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Asia-Pacific Journal of Clinical Oncology 2015
doi: 10.1111/ajco.12345
ORIGINAL ARTICLE
Radiotherapy utilization in BRAF mutation-tested metastatic melanoma in the targeted therapy era Peter GORAYSKI,1 Marcin DZIENIS,2,3 Matthew FOOTE,1,3 Victoria ATKINSON,2 Elizabeth BURMEISTER4 and Bryan BURMEISTER1 Departments of 1Radiation Oncology and 2Medical Oncology, Princess Alexandra Hospital, Woolloongabba, 3Diamantina Institute, University of Queensland, 4Nursing Practice Development Unit, Princess Alexandra Hospital & Centre for Health Practice Innovation, Griffith University, Brisbane, Queensland, Australia
Abstract Aim: Tumor BRAF mutation testing is routine for all patients with metastatic melanoma (MM) owing to the availability of agents targeting this intracellular pathway. To test whether there is a difference in radiotherapy (RT) utilization according to BRAF mutation status, we performed a retrospective review of RT utilization in a contemporary cohort undergoing BRAF mutation testing. Methods: Clinical records of MM patients undergoing BRAF mutation testing between April 2010 and August 2012 were reviewed. Overall survival (OS) was calculated using Kaplan–Meier methods. Differences between BRAF status were calculated using chi-square tests for categorical variables, median tests for continuous variables and Cox proportional hazards models to compare OS. Results: Up to 158 patients were identified but 17 were excluded due to inadequate clinical data. Of the remaining 141 patients, 69 (49%) tested BRAF mutant (BRAF-m), median age 47 years (range 21–79) with median follow-up of 16.8 months (IQR11.3–25.2). Seventy-two (51%) tested BRAF wild type (BRAF-w), median age 62 years (range 25–84) with median follow-up of 27.1 months (IQR12.5–57.4). Overall, RT utilization was similar: 68% in BRAF-m and 69% in BRAF-w. Mean number of treatment courses was 1.70 for BRAF-m and 2.36 for BRAF-w (Pearson chi-square 3.92, P = 0.05). Up to 51% of BRAF-m and 56% of BRAF-w required ≧2 RT courses. Forty-six percent BRAF-m compared with 29% BRAF-w received brain RT (P = 0.04). Median OS was 17.7 months (IQR7.6–35.5) in BRAF-m and 19 months (IQR7.8–35.1) in BRAF-w (P = 0.99). Conclusion: High RT utilization rates were observed irrespective of BRAF mutation status. Significantly more BRAF-w patients received RT but more BRAF-m patients received brain RT. Key words: BRAF, melanoma, radiotherapy, utilization.
INTRODUCTION Metastatic melanoma (MM) is common in Australia and is associated with poor survival.1 The disease is particularly prevalent in tropical latitude regions like
Correspondence: Dr Peter Gorayski BSc (Hons) BMBS FRACGP, Radiation Oncology, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Qld 4102, Australia. Email: [email protected] Conflict of interest: none Accepted for publication 11 January 2015.
© 2015 Wiley Publishing Asia Pty Ltd
Queensland with high ultraviolet exposure and a predominantly fair-skinned population.2 For patients with stage IV disease, American Joint Committee on Cancer (AJCC) melanoma database predictions for 5- and 10-year overall survivals (OS) are 15–20% and 10–15%, respectively.3 The management of MM is complex given its variable clinical course and poor response to cytotoxic systemic treatments including dacarbazine, fotemustine and temozolomide.4–6 Other systemic immunotherapy options including interleukin-2 and ipilimumab have low response rates and cause significant toxicity.7,8
2
Tumor BRAF mutation testing is routine for all patients with MM owing to the availability of agents targeting this intracellular pathway. Prolongation of progression-free survival (PFS) and OS is associated with the use of BRAF inhibitors.9 Approximately 40–50% of cutaneous melanomas harbor the BRAF V600E mutation.10,11 BRAF mutations cause constitutive activation of the BRAF protein kinase in the RAF/MEK/ ERK pathway stimulating cellular proliferation and survival. Palliative radiotherapy (RT) is commonly utilized in patients with MM to treat symptoms from local progression, improve local control and prevent pathological fracture from bony metastases. RT utilization rates for MM vary considerably. Best theoretical estimates from the literature suggest a rate around 23% across all clinical stages,12 and around 21% for patients with established metastatic disease. To date, there are no data reporting differences in RT utilization in patients with MM according to BRAF status. We hypothesized there would be a difference in the use of palliative RT according to BRAF mutation status due to the availability and increasing use of targeted therapies. To test this hypothesis, we performed a retrospective analysis evaluating RT utilization rates and survival in a contemporary cohort undergoing modern staging and BRAF mutation testing.
