The systemic immunostimulatory effects of radiation therapy producing overall tumor control through the abscopal effect

Mark A. D’Andrea1 & G. Kesava Reddy1

Received: 28 February 2019 / Accepted: 27 May 2019 # Springer-Verlag GmbH Germany, part of Springer Nature 2019

Abstract

Objective Emerging studies show that radiation therapy produces an important out of field (distant) effect known as the ‘‘abscopal effect^ in nonirradiated tumor sites. The objective of this study was to provide an overview of the current state of knowledge and clinical experience of radiation therapy producing abscopal effects in the management of different types of malignant diseases.

Methods Peer-reviewed published clinical evidence on the abscopal effect of radiation therapy was collected using electronic databases such as Medline via PubMed and Google Scholar. The reference lists were searched in the publications that we obtained in an attempt to find additional relevant publications. Non-indexed peer-reviewed journals were manually searched and relevant information was extracted. The search was restricted to English language articles. The clinical data on the abscopal effect of radiation therapy were reviewed and the outcomes have been summarized.

Results Currently, only clinical case reports and anecdotes have slowly converted into solid clinical data and interest is building in the field of radiation therapy, specifically on how local radiation can produce the abscopal effects for the management of different types of malignant tumors. Extensive clinical evidence suggests that the radiation therapy induced abscopal antitumor effects are mediated by immune cells such as the T-lymphocytes. This forms a basis for using radiation therapy in combination with immunotherapy to augment the abscopal response rates in cancer patients. Current evidence demonstrates that radiation therapy induces abscopal responses across many tumor types.

Conclusion Together, the clinical outcomes from published reports suggest that localized radiation therapy is capable of inducing abscopal effects in a wide variety of malignant tumors. With the advent of novel immunotherapies, the potential for immune activation by radiation defines a novel role for radiation therapy in the treatment of systemic disease. A clinical consideration of the abscopal effects produced by radiation therapy could lead to a revolutionary change in the current management of patients including radiation treatment strategies and immunotherapies for various malignant tumors.

Introduction

Radiation therapy plays a crucial role in the treatment of a multitude of malignancies. Approximately 60% of all newly diagnosed cancer patients will receive radiation therapy with a curative intent or in a palliative setting [13]. Conventional external beam radiation therapy doses that are effective at controlling local tumor growth are delivered in multiple small

Traditionally, the antitumor effects of radiation therapy were believed to be immunosuppressive; however, current evidence suggests that radiation therapy has potent immunomodulatory effects, by enhancing tumor immunogenicity and augmenting antitumor responses both locally and systemically [4]. While advances in radiation therapy technologies have largely focused on minimizing adverse local toxicities and optimizing the clin- ical benefits when treating localized tumors, recent investiga- tions have aimed to increase the immunomodulating effects that provide a promising frontier in extending the use of radiation therapy to treat both localized and metastatic diseases. In the recent past, studies have shown that the immunomodulating effects of radiation therapy involve stimulating the local im- mune system, which alters the immunosuppressive tumor mi- croenvironment. Alterations in the microenvironment then prompt reactivation of the immune response, a phenomenon called an abscopal effect of radiation therapy. The abscopal effect of radiation was originally described by Mole in 1953. He noted that localized radiation targeted at a malignant tumor triggered systemic antitumor effects [5]. The term abscopal effect derived from the Latin ab (position away from) and scopus (target or mark). This is also referred to as the Bdistant bystander effect^ and implies that radiation therapy has not only a locolized action on the target tumor tissue but also an out-of- field systemic antitumor effect [6].

Despite the fact that the abscopal effect of radiation has been known for decades, its existence was only rarely de- scribed in sporadic case reports. However, recent advances in the understanding of the immunomodulating effects of ra- diation have provided a renewed interest in investigating its distant antitumor effects thereby leading to additional clinical benefits in a variety of malignancies. Several case studies have shown that the abscopal effects of radiation therapy have been mostly observed in immunogenic tumors such as melanoma, kidney, lung, and hepatic cancers [7]. However, recent novel developments of immunotherapeutic strategies combining targeted immunomodulating systemic agents and immune checkpoint inhibitors with radiation have shown that the abscopal effect can be seen in both solid and hematological malignancies. Accumulating evidence suggests that these sys- temic combinations may complement each other’s therapeutic impact and offer greater clinical efficacy in the treatment of both localized and metastatic cancers. In this review article, we provide an overview of the current state of knowledge and clinical experience of the abscopal effect of radiation therapy.

A historical perspective of radiation therapy

The history of the use of radiation in medicine can be divided into four eras: the initial discovery era; the orthovoltage era; the megavoltage era; the new millennium era. During the initial discovery era, the fundamentals of radiation were established.

accelerators for photons that were successfully applied to treat different kinds of tumors. During this era, the efficacy and modern methods of delivering radiation therapy were demon- strated in well-designed clinical trials, the practice of radiation oncology became an independent and well-recognized medi- cal discipline in cancer therapy, and the first radiation oncol- ogy associations were founded [1617].

