- Email: [email protected]
Controversies in defining cancer survivorship
Comment
by 25% in patients who received itraconazole, although no tumours disappeared completely.8 Future trials of other drug combinations, used sequentially or in tandem, including sonidegib and itraconazole, are likely. One potential source of bias in trials of Hedgehog pathway inhibitors is selection of patients. Those with Gorlin’s syndrome represented around 20% of patients treated in the STEVIE study,6 although the number in the BOLT study is unknown. This subgroup of patients might respond differently (more favourably) to Hedgehog pathway inhibitors than most patients who develop basal cell carcinoma. Another issue is that there is no standard definition of locally advanced disease. A new definition proposed by the American Joint Committee on Cancer9 should improve selection of patients for studies, although a degree of subjectivity remains because the thresholds for contraindications might vary between physicians. Skin imaging techniques provide non-invasive assessments of disease, including quasi-histology and tumour size and depth, and can obviate the need for invasive procedures.10 Reflectance confocal microscopy and high-definition optical CT are, in our opinion, useful to assess response to treatment, including Hedgehog pathway inhibitors. In a study where vismodegib was given to 15 patients before Mohs’ surgery, when taken for at least 3 months, the surgical defect size was reduced by 25%.11 This finding suggests the potential for Hedgehog pathway inhibitors to reduce surgical morbidity and possibly to downstage inoperable patients, which is being investigated in larger clinical trials. The management of advanced basal cell carcinoma is rapidly evolving owing to advances in noninvasive imaging techniques, increasing adoption of micrographic surgical techniques, the introduction of
SMO inhibitors, and continuing development of other drugs, some of which are in trials. As clinicians become adept at tailoring treatment to the characteristics of patients and tumours, clinical outcomes for patients with basal cell carcinoma will continue to improve. *Catriona M Maybury, Emma E Craythorne, Teresa Guerrero Urbano, Raj Mallipeddi St John’s Institute of Dermatology (CMM, EEC, RM), and Oncology Department (TCU), Guys and St Thomas’ NHS Foundation Trust, London, UK. St John’s Institute, Division of Genetics and Molecular Medicine, King’s College London, London, UK (CMM) [email protected] TGU has received personal fees from Merck Serono, Roche, and GW Pharma. The other authors declare no competing interests. 1
2 3
4 5
6
7
8
9 10
11
Bielefeld KA, Amini-Nik S, Alman BA. Cutaneous wound healing: recruiting developmental pathways for regeneration. Cell Mol Life Sci 2013; 70: 2059–81. Wong CS, Strange RC, Lear JT. Basal cell carcinoma. BMJ 2003; 327: 794–98. Mosterd K, Krekels GA, Nieman FH, et al. Surgical excision versus Mohs’ micrographic surgery for primary and recurrent basal-cell carcinoma of the face: a prospective randomised controlled trial with 5-years’ follow-up. Lancet Oncol 2008; 9: 1149–56. Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med 2012; 366: 2171–79. Atwood SX, Sarin KY, Whitson RJ, et al. Smoothened variants explain the majority of drug resistance in Basal cell carcinoma. Cancer Cell 2015; 27: 342–53. Migden MR, Guminski A, Gutzmer R, et al. Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial. Lancet Oncol 2015; published online May 14. http://dx.doi. org/10.1016/S1470-2045(15)70100-2. Basset-Seguin N, Hauschild A, Grob J-J, et al. Vismodegib in patients with advanced basal cell cardinoma (STEVIE): an pre-planned interim analysis of an international, open-label trial. Lancet Oncol 2015; published online May 14. http://dx.doi.org/10.1016/S1470-2045(15)70198-1. Kim DJ, Kim J, Spaunhurst K, et al. Open-label, exploratory phase II trial of oral itraconazole for the treatment of basal cell carcinoma. J Clin Oncol 2014; 32: 745–51. Edge SE, Byrd DR, Carducci MA, Compton CA, eds. AJCC cancer staging manual, 7th edn. New York, NY: Springer, 2010. Maier T, Kulichova D, Ruzicka T, Berking C. Noninvasive monitoring of basal cell carcinomas treated with systemic hedgehog inhibitors: pseudocysts as a sign of tumor regression. J Am Acad Dermatol 2014; 71: 725–30. Ally MS, Tang JY, Joseph T, et al. The use of vismodegib to shrink keratocystic odontogenic tumors in patients with basal cell nevus syndrome. JAMA Dermatol 2014; 150: 542–45.
