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1.
Eur J Cancer ; 202: 114003, 2024 May.
Article in English | MEDLINE | ID: mdl-38479120

ABSTRACT

Developing new drugs or generating evidence for existing drugs in new indications for ultra-rare cancers is complex and carries a high-risk of failure. This gets even harder in ultra-rare tumours, which have an annual incidence of 1 per 1,000,000 population or less. Here, we illustrate the problem of adequate evidence generation in ultra-rare tumours, using Alveolar Soft-Part Sarcomas (ASPS) - an ultra-rare sarcoma newly diagnosed in approximately 60 persons a year in the European Union - as an exemplar case showing challenges in development despite being potentially relevant for classes of agents. We discuss some possible approaches for addressing such challenges, especially focussing on constructive collaboration between academic groups, patients and advocates, drug manufacturers, and regulators to optimise drug development in ultra-rare cancers. This article, written by various European stakeholders, proposes a way forward to ultimately get better options for patients with ultra-rare cancers.


Subject(s)
Sarcoma, Alveolar Soft Part , Soft Tissue Neoplasms , Humans , Sarcoma, Alveolar Soft Part/drug therapy , Sarcoma, Alveolar Soft Part/pathology , Soft Tissue Neoplasms/pathology , European Union , Incidence , Drug Development
2.
Gynecol Oncol ; 180: 70-78, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38086166

ABSTRACT

OBJECTIVES: To investigate the practice patterns and quality of care for uterine cancer on a national level in Belgium, including trends in practice over the period 2012-2016. METHODS: Quality indicators were measured using the EFFectiveness of Endometrial Cancer Treatment (EFFECT) database. Multivariable logistic mixed regression was used to test for associations between the quality indicators and year of diagnosis, adjusted for potential confounders and intra-cluster correlations. RESULTS: The EFFECT database includes 4178 patients diagnosed with uterine cancer in the period 2012-2016. Minimally invasive surgery (laparoscopic or robotic-assisted) was applied in 61.6% of patients who had surgery for clinical stage I endometrial carcinoma (EC), increasing from 52.9% in 2012 to 66.4% in 2016. At least pelvic lymph node staging was performed in 69.0% of patients with clinical stage I, high-grade EC; and in 63.9% of patients with clinical stage I-II serous carcinoma, clear cell carcinoma or carcinosarcoma. The latter increased from 48.8% in 2012 to 77.2% in 2016. Adjuvant radiotherapy (external beam and/or brachytherapy) was offered to 33.5% of patients who had surgery without lymph node staging for pathological stage I EC at high-intermediate or high risk of recurrence. Adjuvant chemotherapy was administered to 64.4% of patients with pathological stage III-IVA EC. CONCLUSIONS: Study results indicate an overall good quality of care for patients with uterine cancer in Belgium. Treatment areas with potential room for improvement include the use of minimally invasive surgery, comprehensive surgical staging and adjuvant therapy, which confirms the remaining controversies in uterine cancer treatment and the need for further research.


Subject(s)
Adenocarcinoma, Clear Cell , Brachytherapy , Endometrial Neoplasms , Uterine Neoplasms , Female , Humans , Belgium/epidemiology , Endometrial Neoplasms/surgery , Endometrial Neoplasms/drug therapy , Uterine Neoplasms/epidemiology , Uterine Neoplasms/surgery , Radiotherapy, Adjuvant/methods , Treatment Outcome , Adenocarcinoma, Clear Cell/pathology , Neoplasm Staging , Brachytherapy/methods , Retrospective Studies , Hysterectomy
3.
Cancers (Basel) ; 15(7)2023 Mar 28.
Article in English | MEDLINE | ID: mdl-37046681

