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PURPOSE: The TROG 09.02 CHISEL trial compared conventional radiation therapy (CRT) with stereotactic body radiation therapy (SBRT) in patients with inoperable early-stage non-small cell lung cancer. Patients randomized to SBRT had less local failure and improved overall survival. This analysis reports differences in pulmonary function tests (PFTs) and the 6-minute walk test (SMWT) between patients who received SBRT and those who received CRT. METHODS AND MATERIALS: We analyzed the PFTs and SMWTs of all patients recruited to the CHISEL [trial. During this trial, patients underwent serial PFTs. Linear regression models were used to compare parameters between SBRT and CRT at 3 and 12 months after treatment. RESULTS: One hundred and one patients were enrolled; 33 patients were treated with CRT, 61 were treated with SBRT, and 7 did not receive treatment. Primary tumor size was similar between arms: SBRT 25 mm (standard deviation [SD], 9) and CRT 28 mm (SD, 9). On regression analysis, at 3 and 12 months, there was no evidence of a difference between arms in PFT decline or distance walked in the SMWT. Planning target volume size was significantly larger in the CRT arm, 142.79 cc (SD, 61.14), compared with the SBRT group, 46.15 cc (SD, 23.39). The mean biologically effective dose received by the target was significantly larger in the SBRT group, 125.92 Gy (SD, 21.58), compared with CRT, 65.49 Gy (SD, 6.32). Mean dose to the lungs minus the gross target volume incorporating motion was 8.9 Gy (SD, 2.34) in the CRT group and 4.37 Gy (SD, 1.42) in the SBRT group. CONCLUSIONS: Despite the considerably higher biologically effective doses delivered to the tumor in SBRT, there was no difference in decline in respiratory function observed between the 2 groups.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Radiocirurgia , Radioterapia Conformacional , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Radiocirurgia/métodos , Neoplasias Pulmonares/patologia , Pulmão/patologia , Radioterapia Conformacional/métodosRESUMO
INTRODUCTION: Melanoma surveillance photography (MSP) is a comprehensive surveillance method that comprises two- or three-dimensional total body photography with tagged digital dermoscopy, performed at prescribed intervals. It has the potential to reduce unnecessary biopsies and enhance early detection of melanoma, but it is not yet standard care for all high-risk patients in Australia. This protocol describes a randomised controlled trial (RCT) designed to evaluate the clinical impact and cost-effectiveness of using MSP for the surveillance of individuals at ultra-high or high risk of melanoma from a health system perspective. METHODS AND DESIGN: This is a registry-based, unblinded, multi-site, parallel-arm RCT that will be conducted over 3 years. We aim to recruit 580 participants from three Australian states: Victoria, New South Wales and Queensland, via state cancer registries or direct referral from clinicians. Eligible participants within 24 months of a primary cutaneous melanoma diagnosis will be randomised 1:1 to receive either MSP in addition to their routine clinical surveillance (intervention group) or routine clinical surveillance without MSP (control group). Most participants will continue surveillance with their usual care provider, and the frequency of follow-up visits in both groups will depend on the stage of their primary melanoma and risk factors. The primary outcome measure of the study is the number of unnecessary biopsies (i.e. false positives, being cases where a lesion is biopsied due to suspected melanoma on clinical examination, either with or without MSP, but the resulting histopathology finding is negative for melanoma). Secondary outcomes include the evaluation of health economic outcomes, quality of life and patient acceptability. Two sub-studies will explore the benefit of MSP in high-risk patients prior to a melanoma diagnosis and the diagnostic performance of MSP in the teledermatology setting compared to the en face clinical setting. DISCUSSION: This trial will determine the clinical efficacy, cost-effectiveness and affordability of MSP to facilitate policy decision-making at the national and local levels, across primary and specialist care. TRIAL REGISTRATION: ClinicalTrials.gov NCT04385732 . Registered on May 13, 2020.
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Melanoma , Neoplasias Cutâneas , Humanos , Detecção Precoce de Câncer , Melanoma/diagnóstico por imagem , Neoplasias Cutâneas/diagnóstico por imagem , Fotografação , Vitória , Análise Custo-Benefício , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Objective: To determine the feasibility of a pivotal randomised clinical trial of intravenous (IV) iron and erythropoietin in adult survivors of critical illness with anaemia requiring treatment in the intensive care unit. Design: An investigator-initiated, parallel group, placebo-controlled, randomised feasibility trial. Setting: A tertiary intensive care unit (ICU) in Perth, Western Australia. Participants: Adults with anaemia (haemoglobin <100 g/L), requiring ICU-level care for more than 48 h, and likely to be ready for ICU discharge within 24 h. Interventions: A single dose of IV ferric carboxymaltose and Epoetin alfa (active group) or an equal volume of 0.9% saline (placebo group). Main outcome measures: Study feasibility was considered met if the pilot achieved a recruitment rate of ≥2 participants per site per month, ≥90% of participants received their allocated study treatment, and≥ 90% of participants were followed up for the proposed pivotal trial primary outcome - days alive and at home to day 90 (DAH90). Results: The 40-participant planned sample size included twenty in each group and was enrolled between 1/9/2021 and 2/3/2022. Participants spent a median of 3.4 days (interquartile range 2.8-5.1) in the ICU prior to enrolment and had a mean baseline haemoglobin of 83.7 g/L (standard deviation 6.7). The recruitment rate was 6.7 participants per month [95% confidence interval (CI) 4.8-9.0], DAH90 follow-up was 100% (95% CI 91.2%-100%), and 39 (97.5%, 95% CI 86.8%-99.9%) participants received the allocated study intervention. No serious adverse events were reported. Conclusion: The iron and erythropoietin to heal and recover after intensive care (ITHRIVE) pilot demonstrated feasibility based on predefined participant recruitment, study drug administration, and follow-up thresholds.
