Comment
Compared with available therapies, what might be some of the comparative advantages of polatuzumab vedotin? DLBCL, the most common subtype of nonHodgkin lymphoma, consists of at least two molecular cell of origin subtypes: germinal centre B-cell (GCB) and activated B-cell (ABC).5 Biologically, these subtypes are associated with different somatic mutations and aberrant signalling pathways.6 Drugs such as ibrutinib, proteosome inhibitors, and immunomodulatory agents work preferentially in ABC DLBCL. In a phase 2 study evaluating ibrutinib in patients with relapsed or refractory DLBC, overall responses were noted in 40% of patients with ABC DLBCL compared with 5% in GCB DLBCL.7 Clearly, accurate assignment to the correct molecular subgroup before commencing therapy is an essential requirement. Nonetheless, identification of these molecular subgroups remains challenging even in clinics using refined immunohistochemistry algorithms.8 Polatuzumab vedotin has recently been shown to induce cell death in the vast majority of ABC and GCB DLBCL cell lines, suggesting that it can be used effectively in DLBCL subtypes without the need for sophisticated molecular testing.9 Polatuzumab vedotin’s tolerable safety profile and potential for combination with rituximab makes it an ideal drug to bring forward to the first-line setting. Indeed, an ongoing study is examining polatuzumab vedotin in place of vincristine in patients with newly diagnosed DLBCL receiving R-CHOP (NCT01992653). Such a strategy could improve the outcomes of standard first-line immunochemotherapy in all DLBCL subtypes but would require definitive phase 3 data. In the relapsed setting, antibody–drug conjugates can potentially be incorporated into second-line chemotherapy regimens
to improve salvage therapy and increase the proportion of patients who could receive autologous stem-cell transplantation. Although the role of transplantation in patients with relapsed indolent non-Hodgkin lymphoma is increasingly controversial, antibody– drug conjugates will add to the arsenal of alternative therapies. Soon Thye Lim National Cancer Centre, Singapore, Singapore [email protected] I declare no competing interests. 1
2
3
4 5
6 7
8
9
Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 2010; 28: 4184–90. Schmitz N, Nickelsen M, Ziepert M, et al. Conventional chemotherapy (CHOEP-14) with rituximab or high-dose chemotherapy (MegaCHOEP) with rituximab for young, high-risk patients with aggressive B-cell lymphoma: an open-label, randomised, phase 3 trial (DSHNHL 2002–1). Lancet Oncol 2012; 13: 1250–59. Palanca-Wessels MCA, Czuczman M, Salles G, et al. Safety and activity of the anti-CD79B antibody–drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study. Lancet Oncol 2015; published online April 27, 2015. http://dx.doi.org/10.1016/S1470-2045(15)70128-2. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med 2014; 370: 1008–18. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000; 403: 503–11. Davis RE, Ngo VN, Lenz G, et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 2010; 463: 88–92. Wilson WH, Gerecitano JF, Goy A, et al. The Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib (PCI-32765), has preferential activity in the ABC subtype of relapsed/refractory de novo diffuse large B-cell lymphoma (DLBCL): interim results of a multicenter, open-label, phase 2 study. 54th ASH annual meeting and exposition; Atlanta, GA; Dec 8–11, 2012. 686 (abstr). de Jong D, Rosenwald A, Chhanabhai M, et al. Immunohistochemical prognostic markers in diffuse large B-cell lymphoma: validation of tissue microarray as a prerequisite for broad clinical applications—a study from the Lunenburg Lymphoma Biomarker Consortium. J Clin Oncol 2007; 25: 805–12. Pfeifer M, Zheng B, Erdmann T, et al. Anti-CD22 and anti-CD79B antibody drug conjugates are active in different molecular diffuse large B-cell lymphoma subtypes. Leukemia 2015; published online Feb 24. DOI:10.1038/leu.2015.48.
