Mark A. Henderson

Stereotactic Body Radiation Therapy for Early-Stage Non–Small-Cell Lung Carcinoma: Four-Year Results of a Prospective Phase II Study

PURPOSE The 50-month results of a prospective Phase II trial of stereotactic body radiation therapy (SBRT) in medically inoperable patients are reported. METHODS AND MATERIALS A total of 70 medically inoperable patients had clinically staged T1 (34 patients) or T2 (36 patients) (< or =7 cm), N0, M0, biopsy-confirmed non-small-cell lung carcinoma (NSCLC) and received SBRT as per our previously published reports. The SBRT treatment dose of 60-66 Gy was prescribed to the 80% isodose volume in three fractions. RESULTS Median follow-up was 50.2 months (range, 1.4-64.8 months). Kaplan-Meier local control at 3 years was 88.1%. Regional (nodal) and distant recurrence occurred in 6 (8.6%) and 9 (12.9%) patients, respectively. Median survival (MS) was 32.4 months and 3-year overall survival (OS) was 42.7% (95% confidence interval [95% CI], 31.1-54.3%). Cancer-specific survival at 3 years was 81.7% (95% CI, 70.0-93.4%). For patients with T1 tumors, MS was 38.7 months (95% CI, 25.3-50.2) and for T2 tumors MS was 24.5 months (95% CI, 18.5-37.4) (p = 0.194). Tumor volume (< or =5 cc, 5-10 cc, 10-20 cc, >20 cc) did not significantly impact survival: MS was 36.9 months (95% CI, 18.1-42.9), 34.0 (95% CI, 16.9-57.1), 32.8 (95% CI, 21.3-57.8), and 21.4 months (95% CI, 17.8-41.6), respectively (p = 0.712). There was no significant survival difference between patients with peripheral vs. central tumors (MS 33.2 vs. 24.4 months, p = 0.697). Grade 3 to 5 toxicity occurred in 5 of 48 patients with peripheral lung tumors (10.4%) and in 6 of 22 patients (27.3%) with central tumors (Fishers exact test, p = 0.088). CONCLUSION Based on our study results, use of SBRT results in high rates of local control in medically inoperable patients with Stage I NSCLC.

Phase I feasibility trial of stereotactic body radiation therapy for primary hepatocellular carcinoma

BackgroundHepatocellular carcinoma (HCC) is increasing in incidence and the majority of patients are not candidates for radical therapies. Therefore, interest in minimally invasive therapies in growing.MethodsA Phase I dose escalation trial was conducted at Indiana University to determine the feasibility and toxicity of stereotactic body radiation therapy (SBRT) for primary HCC. Eligible patients had Child-Turcotte-Pugh’s Class (CTP) A or B, were not candidates for resection, had 1–3 lesions and cumulative tumour diameter less than or equal to 6 cm. Dose escalation started at 36 Gy in 3 fractions (12 Gy/fraction) with a subsequent planned escalation of 2 Gy/fraction/level. Dose-limiting toxicity (DLT) was defined as Common Terminology Criteria for Adverse Events v3.0 grade 3 or greater toxicity.ResultsSeventeen patients with 25 lesions were enrolled. Dose was escalated to 48 Gy (16 Gy/fraction) in CTP-A patients without DLT. Two patients with CPC-B disease developed grade 3 hepatic toxicity at the 42-Gy (14 Gy/fraction) level. The protocol was amended for subsequent CTP-B patients to receive a regimen of 5 fractions starting at 40 Gy (8 Gy/fraction) with one patient experiencing progressive liver failure. Four additional patients were enrolled (one died of unrelated causes after an incomplete SBRT course) without DLT. The only factor related to more than one grade 3 or greater liver toxicity or death within 6 months was the CTP score (p=0.03). Six patients underwent a liver transplant. Ten patients are alive without progression with a median FU of 24 months (10–42 months), with local control/stabilisation of the disease of 100%. One and two-year Kaplan-Meier estimates for overall survival are 75% and 60%, respectively.ConclusionsSBRT is a non-invasive feasible and well tolerated therapy in adequately selected patients with HCC. The preliminary local control and survival are encouraging. A confirmatory Phase II trial is currently open to accrual.

A Dose–Volume Analysis of Radiation Pneumonitis in Non–Small Cell Lung Cancer Patients Treated With Stereotactic Body Radiation Therapy

