Advances in the Treatment of Early Stage Non-Small Cell Lung Cancer Using Stereotactic Radiation Therapy

Abstract: Surgery is still the most commonly used treatment for early-stage non-small cell lung cancer (NSCLC). However, many patients with NSCLC have significant comorbidities and are not surgical candidates. Radiation therapy has traditionally been the treatment option for these patients. The literature reports several older series with high local failure rate and a modest overall survival of 30% at 5 years.Evidence suggests that changes would be beneficial, such as dose escalation and changes in technique that would allow radiation to be used like a scalpel.

Key words: lung cancer, stereotactic body radiation therapy, interventional oncology

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Any discussion involving the treatment of early-stage non-small cell lung cancer (NSCLC) needs to begin with a focus on surgical outcomes. Surgery remains the most used, radical treatment for early stage NSCLC.¹ Lobectomy is considered the oncologic procedure of choice for early stage NSCLC based on the results of the Lung Cancer Study Group (LCSG) randomized trial² performed in the 1980s. The investigators showed stage I NSCLC to have a 5-year survival of greater than 70%. More importantly, the local recurrence rate was very low (5%-15%). This study established lobectomy and thoracic surgery as the standard of care for early stage NSCLC.

Unfortunately, many patients with NSCLC have significant comorbidities and are not surgical candidates. Radiation therapy has traditionally been the treatment option for these patients. The literature reports several older series with high local failure rate (60%-75%) and a modest overall survival of 30% at 5 years.^3-5 However, enough evidence has been generated to suggest that dose escalation would be beneficial.⁶ The ability to improve outcomes required a change in technique to have radiation function like a scalpel.

Performing stereotactic radiation treatment is not entirely new. These principles stem from radiosurgery, which has been performed in the brain for several decades using devices like a Gamma Knife (Elekta). While the definition of stereotactic body radiation therapy (SBRT) can vary, it generally involves (1) a fraction size >5 Gy, (2) precise patient immobilization, (3) image guidance or at least coordinated system guidance, and (4) conformal multifield treatment to a defined target. Technology has assisted the development of stereotactic radiation therapy by improving the imaging component of a linear accelerator; the treatment machine can now track a tumor before delivering radiation dose.

Trials Using SBRT

Robert Timmerman at Indiana University pioneered the early work on stereotactic body radiotherapy for early-stage lung cancer in the United States. He performed a Phase I/II clinical trial⁷ for patients with operable stage IA/IB NSCLC who were not surgical candidates. Radiation was given in three fractions; the dose per fraction for each cohort was increased beginning at 8 Gy in 2 Gy increments. For stage IA patients, they reached 20 Gy per fraction and the maximum tolerated dose was not reached. For stage IB the maximum tolerated dose was reached at 22 Gy per fraction. The local failure rate was 4/19 for T1 patients and 6/28 for T2 patients, but most of the failures occurred at the lower doses. They continued to accrue as part of the phase II study for a total of 70 patients.⁸ The local control at 2 years was 95%. Altogether, 28 patients died as a result of cancer (n=5), treatment (n=6), or comorbid illnesses (n=17). Median overall survival was 32.6 months and 2-year overall survival was 54.7%. The high rate of local control did come at a price with some late toxicity. Patients with central tumors (defined as being within 2 cm of the main stem bronchus airway or trachea) had an 11-fold increased risk of experiencing severe toxicity compared with more peripheral locations: 4 of the 6 deaths as a result of toxicity observed in the study were in patients with central tumors.⁹ In addition, tumors with gross tumor target volume of more than 10 mL had an eight-fold risk of high-grade toxicity compared with smaller tumors. Still, given the increase in local control, this was felt to be a better treatment option than standard radiation therapy for patients who cannot undergo surgery.

This technology was further investigated in a Phase II multi-institutional trial conducted by the Radiation Therapy Oncology Group (RTOG).¹⁰ The investigators treated 56 patients with 60 Gy given in three fractions. The local control was impressive: 97% at the primary site, 90% in the same lobe, and 87% local regional control. There was a 15% distant metastatic rate and a 56% overall survival at 3 years. Even more impressive was the limited toxicity observed. Grade 3 toxicity was 23% and grade 4 toxicity was 4%; there were no treatment-related deaths. This should be considered in light of the fact that in most surgical series for similar, but operable, patients, there was a 1%-2% perioperative mortality.

The findings of these small series of patients with short follow-up have been further confirmed in larger series. The Vrije Universiteit Medical Center in Amsterdam reported a cohort of nearly 700 patients.¹¹ This mature series had a median follow-up of 32.9 months. Actuarial 2-year rates of local, regional, and distant recurrence were 4.9%, 7.8%, and 14.7%, respectively. Corresponding 5-year rates of local, regional, and distant recurrence were 10.5%, 12.7%, and 19.9%, respectively. Of the 124 recurrences, 82 (66%) were distant recurrences and 57 (46%) were isolated distant recurrences. New pulmonary lesions characterized as second primary tumors in the lung developed in 42 (6%) of 676 patients at a median of 18 months. The authors showed several important findings regarding SBRT. First, recurrences are infrequent more than 2 years post SBRT. Second, the predominant pattern is out-of-field, solitary distant recurrence presenting early, despite initial PET staging. Thus it is important to ensure that appropriate salvage treatments are considered.

Conclusion

The success of SBRT, and subsequent competition with thoracic surgery, has sparked a series of investigations comparing SBRT vs. surgery. The retrospective studies have several limitations and are difficult to draw conclusions from.^12-15 The American College of Surgeons Oncology Group attempted to perform a phase III study comparing the two; this study closed early because of poor accrual. It is likely that one treatment is not superior to another but instead some patients benefit more from SBRT while others benefit more from surgical resection. Stereotactic body radiation therapy has been proven effective, although further study is needed. Several outcomes appear comparable with thoracic surgery.

Editor’s note: Disclosure: The author has completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The author reports no related disclosures.

Manuscript received April 16, 2015; manuscript accepted June 30, 2015.

Suggested citation: Lally BE. Advances in the treatment of early stage non-small cell lung cancer using stereotactic radiation therapy. Intervent Oncol 360. 2015;3(9):E108-E111.

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