Banu Atalar

Risk of Leptomeningeal Disease in Patients Treated With Stereotactic Radiosurgery Targeting the Postoperative Resection Cavity for Brain Metastases

PURPOSE We sought to determine the risk of leptomeningeal disease (LMD) in patients treated with stereotactic radiosurgery (SRS) targeting the postsurgical resection cavity of a brain metastasis, deferring whole-brain radiation therapy (WBRT) in all patients. METHODS AND MATERIALS We retrospectively reviewed 175 brain metastasis resection cavities in 165 patients treated from 1998 to 2011 with postoperative SRS. The cumulative incidence rates, with death as a competing risk, of LMD, local failure (LF), and distant brain parenchymal failure (DF) were estimated. Variables associated with LMD were evaluated, including LF, DF, posterior fossa location, resection type (en-bloc vs piecemeal or unknown), and histology (lung, colon, breast, melanoma, gynecologic, other). RESULTS With a median follow-up of 12 months (range, 1-157 months), median overall survival was 17 months. Twenty-one of 165 patients (13%) developed LMD at a median of 5 months (range, 2-33 months) following SRS. The 1-year cumulative incidence rates, with death as a competing risk, were 10% (95% confidence interval [CI], 6%-15%) for developing LF, 54% (95% CI, 46%-61%) for DF, and 11% (95% CI, 7%-17%) for LMD. On univariate analysis, only breast cancer histology (hazard ratio, 2.96) was associated with an increased risk of LMD. The 1-year cumulative incidence of LMD was 24% (95% CI, 9%-41%) for breast cancer compared to 9% (95% CI, 5%-14%) for non-breast histology (P=.004). CONCLUSIONS In patients treated with SRS targeting the postoperative cavity following resection, those with breast cancer histology were at higher risk of LMD. It is unknown whether the inclusion of whole-brain irradiation or novel strategies such as preresection SRS would improve this risk or if the rate of LMD is inherently higher with breast histology.

What is the optimal treatment of large brain metastases? An argument for a multidisciplinary approach.

PURPOSE Single-modality treatment of large brain metastases (>2 cm) with whole-brain irradiation, stereotactic radiosurgery (SRS) alone, or surgery alone is not effective, with local failure (LF) rates of 50% to 90%. Our goal was to improve local control (LC) by using multimodality therapy of surgery and adjuvant SRS targeting the resection cavity. PATIENTS AND METHODS We retrospectively evaluated 97 patients with brain metastases >2 cm in diameter treated with surgery and cavity SRS. Local and distant brain failure (DF) rates were analyzed with competing risk analysis, with death as a competing risk. The overall survival rate was calculated by the Kaplain-Meier product-limit method. RESULTS The median imaging follow-up duration for all patients was 10 months (range, 1-80 months). The 12-month cumulative incidence rates of LF, with death as a competing risk, were 9.3% (95% confidence interval [CI], 4.5%-16.1%), and the median time to LF was 6 months (range, 3-17 months). The 12-month cumulative incidence rate of DF, with death as a competing risk, was 53% (95% CI, 43%-63%). The median survival time for all patients was 15.6 months. The median survival times for recursive partitioning analysis classes 1, 2, and 3 were 33.8, 13.7, and 9.0 months, respectively (p = 0.022). On multivariate analysis, Karnofsky Performance Status (≥80 vs. <80; hazard ratio 0.54; 95% CI 0.31-0.94; p = 0.029) and maximum preoperative tumor diameter (hazard ratio 1.41; 95% CI 1.08-1.85; p = 0.013) were associated with survival. Five patients (5%) required intervention for Common Terminology Criteria for Adverse Events v4.02 grade 2 and 3 toxicity. CONCLUSION Surgery and adjuvant resection cavity SRS yields excellent LC of large brain metastases. Compared with other multimodality treatment options, this approach allows patients to avoid or delay whole-brain irradiation without compromising LC.

Cavity volume dynamics after resection of brain metastases and timing of postresection cavity stereotactic radiosurgery.

BACKGROUND An alternative treatment option to whole-brain irradiation after surgical resection of brain metastases is resection cavity stereotactic radiosurgery (SRS). OBJECTIVE To review the dynamics of cavity volume change after surgical resection with the goal of determining the optimal timing for cavity SRS. METHODS Preresection tumor, postresection/pre-SRS cavity, and post-SRS cavity volumes were measured for 68 cavities in 63 patients treated with surgery and postresection cavity SRS. Percent differences between volumes were calculated and correlation analyses were performed to assess volume changes before and after SRS. RESULTS For the majority of tumors, the postresection cavity volume was smaller than the preresection tumor volume by a median percent volume change of -29% (range, -82% to 1258%), with larger preresection tumors resulting in greater cavity shrinkage (P < .001). To determine the optimal timing for cavity SRS, we examined cavity volume dynamics by comparing the early postresection (postoperative days 0-3) and treatment planning magnetic resonance imaging scans (median time to magnetic resonance imaging, 20 days; range, 9-33 days) and found no association between the postresection day number and volume change (P = .75). The volume decrease resulting from tumor resection was offset by the addition of a 2-mm clinical target volume margin, which is our current technique. CONCLUSION The greatest volume change occurs immediately after surgery (postoperative days 0-3) with no statistically significant volume change occurring up to 33 days after surgery for most patients. Therefore, there is no benefit of cavity shrinkage in waiting longer than the first 1 to 2 weeks to perform cavity SRS.

