Outcomes of primary lymphoma of the ocular adnexa (orbital lymphoma) treated with radiotherapy.

AIMS: Low-grade ocular adnexal lymphoma is a rare disease and often treated with local radiotherapy to varying doses. Most previously reported studies have a very heterogeneous patient population and treatments. We report the outcomes from a 10 year cohort of patients at our institution treated with primary radiation therapy. MATERIALS AND METHODS: We analysed a retrospective case series of patients with stage IE low-grade ocular adnexal lymphoma including a review of case notes, histological reports and radiotherapy charts. We assessed local and distant tumour control and relapse rates in addition to toxicity. Disease-free survival was estimated using the Kaplan-Meier method. RESULTS: In total, 81 patients and 85 orbits were treated with primary radiotherapy to a median dose of 30 Gy in 15 fractions over 3 weeks. Seventy-nine per cent were treated with standard MV external beam radiotherapy to the whole orbit and 21% with a lens-sparing technique. The median follow-up was 4.4 years (range 0.2-10.4). Local control rates were 100%, with 5% of patients experiencing disease relapse elsewhere. No patients died from lymphoma. Cumulative acute toxicity rates were 51% (mainly erythema and conjunctivitis) and late toxicity rates were 8% (mainly cataract). The lens-sparing technique was associated with a significant reduction in cataract rate (P = 0.013) and an increase in acute toxicity (P < 0.001). CONCLUSIONS: This study has shown excellent local control rates and acceptable toxicity from the treatment of stage IE low-grade ocular adnexal lymphoma with localised radiotherapy to a median dose of 30 Gy in 15 fractions over 3 weeks.

Sequelae and survivorship in patients treated with (131)I-MIBG therapy.

BACKGROUND: (131)I-meta-iodobenzylguanidine ((131)I-MIBG) has been in therapeutic use since 1980s. Newer treatment modalities are emerging for neuroendocrine tumours (NETs) and chromaffin cell tumours (CCTs), but many of these do not yet have adequate long-term follow-up to determine their longer term efficacy and sequelae. METHODS: Fifty-eight patients with metastatic NETs and CCTs who had received (131)I-MIBG therapy between 2000 and 2011 were analysed. Survival and any long-term haematological or renal sequelae were investigated. RESULTS: In the NET group, the overall median survival and median survival following the diagnosis of metastatic disease was 124 months. The median survival following the commencement of (131)I-MIBG was 66 months. For the CCT group, median survival had not been reached. The 5-year survival from diagnosis and following the diagnosis of metastatic disease was 67% and 67.5% for NETs and CCTs, respectively. The 5-year survival following the commencement of (131)I-MIBG therapy was 68%. Thirty-two patients had long-term haematological sequelae: 5 of these 32 patients developed haematological malignancies. Two patients developed a mild deterioration in renal function. CONCLUSION: Long follow up of (131)I-MIBG therapy reveals a noteable rate of bone marrow toxicities and malignancy and long term review of all patients receiving radionuclide therapies is recommended.

Elevated expression of artemis in human fibroblast cells is associated with cellular radiosensitivity and increased apoptosis.

BACKGROUND: The objective of this study was to determine the molecular mechanisms responsible for cellular radiosensitivity in two human fibroblast cell lines 84BR and 175BR derived from two cancer patients. METHODS: Clonogenic assays were performed following exposure to increasing doses of gamma radiation to confirm radiosensitivity. γ-H2AX foci assays were used to determine the efficiency of DNA double-strand break (DSB) repair in cells. Quantitative PCR (Q-PCR) established the expression levels of key DNA DSB repair genes. Imaging flow cytometry using annexin V-FITC was used to compare artemis expression and apoptosis in cells. RESULTS: Clonogenic cellular hypersensitivity in the 84BR and 175BR cell lines was associated with a defect in DNA DSB repair measured by the γ-H2AX foci assay. The Q-PCR analysis and imaging flow cytometry revealed a two-fold overexpression of the artemis DNA repair gene, which was associated with an increased level of apoptosis in the cells before and after radiation exposure. Overexpression of normal artemis protein in a normal immortalised fibroblast cell line NB1-Tert resulted in increased radiosensitivity and apoptosis. CONCLUSION: We conclude that elevated expression of artemis is associated with higher levels of DNA DSB, radiosensitivity and elevated apoptosis in two radio-hypersensitive cell lines. These data reveal a potentially novel mechanism responsible for radiosensitivity and show that increased artemis expression in cells can result in either radiation resistance or enhanced sensitivity.

