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Clinical Outcomes in Stage III Cutaneous Melanoma Treated With Adjuvant Radiation Therapy
E714
International Journal of Radiation Oncology Biology Physics
3751
Materials/Methods: Three MCC cell lines (MKL-1, MKL-2, and WaGa) were irradiated in dishes with SFRT (8 Gy x 1) using the X rays generated by the Small Animal Radiation Research Platform. Cell death was characterized at various time points using propidium iodide (PI)/annexin VFITC staining, cell cycle analysis, and caspase-3 activity assays. Values presented here represent percent or fold change standard error of the mean. Results: MKL-1, MKL-2, and WaGa cells responded to SFRT with little evidence of early apoptosis (annexin-positive, PI-negative) at 12 hours (3.52.0%, 2.91.3%, and 2.00.2% of treated cells, respectively). However, these cell lines did progress to a largely necrotic cell death (annexin-positive, PI-positive) by 48 hours (51.00.9%, 32.01.6%, and 71.02.0%, respectively). WaGa cells responded more rapidly than MKL1 and MKL-2 lines, with the latter having the slowest response. Cell cycle analysis revealed a stereotypic aneuploidy induced by SFRTdconsistent with mitotic catastrophe. Furthermore, SFRT induced relatively poor caspase-3 activation in MKL-1 (3.50.9 fold) and WaGa (2.10.3-fold) and none in MKL-2 (1.00.1-fold) by 48 hours, as compared with the apoptosis-competent human lymphoblastic lymphoma cell line TK6, which showed a 9.91.4-fold increase in caspase activity. Conclusion: MCC cell line necrosis induced by SFRT is largely the result of mitotic catastrophe with little or no induction of apoptosis. Because necrotic death is more strongly associated with immunogenicity than apoptotic cell death, these data may have implications for the optimal use of SFRT in treating metastatic MCC, especially in the context of concurrent or adjuvant immunotherapy. Author Disclosure: T.D. Mullen: None. P. Nghiem: Research Grant; NIAMS, NCI, EMD-Serono. S. Bhatia: Research Grant; Bristol Myers Squibb, EMD-Serono, Merck, Conkwest, Oncosec, Immune Design. U. Parvathaneni: None. J.L. Schwartz: None.
Clinical Outcomes in Stage III Cutaneous Melanoma Treated With Adjuvant Radiation Therapy P. Mathen,1 B.J. Debenham,2 J.P. Voroney,1 and R.N. Banerjee1; 1 University of Calgary, Calgary, AB, Canada, 2University of Alberta, Edmonton, AB, Canada Purpose/Objective(s): Stage III cutaneous melanoma incorporates a heterogeneous patient group with node-positive disease. Adjuvant radiation therapy (RT) decreases regional recurrence but its use is sporadic, in part due to a high competing risk of distant failure. This study aimed to assess our institutional practice patterns, evaluate clinical outcomes postRT, and identify risk factors for distant metastases in stage III melanoma patients. Materials/Methods: This study received institutional ethics approval. Patients who received adjuvant RT for node-positive melanoma between 2009 and 2014 were included. Kaplan-Meier estimates of overall survival (OS) and 95% confidence intervals (CI) were obtained. Logistic regression was used to explore the association between patient, tumor, and treatment factors for the outcomes of these patients. Results: Forty-one patients were analyzed. Median follow-up was 2 years. In all, 61% presented with palpable nodal disease, and 66% had a sentinel lymph node procedure prior to completion nodal dissection. Patients had an average of 3 involved lymph nodes and 23 total lymph nodes removed. Extracapsular extension was present in 51% of patients. Sixty-one percent of patients received hypofractionated RT (30 Gy/5 fractions or 36 Gy/6 fractions over 2.5-3 weeks) versus 39% who received conventional fractionation (typically 48 Gy/20 fractions). Regional radiation targets included the axilla (39%), head and neck (32%), and groin (29%). At 2 years, regional control was 82% and distant control was 46%. Median OS was 3.7 years. All patients who experienced a regional failure post-RT developed distant metastases and died of melanoma. All patients who were free of distant failure had regional control. Development of distant metastases was strongly associated with extracapsular extension (HR 4.0, 95% CI 1.8-8.7, P<0.0001). T stage, N stage, RT dose, neurotropism, nodal size, location, and number involved were not associated with regional or distant control. Conclusion: Patients who receive adjuvant RT for node-positive melanoma have high rates of regional control but are prone to distant failure. Regional failure is a harbinger of distant disease. Extracapsular extension also predicts distant failure in this population. Future research should compare outcomes with patients that did not receive RT and investigate the role of novel systemic therapies in preventing distant metastases. Author Disclosure: P. Mathen: None. B.J. Debenham: None. J. Voroney: None. R.N. Banerjee: None.