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PURPOSE: The excellent prognosis of patients with low-risk human papillomavirus (HPV)- associated oropharyngeal squamous cell carcinoma has led to concerns about overtreatment and excessive toxicity with radiation therapy and cisplatin, leading to interest in de-intensification trials. We investigated whether cetuximab, an epidermal growth factor receptor targeting antibody, when combined with radiation therapy would result in a decrease in symptom burden and toxicity with similar efficacy compared with weekly cisplatin. METHODS AND MATERIALS: TROG12.01, a randomized, multicenter trial involving 15 sites in Australia and New Zealand enrolled patients with HPV-associated oropharyngeal squamous cell carcinoma, American Joint Committee on Cancer 7th edition stage III (excluding T1-2N1) or stage IV (excluding T4 and/or N3 and/or N2b-c if smoking history >10 pack years and/or distant metastases). Patients were randomized (1:1) to receive radiation therapy (70 Gy in 35 fractions) with either weekly cisplatin, 7 doses of 40 mg/m2, or cetuximab, loading dose of 400 mg/m2 followed by 7 weekly doses of 250 mg/m2. The primary outcome was symptom severity assessed by the MD Anderson Symptom Inventory Head and Neck Symptom Severity Scale from baseline to 13 weeks postcompletion of radiation therapy using the area under the curve. Trial was registered on ClinicalTrials.gov: NCT01855451. RESULTS: Between June 17, 2013, and June 7, 2018, 189 patients were enrolled, with 92 in cisplatin arm and 90 in cetuximab included in the main analysis. There was no difference in the primary endpoint of symptom severity; difference in area under the curve cetuximab-cisplatin was 0.05 (95% confidence interval [CI], -0.19, 0.30), P = .66. The T-score (mean number of ≥grade 3 acute adverse events) was 4.35 (standard deviation 2.48) in the cisplatin arm and 3.82 (standard deviation 1.8) in the cetuximab arm, P = .108. The 3-year failure-free survival rates were 93% (95% CI, 86%-97%) in the cisplatin arm and 80% (95% CI, 70%-87%) in the cetuximab arm (hazard ratio = 3.0 [95% CI, 1.2-7.7]); P = .015. CONCLUSIONS: For patients with low-risk HPV-associated oropharyngeal cancer, radiation therapy and cetuximab had inferior failure-free survival without improvement in symptom burden or toxicity compared with radiation therapy and weekly cisplatin. Radiation therapy and cisplatin remain the standard of care.
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Neoplasias de Cabeça e Pescoço , Neoplasias Orofaríngeas , Infecções por Papillomavirus , Protocolos de Quimioterapia Combinada Antineoplásica , Cetuximab , Quimiorradioterapia/efeitos adversos , Cisplatino , Humanos , Neoplasias Orofaríngeas/terapia , Sobretratamento , Infecções por Papillomavirus/complicações , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
BACKGROUND: Adjuvant radiotherapy has been shown to halve the risk of biochemical progression for patients with high-risk disease after radical prostatectomy. Early salvage radiotherapy could result in similar biochemical control with lower treatment toxicity. We aimed to compare biochemical progression between patients given adjuvant radiotherapy and those given salvage radiotherapy. METHODS: We did a phase 3, randomised, controlled, non-inferiority trial across 32 oncology centres in Australia and New Zealand. Eligible patients were aged at least 18 years and had undergone a radical prostatectomy for adenocarcinoma of the prostate with pathological staging showing high-risk features defined as positive surgical margins, extraprostatic extension, or seminal vesicle invasion; had an Eastern Cooperative Oncology Group performance status of 0-1, and had a postoperative prostate-specific antigen (PSA) concentration of 0·10 ng/mL or less. Patients were randomly assigned (1:1) using a minimisation technique via an internet-based, independently generated allocation to either adjuvant radiotherapy within 6 months of radical prostatectomy or early salvage radiotherapy triggered by a PSA of 0·20 ng/mL or more. Allocation sequence was concealed from investigators and patients, but treatment assignment for individual randomisations was not masked. Patients were stratified by radiotherapy centre, preoperative PSA, Gleason score, surgical margin status, and seminal vesicle invasion status. Radiotherapy in both groups was 64 Gy in 32 fractions to the prostate bed without androgen deprivation therapy with real-time review of plan quality on all cases before treatment. The primary endpoint was freedom from biochemical progression. Salvage radiotherapy would be deemed non-inferior to adjuvant radiotherapy if freedom from biochemical progression at 5 years was within 10% of that for adjuvant radiotherapy with a hazard ratio (HR) for salvage radiotherapy versus adjuvant radiotherapy of 1·48. The primary analysis was done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT00860652. FINDINGS: Between March 27, 2009, and Dec 31, 2015, 333 patients were randomly assigned (166 to adjuvant radiotherapy; 167 to salvage radiotherapy). Median follow-up was 6·1 years (IQR 4·3-7·5). An independent data monitoring committee recommended premature closure of enrolment because of unexpectedly low event rates. 84 (50%) patients in the salvage radiotherapy group had radiotherapy triggered by a PSA of 0·20 ng/mL or more. 5-year freedom from biochemical progression was 86% (95% CI 81-92) in the adjuvant radiotherapy group versus 87% (82-93) in the salvage radiotherapy group (stratified HR 1·12, 95% CI 0·65-1·90; pnon-inferiority=0·15). The grade 2 or worse genitourinary toxicity rate was lower in the salvage radiotherapy group (90 [54%] of 167) than in the adjuvant radiotherapy group (116 [70%] of 166). The grade 2 or worse gastrointestinal toxicity rate was similar between the salvage radiotherapy group (16 [10%]) and the adjuvant radiotherapy group (24 [14%]). INTERPRETATION: Salvage radiotherapy did not meet trial specified criteria for non-inferiority. However, these data support the use of salvage radiotherapy as it results in similar biochemical control to adjuvant radiotherapy, spares around half of men from pelvic radiation, and is associated with significantly lower genitourinary toxicity. FUNDING: New Zealand Health Research Council, Australian National Health Medical Research Council, Cancer Council Victoria, Cancer Council NSW, Auckland Hospital Charitable Trust, Trans-Tasman Radiation Oncology Group Seed Funding, Cancer Research Trust New Zealand, Royal Australian and New Zealand College of Radiologists, Cancer Institute NSW, Prostate Cancer Foundation Australia, and Cancer Australia.
