In patients with glioblastoma, the addition of bevacizumab to radiotherapy and temozolomide induction therapy and the use of bevacizumab maintenance therapy did not influence overall survival. ...Freedom from progression was slightly increased but at the cost of increased toxic effects.
Tumor progression in glioblastoma, the most common primary brain cancer,
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After surgical resection, the standard of care for patients with newly diagnosed glioblastoma and a good Karnofsky performance score (≥70, on a scale of 0 to 100, with higher numbers indicating better functioning) is concurrent radiotherapy and temozolomide, followed by adjuvant temozolomide.
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The prognosis remains poor; no further improvements in outcomes have been documented since the introduction of radiotherapy–temozolomide therapy in 2005.
Glioblastomas are characterized by overexpression . . .
KEYNOTE-164 (NCT02460198) evaluated the antitumor activity of pembrolizumab in previously treated, metastatic, microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) colorectal cancer ...(CRC).
This phase II open-label study involved 128 centers worldwide. Eligible patients were age ≥ 18 years and had metastatic MSI-H/dMMR CRC treated with ≥ 2 prior lines of standard therapy, including fluoropyrimidine, oxaliplatin, and irinotecan with or without anti-vascular endothelial growth factor/epidermal growth factor receptor monoclonal antibody (cohort A) or ≥ 1 prior line of therapy (cohort B). MSI-H/dMMR status was assessed locally. Patients received pembrolizumab 200 mg every 3 weeks for up to 2 years until progression, unacceptable toxicity, or withdrawal. The primary end point was objective response rate by RECIST version 1.1 by independent central review. Secondary end points were duration of response, progression-free survival (PFS), overall survival, safety, and tolerability.
A total of 124 patients with MSI-H/dMMR CRC (61 in cohort A, 63 in cohort B) enrolled. At data cutoff, median follow-up was 31.3 months (range, 0.2-35.6 months) for cohort A and 24.2 months (range, 0.1-27.1 months) for cohort B. Objective response rate was 33% (95% CI, 21% to 46%) and 33% (95% CI, 22% to 46%), respectively, with median duration of response not reached in either cohort. Median PFS was 2.3 months (95% CI, 2.1 to 8.1 months) and 4.1 months (95% CI, 2.1 to 18.9 months). Median overall survival was 31.4 months (95% CI, 21.4 months to not reached) and not reached (95% CI, 19.2 months to not reached). Treatment-related grade 3-4 adverse events occurred in 10 patients (16%) in cohort A and 8 (13%) in cohort B, with the most common occurring in ≥ 2 patients being pancreatitis, fatigue, increased alanine aminotransferase, and increased lipase (2 patients each; 3%) in cohort A.
Pembrolizumab is effective with a manageable safety profile in patients with MSI-H/dMMR CRC.
Immunotherapy-based monotherapy treatment in metastatic pancreatic ductal adenocarcinoma (mPDAC) has shown limited benefit outside of the mismatch repair deficiency setting, while safety and efficacy ...of combining dual-checkpoint inhibitor immunotherapy with chemotherapy remains uncertain. Here, we present results from the CCTG PA.7 study (NCT02879318), a randomized phase II trial comparing gemcitabine and nab-paclitaxel with and without immune checkpoint inhibitors durvalumab and tremelimumab in 180 patients with mPDAC. The primary endpoint was overall survival. Secondary endpoints included progression-free survival and objective response rate. Results of the trial were negative as combination immunotherapy did not improve survival among the unselected patient population (p = 0.72) and toxicity was limited to elevation of lymphocytes in the combination immunotherapy group (p = 0.02). Exploratory baseline circulating tumor DNA (ctDNA) sequencing revealed increased survival for patients with KRAS wildtype tumors in both the combination immunotherapy (p = 0.001) and chemotherapy (p = 0.004) groups. These data support the utility of ctDNA analysis in PDAC and the prognostic value of ctDNA-based KRAS mutation status.
Ganitumab is a fully human monoclonal antibody against type-1 insulin-like growth factor receptor (IGF1R). An open-label phase II study was conducted to evaluate the efficacy and safety of ganitumab ...monotherapy in patients with metastatic Ewing family tumors (EFT) or desmoplastic small round cell tumors (DSRCT).
Patients ≥16 years of age with relapsed or refractory EFT or DSRCT received 12 mg/kg of ganitumab every 2 weeks. Objective response rate (ORR) was the primary end point. Secondary end points included clinical benefit rate (CBR = complete + partial responses + stable disease SD ≥ 24 weeks) and safety and pharmacokinetic profiles of ganitumab. The relationship between tumor response and EWS gene translocation status and IGF-1 levels was evaluated.
