Three randomized trials of SBRT vs surgical resection closed due to poor accrual, but an analysis of patients treated in these trials suggested that SBRT might even be superior to surgery. New trials are underway to further assess the question of whether SBRT can be the definitive treatment for early-stage NSCLC instead of surgery.
Stereotactic body radiation therapy (SBRT) is a novel radiation technique that allows a high dose of radiation to be delivered to a tumor with relatively low dose to the surrounding normal tissue. SBRT has achieved extraordinary clinical success in patients with inoperable early-stage non–small-cell lung cancer (NSCLC). Local control of approximately 90% at 2 to 5 years has been demonstrated in multiple trials. In comparisons with surgical resection (in patients who are fit candidates for surgery), SBRT has provided similar local control, but was associated with worse survival, probably due to differences in the underlying patient populations. Three randomized trials of SBRT vs surgical resection closed due to poor accrual, but an analysis of patients treated in these trials suggested that SBRT might even be superior to surgery. New randomized trials are underway to further assess the question of whether SBRT can be the definitive treatment for early-stage NSCLC instead of surgery.
For many years, the standard of care for inoperable non–small-cell lung cancer (NSCLC) was fractionated (or conventional) radiation therapy. A retrospective trial from the era before three-dimensional conformal radiation therapy (3D-CRT) reported a component of local failure in 70% of patients treated.[1] Multiple trials attempted dose escalation with 3D-CRT in order to improve local control. The University of Michigan reported treating to a dose as high as 102.9 Gy in 2.1-Gy fractions, with a reported 2-year rate of progression-free survival of 24% in patients with early-stage disease. Additionally, there was a crude rate of local failure of 44%.[2] Other institutions utilizing high doses reported 2-year rates of local control ranging from 70% to 88%.[3,4]
Stereotactic body radiation therapy (SBRT), also known as stereotactic ablative body radiation, is a technique in which advanced patient immobilization, treatment delivery, tumor motion control, and set-up verification are utilized to deliver high–dose-per-fraction radiation therapy, typically in 5 fractions or less. Figure 1 shows a radiation treatment plan for a patient treated with SBRT. The landmark Radiation Therapy Oncology Group (RTOG) 0236 trial demonstrated local control rates of 97.6% and 93% at 2 and 5 years, respectively, in patients with inoperable early-stage NSCLC.[5,6] With the success of SBRT in RTOG 0236 and other trials,[7-9] there has been growing interest in the use of this technique in patients with operable disease.
At a practical level, many physicians make the decision between surgery and radiation by trying to determine where a patient falls on a continuum of perceived fitness for surgery. At one end would be the young, healthy patient with a tumor that can be resected with minimal toxicity. At the other end of the continuum would be a patient who, because of significant comorbidities, would have a difficult time tolerating a thoracotomy. The “dividing line” between those treated with radiotherapy and those treated with surgery has traditionally been much closer to the radiotherapy end of the continuum, indicating that even in patients with concerning comorbidities, surgical removal of the tumor has usually been attempted. This was appropriate in the time of conventional radiation therapy, when tumor control with that modality was vastly inferior to the control achievable with surgery. With the advent and success of SBRT, the location of the dividing line has shifted and patients who are borderline operable candidates are now being treated with radiation. The question currently being investigated is whether SBRT can replace surgery even in fit patients who are good candidates for surgery.
One of the earliest studies of the use of SBRT was a retrospective trial by Uematsu and colleagues from Japan, who reported on 50 patients with T1/2 NSCLC who received SBRT. The crude rate of local control was 94% at 3 years, and the overall survival rate was 66%.[7]
Another study from Japan reported on 257 patients treated at 14 different institutions with a variety of dose-fractionation regimens.[8] These investigators observed local progression in 12.5% of the patients treated. Their data also suggested that patients treated with a biologic effective dose greater than 100 Gy had higher rates of local control and overall survival.