The new millennium era has been characterized by major innovations in radiation therapy which have evolved since the late 1990s [1618]. An important progress in radiation therapy was achieved by the introduction of more advanced three- dimensional conformal radiation therapeutic devices and treat- ment planning systems as well as stereotactic radiation thera- py that was more effective, especially for the treatment of complex and irregularly shaped tumors. These advances to- gether with the development of highly sophisticated radiation therapy treatment planning systems have led to the introduc- tion of novel treatment techniques to apply precise radiation to malignant tumors. These include intensity-modulated radia- tion therapy (IMRT) and image-guided radiation therapy y (IGRT) which have transformed the delivery of radiation to the tumor and the overall broadening the range of the appli- cations of radiation therapy.

daily doses, over several weeks. However, innovations in ra- diation therapy technologies have allowed the delivery of highly conformal radiation beams with increased precision while sparing the adjacent normal tissue. In addition to this, the advent of sophisticated imaging methods together with novel irradiation devices has led to the development of three-dimensional (3D) conformal radiation therapy, which uses 3D based beams to deliver higher doses of radiation. Other innovative techniques such as stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT), intensity-modulated radiation therapy (IMRT), and image- guided radiation therapy (IGRT) have transformed the deliv- ery of radiation and broadened its range of clinical applications.

In this era, Wilhelm Conrad Rontgen [8] discovered X-ray in 1895, although X-rays were produced earlier by others unwit- tingly. The discovery of X-ray was soon followed by Becquerel’s report [9] on the phenomenon of radioactivity in 1896, and Madam Curie’s discovery of radium as a source of ionizing radiation [10]. These discoveries paved the way for various novel radiation techniques such as teleradiotherapy, using a long source-to-surface distance (SSD), and later called external beam radiation therapy (EBRT), and brachytherapy, based on short SSD that is implanted into tissues and is deliv- ered with radium needles or surface molds [11].

In 1901, Becquerel and Curie reported on the physiologic effects of radium rays. During the first decade of the twentieth century, interest in studying the clinical use of X-rays increased and a number of studies reported its use in the treatment of skin cancers [12]. In the 1910s, Coolidge developed a new device able to emit higher energy X-rays, to treat deeper cancers [13]. It was only by the 1920s that a better understanding occurred about the biological effects and the total radiation dose and the importance in the fractionation of radiation for the treatment of malignant diseases. To understand the physical properties of X- rays and their biological effects, X-rays were used by Emil Herman Grubbe to treat a patient with breast cancer [14]. In addition to the discovery of X-rays, increased knowledge of gamma rays and the structure of the atom and its orbits with electrons, protons, and neutrons occurred to close out the first era. The orthovoltage era encompassed the late 1920s to 1950s in which a major achievement was made to measure the radiation dose using ionizing chambers with the development of the first accurate dose unit (the Röntgen unit) in 1932 [15]. In this era, the treatment of deep tumors was better addressed using radium- based intracavitary and interstitial irradiation (brachytherapy) due to the absence of deeply penetrating external beam sources. New developments in external beam therapy took place during this era leading to super voltage (approximately 500 kV–2 MV) radiation therapy which was made during this era. In the 1940s, electron beam acceleration became practical and useful as thera- peutic options in radiation medicine. The first device was devel- oped with 2 MeV electrons and subsequently, later devices yielded up to 300 MeV. In the mid-1940s, synchrotron devices were developed which allowed the energy of acceleration to be varied so that a deeper penetration of radiation into the tissue for

optimal cancer treatments could be achieved [1617].

The successive period, from the 1950s to 1990s, was regarded as the era of megavoltage radiation in which studies focused primarily on the development of innovative radiation therapeutic devices that could be used for the treatment of complex tumors located in the deep tissues. This era witnessed the introduction of the Cobalt teletherapy, generating high- energy γ-rays, and later more potent electron linear accelera- tors, able to deliver deeply penetrating megavoltage X-rays. The 1970s and 1980s witnessed the introduction of innovative devices delivering proton beams and computer-assisted

Mechanism of the abscopal effect

Historically, the clinical role of radiation therapy has been primarily focused on controlling and eradicating local disease by maximizing direct tumor cell damage while sparing the surrounding healthy tissues. The tumor cell death has been attributed to the ability of radiation to induce DNA damage leading to the eradication of local disease [19]. However, re- cent technological advances in accurate, high-dose radiation delivery have permitted the feasibility of its use to control the systemic burden in some cases of metastatic cancer. Evidence suggests that the abscopal effect is a consequence of the immunomodulating effects of radiation in the tumor microen- vironment through the clearance of tumors via diverse cell- killing mechanisms (Fig. 1) [20].

