La terapia metronomica con vinorelbina orale nel trattamento del carcinoma polmonare in stadio avanzato: studio clinico di fase II

Riassunto Il tumore del polmone rappresenta la principale causa di morte per neoplasia nel Mondo occidentale, la maggior parte della diagnosi avviene in stadio avanzato e i trattamenti disponibili sono ancora insoddisfacenti. Il paziente anziano rappresenta inoltre un setting in cui il rapporto rischio/beneficio del trattamento deve essere attentamente valutato. L’utilizzo della vinorelbina orale metronomica come trattamento del NCSLC avanzato (IIIB-IV) può rappresentare un’opzione terapeutica, in quanto la vinorelbina orale viene ampiamente utilizzata sia come monochemioterapia che in associazione a derivati del platino nel trattamento del NSCLC stadio IIIB-IV e presenta un profilo di tossicità favorevole particolarmente adatto al paziente anziano e/o fragile. Sulla base di queste considerazioni, è stato condotto uno studio di fase II con l’obiettivo di valutare l’attività (percentuale di risposte obiettive) il clinical benefit e la tollerabilità della vinorelbina orale metronomica, come trattamento di I linea, in pazienti anziani con NSCLC stadio IIIB-IV. Lo studio ha mostrato una ORR del 16% con 2 risposte parziali(RP) e 1 risposta completa (RC). 10su 18 pazienti hanno presentato stabilità di malattia per più di 12 settimane con un clinical benefit ( CB) del 72.2%. Il trattamento è stato ben tollerato. In conclusione, il trattamento di pazienti con NSCLC avanzato con vinorelbina orale metronomica al dosaggio di 50mg tre volte la settimana può rappresentare un trattamento efficace con un vantaggioso profilo di tossicità che risulta particolarmente utile in pazienti che spesso si presentano in condizioni generali non ottimali

TRIBE-2: A phase III, randomized, open-label, strategy trial in unresectable metastatic colorectal cancer patients by the GONO group

Background: Chemotherapy plus bevacizumab is a standard first-line treatment for unresectable metastatic colorectal cancer patients. Different chemotherapy backbones may be chosen, including one to three drugs, based on patients' general conditions and comorbidities, treatments' objectives, and disease characteristics. TRIBE trial demonstrated a significant advantage in terms of progression-free survival and overall survival for FOLFOXIRI plus bevacizumab as compared with FOLFIRI plus bevacizumab. Based on recent evidence, the de-intensification of the upfront regimen after 4-6 months of treatment is nowadays regarded as a valuable option. Moreover, the prolonged inhibition of angiogenesis, and in particular the continuation of bevacizumab beyond the evidence of disease progression, is an efficacious strategy in the treatment of metastatic colorectal cancer patients. Methods/design: TRIBE-2 is a prospective, open-label, multicentric phase III randomized trial in which unresectable and previously untreated metastatic colorectal cancer patients are randomized to receive first-line FOLFOX plus bevacizumab followed by FOLFIRI plus bevacizumab after disease progression or FOLFOXIRI plus bevacizumab followed by the re-introduction of the same regimen after disease progression. The primary endpoint is to compare the efficacy of the two proposed treatment strategies in terms of Progression Free Survival 2. Discussion: The TRIBE-2 study aims at answering the question whether the upfront use of FOLFOXIRI improves the clinical outcome of metastatic colorectal cancer patients, when compared with the pre-planned, sequential use of oxaliplatin-based and irinotecan-based doublets. Both proposed treatment strategies are designed to exploit the effectiveness of the prolonged inhibition of angiogenesis, alternating short (up to 4 months) induction periods and less intensive maintenance phases. Trial registration: TRIBE2 is registered at Clinicaltrials.gov: NCT02339116. January 12, 2015. TRIBE-2 is registered at EUDRACT 2014-004436-19, October 10, 2014

Evaluation of HER2 and p53 expression in predicting response to docetaxel-based first-line chemotherapy in advanced breast cancer