3752 Merkel Cell Carcinoma Cell Death in Response to Single-Fraction Irradiation: Implications for Immune Therapy T.D. Mullen,1 P. Nghiem,2 S. Bhatia,2 U. Parvathaneni,3 and J.L. Schwartz4; 1University of Washington Medical Center, Seattle, WA, 2University of Washington, Seattle, WA, 3University of Washington, Department of Radiation Oncology, Seattle, WA, 4University of Washington, Seattle, WA, United States Purpose/Objective(s): Merkel cell carcinoma is an aggressive virusassociated cancer with a strong rationale for immunotherapy. Singlefraction 8-Gy radiation therapy (SFRT) has been associated with excellent local response rates in a palliative setting. Precise mechanisms of tumor control with SFRT are unknown, although clinical data suggest an important role of the immune system in these responses. Emerging data suggest that the mode of cell may be important for tumor immunogenicity and anti-tumor responses, with necrosis being more immunogenic and apoptosis being nonimmunogenic or even tolerogenic in some systems. We sought to characterize how MCC cells die in vitro in a cell-autonomous fashion when exposed to SFRT by testing the hypothesis that these cells undergo a mixed apoptotic and necrotic cell death.
3753 Hypofractionated Stereotactic Body Radiation Therapy for the Definitive Treatment of Sarcoma M. Cengiz,1 A. Dauletkazin,1 F. Yildiz,2 G. Yazici,2 F. Akyol,2 F. Zorlu,2 M. Gurkaynak,2 and G. Ozyigit2; 1Hacettepe University, Faculty of Medicine, Ankara, Turkey, 2Hacettepe University Medical School, Ankara, Turkey Purpose/Objective(s): The aim of this study was to evaluate the efficacy and toxicity of definitive hypofractionated SBRT in patients with sarcoma. Materials/Methods: A total of 37 patients with sarcoma treated between September 2007 and June 2015 were retrospectively evaluated. Among them, the most common site of tumor location was head and neck (nZ18), and the most common histopathological diagnoses were osteosarcoma (nZ10) and leiomyosarcoma (nZ7). SBRT was the definitive primary treatment in 22 (59.5%) patients, and reirradiation was that in 15 patients (40.5%). The median age was 40 years (range, 11-68 years). There were 22 (59.5%) male and 15 (40.5%) female patients. All patients were treated with robotic radiosurgery. The median total dose was 32.5 Gy (range, 2050 Gy) delivered in a median of 5 fractions (1-5 fractions). Results: At 32 months (range, 2-92 months) of median follow-up, 2- and 5-year overall survival (OS) rates were 62.1% and 39.7%, respectively. Two- and 5-year progression-free survival (PFS) rates were 56% and 29.5%, respectively. Two- and 5-year local PFS rates were 56% and 30.8%. The univariate and multivariate analyses for OS showed that patient age (PZ0.017), performance status (PZ0.001), sex (PZ0.02), and tumor size (PZ0.04) were important prognostic factors. The univariate analysis for local PFS showed patient performance status (PZ0.014), sex (PZ0.004), and tumor size (PZ0.002) were important prognostic factors. In multivariate analyses, patient’s age, sex, tumor size, radiation dose, and reirradiation were important prognostic factors. Grade 3 toxicity was recorded in only 1 patient as trismus. Conclusion: Hypofractionated SBRT is well tolerated and resulted in relatively good local control and survival in patients with sarcomas. SBRT also looks like a safe and effective treatment for reirradiation of recurrent sarcoma.
