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Background: In the last decade, a series of analyses failed to identify predictive biomarkers of resistance/susceptibility for anti-angiogenic drugs in metastatic colorectal cancer (mCRC). We conducted an exploratory preplanned analysis of serum pro-angiogenic factors (SErum aNgiogenesis-cenTRAL) in 72 mCRC patients enrolled in the phase II CENTRAL (ColorEctalavastiNTRiAlLdh) trial, with the aim to identify potential predictive factors for sensitivity/resistance to first line folinic acid-fluorouracil-irinotecan regimen (FOLFIRI) plus bevacizumab. Methods: First-line FOLFIRI/bevacizumab patients were prospectively assessed for the following circulating pro-angiogenic factors, evaluated with ELISA (enzyme-linked immunosorbent assay)-based technique at baseline and at every cycle: Vascular endothelial growth factor A (VEGF-A), hepatocyte growth factor (HGF), stromal derived factor-1 (SDF-1), placental derived growth factor (PlGF), fibroblast growth factor-2 (FGF-2), monocyte chemotactic protein-3 (MCP-3), interleukin-8 (IL-8). Results: Changes in circulating FGF-2 levels among different blood samples seemed to correlate with clinical outcome. Patients who experienced an increase in FGF-2 levels at the second cycle of chemotherapy compared to baseline, had a median Progression Free Survival (mPFS) of 12.85 vs. 7.57 months (Hazard Ratio&mdash, HR: 0.73, 95% Confidence Interval&mdash, CI: 0.43-1.27, p = 0.23). Similar results were seen when comparing FGF-2 concentrations between baseline and eight-week time point (mPFS 12.98 vs. 8.00 months, HR: 0.78, 95% CI: 0.46&ndash, 1.33, p = 0.35). Conclusions: Our pre-planned, prospective analysis suggests that circulating FGF-2 levels&rsquo, early increase could be used as a marker to identify patients who are more likely to gain benefit from FOLFIRI/bevacizumab first-line therapy.

Background: Previous findings suggested that bevacizumab might be able to improve response rate (RR) in colorectal cancer patients with high lactic dehydrogenase (LDH) basal levels. Methods: We conducted a phase II trial to prospectively ascertain whether bevacizumab in combination with FOLFIRI could have an improved clinical activity in patients with high LDH serum levels. Primary end point of the study was RR; secondary end points were median overall survival and median progression-free survival (mPFS). Results: A total of 81 patients were enrolled. No difference in terms of ORR (39% vs 31% for low vs high LDH level stratum, P=0.78) and mPFS (14.16 vs 10.29 months, HR: 1.07, 95% CI: 0.51–2.24, P=0.83) between the strata was observed, whereas overall survival (OS) was significantly longer for patients with low LDH (24.85 vs 15.14 months, HR: 4.08, 95% CI: 1.14–14.61, P=0.0004). In a not-pre-planned exploratory analysis using different cut-off ranges for LDH, we observed RR up to 70%, with no improvement in progression-free survival or OS. Conclusions: The CENTRAL trial failed to demonstrate that high LDH levels were related to a significantly improved RR in patients receiving first-line FOLFIRI and bevacizumab. The LDH serum levels should then no further be investigated as a predictive factor in this setting.

Purpose There is no consensus on the use of cetuximab in elderly patients with metastatic colorectal cancer. To this end, a survey was carried in 17 Italian oncology centers. Methods The centers answered a 29-item questionnaire structured as follows: (i) demographic characteristics; (ii) medical history; (iii) assessment of RAS/BRAF mutations and DPD/UGT polymorphism before treatment; (iv) treatment schemes and side effects; (v) geriatric assessment and customization of treatment. Results One-third of patients are over 80 years old. The RAS/BRAF mutational status is not primarily evaluated by 17.6% of the centers, while DPD and UGT polymorphism is not evaluated by 82.4% and 76.5% of the centers. The most common therapeutic scheme is cetuximab/FOLFIRI and diarrhea is the main cause of suspension/reduction of treatment. The 70% of centers use systemic tetracyclines for skin toxicity. The 23.5% of the centers do not carry out any geriatric evaluation before the start of the therapy and those who perform it prefer the G8 (70.6%) and VES-13 (29.4%) scales. Conclusions Greater efforts should be made to improve the evaluation of the patient both about mutational and genetic procedures with geriatric evaluation. As for cetuximab in elderly patients, randomized studies are needed to provide guidance to physicians.

