The relationship between tumour dosimetry, response, and overall survival in patients with unresectable Neuroendocrine Neoplasms (NEN) treated with 177Lu DOTATATE (LuTate).

Peptide Receptor Radionuclide Therapy (PRRT) delivers targeted radiation to Somatostatin Receptor (SSR) expressing Neuroendocrine Neoplasms (NEN). We sought to assess the predictive and prognostic implications of tumour dosimetry with respect to response by 68 Ga DOTATATE (GaTate) PET/CT molecular imaging tumour volume of SSR (MITVSSR) change and RECIST 1.1, and overall survival (OS). METHODS: Patients with gastro-entero-pancreatic (GEP) NEN who received LuTate followed by quantitative SPECT/CT (Q-SPECT/CT) the next day (Jul 2010 to Jan 2019) were retrospectively reviewed. Single time-point (STP) lesional dosimetry was performed for each cycle using population-based pharmacokinetic modelling. MITVSSR and RECIST 1.1 were measured at 3-months post PRRT. RESULTS: Median of 4 PRRT cycles were administered to 90 patients (range 2-5 cycles; mean 27.4 GBq cumulative activity; mean 7.6 GBq per cycle). 68% received at least one cycle with radiosensitising chemotherapy (RSC). RECIST 1.1 partial response was 24%, with 70% stable and 7% progressive disease. Cycle 1 radiation dose in measurable lesions was associated with local response (odds ratio 1.5 per 50 Gy [95% CI: 1.1-2.0], p = 0.002) when adjusted by tumour grade and RSC. Median change in MITVSSR was -63% (interquartile range -84 to -29), with no correlation with radiation dose to the most avid lesion on univariable or multivariant analyses (5.6 per 10 Gy [95% CI: -1.6, 12.8], p = 0.133). OS at 5-years was 68% (95% CI: 56-78%). Neither baseline MITVSSR (hazard ratio 1.1 [95% CI: 1.0, 1.2], p = 0.128) nor change in baseline MITVSSR (hazard ratio 1.0 [95% CI: 1.0, 1.1], p = 0.223) were associated with OS when adjusted by tumour grade and RSC but RSC was (95% CI: 0.2, 0.8, p = 0.012). CONCLUSION: Radiation dose to tumour during PRRT was predictive of radiologic response but not survival. Survival outcomes may relate to other biological factors. There was no evidence that MITVSSR change was associated with OS, but a larger study is needed.

Prognostic stratification of HPV-associated oropharyngeal cancer based on CD103+ immune cell abundance in patients treated on TROG 12.01 and De-ESCALaTE randomized trials.

BACKGROUND: High CD103+ intratumoral immune cell (ITIC) abundance is associated with better prognosis in unselected patients with human papilloma virus-associated oropharyngeal squamous cell carcinoma (HPV-associated OPSCC) treated with cisplatin and radiotherapy (CIS/RT). Substituting cetuximab (CETUX) for CIS with RT in HPV-associated OPSCC resulted in inferior efficacy. Our aim was to determine whether quantification of CD103 ITIC could be used to identify a population of HPV-associated OPSCC with superior prognosis. PATIENTS AND METHODS: We pooled data from the TROG 12.01 and De-ESCALaTE randomized trials that compared CETUX/70GyRT with CIS/70GyRT in low-risk HPV-associated OPSCC: American Joint Committee on Cancer 7 stage III (excluding T1-2N1) or stage IV (excluding N2b-c if smoking history >10 pack-years and/or distant metastases), including all patients with available tumor samples. The primary endpoint was failure-free survival (FFS) in patients receiving CETUX/RT comparing CD103+ ITIC high (≥30%) versus low (<30%). High and low CD103 were compared using Cox regression adjusting for age, stage and trial. RESULTS: Tumor samples were available in 159/182 patients on TROG 12.01 and 145/334 on De-ESCALaTE. CD103+ ITIC abundance was high in 27% of patients. The median follow-up was 3.2 years. The 3-year FFS in patients treated with CETUX/RT was 93% [95% confidence interval (CI) 79% to 98%] in high CD103 and 74% (95% CI 63% to 81%) in low CD103 [adjusted hazard ratio = 0.22 (95% CI 0.12-0.41), P < 0.001]. The 3-year overall survival in patients treated with CETUX/RT was 100% in high CD103 and 86% (95% CI 76% to 92%) in low CD103, P < 0.001. In patients treated with CIS/RT, there was no significant difference in FFS. CONCLUSIONS: CD103+ ITIC expression separates CETUX/RT-treated low-risk HPV-associated OPSCC into excellent and poor prognosis subgroups. The high CD103 population is a rational target for de-intensification trials.

Identification of an excellent prognosis subset of human papillomavirus-associated oropharyngeal cancer patients by quantification of intratumoral CD103+ immune cell abundance.

