- Email: [email protected]
The legacy of cancer on depression and anxiety
Comment
9
Gellad ZF, Voils CI, Lin L, Provenzale D. Clinical practice variation in the management of diminutive colorectal polyps: results of a national survey of gastroenterologists. Am J Gastroenterol 2013; in press.
10
Lieberman D, Moravec M, Holub J, Michaels L, Eisen G. Polyp size and advanced histology in patients undergoing colonoscopy screening: implications for CT colonography. Gastroenterology 2008; 135: 1100–15.
Depression and anxiety are common in patients with cancer and psychological morbidity is associated with reduced quality of life, poor adherence to treatment and self-care, impaired physical, social, and family functioning, worse symptoms, and diminished will to live.1,2 In The Lancet Oncology, Mitchell and colleagues3 report results of a systematic review and meta-analysis, done to investigate whether the increased risk of depression and anxiety is evident among long-term cancer survivors compared with their spouses and healthy controls. For depression, the findings are reassuring: assessment of 16 analyses comparing the prevalence depression in people 2 years or more after diagnosis (11·6%, 95% CI 7·7–16·2) and healthy controls (10·2%, 8·0–12·6) shows no significant difference in the relative risk (RR) of depression (1·11, 95% CI 0·96–1·27; p=0·17). However, a question remains; which long-term cancer survivors do these findings apply to? Mitchell and colleagues conclude that their results are relevant to people whose disease is in remission, but this statement goes beyond the evidence presented in their report. Furthermore, they did not investigate the effect of mediating factors—eg, physical function, symptoms, and work status—which can be adversely affected by cancer or its treatment.4 Therefore, these results should be interpreted with caution. Cancer is increasingly experienced as a chronic illness; evidence of increased psychological morbidity in patients with chronic illness suggests that depression is likely be an issue in cancer survivorship.5 Research into risk factors for depression and anxiety in chronic illness, their causes, and treatment should help to inform research and clinical practice in cancer,5 particularly because many long-term cancer survivors will have co-morbidities.4 Much of this research has been focused on depression, with anxiety being neglected by comparison.6 Effective interventions also need to be tested and developed.7 Mitchell and colleagues report that the risk of anxiety is higher in long-term cancer survivors (prevalence 17·9%, 95% CI 12·8–23·6) compared with healthy www.thelancet.com/oncology Vol 14 July 2013
individuals (13·9%, 9·8–18·5; RR 1·27, 95% CI 1·08–1·50; p=0·0039), even 10 years after diagnosis. However, little can be learnt about anxiety severity, its cause, or specific diagnoses from the studies included in the metaanalysis: research using more robust methods is needed. Fear of cancer recurrence is not mentioned in the report. Almost half (47%) of cancer survivors 5 years after diagnosis in England report fear of recurrence.8 Such fear might be seen as a normal, expected response to cancer, and therefore not needing intervention. However, severe fear of cancer recurrence is associated with reduced quality of life and functional impairment.9 Risk factors for fear of recurrence and strategies to reduce it have not been widely investigated.9 New recommendations4 to improve survivorship outcomes in England could improve fear of recurrence, and anxiety in general. Little is known about cancer’s lasting effect on families.10 The results of Mitchell and colleagues suggest that the prevalence of depression or anxiety does not differ significantly between long-term cancer survivors and their spouses. However, these results do not say as much about long-term survivorship as it at first seems. The studies included for comparisons with spouses included different populations of patients with cancer than did those for the comparisons with healthy individuals: mean time since cancer diagnosis in the spousal comparisons was 4·35 years versus 7·3 years in the comparisons with healthy controls, and the prevalences of depression and anxiety in long-term survivors were much higher in the spousal comparisons than healthy control comparisons (depression 26·7% vs 11·6%; anxiety 28·0% vs 17·9%). Irrespective of these differences, knowing whether the risk of psychological morbidity of spouses differs from that of patients is not the key question: what matters is whether the spouses of long-term cancer survivors are at greater risk than spouses of healthy individuals, or exceed population norms.11 The long-term consequences of cancer on spouses’ mental health remains largely unknown. Nevertheless, these findings strengthen calls to ensure support for families.
Suzanne Grala/Science Photo Library
The legacy of cancer on depression and anxiety
Published Online June 5, 2013 http://dx.doi.org/10.1016/ S1470-2045(13)70238-9 See Articles page 721
675
Comment
Although Mitchell and co-workers clearly show the gaps in research, what implications do their findings have for clinicians? They show that long-term cancer survivors do not have an increased risk of depression, but this finding does not apply to all patients, and knowing the causes of depression in chronic illness is helpful to understand why.5 The increased risk of anxiety in long-term cancer survivors justifies taking a fresh look at anxiety in these patients, including methods for identification of those at high risk, and provision of appropriate care and treatment. The psychological legacy of cancer for patients and families can continue into long-term survivorship: the challenge for clinicians, service providers, and commissioners is to tackle this legacy at a time of increased demand and reduced resources.4
1
2
3
4
5 6 7
8
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Julia Addington-Hall Faculty of Health Sciences, University of Southampton, Highfield, Southampton, SO17 1BJ, UK [email protected] I declare that I have no conflicts of interest.