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Adenocarcinoma/radioterapia , Prostatectomia , Neoplasias da Próstata/radioterapia , Terapia de Salvação , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adulto , Idoso , Austrália , Progressão da Doença , Intervalo Livre de Doença , Fracionamento da Dose de Radiação , Humanos , Masculino , Doenças Urogenitais Masculinas/epidemiologia , Doenças Urogenitais Masculinas/etiologia , Pessoa de Meia-Idade , Nova Zelândia , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Radioterapia Adjuvante/efeitos adversos , Terapia de Salvação/efeitos adversos , Resultado do TratamentoRESUMO
OBJECTIVE: Accurate determination of human papilloma virus (HPV) status is critical when identifying patients with oropharyngeal squamous cell carcinoma (OPSCC) who may be candidates for de-escalation trials. In this study we investigated whether local p16 screening, by immunohistochemistry (IHC), has high positive predictive value (PPV) for HPV status in a good prognosis HPV positive OPSCC (HPVOPSCC) population treated on a clinical trial. METHODS AND MATERIALS: Patients enrolled on the TROG 12.01 randomised trial for good prognosis HPVOPSCC were randomised based on local p16 IHC testing but subsequently had central p16 IHC and HPV RNA in situ hybridisation (HPV RNA ISH) testing. Correlations between the local and central p16 and central HPV RNA ISH were studied. The main outcome was the positive predictive value (PPV) of local pathology laboratory testing of p16. RESULTS: 176/182 patients had samples available for central testing. 172/176 were evaluable for central testing of p16, and all were confirmed to be p16 positive (172/172, 100%, 95% CI = [97.9%, 100%]). Similarly, 100% of those evaluable for HPV RNA ISH (155/155, 100%, 95% CI = [97.6%, 100%]) were confirmed HPV positive, indicating p16 overexpression driven by transcriptionally active HPV and a PPV of 100% for local p16 testing. CONCLUSIONS: Our results validate the suitability of local pathology laboratory p16 testing alone, in populations with a high attributable fraction of OPSCC due to HPV, to screen and enrol low risk HPVOPSCC patients onto de-intensification trials. This obviates the need for upfront more complex and expensive HPV assays and/or central laboratory testing.
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Alphapapillomavirus , Proteínas Oncogênicas Virais/metabolismo , Neoplasias Orofaríngeas/diagnóstico , Neoplasias Orofaríngeas/etiologia , Infecções por Papillomavirus/complicações , Alphapapillomavirus/genética , Biomarcadores Tumorais , Detecção Precoce de Câncer , Feminino , Humanos , Imuno-Histoquímica , Hibridização In Situ , Masculino , Estadiamento de Neoplasias , Proteínas Oncogênicas Virais/genética , Infecções por Papillomavirus/virologia , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Immune checkpoint blockade such as ipilimumab and anti-PD1 monoclonal antibodies have significantly improved survival in advanced melanoma. Biomarkers are urgently needed as a majority of patients do not respond, despite treatment-related toxicities. We analysed pre-treatment 18F-fluorodeoxyglucose positron emission tomography/computerised tomography (FDG PET/CT) parameters to assess its correlation with patient outcome. METHODS: This retrospective study evaluated pre-treatment FDG PET/CT scans in a discovery cohort of patients with advanced melanoma treated with ipilimumab or anti-PD1. Pre-treatment scans were assessed for maximum tumoral standardised uptake value (SUVmax), metabolic tumour volume (MTV) and spleen to liver ratio (SLR). Progression-free survival (PFS) and overall survival (OS) were characterised and modelled using univariable and multivariable analyses. Correlation of SLR and OS was validated in an independent cohort. Blood parameters and stored sera of patients from the discovery cohort was analysed to investigate biological correlates with SLR. RESULTS: Of the 90 evaluable patients in the discovery cohort: 50 received ipilimumab monotherapy, 20 received anti-PD1 monotherapy, and 20 patients received ipilimumab followed by anti-PD1 upon disease progression. High SLR > 1.1 was associated with poor PFS (median 1 vs 3 months; HR 3.14, p = 0.008) for patients treated with ipilimumab. High SLR was associated with poor OS after ipilimumab (median 1 vs 21 months; HR 5.83, p = 0.0001); as well as poor OS after first line immunotherapy of either ipilimumab or anti-PD1 (median 1 vs 14 months; HR 3.92, p = 0.003). The association of high SLR and poor OS after ipilimumab was validated in an independent cohort of 110 patients (median 2.3 months versus 11.9 months, HR 3.74). SLR was associated with poor OS in a multi-variable model independent of stage, LDH, absolute lymphocyte count and MTV. CONCLUSIONS: Pre-treatment Spleen to liver ratio (SLR) > 1.1 was associated with poor outcome after ipilimumab in advanced melanoma. This parameter warrants prospective evaluation.