BACKGROUND: Accurate prognostic stratification of human papillomavirus-associated oropharyngeal cancers (HPV+OPSCC) is required to identify patients potentially suitable for treatment deintensification. We evaluated the prognostic significance of CD103, a surface marker associated with tissue-resident memory T cells (TRMs), in two independent cohorts of patients with HPV+OPSCC. PATIENTS AND METHODS: The abundance and distribution of CD103+ immune cells were quantified using immunohistochemistry in a cohort of 189 HPV+OPSCC patients treated with curative intent and correlated with outcome. Findings were then validated in an independent cohort comprising 177 HPV+OPSCCs using univariable and multivariable analysis. Intratumoral CD103+ immune cells were characterized by multispectral fluorescence immunohistochemistry and gene expression analysis. RESULTS: High intratumoral abundance of CD103+ immune cells using a ≥30% cut-off was found in 19.8% of tumors in the training cohort of HPV+OPSCC patients and associated with excellent prognosis for overall survival (OS) with adjusted hazard ratio (HR) of 0.13 [95% confidence interval (CI) 0.02-0.94, P = 0.004]. In the independent cohort of HPV+OPSCCs, 20.4% had high intratumoral CD103+ abundance and an adjusted HR for OS of 0.16 (95% CI 0.02-1.22, P = 0.02). Five year OS of patients with high intratumoral CD103 was 100% across both cohorts. The C-statistic for the multivariate prognostic model with stage and age was significantly improved in both cohorts with the addition of intratumoral CD103+ cell abundance. On the basis of spatial location, co-expression of CD8 and CD69, and gene expression profiles, intratumoral CD103+ cells were consistent with TRMs. CONCLUSION: Quantification of intratumoral CD103+ immune cell abundance provides prognostic information beyond that provided by clinical parameters such as TNM-staging, identifying a population of low risk HPV+OPSCC patients who are good candidates for trials of deintensification strategies.

Prognostic factors and patterns of failure after surgery for T4 rectal cancer in the beyond total mesorectal excision era.

BACKGROUND: Despite advances in the rates of total mesorectal excision (TME) for rectal cancer surgery, decreased local recurrence rates and increased 5-year survival, there still exists large variation in the quality of treatment received. Up to 30 per cent of rectal cancers are locally advanced at presentation and approximately 5-10 per cent still breach the mesorectal plane and invade adjacent structures despite neoadjuvant therapy. With the evolution of extended resections for rectal cancers beyond the TME plane, proponents advocate that these resections should be performed only in specialist centres. The aim was to assess the prognostic factors and patterns of failure after beyond TME surgery for T4 rectal cancers. METHODS: Data were collected from prospective databases at three high-volume institutions specializing in beyond TME surgery for T4 rectal cancers between 1990 and 2013. The primary outcome measures were overall survival, local recurrence and patterns of first failure. RESULTS: Three hundred and sixty patients were identified. The negative resection margin (R0) rate was 82·8 per cent (298 patients) and the local recurrence rate was 12·5 per cent (45 patients). The type of surgical procedure (Hartmann's: hazard ratio (HR) 4·49, 95 per cent c.i. 1·99 to 10·14; P = 0·002) and lymphovascular invasion (HR 2·02, 1·08 to 3·77; P = 0·032) were independent predictors of local recurrence. The 5-year overall survival rate for all patients was 61 (95 per cent c.i. 55 to 67) per cent. The 5-year cumulative incidence of first failure was 8 per cent for local recurrence, 6 per cent for local and distant disease, and 18 per cent for distant disease. CONCLUSION: This study has demonstrated that a coordinated approach in specialist centres for beyond TME surgery can offer good oncological and long-term survival in patients with T4 rectal cancers.

ANTECEDENTES: A pesar de las mejoras en los porcentajes de extirpación total del mesorrecto (total mesorectal excision, TME) en la cirugía de cáncer de recto, la disminución de los porcentajes de recidiva local y el aumento de la supervivencia a 5 años, todavía existe una gran variabilidad en la calidad del tratamiento recibido. Hasta el 30% de los cánceres de recto están localmente avanzados en el momento del diagnóstico y aproximadamente el 5-10% sobrepasarán el plano mesorrectal e invadirán las estructuras adyacentes a pesar del tratamiento neoadyuvante. Con la evolución de las resecciones ampliadas para los cánceres de recto que sobrepasan el plano de la TME, los defensores recomiendan que estas resecciones solo se realicen en centros especializados. El objetivo fue evaluar los factores pronósticos y los patrones de recidiva después de la cirugía ampliada más allá de la TME para los cánceres de recto T4. MÉTODOS: Los datos se recogieron a partir de bases de datos prospectivas de tres instituciones de alto volumen especializadas en resecciones ampliadas más allá de la TME para el cáncer de recto T4 entre 1990 y 2013. Los criterios de valoración principal fueron la supervivencia global, la recidiva local y los patrones de la primera recidiva. RESULTADOS: Se identificaron 360 pacientes. El margen de resección fue negativo (R0) en el 82,8% (n = 298) y el porcentaje de recidiva local fue de 12,5% (n = 45). El tipo de cirugía realizada (Hartmann: cociente de riesgos instantáneos, hazard ratio, HR 4,49; i.c. del 95%: 1,99-10,14; P = 0,002) y la invasión linfovascular (HR 2,02; i.c. del 95%: 1,08-3,77; P = 0,032) fueron factores predictivos independientes de recidiva local. La supervivencia global a 5 años para todos los pacientes fue del 61% (i.c. del 95%: 55-67). La incidencia acumulada a los 5 años de la primera recidiva fue de 8% para la recidiva local, 6% para la recidiva local y a distancia, y 18% para la recidiva a distancia. CONCLUSIÓN: Este estudio demuestra que un abordaje coordinado en centros especializados para cirugía más allá de la TME puede ofrecer una buena supervivencia oncológica y a largo plazo en pacientes con cáncer de recto T4.

