QUAD SHOT Radiotherapy and Doublet Immunotherapy in the Management of Anal Mucosal Melanoma: A Case Series of Efficacy and Toxicity of a Novel Treatment Approach and a Review of the Literature

Abstract

Clinical Practice PointsThe improvements in survival seen in recent years with immunotherapy for advanced cutaneous melanoma have not translated to mucosal melanoma (MM), where outcomes remain poor. The quest to optimally harness the pro-immunogenic effects of RT in combination with immune checkpoint inhibitors (ICI) continues, especially in cancers with suboptimal response to ICI.We present here a case series of 3 patients with anal mucosal melanoma treated with a novel combination of QUAD shot radiotherapy to the primary tumor and doublet immune check point inhibitor therapy.All of these patients had a durable local response to radiotherapy, and 2 of them had excellent metastatic disease response. This case series provides the first published experience of the use of QUAD shot regimen radiotherapy with ICI for the management of mucosal melanoma. This provides the basis for larger and more robust studies of this approach which may prove to be practice changing in the future.Introduction and BackgroundThe advent of immune checkpoint inhibitors (ICI) in the management of melanoma has revolutionized treatment paradigms; with a significant survival benefit in advanced cutaneous melanoma.1Hodi FS O'Day SJ McDermott DF et al.Improved survival with ipilimumab in patients with metastatic melanoma.N Engl J Med. 2010; 363: 711-723Crossref PubMed Scopus (10959) Google Scholar, 2Ribas A Puzanov I Dummer R et al.Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial.Lancet Oncol. 2015; 16: 908-918Abstract Full Text Full Text PDF PubMed Scopus (1193) Google Scholar, 3Topalian SL Sznol M McDermott DF et al.Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab.J Clin Oncol. 2014; 32: 1020-1030Crossref PubMed Scopus (1743) Google Scholar, 4SP D'Angelo Larkin J Sosman JA et al.Efficacy and Safety of nivolumab alone or in combination with ipilimumab in patients with mucosal melanoma: a pooled analysis.J Clin Oncol. 2017; 35: 226-235Crossref PubMed Scopus (307) Google Scholar, 5Larkin J Chiarion-Sileni V Gonzalez R et al.Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.N Engl J Med. 2015; 373: 23-34Crossref PubMed Scopus (4942) Google Scholar, 6Weber JS D'Angelo SP Minor D et al.Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): A randomised, controlled, open-label, phase 3 trial.Lancet Oncol. 2015; 16: 375-384Abstract Full Text Full Text PDF PubMed Scopus (1957) Google Scholar, 7Robert C Long GV Brady B et al.Nivolumab in previously untreated melanoma without BRAF mutation.N Engl J Med. 2015; 372: 320-330Crossref PubMed Scopus (3933) Google Scholar, 8Wolchok JD Kluger H Callahan MK et al.Nivolumab plus ipilimumab in advanced melanoma.N Engl J Med. 2013; 369: 122-133Crossref PubMed Scopus (3216) Google Scholar Despite this, improvements in survival have not translated to mucosal melanoma (MM). The objective response rate (ORR) of MM to ICI remains inferior to that of cutaneous melanoma, at 37% vs. 60% for ipilimumab (ipi) and nivolumab (nivo) combination therapy.4SP D'Angelo Larkin J Sosman JA et al.Efficacy and Safety of nivolumab alone or in combination with ipilimumab in patients with mucosal melanoma: a pooled analysis.J Clin Oncol. 2017; 35: 226-235Crossref PubMed Scopus (307) Google Scholar This disease usually has an aggressive course with high rates of local recurrence (LR) and distant metastases9Tas F Keskin S Karadeniz A et al.Noncutaneous melanoma have distinct features from each other and cutaneous melanoma.Oncology. 2011; 81 (34863): 353-358Crossref PubMed Scopus (33) Google Scholar,10Temam S Mamelle G Marandas P et al.Postoperative radiotherapy for primary mucosal melanoma of the head and neck.Cancer. 2005; 103: 313-319Crossref PubMed Scopus (202) Google Scholar and a 5 year overall survival (OS) of 20% to 30%.11Iddings DM Fleisig AJ Chen SL Faries MB Morton DL. Practice patterns and outcomes for anorectal melanoma in the USA, reviewing three decades of treatment: is more extensive surgical resection beneficial in all patients?.Ann Surg Oncol. 