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Antineoplásicos Imunológicos/uso terapêutico , Ipilimumab/uso terapêutico , Melanoma/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Adulto , Idoso , Feminino , Fluordesoxiglucose F18 , Humanos , Fígado/diagnóstico por imagem , Fígado/patologia , Masculino , Melanoma/tratamento farmacológico , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos , Baço/diagnóstico por imagem , Baço/patologiaRESUMO
INTRODUCTION: There is some evidence to suggest that patients with underlying pulmonary fibrosis (PF) have increased risk of adverse respiratory and survival outcomes, when treated with conventional, long-course radiotherapy (RT) for non-small-cell lung cancer (NSCLC). We performed a retrospective analysis to determine the size of these risks. METHODS: Data from 21 patients with PF (cases) were retrospectively analysed for respiratory toxicity and mortality outcomes, and compared with 84 patients without PF (non-cases). Age and mean lung dose were included as covariates in regression analyses. The additional predictive value of other patient, disease and treatment characteristics on radiation pneumonitis (RP) risk and severity was explored. RESULTS: There was a numerical (though not statistically significant) increase in grade ≥ 2 RP among PF cases (OR 2.74, P = 0.074). Cases were significantly more likely to discontinue radical treatment early (OR 6.10, P = 0.015). There was a significant association between increased RP severity and underlying PF (P = 0.039), with RP strongly implicated in the death in 3 of 21 cases (14.3%) compared to 1 non-case (1.2%). Cases experienced increased grade ≥ 2 respiratory toxicity otherwise (OR 4.35, P = 0.020) and poorer median overall survival (0.6 versus 1.7 years, P < 0.001). Two cases, and no non-cases, died during the proposed RT period. None of the analysed patient, disease or treatment factors, was a significant additional predictor of RP risk/severity. CONCLUSION: Patients with PF are at increased risk of treatment discontinuation, respiratory morbidity and mortality, and poor survival following conventional RT for NSCLC. Caution should be exercised when offering high-dose RT to these patients.
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Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/radioterapia , Fibrose Pulmonar/epidemiologia , Pneumonite por Radiação/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Austrália/epidemiologia , Causalidade , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , TempoRESUMO
BACKGROUND: Glomerular filtration rate (GFR) measured by Chromium-51-EDTA excretion (51Cr-GFR) is considered the gold standard of renal function assessment, but serum creatinine in the Cockcroft-Gault (CG) formula is routinely used to estimate GFR for carboplatin dosing. Serum creatinine measured by isotope-dilution-mass-spectrometry (IDMS) can generate spuriously high GFR estimates when used in the CG formula. We hypothesized that GFR calculated using IDMS-creatinine in the CG formula (CG-GFR) exposes patients to inaccurate carboplatin dosing. METHODS: This is a multicenter retrospective study of patients who had a 51Cr-GFR assessment for malignant or non-malignant indications, with a matched CG-GFR. Carboplatin dose based on 51Cr-GFR at AUC5 was used as the reference. RESULTS: 550 patients were analyzed, median age 62 (19-90), 64% female. Indication for GFR evaluation: malignancy (85%), assessment for live kidney donation (12%), other (3%). Median ratio of CG-GFR: 51Cr-GFR 1.04 (0.43-3.38); <0.8 in 72 patients (13%), >1.2 in 180 patients (33%). Despite capping of CG-GFR at 125 mL/min, dosing according to AUC6 would have resulted in 18% of patients being underdosed and 23% overdosed by >100 mg compared to 51Cr-GFR. Subgroup analysis identified BMI (>35, MPE 39%), gender (female MPE 15%), GFR indication (malignancy MPE 11%) as risk factors for overestimate of CG-GFR, and BMI < 20 for underestimate (MPE -3.5%). CONCLUSIONS: The convention of considering AUC5 carboplatin based on 51Cr-GFR, and AUC6 carboplatin based on CG-GFR as equivalent is invalid and should be abandoned. When 51Cr-GFR is unavailable, capping CG-GFR at 125 mL/min is recommended.