FOLFOX and intensified split-course chemoradiation as initial treatment for rectal cancer with synchronous metastases.

BACKGROUND: Optimal initial management of rectal carcinoma with synchronous metastases (RCSM) is controversial - both for patients being treated with curative and palliative intent. This study aims to evaluate the use of an upfront treatment strategy combining FOLFOX chemotherapy with split-course pelvic chemoradiation (FOLFOX + CRT) for patients with RCSM. MATERIAL AND METHODS: An analysis of all patients who commenced treatment with FOLFOX + CRT at our institutions between January 2009 and June 2014 was performed. The regimen consisted of a total of 12 weeks of treatment with split-course pelvic chemoradiation (50.4Gy with concurrent oxaliplatin and 5-FU) alternating with FOLFOX chemotherapy. Restaging imaging was performed following treatment, with subsequent management as per local standard of care. RESULTS: 78 patients (15 with resectable liver-only metastases) were identified. 77 (99%) completed at least 45Gy of radiation and 87% completed ≥75% of planned dose intensity of both oxaliplatin and 5FU. Two (2.6%) patients died within 30 days of treatment. Rates of radiological complete or partial response for local and metastatic disease were 90% and 66%, respectively. 24% patients had radiological disease progression of metastatic disease. Median overall survival for patients with unresectable metastatic disease at baseline was 23 months (95%CI: 19-28). 12 patients underwent radical surgery to both the rectum and liver and had an estimated 3-year overall survival rate of 62% (95%CI: 37-100). For those patients who did not proceed to rectal surgery, only 7% required palliative re-irradiation or surgery at a later date and all >20months from initial treatment. CONCLUSIONS: In patients with unresectable metastatic disease, FOLFOX + CRT provides durable pelvic control for the majority without the need for additional local treatment. For patients with an advanced primary tumor and synchronous resectable liver-only metastases, FOLFOX + CRT can be considered a feasible and tolerable upfront treatment option.

Systematic review and meta-analysis of the accuracy of MRI and endorectal ultrasound in the restaging and response assessment of rectal cancer following neoadjuvant therapy.

AIM: Restaging imaging by MRI or endorectal ultrasound (ERUS) following neoadjuvant chemoradiotherapy is not routinely performed, but the assessment of response is becoming increasingly important to facilitate individualization of management. METHOD: A search of the MEDLINE and Scopus databases was performed for studies that evaluated the accuracy of restaging of rectal cancer following neoadjuvant chemoradiotherapy with MRI or ERUS against the histopathological outcome. A systematic review of selected studies was performed. The methodological quality of studies that qualified for meta-analysis was critically assessed to identify studies suitable for inclusion in the meta-analysis. RESULTS: Sixty-three articles were included in the systematic review. Twelve restaging MRI studies and 18 restaging ERUS studies were eligible for meta-analysis of T-stage restaging accuracy. Overall, ERUS T-stage restaging accuracy (mean [95% CI]: 65% [56-72%]) was nonsignificantly higher than MRI T-stage accuracy (52% [44-59%]). Restaging MRI is accurate at excluding circumferential resection margin involvement. Restaging MRI and ERUS were equivalent for prediction of nodal status: the accuracy of both investigations was 72% with over-staging and under-staging occurring in 10-15%. CONCLUSION: The heterogeneity amongst restaging studies is high, limiting conclusive findings regarding their accuracies. The accuracy of restaging imaging is different for different pathological T stages and highest for T3 tumours. Morphological assessment of T- or N-stage by MRI or ERUS is currently not accurate or consistent enough for clinical application. Restaging MRI appears to have a role in excluding circumferential resection margin involvement.

Phase II trial evaluating the feasibility of interdigitating folfox with chemoradiotherapy in locally advanced and metastatic rectal cancer.

