Integrated treatment of brain metastases.

PURPOSE OF REVIEW: Optimal treatment of brain metastases has been limited to local treatment with few systemic options. Increasing use of systemic targeted therapies, chemotherapy and immunotherapy and combination of local and systemic treatments has resulted in plethora of publications. We review the existing evidence for individual treatments and new evidence for the integration of systemic and combination of local treatments. RECENT FINDINGS: Encouraging efficacy of systemic therapies supports combination of systemic and local treatment albeit with little randomized trial data. Efficacy particularly of targeted agents provides an opportunity to delay local treatments including radiosurgery and whole brain radiotherapy. Randomized trials testing the integration of surgery, radiotherapy and radiosurgery are reviewed with emphasis on patient relevant endpoints to guide the clinician in the choice and sequence of treatments and integrating systemic and local therapies. SUMMARY: There is increasing tendency to use focused radiation for single and oligometastases with or without surgery and decline in whole brain radiotherapy which is limited to multiple metastases in tumours without effective systemic options. Systemic therapies have promising intracranial efficacy and the sequence and combination with localized radiation is awaiting trials. Changes in practice with a move to primary systemic treatment for brain metastases without radiation, should be undertaken with caution and close monitoring.

Target definition in salvage postoperative radiotherapy for prostate cancer: 18F-fluorocholine PET/CT assessment of local recurrence.

PURPOSE: Inadequate clinical target volume (CTV) definition is likely to be a major contributing factor to local recurrence (LR) rate after radiotherapy. Our aims were to identify sites of prostate cancer LR in biochemical recurrence post-prostatectomy using 18F-Fluorocholine (18F-FCH) positron emission tomography/computed tomography (PET/CT) and to compare different CTV-delineation guidelines in a cohort of postoperative patients. MATERIAL AND METHODS: Thirty-six patients presenting with LR within the prostatic bed on 18F-FCH PET/CT between 10/2011 and 06/2016 were included in this retrospective study. Median PSA at the time of 18F-FCH PET/CT was 2.7 ng/mL (0.8-9.4) and median PSA doubling time was 11 months (3-28). For each patient, the CTVRTOG, CTVFROGG and CTVEORTC following the corresponding guidelines were outlined and compared. Forty-one LR were delineated using a gradient-based method and the percentage of FCH uptake included in each CTV was evaluated. RESULTS: The anastomosis was the most common recurrence site (52.8%), followed by the retrovesical region (31.7%) and the bladder neck (7%). The median SUV max value was 4.8 (2.3-16.1). The percentage of LR entirely included in the CTVRTOG was not significantly different from that included in the CTVFROGG (84% versus 83%, p = .5). Significantly more recurrences were included in the CTVRTOG volume compared to the CTVEORTC (84% versus 68%, p=.006), due to a better coverage of the bladder neck and retrovesical regions. Six out of 10 relapses occurring in the posterior region of the anastomosis were not covered by any of the CTVs. CONCLUSIONS: In our study, the CTVRTOG and CTVFROGG ensured the best coverage of LR seen on 18F-FCH PET/CT. When outlining the prostatic fossa, greater coverage of the posterior vesico-urethral region may allow better coverage of potential microscopic disease.

A brain metastasis liquid biopsy: Where are we now?

Brain metastases remain a challenging and feared complication for patients with cancer and research in this area has lagged behind research into metastases to other organs. Due to their location and the risks associated with neurosurgical biopsies, the biology underpinning brain metastases response to treatment and evolution over time remains poorly understood. Liquid biopsies are proposed to overcome many of the limitations present with tissue biopsies, providing a better representation of tumor heterogeneity, facilitating repeated sampling, and providing a noninvasive assessment of tumor biology. Several different liquid biopsy approaches have been investigated including circulating tumor cells, circulating tumor DNA, extracellular vesicles, and tumor-educated platelets; however, these have generally been less effective in assessing brain metastases compared to metastases to other organs requiring improved techniques to investigate these approaches, studies combining different liquid biopsy approaches and/or novel liquid biopsy approaches. Through this review, we highlight the current state of the art and define key unanswered questions related to brain metastases liquid biopsies.

Contrast Clearance Analysis (CCA) to Assess Viable Tumour following Stereotactic Radiosurgery (SRS) to Brain Metastasis in Non-Small Cell Lung Cancer (NSCLC).

