Cancer-related anemia (CRA) is a common sign occurring in more than 30% of cancer patients at diagnosis before the initiation of antineoplastic therapy. CRA has a relevant influence on survival, ...disease progression, treatment efficacy, and the patients' quality of life. It is more often detected in patients with advanced stage disease, where it represents a specific symptom of the neoplastic disease, as a consequence of chronic inflammation. In fact, CRA is characterized by biological and hematologic features that resemble those described in anemia associated to chronic inflammatory disease. Proinflammatory cytokine, mainly IL-6, which are released by both tumor and immune cells, play a pivotal action in CRA etiopathogenesis: they promote alterations in erythroid progenitor proliferation, erythropoietin (EPO) production, survival of circulating erythrocytes, iron balance, redox status, and energy metabolism, all of which can lead to anemia. The discovery of hepcidin allowed a greater knowledge of the relationships between immune cells, iron metabolism, and anemia in chronic inflammatory diseases. Additionally, chronic inflammation influences a compromised nutritional status, which in turn might induce or contribute to CRA. In the present review we examine the multifactorial pathogenesis of CRA discussing the main and novel mechanisms by which immune, nutritional, and metabolic components affect its onset and severity. Moreover, we analyze the status of the art and the perspective for the treatment of CRA. Notably, despite the high incidence and clinical relevance of CRA, controlled clinical studies testing the most appropriate treatment for CRA are scarce, and its management in clinical practice remains challenging. The present review may be useful to indicate the development of an effective approach based on a detailed assessment of all factors potentially involved in the pathogenesis of CRA. This mechanism-based approach is essential for clinicians to plan a safe, targeted, and successful therapy, thereby promoting a relevant amelioration of patients' quality of life.
Hepatocellular carcinoma (HCC) is the typical inflammation-induced neoplasia. It often prospers where a chronic liver disease persists, thus leading a strong rationale for immune therapy. Several ...immune-based treatments, including immune checkpoint inhibitors (ICI), cytokines, adoptive cell transfer, and vaccines, have been tested in the treatment of HCC. In this review, we summarize the role of the ICI in HCC patients in various sets of treatment. As for advanced HCC, the anti-Programmed cell Death protein 1 (PD1) antibodies and the anti-Cytotoxic T-Lymphocyte Antigen
(CTLA-4) antibodies have been examined in patients with enthusiastic results in phase I-II-III studies. Overall, this led the Food and Drug Administration (FDA) to approve pembrolizumab, nivolumab, and nivolumab + ipilimumab in the second-line setting. The anti- Programmed Death-Ligand 1 (PDL-1) antibodies have also been evaluated. Thanks to the results obtained from phase III IMbrave study, atezolizumab + bevacizumab is now the standard of care in the first-line advanced setting of HCC. As for localized HCC, the putative immunological effect of locoregional therapies led to evaluate the combination strategy with ICI. This way, chemoembolization, ablation with radiofrequency, and radioembolization combined with ICI are currently under study. Likewise, the study of adjuvant immunotherapy following surgical resection is underway. In addition, the different ICI has been studied in combination with other ICI as well as with multikinase inhibitors and anti-angiogenesis monoclonal antibody. The evidence available suggests that combining systemic therapies and locoregional treatments with ICI may represent an effective strategy in this context.
Background
Advanced Hepatocarcinoma (HCC) is an important health problem worldwide. Recently, the REFLECT trial demonstrated the non‐inferiority of Lenvatinib compared to Sorafenib in I line setting, ...thus leading to the approval of new first‐line standard of care, along with Sorafenib.
Aims and methods
With aim to evaluate the optimal choice between Sorafenib and Lenvatinib as primary treatment in clinical practice, we performed a multicentric analysis with the propensity score matching on 184 HCC patients.