BACKGROUND: Patients (pts) with metastatic rectal cancer and symptomatic primary, require local and systemic control. Chemotherapy used during chemoradiotherapy (CRT) is adequate for radiosensitisation, but suboptimal for systemic control. The aim of this phase II study was to assess tolerability, local/systemic benefits, of a novel regimen delivering interdigitating intensive chemotherapy with radical CRT. METHODS: Eligible pts had untreated synchronous symptomatic primary/metastatic rectal cancer. A total of 12 weeks of treatment with split-course pelvic CRT (total 50.4 Gy with concurrent oxaliplatin and 5-FU infusion) alternating with FOLFOX chemotherapy. All pts staged with CT, MRI and FDG-PET pre and post treatment. RESULTS: Twenty-six pts were treated. Rectal primary MRI stage: T3 81% and T4 15%. Liver metastases in 81%. Twenty-four pts (92%) completed the 12-week regimen. All patients received planned RT dose, and for both agents over 88% of patients achieved a relative dose intensity of >75%. Grade 3 toxicities: neutropenia 23%, diarrhoea 15%, and radiation skin reaction 12%. Grade 4 toxicity: neutropenia 15%. FDG-PET metabolic response rate for rectal primary 96%, and for metastatic disease 60%. CONCLUSIONS: Delivery of interdigitating chemotherapy with radical CRT was feasible to treat both primary and metastatic rectal cancer. High completion and response rates were encouraging.

Cancer of unknown primary: a population-based analysis of temporal change and socioeconomic disparities.

BACKGROUND: Cancer of unknown primary (CUP) is the fourth most common cause of cancer death. With advanced diagnostics and treatments, we investigated the proportion of cancers diagnosed as CUP, treatment outcomes and association with socioeconomic disparities. METHODS: We analysed trends in CUP diagnosis and outcome within the Surveillance, Epidemiology, and End Results registry between 1973 and 2008. RESULTS: The percentage of all cancers diagnosed as CUP has decreased over time comprising <2% of cancers since 2007. A higher proportion of CUP was diagnosed in the elderly, females, blacks and residents of less affluent or less educated counties. Median survival of all CUP patients was 3 months, with no improvement over time. The 5-year survival significantly improved in those with squamous histology (squamous cell carcinoma; SCC) but only marginally in non-SCC. Factors associated with a longer survival on multivariate analysis included white race; female; <65 years old; most recent decade at diagnosis; SCC; married; a histological diagnosis; and treatment with radiotherapy (all P<0.001). Despite the improvement in survival with radiotherapy, its use was less frequent in females and blacks. CONCLUSION: The percentage of cancers diagnosed as CUP is decreasing but prognosis remains poor, particularly in non-SCC CUP. However, significant socioeconomic disparities exist in diagnosis and survival, suggesting inequalities in access to diagnostic investigations and treatment.

Long-term outcome for gastric marginal zone lymphoma treated with radiotherapy: a retrospective, multi-centre, International Extranodal Lymphoma Study Group study.

BACKGROUND: We evaluated the long-term results of radiotherapy for patients with gastric marginal zone lymphoma (GMZL). PATIENTS AND METHODS: We carried out a retrospective, multi-centre study of patients with low-grade GMZL treated by radiotherapy between 17 July 1981 and 25 March 2004. RESULTS: There were 102 eligible patients. Fifty-eight patients were previously untreated and 44 had recurrent/residual disease after prior treatment (HP eradication, chemotherapy and surgery in 35, 9 and 8 patients, respectively, and 7 had >1 prior therapy). Radiation fields included the stomach /involved nodes in 61 patients and whole abdomen in 41. The median radiotherapy dose to stomach was 40 Gy (range 26-46 Gy) in a median 22 fractions. With a median follow-up after radiotherapy of 7.9 years (range 0.3-24 years), 10- and 15-year freedom from treatment failure (FFTF) was 88% (95% CI 82%-95%). Risk factors for TF were a large-cell component (P = 0.036) and an exophytic growth pattern (P = 0.042). Radiotherapy field size, radiotherapy dose, and failure of prior therapy were not associated with inferior FFTF. Ten-year overall survival was 70% (95% CI 60%-82%). CONCLUSIONS: Radiotherapy achieves cure for the majority of patients with low-grade GMZL, including patients who have had prior therapy. Several features may predict a poorer outcome.

TROG 14.04: Multicentre Study of Feasibility and Impact on Anxiety of DIBH in Breast Cancer Patients.