<p>Abstract</p> <p>Background</p> <p>The human epidermal growth factor receptor 2 (HER2) and p53 pathways may be involved in chemotherapy sensitivity and/or resistance. We explore the value of HER2 and p53 status to foretell docetaxel sensitivity in advanced breast cancer.</p> <p>Methods</p> <p>HER2 and p53 expression was analysed in 36 (median age 55 yrs; range 37-87) metastatic breast cancer patients receiving docetaxel-based first-line chemotherapy. HER2 was determined by immunohistochemistry (IHC) and fluorescence <it>in situ </it>hybridization (FISH), p53 was tested by IHC. We correlate the expression of study parameters with pathologic parameters, RECIST response and survival. The standard cut-off value of 2 was used to determine HER2 overexpression while p53 mean expression level was used to divide low/high expressors tumors.</p> <p>Results</p> <p>Median time to progression and overall survival were 9 (range 2 - 54) and 20 (range 3 - 101) months. Overall response rate was 41.6%. Nine cases showed HER2 overexpression. HER2 was more frequently overexpressed in less differentiated (<it>p </it>= 0.05) and higher stage (<it>p </it>= 0.003) disease. Mean FISH-HER2 values were significantly higher in responder than in non-responder pts (8.53 ± 10.21 vs 2.50 ± 4.12, <it>p </it>= 0.027). Moreover, HER2 overexpression correlates with treatment response at cross-tabulation analysis (<it>p </it>= 0.046). p53 expression was only associated with higher stage disease (<it>p </it>= 0.02) but lack of any significant association with HER status or docetaxel response. No significant relation with survival was observed for any parameter.</p> <p>Conclusion</p> <p>Our data seem to indicate that FISH-determined HER2 status but not p53 is associated with docetaxel sensitivity in metastatic breast cancer.</p

Persistent Megalocystic Ovary Following in Vitro Fertilization in a Postpartum Patient with Polycystic Ovarian Syndrome

SummaryObjectiveOvarian hyperstimulation syndrome (OHSS) is more severe when pregnancy occurs, as the developing pregnancy produces human chorionic gonadotropin, which stimulates the ovary's persistent growth. If no pregnancy occurs, the syndrome will typically resolve within 1 week. In a maintained pregnancy, slow resolution of symptoms usually occurs over 1-2 months.Case ReportA 31-year-old woman, gravida 2, para 1, aborta 1, with polycystic ovary syndrome underwent in vitro fertilization (IVF) with clomiphene citrate and follicle-stimulating hormone/gonadotropin releasing hormone-antagonist stimulation. During transvaginal oocyte retrieval, enlarged bilateral ovaries were noted. She had an episode of OHSS after IVF/embryo transfer, for which paracentesis was performed three times. Pregnancy was achieved. Throughout antenatal examinations, bilateral ovaries were enlarged. She delivered a healthy baby by cesarean section at term. However, 1 month after delivery, the bilateral ovary had not shrunk, and levels of tumor markers CA125 and CA199 were 50.84 and 41.34 U/mL, respectively. At laparotomy for suspected malignancy, both adnexae formed “kissing ovaries”, which were multinodulated with yellow serous fluid. Specimens from wedge resection submitted for frozen section showed a benign ovarian cyst. The final pathology report showed bilateral follicle cysts.ConclusionWith the increasing use of gonadotropins in the management of infertility, ovarian enlargement secondary to hyperstimulation is common. Generally, symptoms appear between the 6th and 13th weeks of pregnancy and disappear thereafter. The hyperstimulated ovary often subsides after the first trimester. This case is unusual as the megalocystic ovary persisted after delivery. To the best of our knowledge, we report the first case of enlarged bilateral ovaries persisting 2 months after delivery

Genetic determinants of telomere length and risk of pancreatic cancer: A PANDoRA study

