- Keywords
- dostarlimab, studie RUBY,
- MeSH
- Survival Analysis MeSH
- Antibodies, Monoclonal, Humanized pharmacology therapeutic use MeSH
- Immunotherapy methods MeSH
- Carboplatin pharmacology therapeutic use MeSH
- Humans MeSH
- Endometrial Neoplasms * drug therapy MeSH
- Paclitaxel pharmacology therapeutic use MeSH
- Antineoplastic Combined Chemotherapy Protocols MeSH
- Randomized Controlled Trials as Topic MeSH
- Check Tag
- Humans MeSH
- Female MeSH
Metastatický duktální karcinom pankreatu (metastatic pancreatic ductal adenocarcinoma – mPDAC) patří mezi maligní onemocnění s nejvyšší letalitou. Dnešní terapeutické možnosti zahrnují podle doporučení Evropské společnosti pro klinickou onkologii (ESMO) v 1. linii dublet chemoterapii gemcitabin + nab-paklitaxel (Gem/Nab-P) nebo modifikovaný režim FOLFIRINOX (mFOLFIRINOX) a u pacientů v horším celkovém stavu monoterapii gemcitabinem. Nepřímé srovnání základních studií s Gem/Nab-P a mFOLFIRINOX v porovnání s gemcitabinem v monoterapii (PRODIGE-4 a MPACT) naznačilo delší celkové přežití (overall survival – OS) u pacientů s mFOLFIRINOX. Je ale třeba vzít v úvahu, že do studie MPACT s Gem/Nab-P byli zařazováni pacienti s celkově horším výkonnostním stavem. Přímé porovnání těchto režimů chemoterapie chybělo. Nepřímá porovnání z reálné praxe ukazují jejich srovnatelnou účinnost z hlediska OS, přežití bez progrese i podílu léčebných odpovědí, konzistentně odlišný je profil bezpečnosti. Nedávno publikovaná studie fáze II/III GENERATE, která přímo porovnávala Gem/Nab-P a mFOLFIRINOX u nepředléčených pacientů s mPDAC, prokázala významně delší OS u pacientů léčených Gem/Nab-P přesahující 17 měsíců při nižší incidenci nehematologické toxicity. Výsledky vyvolaly na kongresu ESMO 2023 živou diskuzi. Porovnání Gem/Nab-P a mFOLFIRINOX se ve své prezentaci na konferenci PragueONCO 2024 věnoval i prof. Prager, který vyzdvihl minimálně srovnatelnou účinnost obou režimů a lepší bezpečnost Gem/Nab-P a doložil přínos Gem/Nab-P také u pacientů starších 70 let a pacientů s výkonnostním stavem (performance status – PS) podle Eastern Cooperative Oncology Group (ECOG) PS 2. Je třeba také vzít v úvahu, že volba 1. linie léčby určuje terapeutické možnosti ve 2. linii. Při aplikaci Gem/Nab-P lze dnes ve 2. linii využít pegylovaný lipozomální irinotekan (nal-IRI) v kombinaci s 5-fluorouracilem a leukovorinem (5-FU/LV), který prokázal prodloužení OS v porovnání s 5-FU/LV ve studii III. fáze NAPOLI-1. U pacientů předléčených režimem mFOLFIRINOX lze ve 2. linii využít gemcitabin nebo Gem/Nab-P. Včasné vyšetření molekulárních prediktivních parametrů umožní identifikovat případy, pro které je k dispozici vhodná cílená léčba nebo imunoterapie.
