Does stereotactic body radiation therapy with image guidance technology improve treatment outcomes in  intra-pulmonary metastasis patients? A randomized controlled study

doi:10.21203/rs.3.rs-1004143/v1

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Does stereotactic body radiation therapy with image guidance technology improve treatment outcomes in intra-pulmonary metastasis patients? A randomized controlled study

https://doi.org/10.21203/rs.3.rs-1004143/v1

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Background

Stereotactic body radiation therapy (SBRT) with image guidance technology aims to improve treatment outcomes in cancer patients. Image guidance radiotherapy (IGRT) is used with SBRT to deliver tumor ablation therapy in 3–5 fractions. This precise radiotherapy delivery method can be applied to various tumor types, and preliminary evidence suggests that it is efficient, accurate, and cost-effective. We present the protocol for a trial aimed at assessing the safety and efficacy profile of SBRT with image guidance technology for the first time. In so doing, the trial seeks to compare the outcomes of patients treated with this method with those of patients treated with conventional fractionated radiotherapy (CFRT).

Methods

This will be a randomized, controlled, prospective study with 102 lung cancer patients undergoing palliative treatment for intra-pulmonary metastasis. The trial will be based at the Liaoning Cancer Hospital Medical Center (a tertiary medical center). Using the random number table method, a random number sequence is generated, and the 102 patients are randomized (1:1) to the experiment group (SBRT with IGRT group) or the control group (CFRT group). The primary outcome is progression-free survival. The secondary outcomes include tumor response measures, overall survival, quality of life scores, and Acute and chronic adverse reactions, recorded over a 2-year follow-up period. After the final patient completes the follow-up study, Statistical Product and Service Solutions (SPSS) software is used for scientific and rigorous data analysis. This is version 1.0 of protocol on October 31, 2020. The recruitment process for this clinical trial commenced on February 1, 2021, and will end on January 31, 2023.

Discussion

Trial registration

This trial is registered with the Chinese Clinical Trial Registry (ChiCTR1900027548) (17 November, 2019). (URL: https://www.docin.com/p-917667939.html)

Intra-pulmonary metastasis

Stereotactic body radiation therapy

Image guidance radiotherapy

Conventional fractionated radiotherapy

Stereotactic body radiation therapy (SBRT), also known as stereotactic ablative radiation therapy, is a technique that involves imaging guidance to help deliver large doses of radiation to target tumors, using fewer fractions than traditional radiation therapy. However, lung tumors tend to be mobile, which makes delivering high-precision treatment challenging. Failure to fully account for the uncertainty caused by patient movement can lead to target loss and inaccurate dose coverage.[1–4] SBRT includes the delivery of high-dose radiation in several fractions and has a sharp dose gradient, which results in precise dose delivery to each treatment target. Use of an image guidance technology helps prevent such errors, improving the accuracy of radiotherapy delivery. During radiotherapy, movements associated with respiration,[5] changes in tumor size and shape or patient physique, and the therapist's positioning habits can introduce treatment positioning errors and affect the accuracy of intensity modulated radiation therapy.[6–8] The use of image-guided radiotherapy (IGRT) can help control the positioning error.[9–10] In general, IGRT is essential for successful SBRT.[11–12] IGRT/SBRT is associated with high levels of precision, accurate dose delivery to the target area, reduced risk of missing the target area, and increased likelihood of achieving desirable treatment outcomes, including improved survival and lower toxicity rates.[13–16]

The analgesic effect of SBRT has been shown to be better than that of CFRT in patients undergoing repeat radiation therapy and in those whose primary tumor is refractory to radiation.[17–18] Some previous reports of phase II studies have shown that SBRT and surgery can prolong PFS in this patient group compared with maintenance therapy alone.[19–20] A large retrospective study published by Zhong et al. has shown clinical benefits of SBRT over CFRT in patients with advanced pancreatic cancer. In this study, which included a total of 8,450 patients with stage cT2-4/N0-1/M0 disease registered in the National Cancer Database (2004–2013), SBRT was associated with longer survival than CFRT. In subsequent tendency score matching analysis, which included 988 patients (494 patients per group), the average 2-year survival rate in the SBRT group was significantly higher than that in the CFRT group.[21] In addition to non-small-cell lung cancer (NSCLC), SBRT is increasingly being used to treat other primary tumors and oligometastatic disease.[22–23] However, findings from randomized controlled studies on SBRT and CFRT for early-stage NSCLC have not shown differences in overall survival (OS) or progression-free survival (PFS), and further research is required to elucidate any differences between these approaches.[24] Therefore, to ensure the efficacy and safety of the IGRT/SBRT compared to those of CFRT in intra-pulmonary metastasis patients, the applicant designed the clinical trial. In future, we will improve the treatment plan for patients with intrapulmonary metastases from lung cancer based on the results of this clinical trial. This clinical trial is expected to further improve the efficacy of radiotherapy for patients and improve the quality of life and survival.