Primary lymphoma of the ocular adnexa (orbital lymphoma) and primary intraocular lymphoma.

Lymphomas of the orbit and eye are rare conditions that should be treated as separate entities due to the differences in presumed aetiology, investigations, management and outcomes. Orbital lymphoma is most often of low-grade histology; thyroid eye disease may predispose and chlamydial infection has been suggested as a trigger. Commonly, stage IE, in most cases, can be managed with radiotherapy alone using either a kilovoltage portal for conjunctival disease or a wedged pair of megavoltage beams for more infiltrative disease to a dose of 30 Gy in 15 fractions over 3 weeks. However, medical therapy is being investigated, including a rituximab-only approach for conjunctival-only presentations. The cure rate for stage IE disease is very high. In contrast, primary ocular lymphoma is often of high-grade histology, in particular diffuse large B-cell lymphoma, and can be regarded as one end of primary central nervous system lymphoma - both eyes and brain being at risk. Immunosuppression predisposes to the disease. Management consists of an initial high-dose chemotherapy regimen with methotrexate. In most cases, this should be followed by radiotherapy to the whole brain and globes to a dose of 30-36 Gy with a boost to bulk/presenting disease. Cure rates are rarely above 50%.

Bevacizumab treatment for vestibular schwannomas in neurofibromatosis type two: report of two cases, including responses after prior gamma knife and vascular endothelial growth factor inhibition therapy.

OBJECTIVES: Vestibular schwannomas are the hallmark of neurofibromatosis type two. They are difficult to treat, due to their bilateral presentation and the quest for hearing preservation. Our report describes a new treatment approach in this clinical scenario. CASE REPORT: We report two cases which confirm that bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, causes regression of vestibular schwannomas in patients with a previous history of gamma knife radiosurgery or failed treatment with another form of vascular endothelial growth factor targeted therapy. CONCLUSION: In 2009, Plotkin et al. reported the volumetric response of vestibular schwannomas to bevacizumab treatment, both in untreated patients and in patients previously treated with erlotinib, an epidermal growth factor receptor inhibitor. The presented cases support the use of bevacizumab to treat vestibular schwannomas. Given the extremely slow growth of these tumours, we note the rapidity of volume reduction following bevacizumab therapy.

(Stereotactic) radiosurgery XIX: spinal radiosurgery--two year experience in a UK centre.

INTRODUCTION: Modern radiotherapy image guidance enables the treatment of extracranial targets with the required accuracy for safe delivery of radiosurgical treatments. The first two years' experience of spinal radiosurgery in a UK radiotherapy centre is reported. MATERIALS AND METHODS: Patients with primary or metastatic spinal lesions were treated using the CyberKnife stereotactic radiotherapy system. Xsight Spine (fiducial-free) tumour tracking software was used in all cases. Treatment was delivered using either a single or a three-fraction schedule, between February 2009 and March 2011. RESULTS: Fifty-three spinal lesions were treated, comprising 14 primary lesions in 12 patients, and 39 metastases in 29 patients. The prescription dose ranged from 8 to 30 Gy in 1-3 fractions. Fifty-nine percent of patients experienced no acute side effects from treatment. There were three cases of acute grade 3 back or nerve root pain, all of which responded to a short course of oral corticosteroids. At a median follow-up of 11.1 months, local control and overall survival were 91 and 65%, respectively. Pain improvement was seen in 75% of symptomatic metastases at 6 months post treatment. CONCLUSIONS: Early UK experience confirms that radiosurgery is well tolerated with excellent local control rates. Longer-term prospective data are needed to clarify the role of spinal radiosurgery for patients in this country.