AIMS: The aim of TROG 14.04 was to assess the feasibility of deep inspiration breath hold (DIBH) and its impact on radiation dose to the heart in patients with left-sided breast cancer undergoing radiotherapy. Secondary end points pertained to patient anxiety and cost of delivering a DIBH programme. MATERIALS AND METHODS: The study comprised two groups - left-sided breast cancer patients engaging DIBH and right-sided breast cancer patients using free breathing through radiotherapy. The primary end point was the feasibility of DIBH, defined as left-sided breast cancer patients' ability to breath hold for 15 s, decrease in heart dose in DIBH compared with the free breathing treatment plan and reproducibility of radiotherapy delivery using mid-lung distance (MLD) assessed on electronic portal imaging as the surrogate. The time required for treatment delivery, patient-reported outcomes and resource requirement were compared between the groups. RESULTS: Between February and November 2018, 32 left-sided and 30 right-sided breast cancer patients from six radiotherapy centres were enrolled. Two left-sided breast cancer patients did not undergo DIBH (one treated in free breathing as per investigator choice, one withdrawn). The mean heart dose was reduced from 2.8 Gy (free breathing) to 1.5 Gy (DIBH). Set-up reproducibility in the first week of treatment assessed by MLD was 1.88 ± 1.04 mm (average ± 1 standard deviation) for DIBH and 1.59 ± 0.93 mm for free breathing patients. Using a reproducibility cut-off for MLD of 2 mm (1 standard deviation) as per study protocol, DIBH was feasible for 67% of DIBH patients. Radiotherapy delivery using DIBH took about 2 min longer than for free breathing. Anxiety was not significantly different in DIBH patients and decreased over the course of treatment in both groups. CONCLUSION: Although DIBH was shown to require about 2 min longer per treatment slot, it has the potential to reduce heart dose in left-sided breast cancer patients by nearly a half, provided careful assessment of breath hold reproducibility is carried out.

Evaluation of the Impact of Magnetic Resonance Imaging with Susceptibility-weighted Imaging for Screening and Surveillance of Radiation-induced Cavernomas in Long-term Survivors of Malignancy.

AIMS: Radiation-induced cavernomas (RIC) are common late toxicities in long-term survivors of malignancy following cerebral irradiation. However, the natural history of RIC is poorly described. We report the first series of long-term surveillance of RIC using modern magnetic resonance imaging (MRI) including highly sensitive susceptibility-weighted imaging (SWI). The aims of this research were to better characterise the natural history of RIC and investigate the utility of MRI-SWI for screening and surveillance. MATERIALS AND METHODS: Eligibility required long-term survivors of malignancy with previous exposure to cerebral irradiation and RIC identified on MRI-SWI surveillance. The number and size of RIC were reported on Baseline MRI-SWI and last Follow-up MRI-SWI. RESULTS: In total, 113 long-term survivors with RIC underwent MRI-SWI surveillance; 109 (96%) were asymptomatic at the time of RIC diagnosis. The median age at cerebral irradiation was 9.3 years; the median radiotherapy dose was 50.4 Gy. The median time from cerebral irradiation to Baseline MRI-SWI was 17.9 years. On Baseline MRI-SWI, RIC multiplicity was present in 89% of patients; 34% had >10 RIC; 65% had RIC ≥4 mm. The median follow-up from Baseline MRI-SWI was 7.3 years. On Follow-up MRI-SWI, 96% of patients had multiple RIC; 62% had >10 RIC; 72% had RIC ≥4 mm. Of the 109 asymptomatic patients at RIC diagnosis, 96% remained free from RIC-related symptoms at 10 years. Only two required neurosurgical intervention for RIC; there was no RIC-related mortality. CONCLUSIONS: RIC are commonly multiple, asymptomatic and typically increase in size and number over time. Our findings suggest that MRI-SWI for screening of RIC is unlikely to influence longer term intervention in asymptomatic cancer survivors. In the absence of neurological symptoms, assessment or monitoring of RIC are insufficient indications for MRI-SWI surveillance for long-term survivors of malignancy with past exposure to cerebral irradiation.

Long-term Survival with 18-Fluorodeoxyglucose Positron Emission Tomography-directed Therapy in Non-small Cell Lung Cancer with Synchronous Solitary Brain Metastasis.

