This phase 2 clinical trial examines the outcomes of patients with early-stage non–small cell lung cancer receiving neoadjuvant stereotactic ablative radiotherapy followed by surgery.
Key Points
Question
What are the outcomes, including the pathologic complete response rate, with neoadjuvant stereotactic ablative radiotherapy followed by surgery for early-stage non–small cell lung cancer?
Findings
In this phase 2 study of 40 patients, the pathologic complete response rate after stereotactic ablative radiotherapy was 60%. The combined treatment approach had excellent local control, a favorable toxicity profile, a 90-day postoperative mortality of 0%, and no decline in quality of life.
Meaning
The lower-than-expected pathologic complete response rate after stereotactic ablative radiotherapy suggests that patients treated with stereotactic ablative radiotherapy alone should be monitored closely for recurrence; although the treatment appears to be safe, additional interventions are required to reduce the regional and distant recurrence risks.
Abstract
Importance
Stereotactic ablative radiotherapy (SABR) is a standard treatment option in patients with medically inoperable early-stage non–small cell lung cancer (NSCLC), yet the pathologic complete response (pCR) rate after SABR is unknown. Neoadjuvant SABR in patients with cancer who are fit for resection has been hypothesized to improve local control and induce antitumor immune activity, potentially leading to better outcomes.
Objectives
To determine the pCR rate after SABR and to assess oncologic and toxicity outcomes after a combined approach of neoadjuvant SABR followed by surgery.
Design, Setting, and Participants
A phase 2, single-arm trial, with patient accrual from September 30, 2014, to August 15, 2017 (median follow-up, 19 months), was performed at a tertiary academic cancer center. Patients 18 years or older with T1T2N0M0 NSCLC and good performance status, with adequate pulmonary reserve to undergo surgical resection, were studied.
Interventions
Patients underwent neoadjuvant SABR using a risk-adapted fractionation scheme followed by surgery 10 weeks later.
Main Outcomes and Measures
The pCR rate as determined by hematoxylin-eosin staining.
Results
Forty patients (mean [SD] age, 68 [8] years; 23 [58%] female) were enrolled. Thirty-five patients underwent surgery and were evaluable for the primary end point. The pCR rate was 60% (95% CI, 44%-76%). The 30- and 90-day postoperative mortality rates were both 0%. Grade 3 or 4 toxic effects occurred in 7 patients (18%). In patients receiving surgery, 2-year overall survival was 77% (95% CI, 48%-91%), local control was 100% (95% CI, not defined), regional control was 53% (95% CI, 22%-76%), and distant control was 76% (95% CI, 45%-91%). Quality of life did not decline after treatment, with no significant changes in mean Functional Assessment of Cancer Therapy for Lung–Trial Outcome Index score during the first year of follow-up.
Conclusions and Relevance
The pCR rate after SABR for early-stage NSCLC was 60%, lower than hypothesized. The combined approach had toxic effects comparable to series of surgery alone, and there was no perioperative mortality. Further studies are needed to evaluate this combined approach compared with surgical resection alone.
Trial Registration
ClinicalTrials.gov identifier: NCT02136355
Introduction
For patients with stage I non–small cell lung cancer (NSCLC) who are unfit for surgical resection, stereotactic ablative radiotherapy (SABR; also called stereotactic body radiation therapy) has become a widely accepted treatment option. Multiple prospective and retrospective studies1,2,3,4 have consistently demonstrated local control rates after SABR of 88% to 96% at 2 to 4 years based on imaging follow-up. In patients with cancer who are fit for resection, however, the role of SABR is controversial. Although some recent studies5,6,7 suggest that SABR may achieve outcomes similar to surgery, others do not,8 and randomized clinical trials are currently under way to compare these 2 modalities. In the interim, surgery remains the standard approach for patients able to tolerate a resection.
Despite the numerous studies1,2,3,4,5,6,7,8 reporting on SABR, uncertainty remains regarding the true local control rates achieved. The highly ablative nature of SABR typically results in radiotherapy-induced lung injury and fibrosis, which can obscure underlying residual disease or an early local recurrence on follow-up imaging.9 Although there are published guidelines and evidence-based systems for conducting and interpreting surveillance imaging for these patients after SABR,10,11 the accurate determination of local control with imaging alone remains challenging.
No prior studies, to our knowledge, have assessed pathologic responses after SABR for NSCLC, and thus the pathologic complete response (pCR) rate is unknown. In contrast, after radiofrequency ablation, 2 ablate-and-resect studies12,13 demonstrated low rates of complete tumor necrosis (<40%), findings that dampened the enthusiasm for pursuing radiofrequency ablation as a curative therapy.
