Background No effective systemic therapy exists for patients with advanced hepatocellular carcinoma. A preliminary study suggested that sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and Raf may be effective in hepatocellular carcinoma. Methods In this multicenter, phase 3, double-blind, placebo-controlled trial, we randomly assigned 602 patients with advanced hepatocellular carcinoma who had not received previous systemic treatment to receive either sorafenib (at a dose of 400 mg twice daily) or placebo. Primary outcomes were overall survival and the time to symptomatic progression. Secondary outcomes included the time to radiologic progression and safety. Results At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P<0.001). There was no significant difference between the two groups in the median time to symptomatic progression (4.1 months vs. 4.9 months, respectively, P=0.77). The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (P<0.001). Seven patients in the sorafenib group (2%) and two patients in the placebo group (1%) had a partial response; no patients had a complete response. Diarrhea, weight loss, hand-foot skin reaction, and hypophosphatemia were more frequent in the sorafenib group. Conclusions In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo.

/pdf/sorafenib-in-advanced-hepatocellular-carcinoma-3xdq9sbovw.pdf

Sorafenib in Advanced Hepatocellular Carcinoma

Background
Decision aids are intended to help people participate in decisions that involve weighing the benefits and harms of treatment options often with scientific uncertainty.

Objectives
To assess the effects of decision aids for people facing treatment or screening decisions.

Search methods
For this update, we searched from 2009 to June 2012 in MEDLINE; CENTRAL; EMBASE; PsycINFO; and grey literature. Cumulatively, we have searched each database since its start date including CINAHL (to September 2008).

Selection criteria
We included published randomized controlled trials of decision aids, which are interventions designed to support patients' decision making by making explicit the decision, providing information about treatment or screening options and their associated outcomes, compared to usual care and/or alternative interventions. We excluded studies of participants making hypothetical decisions.

Data collection and analysis
Two review authors independently screened citations for inclusion, extracted data, and assessed risk of bias. The primary outcomes, based on the International Patient Decision Aid Standards (IPDAS), were:

A) 'choice made' attributes;

B) 'decision-making process' attributes.

Secondary outcomes were behavioral, health, and health-system effects. We pooled results using mean differences (MD) and relative risks (RR), applying a random-effects model.

Main results
This update includes 33 new studies for a total of 115 studies involving 34,444 participants. For risk of bias, selective outcome reporting and blinding of participants and personnel were mostly rated as unclear due to inadequate reporting. Based on 7 items, 8 of 115 studies had high risk of bias for 1 or 2 items each.

Of 115 included studies, 88 (76.5%) used at least one of the IPDAS effectiveness criteria: A) 'choice made' attributes criteria: knowledge scores (76 studies); accurate risk perceptions (25 studies); and informed value-based choice (20 studies); and B) 'decision-making process' attributes criteria: feeling informed (34 studies) and feeling clear about values (29 studies).

A) Criteria involving 'choice made' attributes:

Compared to usual care, decision aids increased knowledge (MD 13.34 out of 100; 95% confidence interval (CI) 11.17 to 15.51; n = 42). When more detailed decision aids were compared to simple decision aids, the relative improvement in knowledge was significant (MD 5.52 out of 100; 95% CI 3.90 to 7.15; n = 19). Exposure to a decision aid with expressed probabilities resulted in a higher proportion of people with accurate risk perceptions (RR 1.82; 95% CI 1.52 to 2.16; n = 19). Exposure to a decision aid with explicit values clarification resulted in a higher proportion of patients choosing an option congruent with their values (RR 1.51; 95% CI 1.17 to 1.96; n = 13).

B) Criteria involving 'decision-making process' attributes:

Decision aids compared to usual care interventions resulted in:

a) lower decisional conflict related to feeling uninformed (MD -7.26 of 100; 95% CI -9.73 to -4.78; n = 22) and feeling unclear about personal values (MD -6.09; 95% CI -8.50 to -3.67; n = 18);

b) reduced proportions of people who were passive in decision making (RR 0.66; 95% CI 0.53 to 0.81; n = 14); and

c) reduced proportions of people who remained undecided post-intervention (RR 0.59; 95% CI 0.47 to 0.72; n = 18).