10 11
Mitchell AJ, Chan M, Bhatti H, et al. Prevalence of depression, anxiety, and adjustment disorder in oncological, haematological, and palliative-care settings: a meta-analysis of 94 interview-based studies. Lancet Oncol 2011; 12: 160–74. Rayner L, Lee W, Price A, et al. The clinical epidemiology of depression in palliative care and the predictive value of somatic symptoms: cross-sectional survey with four-week follow-up. Palliat Med 2010; 25: 229–41. Mitchell AJ, Ferguson DW, Gill J, Paul J, Symonds P. Depression and anxiety in long-term cancer survivors compared with spouses and health controls: a systematic review and meta-analysis. Lancet Oncol 2013; published online June 5. http://dx.doi.org/10.1016/S1470-2045(13)70244-4. Department of Health, Macmillan Cancer Support, National Cancer Survivorship Initiative. Living with and beyond cancer: taking action to improve outcomes (an update to the 2010 The National Cancer Survivorship Initiative Vision). London: Department of Health, 2013. Katon WJ. Epidemiology and treatment of depression in patients with chronic medical illness. Dialogues Clin Neurosci 2011; 13: 7–23. Roy-Byrne PP, Davidson KW, Kessler RC, et al. Anxiety disorders and comorbid medical illness. Gen Hosp Psychiatry 2008; 30: 208–25. Richardson A, Addington-Hall J, Amir Z, et al. Knowledge, ignorance and priorities for research in key areas of cancer survivorship: findings from a scoping review. Br J Cancer 2011; 105: S82–94. Glaser AW, Fraser LK, Corner J, et al. Patient-reported outcomes of cancer survivors in England 15 years after diagnosis: a cross-sectional survey. BMJ Open 2013; 3: e002317. Simard S, Thewes B, Humphris G, et al. Fear of cancer recurrence in adult cancer survivors: a systematic review of quantitative studies. J Cancer Surviv 2013; published online Mar 10. DOI:10.1007/s11764-013-0272-z. Stenberg U, Ruland CM, Miakowski C. Review of the literature on the effects of the caring for a patient with cancer. Psycho-oncology 2010; 19: 1013–25. Turner D, Adams E, Boulton M, et al. Partners and close family members of long-term cancer survivors: health status, psychosocial well-being and unmet supportive care needs. Psycho-oncology 2013; 22: 12–19.
Nancy Kedersha/Immunogen/Science Photo Library
Has targeted therapy for melanoma made chemotherapy obsolete?
See Articles page 733
676
Targeted therapy for BRAF-mutant melanoma has revolutionised the management of patients with metastatic melanoma1,2 and ignited a quest for even more effective strategies. Situated just downstream of BRAF is MEK, which has become a second molecular target of great interest. The MEK inhibitor trametinib was recently approved by the US Food and Drug Administration (FDA), and other MEK inhibitors are in clinical development.3,4 Targeted drugs have pushed cytotoxic chemotherapy research into the background, yet chemotherapy regimens are still offered as first-line therapy in countries where access to targeted drugs is limited. Chemotherapy has a deservedly poor reputation in the treatment of advanced melanoma, but it is now valid to ask whether targeted therapy has made chemotherapy obsolete, or alternatively whether combination with a molecularly targeted agent could breathe new life into old drugs. Caroline Robert and colleagues5 evaluated the combination of dacarbazine with selumetinib, another
MEK inhibitor, in a randomised, placebo-controlled phase 2 trial in 91 patients with BRAF-mutant melanoma. The trial’s primary endpoint of improved overall survival was not met. There were, however, signs of clinical benefit for the combination, with a higher confirmed response rate (29% vs 13%) and longer median progression-free survival (5·6 months, 80% CI 4·9–5·9, vs 3·0 months, 2·8–4·6; hazard ratio 0·63, 80% CI 0·47–0·84, one-sided p=0·021) in the selumetinib plus dacarbazine group compared with the placebo plus dacarbazine group. This benefit came at the cost of increased toxicity in the combination group, including rash, oedema, visual disturbances, bleeding, and infection. The clinical efficacy of the selumetinib-dacarbazine combination was not impressive by the standards now set by BRAF inhibitors. Furthermore, the dacarbazine response rate in the current study (13%)5 was higher than in other recent phase 3 studies,1,2,4 which might www.thelancet.com/oncology Vol 14 July 2013
9
Gellad ZF, Voils CI, Lin L, Provenzale D. Clinical practice variation in the management of diminutive colorectal polyps: results of a national survey of gastroenterologists. Am J Gastroenterol 2013; in press.