P Gorayski et al.
ered following surgery (adjuvant), as a sole nonadjuvant modality (RT alone), or following previous postoperative (adjuvant) RT. Postoperative (adjuvant) RT was defined as treatment delivered following surgery for brain metastases, resection of in-transit disease and/or regional nodal recurrence, or stabilization of bony metastases at risk of pathological fracture. “RT alone” was defined as RT delivered as a sole modality to the brain, bone(s), viscera, in-transit cutaneous sites and unresectable nodal disease. Timing of RT treatments were assessed and included (1) time to first RT treatment, (2) time to last RT treatment, (3) time from first to last RT treatment, and (4) time to brain RT. The starting time point was taken from the date of initial diagnosis of unresectable stage IIIC disease or metastatic disease (stage IV) or the development of nodal/other metastatic disease (if patients were previously diagnosed with earlier stage disease). BRAF inhibitors were temporarily ceased if patients required RT due to toxicity concerns regarding combined modality treatment. All patients were treated with palliative intent in order to relieve symptoms and/or prevent symptomatic deterioration by improving local control. BRAF V600E mutation testing was performed at external institutional laboratories using the real-time polymerase chain reaction test.
Statistics
METHODS Institutional human research ethics approval was obtained to undertake a retrospective analysis of a prospectively maintained database of patients with MM who were seen through the Princess Alexandra Hospital multidisciplinary melanoma unit. Patients were included if they underwent BRAF V600E mutation testing between April 2010 and August 2012. These dates corresponded to the implementation of BRAF mutation testing at our institution. In the final analysis, all patients had distant metastatic disease, irrespective of whether they were initially diagnosed with stage III disease. All time points were taken from the date of diagnosis of metastatic disease or inoperable regional recurrence. Clinical records were reviewed for patient demographics, BRAF mutation status, tumor site at the time of diagnosis of metastatic disease, RT fractionation schedules delivered, site(s) treated and systemic agent(s) used. The primary endpoint was RT utilization. RT utilization was analyzed as a whole, and further assessed in relation to whether treatments were deliv-
© 2015 Wiley Publishing Asia Pty Ltd
OS was calculated using Kaplan–Meier methods from date of primary relapse. Follow-up time was calculated using the reverse Kaplan–Meier method. Differences between BRAF status with categorical variables were tested using the chi-square test, median tests for continuous variables, and Cox proportional hazards models for associations with OS. A P-value of ≤0.05 or less was considered statistically significant.
