Approximately 15% of all patients with non–small cell lung cancer (NSCLC) present with disease in early stages, and yet 5-year survival rates for these individuals never exceed about 54% because of high rates of recurrence following initial treatment.
Presenters at the Education Session “Upfront Management of Operable Non–Small Cell Lung Cancer,” held June 2, discussed current concepts regarding the treatment of early-stage disease, along with efforts to better enhance local control.
Dr. Shirish M. Gadgeel speaks during the Education Session “Upfront Management of Operable Non-Small Cell Lung Cancer.”
Chemotherapy and Targeted Therapy in Early-Stage NSCLC
“If there’s any tumor type where adjuvant chemotherapy makes sense, it’s NSCLC,” Shirish M. Gadgeel, MD, of the Karmanos Cancer Institute, commented. As Dr. Gadgeel illustrated during his talk, adjuvant chemotherapy is the accepted standard of care for patients with stage II or IIIA tumors or stage IB tumors 4 cm or larger based on a wealth of data from randomized trials and meta-analyses that consistently demonstrate a 5% to 11% improvement in 5-year overall survival with this approach.
The fundamentals of adjuvant chemotherapy have changed little since the initial publication of a seminal meta-analysis in 1995 that established the modest survival benefit associated with cisplatin-based chemotherapy following surgery. Combined treatment with cisplatin and vinorelbine has been the most studied regimen to date and is backed by strong long-term results from the BR-10 and ANITA trials. However, current evidence-based guidelines recommend administering four cycles of any of a variety of platinum-based regimens following surgical resection, depending on disease histology.
“The commonly used platinum-based combinations that we use in the advanced setting can be used in the adjuvant setting and are expected to have a benefit,” Dr. Gadgeel stated.
The timing of treatment is important. “One needs to deliver adjuvant chemotherapy as close to surgery as possible, but delayed administration in certain select patients is acceptable so long as it falls within about 4 months after surgery,” Dr. Gadgeel said.
The adjuvant systemic therapy options available to patients may well extend beyond platinum-based chemotherapy in the near future. Knowledge of molecular driver mutations and immunotherapy checkpoints has revolutionized the management of advanced-stage adenocarcinoma thanks to effective targeted agents and immunotherapies. New research is now focused on whether these advances can be extended to the treatment of earlier stage, curable disease.
Several studies—such as RADIANT, SELECT, CTONG 1104, and ALCHEMIST—have evaluated or are currently evaluating EGFR tyrosine-kinase inhibitors (TKIs) in patients with stage I or II to IIIA disease harboring EGFR driver mutations, most with disease-free survival (DFS) as the primary outcome. Similarly, clinical benefit observed with checkpoint inhibitors has prompted assessment of agents targeting the PD-1/PD-L1 axis in patients with early-stage NSCLC.
Several EGFR TKI studies with mature data demonstrate improved DFS following 2 years of treatment, compared with adjuvant chemotherapy. However, recurrence tends to occur shortly after stopping the EGFR TKI, raising concerns about whether such treatment is actually curing patients or just delaying recurrence.
“We need to know the overall survival to truly define the benefits of adjuvant EGFR TKI,” Dr. Gadgeel commented.
Until more robust data demonstrate the utility of targeted therapy and immunotherapy in early-stage disease, Dr. Gadgeel indicated that adjuvant platinum-based chemotherapy remains the standard.
New Radiation Techniques in Early–Stage NSCLC
Dr. Thomas A. DiPetrillo speaks during the Education Session “Upfront Management of Operable Non–Small Cell Lung Cancer.”
“Radiotherapy, luckily, has evolved as technology has improved,” Dr. DiPetrillo stated. Advances in imaging, radiation delivery, treatment planning, and treatment delivery have all converged to allow more precise delivery of radiation. The key upshot is that by sparing the normal tissues, rather than bathing the entire lung in radiation, the fractional dose can be increased to result in better tumor control.
“Thus, the ablative types of radiation are more or less like a nuclear explosion in the tumor,” Dr. DiPetrillo said.
SBRT represents a suitable option for a limited slice of the early-stage NSCLC population. Eligible patients are those with T1-2N0 (i.e., stage IA-IIA) disease who are medically inoperable or who refuse surgery. Ideally, the primary lesions should measure 6 cm or less for optimal results.
