Six versus 12 months' adjuvant trastuzumab in patients with HER2-positive early breast cancer: the PERSEPHONE non-inferiority RCT.

BACKGROUND: The addition of adjuvant trastuzumab to chemotherapy has significantly improved outcomes for people with human epidermal growth factor receptor 2 (HER2)-positive, early, potentially curable breast cancer. Twelve months' trastuzumab, tested in registration trials, was adopted as standard adjuvant treatment in 2006. Subsequently, similar outcomes were demonstrated using 9 weeks of trastuzumab. Shorter durations were therefore tested for non-inferiority. OBJECTIVES: To establish whether or not 6 months' adjuvant trastuzumab is non-inferior to 12 months' in the treatment of HER2-positive early breast cancer using a primary end point of 4-year disease-free survival. DESIGN: This was a Phase III randomised controlled non-inferiority trial. SETTING: The setting was 152 NHS hospitals. PARTICIPANTS: A total of 4088 patients with HER2-positive early breast cancer who it was planned would receive both chemotherapy and trastuzumab took part. INTERVENTION: Randomisation (1 : 1) to 6 months' or 12 months' trastuzumab treatment. MAIN OUTCOMES: The primary end point was disease-free survival. The secondary end points were overall survival, cost-effectiveness and cardiac function during treatment with trastuzumab. Assuming a 4-year disease-free survival rate of 80% with 12 months' trastuzumab, 4000 patients were required to demonstrate non-inferiority of 6 months' trastuzumab (5% one-sided significance, 85% power), defining the non-inferiority limit as no worse than 3% below the standard arm. Costs and quality-adjusted life-years were estimated using a within-trial analysis and a lifetime decision-analytic model. RESULTS: Between 4 October 2007 and 31 July 2015, 2045 patients were randomised to 12 months' trastuzumab and 2043 were randomised to 6 months' trastuzumab. Sixty-nine per cent of patients had ER-positive disease; 90% received anthracyclines (49% with taxanes; 41% without taxanes); 10% received taxanes without anthracyclines; 54% received trastuzumab sequentially after chemotherapy; and 85% received adjuvant chemotherapy (58% were node negative). At 6.1 years' median follow-up, with 389 (10%) deaths and 566 (14%) disease-free survival events, the 4-year disease-free survival rates for the 4088 patients were 89.5% (95% confidence interval 88.1% to 90.8%) in the 6-month group and 90.3% (95% confidence interval 88.9% to 91.5%) in the 12-month group (hazard ratio 1.10, 90% confidence interval 0.96 to 1.26; non-inferiority p = 0.01), demonstrating non-inferiority of 6 months' trastuzumab. Congruent results were found for overall survival (non-inferiority p = 0.0003) and landmark analyses 6 months from starting trastuzumab [non-inferiority p = 0.03 (disease-free-survival) and p = 0.006 (overall survival)]. Six months' trastuzumab resulted in fewer patients reporting adverse events of severe grade [365/1929 (19%) vs. 460/1935 (24%) for 12-month patients; p = 0.0003] or stopping early because of cardiotoxicity [61/1977 (3%) vs. 146/1941 (8%) for 12-month patients; p < 0.0001]. Health economic analysis showed that 6 months' trastuzumab resulted in significantly lower lifetime costs than and similar lifetime quality-adjusted life-years to 12 months' trastuzumab, and thus there is a high probability that 6 months' trastuzumab is cost-effective compared with 12 months' trastuzumab. Patient-reported experiences in the trial highlighted fatigue and aches and pains most frequently. LIMITATIONS: The type of chemotherapy and timing of trastuzumab changed during the recruitment phase of the study as standard practice altered. CONCLUSIONS: PERSEPHONE demonstrated that, in the treatment of HER2-positive early breast cancer, 6 months' adjuvant trastuzumab is non-inferior to 12 months'. Six months' treatment resulted in significantly less cardiac toxicity and fewer severe adverse events. FUTURE WORK: Ongoing translational work investigates patient and tumour genetic determinants of toxicity, and trastuzumab efficacy. An individual patient data meta-analysis with PHARE and other trastuzumab duration trials is planned. TRIAL REGISTRATION: Current Controlled Trials ISRCTN52968807, EudraCT 2006-007018-39 and ClinicalTrials.gov NCT00712140. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 40. See the NIHR Journals Library website for further project information.