Neoadjuvant SABR before surgery has been hypothesized as a mechanism of improving local control, sterilizing the tumor to decrease the risk of tumor seeding during surgery,14 and enhancing oncologic outcomes through radiotherapy-initiated immune responses.15 Measuring the Integration of Stereotactic Ablative Radiotherapy Plus Surgery for Early Stage Non–Small Cell Lung Cancer (MISSILE-NSCLC) was a single-arm, phase 2 trial with the objective of evaluating the pCR rate, oncologic outcomes, and toxic effects associated with an a priori combined treatment approach of SABR followed by surgical resection.
Methods
Study Design
We completed a prospective, single-arm, phase 2 clinical trial in which neoadjuvant SABR was administered to patients with stage I (T1T2N0M0) NSCLC in combination with subsequent surgical resection at a tertiary academic cancer center. The study was approved by the Western University Research Ethics Board, and written informed consent was obtained from all patients. The data were not deidentified. The trial protocol can be found in Supplement 1.
The primary end point was the tumor pCR rate after SABR. Secondary end points included local control, regional control, distant control, toxic effects (based on the Common Terminology Criteria for Adverse Events, version 4.0), and quality of life (QOL). Secondary translational end points, reporting on the value of novel imaging biomarkers and assessing the immunologic effects of SABR on the NSCLC tumor microenvironment, will be reported in the future.
Local recurrence was defined as any new tumor growth greater than 5 mm within the involved lobe (after sublobar resection) or at the resection margins (after lobectomy). Regional recurrence was defined as any recurrence in the hilar, mediastinal, or supraclavicular nodes. Microscopic nodal disease resected at surgery was not counted as recurrence, analogous to other studies16,17 of neoadjuvant therapies before surgery in which such findings are classified as pN1, pN2, or pN3 disease. Distant recurrence was defined as the development of hematogenous metastases. All time-to-event oncologic outcomes were measured from the date of enrollment. The QOL was measured using the Functional Assessment of Cancer Therapy for Lung (FACT-L), including the Trial Outcome Index (TOI), defined as the sum of FACT-General (FACT-G) physical well-being, functional well-being, and the Lung Cancer Subscale. The FACT-L TOI data collected at each time point were compared with pretreatment and classified as increased, stable, or decreased based on a clinically meaningful change of 5 points.18 A prespecified interim safety analysis was performed after 10 patients had completed surgery and was previously published.19
Patients
Eligibility criteria included the following: age of 18 years or older, histologically confirmed NSCLC, tumor stage T1-T2a (≤5 cm), no evidence of nodal disease (N0) or distant metastases (M0), Eastern Cooperative Oncology Group performance status 0 to 2, and adequate pulmonary reserve for resection, defined as a predicted postoperative forced expiratory volume at 1 second of 30% or greater. Exclusion criteria included patients with contraindications to radiotherapy or surgery (in the judgment of the treating physicians); history of lung cancer within the past 5 years; previous thoracic radiotherapy at any time; inability to complete a full course of radiotherapy, surgery, or follow-up visits; and pregnancy or lactation.
The required preenrollment workup included history and physical examination (H&P), histologic confirmation of NSCLC, computed tomography (CT) of the chest and upper abdomen, CT or magnetic resonance imaging of the head, fluorodeoxyglucose F18 positron emission tomography–CT, invasive mediastinal staging (except for patients with peripheral T1 lesions and no 18-fluorodexoxyglucose–avid regional lymph nodes), pulmonary function testing, and a pregnancy test for women of childbearing age.
Radiotherapy
Radiotherapy dose was selected using a risk-adapted approach based on tumor size and location. T1 tumors (≤3 cm) surrounded by lung parenchyma received 54 Gy in 3 fractions (to convert gray to rad, multiply by 100). Tumors greater than 3 cm or with chest wall contact received 55 Gy in 5 fractions. For tumors within 2 cm of the mediastinum or brachial plexus, a dose of 60 Gy in 8 fractions was used. Detailed information is available in the trial protocol in Supplement 1.
Surgical and Pathologic Assessment
Surgery, either lobectomy or sublobar resection, was scheduled to occur 10 weeks after completion of SABR using an open or video-assisted thoracoscopic surgery (VATS) approach. At the time of resection, sampling of high-risk hilar and mediastinal lymph nodes was performed. The decision to choose this 10-week interval between SABR and surgery balanced 2 competing issues: allowing sufficient time for a pathologic response from SABR to occur, while minimizing the risk of progression by avoiding excessive delays to surgery if SABR was unsuccessful.
Resection specimens were submitted to the pathology department for standard gross examination. For sublobar resections, microscopic examination entailed removing the staple line and serially sectioning the specimen every 3 to 4 mm. For lobectomies, the bronchial margin was removed and the index lesion was excised and serially sectioned every 3 to 4 mm.
There is no standard method of assessment of tumor cell viability after radiotherapy. In this trial, uptake of hematoxylin-eosin (H&E) staining and the morphologic appearance of tumor cells on microscopy were used to determine the primary end point. Cells that were degenerated or necrotic were considered to be nonviable. The pathologist (K.K.) was not masked to the fact that patients had received SABR.
