"Radiation Recall Phenomenon" with Novel Cytotoxic Agents: An Emerging Trend in the Last Decade
CC BY-NC-ND 4.0 ? Indian J Med Paediatr Oncol 2021; 42(01): 028-034
DOI: 10.1055/s-0041-1729729
Table 1: Clinical detail of the reported cases of RRD with nivolumab in the past 10 years
Study |
Diagnosis |
Dose and sites of RT |
Time interval between completion of RT and occurrence of RRD |
Treatment |
---|---|---|---|---|
Korman et al, 201711 |
Melanoma |
9 Gy/3# left pelvis for pathologic fracture |
10 days |
Topical corticosteroids |
Dhanushkodi et al, 201912 |
TNBC |
30 Gy to chest wall |
10 days |
Antibiotics, growth factors, and intravenous hydrocortisone |
Rouyer et al, 2018 (RDD with SJS)13 |
Pulmonary epidermoid carcinoma |
50 Gy mediastinum, left hilum, 60 Gy on tumor, 66 Gy on surgical area. 30 Gy to left knee, and 20 Gy to lumbar vertebrae over ~11 months |
15 days after RT + 2 cycles of nivolumab + 5 days after the 2nd cycle of nivolumab |
NR |
van Seggelen et al, 201921 |
GBM |
60 Gy/30 fractions along with temozolomide + stereotactic re-RT (21 Gy/3#) |
5 days after re-RT + 50 days after last nivolumab |
Moderate-potency topical corticosteroids and prednisone |
Abbreviations: GBM, glioblastoma multiforme; NR, not reported; RRD, radiation recall dermatitis; RT, radiotherapy; SJS, Stevens?Johnson syndrome; TNBC, triple-negative breast cancer. Note: #commonly signifies no of fraction of radiation. It is 9 Gy in 3 # |
Radiation Recall Pneumonitis
Radiation recall pneumonitis (RRPn) describes a unique radiographic and clinical presentation of pneumonitis infiltrates in previously irradiated lung tissue after the use of triggering agents. The typical changes of RRPn, detected by contrast-enhanced computed tomography (CECT) scan, include ground-glass opacity, diffuse haziness, infiltrates, or consolidation in the irradiated lung that must match to the shape and size of the radiation portal. Ding et al[14] described this rare phenomenon with 12 reported cases with conventional chemotherapy and found taxane to be the causative agent in the majority of recall pneumonitis.
The first report of RRPn by nivolumab was presented as a poster at ESMO Asia Congress 2016 by Miyoshi et al.[15] A 44-year-old female with Stage IIIB non-small cell carcinoma of lung (NSCLC) underwent concurrent chemoradiotherapy (CRT) (60 Gy in 30 fractions). The patient received nivolumab as third-line chemotherapy for her disease progression. After three nivolumab dosing, and after 7 months of the cessation of RT, she developed clinical and radiological features of RRPn. Two similar cases of NSCLC who received 60 Gy of RT to thoracic region and subsequently developed RRPn with nivolumab had been reported by Shibaki et al.[16] The radiological distribution of pneumonitis infiltrates corroborated the RT portals in both the cases.
Another case of RRPn with the use of nivolumab was reported in a 58-year-old female with dual malignancy.[17] She was first treated with left mastectomy and adjuvant RT to a dose of 55 Gy for breast cancer and later, she received CRT to the upper part of the right hemithorax for adenocarcinoma lung. A new line of treatment with nivolumab was started as she developed metastases. Four weeks after the initiation of nivolumab, she developed clinical and imaging features of RRPn. One more patient with dual malignancy reported RRPn-like pattern after multiple lines of conventional chemotherapy, nivolumab, and stereotactic body RT (SBRT) to thoracic lesion for Stage IV NSCLC.[18] The patient subsequently developed chronic myelogenous leukemia and was started on imatinib. Over the next month, she developed radiological and clinical features of RRPn. Even though the immediate preceding agent was imatinib for this patient, the atypical nature of recall pneumonitis with imatinib warranted this case to be presented along with this review.
The incidence of RRPn induced by nivolumab had also been reported in a patient with renal cell carcinoma after palliative radiation (30 Gy in 10 fractions) to the ribs.[19] Three days after the nivolumab administration, she presented with respiratory symptoms, and CECT scan image suggested recall pneumonitis.
