Recall Pneumonitis Research Articles

Immune Checkpoint Inhibitor Therapy–related Pneumonitis: Patterns and Management

In recent years, the use of immune checkpoint inhibitor (ICI) therapy has rapidly grown, with increasing U.S. Food and Drug Administration approvals of a variety of agents used as first- and second-line treatments of various malignancies. ICIs act through a unique mechanism of action when compared with those of conventional chemotherapeutic agents. ICIs target the cell surface receptors cytotoxic T-lymphocyte antigen-4, programmed cell death protein 1, or programmed cell death ligand 1, which result in immune system-mediated destruction of tumor cells. Immune-related adverse events are an increasingly recognized set of complications of ICI therapy that may affect any organ system. ICI therapy-related pneumonitis is an uncommon but important complication of ICI therapy, with potential for significant morbidity and mortality. As the clinical manifestation is often nonspecific, CT plays an important role in diagnosis and triage. Several distinct radiographic patterns of pneumonitis have been observed: (a) organizing pneumonia, (b) nonspecific interstitial pneumonia, (c) hypersensitivity pneumonitis, (d) acute interstitial pneumonia-acute respiratory distress syndrome, (e) bronchiolitis, and (f) radiation recall pneumonitis. Published guidelines outline the treatment of ICI therapy-related pneumonitis based on the severity of symptoms. Treatment is often effective, although recurrence is possible. This article reviews the mechanism of ICIs and ICI therapy complications, with subsequent management techniques and illustrations of the various radiologic patterns of ICI-therapy related pneumonitis.©RSNA, 2019.

1507P - Nivolumab-induced and radiation recall pneumonitis in patients with non-small cell lung cancer: A multicenter real world analysis of 669 patients

BackgroundImmune checkpoint inhibitors can cause pneumonitis in lung cancer patients. The role of previous thoracic radiation therapy (TRT) as a risk factor is not clear. Furthermore, some patients show radiation recall pneumonitis (RRP) pattern. In this multicenter retrospective study, we analyzed the relationship of previous TRT and other potential risk factors with nivolumab-induced pneumonitis, and the characteristics of RRP. MethodsMedical records of non-small cell lung cancer patients, who received nivolumab between December 2015 and March 2017, were retrospectively reviewed. Baseline clinical characteristics, incidence, and risk factors were analyzed at 5 hospitals. Person’s chi-square test and multivariate logistic regression analysis (age, sex, smoking history, treatment history of TRT, and performance status at the start of nivolumab treatment) were conducted to identify potential risk factors. Imaging analysis for RRP was conducted only for patients treated in National Cancer Center Hospital at the moment. ResultsA total of 669 patients were evaluated, and the incidences of all-grade and ≥ grade 2 pneumonitis were 8.9% (60/669) and 7.2% (47/669), respectively. Two (0.3%) patients died due to the pneumonitis. Incidences of pneumonitis were 12.9% (33/256) and 6.5% (27/413) in patients with and without previous TRT, respectively. History of previous TRT was associated with pneumonitis in multivariate analysis [odds ratio, 1.95; 95% confidence interval 1.13-3.34]. Chest imaging by computed tomography of some of those patients showed RRP pattern with pneumonitis infiltration occurring in the radiation field previously treated, and the direct relation was suggested. Incidences of RRP were 4.2% (4/95) among patients with history of previous TRT and 30.8% (4/13) among patients with previous TRT and who developed nivolumab-induced pneumonitis. ConclusionsIncreasing risk of nivolumab-induced pneumonitis was associated with treatment history of TRT. RRP pattern was one of the characteristic radiographic patterns of nivolumab-induced pneumonitis in patients with previous TRT. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Radiation recall pneumonitis in the setting of immunotherapy and radiation: a focused review

Radiation recall pneumonitis in the setting of immunotherapy and radiation: a focused review

Radiation recall pneumonitis in the setting of immunotherapy and radiation: a focused review.

Radiation recall pneumonitis (RRP) is an entity described as pneumonitis localized to a previously irradiated field after exposure to a systemic agent. It has previously been described in the literature in the context of chemotherapeutic agents as well as certain biologics. With immunotherapy taking a more prominent role in the treatment of several different malignancies and its own baseline risk of pneumonitis, it is important to explore the likelihood of RRP, specifically in those patients who have been previously treated with radiation therapy. The current literature regarding RRP with checkpoint inhibitors is reviewed in this article. Alongside this review, we report a case of RRP after pembrolizumab initiation in a patient in our practice.

