Metformin: Taking away the candy for cancer? Jalving, Mathilde; Gietema, Jourik A; Lefrandt, Joop D ...
European journal of cancer (1990),
09/2010, Volume:
46, Issue:
13
Journal Article
Peer reviewed
Abstract Metformin is widely used in the treatment of diabetes mellitus type 2 where it reduces insulin resistance and diabetes-related morbidity and mortality. Population-based studies show that ...metformin treatment is associated with a dose-dependent reduction in cancer risk. The metformin treatment also increases complete pathological tumour response rates following neoadjuvant chemotherapy for breast cancer, suggesting a potential role as an anti-cancer drug. Diabetes mellitus type 2 is associated with insulin resistance, elevated insulin levels and an increased risk of cancer and cancer-related mortality. This increased risk may be explained by activation of the insulin- and insulin-like growth factor (IGF) signalling pathways and increased signalling through the oestrogen receptor. Reversal of these processes through reduction of insulin resistance by the oral anti-diabetic drug metformin is an attractive anti-cancer strategy. Metformin is an activator of AMP-activated protein kinase (AMPK) which inhibits protein synthesis and gluconeogenesis during cellular stress. The main downstream effect of AMPK activation is the inhibition of mammalian target of rapamycin (mTOR), a downstream effector of growth factor signalling. mTOR is frequently activated in malignant cells and is associated with resistance to anticancer drugs. Furthermore, metformin can induce cell cycle arrest and apoptosis and can reduce growth factor signalling. This review discusses the role of diabetes mellitus type 2 and insulin resistance in carcinogenesis, the preclinical rationale and potential mechanisms of metformin’s anti-cancer effect and the current and future clinical developments of metformin as a novel anti-cancer drug.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Although patients with advanced cancer often experience multiple symptoms simultaneously, clinicians usually focus on symptoms that are volunteered by patients during regular history-taking. We aimed ...to evaluate the feasibility of a Bayesian network (BN) model to predict the presence of simultaneous symptoms, based on the presence of other symptoms. Our goal is to help clinicians prioritize which symptoms to assess. Patient-reported severity of 11 symptoms (scale 0-10) was measured using an adapted Edmonton Symptom Assessment Scale (ESAS) in a national cross-sectional survey among advanced cancer patients. Scores were dichotomized (< 4 and ≥ 4). Using fourfold cross validation, the prediction error of 9 BN algorithms was estimated (Akaike information criterion (AIC). The model with the highest AIC was evaluated. Model predictive performance was assessed per symptom; an area under curve (AUC) of ≥ 0.65 was considered satisfactory. Model calibration compared predicted and observed probabilities; > 10% difference was considered inaccurate. Symptom scores of 532 patients were collected. A symptom score ≥ 4 was most prevalent for fatigue (64.7%). AUCs varied between 0.60 and 0.78, with satisfactory AUCs for 8/11 symptoms. Calibration was accurate for 101/110 predicted conditional probabilities. Whether a patient experienced fatigue was directly associated with experiencing 7 other symptoms. For example, in the absence or presence of fatigue, the model predicted a 8.6% and 33.1% probability of experiencing anxiety, respectively. It is feasible to use BN development for prioritizing symptom assessment. Fatigue seems most eligble to serve as a starting symptom for predicting the probability of experiencing simultaneous symptoms.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Acquired resistance to approved tyrosine kinase inhibitors limits their clinical use in patients with gastrointestinal stromal tumor (GIST). This study investigated the safety, tolerability and ...efficacy of alpelisib, a phosphatidylinositol 3-kinase inhibitor, used in combination with imatinib in patients with advanced GIST who had failed prior therapy with both imatinib and sunitinib.
