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BACKGROUND: The TheraP study reported improved prostate-specific antigen responses with lutetium-177 [177Lu]Lu-PSMA-617 versus cabazitaxel in men with metastatic castration-resistant prostate cancer progressing after docetaxel. In this Article, we report the secondary outcome of overall survival with mature follow-up, and an updated imaging biomarker analysis. We also report the outcomes of participants excluded due to ineligibility on gallium-68 [68Ga]Ga-PSMA-11 and 2-[18F]fluoro-2-deoxy-D-glucose (2-[18F]FDG) PET-CT. METHODS: TheraP was an open-label, randomised phase 2 trial at 11 centres in Australia. Eligible participants had metastatic castration-resistant prostate cancer progressing after docetaxel, and PET imaging with [68Ga]Ga-PSMA-11 and 2-[18F]FDG that showed prostate-specific membrane antigen (PSMA)-positive disease and no sites of metastatic disease with discordant 2-[18F]FDG-positive and PSMA-negative findings. Participants were randomly assigned (1:1) to treatment with [177Lu]Lu-PSMA-617 (every 6 weeks for a maximum of six cycles; starting at 8·5 GBq, decreasing by 0.5 GBq to 6·0 GBq for the sixth cycle) versus cabazitaxel (20 mg/m2 every 3 weeks, maximum of ten cycles). Overall survival was analysed by intention-to-treat and summarised as restricted mean survival time (RMST) to account for non-proportional hazards, with a 36-month restriction time corresponding to median follow-up. This trial is registered with ClinicalTrials.gov, NCT03392428, and is complete. FINDINGS: 291 men were registered from Feb 6, 2018, to Sept 3, 2019; after study imaging, 200 were eligible and randomly assigned to treatment with [177Lu]Lu-PSMA-617 (n=99) or cabazitaxel (n=101). After completing study treatment, 20 (20%) participants assigned to cabazitaxel and 32 (32%) assigned to [177Lu]Lu-PSMA-617 were subsequently treated with the alternative regimen. After a median follow-up of 35·7 months (IQR 31·1 to 39·2), 77 (78%) participants had died in the [177Lu]Lu-PSMA-617 group and 70 (69%) participants had died in the cabazitaxel group. Overall survival was similar among those assigned to [177Lu]Lu-PSMA-617 versus those assigned to cabazitaxel (RMST 19·1 months [95% CI 16·9 to 21·4] vs 19·6 months [17·4 to 21·8]; difference -0·5 months [95% CI -3·7 to 2·7]; p=0·77). No additional safety signals were identified with the longer follow-up in this analysis. 80 (27%) of 291 men who were registered after initial eligibility screening were excluded after [68Ga]Ga-PSMA-11 and 2-[18F]FDG PET. In the 61 of these men with follow-up available, RMST was 11·0 months (95% CI 9·0 to 13·1). INTERPRETATION: These results support the use of [177Lu]Lu-PSMA-617 as an alternative to cabazitaxel for PSMA-positive metastatic castration-resistant prostate cancer progressing after docetaxel. We did not find evidence that overall survival differed between the randomised groups. Median overall survival was shorter for men who were excluded because of low PSMA expression or 2-[18F]FDG-discordant disease. FUNDING: Australian and New Zealand Urogenital and Prostate Cancer Trials Group, Prostate Cancer Foundation of Australia, Endocyte (a Novartis company), Australian Nuclear Science and Technology Organization, Movember, It's a Bloke Thing, CAN4CANCER, and The Distinguished Gentleman's Ride.
