ABSTRACT
AIMS: To establish whether there are geographic differences in treatments and outcomes for patients with kidney cancer (KC) in England which could potentially be improved by the creation of national guidelines. MATERIALS AND METHODS: A multidisciplinary group convened by the charity Kidney Cancer UK developed Quality Performance Indicators (QPIs) for the treatment of KC. Adherence to these QPIs was reported for all patients with a histological diagnosis of KC diagnosed in England between 2017 and 2018. Utilising data extracted from national datasets, logistic and linear probability models were used to estimate geographic variation in the delivery of surgery and systemic anti-cancer therapy at Cancer Alliance and NHS trust levels. Results were adjusted for a priori confounders, including age at diagnosis, area deprivation of residence, and Charlson Comorbidity Index. Differences in overall survival are reported. RESULTS: The cohort comprised 18,640 tumours in 18,421 patients. Of tumours diagnosed, median patient age was 68 (interquartile range 58-77) years and 63.4% were in males. When stratified by Cancer Alliance, the proportions of T1a/T1b/N0/M0 KC that had radical nephrectomy (RN), nephron sparing surgery or ablation ranged from 53.3% (95% CI [48.7, 57.8]) to 80.3% (95% CI [73.0, 86.0]). For stage T1b-3 cancers, the proportion that received RN ranged from 65.6% (95% CI [60.3, 70.5]) to 77.3% (95% CI [72.1, 81.7]). Patients with M0 (n = 12,365) and M1 KC (n = 3312) at diagnosis had 24-month survival of 87.5% and 25.1%, respectively. Of patients diagnosed with M1 KC, 50.3% received systemic anti-cancer therapy, ranging from 39.7% (95% CI [33.7, 46.1]) to 70.7% (95% CI [59.6, 79.8]) between Cancer Alliances. The six-month survival of these patients was 77.4% compared to 27.6% for those that did not receive SACT. CONCLUSION: These major geographical differences in surgical and systemic therapy practice have led to national guideline development.
ABSTRACT
Stereotactic ablative body radiotherapy (SABR) consists of delivering high doses of ionising radiation, typically across three to eight fractions with high precision and conformity. SABR has become increasingly commonplace throughout the last quarter of a century and is offered for the treatment of various primary and metastatic tumour types. Delivering SABR in a single fraction has arisen as an appealing possibility for several reasons. These include fewer hospital visits, greater patient convenience, improved sustainability and lower costs. However, these factors must be balanced against considerations such as toxicity, side-effects and, most importantly, progression-free and overall survival. In this review we seek to analyse the results of studies looking at the efficacy of single-fraction SABR for lung, prostate, renal and pancreas primary tumours, as well as oligometastases. The tumour type to be most widely treated with single-fraction SABR is lung, but its remit continues to expand. We also look at the biological rationale underpinning SABR and how this can be extended to single-fraction regimens. Finally, we turn our attention towards the future directions of SABR and specifically single-fraction regimens. These include the possibility of combining SABR with immunotherapy and technological advances in the field, which could serve to expand the scope of SABR. We conclude by summarising the current clinical studies of single-fraction SABR.