RRPn was also reported in a 20-year-old female with relapsed Hodgkin lymphoma.[20] She was started on nivolumab after the failure of conventional chemotherapy, total lymphoid irradiation (TLI), and stem cell transplant. She developed RRP after 16 months of TLI ([Table 2]).
Table 2: Clinical details of the reported cases of radiation recall pneumonitis with nivolumab in the past 10 years
Study |
Diagnosis |
Dose and sites of RT |
Time interval between completion of RT and occurrence of RRPn |
Treatment |
---|---|---|---|---|
Miyoshi et al, 201715 |
NSCLC |
CRT (60Gy/30#) |
7 months |
NR |
Shibaki et al, 201716 |
NSCLC |
60 Gy/30# to thorax |
2 years gap+4th cycle of Nivolumab (660 days) |
Oral prednisolone |
NSCLC |
60 Gy/30# to thorax |
664 days |
Oral prednisolone |
|
Thor? et al, 201817 |
Ca breast, adenocarcinoma lung |
55Gy for breast ca + CRT for ca lung + palliative RT to bone |
7 months |
NR |
Nakamura et al, 201919 |
Renal cell carcinoma |
30 Gy/10# to ribs |
9 months |
Oral prednisolone for 4 months |
Gupta et al, 201720 |
Relapsed Hodgkin?s lymphoma |
Total lymphoid irradiation |
16 months |
Azithromycin + prednisolone |
Naiditch et al, 201918 |
NSCLC + CML |
54Gy/3# SBRT to thorax |
10 months |
prednisolone |
Abbreviations: CML, chronic myelogenous leukemia; CRT, concurrent chemoradiation; NR, not reported; NSCLC, nonsmall-cell lung carcinoma; RRPn, radiation recall pneumonitis; SBRT, stereotactic body radiation therapy. |
Radiation Recall Myelitis
One case of radiation recall myelitis was reported in a 68-year-old male with metastatic NSCLC while on treatment with pembrolizumab.[12] He developed motor deficit and sphincter dysfunction after 6? months of radiation (30 Gy in 10 fractions to T12?L2 vertebra). The change in the signal intensity detected by magnetic resonance imaging (MRI) exactly corroborated the previously irradiated area. Because the radiation dose received by the thoracic spine was well below the recognized tolerance dose in this case, and other potential causes of myelopathy were ruled out, the most logical explanation was recall myelitis contributed by pembrolizumab.
Abscopal Recall Phenomenon
RT that is a local modality of treatment can also stimulate systemic phenomena, and immune mechanisms triggered by RT are thought to be the underlying driving force behind such events. In 1953, R. H. Mole first coined the term ?abscopal effects? of radiation to describe its effects ?at a distance? (in Latin ab: away, scopal: target) from the irradiated volume. Similarly, the recall phenomenon of radiation can also be elicited at distant sites on very rare occasions.
A male patient with glioblastoma multiforme received 19 courses of nivolumab after completion of standard postoperative CRT (60 Gy in 30 fractions along with temozolomide) as the part of a trial study.[21] One month after the last administration of nivolumab, he was treated with stereotactic re-irradiation (21 Gy/three fractions) for his recurrent disease. Five days after completing reradiation and 50 days after his last nivolumab administration, he developed a maculopapular rash in both armpits that later became generalized. This incidence can be explained by the ?abscopal recall effect? of radiation triggered by nivolumab.
Radiation Recall Phenomenon with BRAF Inhibitors
BRAF inhibitors involve selective inhibition of the mutated BRAF V600E kinase, resulting in reduced signaling through the aberrant mitogen-activated protein kinase pathway, and FDA has approved three BRAF inhibitors, namely, vemurafenib, dabrafenib, and encorafenib, for the treatment of metastatic melanoma.
RT and vemurafenib are being increasingly used concurrently or sequentially, and vemurafenib is known to cause severe cutaneous reactions. Apart from the well-established cutaneous side effects and radiosensitization capacity of vemurafenib, there are several reported cases[22] [23] [24] [25] [26] of RRP, with this BRAF inhibitor.
