Report of an abscopal effect induced by stereotactic body radiotherapy and nivolumab in a patient with metastatic non-small cell lung cancer

Report of an abscopal effect induced by stereotactic body radiotherapy and nivolumab in a patient... Background: The existence of abscopal effects has been suggested already a long time ago, but only recently with the advent of immune checkpoint inhibition in clinical oncology and modern imaging techniques has it become possible to directly observe such effects in patients. They have been well described in patients with malignant melanoma being treated with immune-checkpoint inhibitors and stereotactic radiotherapy, but experience in other malignancies is very limited. Case presentation: Here,wedescribeacase of apatient with metastatic non-small cell lung cancer, who experienced a complete response secondary to an abscopal effect on treatment with anti-PD-1 therapy and stereotactic body radiotherapy to some of the involved sites. Conclusions: Our case reports confirms the existence of abscopal effects in NSCLC and suggests synergism between immune-checkpoint inhibition and local ablative RT. We suggest that this approach is now further studied in prospective clinical trials on oligo-metastatic or oligo-progressing NSCLC. Keywords: Anti-PD-1 therapy, Nivolumab, Immune-checkpoint inhibition, Abscopal effect, Stereotactic body radiotherapy, Non-small cell lung cancer Background systemic immune response. Treatment with immune Mole introduced the term ‘abscopal effect’ in 1953 [1]. It checkpoint inhibitors might overcome tumor-related describes a phenomenon characterized by tumor regression immunosuppression and start, as well as sustain the of untreated metastatic lesions after a local treatment, such immune response towards cancer [3, 4]. as radiotherapy. This is thought to arise because ionizing irradiation causes localized cell death, which induces an Case presentation immune response called immunogenic cell death. This is We report on a 47-year-old male current smoker (40 triggered by increased antigen release, by improved antigen PY), who was diagnosed with lung adenocarcinoma presentation through increased expression of MHC I on (cT1a pN3 cM0, UICC Stage IIIB). He underwent com- the tumor cell surface, as well as by modulation of bination treatment with chemotherapy and cetuximab, cytokines enhancing migration and function of effector followed by radio-therapy in combination with cetuximab CD8+ T cells [2]. However, this event is rare due to and surgical resection as part of a clinical trial (SAKK 16/08; immunotolerance at the tumor site, leading to a reduced NCT01059188). A pathologically complete response was achieved, but only 8 weeks post-operatively, retroperitoneal * Correspondence: christian.britschgi@usz.ch lymph node relapse occurred. Since sensitizing mutations Department of Hematology and Oncology, University Hospital Zürich, were absent, we started palliative chemotherapy (cisplatin / University of Zürich, Zürich, Switzerland Full list of author information is available at the end of the article pemetrexed, followed by pemetrexed maintenance). © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Britschgi et al. Radiation Oncology (2018) 13:102 Page 2 of 4 However, maintenance pemetrexed had to be discontinued initial progression in the absence of any local treatment after two cycles due to severe hematological side effects represents an abscopal effect provoked by PD-1 targeting CTCAE grade 3, requiring in-patient treatment over several in combination with SBRT. days. During cycle 17, a severe pancreatitis CTCAE Grade 3 After full recovery, a PET/CT scan performed four occurred and the patient had to be treated for several weeks after hospital demission revealed progressing days as an in-patient, but eventually recovered fully. In abdominal lymph nodes (Fig. 1a). The patient was the absence of other provoking factors, the most likely enrolled into an expanded access program (EAP) of the differential diagnosis was immune-related pancreatitis anti-programmed death 1 (PD-1) monoclonal antibody and nivolumab was therefore permanently stopped. The nivolumab. A first PET/CT scan after 6 cycles (i.e. 13 weeks patient is today, almost two years after permanently after administration of the first nivolumab dose) showed a stopping nivolumab, still in complete remission and in mixed response. The initially progressing sites were regres- regular follow-up in our department (Fig. 1d). sing, but three new abdominal lymph node metastases appeared (Fig. 1b). Discussion and conclusions The patient was treated with stereotactic body radiother- Here we describe a case of a patient with metastatic apy (SBRT) for this oligo-progression (Fig. 2a and b). Two NSCLC experiencing a complete response on treatment out of the three lymph node metastases were irradiated with anti-PD-1 therapy and SBRT. A biopsy of the (3 ×6 Gy=18 Gy at 80% isodose) (Figs. 1b and 2b). The non-irradiated lesion before SBRT was not clinically third lymph node remained un-irradiated because of close feasible. Therefore, we