Background: Metastatic pancreatic ductal carcinoma (mPDAC) is one of the most lethal malignancies. The European Society for Medical Oncology (ESMO) guidelines recommend a gemcitabine doublet + nab-paclitaxel (Gem/Nab-P) or a modified FOLFIRINOX regimen (mFOLFIRINOX) as options for systemic chemotherapy. Gemcitabine monotherapy is an option for patients in a worse performance status (PS). Indirect comparisons of pivotal trials with Gem/Nab-P and mFOLFIRINOX vs. gemcitabine monotherapy (PRODIGE-4 and MPACT) indicated longer overall survival (OS) in patients treated with mFOLFIRINOX. However, it should be taken into account that the MPACT study with Gem/Nab-P included patients with an overall worse performance status. A direct comparison of these chemotherapy regimens was lacking. Indirect comparisons from real practice show their comparable effectiveness in terms of OS, progression-free survival and overall response rate. The safety profile is consistently different. The recently published phase II/III GENERATE trial, which directly compared Gem/Nab-P and mFOLFIRINOX in treatment-na?ve mPDAC patients, demonstrated significantly longer OS in Gem/Nab-P-treated patients exceeding 17 months with a lower incidence of non-hematologic toxicity. The results sparked a lively discussion at the ESMO 2023 Congress. The comparison of Gem/Nab-P and mFOLFIRINOX was also addressed by prof. Prager in his presentation at the PragueONCO 2024 conference. Prager, who highlighted comparable efficacy of both regimens and better safety of Gem/Nab-P and demonstrated the benefit of Gem/Nab-P also in patients older than 70 years and those with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2. It should also be taken into account that the choice of first line treatment determines the therapeutic options in the 2nd line. If the Gem/Nab-P regimen is used in the first line, pegylated liposomal irinotecan (nal-IRI) in combination with 5-fluorouracil and leucovorin (5-FU/LV) can be used in the second line. This regimen demonstrated prolongation of OS compared to 5-FU/LV in phase III study NAPOLI-1. In patients pretreated with the mFOLFIRINOX regimen, gemcitabine monotherapy or Gem/Nab-P can be used in the second line. Early examination of molecular predictive parameters will enable the identification of cases for which appropriate targeted therapy or immunotherapy is available.
- Keywords
- studie GENERATE, FOLFIRINOX,
- MeSH
- Carcinoma, Pancreatic Ductal drug therapy mortality secondary MeSH
- Gemcitabine * pharmacology therapeutic use MeSH
- Irinotecan pharmacology classification therapeutic use MeSH
- Drug Therapy, Combination methods MeSH
- Humans MeSH
- Survival Rate MeSH
- Paclitaxel * pharmacology therapeutic use MeSH
- Antineoplastic Combined Chemotherapy Protocols pharmacology therapeutic use MeSH
- Check Tag
- Humans MeSH
- Publication type
- Multicenter Study MeSH
Neoadjuvant chemotherapy (NAC) is the preferred treatment option in locally advanced breast cancer (BC). The administration of NAC is associated with a wide range of adverse effects. This pilot observational prospective study examined the effect of NAC using anthracycline + cyclophosphamide (AC) followed by paclitaxel (PTx) on a portfolio of 22 plasma and urinary amino acids, plasma proteins (albumin, prealbumin, transferrin), and products of nitrogen metabolism (urea, creatinine, uric acid) in plasma and urine. Plasma and 24-h urine samples were obtained from ten patients with early breast cancer (N1-3 N0-2 M0), at the following time points: before the start of NAC and during the AC/PTx treatment period (a total of 8 measurements at three-weekly intervals). Amino acids were analyzed using ion exchange chromatography. There were no significant differences in the measured parameters in plasma and urine between pre-NAC and during AC- and PTx-treatment. No trend was detected. A significant difference in the portfolio of plasma and urinary amino acids was found only in the pre-treatment period compared to the control group. Levels of eight plasma amino acids (8/22) were significantly reduced and those of nine urine amino acids were increased (9/22). Nitrogenous catabolites in plasma and urine were not indicative of increased protein catabolism during the anthracycline and taxane treatment periods. A slightly positive nitrogen balance was accompanied by an average weight gain of 3.3 kg (range 0-6 kg). The AC/PTx treatment regimen did not cause significant changes in the monitored laboratory parameters.
