Stereotactic Body Radiotherapy and Ablative Therapies for Lung Cancer

The treatment paradigm for early stage lung cancer and oligometastatic disease to the lung is rapidly changing. Ablative therapies, especially stereotactic body radiation therapy, are challenging the surgical gold standard and have the potential to be the standard for operable patients with early stage lung cancer who are high risk due to co- morbidities. The most commonly used ablative modalities include stereotactic body radiation therapy, microwave ablation, and radiofrequency ablation.

Key points

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The treatment paradigm for early stage lung cancer and oligometastatic disease to the lung is rapidly changing.
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Ablative therapies, especially SABR, are challenging the surgical gold standard and have the potential to be the standard for operable patients with early stage lung cancer who are high risk for morbidities.
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Microwave ablation is another promising novel ablative modality that in the near future would also be available for transbronchial ablation of small lung tumors, especially more central tumors.
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The outcome results of the ablative therapies should be compared with anatomic minimally invasive segmentectomy or lobectomy with lymph node dissection rather than historical surgical data.

Lung cancer remains the leading cause of cancer-related death in men and women in United States. Surgical resection offers the best chance of cure in early stage disease. Surgical resection is also beneficial in a select group of patients with limited pulmonary metastases. Unfortunately, most patients with lung cancer present with advanced-stage disease and are not surgically curable. Among the patients with early stage lung cancer, more than 20% cannot tolerate surgery because of comorbid conditions. Similarly, some patients with limited pulmonary metastases, who would benefit from metasectomy, are deemed high-risk secondary to poor cardiopulmonary reserves.

External beam radiation therapy may be offered as an alternate to surgery in patients with limited-stage disease who are too high-risk for surgery. However, reported 5-year survival with this modality is only 10% to 30%. The outcome data for stage I non–small cell cancer (NSCLC), treated with radiation therapy alone, from Duke University in 156 patients showed 2- and 5-year survival rates of 39% and 13%, respectively. In a study of 71 node-negative patients who received at least 60 Gy of radiotherapy, 3- and 5-year survivals were 19% and 12%, respectively. Another concern with external beam radiation is radiation pneumonitis, which is a potentially life threatening complication in these severely impaired patients. Zierhut and colleagues, in their study of 60 patients with NSCLC, reported an 8.3% incidence of radiation pneumonitis in patients treated with definitive radiotherapy. Several studies have reported a benefit to dose escalation with a dose-response relationship for local control and survival. When dose escalation is attempted using conventional treatment techniques, however, dose-limiting toxicity occurs. Increased doses of radiation result in increased toxicity and damage to surrounding pulmonary parenchyma, which limits safe dose escalation. Dose-volume histogram data show a correlation between risk of pulmonary toxicity and indices of dose to lung parenchyma. The risk of toxicity increases as the area of irradiated adjacent normal lung increases. Radiation fibrosis seems to depend on the volume of the lung that is radiated above a threshold of 20 Gy to 30 Gy and dose escalation is limited primarily by the risk of radiation pneumonitis.

Over the last two decades, ablative alternatives to resection or standard external beam radiation therapy have been introduced into clinical practice for the treatment of limited-stage lung cancer or limited pulmonary metastases. The most common modalities offered by many centers around the world are stereotactic body radiotherapy (SBRT), microwave ablation (MWA), radiofrequency ablation (RFA), cryotherapy, photodynamic therapy, and irreversible electrophoresis.

Stereotactic body radiotherapy

SBRT, also known as stereotactic ablative therapy (SABR), holds the most potential for curative radiotherapy in patients with early stage lung tumors. Stereotactic targeting uses a variety of systems to decrease the effects of lung motion, which translate into target motion, and improve localization techniques by collection of precise measurements to account for tumor motion during treatment planning and delivery of each fraction. These systems allow dramatic reduction of treatment volume, facilitating hypofractionation with markedly increased daily doses and a significantly reduced overall treatment time and decreased irradiation of normal surrounding tissues with an associated reduction in toxicity. This is possible because radiation can be precisely contoured to the tumor with a very rapid fall-off of radiation in the surrounding lung parenchyma. Treatment is typically delivered in three to five fractions over a 1- to 2-week period, ranging on average from 10 Gy to 20 Gy per fraction. The resulting biologic effective dose (BED) of SBRT is typically in excess of 100 Gy, in contrast to a BED of 79.2 Gy with standard fractionation.

