For early-stage non-small cell lung cancer (NSCLC) that is intolerant to surgery, radiotherapy is the standard of care.
Stereotactic radiotherapy (SBRT) has been widely accepted as the treatment of choice for peripheral stage I NSCLC. the RTOG 0236 study showed a 3-year local control rate (local control rate) of 98% and a median survival of 48.1 months with SBRT.
Currently, early-stage NSCLC undergoing SBRT is mainly limited to those who cannot tolerate surgery, such as those who have undergone thoracic surgery, received previous thoracic radiotherapy, and have medical comorbidities such as severe cardiopulmonary disease or severe pulmonary insufficiency.
The value of radiotherapy in operable NSCLC is still unclear.
A retrospective study in the United States showed that the SBRT group had a better local control rate than the surgical group, but a slightly shorter overall survival (OS) period than the surgical group, provided that the patients in the SBRT group were significantly older than the surgical group. A Japanese meta-analysis showed that the 5-year local control and survival rates of SBRT were similar to those of surgery. A secondary analysis of a large prospective Dutch study showed a 30-day mortality rate of 0 after SBRT compared with 2.6% for historically reported lobectomies.
There are no phase III randomized controlled studies comparing the efficacy of classical surgical resection with SBRT in operable NSCLC. the RTOG 0618 phase II study is expected to provide evidence, and another multicenter randomized controlled study jointly conducted in China and the United States is forthcoming.
SBRT in stage I NSCLC is safe and the associated toxicity is acceptable.
The pattern of failure after SBRT was broadly similar, occurring mostly within 3 years after the end of treatment. Among them, only 1/3 were local area treatment failures, which is another perspective that confirms that SBRT as a local treatment can achieve very promising efficacy and is a treatment modality worth promoting. Most studies have shown that the toxicity associated with SBRT treatment is less than 10%. Early acute toxic reactions include malaise, skin reaction, chest pain, radiation esophagitis and radiation pneumonia, and long-term toxic reactions include lung injury, chest pain, rib fracture, etc.
The suitable segmentation pattern and tolerated dose for central NSCLC are still to be determined.
Central NSCLC (within 2 cm of the bronchial tree) is mostly excluded from the SBRT study population, with the main concern being that high bioequivalent dose (BED) radiotherapy may cause irreversible damage to vital structures such as the adjacent trachea, esophagus and large blood vessels. The ongoing phase I/II RTOG 0813 study starts with a milder dose fractionation pattern (50 Gy/5 f) and aims to investigate the yet to be defined fractionation pattern and maximum tolerated dose suitable for central NSCLC.
For stage II NSCLC, the treatment of choice is surgery, while for those who are not surgically resectable, the treatment of choice is radical radiotherapy.
Radiotherapy for patients in this stage is based on conventional segmentation, and the dose should be ≥60 Gy. Dose increments according to the amount of normal tissue surrounding the tumor can be considered to achieve better local control. There is no definite conclusion about the application of synchronous chemotherapy.
Supraglottic sulcus tumors are a special type of tumor with a low incidence, often with direct invasion of adjacent structures such as the brachial plexus, spine, mediastinum, pleura, or ribs, and are usually staged T3 to T4. Simultaneous radiotherapy combined with surgery is considered to be the treatment of choice for resectable supraglottic sulcus tumors. Preoperative radiotherapy is usually administered in a 45 Gy, conventional segmentation fashion, with radical (R0) resection rates of 76% to 97% and 5-year survival rates of 44% to 59%. For inoperable patients, simultaneous radiotherapy is still considered as the standard treatment, and the radical radiotherapy dose is 60-74 Gy in conventional fractionation, with a 5-year survival rate of about 15-23%.
In the American Joint Committee on Cancer (AJCC) 7th edition staging, lesions with multiple tumor nodules in the same lung lobe without lymph node metastasis (T3N0M0) are also classified as stage IIB. The preferred surgical resection for lesions in this stage is primarily lobectomy with adjuvant chemotherapy given after R0 resection and postoperative radiotherapy required after non-R0 resection to improve local control.
Evidence of radical radiotherapy: locally advanced (stage IIIA-IIIB) NSCLC
For inoperable locally advanced NSCLC with tolerable general conditions, concurrent radiotherapy is the preferred standard of care; concurrent is preferable to sequential; cisplatin-based concurrent chemotherapy regimens are preferable to carboplatin.
