Reliability and Efficiency of the CAPRI-3 Metastatic Prostate Cancer Registry Driven by Artificial Intelligence.

BACKGROUND: Manual data collection is still the gold standard for disease-specific patient registries. However, CAPRI-3 uses text mining (an artificial intelligence (AI) technology) for patient identification and data collection. The aim of this study is to demonstrate the reliability and efficiency of this AI-driven approach. METHODS: CAPRI-3 is an observational retrospective multicenter cohort registry on metastatic prostate cancer. We tested the patient-identification algorithm and automated data extraction through manual validation of the same patients in two pilots in 2019 and 2022. RESULTS: Pilot one identified 2030 patients and pilot two 9464 patients. The negative predictive value of the algorithm was maximized to prevent false exclusions and reached 94.8%. The completeness and accuracy of the automated data extraction were 92.3% or higher, except for date fields and inaccessible data (images/pdf) (10-88.9%). Additional manual quality control took over 3 h less time per patient than the original fully manual CAPRI registry (105 vs. 300 min). CONCLUSIONS: The CAPRI-3 patient-identification algorithm is a sound replacement for excluding ineligible candidates. The AI-driven data extraction is largely accurate and complete, but manual quality control is needed for less reliable and inaccessible data. Overall, the AI-driven approach of the CAPRI-3 registry is reliable and timesaving.

Chemoradiation for muscle-invasive bladder cancer using 5-fluorouracil versus capecitabine: A nationwide cohort study.

BACKGROUND AND PURPOSE: Oral capecitabine and intravenous 5-fluorouracil (5-FU) are both used as a radiosensitizer in chemoradiotherapy (CRT). A capecitabine-based regimen is more convenient for both patients and healthcare professionals. Since large comparative studies are lacking, we compared toxicity, overall survival (OS) and disease-free survival (DFS) between both CRT-regimens in patients with muscle-invasive bladder cancer (MIBC). MATERIALS AND METHODS: All patients diagnosed with non-metastatic MIBC between November 2017-November 2019 were consecutively included in the BlaZIB study. Data on patient, tumor, treatment characteristics and toxicity were prospectively collected from the medical files. From this cohort, all patients with cT2-4aN0-2/xM0/x, treated with capecitabine or 5-FU-based CRT were included in the current study. Toxicity in both groups was compared using Fisher-exact tests. Propensity score-based inverse probability treatment weighting (IPTW) was applied to correct for baseline differences between groups. IPTW-adjusted Kaplan-Meier OS and DFS curves were compared using log-rank tests. RESULTS: Of the 222 included patients, 111 (50%) were treated with 5-FU and 111 (50%) with capecitabine. Curative CRT was completed according to treatment plan in 77% of patients in the capecitabine-based group and 62% of the 5-FU group (p = 0.06). Adverse events (14 vs 21%, p = 0.29), 2-year OS (73% vs 61%, p = 0.07) and 2-year DFS (56% vs 50%, p = 0.50) did not differ significantly between groups. CONCLUSIONS: Chemoradiotherapy with capecitabine and MMC is associated with a similar toxicity profile compared to 5-FU plus MMC and no difference in survival was found. Capecitabine-based CRT, as a more patient-friendly schedule, may be considered as an alternative to a 5-FU-based regimen.

Symptomatic Skeletal Events and the Use of Bone Health Agents in a Real-World Treated Metastatic Castration Resistant Prostate Cancer Population: Results From the CAPRI-Study in the Netherlands.