2010; 17: 40-44Crossref PubMed Scopus (104) Google Scholar,12Verschraegen CF Benjapibal M Supakarapongkul W et al.Vulvar melanoma at the M. D. Anderson cancer center: 25 years later.Int J Gynecol Cancer. 2001; 11: 359-364Crossref PubMed Scopus (106) Google Scholar Patients often present with advanced stage disease in anatomical sites where resection is associated with potentially significant functional morbidity. The poor OS coupled with a high risk of distant disease progression make aggressive local therapy unattractive.As the understanding of the immunomodulatory effects of radiation therapy (RT) increases, the quest to optimally harness the pro-immunogenic effects of RT in combination with ICI continues, especially in cancers with suboptimal response to ICI.The management of MM remains a challenge in the current era of immunotherapy; in part due to its rarity and its presentation in heterogeneous anatomical sites and also due to the lack of randomized trials specific for this subtype of melanoma. MM accounts for as little as 1.3% of all melanomas,13Chang AE Karnell LH Menck HR. The national cancer data base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. the American college of surgeons commission on cancer and the American cancer society.Cancer. 1998; 83: 1664-1678Crossref PubMed Scopus (1204) Google Scholar the majority being in the head and neck region. Anorectal MM represents less than 20% of MM,14Hillenbrand A Barth TF Henne-Bruns D Formentini A. Anorectal amelanotic melanoma.Colorectal Dis. 2008; 10: 612-615Crossref PubMed Scopus (43) Google Scholar and less than 1% all colorectal and anal canal cancers.15Cagir B Whiteford MH Topham A Rakinic J Fry RD. Changing epidemiology of anorectal melanoma.Dis Colon Rectum. 1999; 42: 1203-1208Crossref PubMed Scopus (129) Google ScholarFor non-metastatic anal MM the standard initial management remains surgery, although there have been no prospective studies conducted on survival outcomes following surgery. A large retrospective review of 152 patients undergoing surgery for non-metastatic MM reported a median OS of 14 months and a 5 year OS of 11.2%.16Nilsson P J Ragnarsson-Olding B K Importance of clear resection margins in anorectal malignant melanoma.Br J Surg. 2010; 97: 98-103https://doi.org/10.1002/bjs.6784Crossref PubMed Scopus (90) Google Scholar A recent systematic review and meta-analysis by Jutton et al20Plavc G But-Hadzic J Anicin A Lanisnik B Didanovic V Strojan P. Mucosal melanoma of the head and neck: a population-based study from Slovenia, 1985-2013.Radiat Oncol. 2016; 11: 137Crossref PubMed Scopus (17) Google Scholar,21Gilligan D Slevin NJ. Radical radiotherapy for 28 cases of mucosal melanoma in the nasal cavity and sinuses.Br J Radiol. 1991; 64: 1147-1150Crossref PubMed Scopus (133) Google Scholar including 1858 patients who underwent surgery for MM has shown no statistically significant improvement in overall survival in patients undergoing extensive resection as compared to local excision.17Jutten E Kruijff S Francken AB et al.Surgical treatment of anorectal melanoma: a systematic review and meta-analysis.BJS Open. 2021; 5 (PMID: 34958352): zrab107https://doi.org/10.1093/bjsopen/zrab107Crossref PubMed Scopus (3) Google Scholar The role of RT in MM remains poorly defined, with some studies reporting improved local control (LC) with adjuvant RT.18Benlyazid A Thariat J Temam S et al.Postoperative radiotherapy in head and neck mucosal melanoma: a GETTEC study.Arch Otolaryngol Head Neck Surg. 2010; 136: 1219-1225Crossref PubMed Scopus (85) Google Scholar, 19Lazarev S Gupta V Hu K Harrison LB Bakst R. Mucosal melanoma of the head and neck: a systematic review of the literature.Int J Radiat Oncol Biol Phys. 2014; 90: 1108-1118Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 20Plavc G But-Hadzic J Anicin A Lanisnik B Didanovic V Strojan P. Mucosal melanoma of the head and neck: a population-based study from Slovenia, 1985-2013.Radiat Oncol. 