PURPOSE To examine the rates and risk factors of radiation pneumonitis (RP) in non-small cell lung cancer (NSCLC) patients treated with stereotactic body radiotherapy (SBRT). METHODS AND MATERIALS Dosimetry records for 251 patients with lymph node-negative Stage I-IIB NSCLC and no prior chest radiation therapy (RT) treated with SBRT were reviewed. Patients were coded on the basis of the presence of at least Grade (G) 2 RP using the Common Toxicity Criteria version 2 criteria. Radiation doses, V5, V10, V20, and mean lung dose (MLD) data points were extracted from the dose-volume histogram (DVH). RESULTS Median PTV volume was 48 cc. Median prescribed radiation dose was 60 Gy delivered in three fractions to the 80% isodose line. Median age at treatment was 74 years. Median follow-up was 17 months. RP was reported after treatment of 42 lesions: G1 in 19 (8%), G2 in 17 (7%), G3 in 5 (2%), and G4 in 1 (0.4%). Total lung DVHs were available for 143 patients. For evaluable patients, median MLD, V5, V10, and V20 were 4.1 Gy, 20%, 12%, and 4%, respectively. Median MLDs were 4 Gy and 5 Gy for G0-1 and G2-4 groups, respectively (p = 0.14); median V5 was 20% for G0-1 and 24% for G2-4 (p = 0.70); median V10 was 12% in G0-1 and 16% in G2-4 (p = 0.08), and median V20 was 4% in G0-1 and 6.6% in G2-4 (p = 0.05). G2-4 RP was noted in 4.3% of patients with MLD ≤4 Gy compared with 17.6% of patients with MLD >4 Gy (p = 0.02), and in 4.3% of patients with V20 ≤4% compared with 16.4% of patients with V20 >4% (p = 0.03). CONCLUSION Overall rate of G2-4 RP in our population treated with SBRT was 9.4%. Development of symptomatic RP in this series correlated with MLD and V20.

Baseline pulmonary function as a predictor for survival and decline in pulmonary function over time in patients undergoing stereotactic body radiotherapy for the treatment of stage I non-small-cell lung cancer.

PURPOSE To examine the effect of baseline forced expiratory volume in 1 second (FEV(1)) and diffusion capacity for carbon monoxide (Dl(co)) on posttreatment survival and pulmonary function decrease after stereotactic body radiotherapy (SBRT) for patients with early-stage non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS Seventy medically inoperable patients with Stage I NSCLC were treated with definitive SBRT to a dose of 6,000 (Stage IA) or 6,600 cGy (Stage IB), given in three equal fractions. Baseline and serial posttreatment pulmonary function data were collected. RESULTS Median age was 70.5 years, and median follow-up was 2.17 years. Median pretreatment FEV(1) and Dl(co) were 1.05 L and 10.06 mg/min/mm Hg, respectively. There was no significant decrease in survival in patients with baseline FEV(1) and Dl(co) less than the median value and less than the lowest quartile, whereas patients with values greater than the highest quartile of baseline FEV(1) had significantly inferior survival. There was no significant effect of pretreatment FEV(1) or Dl(co) on posttreatment levels. There was a statistically significant decrease in Dl(co) of 1.11 mg/min/mm Hg/y. CONCLUSIONS Poor baseline pulmonary function did not predict decreased survival or pulmonary function after treatment. A statistically significant decrease in Dl(co) after treatment was seen, similar to decreases seen in studies delivering standard thoracic radiotherapy. We conclude that low pretreatment FEV(1) and/or Dl(co) alone should not be used to exclude patients with NSCLC from treatment with SBRT.

A Pilot Trial of Serial 18F-Fluorodeoxyglucose Positron Emission Tomography in Patients With Medically Inoperable Stage I Non–Small-Cell Lung Cancer Treated With Hypofractionated Stereotactic Body Radiotherapy

PURPOSE Routine assessment was made of tumor metabolic activity as measured by 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in Stage I non-small-cell lung cancer (NSCLC). This report describes PET correlates prospectively collected after stereotactic body radiotherapy (SBRT) for patients with medically inoperable NSCLC. METHODS AND MATERIALS 14 consecutive patients with medically inoperable Stage I NSCLC were enrolled. All patients received SBRT to 60-66 Gy in three fractions. Patients underwent serial planned FDG-PET/computed tomography fusion imaging before SBRT and at 2, 26, and 52 weeks after SBRT. RESULTS With median follow-up of 30.2 months, no patients experienced local failure. One patient developed regional failure, 1 developed distant failure, and 1 developed a second primary. The median tumor maximum standardized uptake value (SUV(max)) before SBRT was 8.70. The median SUV(max) values at 2, 26, and 52 weeks after SBRT were 6.04, 2.80, and 3.58, respectively. Patients with low pre-SBRT SUV were more likely to experience initial 2-week rises in SUV, whereas patients with high pre-SBRT SUV commonly had SUV declines 2 weeks after treatment (p = 0.036). Six of 13 patients had primary tumor SUV(max) >3.5 at 12 months after SBRT but remained without evidence of local disease failure on further follow-up. CONCLUSIONS A substantial proportion of patients may have moderately elevated FDG-PET SUV(max) at 12 months without evidence of local failure on further follow-up. Thus, slightly elevated PET SUV(max) should not be considered a surrogate for local treatment failure. Our data do not support routine serial FDG-PET/computed tomography for follow-up of patients receiving SBRT for Stage I NSCLC.

