Improving patient selection for adjuvant therapy in high-risk renal cell carcinoma.
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ABSTRACT:
SUBMITTER: Buller DM
PROVIDER: S-EPMC6685884 | biostudies-literature | 2019 Jul
REPOSITORIES: biostudies-literature
Publications
Improving patient selection for adjuvant therapy in high-risk renal cell carcinoma.
Buller Dylan M DM Ristau Benjamin T BT
Annals of translational medicine 20190701 Suppl 3
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Project description:BackgroundPORTEC-2 was a randomised trial for women with high-intermediate risk (HIR) endometrial cancer, comparing pelvic external beam radiotherapy (EBRT) with vaginal brachytherapy (VBT). We evaluated long-term outcomes combined with the results of pathology review and molecular analysis.Methods427 women with HIR endometrial cancer were randomised between 2002-2006 to VBT or EBRT. Primary endpoint was vaginal recurrence (VR). Pathology review was done in 97.4%, combined with molecular analysis.ResultsMedian follow-up was 116 months; 10-year VR was 3.4% versus 2.4% for VBT vs. EBRT (p = 0.55). Ten-year pelvic recurrence (PR) was more frequent in the VBT group (6.3% vs. 0.9%, p = 0.004), mostly combined with distant metastases (DM). Ten-year isolated PR was 2.5% vs. 0.5%, p = 0.10, and DM 10.4 vs. 8.9% (p = 0.45). Overall survival for VBT vs. EBRT was 69.5% vs. 67.6% at 10 years (p = 0.72). L1CAM and p53-mutant expression and substantial lymph-vascular space invasion were risk factors for PR and DM. EBRT reduced PR in cases with these risk factors.ConclusionLong-term results of the PORTEC-2 trial confirm VBT as standard adjuvant treatment for HIR endometrial cancer. Molecular risk assessment has the potential to guide adjuvant therapy. EBRT provided better pelvic control in patients with unfavourable risk factors.
| S-EPMC6219495 | biostudies-literature
Project description:Locally and regionally advanced renal cell carcinoma (RCC) can recur at high rates even after visually complete resection of primary disease. Both targeted therapies and immunotherapies represent potential agents that might help reduce recurrence of RCC in these patients. This paper reviews the current body of evidence defining their potential impact and examines the large Phase III randomized clinical trials that have been performed to assess the safety and efficacy of these systemic therapies in the adjuvant setting. Given that the findings from these trials have been predominantly negative, this paper also explores the role of other potential adjuvant agents, including single and combination agent targeted therapies and immunotherapies, whose use is currently limited to metastatic RCC. Finally, the use of radiation therapy and the use of advanced imaging modalities in RCC are also considered.
| S-EPMC9884052 | biostudies-literature
Project description:BackgroundAdjuvant sunitinib has significantly improved disease-free survival versus placebo in patients with renal cell carcinoma at high risk of recurrence post-nephrectomy (hazard ratio 0.76; 95% confidence interval, 0.59-0.98; two-sided P = 0.03). We report safety, therapy management, and patient-reported outcomes for patients receiving sunitinib and placebo in the S-TRAC trial.Patients and methodsPatients were stratified by the University of California, Los Angeles Integrated Staging System and Eastern Cooperative Oncology Group performance status score, and randomized (1 : 1) to receive sunitinib (50 mg/day) or placebo. Single dose reductions to 37.5 mg, dose delays, and dose interruptions were used to manage adverse events (AEs). Patients' health-related quality of life, including key symptoms typically associated with sunitinib, were evaluated with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30).ResultsPatients maintained treatment for 9.5 (mean, SD 4.4) and 10.3 (mean, SD 3.7) months in the sunitinib and placebo arms, respectively. In the sunitinib arm, key AEs occurred ∼1 month (median) after start of treatment and resolved within ∼3.5 weeks (median). Many (40.6%) AEs leading to permanent discontinuation were grade 1/2, and most (87.2%) resolved or were resolving by 28 days after last treatment. Patients taking sunitinib showed a significantly lower EORTC QLQ-C30 overall health status score versus placebo, although this reduction was not clinically meaningful. Patients reported symptoms typically related to sunitinib treatment with diarrhea and loss of appetite showing clinically meaningful increases.ConclusionsIn S-TRAC, AEs were predictable, manageable, and reversible via dose interruptions, dose reductions, and/or standard supportive medical therapy. Patients on sunitinib did report increased symptoms and reduced HRQoL, but these changes were generally not clinically meaningful, apart from appetite loss and diarrhea, and were expected in the context of known sunitinib effects.Clinical trial registrationClinicalTrials.gov, NCT00375674.