Fibrotic lung toxicity induced by cytotoxic drugs, radiation and immunotherapy in patients treated for lung cancer.

Patients treated for lung cancer may develop lung toxicity induced by chemotherapy (DILD), radiation or combined radiation recall pneumonitis. In the literature, some cases of immune-mediated pneumonitis have been reported associated with immunotherapy. The clinical and radiologic features of interstitial lung toxicity are unspecific, dyspnoea and dry cough are the most common symptoms while the most frequent radiological pattern is the cryptogenic organizing pneumonia (COP). Why only some individuals treated with these drugs develop interstitial lung toxicity is unclear.In the last few years some studies have reported the utility of KL 6 for the evaluation of DILD. The treatment is based on high doses of systemic steroids or immune suppressor. In this study we report severe interstitial lung damage in patients treated with different anti-blastic, immune and radiation therapies. Treated with surgery, chemotherapy, immuno and radiotherapy for lung cancer, they unfortunately died of severe DILD.

Baseline neutrophil-to-lymphocyte ratio predicts the prognosis of castration-resistant prostate cancer treated with abiraterone acetate.

Abiraterone acetate (AA), a CYP17 inhibitor, now has a crucial role in the treatment of castration-resistant prostate cancer (CRPC), and previous studies have reported several prognostic clinical factors for AA treatment. The neutrophil-to-lymphocyte ratio (NLR) has also been investigated for a CRPC treatments in a few reports, however it has not been identified to be a prognostic factor for AA treatment in Japanese patients. The present study aimed to assess the association of the baseline NLR with the overall survival (OS) in CPRC patients treated by AA. The present study retrospectively reviewed a total of 90 consecutive patients with CRPC treated with AA from 2011 to 2016 at Yokohama City University Medical Center and National Cancer Center Hospital East. The primary endpoint of the study was the OS, which was defined as the survival from the start of AA administration. The secondary endpoint was the prostate-specific antigen (PSA) response. PSA response was defined as a reduction in antigen levels of >50%. Complete blood cell counts were performed, and the NLR was calculated using the neutrophil and lymphocyte counts obtained on the same day or a few days prior to the initiation of AA therapy. The NLR cut-off point was determined to be 3.76 for the OS, and divided into the high NLR group of 34 patients and the low NLR group of 56 patients. A PSA response was obtained in 8 patients (23.5%) in the high NLR group and in 24 (42.9%) in the low NLR group. The difference of PSA response between the two groups was significant (P=0.037). Kaplan-Meier curves demonstrated that a high NLR [NLR ≥3.76; median OS: 8.4 months; 95% confidence interval (CI): 6.325-10.475 months] was correlated with a risk of mortality compared with a low NLR (NLR <3.76; median OS not reached). A multivariate analysis demonstrated that the NLR was an independent predictor for the OS (hazard ratio: 2.682; 95% CI: 1.143-6.293; P=0.023). The findings suggest that the NLR may be a useful novel biomarker for predicting the prognosis of CRPC patients treated with AA.

Nivolumab-Induced Radiation Recall Pneumonitis

Nivolumab-Induced Radiation Recall Pneumonitis

Radiation recall pneumonitis induced by epidermal growth factor receptor-tyrosine kinase inhibitor in patients with advanced nonsmall-cell lung cancer

BackgroundRadiation recall pneumonitis (RRP) is a special form of radiation pneumonitis precipitated by certain pharmacological agents. Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is an effective treatment for advanced nonsmall-cell lung cancer (NSCLC) and has been reported as a potent radiation sensitizer. The incidence and general characteristics of EGFR-TKI-related RRP in patients with NSCLC remain unclear. MethodsClinical records and serial chest images of consecutive patients with advanced NSCLC who had received thoracic radiotherapy (TRT) and EGFR-TKI treatment were retrospectively reviewed. EGFR-TKI-related RRP was diagnosed according to history, clinical manifestations, and radiographic characteristics. Potential risk factors were analyzed. ResultsIn total, 160 patients with NSCLC who received EGFR-TKI after TRT were identified. Of these patients, seven (4.4%) developed EGFR-TKI-related RRP. The median time interval between the end of radiotherapy and RRP was 124 days (range, 80–635 days) and that between the initiation of EGFR-TKI and RRP was 43 days (range, 18–65 days). No risk factor for the development of RRP was identified except that patients in whom EGFR-TKI was initiated within 90 days after the completion of radiotherapy had significantly higher rates of RRP than those of patients who began receiving EGFR-TKI treatment after 90 days (21% vs. 2.1%, p = 0.005). ConclusionIn patients with NSCLC who have a history of TRT, treatment with EGFR-TKI may induce not only interstitial lung disease but also RRP. Physicians should be aware of both unexpected adverse events when using EGFR-TKI.