Investigators from the University of Indiana conducted one of the earliest North American trials of SBRT. In their phase I study, they reported local failure in only 1 patient treated to a dose ≥ 16 Gy × 3.[9]
Lobectomy can be performed either with a traditional open technique or with video-assisted thoracoscopic surgery (VATS). The overall complication rates with open thoracotomy and VATS lobectomy are 31.2% and 16.4%, respectively, according to a systematic review of the literature.[10] Typical complications are atrial fibrillation, pneumonia, and persistent air leak. The median duration of chest tube placement is 5.7 days for thoracotomy and 4.2 days for VATS. Hospital stay also decreases with a VATS technique-from 13.3 to 8.3 days. The estimated 30-day mortality rate from lobectomy is 2.6%.[11]
SBRT has an excellent toxicity profile; the major side effects are fatigue, cough, chest wall pain, and dyspnea.[12] Rib fractures occur in approximately 4% of patients and are associated with dose to the chest wall.[13] It is rare to have late grade 3 or higher toxicity. The 30-day mortality rate is close to 0% in peripheral tumors. Central tumors are associated with increased toxicity and mortality rates of approximately 1% to 2.7%.[14]
When followed with CT imaging after SBRT, more than 90% of patients are found to have radiographic evidence of pulmonary injury in the irradiated lung.[15] This occurs in normal lung tissue that was not specifically targeted for cancer therapy but that may have received a relatively low dose of radiation. The types of lung changes seen after lung irradiation have been reported to vary between homogenous, patchy, and discrete consolidation; these areas may or may not appear to conform to the radiation portal shape.[16] One risk associated with such changes is that fibrosis can potentially hide areas of local recurrence. This, in addition to the decreased long-term survival in medically inoperable patients, can falsely elevate the estimation of local control in patients who undergo SBRT. An example of long-term fibrosis after SBRT is shown in Figure 2.
RTOG 0236 was a phase II trial of patients with peripheral T1/2 NSCLC less than 5 cm in diameter.[5] The radiation dose was 54 Gy, delivered in 3 fractions of 18 Gy each over 1.5 to 2 weeks. Fifty-five evaluable patients were enrolled from 2004 to 2006. At the time of first analysis, only 1 patient had developed a local recurrence, for a 3-year local control rate of 97.6%. The overall survival rate at 3 years was 55%. Five-year follow-up was presented at the 2014 American Society for Radiation Oncology Annual Meeting. At that time, a total of 4 patients had experienced a local failure, for a local control rate of 93%. The overall survival rate at 5 years was 40%.[6]
A systematic review of 45 reports including 3,771 patients treated with SBRT was performed by Solda and colleagues.[17] The rates of 2-year survival and local control were 70% and 91%, respectively. This compared favorably with a 2-year rate of survival of 68% in a surgical cohort.
There have been a number of studies of the use of SBRT in patients with operable disease. Lagerwaard and colleagues reviewed 177 patients (median age, 76 years) from the Vrije University Medical Center in Amsterdam who were potentially operable.[12] Local control rates at 1 and 3 years were 98% and 93%, respectively. The 30-day mortality rate after SBRT was 0%, compared with an expected mortality rate after lobectomy of 2.6%. Overall survival rates at 1 and 3 years were 95% and 85%, respectively. Of note, approximately two-thirds of the patients did not have histologic confirmation of their disease, although this is the standard at the Vrije University Medical Center.
Japan Clinical Oncology Group (JCOG) 0403 was a trial to evaluate the safety and efficacy of SBRT in a patient population that included both operable and inoperable patients.[18] For patients to be considered operable, they had to be classified as such by both the treating institution and the central study coordinator. Almost 40% of the patients initially deemed operable were subsequently considered inoperable because of comorbidities such as oxygen dependence, aortic aneurysm, and cardiac or renal toxicity. At 3 years, the rate of overall survival was 60% in the inoperable patients and 77% in the operable patients. Additionally, the rates of local progression–free survival were 53% and 55% at 3 years in the inoperable and operable patients, respectively. The investigators concluded that the results in the operable arm were favorable enough for SBRT to be considered an alternative to surgery.
These trials, and others, indicate that SBRT can provide excellent local control and survival-with limited toxicity-in patients who would otherwise undergo surgery. The low rate of overall survival in earlier SBRT populations was presumably due to the poorer health and performance status of the patients being treated.
