PubMed | San Gerardo Hospital, Struttura Complessa Oncologia Medica I, Polo Oncologico, Azienda Istituti Ospitalieri di Cremona and 4 more.
Type: Journal Article | Journal: The oncologist | Year: 2015
No prospective trials have specifically addressed the efficacy and safety of panitumumab in elderly patients with metastatic colorectal cancer (CRC). We aimed at assessing the efficacy and safety of single agent panitumumab in frail elderly patients diagnosed with metastatic RAS and BRAF wild-type CRC.Forty elderly patients (aged 75 years) with metastatic RAS-BRAF wild-type CRC received off-label prescriptions of single-agent panitumumab at seven Italian institutions. Treatment was administered as first line in patients with absolute contraindication to any chemotherapy or as second-line treatment after failure of a fluoropyrimidine-based treatment, in the presence of contraindication to irinotecan. The outcome measures included objective response rate (ORR), as well as progression-free survival (PFS), disease control rate (DCR), overall survival (OS), and safety.The median PFS and OS were 6.4 months (95% confidence interval [CI]: 4.9-8 months) and 14.3 months (95% CI: 10.9-17.7 months), respectively. ORR was 32.5%, and DCR was 72.5%. Dose reductions related to adverse events (AEs) were reported in 9 (23%) patients, but no permanent treatment discontinuation caused by was reported. The most frequent grade 3 AE was skin rash, with an incidence of 20%.Panitumumab is effective and well-tolerated in frail elderly patients with RAS-BRAF wild-type metastatic CRC and deemed unfit for chemotherapy. A randomized study is needed to confirm these data.Treatment of elderly patients with metastatic colorectal cancer represents a difficult challenge in clinical practice. A significant proportion of frail elderly patients do not receive treatment, reflecting ongoing uncertainty of clinical benefit and toxicity of chemotherapy. Unfit condition in this cohort of patients further limits antineoplastic prescription and consequently patient survival. RAS and BRAF wild-type status could help select an elderly and unfit population that could benefit from anti-epidermal growth factor receptor single agent therapy. In the present study, single-agent off-label panitumumab was effective and well-tolerated as first-line treatment in frail elderly patients deemed unfit for chemotherapy for metastatic RAS and BRAF wild-type colorectal cancer.
PubMed | University of Udine, Azienda Ospedaliero Universitaria Pisana, Medical Oncology and Hematology Unit, Polo Oncologico and 4 more.
Type: Journal Article | Journal: Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology | Year: 2015
The prognosis of brain metastases (BM) in colorectal cancer (CRC) is extremely poor, but the incidence is increasing. The performance of existing prognostic classifications such as recursive partitioning analysis (RPA) and graded prognostic assessment (GPA) has never been evaluated in this specific setting. Moreover, the development of nomograms for estimating survival in such patients could be extremely helpful for treating physicians.Between 2000 and 2013, data from 227 patients with BM from CRC were collected at 8 Italian institutions. Overall survival (OS) was estimated with the Kaplan-Meier method and statistical comparison between curves was performed using the log-rank test. The discriminative ability for OS of RPA and GPA was assessed by the Harrell C-index from univariable Cox models. Putative prognostic factors for OS were also studied by multivariable Cox analysis, using the Harrell C index to evaluate the model discriminative ability. After a backward variable selection, a nomogram was developed to predict median survival time from individual patient- and tumor-related characteristics. The nomogram was externally validated on an independent series.After a median follow-up of 59 months, fifty percent of patients were still at risk at 5 months. The C index was 0.594 and 0.607 for the RPA and GPA classifications, respectively. The C-index associated with the final multivariable Cox model used for developing the nomogram was 0.643; the favorable prognostic factors for survival were lower age (p=0.061), better Karnofsky performance status (p<0.001), supratentorial site of BM (p<0.001), and lower number of BM (p=0.035). The C index evaluated on the validation series was 0.733, even better than in the development series; also, the calibration of nomogram predictions was good.The C-index associated to the nomogram model was slightly higher than that obtained for the RPA and GPA classifications. Most importantly, the very satisfactory results of nomogram validation on the external series, make us confident that our instrument may assist in prognostic assessment, treatment decision making, and enrollment into clinical trials.
Pietrantonio F.,Fondazione IRCCS Instituto Nazionale dei Tumori |
Cremolini C.,Polo Oncologico |
Petrelli F.,Azienda Ospedaliera Treviglio |
Di Bartolomeo M.,Fondazione IRCCS Instituto Nazionale dei Tumori |
And 7 more authors.
