Late Toxicity and Long-Term Local Control in Patients With Ultra-Central Lung Tumours Treated by Intensity-Modulated Radiotherapy-Based Stereotactic Ablative Body Radiotherapy With Homogenous Dose Prescription.

AIMS: To report late toxicity and long-term outcomes of intensity-modulated radiotherapy (IMRT)-based stereotactic ablative body radiotherapy (SABR) in patients with ultra-central lung tumours. MATERIALS AND METHODS: This is a single-institution retrospective analysis of patients treated with SABR for ultra-central tumours between May 2008 and April 2016. Ultra-central location was defined as tumour (GTV) abutting or involving trachea, main or lobar bronchi. Respiratory motion management and static-field dynamic-IMRT were used, with dose prescribed homogeneously (maximum <120%). Descriptive analysis, Kaplan-Meier method, log-rank test and Cox regression were used to assess outcomes. RESULTS: Sixty-five per cent of patients had inoperable primary non-small cell lung cancer and 35% had lung oligometastases. The median age was 72 (range 34-85) years. The median gross tumour volume and planning target volume (PTV) were 19.6 (range 1.7-203.3) cm3 and 57.4 (range 7.7-426.6) cm3, respectively. The most commonly used dose fractionation was 60 Gy in eight fractions (n = 51, 87.8%). Median BED10 for D98%PTV and D2%PTV were 102.6 Gy and 115.06 Gy, respectively. With a median follow-up of 26.5 (range 3.2-100.5) months, fatal haemoptysis occurred in five patients (8.7%), of which two were directly attributable to SABR. A statistically significant difference was identified between median BED3 for 4 cm3 of airway, for patients who developed haemoptysis versus those who did not (147.4 versus 47.2 Gy, P = 0.005). At the last known follow-up, 50 patients (87.7%) were without local recurrence. Freedom from local progression at 2 and 4 years was 92 and 79.8%, respectively. The median overall survival was 34.3 (95% confidence interval 6.1-61.6) months. Overall survival at 2 and 4 years was 55.1 and 41.2%, respectively. CONCLUSION: In patients with high-risk ultra-central lung tumours, IMRT-based SABR with homogenous dose prescription achieves high local control, similar to that reported for peripheral tumours. Although fatal haemoptysis occurred in 8.7% of patients, a direct causality with SABR was evident in only 3%. Larger studies are warranted to ascertain factors associated with outcomes, especially toxicity, and identify patients who would probably benefit from this treatment.

Stereotactic Ablative Radiation Therapy for Large (≥5 cm) Non-small Cell Lung Carcinoma.

AIMS: Stereotactic ablative radiation therapy (SABR) is a standard of care for medically inoperable early stage non-small cell lung carcinoma. Tumours greater than 5 cm have been excluded from randomised trials using SABR and, hence, it is not used as a standard for larger lung tumours. However, improvements in radiation therapy techniques and the success of SABR in treatment of early stage disease may allow safe delivery of ablative doses to larger tumours. We analysed our experience with tumours ≥5 cm to determine the efficacy and toxicity profile of SABR in this setting. MATERIALS AND METHODS: We evaluated survival, control rates, patterns of failure and toxicity in patients with a tumour diameter larger than 5 cm that had no nodal or distant metastases treated with SABR technology. Patients had been treated in two centres since 2009 and were retrospectively analysed. All patients had positron emission tomography staging, were discussed at a tumour board and were documented to have no nodal or distant metastatic disease. Treatment outcomes were analysed using Kaplan-Meier estimates and compared using the Log-rank test. Cox regression was used to investigate the association between the survival outcomes and predictor variables. RESULTS: In total, 86 patients were identified. Six patients had no follow-up imaging. Therefore, 80 patients were available for analysis. All patients were reclassified according to the updated AJCC eighth edition. The median follow-up was 19.6 months. No patients received neoadjuvant or concurrent systemic therapy. One patient received adjuvant systemic therapy. The median age at treatment was 77 years (range 58-91). Eighty-four per cent were stage T3N0M0 and 16% were staged T4N0M0. The median tumour diameter was 5.8 cm (range 5.0-9.3 cm). The median gross tumour volume, measured on a single phase of the respiratory cycle, was 45.7 cm3 (range 12.1-203.3 cm3). The median overall survival was 20.9 months (95% confidence interval 12.6-29.1 months). One-, 2- and 3-year overall survival was 71%, 48% and 32%, respectively. The median local failure-free survival was 19.5 months (95% confidence interval 14.4-24.6). The median disease-free survival was 15.1 months (95% confidence interval 9.9-20.4 months). Local control at 1, 2 and 3 years was 85% (95% confidence interval 76-94%), 71% (95% confidence interval 58-84%) and 57% (95% confidence interval 40-74%), respectively. Forty-four patients (55%) had any treatment failure (local, mediastinal, intrapulmonary or distant metastases). Out-of-field intrapulmonary disease progression was the most common mode of failure, occurring in 21 patients (26%). Local failure occurred in 19 patients (24%) - alone or in combination with other progression. Distant metastases occurred in 20 patients (25%). Neither histological subtype, tumour size nor gross tumour volume had a statistically significant effect on local failure-free survival. Two patients experienced grade 3 late dyspnoea. There were no other reported grade 3 or higher acute or late toxicities. CONCLUSION: SABR for larger lung tumours ≥5 cm results in high local control and acceptable survival in patients with medically inoperable large non-small cell lung carcinoma treated with radiation alone. Such patients should be considered for SABR owing to fewer treatment fractions and acceptable toxicity. Local control analysis reveals a sustained pattern of local failure emphasising the need for long-term follow-up. Improvements in technical strategies are required to further improve local control.

