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Introduction

Radiotherapy has an important role in the local treatment of malignancies. The mechanism of radiotherapy is mainly through the damage of deoxyribonucleic acid (DNA) inside the malignant cells in the irradiation field. However, the rare phenomenon of spontaneous regression in lesions distant from an irradiation field has been reported and is called ‘abscopal effect’. The abscopal effect was initially suggested by Mole (1) in 1953. While the biological mechanism of this effect has remained to be completely elucidated, immunologic mechanisms are considered to mediate this effect. In recent years, tumor immunity in combination with immune checkpoint inhibitors (ICIs) has become of increasing interest in the abscopal effect. However, this phenomenon is rarely encountered in clinical practice, particularly for an abscopal effect to manifest itself without pharmacologic immunomodulation (pure abscopal effect) (2). The present study reported on two cases with abscopal effects: One showed a pure abscopal effect and the other occurred after resistance to immunotherapy. Fever of unknown cause (FUC) was observed immediately after initiation of radiotherapy in both cases. The relationship between this fever and the abscopal effect was unclear, but radiotherapy does not normally induce a systemic response. The symptoms at presentation, physical exams and laboratory results are provided for each case in the following section.

Case report

Case 1

A male patient aged 78 years was diagnosed with pleomorphic sarcoma of the iliac bone (size, 8.1x12.1x15.5 cm) with pelvic lymph node metastases and bilateral lung metastases at an external hospital in June 2019, and the treatment options of chemotherapy, radiotherapy and palliative care were considered. However, taking into account the patient's age, the patient and his family chose palliative care at our institution, and the patient was referred to the department of palliative medicine of Tsukuba Medical Center Hospital (Ibaraki, Japan) within the same month. Palliative photon radiotherapy of 36 Gy in 12 fractions over 16 days was indicated for iliac pain control and fracture prevention. The day after the start of radiotherapy, the patient complained of fever without respiratory or urinary tract symptoms. Fever of up to 38˚C was observed twice a day during the irradiation period. This fever broke spontaneously in 3 h after it started each time. Blood tests indicated no characteristic findings other than a mild inflammatory reaction and thrombocytopenia [C-reactive protein (CRP), 7.07 mg/dl (normal range: ≤0.3 mg/dl); platelets, 5.6x104/µl (15-45x104/µl). Celecoxib was prescribed for antipyretic and analgesic therapy but was ineffective. The fever continued for 2 days after the end of radiotherapy but then spontaneously resolved. After radiotherapy, no additional treatment was given except for drugs for pain relief. Pain improved gradually and the patient started to be able to walk on his own 3 months after radiotherapy. Computed tomography (CT) indicated significant shrinkage of the primary irradiated tumor and lung metastases. At one year after radiotherapy, the primary tumor size was 3.6x6x5.5 cm. However, 14 months after radiotherapy, the patient complained of left coxalgia again and the iliac tumor had slightly increased. At this time, the tumor size was 4.4x8x6 cm, but lung metastases still remained small and 18fluorodeoxyglucose-positron emission tomography (PET) indicated no accumulation except for the iliac tumor. Reirradiation with photon radiotherapy was impossible because the alimentary tract could not be avoided; therefore, proton therapy of 51 Gy in 17 fractions over 27 days was used for the iliac tumor. During this course, there was no fever. Pain was slightly relieved, but the tumor did not shrink at all. The tumor then rapidly increased in size and lung metastases also progressed markedly. After proton therapy, palliative care was offered and the patient died from lung lymphangitis. The timeline, CT, PET images and the treatment fields of photon and proton radiotherapy are presented in Fig. 1.

Figure 1 Clinical course and imaging series for iliac pleomorphic sarcoma (Case 1) and treatment planning for photon and protonradiotherapy. PBT, proton beam therapy; RT, radiation therapy; PET, positron emission tomography; M, months; y, years.