The results of the 1999 Japanese phase III study showed that the 5-year survival rate in the synchronous radiotherapy group was better than that in the sequential group for inoperable locally advanced patients (15.8% vs. 8.9%, P=0.04), and the results of the RTOG9410 and BRO-CAT studies also confirmed that the local control rate and survival rate of synchronous radiotherapy were better than those of sequential radiotherapy.
There is evidence that cisplatin-based concurrent chemotherapy regimens are superior to carboplatin. The results of our phase II randomized study showed that the PE regimen (cisplatin + etoposide) had a higher 3-year survival rate than PC (paclitaxel + carboplatin), and that the PE regimen also reduced the incidence of side effects other than hematologic toxicity, especially 3rd to 4th degree radiation pneumonia. A newly published meta-analysis further verified that PC significantly increased the incidence of ≥2-degree radiation pneumonia compared with PE; it also showed that the so-called radiation pneumonia is inextricably linked to chemotherapy with or without chemotherapy and regimen selection, in addition to radiotherapy parameters such as radiation dose and irradiation volume.
In patients with operable stage IIIA (N2), it is controversial whether to add surgery after radiotherapy.
The SWOG8805 study showed that in patients with mediastinal lymph node metastases, concurrent radiotherapy + surgery was similar to concurrent radiotherapy for locally advanced NSCLC.
The INT0139 multicenter phase III study used synchronous radiotherapy followed by surgery + chemotherapy or radiotherapy + chemotherapy, resulting in better progression-free survival (PFS) in the surgery group than in the non-surgery group, but treatment-related mortality was higher in the surgery group.
The EORTC08941 phase III study showed no significant difference in either 5-year survival, median survival, or PFS between the surgery and sequential chemoradiotherapy groups after induction chemotherapy. The authors recommend radiotherapy as a better local treatment modality after induction chemotherapy because of the lower number of toxic effects and treatment-related deaths in the sequential chemoradiotherapy group.
The usual recommended radiotherapy dose for radical chemoradiotherapy remains 60 Gy.
The usual recommended radiotherapy dose for radical chemoradiotherapy is 60 Gy, but a retrospective analysis has confirmed that survival is significantly improved when sequential radiotherapy doses >74 Gy. Several phase III dose-escalation studies, such as RTOG0117, have shown that simultaneous radiotherapy doses up to 74 Gy are safe while ensuring that normal tissues are not over-irradiated.
Therefore, the RTOG0617 multicenter phase III study was proposed to enroll 500 inoperable stage IIIA/IIIB patients, and a median survival benefit of 7 months was expected for the high-dose (74 Gy) group. However, an analysis of 423 patients enrolled in 2012 found no survival benefit in the high-dose radiotherapy group, so the study prematurely discontinued enrollment in the high-dose group and used 60 Gy as the recommended dose of concurrent radiotherapy for locally advanced NSCLC.
Synchronous radiotherapy combined with targeted therapy is still in the trial phase.
The high-dose radiotherapy arm of RTOG0617 has been closed, but the multicenter randomized controlled study of synchronous radiotherapy ± cetuximab continues and has completed enrollment of 544 patients at the end of 2011 in anticipation of this outcome analysis.
(Consecutive) Accelerated hyper-segmentation in inoperable locally advanced patients should be used with caution.
Hyper-segmentation or macro-segmentation radiotherapy may also be used as a treatment option for locally advanced NSCLC. However, the clinical application of (sequential) accelerated hyper-segmentation is limited due to the cumbersome nature of treatment delivery and the higher acute toxicity response (esophageal) relative to concurrent radiotherapy.
Evidence of postoperative radiotherapy: stage IIIA (N2) NSCLC
Stage I-II and N0-1 NSCLC do not require postoperative radiotherapy after radical resection, with the exception of those with positive cut margins or large residual tumor; it is still controversial whether postoperative radiotherapy is required for stage IIIA (N2) NSCLC undergoing radical resection.
In resectable stage IIIA(N2) NSCLC, postoperative radiotherapy significantly reduces the rate of local recurrence, but the impact on survival remains uncertain; a meta-analysis published in The Lancet in 1998 showed that postoperative radiotherapy had no significant impact on survival in stage III and pN2 patients, but the use of postoperative radiotherapy for NSCLC has since declined significantly worldwide.