First quinquennial review of intensity-modulated radiotherapy at St Bartholomew's Hospital, London.

Intensity-modulated radiotherapy (IMRT) is a relatively new technique of delivering external beam radiotherapy that is becoming increasingly available in the UK. This paper summarises the introduction and initial clinical work in IMRT over the period 2004-2009. Physics aspects of commissioning are described, including the development of a robust method of quality control using a sweeping gap test. Details of the organisational changes necessary to introduce IMRT are given. The clinical selection and practice in head and neck sites are described, together with promising early results on the maintenance of salivary flow after IMRT. A summary of research into optimal planning for pelvic cancer follows. The controversial areas of breast and paediatric IMRT are discussed with recommendations on practice. The potential for concomitant boost therapy is exemplified in the treatment of brain metastatic disease.

Diagnosis, management and therapeutic outcome in prepubertal Cushing's disease.

OBJECTIVES: Cushing's disease (CD) in prepubertal children is very rare and presents important diagnostic and therapeutic challenges. We report experience of the management of this subpopulation of CD patients. STUDY DESIGN/METHODS: Retrospective patient case note review. RESULTS: Between 1985 and 2008, 17 prepubertal children (13M, 4F), aged 5.7-14.1 years presented to our centre for diagnosis and management of CD. All children had subnormal linear growth and excessive weight gain at presentation. A high proportion (85% of males, 75% of females) had evidence of excessive virilisation. Striae and hypertension were seen in 41% of patients. The investigation with highest sensitivity (100%) for CD was excessive increase of serum cortisol to i.v. CRH (mean increase 113%). Pituitary imaging performed in all the patients showed poor concordance with findings at surgery (31%). In contrast bilateral simultaneous inferior petrosal sinus sampling (BSIPSS), performed in 11/16 subjects showed a high correlation with surgical findings (91%). In 16 patients, transsphenoidal selective adenomectomy (TSS) achieved a cure rate of 44%. However, in the 11 patients who had pre-operative BSIPSS, the cure rate was 64%. Of the 16 patients, 9 patients who were not cured by TSS received external pituitary radiotherapy. CONCLUSIONS: Prepubertal CD had distinctive features with increased frequency in males, abnormal auxology and excessive virilisation. The cortisol response to i.v. CRH administration was particularly exuberant and contributed to diagnosis. BSIPSS was much more helpful than pituitary imaging in localisation of the microadenoma and was associated with improved cure rate by TSS.

The developing role for intensity-modulated radiation therapy (IMRT) in the non-surgical treatment of brain metastases.

Whole brain radiotherapy (WBRT) is the standard non-surgical treatment for brain metastatic disease, but rarely eradicates bulky metastases from most common cancers. Recent literature has demonstrated the safety and efficacy of delivering very high focal doses of radiation (by radiosurgical techniques) to the gross tumour volume of bulky brain metastases, thereby obtaining more certain local control than is achieved by WBRT. In this paper we report a study of 11 patients with bulky brain metastases in whom an intensity-modulated radiation therapy (IMRT) facility has been used to concomitantly boost the gross tumour volume of bulky brain metastatic disease (to 40 Gy) during a standard 30 Gy in 10 fractions WBRT schedule. No acute or subacute morbidity was encountered, and good early control data were noted. We discuss the perceived advantages of such a technique.

Gamma knife radiosurgery: a safe and effective salvage treatment for pituitary tumours not controlled despite conventional radiotherapy.