Systemic therapy for advanced basal cell carcinoma Published Online May 14, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)70233-0 See Articles pages 716 and 729
608
Basal cell carcinoma is the most common cancer to affect people with fair skin. Tumours develop as a result of aberrant signalling in the Hedgehog pathway, which is essential to embryonic skin development and wound repair.1 They usually occur on the head, and in most cases are amenable to treatment with topical therapy, surgery, or radiotherapy.2 Mohs’ surgery involves microscopic examination of the tumour and surrounding skin to improve clearance, and has become the gold standard
for certain high-risk facial basal cell carcinoma, including those that have recurred.3 Some basal cell carcinoma, however, are more challenging than others to manage. Patients with basal cell naevoid syndrome (Gorlin’s syndrome) develop multiple cancers from their teens onwards. Other basal cell carcinomas might be unusually aggressive, recur on the face and require potentially disfiguring surgery, or, in very rare cases, metastasise. In 2012, vismodegib, www.thelancet.com/oncology Vol 16 June 2015
Comment
www.thelancet.com/oncology Vol 16 June 2015
patients who achieved an objective response (13 [30%]) with 150 mg vismodegib was double that seen with 200 mg sonidegib. The overall rates of serious adverse events were similar in the two studies (25% with vismodegib and 24% with sonidegib), and the median duration of response was longer with sonidegib (8 months vs 14 months). The primary aim of STEVIE6 was to establish the incidence of adverse events in patients taking 150 mg vismodegib for at least 12 months, until disease progression or unacceptable toxic effects occurred. Patients were assessed monthly, on day 1 of each treatment cycle, for adverse events. 499 patients were assessed, of whom 468 (94%) had locally advanced basal cell carcinoma and 31 (6%) had metastatic basal cell carcinoma. Only 99 (20%) patients continued vismodegib beyond 12 months. 231 (46%) patients stopped treatment owing to the patient’s choice or because of adverse events, and 70 (14%) discontinuations were due to progressive disease. Overall, adverse events were seen in 491 (98%) of patients, with the most frequent being muscle spasms (in 317 [64%] patients), alopecia (307 [62%]), and dysgeusia (269 [54%]). Serious adverse events were reported in 108 (22%) of patients, and there were 31 deaths, 21 of which were attributed to adverse events but were deemed by investigators to be unrelated (n=19) or possibly related (n=2) to vismodegib. The causes of serious adverse events and death varied. There did seem to be a dose-dependent relation with toxic effects, as the rates of adverse events in most categories increased with increasing duration of treatment. The outcomes for secondary endpoints, including the proportion of patients with objective responses, were consistent with those in ERIVANCE.4 Overall, the side-effect profile and ultimate failure of vismodegib remain barriers to medium and long-term therapy. The Stanford BCC Consortium7 has investigated mechanisms of resistance in basal cell carcinoma by sampling sensitive and resistant tumours in patients taking vismodegib and found that persistent alterations in the Hedgehog signalling pathway (rather than other possibilities, such as TP53) are the most important. Possible new drugs for basal cell carcinoma investigated by this group include itraconazole, another Hedgehog pathway inhibitor. In a small trial, tumour size decreased
Dr Harout Tanielian/Science Photo Library
the first systemic therapy for locally advanced or metastatic basal cell carcinoma refractory to treatment by conventional methods, was licensed in the USA, followed by Europe and Australia. One of the most common genetic alterations in Hedgehog signalling is loss of function in PTCH1, which normally inhibits the signalling activity of SMO. Vismodegib was the first-in-class SMO inhibitor and has delivered good short-term results.4 However, success has been limited by a high rate of resistance, and many patients discontinue treatment due to intolerable sideeffects.4 In The Lancet Oncology, Michael Migden and colleagues5 report results from the phase 2 BOLT study of sonidegib, another SMO inhibitor, and Nicole BassetSeguin and colleagues6 report interim data from the STEVIE trial of vismodegib. BOLT compared treatment with 200 mg and 800 mg sonidegib in 230 patients, of whom 194 (84%) had locally advanced basal cell carcinoma not amenable to surgery and 36 (16%) had metastatic basal cell carcinoma. The primary endpoint was the proportion of patients achieving objective response after at least 6 months of treatment. Central review of the primary efficacy analysis popoulation showed that 20 (36%, 95% CI 24–50) of 55 patients receiving 200 mg sonidegib and 39 (34%, 25–43) of 116 receiving 800 mg achieved an objective response. Among patients with locally advanced disease, 