Early onset recall pneumonitis during targeted therapy with sunitinib

BackgroundSunitinib interacts with radiation therapy, leading to synergism of the toxicities of these treatments. Radiation recall pneumonitis is a rare but serious complication of targeted therapy with tyrosine kinase inhibitors.Case presentationThe case of a patient with metastatic renal cell cancer (RCC) who developed recall pneumonitis on the first cycle of systemic sunitinib treatment is reported here. A 65-year-old man with RCC and bone metastasis underwent radiation therapy on his thoracic vertebrae (Th5-8) with a total dose of 24 Gy. Sunitinib (37.5 mg) was started 14 days after completing the radiation therapy. On the 14th day of sunitinib treatment, the patient developed progressive fever with worsening of dyspnea and general weakness. Treatment with pulse administration of prednisolone 1,000 mg for 3 days was initiated. Thereafter, the symptoms and the radiological findings regarding the interstitial filtration gradually improved over 7 days.ConclusionTo our knowledge, this is the first report of early onset recall pneumonitis during sunitinib therapy. At present, how sunitinib interacts with radiation therapy remains unclear. The possibility that tyrosine kinase inhibitor therapy, including with sunitinib, after radiation therapy may lead to adverse effects should be kept in mind.

A Phase I Trial of Bexarotene in Combination With Docetaxel in Patients With Advanced Solid Tumors

Background: The purpose of this study was to identify dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of docetaxel with a fixed-dose of bexarotene. Patients and Methods: This was a phase I, single-center and open-label trial of dose-escalating docetaxel with a fixed-dose oral bexarotene. Successive cohorts of 3 patients (pts), with confirmed solid tumors refractory to standard therapy or for whom no standard therapy existed, received fixed-dose oral bexarotene (400 mg/m 2 daily) with escalating doses of docetaxel weekly (25, 30, or 35 mg/m 2) for 3 weeks on a 4-week cycle. Cohorts were expanded to 6 pts if a DLT was noted. The MTD was determined based on the occurrence of DLT in at least 2 of 6 pts during the first cycle. Results: Nineteen pts were enrolled. Seven pts were treated at 25 mg/m 2, 6 at 30 mg/m 2, and 6 at 35 mg/m 2 of docetaxel. The MTD for docetaxel was 30 mg/m 2 with 400 mg/m 2 of daily bexarotene. Hypothyroidism, hypertriglyceridemia, and fatigue were common toxicities. Three pts developed pulmonary toxicity (possible radiation recall pneumonitis [n = 2] and pulmonary hypertension because of tumor emboli [n = 1]). Two pts withdrew consent because of Grade 3 fatigue. Ten of 19 pts were noted to have stable disease and received more than 2 cycles of therapy. Of the 10 pts with stable disease, 5 had non–small-cell lung cancer (NSCLC), and of those 5 pts, 1 had a partial response that persisted for eight cycles. Conclusion: The MTD of docetaxel was 30mg/m 2 in combination with daily bexarotene at 400mg/m 2. Careful monitoring may be indicated in pts with previously irradiated lung tumors.

Radiation recall pneumonitis induced by chemotherapy after thoracic radiotherapy for lung cancer

BackgroundRadiation recall pneumonitis (RRP) describes a rare reaction in previously irradiated area of pulmonary tissue after application of triggering agents. RRP remains loosely characterized and poorly understood since it has so far only been depicted in 8 cases in the literature. The objective of the study is to disclose the general characteristics of RRP induced by chemotherapy after thoracic irradiation for lung cancer, and to draw attention to the potential toxicity even after a long time interval from the previous irradiation.MethodsMedical records were reviewed. RRP induced by chemotherapy was diagnosed by the history of chemotherapy after radiotherapy, clinical presentation and radiographic abnormalities including ground-glass opacity, attenuation, or consolidation changes within the radiation field, plus that radiographic examination of the thorax before showed no radiation pneumonitis. RRP was graded according to Common Terminology Criteria for Adverse Events version 3.0. The characteristics of the 12 RRP cases were analyzed.ResultsTwelve patients were diagnosed of RRP, of who 8 received taxanes. The median time interval between end of radiotherapy and RRP, between end of radiotherapy and beginning of chemotherapy, and between beginning of chemotherapy and RRP was 95 days, 42 days and 47 days, respectively. Marked symptomatic and radiographic improvement was observed in the 12 patients after withdrawal of chemotherapy and application of systemic corticosteroids. Seven patients were rechallenged with chemotherapy, of whom four with the same kind of agents, and showed no recurrence with steroid cover.ConclusionsDoctors should pay attention to RRP even after a long time from the previous radiotherapy or after several cycles of consolidation chemotherapy. Taxanes are likely to be associated with radiation recall more frequently. Withdrawal of causative agent and application of steroids are the treatment of choice. Patients may be rechallenged safely with steroid cover and careful observation, which needs to be validated.