2016; 11: 137Crossref PubMed Scopus (17) Google Scholar There is some retrospective evidence for definitive RT for unresectable localized MM of the head and neck region using hypo-fractionated regimens with improved responses.21Gilligan D Slevin NJ. Radical radiotherapy for 28 cases of mucosal melanoma in the nasal cavity and sinuses.Br J Radiol. 1991; 64: 1147-1150Crossref PubMed Scopus (133) Google Scholar, 22Wu AJ Gomez J Zhung JE et al.Radiotherapy after surgical resection for head and neck mucosal melanoma.Am J Clin Oncol. 2010; 33: 281-285Crossref PubMed Scopus (53) Google Scholar, 23Wada H Nemoto K Ogawa Y et al.A multi-institutional retrospective analysis of external radiotherapy for mucosal melanoma of the head and neck in Northern Japan.Int J Radiat Oncol Biol Phys. 2004; 59: 495-500Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar Palliative RT is effective for symptom control of pain, bleeding and tumor growth restraint in patients with locally advanced and/or stage IV disease.24Shi W. Radiation therapy for melanoma.in: Ward WH Farma JM Cutaneous Melanoma: Etiology and Therapy [Internet]. Codon Publications, Brisbane (AU)2017Crossref Google ScholarWhilst RT is highly effective in mediating cell kill via double-stranded DNA damage, there is increasing understanding that it also has an immunomodulatory effect, particularly when used in combination with ICI. RT has the potential to induce a beneficial synergistic effect by converting the tumor into an in-situ vaccine. Preclinical studies suggest that this is due in part to ionizing radiation transforming the irradiated tumor into an immunogenic hub, inducing a pro-inflammatory state more favorable for immunogenic cell death. Immunogenic cell death is a term used to describe the generation of a tumor specific cytotoxic adaptive immune response to dying cells that in turn elicits further cell death and tumor regression.25Formenti SC Demaria S. Radiation therapy to convert the tumor into an in situ vaccine.Int J Radiat Oncol Biol Phys. 2012; 84: 879-880Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar, 26Garnett CT Palena C Chakraborty M Tsang KY Schlom J Hodge JW. Sublethal irradiation of human tumor cells modulates phenotype resulting in enhanced killing by cytotoxic T lymphocytes.Cancer Res. 2004; 64: 7985-7994Crossref PubMed Scopus (415) Google Scholar, 27Goforth R Salem AK Zhu X et al.Immune stimulatory antigen loaded particles combined with depletion of regulatory T-cells induce potent tumor specific immunity in a mouse model of melanoma.Cancer Immunol Immunother. 2009; 58: 517-530Crossref PubMed Scopus (49) Google Scholar, 28Chajon E Castelli J Marsiglia H De Crevoisier R. The synergistic effect of radiotherapy and immunotherapy: a promising but not simple partnership.Crit Rev Oncol/Hematol. 2017; 111: 124-132Crossref PubMed Scopus (73) Google Scholar Several preclinical and clinical studies have demonstrated that hypofractionated RT in 3 to 5 fractions of <10 to 12 Gy each has the ability to inhibit tumor growth in combination with anti-CTLA-4 with increased progression free survival (PFS) and OS. The addition of ICI to RT has been shown to have a synergistic local effect within the RT field as well as inducing tumor response outside the radiotherapy field, the so called abscopal effect.29Dewan MZ Galloway AE Kawashima N et al.Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody.Clin Cancer Res. 2009; 15: 5379-5388Crossref PubMed Scopus (1066) Google Scholar, 30Theurich S Rothschild SI Hoffmann M et al.Local tumor treatment in combination with systemic ipilimumab immunotherapy prolongs overall survival in patients with advanced malignant melanoma.Cancer Immunol Res. 2016; 4: 744-754Crossref PubMed Scopus (98) Google Scholar, 31Formenti SC. Optimizing dose per fraction: a new chapter in the story of the abscopal effect?.Int J Radiat Oncol Biol Phys. 2017; 99: 677-679Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar, 32Postow MA Callahan MK Barker CA et al.Immunologic correlates of the abscopal effect in a patient with melanoma.N Engl J Med. 2012; 366: 925-931Crossref PubMed Scopus (1493) Google ScholarAn effective and well tolerated palliative RT regimen for mucosal malignancy is the ‘QUAD-SHOT’ regimen (QS) of 14 Gy in 4 fractions over 2 days (3.5 Gy per fraction, bi-daily fractionation) repeated at 3 to 4 weekly intervals for a maximum of 3 cycles to a total dose of 42 Gy in 12 fractions.33Corry J Peters LJ Costa ID et al.The 'QUAD SHOT'–a phase II study of palliative radiotherapy for incurable head and neck cancer.Radiother Oncol. 