THE BACKGROUND: There are several different types of breast cancer and some are called 'HER2 positive'. These cancers can often be cured by treatment with chemotherapy and a drug called trastuzumab (also known as Herceptin®; Roche, Basel, Switzerland). Although the first trials of trastuzumab used 12 months treatment, we did not know if less treatment could work as well. A small trial in Finland showed that giving trastuzumab for just 9 weeks was also effective. We know that trastuzumab can have some side effects, including heart problems, so it was important to see if we could reduce the length of treatment time, which is usually 12 months. WHAT DID WE DO?: We wanted to find out if we could treat patients safely with 6 months rather than 12 months of trastuzumab. We carried out a clinical trial called PERSEPHONE, in which over 4000 patients with this type of early breast cancer took part. Half of the patients were given 12 months of trastuzumab and half were given 6 months of trastuzumab. WHAT DID WE FIND?: We found that the two groups of patients had very similar benefit from treatment. At 4 years after diagnosis 90.3% of those who had received 12 months of trastuzumab were alive and free of any breast cancer recurrence, compared with 89.5% of those who had received 6 months. In other words, 125 patients would need to be treated with 12 months' trastuzumab rather than 6 months' trastuzumab for one more person to be alive and cancer-free 4 years from diagnosis. THE SIDE EFFECTS?: Severe side effects of trastuzumab were seen on at least one occasion in 24% of 12-month patients compared with 19% of 6-month patients. More patients receiving 12 months of trastuzumab had to stop trastuzumab early because of heart problems (8% of 12-month patients compared with 3% of 6-month patients). WHAT DOES THIS ALL MEAN?: We have shown that 6 months of trastuzumab has similar outcomes to 12 months in treating patients with HER2-positive early breast cancer but with fewer severe side effects, including heart problems, fewer visits to hospital for patients and significant cost savings for the NHS.

Considerations for a head and neck smoking cessation support programme; A qualitative study of the challenges in quitting smoking after treatment for head and neck cancer.

PURPOSE: Smoking is a major cause of head and neck squamous cell carcinoma (HNSCC), yet many patients who receive a diagnosis continue to smoke. This has an adverse effect on treatment and recovery, and leads to increased risks of recurrence and second cancers. There is evidence that stopping smoking after diagnosis can lead to better outcomes and reversal of risks. However, there is limited evidence for effective smoking cessation interventions in this population, and little about patient opinions regarding quitting smoking and support provided by healthcare professionals. METHODS: This qualitative study was conducted as part of a larger project with the objective of developing a smoking cessation support programme. Eleven patients who had completed head and neck cancer (HNC) treatment were interviewed about smoking and quitting attempts. Interviews were semi-structured and took place face-to-face or over the phone. RESULTS: Participants gave detailed accounts of their smoking journey. Thematic analysis of the data led to the identification of 2 overarching themes and four interlinking themes. Themes describe the 'guilty habit' of smoking, perceived 'barriers to quit', the 'teachable moment' of a diagnosis and the contrary 'social motivation' to both smoke and quit. CONCLUSIONS: The results of this study highlight some missed needs for this group and major gaps in the support that is available. It is intended that the results will be used to develop a support programme for quitting smoking long term in a way that is useful and relevant to this complex population.

A review of the issues and challenges involved in using participant-produced photographs in nursing research.