OBJECTIVE: We report the use of 'gamma knife' (GK) radiosurgery in 25 patients with pituitary adenomas not cured despite conventional therapy, including external beam radiotherapy. PATIENTS AND METHODS: All patients had previously received conventional radiotherapy for a mean of 11.8 years prior to receiving GK; 23 out of 25 had also undergone pituitary surgery on at least one occasion. Seventeen had hyperfunctioning adenomas that still required medical therapy without an adequate biochemical control--ten somatotroph adenomas, six corticotroph adenomas and one prolactinoma, while eight patients had non-functioning pituitary adenomas (NFPAs). RESULTS: Following GK, mean GH fell by 49% at 1 year in patients with somatotroph tumours. Serum IGF1 fell by 32% at 1 year and by 38% at 2 years. To date, 80% of the patients with acromegaly have achieved normalisation of IGF1, and 30% have also achieved a mean GH level of <1.8 ng/ml correlating with normalised mortality. A total of 75% NFPAs showed disease stabilisation or shrinkage post GK. The patient with a prolactinoma showed a dramatic response: 75% reduction in prolactin at 2 years, with a marked shrinkage on magnetic resonance imaging. The results in corticotroph adenomas were variable. Prior to GK, 72% of the patients were panhypopituitary, and 42% of the remainder have developed new anterior pituitary hormone deficiencies to date. No other adverse events have been detected at a mean follow-up of 36.4 months. CONCLUSIONS: These data indicate that GK is a safe and effective adjunctive treatment for patients with NFPAs and acromegaly not satisfactorily controlled with surgery and radiotherapy.

Early experience of tomotherapy-based intensity-modulated radiotherapy for breast cancer treatment.

AIMS: New technology - specifically intensity-modulated radiotherapy (IMRT) - is now being applied to breast radiotherapy and a recent dosimetric analysis confirmed the advantages of IMRT over 'wedge-only' plans. Such application to everyday practice raises new issues and here we present the early experience of IMRT-based breast irradiation in a single centre. MATERIALS AND METHODS: We present cases of breast cancer treated by Tomotherapy-based IMRT, where the perceived advantages of IMRT are considerable. Cases presented are bilateral disease, left breast irradiation, pectus excavatum, prominent contralateral prosthesis and internal mammary chain disease. We discuss the practicalities of such treatment and the advantages over standard breast irradiation techniques. RESULTS: Advantages include better conformity of treatment with lowering of dosages to underlying organs at risk, for example ipsilateral lung and heart. There is improved coverage of the planning target volume, including regional nodes, without field junction problems. Planning, quality assurance and treatment delivery are more time consuming than for standard breast irradiation and the low dose 'bath' is increased. CONCLUSIONS: The standard radiotherapy tangential technique for breast/chest wall treatments has not significantly changed over many decades, whereas across many other tumour sites there have been great advances in radiotherapy technology. The dosimetric advantages of IMRT are readily apparent from our early experience. The wider spread of the lower dose zone (the low dose 'bath' of radiation) is a potential concern regarding late oncogenesis and methods to minimise such risks should be considered.

Salvage external beam radiotherapy after failed primary chemotherapy for bilateral retinoblastoma: rate of eye and vision preservation.

BACKGROUND: Radiation is implicated in the induction of second malignancies in children with bilateral retinoblastoma. There is a need to determine whether this risk can be justified by good visual outcome when external beam radiotherapy (EBRT) is used as a salvage treatment. AIM: To study the effectiveness of EBRT as a salvage treatment after failed primary chemotherapy and focal treatment in bilateral retinoblastoma. METHODS: This is a retrospective observational case series. The outcome measures after EBRT are: rate of eye preservation, rate of tumour control, visual potential, visual acuity and radiation-induced side-effects. RESULTS: Thirty-six eyes (22 patients) were included. The median follow-up after EBRT was 40 months (19-165 months). Thirty-two eyes received lens-sparing radiotherapy, and four received whole-eye radiation. The rate of eye preservation was 83.3% (30/36 eyes). Twenty-four eyes (66.7%) were controlled by EBRT and required no further treatment. Of the 30 preserved eyes, 20 eyes (66.7%) had extramacular tumours without retinal detachment and therefore potential for central vision. The final visual acuity was recorded for 19 eyes. Ten eyes (52.6%) read 6/9-6/5, three eyes (15.8%) read 6/18-6/36, and six eyes (31.6%) read 6/60 or worse. Significant radiation- induced side effects were limited to cataracts and dry eyes with whole-eye radiation. There were no second cancers or deaths. CONCLUSION: Salvage EBRT is highly effective in preserving eyes with useful vision in bilateral retinoblastoma after failed chemotherapy and focal treatments. These results will help the parents and ophthalmologists of such patients to reach an informed decision when weighing up the benefits of EBRT against its potential oncogenic effect.

