Bevacizumab plus FOLFIRI or FOLFOX in chemotherapy-refractory patients with metastatic colorectal cancer: a retrospective study

<p>Abstract</p> <p>Background</p> <p>The anti-VEGF antibody bevacizumab associated with an irinotecan or oxaliplatin-based chemotherapy was proved to be superior to the chemotherapy alone in first or second line treatment of metastatic colorectal cancer (mCRC). However, it was reported to have no efficacy in 3^rdor later-line, alone or with 5FU. The aim of this study was to evaluate the activity of bevacizumab combined with FOLFIRI or FOLFOX in mCRC who have failed prior chemotherapy with fluoropyrimidine plus irinotecan and/or oxaliplatin.</p> <p>Methods</p> <p>Thirty one consecutive patients treated between May 2005 and October 2006 were included in this retrospective study. All of them have progressed under a chemotherapy with fluoropyrimidine plus irinotecan and/or oxaliplatin and received bevacizumab (5 mg/kg) in combination with FOLFIRI or simplified FOLFOX4 every 14 days.</p> <p>Results</p> <p>Ten patients (32.2%) had an objective response (1 CR, 9 PR) and 12 (38.8%) were stabilized. The response and disease control rates were 45.4% and 100% when bevacizumab was administered in 2^ndor 3^rdline and 25% and 55% in 4^thor later line respectively (p = 0.024 and p = 0.008). Among the patients who had previously received the same chemotherapy than that associated with bevacizumab (n = 28) the overall response rate was 35.7% and 39.3% were stabilized. Median progression free survival (PFS) and overall survival (OS) were of 9.7 and 18.4 months respectively. Except a patient who presented a hypertension associated reversible posterior leukoencephalopathy syndrome, tolerance of bevacizumab was acceptable. A rectal bleeding occurred in one patient, an epistaxis in five. Grade 1/2 hypertension occurred in five patients.</p> <p>Conclusion</p> <p>This study suggests that bevacizumab combined with FOLFOX or FOLFIRI may have the possibility to be active in chemorefractory and selected mCRC patients who did not receive it previously.</p

Hyperexpression de la cyclooxygénase-2 dans les cancers colorectaux (incidence pronostique et corrélation avec le phénotype anatomo-pathologique et moléculaire)

Plusieurs études récentes ont mis en évidence une implication de la cyclooxygénase-2 (COX-2) dans la cancérogenèse des cancers colorectaux (CCR). Le but de notre étude était d'évaluer l'incidence pronostique de la surexpression de COX-2 au niveau tumoral, ainsi que sa relation avec les caractéristiques anatomo-pathologiques et le phénotype d'instabilité des microsatellites des tumeurs. Pour cela, nous avons analysé, de façon rétrospective, en immunohistochimie l'expression intra-tumorale de la COX-2 chez 62 patients opérés à visée curative d'un CCR T1-T4NOMO au CHU de Nantes en 1996 et 1997. L'expression de COX-2 était ensuite comparée au phénotype anatomo-pathologique et moléculaire des tumeurs et à la survie des patients. Les résultats obtenus montrent, chez ces patients, que l'hyperexpression de COX-2 est un facteur de mauvais pronostic. Ces résultats ont été comparé aux données de la littérature dont il a été réalisé, préalablement, une mise au point.NANTES-BU Médecine pharmacie (441092101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Facteurs moléculaires pronostiques et prédictifs de la réponse aux traitements du cancer colorectal

Nous avons montré que des mutations de la région non codante (D-Loop) de l'ADN mitochondrial étaient fréquentes dans les tumeurs colorectales, qu'elles survenaient à un stade précoce (adénome) de la carcinogenèse et qu'elles étaient un facteur pronostique ainsi qu'un facteur de résistance à une chimiothérapie adjuvante à base de 5-fluorouracile. Par ailleurs, nous avons montré que les mutations du gène KRAS étaient un facteur de résistance au cetuximab, anticorps anti-REGF utilisé dans le traitement des cancers colorectaux métastatiques, et qu'elles étaient un facteur de mauvais pronostic chez les patients traités par cet anticorps, indépendemment de la toxicité cutanée. L'expression des phosphoprotéines pP70S6K et pMEKl semblent également être prédictive de la réponse et de la survie des patients traités par anticorps anti-REGF, indépendament du statut mutationnel du gène KRAS.We showed that mutations in the non-coding region (D-Loop) of the mitochondrial DNA were frequent in colorectal tumors, that they occured at an early step (adenoma) of the carcinogenesis and that they were a prognostic factor and associated with resistance to 5-fluorouracil-based adjuvant chemotherapy. Moreover, we showed that KRAS gene mutations were associated with a resistance to cetuximab, an anti-EGFR antibody used in the treatment of metastatic colorectal cancer, and that they were a poor prognostic factor in patients treated by this antibody, independently of skin toxicity. The expression of the phosphoproteins pP70S6K and pMEKl also seems to be predictive of response to anti-EGFR antibodies and a prognostic factor in patients treated by them, independantly of KRAS mutation status.PARIS-BIUP (751062107) / SudocSudocFranceF

Significant decrease in interval colorectal cancer incidence after implementing immunochemical testing in a multiple-round guaiac-based screening programme

