Promising Clinical Outcome with Long Term Follow-Up after Stereotactic Body Radiation Therapy for Elderly Patients with Oligometastatic Non-Small Cell Lung Cancer

Objective The ideal treatment strategy for elderly patients with metastatic non-small cell lung cancer (NSCLC) is still controversial. Our objective is to implement radical local therapy to the primary tumor and all metastases in elderly patients with oligometastatic NSCLC and evaluate its long-term ecacy and safety. Patients and Methods All patients were older than 65 years at initial diagnosis and had pathologically conrmed NSCLC with a total of less than or equal to 5 metastases through imaging diagnosis. Radical local therapy was applied to the primary tumor and all metastases to evaluate its OS, PFS, and toxicity. Results A total of 30 elderly patients with NSCLC ( ≤ 5 metastases) received high-dose radical local radiotherapy to the primary tumor and all metastases, with a median age of 73 years (65-82 years). A total of 134 lesions were treated, with a median biologically effective dose at alpha/beta 10 (BED 10 ) value of 102 Gy (78-119 Gy) . The median follow-up period was 34 months (10-68 months) and the median OS was 36 months. The 1-, 2-, 3-, and 5-year OS were 93.3%, 66.7%, 49.6%, and 12.1%, respectively. The median PFS was 12 months, and 1-year PFS was 36.7%. Multivariate analysis: When ECOG PS < 2 and BED 10 ≥ 100 Gy, better OS was obtained (P < 0.001 and P = 0.022); ECOG PS < 2 was an independent prognostic factor for PFS (P = 0.016). Most patients experienced grade 1-2 toxicities, a few experienced grade 3 toxicity (6.66%), and no grade 4-5 toxicities and treatment-related deaths occurred.


Introduction
Lung cancer is the malignant tumor with the highest incidence and mortality all over the world, of which 85% is non-small cell lung cancer (NSCLC) 1 . Approximately 40-50% of patients with NSCLC already present with distant metastases at diagnosis and 50% of them are elderly patients 2 . In 1995, Hellman 3 proposed the concept of "oligometastasis", namely distant metastasis occurs in one or a limited number of organs, showing a target-organ effects. It occurs at the period of mild tumor invasiveness, which is the transition stage between local primary tumor and extensive metastasis. During this stage, the tumor burden is small and there is a possibility of cure. Although there is no uniform conclusion on the de nition of oligometastases, recent studies 4 have de ned oligometastases as 3-5 metastases.
Randomized controlled studies [5][6][7] have shown that radical local therapy (radiotherapy or surgery) to primary tumors and metastases based on systemic therapy can signi cantly improve the progressionfree survival (PFS) or overall survival (OS) of patients with oligometastases and signi cantly improve the prognosis of patients compared with systemic therapy alone. But a systematic literature review 8 reported that the ve-year survival rate of patients with oligometastatic NSCLC was 8.3-86%. This range is equivalent to the variation in OS of patients with stage I-IV NSCLC 9 . However, reports on oligometastases in the elderly are rare, and the reports on whether elderly patients with oligometastases can bene t from radical local therapy are even rarer. Elderly patients with cancer are a special group, with many underlying diseases, poor cardiopulmonary function, poor self-repair ability, decreased treatment willingness, accompanied by different degrees of geriatric syndromes, which greatly increases the di culty of treatment and results in a poor prognosis. In this study, we retrospectively analyzed 30 elderly patients with oligometastatic NSCLC (≤ 5 metastases) who were treated with radical stereotactic body radiation therapy (SBRT) to primary tumors and all metastases to evaluate the long-term e cacy and safety.

Patients
A retrospective analysis was conducted on patients with oligometastatic NSCLC who were initially treated between February 2008 and October 2016 at our department. The inclusion criteria were as follows. (i) All patients were more than 65 years old. (ii) All patients were pathologically con rmed with NSCLC, and the number of metastases was ≤ 5 excluding primary tumor and regional positive lymph nodes, by comprehensive imaging diagnosis (included but not limited to brain magnetic resonance imaging (MRI) + whole-body positron emission tomography/computed tomography (PET/CT) or brain MRI + thoracic/abdominal/pelvic CT, and bone scan was carried out when necessary). (iii) The patient had no progression of primary tumor and metastases after systemic treatment and did not develop any new metastasis for at least 2 weeks. (iv) The patient refused systemic chemotherapy but was willing to receive active treatment. (v) The patient was assessed after multidisciplinary consultation as intolerable to systemic chemotherapy but willing to be treated aggressively. (vi) The patient's underlying disease was well controlled and had quali ed bone marrow hematopoietic function, liver function, and cardiopulmonary reserve. This study was approved by the Ethics Committee of Beijing Geriatric Hospital.
Relevant data were approved, the patients were included in this study only after obtaining orally or written informed consent.

