Faculty Bibliography

Purpose Stereotactic radiosurgery (SRS), whole-brain radiotherapy (WBRT), and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are treatment options for brain metastases in patients with EGFR-mutant non-small-cell lung cancer (NSCLC). This multi-institutional analysis sought to determine the optimal management of patients with EGFR-mutant NSCLC who develop brain metastases and have not received EGFR-TKI. Materials and Methods A total of 351 patients from six institutions with EGFR-mutant NSCLC developed brain metastases and met inclusion criteria for the study. Exclusion criteria included prior EGFR-TKI use, EGFR-TKI resistance mutation, failure to receive EGFR-TKI after WBRT/SRS, or insufficient follow-up. Patients were treated with SRS followed by EGFR-TKI, WBRT followed by EGFR-TKI, or EGFR-TKI followed by SRS or WBRT at intracranial progression. Overall survival (OS) and intracranial progression-free survival were measured from the date of brain metastases. Results The median OS for the SRS (n = 100), WBRT (n = 120), and EGFR-TKI (n = 131) cohorts was 46, 30, and 25 months, respectively ( P < .001). On multivariable analysis, SRS versus EGFR-TKI, WBRT versus EGFR-TKI, age, performance status, EGFR exon 19 mutation, and absence of extracranial metastases were associated with improved OS. Although the SRS and EGFR-TKI cohorts shared similar prognostic features, the WBRT cohort was more likely to have a less favorable prognosis ( P = .001). Conclusion This multi-institutional analysis demonstrated that the use of upfront EGFR-TKI, and deferral of radiotherapy, is associated with inferior OS in patients with EGFR-mutant NSCLC who develop brain metastases. SRS followed by EGFR-TKI resulted in the longest OS and allowed patients to avoid the potential neurocognitive sequelae of WBRT. A prospective, multi-institutional randomized trial of SRS followed by EGFR-TKI versus EGFR-TKI followed by SRS at intracranial progression is urgently needed.

BACKGROUND AND PURPOSE:We examined acute toxicity profiles and outcomes among rectal cancer patients treated with pre-operative chemoradiation using intensity modulated radiotherapy (IMRT) or 3-dimensional conformal radiotherapy (3DCRT) to identify predictive clinical factors associated with increased acute toxicity. MATERIAL AND METHODS:We retrospectively reviewed records of 301 consecutive rectal cancer patients treated with pre-operative chemotherapy and radiotherapy (median dose 5000cGy) at our institution between 2007 and 2014. RESULTS:Of the 301 patients, 203 (67.4%) were treated with IMRT and 98 (32.6%) with 3DCRT. Significantly more patients experienced ⩾grade 2 diarrhea in the 3DCRT group compared to the IMRT group (22% vs 10%, p=0.004), and those who received 3DCRT had 2.7 times greater odds of a higher diarrhea score than those on IMRT, even after adjusting for patient characteristics and chemotherapy (OR 2.71, p=0.01) Fewer patients experienced grade 2 genitourinary toxicity in the IMRT group (6% vs 13% 3DCRT, p=0.04) and there was a trend toward decreased grade 2 proctitis in the IMRT group (22% vs 32% 3DCRT, p=0.07). Patients over the age of 55 had 45% lower odds of proctitis than patients younger than 55. CONCLUSION:The use of IMRT significantly reduced grade ⩾2 diarrhea and GU toxicity during chemoradiation. Younger patients were more likely to report grade 2 or higher proctitis.

PURPOSE:Lung cancer remains the most common cause of both cancer mortality and brain metastases (BM). The purpose of this study was to assess the effect of gene alterations and tyrosine kinase inhibition (TKI) on median survival (MS) and cause of death (CoD) in patients with BM from lung adenocarcinoma (L-adeno). METHODS:A multi-institutional retrospective database of patients with L-adeno and newly diagnosed BM between 2006 and 2014 was created. Demographics, gene alterations, treatment, MS, and CoD were analyzed. The treatment patterns and outcomes were compared with those in prior trials. RESULTS:Of 1521 L-adeno patients, 816 (54%) had known alteration status. The gene alteration rates were 29%, 10%, and 26% for EGFR, ALK, and KRAS, respectively. The time from primary diagnosis to BM for EGFR-/+ was 10/15 months (P=.02) and for ALK-/+ was 10/20 months (P<.01), respectively. The MS for the group overall (n=1521) was 15 months. The MS from first treatment for BM for EGFR and ALK-, EGFR+, ALK+ were 14, 23 (P<.01), and 45 (P<.0001) months, respectively. The MS after BM for EGFR+ patients who did/did not receive TKI before BM was 17/30 months (P<.01), respectively, but the risk of death was not statistically different between TKI-naïve patients who did/did not receive TKI after the diagnosis of BM (EGFR/ALK hazard ratios: 1.06 [P=.84]/1.60 [P=.45], respectively). The CoD was nonneurologic in 82% of patients with known CoD. CONCLUSION:EGFR and ALK gene alterations are associated with delayed onset of BM and longer MS relative to patients without these alterations. The CoD was overwhelmingly nonneurologic in patients with known CoD.

