Robotic stereotactic body radiotherapy for localized prostate cancer: final analysis of the German HYPOSTAT trial.

PURPOSE: We report results of the first German prospective multicenter single-arm phase II trial (ARO 2013-06; NCT02635256) of hypofractionated robotic stereotactic body radiotherapy (SBRT) for patients with localized prostate cancer (HYPOSTAT). METHODS: Patients eligible for the HYPOSTAT study had localized prostate cancer (cT1­3 cN0 cM0), Gleason score ≤ 7, prostate-specific antigen (PSA) ≤ 15 ng/ml, prostate volume ≤ 80 cm3, and an International Prostate Symptom Score (IPSS) ≤ 12. Initially, inclusion was limited to patients ≥ 75 years or patients 70-74 years with additional risk factors. The trial protocol was later amended to allow for enrolment of patients aged ≥ 60 years. The treatment consisted of 35 Gy delivered in 5 fractions to the prostate and for intermediate- or high-risk patients, also to the proximal seminal vesicles using the CyberKnife system (Accuray Inc., Sunnyvale, CA, USA). Primary endpoint was the rate of treatment-related gastrointestinal or genitourinary grade ≥ 2 toxicity based on the RTOG scale 12-15 months after treatment. Secondary endpoints were acute toxicity, late toxicity, urinary function, quality of life, and PSA response. RESULTS: From July 2016 through December 2018, 85 eligible patients were enrolled and received treatment, of whom 83 could be evaluated regarding the primary endpoint. Patients mostly had intermediate-risk disease with a median PSA value of 7.97 ng/ml and Gleason score of 7a and 7b in 43.5% and 25.9% of patients, respectively. At the final follow-up 12-15 months after treatment, no patient suffered from treatment-related gastrointestinal or genitourinary grade ≥ 2 toxicity. Acute toxicity was mostly mild, with three grade 3 events, and the cumulative rate of grade ≥ 2 genitourinary toxicity was 8.4% (95% CI 4.1-16.4%). There were no major changes in urinary function or quality of life. The median PSA value dropped to 1.18 ng/ml 12-15 months after treatment. There was one patient who developed distant metastases. CONCLUSION: Robotic SBRT with 35 Gy in 5 fractions was associated with a favorable short-term toxicity profile. Recruitment for the HYPOSTAT­2 trial (ARO-2018­4; NCT03795337), which further analyses the late toxicity of this regimen with a planned sample size of 500 patients, is ongoing.

Clinical Results of Mean GTV Dose Optimized Robotic-Guided Stereotactic Body Radiation Therapy for Lung Tumors.

INTRODUCTION: We retrospectively evaluated the efficacy and toxicity of gross tumor volume (GTV) mean dose optimized stereotactic body radiation therapy (SBRT) for primary and secondary lung tumors with and without robotic real-time motion compensation. MATERIALS AND METHODS: Between 2011 and 2017, 208 patients were treated with SBRT for 111 primary lung tumors and 163 lung metastases with a median GTV of 8.2 cc (0.3-174.0 cc). Monte Carlo dose optimization was performed prioritizing GTV mean dose at the potential cost of planning target volume (PTV) coverage reduction while adhering to safe normal tissue constraints. The median GTV mean biological effective dose (BED)10 was 162.0 Gy10 (34.2-253.6 Gy10) and the prescribed PTV BED10 ranged 23.6-151.2 Gy10 (median, 100.8 Gy10). Motion compensation was realized through direct tracking (44.9%), fiducial tracking (4.4%), and internal target volume (ITV) concepts with small (≤5 mm, 33.2%) or large (>5 mm, 17.5%) motion. The local control (LC), progression-free survival (PFS), overall survival (OS), and toxicity were analyzed. RESULTS: Median follow-up was 14.5 months (1-72 months). The 2-year actuarial LC, PFS, and OS rates were 93.1, 43.2, and 62.4%, and the median PFS and OS were 18.0 and 39.8 months, respectively. In univariate analysis, prior local irradiation (hazard ratio (HR) 0.18, confidence interval (CI) 0.05-0.63, p = 0.01), GTV/PTV (HR 1.01-1.02, CI 1.01-1.04, p < 0.02), and PTV prescription, mean GTV, and maximum plan BED10 (HR 0.97-0.99, CI 0.96-0.99, p < 0.01) were predictive for LC while the tracking method was not (p = 0.97). For PFS and OS, multivariate analysis showed Karnofsky Index (p < 0.01) and tumor stage (p ≤ 0.02) to be significant factors for outcome prediction. Late radiation pneumonitis or chronic rip fractures grade 1-2 were observed in 5.3% of the patients. Grade ≥3 side effects did not occur. CONCLUSION: Robotic SBRT is a safe and effective treatment for lung tumors. Reducing the PTV prescription and keeping high GTV mean doses allowed the reduction of toxicity while maintaining high local tumor control. The use of real-time motion compensation is strongly advised, however, well-performed ITV motion compensation may be used alternatively when direct tracking is not feasible.