Adjuvant Treatment
Patients with pathologic node-positive disease were referred for an opinion from a medical oncologist regarding adjuvant chemotherapy. For patients with N2 or N3 disease, adjuvant radiotherapy to the mediastinum was considered, provided there was minimal dosimetric overlap with SABR.
Follow-up Evaluation
Patients were assessed with H&P, CT of the chest, pulmonary function tests, and QOL scoring 8 weeks after SABR (ie, 2 weeks before surgery). Imaging response was scored using Response Evaluation Criteria for Solid Tumors, version 1.1 categories20: progressive disease (longest diameter increase ≥30%), partial response (longest diameter decrease ≥20%), complete response (lesion undetectable), or stable disease. Three months after surgery, patients underwent another H&P and QOL scoring. Thereafter, visits included an H&P, pulmonary function tests, CT of the chest, and QOL scoring and occurred at 6, 12, 18, and 24 months and annually thereafter for 5 years. The period of observation for toxic effects was from enrollment until last follow-up (or death). No patients were unavailable or lost to follow-up.
Statistical Analysis
The sample size was calculated to provide an estimate of the true pCR rate after SABR, within a 95% CI of ±10 percentage points (ie, a CI on the pCR rate that was 20% wide). It was estimated that the rate of true pCR after SABR would be 90%. To restrict the 95% CI to ±10%, including an 8% dropout rate, a total of 40 patients were required.
The primary end point, pCR rate, was originally defined as the number of patients with pCR divided by the number of patients undergoing resection. However, after accrual had closed and all patients had completed SABR, 1 lobectomy specimen was not infused with formalin in a timely manner during processing, and the response for that patient could not be determined because of the poor preservation. The primary end point was therefore assessed as the number of patients with a pCR divided by the number of patients with assessable specimens.
Descriptive statistics were generated for baseline characteristics for all patients and for QOL end points for each follow-up visit compared with pretreatment values using the paired t test. In addition, the FACT-L TOI scores were summarized for each follow-up visit based on a clinically meaningful change of 5 points compared with baseline values. Kaplan-Meier estimates were generated for all time-to-event oncologic outcomes for all enrolled patients and patients who completed surgery. All statistical analysis was performed using SAS statistical software, version 9.4 (SAS Institute Inc) using 2-sided statistical testing at the P < .05 significance level.
Results
Forty patients (mean [SD] age, 68 [8] years; 23 [58%] female) were enrolled between September 30, 2014, and August 15, 2017, with 36 completing the prescribed treatment protocol of SABR and surgery (Figure 1). Four patients did not proceed to surgery after SABR, including 3 patients who were determined to be unsuitable for surgery because of radiotherapy-attributable pneumonitis (n = 1), poor performance status (n = 1), and inability to quit smoking with unacceptable pulmonary function (n = 1). The fourth patient developed regional progression of disease on imaging after SABR and received salvage chemoradiotherapy rather than surgery.
Figure 1. Study Flowchart.
pCR indicates pathologic complete response; SABR, stereotactic ablative radiotherapy.
Patient Characteristics
The characteristics for all 40 enrolled patients are summarized in Table 1. Patients had a mean (SD) percentage predicted pretreatment forced expiratory volume in 1 second of 74.0% (16.0%). All tumors were T1 (31 [78%]) or T2 (9 [22%]), and most were adenocarcinomas (26 [65%]). The SABR doses delivered included 54 Gy in 3 fractions (9 [23%]), 55 Gy in 5 fractions (21 [52%]), and 60 Gy in 8 fractions (10 [25%]). The 8-week post-SABR imaging responses were complete response (1 [2%]), partial response (17 [43%]), stable disease (20 [50%]), and progressive disease (2 [5%]). Most patients (n26 [72%]) underwent a lobectomy and a VATS approach (29 [81%]). Two patients underwent a planned open resection, and 5 were converted from a VATS to open approach intraoperatively.
Table 1. Baseline Characteristics for All Enrolled Patients .
| Characteristic | All Patientsa (N = 40) |
|---|---|
| Age at registration, mean (SD), y | 67.7 (7.6) |
| Sex | |
| Male | 17 (42) |
| Female | 23 (58) |
| Previous surgery | 5 (13) |
| Tumor location | |
| Left upper lobe | 4 (10) |
| Left lower lobe | 5 (13) |
| Right upper lobe | 22 (55) |
| Right middle lobe | 5 (13) |
| Right lower lobe | 4 (10) |
| Pretreatment tumor size, mean (SD), cm | 2.7 (1.0) |
| T Stage | |
| T1 | 31 (78) |
| T2 | 9 (22) |
| Tumor histologic type | |
| Adenocarcinoma | 26 (65) |
| Squamous | 13 (33) |
| NSCLC not otherwise classifiable | 1 (2) |
| Pretreatment FEV1, mean (SD), % predicted | 74.0 (16.0) |
| SABR dose fractionation | |
| 54 Gy in 3 fractions | 9 (23) |
| 55 Gy in 5 fractions | 21 (52) |
| 60 Gy in 8 fractions | 10 (25) |
Abbreviations: FEV1, forced expiratory volume in 1 second; NSCLC, non–small cell lung cancer; SABR, stereotactic ablative radiotherapy.