AIMS: To discuss the issues and challenges that may occur when using participant-produced photographs in nursing research. BACKGROUND: The place of visual representation in society is increasingly being recognized and there is a growing discussion on the advantages of implementing visual methods, such as photography, in health and illness research. Integrating photographs has much potential for both nurse researchers and participants but it remains a novel method of gathering qualitative data and many aspects have had little consideration in the nursing and medical literature. This paper presents a discussion of some of the issues that may arise when using photographs as data. It draws on examples of the insights and experiences we had when we asked study participants to produce photographs to complement their interviews designed to explore their experience of living after cancer. DESIGN: Discussion paper DATA SOURCES: This paper is based on our own experiences and supported by literature and theory. IMPLICATIONS FOR NURSING: Disseminating this research has prompted much interest from nurses and clinical staff. This paper should highlight some of the factors that may need to be addressed before employing such a novel method, thus ensuring the research process is positive and the outcome relevant for all parties. CONCLUSION: Examples are used here to illustrate practical, ethical and philosophical issues around the research plan, creating and interpreting photographic data, confidentiality and copyright and analysing and disseminating photographs produced for research.

A 'new normal': Exploring the disruption of a poor prognostic cancer diagnosis using interviews and participant-produced photographs.

Cancer survival is increasing, and many people are living years after cancer treatment. For example, it is predicted that 46 per cent of men and 56 per cent of women diagnosed in 2007 in England and Wales will survive their cancer for 5 years or more. However, 'survivors' may be living with significant physical, psychological and social disruption caused by their illness. Furthermore, huge disparities exist in the outcomes for different cancer 'types', and there has been little investigation of those living with 'poor prognostic' cancers. Our aim was to explore the experience of living after the diagnosis of a poor prognostic cancer. Data were gathered from 30 people via interviews and participants' own photographs. Our findings suggest that a full 'recovery' may be impossible after a cancer diagnosis. Such diagnoses will continue to threaten biographical trajectory and self-identity forever. 'Returning to normal' was considered highly important for participants, but a changed normality had to be accepted in which lives were managed carefully and a constant fear of recurrence created liminality and made 'survivorship' ambiguous. Experience was often complicated by the social response associated with cancer that hindered communication and increased isolation. Participant-produced photographs, used here for the first time specifically by a sample of people with poor prognosis cancer, proved to be an acceptable data collection method and have added a poignancy and 'completeness' to the data that have arguably led to a more comprehensive understanding.

A qualitative systematic review exploring lay understanding of cancer by adults without a cancer diagnosis.

AIM: To explore the lay understanding of cancer. BACKGROUND: Lay understanding of illness is shaped by social identity, personal biography and experience. It informs how ill health is defined, concerns are managed and interventions evaluated. An appreciation of lay understanding is therefore vital to enable relay of effective and appropriate health information to the public and care provision and support to patients. DESIGN: A qualitative systematic review using Thomas and Harden's (2008) approach to thematic synthesis. DATA SOURCES: Key social science, nursing and medical databases, cancer organization websites for grey literature and a hand search of references retrieved from particularly relevant articles and journals. REVIEW METHODS: Thematic synthesis of eligible papers (studies on adults without a cancer diagnosis, generated from WHO-defined 'high-income' countries and published between 1990-2011). Only those focusing on the understanding of cancer, rather than screening or cancer genetics, were included. RESULTS: Six analytical themes were identified from 26 papers, generated from 25 studies. Explorations of the causes of cancer and interpretation of personal risk dominated the published work. These revealed a significant complexity in lay understanding. This review has also highlighted the need for additional work, particularly in gaining an understanding of the stigma and fear that surround cancer. CONCLUSION: The themes identified by this review have the potential to inform the development of appropriate health promotion strategies and clinical services for those living with cancer and lead to a better understanding of problematic areas, such as late presentation, which continues to impede efforts to improve cancer survival.

Endohedral metallofullerenes in self-assembled monolayers.