Critical Reviews in Oncology/Hematology | Year: 2015
Background: The use of anti-EGFR monoclonal antibodies (MoAbs) is restricted in Europe to RAS wild-type metastatic colorectal cancer (mCRC) patients. While up today these targeted agents have been mainly chosen as salvage treatment in later lines, their use in first-line in combination with chemotherapy is highly debated. Methods: MEDLINE/PubMed, Cochrane Library, ASCO University, ESMO/ECCO conferences were searched for randomized controlled trials (RCTs) comparing first-line anti-EGFR MoAbs cetuximab or panitumumab plus chemotherapy to chemotherapy alone or with bevacizumab in patients with RAS wild-type colorectal cancer. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Results: Seven eligible RCTs were identified. In the overall RAS wild-type population (N = 2719), anti-EGFR MoAbs significantly improved OS (HR = 0.81; 95%CI, 0.71-0.92; p = 0.002), PFS (HR = 0.77; 95%CI, 0.60-0.98; p = 0.03) and objective response rate (ORR) (RR = 1.33; 95%CI, 1.09-1.62; p = 0.004). The addition of an anti-EGFR MoAb to chemotherapy alone improved PFS (p< 0.001) and ORR (p< 0.001) with a trend toward longer OS (p = 0.07). As compared to bevacizumab, anti-EGFR MoAbs significantly improved OS (HR = 0.80; 95%CI, 0.69-0.92; p = 0.003), but not PFS (HR = 0.94; 95%CI, 0.74-1.19; p = 0.59) or ORR (RR = 1.10; 95%CI, 0.97-1.25; p = 0.12). No significant differences were found with respect to the chemotherapy backbone (oxaliplatin- versus irinotecan-based). Conclusions: The choice of an anti-EGFR MoAb as first-line biologic is a valid option in RAS wild-type patients candidate to a doublet with infusional 5-FU. While attempting to further refine molecular selection, clinical considerations are crucial in planning the treatment strategy. © 2015 Elsevier Ireland Ltd.
PubMed | University of Rome La Sapienza, Azienda Ospedaliera Treviglio, Polo Oncologico and Fondazione IRCCS Instituto Nazionale dei Tumori
Type: Journal Article | Journal: Critical reviews in oncology/hematology | Year: 2015
The use of anti-EGFR monoclonal antibodies (MoAbs) is restricted in Europe to RAS wild-type metastatic colorectal cancer (mCRC) patients. While up today these targeted agents have been mainly chosen as salvage treatment in later lines, their use in first-line in combination with chemotherapy is highly debated.MEDLINE/PubMed, Cochrane Library, ASCO University, ESMO/ECCO conferences were searched for randomized controlled trials (RCTs) comparing first-line anti-EGFR MoAbs cetuximab or panitumumab plus chemotherapy to chemotherapy alone or with bevacizumab in patients with RAS wild-type colorectal cancer. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.Seven eligible RCTs were identified. In the overall RAS wild-type population (N=2719), anti-EGFR MoAbs significantly improved OS (HR=0.81; 95%CI, 0.71-0.92; p=0.002), PFS (HR=0.77; 95%CI, 0.60-0.98; p=0.03) and objective response rate (ORR) (RR=1.33; 95%CI, 1.09-1.62; p=0.004). The addition of an anti-EGFR MoAb to chemotherapy alone improved PFS (p<0.001) and ORR (p<0.001) with a trend toward longer OS (p=0.07). As compared to bevacizumab, anti-EGFR MoAbs significantly improved OS (HR=0.80; 95%CI, 0.69-0.92; p=0.003), but not PFS (HR=0.94; 95%CI, 0.74-1.19; p=0.59) or ORR (RR=1.10; 95%CI, 0.97-1.25; p=0.12). No significant differences were found with respect to the chemotherapy backbone (oxaliplatin- versus irinotecan-based).The choice of an anti-EGFR MoAb as first-line biologic is a valid option in RAS wild-type patients candidate to a doublet with infusional 5-FU. While attempting to further refine molecular selection, clinical considerations are crucial in planning the treatment strategy.
PubMed | Polo Oncologico, Laboratori Of Ricerca Biotecnologie E Science Microbiologia E Virologia and Medicina Interna e Oncologia
Type: Journal Article | Journal: The new microbiologica | Year: 2016
The use of procalcitonin (PCT) as an early marker of infectious episodes in cancer patients is still controversial. We performed a MEDLINE search of peer-reviewed articles published between January 1990 and December 2015, and finally we analysed 15 articles. PCT seems to have a good diagnostic value of infectious episodes in cancer patients and its accuracy seems greater if we consider major events, such as bloodstream infections and sepsis. Serial evaluations of this protein seem to be more accurate in the diagnostic phase and useful to predict outcome and response to antibacterial treatment. On the other hand, some issues have yet to be solved, such as the use of a validated method of determination, the definition of a standard cut-off, and the heterogeneity among different settings of patients (e.g. early versus advanced-stage cancer, or haematological versus solid tumours). However, it is credible to think that PCT use in everyday clinical practice, preferably in combination with other clinical or laboratory tests, might be of help in finding and detecting early infectious complications in cancer patients.
