Upfront Resection of Locally Advanced NSCLC Followed by Chemoradiotherapy

Stage III non-small cell lung cancer (NSCLC) comprises a heterogeneous group of patients, with concurrent chemoradiotherapy (CRT), until recently, being considered the standard of care (SoC) treatment for fit patients. Prognosis varies depending on the size and extent of the primary tumor and the degree of lymph node involvement. The aim of treatment of stage III NSCLC is to increase both locoregional and systemic control of the disease. For resectable stage III NSCLC, resection alone is associated with poor survival because of a high local recurrence rate and the presence of distant metastatic disease during the course of the disease. Induction chemotherapy and/or radiotherapy followed by surgery has been demonstrated to improve survival in selected patients. Moreover, it has been shown that in highly selected patients with stage IIIB NSCLC, surgical resection as part of multimodality therapy might be associated with improved overall survival (OS). Since a large proportion of patients with stage III NSCLC develop distant disease relapse following CRT, there is a need to treat possible presence of micrometastases and improve systemic control of the disease. Recently, immune checkpoint inhibition (ICI, durvalumab) has been added to CRT successfully and is now SoC treatment in irresectable (e.g. multilevel or bulky N2 disease or presence of N3 lymph node metastases) stage III NSCLC, leaving the role of surgery in this new treatment strategy unclear.

In large volume NSCLC and in cavitating tumors, chances of sterilization of the tumor by CRT alone are reduced, increasing the local recurrence rate, when compared to small size tumors. Between 10-20% of all lung carcinomas present with radiological cavitation, which is believed to be due to tumor necrosis as a consequence of ischemia and/or bronchial obstruction. Necrosis and cavitation of the tumor can cause infectious complications in the short and long term with subsequent impaired quality of life (QoL) and may also lead to interruption of, or the need for postponing, (systemic) treatment. Moreover, cavitation is associated with bleeding complications and even fatal pulmonary hemorrhage after CRT. Besides, lung function might be seriously impaired after CRT for a large tumor, especially in case of a centrally located tumor. It has been suggested that upfront resection with postoperative CRT in patients who have a potentially resectable tumor could be a strategy to prevent complications of tumor cavitation (e.g. infectious complications, bleeding) in large volume tumors. Moreover, in advanced NSCLC, it is suggested that (chemo)immunotherapy (or targeted therapy in case of presence of a driver mutation) improves systemic disease control, making local control of the disease more important during follow-up. To decrease the risk of a local recurrence in a situation of controlled systemic disease, local control by upfront resection of the large volume tumor might be considered.

For stage III NSCLC, immunotherapy can be added prior (neoadjuvant) or following (adjuvant) CRT. In the neoadjuvant setting, several studies have been done or are ongoing, including ICI (single agent or a combination of 2 agents) or ICI in combination with chemotherapy, radiotherapy or CRT followed by resection as a possible treatment for stage III NSCLC (NADIM(-II) trial, LCMC3 trial, NEOSTAR trial, KEYNOTE-671 trial, IMpower-030 trial, CheckMate-816, 77T trial, AEGEAN). So far, most of these studies included only a small number of patients and endpoints have been major pathological response (MPR) (<10% vital tumor present) and complete pathological response (pCR), both being surrogate markers for progression free survival (PFS) and OS. The added toxicity of ICI, especially in combination with chemotherapy, radiotherapy or CRT, still needs to be elucidated and in case of a large volume or cavitating tumor, toxicity might be related to infection and necrosis of the large tumor mass and/or an increase in radiation dose to the organs at risk such as the lungs.

Upfront surgery might benefit patients with large volume stage IIIB/IIIC NSCLC and the potential advantages, e.g. improved local control, reduction of radiotherapy treatment volumes and reduction of long term infectious problems or bleeding complications because of necrosis of the primary tumor, may possibly outweigh the risk of a delayed start of the SoC treatment. A possible drawback of an upfront resection approach is the risk of (locoregional or systemic) tumor progression when delaying planned CRT and adjuvant ICI. The intervention should not prevent the patient from receiving the SoC treatment, so a safety and feasibility check is necessary in evaluating the role of upfront resection in these patients with large volume stage IIIB/IIIC NSCLC.

Aim of the UPLAN-I trial is to evaluate feasibility and safety of upfront resection of the large volume or cavitating tumor in the lung (including hilar with/without mediastinal lymph node dissection if deemed possible by the treating surgeon), followed by concurrent CRT. The role of upfront resection in reducing infectious problems (and bleeding complications) and subsequent impaired QoL, in combination with decreasing the risk of a local recurrence (PFS) and improving OS, are evaluated in the future UPLAN-II trial, however feasibility and safety of this treatment regimen need to be established first (UPLAN-I). Moreover, the role of ctDNA in relation to treatment response and outcome of this treatment regimen will be evaluated in the consecutive UPLAN-II trial.