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Antineoplásicos/uso terapêutico , Carboplatina/uso terapêutico , Creatinina/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Carboplatina/farmacologia , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: Conventional imaging using CT and bone scan has insufficient sensitivity when staging men with high-risk localised prostate cancer. We aimed to investigate whether novel imaging using prostate-specific membrane antigen (PSMA) PET-CT might improve accuracy and affect management. METHODS: In this multicentre, two-arm, randomised study, we recruited men with biopsy-proven prostate cancer and high-risk features at ten hospitals in Australia. Patients were randomly assigned to conventional imaging with CT and bone scanning or gallium-68 PSMA-11 PET-CT. First-line imaging was done within 21 days following randomisation. Patients crossed over unless three or more distant metastases were identified. The primary outcome was accuracy of first-line imaging for identifying either pelvic nodal or distant-metastatic disease defined by the receiver-operating curve using a predefined reference-standard including histopathology, imaging, and biochemistry at 6-month follow-up. This trial is registered with the Australian New Zealand Clinical Trials Registry, ANZCTR12617000005358. FINDINGS: From March 22, 2017 to Nov 02, 2018, 339 men were assessed for eligibility and 302 men were randomly assigned. 152 (50%) men were randomly assigned to conventional imaging and 150 (50%) to PSMA PET-CT. Of 295 (98%) men with follow-up, 87 (30%) had pelvic nodal or distant metastatic disease. PSMA PET-CT had a 27% (95% CI 23-31) greater accuracy than that of conventional imaging (92% [88-95] vs 65% [60-69]; p<0·0001). We found a lower sensitivity (38% [24-52] vs 85% [74-96]) and specificity (91% [85-97] vs 98% [95-100]) for conventional imaging compared with PSMA PET-CT. Subgroup analyses also showed the superiority of PSMA PET-CT (area under the curve of the receiver operating characteristic curve 91% vs 59% [32% absolute difference; 28-35] for patients with pelvic nodal metastases, and 95% vs 74% [22% absolute difference; 18-26] for patients with distant metastases). First-line conventional imaging conferred management change less frequently (23 [15%] men [10-22] vs 41 [28%] men [21-36]; p=0·008) and had more equivocal findings (23% [17-31] vs 7% [4-13]) than PSMA PET-CT did. Radiation exposure was 10·9 mSv (95% CI 9·8-12·0) higher for conventional imaging than for PSMA PET-CT (19·2 mSv vs 8·4 mSv; p<0·001). We found high reporter agreement for PSMA PET-CT (κ=0·87 for nodal and κ=0·88 for distant metastases). In patients who underwent second-line image, management change occurred in seven (5%) of 136 patients following conventional imaging, and in 39 (27%) of 146 following PSMA PET-CT. INTERPRETATION: PSMA PET-CT is a suitable replacement for conventional imaging, providing superior accuracy, to the combined findings of CT and bone scanning. FUNDING: Movember and Prostate Cancer Foundation of Australia. VIDEO ABSTRACT.
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Antígenos de Superfície/administração & dosagem , Glutamato Carboxipeptidase II/administração & dosagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Neoplasias da Próstata/diagnóstico , Imagem Corporal Total/métodos , Idoso , Antígenos de Superfície/farmacologia , Biomarcadores , Glutamato Carboxipeptidase II/farmacologia , Humanos , Metástase Linfática/diagnóstico por imagem , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/diagnóstico por imagem , Estudos Prospectivos , Neoplasias da Próstata/patologia , Sensibilidade e EspecificidadeRESUMO
The disproportionately high prevalence of male cancer is poorly understood. We tested for sex-disparity in the functional integrity of the major tumor suppressor p53 in sporadic cancers. Our bioinformatics analyses expose three novel levels of p53 impact on sex-disparity in 12 non-reproductive cancer types. First, TP53 mutation is more frequent in these cancers among US males than females, with poorest survival correlating with its mutation. Second, numerous X-linked genes are associated with p53, including vital genomic regulators. Males are at unique risk from alterations of their single copies of these genes. High expression of X-linked negative regulators of p53 in wild-type TP53 cancers corresponds with reduced survival. Third, females exhibit an exceptional incidence of non-expressed mutations among p53-associated X-linked genes. Our data indicate that poor survival in males is contributed by high frequencies of TP53 mutations and an inability to shield against deregulated X-linked genes that engage in p53 networks.
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Cromossomos Humanos X , Taxa de Mutação , Neoplasias/genética , Proteína Supressora de Tumor p53/genética , Exoma , Feminino , Regulação Neoplásica da Expressão Gênica , Genes Ligados ao Cromossomo X , Humanos , Masculino , Neoplasias/mortalidade , Mapas de Interação de Proteínas , Programa de SEER , Fatores Sexuais , Proteína Supressora de Tumor p53/metabolismo , Estados Unidos/epidemiologiaRESUMO
Long-term survivors of childhood, adolescent and young adult (AYA) malignancies with past exposure to potentially cardiotoxic treatments are at risk of peripartum cardiac dysfunction. Incidence and risk factors for peripartum cardiac dysfunction and maternal cardiac outcomes in this population were investigated. Eligible long-term survivors were aged <30 years at cancer diagnosis, with ≥1 pregnancy occurring ≥5 years after diagnosis. "Peripartum" cardiac events were defined as occurring within pregnancy or ≤5months after delivery. Cardiac events were classified "symptomatic" or "subclinical". "Peripartum cardiomyopathy" (PPCM) was defined as symptomatic dysfunction without prior cardiac dysfunction. Of 64 eligible women, 5 (7.8%) had peripartum cardiac events: 3 symptomatic, 2 subclinical. Of 110 live births, 2 (1.8%, 95% CI 0.2-6.4) were defined as PPCM: Significantly greater than the published general population incidence of 1:3000 (p < 0.001), representing a 55-fold (95% CI 6.6-192.0) increased risk. Risk factor analyses were hypothesis-generating, revealing younger age at cancer diagnosis and higher anthracycline dose. Postpartum, cardiac function of 4 women (80%) failed to return to baseline. In conclusion, peripartum cardiac dysfunction is an uncommon but potentially serious complication in long-term survivors of paediatric and AYA malignancies previously treated with cardiotoxic therapies. Peripartum cardiac assessment is strongly recommended for at-risk patients.