The pathologic confirmation of cancer has been inconsistent in the multiple studies of SBRT that have been reported. In RTOG 0236, 100% of patients underwent biopsy. In a large retrospective analysis from the Netherlands Cancer Institute, only 35% of patients had pathologic confirmation of disease.[19] Clinical diagnosis was based on a growing lesion on CT and a positive positron emission tomography (PET) scan. Outcomes, including local control and overall survival, were equivalent in the pathologic diagnosis and clinical diagnosis groups.
Similar results were seen in retrospective analyses from the Norwegian Cancer Institute[20] and the Cleveland Clinic[21]; in these, 33% and 35% of patients, respectively, were treated with only a clinical diagnosis. Overall survival and local control were similar regardless of pathologic confirmation in both analyses.
However, the possibility of treating benign disease with high doses of radiation is of concern. It is interesting to note that in the Radiosurgery or Surgery for Early Lung Cancer (ROSEL) study (ClinicalTrials.gov identifier: NCT00687986), which randomized patients between surgery and SBRT, one of the patients who was randomized to the surgery arm had benign disease on final pathology. A retrospective study of one center’s experience with SBRT in patients with lung cancer revealed an improved outcome in patients who did not undergo pathologic confirmation, which suggests that many of the patients who were diagnosed by clinical criteria might not have had malignant disease.[22]
Additionally, mediastinal lymph nodes are rarely histologically evaluated prior to SBRT. PET scans can have a false-negative rate as high as 30%. Investigators from Washington University reported that patients undergoing surgery were clinically upstaged 35% of the time.[23] Endobronchial ultrasound–guided biopsy of mediastinal and hilar lymph nodes is a safe and reliable method for evaluating disease, but it also has a limited sensitivity.[24] There is high-level evidence that supports the use of adjuvant chemotherapy in patients with lymph node metastases.[25] These patients would not be considered for adjuvant therapy after SBRT due to the lack of true pathologic staging.
There is an inherent bias in comparisons of patients in retrospective series who have undergone surgery vs those who have undergone SBRT. Patients who undergo primary radiation therapy typically are not surgical candidates and presumably have a lower expected survival. To remedy this problem, there have been a number of propensity score–matched analyses of patients with stage I disease (Table).
Grills and colleagues analyzed 124 patients with T1/2 N0 NSCLC who underwent SBRT or wedge resection.[26] The mean age and mean comorbidity index were both higher for the patients treated with SBRT, 95% of whom were medically inoperable. In their propensity score–matched analysis, there was no significant difference in regional recurrence, locoregional recurrence, distant metastasis, or freedom from any failure between the two groups. There was a nonsignificant lower risk of local recurrence in the SBRT group (4%) compared with the wedge resection group (20%; P = .7). Overall survival was higher in the wedge resection group.
Verstegen and colleagues conducted a propensity score–matched analysis of 128 patients from the Netherlands who underwent either SBRT or VATS.[27] They reported superior locoregional control in those who received SBRT. Distant recurrence and overall survival were not significantly different.
Investigators from Washington University performed a propensity score–matched analysis of 57 high-risk surgical patients and 57 patients who underwent SBRT.[28] They found no difference in freedom from local recurrence, disease-free survival, or overall survival at 3 years.
An analysis of 120 propensity score–matched elderly patients with stage I disease from the Amsterdam Cancer Registry (60 who underwent surgery and 60 who underwent SBRT) reported no significant difference in overall survival between the two groups.[29] The 3-year overall survival rates were 60% and 42% in the surgery and SBRT arms, respectively (P = .22).
A propensity score–matched analysis was recently performed on two JCOG trials: JCOG 0403, which was discussed previously, and JCOG 0201, which was a trial of radiographic predictors of lobectomy outcome. Unfortunately, the lobectomy trial limited patients to a maximum age of 75 years; thus, the median age in JCOG 0201 was 62 years, much lower than the average age of 79 years in JCOG 0403. Therefore, only 40 patients from the SBRT trial were compared with 219 patients who had undergone lobectomy. The hazard ratio for overall survival significantly favored lobectomy in this analysis; local control was not assessed.[30]
These studies and others suggest that when cofactors are accounted for, SBRT might be equal to resection in patients. It is interesting to note that the local recurrence rate was lower in the SBRT cohort in two of these studies and not reported in the Japanese analysis. These results might be due to the ability of low-dose radiation to treat subclinical disease outside of the gross tumor volume. We know from pathology studies that tumor can extend microscopically 6 to 8 mm beyond the visible border.[31] These are regions that may not be surgically removed, especially by sublobar resection, and that can potentially contain tumor. An alternative explanation might be that the diagnosis of local recurrence can be difficult to make after SBRT, because of radiation fibrosis, which can lead to underreporting of recurrence at short intervals.
