Survival and Prognostic Factors of 40 Patients with Pulmonary Oligometastases Treated with Tomotherapy Hypofractionated Radiotherapy

Background: With continued improvement in radiotherapy technology, hypofractionated radiotherapy has helped achieve good results in the local control and toxicity of pulmonary oligometastases. This study aimed to investigate the ecacy of radiotherapy and the prognostic factors that affect survival in patients with pulmonary oligometastases who undergo helical tomotherapy (TOMO) hypofractionated radiotherapy. Methods: Ninety pulmonary oligometastases in 40 patients (26 males, 14 females; median age 57 years) were retrospectively investigated and treated with hypofractionated radiotherapy in the Department of Oncology and Radiotherapy of the First Aliated Hospital of Bengbu Medical College during 2018-2020. Their Karnofsky performance status (KPS) was ≥ 70 points. The primary endpoints were overall survival (OS), local control (LC), and progression-free survival (PFS), and we determine the related inuencing factors. Results: The median gross tumor volume (GTV) and planning target volume (PTV) were 9.7 cm³ (range 1.1–287.0 cm³) and 56.9 cm³ (range 16.3–494.2 cm³), respectively, the median biological effective dose, α/β=10 (BED10), was 76.8 Gy (range 56-96 Gy), and four-dimensional computed tomography positioning was applied to 52.5% of the patients. All patients completed the treatment plan during a median follow-up of 16.1 months (range 4.9–33.3 months). The 1- and 2-year OS rates were 90.3% and 55.2%, respectively. The 1- and 2-year LC rates were 80.8% and 64.7%, respectively. The 1- and 2-year PFS rates were 47.3% and 28.4%, respectively. Univariate analysis revealed that colorectal primary (p=0.004), age >57 years (p=0.037), and number of organ metastases ≥ 2 (p=0.046) were associated with OS, whereas disease-free interval (DFI) ≤ 17.4 months (p=0.032), number of lung metastases ≥ 2 (p=0.049), and PTV >56.9 cm³ (p=0.041) were associated with LC; and number of metastatic organs ≥ 2 (p=0.015) was independently associated with PFS. In multivariate analysis, colorectal cancer (p=0.010) and age >57 years (p=0.009) were signicantly associated with OS. No > grade 3 toxic reaction. Conclusions: The median OS, LC, and PFS rates of TOMO hypofractionated radiotherapy for pulmonary oligometastases were 24.9, 25.9, and 11.8 months, respectively, showing that good survival rates and low toxicity could still be achieved using the medium dose.

among these, the lung is the most common site of metastasis of most malignant tumors (1). The concept of oligometastases was rst proposed by Hellman et al. in 1995 (2). It refers to a transitional state in which a tumor metastasizes to a limited number of organs before it progresses to multiple distant metastases. Most researchers regard the diagnostic criteria for oligometastases to include not more than ve metastases seen during clinical imaging examinations, and metastasis to not more than three organs. The limited number of metastases provides opportunities for local clinical treatment.
Previous studies have shown that combining effective local treatments with systemic therapy could improve the progression-free survival (PFS) and overall survival (OS) of patients with oligometastases (3)(4)(5), and some patients could even be cured.
Local diseases are usually treated by surgical resection or local ablation. Studies have shown that the 10and 15-year OS rates of patients with complete resection of metastases are 26% and 22%, respectively (6), but not all patients are suitable candidates for radical surgical resection. Radiation therapy is an important choice for patients with lesions in an unsuitable position for surgery, a history of lobectomy or pneumonectomy, inoperability, failure of surgery and chemotherapy, other diseases that are not suitable for surgery, and refusal to undergo surgery. Due to the continuous advancement and development of precision radiotherapy technology, the target area during radiotherapy has become more precise, and protection of normal tissues is currently more reliable. Radiotherapy has the same therapeutic effect as that of surgical resection (7)(8)(9).This study explored the e cacy of radiotherapy and those prognostic factors that affect survival in patients with pulmonary oligometastatic tumors who undergo helical tomotherapy (TOMO) hypofractionated radiotherapy to provide evidence for clinical decision-making and treatment.

