Nasopharyngeal carcinoma: United Kingdom National Multidisciplinary Guidelines.

This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. Although much commoner in the eastern hemisphere, with an age-standardised incidence rate of 0.39 per 100 000 population, cancers of the nasopharynx form one of the rarer subsites in the head and neck.1 This paper provides recommendations on the work up and management of nasopharyngeal cancer based on the existing evidence base for this condition. Recommendations • Patients with nasopharyngeal carcinoma (NPC) should be assessed with rigid and fibre-optic nasendoscopy. (R) • Nasopharyngeal biopsies should be preferably carried out endoscopically. (R) • Multislice computed tomographic (CT) scan of head, neck and chest should be carried out in all patients and magnetic resonance imaging (MRI) where appropriate to optimise staging. (R) • Radiotherapy (RT) is the mainstay for the radical treatment for NPC. (R) • Concurrent chemoradiotherapy offers significant improvement in overall survival in stage III and IV diseases. (R) • Surgery should only be used to obtain tissue for diagnosis and to deal with otitis media with effusion. (R) • Radiation therapy is the treatment of choice for stage I and II disease. (R) • Intensity modulated radiation therapy techniques should be employed. (R) • Concurrent chemotherapy with radiation therapy is the treatment of choice for stage III and IV disease. (R) • Patients with NPC should be followed-up and assessed with rigid and/or fibre-optic nasendoscopy. (G) • Positron emission tomography-computed tomography (PET-CT), CT or MRI scan should be carried out at three months from completion of treatment to assess response. (R) • Multislice CT scan of head, neck and chest should be carried out in all patients and MRI scan whenever possible and specially in advanced cases with suspected recurrence. (R) • Surgery in form of nasopharyngectomy should be considered as a first line treatment of residual or recurrent disease at the primary site. (R) • Neck dissection remains the treatment of choice for residual or metastatic neck disease whenever possible. (R) • Re-irradiation should be considered as a second line of treatment in recurrent disease. (R).

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.

Infection rates after tympanostomy tube insertion, comparing Aboriginal and non-Aboriginal children in the Northern Territory, Australia: a retrospective, comparative study.

OBJECTIVE: To determine if there is a difference in infection rates between Aboriginal and non-Aboriginal children, following tympanostomy and ventilation tube placement, in the Northern Territory, Australia. MATERIALS AND METHODS: A cohort of 213 patients aged zero to 10 years who had undergone tympanostomy and ventilation tube placement at the Royal Darwin Hospital between 1996 and 2004 were identified. Patients were divided into Aboriginal or non-Aboriginal groups, from their medical record. Factors such as age, sex, dwelling (remote or urban) and season were compared for each group, in order to ascertain if they contributed to infection rates. A retrospective analysis of cases was conducted for the two-year post-operative period. RESULTS: There was no statistically significant difference in infection rates between the two groups (37 vs 35 per cent). There was no statistically significant difference when comparing the two groups for age, sex, season, or remote vs urban dwelling. CONCLUSION: Aboriginal children were not prone to more infections following tympanostomy tube placement when compared with non-Aboriginal children.

Pre-treatment haemoglobin concentration in accelerated and conventional radiotherapy for non-small cell lung carcinoma.

Serum haemoglobin has been shown to be an independent prognostic factor for a number of cancers including head and neck, bladder, cervix and anal cancers. This study has investigated the prognostic significance of pre-treatment haemoglobin in 164 consecutive patients receiving radical radiotherapy for non-small cell lung cancer. Forty-six received conventional fractionation to 60 Gy in 30 fractions and the remainder received accelerated fractionation, either CHART, 54 Gy in 36 fractions over 12 days (27 patients) or CHARTWEL, 60 Gy in 40 fractions over 18 days (76 patients). Patients were divided into three equal groups by haemoglobin concentration. The median overall survival in each of the three groups from lowest to highest haemoglobin was 17.5 months (95% CI 7.9 25), 18.4 months (95% CI 15.0 25.9) and 16.3 months (95% CI 13.0-19.6). No significant effect of pre-treatment haemoglobin concentration was seen in predicting overall, local disease free or metastases free survival.

Stereotactic radiosurgery XVI: a treatment for previously irradiated pituitary adenomas.