cannot principally rule out alter- proximity to the small bowel and as reference lesion for native explanations, such as for example a delayed response immunotherapy. It received a radiation scatter dose of to immune checkpoint inhibition. However, the temporal 0.4 Gy only, which is far below clinically significant course is highly suggestive of a true abscopal effect. anti-tumor doses. The patient continued treatment with The existence of abscopal effects has been suggested nivolumab during SBRT and thereafter. A PET/CT scan already several decades ago, but only with the advent of 10 weeks after SBRT (after 13 nivolumab applications in immune-checkpoint inhibitors in clinical routine has it total), showed a complete radiological and metabolic become possible to observe those effects directly in response (CR). Importantly, also the third lymph node patients. There are several case reports and retrospective metastasis, which had previously progressed and was not analyses suggesting that combining immune-checkpoint irradiated, showed a CR (Fig. 1c). Such a response after inhibition with SBRT might be beneficial in patients with Fig. 1 a PET/CT staging before start of treatment with nivolumab: the red arrows indicate the localization of the lymph node metastases. b PET/CT re-staging after 6 cycles of nivolumab with evidence of complete response of the previous metastases and appearance of new metastases, indicated by yellow arrows. Two out of the three new metastases were irradiated, as indicated. c PET/CT restaging 10 weeks after radiotherapy with evidence of complete response. d PET/CT restaging two years after start of nivolumab confirming a stable complete remission Britschgi et al. Radiation Oncology (2018) 13:102 Page 3 of 4 Fig. 2 a Coronal image of the dose distribution of radiotherapy. The patient received 3 × 6 Gy @ 80%. b Image fusion of FDG-PET and treatment plan showing 30% of the prescribed dose (blue) in relation to the untreated FDG-positive lymph node (indicated by the yellow arrow) malignant melanoma [5, 6]. In a first report of 101 concurrent, definite radio-chemotherapy is beneficial in patients treated with the anti-CTLA4 immune-checkpoint patients with stage III NSCLC [10]. inhibitor ipilimumab, 70 received radiotherapy at some Our observation in this case now suggests a synergy of point during their treatment and 31 did not. The median concurrent immune-checkpoint inhibition targeting the overall survival (OS) in a retrospective analysis was PD-1/PD-L1 axis and local ablative radiotherapy in significantly increased in the group, which received RT NSCLC, as well. This approach should now be studied (19 months vs. 10 months for ipilimumab alone [p =0.01]) further in prospective clinical trials in the context of [5]. A similar observation was made in a second analysis oligo-progressing and oligo-metastatic NSCLC. studying specifically patients who received anti-PD-1 Abbreviations immune-checkpoint inhibition and radiotherapy. Of 59 CR: Complete response; NSCLC: Non-small cell lung cancer; PD-1: Programmed patients who received pembrolizumab (n = 28) or nivolumab death-1; SBRT: Stereotactic body radiotherapy (n = 31), 17 also received palliative RT. The combination was not associated with increased toxicity and the objective Availability of data and materials response rate (complete or partial response) was significantly All data generated or analyzed during this study are included in this published article. The datasets used and/or analyzed during the current higher in the group, which had received RT (64.7 vs. study are available from the corresponding author on reasonable request. 33.3%, P = 0.02), including one complete responder who exhibited a classical abscopal effect. Such abscopal Authors’ contributions effects might be especially triggered by RT when limited CB and ACF analyzed and interpreted the patient’s data and wrote the to the involved region, as showed in preclinical models, report, OR and MG performed the SBRT, IAB performed and analyzed the PET-CT scans. All authors edited, approved and read the manuscript. in which spearing of draining lymph nodes is crucial to develop antitumor responses [7]. Taken together, Ethics approval and consent to participate these observations indicate that combining RT with This report has been performed in accordance with the Declaration of Helsinki. immune-checkpoint inhibition (either targeting CTLA4 or PD-1) is well tolerated and has therapeutic potential in Consent for publication malignant melanoma. The patient consented to publication of the data. Experience in other solid malignancies is more limited, given that immune-checkpoint inhibition first entered Competing interests The authors declare that they have no competing interests. clinical routine in melanoma. There are some indications that abscopal effects also exist in NSCLC. A case report described a spontaneous regression of a second pulmon- Publisher’sNote ary lesion after having applied SBRT to a first lesion only Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. [8], and there is also a