Shankar Siva

Stereotactic radiotherapy for pulmonary oligometastases: a systematic review.

Introduction: Hypofractionated stereotactic body radiotherapy (SBRT) is an emerging noninvasive technique for the treatment of oligometastatic cancer. The use of small numbers of large doses, should in theory, achieve high rates of local control. The aim of this literature review is to critically assess the use of SBRT for the treatment of pulmonary metastases as judged by its effect on local control, survival, and toxicity. Methods: A systematic literature search was performed. Both single fraction stereotactic radiosurgery (SRS) and hypofractionated radiotherapy (SBRT) were considered individually. Thirteen institutions reported results regarding SBRT and seven institutions regarding SRS (a total of 29 publications). Outcomes, techniques, radiobiology, and the scientific rigor of the reported studies were analyzed. Results: A wide range of techniques, doses, and dose fractionation schedules were found. Three hundred thirty-four patients with 564 targets were reported in the SBRT series. The 2-year weighted local control was 77.9%. The corresponding 2-year weighted overall survival was 53.7%, with a 4% rate of grade 3 or higher radiation toxicities. One hundred fifty-four patients with 174 targets were treated in the SRS series. The 2-year weighted local control was 78.6%. The corresponding weighted 2-year overall survival was 50.3%, with 2.6% rate of grade 3 or higher toxicities. Conclusion: There was insufficient evidence to recommend a consensus view for optimal tumor parameters, dose fractionation, and technical delivery of treatment. This indicates the need for further prospective studies. However, high local control rates that could potentially lead to a survival benefit justifies the consideration of stereotactic radiotherapy for patients with limited pulmonary oligometastases.

A systematic review of stereotactic radiotherapy ablation for primary renal cell carcinoma

Study Type – Therapy (systematic review)

18F-FDG PET Provides High-Impact and Powerful Prognostic Stratification in the Staging of Merkel Cell Carcinoma: A 15-Year Institutional Experience

Merkel cell carcinoma (MCC) is a rare but aggressive skin cancer with limited evidence on the role of PET scanning. The primary aim of this study was to assess the impact of 18F-FDG PET in the staging and management of MCC. Methods: A single-institution review using clinical outcome data collected until February 2012 was performed of patients with MCC who underwent staging PET scanning between January 1997 and October 2010. Management plans were recorded prospectively at the time of the PET request, and follow-up outcomes were recorded retrospectively. The clinical impact of PET was scored using our previously published criteria: “high” if the PET scan changed the primary treatment modality or intent; “medium” if the treatment modality was unchanged but the radiation therapy technique or dose was altered. The primary objective was to test the hypothesis that the true proportion of patients who have a high- or medium-impact scan would be greater than 25%. Results: The median follow-up of 102 consecutive patients was 4.8 y. The results of staging PET had an impact on patient management in 37% of patients (P < 0.003). High- and medium-impact scans were recorded for 22% and 15% of patients, respectively. PET staging results differed from conventional staging results in 22% of patients, with PET upstaging 17% and downstaging 5%. The 3- and 5-y overall survival was 60% (95% confidence interval, 50%–71%) and 51% (95% confidence interval, 41%–64%), respectively. In stratification by PET-defined stage, the 5-y overall survival was 67% for patients with stage I/II disease but only 31% for patients with stage III disease (log-rank P < 0.001). The 5-y cumulative incidence of locoregional failure, distant failure, and death was 16.6%, 22.3% and 14.3%, respectively. On multivariate analysis, only PET stage (P < 0.001) and primary treatment modality (P = 0.050) were significantly associated with overall survival. The primary treatment modality was not associated with progression-free survival when stratification was by tumor stage. Conclusion: The use of 18F-FDG PET scans had a great impact on patients and may play an important role in the prognostic stratification and treatment of this disease.

Validating and improving CT ventilation imaging by correlating with ventilation 4D-PET/CT using 68Ga-labeled nanoparticles.

