Prof. Kouhen Fadila
Prof. Dahbi Zineb
Lung cancer is a significant global health issue, remaining the leading cause of cancer-related deaths with 2.1 million new cases and 1.8 million deaths.
Complete surgical resection is the treatment of choice for operable early-stage non–small cell lung cancer (NSCLC) and resectable stage IIIA disease. Nevertheless, patients in whom the ipsilateral mediastinal nodes (pN2) have been found to be pathologically affected at the time of surgery, or who have microscopically (R1) or grossly (R2) positive margins, have unacceptable locoregional recurrence rates on the order of 40% to 60%. Consequently, adjuvant treatments, including chemotherapy and radiotherapy, have been extensively studied and evaluated in an effort to improve the prognosis and outcomes of patients with NSCLC.
Adjuvant chemotherapy has shown clear benefits in improving the prognosis of NSCLC, particularly in patients with stage II or III disease. Several trials and meta-analyses, such as the International Adjuvant Lung Cancer Trial (IALT), with more than 1,800 randomly assigned patients with stage I, II, and III disease, have demonstrated the efficacy of adjuvant chemotherapy in reducing the risk of cancer recurrence and improving overall survival.
“The debate as to whether to offer radiotherapy to patients with mediastinal lymph node involvement after surgery has been ongoing for more than 20 years.”— Prof. Kouhen Fadila and Prof. Dahbi Zineb
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On the other hand, the role of postoperative radiotherapy is not as clearly defined and varies depending on the specific circumstances of each patient. Some studies have suggested that postoperative radiotherapy may offer benefits in certain cases, such as when there is a high risk of local recurrence or when the tumor involves the lymph nodes extensively. However, other studies have not consistently shown a significant improvement in survival with the addition of postoperative radiotherapy.
Controversy Over Postoperative Radiotherapy
The debate as to whether to offer radiotherapy to patients with mediastinal lymph node involvement after surgery has been ongoing for more than 20 years. The controversy surrounding postoperative radiotherapy stems from the potential for increased toxicity and side effects associated with radiation therapy. Radiation to the chest area can cause damage to healthy tissues, leading to adverse effects on lung function and potential complications. Therefore, it is essential to carefully weigh the potential benefits and risks of postoperative radiotherapy on an individual basis.
The results of the earlier postoperative radiotherapy meta-analysis indicated a significant detrimental effect on survival among the entire patient group receiving postoperative radiotherapy. Specifically, there were 707 deaths of 1,056 patients in the radiotherapy arm, compared with 661 deaths among the 1,072 patients in the surgery alone arm. This translated to a 21% relative increase in the risk of death or a 7% absolute decrease at 2 years, leading to an overall survival decrease from 55% to 48%. Many of the negative effects of postoperative radiotherapy have been attributed to a high incidence of cardiac and respiratory complications from the use of older two-dimensional radiation techniques, which are no longer seen in modern treatment populations.
In addition, the findings of several recent studies and meta-analysis indicated that postoperative radiotherapy led to significant improvements in both overall and disease-free survival for patients with multiple N2 metastases or involvement of multiple N2 lymph node stations. However, there was no significant difference in survival outcomes between the groups for patients with a single N2 lymph node station involved.
Based on these data, the American Society for Radiation Oncology (ASTRO) guidelines recommend postoperative radiotherapy in the setting of gross primary or nodal residual disease or positive margins.
The Lung ART Trial: Key Results
The results of the large, multi-institutional Lung ART trial (ClinicalTrials.gov identifier NCT00410683) have challenged the current established guidelines. The findings from this trial were presented during the European Society for Medical Oncology (ESMO) Virtual Congress 2020 and published in The Lancet in 2022.
Lung ART is an open-label, randomized, phase III superiority trial comparing mediastinal postoperative radiotherapy with no postoperative radiotherapy in patients with NSCLC who had complete resection, nodal exploration, and cytologically or histologically proven N2 involvement. The primary objective was disease-free survival at 3 years from enrollment, with secondary objectives of safety, tolerability, and overall survival. The trial was powered to demonstrate a 10% improvement in the 3-year disease-free survival rate compared with the control arm.