report of an abscopal effect in a patient with adenocarcinoma of the lung receiving a Author details combination of anti-CTLA4 inhibition (using ipilimumab) Department of Hematology and Oncology, University Hospital Zürich, University of Zürich, Zürich, Switzerland. Department of Radiation Oncology, and SBRT [9]. Moreover, there is evidence from the University Hospital Zürich, University of Zürich, Zürich, Switzerland. randomized phase III trial PACIFIC that consolidation 3 Department of Nuclear Medicine, University Hospital Zürich, University of immune-checkpoint inhibition using durvalumab after Zürich, Zürich, Switzerland. Britschgi et al. Radiation Oncology (2018) 13:102 Page 4 of 4 Received: 25 March 2018 Accepted: 16 May 2018 References 1. Mole RH. Whole body irradiation; radiobiology or medicine? Br J Radiol. 1953;26:234–41. 2. Formenti SC, Demaria S. Systemic effects of local radiotherapy. Lancet Oncol. 2009;10:718–26. 3. Borghaei H, Brahmer JR, Horn L, et al. Nivolumab (nivo) vs docetaxel (doc) in patients (pts) with advanced NSCLC: CheckMate 017/057 2-y update and exploratory cytokine profile analyses. J Clin Oncol. 2016;34(15_suppl):9025–25. 4. Reynders K, Illidge T, Siva S, et al. The abscopal effect of local radiotherapy: using immunotherapy to make a rare event clinically relevant. Cancer Treat Rev. 2015;41:503–10. 5. Koller KM, Mackley HB, Liu J, et al. Improved survival and complete response rates in patients with advanced melanoma treated with concurrent ipilimumab and radiotherapy versus ipilimumab alone. Cancer Biol Ther. 2017;18:36–42. 6. Aboudaram A, Modesto A, Chaltiel L, et al. Concurrent radiotherapy for patients with metastatic melanoma and receiving anti-programmed-death 1 therapy: a safe and effective combination. Melanoma Res. 2017;27:485–91. 7. Zhang X, Niedermann G. Abscopal effects with Hypofractionated schedules extending into the effector phase of the tumor-specific T-cell response. Int J Radiat Oncol Biol Phys. 2018;101:63–73. 8. Cong Y, Shen G, Wu S, Hao R. Abscopal regression following SABR for non-small-cell-lung cancer: a case report. Cancer Biol Ther. 2017;18:1–3. 9. Golden EB, Demaria S, Schiff PB, et al. An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol Res. 2013;1:365–72. 10. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after Chemoradiotherapy in stage III non-small-cell lung Cancer. N Engl J Med. 2017;377:1919–29. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Oncology Springer Journals

Report of an abscopal effect induced by stereotactic body radiotherapy and nivolumab in a patient with metastatic non-small cell lung cancer

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Biomedicine; Cancer Research; Oncology; Radiotherapy; Imaging / Radiology
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Abstract

Background: The existence of abscopal effects has been suggested already a long time ago, but only recently with the advent of immune checkpoint inhibition in clinical oncology and modern imaging techniques has it become possible to directly observe such effects in patients. They have been well described in patients with malignant melanoma being treated with immune-checkpoint inhibitors and stereotactic radiotherapy, but experience in other malignancies is very limited. Case presentation: Here,wedescribeacase of apatient with metastatic non-small cell lung cancer, who experienced a complete response secondary to an abscopal effect on treatment with anti-PD-1 therapy and stereotactic body radiotherapy to some of the involved sites. Conclusions: Our case reports confirms the existence of abscopal effects in NSCLC and suggests synergism between immune-checkpoint inhibition and local ablative RT. We suggest that this approach is now further studied in prospective clinical trials on oligo-metastatic or oligo-progressing NSCLC. Keywords: Anti-PD-1 therapy, Nivolumab, Immune-checkpoint inhibition, Abscopal effect, Stereotactic body radiotherapy, Non-small cell lung cancer Background systemic immune response. Treatment with immune Mole introduced the term ‘abscopal effect’ in 1953 [1]. It checkpoint inhibitors might overcome tumor-related describes a phenomenon characterized by tumor regression immunosuppression and start, as well as sustain the of untreated metastatic lesions after a local treatment, such immune response towards cancer [3, 4]. as radiotherapy. This is thought to arise because ionizing irradiation causes localized cell death, which induces an Case presentation immune response called immunogenic cell death. This is We report on a 47-year-old male current smoker (40 triggered by increased antigen release, by improved antigen PY), who was diagnosed with lung adenocarcinoma presentation through increased expression of MHC I on (cT1a pN3 cM0, UICC Stage IIIB). He underwent com- the tumor cell surface, as well as by modulation of bination treatment with chemotherapy and cetuximab, cytokines enhancing migration and function of effector followed by radio-therapy in combination with cetuximab CD8+ T cells [2]. However, this event is rare due to and surgical