BACKGROUND: Patients with metastatic castration resistant prostate cancer (mCRPC) are at risk of symptomatic skeletal events (SSE). Bone health agents (BHA, ie bisphosphonates and denosumab) and new life-prolonging drugs (LPDs) can delay SSEs. The aim of this study is to investigate the use of BHAs in relation to SSEs in treated real-world mCRPC population. PATIENTS AND METHODS: We included patients from the CAPRI registry who were treated with at least one LPD and diagnosed with bone metastases prior to the start of first LPD (LPD1). Outcomes were SSEs (external beam radiation therapy (EBRT) to the bone, orthopedic surgery, pathologic fracture or spinal cord compression) and SSE-free survival (SSE-FS) since LPD1. RESULTS: One-thousand nine hundred and twenty-three patients were included with a median follow-up from LPD1 of 16.7 months. Fifty-two percent (n = 996) started BHA prior or within 4 weeks after the start of LPD1 (early BHA). In total, 41% experienced at least one SSE. SSE incidence rate was 0.29 per patient year for patients without BHA and 0.27 for patients with early BHA. Median SSE-FS from LPD1 was 12.9 months. SSE-FS was longer in patients who started BHA early versus patients without BHA (13.2 vs. 11.0 months, P = .001). CONCLUSION: In a real-world population we observed an undertreatment with BHAs, although patients with early BHA use had lower incidence rates of SSEs and longer SSE-FS. This finding was irrespective of type of SSE and presence of risk factors. In addition to LPD treatment, timely initiation of BHAs is recommended in bone metastatic CRPC-patients with both pain and/or opioid use and prior SSE.

Real-world Data of Nivolumab for Patients With Advanced Renal Cell Carcinoma in the Netherlands: An Analysis of Toxicity, Efficacy, and Predictive Markers.

BACKGROUND: Nivolumab, a programmed death 1 inhibitor, has been approved as second-line treatment for advanced renal cell carcinoma (RCC) in Europe since 2016. We investigated the toxicity and efficacy of nivolumab as well as potential predictive biomarkers in the Dutch population. PATIENTS AND METHODS: This was a retrospective, multicenter study of the Dutch national registry of nivolumab for the treatment of advanced RCC. The main outcome parameters included toxicity, objective response rate (ORR), overall survival (OS), progression-free survival (PFS), time to progression (TTP), and time to treatment failure (TTF). In addition, potential predictive and prognostic biomarkers for outcomes were evaluated. RESULTS: Data on 264 patients were available, of whom 42% were International Metastatic RCC Database Consortium (IMDC) poor risk at start of nivolumab, 16% had ≥ 3 lines of previous therapy, 7% had non-clear-cell RCC, 11% had brain metastases, and 20% were previously treated with everolimus. Grade 3/4 immune-related adverse events occurred in 15% of patients. The median OS was 18.7 months (95% confidence interval, 13.7-23.7 months). Progression occurred in 170 (64.4%) of 264 patients, with a 6-and 12-months TTP of 49.8% and 31.1%, respectively. The ORR was 18.6% (49 of 264; 95% confidence interval, 14%-23%). Elevated baseline lymphocytes were associated with improved PFS (P = .038) and elevated baseline lactate dehydrogenase with poor OS, PFS, and TTF (P = .000). On-treatment increase in eosinophils by week 8 predicted improved OS (P = .003), PFS (P = .000), and TTF (P = .014), whereas a decrease of neutrophils was associated with significantly better TTF (P = .023). CONCLUSIONS: The toxicity and efficacy of nivolumab for metastatic RCC after previous lines of therapy are comparable with the results in the pivotal phase III trial and other real-world data. On-treatment increase in eosinophil count is a potential biomarker for efficacy and warrants further investigation.

Metronomic cyclophosphamide attenuates mTOR-mediated expansion of regulatory T cells, but does not impact clinical outcome in patients with metastatic renal cell cancer treated with everolimus.

INTRODUCTION: Metastatic renal cell cancer (mRCC) patients have a median overall survival (mOS) of approximately 28 months. Until recently, mammalian target of rapamycin (mTOR) inhibition with everolimus was the standard second-line treatment regimen for mRCC patients, improving median progression-free survival (mPFS). Treatment with everolimus supports the expansion of immunosuppressive regulatory T cells (Tregs), which exert a negative effect on antitumor immune responses. In a phase 1 dose-escalation study, we have recently demonstrated that a low dose of 50 mg oral cyclophosphamide once daily can be safely combined with everolimus in mRCC patients and prevents the everolimus-induced increase in Tregs. MATERIALS AND METHODS: In a multicenter phase 2 study, performed in patients with mRCC not amenable to or progressive on a vascular endothelial growth factor (VEGF)-receptor tyrosine kinase inhibitor (TKI) containing treatment regimen, we assessed whether the addition of this metronomic dosing schedule of cyclophosphamide to therapy with everolimus could result in an improvement of progression-free survival (PFS) after 4 months of treatment. RESULTS: Though results from this study confirmed that combination treatment effectively lowered circulating levels of Tregs, addition of cyclophosphamide did not improve the PFS rate at 4 months. For this reason, the study was abrogated at the predefined interim analysis. CONCLUSION: Although the comprehensive immunomonitoring analysis performed in this study provides relevant information for the design of future immunotherapeutic approaches, the addition of metronomic cyclophosphamide to mRCC patients receiving everolimus cannot be recommended.

