Mounting Evidence Supporting Neoadjuvant ChemoIO Means Surgeons Must Adapt

For a considerable time, surgery was the only curative treatment for lung cancer. Even now, in the era of immunotherapy and targeted therapy, surgery remains indispensable in treating many non-small cell lung cancer (NSCLC) patients. Modern pulmonary surgery has evolved from simple techniques of incisions, ligatures, and sutures to sophisticated techniques including bronchoscopic, thoracoscopic, and remote robotic surgery.

Although tremendous progress has been made in the evolution of surgery, new ideas, theories, and drugs in oncology are yielding greater achievements and are continually improving the long-term survival of NSCLC patients. Indeed, the CheckMate-77T¹ and AEGEAN² trials, both of which highlighted an event-free survival advantage for perioperative chemoimmunotherapy, recently added to the growing body of literature showing the benefits that can be realized when combining the latest advances in both medical and surgical oncology.

Combined with CheckMate 816,³ Keynote671,⁴ Impower010,⁵ Keynote091,⁶ Neotorch,⁷ and Rationale-315,⁸ AEGEAN and CheckMate-77T help to usher in a new era in the surgical treatment of NSCLC. Herein we discuss the corresponding interactions and changes that should be made by lung cancer surgeons in this revolutionary era.

When adopting modern surgical techniques for the treatment of NSCLC, oncological considerations should be included in therapeutic decision-making. This new era not only includes the application of modern surgical techniques; it also requires mastery of the principles and inter-disciplinary progress of lung cancer oncology.

Firstly, NSCLC is a systemic illness, not a single organ disease, and treatment strategies formulated by multidisciplinary teams have been shown to improve long-term survival[9]. Secondly, accurate pathological staging, detailed histological classification, and treatment-informative molecular subtyping are key to developing individualized diagnostic and treatment plans. Additionally, NSCLC patients who undergo upfront surgery traditionally have had significantly improved survival rates after receiving perioperative platinum-based chemotherapy. Even if some patients ultimately undergo surgery only, the choice must be based on the results of a comprehensive assessment. Even for patients with advanced NSCLC, surgical treatment is playing an increasingly important role in the treatment of residual lesions after effective systemic treatment.

The Challenges of Anatomic TNM Staging of NSCLC

For some time, the formulation of treatment strategies has relied heavily on TNM staging. Therefore, all clinical trials in perioperative immunotherapy included participants with “early stage” NSCLC. Patients were included if physicians judged that the patients were candidates for upfront surgery and that resection was possible, according to existing guidelines.

However, the long-term survival rate of these “early staged” NSCLC patients was often unsatisfactory after “so-called” curative surgery, and many patients died postoperatively. When anatomical early stage as described by TNM descriptors is not a guarantee for long-term survival, it is easy to speculate that TNM staging alone does not fully reflect the panorama of NSCLC:

1. More complete comprehensive staging, including TNM descriptors, histological subtypes, molecular classifications,¹⁰ and PD-L1¹¹ expression should be instituted for NSCLC before treatment to formulate individualized preoperative treatment strategies.
2. Preoperative PET-CT examination is indispensable. In addition to identifying abnormalities in common, radiographically occult metastatic sites, PET-CT examinations from skull base to mid-thigh, where available, can help avoid at least 8% of unnecessary surgeries.12
3. Pathological diagnosis is necessary for suspicious regional lymph nodes. Compared to North America, lung cancer physicians in many other countries do not attach great importance to preoperative/and intraoperative pathological staging of hilar/mediastinal lymph nodes. However, the presence or absence of lymph node metastasis is an important determinant in deciding whether patients should undergo direct surgery or receive neoadjuvant treatment followed by surgery. In addition, lymph node status is a prerequisite for determining the extent of resection.
4. Extending access to thoracoscopy/robotic surgery is needed. The discovery of negative pressure in the chest and the invention of positive pressure breathing by tracheal intubation have led to the success of thoracic surgery. The major advantages of thoracoscopic/robotic surgery—lighting, magnification, and proximity—have enabled precise thoracic surgery that “transcends” traditional TNM staging and is another key factor in achieving R0 resection.
5. Further understanding of the diversification of resection extent is needed. From Graham’s first successful pneumonectomy for lung cancer in 1933, Ginsberg established lobectomy as the standard for lung cancer treatment in 1995 in less extensive primary lesions. Today, the more nuanced strategy of determining the nature of the resection based on the features of the lesion reflects our s renewed understanding of surgical treatment for NSCLC: No surgery for pure ground glass opacity (GGO) nodules;¹³ sub-lobectomy for early stage lung cancer with diameter less than 2 cm and negative lymph node status ; neoadjuvant treatment followed by surgery for locally advanced, yet resectable lung cancer; and individualized supplementary surgery for advanced lung cancer in the setting of disease response or stability on systemic treatment.
6. Assessment of minimal residual disease (MRD) refers to the sum of all strategies and methods used to determine the presence of tumors in the body by molecular examination of residual tumor DNA in the blood. MRD is not only a potential indicator predicting whether the tumor can be cured before surgery, but it is also an emerging indicator for judging whether a tumor has been cured after surgery. Sensitivity of MRD detection is limited; there are many methodological bottlenecks that need to be overcome; however, we have seen the promising broad application prospects of MRD in staging, efficacy evaluation, treatment guidance, follow-up, and prognosis of NSCLC.

Continue to Part 2, More Than Ever, Surgeons Must Collaborate to Ensure Patients Receive Appropriate Care.

References:

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