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"Context: To date no efficacious treatments are available for advanced medullary thyroid carcinoma (MTC). Objective: We investigated in vitro and in vivo a new strategy for the therapy of MTC, combining human recombinant IL-2 with lanreotide (LAN), a somatostatin analog. Methods: The in vitro effects of LAN on the sensitivity of TT cells, a MTC cell line, to IL-2-stimulated human peripheral blood mononuclear cells were determined by a lactate dehydrogenase release assay. In addition, we evaluated the toxicity, the effects on quality of life, and the antitumor activity of sc low-dose IL-2 in combination with LAN (90 mg every 28 days) in a series of 6 patients with symptomatic and advanced MTC. Results: The cytotoxicity of IL-2-activated peripheral blood mononuclear cells was significantly increased in TT cells treated with LAN or LAN plus IL-2 compared with that in TT cells without treatment. The therapy was well tolerated, and a statistically significant improvement of quality of life was observed in patients treated with the combination of LAN and IL-2. After 6 months of therapy, partial response and stable disease have been recorded in 2 and 3 patients, respectively, with a significant decrease in calcitonin levels in 3 patients. Conclusions: Both in vitro and in vivo evidence suggests that the combination of LAN and IL-2 may have a role in the management of advanced and symptomatic MTC. However, these preliminary data require further validation in larger randomized trials. . . " Context: To date no efficacious treatments are available for advanced medullary thyroid carcinoma (MTC). Objective: We investigated in vitro and in vivo a new strategy for the therapy of MTC, combining human recombinant IL-2 with lanreotide (LAN), a somatostatin analog. Methods: The in vitro effects of LAN on the sensitivity of TT cells, a MTC cell line, to IL-2-stimulated human peripheral blood mononuclear cells were determined by a lactate dehydrogenase release assay. In addition, we evaluated the toxicity, the effects on quality of life, and the antitumor activity of sc low-dose IL-2 in combination with LAN (90 mg every 28 days) in a series of 6 patients with symptomatic and advanced MTC. Results: The cytotoxicity of IL-2-activated peripheral blood mononuclear cells was significantly increased in TT cells treated with LAN or LAN plus IL-2 compared with that in TT cells without treatment. The therapy was well tolerated, and a statistically significant improvement of quality of life was observed in patients treated with the combination of LAN and IL-2. After 6 months of therapy, partial response and stable disease have been recorded in 2 and 3 patients, respectively, with a significant decrease in calcitonin levels in 3 patients. Conclusions: Both in vitro and in vivo evidence suggests that the combination of LAN and IL-2 may have a role in the management of advanced and symptomatic MTC. However, these preliminary data require further validation in larger randomized trials. Copyright © 2013 by The Endocrine Society.

Purpose Approximately 30% to 40% patients with a superficial bladder cancer treated with Bacille Calmette-Guerin (BCG) or epirubicin do not respond; of the initial responders, 35% have a relapse within 5 years. We compare the therapeutic efficacy and toxicity of intravescical infusions of gemcitabine (GEM) with mitomycin (MMC) in patients with a recurrent superficial bladder cancer. Patients and Methods Patients with a history of a previously treated, recurrent Ta-T1, G1-G3 bladder transitional cell carcinoma were enrolled in the study. The patients received a 6-week course of GEM infusions or 4-week course of MMC. In both arms, for the initial responders who remained free of recurrences, maintenance therapy consisted of 10 monthly treatments during the first year. Results A total of 120 patients were enrolled and randomly assigned to either the MMC or GEM treatment arm. At the end of the study, 109 patients (55 in MMC and 54 in GEM) were assessable. The median duration of follow-up was 36 months for either arm. In the GEM arm, 39 (72%) of 54 patients remained free of recurrence versus 33 (61%) of 55 in MMC arm. Among patients with recurrences, 10 in the MMC arm and six in the GEM arm also had a progressive disease by stage. The incidence of chemical cystitis in the MMC arm was statistically higher than in the GEM arm (P = .012). Conclusion This study demonstrates that GEM has better efficacy and lower toxicity than MMC; therefore, GEM appears as a logical candidate for intrabladder therapy in patients with refractory transitional cancer.