SI conversion factor: To convert gray to rad, multiply by 100.
Data are presented as number (percentage) of patients unless otherwise indicated.
Pathologic Assessment and Response
Pathologic details are listed in Table 2. A pCR was observed in 21 cases (60%; 95% CI, 44%-76%). For patients with residual primary disease, the pathologic stage after neoadjuvant treatment (yp) was ypT1 (n = 12 [34%]) or ypT2 (n = 2 [6%]), with a mean (SD) size of 1.8 (1.0) cm. A median of 6 lymph nodes were sampled per patient (range, 0-16). Three patients had pathologically positive lymph nodes, including 1 with ypN1 involvement and 2 with ypN2 disease.
Table 2. Surgical Details and Pathologic Outcomes for Patients Who Underwent Surgery .
| Characteristic | All Patients Undergoing Surgerya (n = 36) |
|---|---|
| Surgery type | |
| Lobectomy | 26 (72) |
| Wedge resection | 10 (28) |
| Surgical approach | |
| VATS | 29 (81) |
| VATS converted to open | 5 (14) |
| Open | 2 (6) |
| Pathologic T stageb | |
| ypT0 | 21 (60) |
| ypT1 | 12 (34) |
| ypT2 | 2 (6) |
| Pathologic complete responseb | 21 (60) |
| Pathologic N stagec | |
| ypN0 | 32 (91) |
| ypN1 | 1 (3) |
| ypN2 | 2 (6) |
| Pathologic tumor size, mean (SD), cm | 1.8 (1.0) |
| No. of mediastinal lymph nodes sampled, median (range) | 6 (0-16) |
| Lymph node stations sampled, No. (%) | |
| 4 (Left or right) | 24 (67) |
| 5 | 4 (11) |
| 6 | 0 |
| 7 | 19 (53) |
| 8 | 0 (0) |
| 9 (Left or right) | 5 (14) |
| 10-12 (Left or right) | 28 (78) |
| Mediastinal lymph nodes, mean (SD), % positive | 3.5 (17.0) |
| Time from start of SABR to surgery, mean (SD), mo | 2.9 (0.4) |
Abbreviations: SABR, stereotactic ablative radiotherapy; VATS, video-assisted thoracoscopic surgery; yp, pathologic stage after neoadjuvant treatment.
Data are presented as number (percentage) of patients unless otherwise indicated.
Excludes 1 patient with pathologic stage TX (primary tumor not assessable) because of a processing error in the pathology laboratory.
One patient with pathologic nodal stage NX (ie, nodes not assessed).
Oncologic Outcomes
The median follow-up time was 19 months (95% CI, 12-21 months). Nine patients (23%) had recurrence events: 3 (8%) with a regional recurrence only, 5 (13%) with both regional and distant recurrences, and 1 (3%) with both local and distant recurrences. Salvage treatment for patients with recurrence included chemotherapy (n = 6 [15%]), radiotherapy (n = 3 [8%]), and/or surgery (n = 1 [3%]). There were 6 patient deaths (15%) within the follow-up period.
Kaplan-Meier plots are shown in Figure 2 based on all enrolled patients (ie, intention-to-treat outcomes; corresponding plots restricted to the 36 patients who underwent surgery are in the eFigure in Supplement 2). Estimated time-to-event outcomes at 2 years were as follows: overall survival, 75% (95% CI, 48%-89%); local control, 96% (95% CI, 72%-99%); regional control, 56% (95% CI, 26%-77%); and distant control, 72% (95% CI, 45%-87%). In the 36 patients who underwent both SABR and surgery (per-protocol outcomes), the corresponding values were as follows: overall survival, 77% (95% CI, 48%-91%); local control, 100% (95% CI, not defined); regional control, 53% (95% CI, 22%-76%); and distant control, 76% (95% CI, 45%-91%).
Figure 2. Kaplan-Meier Plots for All 40 Patients .
Adverse Events
All treatment-related toxic effects are listed in Table 3. After SABR and before surgery, there were 21 grade 1 and 7 grade 2 toxic effects. No cases of grade 3 or higher toxic effects occurred after SABR. After SABR and surgery, there were 23 grade 1, 29 grade 2, 7 grade 3, and 3 grade 4 toxic effects. Grade 1 or 2 pain was the most common toxic effect, occurring in 24 patients (60%). The 3 cases of grade 4 toxic effects were atelectasis, respiratory failure, and atrial fibrillation.