Patient selection
This retrospective study was approved by the Medical Ethics Committee of the First A liated Hospital of Bengbu Medical College (approval number: 2020KY109). The inclusion criteria were as follows: 1) age ≥ 18 years old, regardless of the sex; 2) the primary tumor needed to be diagnosed histopathologically, and the diagnosis of pulmonary oligometastases was made with at least clear imaging evidence or pathological con rmation; 3) no more than three systemic metastatic organs and no more than ve lung metastases before radiotherapy; 4) Karnofsky Performance Status (KPS) score of ≥ 70 points; 5) Estimated survival time of ≥ 3 months; 6) Volunteering to join the study and sign an informed consent form, with good compliance and follow-up. The exclusion criteria were as follows: 1) KPS score of 70 points; 2) more than ve lung metastases before radiotherapy; 3) the primary tumor and extrapulmonary metastases were not controlled, and 4) poor lung function.

Treatment schedules
All patients were treated using TOMO, and 21 cases (52.5%) were located using four-dimensional computed tomography (4D-CT). All patients underwent professional breathing exercise training before radiotherapy. The radiation dose that was used depended on the location and size of the tumor and the patient's lung function status; peripheral lung metastases were treated using 45-60 Gy in 8-12 fractions; central lung metastases (within 2 cm from the trachea and main bronchus) received a dose of 40-60 Gy in 10-20 fractions, and the treatment volume covered at least 95% of the planned target volume (Table 1). Gross tumor volume (GTV) was de ned as visible lesions on imaging examination, including CT or positron emission tomography/CT evaluation. Planning target volume (PTV) was determined based on the maximum activity interval of the tumor when the patient was breathing calmly as observed under the simulator, and the GTV was formed by expanding 5-8 mm in the three-dimensional direction.
When the tumor was located close to the bronchus, heart, and other important organs, appropriate adjustments for the range of target area and recovery were made after release to not damage the vital organs. The dose division plan was jointly formulated by multiple senior radiation oncologists based on tumor volume, location, and normal tissue dose limits. The biological effective dose, α/β = 10 (BED10), estimation formula for different segmentation schemes was as follows: BED = n*d [1 + d/ (α/β)], where n is the number of divisions, d is the fractionated dose, and the ratio of α/β for pulmonary oligometastases was 10 Gy. All patients underwent TOMO system image veri cation before each treatment to ensure the accuracy of the treatment target area.

De nition of endpoints
Follow-up was conducted using telephone follow-up, outpatient, and inpatient review, and other methods.
The rst follow-up was 4-8 weeks after radiotherapy, and then every 3 months until April 30, 2021. OS was computed from the date of the rst radiotherapy to the date of death or the date of the last follow-up; local control time (LC) was computed from the date of the rst radiotherapy to the progression of the radiotherapy focus, local recurrence was the recurrence within the PTV area, progression-free survival (PFS) was computed from the date of the rst radiotherapy to the date of local, regional, or distant recurrence (whichever occurs rst); use of CR, PR, SD, and PD evaluate short-term e cacy; mainly observe OS, LC, PFS, and toxicity after treatment. The Radiation Therapy Oncology Group radiotherapy injury grading standard was used to evaluate the grade of adverse reactions (10).

Statistical analysis
In survival analysis, the Kaplan-Meier curve represents the cumulative survival rate of OS, LC, and PFS at 1 and 2-years, and the log-rank test was used for curve comparison. To analyze the in uence of potential risk factors on the observation endpoint indicators, univariate and multivariate Cox regression analyses were used at the same time, and factors with P < 0.1 were selected in univariate Cox regression analysis to enter the multivariate Cox regression model analysis (p < 0.05). All analyses were performed using IBM SPSS Statistics, version 25.0, software package.

Patient and tumor characteristics
The clinical data of 90 pulmonary oligometastases in 40 patients who received hypofractionated radiotherapy were collected from January 1, 2018, to December 31, 2020, of the First A liated Hospital of Bengbu Medical College.
The primary tumors were mainly head and neck tumors in 10 cases, colorectal cancer in 8 cases, soft tissue sarcoma in 6 cases, esophageal cancer in 5 cases, and breast cancer and lung cancer in 3 cases, respectively. All patients received systemic treatment, including chemotherapy, targeted therapy, and immunotherapy, before receiving radiotherapy for pulmonary oligometastases. Two patients underwent surgical resection of lung metastases andγ-knife treatment followed by TOMO hypofractionated radiotherapy. Five patients with lung metastases and recurrent or primary tumors, received radiotherapy simultaneously. Twelve cases (30%) of extrapulmonary metastases included sites such as lymph nodes, bones, liver, and brain, of which 10 cases had one metastatic organ, two cases had three metastasis organs, and one case had two metastatic organs, and the primary tumor and extrapulmonary metastases were well controlled. Overall, 22 patients (55%) received simultaneous systemic therapy, including targeted therapy and chemotherapy. The median BED10 was 76.8 Gy (range, 56-96 Gy). Disease-free interval (DFI) was de ned as the interval between the day the primary tumor was controlled and the day when the rst metastasis was con rmed. A patient with Ewing's sarcoma of the buttocks was diagnosed with both the primary focus and lung metastasis. Therefore, the DFI was calculated as 0 (Tables 2 and 3).