| S-EPMC6247664 | biostudies-literature
Project description:IntroductionTo quantify patients' preferences for adjuvant renal cell carcinoma (RCC) treatments.Patients and methodsPreferences were elicited using a discrete-choice experiment requiring RCC patients to choose between 2 hypothetical treatments. Data were analyzed using random-parameters logit and latent-class models.ResultsPatients (n = 250) preferred treatments that increase disease-free and overall survival (OS), are taken less frequently, require no concomitant medication, have a shorter duration, and have lower side-effect risks. The analyses also highlighted their willingness to make tradeoffs between these benefits and risks. Patients were generally tolerant of increases in the risks of treatment-related severe diarrhea, dizziness, and fatigue and were willing to accept increases in these risks in exchange for improvements in overall or disease-free survival. Latent-class analysis identified 3 classes: class 1 (37.5%) and class 2 (26.9%) preferred not to opt out of treatment and prioritized increased OS and disease-free survival, respectively; class 3 (35.5%) preferred to opt out and prioritized mode, duration, and risks.ConclusionsHeterogeneity suggests patient-physician discussions are important when considering RCC treatments.
| S-EPMC11921160 | biostudies-literature
Project description:PurposeTargeted tyrosine kinase inhibitors (TKIs) and immune-checkpoint inhibitors (ICIs) revolutionized the treatment of metastatic renal cell carcinoma (RCC). Efforts to translate these therapies into the adjuvant setting for local and locoregional RCC have been pursued over the past decade. We sought to provide an updated review of the literature regarding adjuvant therapy in RCC, as well as an analysis of patient characteristics that may portend the most favorable responses.Materials and methodsUsing PubMed, Google Scholar, and Wiley Online Library, we reviewed articles between 2000 and 2022. Search terms included "tyrosine kinase inhibitors," "adjuvant," "immunotherapy," and "renal cell carcinoma." The articles included were original and published in English. Information on clinical trials was collected from ClinicalTrials.gov, accessed in June 2022.ResultsLandmark trials investigating adjuvant vascular endothelial growth factor (VEGF) inhibitors produced conflicting results, with only a single trial of sunitinib (S-TRAC) resulting in US Food and Drug Administration-approval on the basis of a slightly prolonged progression-free survival (PFS). Subsequent meta-analyses failed to show a benefit for adjuvant VEGF inhibitors. Several trials evaluating ICIs are currently ongoing, with pembrolizumab (KEYNOTE-564) earning US Food and Drug Administration-approval for a prolonged PFS, although overall survival data are not yet mature. Preliminary results from other adjuvant ICI trials have been conflicting.ConclusionThere remains a lack of clear benefit for the use of adjuvant VEGF inhibitors in local and locoregional RCC. Adjuvant ICI investigations are ongoing, with promising results from KEYNOTE-564. It remains to be seen if PFS is an adequate surrogate end point for overall survival. Selection of patients at greatest risk for recurrence, and identification of those at greatest risk of rare but serious adverse events, may improve outcomes.
| S-EPMC9928983 | biostudies-literature
Project description:Nephrectomy continues to be the cornerstone of treatment for localized renal cell carcinoma (RCC). Despite undergoing nephrectomy, recurrence of disease remains a concern in many patients, and different medical therapies are being investigated as means to decrease this risk. The use of the traditional immunotherapy options has not provided benefit as adjuvant treatment in this disease state. Recently, the treatment of metastatic RCC has experienced key advances with the introduction of targeted agents against the vascular endothelial growth factor (VEGF) molecule and related pathways as well as inhibitors of the mammalian target of rapamycin (mTOR), in addition to improvements in surgical technique. Additionally, there are questions about the optimal timing of systemic therapy in the context of high risk non-metastatic disease. There is optimism that locally advanced RCC might benefit from adjuvant or neoadjuvant treatment with these therapies. Ongoing clinical trials are addressing the role of targeted agents in this disease state.