Hemorrhagic Stroke Associated with Mixed Amphetamine Salts: Acyclovir-Induced Immune Thrombocytopenia: Recall Pneumonitis during Treatment with Sunitinib: Coagulopathy Caused by Cephradine-Induced Factor V Inhibition: Psoriasis Caused by Certolizumab Pegol: Excellent Reviews: Glucocorticoids and Increased Mortality in Hospitalized Patients with C. difficile-Associated Disease; Drug-Induced Osteoporosis; Adverse Drug Reactions (Part 1)

The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the US Food and Drug Administration's (FDA's) Med Watch program (800-FDA-1088). If you have reported an interesting, preventable ADR to Med Watch, please consider sharing the account with our readers.

Radiation Recall Pneumonitis Induced by Gefitinib in a Patient with Lung Adenocarcinoma and EGFR Mutation

背景．Radiation recall pneumonitisは，放射線照射後にさまざまな薬剤で発現しうる照射想起反応のひとつであり，ゲフィチニブによるものは1例の報告のみである．症例．右上葉・中葉の重複肺腺癌術後に再発をきたした55歳の男性．右第6肋骨転移に対し疼痛コントロール目的で放射線治療（45 Gy/9 Fr）後に化学療法（カルボプラチン+ゲムシタビン）を施行したが胸水の増加を認めPDと判定した．この時点で放射線肺臓炎は認めなかった．胸水中の上皮成長因子受容体（EGFR）遺伝子変異は陽性（exon21:L858R）でありゲフィチニブ250 mg/日の内服を開始した．投与2週間後に乾性咳嗽および軽度の労作時呼吸困難が出現し，胸部X線写真およびCTで放射線照射野に一致したスリガラス影を認めた．ゲフィチニブによるradiation recall pneumonitisと診断し内服を中止した．プレドニゾロンの内服で改善傾向である．結論．本症例は放射線治療終了8ヶ月後に発現したradiation recall pneumonitisである．ゲフィチニブによる間質性肺疾患のモニタリングにおいては，先行する放射線照射にも配慮する必要がある．

A phase I trial of bexarotene and docetaxel in patients with advanced solid tumors

14512 Background: A phase I trial of bexarotene and docetaxel in patients with advanced solid tumors. Retinoids play critical roles in normal development and physiology by modulating cell growth, division, reproduction, differentiation, and immune function. Bexarotene (Bex) is a novel synthetic retinoid analogue binding preferentially to members of the RXR subclass of receptors. In a phase I trial of single agent Bex, patients with non-small cell lung cancer (NSCLC) had prolonged stabilization of disease and survival. Retinoids enhance docetaxel (D)induced apoptosis by causing down-regulation of Bcl-2, activation of RAR-gamma and altered expression Bcl-2/Bax. Methods: This Phase 1 study in patients (pts) with advanced neoplasms evaluated the safety and tolerability of fixed dose oral Bex at 400mg/m2 daily with escalating doses of D weekly for 3/4 weeks at 3 dose levels, 25, 30 & 35mg/m2, for up to 6 cycles. In pts exhibiting response or disease stabilization, treatment with Bex was continued until disease progression or intolerable toxicity. Cohorts consisted of 3 pts and were expanded to 6 pts if dose- limiting toxicity (DLT) was noted. Results: 19 pts were enrolled, including NSCLC (8), head & neck (2) esophageal (2) colorectal (2) cancers. 7 pts were treated at 25mg/m2, 6 at 30mg/m2 and 6 at 35mg/m2 of D. The MTD was D at 30mg/m2 with 400mg/m2of daily Bex. Hypothyroidism, hypertriglyceridemia, and fatigue were common.Two pts experienced grade 3 fatigue, and 1 each experienced grade 3 hypertriglyceridemia and hypothyroidism. Of 16 patients assessable for response, and 7 had stable disease for at least 2 cycles. One pt with NSCLC had a partial response that persisted for 8 cycles. 3 pts developed pulmonary toxicity (2 with radiation recall pneumonitis), 2 withdrew consent due to grade 3 fatigue. One pt died due to acute pulmonary hypertension secondary to pulmonary tumor emboli noted at autopsy. 5 pts are presently alive, two longest with NSCLC 35 & 22 months. Conclusions: MTD of D was 30mg/m2 in combination with daily dose Bex 400mg/m2. Care should be taken in patients who have been previously irradiated. A phase II trial of this combination at MTD as second line therapy in NSCLC is planned and correlative studies will be added. No significant financial relationships to disclose.