RESULTS Patient population Up to 158 patients were identified. Two had insufficient tissue for testing and 15 had insufficient follow-up data. Of the remaining patients (n = 141), 69 (49%) tested BRAF mutant (BRAF-m) and 72 (51%) tested BRAF wild type (BRAF-w). Baseline characteristics are shown in Table 1. Median age was 47 years (range 21–79) for BRAF-m and 62 years (range 25–84) for BRAF-w. Median follow-up for the cohort was 19 months (IQR 12–35); 16.8 months
Asia-Pac J Clin Oncol 2015
3
RT utilization in melanoma
Table 1
Patient demographics, clinical staging and systemic agent use
Median age in years (range) Gender: male Metastases at diagnosis Skin, subcutaneous and/or lymph nodes Lungs Brain Other visceral Systemic therapy use Yes No Unknown
BRAF mutant n = 69
BRAF wild type n = 72
P-value
47 (21–79) 33 (48%)
62 (25–84) 59 (82%)
Asia-Pacific Journal of Clinical Oncology 2015
doi: 10.1111/ajco.12345
ORIGINAL ARTICLE
Radiotherapy utilization in BRAF mutation-tested metastatic melanoma in the targeted therapy era Peter GORAYSKI,1 Marcin DZIENIS,2,3 Matthew FOOTE,1,3 Victoria ATKINSON,2 Elizabeth BURMEISTER4 and Bryan BURMEISTER1 Departments of 1Radiation Oncology and 2Medical Oncology, Princess Alexandra Hospital, Woolloongabba, 3Diamantina Institute, University of Queensland, 4Nursing Practice Development Unit, Princess Alexandra Hospital & Centre for Health Practice Innovation, Griffith University, Brisbane, Queensland, Australia
Abstract Aim: Tumor BRAF mutation testing is routine for all patients with metastatic melanoma (MM) owing to the availability of agents targeting this intracellular pathway. To test whether there is a difference in radiotherapy (RT) utilization according to BRAF mutation status, we performed a retrospective review of RT utilization in a contemporary cohort undergoing BRAF mutation testing. Methods: Clinical records of MM patients undergoing BRAF mutation testing between April 2010 and August 2012 were reviewed. Overall survival (OS) was calculated using Kaplan–Meier methods. Differences between BRAF status were calculated using chi-square tests for categorical variables, median tests for continuous variables and Cox proportional hazards models to compare OS. Results: Up to 158 patients were identified but 17 were excluded due to inadequate clinical data. Of the remaining 141 patients, 69 (49%) tested BRAF mutant (BRAF-m), median age 47 years (range 21–79) with median follow-up of 16.8 months (IQR11.3–25.2). Seventy-two (51%) tested BRAF wild type (BRAF-w), median age 62 years (range 25–84) with median follow-up of 27.1 months (IQR12.5–57.4). Overall, RT utilization was similar: 68% in BRAF-m and 69% in BRAF-w. Mean number of treatment courses was 1.70 for BRAF-m and 2.36 for BRAF-w (Pearson chi-square 3.92, P = 0.05). Up to 51% of BRAF-m and 56% of BRAF-w required ≧2 RT courses. Forty-six percent BRAF-m compared with 29% BRAF-w received brain RT (P = 0.04). Median OS was 17.7 months (IQR7.6–35.5) in BRAF-m and 19 months (IQR7.8–35.1) in BRAF-w (P = 0.99). Conclusion: High RT utilization rates were observed irrespective of BRAF mutation status. Significantly more BRAF-w patients received RT but more BRAF-m patients received brain RT. Key words: BRAF, melanoma, radiotherapy, utilization.
INTRODUCTION Metastatic melanoma (MM) is common in Australia and is associated with poor survival.1 The disease is particularly prevalent in tropical latitude regions like
Correspondence: Dr Peter Gorayski BSc (Hons) BMBS FRACGP, Radiation Oncology, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Qld 4102, Australia. Email: [email protected] Conflict of interest: none Accepted for publication 11 January 2015.
© 2015 Wiley Publishing Asia Pty Ltd
Queensland with high ultraviolet exposure and a predominantly fair-skinned population.2 For patients with stage IV disease, American Joint Committee on Cancer (AJCC) melanoma database predictions for 5- and 10-year overall survivals (OS) are 15–20% and 10–15%, respectively.3 The management of MM is complex given its variable clinical course and poor response to cytotoxic systemic treatments including dacarbazine, fotemustine and temozolomide.4–6 Other systemic immunotherapy options including interleukin-2 and ipilimumab have low response rates and cause significant toxicity.7,8
2
Tumor BRAF mutation testing is routine for all patients with MM owing to the availability of agents targeting this intracellular pathway. Prolongation of progression-free survival (PFS) and OS is associated with the use of BRAF inhibitors.9 Approximately 40–50% of cutaneous melanomas harbor the BRAF V600E mutation.10,11 BRAF mutations cause constitutive activation of the BRAF protein kinase in the RAF/MEK/ ERK pathway stimulating cellular proliferation and survival. Palliative radiotherapy (RT) is commonly utilized in patients with MM to treat symptoms from local progression, improve local control and prevent pathological fracture from bony metastases. RT utilization rates for MM vary considerably. Best theoretical estimates from the literature suggest a rate around 23% across all clinical stages,12 and around 21% for patients with established metastatic disease. To date, there are no data reporting differences in RT utilization in patients with MM according to BRAF status. We hypothesized there would be a difference in the use of palliative RT according to BRAF mutation status due to the availability and increasing use of targeted therapies. To test this hypothesis, we performed a retrospective analysis evaluating RT utilization rates and survival in a contemporary cohort undergoing modern staging and BRAF mutation testing.