We report the use of stereotactic radiosurgery delivered through an adapted linear accelerator [stereotactic multiple arc radiation therapy (SMART)] for pituitary adenomas not cured by conventional therapy. All 21 patients had undergone conventional radiotherapy (45-50 Gy); 18 had also undergone prior surgery. This cohort comprised 13 patients with somatotrope adenomas, four with corticotrope adenomas, one with a lactotrope adenoma, and three with nonfunctioning pituitary adenomas (median follow-up: 33 months, range: 3-72 months). SMART has proven effective, safe, and rapidly acting. We observed an accelerated reduction in GH and IGF-I levels in acromegaly, with normalization of GH and IGF-I levels in 58%. Mean GH fell from 21.1 mU/liter to 7.9 mU/liter (7 ng/ml to 2.6 ng/ml, P < 0.01, median 25 months) faster than our predicted fall to 50% at 2 yr with conventional radiotherapy. Mean IGF-I fell from 624 ng/ml to 384 ng/ml (P < 0.001). Tumor growth was controlled in two of three nonfunctioning pituitary adenomas, and three of four corticotrope adenomas. There were no adverse effects from SMART. Notably there have been no visual sequelae or further loss of anterior pituitary function in this heavily pretreated group. Our data indicate that SMART is an effective complementary therapy for pituitary adenomas that have displayed a suboptimal response to conventional therapy including external irradiation.

GLUT1 and CAIX as intrinsic markers of hypoxia in bladder cancer: relationship with vascularity and proliferation as predictors of outcome of ARCON.

Glucose transporter-1 protein (GLUT1) and carbonic anhydrase IX (CAIX) are regulated by hypoxia inducible factor-1 (HIF-1) and have been studied as putative intrinsic cellular markers for hypoxia. This study directly compares CAIX and GLUT1 with pimonidazole binding in a prospective series of bladder cancer patients and also studies the prognostic significance of the markers, in combination with vascularity and proliferation, in a retrospective series of bladder cancer patients treated in a phase II trial of radical radiotherapy with carbogen and nicotinamide (ARCON). A total of 21 patients with a diagnosis of transitional cell carcinoma of the bladder received 0.5 g m(-2) pimonidazole. Serial tumour sections were stained for pimonidazole, GLUT1 and CAIX and compared. Tissue sections obtained from a series of 64 patients previously treated for invasive bladder cancer using ARCON were stained for GLUT1 and CAIX together with Ki-67 and CD31/34. There was a good geographical colocalisation of both intrinsic markers with pimonidazole and a highly significant agreement in individual patients; correlation coefficients were 0.82 (P=0.0001) for GLUT1 and 0.74 (P<0.0001) for CAIX. In both series of patients, the intrinsic hypoxia markers were highly correlated with each other and a correlation with proliferation was also evident in the retrospective study. In univariate and multivariate analyses, GLUT1 and CAIX were independent predictors for overall and cause specific survival. The hypoxia markers did not predict for local control or metastases-free survival although higher Ki-67 indices showed a trend towards local failure. The data suggest that both hypoxia modification and accelerated treatment may be valid treatment options in bladder cancer.

The role of 123I-diagnostic imaging in the follow-up of patients with differentiated thyroid carcinoma as compared to 131I-scanning: avoidance of negative therapeutic uptake due to stunning.

