Lucien A. Nedzi

Variables associated with the development of complications from radiosurgery of intracranial tumors

Between 5/21/86 and 11/1/89, we treated 64 recurrent or inoperable intracranial tumors in 60 patients (40 primary, 24 metastatic) with stereotactic radiosurgery using a modified 6 MeV linear accelerator at the Joint Center for Radiation Therapy. Patients were followed until death or 1/1/90. The median follow-up was 8 months (2-43 months). Fourteen patients experienced complications from 12 hours to 7 months (median 3 months, but only two patients more than 4 months) following radiosurgery. To determine variables related to complication, we calculated integral dose-volume histograms for 61/64 lesions and the surrounding CT-defined normal tissue. We excluded 16 lesions in 15 patients for follow-up less than 4 months (12 patients) or insufficient treatment information (3 patients). The variables for which higher values were associated with significantly more toxicity in a univariate score test were: a) tumor dose inhomogeneity (p less than 0.00001), b) maximum tumor dose (p = 0.00002), c) number of isocenters (p = 0.00002), d) maximum normal tissue dose (p = 0.00005) and e) tumor volume (p = 0.0001). These variables were all highly correlated with tumor dose inhomogeneity (coefficients of rank correlation 0.75-0.81). Tumor dose inhomogeneity had a much higher loglikelihood in a logistic model than any other single variable and a higher loglikelihood than any other two variables combined. None of the 21 patients with metastatic lesions experienced a complication. When we excluded the metastatic lesions, the above five variables remained significant in univariate tests. The mean tumor dose, number of treatment arcs, total degrees of arc, tumor location, previous radiotherapy, tumor geometry, pretreatment performance status, collimator size, and age were not significantly associated with toxicity. We conclude that radiosurgery of intracranial tumors is associated with a low risk of complications for lesions less than 10cc treated with a single isocenter to maximum tumor doses less than 25 Gy with tumor dose inhomogeneity less than 10 Gy, but that treatment of larger lesions will require new treatment strategies which reduce the tumor dose inhomogeneity associated with multiple isocenter treatments.

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.

A Phase 3 Trial of Whole Brain Radiation Therapy and Stereotactic Radiosurgery Alone Versus WBRT and SRS With Temozolomide or Erlotinib for Non-Small Cell Lung Cancer and 1 to 3 Brain Metastases: Radiation Therapy Oncology Group 0320.

BACKGROUND A phase 3 Radiation Therapy Oncology Group (RTOG) study subset analysis demonstrated improved overall survival (OS) with the addition of stereotactic radiosurgery (SRS) to whole brain radiation therapy (WBRT) in non-small cell lung cancer (NSCLC) patients with 1 to 3 brain metastases. Because temozolomide (TMZ) and erlotinib (ETN) cross the blood-brain barrier and have documented activity in NSCLC, a phase 3 study was designed to test whether these drugs would improve the OS associated with WBRT + SRS. METHODS AND MATERIALS NSCLC patients with 1 to 3 brain metastases were randomized to receive WBRT (2.5 Gy × 15 to 37.5 Gy) and SRS alone, versus WBRT + SRS + TMZ (75 mg/m(2)/day × 21 days) or ETN (150 mg/day). ETN (150 mg/day) or TMZ (150-200 mg/m(2)/day × 5 days/month) could be continued for as long as 6 months after WBRT + SRS. The primary endpoint was OS. RESULTS After 126 patients were enrolled, the study closed because of accrual limitations. The median survival times (MST) for WBRT + SRS, WBRT + SRS + TMZ, and WBRT + SRS + ETN were qualitatively different (13.4, 6.3, and 6.1 months, respectively), although the differences were not statistically significant. Time to central nervous system progression and performance status at 6 months were better in the WBRT + SRS arm. Grade 3 to 5 toxicity was 11%, 41%, and 49% in arms 1, 2, and 3, respectively (P<.001). CONCLUSION The addition of TMZ or ETN to WBRT + SRS in NSCLC patients with 1 to 3 brain metastases did not improve survival and possibly had a deleterious effect. Because the analysis is underpowered, these data suggest but do not prove that increased toxicity was the cause of inferior survival in the drug arms.

