Stereotactic body radiation therapy for the treatment of oligoprogression on androgen receptor targeted therapy in castration-resistant prostate cancer

Stereotactic body radiation therapy for the treatment of oligoprogression on androgen receptor... Castration-resistant prostate cancer is an incurable disease. To date, six agents-abiraterone, enzalutamide, docetaxel, cabazitaxel, radium-223 and sipuleucel-T- have shown clinical efficacy in phase III clinical trials, leading to their FDA approval. Patients are typically sequenced through most or all of these agents, and then eventually succumb to their disease. Development of new treatments remains an unmet need. We report a case of a patient who progressed on enzalutamide with a single enlarging metastatic lesion, was treated with ablative stereotactic body radiation therapy while maintaining the same systemic treatment, who then had durable complete remission. Our findings have important clinical implications and suggest novel clinical trials for this difficult to treat disease. INTRODUCTION signaling by directly binding to AR. Acquired resistance to both Abiraterone and enzalutamide have been shown in phase III abiraterone and enzalutamide inevitably develops due to AR clinical trials to have efficacy in patients with castration- mutations and other escape mechanisms [3]. Radiation has resistant prostate cancer (CRPC), leading to improved overall been shown to be effective after progression on AR targeted survival [1,2]. Abiraterone inhibits intratumoral production of therapy, due to non-overlapping mechanism of resistance [4]. androgens, thereby decreasing engagement of the androgen During cancer treatment, progression is due to the develop- receptor (AR) for nuclear signaling. Enzalutamide inhibits AR ment of new mutations in the progressing lesions causing Co-first authors. Co-corresponding authors. Received: June 22, 2017. Revised: September 8, 2017. Accepted: October 11, 2017 © The Author 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/omcr/article-abstract/2018/1/omx078/4794781 by Ed 'DeepDyve' Gillespie user on 16 March 2018 6 T.-C. Nguyen et al. treatment resistance, while responsive or stable lesions have pelvic region including the obturator bed and prostatic resection not acquired those mutations [5]. For prostate cancer treat- bed. ADT was continued throughout radiation therapy. ment, we hypothesize that ablative radiation of lesions pro- Oneyearlater,hedeveloped biochemicalrecurrencewithhis gressing on AR targeted therapy would likely be effective as PSA going up from 0.05 ng/ml to 1.19 ng/ml for which bicalutamide resistant lesions are ablated, while continuing AR targeting to was added to ADT. His PSA continued to rise to 2.05 ng/ml along keep responsive or stable lesions suppressed. with enlarging external iliac lymph nodes (Fig. 1). Bicalutamide Stereotactic body radiation therapy (SBRT) is a highly con- was discontinued and the patient was started on abiraterone formal radiation technique that delivers high-dose radiation to and prednisone with excellent response, with undetectable PSA a tumor while sparing much of the nearby normal organs [6]. and complete response of his lymph nodes for the next 2 years. Compared to conventional palliative radiation therapy, which However, his PSA gradually increased to 0.06 ng/ml and he was is delivered over 10–15 days with the intent to control pain but switched to enzalutamide, which led to stable PSA for another 6 not disease progression, SBRT is commonly delivered in 3–10 months until it increased to 0.4 ng/ml when imaging was done treatments with the intent of disease ablation. There is evi- to evaluate for metastatic disease. CT scan showed an enlarging dence that SBRT achieves local control rates in excess of 90% para-aortic lymph node (Fig. 2A). Thereafter, the patient was by sterilizing the treated area. evaluated for SBRT to the lymph node, which was however, not We report a case of a patient with metastatic prostate can- considered feasible at the time due to its small size. A follow-up cer who progressed with a growing solitary metastatic lymph CT scan 4 months later showed an