Abstract
Background/Aim: We evaluated local control and toxicity in patients receiving radiotherapy associated with immune check point inhibitors and analyzed which oligometastatic disease setting benefits the most from local ablation in terms of advantage in overall survival. Patients and Methods: We retrospectively identified 60 oligoprogressive patients treated with a PD-1 inhibitor in association with radiotherapy on the site of progression (119 lesions). Results: After a median follow-up of 11.7 months (range=1-39 months), we observed complete response (CR) in 45/119, partial response (RP) in 42/119, and stable disease (SD) in 30/119 patients. Nine radionecrotic events occurred. Two patients experienced grade 3 toxicities and 32 patients reported grade 2 toxicities. The number of radiologically evident metastatic organs in patients who received concomitant PD-1 inhibitors and radiotherapy showed a significant increase in survival (respectively, 73% after 12 months and 47% after 24 months) in patients with 0-3 metastatic organs compared to those with more than 3 organ sites involved (p<0.0001). Conclusion: Radiotherapy associated with PD-1 inhibitors is overall safe and efficacious. Patients eligible for intensification of local treatments should have less or equal to 3 metastatic organ sites.
- Radiotherapy
- immunotherapy
- stereotactic radiotherapy
- intensity-modulated radiation therapy
- hypofractionated radiotherapy
- target therapies
- immune checkpoint inhibitor
Metastatic disease is the leading cause of cancer-related mortality and remains a major challenge in the treatment of solid tumors. Most patients with metastatic disease are treated with systemic agents, which prolong survival and may relieve symptoms, but generally fail to be curative. Most of these patients are unable to achieve long-term survival with systemic therapies alone. However, notable exceptions exist, including subgroups of patients with metastatic melanoma (1), non-small cell lung cancer (NSCLC) (2), or kidney cancer (3) treated with immunotherapy, or those with germ cell tumors treated with chemotherapy (4). The high mortality of many patients with metastases has led to the common view that metastatic disease is inevitably widespread and incurable.
However, the oligometastatic hypothesis proposes that the aggressiveness of metastases may vary depending on the presence of one, few, or many systemic sites. This hypothesis challenges the prospect that metastatic disease is an unalterably widespread process and instead proposes a metastatic “virulence” biological spectrum (5-7). Increasing evidence supports the idea that patients with numerically and/or spatially limited metastatic sites, called oligometastatic, can prolong survival thanks to local therapies directed to the metastases, such as radiotherapy.
In light of this, improvements in the clinical and molecular staging of metastatic disease, as well as in the new systemic therapies integration with localized interventions, could guarantee better results for patients with characteristic metastatic profiles. This concept suggests that the effectiveness of personalized therapies directed at solid neoplasms should reflect the metastatic profile of each individual and in this context, localized interventions such as radiotherapy may be very effective in patients with a reduced number of neoplastic secondaries or with a limited number of organs involved. Several prospective randomized studies have shown promising results in patients with oligometastatic disease due to the use of local treatments compared to patients who received only systemic therapy (8-12).
Emerging evidence has also identified both tumor and host-related biological factors that may influence the aggressiveness of the metastatic disease. In this context, the molecular subtyping of clinically evident metastases and relevant experimental data have shown that innate and adaptive immunity is essential for the control of metastasis and are associated with better clinical results after the use of local therapies. Therefore, counteracting the immunosuppression that underlies metastatic dissemination represents an opportunity to substantially improve the clinical outcomes in this patient setting. In this scenario, strategies that increase the immune system responses, such as inhibition of the immune checkpoints, play a crucial role in the management of these diseases. Furthermore, the addition of radiotherapy to immunotherapy in patients with diffuse malignancies is gaining interest, based on the concept that radiotherapy can modulate the host’s immune system, enhancing the response to immunotherapy (13-19).
In this study, we evaluated the local control and toxicity in patients receiving these integrated therapies and analyzed which oligometastatic disease presentations benefit the most from local ablation in terms of prolonging overall survival.
Patients and Methods
We retrospectively identified oligoprogressive patients affected by non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), metastatic melanoma, and nasopharyngeal squamous cell carcinoma treated according to standard treatments with a PD-1 inhibitor in association with stereotactic radiotherapy regimens or hypofractionated radiotherapy regimens. The radiation treatments were administered according to the indications of the Italian Association of Oncological Radiotherapy (AIRO) and the European Society of Therapeutic Radiation Oncology (ESTRO).