The effect of everolimus and low-dose cyclophosphamide on immune cell subsets in patients with metastatic renal cell carcinoma: results from a phase I clinical trial.

For the treatment of metastatic renal cell cancer several strategies are used among which the mTOR inhibitor everolimus. As mTOR plays an important role in the immune system, e.g., by controlling the expression of the transcription factor FoxP3 thereby regulating regulatory T cells (Tregs), it plays a key role in the balance between tolerance and inflammation. Previous reports showed stimulatory effects of mTOR inhibition on the expansion of Tregs, an effect that can be considered detrimental in terms of cancer control. Since metronomic cyclophosphamide (CTX) was shown to selectively deplete Tregs, a phase 1 clinical trial was conducted to comprehensively investigate the immune-modulating effects of several dosages and schedules of CTX in combination with the standard dose of everolimus, with the explicit aim to achieve selective Treg depletion. Our data show that 50 mg of CTX once daily and continuously administered, in combination with the standard dose of 10 mg everolimus once daily, not only results in depletion of Tregs, but also leads to a reduction in MDSC, a sustained level of the CD8+ T-cell population accompanied by an increased effector to suppressor ratio, and reversal of negative effects on three peripheral blood DC subsets. These positive effects on the immune response may contribute to improved survival, and therefore this combination therapy is further evaluated in a phase II clinical trial.

Phase 1 study of everolimus and low-dose oral cyclophosphamide in patients with metastatic renal cell carcinoma.

mTOR inhibitors are frequently used in the treatment of metastatic renal cell cancer (mRCC). mTOR regulates cell growth, proliferation, angiogenesis, and survival, and additionally plays an important role in immune regulation. Since mTOR inhibitors were shown to benefit immunosuppressive regulatory T-cell (Treg) expansion, this might suppress antitumor immune responses. Metronomic cyclophosphamide (CTX) was shown to selectively deplete Tregs. This study was, therefore, designed to determine the optimal dosage and schedule of CTX when combined with everolimus to prevent this potentially detrimental Treg expansion. In this national multi-center phase I study, patients with mRCC progressive on first line anti-angiogenic therapy received 10 mg everolimus once daily and were enrolled into cohorts with different CTX dosages and schedules. Besides immune monitoring, adverse events and survival data were monitored. 40 patients, 39 evaluable, were treated with different doses and schedules of CTX. Combined with 10 mg everolimus once daily, the optimal Treg depleting dose and schedule of CTX was 50 mg CTX once daily. 23 (59%) patients experienced one or more treatment-related ≥ grade 3 toxicity, mostly fatigue, laboratory abnormalities and pneumonitis. The majority of the patients achieved stable disease, two patients a partial response. Median PFS of all cohorts was 3.5 months. In conclusion, the optimal Treg depleting dose and schedule of CTX, when combined with everolimus, is 50 mg once daily. This combination leads to acceptable adverse events in comparison with everolimus alone. Currently, the here selected combination is being evaluated in a phase II clinical trial. TRIAL REGISTRATION: NCT01462214.

An In-Depth Evaluation of the Validity and Logistics Surrounding the Testing of AR-V7 mRNA Expression in Circulating Tumor Cells.