In the last decades the management of hepatocellular carcinoma (HCC) has undergone significant changes following the introduction of novel therapies such as sorafenib, which have improved patient survival. Nevertheless, HCC is still the third most common cause of cancer-related death worldwide. The evidence-based therapy for advanced HCC that is unsuitable for locoregional treatment is limited to sorafenib, with no second-line option available. This article focuses on the development of the MET inhibitor tivantinib in HCC as a promising treatment option for patients who failed sorafenib. A randomized, placebo-controlled phase II study showed activity of tivantinib in patients with high MET expression. Based on these results, the METIV-HCC phase III study in second-line treatment for MET-high patients was initiated to demonstrate the survival advantage of tivantinib compared to placebo.

Non-small-cell lung cancer (NSCLC) is the most common malignancy in industrialized countries, with a 5-year survival rate of only ~15%, as the majority of the patients have advanced-stage disease at diagnosis and the treatment options are limited. Squamous cell carcinoma the second most frequent type of NSCLC and is closely associated with cigarette smoking. We herein present the case of a 72-year-old male smoker, diagnosed with stage IV squamous cell lung carcinoma, with a solitary brain metastasis. After the diagnosis, stereotactic radiotherapy was performed on the brain metastasis. Following radiotherapy, chemotherapy with carboplatin + paclitaxel was initiated. However, after 2 cycles of chemotherapy, disease progression in the lung was observed. Therefore, second-line treatment with pemetrexed was started, which was discontinued after 2 cycles due to further disease progression. Third-line treatment with erlotinib was then administered, with notable benefit, as the patient remains alive after 6 years of treatment with a good performance status. The mutation status of EGFR was unknown.

K-ras wild-type carcinoma is a tumour that is sensitive to treatment with anti-cancer and anti-EGFR drugs: the combination of Cetuximab and Panitumumab with chemotherapy (Cetuximab) or as a single therapy (Panitumumab). Case Report: The clinical case presented here refers to a 68-year-old patient who had been diagnosed with adenocarcinoma of the recto sigmoid with pelvic recurrence three years after surgery. The patient had a severe co-morbidity: correlated B-type liver cirrhosis. First-line chemotherapy was begun with Oxaliplatin plus Capecitabine (CAPOXI) following a relapse, and this continued for six months (six cycles), when the treatment was interrupted because of the disease’s progression and hematological and gastrointestinal toxicity. Following an assessment of the K-ras, diagnosed as wild type, the patient was excluded from second-line chemotherapy treatment because of decompensated cirrhosis and the persistence of thrombocytopenia and leukopenia. The patient was put forward for biological treatment with an anti-EGFR monoclonal antibody (Panitumumab). Panitumumab was administered at a dosage of 6 mg/kg every 2 weeks for 17 months; the treatment was well tolerated, despite the cirrhosis, and the main toxicity was the skin rash. Conclusion: In patients with severe comorbidities such as cirrhosis of the liver and K-ras wild-type carcinomas, therapy with a monoclonal antibody such as Panitumumab is a treatment that is well tolerated, with few serious toxic side-effects; it also offers advantages in terms of survival and clinical benefits.