The main reason for the impact of postoperative radiotherapy on survival is the severe cardiopulmonary toxicity caused by obsolete radiotherapy techniques. With the gradual diffusion of new radiotherapy techniques and significant reduction of radiotherapy side effects, the value of postoperative radiotherapy for stage IIIA (N2) NSCLC has again attracted attention.
A retrospective study based on the Surveillance, Epidemiology and End Results (SEER) database (1988-2000) showed that postoperative radiotherapy significantly improved OS in stage N2 patients. subgroup analysis of the ANITA study also showed that postoperative radiotherapy significantly improved median survival and 5-year survival in pN2 patients. A large randomized controlled phase III study initiated in Europe since 2007 used three-dimensional conformal radiotherapy (3D-CRT), however, no follow-up reports have been seen, indicating that the study has been difficult to conduct. To date, the role of postoperative radiotherapy in resectable stage IIIA (N2) NSCLC remains uncertain.
Postoperative radiotherapy improves the local control rate of pN1 to 2 squamous carcinoma, but has no effect on OS.
A retrospective study published in 2011 by Prof. Wang Luhua included 221 patients with surgically completely resected stage IIIA(N2) NSCLC from 2003 to 2005 at our institution, 96 of whom received postoperative radiotherapy (41 with conformal radiotherapy). Results Postoperative radiotherapy significantly improved OS (P=0.046) and disease-free survival (P=0.009), and also significantly improved local area recurrence-free survival (P=0.025) and distant metastasis-free survival (P=0.001). Both univariate and multifactorial analyses confirmed that postoperative radiotherapy was a significant correlate of improved patient prognosis. Of course, the study also found that resectable stage IIIA (N2) NSCLC is a highly heterogeneous group of diseases and not all patients benefit from postoperative radiotherapy.
In order to continuously improve the individualized treatment for this group of patients, the next work will focus on analyzing the effect of postoperative radiotherapy on different subgroups of patients, analyzing and searching for factors that may benefit from postoperative radiotherapy, and using this as a basis to screen high-risk patients to receive postoperative radiotherapy, while enabling low-risk patients to avoid overtreatment. To further clarify the value of postoperative radiotherapy for resectable stage IIIA (N2) NSCLC, the Department of Radiotherapy of our hospital has taken the lead in organizing and initiating a large-scale national multicenter randomized controlled phase III study, and the subject is progressing well. This study will further enrich the evidence of postoperative radiotherapy for resectable stage IIIA (N2) NSCLC and promote and improve the individualized treatment of lung cancer.
Radiotherapy techniques
CT simulated positioning
The patient is generally positioned in the supine position with the patient’s arms crossed over the elbows and raised in front of the forehead, and is immobilized with a body shield or vacuum pad. Four-dimensional CT or positron emission tomography (PET)-CT localization is recommended.
If not available, CT simulation is preceded by measurement of the mobility of the lesion area in the up-and-down, anterior-posterior, and left-right directions under fluoroscopy of the simulator as reference data for the planned target volume (PTV). Enhanced CT scans are recommended, ranging from supraclavicular, lung and mediastinum, and upper abdomen to the level of the adrenal glands.
Target area outline and radiotherapy plan
The gross tumor target volume (GTV) includes the extent of intrapulmonary tumor seen in the lung window and the extent of mediastinal involvement seen in the mediastinal window. The burr margins of the lesion should be included in the GTV, which is recommended to be divided into GTVp (primary tumor) and GTVnd (metastatic lymph nodes).
The clinical target volume (CTV) is 6 mm external to GTVp for squamous carcinoma and 8 mm external to GTVp for adenocarcinoma. External radiation to the GTVnd area should include the draining area of the involved lymph nodes, and selective prophylactic irradiation of the lymphatic drainage area is not performed; the CTV should not extend beyond the anatomical boundary unless there is a definite presence of external invasion. The CTV after radical surgery includes mainly the surgical stump, the ipsilateral hilum, the ipsilateral mediastinum, and the area of the inferior bulbar lymph nodes.
The PTV is the CTV plus the range of motion of the tumor and the positional error, which is usually 5-10 mm.
3D-CRT or IMRT is recommended, with radical radiotherapy or radiotherapy doses of 60-70 Gy and postoperative radiotherapy doses of 50-60 Gy. The normal tissue limits are shown in the table. Recommended concurrent chemotherapy PE regimen: cisplatin 50 mg/m2 on days 1, 8, 29, and 36 and etoposide 50 mg/m2 on days 1 to 5 and 29 to 33.