A Phase II Toxicity End Point Trial (ICORG 99-09) of Accelerated Dose-escalated Hypofractionated Radiation in Non-small Cell Lung Cancer.

AIMS: The objective of this phase II clinical trial was to prospectively evaluate the safety and efficacy of accelerated hypofractionated three-dimensional conformal radiation therapy (3DCRT) in localised non-resectable/non-operable non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Sixty patients with stage I-III NSCLC were enrolled in a prospective single-arm All Ireland Co-operative Oncology Research Group (ICORG 99-09) toxicity end point phase II trial. The protocol allocated patients between three radiation schedule dose levels (60, 66 or 72 Gy, in 20, 22 and 24 fractions, respectively, 3 Gy daily, five fractions per week) according to combined lung V25Gy (V25Gy ≤ 30%) with built-in early stopping toxicity rules. The primary end point was toxicity with evaluation of dose-limiting toxicity. The secondary objectives included radiological tumour response rate at 3 months after the completion of radiation therapy and the thoracic progression-free survival time. RESULTS: Sixty patients were recruited from August 1999 to June 2009. Forty-nine patients were included in the primary per-protocol analysis. Eleven patients were not evaluable. In the first 30 evaluable patient cohort, severe oesophageal toxicity was reported in two patients (2/49; 4% experiencing grade 5 oesophageal late toxicity, related to the 97% oesophageal length). The trial was temporarily closed and was then reopened to validate an oesophageal dose volume constraint (DVC) of limiting the length of oesophagus fully encompassed by the 97% isodose to less than 1 cm (applied to 21 patients). The trial prospectively showed the safety of the oesophageal DVC, with no oesophageal toxicity above grade 3 thereafter. Thirty-nine per cent of patients had disease progression at 3-4 months after radiotherapy, 22% had stable disease, 20% had a complete response and 14% had a partial response. The median overall survival was 13.6 months (95% confidence interval 10.5-16.7) and overall survival at 1 and 3 years was 57% and 29%, respectively. CONCLUSION: A strategy using accelerated hypofractionated 3DCRT is feasible and reasonably safe for patients with inoperable NSCLC. It is safe to deliver for centrally located tumours if DVCs are applied to the oesophagus, which is the primary dose-limiting toxicity. Further studies are required to assess the efficacy of hypofractionated regimens for centrally located tumours using an oesophageal DVC and monitoring for oesophageal toxicity.

Stereotactic Radiosurgery (SRS) / Stereotactic body radiotherapy (SBRT): Benefit to Irish patients and Irish Healthcare Economy.

Cancer incidence across Europe is projected to rise rapidly over the next decade. This rising cancer incidence is mirrored by increasing use of and indications for stereotactic radiation. This paper seeks to summarize the exponential increase in indications for stereotactic radiotherapy as well as the evolving economic advantages of stereotactic radiosurgery and stereotactic body radiotherapy.

Stereotactic radiosurgery for the treatment of brain metastases; results from a single institution experience.