18 (43%, 95% CI 28–59) of 42 patients with receiving 200 mg sonidegib had an objective response, as did 35 (38%, 28–48) of the 93 patients receiving 800 mg. Among patients with metastatic disease, the numbers were two (15%, 95% CI 2–45) of 13 and four (17%, 5–39) of 23, respectively. BOLT is a well-designed, multicentre, double-blind, randomised trial. The question for clinicians is how well the results compare with those from ERIVANCE,4 which led to FDA approval of vismodegib. Baseline patient demographics were similar in the two studies (60% white men and patients in their 60s). Independent review in ERIVANCE showed that a similar proportion of patients with locally advanced disease who received 150 mg vismodegib achieved an objective response (43%), with a similar dropout rate. The criteria used to assess response in BOLT, however, were more comprehensive, including pathology assessments. For metastatic basal cell carcinoma, the proportion of
609
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
Compared with available therapies, what might be some of the comparative advantages of polatuzumab vedotin? DLBCL, the most common subtype of nonHodgkin lymphoma, consists of at least two molecular cell of origin subtypes: germinal centre B-cell (GCB) and activated B-cell (ABC).5 Biologically, these subtypes are associated with different somatic mutations and aberrant signalling pathways.6 Drugs such as ibrutinib, proteosome inhibitors, and immunomodulatory agents work preferentially in ABC DLBCL. In a phase 2 study evaluating ibrutinib in patients with relapsed or refractory DLBC, overall responses were noted in 40% of patients with ABC DLBCL compared with 5% in GCB DLBCL.7 Clearly, accurate assignment to the correct molecular subgroup before commencing therapy is an essential requirement. Nonetheless, identification of these molecular subgroups remains challenging even in clinics using refined immunohistochemistry algorithms.8 Polatuzumab vedotin has recently been shown to induce cell death in the vast majority of ABC and GCB DLBCL cell lines, suggesting that it can be used effectively in DLBCL subtypes without the need for sophisticated molecular testing.9 Polatuzumab vedotin’s tolerable safety profile and potential for combination with rituximab makes it an ideal drug to bring forward to the first-line setting. Indeed, an ongoing study is examining polatuzumab vedotin in place of vincristine in patients with newly diagnosed DLBCL receiving R-CHOP (NCT01992653). Such a strategy could improve the outcomes of standard first-line immunochemotherapy in all DLBCL subtypes but would require definitive phase 3 data. In the relapsed setting, antibody–drug conjugates can potentially be incorporated into second-line chemotherapy regimens
to improve salvage therapy and increase the proportion of patients who could receive autologous stem-cell transplantation. Although the role of transplantation in patients with relapsed indolent non-Hodgkin lymphoma is increasingly controversial, antibody– drug conjugates will add to the arsenal of alternative therapies. Soon Thye Lim National Cancer Centre, Singapore, Singapore [email protected] I declare no competing interests. 1
2
3
4 5
6 7
8
9
Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 2010; 28: 4184–90. Schmitz N, Nickelsen M, Ziepert M, et al. Conventional chemotherapy (CHOEP-14) with rituximab or high-dose chemotherapy (MegaCHOEP) with rituximab for young, high-risk patients with aggressive B-cell lymphoma: an open-label, randomised, phase 3 trial (DSHNHL 2002–1). Lancet Oncol 2012; 13: 1250–59. Palanca-Wessels MCA, Czuczman M, Salles G, et al. Safety and activity of the anti-CD79B antibody–drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study. Lancet Oncol 2015; published online April 27, 2015. http://dx.doi.org/10.1016/S1470-2045(15)70128-2. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med 2014; 370: 1008–18. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000; 403: 503–11. Davis RE, Ngo VN, Lenz G, et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 2010; 463: 88–92. Wilson WH, Gerecitano JF, Goy A, et al. The Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib (PCI-32765), has preferential activity in the ABC subtype of relapsed/refractory de novo diffuse large B-cell lymphoma (DLBCL): interim results of a multicenter, open-label, phase 2 study. 54th ASH annual meeting and exposition; Atlanta, GA; Dec 8–11, 2012. 686 (abstr). de Jong D, Rosenwald A, Chhanabhai M, et al. Immunohistochemical prognostic markers in diffuse large B-cell lymphoma: validation of tissue microarray as a prerequisite for broad clinical applications—a study from the Lunenburg Lymphoma Biomarker Consortium. J Clin Oncol 2007; 25: 805–12. Pfeifer M, Zheng B, Erdmann T, et al. Anti-CD22 and anti-CD79B antibody drug conjugates are active in different molecular diffuse large B-cell lymphoma subtypes. Leukemia 2015; published online Feb 24. DOI:10.1038/leu.2015.48.