Radiation Recall Dermatitis
Three patients with metastatic, BRAF V600 E-positive melanoma, who developed RRP and RRD after the administration of vemurafenib, were reported by Forschner et al.[27] Treatment with vemurafenib was started 3 to 4 weeks after the cessation of RT for all the three cases. Two patients in this case series received cumulative dose up to 50 Gy to the local site of the disease, which exposed pulmonary tissues as well. Features of RRP developed after 3 to 4 weeks of vemurafenib administration. Another patient who received 30 Gy whole-brain radiotherapy (WBRT) developed RRD in the form of multiple itchy vesicles and papules on the erythematous scalp, 2 weeks after starting vemurafenib. Similar two cases of RRD (cutis verticis gyrata) induced by vemurafenib after WBRT were reported by Harding et al.[28]
Interface dermatitis manifesting as RRD and a keratosis pilaris-like eruption were reported in a 37-year-old male who received adjuvant RT to his left neck (71 Gy in 38 fractions) after neck dissection for residual/recurrent melanoma.[29] He was put on vemurafenib 6 weeks after RT and a geometric area of dermatitis conforming to the previous radiation site developed after 2 weeks.
Localized multiple epidermal cysts were reported as recall phenomenon in a 43-year-old female with metastatic melanoma who received palliative RT to the exophytic tumor in the neck and started with vemurafenib.[30] Three months after RT, the patient was found to have multiple epidermal cysts in the previous irradiation field.
A patient with a diagnosis of BRAF-mutated, Stage IV adenocarcinoma lung received whole-femur palliative RT and, 8 weeks later, was initiated with oral dabrafenib and pazopanib.[31] The patient developed RRD-like manifestations within few hours, corresponding to the previously irradiated area. Similar incidence with concomitant dabrafenib and trametinib has been reported in a patient with nodular melanoma in the parietal region of the scalp.[32] After 2 years of interval, the patient received palliative RT to the right tibia, and RRD was found to develop subsequently.
Radiation Recall Myelitis
A 48-year-old female with metastatic melanoma received seven courses of nivolumab as first-line treatment and four courses of ipilimumab on disease progression.[33] Concomitant with ipilimumab, she received SBRT (56 Gy in eight fractions) to a large pulmonary metastasis. Dabrafenib and trametinib were initiated as third-line treatment, and the patient developed skin rashes on her back in the same volume matching to the previous RT field after 7 months. After 1 month, she developed back pain, and positron emission tomography (PET)-CT scan and MRI showed the evidence of radiation recall myelitis that was limited to her thoracic spine.
Radiation Recall Hematuria and Cystitis
Regorafenib is an oral multikinase inhibitor that targets angiogenic, stromal, and tyrosine kinase receptors. The occurrence of recall hematuria and cystitis after hyperthermia and regorafenib has been reported in a 66-year-old female with rectal adenocarcinoma.[34] The patient was given regorafenib on disease progression after multiple lines of treatment, which includes CRT with FOLFIRI (5-fluorouracil, leucovorin, and irinotecan) and 50.4 Gy of radiation in 28 fractions ~3 years back. Regional deep hyperthermia along with regorafenib was induced weekly using a BSD-2000 device (BDS Medical Corporation, Salt Lake City, Utah, United States) with 300 W/77.0 MHz of power for a growing presacral tumor. The patient started gross hematuria 3 days after commencing hyperthermia. The triggering agent for radiation recall hemorrhagic cystitis for this case is most likely the combination of regorafenib and hyperthermia.
Radiation Recall Phenomenon (Newer Agents) Eribulin
Eribulin induces G2/M cell cycle arrest and apoptosis by binding with microtubules and impairing microtubule growth. The first-ever case of recall reaction to eribulin was recorded in a 61-year-old bilateral breast cancer patient who went through several lines of conventional chemotherapy, RT to chest wall, SBRT to the lung (48 Gy in four fractions) and liver lesions (60 Gy in three fractions), palliative RT to the pelvic region and ribs, and reradiation to supraclavicular lymph nodes.[35] Two weeks after pelvic RT, and 3 months following supraclavicular RT, she was initiated with eribulin and after two cycles of eribulin, recall dermatitis developed over the left breast and supraclavicular area.