Direct dose correlation of MRI morphologic alterations of healthy liver tissue after robotic liver SBRT.

PURPOSE: For assessing healthy liver reactions after robotic SBRT (stereotactic body radiotherapy), we investigated early morphologic alterations on MRI (magnetic resonance imaging) with respect to patient and treatment plan parameters. PATIENTS AND METHODS: MRI data at 6-17 weeks post-treatment from 22 patients with 42 liver metastases were analyzed retrospectively. Median prescription dose was 40 Gy delivered in 3-5 fractions. T2- and T1-weighted MRI were registered to the treatment plan. Absolute doses were converted to EQD2 (Equivalent dose in 2Gy fractions) with α/ß-ratios of 2 and 3 Gy for healthy, and 8 Gy for modelling pre-damaged liver tissue. RESULTS: Sharply defined, centroid-shaped morphologic alterations were observed outside the high-dose volume surrounding the GTV. On T2-w MRI, hyperintensity at EQD2 isodoses of 113.3 ± 66.1 Gy2, 97.5 ± 54.7 Gy3, and 66.5 ± 32.0 Gy8 significantly depended on PTV dimension (p = 0.02) and healthy liver EQD2 (p = 0.05). On T1-w non-contrast MRI, hypointensity at EQD2 isodoses of 113.3 ± 49.3 Gy2, 97.4 ± 41.0 Gy3, and 65.7 ± 24.2 Gy8 significantly depended on prior chemotherapy (p = 0.01) and total liver volume (p = 0.05). On T1-w gadolinium-contrast delayed MRI, hypointensity at EQD2 isodoses of 90.6 ± 42.5 Gy2, 79.3 ± 35.3 Gy3, and 56.6 ± 20.9 Gy8 significantly depended on total (p = 0.04) and healthy (p = 0.01) liver EQD2. CONCLUSIONS: Early post-treatment changes in healthy liver tissue after robotic SBRT could spatially be correlated to respective isodoses. Median nominal doses of 10.1-11.3 Gy per fraction (EQD2 79-97 Gy3) induce characteristic morphologic alterations surrounding the lesions, potentially allowing for dosimetric in-vivo accuracy assessments. Comparison to other techniques and investigations of the short- and long-term clinical impact require further research.

Breathing-motion-compensated robotic guided stereotactic body radiation therapy : Patterns of failure analysis.

PURPOSE: We retrospectively evaluated the patterns of failure for robotic guided real-time breathing-motion-compensated (BMC) stereotactic body radiation therapy (SBRT) in the treatment of tumors in moving organs. PATIENTS AND METHODS: Between 2011 and 2016, a total of 198 patients with 280 lung, liver, and abdominal tumors were treated with BMC-SBRT. The median gross tumor volume (GTV) was 12.3 cc (0.1-372.0 cc). Medians of mean GTV BEDα/ß =10 Gy (BED = biological effective dose) was 148.5 Gy10 (31.5-233.3 Gy10) and prescribed planning target volume (PTV) BEDα/ß =10 Gy was 89.7 Gy10 (28.8-151.2 Gy10), respectively. We analyzed overall survival (OS) and local control (LC) based on various factors, including BEDs with α/ß ratios of 15 Gy (lung metastases), 21 Gy (primary lung tumors), and 27 Gy (liver metastases). RESULTS: Median follow-up was 10.4 months (2.0-59.0 months). The 2­year actuarial LC was 100 and 86.4% for primary early and advanced stage lung tumors, respectively, 100% for lung metastases, 82.2% for liver metastases, and 90% for extrapulmonary extrahepatic metastases. The 2­year OS rate was 47.9% for all patients. In uni- and multivariate analysis, comparatively lower PTV prescription dose (equivalence of 3 × 12-13 Gy) and higher average GTV dose (equivalence of 3 × 18 Gy) to current practice were significantly associated with LC. For OS, Karnofsky performance score (100%), gender (female), and SBRT without simultaneous chemotherapy were significant prognostic factors. Grade 3 side effects were rare (0.5%). CONCLUSIONS: Robotic guided BMC-SBRT can be considered a safe and effective treatment for solid tumors in moving organs. To reach sufficient local control rates, high average GTV doses are necessary. Further prospective studies are warranted to evaluate these points.

