Abstract Purpose This multi-disciplinary, evidence-based guideline for clinically non-metastatic muscle-invasive bladder cancer focuses on the evaluation, treatment, and surveillance of ...muscle-invasive bladder cancer guided toward curative intent. Materials and Methods A systematic review utilizing research from the Agency for Healthcare Research and Quality (AHRQ) as well as additional supplementation by the authors and consultant methodologists was used to develop the guideline. Evidence-based statements were based on body of evidence strengths Grade A, B, or C and were designated as Strong, Moderate, and Conditional Recommendations with additional statements presented in the form of Clinical Principles or Expert Opinions. (Table 1) Results For the first time, for any type of malignancy, the American Urological Association (AUA), the American Society of Clinical Oncology (ASCO), the American Society for Radiation Oncology (ASTRO), and the Society of Urologic Oncology (SUO) have formulated an evidence-based guideline based on a risk-stratified clinical framework for the management of muscle-invasive urothelial bladder cancer. This document is designed to be used in conjunction with the associated treatment algorithm. Conclusions The intensity and scope of care for muscle-invasive bladder cancer should focus on the patient, disease, and treatment response characteristics. This guideline attempts to improve a clinician’s ability to evaluate and treat each patient, but higher quality evidence in future trials will be essential to improve level of care for these patients.
In this trial, the addition of six cycles of docetaxel to androgen-deprivation therapy resulted in longer median progression-free and overall survival than that with ADT alone in patients with ...metastatic prostate cancer.
Regressions of metastatic prostate cancer were first documented in the 1940s and were achieved with surgical castration; subsequently, androgen-deprivation therapy (ADT) became the mainstay of therapy.
1
Attempts to improve the efficacy or decrease the treatment burden of ADT have included the use of antiandrogens alone, intermittent dosing of ADT, and the use of an antiandrogen combined with medical or surgical castration.
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–
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A meta-analysis revealed an increase in survival of 3 percentage points at 5 years with concurrent use of a nonsteroidal antiandrogen at the time of initiation of ADT.
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However, resistance to ADT occurs in most patients, with the . . .
Purpose Docetaxel added to androgen-deprivation therapy (ADT) significantly increases the longevity of some patients with metastatic hormone-sensitive prostate cancer. Herein, we present the outcomes ...of the CHAARTED (Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) trial with more mature follow-up and focus on tumor volume. Patients and Methods In this phase III study, 790 patients with metastatic hormone-sensitive prostate cancer were equally randomly assigned to receive either ADT in combination with docetaxel 75 mg/m
for up to six cycles or ADT alone. The primary end point of the study was overall survival (OS). Additional analyses of the prospectively defined low- and high-volume disease subgroups were performed. High-volume disease was defined as presence of visceral metastases and/or ≥ four bone metastases with at least one outside of the vertebral column and pelvis. Results At a median follow-up of 53.7 months, the median OS was 57.6 months for the chemohormonal therapy arm versus 47.2 months for ADT alone (hazard ratio HR, 0.72; 95% CI, 0.59 to 0.89; P = .0018). For patients with high-volume disease (n = 513), the median OS was 51.2 months with chemohormonal therapy versus 34.4 months with ADT alone (HR, 0.63; 95% CI, 0.50 to 0.79; P < .001). For those with low-volume disease (n = 277), no OS benefit was observed (HR, 1.04; 95% CI, 0.70 to 1.55; P = .86). Conclusion The clinical benefit from chemohormonal therapy in prolonging OS was confirmed for patients with high-volume disease; however, for patients with low-volume disease, no OS benefit was discerned.
The summary presented herein represents Part I of the two-part series dedicated to Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline discussing prognostic and treatment recommendations for patients ...with biochemical recurrence without metastatic disease after exhaustion of local treatment options as well as those with metastatic hormone-sensitive prostate cancer. Please refer to Part II for discussion of the management of castration-resistant disease.
The systematic review utilized to inform this guideline was conducted by an independent methodological consultant. A research librarian conducted searches in Ovid MEDLINE (1998 to January Week 5 2019), Cochrane Central Register of Controlled Trials (through December 2018), and Cochrane Database of Systematic Reviews (2005 through February 6, 2019). An updated search was conducted prior to publication through January 20, 2020. The methodology team supplemented searches of electronic databases with the studies included in the prior AUA review and by reviewing reference lists of relevant articles.
The Advanced Prostate Cancer Panel created evidence- and consensus-based guideline statements to aid clinicians in the management of patients with advanced prostate cancer. Such statements are summarized in figure 1Figure: see text and detailed herein.
This guideline attempts to improve a clinician's ability to treat patients diagnosed with advanced prostate cancer. Continued research and publication of high-quality evidence from future trials will be essential to improve the level of care for these patients.