This phase 1b, multicenter, open-label study consisted of 2 phases: dose escalation and dose expansion. Dose escalation involved 200 mg once daily (QD) alpelisib, initially, followed by 250 and 350 mg. These were combined with 400 mg QD imatinib until maximum tolerated dose (MTD) and/or a recommended phase 2 dose (RP2D) of alpelisib in combination with imatinib was determined. This MTD/RP2D dose was tested to evaluate the clinical activity of this combination in dose expansion.
Fifty-six patients were enrolled, 21 and 35 in the dose escalation and expansion phases, respectively. The MTD of alpelisib given with imatinib was determined as 350 mg QD. Combination treatment showed partial response in 1 (2.9%) and stable disease in 15 (42.9%) patients. Median progression-free survival was 2 months (95% CI 1.8-4.6). Overall, 92.9% patients had adverse events (AEs) while 46.4% had grade 3/4 AEs, hyperglycemia being the most common (23.2%).
The MTD of alpelisib was estimated as 350 mg QD when used in combination with imatinib 400 mg QD after oral administration in patients with advanced GIST. The safety and tolerability profile of this combination was acceptable; however, the combination did not demonstrate sufficient clinical activity to justify additional clinical testing.
ClinicalTrials.gov NCT01735968 (date of initial registration 28/11/2012).
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Copper metabolism MURR1 domain 1 (COMMD1) protein is a multifunctional protein, and its expression has been correlated with patients' survival in different types of cancer. In vitro studies revealed ...that COMMD1 plays a role in sensitizing cancer cell lines to cisplatin, however, the mechanism and its role in platinum sensitivity in cancer has yet to be established. We evaluated the role of COMMD1 in cisplatin sensitivity in A2780 ovarian cancer cells and the relation between COMMD1 expression and response to platinum-based therapy in advanced stage high-grade serous ovarian cancer (HGSOC) patients. We found that elevation of nuclear COMMD1 expression sensitized A2780 ovarian cancer cells to cisplatin-mediated cytotoxicity. This was accompanied by a more effective G2/M checkpoint, and decreased protein expression of the DNA repair gene BRCA1, and the apoptosis inhibitor BCL2. Furthermore, COMMD1 expression was immunohistochemically analyzed in two tissue micro-arrays (TMAs), representing a historical cohort and a randomized clinical trial-based cohort of advanced stage HGSOC tumor specimens. Expression of COMMD1 was observed in all ovarian cancer samples, however, specifically nuclear expression of COMMD1 was only observed in a subset of ovarian cancers. In our historical cohort, nuclear COMMD1 expression was associated with an improved response to chemotherapy (OR = 0.167; P = 0.038), although this association could not be confirmed in the second cohort, likely due to sample size. Taken together, these results suggest that nuclear expression of COMMD1 sensitize ovarian cancer to cisplatin, possibly by modulating the G2/M checkpoint and through controlling expression of genes involved in DNA repair and apoptosis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Context
Taste, smell, and mouthfeel disturbances are underrated and underreported, but important side effects of anti-cancer medication. These symptoms are associated with a lower quality of life ...(QoL). The prevalence and the impact of taste, smell, and mouthfeel disturbances on daily life in patients with a gastrointestinal stromal tumor (GIST) are largely unknown.
Objectives
This exploratory study assessed the prevalence and type of taste, smell, and mouthfeel disturbances and their impact on daily life and QoL in patients with a GIST treated with a tyrosine-kinase inhibitor (TKI).
Methods
Patients currently treated with TKIs for GIST completed a standardized questionnaire. The questionnaire addressed changes in taste, smell, and mouthfeel and, if changes occurred, impact on daily life and QoL. Statistics are descriptive.
Results
A total of 65 GIST patients on TKI treatment completed the questionnaire. Of these patients, 79%, 12%, and 9% currently used imatinib, sunitinib, and regorafenib respectively. Taste, smell, and mouthfeel disturbances were reported by 25 (38%), 15 (23%), and 36 (55%) patients respectively. Salty and sweet tastes were mostly affected, respectively in 14 and 13 patients. A dry mouth was experienced by 29 (45%) patients. Taste disturbances were more often reported to have impact on daily life and QoL (80% and 60%) than smell (47% and 31%) and mouthfeel disturbances (47% and 30%).