Thirty-eight patients (22 with EFT; 16 with DSRCT) received one or more doses of ganitumab. Twenty-four patients (63%) experienced ganitumab-related adverse events. Grade 3 related events included hyperglycemia (n = 2), thrombocytopenia (n = 5), neutropenia (n = 2), leukopenia (n = 1), and transient ischemic attack (n = 1). There were no grade 4 or 5 treatment-related events. Of 35 patients assessed for response, two had partial responses (ORR, 6%) and 17 (49%) had SD. Four patients had SD ≥ 24 weeks, contributing to a CBR of 17%. The pharmacokinetic profile of ganitumab was similar to that observed in the first-in-human trial. Elevation of IGF-1 levels was observed postdose. EWS-Fli1 translocations were analyzed by RNA sequencing and fluorescent in situ hybridization, and novel translocations were observed in EFT and DSCRT. No apparent relationship between tumor response and IGF-1 levels or EWS gene translocations was observed.
Ganitumab was well tolerated and demonstrated antitumor activity in patients with advanced recurrent EFT or DSRCT.
Biological and some clinical evidence suggest that high-dose intravenous vitamin C (IVC) could increase the effectiveness of cancer chemotherapy. IVC is widely used by integrative and complementary ...cancer therapists, but rigorous data are lacking as to its safety and which cancers and chemotherapy regimens would be the most promising to investigate in detail.
We carried out a phase I-II safety, tolerability, pharmacokinetic and efficacy trial of IVC combined with chemotherapy in patients whose treating oncologist judged that standard-of-care or off-label chemotherapy offered less than a 33% likelihood of a meaningful response. We documented adverse events and toxicity associated with IVC infusions, determined pre- and post-chemotherapy vitamin C and oxalic acid pharmacokinetic profiles, and monitored objective clinical responses, mood and quality of life. Fourteen patients were enrolled. IVC was safe and generally well tolerated, although some patients experienced transient adverse events during or after IVC infusions. The pre- and post-chemotherapy pharmacokinetic profiles suggested that tissue uptake of vitamin C increases after chemotherapy, with no increase in urinary oxalic acid excretion. Three patients with different types of cancer experienced unexpected transient stable disease, increased energy and functional improvement.
Despite IVC's biological and clinical plausibility, career cancer investigators currently ignore it while integrative cancer therapists use it widely but without reporting the kind of clinical data that is normally gathered in cancer drug development. The present study neither proves nor disproves IVC's value in cancer therapy, but it provides practical information, and indicates a feasible way to evaluate this plausible but unproven therapy in an academic environment that is currently uninterested in it. If carried out in sufficient numbers, simple studies like this one could identify specific clusters of cancer type, chemotherapy regimen and IVC in which exceptional responses occur frequently enough to justify appropriately focused clinical trials.
ClinicalTrials.gov NCT01050621.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PURPOSE Concomitant temozolomide (TMZ)/radiotherapy followed by adjuvant TMZ has increased survival in patients with glioblastoma multiforme (GBM). However, few options are effective for patients who ...experience treatment failure. We conducted a multicenter, phase II study to assess the efficacy and safety of continuous dose-intense TMZ for recurrent GBM. PATIENTS AND METHODS Patients with malignant glioma at progression after standard TMZ 150 to 200 mg/m(2) x 5 days in a 28-day cycle for three or more cycles were stratified by tumor type (anaplastic glioma group A, GBM, group B). Ninety-one patients with GBM were prospectively divided into three groups (early B1, extended B2, and rechallenge B3) according to the timing of progression during adjuvant therapy. All patients received continuous dose-intense TMZ 50 mg/m(2)/d for up to 1 year or until progression occurred. Response was assessed by using RECIST (Response Evaluation Criteria in Solid Tumors). Results A total of 116 of 120 patients were evaluable for efficacy. For patients with GBM, 6-month progression-free survival (PFS) was 23.9% (B1, 27.3%; B2, 7.4%; B3, 35.7%). One-year survival from time of study entry was 27.3%, 14.8%, and 28.6% for the B1, B2 and B3 groups, respectively. For patients with anaplastic glioma, 6-month PFS was 35.7%; 1-year survival was 60.7%. The most common grades 3 and 4 nonhematologic toxicities were nausea/vomiting (6.7%) and fatigue (5.8%). Grades 3 and 4 hematologic toxicities were uncommon. CONCLUSION Rechallenge with continuous dose-intense TMZ 50 mg/m(2)/d is a valuable therapeutic option for patients with recurrent GBM. Patients who experience progression during the first six cycles of conventional adjuvant TMZ therapy or after a treatment-free interval get the most benefit from therapy.
