The novel application of HFRT using TOMO technology will be performed in a randomized, controlled, prospective, and safety study using the American ADAC Pinnacle treatment planning system (ADAC Laboratories, Milpitas, CA, USA) in 120 enrolled LS-SCLC patients. The number of samples was calculated using IBM SPSS Statistics 19 software. The LS-SCLC patients will be randomized (1:1) to the experiment group (HFRT with TOMO) or the control group (Con-RT) using a random number table. This study does not use the blinded method because HFRT with TOMO and Con-RT have a large difference in the implementation process, which makes blinding difficult. However, the deviation caused by not using the blinded method has no significant effect on the patients’ outcome assessment. In this therapeutic study, LS-SCLC is defined as a lesion confined to one side of the thoracic cavity, mediastinum, anterior oblique muscle, or supraclavicular lymph nodes, but has no obvious superior vena cava compression, vocal cord paralysis, or pleural effusion. Patients who meet the inclusion criteria will be grouped by randomized parallel control into the HFRT with TOMO and Con-RT groups according to randomly assigned results. The study will be carried out at the Liaoning Cancer Hospital Medical Center, a tertiary medical center in Liaoning, China.
This study aims to assess the efficacy and safety of HFRT with TOMO for the treatment of LS-SCLC. We will record the weekly physical examinations, hematological examinations, and liver and kidney function test. The main purpose of this effectiveness study is to determine whether a follow-up trial to evaluate efficacy and safety in a larger cohort would be feasible.
Primary Study Outcome
The primary outcome is PFS time after radiotherapy, which refers to the number of months between the initiation of radiotherapy and the first evidence of progressive disease as defined by the Response Evaluation Criteria In Solid Tumors criteria.
Secondary Study Outcomes
Acute and chronic adverse reactions
The secondary study outcomes are acute and chronic adverse reactions, which will be evaluated according to the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer standard, which define chronic adverse reactions as reactions that occur after radiotherapy or that last for >90 days).
According to the Tumor Lymph Node Metastasis standard established by the American Joint Committee on Cancer and the International Cancer Coalition Cancer Control, overall survival (OS) is the number of months between the initiation of radiotherapy and the last follow-up or death.
The tumor responses are progressive disease (PD), stable disease (SD), complete response (CR), and partial response (PR). PD refers to ≥20% increase in the sum of the maximum diameter of target lesions or the appearance of new lesions. SD refers to the sum of the maximum diameter of the target lesions that did not reach PR but increased to reach PD. CR is the complete disappearance of the tumor after radiotherapy. PR is the product of the reduction of the maximum diameter and maximum vertical diameter of the tumor by 50% after radiotherapy, and no increase in other lesions, which lasts more than 1 month.
Quality of life
The assessment of quality of life (QoL) includes 60 questionnaires on the QoL of LS-SCLC patients at baseline, 4 weeks, 3 months, 6 months, 12 months, and 24 months after HFRT with TOMO and after Con-RT.
Our primary hypothesis is that the use of HFRT with TOMO will increase clinical PFS time for approximately 3–6 months because of better tumor control [12-14]. The PFS and OS rates of patients in this study will be compared with those who are eligible to participate in the study but are receiving standard radiation therapy. If necessary, PFS data can also be compared with data of the historical cohort of patients receiving treatment in our center. Our secondary hypothesis is that the OS rate will increase by approximately 5% because of better local tumor control . In addition, we hypothesize that relevant acute and chronic adverse reactions will decrease and that QoL will improve.
The study population included 120 patients diagnosed with LS-SCLC. The inclusion and exclusion criteria are listed in Table 1.
Table 1 Inclusion and exclusion criteria
• Age ≥18 years
• Stage I–III small cell lung cancer
• No serious cardiopulmonary dysfunction
• Blood routine test result and liver, kidney and heart function are basically normal
• Obvious mental disorders or intolerance to radiotherapy treatment
• Have difficulty following doctor’s orders in completing relevant examinations and treatments
• Karnofsky Performance Score ≤70 points
• Severe ventilation dysfunction of lung function
• Bone marrow suppression above grade
• Moderate to severe cardiac insufficiency
The eligibility of patients who are candidates for HFRT with TOMO or Con-RT group will be discussed upfront by the expert group. The expert panel includes three chief physicians, four attending physicians, and two interventional radiologists.
TOMO is a new type of image-guided intensity-modulated radiation therapy system that uses CT scanning and fan-shaped spiral irradiation. TOMO, which uses imaging-guided radiotherapy and adaptive radiotherapy as its main function, has been used in radiotherapy of chest tumors for more than 10 years and has obtained good clinical efficacy and safety.