Controversies in defining cancer survivorship Improved detection methods and effective treatments have contributed to an increase in long-term survival of patients with cancer in the past decades. Although 5-year survival for all patients with cancer has increased from about 50% in 1975 to almost 70% in 2006, large differences exist between cancer types.1 As a result of this success, the population of people who survive the initial 610
treatment period and are either cured, in remission, or are living with cancer is growing. In 2012, this population (those still alive within 5 years of diagnosis) was estimated to be more than 30 million people worldwide.2 In the USA in 2014, nearly 14·5 million people were either living with, or had previously had cancer, and this number is estimated to increase to nearly 19 million in www.thelancet.com/oncology Vol 16 June 2015
Comment
www.thelancet.com/oncology Vol 16 June 2015
many patients with cancer have acute symptoms such as nausea, vomiting, fatigue, insomnia, pain, and dyspnoea. Although some symptoms can persist once the initial treatment has ended (eg, fatigue and pain), many will resolve without further treatment. Other problems might intensify (eg, cognitive deficits) or only emerge during the post-treatment period (eg, work and insurance issues, sexual difficulties, fear of recurrence, and second malignancies).8–10 Alternatively, surviving cancer can also result in positive changes including enhanced self-esteem, increased appreciation of life, increased spirituality, and close relationships with relatives.8,10 Priorities for a research agenda about cancer survivorship include assessment and monitoring of late effects and toxic effects, life situations (eg, work or insurance issues), and health-related quality of life (QOL). Specific issues that patients with cancer or survivors of this disease are confronted by can change over time, and this has implications for the outcome measures to be used along the disease course. For example, widely used health-related QOL measures (eg, the EORTC QLQ-C30 and the Functional Assessment of Cancer Treatment–General, complemented by their condition-specific modules) are excellent for assessing short-term difficulties, but might be less suitable for use in patients with cancer during long-term followup. Many issues in these questionnaires are associated with active disease and treatment, whereas mid-term and long-term survivorship issues are not addressed. Although several questionnaires have been specifically developed for survivors of cancer during the posttreatment period—including the Quality-of-Life in Adult Cancer Survivors (QLACS), Impact of Cancer (IOC) and Brief Cancer Impact Assessment (BCIA)—these focus mainly on psychological problems and life situations, and do not address many of the late physical effects of cancer and its treatment. We believe that a more comprehensive approach is needed to assess both the physical and psychosocial health issues, socioeconomic issues, and long-term and late symptoms of patients with cancer who have completed their primary treatment and have no evidence of active disease. Such a questionnaire should ensure that the difficulties of survivors of cancer are brought into focus, discussed, and addressed with existing or novel health-care and social interventions.