Conclusion
Taste, smell, and mouthfeel disturbances are frequent side effects of TKIs in GIST patients. Daily life and QoL are affected in a considerable number of those patients.
Trial registration
ClinicalTrials.gov Identifier: NL7827 (2019–06-25).
Purpose
Oral nutritional supplements (ONS) are commonly prescribed to malnourished patients to improve their nutritional status. Taste and smell changes in patients with cancer can affect the ...palatability of ONS. The present study investigated: (1) the palatability of six ONS in testicular cancer patients before, during the first two cycles, and after chemotherapy; (2) the relation between the palatability and taste and smell function; (3) the metallic taste of these ONS.
Methods
Twenty-one testicular cancer patients undergoing first-line cisplatin-based chemotherapy participated. Two milk-based (vanilla; strawberry), two juice-based (apple; orange), and two yoghurt-based (vanilla-lemon; peach-orange) ONS were tested. A questionnaire was used to assess the palatability of ONS and to which extent the attribute ‘metallic’ was applicable. Taste and smell function were measured using taste strips and ‘Sniffin’ Sticks’, respectively.
Results
The palatability of ONS was highly variable among patients. The milk-based strawberry ONS was preferred most before, during, and after chemotherapy. The liking of the milk-based vanilla ONS tended to decrease over time (
p
= 0.053), whereas the liking of the other ONS remained stable. A higher smell threshold and a lower sour taste threshold were correlated to a decreased liking of the milk-based vanilla ONS. The two juice-based ONS tended to taste more metallic during than before chemotherapy.
Conclusion
Health care professionals and patients should be aware that the palatability of ONS can change over time. Regular structured contact between health care professionals and patients regarding the choice of ONS seems warranted.
Abstract Purpose Patients, platelet-derived growth factor receptor alpha ( PDGFRA ) D842V-mutated gastrointestinal stromal tumours (GISTs) are known for their insensitivity to imatinib. However, in ...clinical practice responses have been observed in some patients. We describe the natural history and treatment outcomes in a cohort of PDGFRA exon 18 mutated GIST patients. Patients and methods A retrospective cohort study was conducted in PDGFRA exon 18 mutation GIST patients treated in six expert centres in the Netherlands and the United States. Two independent radiologists assessed radiological response to imatinib according to Choi's criteria in all patients with measurable disease treated with imatinib in neo-adjuvant or palliative intent. Results Seventy-one patients with PDGFRA exon 18 mutation were identified of whom 48 patients (69%) had a D842V mutation. Twenty-two (45.8%) D842V-mutated GIST patients received imatinib treatment, 16 had measurable disease. Fourteen out of the 23 (60.9%) patients with non-D842V mutations received imatinib treatment, eight had measurable disease. Two out of 16 (12.5%) D842V-mutated GIST patients had partial response, 3 patients (18.8%) had stable disease and 9 patients (56.3%) had progressive disease as best response. Two patients did not have follow-up computed tomography scans to assess response. Six out of 8 (75%) patients with non-D842V exon 18 mutations had partial response and two (25%) had stable disease as best response. Conclusion Patients with D842V-mutated GISTs can occasionally respond to imatinib. In the absence of better therapeutic options, imatinib should therefore not be universally withheld in patients with this mutation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Response evaluation for cancer treatment consists primarily of clinical and radiological assessments. In addition, a limited number of serum biomarkers that assess treatment response are available ...for a small subset of malignancies. Through recent technological innovations, new methods for measuring tumor burden and treatment response are becoming available. By utilization of highly sensitive techniques, tumor-specific mutations in circulating DNA can be detected and circulating tumor DNA (ctDNA) can be quantified. These so-called liquid biopsies provide both molecular information about the genomic composition of the tumor and opportunities to evaluate tumor response during therapy. Quantification of tumor-specific mutations in plasma correlates well with tumor burden. Moreover, with liquid biopsies, it is also possible to detect mutations causing secondary resistance during treatment. This review focuses on the clinical utility of ctDNA as a response and follow-up marker in patients with non-small cell lung cancer, melanoma, colorectal cancer, and breast cancer. Relevant studies were retrieved from a literature search using PubMed database. An overview of the available literature is provided and the relevance of ctDNA as a response marker in anti-cancer therapy for clinical practice is discussed. We conclude that the use of plasma-derived ctDNA is a promising tool for treatment decision-making based on predictive testing, detection of resistance mechanisms, and monitoring tumor response. Necessary steps for translation to daily practice and future perspectives are discussed.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Effective systemic treatments have revolutionized the management of patients with metastatic melanoma, including those with brain metastases. The extent to which these treatments influence disease ...trajectories close to death is unknown. Therefore, this study aimed to gain insight into provided treatments and healthcare consumption during the last 3 months of life in patients with melanoma brain metastases.