PURPOSE: Advanced hepatocellular carcinoma (HCC) not eligible for local therapies has limited chances of cure. Sorafenib is a multikinase inhibitor with proven activity in advanced HCC. Octreotide is used in this setting with conflicting results. Treatment with sorafenib and long-acting octreotide was tested in advanced HCC to evaluate safety and activity. METHODS: Fifty patients with advanced HCC, Child-Pugh A or B, received sorafenib at a dosage of 800 mg/day for 28 days with a following week of rest and long-acting octreotide at a dose of 40 mg, administered every 28 days. RESULTS: All patients were assessable for safety and efficacy. Sixteen patients out of 50 (34%) were naïve from other therapies, while all the others were previously treated with local and/or systemic treatments. We achieved 5 partial responses (10%), 33 stable diseases (66%) and 12 progressions of disease (24%). Median time to progression was 7.0 months (95% CI, 3.0-10.9 months), and median overall survival was 12 months (95% CI, 6.3-17.4 months). Treatment was well tolerated. Diarrhoea (6%) and hypertension (4%) were the most frequent grade 3 toxicities. CONCLUSIONS: Our data suggest that the combination between sorafenib and long-acting octreotide is active and well tolerated in patients with advanced HCC and could represent another efficacious chance for the management of this population.

No standard chemotherapy has been so far definitely settled for elderly patients with metastatic breast cancer (MBC). In order to identify a regimen with acceptable efficacy and low burden of non-overlapping toxic effects, a combination consisting of liposomal pegilated doxorubicin (PLD) with alternating oral and intravenous vinorelbine (NVB) has been investigated in a phase II study.Thirty-four consecutive patients (median age 71 years; range 65-82) with MBC have been enrolled. Based on 4-weekly cycles, PLD 40 mg/m(2) plus NVB 25 mg/m(2) i.v., have been administered intravenously on day 1 and oral NVB 60 mg/m(2) on day 15.All patients were assessable for safety and efficacy. In all, 17 responses were documented with three complete responses (CR) and 14 partial responses, with an overall response rate of 50% (95% CI 36-66). Median overall survival time was 13 months and the median time to progression 8 months. Interestingly, all the patients with CR are still alive with a disease-free survival of more than 1 year. The main toxicity was neutropenia: grade 3 in 15% and grade 4 in 11% of patients, respectively. Febrile neutropenia was recorded in three patients not requiring dose reduction. Other frequently reported adverse events included: anemia, nausea, vomiting, stomatitis, all rarely severe. The evaluation of quality of life (QoL) did not show any significant change during the study.Our data suggest that this combination is active and well tolerated in elderly patients with MBC and could represent another efficacious chance for the management of this population.

Some conditions are predisposed to excessive lymphocyte responses, which can progress to a benign condition, ie, atypical cutaneous lymphoid hyperplasia (ACLH), or a malignant lymphoma. Clinical diagnosis of drug-associated pseudolymphoma can be based on a temporal association between drug ingestion and lesion onset followed by resolution without recurrence after discontinuation of drug administration. Herein, we report the case of a 66- year-old man with advanced colon carcinoma with ACLH developed while receiving chemotherapy regimen with oxaliplatin/5-fl uorouracil/leucovorin. The authors postulate that chemotherapy can promote an aberrant immune response to an antigen that can be the drug itself or other self-antigens.

