Brian D. Kavanagh

Multi-institutional phase I/II trial of stereotactic body radiation therapy for lung metastases

PURPOSE To evaluate the efficacy and tolerability of high-dose stereotactic body radiation therapy (SBRT) for the treatment of patients with one to three lung metastases. PATIENTS AND METHODS Patients with one to three lung metastases with cumulative maximum tumor diameter smaller than 7 cm were enrolled and treated on a multi-institutional phase I/II clinical trial in which they received SBRT delivered in 3 fractions. In phase I, the total dose was safely escalated from 48 to 60 Gy. The phase II dose was 60 Gy. The primary end point was local control. Lesions with at least 6 months of radiographic follow-up were considered assessable for local control. Secondary end points included toxicity and survival. RESULTS Thirty-eight patients with 63 lesions were enrolled and treated at three participating institutions. Seventy-one percent had received at least one prior systemic regimen for metastatic disease and 34% had received at least two prior regimens (range, zero to five). Two patients had local recurrence after prior surgical resection. There was no grade 4 toxicity. The incidence of any grade 3 toxicity was 8% (three of 38). Symptomatic pneumonitis occurred in one patient (2.6%). Fifty lesions were assessable for local control. Median follow-up for assessable lesions was 15.4 months (range, 6 to 48 months). The median gross tumor volume was 4.2 mL (range, 0.2 to 52.3 mL). Actuarial local control at one and two years after SBRT was 100% and 96%, respectively. Local progression occurred in one patient, 13 months after SBRT. Median survival was 19 months. CONCLUSION This multi-institutional phase I/II trial demonstrates that high-dose SBRT is safe and effective for the treatment of patients with one to three lung metastases.

Stereotactic body radiation therapy: The report of AAPM Task Group 101

Task Group 101 of the AAPM has prepared this report for medical physicists, clinicians, and therapists in order to outline the best practice guidelines for the external-beam radiation therapy technique referred to as stereotactic body radiation therapy (SBRT). The task group report includes a review of the literature to identify reported clinical findings and expected outcomes for this treatment modality. Information is provided for establishing a SBRT program, including protocols, equipment, resources, and QA procedures. Additionally, suggestions for developing consistent documentation for prescribing, reporting, and recording SBRT treatment delivery is provided.

Radiation-induced proliferation of the human A431 squamous carcinoma cells is dependent on EGFR tyrosine phosphorylation

Accelerated cellular repopulation has been described as a response of tumors to fractionated irradiation in both normal tissue and tumor systems. To identify the mechanisms by which cells enhance their proliferative rate in response to clinically used doses of ionizing radiation (IR) we have studied human mammary and squamous carcinoma cells which are autocrine growth regulated by the epidermal growth factor receptor (EGFR) and its ligands, transforming growth factor-α and EGF. Both EGF and IR induced EGFR autophosphorylation, comparable levels of phospholipase Cγ activation as measured by inositol-1,4,5-triphosphate production, and as a consequence oscillations in cytosolic [Ca2+]. Activities of Raf-1 and mitogen-activated protein kinase (MAPK) were also stimulated by EGF and IR by Ca2+-dependent mechanisms. All these responses to EGF and IR were dependent upon activation of EGFR as judged by the use of the specific inhibitor of EGFR autophosphorylation, tyrphostin AG1478. Importantly, IR-induced proliferation of A431 cells was also inhibited by AG1478. This is the first report which demonstrates a link between IR-induced activation of proliferative signal transduction pathways and enhanced proliferation. We propose that accelerated repopulation of tumors whose growth is regulated by EGFR is initiated by an IR-induced EGFR activation mechanism that mimics the effects of growth factors.

American Society for Therapeutic Radiology and Oncology (ASTRO) and American College of Radiology (ACR) practice guideline for the performance of stereotactic body radiation therapy.

These guidelines are an educational tool designed to assist practitioners in providing appropriate radiologic care for patients. They are not inflexible rules or requirements of practice and are not intended, nor should they be used, to establish a legal standard of care. For these reasons and those set forth below, the developers of this guideline cautions against the use of these guidelines in litigation in which the clinical decisions of a practitioner are called into question. The ultimate judgment regarding the propriety of any specific procedure or course of action must be made by the physician or medical physicist in light of all the circumstances presented. Thus, an approach that differs from the

Stereotactic Body Radiation Therapy in Multiple Organ Sites

INTRODUCTION Stereotactic body radiation therapy (SBRT) uses advanced technology to deliver a potent ablative dose to deep-seated tumors in the lung, liver, spine, pancreas, kidney, and prostate. METHODS SBRT involves constructing very compact high-dose volumes in and about the tumor. Tumor position must be accurately assessed throughout treatment, especially for tumors that move with respiration. Sophisticated image guidance and related treatment delivery technologies have developed to account for such motion and efficiently deliver high daily dose. All this serves to allow the delivery of ablative dose fractionation to the target capable of both disrupting tumor mitosis and cellular function. RESULTS Prospective phase I dose-escalation trials have been carried out to reach potent tumoricidal dose levels capable of eradicating tumors with high likelihood. These studies indicate a clear dose-response relationship for tumor control with escalating dose of SBRT. Prospective phase II studies have been reported from several continents consistently showing very high levels of local tumor control. Although late toxicity requires further careful assessment, acute and subacute toxicities are generally acceptable. Patterns of toxicity, both clinical and radiographic, are distinct from those observed with conventionally fractionated radiotherapy as a result of the unique biologic response to ablative fractionation. CONCLUSION Prospective trials using SBRT have confirmed the efficacy of treatment in a variety of patient populations. Although mechanisms of ablative-dose injury remain elusive, ongoing prospective trials offer the hope of finding the ideal application for SBRT in the treatment arsenal.

