
==== Front
Adv Radiat Oncol
Adv Radiat Oncol
Advances in Radiation Oncology
2452-1094
Elsevier

S2452-1094(24)00139-8
10.1016/j.adro.2024.101576
101576
Teaching Case
Delayed Radiation Recall in Patients Receiving Cabozantinib: A Case Report and Review of the Literature
Miljanic Mihailo MD mihailo.miljanic@utsouthwestern.edu
a⁎
Vujovic Dragan BS b
Song Tidie BS c
Adams Chase BS d
Tucakovic Aleksandra e
Goswami Avishek MBBS f
Kumar Kiran MD, MBA a
a Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas
b Mount Sinai Icahn School of Medicine, New York, New York
c University of Texas Southwestern Medical School, Dallas, Texas
d Tulane Medical School, New Orleans, Louisiana
e University of Georgia, Athens, Georgia
f Kastarba Medical College, Manipal, India
⁎ Corresponding author: Mihailo Miljanic, MD mihailo.miljanic@utsouthwestern.edu
18 7 2024
9 2024
18 7 2024
9 9 10157625 1 2024
25 4 2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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pmcCase Report

A 54-year-old gentleman with a history of stage IV renal cell carcinoma of left kidney origin and no significant comorbidities originally received diagnosis in 2013 and was initially treated with left radical nephrectomy, 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 September 29, 2019, with multiple involved sites, including right and left ribs, left adrenal gland, and C5/C6 spine. Specifically, a computed tomography of the neck was performed on September 29, 2019, showing a mass involving the body and posterior elements of C6 with associated pathologic compression fracture. He underwent a C5/C6 laminectomy and C2 to T2 posterior spinal fusion on October 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 Gy in 5 fractions, as well as a right posterior chest wall metastatic site treated with 20 Gy in 5 fractions on January 06, 2020. The planning target volume was cropped 3 mm 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 therapy course.

Owing to progression on ipilimumab and nivolumab systemic therapy, he was placed on second-line cabozantinib targeted therapy on March 27, 2020, 3 months after his palliative radiation, with 1 site of progression thereafter in the lumbar spine, which was treated with stereotactic body radiation therapy with 25 Gy in 1 fraction, for which he completed treatment on July 01, 2020. Otherwise, his disease remained stable while receiving cabozantinib therapy, until he was seen in the emergency room on December 30, 2021, with a magnetic resonance imaging of the spine demonstrating marked kyphosis developing in the C5 to C7 spine with severe spinal canal stenosis and impending cord compression. Owing to concern for progression, his cabozantinib therapy dosage was increased from 40 mg daily to 60 mg daily on December 30, 2021. Directly following this increase in dosage, he was admitted on February 01, 2022, to the emergency room because of development of a large cervical spine wound and exposed spinous process with no other known inciting cause (Fig. 1A). He was immediately taken to the operating room with spine surgical teams for wound incision and drainage and vacuum placement on February 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 February 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 (Fig. 1B). Notably, tissue pathology following incision and drainage on February 01, 2022, demonstrated fibrotic muscle and devitalized tissue with no malignancy or necrotizing fasciitis present, with wound cultures returning no positive organism growth.Figure 1 Presentation of delayed radiation recall skin and tissue devitalization. (A) Initial presentation on February 1, 2022. (B) Follow-up appointment on March 17, 2022.

Figure 1

Following an outcome with significant toxicity as in the above case, this was discussed at multidisciplinary tumor board and mortality and morbidity conference among field experts, with evaluation showing necrosis and devitalized tissue only in the distribution of the previously given radiation field (Fig. 2). With radiation to the C4 to T1 spine delivered and completed on January 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 irradiated tissue demonstrates increased toxicity following systemic therapy administration with this drug even after completion of radiation therapy. 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, to our knowledge, 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.Figure 2 Radiation field delivered and completed on January 13, 2020, to the C1 to T4 spine.

