H. Benghiat

Effect of cancer treatment on hypothalamic–pituitary function

The past 30 years have seen a great improvement in survival of children and young adults treated for cancer. Cancer treatment can put patients at risk of health problems that can develop many years later, most commonly affecting the endocrine system. Patients treated with cranial radiotherapy often develop dysfunction of the hypothalamic-pituitary axis. A characteristic pattern of hormone deficiencies develops over several years. Growth hormone is disrupted most often, followed by gonadal, adrenal, and thyroid hormones, leading to abnormal growth and puberty in children, and affecting general wellbeing and fertility in adults. The severity and rate of development of hypopituitarism is determined by the dose of radiotherapy delivered to the hypothalamic-pituitary axis. Individual growth hormone deficiencies can develop after a dose as low as 10 Gy, whereas multiple hormone deficiencies are common after 60 Gy. New techniques in radiotherapy aim to reduce the effect on the hypothalamic-pituitary axis by minimising the dose received. Patients taking cytotoxic drugs do not often develop overt hypopituitarism, although the effect of radiotherapy might be enhanced. The exception is adrenal insufficiency caused by glucocorticosteroids which, although transient, can be life-threatening. New biological drugs to treat cancer can cause autoimmune hypophysitis and hypopituitarism; therefore, oncologists and endocrinologists should be vigilant and work together to optimise patient outcomes.

Survival benefit for patients with diffuse intrinsic pontine glioma (DIPG) undergoing re-irradiation at first progression: A matched-cohort analysis on behalf of the SIOP-E-HGG/DIPG working group

BACKGROUNDnOverall survival (OS) of patients with diffuse intrinsic pontine glioma (DIPG) is poor. The purpose of this study is to analyse benefit and toxicity of re-irradiation at first progression.nnnMETHODSnAt first progression, 31 children with DIPG, aged 2-16 years, underwent re-irradiation (dose 19.8-30.0xa0Gy) alone (nxa0=xa016) or combined with systemic therapy (nxa0=xa015). At initial presentation, all patients had typical symptoms and characteristic MRI features of DIPG, or biopsy-proven high-grade glioma. An interval of ≥3 months after upfront radiotherapy was required before re-irradiation. Thirty-nine patients fulfilling the same criteria receiving radiotherapy at diagnosis, followed by best supportive care (nxa0=xa020) or systemic therapy (nxa0=xa019) at progression but no re-irradiation, were eligible for a matched-cohort analysis.nnnRESULTSnMedian OS for patients undergoing re-irradiation was 13.7 months. For a similar median progression-free survival after upfront radiotherapy (8.2 versus 7.7 months; Pxa0=xa0.58), a significant benefit in median OS (13.7 versus 10.3 months; Pxa0=xa0.04) was observed in favour of patients undergoing re-irradiation. Survival benefit of re-irradiation increased with a longer interval between end-of-radiotherapy and first progression (3-6 months: 4.0 versus 2.7; Pxa0<xa0.01; 6-12 months: 6.4 versus 3.3; Pxa0=xa0.04). Clinical improvement with re-irradiation was observed in 24/31 (77%) patients. No grade 4-5 toxicity was recorded. On multivariable analysis, interval to progression (corrected hazard ratioxa0=xa0.27-.54; Pxa0<xa0.01) and re-irradiation (corrected hazard ratioxa0=xa0.18-.22; Pxa0<xa0.01) remained prognostic for survival. A risk score (RS), comprising 5 categories, was developed to predict survival from first progression (ROC: .79). Median survival ranges from 1.0 month (RS-1) to 6.7 months (RS-5).nnnCONCLUSIONSnThe majority of patients with DIPG, responding to upfront radiotherapy, do benefit of re-irradiation with acceptable tolerability.

Linear accelerator stereotactic radiosurgery for vestibular schwannomas: a UK series.