- MeSH
- Amino Acids * urine blood MeSH
- Anthracyclines therapeutic use administration & dosage MeSH
- Cyclophosphamide * therapeutic use MeSH
- Adult MeSH
- Nitrogen * urine MeSH
- Creatinine urine blood MeSH
- Blood Proteins * metabolism analysis MeSH
- Middle Aged MeSH
- Humans MeSH
- Breast Neoplasms * drug therapy blood urine MeSH
- Neoadjuvant Therapy * MeSH
- Paclitaxel * therapeutic use administration & dosage MeSH
- Pilot Projects MeSH
- Prospective Studies MeSH
- Antineoplastic Combined Chemotherapy Protocols therapeutic use MeSH
- Aged MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Observational Study MeSH
We tested the effect of substituents at the (1) C3 ́, C3 ́N, (2) C10, and (3) C2-meta-benzoate positions of taxane derivatives on their activity against sensitive versus counterpart paclitaxel-resistant breast (MCF-7) and ovarian (SK-OV-3) cancer cells. We found that (1) non-aromatic groups at both C3 ́ and C3 ́N positions, when compared with phenyl groups at the same positions of a taxane derivative, significantly reduced the resistance of ABCB1 expressing MCF-7/PacR and SK-OV-3/PacR cancer cells. This is, at least in the case of the SB-T-1216 series, accompanied by an ineffective decrease of intracellular levels in MCF-7/PacR cells. The low binding affinity of SB-T-1216 in the ABCB1 binding cavity can elucidate these effects. (2) Cyclopropanecarbonyl group at the C10 position, when compared with the H atom, seems to increase the potency and capability of the derivative in overcoming paclitaxel resistance in both models. (3) Derivatives with fluorine and methyl substituents at the C2-meta-benzoate position were variously potent against sensitive and resistant cancer cells. All C2 derivatives were less capable of overcoming acquired resistance to paclitaxel in vitro than non-substituted analogs. Notably, fluorine derivatives SB-T-121205 and 121,206 were more potent against sensitive and resistant SK-OV-3 cells, and derivatives SB-T-121405 and 121,406 were more potent against sensitive and resistant MCF-7 cells. (4) The various structure-activity relationships of SB-T derivatives observed in two cell line models known to express ABCB1 favor their complex interaction not based solely on ABCB1.
- MeSH
- Benzoates pharmacology chemistry MeSH
- Drug Resistance, Neoplasm * drug effects MeSH
- Humans MeSH
- MCF-7 Cells MeSH
- Cell Line, Tumor MeSH
- Breast Neoplasms drug therapy pathology MeSH
- Ovarian Neoplasms drug therapy pathology MeSH
- ATP Binding Cassette Transporter, Subfamily B * metabolism genetics MeSH
- Paclitaxel pharmacology MeSH
- Antineoplastic Agents pharmacology chemistry MeSH
- Taxoids pharmacology chemistry MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Paclitaxel (PTX) is a chemotherapeutic agent affecting microtubule polymerization. The efficacy of PTX depends on the type of tumor, and its improvement would be beneficial in patients' treatment. Therefore, we tested the effect of slow sulfide donor GYY4137 on paclitaxel sensitivity in two different breast cancer cell lines, MDA-MB-231, derived from a triple negative cell line, and JIMT1, which overexpresses HER2 and is resistant to trastuzumab. In JIMT1 and MDA-MB-231 cells, we compared IC50 and some metabolic (apoptosis induction, lactate/pyruvate conversion, production of reactive oxygen species, etc.), morphologic (changes in cytoskeleton), and functional (migration, angiogenesis) parameters for PTX and PTX/GYY4137, aiming to determine the mechanism of the sensitization of PTX. We observed improved sensitivity to paclitaxel in the presence of GYY4137 in both cell lines, but also some differences in apoptosis induction and pyruvate/lactate conversion between these cells. In MDA-MB-231 cells, GYY4137 increased apoptosis without affecting the IP3R1 protein, changing the morphology of the cytoskeleton. A mechanism of PTX sensitization by GYY4137 in JIMT1 cells is distinct from MDA-MB-231, and remains to be further elucidated. We suggest different mechanisms of action for H2S on the paclitaxel treatment of MDA-MB-231 and JIMT1 breast cancer cell lines.