Jim Bourg/X90054/Reuters/Corbis
2024.3 This growing population of individuals who have survived cancer creates a range of challenges associated with cancer survivorship. To define the nature and scope of these challenges and to establish the most appropriate research and service delivery agenda, a clear definition of the population of interest is needed. Here is where the problem lies: several definitions of cancer survivorship are available, none of which is universally accepted. The US National Coalition of Cancer Survivors (NCCS) defines an individual as a cancer survivor from the time of diagnosis through the balance of their life.4 An extended version of this definition, used by the US National Cancer Institute (NCI), also includes family members, friends, and caregivers of the patient with cancer because they are viewed as being affected by the survivors’ experience.5 By contrast, the European Organisation of Research and Treatment of Cancer (EORTC) Survivorship Task Force has defined a cancer survivor as any person who has been diagnosed with cancer, has completed his or her primary treatment (with the exception of maintenance therapy), and has no evidence of active disease.6 These three definitions differ in terms of both the target population (ie, patients alone vs including the social network of the patient) and the location of the individual in their disease and treatment trajectory (ie, from the time of diagnosis vs after initial treatment). Although both the NCCS and NCI definitions of cancer survivorship are valuable in emphasising the wide range of problems and needs of patients with cancer (and their social network) generally, these might be of more political than scientific use. We believe that the more restricted EORTC definition might better serve the goal to establish priorities for a research agenda about cancer survivorship. Although a diagnosis of cancer can have a profound effect on the lives of the patient and their family, the issues that both are confronted by only partly overlap. Although both patients and their families’ might have psychosocial and emotional problems,7 the symptom burden and risk of secondary malignancies are specific to the patient with cancer. Furthermore, the issues patients are confronted with during active treatment versus follow-up might overlap, but we think that every disease stage has its own unique set of difficulties. Shortly after diagnosis, multimodal treatment with surgery, chemotherapy, radiotherapy, or targeted therapy is often needed, and as a result
611
Comment
Linda Dirven, Lonneke V van de Poll-Franse, Neil K Aaronson, *Jaap C Reijneveld
3
Department of Neurology, VU University Medical Centre, 1007 MB, Amsterdam, Netherlands (LD, JCR); Quality of Life Group of the European Organisation of Research and Treatment of Cancer, Brussels, Belgium (LD, LVP-F, NKA, JCR); Comprehensive Cancer Organisation Netherlands, Eindhoven, Netherlands (LVP-F); Department of Medical Psychology, Tilburg University, Tilburg, Netherlands (LVP-F); Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, Amsterdam, Netherlands (NKA); and Department of Neurology, Academic Medical Centre, Amsterdam, Netherlands (JCR) [email protected]
4
LVP-F reports a grant from Janssen, outside the submitted work. JCR reports grants from European Organisation of Research and Treatment of Cancer Quality of Life Group, Dutch Cancer Society KWF, Dutch Epilepsy Foundation NEF, and Roche Netherlands, outside the submitted work. LD and NKA declare no competing interests. 1
2
612
5
6
7
8
9
10
American Cancer Society. Cancer treatment and survivorship, facts and figures 2014–2015, 2015. http://www.cancer.org/acs/groups/content/@ research/documents/document/acspc-042801.pdf (accessed April 1, 2015). National Coalition for Cancer Survivorship (NCCS). NCCS Mission, 2015. http://www.canceradvocacy.org/about-us/our-mission/ (accessed April 1, 2015). National Cancer Institute (NCI) Office of Cancer Survivorship. Definitions, 2015. http://cancercontrol.cancer.gov/ocs/statistics/definitions.html (accessed April 1, 2015). Moser EC, Meunier F. Cancer survivorship: A positive side-effect of more successful cancer treatment. Moser EC, Meunier F. European J Cancer 2014; 12: 1–4 Stenberg U, Ruland CM, Miaskowski C. Review of the literature on the effects of caring for a patient with cancer. Psychooncology 2010; 19: 1013–25. Foster C, Wright D, Hill H, Hopkinson J, Roffe L. Psychosocial implications of living 5 years or more following a cancer diagnosis: a systematic review of the research evidence. Eur J Cancer Care (Engl) 2009; 18: 223–47. Harrington CB, Hansen JA, Moskowitz M, Todd BL, Feuerstein M. It’s not over when it’s over: long-term symptoms in cancer survivors—a systematic review. Int J Psychiatry Med 2010; 40: 163–81. Stein KD, Syrjala KL, Andrykowski MA. Physical and psychological long-term and late effects of cancer. Cancer 2008; 112: 2577–92.