Radiotherapy
Radiotherapy planning for all elderly patients was discussed by a multidisciplinary team, including oncologists, radiation oncologists, radiologists, orthopedic surgeons, neurosurgeons, cardiologists, and respiratory physicians. The radiotherapy planning should be conducted based on patient age, cardiopulmonary function, underlying diseases, tumor location, fracture risk, central nervous system symptoms, and bene t-risk assessment. When the patient had obvious central nervous symptoms, local radiotherapy of intracranial metastases was performed rst. If there is a high risk of vertebral fracture after consultation with orthopedic surgeons, xation should be performed rst followed by local radiotherapy. Dose fractionation mode and radiotherapy technique were shown in Table 1.

Toxicity Assessment
Following the guidelines from the National Cancer Institute (NCI), acute and long-term toxicities were de ned before and after 90 days, using Common Terminology Criteria for Adverse Events (5th version, CTCAE). Assessed acute toxicities were dermatitis, pneumonia, fatigue, anemia, leukopenia, thrombocytopenia, and esophagitis. Long-term toxicities were pulmonary brosis and pleural effusion.

Statistical Analysis
Statistical analysis was conducted using R software(version 4.0.3 http://www.Rproject.org).Mean and standard deviation were used to describe the distribution of quantitative data, frequency and constituent ratio were used to describe the distribution of categorical data, Survival analysis was conducted, and Kaplan-Meier plot was used for calculating the survival curves. Univariable and multivariable Cox proportional hazard model were used to assess prognostic factors and calculate the survival hazard ratios (HRs) with 95% con dence interval (95% CI) of PFS and OS. All prognosis-related factors were included in a multivariable Cox model, regardless of their signi cance level of the univariate analysis. A two-sided p-value of 0.05 was considered statistically signi cant in all aforementioned statistical tests.

Patient Characteristics
From February 2008 to October 2016, a total of 30 elderly patients with oligometastatic NSCLC (≤ 5 metastases) received high-dose radical local radiotherapy to the primary tumor and all metastases ( Fig. 1). They had a median age of 73 years (65-82 years). All patients underwent PET-CT before treatment. 11 patients received systemic chemotherapy before radiotherapy with a median chemotherapy cycle number of 2, including 7 cases with pemetrexed + cisplatin and 4 cases with gemcitabine + cisplatin. 6 patients received systemic targeted therapy before radiotherapy, including 5 cases with Ge tinib and 1 case with Icotinib. 10 patients refused systemic chemotherapy, and 3 patients could not tolerate chemotherapy due to severe underlying diseases. A total of 134 lesions were treated with radiotherapy(irradiated metastatic sites included: 11 intracerebral metastases, 7 intrapulmonary metastases, 8 adrenal metastases, 7 intrahepatic metastases, 2 cervical lymph node metastases, 4 metastatic lesions in cervical vertebra, 10 metastatic lesions in thoracic vertebra, 11 metastatic lesions in lumbar vertebra and 4 other bone metastatic lesions), with a median BED 10 of 102 Gy (78-119 Gy) and an average BED 10 of 99.5 Gy. Among all cases, 16 patients received radiotherapy dose BED 10 ≥ 100 Gy to the primary tumor and all metastases. 3 patients underwent local radiotherapy for intracranial metastases due to severe central nervous symptoms, followed by radical local radiotherapy to the primary tumor and all remaining metastases 2 weeks later. 1 patient had a high risk of compression fracture due to the T8 (8th thoracic vertebra) metastasis and was transferred to the Department of Orthopaedics for surgical xation followed by radical local radiotherapy to the primary tumor and all remaining metastases. General clinical characteristics are shown in Table 2.  Table 3.  Table 3:  Table 4.