ABSTRACT

Preclinical data support the activity of celecoxib and fluvastatin in high-grade (HGG) and low-grade gliomas (LGG). A phase I trial (NCT02115074) was designed to evaluate the safety of this combination in children with refractory/relapsed HGG and LGG using four dose levels of fluvastatin with a fixed daily dose of celecoxib. A Continual Reassessment Method was used for fluvastatin dose escalation. Dose-limiting toxicities (DLT) were determined on the first treatment cycle. Twenty patients were included. Ten LGG and ten HGG patients received a median of 3.5 treatment cycles. Two DLTs were reported: one grade 3 maculopapular rash (4 mg/kg dose level) and one grade 4 increase of Creatine Phospho-Kinase (6 mg/kg dose level). We identified the dose of 6 mg/kg/day as the recommended phase II dose (RP2D) of fluvastatin with celecoxib. Four patients with LGG continued treatment beyond 12 cycles because of stable disease, including one patient who received 23 treatment cycles. In children with refractory/relapsed glioma, the RP2D of fluvastatin with celecoxib is 6 mg/kg/day. The long-term stable diseases observed in LGG suggest a possible role of the combination in a maintenance setting, given its good tolerance and low cost for children living in low- and middle-income countries.

6.
PLoS One ; 17(9): e0274115, 2022.
Article in English | MEDLINE | ID: mdl-36094914

ABSTRACT

BACKGROUND: Once a drug gets FDA approved, researchers often attempt to discover new applications in different indications. The clinical impact of such post-approval activities is uncertain. We aimed to compare the clinical impact of research efforts started after approval with those started before for cancer drugs. METHODS: We used Drugs@FDA to perform a retrospective cohort study of secondary approvals for cancer drugs that were initially FDA approved between 2005 and 2017. Clinicaltrials.gov was used to identify the beginning of each research trajectory that resulted in a secondary FDA approval. Each trajectory was classified as pre- or post-approval depending on if it was initiated before or after initial drug licensure. Clinical impact was assessed by comparing secondary approvals and NCCN off-label recommendations deriving from pre- vs. post-approval trajectories, pooled effect sizes, incidence, and level of evidence. RESULTS: We identified 77 broad secondary approvals, 60 of which had at least 6 years follow-up. Of these, 9 (15%) resulted from post-approval trajectories, a proportion that is significantly lower than would be expected if the timing of research didn't impact approval (McNemar's test p = 0.001). Compared to pre-approval trajectories, approvals resulting from post-approval trajectories were for cancers with lower mean incidence (6.11 vs 14.83, p = 0.006) and were based on pivotal trials with smaller pooled effect sizes (0.69 vs 0.57, p = 0.02) that were less likely to be randomized (38.5% vs 64.1%, p = 0.145). We identified 69 NCCN off-label recommendations. The proportion stemming from post-approval trajectories was similar to that for pre-approval (56.5% vs. 43.5%). However, recommendations from post-approval trajectories were significantly more likely to involve rare diseases (76.7% vs 51.4%, p = 0.019) and nonsignificantly less likely to be based on level 1 evidence (11.6% vs 22.9%, p = 0.309). CONCLUSION: Secondary FDA approvals are less likely to result from post-approval trajectories and tend to be less impactful compared to approvals originating from research started before first FDA licensure. However, post-approval trajectories may be as likely to lead to NCCN recommendations for off-label use. Limitations of this work include our use of indirect measures of impact and limited follow-up time for trajectories. Our study protocol was pre-registered (https://osf.io/5g3jw/).


Subject(s)
Antineoplastic Agents , Neoplasms , Antineoplastic Agents/therapeutic use , Drug Approval , Humans , Neoplasms/drug therapy , Retrospective Studies , United States , United States Food and Drug Administration
7.
Int J Gynecol Cancer ; 2022 Sep 22.
Article in English | MEDLINE | ID: mdl-36137575

ABSTRACT

OBJECTIVE: Drug repurposing is an alternative development pathway that utilizes the properties of drugs approved for other diseases and builds on available safety and pharmacological data to develop the drug as a potential treatment for other diseases. A literature-based approach was performed to identify drug repurposing opportunities in cervical cancer to inform future research and trials. METHODS: We queried PubMed for each drug included in two databases (ReDO_DB and CDcervix_DB, which include 300+ non-cancer drugs and 200+ cancer drugs not used in cervical cancer, respectively) and manually assessed all abstracts for relevance and activity in cervix cancer, and type of evidence. Subsequently, we also performed a search of clinical trial databases where we generated a list of registered trials in cervical cancer with all drugs from our databases. RESULTS: Of the 534 drugs from both databases, 174 (33%) had at least one relevant abstract or registered trial in cervical cancer. 94 (18%) drugs had at least human data available, and 52 (10%) drugs were evaluated in registered trials. To prioritize drugs to consider for future trials, all 174 drugs were further assessed for strength of scientific rationale, feasibility for integration in cervical cancer standard of care, evidence of radiosensitization, and potential mechanism of action. Out of the 174 drugs, 38 (22%) potential drug candidates were selected. CONCLUSION: This study resulted in a list of candidate drugs for potential evaluation in cervical cancer. Many drugs might warrant additional (pre)clinical investigation, which could be done in a coordinated manner using platform trials.