Results
The median overall survival (OS) were 15.2 and 10.5 months for Lenvatinib and Sorafenib arm, respectively. The median progression‐free survival (PFS) was 7.0 and 4.5 months for Lenvatinib and Sorafenib arm, respectively. Patients treated with Lenvatinib showed a 36% reduction of death risk (p = 0.0156), a 29% reduction of progression risk (p = 0.0446), a higher response rate (p < 0.00001) and a higher disease control rate (p = 0.002). Sorafenib showed to be correlated with more hand‐foot skin reaction and Lenvatinib with more hypertension and fatigue. We highlighted the prognostic role of Barcelona Clinic Liver Cancer (BCLC) stage, Eastern Cooperative Oncology Group Performance Status (ECOG‐PS), bilirubin, alkaline phosphatase and eosinophils for Sorafenib. Conversely, albumin, aspartate aminotransferase (AST), alkaline phosphatase and Neutrophil‐Lymphocyte Ratio (NLR) resulted prognostic in Lenvatinib arm. Finally, we highlighted the positive predictive role of albumin > Normal Value (NV), ECOG > 0, NLR < 3, absence of Hepatitis C Virus positivity, and presence of portal vein thrombosis in favor of Lenvatinib arm. Eosinophil < 50 and ECOG > 0 negatively predicted the response to Sorafenib.
Conclusion
SLenvatinib showed to better perform in a real‐word setting compared to Sorafenib. More researches are needed to validate the predictor factors of response to Lenvatinib rather than Sorafenib.
Key points
Recently, the REFLECT trial demonstrated the non‐inferiority of Lenvatinib compared to Sorafenib in hepatocellular carcinoma (HCC) I line setting, thus leading to the approval of new first‐line standard of care
With aim to evaluate the optimal choice between Sorafenib and Lenvatinib as primary treatment in clinical practice, we performed a multicentric analysis with the propensity score matching on 184 HCC patients
In our analysis, Lenvatinib showed to better perform in a real‐word setting compared to Sorafenib. More researches are needed to validate the predictor factors of response to Lenvatinib rather than Sorafenib
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
The present study aims to investigate the role of the prognostic nutritional index (PNI) on survival in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib.
This multicentric ...study included a training cohort of 194 HCC patients and three external validation cohorts of 129, 76 and 265 HCC patients treated with Sorafenib, respectively. The PNI was calculated as follows: 10 × serum albumin (g/dL) + 0.005 × total lymphocyte count (per mm3). Univariate and multivariate analyses were performed to investigate the association between the covariates and the overall survival (OS).
A PNI cut-off value of 31.3 was established using the ROC analysis. In the training cohort, the median OS was 14.8 months (95% CI 12-76.3) and 6.8 months (95% CI 2.7-24.6) for patients with a high (>31.3) and low (<31.3) PNI, respectively. At both the univariate and the multivariate analysis, low PNI value (p = 0.0004), a 1-unit increase of aspartate aminotransferase (p = 0.0001), and age > 70 years (p< 0.0038) were independent prognostic factors for OS. By performing the same multivariate analysis of the training cohort, the PNI <31.3 versus >31.3 was found to be an independent prognostic factor for predicting OS in all the three validation cohorts.
PNI represents a prognostic tool in advanced HCC treated with first-line Sorafenib. It is readily available and low-cost, and it could be implemented in clinical practice in patients with HCC.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The aim of our retrospective study is to evaluate the prognostic significance of aspirin in patients with advanced HCC treated with sorafenib.
304 patients with HCC,consecutively treated with ...sorafenib from May 2007 to September 2018, were included in the clinical study. Of Them 93 patients token aspirin. Progression-free survival (PFS)and overall survival (OS)were estimated with the Kaplan–Meier method and compared with the log-rank test.
The concomitant use of sorafenib and aspirin was associated with a median OS of 18.3 months compared to 8.8 months of patients who did not receive aspirin (HR 0.57; P < 0.0001). The concomitant use of sorafenib and aspirin was associated with a median PFS of 7.3 months compared to 3.0 months of patients who did not receive aspirin (HR 0.61; P = 0.0003). In the multivariate analysis, the use of aspirin maintained an independent prognostic value for OS(HR 0.61; P = 0.0013). In second line the concomitant use of regorafenib and aspirin was associated with a median OS of 16.9 months compared to 8.0 months of patients who did not receive aspirin (HR 0.30; P = 0.02).
Globally, our data seem to suggest that aspirin use may improve the clinical outcome of patients with advanced hepatocellular carcinoma receiving sorafenib and regorafenib.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Metastatic CRC (mCRC) is a molecular heterogeneous disease. The aim of this review is to give an overview of molecular-driven treatment of mCRC patients.