The molecular mechanisms underlying the growth inhibition of human tumor cells induced by recombinant interferon-alpha (IFN alpha) are mostly unknown. It has been proposed that this effect could be related to down-regulation and/or impaired function of peptide growth factor receptors (PGF-Rs) in tumor cells exposed to IFN alpha. However, we have previously described that IFN alpha-induced growth inhibition of human epidermoid carcinoma cells is paralleled by up-regulation of epidermal growth factor receptor (EGF-R). Here we report that an increase in EGF-R synthesis is detectable after 3 hr of exposure to cytostatic concentration of IFN alpha in epidermoid KB tumor cells. In these experimental conditions IFN alpha does not depress and even potentiates EGF-R function. IFN alpha-treated KB cells retain sensitivity to the cytotoxic activity of the anti-EGF-R 225 monoclonal antibody (MAb), which acts through receptor blockade, and are sensitized to the growth-promoting effect of EGF. EGF-induced tyrosine (tyr) phosphorylation both of total cellular protein extracts and of the immunoprecipitated EGF-R is increased in IFN alpha-treated cells. We conclude that a cross-talk between IFN alpha and EGF occurs in KB cells since IFN alpha, at cytostatic concentration, potentiates the effects mediated by the EGF-R.

Extracellular ATP can often induce tumor cell cytotoxicity; however, the molecular mechanisms of these effects are mostly unknown. We investigated whether modifications in transmembrane ion fluxes are involved in the determination of ATP-cytotoxicity. We have found that cultured human tumor cells derived from colon (LoVo) and lung (A549) carcinomas are resistant to ATP, while LoVo-Dx cells (a doxorubicin-resistant derivative of LoVo cells) and melanoma GLL-19 cells are highly sensitive to this nucleotide. 48 h exposure to 100 nM verapamil increases sensitivity of LoVo and A549 cells to ATP. This effect is completely reverted by the addition of the calcium ionophore A23187. Conversely, 4 h exposure to 100 nM ouabain, which blocks the Na+/K+ exchange pump, neutralyzes ATP cytotoxicity against LoVo-Dx and GLL-19 cells. Furthermore, ATP-mediated cytotoxic effects on these cells are completely antagonized by ADP-beta-S, a non hydrolyzable analogue of ATP. These findings suggest that transmembrane ion flux modifications play a critical role in ATP cytotoxicity and that ATP binding on surface receptors and probably nucleotide hydrolysis are needed for inducing cytotoxicity on human tumor cells.

The incidence of neutropenia following combination chemotherapy is significant in breast cancer and impairs patients' quality of life. Colony-stimulating factors significantly decrease the risk of febrile neutropenia (FN). Aim of the present study was to assess the efficacy and safety profile of once-per-cycle pegfilgrastim in reducing FN in breast cancer patients treated with docetaxel (75 mg/m(2)), epidoxorubicin (75 mg/m(2)), cyclophosphamide (500 mg/m(2)) administered every 3 weeks. Thirty-five breast cancer patients were enrolled. Chemotherapy was administered in adjuvant, neoadjuvant and metastatic setting respectively in 26, 4 and 5 patients. Toxicity was monitored with programmed clinical evaluation and blood sampling. All patients completed the therapeutic programme consisting of six cycles for overall 210 cycles. The FN appeared in 6 out of 35 patients (17%), requiring dose reduction in 3 patients. Hypertransaminasemia was registered in two patients. In one patient pegfilgrastim administration was stopped because of skin hypersensitivity reaction. In conclusion, pegfilgrastim was able to maintain doses and timing of docetaxel/epidoxorubicin/cyclophosphamide in almost all breast cancer patients treated in this series. The reduced need for daily administration of colony-stimulating factors, blood sampling, antibiotic therapy and hospitalization has a significant impact in terms of both quality of life and pharmaco-economic evaluations.