- MeSH
- Apoptosis * drug effects MeSH
- Drug Resistance, Neoplasm drug effects MeSH
- Humans MeSH
- Morpholines * pharmacology MeSH
- Cell Line, Tumor MeSH
- Breast Neoplasms * drug therapy pathology metabolism MeSH
- Organothiophosphorus Compounds * pharmacology MeSH
- Paclitaxel * pharmacology MeSH
- Reactive Oxygen Species metabolism MeSH
- Sulfides pharmacology MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- MeSH
- Esophagogastric Junction pathology MeSH
- Humans MeSH
- Neoplasm Metastasis MeSH
- Esophageal Neoplasms * therapy MeSH
- Brain Neoplasms surgery radiotherapy secondary MeSH
- Paclitaxel pharmacology therapeutic use MeSH
- Antineoplastic Combined Chemotherapy Protocols MeSH
- Ramucirumab pharmacology therapeutic use MeSH
- Aged MeSH
- Check Tag
- Humans MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Case Reports MeSH
Karcinom pankreatu je onemocnění s vysokou mortalitou, často zachycené v pozdním stadiu. Jedinou kurativní léčbou je chirurgická resekce, výsledky zlepšuje adjuvantní chemoterapie. U pacientů s pokročilým nálezem je v 1. linii paliativní léčby doporučen režim FOLFIRINOX nebo doublet gemcitabin + nab-paklitaxel, ve 2. linii pak po terapii založené na gemcitabinu nal-IRI (pegylovaný lipozomálnî irinotekan) + 5-fluorouracil (5-FU) + leukovorin (LV), nebo režim s 5-FU, a po terapii s 5-FU gemcitabin v monoterapii či v kombinaci. Nové výsledky prezentované na kongresu ESMO 2023 ukázaly, že v 1. linii paliativní léčby je větším přínosem doublet gemcitabin + nab-paklitaxel než FOLFIRINOX. Prezentujeme kazuistiku 50letého muže s progresí karcinomu pankreatu po chirurgické a adjuvantní léčbě, u něhož bylo po selhání gemcitabinu + nab-paklitaxelu v 1. linii paliativní léčby dosaženo již ročního přežití s dobrou kvalitou života při kombinaci nal-IRI + 5-FU/LV.
Pancreatic cancer is a disease with high mortality rates, often detected at late stage. Surgical resection is the only curative treatment, and the outcomes are improved by adjuvant chemotherapy. In patients with an advanced finding, the FOLFIRINOX regimen or the doublet gemcitabine + nab-paclitaxel are recommended in the first-line of palliative treatment; in the second-line, following the gemcitabine-based treatment, nal-IRI (pegylated liposomal irinotecan) + 5-fluorouracil (5-FU) + leucovorin (LV), or the regimen with 5-FU are recommended; and following the therapy with 5-FU, gemcitabine in monotherapy or in combination. New results presented at the 2023 ESMO Congress showed that, in the first-line of palliative treatment, the doublet gemcitabine + nab-paclitaxel had a greater benefit than the FOLFIRINOX regimen. We report a case of a 50-year-old man with progression of pancreatic cancer after surgical and adjuvant treatment in whom, after failure of gemcitabine + nab-paclitaxel in the first-line of palliative treatment, one-year survival with a good quality of life was achieved with the combination of nal-IRI + 5-FU/LV.
