There is no clear consensus regarding systemic treatment of early-stage ovarian cancer (OC). Clinical trials are challenging because of the relatively low incidence and good prognosis. Initial ...results of the International Collaborative Ovarian Neoplasm (ICON)1 trial demonstrated benefit in both overall survival (OS) and recurrence-free survival (RFS) with adjuvant chemotherapy. We report results of 10-year follow-up to establish whether benefits are maintained longer term and discuss how this and other available evidence from randomised trials can be used to guide treatment options regarding the need for, and choice of, adjuvant chemotherapy regimen.
ICON1 recruited women with OC following primary surgery in whom there was uncertainty as to whether adjuvant chemotherapy was indicated. Patients were randomly assigned to adjuvant or no adjuvant chemotherapy. Platinum-based chemotherapy was recommended and 87% received single-agent carboplatin. Analyses of long-term treatment benefits and interaction with risk groups were carried out. A high-risk group of women was defined with stage 1B/1C grade 2/3, any stage 1 grade 3 or clear-cell histology.
With a median follow-up of 10 years, the estimated hazard ratio (HR) for RFS was 0.69 95% confidence interval (CI) 0.51–0.94, P = 0.02 and OS 0.71 (95% CI 0.52–0.98, P = 0.04) in favour of chemotherapy. In absolute terms, there was a 10% (60%–70%) improvement in RFS and a 9% (64%–73%) improvement in OS; the benefit of chemotherapy might be greater in high-risk disease (18% improvement in OS). Uncertainty remains about the optimal chemotherapy regimen. The only randomised trial data available are from a subset of 120 stage 1 patients in ICON3 where the treatment difference, comparing carboplatin with carboplatin/paclitaxel was estimated with relatively wide CIs progression-free survival HR = 0.71 (95% CI 0.39–1.32) and OS HR = 0.98 (95% CI 0.49–1.93).
Extended follow-up from ICON1 confirms that adjuvant chemotherapy should be offered to women with early-stage OC, particularly those with high-risk disease.
ISRCTN11916376 for ICON1 and ISRCTN57157825 for ICON3.
Literature reviews of cancer trials have highlighted the need for better understanding of phase II statistical designs. Understanding the key elements associated with phase II design and knowledge of ...available statistical designs is necessary to enable appropriate phase II trial design.
A systematic literature review was performed to identify phase II trial designs applicable to oncology trials. The results of the review were used to create a library of currently available designs, and to develop a structured approach to phase II trial design outlining key points for consideration.
A total of 122 papers describing new or adapted phase II trial designs were obtained. These were categorised into nine levels, reflecting the practicalities of implementation, and form a library of phase II designs. Key design elements were identified by data extraction. Along with detailed description of the key elements and the library of designs, a structured thought process was developed to form a guidance document for choice of phase II oncology trial design.
The guidance offers researchers a structured and systematic approach to identifying phase II trial designs, highlighting key issues to be considered by both clinicians and statisticians and encouraging an interactive approach to more informed trial design.
Stage I non-small cell lung cancer (NSCLC) is potentially curable, and surgery is considered to be the standard of care for patients with good performance status and minimal co-morbidity. However, a ...significant proportion of patients with stage I NSCLC have a poorer performance status and significant medical co-morbidity that make them at higher risk of morbidity and mortality from surgery. Stereotactic ablative radiotherapy (SABR), which uses modern radiotherapeutic techniques to deliver large doses of radiation, has shown superiority over conventional radiotherapy in terms of local control and toxicity and is a standard of care for patients with stage I NSCLC who are at too high risk for surgery. However, it is not known whether surgery or SABR is the most effective in patients with stage I NSCLC who are suitable for surgery but are less fit and at higher risk surgical complications. Previous randomised studies have failed to recruit in this setting, and therefore, a feasibility study is required to see whether a full randomised control trial would be possible.
SABRTooth is a UK-based, multi-centre, open-label, two-group individually (1:1) randomised controlled feasibility study in patients with peripheral stage I NSCLC considered to be at higher risk from surgical resection. The study will assess the feasibility of conducting a definitive large-scale phase III trial. The primary objective is to assess recruitment rates to provide evidence that, when scaled up, recruitment to a large phase III trial would be possible; the target recruitment being 54 patients in total, over a 21-month period. There are multiple secondary and exploratory objectives designed to explore the optimum recruitment and data collection strategies to help optimise the design of a future phase III trial.