10
Lieberman D, Moravec M, Holub J, Michaels L, Eisen G. Polyp size and advanced histology in patients undergoing colonoscopy screening: implications for CT colonography. Gastroenterology 2008; 135: 1100–15.
Depression and anxiety are common in patients with cancer and psychological morbidity is associated with reduced quality of life, poor adherence to treatment and self-care, impaired physical, social, and family functioning, worse symptoms, and diminished will to live.1,2 In The Lancet Oncology, Mitchell and colleagues3 report results of a systematic review and meta-analysis, done to investigate whether the increased risk of depression and anxiety is evident among long-term cancer survivors compared with their spouses and healthy controls. For depression, the findings are reassuring: assessment of 16 analyses comparing the prevalence depression in people 2 years or more after diagnosis (11·6%, 95% CI 7·7–16·2) and healthy controls (10·2%, 8·0–12·6) shows no significant difference in the relative risk (RR) of depression (1·11, 95% CI 0·96–1·27; p=0·17). However, a question remains; which long-term cancer survivors do these findings apply to? Mitchell and colleagues conclude that their results are relevant to people whose disease is in remission, but this statement goes beyond the evidence presented in their report. Furthermore, they did not investigate the effect of mediating factors—eg, physical function, symptoms, and work status—which can be adversely affected by cancer or its treatment.4 Therefore, these results should be interpreted with caution. Cancer is increasingly experienced as a chronic illness; evidence of increased psychological morbidity in patients with chronic illness suggests that depression is likely be an issue in cancer survivorship.5 Research into risk factors for depression and anxiety in chronic illness, their causes, and treatment should help to inform research and clinical practice in cancer,5 particularly because many long-term cancer survivors will have co-morbidities.4 Much of this research has been focused on depression, with anxiety being neglected by comparison.6 Effective interventions also need to be tested and developed.7 Mitchell and colleagues report that the risk of anxiety is higher in long-term cancer survivors (prevalence 17·9%, 95% CI 12·8–23·6) compared with healthy www.thelancet.com/oncology Vol 14 July 2013
individuals (13·9%, 9·8–18·5; RR 1·27, 95% CI 1·08–1·50; p=0·0039), even 10 years after diagnosis. However, little can be learnt about anxiety severity, its cause, or specific diagnoses from the studies included in the metaanalysis: research using more robust methods is needed. Fear of cancer recurrence is not mentioned in the report. Almost half (47%) of cancer survivors 5 years after diagnosis in England report fear of recurrence.8 Such fear might be seen as a normal, expected response to cancer, and therefore not needing intervention. However, severe fear of cancer recurrence is associated with reduced quality of life and functional impairment.9 Risk factors for fear of recurrence and strategies to reduce it have not been widely investigated.9 New recommendations4 to improve survivorship outcomes in England could improve fear of recurrence, and anxiety in general. Little is known about cancer’s lasting effect on families.10 The results of Mitchell and colleagues suggest that the prevalence of depression or anxiety does not differ significantly between long-term cancer survivors and their spouses. However, these results do not say as much about long-term survivorship as it at first seems. The studies included for comparisons with spouses included different populations of patients with cancer than did those for the comparisons with healthy individuals: mean time since cancer diagnosis in the spousal comparisons was 4·35 years versus 7·3 years in the comparisons with healthy controls, and the prevalences of depression and anxiety in long-term survivors were much higher in the spousal comparisons than healthy control comparisons (depression 26·7% vs 11·6%; anxiety 28·0% vs 17·9%). Irrespective of these differences, knowing whether the risk of psychological morbidity of spouses differs from that of patients is not the key question: what matters is whether the spouses of long-term cancer survivors are at greater risk than spouses of healthy individuals, or exceed population norms.11 The long-term consequences of cancer on spouses’ mental health remains largely unknown. Nevertheless, these findings strengthen calls to ensure support for families.
Suzanne Grala/Science Photo Library
The legacy of cancer on depression and anxiety
Published Online June 5, 2013 http://dx.doi.org/10.1016/ S1470-2045(13)70238-9 See Articles page 721
675
Comment
Although Mitchell and co-workers clearly show the gaps in research, what implications do their findings have for clinicians? They show that long-term cancer survivors do not have an increased risk of depression, but this finding does not apply to all patients, and knowing the causes of depression in chronic illness is helpful to understand why.5 The increased risk of anxiety in long-term cancer survivors justifies taking a fresh look at anxiety in these patients, including methods for identification of those at high risk, and provision of appropriate care and treatment. The psychological legacy of cancer for patients and families can continue into long-term survivorship: the challenge for clinicians, service providers, and commissioners is to tackle this legacy at a time of increased demand and reduced resources.4
1
2
3
4
5 6 7
8
9
Julia Addington-Hall Faculty of Health Sciences, University of Southampton, Highfield, Southampton, SO17 1BJ, UK [email protected] I declare that I have no conflicts of interest.