Hypo-fractionated SBRT for localized prostate cancer: a German bi-center single treatment group feasibility trial.

BACKGROUND: For prostate cancer treatment, treatment options with minimal side effects are desired. External beam radiation therapy (EBRT) is non-invasive, standard of care and delivered in either conventional fractionation over 8 weeks or with moderate hypo-fractionation over about 5 weeks. Recent advances in radiotherapy technology have made extreme hypo-fractionated stereotactic body radiation therapy (SBRT) of prostate cancer feasible, which has not yet been introduced as a standard treatment method in Germany. Initial results from other countries are promising, but long-term results are not yet available. The aim of this study is to investigate feasibility and effectiveness of SBRT for prostate cancer in Germany. METHODS/DESIGN: This German bi-center single group trial (HYPOSTAT) is designed to evaluate feasibility and effectiveness, as measured by toxicity and PSA-response, respectively, of an extreme hypo-fractionated SBRT regimen with five fractions of 7 Gy in treatment of localized low and intermediate risk prostate cancer. The target volume includes the prostate with or without the base of seminal vesicles depending on risk stratification and uncertainty margins that are kept at 3-5 mm. SBRT treatment is delivered with the robotic CyberKnife system, which was recently introduced in Germany. Acute and late toxicity after one year will be evaluated according to Common Terminology Criteria for Adverse Events (CTCAE v. 4.0), Radiation Therapy Oncology Group (RTOG) and International Prostate Symptom Score (IPSS) Scores. The quality of life will be assessed before and after treatment with the EORTC QLQ C30 questionnaire. Hypothesizing that the proportion of patients with grade 2 side effects or higher is less or equal than 2.8%, thus markedly lower than the standard EBRT percentage (17.5%), the recruitment target is 85 patients. DISCUSSION: The HYPOSTAT trial aims at demonstrating short term feasibility of extreme hypo-fractioned SBRT for the treatment of prostate cancer and might be used as the pilot study for a multi-center multi-platform or for randomized-controlled trials comparing conventional radiotherapy with SBRT for localized prostate cancer in the future. The study concept of patient enrollment, follow up and evaluation by multiple public university clinics and actual patient treatment in dedicated private radiosurgery practices with high-tech radiation equipment is unique for clinical trials. STUDY STATUS: The study is ongoing and currently recruiting patients. TRIAL REGISTRATION: Registration number: NCT02635256 ( clinicaltrials.gov ). Registered 8 December 2015.

Dosimetric Implications of Residual Tracking Errors During Robotic SBRT of Liver Metastases.

PURPOSE: Although the metric precision of robotic stereotactic body radiation therapy in the presence of breathing motion is widely known, we investigated the dosimetric implications of breathing phase-related residual tracking errors. METHODS AND MATERIALS: In 24 patients (28 liver metastases) treated with the CyberKnife, we recorded the residual correlation, prediction, and rotational tracking errors from 90 fractions and binned them into 10 breathing phases. The average breathing phase errors were used to shift and rotate the clinical tumor volume (CTV) and planning target volume (PTV) for each phase to calculate a pseudo 4-dimensional error dose distribution for comparison with the original planned dose distribution. RESULTS: The median systematic directional correlation, prediction, and absolute aggregate rotation errors were 0.3 mm (range, 0.1-1.3 mm), 0.01 mm (range, 0.00-0.05 mm), and 1.5° (range, 0.4°-2.7°), respectively. Dosimetrically, 44%, 81%, and 92% of all voxels differed by less than 1%, 3%, and 5% of the planned local dose, respectively. The median coverage reduction for the PTV was 1.1% (range in coverage difference, -7.8% to +0.8%), significantly depending on correlation (P=.026) and rotational (P=.005) error. With a 3-mm PTV margin, the median coverage change for the CTV was 0.0% (range, -1.0% to +5.4%), not significantly depending on any investigated parameter. In 42% of patients, the 3-mm margin did not fully compensate for the residual tracking errors, resulting in a CTV coverage reduction of 0.1% to 1.0%. CONCLUSIONS: For liver tumors treated with robotic stereotactic body radiation therapy, a safety margin of 3 mm is not always sufficient to cover all residual tracking errors. Dosimetrically, this translates into only small CTV coverage reductions.