AIMS: At diagnosis, <1% of patients with non-small cell lung cancer (NSCLC) have synchronous solitary brain metastasis (SSBM). In prior cohorts without 18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) staging, definitive treatment to intracranial and intrathoracic disease showed a 5-year overall survival (OS) of 11-21%. We investigated the long-term survival outcomes for patients with SSBM NSCLC, diagnosed in the FDG-PET/CT era and treated definitively with local therapies to both intracranial and intrathoracic sites of disease. MATERIALS AND METHODS: This retrospective study assessed patients staged with FDG-PET/CT who received definitive lung and SSBM treatment from February 1999 to December 2017. A lung-molecular graded prognostic assessment (lung-molGPA) score was assigned for each patient using age, performance status score, and, where carried out, molecular status. Overall survival and progression-free survival (PFS) were calculated using Kaplan-Meier methods. Cox proportional hazard models determined OS and PFS prognostic factors. RESULTS: Forty-nine patients newly diagnosed with NSCLC and SSBM had a median age of 63 years (range 34-76). The median follow-up of all patients was 3.9 years. Thirty-three patients (67%) had ≥T2 disease, 23 (47%) had ≥N2. At 2 years, 45% of first failures were intracranial only (95% confidence interval 30-59). At 3 and 5 years, OS was 45% (95% confidence interval 32-63) and 30% (95% confidence interval 18-51), respectively. In ≥N1 disease, 5-year OS was 34% (95% confidence interval 18-63). The 3- and 5-year PFS was 8% (95% confidence interval 3-22) and 0%, respectively. Higher lung-molGPA was associated with longer OS (hazard ratio 0.26, 95% confidence interval 0.11-0.61, P = 0.002). Higher lung-molGPA (hazard ratio 0.33, 95% confidence interval 0.15-0.71, P = 0.005) and lower N-stage (hazard ratio 1.56, 95% confidence interval 1.13-2.15, P = 0.007) were associated with longer PFS. CONCLUSIONS: Definitive treatment of patients with NSCLC and SSBM staged with FDG-PET/CT can result in 5-year survivors, including those with ≥N1 disease.

Single Fraction Stereotactic Ablative Body Radiotherapy for Oligometastasis: Outcomes from 132 Consecutive Patients.

AIMS: Stereotactic ablative body radiotherapy (SABR) is currently used to treat oligometastases, but the optimum dose/fractionation schedule is unknown. In this study, we evaluated outcomes after single fraction SABR in patients with oligometastatic disease. MATERIALS AND METHODS: Single institutional retrospective review of patients treated with single fraction SABR for one to three oligometastases between 2010 and 2015. The primary outcome was freedom from widespread disease defined as distant recurrence not amenable to surgery or SABR; or recurrence with four or more metastases. RESULTS: In total, 186 treatments were delivered in 132 patients. The two most common target sites were lung (51%) and bone (40%). The most frequent single fraction prescription dose was 26 Gy (47%). The most common primary malignancy was genitourinary (n = 46 patients). Freedom from widespread disease was 75% at 1 year (95% confidence interval 67-83%) and 52% at 2 years (95% confidence interval 42-63%). Freedom from local progression at 1 year was 90% (95% confidence interval 85-95%) and at 2 years was 84% (95% confidence interval 77-91%). A compression fracture of the lumbar vertebra was the only grade 3+ treatment-related toxicity. CONCLUSIONS: Single fraction SABR is associated with a high rate of freedom from widespread disease, favourable local control and low toxicity comparable with historic multi-fraction SABR reports.

Improved quality of risk-reducing salpingo-oophorectomy in Australasian women at high risk of pelvic serous cancer.

OBJECTIVES: The quality of risk-reducing salpingo-oophorectomy (RRSO) performed in Australasian women was previously reported to be suboptimal. Here we describe the quality of RRSO performed since 2008 in women enrolled in the same cohort and determine whether it has improved. DESIGN: Prospective cohort study of women at high risk of pelvic serous cancer (PSC) in kConFab. Eligible women had RRSO between 2008 and 2014 and their RRSO surgical and pathology reports were reviewed. "Adequate" surgery and pathology were defined as complete removal and paraffin embedding of all ovarian and extra-uterine fallopian tube tissue, respectively. Associations between clinical factors and "adequate" pathology were assessed using logistic regression. Data were compared with published cohort data on RRSO performed prior to 2008 using Chi square test. RESULTS: Of 164 contemporary RRSOs performed in 78 centres, 158/159 (99%) had "adequate" surgery and 108/164 (66%) had "adequate" pathology. Surgery performed by a gynaecologic oncologist rather than a general gynaecologist [OR 8.2, 95%CI (3.6-20.4), p < 0.001], surgery without concurrent hysterectomy [OR 2.5, 95%CI (1.1-6.0), p = 0.03], more recent year of surgery [OR 1.4, 95%CI (1.1-1.8), p = 0.02], and clinical notation that indicated high risk [OR 19.4, 95%CI (3.1-385), p = 0.008] were independently associated with "adequate" pathology. Both surgery and pathology were significantly more likely to be "adequate" (p < 0.001) in this contemporary sample. CONCLUSION: The quality of RRSOs has significantly improved since our last report. Surgery by a gynaecologic oncologist who informs the pathologist that the woman is at high risk for PSC is associated with optimal RRSO pathology.

A Multidisciplinary Evaluation of a Web-based eLearning Training Programme for SAFRON II (TROG 13.01): a Multicentre Randomised Study of Stereotactic Radiotherapy for Lung Metastases.