The complex mechanism behind the therapeutic abscopal effect is not completely understood, but immune-mediated cell death is thought to be a main component of the event. The immunomodulating effect of radiation is supported by several studies which have elucidated how combining radiation with immunotherapy can boost this effect. It is believed that the off- target effects of radiation at non-irradiated distant tumor sites are mediated by tumor antigen–primed T lymphocytes (T cells)

Fig. 1 Schematic drawing of the mechanism of the radiation therapy– induced abscopal effect in various malignant tumors. Irradiation of the tumor causes tumor cell destruction and initiation of the immune process by liberating tumor antigens and producing damage-associated mole- cules, which lead to the maturation of dendritic cells and improved prim- ing and activation of effector cytotoxic T lymphocytes. Tumor antigens

that travel to metastatic sites and promote tumor regression. It is hypothesized that radiation leads to the liberation of tumor an- tigens and the production of damage-associated molecules, which lead to the maturation of dendritic cells and T cell prim- ing in an immunogenic context [20]. In this process, the release of tumor antigens acts as pro-inflammatory mediators, stimu- lating monocyte production of the cytokines such as tumor necrosis factor, interleukin-1 (IL-1), IL-6, and IL-8. Collectively, these events promote tumor cell elimination by primed T cells. The relative importance of these alterations caused by radiation in the tumor microenvironment is still un- clear; however, it is believed that the immune system senses this damage and triggers immune response pathways resulting in several areas of systemic stimulation [21]. Studies have shown that radiation therapy can produce epitope spreading, thereby increasing the diversity of the T cell receptor repertoire of intra- tumoral T cells and broadening the antitumor response [22]. This can induce and improve an immune response specific to the tumor cells [23]. There is now a growing consensus from many studies indicating that combining radiation therapy with immunotherapy provides an opportunity to boost abscopal re- sponse rates.

 

Clinical evidence

 

A systematic literature review was performed in order to find published clinical evidence, primarily in the peer-reviewed liter- ature using electronic databases such as MEDLINE via PubMed and Google Scholar. The combinations of the key word Babscopal effect^ with any of the association to the following terms were used for the search in the database: radiation therapy, advanced cancer, malignant tumors, metastasis, systemic effects, immunomodulation, immunostimulation, immunotherapy, and oncology. We also searched the reference lists in the publications that we obtained in an attempt to find additional relevant publi- cations. Non-indexed journals were manually searched. The search was restricted to English language articles.

Clinical evidence of abscopal effects in response to radiation has been reported since the early 1970s. However, most of the evidence of the abscopal effects of radiation has been in the form of case reports (Tables 1234, and 5) [2475] and small nonrandomized studies [7677]. The clinical outcomes of these reports serve as a basis for the development of innovative ap- proaches for the treatment of various malignancies. In early re- ports, the abscopal effect following radiation has been demon- strated in immunogenic tumors such as melanoma, hepatic, renal, and lung cancers. Innovations in immunotherapeutic strategies which combine targeted immunomodulating agents and immune checkpoint inhibitors with radiation have revealed that the abscopal effect is more promising in both solid tumors and he- matological malignancies.

immunotherapy with nivolumab. Initially, the patient had a right upper lobectomy with combined resection of the parietal pleura and part of the right lower lobe along with a mediastinal lymph node dissection after neoadjuvant chemoradiation therapy. However, 6 months after the lobectomy, the patient developed a solitary liver metastasis and an intrapulmonary metastasis. The patient was then placed on unsuccessful nivolumab therapy. The patient was then treated with radiation therapy to a dose of 40 Gy delivered in 20 fractions to the liver metastatic lesions. Three weeks post-radiation therapy, the patient’s tumor size showed a remarkable reduction as did the intrapulmonary met- astatic lesions distant from the radiation field demonstrating the abscopal response of the radiation therapy.
Golden and colleagues [33] also reported the abscopal effect of radiation therapy in a patient with chemotherapy-refractory metastatic adenocarcinoma of the lung. The patient had progres- sive liver and bone metastases and was treated with ipilimumab followed by fractionated radiation therapy. The patient had an objective response at all disease sites and had no evidence of disease a year after treatment. Thus, this report found that hypo-fractionated radiotherapy induces abscopal responses when combined with checkpoint inhibitor therapy. Furthermore, the clinical outcomes of this case support that a combination of local radiotherapy and immunotherapy appears to be a useful strategy to improve the outcomes of patients with metastatic NSCLC who were historically known to have dismal prognoses.
Siva et al. [34] reported an abscopal response in a patient with synchronous primary lung cancer. In this case, the patient had chemoradiation to the bulky left-sided primary lung ade- nocarcinoma, approximately 5 months prior to the delivery of stereotactic ablative radiation therapy (SABRT) to the right- sided lung. Within 2 weeks of SABRT delivery, previously undetected metastatic progression was discovered. Five months following the delivery of SABRT, an abscopal re- sponse was observed with the disease regression at adrenal and humeral metastatic sites. Yoon and Lee [35] described a case of abscopal effect with multiple metastatic NSCLC. In this case study, the patient was treated with fractional radiation therapy, modulated electro-hyperthermia, and granulocyte colony-stimulating factor (G-CSF) while expecting an abscopal effect from the treatment. Following the completion of the radiation treatment, the patient experienced nearly com- plete remission in the multiple metastatic lymph nodes, which were distantly away from radiation therapy field. The out- comes from this case study suggest a successful abscopal ef- fect with local radiation therapy in combination with oncothermia and G-CSF immune-stimulation.