Currently there are a variety of platforms available for SABR. Some of these systems, especially Acuray Cyberknife (Accuray, Sunnyvale, CA), need placement of gold fiducial for image-guided tumor location during treatment. These can either be placed percutaneously using computed tomography (CT) guidance or transbronchially using navigational bronchoscopy (Electromagnetic Navigation Bronchoscopy, Medtronic, Dublin, Ireland). CT-guided fiducial placement is done under local anesthesia and is complicated by pneumothorax in 13% to 47% of cases. Electromagnetic Navigation Bronchoscopy system is used to place the fiducials around the tumor transbronchially. This technique is associated with less incidence of pneumothorax.

Clinical Results

In one of the earliest studies from Indiana University, Timmerman and colleagues reported the outcome of a phase I dose escalation toxicity study. In this trial 47 medically inoperable patients with T1 and T2 NSCLC were treated with SBRT. Patients were treated with three fractions administered over a 2-week period using a frame-based radiosurgery system. The doses started at 8 Gy per fraction and were escalated to 20 Gy. At a median follow-up of 15.2 months, no late toxicity attributable to therapy was identified. Complete response was seen in 27% of patients and partial response was seen in 60%. With a 15-month follow-up, more than one-third (13 of 37) of patients showed progression of cancer. Among these 13 patients with cancer progression, six (6 of 13) showed local recurrence. These local recurrences were observed more commonly at lower radiation doses and occurred at a median of 13 months after treatment. A superior response rate of 87% with dose escalation was also noted. No patient treated with greater than 18 Gy per fraction showed progression during short-term follow-up.

A phase II trial from the same institution further evaluated efficacy and safety of SABR in this patient population. Doses established in the phase I trial were used to treat 70 patients with stage I NSCLC. For the initial report, 2-year local control was 95%, with a median follow-up of 17.5 months, and overall survival (OS) was 56% at 2 years. Most of the deaths were related to comorbid illnesses seen in this inoperable population, rather than death associated with lung cancer; however, there were six treatment-related deaths. Severe toxicity (grades 3–5) was seen in a greater proportion of patients with “central” tumors, defined as tumors near the proximal bronchial tree (see section on toxicity). The report was later updated after a median follow-up of 50 months, showing 3-year local control and survival of 88% and 42%, respectively.

In the Radiation Therapy Oncology Group (RTOG) 0236 protocol, 55 patients with peripheral, less than 5 cm (T1-T2, N0) tumors were treated with three fractions of 18 Gy with total dose of 54 Gy. Eleven patients had distant metastasis within 1 year of treatment and 22% had disseminated recurrence at the end of 3 years. Although the local control rates were high, the 3 years disease-free and OS rates were 48% and 56%, respectively.

At the American Society of Radiation Oncology’s 56th annual meeting, Timmerman and colleagues presented updated 5-year data from the RTOG 0236 trial. The updated results showed a local recurrence rate of 20%, caused primarily by intralobar recurrence. Additionally, 5-year locoregional and distant recurrence rates were 38% and 31%, respectively. The high incidence of recurrence is probably caused by less optimal staging and use of less than 100 BED doses during RTOG 0236 protocol.

The University of Pittsburgh radiation oncology and thoracic surgery groups have successfully proven a model in which patients for SABR are evaluated by the radiation oncologist and thoracic surgeon. In their early experience, they reported the results of 32 patients treated with CyberKnife stereotactic radiosurgery. They subsequently analyzed 21 medically inoperable patients with stage I NSCLC that were treated with a median dose of 20 Gy in a single fraction using the Cyberknife system. An initial response was observed in 12 patients (12 of 21; 57%), and disease was stable in five (5 of 21; 24%), progressed in three (3 of 21; 14%), and was not evaluable in one (one of 21; 5%). At a mean follow-up of 24 months, the estimated probability of survival at 1-year was 81% (confidence interval [CI], 0.73–0.90). The median survival was 26.4 months (95% CI, 19.6 [not reached]). Local progression occurred in nine patients (42%). The median time to local progression was 12.3 months. This led to the adoption of a more aggressive protocol where all peripheral tumors were treated with 60 Gy in three fractions and more central tumors were treated with 48 Gy in four fractions. Recently they published their outcomes using SABR for recurrent lung neoplasms in 100 patients. The postprocedure 30-day mortality was 0%; median follow-up was 51 months. The median OS for the entire group was 23 months (95% CI, 19–41 months). The probability of 2- and 5-year OS was 49% (95% CI, 40%–60%) and 31% (95% CI, 23%–43%), respectively.