AIMSnTo evaluate non-auditory toxicity and local control after linear accelerator stereotactic radiosurgery (SRS) for the treatment of vestibular schwannomas.nnnMATERIALS AND METHODSnThe institutional policy was to use SRS for radiologically progressing vestibular schwannomas. Case notes and plans were retrospectively reviewed for all patients undergoing SRS for vestibular schwannomas between September 2002 and June 2012. All patients were surgically immobilised using a BrainLab stereotactic head frame. The treatment plan was generated using BrainLab software (BrainScan 5.03). The aim was to deliver 12 Gy to the surface of the target with no margin. Patients with a minimum of 12 months of follow-up were included for toxicity and local control assessment. Radiological progression was defined as growth on imaging beyond 2 years of follow-up. Overall local control was defined in line with other series as absence of surgical salvage.nnnRESULTSnNinety-nine patients were identified. Two patients were lost to follow-up. After a median follow-up interval of 2.4 years, the actuarial radiological progression-free survival at 3 years was 100% and overall local control was also 100%. However, two patients progressed radiologically at 3.3 and 4.5 years, respectively. Twenty-one of 97 (22%) evaluable patients suffered trigeminal toxicity and this was persistent in 8/97 (8%). Two of 97 (2%) suffered long-term facial nerve toxicity (one with associated radiological progression causing hemi-facial spasm alone). One of 97 (1%) required intervention for obstructive hydrocephalus. No statistically significant dosimetric relationship could be shown to cause trigeminal or facial nerve toxicity. However, 7/8 patients with persistent trigeminal nerve toxicity had tumours in contact with the trigeminal nerve.nnnCONCLUSIONSnSRS delivering 12 Gy using a linear accelerator leads to high local control rates, but only prospective evaluation will fully establish short-term toxicity. In this study, persistent trigeminal toxicity occurred almost exclusively in patients whose tumour was in contact with the trigeminal nerve.

WITHDRAWN: Does Dose to an Oral Mucosa Organ at Risk Predict the Duration of Grade 3 Mucositis after Intensity-modulated Radiotherapy for Oropharyngeal Cancer?

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In Regard to Beitler et al

observations and suggests methods of modifying the impact of radiation on immune cells. Cancer Invest 2013;31:140-144. 5. Grossman SA, Ye X, Lesser G, et al. Immunosuppression in patients with high-grade gliomas treated with radiation and temozolomide. Clin Cancer Res 2011;17:5473-5480. 6. Dennis ER, Bussiere MR, Niewmierko A, et al. A comparison of critical structure dose and toxicity risks in patients with low grade gliomas treated with IMRT versus proton radiation therapy. Technol Cancer Res Treat 2013;12:1-9.

Dexamethasone-related adrenal insufficiency in patients with brain and skull base tumours

PurposeThis study aimed to evaluate the prevalence of glucocorticoid-induced adrenal insufficiency in a cohort of patients with brain and skull base tumours and to identify factors which may predict its occurrence.MethodsPatients with brain or skull base tumours attending for a short synacthen test (SST) (adrenocorticotropin hormone (ACTH) stimulation test) at a single institution over a 3-year period were retrospectively identified. Baseline demographics and dexamethasone exposure were examined. Only patients with dexamethasone exposure were included in the final analysis looking at the primary end point of SST failure. Fisher’s exact test, Student’s t test, Mann-Whitney test and the Kendall’s tau-b test were used to evaluate the influence of age, gender, diagnosis and mean pituitary radiation dose on the primary endpoint. Receiver operating characteristic (ROC) curves were generated to explore the impact of duration and total exposure to dexamethasone on likelihood of SST failure.ResultsThirty-one of 51 patients with previous dexamethasone exposure failed their first SST (61%). No significant relationship was demonstrated between age, gender, diagnosis or mean pituitary radiation dose and SST failure. Duration of and total exposure to dexamethasone were significantly associated with SST failure (pxa0=u20090.001 and pxa0=u20090.007, respectively). ROC curves generated values of 78xa0days and 171xa0mgxa0days to give a sensitivity of 94 and 97%, respectively, to detect SST failure.ConclusionsDuration of dexamethasone use and total exposure predict for adrenal insufficiency in patients with brain and skull base tumours. Values derived from this study may be useful to identify patients at higher risk of adrenal suppression who require empirical hydrocortisone pending formal testing of the hypothalamic-pituitary-adrenal axis.

The Expanding Role of Radiosurgery for Brain Metastases

Stereotactic radiosurgery (SRS) has become increasingly important in the management of brain metastases due to improving systemic disease control and rising incidence. Initial trials demonstrated SRS with whole-brain radiotherapy (WBRT) improved local control rates compared with WBRT alone. Concerns with WBRT associated neurocognitive toxicity have contributed to a greater use of SRS alone, including for patients with multiple metastases and following surgical resection. Molecular information, targeted agents, and immunotherapy have also altered the landscape for the management of brain metastases. This review summarises current and emerging data on the role of SRS in the management of brain metastases.

Revised Modelling of the Addition of Synchronous Chemotherapy to Radiotherapy in Squamous Cell Carcinoma of the Head and Neck—A Low α/β?