Subject(s)
Pancreatic Neoplasms , Radiosurgery , Male , Humans , Radiosurgery/methodsABSTRACT
BACKGROUND: The CheckMate 025 trial established nivolumab monotherapy as one of the standards of care in previously treated advanced or metastatic renal cell carcinoma (aRCC). However, supporting real-world data is lacking. This study investigated characteristics, treatment sequences and clinical outcomes of patients who received nivolumab monotherapy for previously treated aRCC in the UK. METHODS: This was a retrospective cohort study of aRCC patients treated with nivolumab at second line or later (2L +) at 4 UK oncology centres. Eligible patients commenced nivolumab (index date) between 01 March 2016 and 30 June 2018 (index period). Study data were extracted from medical records using an electronic case report form. Data cut-off (end of follow-up) was 31 May 2019. RESULTS: In total, 151 patients were included with median follow-up of 15.2 months. Mean age was 66.9 years, male preponderance (72.2%), and mostly Eastern Cooperative Oncology Group performance status grade 0-1 (71.5%). Amongst 112 patients with a known International Metastatic RCC Database Consortium score, distribution between favourable, intermediate, and poor risk categories was 20.5%, 53.6%, and 25.9% respectively. The majority of patients (n = 109; 72.2%) received nivolumab at 2L, and these patients had a median overall survival (OS) of 23.0 months [95% confidence interval: 17.2, not reached]. All patients who received nivolumab at 2L had received TKIs at 1L. Amongst the 42 patients (27.8%) who received nivolumab in third line or later (3L +) the median OS was 12.4 months [95% CI: 8.8, 23.2]. The most common reasons for nivolumab discontinuation were disease progression (2L: 61.2%; 3L: 68.8%) and adverse events (2L: 34.7%; 3L: 28.1%). CONCLUSION: This study provides real-world evidence on the characteristics, treatment sequences, and outcomes of aRCC patients who received 2L + nivolumab monotherapy in the UK. Nivolumab-specific survival outcomes were similar to those achieved in the CheckMate 025 trial.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Renal Cell/pathology , Humans , Kidney Neoplasms/pathology , Male , Nivolumab/therapeutic use , Retrospective Studies , United Kingdom/epidemiologyABSTRACT
The new systemic therapies for cancer are having major impacts on the prognosis of patients with advanced cancers, some achieving long-term survival with targeted therapy or immune checkpoint inhibitors. Interactions of radiotherapy with the new systemic therapies are reviewed. Many agents increase radiosensitivity and particular caution is required combining BRAF inhibitors and radiotherapy because of significant toxicity. Most new systemic therapies can be used safely with palliative doses of radiotherapy, but it is important to be aware of overlapping toxicities depending on the site treated. DNA damage response modulators increase radiosensitivity and may potentially increase radiation toxicity but are at an earlier stage of development. Stereotactic ablative radiotherapy may produce further survival gains in patients responding to targeted therapy and immunotherapy.
Subject(s)
Neoplasms/radiotherapy , Neoplasms/therapy , HumansSubject(s)
Betacoronavirus/isolation & purification , Coronavirus Infections/prevention & control , Coronavirus Infections/transmission , Infection Control/standards , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Pneumonia, Viral/transmission , Practice Guidelines as Topic/standards , Skin Neoplasms/radiotherapy , COVID-19 , Coronavirus Infections/complications , Humans , Pneumonia, Viral/complications , SARS-CoV-2 , Skin Neoplasms/complications , Skin Neoplasms/virology , United KingdomSubject(s)
Antineoplastic Agents , Carcinoma, Basal Cell , Skin Neoplasms , Biphenyl Compounds , Double-Blind Method , Hedgehog Proteins , Humans , PyridinesABSTRACT
BACKGROUND: The SafeTy Events in VIsmodEgib study (STEVIE, ClinicalTrials.gov, NCT01367665), assessed safety and efficacy of vismodegib-a first-in-class Hedgehog pathway inhibitor demonstrating clinical benefit in advanced basal cell carcinoma (BCC)-in a patient population representative of clinical practice. Primary analysis data are presented. PATIENTS AND METHODS: Patients with locally advanced or metastatic BCC received oral vismodegib 150 mg/d until progressive disease, unacceptable toxicity, or withdrawal. Primary objective was safety. Efficacy variables were assessed as secondary end-points. RESULTS: Evaluable adult patients (N = 1215, 1119 locally advanced; 96 metastatic BCC) from 36 countries were treated; 147 patients (12%) remained on study at time of reporting. Median (range) treatment duration was 8.6 (0-44) months. Most patients (98%) had ≥1 treatment-emergent adverse event (TEAE). The incidence of the most common TEAEs was consistent with reports in previous analyses. No association between creatine phosphokinase (CPK) abnormalities and muscle spasm was observed. Serious TEAEs occurred in 289 patients (23.8%). Exposure ≥12 months did not lead to increased incidence or severity of new TEAEs. The majority of the most common TEAEs ongoing at time of treatment discontinuation resolved by 12 months afterwards, regardless of Gorlin syndrome status. Response rates (investigator-assessed) in patients with histologically confirmed measurable baseline disease were 68.5% (95% confidence interval (CI) 65.7-71.3) in patients with locally advanced BCC and 36.9% (95% CI 26.6-48.1) in patients with metastatic BCC. CONCLUSIONS: The primary analysis of STEVIE demonstrates that vismodegib is tolerable in typical patients in clinical practice; safety profile is consistent with that in previous reports. Long-term exposure was not associated with worsening severity/frequency of TEAEs. Investigator-assessed response rates showed high rate of tumour control. CLINICALTRIALS.GOV: NCT01367665.