Required equipment and technical support
The Radiotherapy Department of Liaoning Provincial Cancer Hospital has started TOMO treatment since November 2015 and has established a database. Imaging-guided radiotherapy is performed with the ADAC Pinnacle treatment planning system, radiotherapy special positioning body frame, polymer low-temperature hydrolyzed plastic neck and shoulder membrane, and laser light positioning (for special external positioning system). This project is guided by senior physicians who have been engaged in this work for many years, and excellent physicists provide technical support. The TOMO treatment equipment and radiotherapy planning system produced in the United States are already available. Our department has successfully completed precise radiotherapy based on TOMO technology in many cases.
CT positioning scanning method
The patient lies on a special body frame for radiotherapy, and the polymer low-temperature hydrolyzed plastic body film is used to fix the position. The laser is positioned on the midline of the chest and on both sides (for a special external positioning system), and the corresponding reference points are marked on the body film and body surface. Lead pellets are placed for marking. With the patient calmly breathing, spiral CT scans the chest continuously with a pitch of 3 mm and transmits the data to the ADAC Pinnacle3 TPS workstation via the network. Each patient routinely undergoes large-aperture CT positioning, with the target area delineated according to enhanced CT images.
Formulation and implementation of TOMO radiotherapy plans
A radiotherapy department chief physician and an experienced image diagnosis physician outline the radiotherapy target area on the CT image. The gross tumor volume in the tumor area, set as 0.8 cm, is designated as the clinical target area, and the clinical tumor volume is set as 0.5 cm; the tumor motion range is used as the planned target area planning tumor volume. A medical linear accelerator CT scan is used to correct the positioning error from a three-dimensional perspective to ensure the accuracy of the treatment and to ensure that it can be safely implemented during conventional or large-scale radiotherapy. The TOMO radiotherapy plan can be formulated on the Pinnacle3 treatment planning system. A VARIAN high-energy electron beam accelerator 6-MV X ray (Varian Medical Systems, Palo-Alto, CA, USA) is used for irradiating the tomographic intensity-modulated irradiation field.
Patients who meet the inclusion criteria will be given radiotherapy. In the HFRT with TOMO group, the prescribed dose of the planning tumor volume is 1.5 Gy, twice a day, and the interval between each radiotherapy is at least 12 hours. A total of 30 radiotherapy treatments are performed. In the Con-RT group, the prescribed dose of the planning tumor volume is 2 Gy, once a day. A total of 30 radiotherapy treatments are performed. When the radiotherapy reaches 30 or 40 Gy/20 fractions or times, the large-aperture CT is reset and the two examination images are fused. Based on the review of the CT images, the target area is redrawn to formulate a treatment plan based on the second examination images. Precise radiotherapy is continued until the prescription dose accumulates to 45 Gy/30 times. Concurrent EP chemotherapy during radiotherapy (EP 50 mg/m2, days 1–5, cisplatin 25 mg/m2, days 1–3) is performed for 1 cycle, with an EP program for 21 days as a course; simultaneous chemotherapy is performed for 1 cycle and adjuvant five cycles, for a total of 6 cycles of chemotherapy. CT is reviewed once every 2 cycles of chemotherapy and merged with the previous examination to outline the residual tumor area [16-18]. After the end of chemotherapy, the CT should be rechecked every 2 months and merged with the previous examination. The residual tumor area should be delineated until the target lesion has completely subsided. Follow-up is performed until the tumor recurs locally.
The first follow-up and comprehensive assessment of the effectiveness of treatment will be performed in the fourth week after the completion of HFRT with TOMO and Con-RT. A review will be conducted every 3 months for the next 2 years, including physical examination, enhanced CT scan, blood routine test, liver and kidney functions, and QoL; if necessary, brain-enhanced magnetic resonance imaging and bone imaging examination will be performed to assess the effectiveness of different radiotherapy options.
After the last patient completes follow-up, the trial committee will assess the occurrence of the primary and secondary end points. The primary end point will be expressed as PFS time (months) after treatment. The OS will also be expressed as months. For statistical assumptions, the alpha value will be set to P<0.05. The data will be analyzed by the Social Science Statistical Software Package (IBM Corp., Armonk, NY, USA). Appropriate parametric and non-parametric statistical tests will be conducted to analyze the statistical data of different patient conditions and draw meaningful conclusions. If necessary, multiple comparisons and corrections will be made. Tumor response data (PD, SD, CR, and PR) will be expressed as a percentage.