Telomere deregulation is a hallmark of cancer. Telomere length measured in lymphocytes (LTL) has been shown to be a risk marker for several cancers. For pancreatic ductal adenocarcinoma (PDAC) consensus is lacking whether risk is associated with long or short telomeres. Mendelian randomization approaches have shown that a score built from SNPs associated with LTL could be used as a robust risk marker. We explored this approach in a large scale study within the PANcreatic Disease ReseArch (PANDoRA) consortium. We analyzed 10 SNPs (ZNF676-rs409627, TERT-rs2736100, CTC1-rs3027234, DHX35-rs6028466, PXK-rs6772228, NAF1-rs7675998, ZNF208-rs8105767, OBFC1-rs9420907, ACYP2-rs11125529 and TERC-rs10936599) alone and combined in a LTL genetic score (“teloscore”, which explains 2.2% of the telomere variability) in relation to PDAC risk in 2,374 cases and 4,326 controls. We identified several associations with PDAC risk, among which the strongest were with the TERT-rs2736100 SNP (OR = 1.54; 95%CI 1.35–1.76; p = 1.54 × 10−10) and a novel one with the NAF1-rs7675998 SNP (OR = 0.80; 95%CI 0.73–0.88; p = 1.87 × 10−6, ptrend = 3.27 × 10−7). The association of short LTL, measured by the teloscore, with PDAC risk reached genome-wide significance (p = 2.98 × 10−9 for highest vs. lowest quintile; p = 1.82 × 10−10 as a continuous variable). In conclusion, we present a novel genome-wide candidate SNP for PDAC risk (TERT-rs2736100), a completely new signal (NAF1-rs7675998) approaching genome-wide significance and we report a strong association between the teloscore and risk of pancreatic cancer, suggesting that telomeres are a potential risk factor for pancreatic cancer

FOLFOXIRI/bevacizumab (bev) versus FOLFIRI/bev as first-line treatment in unresectable metastatic colorectal cancer (mCRC) patients (pts): Results of the phase III TRIBE trial by GONO group.

Background: Doublets plus bev are a standard option for the first-line treatment of mCRC. First-line FOLFOXIRI demonstrated superior RR, PFS and OS compared to FOLFIRI. A phase II study of FOLFOXIRI/bev showed promising activity and manageable toxicities. The objective of the TRIBE trial was to confirm the superiority of FOLFOXIRI vs FOLFIRI when bev is added to chemotherapy (CT). Methods: Eligibility criteria included: measurable and unresectable mCRC, age 18-75 years, no prior CT for advanced disease. Pts were randomized to either FOLFIRI/bev (arm A) or FOLFOXIRI/bev (arm B). Both treatments were administered for a maximum of 12 cycles followed by 5FU/bev until progression. Primary endpoint was PFS. Results: Between July 2008 and May 2011 508 pts were randomized. Pts characteristics were (arm A/arm B): median age 60/61, ECOG PS 1-2 11%/10%, synchronous metastases 81%/79%, multiple sites of disease 74%/70%, liver-only disease 18%/23%, prior adjuvant (adj) 12%/12%. At a median follow-up of 26.6 mos 424 pts progressed and 244 died. Median PFS and OS in the intention to treat (ITT) population were 10.9 and 30.9 mos. FOLFOXIRI/bev significantly increased PFS (median 9.7 vs 12.2 mos, HR 0.73 [0.60-0.88] p=0.0012). Subgroup analyses based on stratification factors (PS, prior adj) and baseline characteristics (site of primary, liver only disease, resection of primary, Kohne score) did not evidence significant interactions between treatment and analyzed factors. A trend toward a more consistent effect of FOLFOXIRI/bev was reported in no prior adj (HR 0.68 [0.55-0.83]) compared to prior adj group (HR 1.18 [0.67-2.08], p for interaction=0.071). Response rate (RECIST) was also significantly improved (53% vs 65% p=0.006). FOLFOXIRI/bev did not increase the R0 secondary resection rate in the ITT population (12% vs 15%, p=0.327), or in the liver-only subgroup (28% vs 32%, p=0.823). Conclusions: FOLFOXIRI/bev compared to FOLFIRI/bev, significantly increases PFS and response rate. Subgroup analysis suggests a possible interaction between prior adj CT and PFS benefit. Secondary resection rate does not differ between treatment arms. Clinical trial information: NCT00719797