Survival analysis
Within a median follow-up duration of 16.1 months, all patients undergoing hypofractionated radiotherapy completed the treatment plan. Among the 40 patients, CR, PR, SD, and PD rates were 50.0%, 32.5%, 12.5%, and 5.0%, respectively (Fig. 1). The 1-and 2-year OS rates were 90.3% and 55.2%, respectively. The 1-and 2-year LC rates were 80.8% and 64.7%, respectively. The 1-and 2-year PFS rates were 47.3% and 28.4%, respectively. At the last follow-up, 14 patients had died. One patient died of lung infection caused by bone marrow suppression after radiotherapy, and one patient died of radiation pneumonia due to lung re-metastasis after 2 months of secondary radiotherapy. Most patients died from multiple organ failure caused by extensive bones and brain metastases. A common toxic reaction was radiation pneumonitis; 16 patients (40.0%) developed radiation pneumonitis, of which 10 (25.0%) developed grade 1 radiation pneumonitis and 6 (15.0%) developed grade 2 radiation pneumonitis. Bone marrow suppression was another toxic reaction. ) was an independent prognostic factor for PFS (Fig. 3b).

Discussion
Tomotherapy is currently the most advanced radiotherapy device. It uses a radiotherapy system that has the same source of treatment (6 MV) as impact-guided CT (3.5 MV). It has high imaging accuracy and automatically corrects positioning errors before radiotherapy, which makes the target area conformability and dose distribution more reasonable. TOMO integrates three-dimensional conformal radiation therapy, intensity-modulated radiation therapy, image-guided radiation therapy, dose-guided radiation therapy, adaptive radiation therapy, and other radiotherapy technologies in one, could be clinically used for a variety of tumors throughout the body, especially for frequently occurring tumors and tumors adjacent to important organs and tissues, which improves the accuracy of the target area while reducing the occurrence of complications (11,12). All patients in this study used TOMO to treat lung metastases, and this has a certain research value.
Studies have shown that the survival rate of certain patients with oligometastases can be improved through local treatment, such as surgery, ablation therapy, and radiation therapy (13)(14)(15)(16)(17) with lung metastases, and the median OS and recurrence-free survival rates were 21 and 7 months, respectively (21). This study found that the median OS, LC, and PFS rates were 24.9, 25.9, and 11.8 months, respectively, and these were similar to the results of related studies.
In most studies, the risk factors related to OS, LC, and PFS include functional status, lesion diameter,

Conclusions
In conclusion, the median OS, LC, and PFS of TOMO hypofractionated radiotherapy for pulmonary oligometastases tumors were 24.9, 25.9, and 11.8 months, respectively. Good survival and low toxicity could still be achieved with a medium-dose BED10. The type of primary tumor, the number of organ metastases before radiotherapy, and patients' age were signi cantly associated with the survival rate of patients with pulmonary oligometastases. [Ethics approval and consent to participate] All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The retrospective study has been approved by noti cation by the local ethics committee. Wherever necessary informed consent from the patients has been obtained.
[Consent for publication] Consent to publish individual data was obtained from all participants.
[Availability of data and materials] The datasets supporting the study conclusions are included within this manuscript.
[Authors' contributions] RC and YZ designed and wrote the manuscript for this research. FC, HX, QW and GW provide the patient plan data, clinical support and manuscript revision. RC, ML and XC involved in analysis and interpretation of data. HJ and QS participated in review for result and manuscript. All authors read and approved the nal manuscript. [Funding] Not applicable.

[Con icts of interest]
There were no con icts to declar.