Clinical results of mean GTV dose optimized robotic guided SBRT for liver metastases.

BACKGROUND: We retrospectively evaluated the efficacy and toxicity of gross tumor volume (GTV) mean-dose-optimized and real-time motion-compensated robotic stereotactic body radiation therapy (SBRT) in the treatment of liver metastases. METHODS: Between March 2011 and July 2015, 52 patients were treated with SBRT for a total of 91 liver metastases (one to four metastases per patient) with a median GTV volume of 12 cc (min 1 cc, max 372 cc). The optimization of mean GTV dose was prioritized during treatment planning at the potential cost of planning target volume (PTV) coverage reduction while adhering to safe normal tissue constraints. The delivered median GTV biological effective dose (BED10) was 142.1 Gy10 (range, 60.2 Gy10 -165.3 Gy10) and the prescribed PTV BED10 ranged from 40.6 Gy10 to 112.5 Gy10 (median, 86.1 Gy10). We analyzed local control (LC), progression-free interval (PFI), overall survival (OS), and toxicity. RESULTS: Median follow-up was 17 months (range, 2-49 months). The 2-year actuarial LC, PFI, and OS rates were 82.1, 17.7, and 45.0 %, and the median PFI and OS were 9 and 23 months, respectively. In univariate analysis histology (p < 0.001), PTV prescription BED10 (HR 0.95, CI 0.91-0.98, p = 0.002) and GTV mean BED10 (HR 0.975, CI 0.954-0.996, p = 0.011) were predictive for LC. Multivariate analysis showed that only extrahepatic disease status at time of treatment was a significant factor (p = 0.033 and p = 0.009, respectively) for PFI and OS. Acute nausea or fatigue grade 1 was observed in 24.1 % of the patients and only 1 patient (1.9 %) had a side effect of grade ≥ 2. CONCLUSIONS: Robotic real-time motion-compensated SBRT is a safe and effective treatment for one to four liver metastases. Reducing the PTV prescription dose and keeping a high mean GTV dose allowed the reduction of toxicity while maintaining a high local control probability for the treated lesions.

Number of cerebral lesions predicts freedom from new brain metastases after radiosurgery alone in lung cancer patients.

Numerous patients with few brain metastases receive radiosurgery, either alone or in combination with whole-brain irradiation. The addition of whole-brain irradiation to radiosurgery reduces the rate of intracerebral failures, particularly the development of new cerebral lesions distant from those treated with radiosurgery. Less intracerebral failures mean less neurocognitive deficits. However, whole-brain irradiation itself may lead to a decline in neurocognitive functions. Therefore, a number of physicians have reservations with regard to adding whole-brain irradiation to radiosurgery. Prognostic factors that allow an estimation of the risk of developing new cerebral metastases can facilitate the decision regarding additional whole-brain irradiation. Since primary tumors show a different biology and clinical course, prognostic factors should be identified separately for each primary tumor leading to brain metastasis. The present study investigated 10 characteristics in a series of 98 patients receiving radiosurgery alone for 1-2 cerebral metastases from lung cancer, the most common primary tumor associated with brain metastasis. These characteristics included radiosurgery dose, age, gender, performance status, histology, number of cerebral lesions, maximum total diameter of cerebral lesions, main location of cerebral lesions, extracranial spread and interval from first diagnosis of lung cancer to administration of radiosurgery. On univariate analysis, the number of cerebral lesions prior to radiosurgery (1 vs. 2 lesions) was the only characteristic significantly associated with freedom from new brain metastases (P=0.002). In cases of 2 lesions, 73% of patients developed new cerebral lesions within 1 year. On multivariate analysis, the number of brain metastases remained significant (risk ratio, 2.46; 95% confidence interval, 1.34-4.58; P=0.004). Given the high rates of new cerebral lesions in patients with 2 brain metastases, these patients should be strongly considered for additional whole-brain irradiation.

Single-Fraction Versus 5-Fraction Radiation Therapy for Metastatic Epidural Spinal Cord Compression in Patients With Limited Survival Prognoses: Results of a Matched-Pair Analysis.

