Patients with stage I non–small cell lung cancer (NSCLC) who are medically inoperable have an excellent chance at full local tumor control and long-term survival with stereotactic body radiation therapy. Hak Choy, MD, Professor and Chairman of the Department of Radiation Oncology at The University of Texas Southwestern Medical School in Dallas, has spearheaded trials of this modality, and he described the rationale and recent data at the 14th International Lung Cancer Congress in Huntington Beach, California.
Surgery Still the Best Option, but…
The early-stage NSCLC population includes standard-risk patients who can undergo surgical resection, patients who are deemed at high risk, and medically inoperable patients. Outcome for these groups is determined as much by age and morbidities as by treatment modality.
The alternative to standard surgery is conventional radiation therapy, but reported outcomes with this treatment have varied widely. Overall survival has been report to be 16% to 57%, cancer-specific survival rates have ranged from 19% to 70%, and local failure rates have fallen between 19% and 70%.
High-risk surgical candidates and medically inoperable patients should be considered for stereotactic body radiotherapy in centers where this newer modality is available, according to Dr. Choy.
“Image-guided stereotactic body radiotherapy is potentially highly effective but also potentially dangerous,” Dr. Choy noted. “It’s not about the beams, the machine, or the motion control. It’s also about the high conformal dose.”
But in highly trained hands, stereotactic body radiotherapy is safe and can be delivered efficiently in a manner that spares normal tissues surrounding the tumor. “The delivery of conformal high doses to the tumor is straightforward, especially with the use of many beams or arc therapy. What is hard is doing this while minimizing the doses to the normal tissue around the tumor. This distinguishes a good radiation treatment plan from a poor one,” he said.
“The delivery of small doses to a larger volume of normal tissue is preferable to delivering higher doses to a smaller amount of normal tissue,” he said. “When stereotactic body radiotherapy is carefully planned and properly delivered, there is far less risk compared to conventional radiotherapy, of producing tissue damage,” he said.
“Stereotactic body radiotherapy also offers the advantages of being noninvasive, allowing the course to be completed within a week or two, requiring minimal recovery time, and causing less delay to or interruption of systemic therapy. The use of image guidance and technologic advances in motion control, dosimetry, and accuracy makes stereotactic body radiotherapy the preferred radiotherapy modality,” he said.
Evidence of Efficacy
Evidence of clinical efficacy for stereotactic body radiotherapy has primarily come from large retrospective, multi-institutional groups of stage I medically inoperable or elderly patients, generally showing a local control rate of about 80%.
A recent study involving 582 patients from radiotherapy centers in Germany confirmed its safety and efficacy, despite considerable interinstitutional variability and time trends in stereotactic body radiotherapy practice. Radiotherapy dose was identified as a major factor influencing local tumor control and overall survival. After a mean follow-up of 21 months, 3-year freedom from local progression was 79.6% and overall survival was 47.1%. The biologic effective dose was the most significant factor influencing these outcomes, which improved to 92.5% and 62.2%, respectively.1
The other major stereotactic body radiotherapy dataset reported to date, of 505 stage I/IIB patients from the Elekta Lung Research Group, showed an even higher rate of local control, which was correlated with a median biologically equivalent prescription dose of 105 Gy or more. Failures were primarily distant, severe toxicities were rare, and overall survival rates were encouraging.
Two-year rates of local control, regional control, and distant metastasis were 94%, 89%, and 20%, respectively, and cause-specific and overall survival were 87% and 60% (78% in operable patients, 58% in inoperable), respectively.2
In a study by the Nordic Study Group, 57 patients receiving a total of between 45 Gy and 66 Gy in three fractions had a 3-year local control rate of 92%, overall survival rate of 59.5%, and lung cancer–specific survival rate of 88.4%.3 The Japan Clinical Oncology Group (JCOG) 0403 study found medically inoperable patients to have a 59.9% rate of 3-year survival and an 88% rate of local control.4
The Radiation Therapy Oncology Group (RTOG) 0236 study, the first North American cooperative group trial of stereotactic body radiotherapy, is producing even more impressive outcomes.5 “We waited for 3 years for the data to mature before publishing the results, and our local control rate is near 100%,” Dr. Choy reported.
The study enrolled 59 patients with medically inoperable stage I disease, for whom the prescription dose was 54 Gy total in three fractions. At a median follow-up of 34 months, only one patient had a primary tumor failure, yielding a 3-year primary tumor local control rate of 97.6%. Three patients had recurrence within the involved lobe, and two patients experienced regional failures, for a local-regional control rate of 87.2%.
Rates for disease-free and overall survival at 3 years were 48.3% and 55.8%, respectively, and median overall survival was 48.1 months. “This trial set the standard for North America and Europe,” said Dr. Choy, who is the senior investigator of RTOG 0236.
“The strong and consistent efficacy shown in these trials has led to a near-doubling in the use of radiotherapy for elderly patients over the past dozen or so years. Whereas historically more than one-third of patients were followed by observation alone, only about one-quarter of patients remain untreated, and survival rates are rising for patients not able to have surgery, he said.
An analysis of the Surveillance, Epidemiology, and End Results (SEER)-Medicare database of 10,923 patients with stage I NSCLC treated between 2001 and 2007 evaluated survival outcomes associated with five strategies used in contemporary practice: lobectomy, sublobar resection, conventional radiation therapy, stereotactic body radiotherapy, and observation.6 After a median follow-up time of 3.2 years, stereotactic body radiotherapy was associated with the lowest risk of death within 6 months of diagnosis (hazard ratio [HR] = 0.48), and after 6 months, lobectomy was associated with the best overall and disease-specific survival.
In the propensity-score matched analysis, survival after stereotactic body radiotherapy was similar to that after lobectomy (HR = 0.71), whereas conventional radiation and observation were associated with poor outcomes. The authors concluded that lobectomy led to the best long-term outcomes in fit elderly patients with early-stage NSCLC, but stereotactic body radiotherapy offers efficacy comparable to that of surgery in select populations.
The established indications for stereotactic body radiotherapy are for early-stage (node-negative) NSCLC that is medically inoperable. Less established or emerging indications are for the treatment of limited multifocal NSCLC, oligometastases, reirradiation after local recurrence, and for stereotactic boost for locally advanced disease. ■
Disclosure: Dr. Choy reported no potential conflicts of interest.
1. Guckenberger M, et al: J Thorac Onc 8:1050-1058, 2013.
2. Grills IS, et al: J Thorac Oncol 7:1383-1393, 2012.
3. Baumann P, et al: J Clin Oncol 27:3290-3296, 2009.
4. Nagata Y, et al: Int J Radiat Oncol Biol Phys 78(3 suppl):S27-S28, 2010.
5. Timmerman R, et al: JAMA 303:1070-1076, 2010.
6. Shirvani SM, et al: Int J Radiat Oncol Biol Phys 84:1060-1070, 2012.