AIMS: In technically advanced multicentre clinical trials, participating centres can benefit from a credentialing programme before participating in the trial. Education of staff in participating centres is an important aspect of a successful clinical trial. In the multicentre study of fractionated versus single fraction stereotactic ablative body radiotherapy in lung oligometastases (TROG 13.01), knowledge transfer of stereotactic ablative body radiotherapy techniques to the local multidisciplinary team is intended as part of the credentialing process. In this study, a web-based learning platform was developed to provide education and training for the multidisciplinary trial teams at geographically distinct sites. MATERIALS AND METHODS: A web-based platform using eLearning software consisting of seven training modules was developed. These modules were based on extracranial stereotactic theory covering the following discrete modules: Clinical background; Planning technique and evaluation; Planning optimisation; Four-dimensional computed tomography simulation; Patient-specific quality assurance; Cone beam computed tomography and image guidance; Contouring organs at risk. Radiation oncologists, medical physicists and radiation therapists from hospitals in Australia and New Zealand were invited to participate in this study. Each discipline was enrolled into a subset of modules (core modules) and was evaluated before and after completing each module. The effectiveness of the eLearning training will be evaluated based on (i) knowledge retention after participation in the web-based training and (ii) confidence evaluation after participation in the training. Evaluation consisted of a knowledge test and confidence evaluation using a Likert scale. RESULTS: In total, 130 participants were enrolled into the eLearning programme: 81 radiation therapists (62.3%), 27 medical physicists (20.8%) and 22 radiation oncologists (16.9%). There was an average absolute improvement of 14% in test score (P < 0.001) after learning. This score improvement compared with initial testing was also observed in the long-term testing (>4 weeks) after completing the modules (P < 0.001). For most there was significant increase in confidence (P < 0.001) after completing all the modules.

Efficacy of high-dose palliative radiotherapy for localised, castration-resistant prostate cancer.

AIMS: There are limited outcome data after radiotherapy treatment for clinically localised, castration-resistant prostate cancer. We report our single institution experience on patient outcomes in this group using high-dose palliative radiotherapy (HDPRT). MATERIALS AND METHODS: A retrospective review of patient hospital records was conducted in prostate cancer patients treated with palliative intent radiotherapy and restricted to those who had castration-resistant disease, no evidence of regional or distant disease and who received a local radiotherapy dose equivalent to 40 Gy or greater. RESULTS: Fifty-one patients met the study criteria, 88% of these had high-risk disease at initial diagnosis. The median time to delivery of HDPRT was 66 months and the median follow-up from HDPRT was 54 months. Grade 3 or worse toxicity was experienced in 8%. The estimated freedom from local failure, cause-specific survival and overall survival at 5 years were 81, 65 and 35%, respectively. Local procedures were a significant contributor to local morbidity, with the most common procedure a transurethral resection of the prostate (27% patients). Only two patients died from complications of local failure. CONCLUSION: HDPRT was well tolerated and provided a high rate of local control in a clinically localised castration-resistant prostate cancer population. Although prostate cancer remained the most frequent cause of death, some patients had extended survival without evidence of disease progression.

Predictors of respiratory-induced lung tumour motion measured on four-dimensional computed tomography.

AIMS: The delivery of radical radiotherapy in lung cancer is complicated by respiratory-induced tumour motion. The aim of the study was to correlate tumour motion characteristics with tumour and patient factors, particularly the anatomical lobe and pulmonary zone. MATERIALS AND METHODS: Lung tumour volumes on four-dimensional computed tomography were delineated by a single observer at maximal expiration and propagated through all 10 phases of the breathing cycle. Movements were tracked in the superior-inferior (SI), anterior-posterior (AP) and medio-lateral (ML) directions by changes in the tumour centroid coordinates. Tumour motion characteristics were correlated with anatomical lobe, pulmonary zone, tumour volume, T-stage, smoking status and spirometry. RESULTS: In 101 consecutive patients, the median magnitude of tumour motion in the SI direction was significantly larger in tumours located in lower lobes compared with upper lobes and middle/lingular lobes (0.70 cm versus 0.09 cm versus 0.26 cm, P < 0.01). No significant difference was found in median tumour motion between lower, upper and middle/lingular lobes in the AP (0.16 cm versus 0.13 cm versus 0.16 cm, P = 0.45) and ML (0.08 cm versus 0.08 cm versus 0.13 cm, P = 0.32) directions, respectively. When assessed by zone, the median tumour displacement in the SI direction was significantly larger in the lower zones (0.81 cm) as compared with the middle zones (0.30 cm) and upper zones (0.11 cm), P < 0.01. No difference was observed in the AP (P = 0.45) and ML (P = 0.73) directions. Tumour volume, T-stage and forced expiratory ratio were not statistically significant predictors of respiratory-induced tumour motion. CONCLUSION: Respiratory-induced tumour motion in the SI direction was significantly greater in lower lobe and lower pulmonary zone tumours compared with apical tumours. Tumour volume, T-stage and spirometry did not correlate with the magnitude or direction of respiratory-induced tumour motion. During curative radiotherapy in lung cancer, attention should be paid to motion management, especially for lower lobe tumours.