PURPOSE: This study compared single-fraction to multi-fraction short-course radiation therapy (RT) for symptomatic metastatic epidural spinal cord compression (MESCC) in patients with limited survival prognosis. METHODS AND MATERIALS: A total of 121 patients who received 8 Gy × 1 fraction were matched (1:1) to 121 patients treated with 4 Gy × 5 fractions for 10 factors including age, sex, performance status, primary tumor type, number of involved vertebrae, other bone metastases, visceral metastases, interval between tumor diagnosis and MESCC, pre-RT ambulatory status, and time developing motor deficits prior to RT. Endpoints included in-field repeated RT (reRT) for MESCC, overall survival (OS), and impact of RT on motor function. Univariate analyses were performed with the Kaplan-Meier method and log-rank test for in-field reRT for MESCC and OS and with the ordered-logit model for effect of RT on motor function. RESULTS: Doses of 8 Gy × 1 fraction and 4 Gy × 5 fractions were not significantly different with respect to the need for in-field reRT for MESCC (P=.11) at 6 months (18% vs 9%, respectively) and 12 months (30% vs 22%, respectively). The RT regimen also had no significant impact on OS (P=.65) and post-RT motor function (P=.21). OS rates at 6 and 12 months were 24% and 9%, respectively, after 8 Gy × 1 fraction versus 25% and 13%, respectively, after 4 Gy × 5 fractions. Improvement of motor function was observed in 17% of patients after 8 Gy × 1 fraction and 23% after 4 Gy × 5 fractions, respectively. CONCLUSIONS: There were no significant differences with respect to need for in-field reRT for MESCC, OS, and motor function by dose fractionation regimen. Thus, 8 Gy × 1 fraction may be a reasonable option for patients with survival prognosis of a few months.

Impact of stereotactic radiosurgery dose on control of cerebral metastases from renal cell carcinoma.

AIM: Renal cell carcinoma (RCC) is a relatively radioresistant tumor and may require for higher radiation doses than other tumor types. PATIENTS AND METHODS: Nineteen patients treated with 20 Gy of stereotactic radiosurgery (SRS) alone for one to three cerebral metastases were compared to nine patients treated with 16-18 Gy. RESULTS: SRS with 20 Gy led to significantly better local control than did 16-18 Gy (81% vs. 50% at 12 months; p<0.001). Results were also significant on multivariate analysis (risk ratio: 6.30; p=0.033). SRS dose did not associate with freedom from new cerebral metastases (75% vs. 62% at 12 months; p=0.42) or survival (16% vs. 56% at 12 months; p=0.46). On multivariate analyses, better survival was associated with higher Karnofsky performance score (p<0.001) and absence of extracranial metastatic disease (p=0.006). CONCLUSION: In patients treated with SRS alone, local control of cerebral metastases from RCC was better after 20 Gy than after 16-18 Gy.

A matched-pair analysis comparing 5x4 Gy and 10x3 Gy for metastatic spinal cord compression (MSCC) in patients with favorable survival prognoses.

BACKGROUND: It is currently not possible to get an approval of our ethics committee for a randomized trial cmparing 5x4 Gy and 10x3 Gy for MSCC that includes patients with favorable survival prognoses. Therefore, this matched-pair study following strict matching criteria was perfomed instead. METHODS: In this study, 142 receiving 5x4 Gy were retrospectively matched (1:1) to 142 patients receiving 10x3 Gy with respect to ten characteristics. These characteristics included age, gender, performance status, tumor type, involved vertebrae, other bone metastases, visceral metastases, interval between tumor diagnosis and MSCC, pre-RT ambulatory status, and time developing motor deficits. RESULTS: On multivariate analysis, post-RT motor function was associated with performance status (p<0.001), tumor type (p < 0.001), and time developing motor deficits (p<0.001). RT was successful in 76% of patients receiving 5x4 Gy and 69% receiving 10x3 Gy (p=0.14). Pre.RT ambulatory status showed a strong trend with respect to local control (LC) of MSCC in the multivariate analysis (p=0.058). 1-year LC rates were 87% after 5x4 Gy and 93% after 10x3 Gy (p=0.16). On multivariate analysis, survival (OS) was associated with performance score (p<0.001), visceral metastases (p<0.001), and pre-RT ambulatory status (p=0.004). 1-year OS rates were 68% after 5x4 Gy and 73% after 10x3 Gy (p = 0.64). CONCLUSIONS: In patients irradiated for MSCC who had favorable survival prognoses, post-RT motor function, LC and OS were not significantly different after 5x4 Gy and after 10x3 Gy.