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Radioisótopos de Gálio , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Resultado do Tratamento , Docetaxel/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/radioterapia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Fluordesoxiglucose F18 , Austrália , Antígeno Prostático EspecíficoRESUMO
Background: 177LuPSMA is an effective treatment in metastatic castrate-resistant prostate cancer with trials adopting a standardised dose interval. Adjusting treatment intervals utilising early response biomarkers may improve patient outcomes. Objective: This study evaluated progression-free survival (PFS) and overall survival (OS) based on treatment interval adjustment utilising 177LuPSMA 24-h SPECT/CT (177Lu-SPECT) and early prostate-specific antigen (PSA) response. Design: Retrospective analysis of a clinical 177Lu-PSMA-I&T treatment programme. Methods: In all, 125 men were treated with 6-weekly 177LuPSMA-I&T [median 3 cycles, interquartile range (IQR): 2-4], median dose 8.0 GBq [95% confidence interval (CI): 7.5-8.0]. Imaging screening involved 68GaPSMA-11 PET/diagnostic CT. 177Lu-SPECT/diagnostic CT was acquired following each therapy, and clinical assessments 3-weekly. Following dose 2 (week 6), a composite PSA and 177Lu-SPECT/CT imaging response [partial response (PR), stable disease (SD), and progressive disease (PD)] determined ongoing management. Response group (RG) 1 (marked reduction in PSA/imaging PR) break in treatment until subsequent PSA rise, then re-treatment. RG 2 (stable or reduced PSA and/or imaging SD) 6-weekly treatments until six doses, or no longer clinically benefitting. RG 3 (rise in PSA and/or imaging PD) recommended for an alternative treatment. Results: Overall PSA50% response rate (PSARR) was 60% (75/125), median PSA-PFS 6.1 months (95%CI: 5.5-6.7), and median OS 16.8 months (95%CI: 13.5-20.1). 35% (41/116) were classified as RG 1, 34% (39/116) RG 2, and 31% (36/116) RG 3. PSARRs by RG were 95% (38/41), 74% (29/39), and 8% (3/36); median PSA-PFS rates were 12.1 months (95%CI: 9.3-17.4), 6.1 months (95%CI: 5.8-9.0), and 2.6 months (95%CI: 1.6-3.1); and OS rates were 19.2 months (95%CI: 16.8-20.7), 13.2 months (95%CI: 12.0-18.8), and 11.2 months (95%CI: 8.7-15.6) for RG 1, 2, and 3, respectively. The median months of 'treatment holiday' for RG 1 was 6.1 months (IQR: 3.4-8.7). Nine men had received prior 177LuPSMA-617 and were retreated with 177LuPSMA-I&T, with a PSARR of 56% on re-treatment. Conclusion: Personalising dosing regimens using early response biomarkers with 177LuPSMA has the potential to achieve similar treatment responses to continuous dosing while allowing treatment breaks or intensification. Further evaluation of early response biomarker-guided treatment regimens in prospective trials is warranted. Plain Language Summary: Lutetium-PSMA therapy is a new therapy for metastatic prostate cancer that is well tolerated and effective. However, not all men respond equally, with some responding very well and others progressing early. Personalising treatments require tools that can accurately measure treatment responses, preferably early in the treatment course, so adjustments to treatment can be made. Lutetium-PSMA can measure tumour sites after each therapy by taking whole body 3D images at 24 h using a small radiation wave from the treatment itself. This is called a SPECT scan. Previous work has shown that both prostate-specific antigen (PSA) response and changes in tumour volume on a SPECT scan can predict how patients will respond to treatment as early as dose 2. This study demonstrates that stratifying how men are treated based on the results of the 6-week SPECT scan and PSA response potentially allows a third of men to have break in treatment and that these men have both longer time to disease progression and OS. Men with an increase in tumour volume and increase in PSA early in treatment (6 weeks) had shorter time to disease progression and OS. Men with early biomarker disease progression were offered alternative treatments early in an attempt to allow the opportunity to allow a more effective potential therapy, if one was available. The study is an analysis of a clinical programme, and was not a prospective trial. As such, there are potential biases that could influence results. Hence, while the study is encouraging for the use of early response biomarkers to guide better treatment decisions, this must be validated in a well-designed clinical trial.
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Increasing evidence suggests that the gut microbiome is associated with both cancer chemotherapy (CTX) outcomes and adverse events (AEs). This review examines the relationship between the gut microbiome and CTX as well as the impact of CTX on the gut microbiome. A literature search was conducted in electronic databases Medline, PubMed and ScienceDirect, with searches for "cancer" and "chemotherapy" and "microbiome/microbiota". The relevant literature was selected for use in this article. Seventeen studies were selected on participants with colorectal cancer (CRC; n=5), Acute Myeloid Leukemia (AML; n=3), Non-Hodgkin's lymphoma (n=2), breast cancer (BCa; n=1), lung cancer (n=1), ovarian cancer (n=1), liver cancer (n=1), and various other types of cancers (n=3). Seven studies assessed the relationship between the gut microbiome and CTX with faecal samples collected prior to (n=3) and following CTX (n=4) showing that the gut microbiome is associated with both CTX efficacy and toxicity. Ten other prospective studies assessed the impact of CTX during treatment and found that CTX modulates the gut microbiome of people with cancer and that dysbiosis induced by the CTX is related to AEs. CTX adversely impacts the gut microbiome, inducing dysbiosis and is associated with CTX outcomes and AEs. Current evidence provides insights into the gut microbiome for clinicians, cancer survivors and the general public. More research is required to better understand and modify the impact of CTX on the gut microbiome.
