Patients|[rsquo]| and oncologists|[rsquo]| views on the treatment and care of advanced ovarian cancer in the UK: results from the ADVOCATE study

Ovarian cancer (OC) is the fifth most common cancer in UK women, affecting ~6500 women a year (Cancer Research UK, 2012). It is primarily a disease of older, postmenopausal women, and diagnosis and specialist referral is often delayed due to the insidious/vague nature of the presenting symptoms. By the time most women are diagnosed they have advanced disease (Stages II–IV) and the outcomes of UK patients are still poorer than in comparable countries (Coleman et al, 2011). However, five-year survival has increased from 33% to 44% since 2001 in the UK and deaths have fallen by a fifth (Cancer Research UK, 2012). The National Institute for Health and Clinical Excellence (NICE) technology appraisal guidance No. 55 (NICE, 2003) recommends that paclitaxel in combination with a platinum-based compound or platinum-based therapy alone are offered as part of a first-line treatment package that also includes maximal debulking surgery for patients with advanced disease. However, despite optimal primary therapy, recurrent disease is diagnosed in the majority of patients within 5 years (du Bois et al, 2009). The choice of subsequent therapy at the time of progression or at relapse is dependent on the platinum-free interval. Options for platinum-sensitive patients (>6 months since last therapy) include platinum combinations (with pegylated liposomal doxorubicin hydrochloride (PLDH), paclitaxel and gemcitabine). For patients with platinum-resistant disease (<6 months since last therapy), options include PLDH, weekly paclitaxel, topotecan and etoposide. Addition of other drugs, such as bevacizumab to chemotherapy regimens has until very recently been predominantly limited to clinical trial settings. In December 2011, the European Medicines Agency (EMA) approved bevacizumab for use in combination with carboplatin and paclitaxel chemotherapy, then continued as single-agent maintenance therapy for a total of 15 months as a front-line treatment for women with stage IIIB–IV OC. In England, the National Institute for Clinical Excellence (NICE) is not due to report on their evaluations of bevacizumab until the summer of 2013. Although clinical trials have shown 3–4-month improvement in progression-free survival (PFS) (Burger et al, 2011; Perren et al, 2011) and evidence of improvement in overall survival (OS) for poor-risk subgroups (Kristensen et al, 2011), the prolonged maintenance phase of bevacizumab therapy, typically 8–12 months, and its cost may still prove to be a barrier to its adoption within the NHS. With regards to the clinical management of OC, there are few published data on variations in practice across the UK. Maintaining quality of life (QoL) is the main goal for these patients, together with symptom control and, if possible, prolongation of life. Continued contact with specialist nurses during maintenance treatment may be of benefit, in terms of offering reassurance and timely and appropriate supportive care (Cox et al, 2006; Cox et al, 2008). The influence of social support and clinical outcome has recently been recognised in women with ovarian cancer (Lutgendorf et al, 2012). A higher level of social attachment (i.e. the subjective experience of close emotional bonds) is associated with survival advantage, which has implications for support activities during adjuvant cancer care and beyond. Some centres now use patient-reported outcome (PROs) measures to help clinicians systematically identify and address symptoms of concern to the patient, which together with more traditional clinical objective measures, may lead to better decision making and tailoring of treatment. For example, adjusting chemotherapy dosing according to patient-reported severity of symptoms (Basch and Abernethy, 2011). In addition, patients may have different expectations about treatments and place different values on outcomes from those of health-care professionals (Meropol et al, 2008). They may have preferences about different types of management plans available in terms of treatment and its mode of delivery. Furthermore, health-care professionals may rate their expectations of minimum gain in terms of OS and PFS differently to what they believe their patients would consider. The purpose of this study was to examine the experiences and preferences of women with advanced OC for their care and treatment, and consider these results in terms of oncologists’ current practice within the UK. To ensure that the invitation was comprehensively distributed, the gynaecological lead clinician for every cancer network in England, Wales, Scotland and Northern Ireland was contacted and asked to supply contact details for oncologists treating women with OC or to