The therapies were dispensed after the packaging of a customized immobilization system, CT centering, fusion of images with computed tomography/magnetic resonance imaging/positron emission tomography (based on clinical appropriateness), and compilation of a tridimensional conformational care plan, intensity-modulated radiation therapy, intensity-modulated radiation therapy-simultaneous integrated boost, fractionated stereotactic radiation therapy, or volumetric-modulated arc therapy. Treatment volumes and dose limits are imposed by the structures surrounding the irradiated site. The fractionation was daily and, when appropriate, the positioning was verified by cone beam computed tomography. Gross tumor volume (GTV) was defined as the entire tumor seen on all available images. In cases of a suspected clinically relevant microscopic disease, a clinical target volume (CTV) was generated by expanding the GTV based on the volume, location, and time of onset of the treated lesions. In all cases, a margin was added to create a target planning volume (PTV). Regarding timing between systemic and local treatments, only those patients on active therapy with immune checkpoint inhibitors who received radiation without interrupting medical therapy were included.
All patients who signed informed consent forms before treatment were treated after multidisciplinary discussion and were followed up at regular intervals by the radiotherapy and medical oncology physician during and after therapy. Regarding radiation treatment, patients were re-evaluated after 4 weeks and then, underwent regular checkups at 3-4-month intervals until death or the day of the last follow-up. All patients were followed up at 2-3-week intervals in conjunction with the administration of immunotherapy.
Characteristics of patients and statistical analysis. From August 2017 to March 2020, we treated sixty oligoprogressive patients suffering from metastatic disease with stereotactic radiotherapy or hypofractionated radiotherapy, in conjunction with PD-1 inhibitors, for a total of 119 treated lesions. The intent of direct treatment for metastases was ablative in 70 cases (58.8%) and palliative in 49 cases (32.2%).
Concomitant medical therapy with RT consisted of pembrolizumab in 49 cases (41.17%), nivolumab in 62 cases (52.1%), five radiation treatments were delivered concurrently with atezolizumab (4.2%) and three with durvalumab (2.5%). Primary tumors were represented by: 100 cases of NSCLC (84%), of which 72 were adenocarcinomas (72%), 28 squamous cell (28%), and 11 cases of renal cell carcinoma (9.2%), melanoma (4.2%), and carcinoma of the nasopharynx (1.6%) (Table I). The 3D conformal technique was used in 40 (33.6%) cases and intensity-modulated radiotherapy with or without overdose in 15 (12.6%). The remaining patients received single or multiple fractions, fixed-field, or arc-modulated stereotaxic radiotherapy (53.8%).
Patient characteristics.
Fifty-seven lesions were irradiated within the fourth cycle of immunotherapy (47.8%), whereas 62 thereafter (52.2%). Fifteen out of 60 patients underwent radiation therapy with many radiologically evident metastatic sites (intended as the number of organs involved and not as the total number of secondaries) between 0 and 1 (25%), 36/60 had secondary involvement in 2 or 3 disease sites (60%) and 9/60 more than 3 (15%). At the time of analysis, 30 patients (50%) had died. The median follow-up for all patients was 11.7 months (range=1-39 months). Thirty patients (50%) received a single target treatment, whereas the other 30 (50%) received two or more courses of radiotherapy.
Twenty-nine lesions (24.3%) out of 119 treated were located in the bone and 59 (49.5%) in the brain, which therefore represented the site most involved and was deemed worthy of dedicated statistical analysis. In our institute, brain metastases are usually treated with multiple-fraction SRS (mfSRS) to minimize the increased risk of radiation-induced late brain necrosis (RN) most associated with high-dose single-fraction SRS. Other sites involved were the lung [15/119 (12.6%)], lymph nodes [8/119 (6.2%)], and muscle [4/119 (3.1%)]. Two patients received RT for skin implants, one for renal disease involvement and one for adrenal gland metastases.
The treatment was delivered by a linear accelerator with photons of a nominal energy of 6-15 MV. The average value of the isodose line at the PTV was 95% (range=90-98%). The prescribed doses varied between 20 Gy and 60 Gy in 1-20 fractions [range equivalent dose in 2-Gy fractions (EQD2) 3/10: 28/23.3-46.67/28, Range BED 3/10: 226.8/126-378-151, 2].
The Kaplan-Meier method was used to calculate overall survival (OS) and progression-free survival (PFS) rates. The OS was defined from the end of the radiation treatment until death or the drafting of the statistical analysis. PFS was defined from the termination of radiation treatment until the radiologically determined appearance of new metastatic sites of disease. The receiver operating characteristic (ROC) curves were used to find the limit values for the continuous variables.
