CT/PET indicates computed tomography/positron emission tomography; SBRT, stereotactic body radiation therapy.
Of 26 patients evaluated for OS and DFS, 12 experienced failure and 14 were censored for each outcome. Median OS was 55.2 months (95% CI, 37.7 months to not reached), and median DFS was 55.2 months (95% CI, 31.9 months to not reached). SBRT indicates stereotactic body radiation therapy.
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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
Could the favorable results from clinical experiences using a noninvasive, outpatient stereotactic ablative radiotherapy for medically frail patients with early-stage lung cancer be applicable for treating healthier patients traditionally managed exclusively with surgery?
In this analysis of data from a clinical trial of stereotactic body radiation therapy in 26 patients, targeted tumor control was high such that surgery for salvage was not generally needed. Median survival was higher in these patients with operable disease compared with the historical use in medically frail patients unable to tolerate surgery.
These results support formal comparisons of surgery and stereotactic radiotherapy for early-stage lung cancer, and several trials are under way.
Stereotactic body radiation therapy (SBRT) has become a standard treatment for patients with medically inoperable early-stage lung cancer. However, its effectiveness in patients medically suitable for surgery is unclear.
To evaluate whether noninvasive SBRT delivered on an outpatient basis can safely eradicate lung cancer and cure selected patients with operable lung cancer, obviating the need for surgical resection.
Design, Setting, and Participants
Single-arm phase 2 NRG Oncology Radiation Therapy Oncology Group 0618 study enrolled patients from December 2007 to May 2010 with median follow-up of 48.1 months (range, 15.4-73.7 months). The setting was a multicenter North American academic and community practice cancer center consortium. Patients had operable biopsy-proven peripheral T1 to T2, N0, M0 non–small cell tumors no more than 5 cm in diameter, forced expiratory volume in 1 second (FEV1) and diffusing capacity greater than 35% predicted, arterial oxygen tension greater than 60 mm Hg, arterial carbon dioxide tension less than 50 mm Hg, and no severe medical problems. The data analysis was performed in October 2014.
The SBRT prescription dose was 54 Gy delivered in 3 18-Gy fractions over 1.5 to 2.0 weeks.
Main Outcomes and Measures
Primary end point was primary tumor control, with survival, adverse events, and the incidence and outcome of surgical salvage as secondary end points.
Of 33 patients accrued, 26 were evaluable (23 T1 and 3 T2 tumors; 15 [58%] male; median age, 72.5 [range, 54-88] years). Median FEV1 and diffusing capacity of the lung for carbon monoxide at enrollment were 72.5% (range, 38%-136%) and 68% (range, 22%-96%) of predicted, respectively. Only 1 patient had a primary tumor recurrence. Involved lobe failure, the other component defining local failure, did not occur in any patient, so the estimated 4-year primary tumor control and local control rate were both 96% (95% CI, 83%-100%). As per protocol guidelines, the single patient with local recurrence underwent salvage lobectomy 1.2 years after SBRT, complicated by a grade 4 cardiac arrhythmia. The 4-year estimates of disease-free and overall survival were 57% (95% CI, 36%-74%) and 56% (95% CI, 35%-73%), respectively. Median overall survival was 55.2 months (95% CI, 37.7 months to not reached). Protocol-specified treatment-related grade 3, 4, and 5 adverse events were reported in 2 (8%; 95% CI, 0.1%-25%), 0, and 0 patients, respectively.
Conclusions and Relevance
As given, SBRT appears to be associated with a high rate of primary tumor control, low treatment-related morbidity, and infrequent need for surgical salvage in patients with operable early-stage lung cancer.
ClinicalTrials.gov Identifier: NCT00551369
Stereotactic body radiation therapy (SBRT) is a noninvasive cancer treatment in which numerous small and accurate radiation beams are used to deliver potent doses in 1 to 5 treatments to tumors in extracranial sites.1,2 The NRG Oncology Radiation Therapy Oncology Group (RTOG) 0236 trial,3 as well as several other international cooperative group trials,4,5 has shown that SBRT affords high rates of tumor control while avoiding severe toxic effects in the majority of patients with early-stage lung cancer unable to tolerate surgical resection (ie, medically inoperable). While surgery has long been the standard treatment in patients with operable disease, the convenience, noninvasiveness, and favorable outcomes experienced by patients with medically inoperable disease have logically led to interest in using SBRT for all patients with stage I lung cancer.
