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.

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.

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.

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.

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.

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.

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.

Evaluation of the prognostic role of tumor cell podoplanin expression in locally advanced squamous cell carcinoma of the head and neck.

BACKGROUND AND PURPOSE: To investigate the potential prognostic role of tumor cell podoplanin expression in patients treated with resection followed by irradiation or chemoradiotherapy for locally advanced squamous cell carcinoma of the head and neck (SCCHN). MATERIALS AND METHODS: Podoplanin expression (≤10 % versus > 10 %) and 12 other factors were evaluated in 160 patients for their association with locoregional control (LRC), metastases-free (MFS) and overall survival (OS). Other factors were age, gender, Eastern Cooperative Oncology Group (ECOG) performance status, preradiotherapy (pre-RT) hemoglobin level, tumor site, histological grading, T category, N category, American Joint Committee on Cancer (AJCC) stage, human papillomavirus (HPV) status, extent of resection and concurrent chemotherapy. RESULTS: In multivariate analysis, ECOG performance status 0-1 (risk ratio, RR: 3.01; 95 % confidence interval, CI: 1.42-7.14; p = 0.003), pre-RT hemoglobin levels ≥ 7.45 mmol/l (12 g/dl; RR: 2.03; 95 % CI: 1.04-3.94; p = 0.038), oropharyngeal cancer (RR: 1.25; 95 % CI: 1.01-1.55; p = 0.038) and T category T1-2 (RR: 1.81; 95 % CI: 1.24-2.79; p = 0.002) were significantly associated with improved LRC. T category T1-2 (RR: 1.90; 95 % CI: 1.25-3.06; p = 0.002) and N category N0-2a (RR: 5.22; 95 % CI: 1.96-18.09; p < 0.001) were significantly associated with better MFS. Pre-RT hemoglobin levels ≥ 7.45 mmol/l (RR: 2.44; 95 % CI: 1.27-4.74; p = 0.007), T category T1-2 (RR: 1.97; 95 % CI: 1.36-3.04; p < 0.001) and N category N0-2a (RR: 2.87; 95 % CI: 1.37-6.61; p = 0.005) were significantly associated with improved OS. Podoplanin expression ≤ 10 % showed a trend towards improved OS on both univariate (p = 0.050) and multivariate analysis (RR: 1.86; 95 % CI: 0.96-3.59; p = 0.07). CONCLUSION: Treatment outcomes were significantly associated with performance status, pre-RT hemoglobin level, tumor site and tumor stage. Tumor cell expression of podoplanin ≤ 10 % showed a trend towards improved OS when compared to podoplanin expression of > 10 %.

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.

Prognostic factors for different outcomes in patients with metastatic spinal cord compression from cancer of unknown primary.

BACKGROUND: Patients with cancer of unknown primary account for 10% of patients with metastatic spinal cord compression (MSCC). This retrospective study was performed to identify prognostic factors for functional outcome, local control of MSCC, and survival in 175 of such patients treated with radiotherapy alone. METHODS: Investigated were nine potential prognostic factors including age, gender, Eastern Cooperative Oncology Group performance score (ECOG-PS), number of involved vertebrae, pre-radiotherapy ambulatory status, other bone metastases, visceral metastases, time developing motor deficits before radiotherapy, and the radiation schedule. RESULTS: On multivariate analysis, better functional outcome was associated with absence of visceral metastases (estimate: 0.72; 95%-confidence interval [CI]: 0.07-1.36; p = 0.030) and a slower (>7 days) development of motor deficits (estimate: 1.93; 95%-CI: 1.18-2.68; p < 0.001). Improved local control of MSCC was associated with absence of visceral metastases (risk ratio [RR]: 10.26; 95%-CI: 2.11-74.73; p = 0.004). Improved survival was associated with favorable ECOG-PS (RR: 2.12; 95%-CI: 1.40-3.29; p < 0.001), being ambulatory prior to radiotherapy (RR: 1.98; 95%-CI: 1.40-2.81; p < 0.001), absence of visceral metastases (RR: 2.74; 95%-CI: 1.93-3.91; p < 0.001), and slower development of motor deficits (RR: 1.27; 95%-CI: 1.07-1.51; p = 0.007). Absence of other bone metastases showed a trend (RR: 1.38; 95%-CI: 0.98-1.95; p = 0.07). CONCLUSIONS: This study identified additional independent prognostic factors for functional outcome, local control of MSCC, and survival after radiotherapy of MSCC from cancer of unknown primary. These prognostic factors can help select the best treatment regimen for each individual patient.