A review of clinical trials, retrospective ...studies and case reports was performed regarding molecular biomarkers with therapeutic implications.
wild-type status was confirmed as being crucial for anti-epidermal growth factor receptor (EGFR) monoclonal antibodies and for rechallenge strategy. Antiangiogenic therapies improve survival in first- and second-line settings, irrespective of
status, while tyrosine kinase inhibitors (TKIs) remain promising in refractory mCRC. Promising results emerged from anti-HER2 drugs trials in HER2-positive mCRC. Target inhibitors were successful for
mutant mCRC patients, while immunotherapy was successful for microsatellite instability-high/defective mismatch repair (MSI-H/dMMR) or DNA polymerase epsilon catalytic subunit (
) mutant patients. Data are still lacking on
, and TGF-β, which require further research.
Several molecular biomarkers have been identified for the tailored treatment of mCRC patients and multiple efforts are currently ongoing to increase the therapeutic options. In the era of precision medicine, molecular-biology-driven treatment is the key to impro patient selection and patient outcomes. Further research and large phase III trials are required to ameliorate the therapeutic management of these patients.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Purpose: To test the efficacy and safety of an integrated treatment based on a pharmaconutritional support, antioxidants,
and drugs, all given orally, in a population of advanced cancer patients with ...cancer-related anorexia/cachexia and oxidative
stress.
Patients and Methods: An open early-phase II study was designed according to the Simon two-stage design. The integrated treatment
consisted of diet with high polyphenols content (400 mg), antioxidant treatment (300 mg/d α-lipoic acid + 2.7 g/d carbocysteine
lysine salt + 400 mg/d vitamin E + 30,000 IU/d vitamin A + 500 mg/d vitamin C), and pharmaconutritional support enriched with
2 cans per day ( n -3)-PUFA (eicosapentaenoic acid and docosahexaenoic acid), 500 mg/d medroxyprogesterone acetate, and 200 mg/d selective cyclooxygenase-2
inhibitor celecoxib. The treatment duration was 4 months. The following variables were evaluated: ( a ) clinical (Eastern Cooperative Oncology Group performance status); ( b ) nutritional lean body mass (LBM), appetite, and resting energy expenditure; ( c ) laboratory proinflammatory cytokines and leptin, reactive oxygen species (ROS) and antioxidant enzymes; ( d ) quality of life (European Organization for Research and Treatment of Cancer QLQ-C30, Euro QL-5D, and MFSI-SF).
Results: From July 2002 to January 2005, 44 patients were enrolled. Of these, 39 completed the treatment and were assessable.
Body weight increased significantly from baseline as did LBM and appetite. There was an important decrease of proinflammatory
cytokines interleukin-6 (IL-6) and tumor necrosis factor-α, and a negative relationship worthy of note was only found between
LBM and IL-6 changes. As for quality of life evaluation, there was a marked improvement in the European Organization for Research
and Treatment of Cancer QLQ-C30, Euro QL-5D VAS , and multidimensional fatigue symptom inventory-short form scores. At the end of the study, 22 of the 39 patients were “responders”
or “high responders.” The minimum required was 21; therefore, the treatment was effective and more importantly was shown to
be safe.
Conclusion: The efficacy and safety of the treatment have been shown by the study; therefore, a randomized phase III study
is warranted. (Cancer Epidemiol Biomarkers Prev 2006;15(5):1030–4)
Fatigue is a multidimensional symptom that is described in terms of perceived energy, mental capacity, and psychological status: it can impair daily functioning and lead to negative effects on ...quality of life. It is one of the most common side effects of chemotherapy and radiotherapy. In recent studies,
l-carnitine (LC) supplementation has been demonstrated to be able to improve fatigue symptoms in patients with cancer.
In the present study we tested the efficacy and safety of LC supplementation in a population of patients who had advanced cancer and developed fatigue, high blood levels of reactive oxygen species, or both. As outcome measures we evaluated fatigue and quality of life in relation to oxidative stress, nutritional status, and laboratory variables, mainly levels of reactive oxygen species, glutathione peroxidase, and proinflammatory cytokines. From March to July 2004, 12 patients who had advanced tumors (50% at stage IV) at different sites were enrolled (male-to-female ratio 2:10, mean age 60 y, range 42–73). Patients were only slightly anemic (hemoglobin 10.9 g/dL) and hemoglobin levels did not change after treatment. LC was administered orally at 6 g/d for 4 wk. All patients underwent antineoplastic treatment during LC supplementation.