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BACKGROUND: Lutetium-177 [177Lu]Lu-PSMA-617 is a radiolabelled small molecule that delivers ß radiation to cells expressing prostate-specific membrane antigen (PSMA), with activity and safety in patients with metastatic castration-resistant prostate cancer. We aimed to compare [177Lu]Lu-PSMA-617 with cabazitaxel in patients with metastatic castration-resistant prostate cancer. METHODS: We did this multicentre, unblinded, randomised phase 2 trial at 11 centres in Australia. We recruited men with metastatic castration-resistant prostate cancer for whom cabazitaxel was considered the next appropriate standard treatment. Participants were required to have adequate renal, haematological, and liver function, and an Eastern Cooperative Oncology Group performance status of 0-2. Previous treatment with androgen receptor-directed therapy was allowed. Men underwent gallium-68 [68Ga]Ga-PSMA-11 and 2-flourine-18[18F]fluoro-2-deoxy-D-glucose (FDG) PET-CT scans. PET eligibility criteria for the trial were PSMA-positive disease, and no sites of metastatic disease with discordant FDG-positive and PSMA-negative findings. Men were randomly assigned (1:1) to [177Lu]Lu-PSMA-617 (6·0-8·5 GBq intravenously every 6 weeks for up to six cycles) or cabazitaxel (20 mg/m2 intravenously every 3 weeks for up to ten cycles). The primary endpoint was prostate-specific antigen (PSA) response defined by a reduction of at least 50% from baseline. This trial is registered with ClinicalTrials.gov, NCT03392428. FINDINGS: Between Feb 6, 2018, and Sept 3, 2019, we screened 291 men, of whom 200 were eligible on PET imaging. Study treatment was received by 98 (99%) of 99 men randomly assigned to [177Lu]Lu-PSMA-617 versus 85 (84%) of 101 randomly assigned to cabazitaxel. PSA responses were more frequent among men in the [177Lu]Lu-PSMA-617 group than in the cabazitaxel group (65 vs 37 PSA responses; 66% vs 37% by intention to treat; difference 29% (95% CI 16-42; p<0·0001; and 66% vs 44% by treatment received; difference 23% [9-37]; p=0·0016). Grade 3-4 adverse events occurred in 32 (33%) of 98 men in the [177Lu]Lu-PSMA-617 group versus 45 (53%) of 85 men in the cabazitaxel group. No deaths were attributed to [177Lu]Lu-PSMA-617. INTERPRETATION: [177Lu]Lu-PSMA-617 compared with cabazitaxel in men with metastatic castration-resistant prostate cancer led to a higher PSA response and fewer grade 3 or 4 adverse events. [177Lu]Lu-PSMA-617 is a new effective class of therapy and a potential alternative to cabazitaxel. FUNDING: Prostate Cancer Foundation of Australia, Endocyte (a Novartis company), Australian Nuclear Science and Technology Organization, Movember, The Distinguished Gentleman's Ride, It's a Bloke Thing, and CAN4CANCER.