In humans, two main metabolic enzymes synthesize hydrogen sulfide (H2 S): cystathionine γ lyase (CSE) and cystathionine β synthase (CBS). A third enzyme, 3-mercaptopyruvate sulfurtransferase (3-MST), synthesizes H2 S in the presence of the substrate 3-mercaptopyruvate (3-MP). The immunohistochemistry analysis performed on human melanoma samples demonstrated that CSE expression was highest in primary tumors, decreased in the metastatic lesions and was almost silent in non-lymph node metastases. The primary role played by CSE was confirmed by the finding that the overexpression of CSE induced spontaneous apoptosis of human melanoma cells. The same effect was achieved using different H2 S donors, the most active of which was diallyl trisulfide (DATS). The main pro-apoptotic mechanisms involved were suppression of nuclear factor-κB activity and inhibition of AKT and extracellular signal-regulated kinase pathways. A proof of concept was obtained in vivo using a murine melanoma model. In fact, either l-cysteine, the CSE substrate, or DATS inhibited tumor growth in mice. In conclusion, we have determined that the l-cysteine/CSE/H2 S pathway is involved in melanoma progression.

2047Background: There is no established treatment regimen for recurrent GBM. GBMs have activation of multiple signaling pathways in the tumor microenvironment, including the receptor tyrosine kinas...

Both oxaliplatin (OXA) and gemcitabine (GEM) have shown single agent activity in patients with recurrent ovarian cancer. Response rates to second-line therapies remain low and there is a need to develop more effective regimens. In view of the synergistic effect of using GEM followed by OXA, we studied these agents in elderly patients with recurrent ovarian cancer refractory or resistant to first-line chemotherapy using platinum with or without paclitaxel. The aim of the study was to evaluate the efficacy and toxicity of combination GEM 1000 mg/m(2) Day 1 i.v. and OXA 100 mg/m(2) in 2h infusion Day 2; treatment was repeated every 2 weeks for 6 courses or until progression of disease or intolerable toxicity. The study was monoinstitutional and started in November 2002. 21 patients, median age 68.6 years (range 65-82) have been treated. Median Performance Status was 0-1, all had at least 1 prior platinum based chemotherapy and 11 had received also a taxane. Patients received a median of 6 cycles of treatment (range 4-11). There were 2 patient (9%) with complete response, 3 patients (14%) achieved a partial response. Low profile toxicity (grade 1-2, WHO criteria) was observed: nausea/vomiting 52%, thrombocytopenia 13%, neuropathy 28%. The GEMOX combination is well tolerated and even in this small group of patients, encouraging responses were documented.

Aberrant activation of some members of human epidermal growth factor receptor (HER) family plays a key role in breast carcinogenesis. Lapatinib is an oral dual tyrosine kinase inhibitor selective for inhibition of epidermal growth factor receptor (EGFR/ErbB1) and HER2/ErbB2. Having more targets, probably its antitumor activity could be more efficient. Clinical data have shown that lapatinib is active in HER2-positive breast cancer as monotherapy, in combination with trastuzumab, and in trastuzumab-resistant patients. Phase I clinical trials have shown also that lapatinib is well tolerated, with mild diarrhea and skin rush as common toxic effects and low incidence of cardiotoxicity. Phase II and III clinical trials' data provide encouraging evidence of the clinical effectiveness of lapatinib in advanced or metastatic breast cancer and for its potential in patients with brain metastases. Interim results from the large, phase III trial in 392 patients showed that in combination with capecitabine lapatinib almost doubled time to progression when compared with capecitabine alone. Several clinical trials that explore the efficacy of lapatinib in combination with conventional chemotherapeutic agents [paclitaxel (Taxol), capecitabine and platinoids], hormonotherapy and other target therapies are ongoing in advanced breast cancer or in neo-adjuvant and adjuvant settings. Our improved understanding of the biology of breast cancer and the use of biomarkers for identification of specific subtypes are allowing us to bring patient-specific novel therapies such as lapatinib to the clinic.