Decision aids appeared to have a positive effect on patient-practitioner communication in all nine studies that measured this outcome. For satisfaction with the decision (n = 20), decision-making process (n = 17), and/or preparation for decision making (n = 3), those exposed to a decision aid were either more satisfied, or there was no difference between the decision aid versus comparison interventions. No studies evaluated decision-making process attributes for helping patients to recognize that a decision needs to be made, or understanding that values affect the choice.

C) Secondary outcomes

Exposure to decision aids compared to usual care reduced the number of people of choosing major elective invasive surgery in favour of more conservative options (RR 0.79; 95% CI 0.68 to 0.93; n = 15). Exposure to decision aids compared to usual care reduced the number of people choosing to have prostate-specific antigen screening (RR 0.87; 95% CI 0.77 to 0.98; n = 9). When detailed compared to simple decision aids were used, fewer people chose menopausal hormone therapy (RR 0.73; 95% CI 0.55 to 0.98; n = 3). For other decisions, the effect on choices was variable.

The effect of decision aids on length of consultation varied from 8 minutes shorter to 23 minutes longer (median 2.55 minutes longer) with 2 studies indicating statistically-significantly longer, 1 study shorter, and 6 studies reporting no difference in consultation length. Groups of patients receiving decision aids do not appear to differ from comparison groups in terms of anxiety (n = 30), general health outcomes (n = 11), and condition-specific health outcomes (n = 11). The effects of decision aids on other outcomes (adherence to the decision, costs/resource use) were inconclusive.

Authors' conclusions
There is high-quality evidence that decision aids compared to usual care improve people's knowledge regarding options, and reduce their decisional conflict related to feeling uninformed and unclear about their personal values. There is moderate-quality evidence that decision aids compared to usual care stimulate people to take a more active role in decision making, and improve accurate risk perceptions when probabilities are included in decision aids, compared to not being included. There is low-quality evidence that decision aids improve congruence between the chosen option and the patient's values.

New for this updated review is further evidence indicating more informed, values-based choices, and improved patient-practitioner communication. There is a variable effect of decision aids on length of consultation. Consistent with findings from the previous review, decision aids have a variable effect on choices. They reduce the number of people choosing discretionary surgery and have no apparent adverse effects on health outcomes or satisfaction. The effects on adherence with the chosen option, cost-effectiveness, use with lower literacy populations, and level of detail needed in decision aids need further evaluation. Little is known about the degree of detail that decision aids need in order to have a positive effect on attributes of the choice made, or the decision-making process.

/pdf/decision-aids-for-people-facing-health-treatment-or-1j1706q17l.pdf

Decision aids for people facing health treatment or screening decisions

CA : A Cancer Journal for Clinicians

Background Interferon alfa is widely used for metastatic renal-cell carcinoma but has limited efficacy and tolerability. Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, may benefit patients with this disease. Methods In this multicenter, phase 3 trial, we randomly assigned 626 patients with previously untreated, poor-prognosis metastatic renal-cell carcinoma to receive 25 mg of intravenous temsirolimus weekly, 3 million U of interferon alfa (with an increase to 18 million U) subcutaneously three times weekly, or combination therapy with 15 mg of temsirolimus weekly plus 6 million U of interferon alfa three times weekly. The primary end point was overall survival in comparisons of the temsirolimus group and the combination-therapy group with the interferon group. Results Patients who received temsirolimus alone had longer overall survival (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.58 to 0.92; P=0.008) and progression-free survival (P<0.001) than did patie...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa066838

Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma.

https://rihuc.huc.min-saude.pt/bitstream/10400.4/1818/1/renal%20cell%20carcinoma.pdf

EAU Guidelines on Renal Cell Carcinoma: 2014 Update

Immunotherapy Resistance Mechanisms in Renal Cell Cancer

TPS4135 Background: Ganitumab (AMG 479) is an investigational, fully human, monoclonal antibody inhibitor of the IGF1R. In a randomized phase II study in patients with metastatic pancreatic cancer,...

