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

cell carcinoma – RCC) stanowi ok. 3% litych guzów u dorosłych. U ok. 30% chorych w chwili rozpoznania RCC stwierdza się przerzuty, które najczęściej dotyczą płuc. Cel pracy: Ocena remisji przerzutów płucnych zaawansowanego raka nerki po nefrektomii i chemioimmunoterapii. Materiał i metody: Analizą objęto dane kliniczne 54 chorych na raka nerki z przerzutami płucnymi. Wszystkich chorych przed leczeniem systemowym poddano nefrektomii (bez metastazektomii), a stadium przerzutowe choroby dokumentowano za pomocą tomografii komputerowej. Terapię oparto na IL-2 s.c., IFN-α s.c., 5-FU i.v. Stan ogólny oceniany był na podstawie skali ECOG, a odpowiedź zmian docelowych wg kryteriów RECIST. Wyniki: Ocena 54 chorych wg skali ECOG: 0 – u 5 chorych, 1 – u 43, 2 – u 6. Po zastosowaniu chemioimmunoterapii zaobserwowano 5 odpowiedzi całkowitych (CR – 9%) oraz 12 odpowiedzi częściowych (PR – 22%). Obiektywne odpowiedzi zanotowano w 17 przypadkach. Średni czas trwania CR wynosił 24 miesiące (znacząco wpływał na wydłużenie przeżycia chorych). Ocena grupy wg skali ECOG: 0 u nikogo, 1 – u 4 chorych, 2 – u 1 chorego. Odpowiedź częściowa trwała średnio 12 miesięcy (zazwyczaj progresja choroby nowotworowej). Toksyczność zastosowanego schematu była przemijająca, z dobrą tolerancją leczenia przez chorych. Wnioski: 1. Skojarzenie nefrektomii i następowej chemioimmunoterapii jest bezpieczną i skuteczną metodą leczenia chorych z przerzutami raka nerki do płuc. 2. Dzięki zastosowanej immunochemioterapii uzyskano u 5 osób CR, co znamiennie wydłużyło przeżycie chorych. 3. Leczenie chorych z przerzutowym RCC powinno być prowadzone w wyspecjalizowanych ośrodkach i mieć charakter interdyscyplinarny.

https://www.termedia.pl/Journal/-3/pdf-14210-1?filename=Skutecznosc i bezpieczenstwo.pdf

Efficacy and safety of surgical and chemoimmunotherapy combination treatment in patients with renal carcinoma and pulmonary metastases

The Role of Diabetes in Molecular Pathogenesis of Cancer

PURPOSE
Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit. This randomized, double-blind, placebo-controlled phase III study evaluated efficacy and safety of pazopanib monotherapy in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma (RCC).


PATIENTS AND METHODS
Adult patients with measurable, locally advanced, and/or metastatic RCC were randomly assigned 2:1 to receive oral pazopanib or placebo. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, tumor response rate (Response Evaluation Criteria in Solid Tumors), and safety. Radiographic assessments of tumors were independently reviewed.


RESULTS
Of 435 patients enrolled, 233 were treatment naive (54%) and 202 were cytokine pretreated (46%). PFS was significantly prolonged with pazopanib compared with placebo in the overall study population (median, PFS 9.2 v 4.2 months; hazard ratio [HR], 0.46; 95% CI, 0.34 to 0.62; P < .0001), the treatment-naive subpopulation (median PFS 11.1 v 2.8 months; HR, 0.40; 95% CI, 0.27 to 0.60; P < .0001), and the cytokine-pretreated subpopulation (median PFS, 7.4 v 4.2 months; HR, 0.54; 95% CI, 0.35 to 0.84; P < .001). The objective response rate was 30% with pazopanib compared with 3% with placebo (P < .001). The median duration of response was longer than 1 year. The most common adverse events were diarrhea, hypertension, hair color changes, nausea, anorexia, and vomiting. There was no evidence of clinically important differences in quality of life for pazopanib versus placebo.


CONCLUSION
Pazopanib demonstrated significant improvement in PFS and tumor response compared with placebo in treatment-naive and cytokine-pretreated patients with advanced and/or metastatic RCC.

Pazopanib in Locally Advanced or Metastatic Renal Cell Carcinoma: Results of a Randomized Phase III Trial.

