BACKGROUND:In Western countries, ovarian cancer (OC) still represents the leading cause of gynecological cancer-related deaths, despite the remarkable gains in therapeutical options. Novel biomarkers of early diagnosis, prognosis definition and prediction of treatment outcomes are of pivotal importance. Prior studies have shown the potentials of micro-ribonucleic acids (miRNAs) as biomarkers for OC and other cancers.METHODS:We focused on the prognostic and/or predictive potential of miRNAs in OC by conducting a comprehensive array profiling of miRNA expression levels in ovarian tissue samples from 17 non-neoplastic controls, and 60 tumor samples from OC patients treated at the Regina Elena National Cancer Institute (IRE). A set of 54 miRNAs with differential expression in tumor versus normal samples (T/N-deregulated) was identified in the IRE cohort and validated against data from the Cancer Genoma Atlas (TCGA) related to 563 OC patients and 8 non-neoplastic controls. The prognostic/predictive role of the selected 54 biomarkers was tested in reference to survival endpoints and platinum resistance (P-res).RESULTS:In the IRE cohort, downregulation of the 2 miRNA-signature including miR-99a-5p and miR-320a held a negative prognostic relevance, while upregulation of miR-224-5p was predictive of less favorable event free survival (EFS) and P-res. Data from the TCGA showed that downregulation of 5 miRNAs, i.e., miR-150, miR-30d, miR-342, miR-424, and miR-502, was associated with more favorable EFS and overall survival outcomes, while miR-200a upregulation was predictive of P-res. The 9 miRNAs globally identified were all included into a single biologic signature, which was tested in enrichment analysis using predicted/validated miRNA target genes, followed by network representation of the miRNA-mRNA interactions.CONCLUSIONS:Specific dysregulated microRNA sets in tumor tissue showed predictive/prognostic value in OC, and resulted in a promising biological signature for this disease.

The treatment of refractory metastatic breast cancer is primarily palliative, without a significant impact on overall survival. Among the innovative combinations in this unfavourable setting, paclitaxel and gemcitabine showed a possible synergistic action and an encouraging activity in some clinical trials. This phase II study was carried out to evaluate paclitaxel-gemcitabine combination in very heavily pretreated advanced breast cancer on a bi-weekly schedule.Thirty-nine women with advanced breast cancer were treated with paclitaxel 150 mg/m2 as 3 hrs infusion, and gemcitabine 1,500 mg/m2 as 30 mins infusion, both drugs administered on days 1, 15, with cycles repeated every 28 days. All but two patients received granulocyte colony stimulating factor (G-CSF) on days 7 to 9 and 20 to 22 of every cycle. More than two third (71%) of the patients had previously received two or more chemotherapy regimens for advanced disease, including almost all active agents in this disease. Objective responses were observed in 18 out of 34 evaluable patients (53%; 95% CI, 36% to 70%). Disease remained stable in 7 patients (21%). Responses by sites were 67% in soft tissue and in bone, and 48% in visceral disease. Median time to progression and overall survival were 9 and 20 months, respectively. Treatment was well tolerated, with G3-4 neutropenia in 8%, and G 1-2 thrombocytopenia in 13% of the patients; non-hematological toxicities were mild, with G3 hepatotoxicity in 5% of the patients, and G3 peripheral neurotoxicity in 10% of the patients. Biweekly paclitaxel/gemcitabine combination with G-CSF support appears to be very active as salvage therapy in heavily pretreated breast cancer patients, with a very favourable safety profile.

Background: Protracted venous infusion of 5-FU increases response rates and reduces toxicity when compared to bolus administration: the mechanism of action of this drug appears to depend on the dose and on the schedule. In some trials 5FU was given as a rapid intravenous push: 30% incidence of severe mucositis or diarrhea was observed. These side effects decreased to less than 10% in trials in which 5 FU was infused over 30 min and much less toxicity was reported when the same dose of 5-FU was given over 1 hour or over 2 hours. The CMF i.v. schedule with bolus administration of all three drugs, in the adjuvant setting of breast cancer, has been shown to be associated with frequent toxicity. Protracted 5-FU infusion in the CMF schedule can reduce toxicity and improve the quality of life. Methods and Results: From July 2003 to December 2004, 42 patients with breast cancer, mean age 58 years (range 43–75) were treated with adjuvant CMF (1.8 every 28 days) with protracted 5-FU infusion (1 hour). Toxicity and compliance were compared to those of 40 patients previously treated in our institution with CMF bolus 5-FU (10 min). Six cycles were administered in all patients. Toxicity was coded by NCI – CTC. We observed that the patients treated with CMF protracted infusion 5-FU showed nausea G2/3: 28% vs 40%, emesis G2-3: 16% vs 27%, diarrhea G2: 0% vs 2%, asthenia: 14% vs 27%, neutropenia: G2: 21%, G3: 4%, G4: 4%, vs G2: 25%, G3: 7%, G4: 7%, mucositis G2-3: 10% vs 15%, and hand-foot syndrome: 2% vs 0%. Compliance in CMF protracted infusion 5-FU was: 6 cycles administered in 90 % vs 85%, day 8 omitted in 23 % vs 25%, dose reduction in 28% vs 30%. Conclusions: In our experience, protracted infusion 5-FU may reduce the gastrointestinal toxicity, particularly nausea compared to bolus infusion of the same drug. We suggest that less toxic treatment schedules are mandatory mainly in frail and/or elderly patients. These preliminary data need further investigations.