Dose-Response Modeling of the Visual Pathway Tolerance to Single-Fraction and Hypofractionated Stereotactic Radiosurgery☆☆☆

Patients with tumors adjacent to the optic nerves and chiasm are frequently not candidates for single-fraction stereotactic radiosurgery (SRS) due to concern for radiation-induced optic neuropathy. However, these patients have been successfully treated with hypofractionated SRS over 2-5 days, though dose constraints have not yet been well defined. We reviewed the literature on optic tolerance to radiation and constructed a dose-response model for visual pathway tolerance to SRS delivered in 1-5 fractions. We analyzed optic nerve and chiasm dose-volume histogram (DVH) data from perioptic tumors, defined as those within 3mm of the optic nerves or chiasm, treated with SRS from 2000-2013 at our institution. Tumors with subsequent local progression were excluded from the primary analysis of vision outcome. A total of 262 evaluable cases (26 with malignant and 236 with benign tumors) with visual field and clinical outcomes were analyzed. Median patient follow-up was 37 months (range: 2-142 months). The median number of fractions was 3 (1 fraction n = 47, 2 fraction n = 28, 3 fraction n = 111, 4 fraction n = 10, and 5 fraction n = 66); doses were converted to 3-fraction equivalent doses with the linear quadratic model using α/β = 2Gy prior to modeling. Optic structure dose parameters analyzed included Dmin, Dmedian, Dmean, Dmax, V30Gy, V25Gy, V20Gy, V15Gy, V10Gy, V5Gy, D50%, D10%, D5%, D1%, D1cc, D0.50cc, D0.25cc, D0.20cc, D0.10cc, D0.05cc, D0.03cc. From the plan DVHs, a maximum-likelihood parameter fitting of the probit dose-response model was performed using DVH Evaluator software. The 68% CIs, corresponding to one standard deviation, were calculated using the profile likelihood method. Of the 262 analyzed, 2 (0.8%) patients experienced common terminology criteria for adverse events grade 4 vision loss in one eye, defined as vision of 20/200 or worse in the affected eye. One of these patients had received 2 previous courses of radiotherapy to the optic structures. Both cases were meningiomas treated with 25Gy in 5 fractions, with a 3-fraction equivalent optic nerve Dmax of 19.2 and 22.2Gy. Fitting these data to a probit dose-response model enabled risk estimates to be made for these previously unvalidated optic pathway constraints: the Dmax limits of 12Gy in 1 fraction from QUANTEC, 19.5Gy in 3 fractions from Timmerman 2008, and 25Gy in 5 fractions from AAPM Task Group 101 all had less than 1% risk. In 262 patients with perioptic tumors treated with SRS, we found a risk of optic complications of less than 1%. These data support previously unvalidated estimates as safe guidelines, which may in fact underestimate the tolerance of the optic structures, particularly in patients without prior radiation. Further investigation would refine the estimated normal tissue complication probability for SRS near the optic apparatus.

Use of volumetric modulated arc radiotherapy in patients with early stage glottic cancer.

AIMS AND BACKGROUND We compared conformal, intensity-modulated radiotherapy (IMRT) and intensity-modulated arc therapy (IMAT) in early stage glottic cancer in terms of dosimetric features as target coverage, dose to the organs at risk and total treatment time. METHODS AND MATERIALS Five consecutive T1 glottic squamous cell carcinoma patients were selected for the study. Three-dimensional conformal radiotherapy (3D-CRT), 3-field or 5-field intensity-modulated radiotherapy (3F-IMRT and 5F-IMRT), or IMAT, which was in 2 different forms--a regular IMAT (R-IMAT) and an alternative IMAT (A-IMAT) with an unirradiated section, was planned for each patient. The prescribed dose was 63 Gy in 28 fractions. The minimum dose for 95% of the clinical target volume (D95), maximum dose point at clinical target volume (Dmax), total monitor units, left and right carotid artery doses (V35 and V50 - percentage of volume receiving 35 Gy and 50 Gy), and total treatment time were calculated for each plan. RESULTS Median D95 values in the 5 plans studied with each technique ranged between 63 and 63.3 Gy (P = NS). Median Dmax values for each technique ranged between 65.4 and 70.8 Gy. The number of hot spots with IMRT and IMAT was significantly higher than with 3D-CRT plans. Conformal radiotherapy plans median V35 (93.6%) and V50 (76.6-83.3%) values for carotid arteries were significantly higher than with IMRT and IMAT (2.9%-11.4% and 0.0%). Average treatment times for 3D-CRT, 3F-IMRT, 5F-IMRT, R-IMAT and A-IMAT techniques were calculated as 64, 119, 147, 39 and 32 seconds, respectively. CONCLUSIONS IMAT has significantly decreased the treatment time compared to IMRT and 3D-CRT with acceptable homogeneous clinical target volume coverage and low carotid dose.