P Gorayski et al.
ered following surgery (adjuvant), as a sole nonadjuvant modality (RT alone), or following previous postoperative (adjuvant) RT. Postoperative (adjuvant) RT was defined as treatment delivered following surgery for brain metastases, resection of in-transit disease and/or regional nodal recurrence, or stabilization of bony metastases at risk of pathological fracture. “RT alone” was defined as RT delivered as a sole modality to the brain, bone(s), viscera, in-transit cutaneous sites and unresectable nodal disease. Timing of RT treatments were assessed and included (1) time to first RT treatment, (2) time to last RT treatment, (3) time from first to last RT treatment, and (4) time to brain RT. The starting time point was taken from the date of initial diagnosis of unresectable stage IIIC disease or metastatic disease (stage IV) or the development of nodal/other metastatic disease (if patients were previously diagnosed with earlier stage disease). BRAF inhibitors were temporarily ceased if patients required RT due to toxicity concerns regarding combined modality treatment. All patients were treated with palliative intent in order to relieve symptoms and/or prevent symptomatic deterioration by improving local control. BRAF V600E mutation testing was performed at external institutional laboratories using the real-time polymerase chain reaction test.
Statistics
METHODS Institutional human research ethics approval was obtained to undertake a retrospective analysis of a prospectively maintained database of patients with MM who were seen through the Princess Alexandra Hospital multidisciplinary melanoma unit. Patients were included if they underwent BRAF V600E mutation testing between April 2010 and August 2012. These dates corresponded to the implementation of BRAF mutation testing at our institution. In the final analysis, all patients had distant metastatic disease, irrespective of whether they were initially diagnosed with stage III disease. All time points were taken from the date of diagnosis of metastatic disease or inoperable regional recurrence. Clinical records were reviewed for patient demographics, BRAF mutation status, tumor site at the time of diagnosis of metastatic disease, RT fractionation schedules delivered, site(s) treated and systemic agent(s) used. The primary endpoint was RT utilization. RT utilization was analyzed as a whole, and further assessed in relation to whether treatments were deliv-
© 2015 Wiley Publishing Asia Pty Ltd
OS was calculated using Kaplan–Meier methods from date of primary relapse. Follow-up time was calculated using the reverse Kaplan–Meier method. Differences between BRAF status with categorical variables were tested using the chi-square test, median tests for continuous variables, and Cox proportional hazards models for associations with OS. A P-value of ≤0.05 or less was considered statistically significant.
RESULTS Patient population Up to 158 patients were identified. Two had insufficient tissue for testing and 15 had insufficient follow-up data. Of the remaining patients (n = 141), 69 (49%) tested BRAF mutant (BRAF-m) and 72 (51%) tested BRAF wild type (BRAF-w). Baseline characteristics are shown in Table 1. Median age was 47 years (range 21–79) for BRAF-m and 62 years (range 25–84) for BRAF-w. Median follow-up for the cohort was 19 months (IQR 12–35); 16.8 months
Asia-Pac J Clin Oncol 2015
3
RT utilization in melanoma
Table 1
Patient demographics, clinical staging and systemic agent use
Median age in years (range) Gender: male Metastases at diagnosis Skin, subcutaneous and/or lymph nodes Lungs Brain Other visceral Systemic therapy use Yes No Unknown
BRAF mutant n = 69
BRAF wild type n = 72
P-value
47 (21–79) 33 (48%)
62 (25–84) 59 (82%)
