Ronald C. McGarry

Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer

PURPOSE Surgical resection is standard therapy in stage I non-small-cell lung cancer (NSCLC); however, many patients are inoperable due to comorbid diseases. Building on a previously reported phase I trial, we carried out a prospective phase II trial using stereotactic body radiation therapy (SBRT) in this population. PATIENTS AND METHODS Eligible patients included clinically staged T1 or T2 (< or = 7 cm), N0, M0, biopsy-confirmed NSCLC. All patients had comorbid medical problems that precluded lobectomy. SBRT treatment dose was 60 to 66 Gy total in three fractions during 1 to 2 weeks. RESULTS All 70 patients enrolled completed therapy as planned and median follow-up was 17.5 months. The 3-month major response rate was 60%. Kaplan-Meier local control at 2 years was 95%. Altogether, 28 patients have 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%. Grade 3 to 5 toxicity occurred in a total of 14 patients. Among patients experiencing toxicity, the median time to observation was 10.5 months. Patients treated for tumors in the peripheral lung had 2-year freedom from severe toxicity of 83% compared with only 54% for patients with central tumors. CONCLUSION High rates of local control are achieved with this SBRT regimen in medically inoperable patients with stage I NSCLC. Both local recurrence and toxicity occur late after this treatment. This regimen should not be used for patients with tumors near the central airways due to excessive toxicity.

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 III Study of Cisplatin, Etoposide, and Concurrent Chest Radiation With or Without Consolidation Docetaxel in Patients With Inoperable Stage III Non–Small-Cell Lung Cancer: The Hoosier Oncology Group and U.S. Oncology

PURPOSE Concurrent chemoradiotherapy is standard treatment for patients with inoperable stage III non-small-cell lung cancer (NSCLC). A phase II study by the Southwest Oncology Group using consolidation docetaxel after cisplatin (P), etoposide (E), and radiation (XRT) resulted in a median survival time (MST) of 26 months. This randomized phase III trial evaluated whether consolidation docetaxel was responsible for this improved survival. PATIENTS AND METHODS Eligible patients had stage IIIA or IIIB NSCLC, baseline performance status of 0 to 1, forced expiratory volume in 1 second >or= 1 L, and less than 5% weight loss. Patients received P 50 mg/m(2) intravenously (IV) on days 1, 8, 29, and 36 and E 50 mg/m(2) IV on days 1-5 and 29-33 concurrently with chest XRT to 59.40 Gy. Patients who did not experience progression were randomly assigned to docetaxel 75 mg/m(2) IV every 21 days for three cycles versus observation. The primary end point was to compare overall survival (Kaplan-Meier analysis). RESULTS On the basis of evidence of futility, a data and safety monitoring board recommended early termination after an analysis of the initial 203 patients. Patient characteristics (n = 203) were as follows: 34% female; median age, 63 years; 39.4% stage IIIA; and 60.6% stage IIIB. One hundred forty-seven (72.4%) of 203 patients were randomly assigned to docetaxel (n = 73) or observation (n = 74). Grade 3 to 5 toxicities during docetaxel included febrile neutropenia (10.9%) and pneumonitis (9.6%); 28.8% of patients were hospitalized during docetaxel (v 8.1% in observation arm), and 5.5% died as a result of docetaxel. The MST for all patients (n = 203) was 21.7 months; MST was 21.2 months for docetaxel arm compared with 23.2 months for observation arm (P = .883). CONCLUSION Consolidation docetaxel after PE/XRT results in increased toxicities but does not further improve survival compared with PE/XRT alone in patients with stage III inoperable NSCLC.

Stereotactic body radiation therapy: a novel treatment modality

Stereotactic body radiation therapy (SBRT) involves the delivery of a small number of ultra-high doses of radiation to a target volume using very advanced technology and has emerged as a novel treatment modality for cancer. The role of SBRT is most important at two cancer stages—in early primary cancer and in oligometastatic disease. This modality has been used in the treatment of early-stage non-small-cell lung cancer, prostate cancer, renal-cell carcinoma, and liver cancer, and in the treatment of oligometastases in the lung, liver, and spine. A large body of evidence on the use of SBRT for the treatment of primary and metastatic tumors in various sites has accumulated over the past 10–15 years, and efficacy and safety have been demonstrated. Several prospective clinical trials of SBRT for various sites have been conducted, and several other trials are currently being planned. The results of these clinical trials will better define the role of SBRT in cancer management. This article will review the radiobiologic, technical, and clinical aspects of SBRT.