International Journal of Radiation Oncology Biology Physics
3751
Materials/Methods: Three MCC cell lines (MKL-1, MKL-2, and WaGa) were irradiated in dishes with SFRT (8 Gy x 1) using the X rays generated by the Small Animal Radiation Research Platform. Cell death was characterized at various time points using propidium iodide (PI)/annexin VFITC staining, cell cycle analysis, and caspase-3 activity assays. Values presented here represent percent or fold change standard error of the mean. Results: MKL-1, MKL-2, and WaGa cells responded to SFRT with little evidence of early apoptosis (annexin-positive, PI-negative) at 12 hours (3.52.0%, 2.91.3%, and 2.00.2% of treated cells, respectively). However, these cell lines did progress to a largely necrotic cell death (annexin-positive, PI-positive) by 48 hours (51.00.9%, 32.01.6%, and 71.02.0%, respectively). WaGa cells responded more rapidly than MKL1 and MKL-2 lines, with the latter having the slowest response. Cell cycle analysis revealed a stereotypic aneuploidy induced by SFRTdconsistent with mitotic catastrophe. Furthermore, SFRT induced relatively poor caspase-3 activation in MKL-1 (3.50.9 fold) and WaGa (2.10.3-fold) and none in MKL-2 (1.00.1-fold) by 48 hours, as compared with the apoptosis-competent human lymphoblastic lymphoma cell line TK6, which showed a 9.91.4-fold increase in caspase activity. Conclusion: MCC cell line necrosis induced by SFRT is largely the result of mitotic catastrophe with little or no induction of apoptosis. Because necrotic death is more strongly associated with immunogenicity than apoptotic cell death, these data may have implications for the optimal use of SFRT in treating metastatic MCC, especially in the context of concurrent or adjuvant immunotherapy. Author Disclosure: T.D. Mullen: None. P. Nghiem: Research Grant; NIAMS, NCI, EMD-Serono. S. Bhatia: Research Grant; Bristol Myers Squibb, EMD-Serono, Merck, Conkwest, Oncosec, Immune Design. U. Parvathaneni: None. J.L. Schwartz: None.
Clinical Outcomes in Stage III Cutaneous Melanoma Treated With Adjuvant Radiation Therapy P. Mathen,1 B.J. Debenham,2 J.P. Voroney,1 and R.N. Banerjee1; 1 University of Calgary, Calgary, AB, Canada, 2University of Alberta, Edmonton, AB, Canada Purpose/Objective(s): Stage III cutaneous melanoma incorporates a heterogeneous patient group with node-positive disease. Adjuvant radiation therapy (RT) decreases regional recurrence but its use is sporadic, in part due to a high competing risk of distant failure. This study aimed to assess our institutional practice patterns, evaluate clinical outcomes postRT, and identify risk factors for distant metastases in stage III melanoma patients. Materials/Methods: This study received institutional ethics approval. Patients who received adjuvant RT for node-positive melanoma between 2009 and 2014 were included. Kaplan-Meier estimates of overall survival (OS) and 95% confidence intervals (CI) were obtained. Logistic regression was used to explore the association between patient, tumor, and treatment factors for the outcomes of these patients. Results: Forty-one patients were analyzed. Median follow-up was 2 years. In all, 61% presented with palpable nodal disease, and 66% had a sentinel lymph node procedure prior to completion nodal dissection. Patients had an average of 3 involved lymph nodes and 23 total lymph nodes removed. Extracapsular extension was present in 51% of patients. Sixty-one percent of patients received hypofractionated RT (30 Gy/5 fractions or 36 Gy/6 fractions over 2.5-3 weeks) versus 39% who received conventional fractionation (typically 48 Gy/20 fractions). Regional radiation targets included the axilla (39%), head and neck (32%), and groin (29%). At 2 years, regional control was 82% and distant control was 46%. Median OS was 3.7 years. All patients who experienced a regional failure post-RT developed distant metastases and died of melanoma. All patients who were free of distant failure had regional control. Development of distant metastases was strongly associated with extracapsular extension (HR 4.0, 95% CI 1.8-8.7, P<0.0001). T stage, N stage, RT dose, neurotropism, nodal size, location, and number involved were not associated with regional or distant control. Conclusion: Patients who receive adjuvant RT for node-positive melanoma have high rates of regional control but are prone to distant failure. Regional failure is a harbinger of distant disease. Extracapsular extension also predicts distant failure in this population. Future research should compare outcomes with patients that did not receive RT and investigate the role of novel systemic therapies in preventing distant metastases. Author Disclosure: P. Mathen: None. B.J. Debenham: None. J. Voroney: None. R.N. Banerjee: None.