Intensity modulated radiotherapy (IMRT) in bilateral retinoblastoma

Intensity modulated radiotherapy (IMRT) in bilateral retinoblastoma Background. External beam radiotherapy (EBRT) for retinoblastoma has traditionally been done with conventional radiotherapy techniques which resulted high doses to the surrounding normal tissues. Case report. A 20 month-old girl with group D bilateral retinoblastoma underwent intensity modulated radiotherapy (IMRT) to both eyes after failing chemoreduction and focal therapies including cryotherapy and transpupillary thermotherapy. In this report, we discuss the use of IMRT as a method for reducing doses to adjacent normal tissues while delivering therapeutic doses to the tumour tissues compared with 3-dimensional conformal radiotherapy (3DCRT). At one year follow-up, the patient remained free of any obvious radiation complications. Conclusions. Image guided IMRT provides better dose distribution than 3DCRT in retinoblastoma eyes, delivering the therapeutic dose to the tumours and minimizing adjacent tissue damage.

The Rare Cancer Network: ongoing studies and future strategy

The Rare Cancer Network (RCN) was formed in the early 1990’s to create a global network that could pool knowledge and resources in the studies of rare malignancies whose infrequency prevented both their study with prospective clinical trials. To date, the RCN has initiated 74 studies resulting in 46 peer reviewed publications. The First International Symposium of the Rare Cancer Network took place in Nice in March of 2014. Status updates and proposals for new studies were heard for fifteen topics. Ongoing studies continue for cardiac sarcomas, thyroid cancers, glomus tumors, and adult medulloblastomas. New proposals were presented at the symposium for primary hepatic lymphoma, solitary fibrous tumors, Rosai-Dorfman disease, tumors of the ampulla of Vater, salivary gland tumors, anorectal melanoma, midline nuclear protein in testes carcinoma, pulmonary lymphoepithelioma-like carcinoma, adenoid cystic carcinoma of the trachea, osteosarcomas of the mandible, and extra-cranial hemangiopericytoma. This manuscript presents the abstracts of those proposals and updates on ongoing studies, as well a brief summary of the vision and future of the RCN.

In regard to Zhou et al "Baseline serum lactate dehydrogenase levels for patients treated with intensity-modulated radiotherapy for nasopharyngeal carcinoma: a predictor of poor prognosis and subsequent liver metastasis" (Int J Radiat Oncol Biol Phys 2012;82:e359-e365).

damage (8). Interestingly, the authors reported a toxicity profile for the patients treated with 50 Gy that is more compatible with the results presented by other teams referenced in this article. The important message provided by the authors is that too-high prescription and skin doses and large-volume implants lead to poor long-term cosmetic results after APBI using IB. However, using adequate technique, treatment planning, dose prescription, and total dose, IB is a safe modality to provide APBI to selected patients (9).

Treatment outcome and prognostic factors for adult patients with medulloblastoma: The Rare Cancer Network (RCN) experience

BACKGROUND AND PURPOSE The optimal treatment for adults with newly diagnosed medulloblastoma (MB) has not been defined. We report a large series of cases from the Rare Cancer Network. MATERIAL AND METHODS Thirteen institutions enrolled 206 MB patients who underwent postoperative radiotherapy (RT) between 1976 and 2014. Log-rank univariate and Cox-modeled multivariate analyses were used to analyze data collected. RESULTS Median patient age was 29 years; follow-up was 31 months. All patients had the tumor resected; surgery was complete in 140 (68%) patients. Postoperative RT was given in 202 (98%) patients, and 94% received craniospinal irradiation (CSI) and, usually, a posterior fossa boost. Ninety-eight (48%) patients had chemotherapy, mostly cisplatin and vincristine-based. The 10-year local control, overall survival, and disease-free survival rates were 46%, 51%, and 38%, respectively. In multivariate analyses, Karnofsky Performance Status (KPS) ≥80 and CSI were significant for disease-free and overall survival (P ≤ .04 for all); receiving chemotherapy and KPS ≥80 correlated with better local-control rates. CONCLUSIONS Patients with high KPS who received CSI had better rates of disease-free and overall survival. Chemotherapy was associated with better local control. These results may serve as a benchmark for future studies designed to improve outcomes for adults with medulloblastoma.