A method has been developed for the attachment of a dithiolane group to endohedral metallofullerenes via a 1,3-dipolar cycloaddition reaction. This sulfur-containing functional group serves as an anchor, enabling efficient immobilisation of endohedral fullerenes on Au(111) surfaces at room temperature, directly from the solution phase. The functionalised fullerenes form disordered monolayers that exhibit no long-range ordering, which is attributed to both the strong bonding of the dithiolane anchor to the surface and to the conformational flexibility of the functional group. Endohedral fullerenes Er(3)N@C(80) and Sc(3)N@C(80) have been used as models for functionalisation and subsequent surface deposition. Their chemical reactivity towards dithiolane functionalisation and their surface behaviour have been compared to that of C(60). The endohedral fullerenes appear to be significantly less reactive towards the functionalisation than C(60), however they bind in a similar manner to a gold surface as their dithiolane terminated C(60) counterparts. The optical activity of Er(3)N@C(80) molecules is preserved after attachment of the functional group. We report a splitting of the endohedral Er(3+) emission lines due to the reduction in symmetry of the functionalised fullerene cage, as compared to the highly symmetrical icosahedral C(80) cage of pristine Er(3)N@C(80).

Reducing the symptoms of lymphoedema: is there a role for aromatherapy?

Lymphoedema is a chronic and debilitating condition caused by lymphatic insufficiency, which may have serious physical, social and psychological implications for the patient. It is usually managed by a combination of strategies aimed at protecting and decongesting the oedematous limb(s) and stimulating the development of supplementary lymphatic pathways to control swelling in the long-term. However, it is not known which therapies are the most effective. Anecdotally, the addition of aromatherapy oils to massage cream may have a positive effect on symptom relief in people with cancer, although evidence is again lacking. This paper describes a randomized trial of self-massage and skin care using a cream containing aromatherapy oils versus self-massage and skin care using a cream without aromatherapy oils on objective limb volume measurements and symptom relief as measured by the Measure Yourself Medical Outcome Profile 2 (MYMOP2) in a sample of people with lymphoedema. Results indicate that self-massage and skin care significantly improved patient-identified symptom relief and wellbeing for this sample. It also slightly, but not significantly reduced limb volume. However, aromatherapy oils, carefully chosen on the basis that they should benefit this group, did not appear to influence any improvement in these measures.

The information requirements of people with cancer: where to go after the "patient information leaflet"?

Information is crucial for people with cancer for both successful treatment and rehabilitation and to facilitate user involvement and informed decision making. Research has tended to concentrate on biomedical sources, such as hospital-produced information. There have been few inductive investigations of patients' use of information available outside this environment, despite the media and Internet being identified as pervasive sources of cancer information. This article reports on a study that utilized naturalistic inquiry to explore the extent and manner in which the media and Internet are utilized as information sources by people with cancer. Results confirm that the media was used considerably by the study sample and was an important contributor to knowledge and facilitator for decision making. Participants were not passive receivers of media messages but interpreted it depending on their particular needs or their rating of the media source. Consumption of media-produced information was constrained by certain factors, such as the participants' physical inability to access sources, and needs were not always satisfied because media discourse and "newsworthiness" restricted the reporting of what was sought. The study highlights the importance of the media and Internet as an information source for people with cancer and calls for a greater awareness of this phenomenon.

BRCA1 and BRCA2 genetic testing for ovarian cancer: is it all good news?

In England and Wales, ovarian cancer is responsible for about 15 deaths per 100,000 women annually (NHS Executive 1999). It is estimated that only 5-10% of ovarian cancer cases have a hereditary basis (Watson et al. 1996, Hallowell 1999, Eeles & Powles 2000), although recent media excitement may have led some people to believe the odds are higher. The majority of these hereditary cases are thought to be caused by germline mutations in BRCA1 and BRCA2 cancer susceptibility genes (Antoniou et al. 2000, Berchuk et al. 1999). This article will examine current knowledge about BRCA1 and BRCA2 genetic testing for ovarian cancer and follow the journey taken by women who are considering such testing. Genetic counselling and genetic testing will be critically evaluated and the implications for clinical practice, the individual and society as a whole will be discussed.