Delayed Radiation Recall in patients receiving Cabozantinib – A Case Report and Review of the Literature

Case Report A 54 year-old gentleman with a history of Stage IV renal cell carcinoma (RCC) of left kidney origin and no significant comorbidities was originally diagnosed in 2013 and initially treated with left radical nephrectomy at that time revealing a 3.8×3.6 cm clear cell renal cell tumor of the left kidney. He unfortunately presented to our clinic with progression to metastatic disease on 09/29/2019 with multiple involved sites including right and left ribs, left adrenal gland, and C5/C6 spine. Specifically, a CT Neck was performed on 09/29/2019 showing a mass involving the body and posterior elements of C6 with associated pathologic compression fracture. He had a C5/C6 laminectomy and C2-T2 posterior spinal fusion performed on 10/01/2019 following these results, and received Ipilimumab/Nivolumab systemic immunotherapy for 4 cycles. He had multiple metastatic sites treated with palliative radiation including the C4 through T1 spine treated with 20 Gray (Gy) in 5 fractions, as well as a right posterior chest wall metastatic site treated with 20 Gy in 5 fractions on 01/06/2020. The planning target volume (PTV) was cropped 3 millimeters off of the skin in planning, and the patient tolerated his course well with no dermatitis or significant toxicities noted after completion of his radiation course. Due to progression on Ipilimumab and Nivolumab systemic therapy, he was placed on 2nd line Cabozantinib targeted therapy on 3/27/2020 three months after his palliative radiation, with one site of progression thereafter in the lumbar spine which was treated with Stereotactic Body Radiation Therapy (SBRT) with 25 Gy in 1 fraction, for which he completed treatment on 07/01/2020. Otherwise, his disease remained stable while on Cabozantinib therapy, until he is seen in the emergency room on 12/30/2021 with an MRI of the spine at that time demonstrating marked kyphosis developing in the C5-C7 spine with severe spinal canal stenosis and impending cord compression. Due to concern for progression, his Cabozantinib therapy is increased from 40 mg daily to 60 mg daily on 12/30/2021. Directly following this increase in dosage, he is admitted on 02/01/2022 to the emergency room due to development of a large cervical spine wound and exposed spinous process with no other known inciting cause (Figure 1A). He was immediately taken to the operating room with spine surgical teams for wound incision and drainage and vacuum placement on 02/02/2022 revealing devitalized tissue, exposed bone, and no obvious purulence or signs of remaining malignancy on pathology. He returned to the operating room on 02/08/2022 for trapezius rotational flap coverage of the cervical spine wound and halo placement, which was followed by regular wound care and clinically improved wound healing over a period of 6 weeks (Figure 1B). Notably, tissue pathology following incision and drainage on 02/01/2022 demonstrated fibrotic muscle and devitalized tissue with no malignancy or necrotizing fasciitis present, with wound cultures returning no positive organism growth. Following an outcome with significant toxicity as in the above case, this was discussed at multi-disciplinary tumor board and mortality and morbidity conference among field experts, with evaluation showing necrosis and devitalized tissue only in the distribution of the previously give radiation field (Figure 2). With radiation to the C4 to T1 spine delivered and completed on 01/13/2020, there was a significant amount of time in between delivery of treatment and the noted toxicity, however the Cabozantanib dosage increase directly preceded this incident approximately 1 month prior. The patient had no prior history of skin conditions or underlying disorders, and Cabozantanib has been previously shown to cause a radiation recall reaction, whereby previously radiated tissue demonstrates increased toxicity following systemic therapy administration with this drug even after completion of radiation. Following surgical intervention with flap reconstruction, the medication was discontinued and the neck wound healed well over the subsequent 6 months. With the rarity of reported Cabozantinib radiation recall reactions, we present the first known case of a significantly delayed radiation recall reaction with this medication that led to severe toxicity and morbidity years after delivery of an initial radiation course. Radiation recall reactions are an uncommon phenomenon characterized by a severe localized inflammatory response after radiation that can be precipitated by certain medications, including doxorubicin, docetaxel and paclitaxel, and the antimetabolites gemcitabine and