Nuclear expression of p65 (RelA) in patients receiving post-operative radiotherapy for locally advanced squamous cell carcinoma of the head and neck.

BACKGROUND: This study investigated the prognostic role of nuclear expression of p65 in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) receiving post-operative radio(chemo)therapy. METHODS: Nuclear p65-expression (H-score ≤50 versus >50) plus twelve characteristics were analyzed in 151 patients for overall survival (OS), metastases-free survival (MFS) and loco-regional control (LRC). Additional characteristics included age, gender, Karnofsky performance score (KPS), pre-radiotherapy hemoglobin levels, tumor site, histological grading, human papilloma virus (HPV)-status, T-classification, N-classification, American Joint Committee on Cancer (AJCC)-stage, extent of resection and concurrent chemotherapy. Univariate analyses were performed with Kaplan-Meier method and log-rank test, multivariate analyses with Cox proportional hazards model. RESULTS: On univariate analyses, p65-expression had a significant impact on OS (p < 0.001) and LRC (p < 0.001) but not on MFS (p = 0.29). On multivariate analysis, KPS ≥80 (risk ratio [RR] 2.23; p = 0.012), HPV-positivity (RR 5.83; p = 0.020), T1-T2 (RR 1.38; p = 0.048), N0-N2a (RR 2.72; p = 0.005) and complete resection (RR 2.02; p = 0.049) were positively associated with OS; p65-negativity achieved borderline significance (RR 3.02; p = 0.052). Better MFS was associated with KPS ≥80 (RR 2.49; p = 0.015), T1-T2 (RR: 1.74; p = 0.005), N0-N2a (RR: 6.22; p < 0.001) and complete resection (RR 3.43; p = 0.003). Positive associations with LRC were found for p65-negativity (RR 5.06; p = 0.008), T1-T2 (RR: 1.49; p = 0.022), N0-N2a (RR: 2.97; p = 0.004) and favorable tumor site (RR 1.28; p = 0.025). CONCLUSIONS: P65-negativity was significantly associated with improved LRC and achieved borderline significance with respect to improved OS. Thus, p65-expression may be an additional target for novel agents in the treatment of locally advanced SCCHN.

A new tool to predict survival after radiosurgery alone for newly diagnosed cerebral metastases.

Many patients with few cerebral metastases receive radiosurgery alone. The goal of this study was to create a tool to estimate the survival of such patients. To identify characteristics associated with survival, nine variables including radiosurgery dose, age, gender, Eastern cooperative oncology group performance score (ECOG-PS), primary tumor type, number/size of cerebral metastases, location of cerebral metastases, extra-cerebral metastases and time between cancer diagnosis and radiosurgery were analyzed in 214 patients. On multivariate analysis, age (p=0.03), ECOG-PS (p=0.02) and extra-cerebral metastases (p<0.01) had significant impacts on survival. Scoring points for each patient were obtained from 12-month survival rates (in %) related to the significant variables divided by 10. Addition of the scoring points of the three variables resulted in a patient's total predictive score. Two groups were designed, A (10-14 points) and B (16-17 points). Twelve-month survival rates were 33% and 77%, respectively (p<0.001). Median survival times were 8 and 20 months, respectively. Because most patients of group A died from extra-cerebral disease and/or new cerebral lesions, early systemic treatment and additional WBI should be considered. As cause of death in group B was mostly new cerebral metastases, additional WBI appears even more important for this group.

A new instrument for estimating the survival of patients with metastatic epidural spinal cord compression from esophageal cancer.

BACKGROUND: This study was initiated to create a predictive instrument for estimating the survival of patients with metastatic epidural spinal cord compression (MESCC) from esophageal cancer. METHODS: In 27 patients irradiated for MESCC from esophageal cancer, the following nine characteristics were evaluated for potential impact on survival: age, gender, Eastern Cooperative Oncology Group (ECOG) performance score, histology, number of involved vertebrae, ambulatory status before irradiation, further bone metastases, visceral metastases, and dynamic of developing motor deficits before irradiation. In addition, the impact of the radiation regimen was investigated. According to Bonferroni correction, p-values of < 0.006 were significant representing an alpha level of < 0.05. RESULTS: ECOG performance score (p < 0.001), number of involved vertebrae (p = 0.005), and visceral metastases (p = 0.004) had a significant impact on survival and were included in the predictive instrument. Scoring points for each characteristic were calculated by dividing the 6-months survival rates (in %) by 10. The prognostic score for each patient was obtained by adding the scoring points of the three characteristics. The prognostic scores were 4, 9, 10, 14 or 20 points. Three prognostic groups were formed, 4 points (n = 11), 9-14 points (n = 12) and 20 points (n = 4). The corresponding 6-months survival rates were 0%, 33% and 100%, respectively (p < 0.001). Median survival times were 1 month, 5 months and 16.5 months, respectively. CONCLUSIONS: This new instrument allows the physician estimate the 6-months survival probability of an individual patient presenting with MESCC from esophageal cancer. This is important to know for optimally personalizing the treatment of these patients.