- MeSH
- Gemcitabine pharmacology therapeutic use MeSH
- Middle Aged MeSH
- Humans MeSH
- Pancreatic Neoplasms * surgery drug therapy MeSH
- Paclitaxel pharmacology therapeutic use MeSH
- Cancer Survivors MeSH
- Antineoplastic Combined Chemotherapy Protocols MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Publication type
- Case Reports MeSH
BACKGROUND/AIM: Inflammation-based prognostic scores have shown prognostic significance and have been associated with clinical outcomes in various types of cancer. Inflammation is known to promote tumor progression leading to reduced survival. In pancreatic cancer, systemic inflammation is common and contributes to its dismal prognosis. Although the prognosis of pancreatic cancer is improving with the introduction of new drugs, the prognostic indicators are still poorly understood. The present study aimed to evaluate inflammation-based prognostic scores in patients with metastatic pancreatic cancer receiving first-line chemotherapy. PATIENTS AND METHODS: A total of 43 patients with metastatic pancreatic cancer undergoing first-line chemotherapy (gemcitabine+nab-paclitaxel and mFOLFIRINOX) in our institution were analyzed. Baseline clinicopathological and pre-treatment laboratory data were collected. Survival was estimated using the Kaplan-Meier method and survival differences were evaluated using the log-rank test. RESULTS: In the whole cohort, we identified lymphocyte-to-monocyte ratio ≥3, systemic inflammatory response index <2.3, carcinoembryonic antigen <2.5, neutrophil-to-lymphocyte ratio <5, Memorial Sloane Kettering score <2, and prognostic index <2 as prognostic markers associated with improved overall survival in patients receiving first-line chemotherapy. CONCLUSION: The current analysis showed an association between inflammatory-based prognostic markers and overall survival in patients with metastatic pancreatic cancer treated in a real-world setting at a single institution.
- MeSH
- Albumins administration & dosage MeSH
- Deoxycytidine analogs & derivatives administration & dosage therapeutic use MeSH
- Adult MeSH
- Fluorouracil administration & dosage therapeutic use MeSH
- Gemcitabine MeSH
- Irinotecan administration & dosage therapeutic use MeSH
- Kaplan-Meier Estimate MeSH
- Leucovorin administration & dosage therapeutic use MeSH
- Middle Aged MeSH
- Humans MeSH
- Pancreatic Neoplasms * drug therapy mortality pathology MeSH
- Neutrophils pathology MeSH
- Oxaliplatin administration & dosage therapeutic use MeSH
- Paclitaxel administration & dosage MeSH
- Palliative Care * methods MeSH
- Prognosis MeSH
- Antineoplastic Combined Chemotherapy Protocols * therapeutic use MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Inflammation * pathology drug therapy MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Phase III trial data have shown a significant benefit by the addition of a maintenance treatment with niraparib, irrespective of BRCA or HRD status, in patients with advanced high-grade ovarian cancers; and, a significant benefit of the combination of olaparib and bevacizumab compared with bevacizumab monotherapy in HRD positive patients. However, it is unclear whether a PARP inhibitor monotherapy is sufficient, or if the addition of bevacizumab is needed. PRIMARY OBJECTIVES: This trial will investigate if the treatment strategy of carboplatin/paclitaxel/bevacizumab/niraparib is superior to the treatment of carboplatin/paclitaxel/niraparib in an all-comer population. STUDY HYPOTHESIS: Adding bevacizumab to chemotherapy followed by niraparib maintenance improves progression-free survival in patients with newly diagnosed advanced ovarian cancer. TRIAL DESIGN: AGO-OVAR 28/ENGOT-ov57 is an international, multicenter, randomized, prospective phase III trial within the the European Network for Gynecological Oncological Trial (ENGOT), led by the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) study group. All patients should have completed the first cycle of chemotherapy (carboplatin and paclitaxel) as part of the Study Run-In-Period. Prior to day 1 of cycle 2, patients with a valid central tumor BRCA (tBRCA) test result were randomized in a 1:1 ratio into either: Arm 1, to receive five additional cycles of carboplatin and paclitaxel q21d, followed by niraparib for up to 3 years; or Arm 2, to receive five additional cycles of carboplatin and paclitaxel plus bevacizumab q21d, followed by bevacizumab q21d (for up to 1 year), and niraparib for up to 3 years. MAJOR INCLUSION/EXCLUSION CRITERIA: The trial population is composed of adult patients with newly diagnosed, advanced high-grade epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer FIGO III/IV (except FIGO IIIA2 without nodal involvement). Patients who are scheduled for neoadjuvant chemotherapy and interval debulking surgery are also eligible for the trial. PRIMARY ENDPOINT: The primary endpoint is progression-free survival. SAMPLE SIZE: The study plans to recruit 970 patients (485 patients in each arm). ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: The Last-Patient-In is expected to be enrolled in September 2024, with presentation of the primary endpoint in 2028. TRIAL REGISTRATION: NCT05009082; EudraCT Number: 2021-001271-16.
