Stereotactic radiotherapy for lung oligometastases

30–60% of cancer patients develop lung metastases, mostly from primary tumors in the colon-rectum, lung, head and neck area, breast and kidney. Nowadays, stereotactic radiotherapy (SRT) is considered the ideal modality for treating pulmonary metastases. When lung metastases are suspected, complete disease staging includes a total body computed tomography (CT) and/or positron emission tomography-computed tomography (PET-CT) scan. PET-CT has higher specificity and sensitivity than a CT scan when investigating mediastinal lymph nodes, diagnosing a solitary lung lesion and detecting distant metastases. For treatment planning, a multi-detector planning CT scan of the entire chest is usually performed, with or without intravenous contrast media or esophageal lumen opacification, especially when central lesions have to be irradiated. Respiratory management is recommended in lung SRT, taking the breath cycle into account in planning and delivery. For contouring, co-registration and/or matching planning CT and diagnostic images (as provided by contrast enhanced CT or PET-CT) are useful, particularly for central tumors. Doses and fractionation schedules are heterogeneous, ranging from 33 to 60 Gy in 3–6 fractions. Independently of fractionation schedule, a BED10 > 100 Gy is recommended for high local control rates. Single fraction SRT (ranges 15–30 Gy) is occasionally administered, particularly for small lesions. SRT provides tumor control rates of up to 91% at 3 years, with limited toxicities. The present overview focuses on technical and clinical aspects related to treatment planning, dose constraints, outcome and toxicity of SRT for lung metastases.

Stereotactic radiotherapy for adrenal oligometastases

Approximately 50% of melanomas, 30–40% of lung and breast cancers and 10–20% of renal and gastrointestinal tumors metastasize to the adrenal gland. Metastatic adrenal involvement is diagnosed by computed tomography (CT) with contrast medium, ultrasound (which does not explore the left adrenal gland well), magnetic resonance imaging (MRI) with contrast medium and 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18FDGPET-CT) which also evaluates lesion uptake. The simulation CT should be performed with contrast medium; an oral bolus of contrast medium is useful, given adrenal gland proximity to the duodenum. The simulation CT may be merged with PET-CT images with 18FDG in order to evaluate uptaking areas. In contouring, the radiologically visible and/or uptaking lesion provides the gross tumor volume (GTV). Appropriate techniques are needed to overcome target motion. Single fraction stereotactic radiotherapy (SRT) with median doses of 16–23 Gy is rarely used. More common are doses of 25–48 Gy in 3–10 fractions although 3 or 5 fractions are preferred. Local control at 1 and 2 years ranges from 44 to 100% and from 27 to 100%, respectively. The local control rate is as high as 90%, remaining stable during follow-up when BED10Gy is equal to or greater than 100 Gy. SRT-related toxicity is mild, consisting mainly of gastrointestinal disorders, local pain and fatigue. Adrenal insufficiency is rare

Usefulness of robotic radiosurgery for local control of unresectable multiple liver metastases from colorectal cancer: preliminary results

Eight-teen consecutive patients with liver metastases from colorectal cancer, considered unsuitable for surgery, confirmed by ultrasound- or CTguided biopsy or ultrasound-guided FNAB, were enrolled in the study. The inclusion criteria were: age between 50-75, no chemotherapy during the last 30 days, acceptable liver function (ALT and ALT2.5%), Karnofsky performance score 700 mL, respectively. The overall tumor volume ranged from 25 to 185 mL (median 70 mL), and the irradiated volume was 18\ub110 mL. Inhibition of growth or a reduction in size was obtained in 12 of 18 patients: 5 with complete response, and 7 with partial response. There was a local complete response with other single lesions appearing in two patients, and a progressive disease in 4. Among responders, the median post-treatment volume of the tumor was 22 mL (range 5-55mL), and 3 patients with progressive disease died during follow-up, both developing severe liver failure