The survival of patients with hepatocellular carcinoma (HCC) has improved with advancements in various diagnostic tools and treatment modalities. Consequently, bone metastases from HCC are diagnosed more frequently. The aims of the present study was to describe the clinical features and treatment of HCC patients presenting with bone metastases. In particular, we evaluated the role of zoledronic acid in these patients especially with regard to pain reduction, analgesic drug consumption and safety.Between December 2006 and July 2008, we recruited 17 (male:female, 12:5, median age, 68 years; age range, 62-85 years) consecutive patients. Spinal metastases were present in 11 patients (64.7%). Zoledronic acid was administered in all patients (total number of administrations, 107; mean number of administrations, 6.29).A total of 15 patients received at least three administrations of zoledronic acid and reported clinical benefit with pain reduction and tapering of analgesic drugs. Before starting treatment, the mean VAS for patients who received at least three administrations (15/17 patients) of zoledronic acid was 7.1 (+/-0.24), and after 3 months 5.3 (+/-0.20). This improvement was independent of the sex, the extent of metastasis and the concomitant anticancer treatment. No significant side effects were registered in this series of patients. Median survival was 10 months (CI 6,353-13,647).Zoledronic acid may be helpful in treating bone metastases in HCC patients. Patients regularly receiving zoledronic acid showed significant pain relief.

BACKGROUND. Temozolomide (TMZ), an oral methylating imidazotetrazinone, has antitumor activity against gliomas, malignant melanomas, and brain metastasis and is presently administered as a 5-day oral schedule every 4 weeks. METHODS. A single-institution phase 2 clinical trial was conducted to determine the efficacy and the safety profile of a new regimen based on a dose-intensified, protracted course of TMZ after whole-brain radiotherapy (WBRT). Patients were eligible if they had at least 1 bidimensionally measurable brain metastasis from breast cancer and nonsmall cell lung cancer (NSCLC). Twenty-seven patients were treated with 30 grays (Gy) of WBRT with concomitant TMZ (75 mg/m2/day) for 10 days, and subsequent TMZ at a dose of 75 mg/m2 per day for 21 days every 4 weeks, for up to 12 cycles. RESULTS. Two complete responses (7.4%) and 11 partial responses (40.7%) were achieved. The schedule appeared to be well tolerated, with grade 3 toxicity (graded according to National Cancer Institute Common Toxicity Criteria) observed in only 2 patients. The overall median survival was 8.8 months and the median progression-free survival was 6 months. CONCLUSIONS. The concomitant use of WBRT and protracted low-dose TMZ appears to be an active, well-tolerated regimen. The observed antitumor activity suggests the need for further investigation of this schedule in combination with other anticancer agents for the concomitant treatment of brain metastases and primary cancers. Cancer 2008. © 2008 American Cancer Society.

Local therapies such as radiofrequency ablation (RFA) represent a valuable choice in limited hepatocellular carcinoma (HCC) and are increasingly used also in advanced tumors. Medical treatments generally gave frustrating results in advanced HCC especially if comorbidities exist. Several biologic non-chemotherapeutic drugs are currently tested in HCC and, among them, octreotide was evaluated in single series of HCC patients reporting conflicting results. We have treated a series of 35 patients affected by advanced HCC (26 M and 9 F; age range: 55-85 years, median: 73 years) with RFA followed by octreotide to primarily evaluate the safety of combined treatment and to give preliminary evaluation on its activity. We have also evaluated serum VEGF changes during the study. Child A and Child B represented 60% and about 34% of the cases, respectively. Only two patients with Child C compensated cirrhosis were included in this study. All patients have multiple liver HCC nodules and one had bone metastases. Two complete responses, 3 partial responses and 23 disease stabilization for at least three months were obtained (overall response rate, 14,2%; clinical benefit, 80%). Mean overall survival was 31.4 months. The combined treatment was well tolerated. Statistically significant correlation was found between serum VEGF and tumor progression. In conclusion, the combination of RFA and octreotide was active in advanced HCC, however, confirmation in a larger series is required.

