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Safety and Tolerability of Metastasis-Directed Radiation Therapy in the Era of Evolving Systemic, Immune, and Targeted Therapies

Open AccessPublished:July 12, 2022DOI:https://doi.org/10.1016/j.adro.2022.101022

      AbstractPurpose

      Systemic, immune, and target therapies are growing in use in the management of metastatic cancers. The aim of this review was to describe up-to-date published data on the safety and tolerability of metastasis-directed hypofractionated radiation therapy (RT) when combined with newer systemic, immune, and targeted therapies and to provide suggested strategies to mitigate potential toxicities in the clinical setting.

      Methods and Materials

      A comprehensive search was performed for the time period between 1946 and August 2021 using predetermined keywords describing the use of noncentral nervous system palliative RT with commonly used targeted systemic therapies on PubMed and Medline databases. A total of 1022 articles were screened, and 130 met prespecified criteria to be included in this review.

      Results

      BRAF and MEK inhibitors are reported to be toxic when given concurrently with RT; suspension 3 days and 1 to 2 days, respectively, prior and post-RT is suggested. Cetuximab, erlotinib/gefitinib, and osimertinib were generally safe to use concomitantly with conventional radiation. But in a palliative/hypofractionated RT setting, suspending cetuximab during radiation week, erlotinib/gefitinib 1 to 2 days, and osimertinib ≥2 days pre- and post-RT is suggested. Vascular endothelial growth factor inhibitors such as bevacizumab reported substantial toxicities, and the suggestion is to suspend 4 weeks before and after radiation. Less data exist on sorafenib and sunitinib; 5 to 10 days suspension before and after RT should be considered. As a precaution, until further data are available, for cyclin-dependent kinase 4-6 inhibitors, consideration of suspending treatment 1 to 2 days before and after RT should be given. Ipilimumab should be suspended 2 days before and after RT, and insufficient data exist for other immunotherapy agents. Trastuzumab and pertuzumab are generally safe to use in combination with RT, but insufficient data exist for other HER2 target therapy.

      Conclusions

      Suggested approaches are described, using up-to-date literature, to aid clinicians in navigating the integration of newer targeted agents with hypofractionated palliative and/or ablative metastatic RT. Further prospective studies are required.

      Introduction

      The use of cancer-directed therapy is rapidly advancing in the era of individualized patient directed care and with the emergence of numerous systemic, immune, and targeted therapies. For patients with metastatic disease, the role of radiation therapy (RT) is also evolving, with increasing interest in combining radiation with these newer systemic therapies to potentiate an antitumor immune response and in an effort to avoid interruptions of systemic treatment in patients with metastatic disease.
      • Gomez DR
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      • Zhang J
      • et al.
      Local consolidative therapy vs. maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer: Long-term results of a multi-institutional, phase II, randomized study.
      • Lehrer EJ
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      • et al.
      Safety and survival rates associated with ablative stereotactic radiotherapy for patients with oligometastatic cancer: A systematic review and meta-analysis.
      • Palma DA
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      Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): A randomised, phase 2, open-label trial.
      Limited prospective safety and tolerability data exist for combining systemic therapies and RT in the metastatic setting. The aim of this review was to describe up-to-date published data on the safety and tolerability of metastasis-directed hypofractionated RT when combined with newer systemic, immune, and targeted therapies and to provide suggested strategies to mitigate potential toxicities in the clinical setting.

      Methods and Materials

      A comprehensive literature review from peer-reviewed journals was performed through PubMed and Medline from 1946 to August 2021. The search strategy was restricted to English language and human subjects, with subject-specific keywords developed as per authors’ consensus (EG, AB). Controlled vocabulary terms were used when available, referring to palliative RT, stereotactic body RT (SBRT), bone metastases, targeted therapy, check-point inhibitor, BRAF inhibitor, MEK inhibitor, immunotherapy, programmed cell death-1 (PD-1) inhibitor, programmed cell death ligand (PDL-1) inhibitor, tyrosine kinase inhibitor, and cyclin-dependent kinase 4-6 inhibitor (see Supplementary Materials; Appendix 1 for complete list). The most recent search was performed May 17, 2022. Of 1029 screened articles, only prospective studies, retrospective studies, and case reports where the aforementioned treatments and RT were used concomitantly or sequentially with discussion of radiation-induced toxicity were reviewed. A limited number of articles using conventional nonmetastatic RT combined with contemporary systemic therapies are discussed in this paper where there was an absence of data in the palliative RT or SBRT setting. A total of 907 studies were excluded where RT to the central nervous system was delivered or radionuclide therapy was used and safety data were not available. A further 8 publications were added from the authors’ own libraries. A total of 130 publications were selected.
      Publications including typically used palliative and/or metastatic-directed RT fractionation regimens – moderate (defined as >2.2 Gy per fraction [fr]) and ultrahypofractionation (defined as ≥5 Gy per fr [≤10 fr],
      • Morgan SC
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      • et al.
      Hypofractionated radiation therapy for localized prostate cancer: Executive summary of an ASTRO, ASCO, and AUA evidence-based guideline.
      with SBRT specified as ≤6 fr) – were included in this analysis. These 2 regimens are typically used in the palliative and metastatic disease setting. The toxicities were graded according to Common Terminology Criteria for Adverse Events (CTCAE v3.0 or higher)

      Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events (CTCAE). Available at:https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm. Accessed January 15, 2022.

      when information was available.

      Results

      Publications were divided according to class of systemic agent. Based on the limited data available, suggested toxicity mitigation strategies were proposed (Table 1) for each class. When relevant palliative studies were not available, curative intent trials were primarily used, and, finally, when neither of these were available, the drug's elimination half-life (as it leads to the elimination of more than 95% of the drug
      • Thariat J
      • Kirova Y
      • Milano G
      • Mornex F.
      Association d’une chimiothérapie ou d’un traitement ciblé à une irradiation stéréotaxique: état des lieux et recommandations préliminaires [Combination of stereotactic irradiation and chemotherapy or targeted therapies: State of the art and preliminary recommendations].
      ) was considered to guide clinical practice.
      Table 1Summary of suggested approaches
      AgentsDrugSuggestions
      BRAF and MEK inhibitorVemurafenib and dabrafenib; trametinibSuspend 3 d before and after RT.

      Suspend 1-2 d before and after RT.
      EGFR and ALK inhibitorCetuximab; erlotinib and gefitinib; crizotinib and osimertinibSuspend the week of radiation if SBRT. Suspend 1-2 d before and after RT. Suspend ≥2 d before and after RT.
      VEGF inhibitorBevacizumab; sorafenib and sunitinibSuspend 4 d before and after RT.

      Suspend 5-10 d before and after RT.
      Cyclin-dependent kinase (CDK) inhibitors 4-6Palbociclib and ribociclibSuspend 3 d before and after RT.
      ImmunotherapyIpilimumab; otherSuspend 2 d before and after RT if 8 Gy in single fraction to bone. Insufficient data to recommend with moderate and ultrafractionation RT; caution suggested on an individual basis.
      HER2 target therapyTrastuzumab and pertuzumab; lapatinib; T-DM1Generally safe to use concomitantly with RT. Insufficient data to recommend with moderate and ultrafractionation RT; caution suggested on an individual basis. Insufficient data to recommend with moderate and ultrafractionation RT; caution suggested on an individual basis.
      Abbreviations: ALK = anaplastic lymphoma kinase; EGFR = epidermal growth factor receptor; RT = radiation therapy; SBRT = stereotactic body RT; VEGF = vascular endothelial growth factor; CDK = cyclin-dependent kinase; TDM1 = trastuzumab emtansine.