increase in the size of the node while on AR targeted therapy with enzalutamide, but lymph node to 1.5 cm with PSA rising to 2.74 ng/ml (Figs 1 and 2 went on to have durable complete remission after treatment B). The patient then received SBRT 50 Gy in 10 fractions to the with SBRT to the node while continuing enzalutamide. para-aortic lymph node (Fig. 3). During this entire time, enzalu- tamide was continued. Six months post treatment, CT scan showed marked decrease in the size of the para-aortic lymph CASE PRESENTATION node and decline in PSA (Figs 1 and 2C). At the latest follow-up The patient is a 44-year-old male diagnosed with high-risk pros- 6 months thereafter, the patient had been doing well on enzalu- tate cancer [clinical stage T1c, Gleason 4 + 4 = 8, prostate-specific tamide and his PSA remained low. antigen (PSA) 29.2 ng/ml]. He elected for primary treatment with robotic-assisted prostatectomy (final pathology revealed pT3b N1 DISCUSSION M0, Gleason 5 + 4 = 9, with seminal vesicle invasion and involve- ment of bilateral obturator lymph nodes). His PSA post- CRPC is defined as progressive prostate cancer while on ADT prostatectomy was undetectable. Adjuvant radiation was not with serum testosterone <50 mg/dl. Median overall survival is offered due to residual urinary incontinence. He was offered limited, ranging from 9 to 30 months [7]. At present, six agents adjuvant androgen deprivation therapy (ADT) in the form of leu- have shown overall survival benefit in phase III clinical trials prolide which maintained his PSA at undetectable levels for ~3 and are approved for use in patients with CRPC. They include years when it increased to 1.9 ng/ml (Fig. 1). At that time, he docetaxel, abiraterone, enzalutamide, cabazitaxel, sipuleucel-T received salvage external beam radiation therapy (64.8 Gy) to the and radium-223 [7]. Although, the sequencing of these agents has not been clearly defined, certain clinical situations favor the use of one agent over another. Sipuleucel-T seems to require at least 6 months duration after treatment to have beneficial effect. Therefore, it is indicated primarily in minimally symp- tomatic or asymptomatic patients with at least 6 months life # expectancy. Docetaxel is the preferred initial agent in symptom- atic patients with extensive disease burden or with visceral metastases. For asymptomatic patients with less disease burden or non-visceral metastases, the AR targeting agents, abiraterone or enzalutamide, are preferrable over docetaxel, as they are bet- ter tolerated. For patients with progression or relapse post- 0 255075 100 docetaxel not previously on AR targeted therapy, abiraterone or Time (months) enzalutemide are usually the preferred next drugs given their better tolerability profile, followed by cabazitaxel. For patients Figure 1: Trend of PSA over time. # marks salvage radiation to prostate bed and pelvis; & marks starting AR targeted therapy with abiraterone; *marks SBRT with multi-focal painful bony metastases, radium-223, an α- treatment to metastatic para-aortic lymph node. emitter, can be used and has been shown to improve survival. AB C Figure 2: Computed Tomography (CT) scans showing enlarging metastatic para-aortic lymphadenopathy (A) 4 months prior to SBRT, (B) at SBRT; and then responding to treatment and (C) 4 months after SBRT. Downloaded from https://academic.oup.com/omcr/article-abstract/2018/1/omx078/4794781 by Ed 'DeepDyve' Gillespie user on 16 March 2018 PSA (ng/ml) SBRT for the treatment of oligoprogression on AR targeted therapy 7 Figure 3: SBRT for a LEFT iliac lymph node. The prescribed dose was 50 Gy in 5 Gy fractions. Isodose lines are shown in (A, axial; B, sagittal and C, coronal). The dose volume histogram is shown in D. Although these treatments are effective, unfortunately patients CONSENT FOR PUBLICATION eventually run out of treatments and succumb to their disease. Consent to publish has been obtained from patient. The use of SBRT has been applied to the treatment of castration-sensitive prostate cancer (CSPC) with oligometastatic disease, defined as five or fewer metastatic lesions. To date, two AVAILABILITY OF DATA AND MATERIAL