Predicting the survival probability of gastric cancer patients developing metastatic epidural spinal cord compression (MESCC).

To create a tool for estimating the survival of gastric cancer patients developing MESCC, clinical factors were evaluated in 29 patients. Factors were age, gender, performance status, affected vertebrae, ambulatory status, further bone metastases, visceral metastases, time from gastric cancer diagnosis until MESCC and rapidity of developing weakness of legs. On multivariate analyses, visceral metastases (risk ratio: 6.80; p = 0.003) and rapidity of weakening of legs (risk ratio: 2.73; p = 0.023) had a significant effect on survival and were included in the tool. Scoring points for each of the two factors were either 0 or 1, depending on the 6-month survival rates. According to the sum of the points, three groups were built: 0 points (n = 12), 1 point (n = 10) and 2 points (n = 7). Six-month survival rates were 0, 20 and 100 % (p < 0.001). This tool for patients with MESCC from gastric cancer estimates survival probabilities, which is important for tailoring treatment to patients' needs.

Radiosurgery with 20 Gy provides better local contol of 1-3 brain metastases from breast cancer than with lower doses.

AIM: To determine the optimal dose of radiosurgery-alone for patients with 1-3 cerebral metastases from breast cancer. PATIENTS AND METHODS: Patients receiving 20 Gy (n=20) were compared to those receiving 16-18.5 Gy (n=10) for local control, distant brain control and overall survival. Seven other variables were also evaluated. RESULTS: Radiosurgery dose achieved significance on univariate (p=0.002; log-rank and Wilcoxon test) and multivariate analysis (p=0.004) of local control. Twelve-month local control rates were 94% after 20 Gy and 48% after 16-18.5 Gy. On univariate analysis of distant brain control, radiosurgery dose was not a significant factor, with 12-month rates of 73% and 60%, respectively. Regarding overall survival, radiosurgery dose was of borderline significance (p=0.059; Wilcoxon test). Twelve-month overall survival rates were 75% and 40%, respectively. On Cox regression analysis, radiosurgery dose exhibited a trend for improving survival (p=0.10). CONCLUSION: Radiosurgery with 20 Gy resulted in significantly better local control and led to a trend towards improved overall survival compared to treatment with 16-18.5 Gy.

A new tool predicting survival after radiosurgery alone for one or two cerebral metastases from lung cancer.

Radiosurgery is frequently used for patients with few cerebral metastases. Decisions regarding personalized treatment should include the patient's survival prognosis. Prognostic tools should be available for estimating the remaining lifetime for each primary tumor and treatment. We designed such a tool for patients receiving radiosurgery alone for cerebral metastases from lung cancer. Ten variables were analyzed in 98 patients. On multivariate analysis, extra-cranial spread was significantly associated with worse survival (p < 0.001). A trend was observed for poorer performance status (p = 0.08) and greater diameter of cerebral lesions (p = 0.07). Points for the tool were derived from 12-month survival rates of these variables and added, resulting in sum scores of 10-16 points. Three groups were built, 10-12, 14-15, and 16 points with 12-month survival rates of 22, 52, and 79% (p < 0.001). This new tool enables physicians to estimate the survival of lung cancer patients with few cerebral metastases which should impact individualized treatment choices.

Radiosurgery alone versus radiosurgery plus whole-brain irradiation for very few cerebral metastases from lung cancer.