“The existence of driver mutations may be correlated with an increased tumor aggressiveness and probability of distant metastasis, as well as potential resistance to systemic treatments.”— Prof. Kouhen Fadila and Prof. Dahbi Zineb
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The trial was launched with a goal enrollment of 700 patients from 64 hospitals and cancer centers in five countries (France, UK, Germany, Switzerland, and Belgium). However, because of slow and insufficient patient accrual, the new target was lowered to 500 patients, and the expected improvement in 3-year disease-free survival was adjusted to 12%.
Between August 2007 and July 2018, 501 patients were included in the study. Patients were randomly assigned to either the control arm or the postoperative radiotherapy arm, where they received 54 Gy for 5 weeks. The median patient age was 61 (range, 36–85 years). Approximately 66% of patients were male, and the most common histology was adenocarcinoma (73%). A majority of patients received chemotherapy, with 77% receiving it postoperatively and 18% receiving it preoperatively.
After a median follow-up period of 4.8 years, the results showed the 3-year disease-free survival rates were 47% (95% confidence interval [CI] = 40%–54%) with postoperative radiotherapy and 44% (95% CI = 37%–51%) without it. Additionally, the median disease-free survival times were 30.5 months (95% CI = 24–49 months) with postoperative radiotherapy and 22.8 months (95% CI = 17–37 months) for the control group (P = .18). The 3-year overall survival rate was 66.5% with postoperative radiotherapy vs 68.5% without it. Postoperative radiotherapy was also associated with more grade 3 or 4 toxicities (both early and late).
In light of these results, the authors concluded that conformal postoperative radiotherapy should not be recommended as the standard of care for patients with stage IIIA N2 NSCLC.
Limitations of Lung ART and PORT-C Trials
Similarly, the phase III PORT-C randomized clinical trial confirmed that postoperative radiotherapy did not improve disease-free survival. Of note, the Lung ART trial revealed that the postoperative radiotherapy arm had a significantly lower rate of mediastinal relapse compared with the control arm, with a reduction of 25% vs 46%, respectively. These findings highlight the potential benefit of postoperative radiotherapy in preventing mediastinal relapse, despite the lack of a significant impact on overall or disease-free survival.
“Ongoing and future analyses are planned to identify patients for whom postoperative radiotherapy could be recommended.”— Prof. Kouhen Fadila and Prof. Dahbi Zineb
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A significant limitation of both the PORT-C and Lung ART studies lies in the absence of patient-specific genetic mutation analysis. This omission is particularly noteworthy, given the substantial proportion of patients with nonsquamous NSCLC (primarily consisting of adenocarcinoma) within both trials (83.8% in PORT-C and 78.4% in Lung ART). Previous research has established that the existence of driver mutations may be correlated with an increased tumor aggressiveness and probability of distant metastasis, as well as potential resistance to systemic treatments.
These results underscore the complexity and challenges associated with delivering postoperative radiotherapy effectively.
Clinical Practice Implications
Nevertheless, these data failed to change the clinical practice adopted by radiation oncologists. Recently, the European Society for Radiotherapy and Oncology (ESTRO) coordinated a survey involving 22 experts who were asked before and after presentation of the results of the Lung ART trial. Even after being informed about the findings of the Lung ART trial, 82% of these experts still included postoperative radiotherapy in the management of patients with pN2 disease, especially with extracapsular nodal extension, multiple or bulky lymph nodes, incomplete lymph node resection, ineligibility to receive adjuvant chemotherapy, and positive margins.
Further research and analysis are needed to better understand the nuances of postoperative radiotherapy in specific patient populations and to identify the optimal approach for improving outcomes in the adjuvant treatment of NSCLC. Ongoing and future analyses are planned to identify patients for whom postoperative radiotherapy could be recommended. Further studies assessing the feasibility of stereotactic radiotherapy for micro or macro residual disease are also warranted.
DISCLOSURE: Prof. Kouhen Fadila and Prof. Dahbi Zineb reported no conflicts of interest.
Prof. Kouhen Fadila and Prof. Dahbi Zineb are Associate Professors at Mohammed VI University of Health Sciences and radiation oncologists at International University of Cheikh Khalifa.