Median survival was reported with 95% confidence intervals. The survival rates at 6, 12, and24 months were calculated separately based on the performance status and the number of metastatic sites of the disease for the entire population under examination, whereas for patients affected by brain metastasis, they were calculated based on the possibility of systemic disease control.
Subgroup univariate analysis was performed to evaluate the predictive value of the various prognostic factors investigated. The factors studied were: ECOG performance status, number of metastatic sites less than/equal to 3 or greater, number of immune-checkpoints inhibitor (ICI) cycles performed before radiation treatment (cut-off=4), control of extracranial disease in patients with brain metastases. The chi-squared test was performed to compare the toxicity related to the different fractions in patients treated on the brain.
Toxicities were assessed at each follow-up based on the Radiation Therapy Oncology Group Scale (RTOG) for acute and late side effects. The new immune-related response criteria (iRecist) were used for the evaluation of local responses. A p-value<0.05 was considered statistically significant. Data analyses were performed using SPSS v24.
Results
The primary endpoints of this study were local control and toxicity, whereas secondary endpoints included OS and PSF, as assessed by stratifying the risk groups.
Local control and toxicity assessment. After a median follow-up of 11.7 months (range=1-39 months) for all patients, 19 of 59 irradiated brain lesions had complete response (CR), 28/59 partial response (RP), and 10 stable disease (SD). A patient, who underwent panencephalic radiotherapy for multiple brain metastases and with two lesions between 2 and 3 cm in diameter for which no surgical indication was indicated, turned out to be a non-responder and died in absence of systemic disease.
Among the irradiated extracranial metastases, a complete morphological response was observed in 17/60 lesions, a partial response in 23/60, and disease stability in 20/60. All the lesions for which there was a clinical indication to perform a PET/CT scan showed a complete response within 6 months after the end of treatment. There were three locoregional relapses after radiotherapy, two involving bone lesions (right humerus and left pelvis) that required re-irradiation, and one involving a pulmonary nodule located in the right lower lobe which was evident 6 months after RT treatment at a PET/CT scan. The patient continues immunotherapy (IT) with good systemic disease control.
Acute and late toxicities were detected by the RTOG scale. Acute and chronic toxicities were identified on the site of radiotherapy. Among the 59 brain lesions treated, four acute toxicities (6.7%) occurred, including three characterized by a radiologically demonstrated increase in perilesional edema and one characterized by hemorrhage within the irradiated lesion. Both complications were asymptomatic and spontaneously regressed during follow-up. Regarding late brain toxicities, nine radionecrotic events were observed at MRI (15.2%) after a median time of 12 months from treatment.
Among these brain toxicities, six (66.6%) were asymptomatic, while three (33.3%) revealed clinically relevant manifestations, two with epilepsy and one with motor deficit due to the site of onset. All were radiologically checked, treated with low doses of steroids along with ongoing immunotherapy (dexamethasone 2 mg/day). The patient who experienced epilepsy showed systemic progression after 16-months with stable radionecrosis and controlled epilepsy following first-line drug treatment. The patient with motor impairment due to RN is still in follow-up and on active medical therapy with pembrolizumab. The irradiated brain disease is largely controlled and the symptoms due to radionecrosis are stable.
Among the nine radionecrotic events, four (44.5%) occurred on lesions previously irradiated with the 9 Gy × 3 stereotactic technique, who received panencephalic therapy for intracranial progression of disease. Eight patients received radiotherapy on the neck or mediastinal lymph nodes. Among these, three (37.5%) reported acute G2 dysphagia, but none experienced late toxicity.
Among the 15 treatments performed on the lung, only one patient (6.66%) experienced severe treatment-related pneumonia that required hospitalization and adequate medical therapy (steroids and antibiotics). After complete recovery of symptoms, the patient completed the radiation treatment but suspended ICI until the end of radiotherapy. Three out of 15 patients were irradiated with FSBRT for pulmonary localizations. A control total body computed tomography showed the onset of mild fibrosis on the treatment site in the absence of metabolically active neoplastic disease and therefore, follow up is continued.
The patient irradiated with 3 Gy × 10 3D radiotherapy on a left adrenal gland metastasis concomitant with ICI experienced severe diarrhea after three radiotherapy sessions, which led to suspension of active treatment for two weeks. After resolution of symptoms, she completed a course of RT without concomitant immunotherapy.