To our knowledge, the NRG Oncology RTOG 0618 trial was the first North American multicenter, cooperative group study to test SBRT in treating patients with operable early-stage lung cancer. In this report, we describe the 4-year results from RTOG 0618.
Prior to enrollment, the trial was approved by each enrolling site’s local institutional review board and written informed consent was obtained for each patient. Cytologic or histologic proof of non–small cell cancer was required for entry. Eligible patients could have American Joint Committee on Cancer stages T1, T2, or T3 (primary tumor ≤5 cm, peripheral tumors only), N0, M0 cancer based on both mandatory computed tomography and positron emission tomography (PET) screening. Only patients with operable disease suitable at least for a sublobar resection as determined by a thoracic surgeon were eligible according to all of the following baseline characteristics: forced expiratory volume in 1 second and diffusing capacity of the lung for carbon monoxide greater than 35% predicted, arterial oxygen tension greater than 60 mm Hg, arterial carbon dioxide tension less than 50 mm Hg, and absent severe underlying medical problems.
Radiotherapy planning and delivery were identical to the requirements of the RTOG 0236 study described previously.6 Patients effectively received 54 Gy in 3 fractions prescribed to the edge of the tumor target.7
Patients were observed at least every 6 months for 4 years after treatment with computed tomography imaging. Tumor measurements at each follow-up were carried out using the Response Evaluation Criteria in Solid Tumors.8
The primary end point of the study was 2-year actuarial primary tumor control (avoiding recurrence). Primary tumors were said to have recurred if they showed local enlargement (≥20% increase in tumor diameter) and evidence of tumor viability. Marginal failure within 2 cm of the treated tumor was included in determining primary tumor control. The protocol urged centers to confirm tumor viability and distinguish from local masslike treatment effects by repeated biopsy when possible; however, it also could be affirmed by PET.
Secondary end points included assessments of treatment-related toxic effects, disease-free survival (DFS), and overall survival (OS). Disease-free survival included separate assessments of local-regional failure and disseminated recurrence. The protocol design included instructions urging speedy referral to a thoracic surgeon in the event of an isolated local or regional recurrence so that surgical salvage might be considered.
The National Cancer Institute’s Common Toxicity Criteria, version 3.0, was used for grading of adverse events (AEs).9 All AEs reported by participating centers were collected and assessed. In addition, information regarding morbidity following surgical salvage was collected centrally as a secondary protocol end point.
An acceptable tumor control rate at 2 years was considered to be 90% (monthly hazard of 0.00439), and an unacceptable rate was 70% (monthly hazard of 0.01486). With a 1-sided type I error of .05 and statistical power of 90%, a sample of 27 patients was required. A 1-sided z test was used to determine whether the difference between the logarithm of the observed hazard rate and the logarithm of the hypothesized hazard rate of 0.01486 was statistically significant. All outcomes were measured from the start of SBRT until the date of first failure or, if no failure, the date of death or last known alive. Both OS and DFS were estimated using the Kaplan-Meier method10; all other end points were estimated using the cumulative incidence method,11 in which death without an event was considered as a competing risk. The 95% confidence intervals were calculated using the method described by Gaynor et al.12 All analyses were performed using SAS, version 9.2.
Between December 2007 and May 2010, 33 patients were enrolled to the study. The CONSORT diagram is shown in Figure 1. Pretreatment characteristics are presented in the Table. Median follow-up for evaluable patients (n = 26) was 48.1 months (range, 15.4-73.7 months).
One patient experienced a documented recurrence/progression at the primary site, while none had marginal or involved lobe recurrences. The 2-year rate of both primary tumor and local control was 96% (95% CI, 83%-100%), with a monthly hazard of 0.002. The corresponding P value from the comparison to the hypothesized monthly hazard rate of 0.015 is .02. Control of all components of local control–defining sites (primary, marginal, and involved lobe) was durable to this value out to 4 years of median follow-up.
Regional failures were reported in 3 patients, occurring at 11, 14, and 29 months following the start of protocol therapy. Combining local and regional failures, the 4-year local-regional control rate was 88% (95% CI, 73%-97%). Disseminated recurrence was observed in 5 patients, giving a 4-year rate of disseminated failure of 12% (95% CI, 3%-27%).