      RT and BRAF/MEK inhibitor agents

      Vemurafenib and dabrafenib are the 2 most commonly used BRAF inhibitors, mainly in the management of metastatic melanoma. They are shown to be associated with in vitro radiosensitization
      • Dasgupta T
      • Haas-Kogan DA
      • Yang X
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      Genotype-dependent cooperation of ionizing radiation with BRAF inhibition in BRAF V600E-mutated carcinomas.
      ,
      • Sambade MJ
      • Peters EC
      • Thomas NE
      • Kaufmann WK
      • Kimple RJ
      • Shields JM.
      Melanoma cells show a heterogeneous range of sensitivity to ionizing radiation and are radiosensitized by inhibition of B-RAF with PLX-4032.
      and have a t½ of 57 hours

      Lexi-Drugs. Lexicomp app. UpToDate Inc. Accessed August 12, 2022.

      (range, 30-120 hours) and 8 hours,

      Lexi-Drugs. Lexicomp app. UpToDate Inc. Accessed August 12, 2022.

      respectively.
      When BRAF inhibitors are combined with RT, the most commonly report side effect is dermatitis, occurring during or within 7 days of RT.
      • Wang CM
      • Fleming KF
      • Hsu S.
      A case of vemurafenib-induced keratosis pilaris-like eruption.
      • Baroudjian B
      • Boussemart L
      • Routier E
      • et al.
      Dramatic response to radiotherapy combined with vemurafenib. Is vemurafenib a radiosensitizer?.
      • Wallach JB
      • Rietschel P
      • Kalnicki S
      • Fox JL.
      BRAF inhibitor (vemurafenib) concurrent with radiation therapy for metastatic melanoma producing severe skin and oral cavity reactions.
      • Schulze B
      • Meissner M
      • Wolter M
      • Rödel C
      • Weiss C.
      Unusual acute and delayed skin reactions during and after whole-brain radiotherapy in combination with the BRAF inhibitor vemurafenib. Two case reports.
      • Satzger I
      • Degen A
      • Asper H
      • Kapp A
      • Hauschild A
      • Gutzmer R.
      Serious skin toxicity with the combination of BRAF inhibitors and radiotherapy.
      • Anker CJ
      • Ribas A
      • Grossmann AH
      • et al.
      Severe liver and skin toxicity after radiation and vemurafenib in metastatic melanoma.
      • Hecht M
      • Zimmer L
      • Loquai C
      • et al.
      Radiosensitization by BRAF inhibitor therapy-mechanism and frequency of toxicity in melanoma patients.
      • Houriet C
      • Klass ND
      • Beltraminelli H
      • Borradori L
      • Oberholzer PA.
      Localized epidermal cysts as a radiation recall phenomenon in a melanoma patient treated with radiotherapy and the BRAF inhibitor vemurafenib.
      • Lang N
      • Sterzing F
      • Enk AH
      • Hassel JC.
      Cutis verticis gyrata-like skin toxicity during treatment of melanoma patients with the BRAF inhibitor vemurafenib after whole-brain radiotherapy is a consequence of the development of multiple follicular cysts and milia.
      • Levy A
      • Hollebecque A
      • Bourgier C
      • et al.
      Targeted therapy-induced radiation recall.
      • Peuvrel L
      • Ruellan A-L
      • Thillays F
      • et al.
      Severe radiotherapy-induced extracutaneous toxicity under vemurafenib.
      • Pulvirenti T
      • Hong A
      • Clements A
      • et al.
      Acute radiation skin toxicity associated with BRAF inhibitors.
      • Reigneau M
      • Granel-Brocard F
      • Geoffrois L
      • et al.
      Efflorescence of scalp cysts during vemurafenib treatment following brain radiation therapy: A radiation recall dermatitis?.
      • Saco M
      • Mitchell C.
      Severe radiation dermatitis associated with concomitant vemurafenib therapy in a patient with metastatic melanoma.
      In addition to acute skin toxicities, there have been a number of case reports of radiation recall associated with systemic agents that have started more than 7 days from RT completion, with no CTCAE grade 3 or higher toxicity reported, and subsequently they were managed conservatively.
      • Wang CM
      • Fleming KF
      • Hsu S.
      A case of vemurafenib-induced keratosis pilaris-like eruption.
      ,
      • Harding JJ
      • Barker CA
      • Carvajal RD
      • Wolchok JD
      • Chapman PB
      • Lacouture ME.
      Cutis verticis gyrata in association with vemurafenib and whole-brain radiotherapy.
      • Boussemart L
      • Boivin C
      • Claveau J
      • et al.
      Vemurafenib and radiosensitization.
      • Yilmaz M
      • Celik U
      • Hascicek S.
      Radiation recall dermatitis with dabrafenib and trametinib: A case report.
      • Braunstein I
      • Gangadhar TC
      • Elenitsas R
      • Chu EY.
      Vemurafenib-induced interface dermatitis manifesting as radiation-recall and a keratosis pilaris-like eruption.
      • Conen K
      • Mosna-Firlejczyk K
      • Rochlitz C
      • et al.
      Vemurafenib-induced radiation recall dermatitis: Case report and review of the literature.
      • Anker CJ
      • Grossmann KF
      • Atkins MB
      • Suneja G
      • Tarhini AA
      • Kirkwood JM.
      Avoiding severe toxicity from combined BRAF inhibitor and radiation treatment: Consensus guidelines from the Eastern Cooperative Oncology Group (ECOG).
      All CTCAE grade 3 toxicities happened when the BRAF inhibitor was given concurrently or within 2 days of radiation
      • Anker CJ
      • Ribas A
      • Grossmann AH
      • et al.
      Severe liver and skin toxicity after radiation and vemurafenib in metastatic melanoma.
      and when high-dose RT was given (eg, 71 Gy in 28 fr).
      • Braunstein I
      • Gangadhar TC
      • Elenitsas R
      • Chu EY.
      Vemurafenib-induced interface dermatitis manifesting as radiation-recall and a keratosis pilaris-like eruption.
      A dose threshold has not been reported, but from retrospective data by Churilla et al,
      • Churilla TM
      • Chowdhry VK
      • Pan D
      • de la Roza G
      • Damron T
      • Lacombe MA.
      Radiation-induced dermatitis with vemurafenib therapy.
      when treating with 30 Gy in 10 fr, the estimated dose received by the skin was 23 to 31 Gy, resulting in a grade 3 dermatitis.
      Nondermatologic toxicities are less commonly reported in the literature (Supplementary Materials; Appendix 9). Anker et al
      • Anker CJ
      • Ribas A
      • Grossmann AH
      • et al.
      Severe liver and skin toxicity after radiation and vemurafenib in metastatic melanoma.
      reported a CTCAE grade 5 hepatic hemorrhage, which occurred after 20 Gy in 5 fr using parallel opposed beam radiation delivered to T10 to L1 vertebral body. However, the direct causality was unclear due to the growing number and size of known liver metastases, and the low dose of radiation received by the liver (liver mean dose = 2.7 Gy). Underlying liver function was not reported, but additional data suggest avoiding direct liver irradiation when patients on BRAF inhibitors present with a Child-Pugh B7 and higher score.
      • Pan CC
      • Kavanagh BD
      • Dawson LA
      • et al.
      Radiation-associated liver injury.
      A CTCAE grade 5 toxicity, reported by Baroudjian et al,
      • Baroudjian B
      • Boussemart L
      • Routier E
      • et al.
      Dramatic response to radiotherapy combined with vemurafenib. Is vemurafenib a radiosensitizer?.
      resulted in a hemothorax 1 month after palliative right axillary RT using 20 Gy in 4 fr. Reassuringly, they also reported another similar case that had no toxicities with a higher dose of 30 Gy in 6 fr. Two cases of CTACE grade 2 pneumonitis with combined vemurafenib and chest irradiation were reported, but the authors were unable to differentiate if toxicities were solely drug related or not.
      • Forschner A
      • Zips D
      • Schraml C
      • et al.
      Radiation recall dermatitis and radiation pneumonitis during treatment with vemurafenib.
      A patient who received concurrent vemurafenib with palliative RT to the left neck, 50 Gy in 20 fr, developed a CTCAE grade 3 oral mucositis and dermatitis.
      • Wallach JB
      • Rietschel P
      • Kalnicki S
      • Fox JL.
      BRAF inhibitor (vemurafenib) concurrent with radiation therapy for metastatic melanoma producing severe skin and oral cavity reactions.
      According to the authors, this toxicity was not expected, with the oral cavity receiving at most 12 Gy. Hecht et al
      • Hecht M
      • Zimmer L
      • Loquai C
      • et al.
      Radiosensitization by BRAF inhibitor therapy-mechanism and frequency of toxicity in melanoma patients.
      reported only 2 patients (2%) with grade 3 esophagitis with parenteral nutrition needs in their series on spine irradiation in patients with melanoma.
      Trametinib is a MEK-inhibitor targeting the MAPK pathway, used frequently in combination with dabrafenib and mainly used in melanoma and anaplastic thyroid cancer. It has a t½ of 4 to 5 hours.