forward the invitation directly. Additionally, the British Gynaecological Cancer Society alerted its membership by email and provided a website link to the survey. The clinician survey comprised five sections: (1) demographics: plus perceptions of symptoms most troubling to women presenting with OC, (2) routine NHS care for non-clinical trial patients: first-, second-line and subsequent treatments, (3) maintenance therapy: including opinions about minimum gain required for PFS and OS, (4) clinical trial participation and (5) availability of supportive care within their cancer centre/hospital. Likelihood ratio tests were used for model selection, goodness of fit was assessed and model diagnoses were carried out. Clinic staff at the 16 centres distributed a total of 435 information packs to eligible patients; 225 out of 435 (52%) patients returned EOI forms and 202 out of 225 (90%) were interviewed. Mean time since diagnosis for participants was 31.5 months (s.d. 37 months). At the time of interview, 58% (117 out of 202) of women were receiving chemotherapy. Patients’ characteristics including details of surgery are displayed in Table 1b. Patients made many comments about their experiences prior to diagnosis and 21% (43 out of 202) were not satisfied about their GP’s symptom recognition, believing this had led to a delay in diagnosis. Women also felt there was a lack of awareness generally in the public domain about ovarian cancer and its symptoms. Quotes illustrating these two themes are shown in Appendix A. The first-ranked trigger that influenced oncologists’ decisions to initiate a second course of treatment was symptomatic disease progression (75%; 49 out of 65). Second line and subsequent treatments for platinum-sensitive patients was usually carboplatin and paclitaxel (63%; 39 out of 62); for partially platinum-sensitive patients, it was most often carboplatin with paclitaxel (3-weekly) (40%; 25 out of 62); or carboplatin with PLDH (24%; 15 out of 62); and PLDH was the treatment of choice for platinum-resistant patients (68%; 42 out of 62). The majority of women interviewed had received first- and second-line therapy (68%; 138 out of 202), but 15% (31 out of 202) had received four or more courses of chemotherapy (breakdown of chemotherapy regimens available Supplementary Table A). Clinicians reported that fatigue was the most complained about and hardest to ameliorate side effect (50%; 31 out of 62); a finding also reflected in the patient interviews. Although many women were troubled by fatigue (63%; 127 out of 202), only 32% (40 out of 127) received any support or advice for this symptom. In contrast, the majority of women (88%; 71 out of 81) concerned about their symptoms of nausea received practical assistance, usually in the form of anti-emetics. Helpful interventions were not so forthcoming for those ‘bothered’ by constipation 51% (49 out of 97). Worryingly, only 54% (68 out of 127) of women distressed by hair loss said they received sufficient information as to when and how their hair would fall out, and/or how to obtain an NHS wig. When participants were grouped into (1) those with experience of first-line therapy only (n=61) and (2) those with experience of second and subsequent chemotherapies (n=141), the proportions who reported troublesome side effects changed. Compared with Group 2, women in Group 1 experienced more fatigue (72% vs 52%); constipation (69% vs 22%); and hair loss (66% vs 39%). Patients’ views on information resources and receipt of support differed and depended on whether they were on or off active treatment. For example, 14% (12 out of 85) of those off treatment compared with 3% (3 out of 117) on treatment did not have any contact with a specialist nurse. Also, 22% (19 out of 85) off treatment had a telephone number for a nurse but never used it, compared with 9% (11 out of 117) of women on treatment. Patients’ most usual forms of support were family and friends (69%; 139 out of 202) and GPs (58%; 117 out of 202), with only 32% (65 out of 202) relying on the hospital specialist nurse (Figure 3). There was close agreement that in-house material about chemotherapy treatments was given to patients (oncologists 77%; 46 out of 60) (patients 78%; 158 out of 202). However, only 73% (148 out of 202) of patients said that they had received Macmillan booklets compared with clinicians (100%; 60 out of 60) who reported that all patients are given them. The Macmillan Cancer Support website was recommended by 92% (55 out of 60) of oncologists and 49% (99 out of 202) of women said that they had searched for information on OC independently, with 39% (79 out of 202) using the internet; 14 out of 79 (18%) had viewed the Macmillan site. Surprisingly few patients were aware of or had received information from any of the ovarian cancer charities (6%; 