Osimertinib
A male patient with metastatic adenocarcinoma lung was treated initially with conventional chemotherapies and osimertinib that target the mutated epidermal growth factor receptor T790M. The patient received thoracic hypofractionated RT (55 Gy in 20 fractions) for disease progression and developed RRPn within 2 weeks of osimertinib resume.[36] Time interval since the completion of RT and development of RRPn was ~2 months. The logic to explain this event as RRPn was that the patient initially tolerated osimertinib without pulmonary side effects and resumption of osimertinib after thoracic RT resulted in severe inflammatory pneumonitis. It was quickly responsive to corticosteroids, which was another strong argument in favor of RRPn. This report also reinforces the fact that potential pulmonary toxicities may happen when RT and tyrosine kinase inhibitors (TKIs) are used concurrently or sequentially.[37]
Ixabepilone
A 60-year-old female with carcinoma breast underwent postoperative RT to chest wall and multiple lines of chemotherapy for her metastatic disease.[38] The patient also received palliative RT (30.25 Gy to T6 through T12 and 27.50 Gy to T1 through T3 over 13 and 14 days) and 1 week later, she received ixabepilone that is a microtubule-stabilizing agent. Within a week, she developed odynophagia along with the manifestation of RRD on her chest and back, conforming to the radiation portals.
Mogamulizumab
It is a humanized monoclonal antibody targeting the CC chemokine receptor 4 that has shown efficacy against adult T cell leukemia/lymphoma (ATLL), peripheral T cell lymphoma, and cutaneous T cell lymphoma. A 65-year-old male with relapsed ATLL underwent RT (50.4 Gy) to the superior mediastinum.[39] Three weeks after the completion of RT, weekly mogamulizumab was started and after three courses, he developed a geometric area of RRD.
Rare Report of Radiation Recall Myocarditis
It was described in a 56-year-old male with adenocarcinoma of the lung who received stereotactic RT to the chest and cervical lymph nodes (total dose of 70 Gy) and multiple lines of chemotherapy including cisplatin, docetaxel, bevacizumab, erlotinib, gemcitabine, and lastly sorafenib.[40] Five months later, he developed new-onset chest pain, and PET-CT, echocardiography, and cardiac magnetic resonance demonstrated abnormal myocardial wall segments, which corresponded to the previously irradiated area. This is the first-ever reported case of radiation recall myocarditis and underpins the features of visceral recall phenomenon that often remain underdiagnosed due to idiosyncrasy and lack of clinical suspicion.
Managing a Case of Radiation Recall Phenomenon
Diagnosis
The diagnosis of recall phenomenon is usually established by clinical judgment and radiological evidence. Biopsies of the affected areas were taken by few reported cases that revealed nonspecific changes on hematoxylin and eosin staining. Such features on skin biopsies may include vacuolization in basal cells, psoriasiform epidermal hyperplasia, follicular hyperkeratosis, and apoptotic keratinocytes. For visceral recall phenomenon, clinical presentations, history of prior radiation, and radiological changes in that particular organ can sufficiently lead to the diagnosis after ruling out the common causes of inflammatory reactions.
Treatment
Majority of the recall phenomenon regress clinically over a period of few weeks to months with the measurements including (a) immediate withdrawal of the causative agents, (b) administration of topical steroids for recall dermatitis, and (c) administration of systemic steroids with tapered dose schedule for visceral manifestations. Rechallenge with the causative agents without any further reactions is noted with a substantial number of cases. Dose modification of the triggering agents after the recall phenomenon can be considered on the discretion of the treating oncologist.