capecitabine 1. Most data are derived from case reports – however, observational studies have shown a rate of approximately 8% for radiation recall reactions of any severity. Two-thirds of episodes are skin-related, most are not of a severity that leads to necrosis 1, and events typically resolve spontaneously after discontinuation of the precipitating agent. The majority of radiation recall events are acute, though there have been reports of a delayed radiation recall reaction occurring as late as 40 years after the initial delivery of radiation therapy - indicating that a delayed phenomenon is possible though exceptionally rare 2. Our case illustrates a severe radiation recall event precipitated by Cabozantinib in the significantly delayed setting for a patient treated for Stage IV renal cell carcinoma of left kidney origin. Cabozantinib is a multi-tyrosine kinase inhibitor (TKI) with three main targets that include Vascular Endothelial Growth Factor (VEGF), Mesenchymal Epithelial Transition (MET), and the AXL protein. These targets normally drive angiogenesis in a tumor, and propagate metastasis through inducing motility and invasion of tumor cells. Cabozantinib has been approved as a systemic agent in the metastatic setting for renal cell carcinoma following results of the METEOR Phase III randomized trial demonstrating improved progression free survival in comparison with Everolimus, an inhibitor of mammalian target of rapamycin (mTOR) protein 3. Several studies have implicated TKI's with radiation recall effect including sunitinib and sorafenib 4, 5. However, to date radiation recall with Cabozantinib treatment has only been described in one previous report. Kumar et al. described a case of Cabozantinib induced dermatitis 6 though this toxicity was observed in the acute setting and did not require extensive surgical debridement as in our case. Despite this, it was a significant skin reaction that was rated as CTCAE version 4.0 (CTCAE v4.0) grade 4 event, indicating that Cabozantinib can indeed precipitate severe skin radiation recall reactions when administrated after radiation treatments. Boxtel et al. described a phase II clinical trial of Cabozantinib in patients with salivary gland cancer which closed prematurely due to drug-induced wound complications associated with this medication, particularly in previously irradiated 7. One patient in this study developed severe ulcerating wounds in their neck that took over a year of time to heal. However, it is important to recognize that the dosages used in treatment of metastatic renal cell carcinoma spinal metastases in our patient were dramatically lower compared to the standard doses used for definitive salivary gland carcinoma treatment (20-25 Gy versus ≥66 Gy, respectively). While the mechanism behind radiation recall has not been completely elucidated, there are several postulated mechanisms for its occurrence. These proposed mechanisms include (1) the ability of cytotoxic treatment to induce a remembered reaction in the remaining surviving cells, (2) that mutations caused by the radiotherapy yield more vulnerable cells that cannot tolerate cytotoxic treatment thereafter, and (3) a vascular reaction that may occur after radiotherapy resulting in primed tissue for toxicity following drug administration. Cabozantinib has only been previously reported once in the literature as it relates to radiation recall events, however this medication does have a known effect on impaired wound healing due to its action on the VEGF receptor 8. Additionally, Cabozantinib differs from the other tyrosine kinase inhibitors as it inhibits c-MET and AXL, both which have been implicated in the wound healing pathway 7. This report demonstrates that Cabozantinib can potentiate a previously unknown level of tissue toxicity in radiation recall reactions in the delayed setting, with increased dosage administration leading to significant morbidity. To our knowledge, this is the first case reported of such severe and delayed radiation recall events associated with this medication. While radiation recall events appear to be infrequent with Cabozantinib use, this case demonstrates that such reactions can occur in previously irradiated patients even with a history of prior palliative radiation courses. While radiation recall reactions have been reported on rather extensively as it relates to chemotherapy agents 1 no previous reports have reviewed and assessed radiation recall reactions precipitated by targeted agents in detail as shown in Table 1. Here, we highlight that in the literature to date there has been one previous report of Cabozantinib radiation recall toxicity that also resulted in skin necrosis with grade 4 toxicity 6. Meanwhile, the BRAF inhibitor