Adjuvant therapy for renal cell carcinoma: 2023 Canadian Kidney Cancer Forum consensus statement.

INTRODUCTION: Several recent randomized trials evaluated the impact of adjuvant immune checkpoint inhibitor (ICI)-based therapy on post-surgical outcomes in renal cell carcinoma (RCC), with disparate results. The objective of this consensus statement is to provide data-driven guidance regarding the use of ICIs after complete resection of clear-cell RCC in a Canadian context. METHODS: An expert panel of genitourinary medical oncologists, urologic oncologists, and radiation oncologists with expertise in RCC management was convened in a dedicated session during the 2022 Canadian Kidney Cancer Forum in Toronto, Canada. Topic statements on the management of patients after surgery for RCC, including counselling, risk stratification, indications for medical oncology referral, appropriate followup, eligibility and management for adjuvant ICIs, as well as treatment options for patients with recurrence who received adjuvant immunotherapy, were discussed. Participants were asked to vote if they agreed or disagreed with each statement. Consensus was achieved if greater than 75% of participants agreed with the topic statement. RESULTS: A total of 22 RCC experts voted on 14 statements. Consensus was achieved on all topic statements. The panel felt patients with clear-cell RCC at increased risk of recurrence after surgery, as per the Keynote-564 group definitions, should be counselled about recurrence risk by a urologist, should be informed about the potential role of adjuvant ICI systemic therapy, and be offered referral to discuss risks and benefits with a medical oncologist. The panel felt that one year of pembrolizumab is currently the only regimen that should be considered if adjuvant therapy is selected. Panelists emphasized current opinions are based on disease-free survival given the available results. Significant uncertainty regarding the benefit and harms of adjuvant therapy remains, primarily due to a lack of consistent benefit observed across similar trials of adjuvant ICI-based therapies and immature overall survival (OS) data. CONCLUSIONS: This consensus document provides guidance from Canadian RCC experts regarding the potential role of ICI-based adjuvant systemic therapy after surgery. This rapidly evolving field requires frequent evidence-based re-evaluation.

Synchronous Versus Metachronous Metastatic Disease: Impact of Time to Metastasis on Patient Outcome-Results from the International Metastatic Renal Cell Carcinoma Database Consortium.

BACKGROUND: Patients with metastatic renal cell carcinoma (mRCC) may present with primary metastases (synchronous disease) or develop metastases during follow-up (metachronous disease). The impact of time to metastasis on patient outcome is poorly characterised. OBJECTIVE: To characterise overall survival (OS) and time to treatment failure (TTF) based on time to metastasis in mRCC patients treated with targeted therapy (tyrosine kinase inhibitors [TKIs]). DESIGN, SETTING, AND PARTICIPANTS: We used the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) to compare synchronous (metastases within ≤3 mo of initial diagnosis of cancer) versus metachronous disease (evaluated by >3-12 mo, >1-2 yr, >2-7 yr, and >7 yr intervals). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: OS and TFF were assessed using Kaplan-Meier curves. Cox multivariable regressions analyses (MVAs) were adjusted for baseline factors. RESULTS AND LIMITATIONS: Of 7386 patients with mRCC treated with first-line TKIs, 3906 (53%) and 3480 (47%) had synchronous and metachronous metastasis, respectively. More patients with synchronous versus metachronous disease had higher T stage (T1-2: 19% vs 34%), N1 disease (21% vs 6%), presence of sarcomatoid differentiation (15.8% vs 7.9%), Karnofsky performance status <80 (25.9% vs 15.1%), anaemia (62.5% vs 42.3%), elevated neutrophils (18.9% vs 10.9%), elevated platelets (21.6% vs 11.4%), bone metastases (40.4% vs 29.8%), and IMDC poor risk (40.6% vs 11.3%). Synchronous versus metachronous disease by intervals >3-12 mo, >1-2 yr, >2-7 yr, and >7 yr correlated with poor TTF (5.6 mo vs 7.3, 8.0, 10.8, and 13.3 mo, p <  0.0001) and poor OS (median 16.7 mo vs 23.8, 30.2, 34.8, and 41.7 mo, p <  0.0001). In MVAs, the adjusted hazard ratios (95% confidence intervals) were 1.00 (reference), 0.98 (0.90-1.06), 0.81 (0.73-0.91), 0.74 (0.68-0.81), and 0.60 (0.54-0.67), respectively, for OS (p <  0.0001), and 1.00 (reference), 0.99 (0.92-1.06), 0.98 (0.90-1.07), 0.83 (0.77-0.89), and 0.66 (0.60-0.72), respectively, for TTF (p <  0.0001). Data were collected retrospectively. CONCLUSIONS: Timing of metastases after initial RCC diagnosis may impact the outcomes from targeted therapy in mRCC. PATIENT SUMMARY: We looked at the impact of the timing of metastatic outbreak on survival outcomes in kidney cancer patients treated with targeted therapy. We found that the longer time to metastatic development was associated with improved outcome.