Variant alleles in factor V, prothrombin, plasminogen activator inhibitor-1, methylenetetrahydrofolate reductase and risk of thromboembolism in metastatic colorectal cancer patients treated with first-line chemotherapy plus bevacizumab
PubMed | Fondazione IRCCS Instituto Nazionale Tumori, Polo Oncologico, Fondazione IRCCS Instituto Nazionale dei Tumori, Scientific Institute and University of Milan
Type: | Journal: The pharmacogenomics journal | Year: 2016
Single-nucleotide polymorphisms (SNPs) related to hereditary thrombophilia were investigated as risk factors for thromboembolism in cancer patients. Their effect in metastatic colorectal cancer (mCRC) has never been explored so far. Our aim was to analyse the effect of coagulation factor V (FVL G1691A), prothrombin (PT G20210A), methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) and plasminogen activator inhibitor type 1 (PAI-1 5G/4G) allelic variants in this setting. Fifty-two patients treated with first-line chemotherapy plus bevacizumab who developed a thromboembolic event in their lifetime were initially genotyped. A contemporary cohort of 127 patients who did not experience any thromboembolic event was also analysed. DNA was extracted from peripheral blood and genotypes were determined by real-time PCR, using LightSNiP (TIB MOLBIOL) on LightCcler 480 (Roche). The association between thromboembolism and SNPs was investigated by univariable and multivariable analyses. All SNPs were in Hardy-Weinberg equilibrium (
PubMed | VU University Amsterdam, Polo Oncologico, University of Pisa and University of Antwerp
Type: | Journal: OncoTargets and therapy | Year: 2016
Recently, the development of the third-generation epidermal growth factor receptor-small molecule inhibitor (EGFR-TKI) rociletinib had failed. In this review, the wide-ranging aspects of the evolution of EGFR-TKIs were collected, with a special focus on rociletinib. The influence of different oncogenic mutations on EGFR activity was also discussed. Resistance to the first (erlotinib, gefitinib)- and second (afatinib)-generation EGFR-TKIs provided the rationale behind the development of the third-generation inhibitors (rociletinib, osimertinib). On the basis of these data, a comparison of their efficacy on the different mutated EGFRs and the respective resistance mechanisms is further reported. Moreover, the evolution and results of the clinical trials of rociletinib (TIGER trials) are compared with the trials on osimertinib, another third-generation EGFR-TKI that now has been granted US Food and Drug Administration approval. The reasons behind the arrest in the further development of rociletinib are put in the perspective of future drug development.
Bossi P.,Instituto Nazionale Dei Tumori |
Lucchesi M.,Polo Oncologico |
Antonuzzo A.,Polo Oncologico
Current Opinion in Supportive and Palliative Care | Year: 2015
Purpose of review Gastrointestinal toxicities deriving from targeted therapies are main issues in the oncologic setting, as they can negatively impair quality of life, reducing patient's adherence to treatment and dose intensity, so ultimately possibly affecting outcome. We reviewed some methodological questions linked to the assessment of this kind of toxicity, in terms of way of measurement, duration of the assessed toxicity and impact on the global treatment program. Recent findings The scale of toxicity assessment may influence the evaluation itself; reporting the adverse events by the physician is generally less accurate than by the patient, and these two modalities should be integrated in the analysis of gastrointestinal toxicities by targeted treatment. Moreover, the duration of the symptoms and the attention to the lower grade toxicities estimation are generally underreported in clinical trials. The factors that may affect treatment's adherence by the patient are discussed, as they are strictly linked to the appearance and intensity of gastrointestinal toxicities. Summary Methodological issues should be considered in designing new trials with targeted therapies and evaluating the way of assessment of adverse events, mainly gastrointestinal. © 2015 Wolters Kluwer Health, Inc. All rights reserved.
PubMed | Polo Oncologico
Type: Journal Article | Journal: Oncology | Year: 2016
The aim of this study was to evaluate the activity of the combination of 5-fluorouracil/folinic acid and irinotecan (FOLFIRI) as third-line chemotherapy (CT) in metastatic gastric cancer (mGC) patients pretreated with platinum derivatives, fluoropyrimidines, and taxanes.We prospectively collected data of mGC patients treated with third-line FOLFIRI at our institution from 2009 to 2014. Eligible patients should be treated with a fluoropyrimidine-platinum first-line CT and a subsequent taxane-based second-line CT. FOLFIRI consisted of irinotecan 180 mg/m2 and leucovorin 200 mg/m2, followed by 5-fluorouracil 2,800 mg/m2 (administered as 48-hour i.v. continuous infusion from day 1 to 3), with cycles repeated every 2 weeks. Response rate (RR) was evaluated according to RECIST version 1.0, while progression-free (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method.A total of 33 patients were included. The majority (97%) had good performance status (0-1 according to ECOG), while median PFS after first-line and second-line CT was 5.2 and 4.4 months, respectively. Two patients experienced an objective response (RR: 6%), while 14 patients achieved disease stabilization (disease control rate: 42%). Median PFS and OS from the start of third-line CT were 3.3 and 7.5 months, respectively. Hematological and nonhematological grade 3-4 toxicities were uncommon and included neutropenia (6.1%), diarrhea (9.1%), vomiting (3%), and asthenia (3%). Febrile neutropenia was not reported.Third-line CT with FOLFIRI may be an option in heavily pretreated mGC patients with preserved performance status and organ function. This regimen has a favorable safety profile, and signs of activity have been observed after standard first- and second-line CT.