Bone metastases are a common cause of morbidity in elderly patients with solid tumors and myeloma. We studied the safety and the effect of a new bisphosphonate, zoledronic acid (ZA), on pain and on quality of life (QoL) in elderly patients with bone metastases.From January 2004 to December 2005, we have enrolled elderly patients with bone metastasis for receiving ZA administration. Visual analog scale (VAS) and Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire were used to assess potential benefits of ZA therapy.Eighty-six patients were included; the median age was 75.5 years. Before starting treatment, the mean VAS was 6.8 (+/-0.24), after three infusions 5.4 (+/-0.3), and after six courses 4.5 (+/-0.3) with a significant improvement of bone pain. Moreover, we found a statistically significant improvement of QoL measured by FACT-G questionnaire after six courses (p = 0.010). Median baseline and final value of serum creatinine were 0.73 and 0.72 mg/dl, respectively (p = 0.11); creatinine clearance was also normal for most patients. Osteonecrosis of the jaw was diagnosed in one patient who received a prolonged ZA treatment.These data confirm the benefits of ZA on pain and QoL also in elderly patients with bone metastasis from solid tumors.

Background Brain metastases (BM) represent one of the most frequent complications related to cancer, and their treatment continues to evolve. We have evaluated the activity, toxicity and the impact on Quality of Life (QoL) of a concomitant treatment with whole brain radiotherapy (WBRT) and Temozolomide (TMZ) in patients with brain metastases from solid tumors in a prospective Simon two stage study. Methods Fifty-nine patients were enrolled and received 30 Gy WBRT with concomitant TMZ (75 mg/m2/day) for ten days, and subsequently TMZ (150 mg/m2/day) for up to six cycles. The primary end points were clinical symptoms and radiologic response. Results Five patients had a complete response, 21 patients had a partial response, while 18 patients had stable disease. The overall response rate (45%) exceeded the target activity per study design. The median time to progression was 9 months. Median overall survival was 13 months. The most frequent toxicities included grade 3 neutropenia (15%) and anemia (13%), and only one patient developed a grade 4 thrombocytopenia. Age, Karnofsky performance status, presence of extracranial metastases and the recursive partitioning analysis (RPA) were found to be predictive factors for response in patients. Overall survival (OS) and progression-free survival (PFS) were dependent on age and on the RPA class. Conclusion We conclude that this treatment is well tolerated, with an encouraging objective response rate, and a significant improvement in quality of life (p < 0.0001) demonstrated by FACT-G analysis. All patients answered the questionnaires and described themselves as 'independent' and able to act on their own initiatives. Our study found a high level of satisfaction for QoL, this provides useful information to share with patients in discussions regarding chemotherapy treatment of these lesions.

A phase II clinical trial of subcutaneous recombinant Interleukin 2 (rIL-2) given by 5 days pulses followed by a 9 days rest has been performed in patients affected by renal cell carcinoma, malignant melanoma and colorectal cancer. A total of 25 patients entered the study, completed at least six courses of treatment, and were evaluable for toxicity and response to treatment. This schedule of subcutaneous rIL-2 was well tolerated and no World Health Organization grade 3 side effects were observed. A 33.3% response rate was recorded in patients affected by renal cell carcinoma, although no major responses were achieved in patients with malignant melanoma and colorectal cancer. A durable increase of natural killer activity retained by poeripheral blood mononuclear cells was demonstrated in these patients and was paralleled by increased serum levels of interferon gamma and tumor necrosis factor a without changes of circulating interleukin-1d. It is concluded that this schedule of pulse administration of subcutaneous rIL-2 has antitumor activity in renal cell carcinoma and produces durable biomodulatory effects.