International audienceBackground and aims: We aimed to evaluate the effects of switching to faecal immunochemical testing (FIT) on the cumulative 2-year incidence rate of interval cancers, interval cancer rate and test sensitivity within a mature population-based colorectal cancer screening programme consisting of six rounds of biennial guaiac faecal occult blood testing (gFOBT).Methods: The FIT results were compared with those of gFOBT used in each of the previous two rounds. For the three rounds analysed, 279,041 tests were performed by 156,186 individuals. Logistic regression analysis was used to determine interval cancer risk factors (Poisson regression) and to compare the sensitivity of FIT to gFOBT.Results: There were 612 cases of screen-detected cancers and 209 cases of interval cancers. The sex- and age-adjusted cumulative 2-year incidence rates of interval cancers were 55.7 (95% CI, 45.3-68.5), 42.4 (95% CI, 32.6-55.2) and 15.8 (95% CI, 10.9-22.8) per 100,000 person-years after the last two rounds of gFOBT and FIT, respectively. The FIT/gFOBT incidence rate ratio was 0.38 [95% CI, 0.27-0.54] (P < 0.001). Sex- and age-adjusted sensitivity was significantly higher with FIT than with gFOBT (OR = 6.70 [95% CI, 4.48-10.01], P < 0.0001).Conclusions: This population-based study revealed a dramatic decrease in the cumulative incidence rates of interval cancers after switching from gFOBT to FIT. These data provide an additional incentive for countries still using gFOBT to switch to FIT

Influence of cirrhosis on outcomes of patients with advanced intrahepatic cholangiocarcinoma receiving chemotherapy

International audienceBackground: Cirrhosis is a risk factor for intrahepatic cholangiocarcinoma (iCC). However, its impact on the management of advanced disease is not established. Methods: Retrospective analysis of patients (pts) treated with systemic chemotherapy for advanced iCC in the first-line setting at 2 tertiary cancer referral centers, the second center used to validate findings from the first. Cirrhosis was diagnosed based on at least one element among pathological diagnosis, baseline platelet &lt; 150 G/L, portal hypertension and/or dysmorphic liver at imaging. Results: In the first center (n=185), 55 pts (29.7%) had cirrhosis (74.5 % based on pathological diagnosis). Main aetiology of cirrhosis was alcohol for 17 pts (31%), non-alcoolic steato-hepatitis (NASH) for 10 pts (18.2%), and mixed alcohol and NASH for 9 pts (16.4%). 102 (57.0%) pts received gemcitabine-cisplatin, 55 (30.7%) pts received gemcitabine-oxaliplatin, and 11 (6%) pts received gemcitabine, with no difference between cirrhotic and non-cirrhotic pts (p=0.38). Second-line treatment was less frequent in cirrhotic pts (21.8% vs. 50.0%, p=0.001). Cirrhotic pts experienced more grade 3/4 hematologic toxicity than non-cirrhotic pts (38% vs. 20%, respectively, p=0,014), and more grade 3/4 non-hematologic toxicity (28% vs. 15%, respectively, p=0.048). The overall survival (OS) was significantly shorter in cirrhotic pts; median: 9.0 vs. 13.8 months for non-cirrhotic pts (HR = 1.54 [95%CI: 1.09-2.16]; p = 0.014); confirmed on multivariable analysis, adjusted on ALBI-score, ECOG PS, extension of the disease (liver only disease and bilobar) (HR = 1.53 [95% CI: 1.01-2.33]; p=0.046). However, PFS was not significantly shorter in cirrhotic pts: median 9,9 months vs. 11.7 for non-cirrhotics (p = 0.35). In the second center (n=102), similar results were seen: 27 (26.5%) pts had cirrhosis. The cirrhotic pts experienced more grade 3/4 hematologic toxicities than non-cirrhotic pts (55.6% vs. 25.4%, respectively, p=0.005), and more grade 3/4 non-hematologic toxicity (44.4% vs. 12.7%, respectively, p = 0.001). OS was shorter in cirrhotic pts; median 9.1 months vs. 11.7 months for non-cirrhotic pts (HR = 1.81 [95%CI: 1.14-2.87]; p = 0.011). PFS was not significantly shorter in cirrhotic pts: 7.5 months for patients without cirrhosis, and 4.2 months for pts with cirrhosis (p=0.221). Conclusions: Cirrhosis was frequent in pts with advanced iCC, and had a negative impact on patients’ outcomes, with increased chemotherapy-induced toxicity and shorter OS. Formal assessment and consideration of cirrhosis in the therapeutic management should be recommended and could lead to a dose adjustment

Downstaging with Radioembolization or Chemotherapy for Initially Unresectable Intrahepatic Cholangiocarcinoma

International audienceObjective The aim of this retrospective study was to compare the outcomes of patients resected for intrahepatic cholangiocarcinoma (ICC) with upfront surgery or after downstaging treatment. Methods All consecutive patients with ICC between January 1997 and November 2017 were included in a single-center database and retrospectively reviewed. Patients were divided into two groups: upfront resection or resection after downstaging using either chemotherapy alone or selective internal radiation therapy (SIRT) combined with chemotherapy. Survival rates of patients who underwent upfront surgery for ICC were compared with those of patients who underwent surgery after downstaging therapy. Results A total of 169 patients resected for ICC were included: 137 underwent upfront surgery and 32 received downstaging treatment because their tumor was initially unresectable (13 received chemotherapy, 19 received SIRT). Median OS was not different between the two groups: 32.3 months [95% confidence interval (CI) 23.9-40.7] with primary surgery versus 45.9 months (95% CI 32.3-59.4) with downstaging treatment (p = 0.54, log-rank test). In a multivariable Cox regression model, downstaging treatment was not associated with a better or worse prognosis; however, delivery of SIRT as a downstaging treatment was associated with a significant benefit in multivariable analysis (hazard ratio 0.34, 95% CI 0.14-0.84; p = 0.019). Conclusions Overall survival of patients resected after downstaging treatment was not different compared with the OS of patients resected upfront. Patients should therefore again be discussed with the surgeon following medical treatment. SIRT may be an efficient neoadjuvant therapy in patients with resectable ICC, in order to improve surgical results