12 out of 202). A majority 50 out of 60 (83%) oncologists viewed maintenance therapy positively albeit based on data regarding PFS benefits shown in trials. There were interesting differences between the minimum gains in PFS based on what the clinicians thought worthwhile, compared with the gains they believed that their patients would consider (see Table 2). All clinicians said that they would feel more encouraged about offering maintenance therapy if improvements in OS were shown. At the interview, participants were presented with a hypothetical scenario, asking: ‘If you were offered a drug that could prolong your life, but it gave you side effects such as fatigue, feeling sick, numbness or tingling in fingers and toes, how many extra months of life would you want to make having the treatment worthwhile?’ Almost a quarter (21%; 42 out of 202) were unable/did not want to give an answer to the question, a third (52 out of 160) said 1–2 months, 6% (10 out of 160) 3–4 months, 31% (49/160) 5–6 months, and 31% (49/160) 7 months (Table 3). However, when asked: ‘If you were offered a drug that could improve your quality of life but might not prolong it, would you be prepared to try it?’, 86% (173 out of 202) of women said they would be willing to try a drug that improved their QoL even if it would not prolong their life. When asked what was the most important aim of treatment to them, 33% (67 out of 201) said QoL, 9% (19 out of 201) length of life and 57% (115 out of 201) said both were equally important. The summary score from the OV28 symptom scales for the hormonal items was influenced by age, with older women less likely to report hot flushes (OR=0.25, P-value<0.001). Disease was a burden to over 43% of patients, disease and treatment burden were reported more often in those with higher education (OR=1.77, P-value<0.049; OR=2.7, P-value<0.001 respectively). Figure 4 shows the proportion of patients who responded ‘quite a bit/very much’ to having received sufficient information about the topics listed on the EORTC INFO25 questionnaire. Noticeably 80% indicated that they had received adequate information on diagnosis, disease extent, tests, treatments and side effects of treatments. However, fewer women reported receiving sufficient information about disease control (58%), how to cope at home (40%), what help was available outside the hospital (40%) and how to access psychological services (20%). The responses to the information questionnaire were not influenced by age group, on/off treatment, partner/no partner, or education. Participants with a high global score on INFO25, those over 60 years and those with higher education levels were more likely to cite QoL as more important (OR=1.03, P=0.02; (OR=2.44, P=0.02 and (OR=2.43, P=0.011, respectively). When asked ‘How many extra months of life would you want to make having maintenance treatment worthwhile?’, only global QoL score influenced choice. Those with a lower (poorer) global EORTC QLQ30 score (first quartile=50) were more likely to want a treatment to offer more time for it to be worthwhile (OR=1.61, P-value=0.025) compared with those with a higher QoL score (third quartile=50). These surveys provide a summary of oncologists’ treatment practices across the UK and a comparison of their patients’ experiences. Many patients presented with late-stage disease with abdominal pain and swelling. Almost a quarter were not satisfied with the way their GP dealt with their concerns, often diagnosing irritable bowel syndrome or constipation. These findings accord with the Cancer Patient Experiences Survey 2011/12 (DoH 2012); 37% of ovarian cancer patients saw their GP more than twice about their symptoms before being referred for diagnostic tests, compared with just 8% of breast cancer patients. Our current interviews also revealed patients felt strongly that there was a lack of publicity about the signs and symptoms of ovarian compared with breast and more recently lung cancer. One participant made a salient point that some advertisers promote bloating or urinary incontinence as quite normal for women over 50 years, and that drinking/wearing certain products can help. Women often blamed themselves for ignoring such symptoms, and consequently presenting late at diagnosis when disease had spread. Treatments offered across the UK were fairly similar. A large proportion of oncologists were engaged in clinical trials and 26% (52 out of 202) of patients interviewed had received OC treatment within a trial; 12 out of 52 (23%) involved trials of maintenance therapy. Fatigue was the most troublesome side effect for patients, and clinicians acknowledged that it is difficult to treat. Patients were aware of this and appreciated healthcare professionals’ (HCP) advice and/or regular enquiry as to how they were coping. It was noticeable