Recent advances and new insights in the management of early-stage epidermal growth factor receptor-mutated non-small-cell lung cancer.

Patients with early-stage non-small-cell lung cancer (NSCLC) are candidates for curative surgery; however, despite multiple advances in lung cancer management, recurrence rates remain high. Adjuvant chemotherapy has been demonstrated to significantly prolong overall survival (OS), but this benefit is modest and there is an urgent need for effective new therapies to provide a cure for more patients. The high efficacy of tyrosine kinase inhibitors (TKIs) against epidermal growth factor receptor-mutated (EGFR) in patients with advanced EGFR-mutated NSCLC has led to the evaluation of these agents in early stages of the disease. Multiple clinical trials have evaluated the safety and efficacy of EGFR TKIs as an adjuvant treatment, in patients with resected EGFR-mutated NSCLC, and shown that they significantly prolong disease-free survival (DFS), but this benefit does not translate to OS. Recently, an interim analysis of the ADAURA trial demonstrated that, surprisingly, osimertinib improved DFS. This led to the study being stopped early, leaving many unanswered questions about its potential effect on OS and its incorporation as a standard adjuvant treatment in this patient subgroup. These targeted agents are also being evaluated in locally-advanced disease, with promising results, although prospective studies with larger sample sizes are needed to confirm these results. In this article, we review the most relevant studies on the role of EGFR TKIs in the management of early-stage EGFR-mutated NSCLC.

Is there a place for optimizing thoracic radiotherapy in limited-stage small cell lung cancer after twenty years?

Thoracic radiotherapy (TRT) is one of the main treatments in limited-stage small cell lung cancer (LS-SCLC). Hyperfractionated TRT (45 Gy, 1.5 Gy twice daily) has been the standard of care (SOC) since Turrisi and colleagues published the results of their clinical trial in 1999. Two meta-analyses have demonstrated the benefits of concurrent chemotherapy and TRT in terms of intrathoracic disease control at 2 years and 3-year overall survival (OS). The phase 2 trial by Grønberg et al (2016) comparing once-daily hypofractionated TRT to twice-daily hyperfractionated TRT in LS-SCLC found similar outcomes in both groups in terms of response rate, progression-free survival (PFS), grade 3-4 adverse effects, and OS. The CONVERT trial, published in 2017, failed to demonstrate the superiority of the conventional scheme (once-daily TRT) vs twice-daily radiotherapy, despite the application of modern radiotherapy techniques and a quality assurance programme, thus confirming the twice-daily hyperfractionated regimen as the SOC. At the 2020 American Society of Clinical Oncology (ASCO) annual meeting, Grønberg et al reported preliminary findings from a phase 2 trial comparing two different TRT dose regimens (45 Gy vs 60 Gy), both administered twice daily. Those data demonstrated a marked improvement in 2-year survival rates in the high dose arm (70.2% vs 46.1%, P = 0.002), despite similar objective response rates and PFS outcomes. Those findings provide a new treatment alternative to consider: Hyperfractionated, high-dose TRT. However, the results of that trial will need to be validated in a large, randomized phase 3 study. The results of the phase 2 CALCG 30610 trial will help to clarify the optimal dose and regimen. The potential role of upfront immunotherapy, which early data suggest may improve OS, also needs to be determined.

New standard in locally advanced rectal cancer.

In the following review we intend to ascertain the optimal neoadjuvant therapy in patients with locally advanced rectal cancer. In 2004, a study revealed that chemoradiotherapy (CRT) resulted in better local control when performed preoperatively rather than postoperatively, thus neoadjuvant treatment was established as a standard treatment. Subsequently, the Polish study and the Trans-Tasman Radiation Oncology Group showed no statistically significant difference between concomitant CRT over 5 wk vs short-course radiotherapy (RT). Therefore, both were established as standard neoadjuvant treatments. Later, the Stockholm III study demonstrated that short-course RT had a higher complete pathological response than long-course RT. It also showed that a delay between RT and surgery presented fewer complications. This opened a window of time to provide an early and effective systemic treatment to prevent distant metastases. Studies show that short-course RT plus oxaliplatin-based chemotherapy could achieve this. When comparing this total neoadjuvant treatment (TNT) vs concomitant CRT, the former showed greater complete pathological response and lower acute toxicity. Studies presented during 2020 have also shown the benefits of TNT in terms of complete pathological response, as well as disease and metastasis-free survival. Our review suggests that probably TNT should be the new standard treatment for these patients. However, we will have to wait for the full text publications of these studies to confirm this statement.