Abscopal effects in melanoma/skin cancer

Several case studies have been reported abscopal effects of radiation therapy in patients within metastatic melanoma (Table 2). In a recent melanoma case study report, Tsui and

colleagues [36] had demonstrated that palliative local radia- tion therapy (24 Gy, 3 fractions) not only controlled the pri- mary tumor growth but also produced regression of metastatic lung lesions suggesting the abscopal effect of radiation thera- py. Sims-Mourtada and co-investigators [37] also showed the abscopal effects of radiation in a patient with oligometastatic melanoma undergoing concurrent treatment with pembrolizumab and stereotactic body radiation therapy. Following the combination treatment with radiation plus pembrolizumab, the patient experienced both local as well as a systemic response as evidenced by an out-of-the radiation field improvement. In another recent case study, Komori et al.

  • reported that radiation therapy when combined with im- munotherapy agents such as nivolumab or ipilimumab exerted a booster effect on the immune responses to the tumor in a patient with metastatic Sperduto and co- investigators [39] have also shown that when a melanoma patient with multiple brain metastases was treated with radia- tion therapy followed by chemotherapy, the abscopal effect was observed. The patient experienced remarkable improve- ment in tumor growth control and remained free of disease for over 10 years after the completion of treatment.

In another study, Fujimura et al. [40] described the abscopal effects of radiation therapy using two cases of mul- tiple in-transit metastatic melanomas. Both cases were treated with IMRT in combination with ipilimumab or nivolumab. After 3–4 months of therapy, both cases had no further devel- opment of in-transit metastasis for several months suggesting the distant effect of the treatment. The abscopal effect of radi- ation therapy was also observed by Okwan-Duodu and col- leagues [41] in a case of patient with metastatic melanoma. In this case study, the patient underwent whole brain radiation therapy in combination with interleukin-2 immunotherapy. Following the treatment, the patient responded well and the metastatic disease was controlled indicating the abscopal ef- fects of the therapy. Teulings and colleagues [42] reported that the radiation produced a systemic antimelanoma immune re- sponse in a melanoma patient with brain metastatic lesions. Two weeks after completing a course of whole brain radiation therapy (20 Gy, 5 fractions), the patient developed depigmen- tation within and outside of the target volume, at sites not previously irradiated suggesting an abscopal effect of radia- tion therapy.

Stamell and co-investigators [43] also observed an abscopal effect in a recurrent metastatic melanoma patient when treated with palliative radiation therapy in combination with ipilimumab. The combination therapy achieved a robust response in all untreated cutaneous metastases supporting the immune hypothesis for the abscopal effect of radiation thera- py. Postow and colleagues [44] demonstrated a case of the abscopal effect of radiation therapy in a patient with metastatic melanoma who slowly progressed on ipilimumab mainte- nance treatment. Following treatment with palliative radiation

 

also act as pro-inflammatory mediators, stimulating monocyte production of the cytokines such as tumor necrosis factor, interleukin-1 (IL-1), IL-6, and IL-8. These cytokines together with the activated cytotoxic T lym- phocytes facilitate tumor cell elimination by attacking not only the tumor bulk in the irradiated area but also travel to metastatic sites and promote tumor regression or elimination, a process known as abscopal effect

Abscopal effects in lung cancer

There is a growing body of evidence that has emerged from published case studies supporting the abscopal effects of radi- ation therapy in metastatic lung cancer (Table 1). Recently, Bitran and colleagues [24] reported on a case of the abscopal response in a patient with metastatic lung cancer treated with local radiation therapy. The patient presented with a stage IV adenocarcinoma of the left lung with a large metastatic left adrenal lesion. Local radiation therapy to a dose of 27 Gy was delivered in 9 fractions to the left lung followed by immuno- therapy with nivolumab. Follow-up evaluation showed that the left adrenal metastatic lesion regressed significantly indi- cating the abscopal effect of the radiation therapy.

Kim and Kim [25] described the abscopal resolution of liver metastasis in a patient with a primary non-small cell lung cancer. The patient also had unresectable cholangiocarcinoma. After a failed initial chemotherapy, the patient received stereotactic body radiation therapy toa dose of 48 Gy delivered in4 fractions to the right upper lobe non-small cell lung cancer mass. After 3 months post-radiation therapy, the patient showed a spontaneous and complete regression of the metastatic liver lesions indicating the abscopal regression due to radiation therapy.