      Lexi-Drugs. Lexicomp app. UpToDate Inc. Accessed August 12, 2022.

      Therefore, little information on the use as a monotherapy exists.
      A recent phase 2 study by Zhu et al
      • Zhu X
      • Cao Y
      • Liu W
      • et al.
      Stereotactic body radiotherapy plus pembrolizumab and trametinib versus stereotactic body radiotherapy plus gemcitabine for locally recurrent pancreatic cancer after surgical resection: An open-label, randomised, controlled, phase 2 trial.
      compared pancreatic cancer SBRT 35 Gy in 5 fr, in the setting of locally recurrent pancreatic cancer, with pembrolizumab and trametinib versus gemcitabine concurrently. Reported toxicities were more commonly seen in the SBRT plus pembrolizumab and trametinib arm, with CTCAE grade 3 to 4 increased liver enzymes (12% vs 7%) and increased bilirubin (5% vs 0%), with no treatment-related deaths. However, hepatotoxicity is not a common side effect of trametinib, and the authors believed the reported toxicity likely arose from the pembrolizumab. No toxicities have been reported with this drug combination with conventional RT.
      • Wu C
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      • Robb R
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      Phase I trial of trametinib with neoadjuvant chemoradiation in patients with locally advanced rectal cancer.
      A case of CTCAE grade 4 bowel perforation was described at 1 month after palliative RT (20 Gy in 5 fr) with dabrafenib and trametinib, which was started 10 days after radiation.
      • Anker CJ
      • Grossmann KF
      • Atkins MB
      • Suneja G
      • Tarhini AA
      • Kirkwood JM.
      Avoiding severe toxicity from combined BRAF inhibitor and radiation treatment: Consensus guidelines from the Eastern Cooperative Oncology Group (ECOG).
      A recent phase I/II study
      • Wang W
      • Smith JL
      • Carlino MS
      • et al.
      Phase I/II trial of concurrent extracranial palliative radiation therapy with dabrafenib and trametinib in metastatic BRAF V600E/K mutation-positive cutaneous melanoma.
      evaluated the use of dabrafenib and trametinib in patients with metastatic melanoma receiving palliative radiation (20 Gy in 5 fr and 30 Gy in 10 fr). Two patients included in the study received 20 Gy in 5 fr using 3-dimensional conformal RT to the lumbar spine and right ilium/L1 vertebra, respectively, without any significant gastrointestinal (GI) toxicities reported by 12 months.

      Summary and suggested toxicity mitigation strategies

      Guidelines from the Eastern Cooperative Oncology Group and based on data outlined previously, suspension of BRAF inhibitors 3 days before and after radiation
      • Anker CJ
      • Grossmann KF
      • Atkins MB
      • Suneja G
      • Tarhini AA
      • Kirkwood JM.
      Avoiding severe toxicity from combined BRAF inhibitor and radiation treatment: Consensus guidelines from the Eastern Cooperative Oncology Group (ECOG).
      should be considered mainly to avoid skin toxicity. There are insufficient published data to provide a recommendation for MEK inhibitors. Based on trametinib's t½, 1 to 2 days pre- and post-RT might be sufficient.

      RT and epidermal growth factor receptor/anaplastic lymphoma kinase inhibitor agents

      Commonly used epidermal growth factor receptor inhibitors include cetuximab, erlotinib, gefitinib, and osimertinib, with t½ of 112, 36.2, 48, and 48 hours, respectively.

      Lexi-Drugs. Lexicomp app. UpToDate Inc. Accessed August 12, 2022.

      Cetuximab is a monoclonal antibody targeting epidermal growth factor receptor, whereas the other agents are receptor tyrosine kinase inhibitors (TKIs). Crizotinib is an anaplastic lymphoma kinase inhibitor with t½ of 42 hours.

      Lexi-Drugs. Lexicomp app. UpToDate Inc. Accessed August 12, 2022.

      Anaplastic lymphoma kinase TKIs have been reported to potentiate the effect of lung injury when the lungs are within the RT target volume.
      • Pellegrino B
      • Facchinetti F
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      • Silva M
      • Gnetti L
      • Tiseo M.
      Lung toxicity in non-small-cell lung cancer patients exposed to ALK inhibitors: Report of a peculiar case and systematic review of the literature.
      Studies primarily involving the use of these agents in combination with RT for the treatment of head and neck, colorectal, and non-small cell lung cancer (NSCLC) are summarized in Supplementary Materials; Appendix 4.
      There are a lack of data reporting the use of cetuximab combined with hypofractionated and/or palliative RT. The majority of evidence describes cetuximab in combination with radical, conventionally fractionated RT for locally advanced head and neck cancer. These studies report a 6% to 36% risk of CTCAE grade 3 or higher skin reaction, which is significantly increased with cetuximab compared with cisplatin.
      • Gillison ML
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      • Harris J
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      Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): A randomised, multicentre, non-inferiority trial.
      • Mehanna H
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      Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): An open-label randomised controlled phase 3 trial.
      • Gebre-Medhin M
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      ARTSCAN III: A randomized phase III study comparing chemoradiotherapy with cisplatin versus cetuximab in patients with locoregionally advanced head and neck squamous cell cancer.
      • Bonner JA
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      • Giralt J
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      Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival.
      In the palliative setting, only 1 case has reported a grade 3 esophagitis when fluorouracil/cisplatin and cetuximab were combined with 30 Gy in 10 fr spine RT.
      • Chiba T
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      Radiation esophagitis in a patient with oral carcinoma and bone metastasis.
      A retrospective study reported no CTCAE grade 3 or higher toxicity
      • Gamez ME
      • Agarwal M
      • Hu KS
      • Lukens JN
      • Harrison LB.
      Hypofractionated palliative radiotherapy with concurrent radiosensitizing chemotherapy for advanced head and neck cancer using the “QUAD-SHOT regimen.
      when hypofractionated RT was used in 3 patients with metastatic head and neck cancer.
      • Gamez ME
      • Agarwal M
      • Hu KS
      • Lukens JN
      • Harrison LB.
      Hypofractionated palliative radiotherapy with concurrent radiosensitizing chemotherapy for advanced head and neck cancer using the “QUAD-SHOT regimen.
      Other studies reporting head and neck SBRT delivered concomitantly with cetuximab were in recurrent settings.
      • Vargo JA
      • Ferris RL
      • Ohr J
      • et al.
      A prospective phase 2 trial of reirradiation with stereotactic body radiation therapy plus cetuximab in patients with previously irradiated recurrent squamous cell carcinoma of the head and neck.
      • Lartigau EF
      • Tresch E
      • Thariat J
      • et al.
      Multi institutional phase II study of concomitant stereotactic reirradiation and cetuximab for recurrent head and neck cancer.
      • Gebhardt BJ
      • Vargo JA
      • Ling D
      • et al.
      Carotid dosimetry and the risk of carotid blowout syndrome after reirradiation with head and neck stereotactic body radiation therapy.
      Concomitant cetuximab with conventionally chest fractionated thorax RT has been studied in 2 phase 2 studies without major safety concerns
      • Jensen AD
      • Munter MW
      • Bischoff HG
      • et al.
      Combined treatment of nonsmall cell lung cancer NSCLC stage III with intensity-modulated RT radiotherapy and cetuximab: The NEAR trial.
      ,
      • Ramalingam SS
      • Kotsakis A
      • Tarhini AA
      • et al.
      A multicenter phase II study of cetuximab in combination with chest radiotherapy and consolidation chemotherapy in patients with stage III non-small cell lung cancer.
      and with conventionally fractionated RT to the rectum with a 5% to 38% rate of CTCAE grade 3 to 4 diarrhea.
      • Glynne-Jones R
      • Hadaki M
      • Harrison M
      The status of targeted agents in the setting of neoadjuvant radiation therapy in locally advanced rectal cancers.
      Numerous prospective studies have investigated the role of conventionally fractionated RT in combination with erlotinib and gefitinib, reporting CTCAE grade ≤3 toxicities related to nausea, skin, esophagitis, and pneumonitis.