Background: The effect of synchronous chemotherapy in squamous cell carcinoma of the head and neck (SCCHN) has been modelled as additional Biologically Effective Dose (BED) or as a prolonged tumour cell turnover time during accelerated repopulation. Such models may not accurately predict the local control seen when hypofractionated accelerated radiotherapy is used with synchronous chemotherapy. Methods: For the purposes of this study three isoeffect relationships were assumed: Firstly, from the RTOG 0129 trial, synchronous cisplatin chemotherapy with 70 Gy in 35 fractions over 46 days results in equivalent local control to synchronous cisplatin chemotherapy with 36 Gy in 18# followed by 36 Gy in 24# (2# per day) over a total of 39 days. Secondly, in line with primary local control outcomes from the PET-Neck study, synchronous cisplatin chemotherapy with 70 Gy in 35# over 46 days results in equivalent local control to synchronous cisplatin chemotherapy delivered with 65 Gy in 30# over 39 days. Thirdly, from meta-analysis data, 70 Gy in 35# over 46 days with synchronous cisplatin results in equivalent local control to 84 Gy in 70# over 46 days delivered without synchronous chemotherapy. Using the linear quadratic equation the above isoeffect relationships were expressed algebraically to determine values of α, α/β, and k for SCCHN when treated with synchronous cisplatin using standard parameters for the radiotherapy alone schedule (α = 0.3 Gy−1, α/β = 10 Gy, and k = 0.42 Gy10day−1). Results: The values derived for α/β, α and k were 2 Gy, 0.20 and 0.21 Gy−1, and 0.65 and 0.71 Gy2day−1. Conclusions: Within the limitations of the assumptions made, this model suggests that accelerated repopulation may remain a significant factor when synchronous chemotherapy is delivered with radiotherapy in SCCHN. The finding of a low α/β for SCCHN treated with cisplatin suggests a greater tumour susceptibility to increasing dose per fraction and underlines the importance of the completion of randomized trials examining the role of hypofractionated acceleration in SCCHN.

Evaluation of Response to Stereotactic Radiosurgery in Brain Metastases Using Multiparametric Magnetic Resonance Imaging and a Review of the Literature

AIMSnFollowing stereotactic radiosurgery (SRS), brain metastases initially increase in size in up to a third of cases, suggesting treatment failure. Current imaging using structural magnetic resonance imaging (MRI) cannot differentiate between tumour recurrence and SRS-induced changes, creating difficulties with patient management. Combining multiparametric MRI techniques, which assess tissue physiological and metabolic information, has shown promise in answering this clinical question.nnnMATERIALS AND METHODSnMultiparametric MRI techniques, including spectroscopy, diffusion and perfusion imaging, were used for the differentiation of radiation-related changes and tumour recurrence after SRS for intracranial metastases in six cases. All patients presented with enlargement of the treated lesion, an increase in perilesional brain oedema and aggravation or appearance of neurological signs and symptoms from 7 to 29 weeks after primary treatment.nnnRESULTSnMultiparametric imaging helped to differentiate features of tumour progression (nxa0=xa04) from radiation-related changes (nxa0=xa02). A low apparent diffusion coefficient (ADC) <1000xa0×xa010-6xa0mm2/s, high relative cerebral blood volume (rCBV) ratioxa0>xa02.1, high choline:creatine (Cho:Cr) ratioxa0>xa01.8 suggested tumour recurrence. A high ADC > 1000xa0×xa010-6xa0mm2/s, low rCBV ratioxa0<xa02.1, Cho:Cr ratio < 1.8 suggested SRS-induced radiation changes. Multiparametric MRI diagnosis was confirmed by histology or radiological and clinical follow-up.nnnCONCLUSIONnMultiparametric MRI was helpful in the early identification of radiation-related changes and tumour recurrence and may be useful for monitoring treatment changes in intracranial neoplasms after SRS treatment.

EP-1124: Outcomes of patients with 4 or more cerebral metastases treated with stereotactic radiosurgery

Results: Three patterns of tumor spread were found. The first pattern followed the thalamic tributaries of the posterior part of the internal cerebral veins. These were the anterior and superior thalamic veins. For the second pattern the close proximity of the internal cerebral vein branches of the superior thalamic veins was a potential route of spread between the medial surfaces of the thalami. In addition to spread across the midline tumours could also spread along the adjacent tectal, pineal and/or vermian veins. The third pattern of thalamic tumor spread was found in gliomas which use the anterior tributaries of the internal cerebral venous architecture of the posterior and inferior branches from the basal vein of Rosenthal.