BACKGROUND:The aim of this study was to assess the effectiveness of fluorine-18 fluorodeoxyglucose (FDG) PET-CT and dynamic contrast-enhanced (DCE) MRI in differentiating tumor progression and radiation injury in patients with indeterminate enhancing lesions after radiation therapy (RT) for brain malignancies. METHODS:Patients with indeterminate enhancing brain lesions on conventional MRI after RT underwent brain DCE-MRI and PET-CT in a prospective trial. Informed consent was obtained. Lesion outcomes were determined by histopathology and/or clinical and imaging follow-up. Metrics obtained included plasma volume (Vp) and volume transfer coefficient (K(trans)) from DCE-MRI, and maximum standardized uptake value (SUVmax) from PET-CT; lesion-to-normal brain ratios of all metrics were calculated. The Wilcoxon rank sum test and receiver operating characteristic analysis were performed. RESULTS:The study included 53 patients (29 treated for 29 gliomas and 24 treated for 26 brain metastases). Progression was determined in 38/55 (69%) indeterminate lesions and radiation injury in 17 (31%). Vpratio (VP lesion/VP normal brain, P < .001), K(trans) ratio (P = .002), and SUVratio (P = .002) correlated significantly with diagnosis of progression versus radiation injury. Progressing lesions exhibited higher values of all 3 metrics compared with radiation injury. Vpratio had the highest accuracy in determining progression (area under the curve = 0.87), with 92% sensitivity and 77% specificity using the optimal, retrospectively determined threshold of 2.1. When Vpratio was combined with K(trans) ratio (optimal threshold 3.6), accuracy increased to 94%. CONCLUSIONS:Vpratio was the most effective metric for distinguishing progression from radiation injury. Adding K(trans) ratio to Vpratio further improved accuracy. DCE-MRI is an effective imaging technique for evaluating nonspecific enhancing intracranial lesions after RT.

The most effective treatment approach for brain metastases in patients with non-small cell lung cancer (NSCLC) and activating epidermal growth factor receptor (EGFR) mutations is a current subject of investigation. Cranial irradiation is the standard treatment for brain metastases, but tyrosine kinase inhibitors (TKIs) such as erlotinib have also activity against brain metastases in this subset of patients. The combination of TKI and radiotherapy is a promising one, but data is lacking to indicate whether this is superior to erlotinib or whole brain radiation therapy (WBRT) alone. Retrospective data suggest that WBRT achieves more durable intracranial control compared to erlotinib alone. Randomized, prospective studies will be necessary to determine whether TKI, cranial irradiation, or both is the optimal initial treatment for brain metastases in EGFR-mutant NSCLC.

BACKGROUND:The relative contribution of biologic subtype to locoregional recurrence (LRR) in patients treated with neoadjuvant chemotherapy (NAC), mastectomy, and postmastectomy radiotherapy (PMRT) is not clearly defined. METHODS:233 patients with stages 2 and 3 breast cancer who received NAC, mastectomy, and PMRT between 2000 and 2009 were included: 53 % (n = 123) had HR+ (ER or PR+/HER2-), 23 % (n = 53) had HER2+ (HER2+/HR+ or HR-), and 24 % (n = 57) had triple-negative (TN) disease (HR-/HER2-). The 5-year LRR rates were estimated by Kaplan-Meier methods. Cox regression analysis was performed to evaluate covariates associated with LRR. RESULTS:The median follow-up period was 62 months. A pathologic complete response (pCR) was seen in 14 % of the patients. The 5-year LRR rate was 8 % for the entire cohort. The LRR rate was 0 % for the patients with a pCR versus 9 % for the patients without a pCR (p = 0.05). TN disease [Hazard ratio (HR) 4.4; p = 0.003] and pathologic node positivity (HR 9.8; p = 0.03) were associated with LRR. Patients with TN disease had a higher LRR rate than patients with HER2+ or HR+ disease (20 vs. 6 and 4 %; p = 0.005). Among patients without a pCR, TN subtype was associated with increased LRR risk (26 versus 7 % HER+ and 4 % HR+; p < 0.001). CONCLUSIONS:Patients with TN breast cancer had the highest LRR rate after NAC, mastectomy and PMRT. Whereas no LRR was observed among TN patients with a pCR, TN patients with residual disease had a significantly higher LRR risk. Patients with HR+ and HER2+ breast cancer had favorable LRR rates regardless of NAC response, likely due to receipt of adjuvant systemic targeted therapies.