Subject(s)
Anilides/administration & dosage , Antineoplastic Agents/administration & dosage , Basal Cell Nevus Syndrome/drug therapy , Carcinoma, Basal Cell/drug therapy , Pyridines/administration & dosage , Administration, Oral , Adolescent , Adult , Aged , Aged, 80 and over , Anilides/adverse effects , Antineoplastic Agents/adverse effects , Basal Cell Nevus Syndrome/mortality , Basal Cell Nevus Syndrome/pathology , Carcinoma, Basal Cell/mortality , Carcinoma, Basal Cell/secondary , Creatine Kinase/blood , Disease Progression , Disease-Free Survival , Drug Administration Schedule , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Pyridines/adverse effects , Spasm/chemically induced , Time Factors , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: Preclinical work suggests SRC proteins have a role in the development of resistance to vascular endothelial growth factor (VEGF) targeted therapy in metastatic clear-cell renal cancer (mRCC). This hypothesis was tested in this trial using the SRC inhibitor saracatinib and the VEGF inhibitor cediranib. PATIENTS AND METHODS: Patients with disease progression after ≥1 VEGF-targeted therapy were eligible to participate in this double-blind, randomized (1:1) phase II study. The study compared the combination cediranib 30 mg once daily (o.d.) and saracatinib 175 mg o.d. (CS) (n = 69) or cediranib 45 mg o.d. and placebo o.d. (C) (n = 69). Archived tissue was used for biomarker analysis [SRC, focal adhesion kinase (FAK), von Hippel-Lindau, protein tyrosine phosphatase 1b and hypoxia-inducible factor 2α : n = 86]. The primary end point was progression-free survival (PFS) by RECIST v1.1. RESULTS: Between 2010 and 2012, 138 patients were randomized across 16 UK sites. The characteristics of the two groups were well balanced. Partial responses were seen in 13.0% for C and 14.5% for CS (P > 0.05). There was no significant difference in PFS [5.4 months (3.6-7.3 months) for C and 3.9 (2.4-5.3 months) for CS; hazard ratio (HR) 1.18 (0.94-1.48)] or overall survival (OS) [14.2 months (11.2-16.8 months) for C and 10.0 (6.7-13.2 months) for CS; HR 1.28 (1.00-1.63)]. There was no significant difference in the frequency of key adverse events, dose reductions or drug discontinuations. None of the biomarkers were prognostic for PFS or OS. FAK overexpression correlated with an OS benefit [HR 2.29 (1.09-4.82), P > 0.05], but not PFS, for CS. CONCLUSIONS: Saracatinib did not increase the efficacy of a VEGF-targeted therapy (cediranib) in this setting. Biomarker analysis did not identify consistent predictive biomarkers. CLINICALTRIALSGOV: NCT00942877.