      Erlotinib hydrochloride or crizotinib and chemoradiation therapy in treating patients with stage III non-small cell lung cancer. Available at: https://clinicaltrials.gov/show/nct01822496. Accessed June 24, 2022.

      • Zhang X
      • Xie C
      • Li W
      • Zhang P
      • Wu S.
      [Phase II study of radiotherapy plus erlotinib for elder patients with esophageal carcinoma].
      • Xie C
      • Jing Z
      • Luo H
      • et al.
      Chemoradiotherapy with extended nodal irradiation and/or erlotinib in locally advanced oesophageal squamous cell cancer: Long-term update of a randomised phase 3 trial.
      • Jia W
      • Guo H
      • Jing W
      • et al.
      An especially high rate of radiation pneumonitis observed in patients treated with thoracic radiotherapy and simultaneous osimertinib.
      • Zhai Y
      • Hui Z
      • Wang J
      • et al.
      Concurrent erlotinib and radiotherapy for chemoradiotherapy-intolerant esophageal squamous cell carcinoma patients: Results of a pilot study.
      • Iyer R
      • Chhatrala R
      • Shefter T
      • et al.
      Erlotinib and radiation therapy for elderly patients with esophageal cancer - clinical and correlative results from a prospective multicenter phase 2 trial.
      • Xu Y
      • Zheng Y
      • Sun X
      • et al.
      Concurrent radiotherapy with gefitinib in elderly patients with esophageal squamous cell carcinoma: Preliminary results of a phase II study.
      • Ready N
      • Jänne PA
      • Bogart J
      • et al.
      Chemoradiotherapy and gefitinib in stage III non-small cell lung cancer with epidermal growth factor receptor and KRAS mutation analysis: cancer and leukemia group B (CALEB) 30106, a CALGB-stratified phase II trial.
      • Martínez E
      • Martínez M
      • Rico M
      • et al.
      Feasibility, tolerability, and efficacy of the concurrent addition of erlotinib to thoracic radiotherapy in locally advanced unresectable non-small-cell lung cancer: A phase II trial.
      • Song T
      • Du D
      • Zhang X
      • Fang M
      • Wu S.
      Comparative study of radiotherapy plus erlotinib versus chemoradiotherapy for elderly patients with esophageal cancer: A propensity score-matched analysis.
      • Lilenbaum R
      • Samuels M
      • Wang X
      • et al.
      A phase II study of induction chemotherapy followed by thoracic radiotherapy and erlotinib in poor-risk stage III non-small-cell lung cancer: Results of CALGB 30605 (Alliance)/RTOG 0972 (NRG).
      • Wu S-X
      • Wang L-H
      • Luo H-L
      • et al.
      Randomised phase III trial of concurrent chemoradiotherapy with extended nodal irradiation and erlotinib in patients with inoperable oesophageal squamous cell cancer.
      Weickhardt et al,
      • Weickhardt AJ
      • Scheier B
      • Burke JM
      • et al.
      Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer.
      Gan et al,
      • Gan GN
      • Weickhardt AJ
      • Scheier B
      • et al.
      Stereotactic radiation therapy can safely and durably control sites of extra-central nervous system oligoprogressive disease in anaplastic lymphoma kinase-positive lung cancer patients receiving crizotinib.
      and Borghetti et al
      • Borghetti P
      • Bonù ML
      • Roca E
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      Radiotherapy and tyrosine kinase inhibitors in stage IV non-small cell lung cancer: Real-life experience.
      published retrospective studies treating different metastatic sites from GI cancers with concurrent erlotinib or crizotinib using SBRT and hypofractionated palliative RT, and no CTCAE grade 3 or higher toxicity was reported. In the multi-institutional phase II study by Gomez et al,
      • Gomez DR
      • Tang C
      • Zhang J
      • et al.
      Local consolidative therapy vs. maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer: Long-term results of a multi-institutional, phase II, randomized study.
      which treated patients with oligometastatic NSCLC without progression after front-line systemic therapy, 2 patients received SBRT concurrently with crizotinib, and reported toxicities were similar to patients who did not receive concomitant therapy. Gefitinib was also used in combination with lung SBRT in a retrospective study of 122 elderly patients with no pneumonitis reported.
      • Pan D
      • Wang B
      • Zhou X
      • Wang D.
      Clinical study on gefitinib combined with γ-ray stereotactic body radiation therapy as the first-line treatment regimen for senile patients with adenocarcinoma of the lung (final results of JLY20080085).
      In a phase II trial by Swanimath et al,
      • Swaminath A
      • Wright JR
      • Tsakiridis TK
      • et al.
      A phase II trial of erlotinib and concurrent palliative thoracic radiation for patients with non-small-cell lung cancer.
      the safety of palliative hypofractionated thorax RT (30 Gy in 10 fr) with concurrent erlotinib was demonstrated, with only 1 CTCAE grade 3 nausea and 1 CTACE grade 4 dermatitis reported. However, a Chinese study published a high rate of CTCAE grade 3 or higher radiation pneumonitis (54%), including 1 death, when osimertinib was combined with palliative lung RT (30-60 Gy in 10-30 fr).
      • Jia W
      • Guo H
      • Jing W
      • et al.
      An especially high rate of radiation pneumonitis observed in patients treated with thoracic radiotherapy and simultaneous osimertinib.

      Summary and suggested toxicity mitigation strategies

      Cetuximab is commonly used with conventionally fractionated RT; however, in the setting of hypofractionated RT, due to the long t½ and paucity of toxicity data, omitting it during the week of radiation treatment is suggested. Erlotinib and gefitinib have been reported as safe with conventionally fractionated RT, but in the absence of supportive data in the setting of palliative/metastasis-directed RT, a washout period of 1 to 2 days before starting radiation is suggested. Due to lack of prospective data, combining crizotinib or osimertinib with RT is cautioned, and a washout period of at least 2 days is recommended. In cases where radiation is delivered to the lung, attention should be given to lung dosimetry, especially in the setting of patients with interstitial pneumonitis.