TPS2085 Background: GBM is the most common and malignant form of primary brain tumor with a high recurrence rate after surgery, radiation therapy and temozolomide. Currently, there is no established regimen for the treatment of recurrent GBM. GBMs are highly vascularized tumors with high expression of pro-angiogenic factors and activation of multiple signaling pathways in the tumor microenvironment, including the receptor tyrosine kinases, VEGFR, FGFR, and PDGFR, which control the tumor vasculature. REG, an oral multikinase inhibitor, inhibits these angiogenic kinases and the mutant oncogenic kinases KIT, RET and B-RAF. REG was demonstrated to be safe and effective in metastatic colon-rectal cancer, hepatocellular carcinoma and GIST PTS. It was shown that REG inhibits tumor angiogenesis and tumor cell proliferation in rat GBM tumor xenografts (Wilhelm S.M, et al. Regorafenib: a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int. J. Cancer:129,245-255.2011). Methods: Primary aim of the study is to assess the role of REG activity in prolonging the overall survival in relapsed GBM PTS after surgery and Stupp regimen; secondary aims are to analyze progression free survival, objective response rate, disease control rate and quality of life. Eligible PTS with ECOG PS 0-1, documented progression of disease (after Stupp treatment) as defined by RANO criteria, adequate bone marrow, liver and renal function are randomized in a 1:1 ratio to REG 160 mg/die (3 weeks on, 1 week off) or lomustine 110 mg/m2 (every 6 weeks). A total of 112 PTS will be randomized (α = 0.20, β = 0.20) and stratified based on surgery at recurrence. Disease evaluation is performed with gadolinium brain MRI every 8 weeks according to RANO criteria. Additional exploratory objectives include analysis of specific angiogenic and metabolic biomarkers in tissue as possible predictors of response to REG. The trial started in Nov 2015; as of Jan 2017, 105 PTS have been enrolled. Final analysis is planned in Dec 2017. Clinical trial information: NCT02926222.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. In the past few years, the mechanisms of hepato-carcinogenesis have been elucidated and the involvement of a number of pathways, including angiogenesis, aberrant signal transduction, and dysregulated cell cycle control have been demonstrated. Myeloid lineage cells, such as macrophages and monocytes, have been reported to regulate angiogenesis in mouse models. TIE2, a receptor of angiopoietins, conveys pro-angiogenic signals and identifies a monocyte/macrophage subset with pro-angiogenic activity. Recently, one study suggests that TIE2-expressing monocyte/macrophage (TEMs) frequency can be used as a diagnostic marker for HCC.

Cyclin-dependent kinases (cdks) are serine-threonine protein kinases that play a key role in the regulation of the mitotic cycle, in transcription initiation, and in the control of specific metabolic pathways in eukaryotic cells. cdk activity is controlled via phosphodephosphorylation of the catalytic subunits of these enzymes and their physical association with cyclins and cdk inhibitors. In adult rats, estrogen stimulation results in massive proliferation of endometrial epithelial cells, accompanied by functional and structural modifications in all other tissue components of the uterus. We report here that administration of 17β-estradiol (E2) to adult ovariectomized rats induces within the first 25 h significant activation of cdk 4, 5, and 6, but not cdk 2, in the uterus, accompanied by increased expression of D-type (D1-3), A and E cyclin messenger RNAs (mRNAs). Furthermore, expression of the cdk inhibitor p27Kip1, a key regulator of uterine functions, is induced by E2 in this organ. Analysis of RNA ex...

The management of hepatocellular carcinoma (HCC) has substantially changed in the past few decades, the introduction of novel therapies (such as sorafenib) have improved patient survival. Nevertheless, HCC remains the third most common cause of cancer-related deaths worldwide. Decision-making largely relies on evidence-based criteria, as showed in the US and European clinical practice guidelines, which endorse five therapeutic recommendations:resection; transplantation; radiofrequency ablation; chemoembolization; and sorafenib. Many molecularly targeted agents that inhibit angiogenesis, epidermal growth factor receptor, and mammalian target of rapamycin are at different stages of clinical development in advanced HCC. Future research should continue to unravel the mechanism of hepatocarcinogenesis and to identify key relevant molecular targets for therapeutic intervention. Identification and validation of potential surrogate and predictive biomarkers hold promise to individualize patient's treatment to maximize clinical benefit and minimize the toxicity and cost of targeted agents.

e15116Background: Previous findings suggested that bevacizumab might improve clinical outcome in colorectal cancer patients with high basal LDH levels. We conducted a prospective trial to ascertain...