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Research into factors affecting treatment response or survival in patients with cancer frequently involves cohorts that span the most common range of clinical outcomes, as such patients are most readily available for study. However, attention has turned to highly unusual patients who have exceptionally favourable or atypically poor responses to treatment and/or overall survival, with the expectation that patients at the extremes may provide insights that could ultimately improve the outcome of individuals with more typical disease trajectories. While clinicians can often recount surprising patients whose clinical journey was very unusual, given known clinical characteristics and prognostic indicators, there is a lack of consensus among researchers on how best to define exceptional patients, and little has been proposed for the optimal design of studies to identify factors that dictate unusual outcome. In this Opinion article, we review different approaches to identifying exceptional patients with cancer and possible study designs to investigate extraordinary clinical outcomes. We discuss pitfalls with finding these rare patients, including challenges associated with accrual of patients across different treatment centres and time periods. We describe recent molecular and immunological factors that have been identified as contributing to unusual patient outcome and make recommendations for future studies on these intriguing patients.
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Sobreviventes de Câncer , Neoplasias/terapia , Humanos , Linfócitos do Interstício Tumoral/imunologia , Mutação , Neoplasias/genética , Neoplasias/mortalidade , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is widely used to treat inoperable stage 1 non-small-cell lung cancer (NSCLC), despite the absence of prospective evidence that this type of treatment improves local control or prolongs overall survival compared with standard radiotherapy. We aimed to compare the two treatment techniques. METHODS: We did this multicentre, phase 3, randomised, controlled trial in 11 hospitals in Australia and three hospitals in New Zealand. Patients were eligible if they were aged 18 years or older, had biopsy-confirmed stage 1 (T1-T2aN0M0) NSCLC diagnosed on the basis of 18F-fluorodeoxyglucose PET, and were medically inoperable or had refused surgery. Patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1, and the tumour had to be peripherally located. Patients were randomly assigned after stratification for T stage and operability in a 2:1 ratio to SABR (54 Gy in three 18 Gy fractions, or 48 Gy in four 12 Gy fractions if the tumour was <2 cm from the chest wall) or standard radiotherapy (66 Gy in 33 daily 2 Gy fractions or 50 Gy in 20 daily 2·5 Gy fractions, depending on institutional preference) using minimisation, so no sequence was pre-generated. Clinicians, patients, and data managers had no previous knowledge of the treatment group to which patients would be assigned; however, the treatment assignment was subsequently open label (because of the nature of the interventions). The primary endpoint was time to local treatment failure (assessed according to Response Evaluation Criteria in Solid Tumors version 1.0), with the hypothesis that SABR would result in superior local control compared with standard radiotherapy. All efficacy analyses were based on the intention-to-treat analysis. Safety analyses were done on a per-protocol basis, according to treatment that the patients actually received. The trial is registered with ClinicalTrials.gov (NCT01014130) and the Australia and New Zealand Clinical Trials Registry (ACTRN12610000479000). The trial is closed to new participants. FINDINGS: Between Dec 31, 2009, and June 22, 2015, 101 eligible patients were enrolled and randomly assigned to receive SABR (n=66) or standard radiotherapy (n=35). Five (7·6%) patients in the SABR group and two (6·5%) in the standard radiotherapy group did not receive treatment, and a further four in each group withdrew before study end. As of data cutoff (July 31, 2017), median follow-up for local treatment failure was 2·1 years (IQR 1·2-3·6) for patients randomly assigned to standard radiotherapy and 2·6 years (IQR 1·6-3·6) for patients assigned to SABR. 20 (20%) of 101 patients had progressed locally: nine (14%) of 66 patients in the SABR group and 11 (31%) of 35 patients in the standard radiotherapy group, and freedom from local treatment failure was improved in the SABR group compared with the standard radiotherapy group (hazard ratio 0·32, 95% CI 0·13-0·77, p=0·0077). Median time to local treatment failure was not reached in either group. In patients treated with SABR, there was one grade 4 adverse event (dyspnoea) and seven grade 3 adverse events (two cough, one hypoxia, one lung infection, one weight loss, one dyspnoea, and one fatigue) related to treatment compared with two grade 3 events (chest pain) in the standard treatment group. INTERPRETATION: In patients with inoperable peripherally located stage 1 NSCLC, compared with standard radiotherapy, SABR resulted in superior local control of the primary disease without an increase in major toxicity. The findings of this trial suggest that SABR should be the treatment of choice for this patient group. FUNDING: The Radiation and Optometry Section of the Australian Government Department of Health with the assistance of Cancer Australia, and the Cancer Society of New Zealand and the Cancer Research Trust New Zealand (formerly Genesis Oncology Trust).
