Diagnosis of radiation recall hampered by delayed occurrence

MECHANISM OF ACTION

The mechanisms of radiation recall are not yet understood; hypothesized factors include stem cell depletion or acquisition of genetic mutations by stem cells within irradiated volumes, changes in irradiated vasculature, oxidative stress and local DNA damage, up-regulation of drug-specific pathways, and drug hypersensitivity reactions.^1,17 In the case of trastuzumab emtansine (T-DM1)-triggered symptomatic brain edema in patients with brain-metastatic breast cancer who previously underwent stereotactic radiosurgery, it has been hypothesized that radiation up-regulates HER2/neu gene expression, possibly in normal glial cells, increasing subsequent sensitivity to trastuzumab.⁴

Radiation recall is sometimes described as a delayed variant of radiosensitization, but the mechanisms of recall and radiosensitization might well be different.¹ Patients commonly have no history of acute radiation reactions in the affected tissues.¹

As with radiation recall, radiosensitization is emerging as a pattern of dermatologic toxicity with targeted therapies such as epidermal growth factor receptor [EGFR] blockade.^11,18 Clinically, radiation recall is distinguished from drug radiosensitization by its later appearance—weeks, months, or years after radiotherapy—but in most cases, relatively soon after systemic drug or targeted agent therapy.¹ Although there is no clear specific window of risk, most cases occur immediately or within a few weeks of drug administration.¹ Therefore, some researchers suspect that a longer interval between radiotherapy and initiation of chemotherapy (eg, more than 3 weeks¹) might reduce the risk of radiation recall reactions.

MANAGING RADIATION RECALL SYMPTOMS

Management of recall reaction has not undergone randomized, controlled clinical study, but usually involves drug discontinuation or dose reduction, topical or systemic corticosteroids, or nonsteroidal anti-inflammatory therapy, and rechallenge after symptoms abate.^1,2 Patients with radiation recall symptoms should be told to avoid sun exposure and advised to use sunscreen and to avoid tanning beds.¹ Antihistamines might help relieve symptoms in some patients.¹ Isolated case reports have attempted to identify candidate topical agents that might allow treatment without drug discontinuation, such as hyaluronic acid, which increases wound granulation.¹⁹

In mild cases, drug reduction or continued medication at target therapeutic doses with supportive care is viable. Recall reactions associated with systemic agents very rarely resolve without drug discontinuation, but that might not be the case for targeted agents.¹ More research is needed before clinical guidelines can be promulgated, but anecdotal reports suggest that in mild cases triggered by targeted agents such as vemurafenib or erlotinib (Tarceva, generic), monitoring and management of radiation recall symptoms with corticosteroids might allow continued use of the triggering agent without dose reduction.^3,20 In the lung, these can appear as radiographic opacities and consolidation in lung tissues with preexisting radiation fibrosis that can be mistaken for new nonradiation-associated, drug-induced lung damage.³

Optimal time intervals for drug dose reduction or interruption are not well understood, and might reflect triggering agents’ pharmacokinetics. Typically, with systemic anticancer drugs, symptoms resolve within 2 weeks (or even within hours of discontinuation when intravenous drugs are involved).¹ Except in severe cases, rechallenge is commonly attempted after drug interruption.¹ “The risk versus benefit balance and availability of alternative equally-effective agents must be considered,” note Burris and Hurtig.¹

Rechallenge is not always successful.^1,17 Because of the anecdotal nature of the available literature, success rates for rechallenge are not known. Some authors have suggested that corticosteroid premedication prior to rechallenge might reduce the risk of recall recurrence, but this claim has not undergone clinical study.¹

“Although it is not yet possible to design treatment regimens to eliminate the risk of radiation recall, it seems likely that risks can be minimized by using the lowest possible dose of radiation and prolonging the interval between completion of radiotherapy and initiation of chemotherapy,” Burris and Hurtig conclude.¹

1. Burris HA 3rd, Hurtig J. Radiation recall with anticancer agents. Oncologist. 2010;15(11):1227-1237.

2. Caloglu M, Yurut-Caloglu V, Cosar-Alas R, et al. An ambiguous phenomenon of radiation and drugs: recall reactions. Onkologie. 2007;30(4):209-214.