Subject(s)
Benzodioxoles/administration & dosage , Carcinoma, Renal Cell/drug therapy , Quinazolines/administration & dosage , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Aged , Biomarkers, Tumor/genetics , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Disease-Free Survival , Double-Blind Method , Female , Humans , Male , Middle Aged , Neoplasm Metastasis , Prognosis , Proportional Hazards Models , Vascular Endothelial Growth Factor A/geneticsABSTRACT
BACKGROUND: The detection of occult bone metastases is a key factor in determining the management of patients with renal cell carcinoma (RCC), especially when curative surgery is considered. This prospective study assessed the sensitivity of (18)F-labelled sodium fluoride in conjunction with positron emission tomography/computed tomography ((18)F-NaF PET/CT) for detecting RCC bone metastases, compared with conventional imaging by bone scintigraphy or CT. PATIENTS AND METHODS: An adaptive two-stage trial design was utilized, which was stopped after the first stage due to statistical efficacy. Ten patients with stage IV RCC and bone metastases were imaged with (18)F-NaF PET/CT and (99m)Tc-labelled methylene diphosphonate ((99m)Tc-MDP) bone scintigraphy including pelvic single photon emission computed tomography (SPECT). Images were reported independently by experienced radiologists and nuclear medicine physicians using a 5-point scoring system. RESULTS: Seventy-seven lesions were diagnosed as malignant: 100% were identified by (18)F-NaF PET/CT, 46% by CT and 29% by bone scintigraphy/SPECT. Standard-of-care imaging with CT and bone scintigraphy identified 65% of the metastases reported by (18)F-NaF PET/CT. On an individual patient basis, (18)F-NaF PET/CT detected more RCC metastases than (99m)Tc-MDP bone scintigraphy/SPECT or CT alone (P = 0.007). The metabolic volumes, mean and maximum standardized uptake values (SUV mean and SUV max) of the malignant lesions were significantly greater than those of the benign lesions (P < 0.001). CONCLUSIONS: (18)F-NaF PET/CT is significantly more sensitive at detecting RCC skeletal metastases than conventional bone scintigraphy or CT. The detection of occult bone metastases could greatly alter patient management, particularly in the context when standard-of-care imaging is negative for skeletal metastases.
Subject(s)
Bone Neoplasms/diagnostic imaging , Bone Neoplasms/secondary , Fluorodeoxyglucose F18/pharmacokinetics , Kidney Neoplasms/diagnostic imaging , Kidney Neoplasms/pathology , Multimodal Imaging/methods , Research Design , Technetium Tc 99m Medronate/pharmacokinetics , Aged , Carcinoma, Papillary/diagnostic imaging , Carcinoma, Papillary/secondary , Carcinoma, Renal Cell/diagnostic imaging , Carcinoma, Renal Cell/secondary , Female , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasm Staging , Positron-Emission Tomography/methods , Prognosis , Prospective Studies , Radionuclide Imaging , Sensitivity and Specificity , Tomography, X-Ray Computed/methodsABSTRACT
Basal cell carcinoma (BCC) is a common malignancy with a good prognosis in the majority of cases. However, some BCC patients develop a more advanced disease that poses significant management challenges. Such cases include locally advanced, recurrent or metastatic BCC, or tumours that occur in anatomical sites where surgical treatment would result in significant deformity. Until recently, treatment options for these patients have been limited, but increased understanding of the molecular basis of BCC has enabled potential therapies, such as hedgehog signalling pathway inhibitors, to be developed. A clear definition of advanced BCC as a distinct disease entity and formal management guidelines have not previously been published, presumably because of the rarity, heterogeneity and lack of treatment options available for the disease. Here we provide a UK perspective from a multidisciplinary group of experts involved in the treatment of complex cases of BCC, addressing the key challenges associated with the perceived definition and management of the disease. With new treatments on the horizon, we further propose a definition for advanced BCC that may be used as a guide for healthcare professionals involved in disease diagnosis and management.