Brachial plexopathy from stereotactic body radiotherapy in early-stage NSCLC: Dose-limiting toxicity in apical tumor sites

BACKGROUND AND PURPOSE We report frequency of brachial plexopathy in early-stage non-small cell lung cancer treated with stereotactic body radiotherapy. MATERIALS AND METHODS 276 T1-T2, N0 or peripheral T3, N0 lesions were treated in 253 patients with stereotactic radiotherapy at Indiana University and Richard L. Roudebush VAMC from 1998 to 2007. Thirty-seven lesions in 36 patients were identified as apical lesions, defined as epicenter of lesion superior to aortic arch. Brachial plexus toxicity was scored for these apical lesions according to CTCAE v. 3.0 for ipsilateral shoulder/arm neuropathic pain, motor weakness, or sensory alteration. RESULTS The 37 apical lesions (19 Stage IA, 16 IB, and 2 IIB) were treated with stereotactic body radiotherapy to a median total dose of 57 Gy (30-72). The associated brachial plexus of 7/37 apical lesions developed grade 2-4 plexopathy (4 pts--grade 2, 2 pts--grade 3, 1 pt--grade 4). Five patients had ipsilateral shoulder/arm neuropathic pain alone, one had pain and upper extremity weakness, and one had pain progressing to numbness of the upper extremity and paralysis of hand and wrist. The median of the maximum brachial plexus doses of patients developing brachial plexopathy was 30 Gy (18-82). Two-year Kaplan-Meier risk of brachial plexopathy for maximum brachial plexus dose >26 Gy was 46% vs 8% for doses 26 Gy (p=0.04 for likelihood ratio test). CONCLUSIONS Stereotactic body radiotherapy for apical lesions carries a risk of brachial plexopathy. Brachial plexus maximum dose should be kept <26 Gy in 3 or 4 fractions.

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.

Characterization and aerosol dispersion performance of advanced spray-dried chemotherapeutic PEGylated phospholipid particles for dry powder inhalation delivery in lung cancer.

Pulmonary inhalation chemotherapeutic drug delivery offers many advantages for lung cancer patients in comparison to conventional systemic chemotherapy. Inhalable particles are advantageous in their ability to deliver drug deep in the lung by utilizing optimally sized particles and higher local drug dose delivery. In this work, spray-dried and co-spray dried inhalable lung surfactant-mimic PEGylated lipopolymers as microparticulate/nanoparticulate dry powders containing paclitaxel were rationally designed via organic solution advanced spray drying (no water) in closed-mode from dilute concentration feed solution. Dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylethanolamine poly(ethylene glycol) (DPPE-PEG) with varying PEG chain length were mixed with varying amounts of paclitaxel in methanol to produce co-spray dried microparticles and nanoparticles. Scanning electron microscopy showed the spherical particle morphology of the inhalable particles. Thermal analysis and X-ray powder diffraction confirmed the retention of the phospholipid bilayer structure in the solid-state following spray drying, the degree of solid-state molecular order, and solid-state phase transition behavior. The residual water content of the particles was very low as quantified analytically Karl Fisher titration. The amount of paclitaxel loaded into the particles was quantified which indicated high encapsulation efficiencies (43-99%). Dry powder aerosol dispersion performance was measured in vitro using the Next Generation Impactor (NGI) coupled with the Handihaler dry powder inhaler device and showed mass median aerodynamic diameters in the range of 3.4-7 μm. These results demonstrate that this novel microparticulate/nanoparticulate chemotherapeutic PEGylated phospholipid dry powder inhalation aerosol platform has great potential in lung cancer drug delivery.