Rak nerki stanowi okolo 3% wszystkich rozpoznawanych nowotworow zlośliwych. W okresie ostatnich 10
lat stale obserwuje sie postep w zakresie leczenia zaawansowanego i przerzutowego raka nerki. Nowe
formy terapii pojawily sie w wyniku prowadzonych prac z zakresu poznania patofizjologii raka nerki na
poziomie molekularnym. Wśrod potencjalnych celow molekularnych, ktore mogą miec znacznie kliniczne
w postaci pojawienia sie nowego sposobu leczenia, jest receptor naskorkowego czynnika wzrostu (EGFR).
Szlak sygnalowy EGFR jest istotnym elementem w powstawaniu i progresji wielu chorob nowotworowych.
W przypadku raka nerki wiedza w zakresie znaczenia tego szlaku molekularnego jest niewielka i cześciowo
ma związek z niepowodzeniem leczenia chorych na te chorobe nowotworową z zastosowaniem substancji
blokujących EGFR, a ktore juz stosuje sie w codziennej praktyce lekarskiej, np. podczas leczenia raka
jelita grubego, nowotworow glowy i szyi czy tez raka piersi. W tym artykule autorzy omowili role szlaku
sygnalowego EGFR w odniesieniu do komorek raka nerki oraz opisali wyniki prob klinicznych blokowania
szlaku EGFR u chorych na raka nerki.
 Onkol. Prak. Klin. 2011; 7, 4: 197–207

/pdf/inhibition-of-molecular-signaling-of-epidermal-growth-factor-2gbwbw89o0.pdf

Inhibition of molecular signaling of epidermal growth factor receptor (EGFR) and its clinical potential for treating renal cell cancer

Do obecnie powszechnie stosowanych pochodnych platyny nale¿1 cisplatyna, karboplatyna oraz oksaliplatyna. Wspóln1 cech1 tych zwi1zków nieorganicznych jest zawartoœæ w centralnym po3o¿eniu w cz1steczce atomu metalu ciê¿kiego – platyny. Jako pierwsza zosta3a zsyntetyzowana w 1845 r. cisplatyna, czyli ponad 100 lat przed wykazaniem jej cytostatycznego dzia3ania przez Rosenberga i wsp. [1, 2], którzy stwierdzili zahamowanie podzia3ów komórkowych Escherichia coli, umieszczonych w roztworze jonów chloru i jonów amonowych, do których do3o¿ono elektrody platynowe. Karboplatyna, wprowadzona do badañ klinicznych w 1981 r., wykazuje podobny mechanizm dzia3ania, chocia¿ profil aktywnoœci przeciwnowotworowej oraz toksycznoœci nie pokrywa siê dok3adnie z cisplatyn1. W nastêpnych latach poddano badaniom klinicznym wiele innych zwi1zków platyny, zarówno dwujak i czterowartoœciowej, w konformacji cis oraz trans, co pozwoli3o wprowadziæ do szerokiego lecznictwa kolejny lek – oksaliplatynê. Wprowadzenie pochodnych platyny do arsena3u œrodków przeciwnowotworowych znacznie rozszerzy3o mo¿liwoœci terapeutyczne i skutecznoœæ leczenia wielu nowotworów, zw3aszcza j1der, jajników, raka p3uc, pêcherza moczowego, nowotworów g3owy i szyi, ch3oniaków nieziarniczych [3–7]. Ponadto cisplatyna jest wykorzystywana w schematach skojarzonego leczenia wraz z radioterapi1, gdzie dzia3a jako radiouczulacz [8, 9]. Jednak stosowanie tych leków mo¿e powodowaæ wyst1pienie ró¿norodnych objawów ubocznych, przy czym szczególnym problemem terapeutycznym jest mo¿liwoœæ wyst1pienia ciê¿kiego uszkodzenia nerek z ich nastêpow1 niewydolnoœci1. Dlatego szczególnie istotnym jest poszukiwanie nowych leków, które w sposób wybiórczy maj1 dzia3anie protekcyjne w stosunku do zdrowych tkanek, a nie zmieniaj1 si3y dzia3ania przeciwnowotworowego pochodnych platyny.

/pdf/renal-nephroprotection-during-chemotherapy-with-platinum-5d80gpi1kq.pdf

Cezary Szczylik

Papers

Efficacy and safety of surgical and chemoimmunotherapy combination treatment in patients with renal carcinoma and pulmonary metastases

The Role of Diabetes in Molecular Pathogenesis of Cancer

Pazopanib in Locally Advanced or Metastatic Renal Cell Carcinoma: Results of a Randomized Phase III Trial.

Inhibition of molecular signaling of epidermal growth factor receptor (EGFR) and its clinical potential for treating renal cell cancer

Renal nephroprotection during chemotherapy with platinum compounds in cancer patients