Local control and toxicity for centrally located NSCLC: SABR in no fly zone

Purpose or Objective: Only few experiences had investigated the use of SABR for locally advanced NSCL centrally located. The RTOG 0236 Trial warns about the risks of SBRT in NSCLS located within 2 cm of the bronchial tree, the edophagus, heart and pericardium. The aim of this study is to evaluate the use of hypofracionated ablative radiotherapy in this setting of disease in terms of local control, toxicities and overall survival (OS). Material and Methods: Between Jun 2011 and March 2015 36 patients (pts) were treated with Hypofrationated Image guided-Volumetric Modulated Arc Therapy (IGRT-VMA T) for centrally located NSCLC stage III-IV or centrally recurrent NSCLC biopsy-proven. Target was contoured using volumetric mdc enhanced CT and PET/CT scan and OAR according RTOG 0236 Trial criteria. Dose Constraints used were: Single lung V10<20%, Dmax bronchus 38 Gy, Dmax esophagus 35 Gy, Spinal Cord 22.5 Gy, Heart and pericardium 38 Gy. The dose was prescribed to 80% isodose. The VMAT treatment was delivered by 6MV beam modulator Linac with 4 mm MLC and in breath hold using ABC device. Patient set-up and isocenter position was controlled before each fraction by CBCT . T arget volume ranged from 21 to 150 cm3 (median 49.5). Median delivered dose was 40 Gy/5fx (median BED 10 of 100 Gy). Toxicities were assessed by CTCAE 4.0 criteria and the response was evaluated 2 months after the end of SBRT and every 4 month successively by CT and PET/CT. Results: Median follow-up was 18 months (range 3 – 45). 25 pts are still alive (69.5%) and 8 of them have NED. 19/36 (52.8%) of treated lesions show complete respons and 10 (27.7%) partial response. Local control was 89% at 12 months and 67% at 18 months. OS was 84% and 73% at 12 and 18 months respectively. Acute toxicity worse than G2 was observed only in 1 pt. Late toxicity G3 was observed in 3 pts (esophageal stenosis in 1 case and bronco-esophageal fistula in 2 pts). Both fistulas occour in the same site of local recurrence Conclusion: In our experience hypofractionated treatment with ablative dose for NSCLC locate in “no fly zone” is safe if dose constraints for OAR are respected. The two major late toxicities observed occurred in the same site of local recurrence. The treatments with BED 10 values of 100 Gy or more are effective leading to LC rate of 89% and 67% at 12 and 18 month respectlively. Although OS is not the primary endpoint of this study, beacuse include also metastatic and recurrent disease, nevertheless shows interesting values (84% at 12 months and 73% at 18 months

Image-guided Robotic Stereotactic Radiosurgery for Unresectable Liver Metastases: Preliminary Results

The aim of this study was to evaluate the usefulness of image-guided robotic stereotactic radiosurgery for the local control of unresectable liver metastases from colorectal and non-colorectal cancer. Twenty-seven consecutive patients (median age 62 years, range 47-80 years) with liver metastases considered unsuitable for surgery were enrolled in the study. The diagnosis was colorectal cancer liver metastasis in 11 (41% ) and other secondary malignancies in 16 (59% ) patients. The patients were treated with 25 to 60 Gy (median 36 Gy) delivered in 3 consecutive fractions, and the isodose value covering the planning target volume was 80% of the prescribed dose. Overall, the mean tumour volume was 81.6\ub135.9 ml. Inhibition of growth or a reduction in size was obtained in 20 (74.1% ) patients: 7 with complete response and 13 with partial response. There was a local complete response with other single lesions appearing in 3 (11.1% ) patients and progressive disease in 4 (14.8% ). The median post-treatment volume of the tumour was 24 ml (range 0-54 ml) among the responders. Mild or moderate transient hepatic dysfunction was evident in 9 patients and minor complications in five. Two patients with progressive disease died of liver failure. Inconclusion, in patients with liver metastases unsuitable for surgery, stereotactic radiosurgery achieves high rates of local disease control, representing an acceptable alternative therapy, but should be further studied in larger series

Stereotactic radiotherapy for liver oligometastases

The liver is the first metastatic site in 15–25% of colorectal cancer patients and one of the first metastatic sites for lung and breast cancer patients. A computed tomography (CT) scan with contrast medium is a standard procedure for assessing liver lesions but magnetic resonance imaging (MRI) characterizes small lesions better thanks to its high soft-tissue contrast. Positron emission tomography with computed tomography (PET-CT) plays a complementary role in the diagnosis of liver metastases. Triphasic (arterial, venous and time-delayed) acquisition of contrast-medium CT images is the first step in treatment planning. Since the liver exhibits a relatively wide mobility due to respiratory movements and bowel filling, appropriate techniques are needed for target identification and motion management. Contouring requires precise recognition of target lesion edges. Information from contrast MRI and/or PET-CT is crucial as they best visualize metastatic disease in the parenchyma. Even though different fractionation schedules were reported, doses and fractionation schedules for liver stereotactic radiotherapy (SRT) have not yet been established. The best local control rates were obtained with BED10 values over 100 Gy. Local control rates from most retrospective studies, which were limited by short follow-ups and included different primary tumors with intrinsic heterogeneity, ranged from 60% to 90% at 1 and 2 years. The most common SRT-related toxicities are increases in liver enzymes, hyperbilirubinemia and hypoalbuminemia. Overall, late toxicity is mild even in long-term follow-ups.