Stereotactic Body Radiation Therapy Can Be Used Safely to Boost Residual Disease in Locally Advanced Non-Small Cell Lung Cancer: A Prospective Study

PURPOSE To report the results of a prospective, single-institution study evaluating the feasibility of conventional chemoradiation (CRT) followed by stereotactic body radiation therapy (SBRT) as a means of dose escalation for patients with stage II-III non-small cell lung cancer (NSCLC) with residual disease. METHODS AND MATERIALS Patients without metastatic disease and with radiologic evidence of limited residual disease (≤5 cm) within the site of the primary tumor and good or complete nodal responses after standard CRT to a target dose of 60 Gy were considered eligible. The SBRT boost was done to achieve a total combined dose biological equivalent dose >100 Gy to the residual primary tumor, consisting of 10 Gy × 2 fractions (20 Gy total) for peripheral tumors, and 6.5 Gy × 3 fractions (19.5 Gy total) for medial tumors using the Radiation Therapy Oncology Group protocol 0813 definitions. The primary endpoint was the development of grade ≥3 radiation pneumonitis (RP). RESULTS After a median follow-up of 13 months, 4 patients developed acute grade 3 RP, and 1 (2.9%) developed late and persistent grade 3 RP. No patients developed grade 4 or 5 RP. Mean lung dose, V2.5, V5, V10, and V20 values were calculated for the SBRT boost, and none were found to significantly predict for RP. Only advancing age (P=.0147), previous smoking status (P=.0505), and high CRT mean lung dose (P=.0295) were significantly associated with RP development. At the time of analysis, the actuarial local control rate at the primary tumor site was 82.9%, with only 6 patients demonstrating recurrence. CONCLUSIONS Linear accelerator-based SBRT for dose escalation of limited residual NSCLC after definitive CRT was feasible and did not increase the risk for toxicity above that for standard radiation therapy.

Dose–Volume Analysis of Radiation Pneumonitis in Non–Small-Cell Lung Cancer Patients Treated With Concurrent Cisplatinum and Etoposide With or Without Consolidation Docetaxel

PURPOSE To examine the rates and risk factors for radiation pneumonitis (RP) in non-small-cell lung cancer (NSCLC) patients treated with chemoradiotherapy. METHODS AND MATERIALS We reviewed dosimetry records from Stage III NSCLC patients treated on a prospective randomized trial. Patients received concurrent cisplatinum/etoposide with radiation therapy to 59.4 Gy. A total of 243 patients were enrolled; 167 did not experience progression and were randomized to observation (OB) or consolidation docetaxel (CD). Toxicity was coded based on the presence of Grade 0 to 1 vs. Grade 2 to 5 RP using the Common Toxicity Criteria and Adverse Events (CTCAE) v3.0. RESULTS Median age and follow-up were 63 years and 16 months, respectively. Overall, Grade 0 to 1 and Grade 2 to 5 RP were reported in 226 patients and 17 patients (7%) respectively. Median mean lung dose (MLD), V5, V20, and V30 for evaluable patients were 18 Gy, 52%, 35%, and 29%. MLD in Grade 0 to 1 and Grade 2 to 5 patients was 1,748 c Gy and 2,013 cGy in respectively (p = 0.12). Grade 2 to 5 RP developed in 2.2% and 19% of patients with MLD < 18 Gy and MLD > 18 Gy, respectively (p = 0.015). Mean V20 was 33.7% and 37.7% for Grade 0 to 1 and Grade 2 to 5 groups, respectively (p = 0.29). Grade 2 to 5 RP developed in 4.8% and 17% of patients with V20 < 35% and V20 > 35%, respectively. The OB and CD groups had similar MLD and V20, and the RP rates were 3.6% and 14.6%, respectively (p = 0.015). Patients who developed Grade 0 to 1 and Grade 2 to 5 RP had similar mean V5, V10, V15, V20, V25, V30, age, smoking history, and tumor characteristics. CONCLUSIONS The overall rate of Grade 2 to 5 RP was 7% in patients treated with chemoradiotherapy. In this analysis, predictive factors for RP were MLD > 18 Gy and treatment with CD.