BACKGROUND AND OBJECTIVE: Brain metastases are common in lung cancer and increasingly treated using targeted radiotherapy techniques such as stereotactic radiosurgery (SRS). Using MRI, post-SRS changes may be difficult to distinguish from progressive brain metastasis. Contrast clearance analysis (CCA) uses T1-weighted MRI images to assess the clearance of gadolinium and can be thus used to assess vascularity and active tumours. DESIGN AND METHODS: We retrospectively assessed CCAs in 62 patients with non-small cell lung cancer (NSCLC) undergoing 104 CCA scans in a single centre. RESULTS: The initial CCA suggested the aetiology of equivocal changes on standard MRI in 80.6% of patients. In all patients whose initial CCA showed post-SRS changes and who underwent serial CCAs, the initial diagnosis was upheld with the serial imaging. In only two cases of a presumed progressive tumour on the initial CCA, subsequent treatment for radionecrosis was instigated; a retrospective review and re-evaluation of the CCAs show that progression was reported where a thin rim of rapid contrast clearance was seen, and this finding has been subsequently recognised as a feature of post-treatment change on CCAs. The lack of concordance with CCA findings in those who underwent surgical resection was also found to be due to the over-reporting of the thin blue rim as disease in the early cases of CCA use and, in three cases, potentially related to timelines longer than 7 days prior to surgery, both factors being unknown during the early implementation phase of CCA at our centre but subsequently learned. CONCLUSIONS: Our single-centre experience shows CCA to be feasible and useful in patients with NSCLC in cases of diagnostic uncertainty in MRI. It has helped guide treatment in the majority of patients, with subsequent outcomes following the implementation of the treatment based on the results, suggesting correct classification. Recommendations from our experience of the implementation include the careful consideration of the thin rim of the rapid contrast clearance and the timing of the CCA prior to surgery for suspected brain metastasis progression.

Survival after Stereotactic Radiosurgery in the Era of Targeted Therapy: Number of Metastases No Longer Matters.

Randomised control trial data support the use of stereotactic radiosurgery (SRS) in up to 4 brain metastases (BMs), with non-randomised prospective data complementing this for up to 10 BMs. There is debate in the neuro-oncology community as to the appropriateness of SRS in patients with >10 BMs. We present data from a large single-centre cohort, reporting survival in those with >10 BMs and in a >20 BMs subgroup. A total of 1181 patients receiving SRS for BMs were included. Data were collected prospectively from the time of SRS referral. Kaplan-Meier graphs and logrank tests were used to compare survival between groups. Multivariate analysis was performed using the Cox proportional hazards model to account for differences in group characteristics. Median survival with 1 BM (n = 379), 2-4 BMs (n = 438), 5-10 BMs (n = 236), and >10 BMs (n = 128) was 12.49, 10.22, 10.68, and 10.09 months, respectively. Using 2-4 BMs as the reference group, survival was not significantly different in those with >10 BMs in either our univariable (p = 0.6882) or multivariable analysis (p = 0.0564). In our subgroup analyses, median survival for those with >20 BMs was comparable to those with 2-4 BMs (10.09 vs. 10.22 months, p = 0.3558). This study contributes a large dataset to the existing literature on SRS for those with multi-metastases and supports growing evidence that those with >10 BMs should be considered for SRS.

Bilateral adrenal-renal fusion: A radiological diagnosis.

In normal anatomy, the kidneys and adrenal glands are contained within the renal fascia and separated by a connective tissue capsule derived from mesenchymal tissue. Incomplete encapsulation can occur during embryonic development, resulting in adrenal-renal fusion. The true incidence of this developmental anomaly is unknown, as it has primarily been described in the literature following incidental detection on surgical or histological examination. We report the first documented case of bilateral adrenal-renal fusion, diagnosed radiologically.

Segmental mediolytic arteriopathy in a patient with intraperitoneal bleeding.

Segmental mediolytic arteriopathy (SMA) is a rare condition. It was first defined in 1976 and has been well described in the literature, although to date the aetiology of the condition is unknown. In most case reports SMA is diagnosed retrospectively once tissue has undergone histological examination. We present the first known case of SMA of the colic, mid-jejunal, common hepatic, intrahepatic and gastric arteries to be diagnosed at angiography after multiple episodes of undiagnosed intraperitoneal bleeding, and, perhaps related to this, one of the few reported patients with SMA involving multiple intra-abdominal arteries to have survived.

