Post-Operative Radiotherapy Not Tied to Better Disease-Free Survival in NSCLC

Post-operative radiotherapy (PORT) following complete resection, and after neoadjuvant chemotherapy, was not associated with increased disease-free survival (DFS) versus no PORT in patients with non-small-cell lung cancer (NSCLC), according to phase III trial results.

The 3-year DFS rate in patients who received PORT was 47% compared with 44% in the control arm (no PORT), with an adjusted DFS hazard ratio of 0.86 (95% CI 0.68-1.08, P=0.18), reported Cécile Le Pechoux, MD, of the Institut Gustave Roussy in Paris, and colleagues.

The study’s results provide “robust evidence that 3D conformal PORT cannot generally be recommended as part of the standard of care in patients with resected stage IIIAN2 NSCLC,” they wrote in the Lancet Oncology.

The role of PORT in patients with completely resected NSCLC with mediastinal nodal involvement (pN2) has been controversial, particularly after a 1998 meta-analysis that cast doubt on the benefits associated with PORT, Le Pechoux’s group explained.

“However, there was still potential for its use in patients with mediastinal nodal involvement,” they wrote. “Since then, in addition to an improvement in radiotherapy techniques, there have been substantial improvements in the selection of patients with 18F-fluorodeoxyglucose (18F-FDG) PET-CT scan and brain imaging, and also in clinical management relating to thoracic surgery or intensive care, or both.”

Le Pechoux and colleagues conducted the Lung Adjuvant Radiotherapy Trial (Lung ART), a randomized superiority trial, in order to evaluate the role of PORT in routine settings in patients with completely resected stage IIIAN2 NSCLC.

Between August 2007 and July 2018, 501 patients in 64 hospitals and cancer centers in five different countries were randomized after the completion of surgery or adjuvant chemotherapy to the PORT group (n=252) or the control group (n=249).

Most (91%) patients were staged with 18F-FDG-PET/CT, all patients had baseline brain imaging, and almost all received neoadjuvant or adjuvant chemotherapy. PORT was administered with either 3-D conformal radiotherapy (89%) or intensity-modulated radiotherapy (11%).

At the data analysis cutoff, the median follow-up was 4.8 years in both study cohorts. Among the 501 patients, 296 (59%) had a recurrence or died, 144 (57%) in the PORT group and 152 (61%) in the control group.

In addition to the 3-year DFS rates, Le Pechoux and colleagues observed that the median DFS was 30.5 months (95% CI 24.0-48.5) in the PORT group and 22.8 months (95% CI 17.0-36.5) in the control group.

The authors observed that of the 296 patients with DFS events:

• 36% had mediastinal relapse, including 25% of 144 patients in the PORT group and 46% of 152 patients in the control group
• 21% (n=61) had brain failure: 24% (n=34) and 18% (n=27) in each group, respectively
• 48% (n=142) had extracranial metastatic failure: 49% (n=71) and 47% (n=71)
• 10% (n=29) had death as the first event: 15% (n=21) and 5% (n=8)

As for adverse events (AEs), the most common grade 3-4 AEs were pneumonitis (5% of 241 patients in the PORT group vs one patient of 246 in the control group), lymphopenia (4% vs 0%, respectively), and fatigue (3% vs <1%). Late-grade 3 and 4 cardiopulmonary toxicity was reported in 11% of patients in the PORT group and 5% in the control group.

“Because mediastinal relapse was substantially reduced by radiotherapy, other analyses are warranted to identify the patients for whom PORT could be used,” the authors stated. “Even if there was no deleterious effect of PORT in terms of overall survival, more toxicities were observed in the PORT group than the control group, especially cardiopulmonary toxicity, that need to be further explored.”

In an accompanying comment, Lizza E. Hendricks, MD, PhD, and Kirk K.M. De Ruysscher, MD, PhD, both of the Maastricht University Medical Center in the Netherlands, observed that historically the 3-year DFS rates have been about 30% for resected stage III NSCLC.

However, they noted that despite the fact that Lung ART was negative for its primary endpoint of investigator-assessed DFS, both groups in the study had rates exceeding 40%, “probably reflecting the introduction of 18F-FDG-PET and brain imaging and improved preoperative and postoperative care.”

“Lung ART underscores the importance of adequate staging, surgery, supportive care, and radiotherapy techniques,” Hendricks and De Ruysscher wrote.