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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

  • Martin J. Higgins
    Correspondence
    Address for correspondence: Martin J. Higgins, MB BCh BAO (Hons), FFRRCSI, Department of Radiation Oncology, Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, Victoria, 3000, Australia
    Affiliations
    Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia
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  • Ramin Alipour
    Affiliations
    Department of Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia
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  • Kathy Pope
    Affiliations
    Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia
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  • Kim Ann Ung
    Affiliations
    Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia
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  • David L. Kok
    Affiliations
    Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    Department of Clinical Pathology, University of Melbourne, Melbourne, Victoria, Australia

    The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia
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  • Margaret S-T Chua
    Affiliations
    Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia
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Published:March 13, 2022DOI:https://doi.org/10.1016/j.clcc.2022.03.001

      Keywords

      Clinical Practice Points

      The 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 Background

      The advent of immune checkpoint inhibitors (ICI) in the management of melanoma has revolutionized treatment paradigms; with a significant survival benefit in advanced cutaneous melanoma.
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      Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.
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      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.
      • SP D'Angelo
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      Efficacy and Safety of nivolumab alone or in combination with ipilimumab in patients with mucosal melanoma: a pooled analysis.
      This disease usually has an aggressive course with high rates of local recurrence (LR) and distant metastases
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      Postoperative radiotherapy for primary mucosal melanoma of the head and neck.
      and a 5 year overall survival (OS) of 20% to 30%.
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      ,
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      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,
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      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.
      the majority being in the head and neck region. Anorectal MM represents less than 20% of MM,
      • Hillenbrand A
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      and less than 1% all colorectal and anal canal cancers.
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      For 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%.
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      A recent systematic review and meta-analysis by Jutton et al
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      ,
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      Radical radiotherapy for 28 cases of mucosal melanoma in the nasal cavity and sinuses.
      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.
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      • et al.
      Surgical treatment of anorectal melanoma: a systematic review and meta-analysis.
      The role of RT in MM remains poorly defined, with some studies reporting improved local control (LC) with adjuvant RT.
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      Postoperative radiotherapy in head and neck mucosal melanoma: a GETTEC study.
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      Mucosal melanoma of the head and neck: a population-based study from Slovenia, 1985-2013.
      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.
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      Radical radiotherapy for 28 cases of mucosal melanoma in the nasal cavity and sinuses.
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      Palliative RT is effective for symptom control of pain, bleeding and tumor growth restraint in patients with locally advanced and/or stage IV disease.
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      Radiation therapy for melanoma.
      Whilst 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.
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      Radiation therapy to convert the tumor into an in situ vaccine.
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      • Tsang KY
      • Schlom J
      • Hodge JW.
      Sublethal irradiation of human tumor cells modulates phenotype resulting in enhanced killing by cytotoxic T lymphocytes.
      • Goforth 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.
      • Chajon E
      • Castelli J
      • Marsiglia H
      • De Crevoisier R.
      The synergistic effect of radiotherapy and immunotherapy: a promising but not simple partnership.
      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.
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      Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody.
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      An 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.
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      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,
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      as well as in gynecological malignancies.
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      The 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.
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      Case Series

      We 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 1

      A 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 1
      Figure 1Timeline of treatment course and response for case 1.
      Figure 2
      Figure 2Timeline of primary tumor and distant metastasis response for case 1.

      Case 2

      A 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 3
      Figure 3Timeline of treatment course and response for case 2.
      Figure 4
      Figure 4Timeline of primary tumor and distant metastasis response for case 2.

      Case 3

      A 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 5
      Figure 5Timeline of treatment course and response for case 3.
      Figure 6
      Figure 6Timeline of primary tumor and distant metastasis response for case 3.

      Radiation Therapy Techniques and Volumes

      Cases 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%.

