The door is open for expanded use of stereotactic body radiation therapy (SBRT) in patients with inoperable early-stage lung cancer and for patients with oligometastatic stage IV non-small cell lung cancer (NSCLC), according to results of two studies presented at the 56th Annual Meeting of the American Society for Radiation Oncology (ASTRO).

Early-Stage Inoperable Lung Cancer

In one of the two studies, a cooperative group trial (RTOG 0236) using stereotactic body radiation therapy (SBRT), 5-year follow-up of a cohort of 59 frail elderly patients with inoperable lung cancer showed a low recurrence rate at the primary tumor site (the radiated field) and no progressive late toxicity.¹ These findings confirmed and extended 3-year results presented earlier at the 2009 ASTRO Annual Meeting and published in JAMA,² noted lead author Robert Timmerman, MD, Professor and Vice-Chair of the Department of Radiation Oncology at the University of Texas Southwestern Medical Center in Dallas.

Dr. Timmerman noted that SBRT has not been universally adopted in this setting despite the positive results presented earlier because of concerns about late toxicity. He indicated that these longer-term data could shift the standard of care to SBRT for patients with early-stage inoperable lung cancer.

Oligometastatic NSCLC

A second study was a large, international, individual patient data meta-analysis showing that SBRT or surgery can achieve long-term survival in some patients with oligometastatic stage IV NSCLC (ie, only a few metastatic lesions, primarily in the lung and brain).³ Results of this study were used to develop a risk-stratification model that could prove helpful in identifying which patients are the best candidates for SBRT or surgery.

“We observed a 29.4% 5-year overall survival, which is much higher than what is usually seen in stage IV patients. In our study,⁴ which included patients with one to five metastatic sites, we found that the longest survival was associated with metachronous metastases [appearing after the original lung cancer],” said lead author Allison Ashworth, MD, a Radiation Oncologist who completed the study as part of her training at the London Health Sciences Centre at Western University in London, Ontario, Canada.

“We hope this study will be used to select which patients with stage IV NSCLC are most likely to benefit from aggressive treatments,” Dr. Ashworth said.

“One limitation of our study is a selection bias with younger, healthier patients than those typically diagnosed with stage IV NSCLC. Ultimately, we need randomized clinical trials to determine whether the longer survival is due to the treatments or because the patients have less aggressive disease,” she added.

RTOG 0236

The phase II trial reported by Dr. Timmerman was conducted from May 2004 until October 2006 and included 59 frail elderly patients with medically inoperable stage I NSCLC (median age, 72). These patients had multiple comorbidities that precluded surgery.

All patients received SBRT in three fractions of 18 Gy (total of 54 Gy) over 1.5 to 2 weeks. SBRT requires image guidance to deliver high doses of radiation to the tumor site in less time than standard radiation, minimizing exposure to healthy tissues.

At 5 years, the rates of disease-free survival and overall survival were 26% and 40%, respectively. Median overall survival was 4 years.

“Primary tumor recurrence in the treated area remained very low owing to the potent SBRT regimen,” Dr. ­Timmerman said.

Four patients had recurrences at the primary tumor site, yielding an estimated 5-year primary tumor failure rate of 7%; nine additional patients had recurrences within the involved lobe, posing a 5-year primary tumor and involved lobe (local) failure rate of 20%.

The 5-year local-regional failure rate was 38% (n = 7); 5-year disseminated failure rate was 31% (n = 15).  These failures occurred mostly at untreated sites, Dr. Timmerman noted.

Treatment-related grade 3 and 4 adverse events occurred in 17 patients, which was similar to the initial report at 3 years’ follow-up. Dr. Timmerman noted that the fact that severe toxicity remained relatively unchanged with longer follow-up should allay concerns about increased long-term toxicity with SBRT.

“This study [RTOG 0236] should hold weight because it was done within the cooperative groups and the data were presented at [major oncology] meetings. The original data were practice-changing, and these longer-term results are more practice-changing,” Dr. Timmerman said.

A phase III trial comparing SBRT to surgery for operable patients will be done as a multicenter, multinational trial through the ACCRU Foundation (an affiliate of the National Institutes of Health cooperative group Alliance), and at the University of Texas Southwestern Medical Center in Dallas. “We want to get high-level evidence in operable patients,” Dr. Timmerman said.

Individual Patient Data

The individual patient data meta-analysis reported by Dr. Ashworth included 757 patients diagnosed with stage IV NSCLC at 20 cancer centers worldwide. All patients had one to five oligometastases treated with surgery and SBRT; in all cases, the original lung tumor was treated aggressively.

Overall survival at 5 years was 29.4%, which is higher than typical for stage IV patients. Factors that predicted for survival included synchronous vs metachronous metastasis and presence of nodal disease, she said.

Based on these results, the following risk stratification model was developed for survival:

• Low risk/best survival: metachronous metastases (5-year overall survival of 47.5%)
• Intermediate risk: synchronous metastases and node negativity (5-year overall survival 36.2%)
• High-risk/worst survival: synchronous metastases and node positivity (5-year overall survival of 13.8%).

Dr. Ashworth noted that the most appropriate treatment for these patients should be discussed by a multidisciplinary tumor board. “Selection of patients for the right treatment is critical.… This study should help pave the way for optimal treatment selection for this group of patients,” Dr. Ashworth said. ■

Disclosure: Dr. Timmerman’s institution has a research grant to study image-guided hypofractionated radiotherapy from Varian Medical Systems, for which he is a principal investigator. Dr. Ashworth reported no potential conflicts of interest.

References

1. Timmerman R, Hu C, Michalski J, et al: Long-term results of RTOG 0236: A phase II trial of SBRT in the treatment of patients with medically inoperable stage I non-small cell lung cancer. ASTRO Annual Meeting. Abstract 56. Presented September 15, 2014.

2. Timmerman R, Paulus R, Choy H: SBRT for early stage lung cancer. JAMA 303:1070-1076, 2010.

3. Ashworth AB, Senan S, Palma DA, et al: Can we identify long-term, survivors in oligometastatic non-small cell lung cancer? ASTRO Annual Meeting. Presented September 16, 2014. Abstract 168.

4. Ashworth AB, Senan S, Palma DA, et al: An individual patient data metaanalysis of outcomes and prognostic factors after treatment of oligometastatic non–small-cell lung cancer. Clin Lung Cancer 15:346-355, 2014.