Case 2

A 59-year-old male patient was diagnosed with renal cell cancer based on CT at the time of admission to Tsukuba Medical Center Hospital (Ibaraki, Japan) due to capsular hemorrhage in March 2016. After recovering from this hemorrhage, a close examination for renal cell carcinoma (RCC) revealed metastasis to renal hilum lymph nodes and lung metastases, and the clinical stage was T3aN1M1. Nephrectomy was performed in 2016 and the pathological results indicated clear cell carcinoma. Sunitinib was started one month after nephrectomy, and lung and lymph node metastases decreased. Sunitinib was continued for 10 months, then after the lung metastases increased and right adrenal metastasis appeared, treatment was switched to axitinib and the metastases shrank again. However, severe chemical dehydration occurred 5 months after the start of axitinib; therefore, nivolumab was started thereafter and continued for 8 months, despite slight progression of lung and adrenal metastases 2 months after the start of nivolumab. However, nivolumab was then stopped due to severe immune-related adverse events of pituitary insufficiency followed by infectious endocarditis and severe ischemic enteritis. Subsequently, no additional drug therapy was given and in the 8 months after stopping nivolumab, right adrenal metastasis increased to 70x54 mm. Other metastases remained small. At that time, the size of the lung metastasis was 12.8x4.4 mm. Therefore, resection of the adrenal metastasis was attempted; however, this proved to be impossible due to strong adhesion. Radiotherapy was then considered and photon radiotherapy of 50 Gy in 25 fractions over 36 days was delivered with palliative intent. On the first day of the radiotherapy, the patient had a fever of 37.5˚C after returning home from radiotherapy. On the second day, blood tests were performed because the fever persisted and a high inflammatory response was observed: White blood cells (WBC), 14,300/µl (normal range: 3,100-8,400/µl); and CRP, 11.38 mg/dl. The fever was not broken with oral aspirin and the inflammatory reaction rapidly increased; the body temperature reached 39.2˚C and CRP was 32.46 mg/dl. CT was performed to search for the cause of inflammation on the 6th day, but it could not be identified. At this time, the adrenal metastasis increased to 97x69 mm and one of the lung metastases had slightly increased to 13.6x4.8 mm, compared to 4 months earlier. Urine tests and blood and urine cultures were all negative. Therefore, it was considered that the inflammation was caused by the tumor itself, and radiotherapy was continued despite the high inflammatory response. The inflammatory reaction gradually decreased spontaneously during the treatment period. The treatment course of Case 2 is presented in Fig. 2. After radiotherapy, the adrenal metastasis shrunk gradually and had reached a size of 35x25 mm by June 2022. The pulmonary metastases also slightly shrank to 9.7x3.1 mm. The treatment field and CT images of the lung and adrenal metastases until June 2022 are presented in Fig. 3.

Figure 2 Clinical course during radiotherapy (Case 2). CRP, C-reactive protein; WBC, white blood cells; RT, radiation therapy; IrAE, immune-related adverse events.

Figure 3 Images for adrenal and lung metastases (Case 2). Lesions are indicated by yellow arrows. IC, iso-center; RT, radiation therapy; M, months; y, years.

However, in December 2022, the lung metastasis exhibited certain changes of calcification and dilatation of downstream bronchus with endobronchial effusion. This finding suggested secondary tracheal atresia, fungal infection or tumor recurrence. However, blood tests were all negative for serum beta-D-glucan (3), Aspergillus antigen, Mycobacterium avium complex antibody and the QuontiFeron test (4), which ruled out a fungal or mycobacterium infection. After one month, the lung tumor had continued to grow and PET accumulation was observed, so this change of lung metastasis was diagnosed as recurrence. There was no PET accumulation for adrenal metastasis. Bronchoscopy was not performed due to hemorrhage risk. Considering oligo-progression and previous adverse effects of tyrosine kinase inhibitor and ICI, stereotactic body radiotherapy (SBRT) to the lung metastasis with a dose of 48 Gy in 4 fractions was performed in February 2023. This time, no fever or CRP/WBC elevation was observed. After 3 months from the SBRT, tumor consolidation was observed and ground glass opacity around the tumor was enlarged. This change suggested tumor progression, tumor hemorrhage or inflammation after SBRT. In addition, new subpleural nodules were observed and lung atelectasis or lung metastasis was considered for this nodule. The size of the adrenal metastasis has remained unchanged since June 2022. This patient will continue to be followed up. The CT and PET images and treatment field of the lung are presented in Fig. 4.

Figure 4 Images of lung for Case 2. SBRT was performed for increasing lung metastasis. After the SBRT, enlargement of ground glass opacity around the tumor and a new nodule (arrow) were observed. RT, radiation therapy; PET, positron emission tomography; M, months; y, years; SBRT, stereotactic body radiotherapy.