Skin metastases from urothelial carcinoma of the bladder are uncommon, and there are few cases reported in literature. The present case report describes the results of a combination of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) administered as second-line chemotherapy in a cisplatin-resistant metastatic bladder cancer patient. The improvement in cutaneous lesions and pain reduction obtained prompt further exploration of the activity of this regimen in a second-line approach.

BACKGROUND: The FAST is a 2 × 2 factorial trial addressing two questions: (1) the role of replacing cisplatin (P) with a non-platinum agent, vinorelbine (N), and (2) the role of adding a third agent, ifosfamide (I), in a doublet based on gemcitabine (G). METHODS: A total of 433 stage IIIB-IV non-small cell lung cancer (NSCLC) patients were randomised to one of four arms: gemcitabine-cisplatin (GP), gemcitabine-vinorelbine, gemcitabine-ifosfamide- cisplatin or gemcitabine-ifosfamide-vinorelbine. Two comparisons were performed: N- vs P-containing regimens and I-triplets vs non-I doublets. RESULTS: For N- vs P-containing regimens, adjusted overall survival was 9.7 vs 11.3 months (P=0.044), progression-free survival was 4.9 vs 6.4 months (P=0.020) and response rate was 24% vs 31% (P=0.124), respectively. No statistically significant difference was observed between doublets and triplets. Grade 3-4 haematological toxicity was significantly more frequent in P-containing therapy; grade 3-4 leucopenia was significantly more common in triplets. Concerning non-haematological toxicity, grade 3-4 nausea-vomiting was significantly increased in P-containing regimens. CONCLUSIONS: This trial provides evidence of a slight survival superiority of GP-containing regimens over platinum-free N-containing chemotherapy. This trial also confirms that the addition of a third chemotherapy agent (I) to a standard G-based doublet does not improve treatment outcome. © 2012 Cancer Research UK. All rights reserved.

To investigate the therapeutic value and safety of the biweekly regimen of 5-fluorouracil (5-FU) and leucovorin (LV) plus irinotecan (CPT-11) in patients with previously untreated advanced gastric cancer (AGC). A total of 50 patients (M/F 35/15; median age = 65) with AGC, none of whom had received chemotherapy for advanced disease, were accrued in this trial. Fifteen patients (30%) were 70 years old or older. At the time of their accrual, cytotoxic chemotherapy, consisting of LV 100 mg/m(2) (2-hour i.v. infusion) followed by 5-FU 400 mg/m(2) (bolus) and 5-FU 600 mg/m(2) (22-hour continuous infusion) on therapeutic days 1 and 2 plus CPT-11 180 mg/m(2) (1-hour infusion) on day 1, was initiated. Treatment courses were repeated every 2 weeks until evidence of progressive disease, unacceptable toxicity or withdrawal of consent. All patients were assessable for toxicity and 48 of 50 for response evaluation, having completed at least four courses of chemotherapy. Complete response was achieved in 2 patients (4%, intent to treat) and partial response in 16 (32%) (overall response rate, 36%; 95% confidence interval [CI]: 22%-50%). Twenty-four patients (48%) had stable disease and 6 patients (16%) progressed. The median time to progression was 8 months (95% CI: 6-10 months) and median overall survival 14 months (95% CI: 6-22 months). Between the subgroups of patients70 years old and 70 or older, there were no significant differences in efficacy. One toxic death occurred. Treatment tolerance was generally mild to moderate and easy to treat. The main grade 3/4 toxicities were neutropenia (32%), diarrhea (16%), and anemia (8%). Grade 3-4 neutropenia was the only treatment-related serious adverse event significantly more common in patients older than those aged70 (53.3% vs 22.8%, respectively; P = 0.03). Our data suggest that the biweekly regimen of LV and 5-FU plus CPT-11 in untreated patients with AGC is active and has an acceptable safety profile. Further evaluation of this regimen seems to be warranted in a phase III trial.