However, the difference in toxicity according to treatment site was not statistically significant and we found no significant association between increased EQD2 and radioimmune-related adverse events of any degree. Twenty-nine patients (24%) reported grade 2 fatigue and asthenia during radiation treatment. None of the patients irradiated on the bone, skin, and muscle metastases presented treatment-related toxicities.
Survival functions. Twenty-nine patients (51%) died at the time of this retrospective study, with a median cumulative survival of 64% after one year and 45% after 21 months. Stratification of patients based on performance status (0-1 vs. 2) did not show significant advantages in terms of OS or PFS for patients with a better ECOG PS (p=0.463). Twenty-three patients (60.9%) received more than 4 cycles of ICI before radiation treatment, but this setting of patients did not show an OS or PFS advantage compared to those who received four or fewer courses of immunotherapy before the RT (p=0.381).
The number of radiologically evident metastatic sites in patients who received radiotherapy concomitantly with PD-1 inhibitors showed a significant increase in overall survival (respectively, 73% after 12 months and 47% after 24 months) in patients with 0-3 metastatic organs compared to other patients with more than three different organ sites involved (p<0.0001).
Cerebral progression after extracranial RT was not associated with a significant survival reduction; in the 51 patients who experienced it, it was related to a high percentage of local intracranial control obtained with FSBRT and salvage WBRT (p=0.508).
The median PFS in patients undergoing radiotherapy was 4 months (range=1-38 months). Similarly, the OS was not significantly affected by PS (p=0.18) or by pre-RT IT cycles (p=0.696). Patients with three or fewer metastatic organ sites obtained a significant advantage after RT in terms of systemic (p≤0.0001) and brain (p=0.002) PFS.
In the subgroup of patients irradiated on the brain, which constitute a large subgroup, the median OS was 13 months (range=7.5-38 months). Despite the low median PFS of 4 months (range=1-38 months), division into subgroups showed that the main factor affecting prognosis was the total number of extracranial metastatic diseases (≤3) (p≤0.0001) or systemic disease control (p=0.001) (Figures 1-6).
Overall survival for all patients.
Survival function in all patients based on the number of metastatic organ sites. The number of radiologically evident metastatic sites in patients who received radiotherapy concomitantly with PD-1 inhibitors showed a significant increase in overall survival (respectively, 73% after 12 months and 47% after 24 months) in patients with 0-3 metastatic organs compared to other patients with more than three different organ sites involved (p<0.0001).
Survival function in all patients based on the extracranial stability of the disease intended as no new metastases within 6 months following radiation treatment (1, red) vs. extracranial progression within 6 months after RT (0, blue). p=0.001.
Patients who received intracranial treatment with extracranial stability of disease (1, red line), defined as no new metastases within 6 months following radiation treatment, had significant better OS compared to patients with extracranial progression within 6 months after RT (0, blue). Cerebral progression after extracranial RT was not associated with a significant survival reduction; in the 51 patients who experienced it, it was related to a high percentage of local intracranial control obtained with FSBRT and salvage WBRT (p=0.508).
Survival function in all patients based on the number of metastatic organ sites who receive intracranial treatment. The number of radiologically evident metastatic sites in patients who received radiotherapy concomitantly with PD-1 inhibitors showed a significant increase in the overall survival of patients with 0-3 metastatic organs (blue and red lines) compared to other patients with more than three different organ sites involved (green) (p<0.0001).
Overall survival of patients who received intracranial radiotherapy (Median=13 months).
Discussion
Local control and survival improvement in oligometastatic patients. Metastatic disease is anatomically defined by the number and sites of clinically detectable secondary lesions. However, many additional factors influence the possibility of disease control and therefore, also influence the definition of oligometastatic disease, for example, the interval between treatment of the primary tumor and the development of metastases (i.e., synchronous vs. metachronous metastases), the total disease burden, the rate of metastatic spread and the presence of lymph node metastases.
Numerous studies have demonstrated the efficacy of local control in terms of PFS in oligometastatic patients (20-24) but unfortunately few have studied this in patients receiving immune checkpoint inhibitors.
Two phase-II randomized prospective studies investigated the integration of radiotherapy with systemic treatment in patients with clinically defined oligometastatic disease. In the SABR-COMET study (25), 99 patients with different tumor histologies (including breast, colorectal, lung, and prostate cancer) were randomly assigned to receive standard systemic therapy with (n=66) or without (n=33) SABR, directed to all known sites of metachronous metastases. SABR was delivered to five or fewer metastases with no more than three organs involved; ninety-three percent of patients had from one to three metastatic sites.