Figure 2

Discussion and Review of the Literature

Radiation recall reactions are an uncommon phenomenon characterized by a severe localized inflammatory response after radiation therapy 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, although 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, although it is 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 multityrosine kinase inhibitor with 3 main targets that include vascular endothelial growth factor, mesenchymal-epithelial transition, and the AXL protein. These targets normally drive angiogenesis in a tumor and propagate metastasis by 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 protein.3

Several studies have implicated tyrosine kinase inhibitors with radiation recall effect including sunitinib and sorafenib.4,5 However, to date, radiation recall with cabozantinib treatment has only been described in 1 previous report. Kumar et al6 described a case of cabozantinib-induced dermatitis, although 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 National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 grade 4 event, indicating that cabozantinib can indeed precipitate severe skin radiation recall reactions when administrated after radiation treatments.

Boxtel et al7 described a phase II clinical trial of cabozantinib in patients with salivary gland cancer, which closed prematurely because of drug-induced wound complications associated with this medication, particularly in previously irradiated cases.7 One patient in this study developed severe ulcerating wounds in their neck that took over 1 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 with the standard doses used for definitive salivary gland carcinoma treatment (20-25 Gy vs ≥66 Gy, respectively).

Although 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 radiation therapy yield more vulnerable cells that cannot tolerate cytotoxic treatment thereafter, and (3) a vascular reaction that may occur after radiation therapy resulting in primed tissue for toxicity following drug administration. Cabozantinib has only been previously reported once in the literature because it relates to radiation recall events; however, this medication does have a known effect on impaired wound healing because of its action on the vascular endothelial growth factor receptor.8 Additionally, cabozantinib differs from the other tyrosine kinase inhibitors because it inhibits c-mesenchymal-epithelial transition and AXL, both of 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. Although 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.

Although radiation recall reactions have been reported on rather extensively because they relate to chemotherapy agents,1 no previous reports have reviewed and assessed radiation recall reactions precipitated by targeted agents in detail as shown in Table 1.6,9, 10, 11, 12, 13, 14 Here, we highlight that in the literature, to date, there has been 1 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 3 previous reports, all of which have led to grade 2 dermatitis events.9, 10, 11 The multikinase inhibitor sorafenib has also demonstrated the ability to induce multiple radiation recall reactions, all of which have involved grade 1 to 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 to 2 dermatitis reactions that are generally self-limited (Table 1). Yet, with cabozantinib, both radiation recall reactions have resulted in severe skin toxicity leading to necrosis6Table 1 Summary characteristics of radiation recall events reported in the literature following administration of targeted systemic therapy

Table 1Reference	Year published	Patient gender	Patient primary disease	Systemic agent	Radiation course and location	Toxicity type	Toxicity grade	
Miljanic et al	2024	Male	Renal cell carcinoma	Cabozantinib	Neck: 30 Gy in 10 fractions	Neck skin necrosis	4	
Kumar et al6	2019	Male	Renal cell carcinoma	Cabozantinib	Neck: Regimen not described	Neck skin necrosis	4	
Yilmaz et al	2020	Male	Melanoma	Dabrafenib and Trametinib	Right leg: 20 Gy in 10 fractions	Leg dermatitis	2	
Awad et al	2016	Male	Non-small cell lung cancer	Erlotinib	Lung: 30 Gy in 12 fractions	Pneumonitis	2	
Varan et al	2022	Female	Synovial sarcoma	Pazopanib	Right thigh: 60 Gy in 30 fractions	Thigh myositis	3	
Stieb et al12	2016	Male	Hepatocellular carcinoma	Sorafenib	Right arm and trunk: 20-36 Gy in 5-12 fractions	Right arm and Trunk Dermatitis	2	
Conen et al9	2014	Male	Melanoma	Vemurafenib	Axillary lymph nodes: 35 Gy in 5 fractions	Left chest dermatitis	2	
Erjan et al	2021	Female	Breast carcinoma	Ribociclib	Chest: 37.5 Gy in 5 fractions	Chest wall dermatitis	2	
Greliak et al10	2019	Male	Melanoma	Vemurafenib	Face and neck: 66 Gy in 33 fractions	Neck dermatitis	2	
Mehta et al13	2018	Male	Hepatocellular carcinoma	Sorafenib	Right forearm: 30 Gy in 10 Fractions	Right arm dermatitis	1	
Braunstein et al11	2014	Male	Melanoma	Vemurafenib	Left neck: 71 Gy in 38 fractions	Neck dermatitis	2	
Yuasa et al	2013	Male	Renal cell carcinoma	Sunitinib	Thoracic vertebrae (T5-T8): 24 Gy in 6 fractions	Pneumonitis	2	
Hsieh et al14	2014	Male	Hepatocellular carcinoma	Sorafenib	Liver: 48 Gy in 6 fractions	Right flank dermatitis	2	
Miya et al	2003	Male	Large cell carcinoma	Gefitinib	Mediastinum: Regimen not described	Pneumonitis	2	
Clark et al	2014	Female	Clear cell carcinoma	Everolimus	Lung: 39 Gy in 13 fractions	Pneumonitis	3	
Azad et al	2013	Male	Renal cell carcinoma	Pazopanib	T9 and right humerus: 30 Gy in 10 fractions	Thoracic back and right arm dermatitis	3	