2005; 77: 137-142Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar This treatment regimen was designed to deliver a high biologically equivalent dose to tumor while being just below the threshold for producing mucositis during each cycle. There is now extensive experience of using it to palliate symptoms in patients with incurable mucosal squamous cell carcinoma of the head and neck,33Corry J Peters LJ Costa ID et al.The 'QUAD SHOT'–a phase II study of palliative radiotherapy for incurable head and neck cancer.Radiother Oncol. 2005; 77: 137-142Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar as well as in gynecological malignancies.34Lin MY Kondalsamy-Chennakesavan S Bernshaw D Khaw P Narayan K. Carcinoma of the cervix in elderly patients treated with radiotherapy: patterns of care and treatment outcomes.J Gynecol Oncol. 2016; 27: e59Crossref PubMed Scopus (11) Google ScholarThe limited side effect profile and high biological effective dose of QS radiotherapy make it an attractive regimen for the treatment of MM. In addition, we hypothesize that combination of QS radiotherapy with doublet ICI treatment will further improve outcomes through their synergistic action. However this multimodal treatment is novel and currently there is little published experience with this regimen in the medical literature to document its efficacy and tolerability, although initial clinical experience in advanced head and neck squamous cell carcinoma is promising.35Basree M. Mitchell D. Dibs K. et al.Initial experience with palliative “QUAD-SHOT” radiotherapy with concurrent and adjuvant PD-1 inhibitor for recurrent And/Or metastatic head and neck cancer.Int J Radiat Oncol Biol, Phys. 2020; 108 (Supplement p.e826)Abstract Full Text Full Text PDF Google ScholarCase SeriesWe present here our initial experience of 3 consecutively treated patients with metastatic anorectal MM treated at a single institution between 2018 and 2021 with concurrent QS RT and ICI followed by adjuvant ICI. The immunotherapy regimen was planned for 4 cycles of induction Ipilimumab 3mg/kg and Nivolumab 1mg/kg intravenously every 3 weeks followed by maintenance Nivolumab 3 mg/kg every 2 weeks for 2 years. This study was approved by our institution's ethics review board.Case 1A 50-year-old male presented with altered bowel habit, PR bleeding, severe perianal pain, weight loss and headaches. Biopsies of an anal lesion and right axillary lymph node showed NRAS mutant, BRAF and C-KIT wild-type (wt) anal MM. Staging PET/CT and MRI brain revealed a locally advanced tumor in the anal canal and lower rectum (100 mm length, 40 mm diameter), extensive visceral, peritoneal, soft tissue and nodal metastases and a single 12 mm lesion in the right temporal lobe. He commenced QS RT to the primary site only and ipi/nivo (ipilimumab and nivolumab). He did not have any local treatment for the brain metastasis. QS RT was repeated for 3 cycles, with 4 cycles of ipi/nivo followed by nivo maintenance. He had a complete metabolic response (CMR) at the anus and all extra-cranial metastatic sites on PET restaging and stable intracranial disease. He experienced G2 skin reaction and G1 urinary frequency. Details of treatment course and response are illustrated in Figure 1, Figure 2. At last imaging follow up this patient remains alive with a CMR of extracranial disease and a single stable brain lesion 24 months on from commencement of treatment.Figure 2Timeline of primary tumor and distant metastasis response for case 1.