Summary Background First-line chemotherapy for patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma is associated with short response duration, poor survival, and ...high toxicity. This study assessed atezolizumab (anti-programmed death-ligand 1 PD-L1) as treatment for metastatic urothelial cancer in cisplatin-ineligible patients. Methods For this single-arm, multicentre, phase 2 study, in 47 academic medical centres and community oncology practices in seven countries in North America and Europe, we recruited previously untreated patients with locally advanced or metastatic urothelial cancer who were cisplatin ineligible. Patients were given 1200 mg intravenous atezolizumab every 21 days until progression. The primary endpoint was independently confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (central review), assessed in prespecified subgroups based on PD-L1 expression and in all patients. All participants who received one or more doses of atezolizumab were included in the primary and safety analyses. This study was registered with ClinicalTrials.gov , number NCT02108652. Findings Between June 9, 2014, and March 30, 2015, we enrolled 123 patients, of whom 119 received one or more doses of atezolizumab. At 17·2 months' median follow-up, the objective response rate was 23% (95% CI 16 to 31), the complete response rate was 9% (n=11), and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2·7 months (2·1 to 4·2). Median overall survival was 15·9 months (10·4 to not estimable). Tumour mutation load was associated with response. Treatment-related adverse events that occurred in 10% or more of patients were fatigue (36 30% patients), diarrhoea (14 12% patients), and pruritus (13 11% patients). One treatment-related death (sepsis) occurred. Nine (8%) patients had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12%) patients. Interpretation Atezolizumab showed encouraging durable response rates, survival, and tolerability, supporting its therapeutic use in untreated metastatic urothelial cancer. Funding F Hoffmann-La Roche, Genentech.
Cisplatin-based combination chemotherapy is considered standard first-line treatment for patients with metastatic urothelial carcinoma. However, a large proportion of patients with metastatic ...urothelial carcinoma are considered "unfit" for cisplatin. The purpose of this review is to define unfit patients and to identify treatment options for this subgroup of patients.
In this review, the criteria used to define unfit patients are explored and the results of prospective clinical trials evaluating chemotherapeutic regimens in unfit patients are summarized.
Several phase II trials and a single, large phase III trial have explored chemotherapeutic regimens for the treatment of unfit patients with metastatic urothelial carcinoma. Heterogeneous eligibility criteria have been used to define unfit patients in these studies. A uniform definition of unfit is proposed on the basis of the results of a survey of genitourinary medical oncologists. According to this definition, unfit patients would meet at least one of the following criteria: Eastern Cooperative Oncology Group performance status of 2, creatinine clearance less than 60 mL/min, grade ≥ 2 hearing loss, grade ≥ 2 neuropathy, and/or New York Heart Association Class III heart failure.
Additional studies to optimize treatment for this important subset of patients are needed. A uniform definition of unfit patients will lead to more uniform clinical trials, enhanced ability to interpret the results of these trials, and a greater likelihood of developing a viable strategy for regulatory approval.
A MESSAGE FROM ASCO'S PRESIDENT I remember when ASCO first conceived of publishing an annual report on the most transformative research occurring in cancer care. Thirteen reports later, the progress ...we have chronicled is remarkable, and this year is no different. The research featured in ASCO's Clinical Cancer Advances 2018 report underscores the impressive gains in our understanding of cancer and in our ability to tailor treatments to tumors' genetic makeup. The ASCO 2018 Advance of the Year, adoptive cell immunotherapy, allows clinicians to genetically reprogram patients' own immune cells to find and attack cancer cells throughout the body. Chimeric antigen receptor (CAR) T-cell therapy-a type of adoptive cell immunotherapy-has led to remarkable results in young patients with acute lymphoblastic leukemia (ALL) and in adults with lymphoma and multiple myeloma. Researchers are also exploring this approach in other types of cancer. This advance would not be possible without robust federal investment in cancer research. The first clinical trial of CAR T-cell therapy in children with ALL was funded, in part, by grants from the National Cancer Institute (NCI), and researchers at the NCI Center for Cancer Research were the first to report on possible CAR T-cell therapy for multiple myeloma. These discoveries follow decades of prior research on immunology and cancer biology, much of which was supported by federal dollars. In fact, many advances that are highlighted in the 2018 Clinical Cancer Advances report were made possible thanks to our nation's support for biomedical research. Funding from the US National Institutes of Health and the NCI helps researchers pursue critical patient care questions and addresses vital, unmet needs that private industry has little incentive to take on. Federally supported cancer research generates the biomedical innovations that fuel the development and availability of new and improved treatments for patients. We need sustained federal research investment to accelerate the discovery of the next generation of cancer treatments. Another major trend in this year's report is progress in precision medicine approaches to treat cancer. Although precision medicine offers promise to people with cancer and their families, that promise is only as good as our ability to make these treatments available to all patients. My presidential theme, "Delivering Discoveries: Expanding the Reach of Precision Medicine," focuses on tackling this formidable challenge so that new targeted therapies are accessible to anyone who faces a cancer diagnosis. By improving access to high-quality care, harnessing big data on patient outcomes from across the globe, and pursuing innovative clinical trials, I am optimistic that we will speed the delivery of these most promising treatments to more patients. Sincerely, Bruce E. Johnson, FASCO ASCO President, 2017 to 2018.