Lin and co-investigators [26] reported recently on a case of the abscopal effect after delivering stereotactic brain radiation therapy as a second-line treatment in a patient with lung adeno- carcinoma. The patient was initially diagnosed with poorly dif- ferentiated stage IV adenocarcinoma in the right lobe of the lung. Initial chemotherapy with paclitaxel and nedaplatin failed and the patient’s primary tumor enlarged. The patient later underwent immunotherapy with atezolizumab. Although the primary tumor and mediastinal lymph nodes were reduced after immunotherapy, the patient developed metastasis to the brain in the right parietal lobe. Stereotactic brain radiation therapy was administered to a dose of 48 Gy in 8 fractions and immunother- apy with atezolizumab was continued. Three months after radi- ation therapy to the brain, the nodules in the basal segment of the right lower lung had shrunk and the number of subpleural lesions in the basal segment of the left lower lung had reduced in size. In addition, multiple lymph nodes in the mediastinum had become smaller. These findings indicated the clinical evi- dence for the abscopal responses of radiation therapy.

Hamilton et al. [27] reported an abscopal effect after radio- surgery for solitary brain metastasis in a patient with advanced non-small cell lung cancer (NSCLC). The patient had a poorly differentiated NSCLC with a brain metastatic lesion. The pa- tient underwent radiosurgery to the solitary brain lesion. A total peripheral dose of 25 Gy was delivered in 5 fractions. One month following brain radiation therapy, a reduction in lesion size was observed in the brain. After 2 months post- treatment, a complete resolution of the original left upper lobe pleural-based mass was noticed indicating the abscopal re- sponse of the radiation therapy.

Britschgi and co-investigators [28] described a case of a metastatic non-small cell lung cancer patient who had a com- plete response secondary to an abscopal effect of stereotactic body radiation therapy delivered in combination with anti- programmed cell death protein 1 (PD-1) immunotherapy with nivolumab. Following the progression with the nivolumab therapy, the patient received stereotactic body radiation thera- py to a dose of 18 Gy delivered in 6 fractions to two of the three lymph node metastatic lesions while continuing immu- notherapy. Ten weeks post-radiation therapy, a complete ra- diological and metabolic response was seen in not only the irradiated lymph node metastatic lesions but also in the non- irradiated lesion of the third lymph node revealing the abscopal effect of radiation therapy.
Cong et al. [29] reported an abscopal response in a patient with metastatic NSCLC. Following the diagnosis of NSCLC, after a failed first-line chemotherapy with cisplatin and pemetrexed, the patient received gefitinib therapy. In addition, the patient received the first dendritic cells and cytokine- induced killers (DC-CIK) immunotherapy. However, the pa- tient showed a marked tumor progression in the lung. The patient then received stereotactic ablative radiation therapy (SABRT) to a dose of 37.5 Gy in 5 daily fractions for the paramediastinal foci. A follow-up chest X-ray performed 10 months after completion of SABRT showed a complete regression of pulmonary lesions suggesting an abscopal re- sponse of radiation therapy.
Katayama and colleagues [30] reported the abscopal effects of radiation therapy in a patient with metastatic NSCLC. This patient underwent whole brain radiation therapy (WBRT) plus a boost of radiation therapy to a total dose of 45 Gy delivered in 15 fractions. The metastatic brain tumor presented with cerebral edema from the left temporal lobe to the occipital lobe rapidly progressed after the enucleation of their brain tumor. The patient also received palliative radiation (30 Gy in 10 fractions) for a third lumbar vertebral metastasis. The tumor in the left upper lobe of the lung and his mediastinal lymph nodes had regressed in size indicating the abscopal effects of radiation therapy. Furthermore, these authors con- cluded that the abscopal effect can occur after the irradiation of metastatic lesions without chemotherapeutic or immuno- therapeutic interventions.

effect of radiation therapy in a patient with neuroendocrine atypical carcinoid lung cancer. In this case, the patient underwent palliative radiation with 30 Gy delivered in 10 fractions targeted to a symptomatic calvarial metastasis. One month after radiation, she noted a rapid im- provement in her skin nodules suggesting the abscopal effects of radiation therapy. The patient had a durable complete re- sponse post-radiation even after 18 months had passed.
Komatsu and co-investigators [32] reported on a case of the abscopal response in a lung cancer patient who progressed on

therapy (28.5 Gy, 3 fractions), tumor regression was observed in both the irradiated tumor and non-irradiated metastases suggesting the abscopal effect of radiation therapy. The abscopal effects of radiation therapy were also reported by Hiniker et al. [45] in the case of a patient with recurrent stage IIA cutaneous melanoma. Radiation therapy in combination with ipilimumab not only produced a complete regression of the primary tumor but also achieved a complete resolution of all metastatic liver lesions suggesting the abscopal effect of radiation therapy. Kingsley [46] has also shown the abscopal effects of radiation therapy in a patient with inguinal, pelvic, and para-aortic lymphadenopathy from melanoma. Following irradiation of only the inguinal lymphatics with 14.4 Gy of fast neutrons in 12 fractions over 35 days, the patient experienced regression of all lymphadenopathy supporting the abscopal effects of the irradiation.