      Discussion

      In 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.
      • Furney SJ
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      Genome sequencing of mucosal melanomas reveals that they are driven by distinct mechanisms from cutaneous melanoma.
      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.
      • SP D'Angelo
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      Efficacy and Safety of nivolumab alone or in combination with ipilimumab in patients with mucosal melanoma: a pooled analysis.
      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.
      • Kim HJ
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      Effect of radiotherapy combined with pembrolizumab on local tumor control in mucosal melanoma patients.
      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 tumor
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      ,
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      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.
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      Ultimately the goal is to balance the pro-immunogenic and immunosuppressive abilities of RT.
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      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.
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      These newly primed T-cells work synergistically with immunotherapeutic agents to promote immune-mediated tumor destruction.
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      Low 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.
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      It is also hypothesized that pulsed RT has the ability to reprogram the TME in favor of anti-tumor outcomes by enhancing the cross talk between B- and NK-cells by faster antibody production upon re-exposure to the same tumor-specific antigen. Cyclical, metronomic RT may also have the ability to diversify tumor antigens.
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      overcoming the immunosuppressive effects in the stromal TME.
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      This approach has been shown in a phase II trial to improve lesion-specific response of metastatic NSCLC and melanoma patients after progression on ICI.
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      QS RT is a low dose per fraction, cyclical RT regimen. Each cycle of QS RT equates to a BED10 of 18.9 Gy (biologically equivalent dose using a/b ratio of 10), and only 18.2 Gy in 2 Gy per fraction equivalent (EQD2) using a/b 3 for late effects (EQD23) and EQD210 of 15.75 for early effects. In this series, all 3 patients were treated with QS RT, up to 3 cycles to the primary site. Patient 2 received only 1 cycle (14 Gy in 4 fractions) to a bulky primary anorectal melanoma and experienced a complete local response that lasted until death 15 months later. This is far below the dose expected to eradicate melanoma with RT alone. Patients 1 received 3 cycles of QS (total dose 42 Gy in 12 fractions). Whilst this is considered to be at the higher end of fractionated radiotherapy doses and equates to a BED10 of approximately 57 Gy (EQD210 47.25), it is delivered over a prolonged overall treatment time and thus is a lower effective dose. Early clinical and radiological responses were evident after 1 or 2 cycles and remained sustained. This suggests a synergistic effect with QS RT and ipi/nivo.
      While we did not observe abscopal effects directly related to QS RT, the combination of RT with ipi/nivo has translated to favorable systemic control so far in 2 of the 3 patients in our cohort. After completion of concurrent QS RT and induction ipi/nivo, patient 1 received 2 years of maintenance nivolumab with ongoing CMR and a sustained PFS of at least 23.2 months. Patient 3 only had 2 cycles of maintenance nivolumab due to GI toxicity, but she experienced a PFS of 15.8 months prior to intra and extra cranial progression, requiring SRS at 18.7 months to one new and one progressive intracranial lesion, with 5 other brain lesions present at diagnosis remaining stable. In the checkmate 204 study, there was a 57% intracranial benefit rate (compete response, partial response or stable disease) in patients with asymptomatic brain metastases from melanoma treated with doublet immunotherapy, with 26% of patients experiencing a complete response, although this was not specific to MM brain metastases.
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      Conversely, patient 2 had progressive systemic disease despite radio-responsiveness of the primary anal lesion. Interestingly, the metastatic lesions treated with 20 Gy in 5 fractions shortly after 1 cycle of QS RT with concurrent ipi/nivo resulted in a CMR at those sites, but subsequent metastases treated with the same fractionation concurrent with single agent nivolumab (after induction doublet immunotherapy had finished) did not respond and all untreated lesions continued to progress rapidly.
      Of the 3 patients presented in our study, 2 did not experience any acute toxicities and 1 patient developed G3 colitis following cycle 3 of ipi/nivo which was felt to be immune-mediated. A pooled analysis of patients with melanoma undergoing combination immunotherapy without RT showed combined rates of G3 and G4 adverse events of 40% and 54.9% for mucosal and cutaneous melanoma, respectively.
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      • Sosman JA
      • et al.
      Efficacy and Safety of nivolumab alone or in combination with ipilimumab in patients with mucosal melanoma: a pooled analysis.
      All 3 patients in our case series avoided a defunctioning colostomy which is incredibly important in a cohort of patients where prognosis is generally poor and maintaining quality of life is a major goal for both clinicians and patients.

      Conclusion

      This report provides a unique insight into the potential immunomodulatory benefits of QS RT and ICI. This low dose per fraction, cyclical regimen further supports some of the preclinical and early clinical basis of repetitive antigen presentation and stromal disruption leading to enhanced innate and adaptive immunity. This treatment paradigm was well tolerated and shows excellent rates of complete and durable LC in our patient cohort. The favorable responses seen in this case series serve as a signal to the unique synergistic effect of the QUAD SHOT regimen with combination ICI and is hypothesis generating. Future prospective studies investigating this combination are warranted.

      Disclosure

      There are no conflicts of interest to declare.
      This study was approved by the ethics review board of our institution.

      Acknowledgments

      There was no funding provided for this research.

      Author Contributions

      All authors contributed substantially to: The conception and design of the study, acquisition of data, analysis and interpretation of data; drafting the article or revising it critically for important intellectual content; final approval of the version to be submitted.

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