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Dipeptídeos/uso terapêutico , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Lutécio/uso terapêutico , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Radioisótopos/uso terapêutico , Taxoides/uso terapêutico , Administração Intravenosa , Idoso , Antígenos de Superfície/genética , Glutamato Carboxipeptidase II/genética , Humanos , Masculino , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Antígeno Prostático Específico/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/radioterapia , Resultado do TratamentoAssuntos
Antineoplásicos/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Carcinoma Basocelular/tratamento farmacológico , Piridinas/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Carcinoma Basocelular/patologia , Método Duplo-Cego , Humanos , Neoplasias Cutâneas/patologia , Resultado do TratamentoRESUMO
BACKGROUND: The oncogenic BRAF inhibitor vemurafenib improves outcomes for patients with advanced BRAFV600 mutation-positive melanoma compared with cytotoxic chemotherapy. Vemurafenib is now approved for use in this patient population. PATIENTS AND METHODS: In this open-label, multicentre study, patients with previously treated or untreated melanoma and the BRAFV600 mutation received vemurafenib 960 mg twice daily. The primary endpoint was safety. In a post hoc analysis, overall survival (OS) was analysed according to a prognostic scoring system developed using Eastern Cooperative Oncology Group performance status, existence of brain metastases and baseline serum lactate dehydrogenase level. The index was validated using data from patients treated with vemurafenib or dacarbazine in three clinical trials and data from patients treated with vemurafenib plus cobimetinib in two studies. The study is registered with ClinicalTrials.gov (NCT01307397). RESULTS: Between March 2011 and January 2013, 3224 patients were enrolled, and 3219 patients received ≥1 dose of vemurafenib (safety population); median follow-up time was 33.4 months. Vemurafenib's long-term benefits were confirmed, and no new safety signals identified. The prognostic index showed between-group differences in OS, with tight, non-overlapping confidence intervals. Validation in a pooled group of 666 vemurafenib-treated clinical trial patients revealed a similar pattern; the pattern was similar in 280 patients treated with vemurafenib plus cobimetinib. CONCLUSIONS: Final results from the vemurafenib safety study confirm vemurafenib's tolerability in BRAFV600 mutation-positive patients and resemble those seen in real-world clinical practice. This index may be useful in patients on combination therapy and as a basis for further work.
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Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/secundário , Melanoma/patologia , Mutação , Nomogramas , Proteínas Proto-Oncogênicas B-raf/genética , Vemurafenib/uso terapêutico , Idoso , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Melanoma/tratamento farmacológico , Melanoma/genética , Prognóstico , Taxa de Sobrevida , Estudos de Validação como AssuntoRESUMO
BACKGROUND: 177Lu-PSMA-617 (Lu-PSMA) is an emerging therapy in men with metastatic castration-resistant prostate cancer. Paired theranostic agents have the potential to visually identify phenotypes that will respond to targeted therapy. This study examined the value of 68Ga-HBEDD PSMA-11; prostate-specific membrane antigen (PSMA) positron emission tomography (PET) in predicting treatment response and disease progression in Lu-PSMA therapy within the context of a phase 2 prospective pilot trial. PATIENTS AND METHODS: Men with progressive, symptomatic metastatic castration-resistant prostate cancer previously treated with antiandrogens (abiraterone and/or enzalutamide) and taxane-based chemotherapy were prospectively enrolled. Eligibility criteria included uptake on PSMA PET above or equal to liver activity, with no 18F-Fluoro-deoxyglucose (FDG) PET-discordant disease. Men received up to 4 cycles of Lu-PSMA at 6 weekly intervals. Repeat FDG/PSMA PET imaging was performed after completion of therapy or at prostate-specific antigen (PSA) progression. The study assessed treatment response to Lu-PSMA using PSA response and correlated treatment response (PSA) to molecular imaging parameters at enrollment. RESULTS: Fourteen of 18 men screened underwent Lu-PSMA therapy. Ten (71%) of 14 had a PSA response (mean reduction, 59%). A ≥ 50% reduction in PSA occurred in 5 (36%), and ≥ 30% in 9 (64%). PSMA PET standardized uptake value (SUV) at screening was predictive of ≥ 30% PSA reduction: SUV max value 17 ± 9 versus 44 ± 15 (P < .007), and PSMA SUV mean 6 ± 4 versus 10 ± 4 (P < .04). FDG parameters alone, and volume or site of disease did not predict PSA response. No imaging parameters predicted ≥ 50% PSA reduction. Nine of 14 men were reimaged after treatment, revealing 3 distinct patterns of progression. CONCLUSION: PSMA PET plays an important role in predicting treatment response to Lu-PSMA and in identifying subsequent patterns of failure, which may aid in determining the next best treatment options.