Table 3. Number of Patients Who Experienced Related Adverse Events .
| Adverse Event | Overall Gradea (Any Time Point) | Post-SABR Grade | Postsurgery Grade | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | 1 | 2 | 3 | 4 | 5 | 1 | 2 | 3 | 4 | 5 | |
| Air leak | 0 | 3 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 0 | 0 | 0 |
| Atelectasis | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Atrial fibrillation | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 |
| Bone fracture | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Bronchopleural fistula | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 |
| Chyle leak | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Confusion | 2 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 1 | 0 | 0 |
| Constipation | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| COPD | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Cough | 2 | 1 | 0 | 0 | 0 | 2 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Dysphagia | 1 | 1 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Dyspnea | 4 | 1 | 0 | 0 | 0 | 3 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 |
| Empyema | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Fatigue | 9 | 2 | 0 | 0 | 0 | 9 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Hypotension | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Infection | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Nausea | 0 | 2 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Pain | 15 | 12 | 0 | 0 | 0 | 3 | 1 | 0 | 0 | 0 | 13 | 11 | 0 | 0 | 0 |
| Pneumonia | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 0 |
| Pneumonitis | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Pneumothorax | 4 | 4 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 4 | 4 | 0 | 0 | 0 |
| Pulmonary embolus | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Respiratory failure | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Vasovagal episode | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Vomiting | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
Abbreviations: COPD, chronic obstructive pulmonary disease; SABR, stereotactic ablative radiotherapy.
Patients experiencing multiple adverse events by grade: grade 1 or higher (n = 26), grade 2 or higher (n = 13), grade 3 or higher (n = 2), and grade 4 (n = 1).
Quality of Life
The QOL results are summarized in the eTable in Supplement 2. In the FACT-G component, no significant changes in QOL score were found during follow-up because significant decreases in physical well-being were offset by significant improvements in emotional well-being over time. Similarly, on average across the whole cohort, no significant changes in the FACT-L TOI scores occurred over time. At 9 months after surgery, 5 patients (25%) had a clinically meaningful improvement in QOL as measured by the FACT-L TOI, whereas 7 patients (35%) experienced a clinically meaningful decline.
Discussion
To our knowledge, this is the first prospective trial to evaluate an a priori combined treatment approach of SABR followed by surgery, demonstrating a pCR rate of 60% at a mean (SD) of 10 weeks after SABR, with reasonable toxicity and perioperative mortality outcomes compared with studies of surgery alone21 and no decline in QOL. The observed pCR rate of 60% is lower than we hypothesized but higher than reported with SABR in other clinical contexts. The pCR rates in the range of 14% to 36% have been reported for SABR for hepatocellular, pancreatic, and breast cancers.22,23,24,25,26 The pCR rate herein also appears to be better than those historically described for radiofrequency ablation for NSCLC, reported as less than 40% in 2 studies.12,13 The pCR rates with immunotherapy appear to be even lower; a study of neoadjuvant programmed death 1 blockade with nivolumab before surgical resection for NSCLC showed a major response rate of 45% but a pCR rate of only 15%.16 Therefore, compared with other treatments for NSCLC, the pCR rate after SABR was high yet still lower than anticipated by our trial design.
There are 2 major hypotheses that may reconcile the difference in the pCR rate that we observed after SABR (60%) with the observed local control rates (approximately 90%1,2,3,4) after SABR in studies using imaging follow-up. First, it is possible that studies using imaging follow-up underestimate the true rates of local recurrence because of CT changes that occur after SABR. After SABR, the tumor is often obscured by fibrosis, which can impair and delay detection of recurrence. Most prior studies1,2,4 of SABR included patients with medically inoperable early-stage NSCLC in which the competing risk of death attributable to comorbidity may also preclude the detection of local recurrence.
Second, however, is the hypothesis that cells classified as viable based on H&E staining at 10 weeks after radiotherapy may not be sufficiently viable to reproduce and lead to clinically important recurrences. Neither the reproductive viability of cells that take up H&E nor the amount of time needed to allow for complete regression of disease after SABR is clear. Despite its limitations, H&E staining is a commonly used method of assessment of response after radiotherapy.17,27,28,29 To our knowledge, no other standard method of pathologic assessment after SABR exists. More time may have been required for pCRs to develop. Data from other cancers suggest that a longer period after radiotherapy may be associated with higher pCR rates.30,31
Regardless of these uncertainties regarding the H&E staining, the pCR rate of 60% at 10 weeks suggests that practitioners should be cautious in the use of SABR in patients with cancers who are fit for resection. Such patients who refuse surgery should be followed up closely for recurrence, with early reconsideration of surgery if suspicious imaging findings develop. However, a prior study3 of SABR (without planned resection) in patients with cancers fit for resection found that the need for surgical salvage was uncommon, occurring in only 1 of 26 evaluable patients.