3752 Merkel Cell Carcinoma Cell Death in Response to Single-Fraction Irradiation: Implications for Immune Therapy T.D. Mullen,1 P. Nghiem,2 S. Bhatia,2 U. Parvathaneni,3 and J.L. Schwartz4; 1University of Washington Medical Center, Seattle, WA, 2University of Washington, Seattle, WA, 3University of Washington, Department of Radiation Oncology, Seattle, WA, 4University of Washington, Seattle, WA, United States Purpose/Objective(s): Merkel cell carcinoma is an aggressive virusassociated cancer with a strong rationale for immunotherapy. Singlefraction 8-Gy radiation therapy (SFRT) has been associated with excellent local response rates in a palliative setting. Precise mechanisms of tumor control with SFRT are unknown, although clinical data suggest an important role of the immune system in these responses. Emerging data suggest that the mode of cell may be important for tumor immunogenicity and anti-tumor responses, with necrosis being more immunogenic and apoptosis being nonimmunogenic or even tolerogenic in some systems. We sought to characterize how MCC cells die in vitro in a cell-autonomous fashion when exposed to SFRT by testing the hypothesis that these cells undergo a mixed apoptotic and necrotic cell death.
3753 Hypofractionated Stereotactic Body Radiation Therapy for the Definitive Treatment of Sarcoma M. Cengiz,1 A. Dauletkazin,1 F. Yildiz,2 G. Yazici,2 F. Akyol,2 F. Zorlu,2 M. Gurkaynak,2 and G. Ozyigit2; 1Hacettepe University, Faculty of Medicine, Ankara, Turkey, 2Hacettepe University Medical School, Ankara, Turkey Purpose/Objective(s): The aim of this study was to evaluate the efficacy and toxicity of definitive hypofractionated SBRT in patients with sarcoma. Materials/Methods: A total of 37 patients with sarcoma treated between September 2007 and June 2015 were retrospectively evaluated. Among them, the most common site of tumor location was head and neck (nZ18), and the most common histopathological diagnoses were osteosarcoma (nZ10) and leiomyosarcoma (nZ7). SBRT was the definitive primary treatment in 22 (59.5%) patients, and reirradiation was that in 15 patients (40.5%). The median age was 40 years (range, 11-68 years). There were 22 (59.5%) male and 15 (40.5%) female patients. All patients were treated with robotic radiosurgery. The median total dose was 32.5 Gy (range, 2050 Gy) delivered in a median of 5 fractions (1-5 fractions). Results: At 32 months (range, 2-92 months) of median follow-up, 2- and 5-year overall survival (OS) rates were 62.1% and 39.7%, respectively. Two- and 5-year progression-free survival (PFS) rates were 56% and 29.5%, respectively. Two- and 5-year local PFS rates were 56% and 30.8%. The univariate and multivariate analyses for OS showed that patient age (PZ0.017), performance status (PZ0.001), sex (PZ0.02), and tumor size (PZ0.04) were important prognostic factors. The univariate analysis for local PFS showed patient performance status (PZ0.014), sex (PZ0.004), and tumor size (PZ0.002) were important prognostic factors. In multivariate analyses, patient’s age, sex, tumor size, radiation dose, and reirradiation were important prognostic factors. Grade 3 toxicity was recorded in only 1 patient as trismus. Conclusion: Hypofractionated SBRT is well tolerated and resulted in relatively good local control and survival in patients with sarcomas. SBRT also looks like a safe and effective treatment for reirradiation of recurrent sarcoma.