Stereotactic Body Radiation Therapy for Inoperable Early Stage Lung Cancer (RTOG 0236)
Timmerman
JAMA. 2010;303(11):1070-1076.

 

Context  Patients with early stage but medically inoperable lung cancer have a poor rate of primary tumor control (30%-40%) and a high rate of mortality (3-year survival, 20%-35%) with current management.

Objective  To evaluate the toxicity and efficacy of stereotactic body radiation therapy in a high-risk population of patients with early stage but medically inoperable lung cancer.

Design, Setting, and Patients  Phase 2 North American multicenter study of patients aged 18 years or older with biopsy-proven peripheral T1-T2N0M0 non–small cell tumors (measuring <5 cm in diameter) and medical conditions precluding surgical treatment. The prescription dose was 18 Gy per fraction x 3 fractions (54 Gy total) with entire treatment lasting between 11/2 and 2 weeks. The study opened May 26, 2004, and closed October 13, 2006; data were analyzed through August 31, 2009.

Results  A total of 59 patients accrued, of which 55 were evaluable (44 patients with T1 tumors and 11 patients with T2 tumors) with a median follow-up of 34.4 months (range, 4.8-49.9 months). Only 1 patient had a primary tumor failure; the estimated 3-year primary tumor control rate was 97.6% (95% confidence interval [CI], 84.3%-99.7%). Three patients had recurrence within the involved lobe; the 3-year primary tumor and involved lobe (local) control rate was 90.6% (95% CI, 76.0%-96.5%). Two patients experienced regional failure; the local-regional control rate was 87.2% (95% CI, 71.0%-94.7%). Eleven patients experienced disseminated recurrence; the 3-year rate of disseminated failure was 22.1% (95% CI, 12.3%-37.8%).

The rates for disease-free survival and overall survival at 3 years were 48.3% and 55.8%  respectively. The median overall survival was 48.1 months (95% CI, 29.6 months to not reached). Protocol-specified treatment-related grade 3 adverse events were reported in 7 patients (12.7%; 95% CI, 9.6%-15.8%); grade 4 adverse events were reported in 2 patients (3.6%; 95% CI, 2.7%-4.5%). No grade 5 adverse events were reported.

Conclusion  Patients with inoperable non–small cell lung cancer who received stereotactic body radiation therapy had a survival rate of 55.8% at 3 years, high rates of local tumor control, and moderate treatment-related morbidity.



INTRODUCTION
   

While anatomical resection is the standard treatment for early stage lung cancer, some patients cannot tolerate surgery due to comorbidities such as emphysema and heart disease. These patients are deemed medically inoperable and are generally offered conventional radiotherapy (most commonly given during 20-30 outpatient treatments) or observed without specific cancer therapy. Outcomes are not ideal with either approach. Conventional radiotherapy fails to durably control the primary lung tumor in 60% to 70% of patients.More than half of patients ultimately die specifically from progressive lung cancer with observation and 2-year survival is less than 40% with either approach.
 

Stereotactic body radiation therapy (SBRT) is a noninvasive cancer treatment in which numerous small, highly focused, and accurate radiation beams are used to deliver potent doses in 1 to 5 treatments to tumor targets in extracranial sites. Consensus publications describing the conduct and technical requirements of SBRT have been published. Numerous single institution studies have shown that SBRT is an effective and well-tolerated treatment for early stage lung cancer in medically inoperable patients. The Radiation Therapy Oncology Group (RTOG) 0236 trial was the first North American multicenter, cooperative group study to test SBRT in treating medically inoperable patients with early stage non–small cell lung cancer. In this article, the 3-year results from RTOG 0236 are described.


METHODS

 

Patient Eligibility
 

Patients had to be aged 18 years or older with a Zubrod performance status score of 0 (fully active, unrestricted), 1 (restricted activities but able to work), or 2 (cares for self but unable to work). Cytological or histological proof of non–small cell cancer was required for entry. Eligible patients could have American Joint Committee on Cancer stages T1-T2 (≤5 cm) or T3 (≤5 cm peripheral tumors only) N0M0 cancer based on both mandatory computed tomography (CT) and positron emission tomography (PET) screening. While a subset of patients with T3 tumors were eligible, ultimately none were enrolled making the study results not necessarily pertinent to the T3 subset. The treated tumor was required to be greater than 2 cm in all directions from the proximal bronchial tree, which was defined as the distal 2 cm of the trachea, carina, and named major lobar bronchi up to their first bifurcation. Patients were ineligible if they had a synchronous malignancy within 2 years of entry. Patients also were ineligible if they had a history of prior radiotherapy to the thorax; active systemic, pulmonary, or pericardial infection; or were pregnant or lactating. Patients with plans to receive conventional radiotherapy, chemotherapy, biological therapy, vaccine therapy, or surgery as treatment (except at disease progression) were ineligible. Operable patients were ineligible. Data regarding race and ethnicity were collected from the registering site as per reporting requirements of the study sponsor (the US National Cancer Institute); however, this information was not used in patient selection. All patients were required to sign informed consent prior to study registration.

Prior to enrollment, patients were required to be evaluated by an experienced thoracic surgeon or pulmonologist to determine operability. Standard indicators defining a patient to be medically inoperable included baseline forced expiratory volume in the first second of expiration (FEV1) of less than 40% predicted, predicted postoperative FEV1 of less than 30% predicted, carbon monoxide diffusing capacity of less than 40% predicted, baseline hypoxemia or hypercapnia, severe pulmonary hypertension; diabetes mellitus with end-organ damage; severe cerebral, cardiovascular, or peripheral vascular disease; or severe chronic heart disease.

