Neal Rebueno

STEREOTACTIC BODY RADIATION THERAPY FOR PATIENTS WITH LUNG CANCER PREVIOUSLY TREATED WITH THORACIC RADIATION

PURPOSE Stereotactic body radiation therapy (SBRT) provides excellent local control with acceptable toxicity for patients with early-stage non-small cell lung cancer. However, the efficacy and safety of SBRT for patients previously given thoracic radiation therapy is not known. In this study, we retrospectively reviewed outcomes after SBRT for recurrent disease among patients previously given radiation therapy to the chest. MATERIALS AND METHODS A search of medical records for patients treated with SBRT to the thorax after prior fractionated radiation therapy to the chest at The University of Texas M. D. Anderson Cancer Center revealed 36 such cases. The median follow-up time after SBRT was 15 months. The endpoints analyzed were overall survival, local control, and the incidence and severity of treatment-related toxicity. RESULTS SBRT provided in-field local control for 92% of patients; at 2 years, the actuarial overall survival rate was 59%, and the actuarial progression-free survival rate was 26%, with the primary site of failure being intrathoracic relapse. Fifty percent of patients experienced worsening of dyspnea after SBRT, with 19% requiring oxygen supplementation; 30% of patients experienced chest wall pain and 8% Grade 3 esophagitis. No Grade 4 or 5 toxic effects were noted. CONCLUSIONS SBRT can provide excellent in-field tumor control in patients who have received prior radiation therapy. Toxicity was significant but manageable. The high rate of intrathoracic failure indicates the need for further study to identify patients who would derive the most benefit from SBRT for this purpose.

Stereotactic ablative radiation therapy for centrally located early stage or isolated parenchymal recurrences of non-small cell lung cancer: how to fly in a "no fly zone".

PURPOSE We extended our previous experience with stereotactic ablative radiation therapy (SABR; 50 Gy in 4 fractions) for centrally located non-small cell lung cancer (NSCLC); explored the use of 70 Gy in 10 fractions for cases in which dose-volume constraints could not be met with the previous regimen; and suggested modified dose-volume constraints. METHODS AND MATERIALS Four-dimensional computed tomography (4DCT)-based volumetric image-guided SABR was used for 100 patients with biopsy-proven, central T1-T2N0M0 (n=81) or isolated parenchymal recurrence of NSCLC (n=19). All disease was staged with positron emission tomography/CT; all tumors were within 2 cm of the bronchial tree, trachea, major vessels, esophagus, heart, pericardium, brachial plexus, or vertebral body. Endpoints were toxicity, overall survival (OS), local and regional control, and distant metastasis. RESULTS At a median follow-up time of 30.6 months, median OS time was 55.6 months, and the 3-year OS rate was 70.5%. Three-year cumulative actuarial local, regional, and distant control rates were 96.5%, 87.9%, and 77.2%, respectively. The most common toxicities were chest-wall pain (18% grade 1, 13% grade 2) and radiation pneumonitis (11% grade 2 and 1% grade 3). No patient experienced grade 4 or 5 toxicity. Among the 82 patients receiving 50 Gy in 4 fractions, multivariate analyses showed mean total lung dose >6 Gy, V20 >12%, or ipsilateral lung V30 >15% to independently predict radiation pneumonitis; and 3 of 9 patients with brachial plexus Dmax >35 Gy experienced brachial neuropathy versus none of 73 patients with brachial Dmax <35 Gy (P=.001). Other toxicities were analyzed and new dose-volume constraints are proposed. CONCLUSIONS SABR for centrally located lesions produces clinical outcomes similar to those for peripheral lesions when normal tissue constraints are respected.

Aortic dose constraints when reirradiating thoracic tumors.