resection as part of a clinical trial (SAKK 16/08; immunotolerance at the tumor site, leading to a reduced NCT01059188). A pathologically complete response was achieved, but only 8 weeks post-operatively, retroperitoneal * Correspondence: christian.britschgi@usz.ch lymph node relapse occurred. Since sensitizing mutations Department of Hematology and Oncology, University Hospital Zürich, were absent, we started palliative chemotherapy (cisplatin / University of Zürich, Zürich, Switzerland Full list of author information is available at the end of the article pemetrexed, followed by pemetrexed maintenance). © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Britschgi et al. Radiation Oncology (2018) 13:102 Page 2 of 4 However, maintenance pemetrexed had to be discontinued initial progression in the absence of any local treatment after two cycles due to severe hematological side effects represents an abscopal effect provoked by PD-1 targeting CTCAE grade 3, requiring in-patient treatment over several in combination with SBRT. days. During cycle 17, a severe pancreatitis CTCAE Grade 3 After full recovery, a PET/CT scan performed four occurred and the patient had to be treated for several weeks after hospital demission revealed progressing days as an in-patient, but eventually recovered fully. In abdominal lymph nodes (Fig. 1a). The patient was the absence of other provoking factors, the most likely enrolled into an expanded access program (EAP) of the differential diagnosis was immune-related pancreatitis anti-programmed death 1 (PD-1) monoclonal antibody and nivolumab was therefore permanently stopped. The nivolumab. A first PET/CT scan after 6 cycles (i.e. 13 weeks patient is today, almost two years after permanently after administration of the first nivolumab dose) showed a stopping nivolumab, still in complete remission and in mixed response. The initially progressing sites were regres- regular follow-up in our department (Fig. 1d). sing, but three new abdominal lymph node metastases appeared (Fig. 1b). Discussion and conclusions The patient was treated with stereotactic body radiother- Here we describe a case of a patient with metastatic apy (SBRT) for this oligo-progression (Fig. 2a and b). Two NSCLC experiencing a complete response on treatment out of the three lymph node metastases were irradiated with anti-PD-1 therapy and SBRT. A biopsy of the (3 ×6 Gy=18 Gy at 80% isodose) (Figs. 1b and 2b). The non-irradiated lesion before SBRT was not clinically third lymph node remained un-irradiated because of close feasible. Therefore, we cannot principally rule out alter- proximity to the small bowel and as reference lesion for native explanations, such as for example a delayed response immunotherapy. It received a radiation scatter dose of to immune checkpoint inhibition. However, the temporal 0.4 Gy only, which is far below clinically significant course is highly suggestive of a true abscopal effect. anti-tumor doses. The patient continued treatment with The existence of abscopal effects has been suggested nivolumab during SBRT and thereafter. A PET/CT scan already several decades ago, but only with the advent of 10 weeks after SBRT (after 13 nivolumab applications in immune-checkpoint inhibitors in clinical routine has it total), showed a complete radiological and metabolic become possible to observe those effects directly in response (CR). Importantly, also the third lymph node patients. There are several case reports and retrospective metastasis, which had previously progressed and was not analyses suggesting that combining immune-checkpoint irradiated, showed a CR (Fig. 1c). Such a response after inhibition with SBRT might be beneficial in patients with Fig. 1 a PET/CT staging before start of treatment with nivolumab: the red arrows indicate the localization of the lymph node metastases. b PET/CT re-staging after 6 cycles of nivolumab with evidence of complete response of the previous metastases and appearance of new metastases, indicated by yellow arrows. Two out of the three new metastases were irradiated, as indicated. c PET/CT restaging 10 weeks after radiotherapy with evidence of complete response. d PET/CT restaging two years after start of nivolumab confirming a stable complete remission Britschgi et al. Radiation Oncology (2018) 13:102 Page 3 of 4 Fig. 2 a Coronal image of the dose distribution of radiotherapy. The patient received 3 × 6 Gy @ 80%. b Image fusion of FDG-PET and treatment plan showing 30% of the prescribed dose (blue) in relation to the untreated FDG-positive lymph node (indicated by the yellow arrow) malignant melanoma [5, 6]. In a first report of 101 concurrent, definite radio-chemotherapy is beneficial in patients treated with the anti-CTLA4 immune-checkpoint patients with stage III NSCLC [10]. inhibitor ipilimumab, 70 received radiotherapy at some Our observation in this case now suggests a synergy of point during their treatment and 31 did not. The median concurrent immune-checkpoint inhibition targeting the overall survival (OS) in a retrospective analysis was PD-1/PD-L1 axis and local