A phase III, multicenter, randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine (G) as first-line therapy for metastatic adenocarcinoma of the pancreas: The GAMMA trial.

We reviewed the literature on the relationship between the Fanconi anemia pathway (FA) and response to chemotherapy in patients with ovarian cancer. Despite continuous developments in medicine, ovarian cancer remains a challenge for both, physicians and researchers
seeking ways to achieve better results of chemotherapy combined with other targeted therapies. Clinically relevant resistance to chemotherapy is a major problem in treating ovarian cancer. Researchers continue to investigate mechanisms responsible for drug resistance in order to develop better therapeutic methods against ovarian cancer. Among the resistance mechanisms, defects in DNA repair, including the FA pathway, may be important in increasing the sensitivity of ovarian cancer cells to chemotherapy agents at the clinical level. A growing number of data has
shown that disruption of the FA genes may be a useful predictor of OC sensitivity to chemotherapy agents whose activity is based on DNA crosslinking mechanisms..

/pdf/the-role-of-the-fanconi-anemia-pathway-in-the-cctzbng5eo.pdf

The role of the Fanconi anemia pathway in the pathophysiology of ovarian cancer

#2028 Background: Brain is increasingly a site of relapse in breast cancer patients, however the molecular patho-physiology of this process is not well understood. Using a novel assay allowing high-throughput analysis of gene expression from formalin-fixed paraffin-embedded (FFPET) tumor samples, we compared molecular characteristics of BM with those of the PBC in a series of breast cancer patients who underwent excision of brain metastasis.  Methods: In each patient we performed molecular analysis of paired archived FFPET specimens from both the PBC and excised BM. Of the 37 pairs of PBC/BM samples, 24 pairs had sufficient pathology material for molecular analysis. Patient characteristics: mean age at PBC diagnosis was 46.7 years (range 27-67 years); 7 (29%) ER+, 17 (71%) ER-, 12 (50%) HER2-positive(3+). We performed cDNA-mediated annealing, selection, extension and ligation (DASL) assay (Illumina Corp) for expression of 502 known cancer genes, using 200 ng RNA. Statistical analysis for microarrays (SAM) accounting for the pairing of the primary and metastasized tumors was used to identify differentially expressed genes while controlling the false discovery rate (FDR Results: In only 7 (29%) cases matched PBC and BM pair clustered together on unsupervised hierarchical clustering, the pairs in remaining cases clustered apart. Comparison of the two groups (PBC and BM) showed that 41 genes were up regulated in BM, including proliferation genes (CDC2, CDC25a, CCNA2 and E2F family), anti-apoptotic (BIRC5), DNA repair (RAD51, -54b, XRCC2, BRCA2, BARD1, TOP1), angiogenesis (VEGF), and development of drug resistance (ABCB1, -G2). In contrast, the 43 genes that were down regulated in BM included those associated with invasion (MMP2, -3, -14), cellular motility, and epithelial to mesenchymal transformation (CDH11). Additional analysis to validate these trends and to identify potential therapeutic targets is underway.  Conclusions: Although some BM retain remarkable similarity to the PBC, majority exhibit considerable deviation in their gene expression profile. These “adaptive” changes include greater resistance to drug therapy, increased DNA repair, a reversal back to the epithelial phenotype and decreased capacity for cell motility and invasion. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2028.

Molecular characteristics of matched brain metastasis (BM) versus the primary breast cancer (PBC).

5529 Background: Ovarian cancer is the most lethal gynecologic cancer and its standard treatment consists of cytoreductive surgery followed by paclitaxel/platinum-based chemotherapy. Additional pro...

Cezary Szczylik

Papers

Immunotherapy Resistance Mechanisms in Renal Cell Cancer

A phase III, multicenter, randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine (G) as first-line therapy for metastatic adenocarcinoma of the pancreas: The GAMMA trial.

The role of the Fanconi anemia pathway in the pathophysiology of ovarian cancer

Molecular characteristics of matched brain metastasis (BM) versus the primary breast cancer (PBC).

Tau expression as a predictive marker in ovarian cancer patients (pts) treated with platinum/paclitaxel chemotherapy