This study reports that extracellular ATP is a critical factor involved in LAK cell-mediated cytotoxicity. Human colon carcinoma LoVo cells were resistant to LAK cells as well as to ATP, while their multidrug resistant (MDR-1+) derivative, LoVo-Dx cells, were sensitive to both LAK and ATP. LoVo-Dx cells, became resistant to LAK cells and ATP after 48 h pretreatment with Phorbol 12-Myristate-13-Acetate (PMA), while 48 h pretreatment with verapamil in parallel sensitized LoVo cells to LAK cells and to ATP as well. The sensitivity to ATP and LAK cells was not related to the expression of extracellular ecto-ATPase activity on cell targets membranes. Conversely, apyrase, an enzyme with powerful ecto-ATPase activity, abolished the LAK- and ATP-mediated cytotoxicity. Furthermore, ADP-β-S, an antagonist of ATP, abolished both LAK and ATP-mediated cell killing. Purine binding sites have been detected by radioreceptor assays with ADP-β[35S] on the cell surface of ATP and LAK-sensitive LoVo-Dx cells. By contrast, no nucleotide receptor was found on the ATP and LAK-resistant cells. Such a putative cytotoxic purinoreceptor has been categorized as P2x purinergic receptor by a panel of synthetic nucleotides. These results demonstrate that extracellular ATP is needed for an efficient LAK cell-mediated killing of tumor cells. We propose that ATP acts as a natural amplifier of physical, or immune cytotoxic damages since it may be released in large amounts from target cells injured by several cytotoxic mediators secreted by LAK effectors.

Bryostatin 1 interferes with protein kinase C (PKC) signaling which is involved in the activation of human and murine cytotoxic T lymphocytes, and in the growth and differentiation of tumor cells. Bryostatin 1 has immunomodulating and antitumor properties as demonstrated by preclinical and clinical studies. Here we report that bryostatin 1 increases the susceptibility to lymphokine activated killers and modifies the pattern of beta 1 integrin expression of human tumor cells. On the basis of these results the use of bryostatin 1 in combination with immunostimulating cytokines such as interleukin-2 in the treatment of human cancer is suggested.

We have demonstrated that interferon-alpha (IFN alpha) upregulates the epidermal growth factor receptor (EGF-R) on human epidermoid carcinoma cells. Here we report that IFN alpha induces growth inhibition and upregulation of transferrin receptor (TRF-R) on epidermoid cancer KB cells. IFN alpha does not alter TRF-R affinity for its ligand and induces a two-fold increase of TRF binding sites. IFN alpha does not modify receptor internalization and cycling. Intracellular iron levels are known to regulate TRF-R expression: we have, therefore, evaluated whether changes in the iron content could be determined by IFN alpha. Iron levels are transiently increased after addition of fresh growth medium in untreated controls but not in KB cells exposed for 48 h to IFN alpha. Iron depletion is however completely reversed 24 h later when maximal TRF-R upregulation occurs in IFN alpha-treated cells. We suggest that IFN alpha-induced iron depletion elicits a homeostatic cellular response through upregulation of TRF-R.

1085 Background: Oral vinorelbine (VNR) is particularly useful in elderly patients due to its favorable toxicity profile. Several studies demonstrated that this drug seems to represent an active treatment for metastatic breast cancer (MCB). We evaluated the clinical efficacy and tolerance of metronomic chemotherapy with oral VNR. Methods: Women were eligible if they had a histologically proven untreated MBC and were > 70 years old. A two-staged Simon accrual design was adopted for this phase II trial. Patients were required to have negative estrogen receptor status, at least one bidimensionally measurable target lesion, Karnofsky performance status >70; life expectancy > 3 months. Each patient received oral vinorelbine 80 mg/m2 fractionated in days 1, 3, and 5, three week on-one week off, every 4 weeks, for a maximum of six cycles unless disease progression or unacceptable toxicity. Results: Thirty-two patients with MBC were eligible, assessable for response, and toxicity. The median age was 75 years (range 70–84), sixteen patients (50%) had a Karnofsky performance status of 90–100. The main comorbidities recorded were: hypertension in 9 (28%) patients and diabetes mellitus in 6 (19%). The overall response rate (on an intent-to-treat basis) was 41% (13 of 32; 95% CI, 20%-54%). Two complete response and 11 partial responses were noted. In addition, other 10 patients (31%) had stable disease of > 4 months duration, and 9 patients (28 %) had disease progression. Median time to disease progression was 7.1 months and median overall survival was 12.7 months. The schedule was well tolerated, grade 3 toxicity was observed only in two patients. Conclusions: Metronomic oral VNR can be safely administered to elderly patients with MBC and is active in this population. Final data analysis will be presented. No significant financial relationships to disclose.

