptoms when recommending plans for symptom management, in order to be more effective in the overall management of a larger spectrum of symptoms. However, all these studies have some methodological shortcoming, as many of the identified clusters reflect the measurement symptom tool used each time, some have small sample sizes and are often secondary analyses. Patients who experience symptom clusters are more distressed and have more severe symptom-reporting than those who experience single symptoms, and they form a particular group of patients in need of more careful intervention. More recently we have carried out a qualitative study with 19 patients and their caregivers assessed at diagnosis, and 3, 6 and 12 months post-diagnosis. We have identified, for a first time using such methodology and the patients experience, a consistent and stable symptom cluster of fatigue, breathlessness and cough, which we called it ‘respiratory distress’ symptom cluster (Molassiotis et al, 2011). Two other messages came out clearly from this study: a) that the patients’ symptom experiences and coping efforts need to be understood within the context of a panorama of symptoms which frequently co-occur and which may interact in complex ways. This suggests that it may therefore be potentially problematic within the lung cancer population to determine a patient's experience of a single symptom in isolation given the complex array of symptoms that patients may experience. b) cough, which is under-represented in research within this population, may play an important role in shaping the patients' symptom experience, and may be linked with breathlessness more strongly than we currently think. Also both breathlessness and cough lead to anxiety and emotional distress. How do we improve the symptom cluster experience? We need to develop symptom interventions that are moving from a reductionist model of focusing on a single symptom to understanding the clinical usefulness and relationships of symptoms through symptom clusters and developing interventions that affect all symptoms in the cluster. This area is still in its infancy and there are only a couple of ongoing trials with such more ‘complex’ interventions. How do these broader interventions look like? Complementary therapies may be good ‘candidates’ for such an approach; indeed, we have carried out a trial using acupuncture to manage cancer-related fatigue in breast cancer patients, and we have seen that many patients reported also reductions in hot flushes and joint pains too. Mindfulness therapy may be a good option for the common mood-related symptom cluster. Educational interventions could also be appropriate approaches. However, how one structures and develops a new intervention to attend to clusters of symptoms needs significant thinking and energy. Our team is currently testing a new such intervention focusing on the respiratory distress symptom cluster. However, to ‘shape’ the intervention we followed several steps: Through patient and caregiver interviews (Ellis et al, 2012) important implications for patient participation and adherence to the intervention were identified, including the perceived relevance of potential techniques; appreciable benefits in the short-term; convenience; patient preferences; timing of the intervention; venue; caregiver involvement; the provider of the intervention, and contact with other patients. Through health care professionals’ focus group interviews (Wagland et al, 2012) it was clear that to have a successful intervention we had to consider also staffing time and space, and there was a recognition that the preference of most patients to make as few hospital visits as possible also complicated the teaching of such interventions. Moreover, it was recognized that there may only be a small window of opportunity in which to effectively teach lung cancer patients a novel non-pharmacological intervention as the period between diagnosis and the onset of severe symptoms is often short. Finally, we assessed patient preferences for the intervention components through a discrete choices experiment (Molassiotis et al, 2012). After this work, we developed the intervention that includes primarily diaphragmatic breathing exercises, cough suppression exercises, and acupressure (main intervention) together with anxiety management, vocal hygiene, and energy conservation techniques, delivered through two educational sessions as a self-management strategy that involves both patients and caregivers. Currently we are testing this intervention in a pilot trial aiming to explore the impact of this novel non-pharmacological supportive intervention on symptom distress, coping and service utilisation in patients with lung cancer and their caregivers, and to test the feasibility of carrying out a trial using this intervention, including practical and logistical issues of providing the intervention in practice. The trial has currently recruited 60/100 patients and is envisaged to complete recruitment by the end of 2013. Preliminary findings from the trial will be presented.