PURPOSE CT ventilation imaging is a novel functional lung imaging modality based on deformable image registration. The authors present the first validation study of CT ventilation using positron emission tomography with (68)Ga-labeled nanoparticles (PET-Galligas). The authors quantify this agreement for different CT ventilation metrics and PET reconstruction parameters. METHODS PET-Galligas ventilation scans were acquired for 12 lung cancer patients using a four-dimensional (4D) PET/CT scanner. CT ventilation images were then produced by applying B-spline deformable image registration between the respiratory correlated phases of the 4D-CT. The authors test four ventilation metrics, two existing and two modified. The two existing metrics model mechanical ventilation (alveolar air-flow) based on Hounsfield unit (HU) change (VHU) or Jacobian determinant of deformation (VJac). The two modified metrics incorporate a voxel-wise tissue-density scaling (ρVHU and ρVJac) and were hypothesized to better model the physiological ventilation. In order to assess the impact of PET image quality, comparisons were performed using both standard and respiratory-gated PET images with the former exhibiting better signal. Different median filtering kernels (σm = 0 or 3 mm) were also applied to all images. As in previous studies, similarity metrics included the Spearman correlation coefficient r within the segmented lung volumes, and Dice coefficient d20 for the (0 - 20)th functional percentile volumes. RESULTS The best agreement between CT and PET ventilation was obtained comparing standard PET images to the density-scaled HU metric (ρVHU) with σm = 3 mm. This leads to correlation values in the ranges 0.22 ≤ r ≤ 0.76 and 0.38 ≤ d20 ≤ 0.68, with r = 0.42 ± 0.16 and d20 = 0.52 ± 0.09 averaged over the 12 patients. Compared to Jacobian-based metrics, HU-based metrics lead to statistically significant improvements in r and d20 (p < 0.05), with density scaled metrics also showing higher r than for unscaled versions (p < 0.02). r and d20 were also sensitive to image quality, with statistically significant improvements using standard (as opposed to gated) PET images and with application of median filtering. CONCLUSIONS The use of modified CT ventilation metrics, in conjunction with PET-Galligas and careful application of image filtering has resulted in improved correlation compared to earlier studies using nuclear medicine ventilation. However, CT ventilation and PET-Galligas do not always provide the same functional information. The authors have demonstrated that the agreement can improve for CT ventilation metrics incorporating a tissue density scaling, and also with increasing PET image quality. CT ventilation imaging has clear potential for imaging regional air volume change in the lung, and further development is warranted.

Impact of post-therapy positron emission tomography on prognostic stratification and surveillance after chemoradiotherapy for cervical cancer

A study was undertaken to investigate the detection of relapse and survival outcomes in patients with cervical cancer treated with curative intent chemoradiotherapy, and evaluated with a post‐therapy 18F‐fluorodeoxyglucose positron emission tomography (FDG‐PET) scan.

Outcomes of stereotactic radiotherapy for cranial and extracranial metastatic renal cell carcinoma: A systematic review

Abstract Background. Stereotactic radiotherapy is a non-invasive, ablative technique which may be particularly effective in treating metastatic renal cell carcinoma (RCC). The study objective was to analyse outcomes and toxicity of stereotactic radiotherapy in metastatic RCC. Material and methods. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic review of Medline was performed in March 2013. Exclusion criteria included mixed histology studies and case series. Local control, overall survival and toxicities were analysed. Results. From 148 publications identified, 16 and 10 publications for cranial and extracranial metastatic RCC met inclusion criteria, respectively. There were 810 intracranial patients and 2433 targets. The weighted local control was 92%. Overall survival ranged from 6.7 to 25.6 months. Significant Grade 3–4 toxicity ranged from 0% to 6%. The weighted rate of treatment-related mortality was 0.6%, all secondary to intratumoral haemorrhage. There were 389 extracranial patients and 730 targets. The weighted local control was 89%. Median overall survival ranged from 11.7 to 22 months. Grade 3–4 toxicity ranged from 0% to 4%. Treatment-related mortality was 0.5%. Conclusion. Stereotactic radiotherapy is associated with excellent local control and low rates of toxicity for intracranial and extracranial metastatic RCC. Future randomised studies are required to confirm the additional benefit of Stereotactic Ablative Body Radiotherapy (SABR) above standard conservative or palliative approaches.