BACKGROUND AND PURPOSE Improved radiation delivery and planning has allowed, in some instances, for the retreatment of thoracic tumors. We investigated the dose limits of the aorta wherein grade 5 aortic toxicity was observed after reirradiation of lung tumors. MATERIAL AND METHODS In a retrospective analysis, 35 patients were identified, between 1993 and 2008, who received two rounds of external beam irradiation that included the aorta in the radiation fields of both the initial and retreatment plans. We determined the maximum cumulative dose to 1 cm(3) of the aorta (the composite dose) for each patient, normalized these doses to 1.8 Gy/fraction, and corrected them for long-term tissue recovery between treatments (NIDR). RESULTS The median time interval between treatments was 30 months (range, 1-185 months). The median follow-up of patients alive at analysis was 42 months (range, 14-70 months). Two of the 35 patients (6%) were identified as having grade 5 aortic toxicities. There was a 25% rate of grade 5 aortic toxicity for patients receiving composite doses ≥120.0 Gy (vs. 0% for patients receiving <120.0 Gy) (P=0.047). CONCLUSIONS Grade 5 aortic toxicities were observed with composite doses ≥120.0 Gy (NIDR ≥90.0 Gy) to 1cm(3) of the aorta.

Radiation for Hodgkin's Lymphoma in Young Female Patients: A New Technique to Avoid the Breasts and Decrease the Dose to the Heart

PURPOSE To demonstrate how, in young female patients with Hodgkins lymphoma, using an inclined board technique can further decrease the volume of breasts and heart in the treatment field. METHODS AND MATERIALS An inclined board was constructed with the ability to mount an Aquaplast face mask, a Vacu-Lock, and a hip stopper. Eight female patients with early-stage Hodgkins lymphoma were planned and compared using the conventional flat position and the inclined board position. All patients on the inclined board were planned with 90° degree table position and 15° gantry angle rotation to compensate for the beam divergence resulting from the patients position on the inclined board. Dose-volume histograms were generated, as well as the mean V30 and V5 of both breasts and heart using both treatment positions. RESULTS The mean value of V30 of the right breast, left breast, and heart decreased from 3%, 3%, and 13%, respectively, using the flat position to 0, 0.4%, and 5%, respectively, using the inclined board. The mean value of V5 of the right breast, left breast, and heart decreased from 6%, 13%, and 36%, respectively, using the flat position to 2%, 8%, and 29%, respectively, using the inclined board. CONCLUSIONS Compared with conventional flat positioning, this simple device and technique allows better sparing of the breasts and the heart while maintaining comparable target coverage and total lung dose.

Cardiac 18F-fluorodeoxyglucose uptake on positron emission tomography after thoracic stereotactic body radiation therapy

BACKGROUND AND PURPOSE Previous studies have shown that increased cardiac uptake of (18)F-fluorodeoxyglucose (FDG) on positron emission tomography (PET) may be an indicator of myocardial injury after radiotherapy. We reviewed patients treated with thoracic stereotactic body radiation therapy (SBRT) and established correlations between SBRT dose and observed changes in cardiac FDG-PET uptake. MATERIAL AND METHODS Retrospective analysis identified 39 patients that were treated with SBRT for lung tumors close to the heart. Patients were grouped according to whether or not they had changes in cardiac FDG-PET uptake within the planned SBRT field. RESULTS At a median follow-up interval of 39 months (range, 6-81 months), nine patients (23%) showed increased cardiac FDG uptake associated with the heart V₂₀. Of the 19 patients who received 20 Gy to ≥5 cm(3) of the heart, nine (47%) developed increased FDG uptake (vs. 0% for the 20 patients who received 20 Gy to <5 cm(3)) (P=0.0004), all within the 20-Gy isodose line. Patients with hypercholesterolemia prior to SBRT were also more likely to show increased cardiac FDG uptake (P=0.0190). CONCLUSION Increased FDG uptake in the heart after SBRT was observed when the 20 Gy isodose line exceeded 5 cm(3) of the heart.