10 11
Mitchell AJ, Chan M, Bhatti H, et al. Prevalence of depression, anxiety, and adjustment disorder in oncological, haematological, and palliative-care settings: a meta-analysis of 94 interview-based studies. Lancet Oncol 2011; 12: 160–74. Rayner L, Lee W, Price A, et al. The clinical epidemiology of depression in palliative care and the predictive value of somatic symptoms: cross-sectional survey with four-week follow-up. Palliat Med 2010; 25: 229–41. Mitchell AJ, Ferguson DW, Gill J, Paul J, Symonds P. Depression and anxiety in long-term cancer survivors compared with spouses and health controls: a systematic review and meta-analysis. Lancet Oncol 2013; published online June 5. http://dx.doi.org/10.1016/S1470-2045(13)70244-4. Department of Health, Macmillan Cancer Support, National Cancer Survivorship Initiative. Living with and beyond cancer: taking action to improve outcomes (an update to the 2010 The National Cancer Survivorship Initiative Vision). London: Department of Health, 2013. Katon WJ. Epidemiology and treatment of depression in patients with chronic medical illness. Dialogues Clin Neurosci 2011; 13: 7–23. Roy-Byrne PP, Davidson KW, Kessler RC, et al. Anxiety disorders and comorbid medical illness. Gen Hosp Psychiatry 2008; 30: 208–25. Richardson A, Addington-Hall J, Amir Z, et al. Knowledge, ignorance and priorities for research in key areas of cancer survivorship: findings from a scoping review. Br J Cancer 2011; 105: S82–94. Glaser AW, Fraser LK, Corner J, et al. Patient-reported outcomes of cancer survivors in England 15 years after diagnosis: a cross-sectional survey. BMJ Open 2013; 3: e002317. Simard S, Thewes B, Humphris G, et al. Fear of cancer recurrence in adult cancer survivors: a systematic review of quantitative studies. J Cancer Surviv 2013; published online Mar 10. DOI:10.1007/s11764-013-0272-z. Stenberg U, Ruland CM, Miakowski C. Review of the literature on the effects of the caring for a patient with cancer. Psycho-oncology 2010; 19: 1013–25. Turner D, Adams E, Boulton M, et al. Partners and close family members of long-term cancer survivors: health status, psychosocial well-being and unmet supportive care needs. Psycho-oncology 2013; 22: 12–19.
Nancy Kedersha/Immunogen/Science Photo Library
Has targeted therapy for melanoma made chemotherapy obsolete?
See Articles page 733
676
Targeted therapy for BRAF-mutant melanoma has revolutionised the management of patients with metastatic melanoma1,2 and ignited a quest for even more effective strategies. Situated just downstream of BRAF is MEK, which has become a second molecular target of great interest. The MEK inhibitor trametinib was recently approved by the US Food and Drug Administration (FDA), and other MEK inhibitors are in clinical development.3,4 Targeted drugs have pushed cytotoxic chemotherapy research into the background, yet chemotherapy regimens are still offered as first-line therapy in countries where access to targeted drugs is limited. Chemotherapy has a deservedly poor reputation in the treatment of advanced melanoma, but it is now valid to ask whether targeted therapy has made chemotherapy obsolete, or alternatively whether combination with a molecularly targeted agent could breathe new life into old drugs. Caroline Robert and colleagues5 evaluated the combination of dacarbazine with selumetinib, another
MEK inhibitor, in a randomised, placebo-controlled phase 2 trial in 91 patients with BRAF-mutant melanoma. The trial’s primary endpoint of improved overall survival was not met. There were, however, signs of clinical benefit for the combination, with a higher confirmed response rate (29% vs 13%) and longer median progression-free survival (5·6 months, 80% CI 4·9–5·9, vs 3·0 months, 2·8–4·6; hazard ratio 0·63, 80% CI 0·47–0·84, one-sided p=0·021) in the selumetinib plus dacarbazine group compared with the placebo plus dacarbazine group. This benefit came at the cost of increased toxicity in the combination group, including rash, oedema, visual disturbances, bleeding, and infection. The clinical efficacy of the selumetinib-dacarbazine combination was not impressive by the standards now set by BRAF inhibitors. Furthermore, the dacarbazine response rate in the current study (13%)5 was higher than in other recent phase 3 studies,1,2,4 which might www.thelancet.com/oncology Vol 14 July 2013