The use of large population databases can be helpful in analyzing the effectiveness of different therapies. Since a large proportion of US cancer cases are included in databases such as the Surveillance, Epidemiology, and End Results (SEER) database and the National Cancer Database (NCDB), analyses of these databases have enormous power to detect differences and to examine scenarios that would otherwise require large, expensive, and time-consuming randomized trials to investigate. However, these databases are also limited by a lack of detailed patient information and quality assessment. These databases have been used to examine the role of surgery and SBRT in early-stage NSCLC.
An analysis of the SEER population database revealed that surgery (either lobectomy or sublobar resection) was associated with a 90-day mortality rate of 3.7% to 4%, compared with 1.3% for SBRT.[32] However, at 3 years, patients treated with lobectomy had superior overall survival. An analysis of the NCDB dataset compared 111,731 patients who underwent surgery with 5,887 who received SBRT.[33] Similar to the SEER analysis, this analysis found that overall survival was more favorable in the patients who had surgical resection.
In the current era of rapid change in the area of healthcare economics, cost-effectiveness will also be a consideration in the treatment of all diseases going forward.
Smith and colleagues, of the University of Texas MD Anderson Cancer Center, examined the SEER-Medicare Linked Database to estimate the cost of lobectomy, sublobar resection, and SBRT in early-stage NSCLC.[34] They found that these procedures, in 2014 dollars, cost approximately $82,000, $78,000, and $55,000, respectively. A cost-effectiveness analysis found that lobectomy was likely to be the most cost-effective procedure, followed by SBRT, and then sublobar resection.
A small secondary analysis of the ROSEL trial showed an improved global health-related quality of life and a decreased indirect cost with SBRT as compared with surgery.[35]
Three independent randomized trials have attempted to investigate surgery vs SBRT in patients with operable disease. The ROSEL trial was performed in the Netherlands. The STARS trial was based in the United States and compared SBRT performed using a specific treatment device (CyberKnife) against lobectomy. The American College of Surgeons Oncology Group (ACOSOG) trial Z4099 compared SBRT with sublobar resection in high-risk patients.
Unfortunately, all three trials closed due to lack of accrual. Enrollment was hampered by the inherent biases of both patients and physicians. The results of two of the trials, ROSEL and STARS, were subsequently pooled and analyzed.[36] However, there were only 58 patients in the two trials combined. Of these, 31 patients were randomized to SBRT and 27 to surgery with lobectomy. Median follow-up was 40 months in the SBRT group and 35 months in the surgery group. The 3-year overall survival rate was 95% in the SBRT group and 79% with surgery (P = .037). Six patients died after surgery, compared with only one after SBRT.
This analysis was criticized for the small number of patients accrued across many centers over 5 years. The toxicity in the surgery group was higher than in many surgical series. Lobectomy was not performed in 11% of the patients. Although the analysis reported statistical significance, it cannot be used as evidence for the superiority of SBRT. These were two trials with different enrollment criteria that were combined in a post hoc analysis with a minimal number of patients. However, the analysis does suggest that further exploration of the relative merits of SBRT vs surgery in resectable NSCLC is warranted.
To this end, at least three new trials will be evaluating SBRT vs surgery for high-risk surgical patients. The Joint Lung Cancer Trialist’s Coalition has initiated the STABLE-MATES trial (ClinicalTrials.gov identifier: NCT02468024). In an effort to improve accrual, this trial will prerandomize patients and inform them of their assignment at the time of protocol discussion. In the United Kingdom, the SABRTooth trial is underway. This is a small study in high-risk surgical patients with peripheral tumors and will be used to determine whether a larger phase III trial is feasible. The VALOR trial (ClinicalTrials.gov identifier: NCT02984761) will accrue patients in US Veterans Affairs hospitals.