8.
BMC Cancer ; 22(1): 600, 2022 Jun 01.
Article in English | MEDLINE | ID: mdl-35650593

ABSTRACT

BACKGROUND: With the aim of obtaining more uniformity and quality in the treatment of corpus uteri cancer in Belgium, the EFFECT project has prospectively collected detailed information on the real-world clinical care offered to 4063 Belgian women with primary corpus uteri cancer. However, as data was collected on a voluntary basis, data may be incomplete and biased. Therefore, this study aimed to assess the completeness and potential selection bias of the EFFECT database. METHODS: Five databases were deterministically coupled by use of the patient's national social security number. Participation bias was assessed by identifying characteristics associated with hospital participation in EFFECT, if any. Registration bias was assessed by identifying patient, tumor and treatment characteristics associated with patient registration by participating hospitals, if any. Uni- and multivariable logistic regression were applied. RESULTS: EFFECT covers 56% of all Belgian women diagnosed with primary corpus uteri cancer between 2012 and 2016. These women were registered by 54% of hospitals, which submitted a median of 86% of their patients. Participation of hospitals was found to be biased: low-volume and Walloon-region centers were less likely to participate. Registration of patients by participating hospitals was found to be biased: patients with a less favorable risk profile, with missing data for several clinical-pathological risk factors, that did not undergo curative surgery, and were not discussed in a multidisciplinary tumor board were less likely to be registered. CONCLUSIONS: Due to its voluntary nature, the EFFECT database suffers from a selection bias, both in terms of the hospitals choosing to participate and the patients being included by participating institutions. This study, therefore, highlights the importance of assessing the selection bias that may be present in any study that voluntarily collects clinical data not otherwise routinely collected. Nevertheless, the EFFECT database covers detailed information on the real-world clinical care offered to 56% of all Belgian women diagnosed with corpus uteri cancer between 2012 and 2016, and may therefore act as a powerful tool for measuring and improving the quality of corpus uteri cancer care in Belgium.


Subject(s)
Endometrial Neoplasms , Uterine Neoplasms , Belgium/epidemiology , Bias , Endometrial Neoplasms/epidemiology , Endometrial Neoplasms/therapy , Female , Humans , Selection Bias , Uterine Neoplasms/epidemiology , Uterine Neoplasms/therapy
11.
Ann Intensive Care ; 11(1): 139, 2021 Sep 22.
Article in English | MEDLINE | ID: mdl-34553274

ABSTRACT

BACKGROUND: The optimal mean arterial pressure (MAP) in cases of septic shock is still a matter of debate in patients with prior hypertension. An MAP between 75 and 85 mmHg can improve glomerular filtration rate (GFR) but its effect on tubular function is unknown. We assessed the effects of high MAP level on glomerular and tubular renal function in two intensive care units of a teaching hospital. Inclusion criteria were patients with a history of chronic hypertension and developing AKI in the first 24 h of septic shock. Data were collected during two 6 h periods of MAP regimen administered consecutively after haemodynamic stabilisation in an order depending on the patient's admission unit: a high-target period (80-85 mmHg) and a low-target period (65-70 mmHg). The primary endpoint was the creatinine clearance (CrCl) calculated from urine and serum samples at the end of each MAP period by the UV/P formula. RESULTS: 26 patients were included. Higher urine output (+0.2 (95%:0, 0.4) mL/kg/h; P = 0.04), urine sodium (+6 (95% CI 0.2, 13) mmol/L; P = 0.04) and lower serum creatinine (- 10 (95% CI - 17, - 3) µmol/L; P = 0.03) were observed during the high-MAP period as compared to the low-MAP period, resulting in a higher CrCl (+25 (95% CI 11, 39) mL/mn; P = 0.002). The urine creatinine, urine-plasma creatinine ratio, urine osmolality, fractional excretion of sodium and urea showed no significant variation. The KDIGO stage at inclusion only interacted with serum creatinine variation and low level of sodium excretion at inclusion did not interact with these results. CONCLUSIONS: In the early stage of sepsis-associated AKI, a high-MAP target in patients with a history of hypertension was associated with a higher CrCl, but did not affect the kidneys' ability to concentrate urine, which may reflect no effect on tubular function.