Surveillance, epidemiology, and end results (SEER) program. SEER stat fact sheets: all cancer sites, 2015. http://seer.cancer.gov/statfacts/html/all.html (accessed April 1, 2015). IARC. GLOBOCAN: estimated cancer incidence, mortality and prevalence worldwide in 2012: all cancers (excluding non-melanoma skin cancer) estimated incidence, mortality and prevalence worldwide in 2012. http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx (accessed April 1, 2015).
www.thelancet.com/oncology Vol 16 June 2015
by 25% in patients who received itraconazole, although no tumours disappeared completely.8 Future trials of other drug combinations, used sequentially or in tandem, including sonidegib and itraconazole, are likely. One potential source of bias in trials of Hedgehog pathway inhibitors is selection of patients. Those with Gorlin’s syndrome represented around 20% of patients treated in the STEVIE study,6 although the number in the BOLT study is unknown. This subgroup of patients might respond differently (more favourably) to Hedgehog pathway inhibitors than most patients who develop basal cell carcinoma. Another issue is that there is no standard definition of locally advanced disease. A new definition proposed by the American Joint Committee on Cancer9 should improve selection of patients for studies, although a degree of subjectivity remains because the thresholds for contraindications might vary between physicians. Skin imaging techniques provide non-invasive assessments of disease, including quasi-histology and tumour size and depth, and can obviate the need for invasive procedures.10 Reflectance confocal microscopy and high-definition optical CT are, in our opinion, useful to assess response to treatment, including Hedgehog pathway inhibitors. In a study where vismodegib was given to 15 patients before Mohs’ surgery, when taken for at least 3 months, the surgical defect size was reduced by 25%.11 This finding suggests the potential for Hedgehog pathway inhibitors to reduce surgical morbidity and possibly to downstage inoperable patients, which is being investigated in larger clinical trials. The management of advanced basal cell carcinoma is rapidly evolving owing to advances in noninvasive imaging techniques, increasing adoption of micrographic surgical techniques, the introduction of
SMO inhibitors, and continuing development of other drugs, some of which are in trials. As clinicians become adept at tailoring treatment to the characteristics of patients and tumours, clinical outcomes for patients with basal cell carcinoma will continue to improve. *Catriona M Maybury, Emma E Craythorne, Teresa Guerrero Urbano, Raj Mallipeddi St John’s Institute of Dermatology (CMM, EEC, RM), and Oncology Department (TCU), Guys and St Thomas’ NHS Foundation Trust, London, UK. St John’s Institute, Division of Genetics and Molecular Medicine, King’s College London, London, UK (CMM) [email protected] TGU has received personal fees from Merck Serono, Roche, and GW Pharma. The other authors declare no competing interests. 1
2 3
4 5
6
7
8
9 10
11
Bielefeld KA, Amini-Nik S, Alman BA. Cutaneous wound healing: recruiting developmental pathways for regeneration. Cell Mol Life Sci 2013; 70: 2059–81. Wong CS, Strange RC, Lear JT. Basal cell carcinoma. BMJ 2003; 327: 794–98. Mosterd K, Krekels GA, Nieman FH, et al. Surgical excision versus Mohs’ micrographic surgery for primary and recurrent basal-cell carcinoma of the face: a prospective randomised controlled trial with 5-years’ follow-up. Lancet Oncol 2008; 9: 1149–56. Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med 2012; 366: 2171–79. Atwood SX, Sarin KY, Whitson RJ, et al. Smoothened variants explain the majority of drug resistance in Basal cell carcinoma. Cancer Cell 2015; 27: 342–53. Migden MR, Guminski A, Gutzmer R, et al. Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial. Lancet Oncol 2015; published online May 14. http://dx.doi. org/10.1016/S1470-2045(15)70100-2. Basset-Seguin N, Hauschild A, Grob J-J, et al. Vismodegib in patients with advanced basal cell cardinoma (STEVIE): an pre-planned interim analysis of an international, open-label trial. Lancet Oncol 2015; published online May 14. http://dx.doi.org/10.1016/S1470-2045(15)70198-1. Kim DJ, Kim J, Spaunhurst K, et al. Open-label, exploratory phase II trial of oral itraconazole for the treatment of basal cell carcinoma. J Clin Oncol 2014; 32: 745–51. Edge SE, Byrd DR, Carducci MA, Compton CA, eds. AJCC cancer staging manual, 7th edn. New York, NY: Springer, 2010. Maier T, Kulichova D, Ruzicka T, Berking C. Noninvasive monitoring of basal cell carcinomas treated with systemic hedgehog inhibitors: pseudocysts as a sign of tumor regression. J Am Acad Dermatol 2014; 71: 725–30. Ally MS, Tang JY, Joseph T, et al. The use of vismodegib to shrink keratocystic odontogenic tumors in patients with basal cell nevus syndrome. JAMA Dermatol 2014; 150: 542–45.