      Vascular endothelial growth factor inhibitor agents

      Bevacizumab is a humanized monoclonal antibody that binds and neutralizes vascular endothelial growth factor (VEGF)-A with a t½ of 20 days.

      Lexi-Drugs. Lexicomp app. UpToDate Inc. Accessed August 12, 2022.

      It is most commonly used in the management of gynecologic, colorectal, and hepatocellular malignancies (Supplementary Materials; Appendix 5).
      Bleeding after surgery in patients receiving bevacizumab is commonly reported. A meta-analysis
      • Hapani S
      • Chu D
      • Wu S.
      Risk of gastrointestinal perforation in patients with cancer treated with bevacizumab: A meta-analysis.
      described the incidence of GI perforation at 1% with an associated mortality rate of 21% in patients receiving bevacizumab, with history of prior radiation reported as a risk factor. Barney et al
      • Barney BM
      • Markovic SN
      • Laack NN
      • et al.
      Increased bowel toxicity in patients treated with a vascular endothelial growth factor inhibitor (VEGFI) after stereotactic body radiation therapy (SBRT).
      further reported a 9% rate of serious bowel injury (CTCAE grade 3-4 GI ulceration, CTCAE grade 4-5 GI perforation) post-SBRT (median dose, 50 Gy in 5 fr) in patients who received VEGF inhibitors before and after radiation, with reported toxicities higher (up to 35%) when systemic therapy was given after radiation. No clinically significant CTCAE grade 3 or higher bowel toxicities occurred in patients not receiving VEGF inhibitor after SBRT. These findings suggest a synergistically deleterious effect with the combination of VEGF inhibitors and SBRT. Note that no toxicities were reported when a maximum bowel dose of 18 Gy was recorded.
      Sorafenib and sunitinib are multireceptor TKIs targeting, among others, the kinase c-raf, VEGFfr 2/3, and platelet-derived growth factor-αl, with a t½ of 25 to 48 and 40 to 60 hours, respectively.

      Lexi-Drugs. Lexicomp app. UpToDate Inc. Accessed August 12, 2022.

      These agents are mostly used in hepatocellular carcinoma, renal cell carcinoma, GI stromal tumor, and thyroid carcinoma (Supplementary Materials; Appendix 5).
      Peters et al
      • Peters NAJB
      • Richel DJ
      • Verhoeff JJC
      • Stalpers LJA.
      Bowel perforation after radiotherapy in a patient receiving sorafenib.
      reported a CTCAE grade 5 bowel perforation with a single dose of palliative RT to the spine (8 Gy in 1 fr) when sorafenib was stopped 2 days before radiation and restarted 3 days post. Murray et al
      • Murray L
      • Longo J
      • Wan J
      • et al.
      Phase I dose escalation study of concurrent palliative radiation therapy with sorafenib in three anatomical cohorts (thorax, abdomen, pelvis): The TAP study.
      reported severe toxicities with concurrent sorafenib and palliative radiation (30 Gy in 10 fr), as 1 CTCAE grade 3 esophagitis, 1 CTCAE grade 3 transaminase elevation, and 1 CTCAE grade 5 bowel perforation (tumor was invading the bowel in this case). Two phase I studies
      • Goody RB
      • Brade AM
      • Wang L
      • et al.
      Phase I trial of radiation therapy and sorafenib in unresectable liver metastases.
      • Brade AM
      • Ng S
      • Brierley J
      • et al.
      Phase 1 trial of sorafenib and stereotactic body radiation therapy for hepatocellular carcinoma.
      showed that concurrent sorafenib with liver SBRT resulted in clinically meaningful toxicities, such as GI bleeding.
      A phase II trial
      • Tong CCL
      • Ko EC
      • Sung MW
      • et al.
      Phase II trial of concurrent sunitinib and image-guided radiotherapy for oligometastases.
      published important GI toxicities associated with a combination of sunitinib and SBRT (50 Gy in 10 fr) for oligometastatic disease. Also, Staehler et al
      • Staehler M
      • Haseke N
      • Nuhn P
      • et al.
      Simultaneous anti-angiogenic therapy and single-fraction radiosurgery in clinically relevant metastases from renal cell carcinoma.
      studied the association of sorafenib and sunitinib with spine stereotactic radiosurgery (20 Gy in 1 fr), reporting 1 CTCAE grade 3 bleed and 1 CTCAE grade 5 GI hemorrhage that was considered likely related to sunitinib rather than RT.

      Summary and suggested toxicity mitigation strategies

      Combining VEGF-inhibitor agents with any fractionation schedule of radiation appears unsafe. Bevacizumab should be stopped at least 4 weeks before RT and recommence at least 4 weeks post-RT. For TKIs targeting VEGF, at least 5 to 10 days pre- and post-RT should be considered, especially if GI mucosa is within the irradiated field.

      CDK4-6 inhibitor agents

      Palbociclib is a reversible small molecule cyclin-dependant kinase inhibitor selective for CDK 4 and 6, which has a role in regulating progression through the cell cycle and has a t½ of 29 hours.

      Lexi-Drugs. Lexicomp app. UpToDate Inc. Accessed August 12, 2022.

      Ribociclib and abemaciclib are CDK 4 to 6 inhibitors with t½ of 30 to 55 hours and 18.3 hours.

      Lexi-Drugs. Lexicomp app. UpToDate Inc. Accessed August 12, 2022.