Background: Biliary tract cancers are uncommon tumors with a poor prognosis. Since most patients present with invasive and inoperable disease at diagnosis, treatment consists of palliative chemotherapy, with poor response rates and a median survival of less than 6 months. Oxaliplatin and gemcitabine have shown interesting activity as single agents in this patient group. Objective: A single-institution phase II study was performed to evaluate the efficacy and safety of combination therapy with oxaliplatin and gemcitabine in locally advanced and metastatic biliary tract carcinomas. Patients and Methods: Combination chemotherapy consisted of gemcitabine 1,000 mg/m2 on day 1 and oxaliplatin 100 mg/m2 on day 2 every 2 weeks. Treatment was administered until disease progression, unacceptable toxicity or patient refusal. Thirty-five consecutive patients with advanced biliary tract carcinoma, aged 18–80 years, with Eastern Cooperative Oncology Group performance status ≤2 were entered into our study from November 2003. Results: Thirty- four patients were evaluable for response and toxicity. According to RECIST criteria, 2 patients had a complete response and 12 had a partial response, with an overall response rate of 41%. Overall survival in our patients was 10 months (range 2–30). According to WHO criteria, 3 patients (9%) suffered from grade 3 neutropenia and 7 patients (21%) from grade 3 thrombocytopenia. Only 3 patients (9%) had grade 3 neuropathy. Conclusions: The GEMOX combination seems to be active with a favorable safety profile in first-line chemotherapy of advanced biliary tract cancers.

Background: A phase II study was conducted to evaluate the efficacy and safety of a combination regimen of a reduced dose intensity of docetaxel (Taxotere) plus capecitabine in pretreated patients with metastatic gastric cancer. Patients and methods: Twenty-eight patients with documented progression on or within 3 months of a cisplatin-based chemotherapy were enrolled between April 2004 and November 2006. Docetaxel (60 mg/m 2 on day 1) plus capecitabine (1000 mg/m 2 twice daily on days 1-14) were given every 3 weeks. Results: All patients were assessable for safety and 25 (89%) for tumor response. Median age was 63 years, and median follow-up was 13.3 months. Overall response rate was 29% (95% confidence interval 11% to 46%), while an additional 36% had stable disease. The median time to progression and median overall survival was 4 and 6 months, respectively. The most common clinical adverse events (all grades) were neutropenia (78%), hand foot symdrome (HFS) (53%), fatigue and alopecia (50%) and diarrhea (43%). However, with the exception of grade 3-4 neutropenia, which was seen in 36% of patients, other severe adverse events were rare. There were no treatment-related deaths. Treatment delays or dose reductions were necessary in 18 out of 104 cycles. Conclusions: A reduced dose intensity of docetaxel plus capecitabine is a valuable regimen for second-line treatment in this setting of patients. This approach warrants further investigation as a promising chemotherapy option for chemonaive patients with metastatic gastric cancer.

To investigate the therapeutic value and safety of a third-line treatment with raltitrexed and mitomycin-C (MMC) in patients with advanced colorectal cancer (ACC) pretreated with combination regimens including 5-fluorouracil (5-FU), irinotecan (CPT-11) and oxaliplatin (L-OHP).A total of 21 patients (PS 1/2, 19/2; M/F 15/6; median age = 73) with ACC, all of whom had developed progressive disease while receiving or within 6 months of discontinuing two sequential chemotherapy lines with 5-FU, CPT-11 and L-OHP, were accrued in this study. At the time of their relapse, cytotoxic chemotherapy, consisting of intravenous raltitrexed 3 mg/m2 plus MMC 6 mg/m2 on therapeutic day 1, was initiated. Treatment courses were repeated every 4 weeks for a total of six courses unless there was prior evidence of progressive disease, unacceptable toxicity or patient refusal occurred.All the patients were assessable for toxicity and 16 for response evaluation, having completed at least two courses of chemotherapy. The overall response rate was 0%. Seven patients (33.6%) had a stable disease and nine patients (43%) progressed. The median time to progression was 2.3 months (95% CI: 1.65-2.95%) and median overall survival (OS) 5 months (95% CI: 2.52-7.48%). No toxic deaths occurred. Third-line treatment tolerance was generally mild to moderate and easy to treat. WHO grade 3/4 anemia, neutro- and thrombocytopenia occurred in 9.5%, 4.7% and 4.7% of the patients, respectively. However, these toxicities did not have a significant impact on global quality of life.Our data suggest that the association of raltitrexed and MMC in patients with ACC pretreated with combination regimens including 5-FU, CPT-11 and L-OHP is feasible and could contribute to increase patients' OS time. Further evaluation of this regimen seems to be warranted.