BACKGROUND: Stereotactic radiosurgery is frequently used for the treatment of brain metastases. This study provides a retrospective evaluation of patients with secondary lesions of the brain treated with stereotactic radiosurgery (SRS) at our institution. AIMS: To provide outcome data from a single institutional experience with SRS and identify any significant prognostic factors in the cohort. METHODS: Sixty-seven patients received first time SRS to 86 intracranial metastases between 2007 and 2010. Sixteen patients were excluded from this study due to the absence of post-treatment neuroimaging, resulting in 51 patients with 64 treated lesions. Of these patients, 37 (72.5%) received SRS electively, while 14 (27.5%) received salvage SRS after brain metastasis progression following whole brain radiotherapy. RESULTS: Median survival for the entire group was 15 months from the date of radiosurgery. Patients without active extracranial disease had statistically significant survival time than those with active extracranial disease (P=0.03). 45 (70.3%) lesions achieved local tumour control in 34 patients (66.7%) with a mean follow-up period of 10.7 months (range 1.7-33.6 months, 95 % confidence interval 6.6-9.8 months). CONCLUSIONS: The results reported in this study equate to those reported in other series consolidating SRS as an effective treatment option with few serious complications. Developments in systemic disease control will see further improvements in overall survival.

Management of synchronous rectal and prostate cancer.

PURPOSE: Although well described, there is limited published data related to management on the coexistence of prostate and rectal cancer. The aim of this study was to describe a single institution's experience with this and propose a treatment algorithm based on the best available evidence. METHODS: From 2000 to 2011, a retrospective review of institutional databases was performed to identify patients with synchronous prostate and rectal cancers where the rectal cancer lay in the lower two thirds of the rectum. Operative and non-operative outcomes were analysed and a management algorithm is proposed. RESULTS: Twelve patients with prostate and rectal cancer were identified. Three were metachronous diagnoses (>3-month time interval) and nine were synchronous diagnoses. In the synchronous group, four had metastatic disease at presentation and were treated symptomatically, while five were treated with curative intent. Treatment included pelvic radiotherapy (74 Gy) followed by pelvic exenteration (three) and watchful waiting for rectal cancer (one). The remaining patient had a prostatectomy, long-course chemoradiotherapy and anterior resection. There were no operative mortalities and acceptable morbidity. Three remain alive with two patients disease-free. CONCLUSIONS: Synchronous detection of prostate cancer and cancer of the lower two thirds of the rectum is uncommon, but likely to increase with rigorous preoperative staging of rectal cancer and increased awareness of the potential for synchronous disease. Treatment must be individualized based on the stage of the individual cancers taking into account the options for both cancers including EBRT (both), surgery (both), hormonal therapy (prostate), surgery (both) and watchful waiting (both).

Recurrent malignant pilomatrixoma invading the cranial cavity: Improved local control with adjuvant radiation.

We report the case of a 41-year-old mentally retarded male with recurrent pilomatrix carcinoma of the occipital region which invaded the occipital bone, left cerebellum and left temporal lobe. At his initial presentation the patient had a craniotomy and subtotal excision of the lesion with positive margins. He received no adjuvant therapy. After an early intracranial recurrence he had subtotal debulking and was referred for external beam radiotherapy. At 27 months follow-up after adjuvant external beam radiotherapy the intracranial component has not progressed and the patient remains clinically well.

Alveolar haemorrhage in anti-glomerular basement membrane disease without detectable antibodies by conventional assays.

Anti-glomerular basement membrane (anti-GBM) disease represents the spectrum of disease attributable to circulating anti-GBM antibodies. While active anti-GBM disease in the absence of circulating anti-GBM antibodies has been described, it is considered rare with the use of current routinely available assays. We report four subjects with features consistent with active anti-GBM antibody disease without detectable antibodies by routinely available enzyme linked immunosorbent assay (ELISA) and immunoblot techniques. All were smokers who presented with diffuse alveolar haemorrhage, minimal renal involvement, and undetectable anti-GBM antibodies. Seronegative anti-GBM disease with predominant pulmonary involvement may be more common than previously appreciated and should be part of the differential diagnosis for otherwise unexplained diffuse alveolar haemorrhage. Renal biopsy with immunofluorescent studies should be considered in the diagnostic evaluation of such subjects, including those with idiopathic pulmonary haemosiderosis.

Complications of treatment with local field external beam radiotherapy for localized prostate cancer.