Discussion and literature review

Abscopal effect has been reported in various carcinomas. Siva et al (5) suggested that this effect is transmitted by an acute inflammatory cytokine cascade and the immune system. Ionizing radiation releases cytokines, which elicit augmented tumor surveillance, inhibit tumor growth and have direct tumoricidal properties (6). In addition, ionizing radiation directly elicits innate immune recognition of a tumor: Dendritic cells are activated by irradiated dying cells and antitumor T cells are activated by the cross-presentation of tumor-derived antigens presented to T cells (7).

In clinical practice, however, an abscopal effect of radiotherapy alone is rare. In a literature review of abscopal effects of radiotherapy, only 46 cases reported between 1969 and 2014 were retrieved (8). However, the number of reports of abscopal effect in patients treated with a combination of radiotherapy and ICI has increased (9-17). In only one year, 2021, 21 case reports of abscopal effect promoted after radiotherapy were yielded (15,18-37). This is thought to be due to T-cell activation by a damage signal from irradiated dying cells and upregulation of programmed death receptor-1 and programmed cell death 1-ligand 1 (38,39), and an ICI disarms immune escape mechanisms, and this may increase the effects of the innate immune response activated by radiotherapy. Grimaldi et al (40) reported an abscopal response in 52% of patients with melanoma who received ipilimumab followed by radiotherapy.

In the present study, two cases of abscopal effect were reported. The most characteristic feature of the two cases is that both patients had FUC soon after the start of radiotherapy. Case 1, the patient with pleomorphic sarcoma, featured a pure abscopal effect. In this case, a fever was observed during the initial irradiation period, but since it was mild and there were no signs of infection, not much attention was paid to it. By contrast, the re-irradiation using proton therapy did not cause fever and no abscopal effect was observed. Case 2, a patient with RCC, exhibited an abscopal effect following radiotherapy after ICI. RCC frequently has periods of disease quiescence; however, lung metastasis in this case had an increasing trend at the start of radiotherapy; therefore, it was expected to increase after radiotherapy to the adrenal metastasis. In general, the prognosis of RCC after disease progression during treatment with an ICI is poor. In a retrospective analysis of 33 patients from 7 clinical trials, Barata et al (41) found a median progression-free survival (PFS) from initiation of molecular targeted therapy after progression on an ICI of 6.4 months (95% CI: 4.4-8.4 months). Roviello et al (42) obtained a PFS of 5 and 3 months (95% CI: 1-6 vs. 2-5; P=0.6) for patients who received active treatment and best supportive care, respectively, after progression of metastatic RCC while on nivolumab and cabozantinib. However, in Case 2 of the present study, adrenal metastasis was well controlled with a palliative dose and lung metastasis shrank over 3 years. This may be due to enhanced immune response to nivolumab and the strong inflammatory response observed during radiotherapy was also related to immune response. After almost 4 years, the lung metastasis recurred and SBRT was performed. This time, no inflammatory response was observed, and the disease is suspected to be progressing.

There was no evidence of a relationship between the abscopal effect and fever during radiotherapy. However, the abscopal effect is known to involve the activation of inflammatory cytokines and these two phenomena are both so unusual that they may not be coincidental. The two cases in the present study were treated palliatively and detailed data are missing. However, given that an inflammatory cytokine cascade is involved in the abscopal effect, it may be concluded that FUC during radiotherapy may be a hint to the abscopal effect, not by coincidence, although it is frequently considered as a tumor fever without much of a concern.

In conclusion, abscopal effect is rare and difficult to predict. A total of 2 cases of abscopal effect with FUC during radiotherapy were encountered at our institution. Awareness of FUC during radiotherapy may offer the possibility of better patient follow-up.

Acknowledgements

Not applicable.

Funding

Funding: No funding was received.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Authors' contributions

YO conducted photon radiotherapy on the 2 patients and wrote a draft of the manuscript. MM and HS conducted proton therapy on Case 1. MT and YO followed up Case 2. TH provided care for Case 1. MK, KT and KK provided care for Case 2. All authors contributed to manuscript revision, and have read and agreed to be accountable for the content of the work. All authors have read and approved the final manuscript. YO and MM checked and confirmed the authenticity of all the raw data.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Written informed consent for the publication of this manuscript, including case data and images, was obtained from each patient.

Competing interests

The authors declare that they have no competing interests.

References