Overexpression of the cyclin D1 (CCND1) gene, encoding a downstream effector of mitogenic signals that plays a central role in G1 phase progression, is often found in cancerous cells. In sporadic breast cancer (BC), this is one of the most frequent and early genetic lesions identified so far, found in more than 50% of the tumors. Inhibitors of the mevalonate/protein prenylation pathway belong to a new family of cancer therapeutic agents that act by blocking intracellular mitogenic signal transduction pathways, thereby preventing expansion of pre-cancerous foci and inhibiting growth of transformed cells. It is not known at present whether constitutively high intracellular levels of cyclin D1 might interfere with the cytostatic actions of mevalonate/protein prenylation inhibitors. This possibility was investigated here by assessing the cell cycle effects of Simvastatin, a non-toxic upstream inhibitor of the mevalonate pathway, on human BC MCF-7 cells expressing either normal or enhanced levels of cyclin D1 from of a stably transfected, tet-inducible expression vector. Results show that constitutive overexpression of this protein, such as that found in sporadic BCs, does not influence the growth inhibitory effects of Simvastatin in vitro. In addition, D1-overexpressing embryo fibroblasts were also found to be responsive to the cell cycle effects of mevalonate/protein prenylation pathway blockade, further suggesting that high intracellular levels of cyclin D1 do not prevent the cytostatic actions of compounds targeting this metabolic pathway.

Antiestrogens are widely used for breast cancer treatment, where they act primarily by inhibiting the mitogenic action of estrogens on tumor cells. The effects of the pure antiestrogen ICI 182,780 on estrogen-regulated cell cycle phase-specific events were investigated here in synchronously cycling human breast cancer (HBC) cells. In early G 1 -arrested MCF-7 or ZR-75.1 cells, 17β-estradiol (E2) induces rapid activation of the cyclin/Cdk/pRb pathway, as demonstrated by D-type G 1 cyclins accumulation during the first few hours of hormonal stimulation, followed by sequential accumulation of E, A and B1 cyclins and progressive pRb phosphorylation, as cells progress through the cell cycle. When added to quiescent cells together with E2, ICI 182,780 prevents all of the above hormonal effects. Interestingly, in mid-G 1 cells (2–8 h into estrogen stimulation) the antiestrogen causes rapid reversal of hormone-induced D-type cyclins accumulation and pRb phosphorylation, and still fully inhibits G 1 –S transition rate, while in late-G 1 cells it does not prevent S phase entry but still inhibits significantly DNA synthesis rate, S-phase cyclins accumulation and pRb hyperphosphorylation. These results indicate that pure antiestrogens prevent multiple estrogen-induced cell cycle-regulatory events, each timed to allow efficient G 1 completion, G 1 –S transition, DNA synthesis and cell cycle completion.

Inhibitors of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase, such as Simvastatin and Lovastatin, reduce the rate of DNA synthesis and proliferation of a wide variety of cell types in vitro, by inducing a cell cycle arrest in G1. In estrogen-free medium, DNA synthesis is reduced by more that 90% following exposure of normal and transformed human breast epithelia] cells to 20 microM Simvastatin or Lovastatin for 24 to 42 hrs. We show here that stimulation of estrogen responsive MCF-7 cells with nanomolar concentrations of 17beta-estradiol (E2) prevents inhibition of DNA synthesis by these compounds. The effect of the hormone is antagonized by both steroidal and non steroidal antiestrogens, and it is not detectable in estrogen receptor-negative MCF-10a cells. Cell cycle analysis demonstrates that HMG-CoA reductase inhibitors are unable to induce G1 arrest of MCF-7 cells in the presence of E2.