that women who had received only one course of chemotherapy reported side effects as being more troublesome than did those who had experience of more than two further lines of treatment. Intuitively this makes sense, as women might be more prepared the second time and devised ways to cope with the unwanted side effects. Although some centres offered an excellent supportive service to women, with induction visits to the chemotherapy suite, and discussing in detail the treatments and side effects, others were lacking. One surprising finding was that hair loss was not uniformly well dealt with in terms of advice and wig-fitting. A significant proportion of the women greatly disturbed by hair loss were unprepared as to how and when their hair would fall out and/or how and where to obtain a wig in the NHS. Providing a leaflet or cursory mention that hair loss is an inevitable consequence of treatment was not helpful for patients. Patients’ views about information resources and receipt of support differed from that reported by oncologists in the online survey as available at their hospital/centre. Few women made use of the specialist nurse during the period following the end of a course of chemotherapy or at their follow-up appointment. Several patients, no longer having active treatment expressed a feeling of abandonment and felt a need for regular contact in the form of a supportive telephone call. This was more noticeable in women without a partner, who overall reported a poorer QoL. The majority of women relied on family and friends for support. The Cancer Patient Experiences Survey 2011/12 reported that although 91% of ovarian cancer patients were given the name of the specialist nurse in charge of their care, only 68% said that she was easy to contact. The survey also revealed that 40% of women with ovarian cancer were not given written information about their cancer (DoH 2012). The information needs of the women we interviewed was met for most of the tangible, practical aspects of treatment and care, such as diagnosis, tests and treatments, but much less so for the psychosocial aspects, such as whether the disease was under control and how to cope at home. This is an area that needs greater attention in view of the fact that maintaining quality of life, together with symptom control is the main goal for these patients. The majority of oncologists were positive about maintenance therapy based on PFS benefits, but availability was a barrier to its prescription. The clinician survey was conducted before the decision to accept bevacizumab for advanced OC onto the priority list of the Cancer Drugs Fund (CDF) in England, and few patients interviewed had received the drug outside of a cilinical trial setting. Patients’ views were similar to clinicians regarding OS, with 62% requiring a gain of 5 months of life to make the treatment worthwhile. It should be noted that PFS gains were not explored in the patient interview as PFS is not a familiar term and rarely used by clinicians when discussing treatments with patients (Fallowfield and Fleissig, 2012). Two previous studies have attempted to explore ovarian cancer patients’ preferences for care, one focussed exclusively on patients’ choice regarding different first-line therapies (Elit et al, 1996), the other examined treatment preferences in recurrent ovarian cancer, tackling issues of quality and quantity of life (Donovan et al, 2002). The latter found that on average patients would switch from ‘salvage therapy’ to palliative care when the median survival associated with therapy was reduced to 5 months. There was no association between any dimensions of QoL and the time point at which patients would switch to palliative care. However, a regression analysis showed that as family and friends’ involvement increased, the period of survival associated with salvage therapy women still found acceptable decreased. In the current study, single women with poorer global QoL scores were more likely to want a treatment to offer more time for it to be worthwhile than those with higher QoL scores. In our interviews, patients assumed maintenance therapy would have similar toxicity to chemotherapy and it is possible that newer biological agents with different side effects may change patients’ perceptions. Shorter timespan gains could be perceived as worthwhile for therapies with less burdensome side effect profiles. In the recent analysis of the ICON7 trial, QoL was measured using the EORTC QLQ C30 and OV28. Results showed that bevacizumab continuation treatment was associated with a small but clinically significant decrement in Global QoL compared with standard treatment (Stark et al, 2013). However, the authors note that the Gynaecological Oncology Group (GOG 218) double-blind, placebo control study used a different instrument