      Few retrospective data
      • Meattini I
      • Desideri I
      • Scotti V
      • Simontacchi G
      • Livi L.
      Ribociclib plus letrozole and concomitant palliative radiotherapy for metastatic breast cancer.
      • Kawamoto T
      • Shikama N
      • Sasai K.
      Severe acute radiation-induced enterocolitis after combined palbociclib and palliative radiotherapy treatment.
      • Hans S
      • Cottu P
      • Kirova YM.
      Preliminary results of the association of palbociclib and radiotherapy in metastatic breast cancer patients.
      • Kalash R
      • Iarrobino NA
      • Beriwal S
      • Sun M
      • Glaser SM
      • Champ CE.
      Palbociclib enhances pulmonary fibrosis in patients undergoing thoracic radiation therapy: A case series and review of the literature.
      • Chowdhary M
      • Sen N
      • Chowdhary A
      • et al.
      Safety and efficacy of palbociclib and radiation therapy in patients with metastatic breast cancer: Initial results of a novel combination.
      • Ippolito E
      • Greco C
      • Silipigni S
      • et al.
      Concurrent radiotherapy with palbociclib or ribociclib for metastatic breast cancer patients: Preliminary assessment of toxicity.
      • Messer JA
      • Ekinci E
      • Patel TA
      • Teh BS.
      Enhanced dermatologic toxicity following concurrent treatment with palbociclib and radiation therapy: A case report.
      • Kim KN
      • Shah P
      • Clark A
      • et al.
      Safety of cyclin-dependent kinase4/6 inhibitor combined with palliative radiotherapy in patients with metastatic breast cancer.
      exist on the use of CDK4/6 inhibitors (Supplementary Materials; Appendix 6) in combination with RT. Beddock et al
      • Beddok A
      • Xu HP
      • Henry AA
      • et al.
      Concurrent use of palbociclib and radiation therapy: Single-centre experience and review of the literature.
      evaluated the combination of palbociclib and RT in patients with metastatic breast cancer. Palliative metastases were treated with standard palliative regimens to 17 vertebral body metastases, 7 peripheral bone metastases, and 1 choroidal metastasis. One patient had CTCAE grade 3 pain after radiation, and 2 patients needed to stop palbociclib during RT due to CTCAE grade 3 dermatitis and CTCAE grade 2 dysphagia. No late toxicity was described. In 3 patients with metastatic breast cancer treated with palliative lung RT (20 Gy in 5 fr) concurrently with palbociclib, 2 patients developed radiation pneumonitis refractory to corticosteroids and all developed pulmonary fibrosis.
      • Hans S
      • Cottu P
      • Kirova YM.
      Preliminary results of the association of palbociclib and radiotherapy in metastatic breast cancer patients.
      Norman et al
      • Norman H
      • Lee KT
      • Stearns V
      • Alcorn SR
      • Mangini NS.
      Incidence and severity of myelosuppression with palbociclib after palliative bone radiation in advanced breast cancer: A single center experience and review of literature.
      demonstrated higher CTCAE grade 3 lymphopenia during cycle 1 of palbociclib in patients with breast cancer receiving 20 to 30 Gy in 5 to 10 fr RT within 1 year of palbociclib; patients who received 10 fr were more likely to have cycle 1 interrupted than those receiving shorter radiation courses.
      A single-center retrospective study
      • Guerini AE
      • Pedretti S
      • Salah E
      • et al.
      A single-center retrospective safety analysis of cyclin-dependent kinase 4/6 inhibitors concurrent with radiation therapy in metastatic breast cancer patients.
      was published on the use of concomitant palbociclib (50%), ribociclib (33%), and abemaciclib (17%) with multisite palliative RT in patients with metastatic breast cancer. RT was mostly well tolerated, with 1 patient who received 30 Gy in 10 fr to the pelvis developing a CTCAE grade 3 ileitis requiring hospitalization. The patient subsequently recovered. Two other cases of CTCAE grade 3 colitis were reported with concomitant palbociclib and 30 Gy in 10 fr to the pelvis.
      • Ratosa I
      • Orazem M
      • Scoccimarro E
      • et al.
      Cyclin-dependent kinase 4/6 inhibitors combined with radiotherapy for patients with metastatic breast cancer.
      ,
      • Dasgupta A
      • Sahgal A
      • Warner E
      • Czarnota GJ.
      Safety of palbociclib concurrent with palliative pelvic radiotherapy: Discussion of a case of increased toxicity and brief review of literature.
      Interestingly, Lee et al
      • Lee C-L
      • Oh P
      • Xu ES
      • et al.
      Blocking cyclin-dependent kinase 4/6 during single dose versus fractionated radiation therapy leads to opposite effects on acute gastrointestinal toxicity in mice.
      reported that due to higher surviving crypts in the small intestine, a protective GI effect of CDK4/6 inhibitors was found when delivered before a single fr of RT compared to fractionated RT, which led to an increased risk of GI toxicity.

      Summary and suggested toxicity mitigation strategies

      Based on the limited, largely retrospective data available, stopping CDK 4 to 6 inhibitor 3 days before and after radiation is suggested.

      Immune checkpoint inhibitors: Cytotoxic T-lymphocyte-associated protein-4, PD-1, and PD-L1 inhibitors

      Immune checkpoint inhibitors work to remove inhibitory signals between tumor cells and T- cells, igniting an immune response. Cytotoxic T-lymphocyte-associated protein-4 inhibitors, such as ipilimumab, are thought to act early in the immune cycle and primarily in lymph nodes. Furthermore, cytotoxic T-lymphocyte-associated protein-4 inhibitors are believed to remove immunosuppressive molecules such as T-regulatory cells.
      • Hwang WL
      • Pike LRG
      • Royce TJ
      • Mahal BA
      • Loeffler JS.
      Safety of combining radiotherapy with immune-checkpoint inhibition.
      The t½ for ipilimumab, nivolumab, and pembrolizumab is 15.4, 25, and 22 days, respectively.

      Lexi-Drugs. Lexicomp app. UpToDate Inc. Accessed August 12, 2022.

      PD-L-1 inhibitors such as durvalumab, atezolizumab, and avelumab have a t½ of 18, 27, and 6.1 days, respectively

      Lexi-Drugs. Lexicomp app. UpToDate Inc. Accessed August 12, 2022.

      (Supplementary Materials; Appendix 7).
      Immunotherapy appears generally safe with minimal side effects reported in patients who received conventionally fractionated RT in combination with durvalumab
      • Antonia SJ
      • Villegas A
      • Daniel D
      • et al.
      Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer.
      (pneumonitis), pembrolizumab,
      • Shaverdian N
      • Lisberg AE
      • Bornazyan K
      • et al.
      Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: A secondary analysis of the KEYNOTE-001 phase 1 trial.
      ,
      • Hwang WL
      • Niemierko A
      • Hwang KL
      • et al.
      Clinical outcomes in patients with metastatic lung cancer treated with PD-1/PD-L1 inhibitors and thoracic radiotherapy.
      and nivolumab
      • Peters S
      • Felip E
      • Dafni U
      • et al.
      Progression-free and overall survival for concurrent nivolumab with standard concurrent chemoradiotherapy in locally advanced stage IIIA-B NSCLC: Results from the European Thoracic Oncology Platform NICOLAS Phase II Trial (European Thoracic Oncology Plat).
      (pneumonitis, esophageal fistulation).
      Luke et al
      • Luke JJ
      • Lemons JM
      • Karrison TG
      • et al.
      Safety and clinical activity of pembrolizumab and multisite stereotactic body radiotherapy in patients with advanced solid tumors.
      described a 10% incidence of CTACE grade 3 or more radiation-related toxicities in a phase I study of patients who received pembrolizumab within 7 days of SBRT. Three CTCAE grade 3 pneumonitis, 2 CTCAE grade 3 colitis, and 1 CTCAE grade 3 hepatic toxicity all within the radiation field were reported. In the setting of metastatic NSCLC, a phase 1 trial
      • Mattes MD
      • Eubank TD
      • Almubarak M
      • et al.
      A prospective trial evaluating the safety and systemic response from the concurrent use of radiation therapy with checkpoint inhibitor immunotherapy in metastatic non-small cell lung cancer.
      and PEMBRO-RT
      • Theelen WSME
      • Peulen HMU
      • Lalezari F
      • et al.
      Effect of pembrolizumab after stereotactic body radiotherapy vs pembrolizumab alone on tumor response in patients with advanced non-small cell lung cancer: Results of the PEMBRO-RT phase 2 randomized clinical trial.
      suggested that combining RT with pembrolizumab was well tolerated. One patient developed a nephritis post-SBRT to a retroperitoneal lesion, which was close to the kidney, after a third course of pembrolizumab, and another patient developed a vertebral body compression fracture post spine SBRT. Ho et al
      • Ho AY
      • Barker CA
      • Arnold BB
      • et al.
      A phase 2 clinical trial assessing theefficacy and safety of pembrolizumab and radiotherapy in patients with metastatic triple-negative breast cancer.
      al\220 in the reference list as and re-number the references in the reference list and in the text citation - Ho AY, Barker CA, Arnold BB, et al. A phase 2 clinical trialassessing theefficacy and safety of pembrolizumab and radiotherapy in patients with metastatic triple-negative breast cancer. Cancer. 2020;126:850-860."?>, in a similar phase II trial, using SBRT (30 Gy in 5 fr) concomitant with pembrolizumab to treat a patient with metastatic triple negative breast cancer, reported tolerable adverse effects with no CTCAE grade 3 or higher toxicities. A recent phase 2 trial of palliative RT (30 Gy in 10 fr) to the esophagus delivered concomitantly with pembrolizumab showed 1 CTCAE grade 3 diarrhea and 1 CTCAE grade 4 enterocolitis that required discontinuation of treatment.
      • Chao J
      • He T-F
      • D'Apuzzo M
      • et al.
      A phase 2 trial combining pembrolizumab and palliative radiation therapy in gastroesophageal cancer to augment abscopal immune responses.
      In addition to the many retrospective studies,
      • Barker CA
      • Postow MA
      • Khan SA
      • et al.
      Concurrent radiotherapy and ipilimumab immunotherapy for patients with melanoma.
      • Liniker E
      • Menzies AM
      • Kong BY
      • et al.
      Activity and safety of radiotherapy with anti-PD-1 drug therapy in patients with metastatic melanoma.
      • Qin R
      • Olson A
      • Singh B
      • et al.
      Safety and efficacy of radiation therapy in advanced melanoma patients treated with ipilimumab.
      • Bang A
      • Wilhite TJ
      • Pike LRG
      • et al.
      Multicenter evaluation of the tolerability of combined treatment with PD-1 and CTLA-4 immune checkpoint inhibitors and palliative radiation therapy.
      • Postow MA
      • Knox SJ
      • Goldman DA
      • et al.
      A prospective, phase 1 trial of nivolumab, ipilimumab, and radiotherapy in patients with advanced melanoma.
      4 prospective studies evaluated palliative RT with ipilimumab and described a rate of 14% to 34% of CTACE grade 3 or higher toxicities,
      • Hiniker SM
      • Reddy SA
      • Maecker HT
      • et al.
      A prospective clinical trial combining radiation therapy with systemic immunotherapy in metastatic melanoma.
      • Kwon ED
      • Drake CG
      • Scher HI
      • et al.
      Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): A multicentre, randomised, double-blind, phase 3 trial.
      • Tang C
      • Welsh JW
      • de Groot P
      • et al.
      Ipilimumab with stereotactic ablative radiation therapy: Phase I results and immunologic correlates from peripheral T cells.
      • Welsh JW
      • Tang C
      • de Groot P
      • et al.
      Phase II trial of ipilimumab with stereotactic radiation therapy for metastatic disease: Outcomes, toxicities, and low-dose radiation-related abscopal responses.
      similar to drug-related toxicities only in other studies. An incidence of 1% CTCAE grade 5 immune-related bowel perforation was reported in a Kwon et al
      • Kwon ED
      • Drake CG
      • Scher HI
      • et al.
      Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): A multicentre, randomised, double-blind, phase 3 trial.
      phase III trial that studied ipilimumab versus placebo within 2 days before RT in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy. It was not associated with patients who received pelvic RT, and toxicity rates were again all consistent with published drug-only treatment literature.