Controversies in defining cancer survivorship Improved detection methods and effective treatments have contributed to an increase in long-term survival of patients with cancer in the past decades. Although 5-year survival for all patients with cancer has increased from about 50% in 1975 to almost 70% in 2006, large differences exist between cancer types.1 As a result of this success, the population of people who survive the initial 610
treatment period and are either cured, in remission, or are living with cancer is growing. In 2012, this population (those still alive within 5 years of diagnosis) was estimated to be more than 30 million people worldwide.2 In the USA in 2014, nearly 14·5 million people were either living with, or had previously had cancer, and this number is estimated to increase to nearly 19 million in www.thelancet.com/oncology Vol 16 June 2015
Comment
www.thelancet.com/oncology Vol 16 June 2015
many patients with cancer have acute symptoms such as nausea, vomiting, fatigue, insomnia, pain, and dyspnoea. Although some symptoms can persist once the initial treatment has ended (eg, fatigue and pain), many will resolve without further treatment. Other problems might intensify (eg, cognitive deficits) or only emerge during the post-treatment period (eg, work and insurance issues, sexual difficulties, fear of recurrence, and second malignancies).8–10 Alternatively, surviving cancer can also result in positive changes including enhanced self-esteem, increased appreciation of life, increased spirituality, and close relationships with relatives.8,10 Priorities for a research agenda about cancer survivorship include assessment and monitoring of late effects and toxic effects, life situations (eg, work or insurance issues), and health-related quality of life (QOL). Specific issues that patients with cancer or survivors of this disease are confronted by can change over time, and this has implications for the outcome measures to be used along the disease course. For example, widely used health-related QOL measures (eg, the EORTC QLQ-C30 and the Functional Assessment of Cancer Treatment–General, complemented by their condition-specific modules) are excellent for assessing short-term difficulties, but might be less suitable for use in patients with cancer during long-term followup. Many issues in these questionnaires are associated with active disease and treatment, whereas mid-term and long-term survivorship issues are not addressed. Although several questionnaires have been specifically developed for survivors of cancer during the posttreatment period—including the Quality-of-Life in Adult Cancer Survivors (QLACS), Impact of Cancer (IOC) and Brief Cancer Impact Assessment (BCIA)—these focus mainly on psychological problems and life situations, and do not address many of the late physical effects of cancer and its treatment. We believe that a more comprehensive approach is needed to assess both the physical and psychosocial health issues, socioeconomic issues, and long-term and late symptoms of patients with cancer who have completed their primary treatment and have no evidence of active disease. Such a questionnaire should ensure that the difficulties of survivors of cancer are brought into focus, discussed, and addressed with existing or novel health-care and social interventions.