BACKGROUND: It is unclear whether patients with few cerebral metastases benefit from whole-brain irradiation added to radiosurgery. Since primary tumors disseminating to the brain show different behavior, this question should be answered separately for each tumor type. This study compared both treatments in patients with 1-3 cerebral metastases from lung cancer. METHODS: Ninety-eight patients receiving radiosurgery alone were retrospectively compared to 50 patients receiving radiosurgery plus whole-brain irradiation for local control, distant cerebral control and overall survival. Ten other characteristics were additionally considered including radiosurgery dose, age, gender, Eastern Cooperative Oncology Group (ECOG) performance score, histology, number of cerebral metastases, maximum diameter of all cerebral metastases, site of cerebral metastases, extra-cerebral metastases, and interval from lung cancer diagnosis to irradiation. RESULTS: The treatment approach had no significant impact on local control (p = 0.61). On multivariate analysis of local control, ECOG performance score was significant (risk ratio [RR]: 2.10; p < 0.001). The multivariate analysis of distant brain control revealed significant positive associations with radiosurgery plus whole-brain irradiation (RR: 4.67; p < 0.001) and one cerebral metastasis (RR: 2.62; p < 0.001). Treatment approach was not significantly associated with overall survival (p = 0.32). On multivariate analysis, significant associations with overall survival were found for maximum diameter of all cerebral metastases (RR: 1.81; p = 0.008), extra-cerebral metastases (RR: 2.98; p < 0.001), and interval from lung cancer diagnosis to irradiation (RR: 1.19; p < 0.001). CONCLUSION: Addition of whole-brain irradiation to radiosurgery significantly improved distant brain control in patients with few cerebral metastases from lung cancer. This improvement did not translate into better overall survival.

Do patients with very few brain metastases from breast cancer benefit from whole-brain radiotherapy in addition to radiosurgery?

BACKGROUND: An important issue in palliative radiation oncology is the whether whole-brain radiotherapy should be added to radiosurgery when treating a limited number of brain metastases. To optimize personalized treatment of cancer patients with brain metastases, the value of whole-brain radiotherapy should be described separately for each tumor entity. This study investigated the role of whole-brain radiotherapy added to radiosurgery in breast cancer patients. METHODS: Fifty-eight patients with 1-3 brain metastases from breast cancer were included in this retrospective study. Of these patients, 30 were treated with radiosurgery alone and 28 with radiosurgery plus whole-brain radiotherapy. Both groups were compared for local control of the irradiated metastases, freedom from new brain metastases and survival. Furthermore, eight additional factors were analyzed including dose of radiosurgery, age at radiotherapy, Eastern Cooperative Oncology Group (ECOG) performance score, number of brain metastases, maximum diameter of all brain metastases, site of brain metastases, extra-cranial metastases and the time from breast cancer diagnosis to radiotherapy. RESULTS: The treatment regimen had no significant impact on local control in the univariate analysis (p=0.59). Age ≤59 years showed a trend towards improved local control on univariate (p=0.066) and multivariate analysis (p=0.07). On univariate analysis, radiosurgery plus whole-brain radiotherapy (p=0.040) and ECOG 0-1 (p=0.012) showed positive associations with freedom from new brain metastases. Both treatment regimen (p=0.039) and performance status (p=0.028) maintained significance on multivariate analysis. ECOG 0-1 was positively correlated with survival on univariate analysis (p<0.001); age ≤59 years showed a strong trend (p=0.054). On multivariate analysis, performance status (p<0.001) and age (p=0.041) were significant. CONCLUSIONS: In breast cancer patients with few brain metastases, radiosurgery plus whole-brain radiotherapy resulted in significantly better freedom from new brain metastases than radiosurgery alone. However, this advantage did not lead to significantly better survival.

Comparison of two dose levels of stereotactic radiosurgery for 1-3 brain metastases from non-small cell lung cancer.

AIM: Two dose groups of patients treated with stereotactic radiosurgery (SRS) alone for 1-3 brain metastases from non-small cell lung cancer (NSCLC) were compared for outcomes. PATIENTS AND METHODS: Based on the SRS dose administered to the margins of the brain lesions, 46 patients were assigned to groups treated with 15-18 Gy (n=13) or with 20 Gy (n=33). Seven additional factors were investigated: age (≤ 58 vs. ≥ 59 years), gender, Karnofsky performance score (KPS 70-80 vs. 90-100), number of brain metastases (1 vs. 2-3), histology (adenocarcinoma vs. other) extracerebral metastases and interval from NSCLC diagnosis to SRS (≤ 6 vs. >6 months). RESULTS: Local control rates for 15-18-Gy and 20-Gy groups were 75% and 92% at one year (p=0.043). SRS dose was significant on multivariate analysis (p=0.030). SRS dose was not associated with freedom from new brain metastases (p=0.24) or survival (p=0.37). CONCLUSION: SRS with 20 Gy resulted in better control of the irradiated metastases than 15-18 Gy did.