Discussion
Generally, for elderly patients with metastases, maintaining or improving the quality of life is often the primary goal of treatment decisions, while prolonging survival is the second 10 . Compared with young patients, elderly patients have a higher incidence of unexpected risks and toxicities due to tumor treatment, but the treatment-related bene ts are lower. It has been reported that the rates of patients receiving guideline-recommended chemotherapy treatment decreased more with increasing age than with comorbidities 11 . In this study, 11 patients received systemic chemotherapy before radiotherapy, with a median chemotherapy cycle number of 2. 13 patients did not receive systemic therapy, of which, 10 patients refused systemic chemotherapy (6 patients refused chemotherapy due to age) and 3 patients could not tolerate chemotherapy due to severe underlying diseases. Although elderly cancer patients have many underlying diseases, organ function decline, and decreased willingness to treat, accompanied by different degrees of geriatric syndromes, they are also a highly heterogeneous group. With the introduction of the concept of "oligometastatic disease", its milder biological characteristics affect treatment decisions, thus treatment decisions for metastases in the elderly should be individualized, multidisciplinary, and humanistic.
The traditional view considers local radiotherapy as a palliative care for elderly patients with advanced metastatic tumors, which can effectively reduce pain and prevent the occurrence of bone-related events, rather than being applied in the treatment of oligometastatic diseases. With the development of radiotherapy technology, SBRT presents the characteristics of "high accuracy, high local control rate, and less toxic side effects", which can achieve radical cure of tumors. Previous studies [12][13][14] have shown that SBRT is as effective as surgery in the treatment of early NSCLC and is the preferred local therapy for patients who cannot tolerate surgery or refuse surgery. Later, SBRT was applied to the local therapy of solitary metastases, and the outcomes were also satisfactory. De Rose et al. 15 [5][6][7] have shown that this change in treatment strategy can bring survival bene ts to patients and signi cantly improve prognosis. However, the intervention timing for local therapy is still controversial, and many studies [5][6][7]20 have reported systemic therapy followed by radical local therapy. The bene t is that it can maximize tumor shrinkage, reduce systemic tumor burden, and reduce the risk of further distant metastasis, but the di culty is the intervention timing of radical local therapy during systemic therapy. If the intervention is too early, the tumor burden fails to reach the maximum reduction, and the local therapy-related toxicity is increased. If it is too late, it might lead to local progression and even distant metastasis due to tumor cell resistance, miss the best timing of local therapy and greatly reduce the probability of survival bene t brought to patients by the biological inertia of "oligometastatic" disease itself. Another study (NCT: 02893332) was designed to perform local therapy followed by sequential systemic therapy for the rst time. In our study, ECOG PS < 2 and BED 10 ≥ 100 Gy were independent factors for survival prognosis. A good physical score indicated that their quality of life was satisfactory, nutritional intake was su cient, and body immune function could still play a partial role, which ensured treatment continuity when the disease progressed. BED10 ≥ 100 Gy indicated a high local control rate in hypofractionated radiotherapy lesions, which can translate into a survival bene t in elderly patients with oligometastases. Recent studies [21][22][23] have shown that the body can produce systemic anti-tumor immune effects, known as distant effects, enhance cellular immunity, and even kill distant metastases after radiation therapy, especially SBRT irradiation to the local tumor. Recent advances in immunotherapy have led to a change in the treatment standard of advanced NSCLC, and inhibitors of programmed cell death-1 (PD-1) or its ligand PD-L1 have become an important part of rst-line systemic therapy. Immunotherapy is more suitable as systemic therapy for advanced NSCLC in the elderly, and several prospective studies on immunotherapy combined with SBRT for oligometastatic NSCLC are currently ongoing, such as NCT02316002, NCT03275597, and NCT03965468.
This study has the following shortcomings. (i) The sample size is small. (ii) This study is a retrospective study that cannot replace a prospective randomized controlled study because there are many in uencing factors on whether elderly patients with oligometastatic NSCLC receive radical local therapy to the primary tumor and all metastases, which are often related to the patient's general physical condition, medical compliance, economic status, tolerance of systemic therapy, physician treatment mode, etc. (iii) We did not evaluate elderly patients with comprehensive geriatric assessment (CGA) and did not further clarify which type of oligometastatic NSCLC can bene t more from radical local radiotherapy given to the primary tumor and all metastases, which could help make appropriate treatment decisions for elderly patients with oligometastatic NSCLC.

Conclusion
In conclusion, radical local radiotherapy to the primary tumor and all metastases in elderly patients with oligometastatic NSCLC can improve their survival with tolerable toxicity, which is an optional new treatment modality. The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.