Presenter: R.D. Timmerman Presenter's Affiliation: University of Texas Southwestern Medical Center, Dallas, TX Type of Session: Scientific
Lung cancer remains the most frequent cause of cancer death among men and women in North America.
Approximately 75% of patients with bronchogenic carcinoma are diagnosed with non-small cell lung cancer (NSCLC), but only 15-20% of NSCLC patients present with early or localized disease.
Surgical resection for patients with T1-2, NO tumors results in five-year survival rates of 60-70% and is currently the standard of care for patients with early stage operable lesion.
For patients with medically inoperable early stage disease, standard dose and fractionation radiotherapy has resulted in poor overall survival rates, with five-year survival rates ranging from 10-30%, or only moderately higher with dose escalation.
To allow for decreased morbidity experienced among patients with early stage NSCLC treated with larger “prophylactic nodal” radiation fields, many groups have recently achieved similar survival rates by using dose escalation techniques targeting only known disease with margin. • Stereotactic body radiation therapy (SBRT) allows precise targeting and radiotherapy delivery with even more dramatic reduction of radiation treatment volumes to allow for hypofractionation with significantly increased daily doses. • The Indiana University completed a phase I dose escalation protocol for the treatment of 37 patients with medically inoperable Stage I NSCLC. Patients were treated with SBRT in dose escalation cohorts beginning in 8 Gy fractions to 24 Gy. Dose limiting pneumonitis or pericarditis occurred in two of five patients with larger T2 tumors (> 5 to ? 7 cm) at a dose of 72 Gy in three fractions, defining the maximum tolerated dose for this subgroup to be 66 Gy in three fractions. • Based on the Indiana University trial, the Radiation Therapy Oncology Group (RTOG) initiated protocol RTOG 0236, a Phase II trial utilizing SBRT with an ablative prescription dose to treat early-stage medically inoperable patient with NSCLC.
Materials and Methods
All patients were required to have documented baseline medical conditions that precluded lobectomy. Eligibility criteria included patients with T1, T2 (? 5 cm), T3 (? 5 cm chest wall primary tumors), N0, M0 medically inoperable NSCLC. Patients with tumors of any T-stage in the zone of the proximal bronchial tree or patients with T3 tumors based on mediastinal invasion or less than 2 cm toward carina invasion were excluded.
Patients were treated over one-and-a-half to two weeks to radiation doses of 20 Gy per fraction for 3 fractions, for a total dose of 60 Gy, assuming all water density (without heterogeneity corrections). Subsequent analysis determined the actual treatment dose to be 18 Gy fractions to 54 Gy when correcting for proper tissue heterogeneity. Radiation dose constraints were applied to the spinal cord, esophagus, ipsilateral brachial plexus, heart, trachea and ipsilateral bronchus, and whole lung.
Patients were treated according to rigorous central accreditation and quality assurance assessments.
The primary endpoint of the study was local control, with secondary endpoints including treatment-related toxicity, patterns of failure, disease free survival, and overall survival. Local failure was defined as enlargement of at least 20% on CT, with either PET uptake similar to the patient's pretreatment imaging or biopsy confirming malignancy. Marginal failures within 1 cm of the treated lesion were considered local failures for analysis.
This study was opened from May 2004 to October 2006. During that time, 59 patients were accrued to the study, and 55 evaluable patients comprised the analysis.
44 patients had T1 lesions, and 11 patients had T2 tumors. The median age of patients was 72 years, and 52% of patients were female.
Quality assurance assessed contouring compliance and indicated 98% of targets and 73% of normal tissue structures were outlined per protocol or with only minor deviations from protocol.
Protocol-related toxicity included 13 patients (24%) with Grade 3 toxicity, and two patients (4%) with Grade 4 adverse events. The most common adverse events were pulmonary/upper respiratory and musculoskeletal. No Grade 5 treatment-related deaths were observed. No specific protocol-related skin or rib toxicities were outlined, although one patient each experience Grade 3 skin and rib adverse events.
At a median follow-up of 24.8 months, only three patients (5%) had a local failure, for a 2-year local control rate of 93.7% [95% CI, 81.5%, 98.0%]. At a median follow-up of 34.4 months, the true 3-year local control rate was 98%, with one patient failing within the PTV and two patients failing regionally, both more than two years after therapy. No marginal failures were observed.
Distant failures were observed in eight patients (15%) at two years and 11 patients (20%) at three years. Of these, six patients (11%) failed distantly within one year of treatment.
The two-year estimates of disease-free and overall survival were 66.6% (95% CI, 52.2%, 77.5%) and 72.0% (95% CI, 57.9%, 82.1%), respectively. At three years, the cause-specific survival was 82%. The estimated median overall survival was 48.1 months.
At a dose of 54 Gy in three fractions using heterogeneity corrections, SBRT is associated with very high rates of local tumor control for patients with medically inoperable peripherally located NSCLC.
SBRT overall was well tolerated with only moderate treatment-related morbidity.
Among patients with distant failures, the high proportion occurring within the first year may be related to inaccurate staging. All of these patients were staged clinically, with no pathologic assessment of regional nodal metastasis.
Despite a generally frail patient medically inoperable population, the three-year disease-free and overall survival rates were encouraging in this study.
54 Gy in three fractions with heterogeneity correction should be the standard radiation regimen when treating patients with early stage NSCLC on all future RTOG SBRT trials.
This is the first North American Cooperative Group Trial assessing SBRT for patients with medically inoperable NSCLC. RTOG 0236 has demonstrated that SBRT is a promising technique that allows for dose escalation through a significant reduction in the high dose treatment volume, while providing excellent rates of local control and cause-specific survival.
The results of this trial are particularly favorable in comparison to the Indiana University trial. The higher percentage of patients with T1 lesions, when compared to T2 lesions, in this study may account for the higher rates of local control and overall survival demonstrated in this study.
As Grade 3 skin and rib toxicities were observed in this trial, future RTOG trials have included these as protocol-related toxicities with specific radiation dose constraints.
When treating patients with SBRT, particularly off of protocol, patient positioning and immobilization are extremely important. Patients should be placed in a stable position that allows accurate and reproducible target position from treatment to treatment. A type of validated immobilization system should be used, such that the Gross Tumor Volume does not deviate beyond the confines of the Planning Treatment Volume with any significant probability (< 5%).
The treatment of patients with early stage NSCLC will be of increasing importance as the percentage of patients diagnosed with stage I disease is projected to increase as the sensitivity of CT and PET imaging improves.
SBRT may narrow the large disparity in survivals currently evident between surgically treated patients with stage I NSCLC and patients treated with standard fractionation radiation therapy. The local control and overall survival rates achieved in this study are very comparable to previously published surgical series data. A large randomized trial that would compared limited surgery (lobectomy, not pneumonectomy) with SBRT for patients with operable early stage peripheral NSCLC could change the treatment paradigm for patients with early stage disease. Although such a trial is currently being discussed, any trial comparing surgery with SBRT likely will not open in the near future and may have poor accrual among North American centers.
RTOG 0618, “A Phase II Trial of Stereotactic Body Radiation Therapy (SBRT) in the Treatment of Patients with Operable Stage I/II Non-Small Cell Lung Cancer,” was activated on 12/18/07 and has already completed greater than two-thirds of its planned accrual. While waiting for a surgery versus SBRT trial to open, this RTOG study may provide additional information to providers caring for patients with early stage operable NSCLC.
Mar 17, 2010 - In patients with early-stage but inoperable lung cancer, treatment with stereotactic body radiation therapy may significantly improve rates of tumor control, according to a study in the March 17 issue of the Journal of the American Medical Association.