Multiple studies have shown that BED of 100 Gy or more leads to better outcomes with less local recurrence. Onishi and colleagues reported on an amalgamation of multi-institutional data from Japan that included 257 patients (164 patients with stage IA disease and 93 with stage IB disease) with a median tumor size of 2.8 cm (range, 0.7–5.8 cm). The median follow-up period for the entire cohort was 38 months. The patients were divided into two groups based on the dose they received, 215 patients received 100 Gy BED and the other 42 patients received less than 100 Gy BED. The overall local control rate for the entire cohort was 86%. The group that received 100 Gy BED had a local control rate of 91.6%, whereas those who received a BED less than 100 Gy had a local control rate of only 57.1% ( P <.001). The 3- and 5-year OS for the entire cohort was 56.8% and 47.2%, respectively. The 3-year OS rate in medically operable patients was 88.4% for BED greater than 100 Gy compared with 69.4% for less than 100 Gy. The 5-year OS for the BED 100 Gy cohort was 53.9%, compared with only 19.7% for less than 100 Gy ( P <.05).

In another Japanese trial, Japan Clinical Oncology Group 0403, Nagata and colleagues initially published the results inoperable patients in 2010, in operable in 2012, and follow-up in 2015. The aim of the study was to evaluate the safety and efficacy of SBRT in patients with histologically or cytologically proven NSCLC. Between July 2004 and November 2008, a total of 169 patients from 15 institutions were registered. One hundred inoperable and 64 operable patients (total 164) were eligible. Patient characteristics were 122 male and 47 female; median age, 78 years (range, 50–91 years); and 90 adenocarcinomas, 61 squamous cell carcinomas, and 18 others. Of the 100 inoperable patients, the 3-year OS was 59.9%. Grade 3 and 4 toxicities were observed in 10 and 2 patients, respectively. No grade 5 toxicity was observed. The 3-year OS for operable patients was better and was 76.5%. The progression-free survival was 54.5%. Grade 3 toxicities were observed in five patients. No grade 4 and 5 toxicities were observed.

RTOG protocol 0618 was a phase II trial using SBRT to treat early stage NSCLC in operable patients (deemed surgically resectable). Patients with biopsy-proven peripheral T1 to T3 tumors were treated with 18 Gy in three fractions delivered in 2 weeks. The study opened December 2007 and closed May 2010 after accruing a total of 33 patients. Of 26 evaluable patients, 23 had T1 and three had T2 tumors. Median age was 72 years. Four patients (16%) had SBRT-related grade 3 toxicity, whereas none had grade 4 to 5 adverse events. Median follow-up was 25 months. Two-year estimates of local failure, regional failure, and distant failure were 19.2%, 11.7%, and 15.4%, respectively. Two-year estimates of progression-free survival and OS are 65.4% and 84.4%, respectively.

The results of RTOG 0915 trial were recently published. This was a randomized phase II study comparing two SBRT schedules for medically inoperable patients with stage I peripheral NSCLC. The aim of the study was to compare two SBRT schedules for medically inoperable early stage lung cancer to determine which produces the lowest rate of grade 3 and higher protocol-specified adverse events at 1 year. Patients with biopsy-proven peripheral T1 or T2 were randomized either to receive 34 Gy in one fraction (arm 1) or 48 Gy in four consecutive daily fractions (arm 2). Ninety-four patients were accrued between September 2009 and March 2011. The median follow-up time was 30.2 months. Of 84 analyzable patients, 39 were in arm 1 and 45 in arm 2. Four (10.3%) patients on arm 1 and six (13.3%) patients on arm 2 experienced adverse events. The 2-year OS and disease-free survival rate was 61.3% and 56.4% for arm 1 and 77.7% and 71% for arm 2. The short follow-up is the major limitation of this study because the adverse events, such as pneumonitis, rib fracture, and nerve injury, can happen beyond 1 year posttreatment. The survival seems to be better with multifraction rather than single fraction arm 2. Until further comparison is performed patients should be treated in three to five fractions.