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Dipeptídeos/uso terapêutico , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Processamento de Imagem Assistida por Computador/métodos , Lutécio/uso terapêutico , Tomografia por Emissão de Pósitrons/métodos , Neoplasias de Próstata Resistentes à Castração/radioterapia , Radioisótopos/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Prognóstico , Estudos Prospectivos , Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem , Neoplasias de Próstata Resistentes à Castração/secundário , Taxa de SobrevidaRESUMO
AIM: Cabazitaxel is a next generation taxane that has been shown to improve overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC) whose disease progressed during or after docetaxel-based therapy. A worldwide early access program (EAP) study was established to provide access to cabazitaxel ahead of commercial availability and to evaluate its safety and tolerability. The Australian EAP included patient-reported outcomes to evaluate the impact of cabazitaxel on quality of life (QoL). The final safety and QoL results from the Australian EAP for cabazitaxel are reported. METHODS: Australian patients with mCRPC previously treated with a docetaxel-containing regimen received cabazitaxel (25 mg/m2 ) every 3 weeks plus prednisone/prednisolone (10 mg daily) until disease progression, death, unacceptable toxicity, physician's decision or patient's refusal of further treatment. QoL data was collected using the AQoL-8D questionnaire. RESULTS: 104 patients from 18 Australian sites (median age at baseline, 70) enrolled in the EAP and completed at least one AQoL-8D questionnaire. Patients received a median of 6 cycles of cabazitaxel. 67 patients (64.4%) experienced grade ≥3 treatment-emergent adverse events (TEAEs); the most frequent TEAEs were neutropenia, febrile neutropenia, diarrhoea, and vomiting. QoL scores remained stable with increasing treatment cycles. CONCLUSION: The results suggest that the safety profile cabazitaxel is manageable in the Australian clinical practice setting and that QoL is maintained with little or no detrimental effect of cabazitaxel in patients continuing on treatment without disease progression.
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Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Qualidade de Vida/psicologia , Taxoides/uso terapêutico , Idoso , Austrália , Humanos , Masculino , Metástase Neoplásica , Neoplasias de Próstata Resistentes à Castração/patologia , Taxoides/farmacologiaRESUMO
BACKGROUND: There is limited data on the efficacy of anti-programmed death 1 (PD-1) antibodies in patients (pts) with melanoma brain metastasis (BM), particularly those which are symptomatic. METHOD: We retrospectively assessed pts with melanoma BM treated with PD-1 antibodies, nivolumab and pembrolizumab. Clinicopathologic and treatment parameters were collected and outcomes determined for intracranial (IC) response rate (RR) using a modified RECIST criteria, with up to five IC target lesions used to determine IC response, disease control rate (DCR) and progression-free survival (PFS). RESULTS: A total of 66 pts were identified with a median follow up of 7.0 months (range 0.8-24.5 months). A total of 68% were male and 45% BRAF V600 mutation positive. At PD-1 antibody commencement, 50% had an elevated LDH; 64% had local therapy to BM prior to commencing anti-PD1, of which 5% had surgical resection, 14% stereotactic radiosurgery (SRS), 18% whole-brain radiotherapy (WBRT), 27% had surgery and radiotherapy. Twenty-one per cent started anti-PD-1 as first line systemic therapy. No pt had prior anti-PD-1 treatment. The IC overall RR was 21 and DCR 56%. Responses occurred in 21% of pts with symptomatic BM. The median OS was 9.9 months (95% CI 6.93-17.74). Pts with symptomatic BM had shorter PFS than those without symptoms (2.7 vs 7.4 months, P=0.035) and numerically shorter OS (5.7 vs 13.0 months, P=0.068). Pts requiring corticosteroids also had a numerically shorter PFS (3.2 vs 7.4 months, P=0.081) and OS (4.8 vs 13.1 months, P=0.039). CONCLUSIONS: IC responses to anti-PD-1 antibodies occur in pts with BM, including those with symptomatic BM requiring corticosteroids. Prospective trials evaluating anti-PD-1 therapy in pts with BM are underway.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/terapia , Melanoma/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/secundário , Terapia Combinada , Craniotomia , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , L-Lactato Desidrogenase/sangue , Masculino , Melanoma/complicações , Melanoma/secundário , Pessoa de Meia-Idade , Nivolumabe , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Radiocirurgia , Critérios de Avaliação de Resposta em Tumores Sólidos , Estudos Retrospectivos , Taxa de Sobrevida , Avaliação de Sintomas , Adulto JovemRESUMO
BACKGROUND: It is unknown whether melanoma patients achieving complete response (CR) with targeted therapy can safely discontinue treatment. METHODS: All patients treated with BRAF/MEK inhibitors achieving CR and ceasing treatment before progression were identified. Clinical data at treatment initiation, cessation and progression were examined. RESULTS: A total of 12 eligible patients were identified, with median follow-up of 16 months, of whom 6 (50%) recurred at a median of 6.6 months after treatment cessation. One patient lost to follow-up until presentation with symptomatic recurrence was the only relapser to die. At relapse, the remaining five patients had an LDH <1.2 times ULN, four were ECOG 0 and one ECOG 1. Baseline characteristics and time to CR and to discontinuation did not influence the rate of relapse. CONCLUSIONS: A large proportion of patients achieving CR with BRAF/MEK inhibitors relapse after treatment cessation. The optimal treatment duration in such patients is unclear, particularly where alternative treatments are available.