Validation of a 4D-PET maximum intensity projection for delineation of an internal target volume

PURPOSE The delineation of internal target volumes (ITVs) in radiation therapy of lung tumors is currently performed by use of either free-breathing (FB) (18)F-fluorodeoxyglucose-positron emission tomography-computed tomography (FDG-PET/CT) or 4-dimensional (4D)-CT maximum intensity projection (MIP). In this report we validate the use of 4D-PET-MIP for the delineation of target volumes in both a phantom and in patients. METHODS AND MATERIALS A phantom with 3 hollow spheres was prepared surrounded by air then water. The spheres and water background were filled with a mixture of (18)F and radiographic contrast medium. A 4D-PET/CT scan was performed of the phantom while moving in 4 different breathing patterns using a programmable motion device. Nine patients with an FDG-avid lung tumor who underwent FB and 4D-PET/CT and >5 mm of tumor motion were included for analysis. The 3 spheres and patient lesions were contoured by 2 contouring methods (40% of maximum and PET edge) on the FB-PET, FB-CT, 4D-PET, 4D-PET-MIP, and 4D-CT-MIP. The concordance between the different contoured volumes was calculated using a Dice coefficient (DC). The difference in lung tumor volumes between FB-PET and 4D-PET volumes was also measured. RESULTS The average DC in the phantom using 40% and PET edge, respectively, was lowest for FB-PET/CT (DCAir = 0.72/0.67, DCBackground 0.63/0.62) and highest for 4D-PET/CT-MIP (DCAir = 0.84/0.83, DCBackground = 0.78/0.73). The average DC in the 9 patients using 40% and PET edge, respectively, was also lowest for FB-PET/CT (DC = 0.45/0.44) and highest for 4D-PET/CT-MIP (DC = 0.72/0.73). In the 9 lesions, the target volumes of the FB-PET using 40% and PET edge, respectively, were on average 40% and 45% smaller than the 4D-PET-MIP. CONCLUSION A 4D-PET-MIP produces volumes with the highest concordance with 4D-CT-MIP across multiple breathing patterns and lesion sizes in both a phantom and among patients. Freebreathing PET/CT consistently underestimates ITV when compared with 4D PET/CT for a lesion affected by respiration.

A Pattern of Early Radiation-Induced Inflammatory Cytokine Expression Is Associated with Lung Toxicity in Patients with Non-Small Cell Lung Cancer

Purpose Lung inflammation leading to pulmonary toxicity after radiotherapy (RT) can occur in patients with non-small cell lung cancer (NSCLC). We investigated the kinetics of RT induced plasma inflammatory cytokines in these patients in order to identify clinical predictors of toxicity. Experimental Design In 12 NSCLC patients, RT to 60 Gy (30 fractions over 6 weeks) was delivered; 6 received concurrent chemoradiation (chemoRT) and 6 received RT alone. Blood samples were taken before therapy, at 1 and 24 hours after delivery of the 1st fraction, 4 weeks into RT, and 12 weeks after completion of treatment, for analysis of a panel of 22 plasma cytokines. The severity of respiratory toxicities were recorded using common terminology criteria for adverse events (CTCAE) v4.0. Results Twelve cytokines were detected in response to RT, of which ten demonstrated significant temporal changes in plasma concentration. For Eotaxin, IL-33, IL-6, MDC, MIP-1α and VEGF, plasma concentrations were dependent upon treatment group (chemoRT vs RT alone, all p-values <0.05), whilst concentrations of MCP-1, IP-10, MCP-3, MIP-1β, TIMP-1 and TNF-α were not. Mean lung radiation dose correlated with a reduction at 1 hour in plasma levels of IP-10 (r2 = 0.858, p<0.01), MCP-1 (r2 = 0.653, p<0.01), MCP-3 (r2 = 0.721, p<0.01), and IL-6 (r2 = 0.531, p = 0.02). Patients who sustained pulmonary toxicity demonstrated significantly different levels of IP-10 and MCP-1 at 1 hour, and Eotaxin, IL-6 and TIMP-1 concentration at 24 hours (all p-values <0.05) when compared to patients without respiratory toxicity. Conclusions Inflammatory cytokines were induced in NSCLC patients during and after RT. Early changes in levels of IP-10, MCP-1, Eotaxin, IL-6 and TIMP-1 were associated with higher grade toxicity. Measurement of cytokine concentrations during RT could help predict lung toxicity and lead to new therapeutic strategies.