Stereotactic radiosurgery: Principles and comparison of treatment methods

Methods of stereotactic radiosurgery are reviewed and compared with respect to technical factors and published clinical results. Heavy-ion beams, the Leksell cobalt-60 gamma knife, and the conventional linear accelerator (linac) are compared with respect to dosimetry, radiobiology, treatment planning, cost, staffing requirements, and ease of use. Clinical results on the efficacy of treatment of arteriovenous malformations are tabulated, and other applications of radiosurgery are described. It is concluded that although there are dosimetric and radiobiological advantages to charged-particle beams that may ultimately prove critical in the application of radiosurgery to large (> 30 mm) lesions, these advantages have not yet demonstrated clinical effect. On the other hand, equally excellent clinical results are obtained for small lesions with photon beams--the gamma knife and the linac. There are only minor differences between gamma and x-ray beam dose distributions for small, spherical-shaped targets. Mechanical precision is superior for the gamma knife as compared with the linac. The superior mechanical precision is of limited importance for most clinical targets, because inaccuracy of cranial target localization based on radiological imaging is greater than the typical linac imprecision of +/- 1 mm. Treatment planning for the linac is not standardized, but existing systems are based on well-known algorithms. The linac allows flexible, ready access to individualized beam control, without intrinsic field size limitations. Thus, it is more readily possible to achieve homogeneous dose distributions for nonspherical targets with one or more dimensions greater than 25 mm, as compared with that achieved with the gamma unit.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment planning for stereotactic radiosurgery of intra-cranial lesions

Stereotactic radiosurgery of intra-cranial lesions is a treatment modality where a well defined target volume receives a high radiation dose in a single treatment. Our technique delivers this dose using a set of non-coplanar arcs and small circular collimators. We use a standard linear accelerator in our treatments, and the adjustable treatment parameters are: isocenter location, gantry arc rotation interval, couch angle, collimator field size, and dose. The treatment planning phase of the treatment determines these parameters such that the target volume is sufficiently irradiated, and dose to surrounding healthy tissue and critical, dose-limiting structures is minimized. The attachment of a BRW localizing frame to the patients cranium combined with CT imaging (and optionally MRI or angiography) provides the required accuracy for localizing individual structures in the treatment volume. The treatment is fundamentally 3-dimensional and requires a volumetric assessment of the treatment plan. The selection of treatment arcs relies primarily on geometric constraints and the beams eye view concept to avoid irradiating critical structures. The assessment of a treatment plan involves isodose distributions throughout the volume and integral dose-volume histograms. We present the essential concepts of our treatment planning approach, and illustrate these in three clinical cases.

Stereotactic radiosurgery of the brain using a standard linear accelerator: a study of early and late effects

Between February 1986 and December 1988, 44 patients were treated with stereotactic radiosurgery using a standard linear accelerator. Twenty one patients were treated for cerebrovascular abnormalities and 23 patients were treated for intracranial tumors. Fifteen of the 23 patients treated for intracranial tumors had received previous radiotherapy. The range of doses given by radiosurgery was 1000-2500 cGy. Nausea and vomiting occurred in seven patients within six hours of treatment. The incidence and symptoms were correlated with the dose of radiation to the vomiting center (area postrema) with the median dose to the postrema in symptomatic patients being 618 cGy compared to a range of less than 5 to 184 cGy in the remaining 36 asymptomatic patients. Temporary alopecia occurred in a single patient who received 400 cGy to the scalp. Alopecia did not occur in the remaining 43 patients who received from less than 5 to 175 cGy. Two patients treated for arteriovenous malformations developed an enhancing lesion on CT scanning (one with cerebral edema) on follow-up CT scanning six and twenty-eight months following radiosurgery. The location of these enhancing lesions corresponded to the volumes treated. In one patient, the enhancing pattern and edema disappeared within 18 months of treatment and no neurological deficits developed. Aphasia occurred in one patient treated for a recurrent glioma two hours following treatment to the left temporal lobe and cleared within 12 h of radiosurgery. One patient with an arteriovenous malformation of the pons developed weakness of the contralateral arm and leg six weeks following treatment and this has slowly resolved over the last 12 months. In conclusion, the complications to date have been self-limited and appear to be directly related to the dose and area of brain treated. Prior radiation therapy has not been associated with increased risk of complication in patients treated with radiosurgery for recurrent tumors to date.

Predisposition to atypical teratoid/rhabdoid tumor due to an inherited INI1 mutation.

Germline mutations of the INI1 gene predispose children to the development of rhabdoid tumors. Reports of familial cases, however, are extremely rare.