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Antineoplásicos/uso terapêutico , Melanoma/tratamento farmacológico , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Adulto , Idoso , Feminino , Humanos , Masculino , Melanoma/genética , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Recidiva , Análise de SobrevidaRESUMO
18-Fluorodeoxyglucose positron emission tomography (FDG-PET) scans were performed on 27 patients with unresectable stage IIIC or IV melanoma after prolonged treatment with anti-PD-1 antibodies to examine the hypothesis that patients with prolonged response to treatment may have metabolically inactive lesions by FDG-PET. Scans were performed at a median of 15.2 months (range 12-29 months) after starting treatment. Overall, 15 of 27 (56%) patients had a positive FDG-PET scan. Eight patients with positive scans underwent biopsy; 5 of 8 (62%) were melanoma and 3 of 8 (38%) were immune cell infiltrates. Of the 12 patients with negative FDG-PET scans, six had residual computerized tomography-visible lesions, five have ceased treatment, and none have recurred with follow-up of 6-10 months. Patients with residual metastases after a prolonged period without progression on anti-PD-1 therapy may have metabolically inactive lesions. Isolated metabolically active lesions in clinically well patients may reveal immune cell infiltrates rather than melanoma.
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Antineoplásicos/uso terapêutico , Fluordesoxiglucose F18/metabolismo , Neoplasias Hepáticas/metabolismo , Melanoma/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Compostos Radiofarmacêuticos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Masculino , Melanoma/diagnóstico por imagem , Melanoma/tratamento farmacológico , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Currently there are very few biomarkers to identify head and neck squamous cell carcinoma (HNSCC) cancer patients at a greater risk of recurrence and shortened survival. This study aimed to investigate whether a marker of systemic inflammation, the neutrophil-to-lymphocyte ratio (NLR), was predictive of clinical outcomes in a heterogeneous cohort of HNSCC cancer patients. METHODS: We performed a retrospective analysis to identify associations between NLR and clinicopathological features to recurrence free survival (RFS) and overall survival (OS). Univariate analysis was used to identify associations and selected variables were included in multivariable Cox regression analysis to determine predictive value. RESULTS: A total of 145 patients with stage I-IV HNSCC that had undergone radiotherapy were analysed. Seventy-six of these patients had oropharyngeal cancer and 69 had non-oropharyngeal HNSCC and these populations were analysed separately. NLR was not associated to any clinicopathological variable. On univariate analysis, NLR showed associations with RFS and OS in both sub-populations. Multivariable analysis showed patients with NLR > 5 had shortened OS in both sub-populations but NLR > 5 only predicted RFS in oropharyngeal patients. Poor performance status predicted OS in both sub-populations and current smokers had shortened OS and RFS in non-oropharyngeal patients. CONCLUSIONS: The results show patients with NLR > 5 predict for shorter overall survival. Further prospective validation studies in larger cohorts are required to determine the clinical applicability of NLR for prognostication in HNSCC patients.