SABR has been postulated to activate antitumor systemic immune response in some patients through several potential mechanisms, including causing the release of neoantigens from damaged tumor cells.32 MISSILE-NSCLC will address this in the future with correlative immunologic studies, but we also indirectly tested this hypothesis by assessing oncologic outcomes, with the hypothesis that if an immunologic effect is common, outcomes should be better than in series of SABR or surgery alone. This did not appear to be the case. Evidence of an interplay between SABR and the immune system must come from studies directly assessing immunologic markers, perhaps ideally with studies that incorporate SABR and immunotherapy and studies examining the immune response over time after SABR.
Strengths and Limitations
This study should be considered within the context of its strengths and limitations. The study was conducted at a high-volume tertiary center, which may contribute to the favorable toxicity and QOL outcomes and may reduce generalizability to lower-volume centers.33 Ascertainment of the primary end point using H&E staining, although widely used in radiation oncology, is subject to uncertainties, as discussed above. The hypothesized pCR rate of 90% may have been overly optimistic, especially given the short time frame of 10 weeks between SABR and surgery; however, there were no data available at the time of trial design that would have led us to choose a lower hypothesized pCR rate (eg, 50%) at 10 weeks. The role of the immune system in achieving a pCR and the timing of immune clearance of tumor cells are likely critical to this process and require further study. Markers such as Ki-67 and MIB-1 were not assessed because they are markers of proliferation not viability, but these and other novel markers should be assessed in future studies. Follow-up for secondary end points remained short, and further follow-up is needed to assess long-term outcomes. Late recurrences may change the survival estimates described herein. The frequency of follow-up CT scans in this study was chosen as a balance between early detection of recurrence vs increased cost and radiation exposure with increasing frequency. Although our follow-up schedule is similar to other studies (including the Trial of Either Surgery or Stereotactic Radiotherapy for Early Stage [IA] Lung Cancer [ROSEL]34), more frequent imaging may have detected recurrences at an earlier time point. Future research is needed on the use of SABR in patients with operable early-stage NSCLC, and several ongoing studies32 are now addressing SABR with immunotherapy in various combinations as neoadjuvant therapy before resection.
Conclusions
The pCR rate after SABR for early-stage NSCLC was 60%, lower than hypothesized. The combined approach had comparable toxic effects to series of surgery alone, and there was no perioperative mortality. Further studies are needed to evaluate this combined approach compared with surgical resection alone as well as the role of SABR and immunotherapy.
Trial Protocol
eFigure. Kaplan-Meier plots for patients receiving surgery for (a) overall survival, (b) local control, (c) regional control, and (d) distant control (n = 36)
eTable. Summary of quality of life end points for all patients and stratified by follow-up visit (n = 40)
Data Sharing Statement
References
- 1.Senthi S, Lagerwaard FJ, Haasbeek CJ, Slotman BJ, Senan S. Patterns of disease recurrence after stereotactic ablative radiotherapy for early stage non-small-cell lung cancer: a retrospective analysis. Lancet Oncol. 2012;13(8):802-809. doi: 10.1016/S1470-2045(12)70242-5 [DOI] [PubMed] [Google Scholar]
- 2.Fakiris AJ, McGarry RC, Yiannoutsos CT, et al. . Stereotactic body radiation therapy for early-stage non-small-cell lung carcinoma: four-year results of a prospective phase II study. Int J Radiat Oncol Biol Phys. 2009;75(3):677-682. doi: 10.1016/j.ijrobp.2008.11.042 [DOI] [PubMed] [Google Scholar]