12.
Acta Oncol ; 60(9): 1146-1153, 2021 Sep.
Article in English | MEDLINE | ID: mdl-34338111

ABSTRACT

BACKGROUND: The prognosis of pancreatic cancer is poor and new treatment strategies are urgently needed. To identify non-cancer drugs that could be re-purposed for cancer, we investigated the association between the use of selected drugs and cancer-specific mortality in a nationwide cohort of pancreatic cancer patients. MATERIAL AND METHODS: The study is based on linkage between the Cancer Registry of Norway and the Norwegian Prescription Database, comprising 2614 pancreatic cancer patients diagnosed between 2007 and 2014. We evaluated the association between use at diagnosis of a pre-defined list of non-cancer drugs, including metformin, antihypertensives, and statins, and pancreatic cancer-specific mortality, using Cox regression. Patients were defined as users of a particular drug if it was prescribed before diagnosis, and the prescription covered the date of diagnosis. RESULTS: In total, 2096 (80.2%) patients died from pancreatic cancer; median survival was 6 months. Statin users (n = 621) had lower mortality (hazard ratio (HR): 0.86; 95% confidence interval (CI) 0.76-0.97) compared to non-users (n = 1993). This association was more pronounced (P-heterogeneity 0.062) in users of hydrophilic (n = 37, HR: 0.61; 95% CI 0.42-0.90) than lipophilic (n = 587, HR: 0.87; 95% CI 0.78-0.98) statins. An indication for lower mortality (HR: 0.85; 95% CI 0.69-1.05) was observed in users of non-selective beta-blockers (n = 113) compared to non-users (n = 2501). Notably, when compared to users of other antihypertensives (n = 643), users of non-selective beta-blockers (n = 40) had lower mortality (HR 0.67; 95% CI 0.47-0.96). The use of other drugs, including selective beta-blockers and metformin, was not associated with mortality. CONCLUSION: The findings suggest an association between the use of statins and non-selective beta-blockers and reduced pancreatic cancer mortality, and add to the literature supporting the design of randomised clinical trials to evaluate those drugs in the management of pancreatic cancer.


Subject(s)
Adenocarcinoma , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Metformin , Pancreatic Neoplasms , Adenocarcinoma/drug therapy , Cohort Studies , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Metformin/therapeutic use , Pancreatic Neoplasms/drug therapy , Registries
13.
Neurooncol Adv ; 3(1): vdab075, 2021.
Article in English | MEDLINE | ID: mdl-34377985

ABSTRACT

BACKGROUND: The dismal prognosis of glioblastoma (GBM) may be related to the ability of GBM cells to develop mechanisms of treatment resistance. We designed a protocol called Coordinated Undermining of Survival Paths combining 9 repurposed non-oncological drugs with metronomic temozolomide-version 3-(CUSP9v3) to address this issue. The aim of this phase Ib/IIa trial was to assess the safety of CUSP9v3. METHODS: Ten adults with histologically confirmed GBM and recurrent or progressive disease were included. Treatment consisted of aprepitant, auranofin, celecoxib, captopril, disulfiram, itraconazole, minocycline, ritonavir, and sertraline added to metronomic low-dose temozolomide. Treatment was continued until toxicity or progression. Primary endpoint was dose-limiting toxicity defined as either any unmanageable grade 3-4 toxicity or inability to receive at least 7 of the 10 drugs at ≥ 50% of the per-protocol doses at the end of the second treatment cycle. RESULTS: One patient was not evaluable for the primary endpoint (safety). All 9 evaluable patients met the primary endpoint. Ritonavir, temozolomide, captopril, and itraconazole were the drugs most frequently requiring dose modification or pausing. The most common adverse events were nausea, headache, fatigue, diarrhea, and ataxia. Progression-free survival at 12 months was 50%. CONCLUSIONS: CUSP9v3 can be safely administered in patients with recurrent GBM under careful monitoring. A randomized phase II trial is in preparation to assess the efficacy of the CUSP9v3 regimen in GBM.