We performed this analysis to document the rate and severity of complications both during and after local field irradiation for localized prostate cancer and to assess the influence of three-dimensional conformal radiation therapy (3DCRT) on these complications. Bowel, urinary and cutaneous toxicities were noted in all patients treated with primary radiotherapy (RT) for prostate cancer using Radiation Therapy Oncology Group/European Organization for Research on Treatment of Cancer scores. Evaluations were performed weekly during RT, 6 weeks after RT and 3 monthly thereafter. Data on 111 were analysed. We also compared the complications of conventional and 3DCRT. The serious complication rates identified in this study compare favourably with those reported in the literature. Only 3.6%, 0.8% and 0% had acute grade 3 or 4 urinary, bowel or skin reactions respectively. Only two patients had chronic grade 3 or 4 urinary complications. Thus far no patients have developed chronic bowel or skin complications greater than grade 2. Despite dose escalation from 66 Gy to 70 Gy (with 3DCRT), there was a trend towards reduced toxicity when 3DCRT was compared with conventional radiation. RT is a well-tolerated treatment for early stage carcinoma of the prostate and our complication rates are compatible with international experiences. Further follow-up is required to determine the efficacy of treatment, the incidence of impotence and the final number of late complications.

Target volume definition for three-dimensional conformal radiation therapy of lung cancer.

Three-dimensional conformal radiation therapy (3DCRT) is a mode of high precision radiotherapy which has the potential to improve the therapeutic ratio of radiation therapy for locally advanced non-small cell lung cancer. The preliminary clinical experience with 3DCRT has been promising and justifies further endeavour to refine its clinical application and ultimately test its role in randomized trials. There are several steps to be taken before 3DCRT evolves into an effective single modality for the treatment of lung cancer and before it is effectively integrated with chemotherapy. This article addresses core issues in the process of target volume definition for the application of 3DCRT technology to lung cancer. The International Commission on Radiation Units and Measurements Report no. 50 definitions of target volumes are used to identify the factors influencing target volumes in lung cancer. The rationale for applying 3DCRT to lung cancer is based on the frequency of failure to eradicate gross tumour with conventional approaches. It may therefore be appropriate to ignore subclinical or microscopic extensions when designing a clinical target volume, thereby restricting target volume size and allowing dose escalation. When the clinical target volume is expanded to a planning target volume, an optimized margin would result in homogeneous irradiation to the highest dose feasible within normal tissue constraints. To arrive at such optimized margins, multiple factors, including data acquisition, data transfer, patient movement, treatment reproducibility, and internal organ and target volume motion, must be considered. These factors may vary significantly depending on technology and techniques, and published quantitative analyses are no substitute for meticulous attention to detail and audit of performance.

Appearances can be deceptive: an APC 1893del4 mutation with unusual properities. Mutations in brief no. 171. Online.

During a systematic search for germ-line APC mutations causative of familial adenomatous polyposis, we discovered what appeared to be an insertion mutation while simply checking exon 14PCR products by agarose gel electrophoresis (AGE). On AGE, exon 14PCR product from the known affected member of this family gave two bands: one of normal length, the other retarded on the gel equivalent to an increase in length of some 20-25 bp. Direct sequencing of DNA purified from the two bands gave identical results, and was consistent with amplification from the same two alleles: one wild-type, and the other having an 1893del4 mutation. This suggested that the normal length band on AGE consisted of DNA homoduplexes (normal:normal and mutant:mutant) and the retarded band consisted of DNA heteroduplexes (normal:mutant and mutant:normal). This hypothesis was tested by subjecting purified material from each of the two bands alone to a single cycle of heat denaturation and annealing, which showed that either band was equally capable of regenerating both bands. Because the anomalous migration of the heteroduplexes is observed in the presence of ethidium bromide, it implies that they have a cruciform of cruciform-like structure. This case illustrates the necessity to be aware of anomalous DNA migration and always sequence all putative mutations.

Development and validation of a measure of adolescent dissociation: the Adolescent Dissociative Experiences Scale.

This study describes the initial reliability and validity data on the Adolescent Dissociative Experiences Scale (A-DES), a screening measure for pathological dissociation during adolescence. The A-DES showed good scale and subscale reliability, and, as hypothesized, increased scores were associated with reported trauma in a patient population. A-DES scores were able to distinguish dissociative disordered adolescents from a normal sample and from a patient sample with a variety of diagnoses.

APC mutations in familial adenomatous polyposis families in the Northwest of England.

We have investigated a series of FAP patients in the Northwest of England in order to identify and characterise the specific APC mutations. Using SSCP, we found 27 mutations in a total of 50 families investigated. The mutations were predominantly frameshift or nonsense mutations and there were two splice site changes. We have described two patients with severe Gardner's phenotype from different ethnic backgrounds who share the same mutation at codon 1537. Although the frequency of the most common mutation appears low, it is not dissimilar to that reported by other groups.