Design

This is a randomized, controlled, prospective study with 102 lung cancer patients undergoing palliative treatment for intra-pulmonary metastasis. The trial will be based at the Liaoning Cancer Hospital Medical Center (a tertiary medical center). Using the random number table method, a random number sequence is generated, and the 102 patients are randomized (1:1) to the experiment group (SBRT with IGRT group) or the control group (CFRT group). This study will not use a blinding process for the trial participants, because the treatment process enable a clear differentiation between the experimental group and the control group. The primary outcome is progression-free survival. The secondary outcomes include tumor response measures, overall survival, quality of life scores, and Acute and chronic adverse reactions, recorded over a 2-year follow-up period. After the final patient completes the follow-up study, Statistical Product and Service Solutions (SPSS) software is used for scientific and rigorous data analysis.

The trial sponsors are the Shenyang Major Scientific Research Projects (No. 191124090) and Cancer Research Program of National Cancer Center (NCC2017A08). This is version 1.0 of protocol on October 31, 2020. The recruitment process for this clinical trial commenced on February 1, 2021, and will end on January 31, 2023.

Patient and Public Involvement

The public is not involved in the design of this study. The results of the study will be presented at a conference or academic journal, and the public will not be involved in the dissemination plan of the study findings during this process.

Study Participants

The patient's treating physician obtains the patient's consent and explains the trial to those patients who meet the inclusion criteria. The computer will automatically generate the allocation sequence using the random number table method. Team investigators will recruit participants and assign them to the intervention. The order in which assignments will be implemented is a sequential number sequence, opaque, sealed, and not known in advance by the investigator who contacts the participant prior to assigning the intervention.

The study population included 102 lung cancer patients diagnosed with intra-pulmonary metastasis. The inclusion and exclusion criteria are listed in Table 1.

Table 1 Inclusion and exclusion criteria

Inclusion criteria

Exclusion criteria

Age ≥18 years
Lung cancer patients diagnosed with intra-pulmonary metastasis
No serious cardiopulmonary dysfunction
Blood routine test result and liver, kidney and heart function are basically normal
Anticipated survival time of >6 months.

Presence of a mental disorder or intolerance to radiotherapy treatment
Difficulties in understanding the presented information and in complying with trial requirements and recommendations
Presence of advanced disease along with anemia, weight loss, or cachexia
Presence of complications, including perforation in esophageal cancer or a large amount of effusion in lung cancer
Diagnosis of acute inflammation
History of heart failure
History of severe pulmonary insufficiency

Sample Size

It will be necessary to evaluate whether there is a difference between the two groups. The sample size of the experimental group (SBRT with IGRT group) will be set as n₁ and the sample size of the control group (CFRT group) as n₂, n₁=n₂. The two groups will have the same sample sizes, therefore a single-sided test will be used. The sample size calculation formula will be:

Where σ will be the overall standard deviation, estimated to be 1.84, δ will be the difference between the two sets of numerical variables, estimated to be 1, Z_α will be the standard normal value corresponding to the inspection level α, Z_β will be the standard normal value corresponding to β, If σ=1.8 months, δ=1 month, α=0.05, β=0.20, Z_α/2=Z_0.05/2=1.96, and Z_β=Z_0.20=0.842, then by substituting the above formula will give:

That is, 51 cases will be in the control group and 51 cases in the experimental group, with the total sample size being 102 cases.

Primary Study Outcome

PFS will be the primary study outcome. PFS is defined as the number of months from the start of IGRT/SBRT to the occurrence of the first evidence of disease progression, according to the Response Evaluation Criteria in Solid Tumors.

Secondary Study Outcomes

Tumor response measures

Tumor response measures are progressive disease (PD), stable disease (SD), complete response (CR), and partial response (PR). PD is the sum of the largest diameter of the target lesion increased by≥20% or new lesions appear. SD is the sum of the largest diameter of the target lesion that did not reach PR but increased to PD. CR is the complete disappearance of the tumor after radiotherapy. PR is the sum of the largest diameter of the tumor after radiotherapy and the largest vertical diameter by 50% and no increase in other lesions for a duration of more than 1 month.