Abscopal effects of radiation therapy were also ob- served in other skin cancers such as sarcoma and Merkel cell carcinoma. Orton and co-investigators [47] reported the first case of a complete abscopal resolution of untreated lung metastases in a patient with a primary pleomorphic sarcoma of the head and neck treated with hypo- fractionated radiation therapy. Similarly, Cotter et al. [48] demonstrated the abscopal effect in a patient with metasta- tic Merkel cell carcinoma following irradiation. The local- ized radiation therapy not only controlled the tumor growth but also achieved complete resolution of all metastatic un- treated lesions supporting the abscopal effect.

Abscopal effects in renal cell carcinoma

Abscopal effects of radiation therapy were reported sporadically in patients with renal cell carcinoma (RCC) using case studies (Table 3). In a most recent case series study, Giulio and col- leagues [49] reported abscopal effect of radiation therapy in one of the three patients with metastatic RCC. After treatment with stereotactic body radiation therapy and subsequent treat- ment with anti-PD-1 inhibitor, with nivolumab, the patient expe- rienced not only regression of the treated tumors but also achieved a distant response suggesting the abscopal effect. LaPlant and co-investigators [50] have shown that radiation ther- apy in combination with immune check point inhibitors exerted abscopal responses in RCC patient with innumerable pulmonary metastases. The patient remains disease-free without evidence of pulmonary or nodal metastases even 1 year after completing the combination therapy. Ishiyama et al. [51] have shown the spon- taneous regression of thoracic metastases with the progression of brain metastases in a patient with metastatic RCC following SRS and SBRT to bone and spine lesions. Specifically, after irradia- tion, they reported a regression of the lung and lymph node metastases supporting the abscopal effects of radiation therapy.

Wersäll and colleagues [52] reported abscopal responses in 4 cases of 28 patients with metastatic RCC treated with the

stereotactic radiation therapy (SRT). In 3 of the 4 patients, un- treated metastatic disease completely regressed without a relapse at the time of reporting which ranged from 2 to 4 years post therapy. MacManus et al. [53] reported a representative case in which the patient had a large primary RCC with lung and medi- astinal lymph node metastases that regressed after irradiation of the primary tumor. Fairlamb [54] also reported an abscopal effect in two patients with RCC. One of the two treated patients expe- rienced a resolution in the pulmonary metastatic lesions and remained free of disease for over 4.0 years.

Abscopal effects in hepatocellular carcinoma

Although there are few case reports of abscopal effect in hepatocellular carcinoma (HCC), these cases primarily de- scribed regression of HCC itself due to radiation treatment delivered at a metastatic site (Table 4). Lock and col- leagues [55] described a case of the abscopal effect in a patient with metastatic HCC. Following local radiation therapy to the liver, the patient had a treatment response   in the liver and a complete response in the lung. Similarly, Okuma et al. [56] reported a case of the abscopal effect in a HCC patient who underwent an extended right hepatic lo- bectomy. The patient subsequently developed a single right lower lobe lung metastasis and a single mediastinal lymph node metastasis. The patient then underwent external beam radiation therapy which was delivered to the mediastinal lymph node. No other therapies were administered to the patient. Follow-up examination indicated not only a reduc- tion in the lymph node size but also the spontaneous shrinking of the lung metastasis supporting the induction  of an abscopal effect by the radiation therapy.
In another report, Nakanishi and colleagues [57] reported an abscopal effect of radiation therapy in a patient with HCC. In this case study, the patient had a selective transcatheter arterial embolization and localized external beam radiation therapy to the disease in the right lobe only. After 5 months, the patient’s follow-up examination revealed the regression of bi-lobar disease. Nam and co-investigators [58] also described a case of abscopal regression of HCC and all bony metastatic sites following the completion of palliative radiation to a skull lesion. In this case, the patient initially refused any traditional therapy and instead started ingesting a mushroom called Agaricus (Phellinus linteus) for 18 months. However, the pa- tient developed skull lesions. Then, the patient underwent pal- liative radiation therapy to a  skull lesion. Follow-up at   3 months indicated a treatment response of the liver disease and regression of the untreated lesions indicating the abscopal effect of the radiation. In another case, Ohba et al. [59] report- ed an abscopal response in a patient with metastatic HCC. Two years after the initial liver-directed therapy, the patient was not responsive and developed vertebral bony metastasis. External beam radiation therapy was used as a palliative

therapy to control the pain in the involved vertebra. The pain has reduced considerably and the patient’s α-fetoprotein was found to be decreased. Imaging evaluation showed a resolu- tion of the bony lesion and regression of the liver lesions to a very small size 10 months after the radiation treatment.