The DFS and OS at 4 years was 57% (95% CI, 36% to 74%) and 56% (95% CI, 35% to 73%), respectively, as shown in Figure 2. Median DFS and OS for all patients was 55.2 months (95% CI, 31.9 months to not reached) and 55.2 months (95% CI, 37.7 months to not reached), respectively.
No grade 4 to 5 treatment-related AEs were reported. Four patients (15%) were reported to experience grade 3 AEs assigned definitely, probably, or possibly related to protocol therapy. Two of these AEs were related to posttreatment decline in diffusing capacity, 1 to peripheral sensory neuropathy, and 1 to chest wall complications (rib fracture).
As with RTOG 0236, RTOG 0618 also showed a high rate of primary tumor control (96% at 4 years). Unlike SBRT, lobectomy with regional lymph node dissection provides primary tumor, involved lobe, and regional clearance, although survival is profoundly worse if there is extension beyond the primary tumor.13 Even without a regional therapy, SBRT as delivered showed a reasonably low rate of involved lobe or regional failure, possibly indicating that patients were well staged with PET. Indeed, for patients whose disease was clinically stage I based on computed tomography/PET, the negative predictive value is as high as 95%.14
In RTOG 0236, 26% of patients had grade 3 to 4 toxic effects, while only 14% of patients in the present trial had grade 3 events (no grade 4). Because the delivered therapies were identical, one can assume that the selection of healthier patients more capable of withstanding the potent therapy accounts for the difference. Similarly, disseminated recurrence was lower for the report on patients with operable disease. With these and other factors, survival is better in the operable population, with fewer competing causes of death.
This was a small pilot study only enrolling 33 patients. With no control or randomized arm, comparisons with other experience should be interpreted with caution.
RTOG 0618 demonstrated that high rates of intrathoracic control can be achieved with a noninvasive, outpatient alternative to surgery in a healthier group of patients with early-stage lung cancer. This tumor control was achieved with a relatively low rate of toxic effects. Collectively, SBRT for this operable population may be a viable alternative to surgical resection, which would ideally be compared in a phase 3, randomized clinical trial. Further attempts to perform such a trial are ongoing (eg, VALOR, Stablemates, and SAbRtooth).
Accepted for Publication: February 19, 2018.
Corresponding Author: Robert D. Timmerman, MD, University of Texas Southwestern Medical Center, 5801 Forest Park Rd, Dallas, TX 75390-9183 (firstname.lastname@example.org).
Published Online: May 31, 2018. doi:10.1001/jamaoncol.2018.1251
Author Contributions: Dr Timmerman had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Timmerman, Pass, Edelman, Bradley, Choy.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Timmerman, Paulus, Pass, Edelman, Robinson.
Critical revision of the manuscript for important intellectual content: Paulus, Pass, Gore, Galvin, Straube, Nedzi, McGarry, Robinson, Schiff, Chang, Loo, Bradley, Choy.
Statistical analysis: Paulus, Bradley.
Obtained funding: Timmerman.
Administrative, technical, or material support: Pass, Gore, Edelman, Straube, Nedzi, Schiff, Bradley, Choy.
Study supervision: Timmerman, Galvin, Bradley, Choy.
Conflict of Interest Disclosures: Dr Timmerman reports receiving a research grant for technology development from Varian Medical Systems, Accuray, Inc, and Elekta Oncology. Each of these companies manufactures equipment used in the performance of stereotactic body radiation therapy. Dr Robinson reports grants from Varian Medical Systems. Dr Loo reports grants to his institution and honoraria for educational lectures from Varian Medical Systems and grants to his institution from RaySearch Laboratories. Dr Loo is also a Board Member of TibaRay, Inc. Dr Bradley reports grants from ViewRay, Inc. No other disclosures are reported.
Funding/Support: This project was supported by grants U10CA21661, U10CA180868, U10CA180822, and CA81647 from the National Cancer Institute.
Role of the Funder/Sponsor: The sponsor initially approved the study concept and the original protocol and required regular updates regarding protocol accrual and data safety monitoring. The sponsor had no role in the analysis and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
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