To know whether SABR is a better, equivalent or inferior alternative to surgery for higher risk patients is a key question in lung cancer. Other studies comparing SABR to surgery have closed early due to poor recruitment, and therefore, the SABRTooth feasibility study has been designed around the UK National Health Service (NHS) cancer pathway incorporating many design features in order to maximise recruitment for a future definitive phase III trial.
controlled-trials.com ISRCTN13029788.
Background
Human melanoma cells express high-affinity glucocorticoid receptors, and adrenalectomy has been shown to have antimelanoma effects in animal models. Long-term regression of distant ...metastatic melanoma was observed in one patient after bilateral adrenalectomy, prompting a review of adrenalectomy for melanoma metastases performed at this center.
Methods
A retrospective study in which all patients treated at the Sydney Melanoma Unit and recorded as having adrenal gland metastases between January 1987 and January 2004 were identified and their survival analyzed.
Results
One hundred eighty-six patients with adrenal gland metastases were identified. Adrenalectomy was performed in 23 patients; the other 163 patients were treated nonsurgically. The adrenal glands were the sole site of disease in five patients. All symptomatic patients were free of pain after recovery from the surgical procedure. Thirteen patients were rendered clinically and radiologically disease-free by their surgery. There was no postoperative mortality within 30 days. Median overall survival after adrenalectomy was 16 months (2-year survival, 39%), compared with 5 months for patients with documented adrenal metastases treated nonsurgically (
P
< .00001). In one patient, nonresected visceral metastases elsewhere regressed completely after bilateral adrenalectomy; he remained well and free of disease 80 months after adrenalectomy. Regression of distant visceral metasatatic disease also occurred in a second patient after unilateral adrenalectomy.
Conclusions
Adrenalectomy for melanoma metastatic to the adrenal gland provides good palliation of symptoms and is associated with prolonged survival in a selected cohort of patients. We report for the first time sustained complete regression of distant metastatic melanoma after bilateral adrenalectomy, suggesting a possible role for adrenal hormones in modifying melanoma progression in certain patients.
Abstract
BACKGROUND
We previously reported safety data from a phase Ib, open-label study of intravenous oncolytic virus pelareorep with GM-CSF alongside standard chemoradiotherapy in newly diagnosed ...glioblastoma confirming that the combination is well tolerated. We now report on long-term follow up and analysis of translational samples from tumour and blood in a subset of patients.
METHODS
15 patients with newly diagnosed GBM were treated with GM-CSF 50μg subcutaneously on days 1-3 and intravenous pelareorep on days 4-5 in weeks 1 and 4 of chemoradiotherapy, and subsequently in week 1 of each adjuvant temozolomide course: 7 patients received 1x1010TCID50 (dose level 1); 8 received 3x1010TCID50 (dose level 2). The primary objective was to determine the maximum tolerated dose of pelareorep and GM-CSF with standard chemoradiotherapy. Following a protocol amendment we also collected survival data in all patients up to August 2021. Serial blood samples were taken from three patients, at baseline, during chemoradiotherapy and in the first adjuvant cycle. Peripheral blood mononuclear cells were analysed for immune checkpoint expression by flow cytometry, RNAseq gene expression and T-cell receptor clonality, whilst plasma cytokines were quantified by Luminex.
RESULTS
This combination was well tolerated with 87% of patients completing treatment as planned. Survival data analysis showed that median OS was 12.6 months in dose level 1 and 16.1 months in dose level 2, median OS for all patients was 13.1 months. The 24-month survival estimate for all patients was 25.0%, 16.7% for dose level 1 and 33.3% for dose level 2. One patient in dose level 1 remains alive at 43 months post registration without further treatment. Laboratory data showed that pelareorep infusion resulted in inflammatory cytokine and chemokine secretion, immune checkpoint modulation, and upregulation of inflammatory pathways. There was also increased peripheral clonal tumour-specific T-cell proliferation following pelareorep infusion.
CONCLUSION
Although based on small numbers, these long-term follow up data suggest this may be an active combination in a subset of GBM patients. Translational data confirm that pelareorep potentially activates tumour-targeting immune pathways in GBM, with consequential immune checkpoint modulation. These data support a combination clinical trial of pelareorep, radiotherapy and immune checkpoint blockade in GBM.
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