Patients with cancer-associated thrombosis (CAT) are at high risk of recurrent venous thromboembolism (VTE) and major bleeding complications. Risks vary significantly between individuals based on ...cancer status, treatment, and other characteristics. To facilitate the evidence-based management of anticoagulant therapy in this patient population, a committee of 11 Canadian clinical experts updated a consensus-based algorithm for the acute and extended treatment of symptomatic and incidental CAT that was developed in 2018. Following a systematic review of the literature, updates to the algorithm were discussed during an online teleconference, and the algorithm was subsequently refined based on feedback from committee members. Clinicians using this treatment algorithm should consider bleeding risk, type of cancer, and drug-drug interactions, as well as patient and clinician preferences, in tailoring anticoagulation for patients with CAT. Anticoagulant therapy should be adapted as the patient's cancer status and management change over time.
Single-agent regorafenib is approved in Canada for metastatic colorectal cancer (mCRC) patients who have failed previous lines of therapy. Identifying prognostic biomarkers is key to optimizing ...therapeutic strategies for these patients. In this clinical study (NCT01949194), we evaluated the safety and efficacy of single-agent regorafenib as a second-line therapy for mCRC patients who received it after failing first-line therapy with an oxaliplatin or irinotecan regimen with or without bevacizumab. Using various omics approaches, we also investigated putative biomarkers of response and resistance to regorafenib in metastatic lesions and blood samples in the same cohort. Overall, the safety profile of regorafenib seemed similar to the CORRECT trial, where regorafenib was administered as ≥ 2 lines of therapy. While the mutational landscape showed typical mutation rates for the top five driver genes (APC, KRAS, BRAF, PIK3CA, and TP53), KRAS mutations were enriched in intrinsically resistant lesions. Additional exploration of genomic-phenotype associations revealed several biomarker candidates linked to unfavorable prognoses in patients with mCRC using various approaches, including pathway analysis, cfDNA profiling, and copy number analysis. However, further research endeavors are necessary to validate the potential utility of these promising genes in understanding patients' responses to regorafenib treatment.
Lenvatinib is an oral multikinase inhibitor indicated for the first-line treatment of unresectable hepatocellular carcinoma (uHCC). In the Phase III REFLECT trial, lenvatinib was noninferior in the ...primary endpoint of overall survival versus sorafenib, the only systemic therapy funded in Canada prior to the introduction of lenvatinib. Lenvatinib also demonstrated statistically significant improvement compared to sorafenib in secondary endpoint progression-free survival, time to progression, and objective response rate. The aim of this analysis was to estimate the cost-effectiveness of lenvatinib versus sorafenib for the first-line treatment of patients with uHCC from a Canadian perspective. A cost-utility analysis was conducted using partitioned survival modelling, with health states representing progression-free disease, progressed disease, and death. Health effects were measured using quality-adjusted life years (QALYs), and costs were represented in Canadian dollars. Clinical inputs were derived from the REFLECT trial, with outcomes extrapolated using parametric survival models. EQ-5D data collected in REFLECT were used to determine health state utility values, and estimates of resource use came from a survey of clinicians. The model predicted incremental costs of-$5,021 and incremental QALYs of 0.17, making lenvatinib dominant over sorafenib. The model demonstrates lenvatinib to be a cost-effective use of resources versus sorafenib in Canada for the treatment of uHCC. Overall costs are lower compared with sorafenib, while health benefits are greater, with modelled progression-free and overall survival extended by 4.1 and 2.6 months in the lenvatinib arm, respectively.
Background: We explored image-guided adaptive endorectal brachytherapy patients electing non-operative management for rectal cancer. We present the first pre-planned interim analysis. Methods: In ...this open-label phase II–III randomized study, patients with operable cT2-3ab N0 M0 rectal cancer received 45 Gy in 25 fractions of pelvic external beam radiotherapy (EBRT) with 5-FU/Capecitabine. They were randomized 1:1 to receive either an EBRT boost of 9 Gy in 5 fractions (Arm A) or three weekly adaptive brachytherapy (IGAEBT) boosts totaling 30 Gy (Arm B). Patient characteristics and toxicity are presented using descriptive analyses; TME-free survival between arms with the intention to treat the population is explored using the Kaplan–Meier method. Results: A total of 40 patients were in this analysis. Baseline characteristics were balanced; acute toxicities were similar. Complete clinical response (cCR) was 50% (n = 10/20) in Arm A and 90% in Arm B (n = 18/20). Median follow-up was 1.3 years; 2-year TME-free survival was 38.6% (95% CI: 16.5–60.6%) in the EBRT arm and 76.6% (95% CI: 56.1–97.1%) in the IGAEBT arm. Conclusions: Radiation intensification with IGAEBT is feasible. This interim analysis suggests an improvement in TME-free survival when comparing IGAEBT with EBRT, pending confirmation upon completion of this trial.
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