retrospective studies have been completed showing a strong trend towards improved long-term disease control and out- Any applicable data can be provided upon request. comes. Schick et al. published a series of 50 patients with CSPC with a total of 79 metastatic lesions including lymph nodes, bonesand lungs[8]. Their cohort showed a 3-year biochemical REFERENCES recurrence free survival of 55%, clinical recurrence free survival 1. Ryan CJ,Smith MR,deBonoJS, Molina A, Logothetis CJ, of 59% and 3-year overall survival of 92%. None of their patients de Souza P, et al. Abiraterone in metastatic prostate showed Grade 3 or worse adverse events. Similarly, Muacevic cancer without previous chemotherapy. NEJM 2013;368: et al. completed a series of 40 patients with CSPC with a total of 139–48. 64 bony lesions [9]. Their 2-year local control was 95.5%. 2. Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg Our case report is the first to show that SBRT can be effect- CN, Higano CS, et al. Enzalutamide in metastatic prostate ively added to control oligoprogression while on AR targeted cancer before chemotherapy. NEJM 2014;371:424–33. therapy for CRPC, with improved disease control. We have previ- 3. Boudadi K, Antonarakis ES. Resistance to novel antiandro- ously shown such treatment approach using SBRT can be gen therapies in metastatic castration-resistant prostate applied to gastrointestinal cancer patients with oligoprogression cancer. Clin Med Insights Oncol 2016;10:1–9. on chemotherapy [10]. Our data suggests that larger studies 4. Parker C, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, using SBRT for oligoprogression should be proposed to assess Fosså SD, et al. Alpha emitter radium-223 and survival in survival outcomes for the treatment of CRPC. Incorporating more metastatic prostate cancer. NEJM 2013;369:213–23. sensitive imaging techniques for prostate cancer like C-Choline 5. Yeh C-N, Chen T-W, Tseng J-H, Liu Y-Y, Wang S-Y, Tsai C- or Axumin PET-CT scans, oligoprogression may be detected earl- Y, et al. Surgical management in metastatic gastrointestinal ier in the disease course and treatment with SBRT may even be stromal tumor (GIST) patients after imatinib mesylate treat- more effective. ment. J Surgical Oncol 2010;102:599–603. 6. Lo SS, Fakiris AJ, Chang EL, Mayr NA, Wang JZ, Papiez L, CONCLUSION et al. Stereotactic body radiation therapy: a novel treatment This case report emphasize use of SBRT as an additional tool in modality. Nat Rev Clin Oncol 2010;7:44–54. long-term control of oligoprogression of CRPC while preserving 7. Kirby M, Hirst C, Crawford ED. Characterizing the the mainline therapy. castration-resistant prostate cancer population: a system- atic review. Int J Clin Pract 2011;65:1180–92. 8. Schick U, Jorcano S, Nouet P, Rouzaoud M, Vees H, Zilli T, CONFLICT OF INTEREST STATEMENT et al. Androgen deprivation and high dose radiotherapy for The authors declare that they have no competing interests. oligometastatic prostate cancer patients with less than five regional and /or distant metastases. Acta Oncol 2013;52: FUNDING 1622–8. 9. Muacevic A, Kufeld M, Rist C, Wowra B, Stief C, Staehler M. No funding was required for this report. Safety and feasibility of image guided robotic radiosurgery for patients with limited bone metastases of prostate can- DECLARATIONS cer. Urol Oncol 2013;31:455–60. Ethics approval and consent to participate: We followed 10. Wray J, Hawamdeh RF, Hasija N, Dagan R, Yeung AR, University of Florida (UF) Institutional Review Board (IRB) Lightsey JL, et al. Stereotactic body radiation therapy for oli- guidelines for this case study. UF IRB grants waiver or does not goprogression of metastatic disease from gastrointestinal require prior IRB approval for this study. http://irb.ufl.edu/wp- cancers: a novel approach to extend chemotherapy efficacy. content/uploads/op-casereports.pdf Oncol Lett 2017;13:1087–94. Downloaded from https://academic.oup.com/omcr/article-abstract/2018/1/omx078/4794781 by Ed 'DeepDyve' Gillespie user on 16 March 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Oxford Medical Case Reports Oxford University Press