Stereotactic Ablative Body Radiation Therapy for Primary Kidney Cancer: A 3-Dimensional Conformal Technique Associated With Low Rates of Early Toxicity

PURPOSE To describe our 3-dimensional conformal planning approaches and report early toxicities with stereotactic body radiation therapy for the management of primary renal cell carcinoma. METHODS AND MATERIALS This is an analysis of a phase 1 trial of stereotactic body radiation therapy for primary inoperable renal cell carcinoma. A dose of 42 Gy/3 fractions was prescribed to targets ≥5 cm, whereas for <5 cm 26 Gy/1 fraction was used. All patients underwent a planning 4-dimensional CT to generate a planning target volume (PTV) from a 5-mm isotropic expansion of the internal target volume. Planning required a minimum of 8 fields prescribing to the minimum isodose surrounding the PTV. Intermediate dose spillage at 50% of the prescription dose (R50%) was measured to describe the dose gradient. Early toxicity (<6 months) was scored using the Common Terminology Criteria for Adverse Events (v4.0). RESULTS From July 2012 to August 2013 a total of 20 patients (median age, 77 years) were recruited into a prospective clinical trial. Eleven patients underwent fractionated treatment and 9 patients a single fraction. For PTV targets <100 cm(3) the median number of beams used was 8 (2 noncoplanar) to achieve an average R50% of 3.7. For PTV targets >100 cm(3) the median beam number used was 10 (4 noncoplanar) for an average R50% value of 4.3. The R50% was inversely proportional to decreasing PTV volume (r=-0.62, P=.003) and increasing total beams used (r=-0.51, P=.022). Twelve of 20 patients (60%) suffered grade ≤2 early toxicity, whereas 8 of 20 patients (40%) were asymptomatic. Nausea, chest wall pain, and fatigue were the most common toxicities reported. CONCLUSION A 3-dimensional conformal planning technique of 8-10 beams can be used to deliver highly tolerable stereotactic ablation to primary kidney targets with minimal early toxicities. Ongoing follow-up is currently in place to assess long-term toxicities and cancer control.

Complications from Stereotactic Body Radiotherapy for Lung Cancer

Stereotactic body radiotherapy (SBRT) has become a standard treatment option for early stage, node negative non-small cell lung cancer (NSCLC) in patients who are either medically inoperable or refuse surgical resection. SBRT has high local control rates and a favorable toxicity profile relative to other surgical and non-surgical approaches. Given the excellent tumor control rates and increasing utilization of SBRT, recent efforts have focused on limiting toxicity while expanding treatment to increasingly complex patients. We review toxicities from SBRT for lung cancer, including central airway, esophageal, vascular (e.g., aorta), lung parenchyma (e.g., radiation pneumonitis), and chest wall toxicities, as well as radiation-induced neuropathies (e.g., brachial plexus, vagus nerve and recurrent laryngeal nerve). We summarize patient-related, tumor-related, dosimetric characteristics of these toxicities, review published dose constraints, and propose strategies to reduce such complications.