Abscopal effects in other solid tumors

The abscopal effect of radiation therapy was reported sporad- ically in cases of other malignant tumors such as colorectal, bladder, esophagus, breast, thyroid, pancreatic, thymoma, and other cancers (Table 5). Ebner and colleagues [60] reported the first two cases of an abscopal response following heavy- ion irradiation in patients with metastatic colorectal cancer. In this study, the two patients had an abscopal response after treatment with carbon ion irradiation. In one case, the patient experienced disease remission of 46 months with a reduction in the size of the non-irradiated tumor. In the second case, the patient had remission and stable disease of 92 months with a reduction in the size of the non-irradiated tumor. More specif- ically, abscopal responses were observed in the lymph nodes downstream of the treated site in both patients. Joe et al. [61] reported the first case of the abscopal effect of radiation ther- apy in squamous carcinoma of the anus with metastases to pelvic lymph nodes, liver, and bone. In this case, the patient had an abscopal response after treatment with palliative radi- ation therapy to the pelvis. Specifically, following treatment with palliative radiation therapy, the patient experienced a complete response not only in the primary anal tumor but also in bone and multiple liver metastases.

Smith and co-investigators [62] described an abscopal ef- fect in a patient with pulmonary metastases from transitional cell carcinoma of the bladder. In this study, two cases of spon- taneous complete regression of the lung metastases from the transitional cell carcinoma were reported. In one case, the regression of the metastatic lesions occurred after a course of radiation to the primary bladder cancer. In the second case, the lung lesions disappeared without treatment to the primary or metastatic cancers. Similarly, Lome and colleagues [63]

reported a case of pulmonary metastases from transitional cell carcinoma of the bladder following treatment with radiation therapy. In this case study, the lung nodules disappeared after a course of radiation therapy to the urinary bladder suggesting its abscopal effectTakaya et al. [64] reported a case of an abscopal regression in a patient who had an advanced uterine cervical carcinoma with para-aortic lymph node metastases. In this case, the patient was treated with external beam whole pelvis and intracavitary irradiation to the primary pelvic le- sion. At follow-up, the patient was found to have not only a complete response of the primary pelvic lesion, but also the regression of her para-aortic lymph node metastases indicating an abscopal effect of radiation therapy.

Rees and Ross [65] described two cases of abscopal regres- sion following radiation therapy in patients with metastatic esophageal cancer. Although the abscopal regression of the lung metastases from esophageal carcinoma was short lived after radiation therapy, in another patient, the abscopal re- sponse lasted approximately 20 months. In metastatic breast cancer, recently, Leung and colleagues [66] described the first case of the abscopal response following treatment with radia- tion therapy. In this case study, the patient with metastatic breast cancer received multiple fractions of high-dose radia- tion therapy that directly targeted the local breast tumor. An amelioration of distant bone metastasis was seen in the patient following radiation therapy indicating the abscopal response. Azami and co-investigators [67] reported on a case of the abscopal response in a patient with a metastatic breast cancer who received local radiation therapy. At presentation, the pa- tient had a sizable breast mass and subsequent evaluation re- vealed metastatic osteolytic lesions in the left femur, lumbar vertebrae, and sacrum. The patient received localized pallia- tive radiation therapy to a total dose of 60 Gy delivered in 30 fractions to the breast tumor. In addition, the patient received radiation therapy to some of her bone metastases. Follow-up evaluation after 10 months revealed a dramatic disease remis- sion, determined as complete response, not only in all the irradiated sites but also in all the sites that were non- irradiated suggesting the abscopal response.

Tubin and colleagues [68] described an abscopal response of radiation therapy in a patient with metastatic medullary thyroid carcinoma. These investigators, for the first time, ob- served the rare radiobiological phenomenon of the spontane- ous regression of an un-irradiated tumor in a course of radia- tion of another, distant lesion in a patient affected by thyroid carcinoma. The abscopal effect of radiation therapy was also reported by Sato et al. [69] in the case of a patient with locally and peritoneally recurrent gastric cancer. In this case study, the patient experienced an abscopal response after treatment with intensity-modulated radiation therapy (IMRT) with concur- rent adoptive T cell immunotherapy.

Shi and co-investigators [70] reported an abscopal response in a patient with advanced metastatic pancreatic cancer. Initially, the patient was administered single-agent chemother- apy gemcitabine. After the first cycle of gemcitabine therapy, the patient developed multiple metastases in the liver. The patient was then switched to another single-agent chemother- apy with paclitaxel. However, the patient’s primary tumor progressed and an additional right pleura metastasis was de- veloped. Later, the patient had failed targeted therapy with apatinib. The patient underwent palliative radiation therapy to a total dose of 45 Gy delivered in 15 fractions to her primary pancreatic tumor. Concurrently, the patient also had treatment with a granulocyte-macrophage colony-stimulating factor. Within weeks, the primary tumor on the pancreas shrunk sig- nificantly. Remarkably, the metastases had also shrunk signif- icantly indicating the abscopal effect of radiation therapy.