- 3.Timmerman RD, Paulus R, Pass HI, et al. . Stereotactic body radiation therapy for operable early-stage lung cancer: findings from the NRG Oncology RTOG 0618 Trial. JAMA Oncol. 2018;4(9):1263-1266. doi: 10.1001/jamaoncol.2018.1251 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Timmerman RD, Hu C, Michalski JM, et al. . Long-term results of stereotactic body radiation therapy in medically inoperable stage I non–small cell lung cancer. JAMA Oncol. 2018;4(9):1287-1288. doi: 10.1001/jamaoncol.2018.1258 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Chang JY, Senan S, Paul MA, et al. . Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Oncol. 2015;16(6):630-637. doi: 10.1016/S1470-2045(15)70168-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Wolff HB, Alberts L, Kastelijn EA, et al. . Differences in longitudinal health utility between stereotactic body radiation therapy and surgery in stage I non-small cell lung cancer. J Thorac Oncol. 2018;13(5):689-698. doi: 10.1016/j.jtho.2018.01.021 [DOI] [PubMed] [Google Scholar]
- 7.Paix A, Noel G, Falcoz PE, Levy P. Cost-effectiveness analysis of stereotactic body radiotherapy and surgery for medically operable early stage non small cell lung cancer. Radiother Oncol. 2018;128(3):534-540. doi: 10.1016/j.radonc.2018.04.013 [DOI] [PubMed] [Google Scholar]
- 8.Chen H, Laba JM, Boldt RG, et al. . Stereotactic ablative radiation therapy versus surgery in early lung cancer: a meta-analysis of propensity score studies. Int J Radiat Oncol Biol Phys. 2018;101(1):186-194. doi: 10.1016/j.ijrobp.2018.01.064 [DOI] [PubMed] [Google Scholar]
- 9.Huang K, Dahele M, Senan S, et al. . Radiographic changes after lung stereotactic ablative radiotherapy (SABR): can we distinguish fibrosis from recurrence? a systematic review of the literature. Pract Radiat Oncol. 2013;3(2)(suppl 1):S11-S12. doi: 10.1016/j.prro.2013.01.039 [DOI] [PubMed] [Google Scholar]
- 10.Huang K, Senthi S, Palma DA, et al. . High-risk CT features for detection of local recurrence after stereotactic ablative radiotherapy for lung cancer. Radiother Oncol. 2013;109(1):51-57. doi: 10.1016/j.radonc.2013.06.047 [DOI] [PubMed] [Google Scholar]
- 11.Nguyen TK, Senan S, Bradley JD, et al. . Optimal imaging surveillance after stereotactic ablative radiation therapy for early-stage non-small cell lung cancer: findings of an International Delphi Consensus Study. Pract Radiat Oncol. 2018;8(2):e71-e78. doi: 10.1016/j.prro.2017.10.008 [DOI] [PubMed] [Google Scholar]
- 12.Schneider T, Reuss D, Warth A, et al. . The efficacy of bipolar and multipolar radiofrequency ablation of lung neoplasms: results of an ablate and resect study. Eur J Cardiothorac Surg. 2011;39(6):968-973. doi: 10.1016/j.ejcts.2010.08.055 [DOI] [PubMed] [Google Scholar]
- 13.Nguyen CL, Scott WJ, Young NA, Rader T, Giles LR, Goldberg M. Radiofrequency ablation of primary lung cancer: results from an ablate and resect pilot study. Chest. 2005;128(5):3507-3511. doi: 10.1016/S0012-3692(15)52923-1 [DOI] [PubMed] [Google Scholar]
- 14.Tanvetyanon T, Clark JI, Campbell SC, Lo SS. Neoadjuvant therapy: an emerging concept in oncology. South Med J. 2005;98(3):338-344. doi: 10.1097/01.SMJ.0000145313.92610.12 [DOI] [PubMed] [Google Scholar]
- 15.Weichselbaum RR, Liang H, Deng L, Fu YX. Radiotherapy and immunotherapy: a beneficial liaison? Nat Rev Clin Oncol. 2017;14(6):365-379. doi: 10.1038/nrclinonc.2016.211 [DOI] [PubMed] [Google Scholar]
- 16.Forde PM, Chaft JE, Smith KN, et al. . Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med. 2018;378(21):1976-1986. doi: 10.1056/NEJMoa1716078 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Albain KS, Swann RS, Rusch VW, et al. . Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet. 2009;374(9687):379-386. doi: 10.1016/S0140-6736(09)60737-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Cella D, Eton DT, Fairclough DL, et al. . What is a clinically meaningful change on the Functional Assessment of Cancer Therapy-Lung (FACT-L) Questionnaire? results from Eastern Cooperative Oncology Group (ECOG) Study 5592. J Clin Epidemiol. 2002;55(3):285-295. doi: 10.1016/S0895-4356(01)00477-2 [DOI] [PubMed] [Google Scholar]
- 19.Palma DA, Nguyen TK, Kwan K, et al. . Short report: interim safety results for a phase II trial measuring the integration of stereotactic ablative radiotherapy (SABR) plus surgery for early stage non-small cell lung cancer (MISSILE-NSCLC). Radiat Oncol. 2017;12(1):30. doi: 10.1186/s13014-017-0770-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Eisenhauer EA, Therasse P, Bogaerts J, et al. . New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. doi: 10.1016/j.ejca.2008.10.026 [DOI] [PubMed] [Google Scholar]