Comparison of setup accuracy and intrafraction motion using stereotactic frame versus 3-point thermoplastic mask-based immobilization for fractionated cranial image guided radiation therapy.

PURPOSE: Prospectively compare patient setup accuracy and intrafraction motion of a standard 3-point thermoplastic mask with the Gill-Thomas-Cosman relocatable stereotactic frame, during fractionated cranial radiation therapy using the ExacTrac system (Brainlab AG Feldkirchen, Germany) for daily online correction. METHODS AND MATERIALS: The number of fractions with all postcorrection and post-treatment errors <2 mm was assessed in 21 patients undergoing fractionated stereotactic radiation therapy (13 frame setup, 8 mask setup) using daily online correction. Achievable patient setup accuracy and total intrafraction motion were evaluated. The relative contributions of movement during floor rotation and patient movement to intrafraction motion were calculated. RESULTS: With daily online correction, patient setup margins can be reduced from 1, 5, and 4 mm in the lateral, longitudinal, and vertical axes for mask setup and from 1-2, 2, and 1 mm, respectively, for frame setup to <1 mm isotropically for either immobilization system. Intrafraction movement was small for frame setup (mean [SD], -0.3 [0.3], -1.1[0.4], and -0.2 [0.6] in lateral, longitudinal and vertical axes, respectively; maximum, -2.7 mm [longitudinal axis]), and mask-setup (mean [SD], -0.4 [0.5], -0.8 [0.7], and 0.0 [0.3], respectively; maximum, -2.0 mm [longitudinal axis]) and is mainly due to floor rotation. Postcorrection and post-treatment errors were all <2 mm in 95% and 99% of fractions in the mask and frame, respectively, meeting the criteria for a 3-mm clinical target volume-planning target volume margin for either immobilization method. CONCLUSIONS: Daily online correction can compensate for less precise immobilization and permits stereotactic margins to be used for standard thermoplastic masks without the need for specialized mask systems.

Brain metastases.

INTRODUCTION: Metastases to the central nervous system may occur with tumours of any primary origin. Brain (cerebral) metastases may be either single or multiple, with or without disseminated disease elsewhere. Brain metastases may present with focal or generalised symptoms, although up to one third of people may be asymptomatic. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of interventions for managing brain metastases in adults? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We identified 38 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: corticosteroids, surgery, radiosurgery, whole-brain radiotherapy (external beam), cytotoxic chemotherapy (systemic), surgery plus radiosurgery, surgery plus whole-brain radiotherapy (external beam), whole-brain radiotherapy plus radiosurgery, surgery plus radiosurgery plus whole-brain radiotherapy (external beam), and whole-brain radiotherapy (external beam) plus radiation sensitisers.

Characteristics of response of oral and pharyngeal mucosa in patients receiving chemo-IMRT for head and neck cancer using hypofractionated accelerated radiotherapy.

PURPOSE: This study describes the acute response of oral and pharyngeal mucosa to chemo-IMRT schedules using different doses per fraction. MATERIALS AND METHODS: Patients, treated in prospective trials of concomitant chemo-IMRT with 2.17 Gy, 2.25 Gy and 2.4 Gy per fraction and identical dose of cisplatin, were included in this study. Acute toxicity was recorded prospectively using the CTCAE v2.0. We describe the incidence and prevalence of grade 3 oral mucositis and dysphagia over time and report the influence of overall treatment time (OTT). The association between the lengths of pharyngeal mucosa receiving 50 Gy (L50) and 60 Gy (L60) and grade 3 dysphagia was tested. RESULTS: The incidence and the peak prevalence of grade 3 dysphagia were significantly higher in patients receiving 2.4 Gy per fraction. The peak prevalence of grade 3 dysphagia was higher and the recovery was slower in patients with lower OTT (median 38 days vs. 42 days) treatment. There was a significant correlation between L50, L60 and grade 3 dysphagia. A L50 and L60 greater than 8 cm resulted in greater than 60% and 70% incidence of grade 3 dysphagia, respectively. CONCLUSION: The length of pharyngeal mucosa receiving doses close to the prescription dose correlates with grade 3 dysphagia. It was observed that incidence of grade 3 dysphagia was lower and recovery from it was quicker in patients with greater OTT.