Overall survival

Overall survival (OS) is defined as the number of months from the start of radiotherapy to the last follow-up or death, according to the criteria established by the American Joint Committee on Cancer and the International Union for Cancer Control Committee.

Quality of life scores

Quality of life (QoL) is assessed including EORTC QLQ-C30 (version 3) for lung cancer patients with intra-pulmonary metastasis at baseline, 4 weeks, 3 months, 6 months, 12 months and 24 months.

Acute and chronic adverse reactions

Acute and chronic adverse reactions are assessed according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria, which define chronic adverse reactions as reactions occurring after radiotherapy lasting more than 90 days.

Study Outline

VARIAN’s high-energy line accelerator, an IGRT device, American ADAC treatment planning system, a radiotherapy-specific neck and shoulder positioning rack, a neck and shoulder film made of low-temperature hydrolyzed polymer, and a positioning laser lamp (part of a dedicated external positioning system) are available at our radiotherapy department. In addition, a 3.0-T magnetic resonance imaging (MRI) scanner and a positron emission tomography (PET)/CT scanner are available at the study site. Equipment and technical support details are presented in Table 3.

Table 3 Summary of the available equipment
Device	Device model	Manufacturer	Factory number
3D-TPS	Pinnacle³	Philips	20028
TPS	Pinnacle Smart Enterprise	Philips	20030126
3D water tank	RFA-300	IBA	20021210
Linear electron accelerator	IX6117	Varian	20151217
Image fusion software	MIM	MIM Software	20151125
Linear electron accelerator	UNIQUE	Varian	20140122
TOMO	Tomotherapy HD	Accuracy	20151125
Medical linear accelerators	Clinac IX	Varian	20151203
CT	SOMATOM	Siemens	20140731

3D-TPS, three-dimensional treatment planning system; 3D water tank, three-dimensional (3D) water tank scanning system; TOMO, tomotherapy system

CT-based tumor localization method

The patient will be placed in a supine position on a radiotherapy-specific body frame and stabilized with the low-temperature hydrolyzed polymer film. The laser will be aimed at the midline of the chest and on both sides of the body, and the corresponding reference points will be marked on the body membrane and surface. Next, the lead particles will be placed for marking. Spiral CT will be performed while the patient is breathing calmly; the chest scan will be continuous in nature, using 2-mm slice thickness, and the data will be transmitted to the ADAC Pinnacle3 TPS workstation. PET/MRI images will be collected at the imaging department in two dimensions; subsequently, MRI or PET images will be fused with CT images using MIM software.

Radiotherapy target area outline

The chief physician of the radiotherapy department and an experienced diagnostic imaging physician will be tasked with combining imaging data to outline the radiotherapy target area on the CT fusion image. Planning target volume (PTV) is based on the gross tumor volume (GTV) considering factors such as positioning errors/positional movement between simulation and treatment. Overall, 105% of the prescribed dose must be delivered within the PTV, and the dose gradient outside the target area should show a rapid drop.[25]

Treatment plan

Eligible patients will receive IGRT/SBRT. The motion of the target area will be evaluated by a CT scan acquired in 10 respiratory phases, using a 4D-CT scanner.[26-27] When the range of tumor movement exceeds 1.5 cm, abdominal compression/accelerator gating and ABC methods will be used to reduce organ movement. Based on the IGRT method, the VARIAN high-energy linear accelerator will be used to deliver radiotherapy to the target areas using a 6–10 MV photon beam; the dose of radiation will be personalized as follows:

1.peripheral tumors smaller than 2 cm and located within 1 cm from the chest wall will receive a DT of 25–34 Gy/1F,

2.peripheral tumors farther than 1 cm from the chest wall will receive a DT of 45–60 Gy/3F,

3.central or peripheral tumors that are 4-5 cm in size and are located within 1 cm from the chest wall will receive a DT of 48–50 Gy/4F,

4.other tumors located within 1 cm from the chest wall will receive a DT of 50–55 Gy/5F, and central tumors will receive a DT of 60–70 Gy/8–10F.[28]

Radiotherapy will be performed once per day over a continuous period of 5 days; subsequently, treatment effects will be assessed.

Post-radiotherapy follow-up

Patients will be reviewed at months 1, 3 and 6 after radiotherapy to assess the efficacy and whether there is recurrence. Six months to two years after treatment, the review will be conducted every six months. The examinations will include CT scan of the lungs, routine blood tests, and liver and kidney function tests. In addition, we perform the QoL assessment at each review of the patient. The effect of IGRT/SBRT radiotherapy is evaluated according to the primary and secondary evaluation criteria established by the committee. The follow-up period for PFS is 2 years. The outline of the study is shown in Figure 1.