Stereotactic body radiation therapy for the treatment of oligoprogression on androgen receptor targeted therapy in castration-resistant prostate cancer

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Abstract

Castration-resistant prostate cancer is an incurable disease. To date, six agents-abiraterone, enzalutamide, docetaxel, cabazitaxel, radium-223 and sipuleucel-T- have shown clinical efficacy in phase III clinical trials, leading to their FDA approval. Patients are typically sequenced through most or all of these agents, and then eventually succumb to their disease. Development of new treatments remains an unmet need. We report a case of a patient who progressed on enzalutamide with a single enlarging metastatic lesion, was treated with ablative stereotactic body radiation therapy while maintaining the same systemic treatment, who then had durable complete remission. Our findings have important clinical implications and suggest novel clinical trials for this difficult to treat disease. INTRODUCTION signaling by directly binding to AR. Acquired resistance to both Abiraterone and enzalutamide have been shown in phase III abiraterone and enzalutamide inevitably develops due to AR clinical trials to have efficacy in patients with castration- mutations and other escape mechanisms [3]. Radiation has resistant prostate cancer (CRPC), leading to improved overall been shown to be effective after progression on AR targeted survival [1,2]. Abiraterone inhibits intratumoral production of therapy, due to non-overlapping mechanism of resistance [4]. androgens, thereby decreasing engagement of the androgen During cancer treatment, progression is due to the develop- receptor (AR) for nuclear signaling. Enzalutamide inhibits AR ment of new mutations in the progressing lesions causing Co-first authors. Co-corresponding authors. Received: June 22, 2017. Revised: September 8, 2017. Accepted: October 11, 2017 © The Author 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/omcr/article-abstract/2018/1/omx078/4794781 by Ed 'DeepDyve' Gillespie user on 16 March 2018 6 T.-C. Nguyen et al. treatment resistance, while responsive or stable lesions have pelvic region including the obturator bed and prostatic resection not acquired those mutations [5]. For prostate cancer treat- bed. ADT was continued throughout radiation therapy. ment, we hypothesize that ablative radiation of lesions pro- Oneyearlater,hedeveloped biochemicalrecurrencewithhis gressing on AR targeted therapy would likely be effective as PSA going up from 0.05 ng/ml to 1.19 ng/ml for which bicalutamide resistant lesions are ablated, while continuing AR targeting to was added to ADT. His PSA continued to rise to 2.05 ng/ml along keep responsive or stable lesions suppressed. with enlarging external iliac lymph nodes (Fig. 1). Bicalutamide Stereotactic body radiation therapy (SBRT) is a highly con- was discontinued and the patient was started on abiraterone formal radiation technique that delivers high-dose radiation to and prednisone with excellent response, with undetectable PSA a tumor while sparing much of the nearby normal organs [6]. and complete response of his lymph nodes for the next 2 years. Compared to conventional palliative radiation therapy, which However, his PSA gradually increased to 0.06 ng/ml and he was is delivered over 10–15 days with the intent to control pain but switched to enzalutamide, which led to stable PSA for another 6 not disease progression, SBRT is commonly delivered in 3–10 months until it increased to 0.4 ng/ml when imaging was done treatments with the intent of disease ablation. There is evi- to evaluate for metastatic disease. CT scan showed an enlarging dence that SBRT achieves local control rates in excess of 90% para-aortic lymph node (Fig. 2A). Thereafter, the patient was by sterilizing the treated area. evaluated for SBRT to the lymph node, which was however, not We report a case of a patient with metastatic prostate can- considered feasible at the time due to its small size. A follow-up cer who progressed with a growing solitary metastatic lymph CT scan 4 months later showed an increase in the size of the node while on AR targeted therapy