The efficacy and safety of sunitinib given on an individualised schedule as first-line therapy for metastatic renal cell carcinoma: A phase 2 clinical trial.

BACKGROUND: Sunitinib is administered on a rigid schedule that may not be optimal for all patients. We hypothesised that toxicity-driven dose and schedule changes would optimise drug exposure and outcome for each patient. MATERIALS AND METHODS: In a phase 2 trial, 117 patients with metastatic clear cell renal cell cancer were started on sunitinib 50 mg/day with the aim to treat for 28 days. Treatment breaks were reduced to 7 days. Sunitinib dose and the number of days on therapy were individualised based on toxicity aiming for ≤ grade II toxicity with dose escalation in patients with minimal toxicity. The null hypothesis for the primary end-point was a progression-free survival (PFS) of 8.5 months based on a study with similar eligibility criteria. RESULTS: The null hypothesis was rejected (p < 0.001) with a median PFS of 12.5 months (95% confidence interval [CI]: 9.6-16.5). The median overall survival was 38.5 months (95% CI: 28.3-not reached). The objective response rate (46.1%) and stable disease rate (38.5%) translated into a clinical benefit for 84.6% of patients with no decline in quality of life scores during therapy. Fewer patients were dose reduced (26.5% vs. 50%) or discontinued due to toxicity (7.7 vs. 18-20%) compared to standard sunitinib dosing, and 20 (18.4%) patients were dose escalated to 62.5 mg (12) and 75 mg (8) with a wide individual variation in the optimal dose and treatment duration. CONCLUSIONS: Individualised sunitinib therapy is feasible, safe and an effective method to manage toxicity with one of the best efficacy seen for oral vascular endothelial growth factor inhibitors in metastatic renal cell carcinoma. CLINICALTRIALS. GOV IDENTIFIER: NCT01499121.

Treatment of muscle-invasive bladder cancer in Canada: A survey of genitourinary medical oncologists and urologists.

INTRODUCTION: Uptake of neoadjuvant chemotherapy (NC) for muscle invasive bladder cancer (MIBC) has been low despite evidence of a survival benefit. The primary aim of this study was to better understand why the rates are low and determine what factors specifically influence the decision to recommend NC for MIBC. METHODS: A 31-question survey was emailed between 2009 and 2011 to medical oncologists belonging to the Canadian Association of Genitourinary Medical Oncologists (CAGMO); and to urologists belonging to the Canadian Urologic Oncology Group (CUOG). We gathered data on practice characteristics, referrals for NC, factors influencing NC use, and chemotherapy regimens offered. Responses were summarized using descriptive statistics. RESULTS: In total, 26/30 (87%) medical oncologists and 25/84 (30%) urologists, who were primarily academic, completed the survey. Most clinicians (medical oncologists 96%, urologists 88%) recommended NC for MIBC, because they considered it to be the standard of care, but most medical oncologists saw ≤6 referrals annually. Performance status, presence of comorbidities and renal function were key considerations in offering NC. NC was not offered if performance status ≥2 (medical oncologists 38%, urologists 44%), age >80 (medical oncologists 46%, urologists 39%), or glomerular filtration rate ≤40 mL/min (medical oncologists 81%, urologists 50%). CONCLUSIONS: Most academic clinicians in Canada believe that cisplatin-based combination NC is the standard of care for MIBC and recommend it for patients with adequate performance status and renal function. Using a multidisciplinary approach to treat this disease may be one strategy to increase referral rates for NC and uptake of NC.