Purpose: Immune dysfunction reported in renal cell carcinoma (RCC) patients may contribute to tumor progression. Myeloid-derived suppressor
cells (MDSC) represent one mechanism by which tumors induce ...T-cell suppression. Several factors pivotal to the accumulation
of MDSC are targeted by the tyrosine kinase inhibitor, sunitinib. The effect of sunitinib on MDSC-mediated immunosuppression
in RCC patients has been investigated.
Experimental Design: Patient peripheral blood levels of MDSC and regulatory T-cell (Treg) and T-cell production of IFN-γ were evaluated before
and after sunitinib treatment. Correlations between MDSC and Treg normalization as well as T-cell production of IFN-γ were
examined. The in vitro effect of sunitinib on patient MDSC was evaluated.
Results: Metastatic RCC patients had elevated levels of CD33 + HLA-DR â and CD15 + CD14 â MDSC, and these were partially overlapping populations. Treatment with sunitinib resulted in significant reduction in MDSC
measured by several criteria. Sunitinib-mediated reduction in MDSC was correlated with reversal of type 1 T-cell suppression,
an effect that could be reproduced by the depletion of MDSC in vitro . MDSC reduction in response to sunitinib correlated with a reversal of CD3 + CD4 + CD25 hi Foxp3 + Treg cell elevation. No correlation existed between a change in tumor burden and a change in MDSC, Treg, or T-cell production
of IFN-γ. In vitro addition of sunitinib reduced MDSC viability and suppressive effect when used at â¥1.0 μg/mL. Sunitinib did not induce MDSC
maturation in vitro .
Conclusions: Sunitinib-based therapy has the potential to modulate antitumor immunity by reversing MDSC-mediated tumor-induced immunosuppression.
Purpose: Immune dysfunction is well documented in renal cell carcinoma (RCC) patients and likely contributes to tumor evasion. This
dysfunction includes a shift from a type-1 to a type-2 T-cell ...cytokine response and enhanced T-regulatory (Treg) cell expression.
Given the antitumor activity of select tyrosine kinase inhibitors such as sunitinib in metastatic RCC (mRCC) patients, it
is relevant to assess their effect on the immune system.
Experimental Design: Type-1 (IFNγ) and type-2 (interleukin-4) responses were assessed in T cells at baseline and day 28 of treatment with sunitinib
(50 mg/d) by measuring intracellular cytokines after in vitro stimulation with anti-CD3/anti-CD28 antibodies.
Results: After one cycle of treatment, there was a significant increase in the percentage of IFNγ-producing T cells (CD3 + , P < 0.001; CD3 + CD4 + , P = 0.001), a reduction in interleukin-4 production (CD3 + cells, P = 0.05), and a diminished type-2 bias ( P = 0.005). The increase in type-1 response may be partly related to modulation of Treg cells. The increased percentage of
Treg cells noted in mRCC patients over healthy donors ( P = 0.001) was reduced after treatment, although not reaching statistical significance. There was, however, an inverse correlation
between the increase in type-1 response after two cycles of treatment and a decrease in the percentage of Treg cells ( r = −0.64, P = 0.01). In vitro studies suggest that the effects of sunitinib on Treg cells are indirect.
Conclusions: The demonstration that sunitinib improved type-1 T-cell cytokine response in mRCC patients while reducing Treg function provides
a basis for the rational combination of sunitinib and immunotherapy in mRCC.
To update eligibility and outcome measures in trials that evaluate systemic treatment for patients with progressive prostate cancer and castrate levels of testosterone.
A committee of investigators ...experienced in conducting trials for prostate cancer defined new consensus criteria by reviewing previous criteria, Response Evaluation Criteria in Solid Tumors (RECIST), and emerging trial data.
The Prostate Cancer Clinical Trials Working Group (PCWG2) recommends a two-objective paradigm: (1) controlling, relieving, or eliminating disease manifestations that are present when treatment is initiated and (2) preventing or delaying disease manifestations expected to occur. Prostate cancers progressing despite castrate levels of testosterone are considered castration resistant and not hormone refractory. Eligibility is defined using standard disease assessments to authenticate disease progression, prior treatment, distinct clinical subtypes, and predictive models. Outcomes are reported independently for prostate-specific antigen (PSA), imaging, and clinical measures, avoiding grouped categorizations such as complete or partial response. In most trials, early changes in PSA and/or pain are not acted on without other evidence of disease progression, and treatment should be continued for at least 12 weeks to ensure adequate drug exposure. Bone scans are reported as "new lesions" or "no new lesions," changes in soft-tissue disease assessed by RECIST, and pain using validated scales. Defining eligibility for prevent/delay end points requires attention to estimated event frequency and/or random assignment to a control group.
PCWG2 recommends increasing emphasis on time-to-event end points (ie, failure to progress) as decision aids in proceeding from phase II to phase III trials. Recommendations will evolve as data are generated on the utility of intermediate end points to predict clinical benefit.
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