In suitable individuals, SBRT proves remarkably effective, yielding local control rates ranging from 88% to 98%. Although different fractionation schema have been evaluated, results suggest that higher control rates are achieved when the biologically equivalent dose exceeds 95 Gy.
Dr. DiPetrillo noted that SBRT is well-tolerated and relatively safe so long as constraints are carefully followed. Less than 5% of patients face a risk of grade 4 or 5 pneumonitis, which typically arises 3 to 12 months after SBRT when it does occur. Declines in pulmonary function are uncommon but not unheard of.
When treating central tumors with SBRT, Dr. DiPetrillo advised caution, given the risk of adversely affecting more normal tissue and major structures (e.g., the hilum). Toxicities associated with SBRT of central lesions can include airway fibrosis/stenosis, lobar collapse, and bleeding. Current data support safe and effective treatment using 50 Gy delivered in four or five fractions.
While discussing how to advance the use of radiation therapy in early-stage NSCLC, Dr. DiPetrillo indicated, “A local focused treatment of radiation changes the immune milieu of the body and potentially can make [immunotherapy] a very attractive treatment for the future.”
Dr. Hiran Fernando speaks during the Education Session “Upfront Management of Operable Non-Small Cell Lung Cancer.”
Surgical Advances in NSCLC
Hiran Fernando, MD, of the Inova Schar Cancer Institute, brought listeners up to speed on the different surgical procedures currently employed in different parts of the world to manage early-stage (primarily stage I) NSCLC. Although thoracotomy used to be the standard approach for lobectomy, more recent evidence illustrates that minimally invasive surgery excels over open surgery, decreasing short-term morbidity and increasing the speed of return to normal function. However, among the variety of minimally invasive approaches available, it is unclear which offers the best alternative to thoracotomy.
Video-assisted thoracic surgery (VATS), introduced in the mid- to late 1990s and currently a popular approach all over world, involves the manipulation of instruments placed through small ports strategically inserted between the ribs. Retrospective analyses comparing multiport VATS with thoracotomy demonstrate numerous benefits with the minimally invasive approach, including shorter chest tube duration, a shorter length of stay, and improved survival at 4 years. More recent prospective data from a randomized trial in which patients and observers were initially blinded to the surgical technique used reported less postoperative pain and better quality of life with VATS compared with anterolateral thoracotomy throughout the first year after surgery.1
Robot-assisted thoracic surgery (RATS) offers the same advantages as VATS when compared with open surgery and is generally similar to VATS in that instruments are manipulated through several small ports. However, RATS does not necessarily require an access incision, and use of a 3-D camera offers a magnified view of internal structures. Another key point of differentiation Dr. Fernando noted is that articulation of the instruments in RATS occurs inside the chest very near the resection site, as opposed to VATS where articulation occurs at the site of port entry at the ribs, which puts pressure on the intercostal nerves, causing pain. RATS does have a few drawbacks, including a higher cost than VATS and the need for an experienced assistant at the field while the surgeon controls the robot.
Another VATS approach quickly gaining popularity in Europe and Asia is uniportal lobectomy in which, through close cooperation of the surgical team, all instruments are inserted and manipulated through a single access incision. This approach offers better cosmesis and possibly less pain and does not increase costs compared with standard VATS.
After covering the different surgical approaches for early-stage NSCLC, Dr. Fernando discussed the different types of resection, which vary based on a patient’s surgical risk.
For patients with standard-risk operable NSCLC, lobar resection remains the gold standard, although sublobar resection may be reasonable for peripheral tumors no larger than 2 cm. Recently reported data from the large, randomized JCOG0802 trial described no difference in postoperative mortality and adverse events with segmentectomy compared with lobectomy, although a slightly higher rate of alveolar fistula was observed. Long-term data from this trial are still awaited, but “we may see a change in standard of care in the future,” Dr. Fernando said.
For patients with high-risk operable disease, sublobular resection is standard, although Dr. Fernando cautioned that not all sublobular resections are the same. Segmentectomy should be favored over wedge resection given the larger number of lymph node stations sampled, the larger number of nodes removed, and the wider surgical margins.
Dr. Fernando also noted that for this patient population, “there’s a feeling that SBRT may be as good as a wedge resection or as segmentectomy, and I don’t think this is the case. It hasn’t been proven yet.” The ongoing STABLEMATES trial will help address this issue.
–Kara Nyberg, PhD