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Case 2A 47-year-old male presented with perianal pain and weight loss. Anal biopsy showed BRAF, NRAS and C-KIT wt MM. Staging PET/CT revealed metastases to a left-sided mesorectal node and a 12 mm metastasis to the greater curvature of the stomach. MRI of the pelvis showed a bulky circumferential 54 mm (supero-inferiorly) x 38 mm (axial) anal mass. He commenced ipi/nivo and QS RT to the primary tumor and adjacent mesorectal lymph node (Figure 3). He did not experience any acute toxicity and had a rapid clinical response with resolution of anal pain and the anal tumor on digital rectal examination. Given the excellent response only 1 cycle of QS was given. Restaging PET/CT after 4 cycles of ipi/nivo showed a CMR at the primary site and the mesorectal node but progression of the stomach metastasis, as well as new metabolically active lesions in the tail and uncinate process of the pancreas and the right 6th rib. Subsequent palliative RT 20 Gy in 5# delivered with concurrent nivolumab to extra cranial metastases yielded a sub-optimal response with progression of multiple irradiated and unirradiated sites. Details of further management and disease response are in Figure 4. This patient died due to progressive systemic disease 15 months post 1 cycle of QS RT with durable CMR at the anal primary and no long-term side effects of radiotherapy.Figure 3Timeline of treatment course and response for case 2.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 4Timeline of primary tumor and distant metastasis response for case 2.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Case 3A 73-year-old female presented with biopsy proven BRAF and NRAS wt, C-KIT mutant anal MM with multiple bilateral lung metastases, and 6 brain metastases, largest 6mm. The C-KIT mutation was the L576P variant. She underwent a trans-anal wide local excision of the anal primary with positive deep and radial resection margins on histological examination. Multidisciplinary consensus was to offer 2 cycles of QS RT and commence combination ipi/nivo (Figure 5). Following cycle 3 of ipi/nivo she developed grade 3 (G3) colitis, requiring IV methyl prednisolone and later infliximab. She responded well to infliximab with rapid resolution of symptoms. A restaging PET/CT after 2 cycles of QS RT and 3 cycles of ipi/nivo showed no LR at the anus, CMR of lung lesions, and no new metastases (Figure 5). MRI brain at this time showed reduction in size of all lesions. The colitis was felt to be immune-mediated and therefore she did not proceed to cycle 4 of ipi/nivo. Subsequent rechallenge with single agent nivolumab resulted in G3 colitis requiring infliximab and cessation of systemic therapy. Subsequent disease course and management are outlined in Figures 5 and 6. She remained in CMR at rectum and all extra cranial metastatic sites until she developed small bowel metastases 15.7 months after commencement of treatment. On last follow up 17.8 months from start of therapy she remains alive without signs of LR at the anus.Figure 5Timeline of treatment course and response for case 3.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 6Timeline of primary tumor and distant metastasis response for case 3.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Radiation Therapy Techniques and VolumesCases 1, and 2 - 3D-conformal radiotherapy technique with 3 to 4 fields. GTV (gross tumor volume) is anal tumor. CTV (clinical target volume) included the entire circumference of the anal canal at the level of the GTV. PTV (planning target volume) was formed using a uniform expansion of 1 cm from CTV. PTV volume ranged from 84.3 cc to 676.1 cc. Volume of PTV covered by 95% of prescribed dose (V95) ranged from 98.8% to 100%.Case 3 – Volumetric modulated arc therapy (VMAT). Pre-op GTV delineated based on pre-op MRI (full circumference of anus at level of tumor), expanded by 5 mm to CTV and 5 mm to PTV. PTV V95 is 100%.DiscussionIn this case series, we provide the first published experience of QUAD SHOT radiotherapy in combination with doublet ICI for the treatment of anal MM. All patients have had remarkable sustained LC at the primary site. QS RT was delivered in varying total doses ranging from as little as 14 Gy to 42 Gy in 4 to 12 fractions concurrent with induction ipi/nivo.Patients with MM have inferior responses to combination immunotherapy compared to cutaneous melanoma, this may in part be due to the lower mutational burden and lower immunogenicity.36Furney SJ Turajlic S Stamp G et al.Genome sequencing of mucosal melanomas reveals that they are driven by distinct mechanisms from cutaneous melanoma.J Pathol. 