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Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/radioterapia , Radiocirurgia/métodos , Idoso , Idoso de 80 Anos ou mais , Austrália , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/patologia , Masculino , Nova Zelândia , Radiocirurgia/efeitos adversos , Resultado do TratamentoRESUMO
Imaging of somatostatin receptor expression is an established technique for staging of neuroendocrine neoplasia and determining the suitability of patients for peptide receptor radionuclide therapy. PET/CT using 68Ga-labeled somatostatin analogs is superior to earlier agents, but the rapid physical decay of the radionuclide poses logistic and regulatory challenges. 64Cu has attractive physical characteristics for imaging and provides a diagnostic partner for the therapeutic radionuclide 67Cu. Based on promising preclinical studies, we have performed a first-time-in-humans trial of 64Cu-MeCOSar-Tyr3-octreotate (64Cu-SARTATE) to assess its safety and ability to localize disease at early and late imaging time-points. Methods: In a prospective trial, 10 patients with known neuroendocrine neoplasia and positive for uptake on 68Ga-DOTA-octreotate (68Ga-DOTATATE) PET/CT underwent serial PET/CT imaging at 30 min, 1 h, 4 h, and 24 h after injection of 64Cu-SARTATE. Adverse reactions were recorded, and laboratory testing was performed during infusion and at 1 and 7 d after imaging. Images were analyzed for lesion and normal-organ uptake and clearance to assess lesion contrast and perform dosimetry estimates. Results:64Cu-SARTATE was well tolerated during infusion and throughout the study, with 3 patients experiencing mild infusion-related events. High lesion uptake and retention were observed at all imaging time-points. There was progressive hepatic clearance over time, providing the highest lesion-to-liver contrast at 24 h. Image quality remained high at this time. Comparison of 64Cu-SARTATE PET/CT obtained at 4 h to 68Ga-DOTATATE PET/CT obtained at 1 h indicated comparable or superior lesion detection in all patients, especially in the liver. As expected, the highest early physiologic organ uptake was in the kidneys, liver, and spleen. Conclusion:64Cu-SARTATE is safe and has excellent imaging characteristics. High late-retention in tumor and clearance from the liver suggest suitability for diagnostic studies and for prospective dosimetry for 67Cu-SARTATE peptide receptor radionuclide therapy, and the half-life of 64Cu would also facilitate good-manufacturing-practice production and distribution to sites without access to 68Ga.
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Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/radioterapia , Octreotida/análogos & derivados , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Compostos Radiofarmacêuticos/metabolismo , Receptores de Peptídeos/metabolismo , Idoso , Transporte Biológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/metabolismo , Octreotida/efeitos adversos , Octreotida/metabolismo , Estudos Prospectivos , Radiometria , Compostos Radiofarmacêuticos/efeitos adversos , SegurançaRESUMO
BACKGROUND: Several unanswered questions surround the management of retroperitoneal sarcoma (RPS). Guidelines recommend treatment by a multidisciplinary team at a specialized referral centre. The objective of this study was to describe the management of RPS at an Australian specialist sarcoma centre, comparing outcomes to international standards and analysing for predictors of local failure. METHODS: A retrospective review of a prospectively maintained database was performed on patients with RPS treated between 2008 and 2016. A 5-year outcome analyses focussed on patients undergoing curative-intent surgery for primary, non-metastatic RPS. RESULTS: Eighty-eight patients underwent surgery for primary RPS. Five-year overall survival was 66%, 5-year freedom from local recurrence was 65% and 5-year freedom from distant metastasis was 71%. Overall survival was associated with tumour grade (hazard ratio (HR) 6.1, P < 0.001) and histologic organ invasion (HR 5.7, P < 0.001). Variables associated with improved freedom from local recurrence were macroscopically complete resection (HR 0.14, P < 0.001) and neoadjuvant radiotherapy (HR 0.33, P = 0.014). Treatment at a specialist sarcoma centre was associated with a higher rate of preoperative biopsy and neoadjuvant radiotherapy (both with P < 0.001). There was a trend towards improved local control for patients undergoing surgery at a specialist centre (P = 0.055). CONCLUSION: This is the largest Australian series of RPS and outcomes are comparable to major international sarcoma centres. Patients treated at a specialist centre had higher rates of preoperative diagnosis and tailored therapy which was associated with improved outcomes. Patients with suspected RPS should be referred to a specialist centre for optimal preoperative evaluation and multidisciplinary management.
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Neoplasias Retroperitoneais/terapia , Sarcoma/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Austrália , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Neoplasias Retroperitoneais/mortalidade , Estudos Retrospectivos , Sarcoma/mortalidade , Análise de Sobrevida , Centros de Atenção Terciária , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: A priori identification of the small proportion of radiation therapy patients who prove to be severely radiosensitive is a long-held goal in radiation oncology. A number of published studies indicate that analysis of the DNA damage response after ex vivo irradiation of peripheral blood lymphocytes, using the γ-H2AX assay to detect DNA damage, provides a basis for a functional assay for identification of the small proportion of severely radiosensitive cancer patients undergoing radiotherapy. METHODS AND MATERIALS: We introduce a new, more rigorous, integrated approach to analysis of radiation-induced γ-H2AX response, using Bayesian statistics. RESULTS: This approach shows excellent discrimination between radiosensitive and non-radiosensitive patient groups described in a previously reported data set. CONCLUSIONS: Bayesian statistical analysis provides a more appropriate and reliable methodology for future prospective studies.
