We assessed the risk of second brain tumors in a cohort of patients with pituitary adenoma treated with conservative surgery and external beam radiotherapy. Four hundred and twenty-six patients ...(United Kingdom residents) with pituitary adenomas received radiotherapy at the Royal Marsden Hospital (RMH) between 1962 and 1994. They were followed up for 5749 person-years. The cumulative incidence of second intracranial tumors and systemic malignancy was compared with population incidence rates through the Thames Cancer Registry and the National Health Service Central Register (previously OPCS) to record death and the potential causes. Eleven patients developed a second brain tumor, including five meningiomas, four high grade astrocytomas, one meningeal sarcoma, and one primitive neuroectodermal tumor. The cumulative risk of second brain tumors was 2.0% 95% confidence interval (CI), 0.9–4.4% at 10 yr and 2.4% (95% CI, 1.2–5.0%) at 20 yr, measured from the date of radiotherapy. The relative risk of second brain tumor compared with the incidence in the normal population was 10.5 (95% CI, 4.3–16.7). The relative risk was 7.0 for neuroepithelial and 24.3 for meningeal tumors. The relative risks were 24.2 (95% CI, 4.8–43.5), 2.9 (95% CI, 0–8.5), and 28.6 (95% CI, 0.6–56.6) during the intervals 5–9, 10–19, and more than 20 yr after radiotherapy (four cases occurred >20 yr after treatment). There was no evidence of excess risk of second systemic malignancy. An additional 10-yr update confirmed our previous report of an increased risk of second brain tumors in patients with pituitary adenoma treated with surgery and radiotherapy. The 2.4% risk at 20 yr remains low and should not preclude the use of radiotherapy as an effective treatment option. However, an increased risk of second brain tumors continues beyond 20 and 30 yr after treatment.
We have previously shown that raised p-S6K levels correlate with resistance to chemotherapy in ovarian cancer. We hypothesised that inhibiting p-S6K signalling with the dual m-TORC1/2 inhibitor in ...patients receiving weekly paclitaxel could improve outcomes in such patients.
In dose escalation, weekly paclitaxel (80mg/m2) was given 6/7weeks in combination with two intermittent schedules of vistusertib (dosing starting on the day of paclitaxel): schedule A, vistusertib dosed bd for 3 consecutive days per week (3/7days) and schedule B, vistusertib dosed bd for 2 consecutive days per week (2/7days). After establishing a recommended phase II dose (RP2D), expansion cohorts in high-grade serous ovarian cancer (HGSOC) and squamous non-small-cell lung cancer (sqNSCLC) were explored in 25 and 40 patients, respectively.
The dose-escalation arms comprised 22 patients with advanced solid tumours. The dose-limiting toxicities were fatigue and mucositis in schedule A and rash in schedule B. On the basis of toxicity and pharmacokinetic (PK) and pharmacodynamic (PD) evaluations, the RP2D was established as 80mg/m2 paclitaxel with 50mg vistusertib bd 3/7days for 6/7weeks. In the HGSOC expansion, RECIST and GCIG CA125 response rates were 13/25 (52%) and 16/25 (64%), respectively, with median progression-free survival (mPFS) of 5.8months (95% CI: 3.28–18.54). The RP2D was not well tolerated in the SqNSCLC expansion, but toxicities were manageable after the daily vistusertib dose was reduced to 25mg bd for the following 23 patients. The RECIST response rate in this group was 8/23 (35%), and the mPFS was 5.8months (95% CI: 2.76–21.25).
In this phase I trial, we report a highly active and well-tolerated combination of vistusertib, administered as an intermittent schedule with weekly paclitaxel, in patients with HGSOC and SqNSCLC.
ClinicialTrials.gov identifier: CNCT02193633
Summary
Objective To assess the medium‐term outcome in a cohort of patients with residual or recurrent pituitary adenoma treated with fractionated stereotactic conformal radiotherapy (SCRT).