2013; 230: 261-269Crossref PubMed Scopus (130) Google Scholar Subset analysis of patients with MM from pooled analysis of clinical trials in patients with advanced melanoma, receiving immunotherapy alone, showed an ORR of only 37.1% to combination therapy (ipi/nivo), and an ORR of 23.3% and 8.3% for nivolumab and ipilimumab monotherapy, respectively. The complete response rate of MM to combination therapy was only 2.9% and this analysis also showed a PFS of just 5.9 months.4SP D'Angelo Larkin J Sosman JA et al.Efficacy and Safety of nivolumab alone or in combination with ipilimumab in patients with mucosal melanoma: a pooled analysis.J Clin Oncol. 2017; 35: 226-235Crossref PubMed Scopus (307) Google Scholar There is no evidence that radiotherapy to a primary or metastatic site of mucosal melanoma will reliably induce a systemic response and so immunotherapy alone is the current standard therapy for those with metastatic mucosal melanoma, despite the poor outcomes in terms of ORR and PFS.A retrospective review of radiotherapy +/- single agent pembrolizumab for primary or metastatic MM included 12 patients treated concurrently with RT and ICI, of which only 3 patients had anal MM, none of whom had RT to the primary tumor.37Kim HJ Chang JS Roh MR et al.Effect of radiotherapy combined with pembrolizumab on local tumor control in mucosal melanoma patients.Front. Oncol. 2019; 9: 835Crossref PubMed Scopus (25) Google Scholar The 1-year LC rate of 94.1% was significantly better in the ICI and RT combination group. The median radiation dose was 5 Gy per fraction and median total dose was 36 Gy. There were 2 recent case reports on anal MM treated with RT to the primary anal tumor38Wallington DG Rashid AS Buchwald ZS Sudmeier LJ Khan MK. Complete and durable response after radiation therapy to primary tumor site of a patient with metastatic anorectal mucosal melanoma with oligoprogression on nivolumab.Adv Radiat Oncol. 2020; 5: 503-510Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar,39Wang WJ Lee KD Chen WY et al.Combining hypofractionated radiation therapy with immunotherapy for anorectal malignant melanoma: a case report.Ther Radiol Oncol. 2019; 3: 1Crossref Google Scholar and single agent ICI given concurrently within 1 month of RT. One patient with progressive stage IV disease on maintenance nivolumab, treated with 45 Gy in 15 fractions to the primary tumor only, experienced a durable complete response at the anal primary and distant metastases, ongoing at 33 months post-RT without treatment-related toxicity. The other patient, who had localized anal disease, treated with 25 Gy in 5 fractions, experienced acute G3 diarrhoea. After an initial near complete response, there was biopsy-proven local progression 9 months later and the patient developed peritoneal metastases shortly after.There is limited data on the efficacy and effectiveness of QS RT with immunotherapy in other tumor types. A retrospective analysis of 15 patients with recurrent and/or metastatic head and neck squamous cell carcinoma showed the QS regimen with concurrent and adjuvant ICI resulted in an ORR of 60% and PFS and median OS of 6.5 months and 7.1 months, with only 20% G3 mucositis or dermatitis.35Basree M. Mitchell D. Dibs K. et al.Initial experience with palliative “QUAD-SHOT” radiotherapy with concurrent and adjuvant PD-1 inhibitor for recurrent And/Or metastatic head and neck cancer.Int J Radiat Oncol Biol, Phys. 2020; 108 (Supplement p.e826)Abstract Full Text Full Text PDF Google ScholarThe immunomodulatory benefits of RT with ICI demonstrated by pre-clinical studies and clinical evidence of abscopal effect led to the initiation of a multitude of clinical trials and studies,40Romano E Honeychurch J Illidge TM. Radiotherapy-immunotherapy combination: how will we bridge the gap between pre-clinical promise and effective clinical delivery?.Cancers (Basel). 