3. Arakawa H, Johkoh T, Sakai F, et al. Exacerbation of radiation fibrosis with ­erlotinib: another pattern of radiation recall phenomenon. Jpn J Radiol. 2011;29(8):587-589.

4. Carlson JA, Nooruddin Z, Rusthoven C, et al. Trastuzumab emtansine and stereotactic radiosurgery: an unexpected increase in clinically significant brain edema [published online ahead of print February 3, 2014]. Neuro Oncol. 2014. doi:10.1093/neuonc/not329.

5. Melnyk SM, More KF, Miles EF. Idiopathic radiation recall dermatitis developing nine months after cessation of cisplatin therapy in treatment of squamous cell carcinoma of the tonsil. Case Rep Oncol Med. 2012;2012:271801. doi:10.1155/2012/271801.

6. Foster LM, Mahoney ME, Harmon MW, et al. Radiation recall reaction with letrozole therapy in breast cancer [published online ahead of print January 3, 2014]. Clin Breast Cancer. 2014;pii:S1526-8209(13):00316-9. doi:10.1016/j.clbc.2013.12.011.

7. Takiar V, Strom EA, Baumann DP, et al. Locoregional interaction of ixabepilone (ixempra) after breast cancer radiation. Oncologist. 2013;18(3):265-270.

8. Haas RL, de Klerk G. An illustrated case of doxorubicin-induced radiation recall dermatitis and a review of the literature. Neth J Med. 2011;69(2):72-75.

9. Eckardt MA, Bean A, Selch MT, Federman N. A child with gemcitabine-induced severe radiation recall myositis resulting in a compartment syndrome. J Pediatr Hematol Oncol. 2013;35(2):156-161.

10. Levy A, Hollebecque A, Bourgier C, et al. Targeted therapy-induced radiation recall. Eur J Cancer. 2013;49(7):1662-1668.

11. Niyazi M, Maihoefer C, Krause M, et al. Radiotherapy and “new” drugs-new side effects? Radiat Oncol. 2011;6:177.

12. Bourgier C, Massard C, Moldovan C, et al. Total recall of radiotherapy with mTOR ­inhibitors: a novel and potentially frequent side-effect? Ann Oncol. 2011;22(2):485-486.

13. Yuasa T, Kitsukawa S, Sukegawa G, et al. Early onset recall pneumonitis during targeted therapy with sunitinib. BMC Cancer. 2013;13:3. http:www.biomedcentral.com/1471-2407/13/3. Accessed March 13, 2014.

14. Oh D, Park HC, Lim HY, Yoo BC. Sorafenib-triggered radiation recall dermatitis with a disseminated exanthematous reaction. Radiat Oncol J. 2013;31(3):171-174.

15. Azad A, Maddison C, Stewart J. Radiation recall dermatitis induced by pazopanib. Onkologie. 2013;36(11):674-676. doi:10.1159/000355649.

16. Kodym E, Kalinska R, Ehringfeld C, et al. Frequency of radiation recall dermatitis in adult cancer patients. Onkologie. 2005;28(1):18-21.

17. Barlési F, Tummino C, Tasei AM, Astoul P. Unsuccessful rechallenge with pemetrexed after a previous radiation recall dermatitis. Lung Cancer. 2006;54(3):423-425.

18. Furlow B. New patterns of dermatologic toxicity with radiation and EGFR blockade. Oncol Nurse Advis. 2012;3(4):2931. http://www.oncologynurseadvisor.com/new-patterns-of-dermatologic-toxicity-with-radiation-and-egfr-blockade/article/246307/. Accessed March 13, 2014.

19. Bauer SM, Bauer C. The use of sodium hyaluronate for the treatment of radiation recall dermatitis. J Oncol Pharm Pract. 2009;15(2):123-126. http://opp.sagepub.com/content/15/2/123.refs?patientinform-links=yes&legid=spopp;15/2/123 [subscription required]. Accessed March 13, 2014.

20. Boussemart L, Boivin C, Claveau J, et al. Vemurafenib and radiosensitization. JAMA Dermatol. 2013;149(7):855-857. doi:10.1001/jamadermatol.2013.4200.