Measuring the systemic effects of inhaled beclomethasone: timed morning urine collections compared with 24 hour specimens.

BACKGROUND: Inhaled glucocorticoid therapy has systemic effects including hypothalamic-pituitary-adrenal (HPA) suppression. The optimal test for detecting these effects has not been defined. METHODS: Timed urine collections and 09.00 hour plasma cortisol levels were obtained from 12 normal volunteers receiving inhaled placebo, beclomethasone (BDP) 800 or 2000 micrograms/day. The 24 hour urine samples were collected as follows: first hour after waking (hour 1), the next two hours after waking (hours 2 and 3), remainder of day, and overnight, with results expressed as urine cortisol/creatinine (UCC) ratios and as hourly cortisol output in the timed collections. Twenty four hour urinary cortisol excretion was also calculated. Medication was blinded and given in random order with a washout period of at least 11 days between each treatment arm. RESULTS: None of the UCC ratios changed with BDP 800 micrograms/day. UCC ratios at hour 1, hour 2 and 3, and overnight, and 24 hour urinary free cortisol excretion were reduced after BDP 2000 micrograms/day, whilst remainder of day UCC ratio and the plasma cortisol level did not change significantly. Cortisol output showed similar changes. In a follow up study BDP 1400 micrograms/day also reduced UCC ratios for the first two hours after waking. CONCLUSIONS: UCC ratios are as sensitive as the more cumbersome 24 hour urinary free cortisol excretion, and more sensitive than single morning plasma cortisol measurements, in detecting the effects of inhaled beclomethasone on the HPA axis.

Severe Gardner syndrome in families with mutations restricted to a specific region of the APC gene.

Familial adenomatous polyposis (FAP) is associated with a number of extraintestinal manifestations, which include osteomas, epidermoid cysts, and desmoid tumors, often referred to as "Gardner syndrome." Recent studies have suggested that some of the phenotypic features of FAP are dependent on the position of the mutation within the APC gene. In particular, the correlation between congenital hypertrophy of the retinal pigment epithelium (CHRPE) and APC genotype indicates that affected families may be divided into distinct groups. We have investigated the association between the dentoosseous features of GS on dental panoramic radiographs (DPRs) and APC genotype in a regional cohort of FAP families. DPRs were performed on 84 affected individuals from 36 families, and the dento-osseous features of FAP were quantified by a weighted scoring system. Significant DPR abnormalities were present in 69% of affected individuals. The APC gene mutation was identified in 27 of these families, and for statistical analysis these were subdivided into three groups. Group 1 comprised 18 affected individuals from seven families with mutations 5' of exon 9; these families (except one) did not express CHRPE. Groups 2 comprised 38 individuals from 16 families with mutations between exon 9 and codon 1444, all of whom expressed CHRPE. Group 3 comprised 11 individuals from four families with mutations 3' of codon 1444, none of whom expressed CHRPE. Families with mutations 3' of codon 1444 had significantly more lesions on DPRs (P < .001) and appeared to have a higher incidence of desmoid tumors. These results suggest that the severity of some of the features of Gardner syndrome may correlate with genotype in FAP.

Palliation of irresectable hilar cholangiocarcinoma with biliary drainage and radiotherapy.

Twelve patients with irresectable or recurrent hilar cholangiocarcinoma were treated with internal biliary drainage followed by intraluminal (iridium-192) and external-beam radiotherapy. Biliary drainage was accomplished by means of a combined surgical and interventional radiological approach. Initial biliary decompression was performed surgically by tumour resection, intrahepatic biliary enteric bypass or distal biliary-enteric anastomosis with a temporary stent. Maintenance of internal biliary drainage and application of intraluminal radiotherapy were accomplished radiologically with the use of percutaneous dilatation and metallic expandable biliary endoprostheses. Median survival was 14.5 months; all 12 patients survived for at least 6 months. Early complications during radiotherapy were minor and included two patients with cholangitis and one with transient haemobilia. Jaundice was relieved in ten of 12 patients, while episodes of cholangitis were seen during long-term follow-up in 11 (median 1.5 episodes per patient). Internal biliary drainage, in conjunction with radiotherapy, appears to be safe and effective palliation of irresectable or recurrent hilar cholangiocarcinoma. Patients can maintain a reasonable quality of life with an acceptable incidence of cholangitis, without the hindrance of external drainage devices.