Recent reports have emphasized the clinical relevance of detecting AR-V7 in circulating tumor cells (CTCs). Our aim was to set up a validated multicenter pipeline to measure AR-V7 by quantitative RT-PCR (RT-qPCR) in RNA isolated from CellSearch-enriched CTCs to provide an AR-V7-positive or AR-V7-negative score in a clinically acceptable time range. CellSearch-enirched CTCs from patients with metastatic castration-resistant prostate cancer were characterized by RT-qPCR. After optimization, it was prospectively tested whether it was possible to report the AR-V7 status within 11 days (PRELUDE study). In the range of the RNA equivalent of 0.2 to 12 VCaP cells, the CV for AR-V7 was 9% (n = 37). The limit of detection was 0.3, and the limit of quantitation was 3 cells in the final RT-qPCR. No differences were observed between AR-V7 data generated by five technicians or in two different laboratories. For the 45 patients in PRELUDE, 13 patients were ineligible, 22 patients were AR-V7 negative, and 10 were AR-V7 positive. The median time to inform the physician of the test result was 7 days (range, 2 to 11 days). This assay can establish the AR-V7 status in CTCs from patients with metastatic castration-resistant prostate cancer. Furthermore, it was possible to provide an AR-V7 outcome within 11 days, indicating that it may be used to choose between an anti-androgen receptor or taxane-based cabazitaxel treatment.

Alternating Treatment With Pazopanib and Everolimus vs Continuous Pazopanib to Delay Disease Progression in Patients With Metastatic Clear Cell Renal Cell Cancer: The ROPETAR Randomized Clinical Trial.

IMPORTANCE: To our knowledge, this is the first randomized clinical trial evaluating an alternating treatment regimen in an attempt to delay disease progression in clear cell renal cell carcinoma. OBJECTIVE: To test our hypothesis that an 8-week rotating treatment schedule with pazopanib and everolimus delays disease progression, exhibits more favorable toxic effects, and improves quality of life when compared with continuous treatment with pazopanib. DESIGN, SETTING, AND PARTICIPANTS: This was an open-label, randomized (1:1) study (ROPETAR trial). In total, 101 patients with treatment-naive progressive metastatic clear cell renal cell carcinoma were enrolled between September 2012 and April 2014 from 17 large peripheral or academic hospitals in The Netherlands and followed for at least one year. INTERVENTIONS: First-line treatment consisted of either an 8-week alternating treatment schedule of pazopanib 800 mg/d and everolimus 10 mg/d (rotating arm) or continuous pazopanib 800 mg/d (control arm) until progression. After progression, patients made a final rotation to either pazopanib or everolimus monotherapy (rotating arm) or initiated everolimus (control arm). MAIN OUTCOME AND MEASURES: The primary end point was survival until first progression or death. Secondary end points included time to second progression or death, toxic effects, and quality of life. RESULTS: A total of 52 patients were randomized to the rotating arm (median [range] age, 65 [44-87] years) and 49 patients to the control arm (median [range] age, 67 [38-82] years). Memorial Sloan Kettering Cancer Center risk category was favorable in 26% of patients, intermediate in 58%, and poor in 15%. Baseline characteristics and risk categories were well balanced between arms. One-year PFS1 for rotating treatment was 45% (95% CI, 33-60) and 32% (95% CI, 21-49) for pazopanib (control). Median time until first progression or death for rotating treatment was 7.4 months (95% CI, 5.6-18.4) and 9.4 months (95% CI, 6.6-11.9) for pazopanib (control) (P = .37). Mucositis, anorexia, and dizziness were more prevalent in the rotating arm during first-line treatment. No difference in quality of life was observed. CONCLUSIONS AND RELEVANCE: Rotating treatment did not result in prolonged progression-free-survival, fewer toxic effects, or improved quality of life. First-line treatment with a vascular endothelial growth factor inhibitor remains the optimal approach in metastatic clear cell renal cell carcinoma. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01408004.

Tolerability of Capecitabine Monotherapy in Metastatic Colorectal Cancer: A Real-World Study.