with enzalutamide, but lymph node to 1.5 cm with PSA rising to 2.74 ng/ml (Figs 1 and 2 went on to have durable complete remission after treatment B). The patient then received SBRT 50 Gy in 10 fractions to the with SBRT to the node while continuing enzalutamide. para-aortic lymph node (Fig. 3). During this entire time, enzalu- tamide was continued. Six months post treatment, CT scan showed marked decrease in the size of the para-aortic lymph CASE PRESENTATION node and decline in PSA (Figs 1 and 2C). At the latest follow-up The patient is a 44-year-old male diagnosed with high-risk pros- 6 months thereafter, the patient had been doing well on enzalu- tate cancer [clinical stage T1c, Gleason 4 + 4 = 8, prostate-specific tamide and his PSA remained low. antigen (PSA) 29.2 ng/ml]. He elected for primary treatment with robotic-assisted prostatectomy (final pathology revealed pT3b N1 DISCUSSION M0, Gleason 5 + 4 = 9, with seminal vesicle invasion and involve- ment of bilateral obturator lymph nodes). His PSA post- CRPC is defined as progressive prostate cancer while on ADT prostatectomy was undetectable. Adjuvant radiation was not with serum testosterone <50 mg/dl. Median overall survival is offered due to residual urinary incontinence. He was offered limited, ranging from 9 to 30 months [7]. At present, six agents adjuvant androgen deprivation therapy (ADT) in the form of leu- have shown overall survival benefit in phase III clinical trials prolide which maintained his PSA at undetectable levels for ~3 and are approved for use in patients with CRPC. They include years when it increased to 1.9 ng/ml (Fig. 1). At that time, he docetaxel, abiraterone, enzalutamide, cabazitaxel, sipuleucel-T received salvage external beam radiation therapy (64.8 Gy) to the and radium-223 [7]. Although, the sequencing of these agents has not been clearly defined, certain clinical situations favor the use of one agent over another. Sipuleucel-T seems to require at least 6 months duration after treatment to have beneficial effect. Therefore, it is indicated primarily in minimally symp- tomatic or asymptomatic patients with at least 6 months life # expectancy. Docetaxel is the preferred initial agent in symptom- atic patients with extensive disease burden or with visceral metastases. For asymptomatic patients with less disease burden or non-visceral metastases, the AR targeting agents, abiraterone or enzalutamide, are preferrable over docetaxel, as they are bet- ter tolerated. For patients with progression or relapse post- 0 255075 100 docetaxel not previously on AR targeted therapy, abiraterone or Time (months) enzalutemide are usually the preferred next drugs given their better tolerability profile, followed by cabazitaxel. For patients Figure 1: Trend of PSA over time. # marks salvage radiation to prostate bed and pelvis; & marks starting AR targeted therapy with abiraterone; *marks SBRT with multi-focal painful bony metastases, radium-223, an α- treatment to metastatic para-aortic lymph node. emitter, can be used and has been shown to improve survival. AB C Figure 2: Computed Tomography (CT) scans showing enlarging metastatic para-aortic lymphadenopathy (A) 4 months prior to SBRT, (B) at SBRT; and then responding to treatment and (C) 4 months after SBRT. Downloaded from https://academic.oup.com/omcr/article-abstract/2018/1/omx078/4794781 by Ed 'DeepDyve' Gillespie user on 16 March 2018 PSA (ng/ml) SBRT for the treatment of oligoprogression on AR targeted therapy 7 Figure 3: SBRT for a LEFT iliac lymph node. The prescribed dose was 50 Gy in 5 Gy fractions. Isodose lines are shown in (A, axial; B, sagittal and C, coronal). The dose volume histogram is shown in D. Although these treatments are effective, unfortunately patients CONSENT FOR PUBLICATION eventually run out of treatments and succumb to their disease. Consent to publish has been obtained from patient. The use of SBRT has been applied to the treatment of castration-sensitive prostate cancer (CSPC) with oligometastatic disease, defined as five or fewer metastatic lesions. To date, two AVAILABILITY OF DATA AND MATERIAL retrospective studies have been completed showing a