ablative radiotherapy in significantly increased in the group, which received RT NSCLC, as well. This approach should now be studied (19 months vs. 10 months for ipilimumab alone [p =0.01]) further in prospective clinical trials in the context of [5]. A similar observation was made in a second analysis oligo-progressing and oligo-metastatic NSCLC. studying specifically patients who received anti-PD-1 Abbreviations immune-checkpoint inhibition and radiotherapy. Of 59 CR: Complete response; NSCLC: Non-small cell lung cancer; PD-1: Programmed patients who received pembrolizumab (n = 28) or nivolumab death-1; SBRT: Stereotactic body radiotherapy (n = 31), 17 also received palliative RT. The combination was not associated with increased toxicity and the objective Availability of data and materials response rate (complete or partial response) was significantly All data generated or analyzed during this study are included in this published article. The datasets used and/or analyzed during the current higher in the group, which had received RT (64.7 vs. study are available from the corresponding author on reasonable request. 33.3%, P = 0.02), including one complete responder who exhibited a classical abscopal effect. Such abscopal Authors’ contributions effects might be especially triggered by RT when limited CB and ACF analyzed and interpreted the patient’s data and wrote the to the involved region, as showed in preclinical models, report, OR and MG performed the SBRT, IAB performed and analyzed the PET-CT scans. All authors edited, approved and read the manuscript. in which spearing of draining lymph nodes is crucial to develop antitumor responses [7]. Taken together, Ethics approval and consent to participate these observations indicate that combining RT with This report has been performed in accordance with the Declaration of Helsinki. immune-checkpoint inhibition (either targeting CTLA4 or PD-1) is well tolerated and has therapeutic potential in Consent for publication malignant melanoma. The patient consented to publication of the data. Experience in other solid malignancies is more limited, given that immune-checkpoint inhibition first entered Competing interests The authors declare that they have no competing interests. clinical routine in melanoma. There are some indications that abscopal effects also exist in NSCLC. A case report described a spontaneous regression of a second pulmon- Publisher’sNote ary lesion after having applied SBRT to a first lesion only Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. [8], and there is also a report of an abscopal effect in a patient with adenocarcinoma of the lung receiving a Author details combination of anti-CTLA4 inhibition (using ipilimumab) Department of Hematology and Oncology, University Hospital Zürich, University of Zürich, Zürich, Switzerland. Department of Radiation Oncology, and SBRT [9]. Moreover, there is evidence from the University Hospital Zürich, University of Zürich, Zürich, Switzerland. randomized phase III trial PACIFIC that consolidation 3 Department of Nuclear Medicine, University Hospital Zürich, University of immune-checkpoint inhibition using durvalumab after Zürich, Zürich, Switzerland. Britschgi et al. Radiation Oncology (2018) 13:102 Page 4 of 4 Received: 25 March 2018 Accepted: 16 May 2018 References 1. Mole RH. Whole body irradiation; radiobiology or medicine? Br J Radiol. 1953;26:234–41. 2. Formenti SC, Demaria S. Systemic effects of local radiotherapy. Lancet Oncol. 2009;10:718–26. 3. Borghaei H, Brahmer JR, Horn L, et al. Nivolumab (nivo) vs docetaxel (doc) in patients (pts) with advanced NSCLC: CheckMate 017/057 2-y update and exploratory cytokine profile analyses. J Clin Oncol. 2016;34(15_suppl):9025–25. 4. Reynders K, Illidge T, Siva S, et al. The abscopal effect of local radiotherapy: using immunotherapy to make a rare event clinically relevant. Cancer Treat Rev. 2015;41:503–10. 5. Koller KM, Mackley HB, Liu J, et al. Improved survival and complete response rates in patients with advanced melanoma treated with concurrent ipilimumab and radiotherapy versus ipilimumab alone. Cancer Biol Ther. 2017;18:36–42. 6. Aboudaram A, Modesto A, Chaltiel L, et al. Concurrent radiotherapy for patients with metastatic melanoma and receiving anti-programmed-death 1 therapy: a safe and effective combination. Melanoma Res. 2017;27:485–91. 7. Zhang X, Niedermann G. Abscopal effects with Hypofractionated schedules extending into the effector phase of the tumor-specific T-cell response. Int J Radiat Oncol Biol Phys. 2018;101:63–73. 8. Cong Y, Shen G, Wu S, Hao R. Abscopal regression following SABR for non-small-cell-lung cancer: a case report. Cancer Biol Ther. 2017;18:1–3. 9. Golden EB, Demaria S, Schiff PB, et al. An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol Res. 2013;1:365–72. 10. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after Chemoradiotherapy in stage III non-small-cell lung Cancer. N Engl J Med. 2017;377:1919–29.

Journal

Radiation OncologySpringer Journals

Published: May 31, 2018

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