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Biomarcadores Tumorais/imunologia , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/patologia , Neutrófilos/citologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/mortalidade , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Carcinoma de Células Escamosas de Cabeça e Pescoço , Análise de SobrevidaAssuntos
Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Lesões por Radiação/induzido quimicamente , Dermatopatias/etiologia , Adulto , Idoso , Feminino , Humanos , Masculino , Melanoma/tratamento farmacológico , Melanoma/enzimologia , Melanoma/genética , Melanoma/radioterapia , Proteínas Proto-Oncogênicas B-raf/genética , Lesões por Radiação/enzimologia , Lesões por Radiação/genética , Dermatopatias/induzido quimicamente , Dermatopatias/enzimologia , Dermatopatias/genéticaRESUMO
Toxicities resulting from platinum based chemotherapy in head and neck cancer is a cause for much concern. There is a lack of clinical criteria for defining these patient populations, which has posed serious problems associated with increased morbidity and consequently an adverse effect on patients' quality of life. In addition, there is a lack of consensus on clinical criteria for defining such patient populations, who may be unsuitable for concurrent chemoradiotherapy. A group of experts in the field of head and neck cancer from the Asia Pacific Region convened in August 2014 in Korea to discuss the development of a set of clinical criteria in order to fill the knowledge gap and provide a reference tool for head and neck oncologists. This paper reports the final output from this meeting and the accompanying literature review, with the aim of aiding clinical decision making with the help of some clinical criteria to identify platinum unsuitable patient populations in head and neck cancer management. Some alternative treatment options are also discussed in this paper.
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Antineoplásicos/efeitos adversos , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia/efeitos adversos , Cisplatino/efeitos adversos , Neoplasias de Cabeça e Pescoço/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ásia , Quimiorradioterapia/métodos , Humanos , Qualidade de Vida , Resultado do TratamentoRESUMO
BACKGROUND: The degree of response and the duration of survival of patients treated with mitogen-activated protein kinase (MAPK) inhibitors are highly variable. Whether baseline clinicopathologic factors can predict the clinical course with treatment is largely unknown. METHODS: For 142 consecutive immunotherapy- and MAPK inhibitor-naive patients with BRAF-mutant metastatic melanoma who were treated during clinical trials with BRAF inhibitors (n = 111) or a combination of dabrafenib and trametinib (n = 31), clinicopathologic factors were correlated with the response to MAPK inhibitors and survival. RESULTS: The median follow-up was 15.7 months (range, 0.6-60.5 months). The 2-, 3-, and 4-year overall survival (OS) rates were 43%, 24%, and 24%, respectively. A multivariate analysis demonstrated that the only clinicopathologic factors associated with longer progression-free survival (PFS) and OS were female sex and a normal pretreatment serum lactate dehydrogenase (LDH) level. The BRAF V600E genotype and an absence of primary melanoma ulceration were also independently associated with longer PFS but not OS. The median OS was 23.5 months for patients with normal LDH levels and 7.3 months for those with elevated LDH levels (hazard ratio, 0.31; P < .001). Complete responders had the best survival, but disease progression still occurred in 2 of 7 patients. CONCLUSIONS: Long-term survival occurs for a minority of patients receiving MAPK inhibitor treatment alone. Sex, serum LDH, BRAF genotype, and primary melanoma ulceration status are independent factors associated with treatment outcomes. Patients with a complete response to treatment have the best survival, but relapses still occur.
Assuntos
Antineoplásicos/uso terapêutico , MAP Quinase Quinase Quinases/antagonistas & inibidores , Melanoma/tratamento farmacológico , Melanoma/fisiopatologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/fisiopatologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Quimioterapia Combinada , Feminino , Seguimentos , Genótipo , Humanos , Imidazóis/uso terapêutico , Indóis/uso terapêutico , L-Lactato Desidrogenase/sangue , Masculino , Melanoma/secundário , Pessoa de Meia-Idade , Oximas/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Fatores Sexuais , Neoplasias Cutâneas/secundário , Sulfonamidas/uso terapêutico , Taxa de Sobrevida , Resultado do Tratamento , Vemurafenib , Adulto JovemRESUMO
INTRODUCTION: The neutrophil-to-lymphocyte ratio (NLR) is an index of systemic inflammatory burden in malignancy. An elevated NLR has been associated with poor prognosis in a number of cancer sites. We investigated its role in a cohort of patients with locally advanced head and neck cancer. METHODS: Eligible patients had primary mucosal squamous cell carcinoma treated with chemoradiotherapy and a minimum follow-up of 12 months (unless deceased). NLR was analysed as <5 vs. ≥5 and above and below the median. The primary endpoint was overall survival (OS) and secondary endpoints metastasis free survival and locoregional relapse free survival. Actuarial Kaplan-Meier statistics and log rank test were used. Univariate analysis for age (continuous), Eastern Cooperative Oncology Group performance status (0 vs. 1), gender (male vs. female), smoking (yes vs. no), American Joint Committee on Cancer stage (III vs. IV) and NLR (<5 vs. ≥5 and <3.3 vs. ≥3.3) were performed. RESULTS: Forty-six patients were included in this analysis. Median NLR was 3.3 (0.4-22.8). After a median follow-up of 34 months (13-47 months), the 2-year estimated OS, metastasis free survival and locoregional relapse free survival for NLR <5 vs. ≥5 were 89% vs. 61% (p = 0.017), 84% vs. 64% (p = 0.083) and 81% vs. 70% (p = 0.17) respectively. On univariate analysis NLR ≥5 (p = 0.025), older age (p = 0.01) and ECOG 1 (p = 0.025) were significant for OS. CONCLUSION: In this cohort of locally advanced head and neck cancer patients treated with chemoradiotherapy, pre-treatment NLR ≥5 was prognostic for mortality. Further studies are required to confirm these results and to assess the interaction with other prognostic factors.