Jim Bourg/X90054/Reuters/Corbis
2024.3 This growing population of individuals who have survived cancer creates a range of challenges associated with cancer survivorship. To define the nature and scope of these challenges and to establish the most appropriate research and service delivery agenda, a clear definition of the population of interest is needed. Here is where the problem lies: several definitions of cancer survivorship are available, none of which is universally accepted. The US National Coalition of Cancer Survivors (NCCS) defines an individual as a cancer survivor from the time of diagnosis through the balance of their life.4 An extended version of this definition, used by the US National Cancer Institute (NCI), also includes family members, friends, and caregivers of the patient with cancer because they are viewed as being affected by the survivors’ experience.5 By contrast, the European Organisation of Research and Treatment of Cancer (EORTC) Survivorship Task Force has defined a cancer survivor as any person who has been diagnosed with cancer, has completed his or her primary treatment (with the exception of maintenance therapy), and has no evidence of active disease.6 These three definitions differ in terms of both the target population (ie, patients alone vs including the social network of the patient) and the location of the individual in their disease and treatment trajectory (ie, from the time of diagnosis vs after initial treatment). Although both the NCCS and NCI definitions of cancer survivorship are valuable in emphasising the wide range of problems and needs of patients with cancer (and their social network) generally, these might be of more political than scientific use. We believe that the more restricted EORTC definition might better serve the goal to establish priorities for a research agenda about cancer survivorship. Although a diagnosis of cancer can have a profound effect on the lives of the patient and their family, the issues that both are confronted by only partly overlap. Although both patients and their families’ might have psychosocial and emotional problems,7 the symptom burden and risk of secondary malignancies are specific to the patient with cancer. Furthermore, the issues patients are confronted with during active treatment versus follow-up might overlap, but we think that every disease stage has its own unique set of difficulties. Shortly after diagnosis, multimodal treatment with surgery, chemotherapy, radiotherapy, or targeted therapy is often needed, and as a result
611
Comment
Linda Dirven, Lonneke V van de Poll-Franse, Neil K Aaronson, *Jaap C Reijneveld
3
Department of Neurology, VU University Medical Centre, 1007 MB, Amsterdam, Netherlands (LD, JCR); Quality of Life Group of the European Organisation of Research and Treatment of Cancer, Brussels, Belgium (LD, LVP-F, NKA, JCR); Comprehensive Cancer Organisation Netherlands, Eindhoven, Netherlands (LVP-F); Department of Medical Psychology, Tilburg University, Tilburg, Netherlands (LVP-F); Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, Amsterdam, Netherlands (NKA); and Department of Neurology, Academic Medical Centre, Amsterdam, Netherlands (JCR) [email protected]
4
LVP-F reports a grant from Janssen, outside the submitted work. JCR reports grants from European Organisation of Research and Treatment of Cancer Quality of Life Group, Dutch Cancer Society KWF, Dutch Epilepsy Foundation NEF, and Roche Netherlands, outside the submitted work. LD and NKA declare no competing interests. 1
2
612
5
6
7
8
9
10
American Cancer Society. Cancer treatment and survivorship, facts and figures 2014–2015, 2015. http://www.cancer.org/acs/groups/content/@ research/documents/document/acspc-042801.pdf (accessed April 1, 2015). National Coalition for Cancer Survivorship (NCCS). NCCS Mission, 2015. http://www.canceradvocacy.org/about-us/our-mission/ (accessed April 1, 2015). National Cancer Institute (NCI) Office of Cancer Survivorship. Definitions, 2015. http://cancercontrol.cancer.gov/ocs/statistics/definitions.html (accessed April 1, 2015). Moser EC, Meunier F. Cancer survivorship: A positive side-effect of more successful cancer treatment. Moser EC, Meunier F. European J Cancer 2014; 12: 1–4 Stenberg U, Ruland CM, Miaskowski C. Review of the literature on the effects of caring for a patient with cancer. Psychooncology 2010; 19: 1013–25. Foster C, Wright D, Hill H, Hopkinson J, Roffe L. Psychosocial implications of living 5 years or more following a cancer diagnosis: a systematic review of the research evidence. Eur J Cancer Care (Engl) 2009; 18: 223–47. Harrington CB, Hansen JA, Moskowitz M, Todd BL, Feuerstein M. It’s not over when it’s over: long-term symptoms in cancer survivors—a systematic review. Int J Psychiatry Med 2010; 40: 163–81. Stein KD, Syrjala KL, Andrykowski MA. Physical and psychological long-term and late effects of cancer. Cancer 2008; 112: 2577–92.
Surveillance, epidemiology, and end results (SEER) program. SEER stat fact sheets: all cancer sites, 2015. http://seer.cancer.gov/statfacts/html/all.html (accessed April 1, 2015). IARC. GLOBOCAN: estimated cancer incidence, mortality and prevalence worldwide in 2012: all cancers (excluding non-melanoma skin cancer) estimated incidence, mortality and prevalence worldwide in 2012. http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx (accessed April 1, 2015).
www.thelancet.com/oncology Vol 16 June 2015