Vemurafenib has been previously implicated in three previous reports, all of which have led to grade 2 dermatitis events 9,10,11. The multi-kinase inhibitor Sorafenib has also demonstrated the ability to induce multiple radiation recall reactions, all of which have involved grade 1-2 dermatitis 12,13,14. Indeed, the majority of radiation recall reactions precipitated by targeted agents as shown in our review result in grade 1-2 dermatitis reaction that are generally self-limited (Table 1). Yet, with Cabozantinib, both radiation recall reactions have resulted in severe skin toxicity leading to necrosis 6.Table 1Summary Characteristics of Radiation Recall Events Reported in the Literature following Administration of Targeted Systemic TherapyReferenceYearPublishedPatient GenderPatient Primary DiseaseSystemic AgentRadiation Course and LocationToxicityTypeToxicity GradeMiljanic et al.2024MaleRenal Cell CarcinomaCabozantinibNeck: 30 Gray in 10 FractionsNeck Skin Necrosis4Kumar et al.2019MaleRenal Cell CarcinomaCabozantinibNeck: Regimen Not DescribedNeck Skin Necrosis4Yilmazet al.2020MaleMelanomaDabrafenib and TrametinibRight Leg: 20 Gray in 10 FractionsLeg Dermatitis2Awadet al.2016MaleNon-Small Cell Lung CancerErlotinibLung: 30 Gray in 12 FractionsPneumonitis2Varanet al.2022FemaleSynovial SarcomaPazopanibRight Thigh: 60 Gray in 30 FractionsThigh Myositis3Stiebet al.122016MaleHepatocellular CarcinomaSorafenibRight arm and trunk: 20-36 Gray in 5-12 FractionsRight arm and Trunk Dermatitis2Conenet al.92014MaleMelanomaVemurafenibAxillary Lymph Nodes: 35 Gray in 5 FractionsLeft Chest Dermatitis2Erjanet al.2021FemaleBreast CarcinomaRibociclibChest: 37.5 Gray in 5 FractionsChest Wall Dermatitis2Greliaket al.102019MaleMelanomaVemurafenibFace and Neck: 66 Gray in 33 FractionsNeck Dermatitis2Mehta et al.132018MaleHepatocellular CarcinomaSorafenibRight Forearm: 30 Gray in 10 FractionsRight Arm Dermatitis1Braunsteinet al.112014MaleMelanomaVemurafenibLeft Neck: 71 Gray in 38 FractionsNeck Dermatitis2Yuasa et al.2013MaleRenal Cell CarcinomaSunitinibThoracic Vertebrae (T5-8): 24 Gray in 6 FractionsPneumonitis2Hsieh et al.142014MaleHepatocellular CarcinomaSorafenibLiver: 48 Gray in 6 FractionsRight Flank Dermatitis2Miyaet al.2003MaleLarge Cell CarcinomaGefitinibMediastinum: Regimen Not DescribedPneumonitis2Clark et al.2014FemaleClear Cell CarcinomaEverolimusLung: 39 Gray in 13 FractionsPneumonitis3Azad et al.2013MaleRenal Cell CarcinomaPazopanibT9 and Right Humerus: 30 Gray in 10 FractionsThoracic Back and Right Arm Dermatitis3 Open table in a new tab Our case represents one such instance of a severe radiation recall event requiring extensive surgical management, and highlights that Cabozantinib can potentiate a significant level of tissue toxicity in radiation recall reactions with increased dosage administration that may lead to extensive morbidity in patients. As such, this medication warrants careful consideration prior to administration in patients with a previous history of radiation therapy. Based on our experience and analysis of previous radiation recall reactions with Cabozantinib, we recommend detailed review of patient treatment history assessing whether patients have received radiation therapy before initiation of this medication, beginning at an initially reduced dose of 40 mg daily, carefully observing for signs and symptoms of radiation recall in this population, and discontinuing the medication immediately upon observation of a severe skin reaction in a previously irradiated area. Conflicts of Interest No conflicts of interest were present for the preparation and submission of this manuscript for the authors listed. Reference 1. Burris, H.A., III and J. Hurtig, Radiation Recall with Anticancer Agents. The Oncologist, 2010. 15(11): p. 1227-1237. 2. Jamaluddin, M.F., et al., Recurrent radiation recall dermatitis 40 years after radiation therapy for breast cancer. Breast J, 2021. 27(6): p. 543-546. 3. Choueiri, T.K., et al., Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med, 2015. 373(19): p. 1814-23. 4. Chung, C., et al., Radiation recall dermatitis triggered by multi-targeted tyrosine kinase inhibitors: sunitinib and sorafenib. Anticancer Drugs, 2010. 21(2): p. 206-9. 5. Mehta, K., et al., Radiation Recall Dermatitis in Patients Treated with Sorafenib. Case Reports in Oncological Medicine, 2018. 2018: p. 2171062. 6. Kumar, V., et al., Radiation Recall Dermatitis Consecutive to Cabozantinib Use. American Journal of Therapeutics, 2019. 26(4): p. e559-e561. 7. van Boxtel, W., et al., Excessive toxicity of cabozantinib in a phase II study in patients with recurrent and/or metastatic salivary gland cancer. Eur J Cancer, 2022. 161: p. 128-137. 8. 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