Kidney cancer survivorship survey of urologists and survivors: The gap in perceptions of care, but agreement on needs.

INTRODUCTION: There is lack of evidence-based literature addressing comprehensive long-term care for kidney cancer (KC) survivors. Additionally, it is unclear if the concerns of KC patients/caregivers are being adequately addressed. Therefore, Kidney Cancer Canada, a patient-led support organization for Canadians with KC, commissioned this first recorded survivorship survey specific to KC patients/caregivers. METHODS: We conducted a cross-sectional online survey of Canadian patients/caregivers diagnosed with localized KC, and a separate parallel survey of Canadian urologists. The primary objectives were to assess patient/caregivers' and urologists' perceptions of information provided, as well as the physical/psychological/emotional impact of KC treatment. RESULTS: Urologists recalled providing information about surgical complications (90%) and their management (63%), while patients/caregiver recalled much less (33% and 35%). Of the urologists, 93% recalled providing information on cancer recurrence, but only 42% of patients/caregivers remembered receiving this information. Concerns identified by patients/caregivers and urologists were similar: fear of recurrence, concerns about cancer, fatigue, and anxiety. Importantly, all agreed that survivorship information was paramount. Education of both patients/caregivers and physicians and the development of guidelines were factors identified to ensure optimal KC survivorship. Study limitations include potential biases in recall and selection of participants. CONCLUSION: There was some discordance between urologists' and patients/caregivers' rates of recall of information provided. Patients/caregivers would have desired more information about their cancer, long-term follow-up, and potential complications. A survivorship care plan (SCP) tailored to KC may be an effective measure to address these needs. The impact of this SCP on survivor outcomes should be rigorously assessed.

Factors influencing a specific pathologic diagnosis of non-small-cell lung carcinoma.

INTRODUCTION: Historically, a non-small-cell lung carcinoma diagnosis, without pathologic subclassification, provided sufficient information to guide therapy. Evidence now demonstrates that pathologic subtype classification is central in selecting optimal treatment. This review aimed to identify factors associated with a specific pathologic diagnosis. METHODS: All nonoperative cases of non-small-cell lung carcinoma (NSCLC) referred to the medical oncology divisions of the Ottawa Hospital Cancer Centre (2008) and Princess Margaret Hospital, Toronto (2007-2010) were identified. The charts were reviewed for demographics, diagnostic methods, and final diagnosis. Logistic regression was performed to identify variables associated with a specific diagnosis. RESULTS: Of 739 patient records analyzed, 377 (51%) were men, 299 (40%) were aged over 70 years, and 510 (69%) had an Eastern Cooperative Oncology Group performance status of 0-2. Three hundred and eighty five (52%) of patients were diagnosed in a tertiary academic center. The lung primary was sampled in 503 (68%) of patients. Computed tomography-guided biopsy (n = 370, 50%) and bronchoscopy (n = 179, 24%) were the most common techniques. Four hundred and seventy seven (65%) of biopsies were cytologic specimens alone, and immunohistochemistry was performed in 337 (46%) of cases. The most common diagnoses were adenocarcinoma (n = 338, 46%), NSCLC not otherwise specified (n = 254, 34%), and squamous cell carcinoma (n = 115, 16%). Overall, 456 (62%) of patients received a specific pathologic diagnosis. Factors significantly associated with attaining a specific pathologic diagnosis were diagnosis outside an academic center (adjusted odds ratios [OR] 2.1 [95% CI, 1.41-3.14]; P = .0003), histologic laboratory samples (adjusted OR 1.58 [95% CI, 1.003-2.49]; P = .049), and immunohistochemical testing (adjusted OR 1.82 [95% CI, 1.25-2.70], P = .0021). CONCLUSIONS: A significant minority of patients with NSCLC do not receive a specific pathologic diagnosis. In an era of individualized medicine, this may potentially impact optimal clinical management.

Fostering partnerships in survivorship care: report of the 2011 Canadian genitourinary cancers survivorship conference.