Retrospective, single-center study, including consecutive patients with melanoma brain metastases diagnosed between June-2015 and June-2018, referred to the medical oncologist, and died before November-2019. Patient and tumor characteristics, anti-tumor treatments, healthcare consumption, presence of neurological symptoms, and do-not-resuscitate status were extracted from medical charts.
100 patients were included. A BRAF-mutation was present in 66 patients. Systemic anti-tumor therapy was given to 72% of patients during the last 3 months of life, 34% in the last month, and 6% in the last week. Patients with a BRAF-mutation more frequently received systemic treatment during the last 3 (85% vs. 47%) and last month (42% vs. 18%) of life than patients without a BRAF-mutation. Furthermore, patients receiving systemic treatment were more likely to visit the emergency room (ER, 75% vs. 36%) and be hospitalized (75% vs. 36%) than those who did not.
The majority of patients with melanoma brain metastases received anti-tumor treatment during the last 3 months of life. ER visits and hospitalizations occurred more often in patients on anti-tumor treatment. Further research is warranted to examine the impact of anti-tumor treatments close to death on symptom burden and care satisfaction.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Death anxiety is common in patients with metastatic cancer, but its relationship to brain metastases and cognitive decline is unknown. Early identification of death anxiety and its determinants ...allows proactive interventions to be offered to those in need.
To identify psychological, physical, and disease-related (including brain metastases and cognitive impairment) factors associated with death anxiety in metastatic non-small cell lung cancer (mNSCLC) patients.
A cross-sectional pilot study with mNSCLC outpatients completing standardized neuropsychological tests and validated questionnaires measuring death anxiety, cognitive concerns, illness intrusiveness, depression, demoralization, self-esteem, and common cancer symptoms. We constructed a composite for objective cognitive function (mean neuropsychological tests z-scores).
Study measures were completed by 78 patients (50% females; median age 62 years range 37–82). Median time since mNSCLC diagnosis was 11 months (range 0–89); 53% had brain metastases. At least moderate death anxiety was reported by 43% (n = 33). Objective cognitive impairment was present in 41% (n = 32) and perceived cognitive impairment in 27% (n = 21). Death anxiety, objective, and perceived cognitive impairment did not significantly differ between patients with and without brain metastases. In univariate analysis, death anxiety was associated with demoralization, depression, self-esteem, illness intrusiveness, common physical cancer symptoms, and perceived cognitive impairment. In multivariate analysis, demoralization (P < 0.001) and illness intrusiveness (P = 0.001) were associated with death anxiety.
Death anxiety and brain metastases are common in patients with mNSCLC but not necessarily linked. The association of death anxiety with both demoralization and illness intrusiveness highlights the importance of integrated psychological and symptom management. Further research is needed on the psychological impact of brain metastases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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