Subject(s)
Carcinoma, Basal Cell/therapy , Skin Neoplasms/therapy , Humans , United KingdomABSTRACT
BACKGROUND: Most persons who are infected with human immunodeficiency virus type 1 (HIV-1) are also infected with herpes simplex virus type 2 (HSV-2), which is frequently reactivated and is associated with increased plasma and genital levels of HIV-1. Therapy to suppress HSV-2 reduces the frequency of reactivation of HSV-2 as well as HIV-1 levels, suggesting that suppression of HSV-2 may reduce the risk of transmission of HIV-1. METHODS: We conducted a randomized, placebo-controlled trial of suppressive therapy for HSV-2 (acyclovir at a dose of 400 mg orally twice daily) in couples in which only one of the partners was seropositive for HIV-1 (CD4 count, > or = 250 cells per cubic millimeter) and that partner was also infected with HSV-2 and was not taking antiretroviral therapy at the time of enrollment. The primary end point was transmission of HIV-1 to the partner who was not initially infected with HIV-1; linkage of transmissions was assessed by means of genetic sequencing of viruses. RESULTS: A total of 3408 couples were enrolled at 14 sites in Africa. Of the partners who were infected with HIV-1, 68% were women, and the baseline median CD4 count was 462 cells per cubic millimeter. Of 132 HIV-1 seroconversions that occurred after randomization (an incidence of 2.7 per 100 person-years), 84 were linked within couples by viral sequencing: 41 in the acyclovir group and 43 in the placebo group (hazard ratio with acyclovir, 0.92, 95% confidence interval [CI], 0.60 to 1.41; P=0.69). Suppression with acyclovir reduced the mean plasma concentration of HIV-1 by 0.25 log(10) copies per milliliter (95% CI, 0.22 to 0.29; P<0.001) and the occurrence of HSV-2-positive genital ulcers by 73% (risk ratio, 0.27; 95% CI, 0.20 to 0.36; P<0.001). A total of 92% of the partners infected with HIV-1 and 84% of the partners not infected with HIV-1 remained in the study for 24 months. The level of adherence to the dispensed study drug was 96%. No serious adverse events related to acyclovir were observed. CONCLUSIONS: Daily acyclovir therapy did not reduce the risk of transmission of HIV-1, despite a reduction in plasma HIV-1 RNA of 0.25 log(10) copies per milliliter and a 73% reduction in the occurrence of genital ulcers due to HSV-2. (ClinicalTrials.gov number, NCT00194519.)
Subject(s)
AIDS-Related Opportunistic Infections/drug therapy , Acyclovir/therapeutic use , Antiviral Agents/therapeutic use , HIV Infections/transmission , HIV-1 , Herpes Genitalis/drug therapy , Herpesvirus 2, Human , Acyclovir/adverse effects , Adolescent , Adult , Antiviral Agents/adverse effects , CD4 Lymphocyte Count , Female , Follow-Up Studies , HIV Infections/complications , HIV-1/genetics , HIV-1/isolation & purification , Herpes Genitalis/complications , Humans , Intention to Treat Analysis , Kaplan-Meier Estimate , Male , Patient Compliance , Pregnancy , RNA, Viral/blood , Unsafe Sex/statistics & numerical data , Young AdultABSTRACT
BACKGROUND: Voluntary HIV counselling and testing (VCT) has been shown to be an acceptable and effective tool in the fight against HIV/AIDS. Couple HIV Counselling and Testing (CHCT) however, is a relatively new concept whose acceptance and efficacy is yet to be determined. OBJECTIVE: To describe factors that motivate couples to attend VCT as a couple. DESIGN: A cross sectional qualitative study. SETTING: Moi Teaching and Referral Hospital and Moi University, School of Medicine, Eldoret, Kenya SUBJECTS: Seventy one individuals were interviewed during KII (9) and dyad interviews (31 couples). Ten FGDs involving a total of 109 individuals were held. RESULTS: Cultural practices, lack of CHCT awareness, stigma and fear of results deter CHCT utilisation. Location of centre where it is unlikely to be associated with HIV testing, qualified professional staff and minimal waiting times would enhance CHCT utilisation. CONCLUSIONS: CHCT as a tool in the fight against HIV/AIDS in this region of Kenya is feasible as the factors that would deter couples are not insurmountable.