Fatigue, as measured by the Multidimensional Fatigue Symptom Inventory—Short Form, decreased significantly, particularly for the General and Physical scales, and for quality of life in each subscale of quality of life in relation to oxidative stress. Nutritional variables (lean body mass and appetite) increased significantly after LC supplementation. Levels of reactive oxygen species decreased and glutathione peroxidase increased but not significantly. Proinflammatory cytokines did not change significantly.
Improvement of symptoms with respect to fatigue and quality of life in relation to oxidative stress may be explained mainly by an increase in lean body mass, which may be considered the most important nutritional or functional parameter in assessing the cachectic state of patients. In this view, fatigue with related symptoms can well be considered an important constituent of cancer-related anorexia cachexia syndrome.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Objective: Cancer-related anorexia/cachexia syndrome and oxidative stress play a key role in the progression and outcome of
neoplastic disease. Patients and Methods: On the basis of our previously ...published studies and clinical experience, we have
developed an innovative approach consisting of diet with high polyphenol content (400 mg), p.o. pharmaconutritional support
enriched with n − 3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid) 2 cans (237 mL each) per day, medroxiprogesterone acetate
500 mg/d, antioxidant treatment with α-lipoic acid 300 mg/d plus carbocysteine lysine salt 2.7 g/d plus vitamin E 400 mg/d
plus vitamin A 30,000 IU/d plus vitamin C 500 mg/d, and selective cyclooxygenase-2 inhibitor Celecoxib 200 mg/d. The treatment
is administered for 16 weeks. The following variables are evaluated: ( a ) clinical variables (stage and Eastern Cooperative Oncology Group performance status); ( b ) nutritional variables (lean body mass, appetite, and resting energy expenditure); ( c ) laboratory variables (serum levels of proinflammatory cytokines, C-reactive protein, and leptin and blood levels of reactive
oxygen species and antioxidant enzymes); and ( d ) quality of life variables (European Organization for Research and Treatment of Cancer QLQ-C30, EQ-5D index , and EQ-5D VAS ). A phase II nonrandomized study has been designed to enroll 40 patients with advanced cancer at different sites with symptoms
of cancer-related anorexia/cachexia syndrome and oxidative stress. Results: As of January 2004, 28 patients have been enrolled:
25 patients were evaluable and 14 of them have completed the treatment (20 patients have completed 2 months of treatment).
As for clinical response, five patients improved, three patients remained unchanged, and six patients worsened. The Eastern
Cooperative Oncology Group performance status (grade) 1 remained unchanged. As for nutritional/functional variables, the lean
body mass increased significantly at 2 and 4 months. As for laboratory variables, reactive oxygen species decreased significantly
and proinflammatory cytokines interleukin-6 and tumor necrosis factor-α decreased significantly. As for quality of life, it
comprehensively improved after treatment. Conclusions: The treatment has been shown to be effective for clinical response,
increase of lean body mass, decrease of reactive oxygen species and proinflammatory cytokines, and improvement of quality
of life. The treatment has been shown to be safe with good compliance of patients. The study is in progress (14 further patients
will be included).
Abstract Aim of the present phase II non-randomized study was to verify whether palonosetron might be able to prevent acute and especially delayed CINV for either HEC or MEC, starting from the second ...chemotherapy cycle, in patients who had failed to respond to a different antiemetic 5-HT3 antagonist during the first cycle. Stratification factor was age <65 years vs. ≥65 years of patients included. Forty-seven cancer patients (23 elderly and 24 non-elderly) scheduled to receive HEC or MEC regimens who had experienced CINV grade 3–4 during the first chemotherapy course and for whom the same course of chemotherapy regimen was further scheduled were enrolled. Complete response (CR) and complete control (CC) rates for the acute, delayed and overall phases of CINV were not significantly different between elderly and non-elderly patients. Palonosetron was safe: only grade 1–2 toxicities were observed with a peak of 12.9% for asthenia with no significant difference between elderly and non-elderly patients. In conclusion, single dose palonosetron (250 μg) should be considered a safe and effective second generation 5-HT3 antagonist in the prevention of nausea and vomiting induced by HEC or MEC, irrespective of patients’ age.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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