After a median follow-up of approximately 2 years, median OS (the primary outcome) was better in the group that received SABR [41 months (95%CI=26 months - not achieved)] compared to the control group [28 months (range=19-33 months)]. Median PFS was also improved in the SABR group compared to the control group at 12 months vs. 6 months [HR=0.47 (0.30-0.76); p=0.0012].
In a parallel study, Gomez et al. (26) randomized 49 patients with oligometastatic NSCLC to receive standard systemic maintenance therapy or surveillance with (n=25) or without (n=24) local consolidation therapy, including surgery or radiotherapy (e.g., conventional fractionation radiotherapy associated with chemotherapy, SABR, hypofractionated radiotherapy, or palliative radiotherapy regimens). Eligible patients had an ECOG PS of 0-2 and three or fewer non-progressing lesions after first-line systemic therapy, which consisted of four or more standard platinum-based chemotherapy courses or at least 3 months of treatment with EGFR mutation-targeting drugs (e.g., erlotinib) or anti-ALK (e.g., crizotinib). After a median follow-up of 38.8 months, median PFS was better in the group that received local consolidation with radiotherapy (14.2 months) compared to the control group (4.4 months; p=0.022), as well as the median OS [41.2 months (18.9 months - not reached) versus 17.0 months (10.1-39.8 months); p=0.017]. 82% of patients with metastatic progression in the control group progressed to known metastasis sites, compared with only 15% in the treatment group that received local treatment.
In the United States, there are still ongoing phase III studies sponsored by the National Cancer Institute: NRG-BR002 (NCT02364557), NRG-LU002 (NCT03137771), and the international studies SABR-COMET 10 (NCT03721341) and CORE (NCT02759783). These studies are intended to evaluate whether the radiotherapy targeted at all metastatic sites improves survival in patients with limited metastatic disease from NSCLC, breast, prostate, and other cancers.
In support of this, a meta-analysis of 23 out of 757 NSCLC patients treated with surgery or curative radiotherapy (or in combination) of the primary tumor and all metastatic sites (from one to five lesions), demonstrated that in patients with synchronous metastases and lymph node involvement 5-year OS was shorter than in patients with negative lymph node disease and metachronous metastasis (24).
In another study, Pastorino et al. (27) showed that patients with lung metastases could be stratified according to the PFS interval (between the treatment of the primary tumor and diagnosis of metastasis), the number of metastases, and resectability. Among the 4,572 patients in the study, the median OS was 61 months in patients with a single and resectable lung metastasis and a PFS interval of 3 years or more, but was only 14 months in patients with unresectable disease, and 24 months in those with multiple lung metastases and a PFS interval of fewer than 3 years.
Taken as a whole, the evidence provided by these studies indicate that patients with oligometastatic disease appear to be an extremely heterogeneous population, predominantly defined by clinical criteria but also strongly influenced by other underlying characteristics, related not only to modalities such as the burden of disease, number, and size of metastases, time of progression, and possible lymph node involvement., but also to tumor histological factors and treatments options.
Based on the results of this study, it can be suggested, that in metastatic patients receiving active treatment with PD-1 inhibitors who are susceptible to intra or extracranial RT, the definition of oligometastatic disease should include many metastatic sites (organs involved), less than or equal to 3, to identify those patients eligible for local treatment intensification (p≤0.0001).
Toxicity
Overall toxicity rates. Only recently, few prospective studies examined immune and radiotherapy combined treatment potential toxicity (28-30). In these studies, grade 3-5 toxicity ranged from 5-10% in patients receiving PD-1 inhibitors, and in general, rates were similar to those of patients receiving systemic therapy alone. Furthermore, there are few serious side effects attributed to the radiation component of the treatment. Recently, Theelen et al. (31) and McBride et al. (32) presented preliminary data at the ASCO meeting (2018) from two randomized phases II trials examining the use of PD-1 inhibition with or without hypofractionated radiotherapy in patients with metastatic NSCLC and metastatic HNSCC.
Theelen et al. (31) demonstrated a grade 3 toxicity rate of 17% in the experimental arm versus 22% in the control arm, whereas McBride (32) et al. demonstrated grade 3+ toxicity of 15% and 11% in the control and experimental arm, respectively. In addition, the PACIFIC randomized phase III trial of patients with locally advanced stage 3 NSCLC demonstrated a reassuring grade 3+ toxicity profile between ICI and control groups (33).