Subject(s)
AIDS Serodiagnosis , Directive Counseling/statistics & numerical data , Family Characteristics , HIV Infections/prevention & control , Cross-Sectional Studies , Culture , Directive Counseling/methods , Feasibility Studies , Focus Groups , HIV Infections/transmission , HIV-1 , Health Care Surveys , Health Knowledge, Attitudes, Practice , Humans , Kenya/epidemiology , Patient Acceptance of Health Care/statistics & numerical data , Preventive Medicine , Qualitative Research , Risk FactorsABSTRACT
Cancer-related fatigue is the most prevalent and distressing symptom experienced by patients with advanced cancer. Central nervous system stimulants have been shown to relieve fatigue in nonmalignant disease. Modafinil is a stimulant with a selective site of action in the brain that is better tolerated than traditional stimulants, such as methylphenidate. The aim of this study was to determine the feasibility of conducting a randomised controlled trial to assess the efficacy and safety of modafinil for the treatment of fatigue in patients with lung cancer. Twenty patients with non-small cell lung cancer were recruited to this open-label study. Modafinil was taken in a fixed dose-titration schedule of 100 mg daily for 7 days followed by 200 mg daily for 7 days. Fifteen patients completed the study. During the study period, there was a rapid and statistically significant reduction in the primary outcome, fatigue (P = 0.001) and the secondary outcomes of daytime sleepiness and depression/anxiety. This improvement in fatigue was also clinically significant. Ten patients chose to continue modafinil after the study and the drug was well-tolerated. It would be both feasible and worthwhile to conduct a definitive randomised controlled trial to determine the role of modafinil in the treatment of cancer-related fatigue.
Subject(s)
Benzhydryl Compounds/therapeutic use , Carcinoma, Non-Small-Cell Lung/complications , Central Nervous System Stimulants/therapeutic use , Fatigue/drug therapy , Lung Neoplasms/complications , Aged , Aged, 80 and over , Fatigue/etiology , Feasibility Studies , Female , Humans , Male , Middle Aged , Modafinil , Pilot Projects , Prospective Studies , Randomized Controlled Trials as Topic , Treatment OutcomeABSTRACT
OBJECTIVE: To describe the perceptions of key stakeholders regarding the counselling needs of HIV sero-discordant couples as part of preparation for a clinical trial involving HIV sero-discordant couples. DESIGN: Qualitative study using key informant and couple interviews. SETTING: Moi Teaching and Referral Hospital (MTRH). SUBJECTS: A purposive sample of nine key informants and 31 couple interviews totaling 71 participants. The couple interviews consisted of HIV untested, HIV concordant (positive and negative) and discordant couples. RESULTS: Seventy one individuals participated in nine key informant and 31 couple interviews. The responses identified the following as key issues in counselling HIV discordant couples: The need for education on the meaning of HIV sero-discordancy including potential sources of infection; assistance in disclosing HIV test results to one's partner; discussion of the stigma surrounding formula feeding. Overall, the participants supported safer sexual practices in discordant partnerships. CONCLUSIONS: Psychosocial support of HIV sero-discordant couples should include messages about the meaning, mechanisms and implications of sero-discordancy. Culturally appropriate HIV-disclosure and safer sex messages are also needed to support these partnerships.
Subject(s)
HIV Infections/psychology , HIV Seroprevalence , Health Knowledge, Attitudes, Practice , Social Perception , Cross-Sectional Studies , Female , HIV Infections/epidemiology , HIV Infections/transmission , Health Surveys , Humans , Interviews as Topic , Kenya/epidemiology , Male , Qualitative Research , Tape RecordingABSTRACT
The E5 protein family of papillomaviruses comprises small hydrophobic proteins which are associated with the cell endomembrane compartments. The functions of the E5 proteins, particularly those of HPV, are still far from clear. We have reported that the E5 proteins of BPV-1, BPV-4, HPV-16 and HPV-6 down-regulate MHC class I, potentially helping the virus evade the host immune response. Others have described MHC class I down-regulation by HPV-2 E5. We report here that another E5 protein, HPV-83 E5, likewise down-regulates MHC class I and propose that interference with expression, assembly and/or transport of MHC class I is a common property of all E5 proteins evolved by the virus to circumvent host immunosurveillance and thus establish productive infection.