| S-EPMC3895463 | biostudies-literature
Project description:PurposePatients with resected localized clear-cell renal cell carcinoma (ccRCC) remain at variable risk of recurrence. Incorporation of biomarkers may refine risk prediction and inform adjuvant treatment decisions. We explored the role of tumor genomics in this setting, leveraging the largest cohort to date of localized ccRCC tissues subjected to targeted gene sequencing.Experimental designThe somatic mutation status of 12 genes was determined in 943 ccRCC cases from a multinational cohort of patients, and associations to outcomes were examined in a Discovery (n = 469) and Validation (n = 474) framework.ResultsTumors containing a von-Hippel Lindau (VHL) mutation alone were associated with significantly improved outcomes in comparison with tumors containing a VHL plus additional mutations. Within the Discovery cohort, those with VHL+0, VHL+1, VHL+2, and VHL+≥3 tumors had disease-free survival (DFS) rates of 90.8%, 80.1%, 68.2%, and 50.7% respectively, at 5 years. This trend was replicated in the Validation cohort. Notably, these genomically defined groups were independent of tumor mutational burden. Amongst patients eligible for adjuvant therapy, those with a VHL+0 tumor (29%) had a 5-year DFS rate of 79.3% and could, therefore, potentially be spared further treatment. Conversely, patients with VHL+2 and VHL+≥3 tumors (32%) had equivalent DFS rates of 45.6% and 35.3%, respectively, and should be prioritized for adjuvant therapy.ConclusionsGenomic characterization of ccRCC identified biologically distinct groups of patients with divergent relapse rates. These groups account for the ∼80% of cases with VHL mutations and could be used to personalize adjuvant treatment discussions with patients as well as inform future adjuvant trial design.
| S-EPMC10068441 | biostudies-literature
Project description:Standard of care for high-risk cutaneous squamous cell carcinoma (cSCC) is surgical excision of the primary lesion with clear margins when possible, and additional resection of positive margins when feasible. Even with negative margins, certain high-risk factors warrant consideration of adjuvant therapy. However, which patients might benefit from adjuvant therapy is unclear, and supporting evidence is conflicting and limited to mostly small retrospective cohorts. Here, we review literature from the last decade regarding adjuvant radiation therapy and systemic therapy in high-risk cSCC, including recent and current trials and the role of immune checkpoint inhibitors. We demonstrate evidence gaps in adjuvant therapy for high-risk cSCC and the need for prognostic tools, such as gene expression profiling, to guide patient selection. More large-cohort clinical studies are needed for collecting high-quality, evidence-based data for determining which patients with high-risk cSCC may benefit from adjuvant therapy and which therapy is most appropriate for patient management.
| S-EPMC8453797 | biostudies-literature
Project description:BackgroundIt is unclear whether patients with renal cell carcinoma (RCC) are routinely assessed for recurrence risk post-nephrectomy and whether patients at high recurrence risk are seen by providers who can evaluate candidacy for adjuvant systemic therapy (AST) and clinical trials.Materials and methodsWe identified all patients with locoregional RCC who underwent nephrectomy via an institutional database within Duke University Health System between 1 April 2015 and 31 December 2019. Medical records were reviewed to identify patient characteristics, post-nephrectomy referrals, treatment, and follow-up. Patients with tumor stage ≥3 and grade ≥2, regional lymph node metastasis, or both, were classified as high recurrence risk.ResultsOf 618 patients with locoregional RCC who underwent nephrectomy, 136 (22%) had high recurrence risk. Of those, 25 patients with high-risk disease (18%) were referred to medical oncology for discussion of AST; 23 (92%) of these referrals took place in 2018-2019. One patient received adjuvant sunitinib and two patients participated in adjuvant immunotherapy trials. The decision not to receive AST was primarily made by the oncologist in 10 (46%), the patient in 8 (36%), and unrecorded in 4 (18%) of 22 cases, for multiple reasons. Individual surgeons referred high-risk patients for discussion of AST with varying frequency, ranging from 0% to 100% in 2019.ConclusionsDespite increasing number of patients with locoregional RCC at high recurrence risk referred to medical oncologists after nephrectomy, few patients received AST, including participation in clinical trials. With increasing AST options and ongoing clinical trials in this space, these findings highlight the need for continued efforts at identifying effective AST and referring patients most likely to benefit to medical oncologists. ClinicalTrials.gov, NCT04309617.
| S-EPMC8683553 | biostudies-literature
Project description:At the present time, the standard of care for patients who have received nephrectomy for localized renal cell carcinoma (RCC) is radiographic surveillance. With a number of novel targeted agents showing activity in the setting of metastatic RCC, there has been great interest in exploring the potential of the same agents in the adjuvant setting. Herein, we discuss the evolution of adjuvant trials in RCC, spanning from the immunotherapy era to the targeted therapy era. Pitfalls of current studies are addressed to provide a context for interpreting forthcoming results. Finally, we outline avenues to incorporate promising investigational agents, such as PD-1 (programmed death-1) inhibitors and MNNG transforming gene inhibitors, in future adjuvant trials.
| S-EPMC4122473 | biostudies-other