      Bristol-Myers. Yervoy (ipilimumab) package insert. Available at: http://packageinserts.bms.com/pi/pi_yervoy.pdf. Accessed August 17, 2021.

      In the metastatic setting, nivolumab with moderate and ultrahypofractionation appears to be safe, with less than 13% CTCAE grade 3 toxicities reported in several studies and no grade 4 to 5 toxicities.
      • Postow MA
      • Knox SJ
      • Goldman DA
      • et al.
      A prospective, phase 1 trial of nivolumab, ipilimumab, and radiotherapy in patients with advanced melanoma.
      ,
      • Fiorica F
      • Belluomini L
      • Stefanelli A
      • et al.
      Immune checkpoint inhibitor nivolumab and radiotherapy in pretreated lung cancer patients: Efficacy and safety of combination.
      • Amin NP
      • Zainib M
      • Parker SM
      • Agarwal M
      • Mattes MD.
      Multi-institutional report on toxicities of concurrent nivolumab and radiation therapy.
      • McBride 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.
      • 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.
      With a median follow-up of 10 months, similar radiation pneumonitis rates were reported when immune checkpoint inhibitors were given within a year of palliative RT (30 Gy in 10 fr) to the thorax.
      • Saito S
      • Abe T
      • Iino M
      • et al.
      Incidence and risk factors for pneumonitis among patients with lung cancer who received immune checkpoint inhibitors after palliative thoracic radiotherapy.
      Interestingly, 2 cases of radiation recall pneumonitis have been reported up to 2 years after radiation with nivolumab.
      • Shibaki R
      • Akamatsu H
      • Fujimoto M
      • Koh Y
      • Yamamoto N.
      Nivolumab induced radiation recall pneumonitis after two years of radiotherapy.

      Summary and suggested toxicity mitigation strategies

      Several studies have reported that the combination of immunotherapy and palliative/hypofractionated RT has a potentially positive synergistic effect, while also suggesting safety in this setting. Data exist suggesting the safety of stopping ipilimumab within 2 days of single fr (8Gy) RT to the bone. However, caution should be considered for other immunotherapy agents that are less well described, with particular attention recommended when considering the RT field of treatment (eg, lungs, abdomen).

      HER2 target therapies: Trastuzumab and pertuzumab

      Trastuzumab is a humanized recombinant monoclonal antibody binding the extracellular domain of HER2 receptors that are currently used with breast cancer. Pertuzumab is a recombinant humanized Immunoglobulin G antibody that blocks dimerization receptors and thereby HER2-dependent signaling pathways.
      • Levêque D
      • Gigou L
      • Bergerat JP.
      Clinical pharmacology of trastuzumab.
      Estimated half-life is 28113 and 18 days,

      Lexi-Drugs. Lexicomp app. UpToDate Inc. Accessed August 12, 2022.