Radiation Recall Pneumonitis Induced by Gemcitabine

Radiation recall pneumonitis describes a very rare reaction in a previously irradiated area of pulmonary tissue after application of pharmacological agents. A case of recall pneumonitis induced by gemcitabine is reported. A 64-year-old female patient with metastasized esophageal carcinoma received simultaneous chemoradiotherapy of the upper mediastinum with 50.4 Gy and cisplatin/5-fluorouracil. 8 months later she was scheduled for salvage chemotherapy with gemcitabine (1,000 mg/m(2) days 1 and 8) and docetaxel (75 mg/m(2) day 8) due to locally progressive disease. After having received gemcitabine on day 1 of the second course, the patient developed dry cough, subfebrile temperatures and dyspnea within 48 h. A CT of the thorax revealed newly developed bilateral pulmonary ground-glass opacity corresponding to the previous radiation fields. Chemotherapy was stopped and systemic application of prednisolone was initiated. 2 months later symptoms had resolved with a control CT of the thorax showing complete regression of the pulmonary changes. Gemcitabine-induced recall pneumonitis is a rarely reported phenomenon and should be taken into account even after extended time interval to the previous radiotherapy.

A phase I trial of bexarotene and docetaxel in patients with advanced solid tumors

13085 Background: Retinoids have been used to treat a wide variety of malignancies. Bexarotene is a synthetic retinoid that binds preferentially to the RXR subclass of retinoid receptors. In the initial phase I trial of bexarotene, a subset of patients with non-small cell lung cancer (NSCLC) had prolonged stabilization of disease and survival. In vitro evidence suggests that the effects of retinoids may be enhanced when used in conjunction with taxanes. This is a phase I trial designed to determine the maximum tolerated dose of docetaxel in combination with a fixed dose of bexarotene. Methods: Patients with pathologically confirmed solid tumors for whom no standard therapies exist, who have an ECOG performance status ≤2, adequate organ function and normal serum triglycerides were eligible. Each cycle was 4 weeks long. Oral bexarotene was given at 400 mg/m2 daily. Docetaxel was given weekly for 3 out of 4 weeks at two dose levels, 25 or 30 mg/m2, for up to 6 cycles. For patients exhibiting disease stabilization or response, treatment with bexarotene was continued until disease progression. Restaging studies were performed after every 2 cycles. Results: To date 10 patients have been enrolled, half of whom had NSCLC - 7 male, mean age = 61 (range 37–73), 100% PS = 0 or 1. 29 cycles were completed (range 1 to 8). 7 patients have been treated at 25 mg/m2 and 3 at 30 mg/m2 of docetaxel. Hypothyroidism, hypertriglyceridemia, and fatigue were common but generally mild. Two patients experienced grade III fatigue, and 1 each experienced grade III hypertriglyceridemia, neutropenia, and cough. There were no grade IV toxicities. Two patients were taken off study because of non-fatal radiation recall pneumonitis that was controlled with steroids. In this heavily pretreated population, of 8 patients assessable for response, 5 had stable disease for at least 2 cycles. One patient with NSCLC had a partial response that persisted for 6 cycles. Conclusions: Bexarotene and docetaxel (at a minimum of 25 mg/m2) can be safely coadministered. Care should be taken in patients who have been previously irradiated. Enrolment and dose escalation for the phase I trial is still ongoing. A phase II trial of the combination as second line therapy in NSCLC is planned. [Table: see text]

P-625 Radiation recall pneumonitis induced by gefitinib (‘Iressa’)

P-625 Radiation recall pneumonitis induced by gefitinib (‘Iressa’)