PURPOSE: New models of survivorship care are required to address the needs of genitourinary (GU) cancer survivors. Current approaches do not effectively engage cancer survivors or advocacy groups. A group of clinicians in collaboration with the Canadian Urologic Association held a forum for GU cancer survivors, advocacy groups, and health professionals to explore ways to collaboratively enhance survivorship care. METHODS: Participants attended a 2-day conference that included presentations, breakout groups, and a postconference survey. Discussions by breakout groups were recorded and analyzed alongside open-ended survey responses for common themes. Basic statistics were calculated. RESULTS: Conference participants (n = 42) included 18 cancer survivors/caregivers, 21 health professionals, and 3 researchers representing bladder, kidney, prostate, and testis cancer groups. Breakout group discussions and responses to the postconference survey (83.3 % response rate) showed strong support for greater collaboration among all parties. Strategies to facilitate collaboration reflected a need to: (1) raise awareness of the shared and unique needs of GU cancer survivors and the expertise of cancer advocacy groups, (2) facilitate communication and collaborative opportunities among clinicians/researchers and cancer survivors/advocacy groups, (3) facilitate collaborative programming and fund-raising among GU advocacy groups, and (4) synthesize and facilitate access to GU cancer survivorship resources and services. CONCLUSIONS: There is strong support for formal collaboration to enhance survivorship care among a critical mass of GU cancer survivors, advocacy groups, clinicians, and researchers. Responsibility for collaboration lies with all stakeholder groups. Strategies to foster such partnerships should employ integrated knowledge translation approaches that actively engage all parties throughout the entire research to practice process. IMPLICATIONS FOR CANCER SURVIVORS: Successful partnerships between cancer survivors, advocacy groups, clinicians, and researchers require familiarity with each other's expertise, along with sufficient resources and organizational structures. GU survivorship advocacy groups need to work more closely together to ensure a strong, unified voice when interacting with clinicians and researchers.

A phase II study of the antisense oligonucleotide GTI-2040 plus docetaxel and prednisone as first-line treatment in castration-resistant prostate cancer.

PURPOSE: GTI-2040 is a novel antisense oligonucleotide to the R2 subunit of ribonucleotide reductase. This phase II trial was conducted to determine the efficacy and tolerability of GTI-2040 when combined with docetaxel and prednisone for the treatment of patients with castration-resistant prostate cancer (CRPC). METHODS: Chemo-naïve CRPC patients with adequate performance status and organ function were treated with docetaxel 75 mg/m(2) IV on day 1 plus GTI-2040 5 mg/kg/day by continuous intravenous infusion day 1-14 on a 21 day cycle, with prednisone 5 mg orally twice daily. The primary endpoint was PSA response rate. Pharmacokinetic studies of GTI-2040 and pharmacodynamic studies on peripheral blood mononuclear cells (PBMC) were also performed. RESULTS: Twenty-two patients in total (19 from this study and 3 from a prior phase I/II study at this institution) were treated at the recommended phase II dose. A confirmed PSA response was seen in 9/22 patients (41%). Of 16 patients with measurable disease, there was 1 partial response (PR) and 12 stable disease (SD) lasting 3.6 months (median), as best response. The most common toxicities were anemia, fatigue, lymphopenia, leucopenia and neutropenia. Grade 3+ toxicities included neutropenia, lymphopenia, leucopenia, fatigue, febrile neutropenia and hypophosphatemia. CONCLUSIONS: The PSA response rate of GTI-2040 in combination with docetaxel and prednisone just met the minimum phase II criteria for further enrollment. However, after evaluation of all the clinical data, further study of this dose and schedule of GTI-2040 in CRPC was not recommended.

Doctor's dilemma: incorporating tumor markers into clinical decision-making.

Physicians are often faced with the dilemma of how to incorporate tumor markers into routine clinical decision-making. Tumor markers may influence clinical decisions at various stages of cancer therapy: screening, diagnosis, prognosis, detection of early relapse, and monitoring of therapy. We use the examples of beta-human chorionic gonadotrophin (beta-HCG) and alpha-fetoprotein (AFP) as markers for germ cell tumors (GCT), and prostate-specific antigen (PSA) as a marker for prostate cancer, to illustrate their use and limitations for these purposes. We then focus on monitoring and choice of treatment by presenting three vignettes; these highlight the potential benefits and problems associated with the use of tumor markers for monitoring and detection of early relapse in asymptomatic patients.