5104 Background: Both OXA and GEM have shown single agent activity in pts with ROC. Responce rates to second-line therapies remain low and there is a need to develop more effective regimens. In view of the synergistic effect using the sequence GEM followed by OXA ( Faivre S, Cancer Chemother Pharmacol 1999, 44(2): 117–23), we studied these agents in pts with ROC heavely pretreated. The aim of the study was to evaluate the efficacy and toxicity of combination of GEM 1000 mg/m2 D1 IV and OXA 100 mg/m2 in 2h infusion D2, treatment was repeated every 2 weeks until progression of desease or intollerable toxicity Methods: The study was monoinstitutional and started in November 2002.To date 15 patients, median age 66 years (range 52–82) have been treated. Median Karnofski Performance Status was 70 % (range 60–90), all had at least 1 prior platinum based chemotherapy and 11 had received a taxane Results: At November 2003 of 15 patients entered onto study, 13 were assesable. Pts received a median of 6 cycles of tr...

A number of second line treatments have been proposed in patients with advanced pretreated non-small cell lung cancer (NSCLC). However, either single agents or two or three drug combinations achieved very poor results with no superiority of any combination over monotherapy. We have treated 42 patients (30 males) affected by advanced/metastatic NSCLC progressing during front line cisplatin-based chemotherapy with a combination of topotecan (1.2 mg/m2) plus ifosfamide (1200 mg/m2) for 3 consecutive days every 3 weeks. The median age was 63 years (range 43-76); cell types were: squamous carcinoma (n=17), adenocarcinoma (n=16), large cell carcinoma (n=3), broncho-alveolar carcinoma (n=2) and undifferentiated carcinoma (n=4). All patients were treated with a platinum containing chemotherapy: 39 patients with cisplatin, 2 patients with carboplatin and 1 patient with oxaliplatin, respectively. The ECOG PS was 0 in 8 patients (19%), 1 in 11 patients (26%), and 2 in 23 patients (55%). The median number of courses administered was 3 (range 1-8). Grade 3-4 neutropenia was the dose limiting toxicity, observed in 36% of patients. Moreover, grade 3-4 anemia and thrombocytopenia were observed in 17% and in 12% of patients, respectively. One PS 2 patient died of grade 4 hematological toxicity after the first cycle. No complete response was observed. Six (14.2%) subjects obtained a partial response (PR). In addition, 1 (2.4%) minimal response (MR) plus 14 (34%) stable diseases (SD) and 21 (51%) progressive diseases (PD) were observed. Median time to disease progression and median survival were 9 weeks (range 1-13) and 26 weeks (range 1-91+), respectively. The 1-year survival rate was 14%. Combination of topotecan and ifosfamide demonstrated antitumor activity in patients with relapsing or refractory NCSLC with a modest side effect profile and an overall disease control (PR + MR + SD) of 50.7%. Nevertheless, the still low response rate and the shortness of median survival indicates the need for more effective second line treatments in this disease.

The Comprehensive Geriatric Assessment (CGA) represents the future of the geriatric oncology to reduce toxicities and treatment-related hospitalization in the elderly. Most patients receiving docetaxel for metastatic castration-resistant prostate cancer are in their seventies or older. We explored the efficacy of the CGA in predicting chemotherapy feasibility and response to docetaxel in a cohort of 24 patients aged at least 70. This was an observational, prospective study involving 24 patients who were 70 years of age or older and about to start chemotherapy with docetaxel for metastatic castration-resistant prostate cancer; we performed a CGA including five domains and divided our patients into 'healthy' and 'frail'; the relations between general condition and (i) early chemotherapy discontinuation and (ii) response to docetaxel were explored. We found a statistically significant relationship between frailty assessed by CGA and early docetaxel discontinuation; we also found an association between frailty and response to chemotherapy, but this did not reach statistical significance. A geriatric assessment before starting chemotherapy may help clinicians to recognize frail patients, and hence to reduce toxicities and early treatment discontinuation. Further analyses are required to simplify the CGA tools and to facilitate its incorporation into routine clinical practice.