- 21.Swanson SJ, Herndon JE II, D’Amico TA, et al. . Video-assisted thoracic surgery lobectomy: report of CALGB 39802: a prospective, multi-institution feasibility study. J Clin Oncol. 2007;25(31):4993-4997. doi: 10.1200/JCO.2007.12.6649 [DOI] [PubMed] [Google Scholar]
- 22.Mohamed M, Katz AW, Tejani MA, et al. . Comparison of outcomes between SBRT, yttrium-90 radioembolization, transarterial chemoembolization, and radiofrequency ablation as bridge to transplant for hepatocellular carcinoma. Adv Radiat Oncol. 2015;1(1):35-42. doi: 10.1016/j.adro.2015.12.003 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Facciuto ME, Singh MK, Rochon C, et al. . Stereotactic body radiation therapy in hepatocellular carcinoma and cirrhosis: evaluation of radiological and pathological response. J Surg Oncol. 2012;105(7):692-698. doi: 10.1002/jso.22104 [DOI] [PubMed] [Google Scholar]
- 24.Katz AW, Chawla S, Qu Z, Kashyap R, Milano MT, Hezel AF. Stereotactic hypofractionated radiation therapy as a bridge to transplantation for hepatocellular carcinoma: clinical outcome and pathologic correlation. Int J Radiat Oncol Biol Phys. 2012;83(3):895-900. doi: 10.1016/j.ijrobp.2011.08.032 [DOI] [PubMed] [Google Scholar]
- 25.Rajagopalan MS, Heron DE, Wegner RE, et al. . Pathologic response with neoadjuvant chemotherapy and stereotactic body radiotherapy for borderline resectable and locally-advanced pancreatic cancer. Radiat Oncol. 2013;8:254. doi: 10.1186/1748-717X-8-254 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Bondiau PY, Courdi A, Bahadoran P, et al. . Phase 1 clinical trial of stereotactic body radiation therapy concomitant with neoadjuvant chemotherapy for breast cancer. Int J Radiat Oncol Biol Phys. 2013;85(5):1193-1199. doi: 10.1016/j.ijrobp.2012.10.034 [DOI] [PubMed] [Google Scholar]
- 27.Suzuki T, Sadahiro S, Tanaka A, et al. . Biopsy specimens obtained 7 days after starting chemoradiotherapy (CRT) provide reliable predictors of response to CRT for rectal cancer. Int J Radiat Oncol Biol Phys. 2013;85(5):1232-1238. doi: 10.1016/j.ijrobp.2012.09.031 [DOI] [PubMed] [Google Scholar]
- 28.Waldron JN, Gilbert RW, Eapen L, et al. . Results of an Ontario Clinical Oncology Group (OCOG) prospective cohort study on the use of FDG PET/CT to predict the need for neck dissection following radiation therapy of head and neck cancer (HNC). J Clin Oncol. 2011;29(15)(suppl):5504-5504. doi: 10.1200/jco.2011.29.15_suppl.5504 [DOI] [Google Scholar]
- 29.Eberhardt WE, Pöttgen C, Gauler TC, et al. . Phase III study of surgery versus definitive concurrent chemoradiotherapy boost in patients with resectable stage IIIA(N2) and selected IIIB non-small-cell lung cancer after induction chemotherapy and concurrent chemoradiotherapy (ESPATUE). J Clin Oncol. 2015;33(35):4194-4201. doi: 10.1200/JCO.2015.62.6812 [DOI] [PubMed] [Google Scholar]
- 30.Sloothaak DA, Geijsen DE, van Leersum NJ, et al. ; Dutch Surgical Colorectal Audit . Optimal time interval between neoadjuvant chemoradiotherapy and surgery for rectal cancer. Br J Surg. 2013;100(7):933-939. doi: 10.1002/bjs.9112 [DOI] [PubMed] [Google Scholar]
- 31.Shaikh T, Ruth K, Scott WJ, et al. . Increased time from neoadjuvant chemoradiation to surgery is associated with higher pathologic complete response rates in esophageal cancer. Ann Thorac Surg. 2015;99(1):270-276. doi: 10.1016/j.athoracsur.2014.08.033 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Ko EC, Raben D, Formenti SC. The integration of radiotherapy with immunotherapy for the treatment of non-small cell lung cancer. Clin Cancer Res. 2018;24(23):5792-5806. doi: 10.1158/1078-0432.CCR-17-3620 [DOI] [PubMed] [Google Scholar]
- 33.Møller H, Riaz SP, Holmberg L, et al. . High lung cancer surgical procedure volume is associated with shorter length of stay and lower risks of re-admission and death: national cohort analysis in England. Eur J Cancer. 2016;64:32-43. doi: 10.1016/j.ejca.2016.05.021 [DOI] [PubMed] [Google Scholar]
- 34.ClinicalTrials.gov Trial of Either Surgery or Stereotactic Radiotherapy for Early Stage (IA) Lung Cancer (ROSEL). NCT00687986. https://clinicaltrials.gov/ct2/show/NCT00687986. Accessed January 9, 2019.
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol
eFigure. Kaplan-Meier plots for patients receiving surgery for (a) overall survival, (b) local control, (c) regional control, and (d) distant control (n = 36)
eTable. Summary of quality of life end points for all patients and stratified by follow-up visit (n = 40)
Data Sharing Statement