Chest Wall Toxicity After Stereotactic Body Radiotherapy for Malignant Lesions of the Lung and Liver

PURPOSE To quantify the frequency of rib fracture and chest wall (CW) pain and identify the dose-volume parameters that predict CW toxicity after stereotactic body radiotherapy (SBRT). METHODS AND MATERIALS The records of patients treated with SBRT between 2000 and 2008 were reviewed, and toxicity was scored according to Common Terminology Criteria for Adverse Events v3.0 for pain and rib fracture. Dosimetric data for CW and rib were analyzed and related to the frequency of toxicity. The risks of CW toxicity were then further characterized according to the median effective concentration (EC(50)) dose-response model. RESULTS A total of 347 lesions were treated with a median follow-up of 19 months. Frequency of Grade I and higher CW pain and/or fracture for CW vs. non-CW lesions was 21% vs. 4%, respectively (p < 0.0001). A dose of 50 Gy was the cutoff for maximum dose (Dmax) to CW and rib above which there was a significant increase in the frequency of any grade pain and fracture (p = 0.03 and p = 0.025, respectively). Volume of CW receiving 15 Gy - 40 Gy was highly predictive of toxicity (R(2) > 0.9). According to the EC(50) model, 5 cc and 15 cc of CW receiving 40 Gy predict a 10% and 30% risk of CW toxicity, respectively. CONCLUSION Adequate tumor coverage remains the primary objective when treating lung or liver lesions with SBRT. To minimize toxicity when treating lesions in close proximity to the CW, Dmax of the CW and/or ribs should remain <50 Gy, and <5 cc of CW should receive ≥ 40 Gy.

Gamma-Knife-Based Stereotactic Radiosurgery for Uveal Melanoma

Nineteen patients with uveal melanoma were treated with Gamma-Knife-based stereotactic radiosurgery (SRS). The radiation dose was 40 Gy prescribed to the 50% isodose line for all patients. The median follow-up was 40 months. The 3- and 5-year overall survival rates were 86 and 55%, respectively. The 3- and 5-year tumor control rates were both 94%. Six of the 19 treated patients (32%) developed distant metastasis 31–75 months after SRS. Out of the 19 patients treated with SRS, 2 had improved, 4 had stable and 13 had worse vision in the treated eye. Gamma-Knife-based SRS appears to provide excellent local control of uveal melanoma. The risk of distant metastasis is significant. Effective systemic therapy is to be explored to improve the treatment outcome of uveal melanoma.

Stereotactic body radiation therapy for early-stage non-small-cell lung cancer

Stereotactic body radiation therapy has emerged as a novel oncologic therapy and experience with the use of stereotactic body radiation therapy for the treatment of early-stage non-small-cell lung cancer has grown over the last 10 years. This article reviews the radiobiologic, physical/technical and clinical aspects of stereotactic body radiation therapy for early-stage non-small-cell lung cancer. The literature is also reviewed.

Endocrine Response after Gamma Knife-Based Stereotactic Radiosurgery for Secretory Pituitary Adenoma

Purpose: To examine treatment outcomes of Gamma Knife-based stereotactic radiosurgery (GK-based SRS) for secretory pituitary adenomas. Materials and Methods: 25 patients were treated with GK-based SRS for secretory pituitary adenomas with ≧12 months of follow-up. Results: For prolactinomas, 2 of 4 patients (50%) showed normalization of serum prolactin at a mean time of 18 months. One of 4 had a ≧50% decrease but still abnormal prolactin levels. For adrenocorticotrophic hormone-secreting tumors, 6 of 12 patients (50%) showed normalization of their endocrine levels at a median of 10 months. An additional 2 (17%) had a ≧50% decrease. For growth hormone-secreting tumors, 4 of 9 patients (44%) showed normalization of endocrine levels at a median time of 30 months. Two patients (22%) had ≧50% lower but abnormal endocrine levels. Conclusion: GK-based SRS provides a reasonable rate of endocrine normalization of secretory pituitary adenoma. The time to endocrine response is shorter than reported for fractionated external beam radiotherapy. There is a low risk of optic neuropathy.

Gamma Knife Stereotactic Radiosurgery for Low-Grade Astrocytomas

Patients with low-grade astrocytoma (LGA; 8 pilocytic astrocytomas, 2 subependymal giant cell astrocytomas, 2 fibrillary astrocytomas) were selected for treatment with gamma knife stereotactic radiosurgery (GKSRS) based on having a demarcated appearance on CT or MRI and the possibility of dose sparing of adjacent eloquent structures. A median dose of 13 Gy was prescribed to the 50% isodose line, which covered the gross tumor. The median patient age was 17.4 years. The median target volume was 4.4 cm3. With a median follow-up of 48.2 months, 4-year tumor control and overall survival were 77 and 83%, respectively. Only 2 patients experienced symptomatic treatment-related toxicity. GKSRS can provide local control in cases of unresectable or recurrent LGA with a low incidence of side effects in carefully selected patients.