2021; 13: 457Crossref PubMed Scopus (14) Google Scholar however the optimal strategy to combine RT with immunotherapy remains elusive with inconsistent results.41Xing D Siva S Hanna GG. The abscopal effect of stereotactic radiotherapy and immunotherapy: fool's gold or El dorado?.Clin Oncol (R Coll Radiol). 2019; 31: 432-443Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar The challenges in successfully translating in vitro findings to effective in vivo therapeutic strategies are influenced by multiple factors such as the unique interplay of immune cells in the tumor microenvironment (TME) in vivo, differences in tumor pathology, variability in RT dose/fractionation, RT dose rate, tumor volume, sequencing and the type of immunotherapy.42Barker HE Paget JT Khan AA Harrington KJ. The tumor microenvironment after radiotherapy: mechanisms of resistance and recurrence.Nat Rev Cancer. 2015; 15 (Erratum in: Nat Rev Cancer. 2015 Aug;15(8):509): 409-425https://doi.org/10.1038/nrc3958Crossref PubMed Scopus (1059) Google Scholar Ultimately the goal is to balance the pro-immunogenic and immunosuppressive abilities of RT.Many of the clinical trials to date have focused on combining SABR using moderate to high dose (typically 8-20 Gy) per fraction in 1 to 5 fractions with ICI with varying levels of success.43McBride S Sherman E Tsai CJ et al.Randomized phase II trial of nivolumab with stereotactic body radiotherapy versus nivolumab alone in metastatic head and neck squamous cell carcinoma.J Clin Oncol. 2021; 39: 30-37Crossref PubMed Scopus (114) Google Scholar, 44Ratnayake G Reinwald S Shackleton M et al.Stereotactic radiation therapy combined with immunotherapy against metastatic melanoma: long-term results of a phase 1 clinical trial.Int J Radiat Oncol Biol Phys. 2020; 108: 150-156Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 45Akanda ZZ Neeson PJ John T et al.A narrative review of combined stereotactic ablative radiotherapy and immunotherapy in metastatic non-small cell lung cancer.Transl Lung Cancer Res. 2021; 10: 2766-2778Crossref PubMed Scopus (3) Google Scholar High dose RT has the capacity to prime an adaptive T-cell-mediated immune response, through mechanisms that enhance antigen presentation, activation of dendritic cells, and cross-presentation of tumor-associate antigens.26Garnett CT Palena C Chakraborty M Tsang KY Schlom J Hodge JW. Sublethal irradiation of human tumor cells modulates phenotype resulting in enhanced killing by cytotoxic T lymphocytes.Cancer Res. 2004; 64: 7985-7994Crossref PubMed Scopus (415) Google Scholar, 27Goforth R Salem AK Zhu X et al.Immune stimulatory antigen loaded particles combined with depletion of regulatory T-cells induce potent tumor specific immunity in a mouse model of melanoma.Cancer Immunol Immunother. 2009; 58: 517-530Crossref PubMed Scopus (49) Google Scholar, 28Chajon E Castelli J Marsiglia H De Crevoisier R. The synergistic effect of radiotherapy and immunotherapy: a promising but not simple partnership.Crit Rev Oncol/Hematol. 2017; 111: 124-132Crossref PubMed Scopus (73) Google Scholar These newly primed T-cells work synergistically with immunotherapeutic agents to promote immune-mediated tumor destruction.46Menon H. Chen D. Ramapriyan R. et al.Influence of low-dose radiation on abscopal responses in patients receiving high-dose radiation and immunotherapy.J Immunother Cancer. 2019; 7: 237Crossref PubMed Scopus (48) Google ScholarLow to moderate doses of pulsed or cyclical RT to improve systemic control with ICI are also under active investigation. He et al. (2021) demonstrated that pulsed RT to primary and secondary tumors, sequentially 6 days apart, led to upregulation of pro-inflammatory cytokines responsible for activation of innate and adaptive immunity in mouse models. This enhancement is further augmented with concurrent systemic anti-CTLA4.47He K B