      respectively.
      As the first anti-HER2 molecule used in clinical practice, much data exist on the safety and toxicity of combining trastuzumab and conventional RT, specifically with breast
      • Ajgal Z
      • de Percin S
      • Dieras V
      • et al.
      Combination of radiotherapy and double blockade HER2 with pertuzumab and trastuzumab for HER2-positive metastatic or locally recurrent unresectable and/or metastatic breast cancer: Assessment of early toxicity.
      • Advani PP
      • Ballman KV
      • Dockter TJ
      • Colon-Otero G
      • Perez EA.
      Long-term cardiac safety analysis of NCCTG N9831 (Alliance) adjuvant trastuzumab trial.
      • Ganz PA
      • Romond EH
      • Cecchini RS
      • et al.
      Long-term follow-up of cardiac function and quality of life for patients in NSABP protocol B-31/NRG oncology: A randomized trial comparing the safety and efficacy of doxorubicin and cyclophosphamide (AC) followed by paclitaxel with AC followed by paclitax.
      • Horton JK
      • Halle J
      • Ferraro M
      • et al.
      Radiosensitization of chemotherapy-refractory, locally advanced or locally recurrent breast cancer with trastuzumab: A phase II trial.
      • Dackus GMHE
      • Jóźwiak K
      • van der Wall E
      • et al.
      Concurrent versus sequential use of trastuzumab and chemotherapy in early HER2+ breast cancer.
      • Jacob J
      • Belin L
      • Pierga JY
      • et al.
      Concurrent administration of trastuzumab with locoregional breast radiotherapy: Long-term results of a prospective study.
      • Halyard MY
      • Pisansky TM
      • Dueck AC
      • et al.
      Radiotherapy and adjuvant trastuzumab in operable breast cancer: Tolerability and adverse event data from the NCCTG phase III trial N9831.
      and esophagus.
      • Safran H
      • Dipetrillo T
      • Akerman P
      • et al.
      Phase I/II study of trastuzumab, paclitaxel, cisplatin and radiation for locally advanced, HER2 overexpressing, esophageal adenocarcinoma.
      ,
      • Safran H
      • Winter KA
      • Wigle DA
      • et al.
      Trastuzumab with trimodality treatment for esophageal adenocarcinoma with HER2 overexpression: NRG Oncology/RTOG 1010.
      Hypofractionation up to 42.4 Gy in 16 fr appears safe based on retrospective study.
      • De Santis MC
      • Bonfantini F
      • Di Salvo F
      • et al.
      Trastuzumab and hypofractionated whole breast radiotherapy: A victorious combination?.
      To the best of our knowledge, there are no current data describing the combination of ultrahypofractionated breast RT with trastuzumab.
      One case report
      • Katz DA
      • Abrams RA
      • Sclamberg JS
      • Usha L.
      Radiosensitizing effect of anti-HER2/neu agents: Report of 2 cases and review of the literature.
      in the literature described a CTCAE grade 3 radiation enteritis after palliative moderately fractionated radiation with HER2 target therapy in a patient with metastatic breast cancer who was treated to the fifth lumbar vertebra and left hip. The patient developed greater than expected radiation gastroenteritis after 24 Gy in a 30 Gy plan. Another grade 3 gastroenteritis was described 1 month after 50.4 Gy in 28 fractions to a pancreas metastasis from a breast cancer.
      • Katz DA
      • Abrams RA
      • Sclamberg JS
      • Usha L.
      Radiosensitizing effect of anti-HER2/neu agents: Report of 2 cases and review of the literature.
      Only 1 retrospective study evaluated trastuzumab plus pertuzumab with concomitant RT in metastatic breast cancer.
      • Ajgal Z
      • de Percin S
      • Dieras V
      • et al.
      Combination of radiotherapy and double blockade HER2 with pertuzumab and trastuzumab for HER2-positive metastatic or locally recurrent unresectable and/or metastatic breast cancer: Assessment of early toxicity.
      With palliative dose, 1 patient treated with 15 Gy in 5 fr to thoracic vertebra level 8 to 11 developed an asymptomatic decrease of left ventricular ejection fraction (below 50%) 8 months after RT (heart mean dose 4.46 Gy). This patient also had other risk factors: previous right-side breast/locoregional RT and they had received epirubicin. The HER2 regimen was stopped for 3 months, and the patient recovered. Other CTCAE grade 3 toxicities described in this paper where when higher conventionally fractionated doses were used (Supplementary Materials; Appendix 9).

      Summary and suggested toxicity mitigation strategies

      Trastuzumab may be delivered concurrently with radiation, with attention to heart dosimetry suggested. Pertuzumab is often used in combination with trastuzumab, and toxicity rate associated with radiation appear similar, but limited data exist.

      Lapatinib

      Lapatinib is a TKI that acts as a reversible inhibitor of the phosphorylation in the intracellular domain of the HER1/HER2 and downstream receptors. It has a t½ of 24 hours.

      Lexi-Drugs. Lexicomp app. UpToDate Inc. Accessed August 12, 2022.

      There are little data reporting toxicity outcomes when combining lapatinib with hypofractionated RT. A number of phase I and II studies using conventionally fractionated RT have most commonly reported dermatologic side effects only.
      • Kimple RJ
      • Horton JK
      • Livasy CA
      • et al.
      Phase I study and biomarker analysis of lapatinib and concurrent radiation for locally advanced breast cancer.
      • Shepard G
      • Arrowsmith ER
      • Murphy P
      • et al.
      A phase II study with lead-in safety cohort of 5-fluorouracil, oxaliplatin, and lapatinib in combination with radiation therapy as neoadjuvant treatment for patients with localized HER2-positive esophagogastric adenocarcinomas.
      • Harrington K
      • Berrier A
      • Robinson M
      • et al.
      Randomised phase II study of oral lapatinib combined with chemoradiotherapy in patients with advanced squamous cell carcinoma of the head and neck: Rationale for future randomised trials in human papilloma virus-negative disease.
      • Harrington K
      • Temam S
      • Mehanna H
      • et al.
      Postoperative adjuvant lapatinib and concurrent chemoradiotherapy followed by maintenance lapatinib monotherapy in high-risk patients with resected squamous cell carcinoma of the head and neck: A phase III, randomized, double-blind, placebo-controlled study.

      Summary and suggested toxicity mitigation strategies

      To the best of our knowledge, there are no data reporting lapatinib being used in combination with hypofractionated or palliative RT, and the use of the half-life of lapatinib is suggested until further data become available to mitigate potential side effects.

      T-DM1

      Trastuzumab emtansine (T-DM1) is a systemic therapy combining trastuzumab with mertansine that inhibits mitosis, with a half-life of 3.5 days,

      Lexi-Drugs. Lexicomp app. UpToDate Inc. Accessed August 12, 2022.

      most commonly used in HER2-positive breast cancer.
      The majority of existing data are from when T-DM1 is combined with conventionally fractionated RT.
      • Krop IE
      • Suter TM
      • Dang CT
      • et al.
      Feasibility and cardiac safety of trastuzumab emtansine after anthracycline-based chemotherapy as (neo)adjuvant therapy for human epidermal growth factor receptor 2-positive early-stage breast cancer.
      • von Minckwitz G
      • Huang C-S
      • Mano MS
      • et al.
      Trastuzumab emtansine for residual invasive HER2-positive breast cancer.
      • Corbin KS
      • Breen WG
      • Strauss JB.
      Radiation dermatitis in patients treated with concurrent trastuzumab emtansine (T-DM1).
      • Loibl S
      • Huang C-S
      • Mano MS
      • et al.
      96O Adjuvant trastuzumab emtansine (T-DM1) vs trastuzumab (T) in patients (pts) with residual invasive disease after neoadjuvant therapy for HER2+ breast cancer: Subgroup analysis from KATHERINE.
      • Zolcsák Z
      • Loirat D
      • Fourquet A
      • Kirova YM.
      Adjuvant trastuzumab emtansine (T-DM1) and concurrent radiotherapy for residual invasive HER2-positive breast cancer: Single-center preliminary results.
      Side effects reported in this setting are minimal (radiation dermatitis, pneumonitis, and cardiac toxicities), and safety has been reported when administrated with concurrent RT in a recent systemic review.
      • Piroth MD
      • Krug D
      • Sedlmayer F
      • et al.
      Post-neoadjuvant treatment with capecitabine and trastuzumab emtansine in breast cancer patients-sequentially, or better simultaneously?.

      Summary and suggested toxicity mitigation strategies

      Limited data exist for patients receiving palliative RT concurrently with T-DM1. Combination with conventional fractionation appears safe.

      Discussion

      Limited data exist assessing the safety and tolerability of combined palliative RT regimens in patients with metastatic disease receiving systemic, immune, and targeted therapies, as summarized in this review. There is also a lack of reported RT data, with very few studies detailing normal tissue dose volume histograms, planning parameters, and delivered dose, limiting more sensitive analysis. Furthermore, much of the published data used a combination of systemic therapies (vs mono-therapy), making it difficult to establish the cause and effect of therapies alone or in combination. Reporting bias is reflected by only published data being available for review, and real-time clinical data may not be reflected accurately.
      Deciding on an appropriate washout period requires consultation with the multidisciplinary team, including medical oncology, to determine the risk/benefit ratio in continuing systemic therapies, especially in the setting of urgent or emergency palliative RT and patients with oligo-progressive disease on continuous systemic therapy.

      Conclusions

      There is an urgent need for further prospective data reporting the safety, efficacy, and ideal timing of concurrent systemic, targeted, and immune therapies with moderate and ultrahypofractionated RT in the palliative setting.

      Appendix. Supplementary materials

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