Systemic therapy for advanced basal cell carcinoma Published Online May 14, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)70233-0 See Articles pages 716 and 729
608
Basal cell carcinoma is the most common cancer to affect people with fair skin. Tumours develop as a result of aberrant signalling in the Hedgehog pathway, which is essential to embryonic skin development and wound repair.1 They usually occur on the head, and in most cases are amenable to treatment with topical therapy, surgery, or radiotherapy.2 Mohs’ surgery involves microscopic examination of the tumour and surrounding skin to improve clearance, and has become the gold standard
for certain high-risk facial basal cell carcinoma, including those that have recurred.3 Some basal cell carcinoma, however, are more challenging than others to manage. Patients with basal cell naevoid syndrome (Gorlin’s syndrome) develop multiple cancers from their teens onwards. Other basal cell carcinomas might be unusually aggressive, recur on the face and require potentially disfiguring surgery, or, in very rare cases, metastasise. In 2012, vismodegib, www.thelancet.com/oncology Vol 16 June 2015
Comment
www.thelancet.com/oncology Vol 16 June 2015
patients who achieved an objective response (13 [30%]) with 150 mg vismodegib was double that seen with 200 mg sonidegib. The overall rates of serious adverse events were similar in the two studies (25% with vismodegib and 24% with sonidegib), and the median duration of response was longer with sonidegib (8 months vs 14 months). The primary aim of STEVIE6 was to establish the incidence of adverse events in patients taking 150 mg vismodegib for at least 12 months, until disease progression or unacceptable toxic effects occurred. Patients were assessed monthly, on day 1 of each treatment cycle, for adverse events. 499 patients were assessed, of whom 468 (94%) had locally advanced basal cell carcinoma and 31 (6%) had metastatic basal cell carcinoma. Only 99 (20%) patients continued vismodegib beyond 12 months. 231 (46%) patients stopped treatment owing to the patient’s choice or because of adverse events, and 70 (14%) discontinuations were due to progressive disease. Overall, adverse events were seen in 491 (98%) of patients, with the most frequent being muscle spasms (in 317 [64%] patients), alopecia (307 [62%]), and dysgeusia (269 [54%]). Serious adverse events were reported in 108 (22%) of patients, and there were 31 deaths, 21 of which were attributed to adverse events but were deemed by investigators to be unrelated (n=19) or possibly related (n=2) to vismodegib. The causes of serious adverse events and death varied. There did seem to be a dose-dependent relation with toxic effects, as the rates of adverse events in most categories increased with increasing duration of treatment. The outcomes for secondary endpoints, including the proportion of patients with objective responses, were consistent with those in ERIVANCE.4 Overall, the side-effect profile and ultimate failure of vismodegib remain barriers to medium and long-term therapy. The Stanford BCC Consortium7 has investigated mechanisms of resistance in basal cell carcinoma by sampling sensitive and resistant tumours in patients taking vismodegib and found that persistent alterations in the Hedgehog signalling pathway (rather than other possibilities, such as TP53) are the most important. Possible new drugs for basal cell carcinoma investigated by this group include itraconazole, another Hedgehog pathway inhibitor. In a small trial, tumour size decreased
Dr Harout Tanielian/Science Photo Library
the first systemic therapy for locally advanced or metastatic basal cell carcinoma refractory to treatment by conventional methods, was licensed in the USA, followed by Europe and Australia. One of the most common genetic alterations in Hedgehog signalling is loss of function in PTCH1, which normally inhibits the signalling activity of SMO. Vismodegib was the first-in-class SMO inhibitor and has delivered good short-term results.4 However, success has been limited by a high rate of resistance, and many patients discontinue treatment due to intolerable sideeffects.4 In The Lancet Oncology, Michael Migden and colleagues5 report results from the phase 2 BOLT study of sonidegib, another SMO inhibitor, and Nicole BassetSeguin and colleagues6 report interim data from the STEVIE trial of vismodegib. BOLT compared treatment with 200 mg and 800 mg sonidegib in 230 patients, of whom 194 (84%) had locally advanced basal cell carcinoma not amenable to surgery and 36 (16%) had metastatic basal cell carcinoma. The primary endpoint was the proportion of patients achieving objective response after at least 6 months of treatment. Central review of the primary efficacy analysis popoulation showed that 20 (36%, 95% CI 24–50) of 55 patients receiving 200 mg sonidegib and 39 (34%, 25–43) of 116 receiving 800 mg achieved an objective response. Among patients with locally advanced disease, 18 (43%, 95% CI 28–59) of 42 patients with receiving 200 mg sonidegib had an objective response, as did 35 (38%, 28–48) of the 93 patients receiving 800 mg. Among patients with metastatic disease, the numbers were two (15%, 95% CI 2–45) of 13 and four (17%, 5–39) of 23, respectively. BOLT is a well-designed, multicentre, double-blind, randomised trial. The question for clinicians is how well the results compare with those from ERIVANCE,4 which led to FDA approval of vismodegib. Baseline patient demographics were similar in the two studies (60% white men and patients in their 60s). Independent review in ERIVANCE showed that a similar proportion of patients with locally advanced disease who received 150 mg vismodegib achieved an objective response (43%), with a similar dropout rate. The criteria used to assess response in BOLT, however, were more comprehensive, including pathology assessments. For metastatic basal cell carcinoma, the proportion of
609
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