Usefulness of robotic radiosurgery for local control of unresectable multiple liver metastases from colorectal cancer: preliminary results

The median survival of untreated patients with liver metastases ranges between 6 and 18 months, but unfortunately surgery may be performed in only 20% of cases. The aim of this preliminary study was to evaluate the usefulness of CyberKnife_ (Accuray Inc, Sunnyvale, CA) image-guided robotic stereotactic radiosurgery for local control of unresectable liver metastases. Patients and Methods: Eight-teen consecutive patients with liver metastases from colorectal cancer, considered unsuitable for surgery, confirmed by ultrasound- or CTguided biopsy or ultrasound-guided FNAB, were enrolled in the study. There were 11 men and 7 women, with an overall median age of 59 years (range 49-73 years). The inclusion criteria were: age between 50-75, no chemotherapy during the last 30 days, acceptable liver function (ALT and ALT2.5%), Karnofsky performance score <3, no extra-hepatic disease on 18-FDG CT-PET, tumor size and estimated residual liver volume on CT-scan 700 mL, respectively. Results: The overall tumor volume ranged from 25 to 185 mL (median 70 mL), and the irradiated volume was 18\ub110 mL (range 11-40 mL). The mean post-treatment followup was 11 months. Inhibition of growth or a reduction in size was obtained in 12 of 18 patients: 5 with complete response, and 7 with partial response. There was a local complete response with other single lesions appearing in two patients, and a progressive disease in 4. Among responders, the median post-treatment volume of the tumor was 22 mL (range 5-55mL), with an overall reduction rate of more than 70%. Toxic events were observed in 11 patients: transient hepatic dysfunction was evident in 7, and pleural effusion, pulmonary embolism, partial portal vein thrombosis, and upper gastrointestinal tract bleeding in one patient each. Three patients with progressive disease died during follow-up, both developing severe liver failure. Conclusions: Using stereotactic radiosurgery a good local control of the disease may be achieved, with limited toxicity. This promising treatment strategy should be further studied in larger series, representing an acceptable alternative in patients with liver metastases unsuitable for surgery

Progression-free Survival Following Stereotactic Body Radiotherapy for Oligometastatic Prostate Cancer Treatment-naive Recurrence: A Multi-institutional Analysis

The literature on metastasis-directed therapy for oligometastatic prostate cancer (PCa) recurrence consists of small heterogeneous studies. This study aimed to reduce the heterogeneity by pooling individual patient data from different institutions treating oligometastatic PCa recurrence with stereotactic body radiotherapy (SBRT). We focussed on patients who were treatment naive, with the aim of determining if SBRT could delay disease progression. We included patients with three or fewer metastases. The Kaplan-Meier method was used to estimate distant progression-free survival (DPFS) and local progression-free survival (LPFS). Toxicity was scored using the Common Terminology Criteria for Adverse Events. In total, 163 metastases were treated in 119 patients. The median DPFS was 21 mo (95% confidence interval, 15-26 mo). A lower radiotherapy dose predicted a higher local recurrence rate with a 3-yr LPFS of 79% for patients treated with a biologically effective dose <= 100 Gy versus 99% for patients treated with > 100 Gy (p = 0.01). Seventeen patients (14%) developed toxicity classified as grade 1, and three patients (3%) developed grade 2 toxicity. No grade >= 3 toxicity occurred. These results should serve as a benchmark for future prospective trials. Patient summary: This multi-institutional study pools all of the available data on the use of stereotactic body radiotherapy for limited prostate cancer metastases. We concluded that this approach is safe and associated with a prolonged treatment progression-free survival. (C) 2015 Published by Elsevier B.V. on behalf of European Association of Urology

Knockout of the PKN Family of Rho Effector Kinases Reveals a Non-redundant Role for PKN2 in Developmental Mesoderm Expansion

In animals, the protein kinase C (PKC) family has expanded into diversely regulated subgroups, including the Rho family-responsive PKN kinases. Here, we describe knockouts of all three mouse PKN isoforms and reveal that PKN2 loss results in lethality at embryonic day 10 (E10), with associated cardiovascular and morphogenetic defects. The cardiovascular phenotype was not recapitulated by conditional deletion of PKN2 in endothelial cells or the developing heart. In contrast, inducible systemic deletion of PKN2 after E7 provoked collapse of the embryonic mesoderm. Furthermore, mouse embryonic fibroblasts, which arise from the embryonic mesoderm, depend on PKN2 for proliferation and motility. These cellular defects are reflected in vivo as dependence on PKN2 for mesoderm proliferation and neural crest migration. We conclude that failure of the mesoderm to expand in the absence of PKN2 compromises cardiovascular integrity and development, resulting in lethality