Institutional Enrollment and Survival among NSCLC Patients Receiving Chemoradiation: NRG Oncology Radiation Therapy Oncology Group (RTOG) 0617

BACKGROUND The purpose of this analysis is to evaluate the effect of institutional accrual volume on clinical outcomes among patients receiving chemoradiation for locally advanced non-small cell lung cancer (LA-NSCLC) on a phase III trial. METHODS Patients with LA-NSCLC were randomly assigned to 60 Gy or 74 Gy radiotherapy (RT) with concurrent carboplatin/paclitaxel +/- cetuximab on NRG Oncology RTOG 0617. Participating institutions were categorized as low-volume centers (LVCs) or high-volume centers (HVCs) according to the number of patients accrued (≤3 vs > 3). All statistical tests were two-sided. RESULTS Range of accrual for LVCs (n = 195) vs HVCs (n = 300) was 1 to 3 vs 4 to 18 patients. Baseline characteristics were similar between the two cohorts. Treatment at a HVC was associated with statistically significantly longer overall survival (OS) and progression-free survival (PFS) compared with treatment at a LVC (median OS = 26.2 vs 19.8 months; HR = 0.70, 95% CI = 0.56 to 0.88, P = .002; median PFS: 11.4 vs 9.7 months, HR = 0.80, 95% CI = 0.65-0.99, P = .04). Patients treated at HVCs were more often treated with intensity-modulated RT (54.0% vs 39.5%, P = .002), had a lower esophageal dose (mean = 26.1 vs 28.0 Gy, P = .03), and had a lower heart dose (median = V5 Gy 38.2% vs 54.1%, P = .006; V50 Gy 3.6% vs 7.3%, P < .001). Grade 5 adverse events (AEs) (5.3% vs 9.2%, P = .09) and RT termination because of AEs (1.3% vs 4.1%, P = .07) were less common among patients treated at HVCs. HVC remained independently associated with longer OS (P = .03) when accounting for other factors. CONCLUSION Treatment at institutions with higher clinical trial accrual volume is associated with longer OS among patients with LA-NSCLC participating in a phase III trial.

Consolidative Radiotherapy for Limited Metastatic Non–Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial

Importance Patterns-of-failure studies suggest that in metastatic non–small-cell lung cancer (NSCLC) sites of gross disease at presentation are the first to progress when treated with chemotherapy. This knowledge has led to increased adoption of local ablative radiation therapy in patients with stage IV NSCLC, though prospective randomized evidence is limited. Objective To determine if intervening with noninvasive stereotactic ablative radiotherapy (SAbR) prior to maintenance chemotherapy in patients with non–progressive limited metastatic NSCLC after induction therapy led to significant improvements in progression-free survival (PFS). Design, Setting, and Participants This is a single-institution randomized phase 2 study of maintenance chemotherapy alone vs SAbR followed by maintenance chemotherapy for patients with limited metastatic NSCLC (primary plus up to 5 metastatic sites) whose tumors did not possess EGFR-targetable or ALK-targetable mutations but did achieve a partial response or stable disease after induction chemotherapy. Interventions Maintenance chemotherapy or SAbR to all sites of gross disease (including SAbR or hypofractionated radiation to the primary) followed by maintenance chemotherapy. Main Outcomes and Measures The primary end point was PFS; secondary end points included toxic effects, local and distant tumor control, patterns of failure, and overall survival. Results A total of 29 patients (9 women and 20 men) were enrolled; 14 patients (median [range] age, 63.5 [51.0-78.0] years) were allocated to the SAbR-plus-maintenance chemotherapy arm, and 15 patients (median [range] age, 70.0 [51.0-79.0] years) were allocated to the maintenance chemotherapy–alone arm. The trial was stopped to accrual early after an interim analysis found a significant improvement in PFS in the SAbR-plus-maintenance chemotherapy arm of 9.7 months vs 3.5 months in the maintenance chemotherapy–alone arm (P = .01). Toxic effects were similar in both arms. There were no in-field failures with fewer overall recurrences in the SAbR arm while those patients receiving maintenance therapy alone had progression at existing sites of disease and distantly. Conclusions and Relevance Consolidative SAbR prior to maintenance chemotherapy appeared beneficial, nearly tripling PFS in patients with limited metastatic NSCLC compared with maintenance chemotherapy alone, with no difference in toxic effects. The irradiation prevented local failures in original disease, the most likely sites of first recurrence. Furthermore, PFS for patients with limited metastatic disease appeared similar to those patients with a greater metastatic burden, further arguing for the potential benefits of local therapy in limited metastatic settings. Trial Registration clinicaltrials.gov Identifier: NCT02045446

The Implementation of Ablative Hypofractionated Radiotherapy for Stereotactic Treatments in the Brain and Body: Observations on Efficacy and Toxicity in Clinical Practice

Radiosurgery has a long history dating back to the 1950s. Only in the last decade or so have advances in radiation delivery and visualization allowed export of this paradigm to extracranial sites. This review evaluates the efficacy and safety of such ablative radiation courses using dose per fraction schedules of 10 Gy or above. Retrospective published experience in functional and benign tumor radiosurgery is reviewed. Prospective controlled clinical trials in ablative cancer therapy of early-stage lung cancer and metastatic disease in the brain, liver, and spine are reviewed.