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An estimated 225,000 men and woman will be diagnosed with lung cancer in 2013 (NCI-SEER Data). Approximately 80% of lung cancer patients will be diagnosed with non-small cell lung cancer (NSCLC), and an estimated 25% will present with early-stage or operable disease (Jones 2009). The overall 5 year survival rate for lung cancer is 16%. However, if detected early the survival rate is 53% (ACS 2010). Improvements in surgical techniques, coupled with more effective chemotherapy regimens, have led to significant survival gains for patients with operable disease (Jones 2009). With improved survival rates, long-term treatment sequelae and quality of life (QOL) are gaining increasing attention in terms of post-treatment management of early stage patients. For patients with inoperable or more advanced disease, measures to improve symptoms and QOL are also being evaluated. An individual is considered a cancer survivor from the time of diagnosis, through the balance of his or her life (NCI- Survivorship Definitions 2004). Lung cancer survivors may experience a myriad of long-term and late effects related to their diagnosis and treatment exposures. Symptoms may include dyspnea, fatigue, decreased physical endurance, depression, inability to sleep and weight loss (Anderson 2011). Anticipated age-related losses in physical function and comorbidities such as chronic obstructive pulmonary disease (COPD), ischemic heart disease and hypertension can add to post treatment complications, long term effects and overall recovery. Exercise therapy continues to gain recognition as an effective intervention in cancer rehabilitation. While early studies mainly focused on breast cancer survivors, a growing number of studies have been conducted over the past several years evaluating exercise following a lung cancer diagnosis in the post treatment setting. A review of literature suggests lung cancer patients are good candidates for pulmonary rehabilitation following treatment. Peddle-McIntyre et al describe progressive resistance exercise training, or PRET, as an intervention that has been successful in improving muscular strength, body composition, physical fitness, physical function and QOL in some cancer survivor groups citing, however, that no studies have focused solely on lung cancer survivors. Their prospective study including early stage NSCLS survivors who had undergone surgical resection preliminarily revealed significant improvement in muscle strength, muscular endurance and peak inspiratory pressure. The 6-minute walk distance (6MWD), regarded as a prognostic indicator in certain chronic illnesses, also demonstrated improvements suspected to correlate with preserving body function and delaying onset of mobility limitations. Several studies have demonstrated the benefits of exercise in COPD patients, who are known to experience respiratory symptoms comparable to lung cancer patients. A prospective study conducted by Anderson et al utilized an established COPD rehabilitation program in lung cancer patients to evaluate impact on fitness and QOL. Patients who had undergone pulmonary surgery as well as those who were surgically ineligible (comprising the majority of participants) were included in the study. Interventions included supervised exercise in the clinic setting and instruction on home exercising. Walking was the main element. Results showed improved physical fitness and performance as measured by the Incremental Shuttle Walk Test (ISWT), Endurance Shuttle Walk Test (ESWT) and spirometry after the exercise intervention. Pulmonary function and self reported QOL, however, did not demonstrate improvement. Spruit et al (2006) conducted a non-randomized clinical trial in patients who had a history of surgery, chemotherapy and/or radiotherapy evaluating an inpatient rehabilitation program on pulmonary function, 6MWD and peak cycling load. Patients were trained in daily cycling, walking, weight training, and gymnastics (focusing on flexibility and mobility). No change was seen in pulmonary function post intervention. However, significant improvements were seen in the 6MWD and peak cycling load. Symptom scores for dyspnea and fatigue also improved significantly. In focusing on patients with newly diagnosed advanced NSCLC with good performance status, Temel et al conducted a study to determine feasibility of implementing a twice weekly physical therapy (PT) run program using aerobic exercise (bicycle and treadmill) and weight training. Functional capacity as measured by the 6-minute walk test (6MWT), muscle strength, QOL and lung cancer symptoms and fatigue were evaluated. Results included no significant post intervention improvement in QOL or fatigue. Lung cancer symptoms, though, were significantly improved. Additionally, no deterioration in the 6MWT or muscle strength were reported. Lastly, Jones et al (2008) studied the effects of aerobic cycle training on changes in VO2peak and QOL among post surgery NSCLC patients. Results included increased VO2peak, improved QOL and decreased fatigue. Exercise therapy is becoming increasingly acknowledged as an integral component of cancer rehabilitation. The limited literature focusing on lung cancer survivors at different stages post diagnosis support exercise training as safe and well tolerated (Jones 2009). Adherence and ability to complete prescribed programs remains an issue, not surprisingly, for this patient population. While studies thus far have other limitations, they illustrate the need for large randomized trials to better determine the timing, support and specific interventions that will optimally benefit lung cancer survivors. References Available as a separate document

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Abstract
. Although EGFR mutations and fusions involving ALK and ROS1 are targetable by currently approved agents, these alterations are present in less than a fifth of patients with non-squamous NSCLC. Treatment options for the majority of patients remain largely empirical. The urgent need to develop therapies capable of targeting cancers without these alterations can only occur with a better understanding of the molecular biology and cytogenetic alterations. Recently, the lung cancer mutation consortium reported longer survival in patients with adenocarcinoma who underwent multiplexed genomic testing for the detection of alterations in 10 genes, and subsequently received matched targeted treatments. [Johnson et al J Clin Oncol 31, 2013 (suppl; abstr 8019)]. A total of 1,007 patients were screened for at-least one genetic alteration, and an actionable alteration that led to the use of targeted therapies was detected in 28% of these patients. The median survival in these patients was 3.5 years, while patients whose tumors did not harbor actionable alterations had a median survival of 2.1 years. It would be reasonable to assume that adapting NGS technologies, which allow comprehensive screening of the entire genome at a higher resolution, will result in improved outcomes in patients whose tumors do not harbor targetable mutations identifiable by commercially available assays. NGS has allowed a better characterization of lung cancer, with the identification of novel mutations and copy number alterations. Preliminary results from TCGA demonstrated that a significant percentage of patients with lung cancer harbor a targetable abnormality. It is still possible that additional less common mutations or alterations will be discovered once the sequencing of 1000 lung cancer samples is completed by TCGA. The next challenge is the development of novel drugs based on specific targetable abnormalities. Although this strategy may require extensive evaluation and multiple trials targeting distinct molecular subtypes of tumors, this departure from the empirical treatment of lung cancer, probably represents the best hope towards achieving meaningful progress.