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Teorema de Bayes , Neoplasias/sangue , Tolerância a Radiação/genética , Biomarcadores , Dano ao DNA , Bases de Dados Factuais , Relação Dose-Resposta à Radiação , Feminino , Histonas/química , Humanos , Linfócitos/efeitos da radiação , Masculino , Modelos Teóricos , Método de Monte Carlo , Neoplasias/radioterapia , Estudos Prospectivos , Radioterapia , Reprodutibilidade dos Testes , Estudos Retrospectivos , Fatores de TempoRESUMO
BACKGROUND: Accurate staging of patients with prostate cancer (PCa) is important for therapeutic decision-making. Relapse after surgery or radiotherapy of curative intent is not uncommon and, in part, represents a failure of staging with current diagnostic imaging techniques to detect disease spread. Prostate-specific membrane antigen (PSMA) positron-emission tomography (PET)/computed tomography (CT) is a new whole-body scanning technique that enables visualization of PCa with high contrast. The hypotheses of this study are that: (i) PSMA-PET/CT has improved diagnostic performance compared with conventional imaging; (ii) PSMA-PET/CT should be used as a first-line diagnostic test for staging; (iii) the improved diagnostic performance of PSMA-PET/CT will result in significant management impact; and (iv) there are economic benefits if PSMA-PET/CT is incorporated into the management algorithm. OBJECTIVES AND METHODS: The proPSMA trial is a prospective, multicentre study in which patients with untreated high-risk PCa will be randomized to gallium-68-PSMA-11 PET/CT or conventional imaging, consisting of CT of the abdomen/pelvis and bone scintigraphy with single-photon emission CT/CT. Patients eligible for inclusion are those with newly diagnosed PCa with select high-risk features, defined as International Society of Urological Pathology grade group ≥3 (primary Gleason grade 4, or any Gleason grade 5), prostate-specific antigen level ≥20 ng/mL or clinical stage ≥T3. Patients with negative, equivocal or oligometastatic disease on first line-imaging will cross over to receive the other imaging arm. The primary objective is to compare the accuracy of PSMA-PET/CT with that of conventional imaging for detecting nodal or distant metastatic disease. Histopathological, imaging and clinical follow-up at 6 months will define the primary endpoint according to a predefined scoring system. Secondary objectives include comparing management impact, the number of equivocal studies, the incremental value of second-line imaging in patients who cross over, the cost of each imaging strategy, radiation exposure, inter-observer agreement and safety of PSMA-PET/CT. Longer-term follow-up will also assess the prognostic value of a negative PSMA-PET/CT. OUTCOME AND SIGNIFICANCE: This trial will provide data to establish whether PSMA-PET/CT should replace conventional imaging in the primary staging of select high-risk localized PCa, or whether it should be used to provide incremental diagnostic information in selected cases.
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Antígenos de Superfície/metabolismo , Meios de Contraste/uso terapêutico , Radioisótopos de Gálio/uso terapêutico , Glutamato Carboxipeptidase II/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Neoplasias da Próstata/diagnóstico por imagem , Compostos Radiofarmacêuticos/uso terapêutico , Antígenos de Superfície/análise , Meios de Contraste/química , Glutamato Carboxipeptidase II/análise , Humanos , Masculino , Estadiamento de Neoplasias , Estudos Prospectivos , Próstata/diagnóstico por imagem , Neoplasias da Próstata/terapia , Compostos Radiofarmacêuticos/químicaRESUMO
AIM: To characterize the outcomes of patients with nonmelanoma solid tumors receiving anti-PD-1 immunotherapy not funded by the Australian Pharmaceutical Benefits Scheme. METHODS: Medical records of patients with metastatic nonmelanoma tumor diagnoses treated with anti-PD-1 (self-funded pembrolizumab or nivolumab through an access program) from January 1, 2014, to December 31, 2016, at Peter MacCallum Cancer Centre, were retrospectively reviewed. Events after December 31, 2016, were censored. RESULTS: Of 47 patients identified, 27 (57%) had lung cancer. Twenty-six had compassionate access to nivolumab (24 lung, one renal, one gastroesophageal with possible new lung primary). Median overall survival was 5.7 months. Eleven (23%) achieved a partial response; none had complete response. Twenty (43%) had disease progression on first imaging; 16 (48%) of these continued treatment beyond radiological progression, with three achieving subsequent partial responses. Ten (21%) were not re-staged mostly due to rapid deterioration or death. At 6 and 12 months, nine (20%) and two (4%) remained on treatment, respectively. Five (12%) discontinued treatment due to immune-related toxicities. Of 34 patients who died, 71% received treatment within the last month of life; 38% died in an acute hospital. None of 25 patients with poor Eastern Cooperative Oncology Group performance scores of 2-4 responded. CONCLUSION: The response rates and overall survival of patients with NSCLC, renal carcinoma and triple negative breast cancer of good performance status receiving anti-PD-1 therapy outside of a clinical trial are consistent with clinical trial data. However, patients with poor ECOG performance status are unlikely to respond. Careful patient selection and counseling about the potential outcomes of self-funding treatment in this setting is needed.