14.
Front Oncol ; 11: 688755, 2021.
Article in English | MEDLINE | ID: mdl-34055652

ABSTRACT

Vaccines used to prevent infections have long been known to stimulate immune responses to cancer as illustrated by the approval of the Bacillus Calmette-Guérin (BCG) vaccine to treat bladder cancer since the 1970s. The recent approval of immunotherapies has rejuvenated this research area with reports of anti-tumor responses with existing infectious diseases vaccines used as such, either alone or in combination with immune checkpoint inhibitors. Here, we have reviewed and summarized research activities using approved vaccines to treat cancer. Data supporting a cancer therapeutic use was found for 16 vaccines. For 10 (BCG, diphtheria, tetanus, human papillomavirus, influenza, measles, pneumococcus, smallpox, typhoid and varicella-zoster), clinical trials have been conducted or are ongoing. Within the remaining 6, preclinical evidence supports further evaluation of the rotavirus, yellow fever and pertussis vaccine in carefully designed clinical trials. The mechanistic evidence for the cholera vaccine, combined with the observational data in colorectal cancer, is also supportive of clinical translation. There is limited data for the hepatitis B and mumps vaccine (without measles vaccine). Four findings are worth highlighting: the superiority of intravesical typhoid vaccine instillations over BCG in a preclinical bladder cancer model, which is now the subject of a phase I trial; the perioperative use of the influenza vaccine to limit and prevent the natural killer cell dysfunction induced by cancer surgery; objective responses following intratumoral injections of measles vaccine in cutaneous T-cell lymphoma; objective responses induced by human papillomavirus vaccine in cutaneous squamous cell carcinoma. All vaccines are intended to induce or improve an anti-tumor (immune) response. In addition to the biological and immunological mechanisms that vary between vaccines, the mode of administration and sequence with other (immuno-)therapies warrant more attention in future research.

16.
Front Pharmacol ; 12: 599598, 2021.
Article in English | MEDLINE | ID: mdl-33796020

ABSTRACT

Background: Most non-small cell lung cancers occur in elderly and frequently comorbid patients. Therefore, it is necessary to evaluate the efficacy of biomodulatory active therapy regimen, concertedly interfering with tumor-associated homeostatic pathways to achieve tumor control paralleled by modest toxicity profiles. Patients and Methods: The ModuLung trial is a national, multicentre, prospective, open-label, randomized phase II trial in patients with histologically confirmed stage IIIB/IV squamous (n = 11) and non-squamous non-small cell (n = 26) lung cancer who failed first-line platinum-based chemotherapy. Patients were randomly assigned on a 1:1 ratio to the biomodulatory or control group, treated with nivolumab. Patients randomized to the biomodulatory group received an all-oral therapy consisting of treosulfan 250 mg twice daily, pioglitazone 45 mg once daily, clarithromycin 250 mg twice daily, until disease progression or unacceptable toxicity. Results: The study had to be closed pre-maturely due to approval of immune checkpoint inhibitors (ICi) in first-line treatment. Thirty-seven patients, available for analysis, were treated in second to forth-line. Progression-free survival (PFS) was significantly inferior for biomodulation (N = 20) vs. nivolumab (N = 17) with a median PFS (95% confidence interval) of 1.4 (1.2-2.0) months vs. 1.6 (1.4-6.2), respectively; with a hazard ratio (95% confidence interval) of 1.908 [0.962; 3.788]; p = 0.0483. Objective response rate was 11.8% with nivolumab vs. 5% with biomodulation, median follow-up 8.25 months. The frequency of grade 3-5 treatment related adverse events was 29% with nivolumab and 10% with biomodulation. Overall survival (OS), the secondary endpoint, was comparable in both treatment arms; biomodulation with a median OS (95% confidence interval) of 9.4 (6.0-33.0) months vs. nivolumab 6.9 (4.6-24.0), respectively; hazard ratio (95% confidence interval) of 0.733 [0.334; 1.610]; p = 0.4368. Seventy-five percent of patients in the biomodulation arm received rescue therapy with checkpoint inhibitors. Conclusions: This trial shows that the biomodulatory therapy was inferior to nivolumab on PFS. However, the fact that OS was similar between groups gives rise to the hypothesis that the well-tolerable biomodulatory therapy may prime tumor tissues for efficacious checkpoint inhibitor therapy, even in very advanced treatment lines where poor response to ICi might be expected with increasing line of therapy.