for measuring QoL (FACT O) and did not report a clinically important difference between standard chemotherapy+bevacizumab vs standard chemotherapy+placebo. They suggest that the difference between the study results is because of disruption to women’s lives from delivery of continuation therapy that was reflected in poorer role functioning, financial worries, attitudes to disease to treatment, hormonal symptoms and rash. A recent commentary on the ICON7 trial advocates that women with ovarian cancer should be asked to assess the inherent trade-offs implicated in new treatments (Havrilesky and Abernethy, 2013). Balancing QoL with the length of it was most important to 57% (115 out of 201) of patients, another third (33%; 67 out of 201) indicated that QoL was the priority, and for just 9% (19 out of 201) length of life was paramount. This distribution is similar to a previous report of preferences among patients with advanced cancer where 55% (252 out of 459) equally valued QoL and length, 27% (123 out of 459) most valued QoL and 18% (84 out of 459) length of life (Merepol et al. 2008). These UK surveys give a view of the treatments and care offered by oncologists and received by women with advanced ovarian cancer. Although the majority of women, once a diagnosis had been established were happy with their care and treatment, a fair proportion gave worrying reports of a lack of information and support. These findings concur with much of the recent ovarian cancer quality profile summaries produced from the National Cancer Patient Experience Survey (CPES) for 2011/12. Increasing women’s awareness of OC symptoms, together with earlier diagnosis may help make this disease more treatable. The authors declare no conflict of interest. ‘I went to the GP repeatedly with lower tummy pains before it then started to swell, once that got bad the GP referred me for investigations’ ID98, 61 years ‘GP took a long time to recognise that my symptoms were something more serious than a urinary tract infection’ ID153, 83 years ‘I was going to the GP for more than a year reporting pain, diarrhoea, weight loss, feeling full quickly when eating, it was treated as irritable bowel syndrome’ ID163, 64 years ‘Very disappointed with the GP and the way my symptoms were ignored and not investigated until it was all too late’ ID 184, 58 years ‘What made me mad was the GP, he didn't listen to me when I went to him, he just kept saying I had constipation, I knew I didn't, I now have a different GP’ ID 191, 46 years ‘seeing adverts on TV and in magazines that tell women to eat yoghurt for bloating makes me very angry and also the adverts that say women commonly have urinary problems and should just buy panty pads annoys me too’ ID30, 58 years ‘there needs to be much greater general awareness about ovarian cancer in GPs' surgeries, but also elsewhere for the public, like they have for breast cancer or now they are making us more aware of the lung cancer symptoms’ ID41, 70 years ‘Not enough general information at the GP surgery about ovarian cancer, not enough awareness in general’ ID66, 66 years ‘I don't think there is enough awareness about the illness amongst women in general. There needs to be more information and education, me and my friends had no idea about it, that I had symptoms of it for probably a long time. There is a lot of ignorance in women about the symptoms’ ID82, 72 years ‘My diagnosis came as a complete shock, not aware of ovarian cancer, breast cancer is in the newspapers more’ ID141, 67 years ‘Ovarian cancer is not something that I know much about, don't know the symptoms, not publicised much, people don’t talk about it’ ID148, 81 years ‘Breast cancer dominates in the news, lots of support and funds raised. Ovarian cancer doesn't seem to have the same sort of impact. OC seems to be kept low key. Never much in the press. Need to publicise it more’ ID178, 50 years We thank the clinicians and patients who gave their time to participate in the surveys. Professors Gore and Ledermann for help with establishing the content of the clinician questionnaire, together with the clinicians and research nurses at the 16 UK centres, and Carolyn Langridge, data manager for the project. S Banerjee acknowledges support from the National Institute of Health Research (NIHR) Biomedical Research Centre. C Gourley acknowledges support for the Edinburgh Cancer Centre from Cancer Research UK and personal fellowship support from the Scottish Funding Council and the Scottish Chief Scientist’s Office. We thank Roche Products Ltd for providing an unrestricted educational grant to enable us to conduct the work. Disclaimer Neither the funding body nor the sponsor had any role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. Supplementary Information accompanies this paper on British Journal of Cancer website