5075 Background: Approximately 30–40% of patients with a superficial bladder cancer treated with Bacille Calmette-Guerin (BCG) or epirubicin do not respond and other 35% of initial responders have a relapse within 5 years. We have compared the therapeutic efficacy and toxicity of intravesical Gemcitabine (GEM) with Mitomycin C (MMC) in patients with recurrent superficial bladder cancer. Methods: Patients with previously treated recurrent Ta-T1, G1-G2 bladder transitional cell carcinoma were enrolled in the present study and randomized to a 6-week course of GEM instillations (2000 mg in 50 ml saline) or 4-week course of MMC (40 mg). In both arms, for the initial responders who remained free of recurrences, maintenance therapy consisted of a 10 monthly treatment during the first year. All patients were followed every 6 months by cystourethroscopy. Results: 120 patients were included in the present study. 109 patients (55 in MMC arm and 54 in GEM arm) were evaluable. The median duration of follow-up was (ide...

12525 Background. Whole brain radiotherapy (WBRT) remains the mainstay of therapy for brain metastasis of solid tumours not amenable to surgical resection. Chemotherapy with temozolomide (TMZ) has emerged as an alterative approach for recurrent brain metastases. It has been already used alone or in combination with radiotherapy in the treatment of primary brain tumours. Protracted administration of TMZ, even at relatively low daily doses, leads to significant and prolonged depletion of enzyme O6-alkylguaninae-DNA alkyltransferase (AGAT) activity, with may enhance the antitumor activity of the agent. Methods. Patients with histologically or cytologically confirmed breast cancer and NSCLC and inoperable brain metastasis were eligible for the study .We have treated 29 consecutive patients (16 F and 13 M, mean age: 55, range 46–76) affected by brain metastases ( 16 non-small-cell lung cancer and 13 breast cancer) with WBRT at 3 Gy/day administered over a two-week period (on wks 1–2), total dose 30 Gy, and an induction with TMZ 50 mg/m2/day during this period, following TMZ 50mg/m2 fractionated in 21 days every 28 days, for up to 12 cycles. Pts who received at least one cycle of TMZ were assessable for response. Results. Twenty-four patients were subjected to the induction therapy and 124 cycles were performed. TMZ was generally well tolerated, and the main toxicities seen were hematologic. The toxicities were generally between grade 1 or 2 in severity although two patients had grade 3 events. Two CR, in patients with breast cancer and NSCLC. Nine partial responses were recorded in 5/11 patients with breast cancer, 4/13 patients with NSCLC, while a stable disease was achieved in other 5 patients. Eight patients showed progressive BM growth during the treatment. The overall response rate was 45.5% (C.I. 38.7–56.9%), while the disease control rate was 77% (C.I. 61.7–82.4%). At the present, the overall survival at 12 months was 64%. Conclusions. We developed a new regimen based on a different strategy: the utilization of a more intensive TMZ dosing schedule that would permit the concomitant use of a second cytotoxic agent on the primary cancer. Final data analysis will be presented. The schedule was safe and well tolerated and has suggested an encouraging activity in brain metastases. No significant financial relationships to disclose.

15173 Background: Local therapies represent a valuable choice in small hepatocellular carcinoma (HCC), however, radiofrequency ablation (RFA) is increasingly used in advanced tumors. Medical treatments generally gave frustrating results in advanced hepatocellular carcinoma. Several biological non chemotherapeutic drugs are currently tested in HCC. Based on the expression of somatostatin receptor subtypes by HCC and the tolerability profile, octreotide was evaluated in single cases and small series of HCC patients and conflicting results are reported. Methods: 35 advanced HCC (26 males, 9 females; age range 55–85 years, median 73 years) were treated with RFA and octreotide with the aim to evaluate safety and determine the effect on disease control and survival. Testing regular and increasing doses of long-acting octreotide (from 20 to 30 mg monthly) were planned in the treatment schedule. Child A and Child B patients were 60% and about 34% of the cases, respectively. Only two patients with Child C compensated cirrhosis were included. All patients have multiple liver HCC nodules and one had bone metastases. Treatment with octreotide was maintained until disease progression or unacceptable toxicity. RFA was performed before or during treatment with octreotide according to medical evaluation. Results: In the majority of patients (65,7%) stable disease was obtained. In 3 patients (8,5%) progression of disease was documented. Clinical progression of underlying cirrhosis was identified in four patients and appear to condition the outcome, independently from HCC. Both medical and local treatments were well tolerated. Statistical evaluation was presented at ASCO 2007. Conclusions: The combined treatment with RFA and octreotide can be feasible in advanced HCC patients. No significant financial relationships to disclose.