BACKGROUND: Capecitabine monotherapy is a treatment option for selected patients with metastatic colorectal cancer (mCRC) and is administered to up to 17% of patients. Data are limited with regard to adverse events and dosing practices associated with capecitabine monotherapy in real-world situations. OBJECTIVES: The aim of this study was to provide real-world data on adverse event rates and dose adjustments/discontinuations associated with capecitabine monotherapy in patients with mCRC. METHODS: This retrospective study analyzed data from CRC patients scheduled to receive up to eight planned cycles of capecitabine monotherapy between 2009 and 2013 at a single large community hospital in The Netherlands. Data on adverse events (hand-foot syndrome [HFS], gastrointestinal (GI) events, hematological adverse events, and cardiotoxicity), as well as relative dose intensities (RDIs), dose reductions, and discontinuations, were evaluated. RESULTS: Data from 86 patients (45 females; mean age at the start of treatment, 69 years) were included. A total of 46.5% of patients experienced HFS and 44.2% experienced a GI event at some time during treatment. Hematological events and cardiotoxicity were rare. Most patients (77%) started at below the recommended dose, and patients at the lowest dose also had the lowest median RDIs. Dose reductions and discontinuations occurred in 15-25% of patients who experienced HFS or GI event over the course of eight cycles. CONCLUSIONS: HFS and GI events were very common in patients treated with capecitabine monotherapy in a real-world clinical setting. Most patients started treatment at below the recommended dose, and 15-25% of patients who had HFS or a GI event had a dose reduction or discontinuation.

[Gastrointestinal amyloidosis in a patient with multiple myeloma]. / Gastro-intestinale amyloïdose bij multipel myeloom.

BACKGROUND: Gastrointestinal amyloidosis is characterized by deposition of amyloid in the gastrointestinal mucosa. This can cause an increased risk of malabsorption, obstruction, gastrointestinal bleeding and perforations. CASE DESCRIPTION: A 52-year-old male presented with rectal bleeding. Endoscopic evaluation revealed non-specific red and purple lesions in the sigmoid colon. Histological results were inconclusive. Six weeks later this patient presented at the emergency room with an intestinal perforation. He also had newly developed renal insufficiency. Further analysis led to the diagnosis of multiple myeloma. After 3 doses of bortezomib and dexamethasone the patient was admitted with abdominal pain and rectal bleeding. Revision of our earlier sigmoid biopsies revealed gastrointestinal amyloidosis. The patient died 4 months after initial presentation. CONCLUSION: Gastrointestinal amyloidosis is a rare disease. Due to non-specific symptoms, diagnosis can easily be missed in patients who have not been diagnosed previously with amyloidosis or a related disease.

The pharmacologic basis of ifosfamide use in adult patients with advanced soft tissue sarcomas.

The treatment outcome of patients with locally advanced and metastatic soft tissue sarcomas is poor. Doxorubicin is regarded as standard treatment, but its use is featured by the occurrence of cardiotoxicity. This hinders the administration of this drug at high doses or in combination with, in theory, attractive newly developed targeted drugs, such as vascular endothelial growth factor (VEGF) pathway inhibitors. The combination of doxorubicin and VEGF pathway inhibitors has been shown to yield an unacceptable high rate of cardiomyopathy. Ifosfamide is the only drug that consistently shows response rates comparable to those of doxorubicin. The lack of cardiotoxicity renders this drug a much more attractive alternative than doxorubicin to be explored at high doses or as part of new drug combinations. This review addresses the clinical pharmacology, metabolism, and present role of ifosfamide in the treatment of locally advanced and/or metastatic soft tissue sarcomas, excluding gastrointestinal stromal tumors, the Ewing-like sarcomas, and other small blue round cell tumors. Furthermore, this review focuses on the anticipated growing role of ifosfamide in the development of new treatment strategies.

Complementary and alternative medicine during cancer treatment: beyond innocence.

Nowadays, complementary and alternative medicine (CAM) is popular all over the world. Billions of dollars are spent in this booming business. For several reasons, young, female, educated, and higher socioeconomic class cancer patients, in particular, have shown interest in these agents. Unfortunately, besides direct (and sometimes serious) side effects, several CAM ingredients are capable of interfering with the metabolism of concurrently used drugs, which may render the therapeutic outcome of the subscribed drug unpredictable. In the case of anticancer drugs, with their usually narrow therapeutic window, this may have dramatic consequences and can lead to unacceptable toxicities in some cases or decreased therapeutic activity in others. Therefore, cancer patients should be warned for these possible interactions and be advised to discuss CAM use openly with their treating physician. The general concept that natural products are harmless should thus be changed into a more realistic and responsible attitude. A tightened legislation and regulation (including Internet advertising and sales) could play a crucial role in this awareness process. This should finally enable safe exploration of the potential advantageous aspects of CAM, while living with cancer.