OBJECTIVE: Some patients with relapsed differentiated thyroid cancer may show rising thyroglobulin (Tg) levels despite a lack of 131I uptake on routine whole body imaging. A significant proportion of these patients, after therapy doses of 131I, may demonstrate positive 131I uptake with a subsequent fall in serum Tg, implying a therapeutic effect. Attempts to identify such patients by increasing the dose of the diagnostic 131I tracer may lead to inhibition of subsequent uptake after the therapy dose, an effect referred to as 'stunning' and associated with a reduction in therapeutic effect. 123I is a short half-life gamma-emitter, thought to be unlikely to cause stunning, which may thus be more suitable than 131I for diagnostic imaging of thyroid cancer. DESIGN AND PATIENTS: The efficacy of the 123I radionuclide was determined in a longitudinal study of 12 patients who were selected only because they showed elevated serum Tg and a negative diagnostic 131I whole body study prior to therapy with 131I. RESULTS: There was almost complete concordance in uptake between 123I diagnostic imaging and the final scans carried out after 131I therapy (hereafter known as therapy studies) in 11 out of 12 patients at their first evaluation, in each of four patients receiving 123I at their second evaluation and in a single patient receiving 123I at a third evaluation. One patient had a positive 123I study but a negative 131I therapy study: following therapy Tg declined from 5.5 pg/l to undetectable levels, implying a therapeutic effect, and suggesting that the negative uptake was not the result of stunning. Two negative diagnostic 123I studies were followed by negative therapy studies, and thus there were no false negatives. 123I correctly identified disease in the nine patients with metastases in the lungs, mediastinum and bone at the first evaluation, in all four patients at the second evaluation and in the single patient at the third evaluation. At the end of the study, patients had received up to three 131I therapy doses, Tg had risen in four patients, fallen in eight and become undetectable in one patient. CONCLUSIONS: 123I is highly sensitive in diagnosing local recurrence and metastatic disease, and produces scintigraphic images which concord well with uptake following 131I therapy. It is proposed that 123I imaging, in combination with serum Tg measurements, should replace 131I tracer imaging as an indicator of the potential efficacy of 131I therapy. Stunning, with its detrimental effects on 131I therapy, may thus be avoided. The possibility of false negative images due to the stunning phenomenon must always be borne in mind if there is a discrepancy between positive 131I imaging studies and a surprisingly negative subsequent 131I therapy scan.

A pilot study to assess the feasibility of prior scalp cooling with palliative whole brain radiotherapy.

The objective of this work was to perform a feasibility study on the use of scalp cooling during palliative whole brain radiotherapy. Seven patients (1 male, 6 female) with good performance status underwent scalp cooling prior to and during radiotherapy for cerebral metastases. Five patients were prescribed 12 Gy in two fractions and two patients were prescribed 20 Gy in five fractions. Phantom thermoluminescent dosemeter (TLD) studies to assess the build-up effect from the scalp cap were performed. Seven out of eight patients that were offered scalp cooling completed treatment uneventfully. One patient reported discomfort on application of the scalp cap and continued treatment without scalp cooling. No patients reported other adverse effects from use of the cap during treatment or at follow-up. TLD studies demonstrated a 55-80% increase in dose to the scalp after application of the scalp cap. All patients experienced hair loss. Scalp cooling caps are well tolerated through a course of palliative whole brain radiotherapy. The scalp dose is significantly increased owing to a bolus effect from the scalp cap.

Hypoxia-inducible expression of tumor-associated carbonic anhydrases.

The transcriptional complex hypoxia-inducible factor-1 (HIF-1) has emerged as an important mediator of gene expression patterns in tumors, although the range of responding genes is still incompletely defined. Here we show that the tumor-associated carbonic anhydrases (CAs) are tightly regulated by this system. Both CA9 and CA12 were strongly induced by hypoxia in a range of tumor cell lines. In renal carcinoma cells that are defective for the von Hippel-Lindau (VHL) tumor suppressor, up-regulation of these CAs is associated with loss of regulation by hypoxia, consistent with the critical function of pVHL in the regulation of HIF-1. Further studies of CA9 defined a HIF-1-dependent hypoxia response element in the minimal promoter and demonstrated that tight regulation by the HIF/pVHL system was reflected in the pattern of CA IX expression within tumors. Generalized up-regulation of CA IX in VHL-associated renal cell carcinoma contrasted with focal perinecrotic expression in a variety of non-VHL-associated tumors. In comparison with vascular endothelial growth factor mRNA, expression of CA IX demonstrated a similar, although more tightly circumscribed, pattern of expression around regions of necrosis and showed substantial although incomplete overlap with activation of the hypoxia marker pimonidazole. These studies define a new class of HIF-1-responsive gene, the activation of which has implications for the understanding of hypoxic tumor metabolism and which may provide endogenous markers for tumor hypoxia.

Simultaneous breast cancer in non-identical Ashkenazi Jewish twins: management dilemmas when genetic testing is negative.