17.
JCO Glob Oncol ; 7: 602-610, 2021 04.
Article in English | MEDLINE | ID: mdl-33909474

ABSTRACT

The International Cancer Research Partnership (ICRP) is an active network of cancer research funding organizations, sharing information about funded research projects in a common database. Data are publicly available to enable the cancer research community to find potential collaborators and avoid duplication. This study presents an aggregated analysis of projects funded by 120 partner organizations and institutes in 2006-2018, to highlight trends in cancer research funding. Overall, the partners' funding for cancer research increased from $5.562 billion (bn) US dollars (USD) in 2006 to $8.511bn USD in 2018, an above-inflation increase in funding. Analysis by the main research focus of projects using Common Scientific Outline categories showed that Treatment was the largest investment category in 2018, followed by Early Detection, Diagnosis, and Prognosis; Cancer Biology; Etiology; Control, Survivorship, and Outcomes; and Prevention. Over the 13 years covered by this analysis, research funding into Treatment and Early Detection, Diagnosis, and Prognosis had increased in terms of absolute investment and as a proportion of the portfolio. Research funding in Cancer Biology and Etiology declined as a percentage of the portfolio, and funding for Prevention and Control, Survivorship and Outcomes remained static. In terms of cancer site-specific research, funding for breast cancer and colorectal cancer had increased in absolute terms but declined as a percentage of the portfolio. By contrast, investment for brain cancer, lung cancer, leukemia, melanoma, and pancreatic cancer increased both in absolute terms and as a percentage of the portfolio.


Subject(s)
Biomedical Research , Pancreatic Neoplasms , Databases, Factual , Humans , Investments
18.
Front Pharmacol ; 12: 627574, 2021.
Article in English | MEDLINE | ID: mdl-33776770

ABSTRACT

A global, comprehensive and open access listing of approved anticancer drugs does not currently exist. Partial information is available from multiple sources, including regulatory authorities, national formularies and scientific agencies. Many such data sources include drugs used in oncology for supportive care, diagnostic or other non-antineoplastic uses. We describe a methodology to combine and cleanse relevant data from multiple sources to produce an open access database of drugs licensed specifically for therapeutic antineoplastic purposes. The resulting list is provided as an open access database, (http://www.redo-project.org/cancer-drugs-db/), so that it may be used by researchers as input for further research projects, for example literature-based text mining for drug repurposing.

19.
Semin Cancer Biol ; 68: 186-191, 2021 01.
Article in English | MEDLINE | ID: mdl-31982510

ABSTRACT

Drug repurposing is a strategy that aims to develop novel cancer treatments through the reuse of existing medicines developed in other disease areas. Such a strategy includes the identification of candidate drugs, clinical development, drug licensing, reimbursement and clinical implementation. This review outlines a literature-based approach to candidate selection with illustrative examples in osteosarcoma, pancreatic cancer and perioperative therapies. Key issues related to the development of clinical trials, drug licensing/approval and clinical adoption are explored to highlight some of the obstacles that must be overcome to successfully repurpose a drug as a new therapeutic option.


Subject(s)
Antineoplastic Agents/therapeutic use , Drug Discovery , Drug Repositioning/methods , Neoplasms/drug therapy , Pharmaceutical Preparations/administration & dosage , Animals , Antineoplastic Agents/isolation & purification , Humans , Pharmaceutical Preparations/isolation & purification
20.
Lancet Oncol ; 21(12): e542, 2020 12.
Article in English | MEDLINE | ID: mdl-33271099
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