strong trend towards improved long-term disease control and out- Any applicable data can be provided upon request. comes. Schick et al. published a series of 50 patients with CSPC with a total of 79 metastatic lesions including lymph nodes, bonesand lungs[8]. Their cohort showed a 3-year biochemical REFERENCES recurrence free survival of 55%, clinical recurrence free survival 1. Ryan CJ,Smith MR,deBonoJS, Molina A, Logothetis CJ, of 59% and 3-year overall survival of 92%. None of their patients de Souza P, et al. Abiraterone in metastatic prostate showed Grade 3 or worse adverse events. Similarly, Muacevic cancer without previous chemotherapy. NEJM 2013;368: et al. completed a series of 40 patients with CSPC with a total of 139–48. 64 bony lesions [9]. Their 2-year local control was 95.5%. 2. Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg Our case report is the first to show that SBRT can be effect- CN, Higano CS, et al. Enzalutamide in metastatic prostate ively added to control oligoprogression while on AR targeted cancer before chemotherapy. NEJM 2014;371:424–33. therapy for CRPC, with improved disease control. We have previ- 3. Boudadi K, Antonarakis ES. Resistance to novel antiandro- ously shown such treatment approach using SBRT can be gen therapies in metastatic castration-resistant prostate applied to gastrointestinal cancer patients with oligoprogression cancer. Clin Med Insights Oncol 2016;10:1–9. on chemotherapy [10]. Our data suggests that larger studies 4. Parker C, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, using SBRT for oligoprogression should be proposed to assess Fosså SD, et al. Alpha emitter radium-223 and survival in survival outcomes for the treatment of CRPC. Incorporating more metastatic prostate cancer. NEJM 2013;369:213–23. sensitive imaging techniques for prostate cancer like C-Choline 5. Yeh C-N, Chen T-W, Tseng J-H, Liu Y-Y, Wang S-Y, Tsai C- or Axumin PET-CT scans, oligoprogression may be detected earl- Y, et al. Surgical management in metastatic gastrointestinal ier in the disease course and treatment with SBRT may even be stromal tumor (GIST) patients after imatinib mesylate treat- more effective. ment. J Surgical Oncol 2010;102:599–603. 6. Lo SS, Fakiris AJ, Chang EL, Mayr NA, Wang JZ, Papiez L, CONCLUSION et al. Stereotactic body radiation therapy: a novel treatment This case report emphasize use of SBRT as an additional tool in modality. Nat Rev Clin Oncol 2010;7:44–54. long-term control of oligoprogression of CRPC while preserving 7. Kirby M, Hirst C, Crawford ED. Characterizing the the mainline therapy. castration-resistant prostate cancer population: a system- atic review. Int J Clin Pract 2011;65:1180–92. 8. Schick U, Jorcano S, Nouet P, Rouzaoud M, Vees H, Zilli T, CONFLICT OF INTEREST STATEMENT et al. Androgen deprivation and high dose radiotherapy for The authors declare that they have no competing interests. oligometastatic prostate cancer patients with less than five regional and /or distant metastases. Acta Oncol 2013;52: FUNDING 1622–8. 9. Muacevic A, Kufeld M, Rist C, Wowra B, Stief C, Staehler M. No funding was required for this report. Safety and feasibility of image guided robotic radiosurgery for patients with limited bone metastases of prostate can- DECLARATIONS cer. Urol Oncol 2013;31:455–60. Ethics approval and consent to participate: We followed 10. Wray J, Hawamdeh RF, Hasija N, Dagan R, Yeung AR, University of Florida (UF) Institutional Review Board (IRB) Lightsey JL, et al. Stereotactic body radiation therapy for oli- guidelines for this case study. UF IRB grants waiver or does not goprogression of metastatic disease from gastrointestinal require prior IRB approval for this study. http://irb.ufl.edu/wp- cancers: a novel approach to extend chemotherapy efficacy. content/uploads/op-casereports.pdf Oncol Lett 2017;13:1087–94. Downloaded from https://academic.oup.com/omcr/article-abstract/2018/1/omx078/4794781 by Ed 'DeepDyve' Gillespie user on 16 March 2018

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Oxford Medical Case ReportsOxford University Press

Published: Jan 1, 2018

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