Radiation-Associated Liver Injury

The liver is a critically important organ that has numerous functions including the production of bile, metabolism of ingested nutrients, elimination of many waste products, glycogen storage, and plasma protein synthesis. The liver is often incidentally irradiated during radiation therapy (RT) for tumors in the upper- abdomen, right lower lung, distal esophagus, or during whole abdomen or whole body RT. This article describes the endpoints, time-course, and dose-volume effect of radiation on the liver.

RADIATION DOSE-VOLUME EFFECTS IN THE STOMACH AND SMALL BOWEL

Published data suggest that the risk of moderately severe (>or=Grade 3) radiation-induced acute small-bowel toxicity can be predicted with a threshold model whereby for a given dose level, D, if the volume receiving that dose or greater (VD) exceeds a threshold quantity, the risk of toxicity escalates. Estimates of VD depend on the means of structure segmenting (e.g., V15 = 120 cc if individual bowel loops are outlined or V45 = 195 cc if entire peritoneal potential space of bowel is outlined). A similar predictive model of acute toxicity is not available for stomach. Late small-bowel/stomach toxicity is likely related to maximum dose and/or volume threshold parameters qualitatively similar to those related to acute toxicity risk. Concurrent chemotherapy has been associated with a higher risk of acute toxicity, and a history of abdominal surgery has been associated with a higher risk of late toxicity.

Chest Wall Volume Receiving >30 Gy Predicts Risk of Severe Pain and/or Rib Fracture After Lung Stereotactic Body Radiotherapy

PURPOSE To identify the dose-volume parameters that predict the risk of chest wall (CW) pain and/or rib fracture after lung stereotactic body radiotherapy. METHODS AND MATERIALS From a combined, larger multi-institution experience, 60 consecutive patients treated with three to five fractions of stereotactic body radiotherapy for primary or metastatic peripheral lung lesions were reviewed. CW pain was assessed using the Common Toxicity Criteria for pain. Peripheral lung lesions were defined as those located within 2.5 cm of the CW. A minimal point dose of 20 Gy to the CW was required. The CW volume receiving >or=20, >or=30, >or=40, >or=50, and >or=60 Gy was determined and related to the risk of CW toxicity. RESULTS Of the 60 patients, 17 experienced Grade 3 CW pain and five rib fractures. The median interval to the onset of severe pain and/or fracture was 7.1 months. The risk of CW toxicity was fitted to the median effective concentration dose-response model. The CW volume receiving 30 Gy best predicted the risk of severe CW pain and/or rib fracture (R(2) = 0.9552). A volume threshold of 30 cm(3) was observed before severe pain and/or rib fracture was reported. A 30% risk of developing severe CW toxicity correlated with a CW volume of 35 cm(3) receiving 30 Gy. CONCLUSION The development of CW toxicity is clinically relevant, and the CW should be considered an organ at risk in treatment planning. The CW volume receiving 30 Gy in three to five fractions should be limited to <30 cm(3), if possible, to reduce the risk of toxicity without compromising tumor coverage.

Stereotactic body radiotherapy for colorectal liver metastases: A pooled analysis

This study was undertaken to determine outcomes of stereotactic body radiotherapy for colorectal liver metastases in a pooled patient cohort.

Interim analysis of a prospective phase I/II trial of SBRT for liver metastases.

Stereotactic Body Radiation Therapy (SBRT) is a potent means of systemic cytoreductive therapy for selected patients with metastatic cancer. We here report an interim analysis of a prospective Phase I/II study of SBRT for liver metastases. Eligible patients with liver metastases met these criteria: (1) maximum tumor diameter < 6 cm; (2) ≤3 discrete lesions; (3) treatment planning confirmed ≥ 700 cm3 of normal liver receives ≤15Gy. The gross tumor volume (GTV) was expanded 5–10 mm to yield the planning target volume, which received 60 Gy in 3 fractions of SBRT over 3–14 days in the Phase II component of the trial. As of July, 2006, 36 patients have been enrolled: 18 in Phase I, 18 in Phase II. The median age was 58 years (range 27–91); the M:F ratio was 20:16. The most common primary sites were lung (n = 10), colorectal (n = 9), and breast (n = 4). Among 21 pts with ≥ 6 months post-SBRT follow-up (median 19 months, range 6–29), one instance of SBRT-related grade 3 toxicity occurred in subcutaneous tissue superficial to the liver. No grade IV toxicity occurred. For 28 discrete lesions treated (median GTV 14 cm3, range 1–98) the 18 month actuarial local control estimate is 93%. This interim analysis indicates that a very high rate of durable in-field tumor control can be safely achieved with SBRT to 1–3 liver lesions as administered in this protocol, to a prescription dose of 60 Gy in 3 fractions.