Treatment of Nelson's syndrome with temozolomide.

A 64-year-old woman was previously treated for Cushing's disease with trans-sphenoidal surgery, external beam radiotherapy and bilateral adrenalectomy. Progression of an aggressive corticotroph adenoma was evident 3 years post-adrenalectomy; involvement of the clivus was treated with surgery and gamma knife radiosurgery. Tumour spread through the skull base, occiput and left ear with persistent facial pain and left ear discharge; progression continued despite second gamma knife treatment. ACTH levels peaked at 2472 and 2265 pmol/l pre- and post-hydrocortisone respectively. Treatment with temozolomide resulted in a significant improvement in symptoms, a reduction of plasma ACTH to 389 pmol/l and regression of tumour on magnetic resonance imaging scan after four cycles of treatment. We propose that temozolomide is an effective and well-tolerated therapeutic tool for the treatment of Nelson's syndrome and a useful addition to the range of therapies available to treat this condition.

Focal radiation therapy for patients with persistent/recurrent pituitary adenoma, despite previous radiotherapy.

With the stricter endocrine definitions of cure following conventionally planned and fractionated radiotherapy for functioning pituitary adenomas, together with the move in the profession (since the advent of high quality MRI) to postpone radiation therapy until macroscopic disease appears after surgery, it is now realised that cure rates following conventional radiotherapy approximate three out of four rather than the >90% cited for more than a decade. Patients with persistent active tumours may be successfully further treated by focal radiation therapy by one of the stereotactic focal techniques. We have experience of such re-treatment radiation therapy in 50 patients. With careful case selection, we here demonstrate that in acromegaly, for example, normalisation of both GH and IGF levels may be achieved in 37-58% of these previously irradiated patients with low risk of late morbidity. Unquestionably, growth delay occurs in many cases but the long term tumour control rate has yet to be established.

Indications for tomotherapy/intensity-modulated radiation therapy in paediatric radiotherapy: extracranial disease.

The potential conformality advantages of intensity-modulated radiation therapy (IMRT; TomoTherapy Hi Art system) over conventional linear accelerator based therapy was assessed in six consecutive children referred for extracranial radiotherapy. IMRT/tomotherapy was considered advantageous for (i) small abdominal tumours, compared with parallel opposed or single portal technology using a conventional linear accelerator, and (ii) re-treatment of an ethmoidal sarcoma, but not for palliation of a small spinal metastasis, or therapy for a whole deep cervical node chain or a pelvic side wall tumour in a young child. Considerations integral to the treatment decision included target volume dose conformality, "low-dose bath" effects (oncogenic and late growth sequelae) and treatment delivery time. IMRT/tomotherapy was the selected modality for therapy when the conformality advantages were perceived to outweigh any disadvantages in three out of the six cases. The dose conformality advantages of IMRT/tomotherapy are sufficient to selectively recommend its availability to the paediatric practice in accordance to the following criteria: (i) where conformality of radiation therapy to the target/tumour is critical and where the margin of safety (from gross/clinical target volume to planning target volume (PTV)) around the tumour is narrow; (ii) where adjacent organs at risk of radiation damage have a low threshold for damage; and (iii) where the "low-dose bath" phenomenon, which occurs between the upper and lower axial limits of the PTV, is not sufficiently disadvantageous (with regard to late oncogenesis or growth retardation) to outweigh the more confined (non-tumour) integral doses received in higher dose corridors through the body when utilizing conventional radiation techniques.