Adjuvant radiotherapy following radical prostatectomy--results of 56 patients.

Patients with adenocarcinoma of the prostate with positive surgical margins and/or seminal vesicle invasion after radical prostatectomy (RP) have a high risk of local recurrence or distant spread of disease. Several investigators reported increased local control rates following adjuvant radiotherapy (RT). However, it is unclear whether this procedure, with or without hormonal therapy (HT), improves the outcome. From 1975 to 1987, 56 patients with adenocarcinoma of the prostate underwent adjuvant RT following RP (pathological stage C1, n = 19; stage C2, n = 17; stage D1, n = 20). In 27 of 56 patients an additional immediate orchiectomy was performed. 48 patients received 4000-5000 cGy to the pelvic lymphatics, including the prostatic fossa, followed by a boost to the prostatic fossa to complete 6400-7000 cGy, whereas 8 patients were treated to the prostatic fossa only. With a median follow-up of 89 months, the overall survival rate of patients with stages C1, C2 and D1 did not differ significantly (10-year overall survival rate 84, 74 and 71, respectively). The local control rate for 5- and 10-years was 96 and 90%, respectively. A significant advantage in overall survival (5- and 10-year rate: 92 versus 93% and 92 versus 63%; P < 0.05, respectively) and clinical disease-free survival (5- and 10-year rate: 92 versus 72% and 92 versus 49%; P < 0.05, respectively) was seen in 27 patients with orchiectomy compared with 29 patients without HT. A total of 15 patients (26%) developed at least one form of late toxicity, in most cases a mild proctitis, cystitis, or penile or leg oedema. However, 6 patients (11%) had severe grade 3 or 4 side-effects that necessitated a cystectomy in 2 cases as well as a colostomy in 2 cases. In all patients with grade 3 or 4 side-effects, 70 Gy as a tumour-encompassing isodose were applied. Adjuvant RT, following RP in stage C and D1 prostate cancer with positive surgical margins and/or seminal vesicle invasion increases local control. Whether immediate HT influences the outcome, as seen in this study, should be proven in prospective clinical trials.

Cytogenetic survey of 32 cancers of the prostate.

Cytogenetic studies after short-term culture were performed on 32 adenocarcinomas of the prostate from patients without prior treatment. The tumor specimens, ranging from stage B1 to D1, were obtained by radical prostatectomy or diagnostic biopsies. Fourteen tumors showed a normal diploid chromosome complement in all metaphases examined. Clonal chromosomal alterations were detected in 16 tumor samples and the remaining two cases contained double minute (dmin) chromosomes in some cells. The most frequent numerical changes included loss the Y chromosome and trisomy 7, both found in four cases. The only recurrent structural aberration was del(10)(q24), seen in three cases both as a sole anomaly and within multiple rearrangements. Six patients showed cytogenetically unrelated clones. The occurrence of the chromosomal changes found in this study shows no relationship to certain histopathologic characteristics of the tumors. The recurrent finding of del(10)(q24) as sole anomaly and the evidence for clonal evolution in one patient demonstrates that this change is an early karyotypic event which may be important for the pathogenesis in at least a subset of prostatic cancers.

Androgens, adrenal androgen precursors, and their metabolism in untreated primary tumors and lymph node metastases of human prostatic cancer.

Activities of several steroid metabolizing enzymes (steroid sulfate-sulfatase, 17 beta-hydroxysteroid dehydrogenase, 5 alpha-reductase, and 3 alpha beta-hydroxysteroid dehydrogenase) as well as total tissue content and subcellular distribution (nuclear-extranuclear) of several androgen precursors, active androgens, and androgen deactivation products (DHEA sulfate, DHEA, 5-androstenediol, 4-androstenedione, testosterone, DHT, and 3 alpha-androstanediol) were quantified in primary tumors and lymph node metastases of human prostatic cancer obtained from patients without previous endocrine manipulation. Primary tumors were compared to benign parts of the same prostates, and the metastases were compared to their primary tumors. All enzymes and steroids found in benign prostatic tissues could also be detected in the malignant tissues. Even the capacity to accumulate active androgens in the nuclei was found to be unchanged in nearly all of the samples. Lower activities of hormone-dependent enzymes were observed in the cancers, suggesting a less efficient utilization of hormonal stimuli. Most striking changes found in the malignant tissues were a subtotal loss of 5 alpha-reductase activity and a metabolic shift to testosterone, which was more pronounced in samples from metastatic disease as compared to samples from non-metastatic disease. In conclusion, primary tumors and metastases of prostatic cancers not treated by endocrine manipulations retain their androgen receptor system and possess the same capacity to metabolize adrenal androgen precursors along the pathway to DHT as benign prostatic tissue. Consequently, they should be able to use at least androstenedione for production of active androgens directly in the target tissue.