10718 Background: Pegylated liposomal doxorubicin and vinorelbine are active single agents in metastatic breast cancer (MBC) and lack overlapping toxicity. The possibility of combining these two drugs therefore seems attractive. Methods: Twenty-five patients with MBC entered a phase II study of pegylated liposomal doxorubicin 40 mg/m2 intravenously (i.v.) on day 1 plus vinorelbine 25 mg/m2 i.v. on day 1 and vinorelbine 60 mg/m2 oral on day 14, every 4 weeks. A two-staged Simon accrual design was adopted for this phase II trial. Patients were required to have measurable disease, previous chemotherapy with or without an anthracycline-containing regimen, and a normal left ventricular ejection fraction (LVEF). Results: Twenty-one patients with MBC were eligible, assessable for response and toxicity. The overall response rate (on an intent-to-treat basis) was 36% (9 of 25; 95% CI, 20%-54%). One complete response and 8 partial responses were noted. In addition, 11 patients (44%) had stable disease of > 4 months duration, and 5 patients (20 %) had disease progression. Median time to disease progression was 10 months (range, 3–38 months) and median overall survival was 15 months (range, 4 to > 62 months). Neutropenia was the most frequent toxicity (grade 4 in 30% of patients and 19% of cycles), but neutropenic fever was seen in only 3 cases. No septic deaths occurred. Nonhematologic grade 3 side effects included skin toxicity (palmar-plantar erythrodysesthesia syndrome, 8%) and mucositis (14%). Late alopecia was seen in 51% of patients (grade 1 in 39%, and grade 2 in 12%). The median LVEFs were 64% (range, 50%-81%) at baseline and 62% (range, 37%-70%) after treatment. Only one patient presented an LVEF decrease to < 50%; however, no clinical heart failure was noted, and this patient recovered normal values after cessation of therapy. Conclusions: The combination of pegylated liposomal doxorubicin and vinorelbine can be safely administered to patients with anthracycline-pretreated MBC and is active in this population. Final data analysis will be presented. No significant financial relationships to disclose.

Krukenberg tumors are uncommon metastatic neoplasms of the ovary with a prominent component of signet ring cells. The occurrence of a Krukenberg tumor in young individuals is rare, with only few cases reported in the second decade of life. The authors describe a case of this tumor diagnosed in an 11-year-old girl, characterized by massive metastatic spread, lack of tumor response and rapidly fatal clinical course. To the best of our knowledge, this is the youngest patient with Krukenberg tumor reported to date.

Introduction Chondrosarcomas and chordomas are usually chemoresistant bone tumors and may have a poor prognosis when advanced. They are usually associated with worsening pain difficult to control. Patients and Methods Zoledronic acid was used in a 63-year-old man with metastatic chondrosarcoma and in a 66-year-old woman with a diagnosis of sacrum chordoma both reporting severe pain related to tumor. Results In the first case, zoledronic acid was able to maintain pain control despite disease progression following chemotherapy, in the other case, zoledronic acid only produced significant clinical benefit. Conclusion Control of pain associated with bone tumors such as chondrosarcoma and chondroma may significantly improve from use of zoledronic acid, independently from tumor response to other treatments. Evaluation on larger series are needed to confirm the clinical effect of this bisphosphonate on such tumors.