EFFECT OF BRAIN STEM AND DORSAL VAGUS COMPLEX DOSIMETRY ON NAUSEA AND VOMITING IN HEAD AND NECK INTENSITY-MODULATED RADIATION THERAPY

Intensity-modulated radiation therapy (IMRT) is becoming the treatment of choice for many head and neck cancer patients. IMRT reduces some toxicities by reducing radiation dose to uninvolved normal tissue near tumor targets; however, other tissues not irradiated using previous 3D techniques may receive clinically significant doses, causing undesirable side effects including nausea and vomiting (NV). Irradiation of the brainstem, and more specifically, the area postrema and dorsal vagal complex (DVC), has been linked to NV. We previously reported preliminary hypothesis-generating dose effects associated with NV in IMRT patients. The goal of this study is to relate brainstem dose to NV symptoms. We retrospectively studied 100 consecutive patients that were treated for oropharyngeal cancer with IMRT. We contoured the brainstem, area postrema, and DVC with the assistance of an expert diagnostic neuroradiologist. We correlated dosimetry for the 3 areas contoured with weekly NV rates during IMRT. NV rates were significantly higher for patients who received concurrent chemotherapy. Post hoc analysis demonstrated that chemoradiation cases exhibited a trend towards the same dose-response relationship with both brainstem mean dose (p = 0.0025) and area postrema mean dose (p = 0.004); however, both failed to meet statistical significance at the p ≤ 0.002 level. Duration of toxicity was also greater for chemoradiation patients, who averaged 3.3 weeks with reported Common Terminology Criteria for Adverse Events (CTC-AE), compared with an average of 2 weeks for definitive RT patients (p = 0.002). For definitive RT cases, no dose-response trend could be ascertained. The mean brainstem dose emerged as a key parameter of interest; however, no one dose parameter (mean/median/EUD) best correlated with NV. This study does not address extraneous factors that would affect NV incidence, including the use of antiemetics, nor chemotherapy dose schedule specifics before and during RT. A prospective study will be required to depict exactly how IMRT dose affects NV.

Incidence and predictors of severe acute esophagitis and subsequent esophageal stricture in patients treated with accelerated hyperfractionated chemoradiation for limited-stage small cell lung cancer

PURPOSE Clinical and dosimetric predictors of severe (grade 3 or greater) acute esophageal toxicity and subsequent esophageal dilation were explored in patients with limited-stage small cell lung cancer treated with accelerated hyperfractionated chemoradiation. METHODS AND MATERIALS A total of 130 patients were identified who were treated to 45 Gy in 1.5-Gy twice-daily fractions with concurrent platinum-based chemotherapy between 2000 and 2009. Data on clinical, disease-related, and treatment-related variables were collected. Patients with percutaneous endoscopic gastrostomy tube insertion or intravenous hydration because of poor oral intake were designated as having acute grade 3 esophagitis. Univariate and multivariate analyses that associated treatment characteristics with esophagitis were assessed via logistic regression, and optimal cut points were identified with recursive partitioning analysis. RESULTS Twenty-five patients developed severe acute esophagitis, at a rate of 26% (18/69) in patients treated with earlier 3-dimensional conformal radiation therapy techniques and 11.5% (7/61) in patients treated with intensity modulated radiation therapy techniques and omission of elective nodal irradiation. The incidence of esophageal stricture was 6% overall (8 of 128 eligible) but 26% (6/23) among those who experienced prior grade 3 acute esophagitis and 2% (2/105) among those with acute esophagitis less than or equal to grade 2. Significant multivariate predictors of acute esophagitis were mean dose and volume of esophagus receiving at least 5% to 35% of the prescribed dose (V5 to V40). Patients with V5 ≥ 74% had a 44.4% risk of severe acute esophagitis (12/27) versus 12.6% (13/103) among those with V5 < 74%. V45 was the only dosimetric predictor for esophageal stricture, with 13.7% of patients in whom V45 was ≥37.5% requiring subsequent dilation. CONCLUSIONS Modern radiation techniques are associated with a lower frequency of severe acute esophagitis than previous paradigms. The proportion of esophagus receiving low- to moderate-range doses (mean, V5 through V40) predicts acute esophagitis, whereas the proportion of esophagus that receives high doses (V45) predicts the development of esophageal stricture that requires dilation. Patients who develop grade 3 acute esophagitis are at significant risk for subsequent esophageal stricture, whereas those with acute esophagitis of grade 2 or less display minimal risk.