Assuntos
Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Linfócitos/patologia , Neutrófilos/patologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Carcinoma de Células Escamosas/sangue , Intervalo Livre de Doença , Feminino , Neoplasias de Cabeça e Pescoço/sangue , Humanos , Contagem de Leucócitos/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , New South Wales/epidemiologia , Prevalência , Reprodutibilidade dos Testes , Fatores de Risco , Sensibilidade e Especificidade , Taxa de SobrevidaRESUMO
INTRODUCTION: The study aims to report outcomes for patients treated using intensity-modulated radiotherapy (IMRT) with simultaneous-integrated boost and weekly cisplatin for American Joint Committee on Cancer stage III/IV mucosal head and neck squamous cell carcinomas (HNSCCs). METHODS: Records for 67 patients treated definitively with IMRT for HNSCC were reviewed. By including only those treated with weekly cisplatin, 45 patients were eligible for analysis. Treatment outcomes, effect of patient, tumour and treatment characteristics on disease recurrence were analysed. RESULTS: All patients completed IMRT to 7000 cGy in 35 fractions, with concurrent weekly cisplatin 40 mg/m(2) (median 6 cycles). Median follow-up was 28 months for living patients. Two-year loco-regional recurrence-free, metastasis-free and overall survival were 85.4, 81.0 and 87.4%, respectively. Local recurrence occurred in three patients, and distant recurrence in eight patients. CONCLUSIONS: Our results show efficacy of IMRT and weekly cisplatin in the treatment of stage III/IV HNSCC at our institution with respect to loco-regional control.
Assuntos
Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia/mortalidade , Cisplatino/uso terapêutico , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/terapia , Recidiva Local de Neoplasia/mortalidade , Radioterapia Conformacional/mortalidade , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Intervalo Livre de Doença , Fracionamento da Dose de Radiação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , New South Wales/epidemiologia , Prevalência , Prognóstico , Fatores de Risco , Carcinoma de Células Escamosas de Cabeça e Pescoço , Taxa de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE: To report toxicity data from the first 13 consecutive patients with locally advanced head and neck squamous cell carcinoma (LAHNSCC), ineligible for cisplatin, treated with concurrent cetuximab and radiotherapy (RT) at our institution. MATERIALS AND METHODS: Data were collected prospectively between August 2007 and May 2008. Planned treatment consisted of a cetuximab loading dose (400mg/m(2)) via intravenous infusion 1 week prior and then weekly (250mg/m(2)) with 70Gy in 35 daily fractions over 7 weeks. RESULTS: Median age was 68 years (range 52-82 years). The predominant primary sites were hypopharyngeal (5) and oropharyngeal (5). Ineligibility for cisplatin consisted of renal impairment (5), hearing impairment (4) and of other major co-morbidities (4). Of the 13 patients, 10 (77%) had grade 3/4 skin reactions and 10 (77%) grade 3/4 mucositis. Six (46%) patients required admission for management of severe skin reactions and/or mucositis with 4 (31%) requiring a treatment break, median 10 days (9-15days). Only 4 (31%) patients managed to complete the planned 8 cycles of cetuximab. Of the 9 patients with 12-week post-therapy data, 7 (78%) achieved a complete response. CONCLUSIONS: Our early experience with cetuximab/RT has demonstrated a higher rate of toxicity compared with the recently reported randomised trial, resulting in low treatment compliance and delays in completing RT.