Radiotherapy Specifications

The gross tumor volume was outlined on pulmonary CT windows, excluding soft tissue densities with standard uptake values of less than 2 on PET scans (likely to be atelectasis). No additional margin was added for possible microscopic extension. An institution-appropriate error margin beyond this gross tumor volume (defined as the planning target volume), which included both set-up error and error related to motion, was limited to no more than 5 mm in the axial dimension and 10 mm in the craniocaudal dimension.

Patients received 60 Gy in 3 fractions of 20 Gy per fraction, which was prescribed to the edge of the planning target volume. Each fraction was separated by at least 40 hours (at most, by 8 days). The entire 3 fraction regimen was required to be completed within 14 days. Only 4 to 10 mV photon beams were allowed. For planning, no tissue density heterogeneity correction was allowed. Later analysis, using proper accounting of density heterogeneity, showed that the RTOG 0236 trial overpredicted the actual planning target volume dose such that the delivered dose was actually closer to 54 Gy in 3 fractions of 18 Gy.

Image guidance capable of confirming the position of the target with each treatment was required. Tumor motion related to respiration was required to be quantified using fluoroscopy or 4-dimensional CT scans. If the motion confirmed with free breathing was greater than the maximum planning target volume expansions allowed by the protocol, a method of motion control such as abdominal compression, gating, or breath holding was required.

Adequate target coverage was achieved when 95% of the planning target volume was covered by 60 Gy and when 99% of the planning target volume received at least 54 Gy. High-dose conformality was controlled such that the volume of tissue outside of the planning target volume receiving a dose greater than 63 Gy must be less than 15% of the planning target volume and the target conformality index (ratio of the volume receiving 60 Gy to the planning target volume: ≤1.2). Moderate dose conformality and gradient quality were controlled by the parameters listed in. The treatment plans also had to meet a number of contoured organ dose constraints .

The main finding in this prospective study was the high rate of primary tumor control (97.6% at 3 years). Primary tumor control is an essential requirement for the cure of lung cancer. Treatments applied for curative intent must be judged at least partly on their ability to control gross disease. Stereotactic body radiation therapy as delivered in RTOG 0236 provided more than double the rate of primary tumor control than previous reports describing conventional radiotherapy., Admittedly, patients deemed medically inoperable have other competing causes of death besides lung cancer.Series reporting results from conventional radiotherapy for similar patient groups report 2-year to 3-year overall survival rates in the 20% to 35% range, which are considerably lower than the 55.8% rate at 3 years reported herein.

In contrast to the trial from Indiana University in which the dose levels used in this trial were first piloted, there were no reported SBRT-related patient deaths in RTOG 0236. Perhaps, this is because patients with centrally located tumors were not eligible for RTOG 0236. In contrast, as described in the update by Fakiris et al, the Indiana University experience included 31% of patients with central tumors. They had 5 treatment-related deaths out of the cohort of 70 patients and a 3-year overall survival rate of 42.7%. While we attempted to obtain complete follow-up on all patients, our study was flawed because autopsies were performed on only a few patients at the time of death and 9 patients died of unknown causes.

The most disappointing finding in this trial was the rate of disseminated recurrence (22.1% at 3 years). Because the primary tumor, involved lobe, and regional failure rates were all low and metastases appeared fairly soon after SBRT, it might be assumed that many of these patients harbored occult tumors at diagnosis that went undetected by initial CT and PET staging. Given that the regional failure rate in the hilum and mediastinum was quite low (only 2 patients), adding pre-SBRT hilar or mediastinal pathological staging, as is commonly done in operable patients, would not likely have altered the rate of disseminated recurrence. Instead, these results would imply that either better whole-body staging to identify patients with occult metastatic disease, or effective adjuvant therapies to eradicate such disease are necessary to improve the outcomes.

Because RTOG 0236 was the first North American cooperative group trial using SBRT, considerable effort was expended in developing the infrastructure to ensure consistent and high-quality treatment across all enrolling centers. The products of these interactions were the compliance criteria, the accreditation and credentialing criteria, the quality assurance assessment criteria and mechanisms, and the data collection and monitoring program all specific to SBRT.20 This infrastructure greatly facilitated the high compliance observed for this protocol and will eventually allow evaluation of relationships between dosimetry, compliance, and adverse events with longer follow-up (more events) from completed trials.

The RTOG 0236 trial was limited largely by the patient population's ability to undergo invasive procedures. Even the initial biopsy required to confirm malignancy for eligibility was potentially threatening to this frail population. Importantly, the trial did not require and seldom used invasive pathological staging and histological confirmation of recurrence. Rather, noninvasive tests like CT and PET were used; both of which are associated with accuracy problems. Control was consistently evaluated by diagnostic CT scan, but PET was only used if the CT scan showed progressive changes. Collectively, these staging and evaluation methods make this experience difficult to compare with the results after surgical management of healthier patients in which both invasive staging and histological confirmation of recurrence is more common.

The RTOG 0236 trial demonstrated that technologically intensive treatments like SBRT can be performed in a cooperative group so long as the proper infrastructure and support are put in place. The RTOG will be building on RTOG 0236 to (1) design a trial to address the rather high rate of disseminated failure observed after treatment, (2) complete a trial to determine a safe and effective dose for central lung tumors (RTOG 0813), and (3) complete a trial to refine the dose of SBRT for peripheral tumors (RTOG 0915).