Discussion
The field of oncology is a rapidly expanding horizon with the frequent advent of newer therapeutic molecules and in the last decade, we experienced tremendous development in immunotherapy and targeted agents. While many of those agents have been found to cause dermatological side effects as the part of irAEs spectrum, the synergistic effects of such agents with RT are more pronounced. Radiation recall events, which are distinct inflammatory reactions of previously irradiated tissues with apparently obscure pathophysiology, are reported in considerable number with such novel cytotoxic agents. In the process of literature search, RRP was found to occur with numerous unconventional agents including monoclonal antibodies,[41] [42] TKIs,[43] [44] [45] [46] [47] hormonal agents,[48] and antibiotics.[49] Four cases of hemorrhagic cystitis as RRP with the use of cabazitaxel were reported in a case series.[50] In certain scenarios, it is extremely difficult to distinguish between ?true? radiation recall and radiation-induced dermatitis because many of those agents are well known to cause radiosensitization and localized cutaneous reactions after RT.[24] The reported time interval between radiation and administration of triggering agent is variable from days to years. If the event occurs within the excepted time limit of usual skin toxicity, the diagnosis of RRD and RT-induced acute dermatitis may present overlapping. On the other hand, if RT was given in the remote past, it may remain underdiagnosed due to lack of clinical suspicion. In our study, we focused mainly on the immunotherapies, BRAF inhibitors, and few more novel cytotoxic agents, used extensively in the last decade. These agents are found to cause recall dermatitis as well as myriad visceral recall phenomena, such as pneumonitis, myocarditis, cystitis, and myelitis. To diagnose such events, clinical judgment and radiological evidence may be considered sufficient for the majority of the cases. Only a few circumstances may require biopsy that reveals nonspecific inflammatory changes. Majority of the cases regress with conservative treatment with or without corticosteroids. Safe rechallenges of the triggering agents are reported in multiple cases as well. With the increasing use of unconventional, novel cytotoxic agents and targeted molecules, concurrent or sequentially with radiation, we expect more incidences of RRP in future that may present with either dermatological or visceral recall reactions.
Conflicts of Interest
There are no conflicts of interest.
Financial Support and Sponsorship
Nil.
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- Wernicke AG, Swistel AJ, Parashar B, Myskowski PL. Levofloxacin-induced radiation recall dermatitis: a case report and a review of the literature. Clin Breast Cancer 2010; 10 (05) 404-406
- Garrahy I, Forman D. Nitrofurantoin-induced radiation recall dermatitis. J Community Hosp Intern Med Perspect 2019; 9 (03) 279-281
- Abadir R, Liebmann J. Radiation reaction recall following simvastatin therapy: a new observation. Clin Oncol (R Coll Radiol) 1995; 7 (05) 325-326
- Extermann M, Vogt N, Forni M, Dayer P. Radiation recall in a patient with breast cancer treated for tuberculosis. Eur J Clin Pharmacol 1995; 48 (01) 77-78
- Camidge R, Price A. Characterizing the phenomenon of radiation recall dermatitis. Radiother Oncol 2001; 59 (03) 237-245
- Hellman S, Botnick LE. Stem cell depletion: an explanation of the late effects of cytotoxins. Int J Radiat Oncol Biol Phys 1977; 2 (1-2) 181-184
- Seymour CB, Mothersill C, Alper T. High yields of lethal mutations in somatic mammalian cells that survive ionizing radiation. Int J Radiat Biol Relat Stud Phys Chem Med 1986; 50 (01) 167-179
- Sibaud V. Dermatologic reactions to immune checkpoint inhibitors: skin toxicities and immunotherapy. Am J Clin Dermatol 2018; 19 (03) 345-361
- Korman AM, Tyler KH, Kaffenberger BH. Radiation recall dermatitis associated with nivolumab for metastatic malignant melanoma. Int J Dermatol 2017; 56 (04) e75-e77
- Dhanushkodi M, Iyer P, Ananthi B, Krishnamurthy A. Nivolumab-induced radiation recall dermatitis (RRD). Indian J Gynecol Oncol 2019; 17: 1-2
- Rouyer L, Bursztejn AC, Charbit L, Schmutz JL, Moawad S. Stevens-Johnson syndrome associated with radiation recall dermatitis in a patient treated with nivolumab. Eur J Dermatol 2018; 28 (03) 380-381
- Ding X, Ji W, Li J, Zhang X, Wang L. Radiation recall pneumonitis induced by chemotherapy after thoracic radiotherapy for lung cancer. Radiat Oncol 2011; 6: 24
- A First Report of Nivolumab induced Radiation Recall Pneumonitis | OncologyPRO. Available from: https:// oncologypro. Esmo. org/meeting-resources/esmo-asia-2016-congress/A-First-Report-of-Nivolumab-induced-Radiation-Recall-Pneumonitis. Accessed April 12, 2021
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