Improvement of conformal arc plans by using deformable margin delineation method for stereotactic lung radiotherapy

Abstract Purpose Stereotactic body radiotherapy (SBRT) is an established treatment technique in the management of medically inoperable early stage non–small cell lung cancer (NSCLC). Different techniques such as volumetric modulated arc (VMAT) and three‐dimensional conformal arc (DCA) can be used in SBRT. Previously, it has been shown that VMAT is superior to DCA technique in terms of plan evaluation parameters. However, DCA technique has several advantages such as ease of use and considerable shortening of the treatment time. DCA technique usually results in worse conformity which is not possible to ameliorate by inverse optimization. In this study, we aimed to analyze whether a simple method – deformable margin delineation (DMD) – improves the quality of the DCA technique, reaching similar results to VMAT in terms of plan evaluation parameters. Methods Twenty stage I–II (T1‐2, N0, M0) NSCLC patients were included in this retrospective dosimetric study. Noncoplanar VMAT and conventional DCA plans were generated using 6 MV and 10 MV with flattening filter free (FFF) photon energies. The DCA plan with 6FFF was calculated and 95% of the PTV was covered by the prescription isodose line. Hot dose regions (receiving dose over 100% of prescription dose) outside PTV and cold dose regions (receiving dose under 100% of prescription dose) inside PTV were identified. A new PTV (PTV‐DMD) was delineated by deforming PTV margin with respect to hot and cold spot regions obtained from conventional DCA plans. Dynamic multileaf collimators (MLC) were set to PTV‐DMD beam eye view (BEV) positions and the new DCA plans (DCA‐DMD) with 6FFF were generated. Three‐dimensional (3D) dose calculations were computed for PTV‐DMD volume. However, the prescription isodose was specified and normalized to cover 95% volume of original PTV. Several conformity indices and lung doses were compared for different treatment techniques. Results DCA‐DMD method significantly achieved a superior conformity index (CI), conformity number (CIP addick), gradient index (R50%), isodose at 2 cm (D2 cm) and external index (CΔ) with respect to VMAT and conventional DCA plans (P < 0.05 for all comparisons). CI ranged between 1.00–1.07 (Mean: 1.02); 1.00–1.18 (Mean: 1.06); 1.01–1.23 (Mean 1.08); 1.03–1.29 (Mean: 1.15); 1.04–1.29 (Mean: 1.18) for DCA‐DMD‐6FFF, VMAT‐6FFF, VMAT‐10FFF DCA‐6FFF and DCA‐10FFF respectively. DCA‐DMD‐6FFF technique resulted significantly better CI compared to others (P = 0.002; < 0.001; < 0.001; < 0.001). R50% ranged between 3.22–4.74 (Mean: 3.99); 3.24–5.92 (Mean: 4.15) for DCA‐DMD‐6FFF, VMAT‐6FFF, respectively. DCA‐DMD‐6FFF technique resulted lower intermediate dose spillage compared to VMAT‐6FFF, though the difference was statistically insignificant (P = 0.32). D2 cm ranged between 35.7% and 67.0% (Mean: 53.2%); 42.1%–79.2% (Mean: 57.8%) for DCA‐DMD‐6FFF, VMAT‐6FFF respectively. DCA‐DMD‐6FFF have significantly better and sharp falloff gradient 2 cm away from PTV compared to VMAT‐6FFF (P = 0.009). CΔ ranged between 0.052 and 0.140 (Mean: 0.085); 0,056–0,311 (Mean: 0.120) for DCA‐DMD, VMAT‐6FFF, respectively. DCA‐DMD‐6FFF have significantly improved CΔ (P = 0.002). VMAT‐ V20 Gy, V2.5 Gy and mean lung dose (MLD) indices are calculated to be 4.03%, 23.83%, 3.42 Gy and 4.19%, 27.88%,3.72 Gy, for DCA‐DMD‐6FFF and DCA techniques, respectively. DCA‐DMD‐6FFF achieved superior lung sparing compared to DCA technique. DCA‐DMD‐6FFF method reduced MUs 44% and 33% with respect to VMAT‐6FFF and 10FFF, respectively, without sacrificing dose conformity (P < 0.001; P < 0.001). Conclusions Our results demonstrated that DCA plan evaluation parameters can be ameliorated by using the DMD method. This new method improves DCA plan quality and reaches similar results with VMAT in terms of dosimetric parameters. We believe that DCA‐DMD is a simple and effective technique for SBRT and can be preferred due to shorter treatment and planning time.