- MeSH
- Bevacizumab MeSH
- Adult MeSH
- Carcinoma, Ovarian Epithelial drug therapy pathology MeSH
- Carboplatin MeSH
- Humans MeSH
- Ovarian Neoplasms * pathology MeSH
- Paclitaxel MeSH
- Prospective Studies MeSH
- Antineoplastic Combined Chemotherapy Protocols therapeutic use MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase III MeSH
- Multicenter Study MeSH
- Randomized Controlled Trial MeSH
Následující kazuistika pojednává o přínosech a potenciálních rizicích jedné z nejmodernějších léčebných modalit, které v klinické onkologii máme k dispozici. Imunoterapie cílená na kontrolní body imunitní reakce dokáže zejména ve dvojkombinaci dosáhnout významné a trvalé léčebné odpovědi u poměrně vysokého procenta pacientů. Tyto impozantní terapeutické výsledky však nejsou bez nežádoucích účinků. Rizikovější stran vývoje toxicity a dávkově dependentní je použití molekuly cílící na receptor CTLA-4. Méně případů autoimunitních reakcí potom pozorujeme při použití anti-PD-1 monoklonálních protilátek, a ještě méně při užití anti-PD-LI monoklonálních protilátek. Jak víme již z mnoha klinických studií, autoimunitně podmíněné nežádoucí účinky imunoterapie jsou většinou spojeny i s léčebným efektem. Přesně tento kauzální důkaz nám bude demonstrovat náš kazuistický případ.
The following case report discusses the benefits and potential risks of one of the most modern treatment modalities available to us in clinical oncology. Immunotherapy targeted at control points of the immune response can achieve a significant and lasting therapeutic response in a relatively high percentage of patients, especially in a double combination. However, these impressive therapeutic results are not without side effects. The use of a molecule targeting the CTLA-4 receptor is riskier for the development of toxicity and is dose-dependent. Fewer cases of autoimmune reactions are then observed with the use of anti-PD-1 monoclonal antibodies and even less with the use of anti-PD-LI monoclonal antibodies. As we already know from many clinical studies, autoimmune-related adverse effects of immunotherapy are mostly associated with the therapeutic effect. The following case study shows exactly this causal evidence.
- MeSH
- Carcinoma, Bronchogenic * diagnosis drug therapy classification MeSH
- Molecular Mechanisms of Pharmacological Action MeSH
- Immunotherapy methods MeSH
- Immune Checkpoint Inhibitors * pharmacology classification therapeutic use MeSH
- Ipilimumab pharmacology therapeutic use MeSH
- Carboplatin pharmacology therapeutic use MeSH
- Clinical Studies as Topic MeSH
- Humans MeSH
- Drug-Related Side Effects and Adverse Reactions classification MeSH
- Nivolumab pharmacology therapeutic use MeSH
- Paclitaxel pharmacology therapeutic use MeSH
- Tomography, X-Ray Computed methods MeSH
- Aged MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Aged MeSH
- Publication type
- Case Reports MeSH