We present the case histories of Ashkenazi Jewish twins of opposite sex who developed breast cancer simultaneously, in whom testing for the anticipated BRCA2 mutations was unexpectedly negative. Their management and the implications of this difficult situation are discussed.

Bilateral renal cancer in children: a difficult, challenging and changing management problem.

Bilateral disease occurs in 6% of patients with Wilms' tumour. Bilateral renal involvement is present in 25%-50% of children with B-cell non-Hodgkin's lymphoma. Paediatric oncologists therefore encounter bilateral renal disease relatively frequently. A patient with bilateral Wilms' tumour is presented, in whom at least 16 synchronous tumours in the kidneys were treated successfully by primary chemotherapy and 'nephron-sparing' surgery, without renal radiotherapy. We believe the successful treatment without radiotherapy will allow greater potential for normal growth in the future. The case history of a patient with renal failure due to the infiltration of both kidneys by lymphoma and who was treated successfully by chemotherapy, is also presented. One kidney has completely returned to normal function and growth; the other has completely failed and almost disappeared, demonstrating complete reversibility of the damage up to some critical point, beyond which, failure and atrophy result. These two case histories demonstrate extreme examples of clinical dilemmas involving bilateral renal tumours and allow discussion of modern management aimed at preserving renal function.

Radiotherapy in the treatment of benign meningioma of the skull base.

OBJECT: This study was undertaken to assess the long-term efficacy and toxicity of conventional fractionated external-beam radiation in the treatment of benign skull base meningioma. METHODS: This is a retrospective study of 82 patients with histologically verified benign skull base meningioma treated by surgery followed by fractionated external-beam radiation at the Royal Marsden Hospital between 1962 and 1992. The 5- and 10-year progression-free survival (PFS) rates were 92% and 83%, respectively, with the site of disease being the only independent prognostic factor for tumor control according to multivariate analysis. The 10-year PFS rate for patients with sphenoid ridge meningiomas was 69% compared with 90% for those with tumors in the parasellar region. The overall 10-year survival rate was 71%, with performance status and patient age found to be significant independent prognostic factors. Six patients had worsening vision, which was due to cataract in five cases and retinopathy in one. There were no recorded cases of cranial nerve neuropathy. CONCLUSIONS: The excellent long-term tumor control and length of survival with minimal toxicity associated with conventional external-beam radiation should serve as a baseline for evaluation of new treatment strategies such as radiosurgery and skull base surgery.

Stereotactic radiosurgery. VII. Radiosurgery versus conventionally-fractionated radiotherapy in the treatment of cavernous sinus meningiomas.

Twenty-eight patients with meningiomas involving the cavernous sinus were referred to the radiosurgical service at St. Bartholomew's Hospital 1989-1998. The majority (8/13) of patients with small (< 3 cm diameter) tumours received radiosurgery whereas the majority of large tumours (> 3 cm diameter; 12/15) received conventionally-fractionated radiotherapy. Other treatment recommendations were fractionated radiosurgery (one case) and conventionally-fractionated radiotherapy to the whole meningeal base and a radiosurgery boost (three cases). Fractionated radiosurgery is optimal where the target volume is small, but abuts critically sensitive nervous system. There have been no progressions of disease at relatively early follow-up. It is argued that subtotal excision followed by appropriate dose radiation therapy is often a strong competitor to attempted radical excision given the attendant morbidity of this latter operation for meningiomas at this site. Patients referred for radiation therapy are best served by a department with both radiosurgery and conventional radiation therapy facilities.

The content and efficacy of conventional methods of follow-up in neuro-oncology: the need for new strategies.

In a combined retrospective and prospective analysis, we examined the content and outcome of conventional follow-up of patients with malignant brain tumours. Most consultations consisted of discussion and advice from the clinic doctor or nurse in certain well defined areas. Clinical examination, including neurological examination, was ineffective at detecting tumour recurrence. All recurrences presented with clinical features noted by the patient or by carers prior to the clinic attendance. The analysis of content and outcome of conventional outpatient consultation suggests that patients with high grade gliomas might be better served by methods of follow-up other than routine hospital attendance. There is a need to develop new follow-up strategies which are patient orientated and which address issues specific to the disease type other than tumour recurrence alone.