...Patients and methods Ninety‐two patients (median age 50 years) with a residual or recurrent nonfunctioning (67) or a secreting (25) pituitary adenoma were treated between 1995 and 2003. Eighteen patients had a GH‐secreting, five PRL‐secreting and two an ACTH‐secreting pituitary adenoma. Vision was impaired in 39 patients, with visual field deficit (35) and/or reduced visual acuity (25). Sixty‐four patients had partial or complete hypopituitarism before SCRT. The treatment was delivered stereotactically by four noncoplanar conformal fixed fields using a 6‐MV linear accelerator to a dose of 45 Gy in 25 fractions.
Results At a median follow‐up of 32 months (range 4–108) the 1, 3 and 5 years actuarial progression‐free survival is 99%, 98% and 98%, and overall survival is 98%. Three patients recurred 5 months, 1 year and 9 years after SCRT requiring surgery. In secreting adenomas, hormone levels declined progressively, becoming normal in more than a third of patients with GH‐secreting and PRL‐secreting pituitary tumours. 50% of baseline GH level was achieved in just under 2 years. The treatment was well tolerated with minimal acute toxicity. Hypopituitarism was the most common long‐term effect; 22% of patients had worsening of pituitary function. One patient developed unilateral quadrantopia without tumour progression.
Conclusion SCRT as a high‐precision technique of localized irradiation achieves tumour and hormone control of pituitary adenomas comparable with previously published data on the efficacy of conventional radiotherapy. Despite the potential advantage of reducing the volume of normal brain irradiated, the theoretical benefit over conventional radiotherapy in terms of the reduction in long‐term morbidity has not yet been demonstrated and requires longer follow‐up. Potential effect on long‐term cognitive function has not been tested.
In a glioblastoma tumour with multi-region sequencing before and after recurrence, we find an IDH1 mutation that is clonal in the primary but lost at recurrence. We also describe the evolution of a ...double-minute chromosome encoding regulators of the PI3K signalling axis that dominates at recurrence, emphasizing the challenges of an evolving and dynamic oncogenic landscape for precision medicine.
Glioblastoma (GBM) is the most common malignant brain cancer occurring in adults, and is associated with dismal outcome and few therapeutic options. GBM has been shown to predominantly disrupt three core pathways through somatic aberrations, rendering it ideal for precision medicine approaches.
We describe a 35-year-old female patient with recurrent GBM following surgical removal of the primary tumour, adjuvant treatment with temozolomide and a 3-year disease-free period. Rapid whole-genome sequencing (WGS) of three separate tumour regions at recurrence was carried out and interpreted relative to WGS of two regions of the primary tumour.
We found extensive mutational and copy-number heterogeneity within the primary tumour. We identified a TP53 mutation and two focal amplifications involving PDGFRA KIT and CDK4, on chromosomes 4 and 12. A clonal IDH1 R132H mutation in the primary, a known GBM driver event, was detectable at only very low frequency in the recurrent tumour. After sub-clonal diversification, evidence was found for a whole-genome doubling event and a translocation between the amplified regions of PDGFRA KIT and CDK4, encoded within a double-minute chromosome also incorporating miR26a-2. The WGS analysis uncovered progressive evolution of the double-minute chromosome converging on the KIT/PDGFRA/PI3K/mTOR axis, superseding the IDH1 mutation in dominance in a mutually exclusive manner at recurrence, consequently the patient was treated with imatinib. Despite rapid sequencing and cancer genome-guided therapy against amplified oncogenes, the disease progressed, and the patient died shortly after.
This case sheds light on the dynamic evolution of a GBM tumour, defining the origins of the lethal sub-clone, the macro-evolutionary genomic events dominating the disease at recurrence and the loss of a clonal driver. Even in the era of rapid WGS analysis, cases such as this illustrate the significant hurdles for precision medicine success.
Abstract Brain metastases are common and the prognosis for patients with multiple brain metastases treated with whole brain radiotherapy is limited. As systemic disease control continues to improve, ...the expectations of radiotherapy for brain metastases are growing. Stereotactic radiosurgery (SRS) as a high precision localised irradiation given in a single fraction prolongs survival in patients with a single brain metastasis and functional independence in those with up to three brain metastases. SRS technology has become commonplace and is available in many radiation oncology and neurosurgery departments. With increasing use there is a need for appropriate patient selection, refinement of dose-fractionation and safe integration of SRS with other treatment modalities. We review the evidence for current practice and new developments in the field, with a specific focus on patient-relevant outcomes.
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