Radionecrosis is a well-characterized effect of stereotactic radiosurgery (SRS) and is occasionally associated with serious neurologic sequelae. Here, we investigated the incidence of and clinical variables associated with the development of radionecrosis and related radiographic changes after SRS for brain metastases in a cohort of patients with long-term follow up. 271 brain metastases treated with single-fraction linear accelerator-based SRS were analyzed. Radionecrosis was diagnosed either pathologically or radiographically. Univariate and multivariate Cox regression was performed to determine the association between radionecrosis and clinical factors available prior to treatment planning. After median follow up of 17.2 months, radionecrosis was observed in 70 (25.8%) lesions, including 47 (17.3%) symptomatic cases. 22 of 70 cases (31.4%) were diagnosed pathologically and 48 (68.6%) were diagnosed radiographically. The actuarial incidence of radionecrosis was 5.2% at 6 months, 17.2% at 12 months and 34.0% at 24 months. On univariate analysis, radionecrosis was associated with maximum tumor diameter (HR 3.55, p < 0.001), prior whole brain radiotherapy (HR 2.21, p = 0.004), prescription dose (HR 0.56, p = 0.02) and histology other than non-small cell lung, breast or melanoma (HR 1.85, p = 0.04). On multivariate analysis, only maximum tumor diameter (HR 3.10, p < 0.001) was associated with radionecrosis risk. This data demonstrates that with close imaging follow-up, radionecrosis after single-fraction SRS for brain metastases is not uncommon. Maximum tumor diameter on pre-treatment MR imaging can provide a reliable estimate of radionecrosis risk prior to treatment planning, with the greatest risk among tumors measuring >1 cm.

PURPOSE/OBJECTIVE:Although vaginal stenosis (VS) is a recognized toxicity in women who receive pelvic radiation therapy (RT), the relationship between RT dose and the volume and extent of toxicity has not been analyzed. We modeled this relationship to identify predictors of VS. METHODS AND MATERIALS/METHODS:We evaluated 54 women, aged 29 to 78 years, who underwent pelvic RT for rectal or anal cancer during 2008 to 2011 and were enrolled in a prospective study evaluating vaginal dilator use. Maximum dilator size was measured before RT (baseline) and 1 month and 12 months after RT. Dilator use was initiated at 1 month. The difference (D) in dilator size before and after RT was recorded. Those with D ≤-1 were classified as having VS (n=35); those with D ≥0 were classified as having no VS (n=19 at 1 month). Dose-volume parameters were extracted, and the generalized equivalent uniform dose (gEUD) was used to build a predictive model. RESULTS:The mean vaginal doses were 50.0 Gy and 36.8 Gy for anal and rectal cancer patients, respectively. One month after RT, a gEUD model using a wide range of a values suggests that sparing of vaginal volume to a low dose may be important. When gEUD (a = -1) was <35 Gy and the mean vaginal dose was <43 Gy, severe VS was reduced (P=.02). A 1-year analysis suggests increasingly negative D values with increasing mean dose. However, patients with compliance <40% were more likely to have toxicity. CONCLUSIONS:Vaginal stenosis is influenced by multiple RT dose-volume characteristics. Mean dose and gEUD constraints together may reduce the risk of severe VS. Patients receiving higher mean vaginal doses should have greater compliance with dilator therapy to minimize risk of toxicity. Further validation with independent datasets is needed.

To provide a comprehensive assessment of patient setup accuracy in 6 degrees of freedom (DOFs) using 2-dimensional/3-dimensional (2D/3D) image registration with on-board 2-dimensional kilovoltage (OB-2 DkV) radiographic images, we evaluated cranial, head and neck (HN), and thoracic and abdominal sites under clinical conditions. A fast 2D/3D image registration method using graphics processing unit GPU was modified for registration between OB-2 DkV and 3D simulation computed tomography (simCT) images, with 3D/3D registration as the gold standard for 6 DOF alignment. In 2D/3D registration, body roll rotation was obtained solely by matching orthogonal OB-2 DkV images with a series of digitally reconstructed radiographs (DRRs) from simCT with a small rotational increment along the gantry rotation axis. The window/level adjustments for optimal visualization of the bone in OB-2 DkV and DRRs were performed prior to registration. Ideal patient alignment at the isocenter was calculated and used as an initial registration position. In 3D/3D registration, cone-beam CT (CBCT) was aligned to simCT on bony structures using a bone density filter in 6DOF. Included in this retrospective study were 37 patients treated in 55 fractions with frameless stereotactic radiosurgery or stereotactic body radiotherapy for cranial and paraspinal cancer. A cranial phantom was used to serve as a control. In all cases, CBCT images were acquired for patient setup with subsequent OB-2 DkV verification. It was found that the accuracy of the 2D/3D registration was 0.0 ± 0.5 mm and 0.1° ± 0.4° in phantom. In patient, it is site dependent due to deformation of the anatomy: 0.2 ± 1.6 mm and -0.4° ± 1.2° on average for each dimension for the cranial site, 0.7 ± 1.6 mm and 0.3° ± 1.3° for HN, 0.7 ± 2.0 mm and -0.7° ± 1.1° for the thorax, and 1.1 ± 2.6 mm and -0.5° ± 1.9° for the abdomen. Anatomical deformation and presence of soft tissue in 2D/3D registration affect the consistency with 3D/3D registration in 6 DOF: the discrepancy increases in superior to inferior direction.