Exploring the Feasibility of Dose Escalation Positron Emission Tomography-Positive Disease with Intensity-Modulated Radiation Therapy and the Effects on Normal Tissue Structures for Thoracic Malignancies

The pattern of failure is one of the major causes of mortality among thoracic patients. Studies have shown a correlation between local control and dose. Intensity-modulated radiation therapy (IMRT) has resulted in conformal dose distributions while limiting dose to normal tissue. However, thoracic malignancies treated with IMRT to highly conformal doses up to 70 Gy still have been found to fail. Thus, the need for dose escalation through simultaneous integrated boost (SIB) may prove effective in minimizing reoccurrences. For our study, 28 thoracic IMRT plans were reoptimized via dose escalation to the gross tumor volume (GTV) and planning target volume (PTV) of 79.2 Gy and 68.4 Gy, respectively. Reoccurrences in surrounding regions of microscopic disease are rare therefore, dose-escalating regional nodes (outside GTV) were not included. Hence, the need to edit GTV margins was acceptable for our retrospective study. A median dose escalation of approximately 15 Gy (64.8-79.2 Gy) via IMRT using SIB was deemed achievable with minimal percent differences received by critical structures compared with the original treatment plan. The targets mean doses were significantly increased based on p-value analysis, while the normal tissue structures were not significantly changed.

The use of image guided laser interstitial thermotherapy to supplement spine stereotactic radiosurgery to manage metastatic epidural spinal cord compression: Proof of concept and dosimetric analysis

Spine stereotactic radiosurgery (SSRS) is a form of stereotactic body radiation therapy by which advanced treatment delivery techniques (eg, intensity modulated radiotherapy) are combined with image guidance and rigid immobilization to deliver a high dose of conformal radiation to the target while minimizing dose to nearby critical structures such as the spinal cord. For well-selected patients, SSRS offers durable local control1 and pain relief.2 However, patients with epidural disease continue to pose a clinical treatment challenge. Patterns of failure analyses have shown a predilection for failure in the epidural space.3 Given that the spinal cord dose restrictions take precedence over tumor coverage, cases with epidural extension generally have suboptimal dose delivery to the gross tumor volume (GTV). Improved local control with single-fraction SSRS has correlated with dosimetric factors such as the

Dose escalation for locally advanced pancreatic cancer: How high can we go?

Purpose There are limited treatment options for locally advanced, unresectable pancreatic cancer (LAPC) and no likelihood of cure without surgery. Radiation offers an option for local control, but radiation dose has previously been limited by nearby bowel toxicity. Advances in on-board imaging and treatment planning may allow for dose escalation not previously feasible and improve local control. In preparation for development of clinical trials of dose escalation in LAPC, we undertook a dosimetric study to determine the maximum possible dose escalation while maintaining known normal tissue constraints. Methods and Materials Twenty patients treated at our institution with either SBRT or dose-escalated hypofractionated IMRT (DE-IMRT) were re-planned using dose escalated SBRT to 70 Gy in 5 fractions to the GTV and 40 Gy in 5 fractions to the PTV. Standard accepted organ at risk (OAR) constraints were used for planning. Descriptive statistics were generated for homogeneity, conformality, OARs and GTV/PTV. Results Mean iGTV coverage by 50 Gy was 91% (±0.07%), by 60 Gy was 61.3% (±0.08%) and by 70 Gy was 24.4% (±0.05%). Maximum PTV coverage by 70 Gy was 33%. Maximum PTV coverage by 60 Gy was 77.5%. The following organ at risk (OAR) constraints were achieved for 90% of generated plans: Duodenum V20 < 30 cc, V30 < 3 cc, V35 < 1 cc; Small Bowel V20 < 15 cc, V30 < 1 cc, V35 < 0.1 cc; Stomach V20 < 20 cc, V30 < 2 cc, V35 < 1 cc. V40 < 0.5 cc was achieved for all OAR. Conclusions Dose escalation to 60 Gy is dosimetrically feasible with adequate GTV coverage. The identified constraints for OARs will be used in ongoing clinical trials.