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 before 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 a 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 on observation of a severe skin reaction in a previously irradiated area.

Disclosures

None.

Sources of support: No financial support or funding was received for this manuscript submission. Research Data: Research data are not available at this time.
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References

1 Burris HA III Hurtig J Radiation recall with anticancer agents The Oncologist 15 2010 1227 1237 21045191
2 Jamaluddin MF Abraham AG Menon G Nakatsui T Roa W. Recurrent radiation recall dermatitis 40 years after radiation therapy for breast cancer Breast J 27 2021 543 546 33763948
3 Choueiri TK Escudier B Powles T Cabozantinib versus everolimus in advanced renal-cell carcinoma N Engl J Med 373 2015 1814 1823 26406150
4 Chung C Dawson LA Joshua AM Brade AM. Radiation recall dermatitis triggered by multi-targeted tyrosine kinase inhibitors: sunitinib and sorafenib Anticancer Drugs 21 2010 206 209 19952730
5 Mehta K Kaubisch A Tang J Pirlamarla A Kalnicki S. Radiation recall dermatitis in patients treated with sorafenib Case Rep Oncol Med 2018 2018 2171062
6 Kumar V Meghal T Wu E Huang Y. Radiation recall dermatitis consecutive to cabozantinib use Am J Ther 26 2019 e559 e561 28816724
7 van Boxtel W Uijen MJM Krens SD Excessive toxicity of cabozantinib in a phase II study in patients with recurrent and/or metastatic salivary gland cancer Eur J Cancer 161 2022 128 137 34920917
8 Lyseng-Williamson KA. Cabozantinib as first-line treatment in advanced renal cell carcinoma: a profile of its use Drugs Ther Perspect 34 2018 457 465 30679901
9 Conen K Mosna-Firlejczyk K Rochlitz C Vemurafenib-induced radiation recall dermatitis: case report and review of the literature Dermatology (Basel, Switzerland) 230 2015 1 4 25472806
10 Greliak A Le Guern A Bataille M Lebas D Wiart T Modiano P Dermite de rappel induite par le vémurafénib [Vemurafenib-induced radiation recall dermatitis] Annales de dermatologie et de venereology 146 2019 382 384
11 Braunstein I Gangadhar TC Elenitsas R Chu EY. Vemurafenib-induced interface dermatitis manifesting as radiation-recall and a keratosis pilaris-like eruption J Cutan Pathol 41 2014 539 543 24517243
12 Stieb S Riesterer O Brüssow C Pestalozzi B Guckenberger M Weiler S. Radiation recall dermatitis induced by sorafenib: A case study and review of the literature Strahlenther Onkol 192 2016 342 348 26907093
13 Mehta K Kaubisch A Tang J Pirlamarla A Kalnicki S. Radiation recall dermatitis in patients treated with sorafenib Case Rep Oncol Med 2018 2018 2171062
14 Hsieh C-H Lin S-C Shueng P-W Kuo D-Y. Recall radiation dermatitis by sorafenib following stereotactic body radiation therapy Onco Targets Ther 7 2014 1111 1114 24971021