Data analysis

After the last patient completes the follow-up study, the committee will assess the occurrence of primary and secondary endpoints. Data will be organized and analyzed using SPSS 25.0 software, and P<0.05 will be considered a statistically significant difference in all statistical tests. Survival time will be defined as the time from the date of diagnosis of lung metastases from lung cancer to the date of death or the date of the most recent follow-up visit. Overall survival and progression-free survival will be calculated using the Kaplan-Meier method; Hazard Ratios (HR) and their 95% confidence intervals (Confidence Intervals, CI) will be calculated using the Cox regression method, and Chi-square tests will be used to analyze the differences between the different variables in patients who died and survived. Quality of life for two years will be scored with the FACT-G. The Chi-square test will be used in combination with propensity matching analysis to minimize differences due to smoking, gender, weight loss, geographic factors, economic status, education level, and to avoid baseline effects to the greatest extent possible.

Evidence from previous studies has suggested that the use of SBRT for early-stage NSCLC and advanced pancreatic cancer can improve patient prognosis. SBRT is associated with a precise treatment plan and delivery, both of which overcome the limitations of previously used methods.[29] The use of IGRT/SBRT helps achieve accurate dose estimates for the target area, thereby improving the rate of treatment delivery to the target lesion. In addition, this increases the likelihood of treatment success, while protecting surrounding tissues and organs and reducing the risk of complications. With this method, radiotherapy is delivered at relatively high doses in few fractions, resulting in tumor damage with a more efficient schedule; this approach is associated with improved tumor control, which is associated with improved patient survival.

The study will provide high-quality clinical evidence to support the efficacy and safety of IGRT/SBRT versus CFRT in the treatment of patients with intrapulmonary metastases from lung cancer and has not yet been reported. The main limitation of this study is theinformation bias caused by patient heterogeneity and missed visits, which may affect the usability of the data. The results of this study will provide evidence for the efficacy and safety profile of this approach and may inform future trials of similar approaches in larger populations. The results of this clinical study will play an important role in improving treatment options for patients with intrapulmonary metastases from lung cancer and in helping frontline physicians plan radiation treatment options for cancer patients.

Trial Status

The recruitment of participants started on 1 Feb 2021 and the trial is expected to continue until 31 Jan 2023.

On submission for publication, version 1.0 of the protocol is being used. 31 Oct 2020.

SBRT, stereotactic body radiation therapy

IGRT, image guidance radiotherapy

CFRT, conventional fractionated radiotherapy

SPSS, Statistical Product and Service Solutions

NSCLC, non-small-cell lung cancer

OS, overall survival

PFS, progression-free survival

PD, progressive disease

SD, stable disease

CR, complete response

PR, partial response

QoL, quality of life

MRI, magnetic resonance imaging

3D, three-dimensional

PTV, Planning target volume

GTV, gross tumor volume

HR, Hazard Ratios

CI, Confidence Intervals

Ethics approval and consent to participate

The ethics approval received by Medical Ethics Committee of Liaoning Cancer Hospital and the number is 2020X0102. Prior to screening, all participants should sign an informed consent form.

Consent for publication

Not applicable.

Availability of data and materials

The data of this study is available from the corresponding author upon reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

Funding for a three-year doctorate scholarship period (2020–2023) was received from the Shenyang Major Scientific Research Projects (No.191124090) and the Cancer Research Program of National Cancer Center (NCC2017A08) in order to conduct and analyze data from this ongoing study.

Authors’ contributions

All authors participated in the development and the design of the study. Xiaofang Zhang wrote the first version of the manuscript. Yingqiu Song and Chenyu Wang is responsible for the data management and statistical considerations of this project. Peng Zhao work as a therapist in this clinical experiment. Lei He strictly controlled the quality of the patient's radiation treatment process. Bo Huang provides pathological reports to patients in clinical trials. Tianlu Wang critically revised the manuscript. All authors read and approved the final version of the manuscript.

Acknowledgements

We are very grateful to the participants who participated in the study because they spend precious time participating in the study.

Authors’ information

¹Department of Radiotherapy, Cancer Hospital of China Medical University, Shenyang, China; ²Department of Information Management, Cancer Hospital of China Medical University, Shenyang, China; ³Department of Pathology, Cancer Hospital of China Medical University, Shenyang, China; ⁴Physical Laboratory in Charge, Department of Radiotherapy Department, Cancer Hospital of China Medical University, Shenyang, China.

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Does stereotactic body radiation therapy with image guidance technology improve treatment outcomes in intra-pulmonary metastasis patients? A randomized controlled study

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