Lesueur and co-investigators [71] reported on the occur- rence of a post-radiation therapy abscopal response in a patient with a metastatic thymoma, which is the first case of the abscopal effect related to a thymic carcinoma reported in the literature. Following palliative radiation therapy to a sternal mass, the patient experienced not only a partial response of the primary tumor but also the complete regression of their lung lesions that were distant from the planned target volume with- out the use of antineoplastic agents or steroid therapy.

Schaub and colleagues [72] reported the first case of an abscopal effect in a patient with a recurrent Merkel cell carcino- ma involving multiple skin and subcutaneous lesions on the face and scalp. The patient had a history of chronic lymphocytic leukemia. The patient was initially diagnosed with Merkel cell carcinoma of the glabellar region, for which he underwent a wide local excision with positive margins, and lymphovascular inva- sion. The patient then received conventionally fractionated radi- ation therapy delivered postoperatively to the primary surgical bed. The patient had an initial local response but progressed with an additional 3 dermal lesions. Despite treatment with immuno- therapy using pembrolizumab, the patient’s facial lesions contin- ued to progress, and new dermal and subcutaneous lesions de- veloped diffusely over his face and scalp. The patient received a short course of neutron radiation therapy (2 × 3 Gy) delivered to five of the most symptomatic lesions while continuing

have shown that radiation therapy exerts synergistic antitumor effects when combined with immunotherapy and produces a durable abscopal effect in a variety of advanced malignancies. Currently, several clinical trials are being conducted to address safety and other limitations of the combination of radiation therapy with novel immunotherapeutic agents. With parallel developments in radiation techniques and innovations in nov- el immunotherapeutic agents, there is a great motivation for cross-disciplinary research on combining these two modalities in cancer treatment. In addition, such efforts can boost the radiation-induced abscopal response rates and continue to im- prove the patients’ chance of increased survival who benefit inadequately from radiation therapy or immunotherapy alone.

Compliance with ethical standards

This article is not a direct report of any investigation with the involvement of human or animal subjects performed by any of the authors.

Funding No funding was received for this study.

Conflict of interest The authors declare that they have no conflict of interest.

Ethical approval This article has no direct invlovement of human par- ticipants or animals for evaluation by any of the authors.

Informed consent Statement of informed consent was not applicable since the manuscript is not a direct report of any investigation with the involvement of human subjects.

 

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pembrolizumab. Two weeks following radiation therapy, a com- plete response was seen in all irradiated facial lesions. Remarkably, an additional four lesions located outside the radia- tion fields also completely regressed suggesting the abscopal effect of neutron radiation therapy.

Barsky and co-investigators [73] reported on the first-ever abscopal effect after palliative radiation therapy and immunother- apy in a patient with malignant pleural mesothelioma. Following his diagnosis, the patient initially received intrapleural interferon- alpha gene therapy but discontinued therapy due to the develop- ment of supraventricular tachycardia and superior vena cava syndrome due to the tumor burden. The patient emergently underwent palliative radiation therapy to a dose of 30 Gy deliv- ered in 10 fractions to his mediastinum and pleura tumor follow- ed by pemetrexed and cisplatin chemotherapy. Two months after radiation therapy, the patient experienced a dramatic treatment response within, as well as outside of, the irradiated field reveal- ing the abscopal effect of neutron radiation therapy.

Desar et al. [74] described an abscopal response of radia- tion therapy in a patient with metastatic diffuse-type giant cell tumor. Following treatment with radiation therapy, the patient experienced not only the response in the right-sided irradiated hilar lesion but also a volumetric and metabolic response of the left-sided non-irradiated pulmonary metastases and an in- crease of uptake in one mediastinal lymph node suggesting an abscopal response from  radiation  therapy. It persisted for 6 months, after which he progressed and died from disease 3 months later. Ehlers and colleagues [75] reported the first case of an abscopal response in a patient with papillary ade- nocarcinoma. Following irradiation of the local tumor, these authors observed not only a local tumor response but also the regression of distant mediastinal lesions suggesting the abscopal effect of radiation therapy.

Conclusion and future perspectives

Radiation therapy has long been recognized as a potent local cytotoxic therapy for the management of malignant tumors. However, radiation therapy can also stimulate a systemic phe- nomenon which can lead to regression and annihilation of non-irradiated, distant tumor lesions. This regression of dis- tant cancer metastases when the primary tumor irradiated is defined as the abscopal effect. The abscopal effects of radia- tion therapy have been documented since the beginning of the twentieth century and have made their way into sporadic clin- ical case reports.

Despite still being a rarely reported phenomenon, interest on the abscopal effects of radiation therapy is growing, partic- ularly after the clinical development of novel immunothera- peutic agents for the treatment of cancers. Current evidence indicates that the abscopal effects of radiation therapy have been observed across all tumor types. Several recent studies

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