Hence, the combination of ICI and radiotherapy appears safe in most patients. It should be emphasized, that the most common grade 3-4 adverse events reported in the literature with ICI and stereotactic radiotherapy (60 Gy delivered in 10 fractions, 50 Gy delivered in 4 fractions) were found with CTLA-4 inhibitors (Ipilimumab), whereas other prospective studies such as the recent work published by Luke et al. (30) report grade 3-4 toxicities in approximately 10% of patients treated with FSBRT and anti-PD-1 inhibitors.
In a systematic review of studies that combined SRS and ICI, although the literature appears limited, concomitant therapy, particularly in the brain, appears to be safe. It is interesting to note that these studies do not report correlations with the timing of treatment or with the dose of biologically effective radiation (BED).
No correlation is reported between radiotherapy sites and associated adverse event rates. Meanwhile, vigilance is needed to identify early the worst toxicities, especially through the communication and collaboration of multidisciplinary teams (29, 30). The incidence of grade 3 adverse reactions for extracranial disease reported in our clinical records is comparable to that found in the literature (about 10%) (28-36).
Cerebral radionecrosis. Several retrospective studies have estimated that after SRS treatment, radionecrosis rates vary from 16% to 33%, and among them, symptomatic patients range from 12% to 21% (37-42). In order to understand whether adding ICI increases the risk of radionecrosis, Kaidar-Person et al. and Martin et al. (39, 42) assessed the comparative rates between patients who received SRS and those who received both SRS and ICI. Martin et al. studied 480 patients who received SRS in a mixed population (melanoma, NSCLC, RCC). They found that patients who received a CTLA-4 or PD-1 inhibitor had higher rates of symptomatic radionecrosis than those who only received SRS (20% vs. 7%, HR=2.56, p=0.004) (42). Patients with metastatic melanoma appeared to be more susceptible to increased rates of symptomatic radionecrosis (HR=4.70, p=0.01). Kaidar-Person et al. also demonstrated an increase in symptomatic radionecrosis rates of 21% compared to 0% in patients who did not receive an ICI (39).
Comparing the impact of CTLA-4 inhibitors and PD-1 inhibitors, the study by Martin et al. demonstrated that both classes of ICI can numerically increase the rates of radionecrosis, although the association with PD-1 inhibition was not statistically significant (HR=3.57, p=0.06) (42).
In 80 patients with melanoma, Minniti et al. reported grade 3 treatment-related adverse events in 11 (24%) patients treated with SRS and ipilimumab and 6 (17%) in patients who received SRS and nivolumab. Radiation-induced brain necrosis (RN) occurred in 15% of patients (43).
It should be noted that in our clinical records, the incidence of secondary radionecrosis in response to combined treatment is lower than that reported in the literature (8.4% in our study). These data must be correlated to the use of fractional stereotactic radiotherapy to brain metastasis, which has already demonstrated a better toxicity profile in the treatment of lesions with a diameter greater than 2.5 cm, even based on one of our institutional clinical records (44, 45). According to us, multifractional stereotactic radiotherapy could be used as a routine in patients who benefit from therapies that reach a higher cerebral concentration than standard therapies, such as ICI.
Conclusion
Despite the limitations due to its retrospective nature and those related to the heterogeneity of the patients and treatments, our study confirms the efficacy and overall safety of radiotherapy associated with PD-1 inhibitors. Furthermore, the subgroup analysis suggests that, in metastatic patients who receive PD-1 inhibitors who are susceptible to intra or extracranial RT, the stratification of those with oligometastatic disease, to identify the patients eligible for intensification of local treatment, should include a number of metastatic sites of less or equal to 3. Further studies are needed to identify other features useful for the definition of less aggressive oligometastatic disease, to guarantee more frequent personalized oncological treatments. The evaluation of global toxicities demonstrates an incidence of extracranial toxicity comparable to that reported in the literature, whereas we observed a reduced incidence of cerebral radionecrosis compared to the reported data, probably due to the multi-fraction cranial stereotactic radiosurgery performed at our center.
Footnotes
Authors’ Contributions
All Authors actively participated in the data collection. The article was written by Dimitri Anzellini and revised by Mattia Falchetto Osti.
Conflicts of Interest
The Authors declare that there are no conflicts of interest in relation to this study.
- Received June 15, 2021.
- Revision received July 15, 2021.
- Accepted August 23, 2021.
- Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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