There are a number of commercial systems available for use in planning and delivering treatment with SBRT; all are able to provide safe and effective care. A key part of an SBRT system is a device for effecting secure patient immobilization, which allows for consistent patient set-up with minimal day-to-day and intra-treatment variation. These devices use supports to keep the patient’s arms up and in a comfortable position; typically a customized mold is made to fit the individual patient. Abdominal compression can be used to reduce respiratory motion.
The components of successful treatment include simulation, treatment planning, treatment verification, and treatment itself.
Simulation is the process in which the patient is placed in the treatment position and imaged. The treatment position is determined at this time. A CT scan is obtained and the isocenter is determined and marked at or near the tumor. Intravenous (IV) contrast is usually not needed, since tumors are generally easily visible on noncontrast images; however, IV contrast may be of value for central tumors that are adjacent to vasculature. During simulation, the patient’s respiration must be assessed to aid in creating an internal target volume (ITV) that accounts for tumor motion. A common technique is to assess a patient’s respiratory cycle and create a four-dimensional or respiratory-correlated CT scan. This extra scan is subsequently imported into the treatment planning system; there it is used to enlarge the gross tumor volume to account for respiratory motion and to create the ITV. The ITV is enlarged to create a clinical target volume and a planning target volume (PTV). Although there is no standard distance by which to enlarge the ITV, margins of 5 to 7 mm are typically used. The physician also must identify organs at risk (OAR), such as the bronchial tree (proximal and distal), esophagus, heart, lungs, spinal cord, and chest wall. Certain OARs will be specified for some patients but not others: for example, the brachial plexus for upper lobe tumors, abdominal organs for lower lobe tumors, and the great vessels for central tumors.
A dosimetrist or physicist will subsequently use this information to develop an individualized treatment plan to deliver adequate dose to the tumor while minimizing dose to OARs. There are many dose conformality and constraint parameters available in the literature.[37] Either 3D-CRT or intensity-modulated radiation therapy (IMRT) can be utilized. IMRT may be of benefit for tumors adjacent to critical structures.
Perhaps the most important aspect of stereotactic treatment is treatment verification prior to treatment delivery, also known as image-guided radiation therapy (IGRT). This allows for small margins to be used when creating PTVs, since additional margin for set-up uncertainty is minimized. These smaller margins create significantly smaller volumes that make treatment much safer. Verification techniques include kilovoltage cone beam imaging, megavoltage cone beam imaging, and CT on rails. In these techniques, a CT scan or CT-like scan is obtained and the physician approves whether the patient is set up correctly. IGRT differs from typical orthogonal imaging verification in that patient set-up is focused on the tumor itself, not a correlate of the tumor, such as the carina or the chest wall. Other techniques for verification utilize two-dimensional imaging, since some tumors are visible on two-dimensional imaging. Alternatively, gold markers or transponders can be inserted in the tumor either during bronchoscopy or via a transthoracic procedure; the seeds or transponder would then be visible or detectable to ensure treatment accuracy. Usually an attempt is made to have the treatment set-up be within 2 mm, and shifts are made and imaging is repeated until this threshold is met.
Once the physician approves the patient set-up, treatment begins. The patient must be monitored during treatment. If there is movement or excessive coughing, the patient may need to be re-imaged prior to resuming treatment.
Early-stage NSCLC remains a significant health problem worldwide. With the advent of screening, it is reasonable to expect it to become even more prevalent.[38] Surgery remains the standard of care for this disease, but the evidence continues to accumulate of the ability of SBRT to provide superb local control, possibly even superior to that of surgery. SBRT will never be able to provide the comprehensive pathologic information that surgical resection can, even if the patient undergoes biopsy. Patients with localized disease are still at risk for regional and distant spread, and the surgical evaluation of the hilum and mediastinum, as well as analysis of the biopsy specimen, will be helpful for determining whether adjuvant therapy is warranted.
It is hoped that the randomized trials currently underway will provide some clarity as to which patients are best treated with radiation. But even if these trials are inconclusive, there will probably be a growing trend toward using SBRT in patients with any perceived risk from thoracotomy. The “dividing line” discussed earlier will likely continue to move toward an increased use of SBRT in early-stage disease.
Financial Disclosure:The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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