Anaplastic thyroid carcinoma is a rare disease with a poor prognosis. Surgery represents the curative treatment for limiting the disease. In the presence of locoregional disease, not suitable for surgery, and for metastastic disease, chemotherapy represents the treatment option. Single agents chemotherapy can produce some responses; doxorubicin is an active drug with a rate of partial response lower than 20%. Association with cisplatin seems to be more active producing a higher rate of complete responses. Liposomal doxorubicin is a new class of anthracyclines, derived from a structural modification of doxorubicin, representing a new form of an old drug with pharmacological characteristics that facilitate a more easy elusion from immune system, a longer half-life, an increased tumor cell uptake and a reduced toxicity if compared with parental drug. Herein we report the first case of an anaplastic thyroid carcinoma treated with the use of liposomal doxorubicin. The encouraging response observed with single agent liposomal doxorubicin (70% according to RECIST criteria) deserves further investigations.

BACKGROUND:This phase II study evaluated the efficacy and the tolerability of a sequential regimen of docetaxel followed by epirubicin-vinorelbine combination as first-line chemotherapy in advanced breast cancer.PATIENTS AND METHODS:Twenty-seven patients received docetaxel 100 mg/m2 (4 cycles) followed by 4 cycles of epirubicin 90 mg/m2 (day 1) combined with vinorelbine 25 mg/m2 (days 1 and 5), with cycles repeated every 3 weeks. G-CSF was administered during epirubicin-vinorelbine treatment.RESULTS:There were 1 (3.7%) CR and 14 (51.9%) PR, for an overall response rate of 55.6% (95% CI, 36.9%-74.3%). Median time to response, time to progression and overall survival were 2, 9 and 25 months, respectively. The dose-limiting toxicity was neutropenia (grade 3 to 4 in 85% of the patients). There was one toxic death due to neutropenic fever. Gastrointestinal side-effects were generally mild According to the Simon two-stage design the response rate was considered unsatisfactory and patient accrual was terminated.CONCLUSION:This sequential regimen appears to be moderately effective; possibly, a modulation of the treatment based on objective responses instead of a fixed number of cycles may be more appropriate in order to obtain better results.

7276 Background: For non-responding pts, no more than 4 courses of a platinum doublet are currently recommended (Pfister et al. JCO 04). Better results might be achieved using different approaches for specific pt subsets (i.e. elderly, PS 2). Based on both the low rate of conversion to response expected continuing the same chemotherapy for pts in SD after 2 courses of GP and the potential hazard of an early discontinuation of P (Novello, ASCO 04 abs. 7069), the present study was designed. Methods: To evaluate the impact of an early switch of P-doublets in pts with advanced NSCLC showing a SD after 2 courses of GP (G 1250 mg/m2 days 1+8, P 75 mg/m2 day 2), 16 eligible pts were switched to ≥2 courses of DP (D 75 mg/m2 and P 75 mg/m2 both on day 1, with CSF primary prophylaxis). Main characteristics were: Age (median): 68 yrs (54–78); M/F: 13/3; ECOG-PS 0/1–2: 4/12; Stage IIIB/IV: 3/10; Histology adeno/others: 7/9. Results: After 2 courses of DP, 5/16 pts (31%) were converted to a PR, 6 remained in SD and 5 progressed. After the 4th course, an additional conversion was seen, for an overall response of 37% (6/16). Median PFS and survival were 6 and 13 mos., respectively. The 1-yr survival was 52%. Main toxicity (G3/4) with sequential DP was greater than with GP, including (% of pts): neutropenia 14% (with no febrile event), anemia and stomatitis 6%, G1–2 asthenia 50%, G1 fluid retention 6%. Dose reductions were required in 32% of courses (18/55). Conclusions: These preliminary results suggest that for pts in SD after 2 courses of chemotherapy this approach is feasible, allowing a promising improvement of response with a conversion rate (37%) greater than expected maintaining the same regimen according to the Novello’s phase III trial (6%). Outcome data also compare favourably with those expected for pts in SD (12 mos.; Hoang WCLC 2003 abs O-274). Although the 2nd step of the trial design continues to the target sample, these preliminary findings may generate hypothesis to be tested in larger randomized trials. (partly supported by AMAN-onlus) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis

BACKGROUND:Ifosfamide (IFO) and cisplatin (CDDP) are active drugs in the treatment of patients with squamous cell carcinoma (SCC) of the head and neck. 13-Cis retinoic acid (RA), along with its antiproliferative and differentiating activity on SCC cell lines, has immunomodulatory and chemopreventive effects. The objective of the current Phase I-II study was to evaluate the combination of CDDP, IFO, and RA in patients with advanced or recurrent SCC of the head and neck. METHODS:Patients with measurable recurrent, metastatic, or locally advanced SCC of the head and neck were eligible. Patients received a fixed dose of 20 mg/m(2) CDDP, and IFO was administered with sodium mercaptoethanesolfonate in three-dose increments (1000 mg/m(2), 1200 mg/m(2), and 1500 mg/m(2)) up to dose limiting toxicity. Both drugs were given for 5 consecutive days every 3 weeks. RA (0.5 mg/kg) was given orally for 5 days per week. RESULTS:Fifty-two patients either with locoregional recurrence or distant metastases (50%) or with locally advanced SCC of the head and neck beyond surgery or radiation therapy (50%) were entered into the trial. Fifteen patients were enrolled in the Phase I study, during which the maximum tolerated dose of IFO was 1500 mg/m(2). In the Phase II study (CDDP 20 mg/m(2) and IFO 1200 mg/m(2)), the response rate was 72% (95% confidence interval, 57-83%). After a median follow-up of 23 months, the median time to disease progression was 10.4 months (range, 2.9-47.2+ months), and the median overall survival was 12.95 months (range, 1.7-47.2+ months). Two patients were converted from a partial response to a complete response with RA. Toxicity was relatively well tolerated and caused no deaths. Grade 3-4 neutropenia was observed in 16 patients, and Grade 2-3 diarrhea toxicity occurred in 9 patients. CONCLUSIONS:The dose and schedule for the combination of CDDP, IFO, and RA that were used in this study are feasible and active in the treatment of patients with SCC of the head and neck, with durable responses and a relatively well tolerated toxicity.

Aims and background We investigated the efficacy and tolerability of two doses of paclitaxel, 175 mg/m2 and 135 mg/m2, over a 3-hr infusion, without prophylactic G-CSF, in heavily pretreated patients with anthracycline-resistant breast cancer. Although paclitaxel may share with anthracyclines a common mechanism of drug resistance, there is evidence that the two drugs are not completely cross resistant. Methods From July 1994 to January 1996, 42 patients were treated every 3 weeks, for a maximum of 6 cycles; paclitaxel dose was established according to pretreatment extension. Results In 41 assessable patients we observed 9 partial responses, for an overall response rate of 22% (95% CI, 10–34%). There was no difference in response rate between the two dose levels. Median duration of response was 9 months, median time to progression 5 months, and median survival 9 months. The dose-limiting toxicity was neutropenia, which was grade 3–4 in 40% (135 mg/m2) and 62% (175 mg/m2) of the patients (P = 0.28); neutropenic fever occurred in 24% of the patients, without significant differences between the two dose levels. Other toxicity was mild to moderate. Conclusions Paclitaxel at doses of 175 mg/m2 or 135 mg/m2 is active and well tolerated in advanced breast cancer patients resistant to anthracyclines. The prophylactic use of colony-stimulating factors seems appropriate in heavily pretreated patients given the higher dose level.

Nintynine pts with ≥ 3cm BC, 56 considered having a resectable tumor (group A, T2 > 3cm or T3, N0-1, M0) and 43 a locally advanced tumor (group B, T4 and/or N2, M0), were treated with PCT consisting of 3 cycles of CEF (CTX 400 mg/m2, EPI 50 mg/m2, 5-FU 500 mg/m2) iv on days 1 and 8, ± G-CSF 300 μg/day so every other day from day 5 to 17. The aims of the study were 1) to substitute conservative for mutilating surgery (group A) or to make resectable unreectable tumors (group B); 2) to improve disease free survial and overall survival (group A and B). Fiftysix pts in the group A and 41 in the group B are evaluable. There were 2 pCR and 46 pPR in group A (85.7%) and 1 pCR and 33 pPR in group B (82.9%). Only 1 pt in group A progressed during treatment. Myclosoppression was the most important side effect, with G3-G4 neutropenia in 42/58 pts (72.41%) treated with CEF plus G-CSF, and in 41/51 pts (80%) treated with CEF alone; the planned dose-intensity of CEF was maintained in 79.31% of the G-CSF pts, and in 31% of the no-G-CSF pts (p<0.0001). For this reason the study is continuing with G-CSF in all of the pts. Breast conserving surgery was carried out in 20/54 pts in group A (37%) and in 8/41 pts in group B(19.5%). The relative low percentage of quandrantectomy in group A was related to a particulary, unfavourable patient population with bifocal or multifocal residual malignancy, or with an extensive intraductal component, and central or retroareolar tumors. After surgery, responsive pts recieved 3 adjuvant cycles of the same CT; non responsive pts recieved 3 cycles of an alternative non-cross resistant adjuvant CT (Vinorelbine + Mitomycin C). Adjuvant CT was followed by RT in pts treated with quadrantectomy or with T4 and/or N2 tumors, and TAM in those with ER+tumors. With a median follow-up of 25 months (range 1–64), we have documented a new disease manifestation in 18 pts in group A (33%) and 16 pts in group B (37.2%). Among the 18 pts who relapsed in group A and the 16 who had a recurrence in group B, 16 and 15, respectively, had a response to PCT (88.8% and 93.7%). The majority of relapsed pts had axillary positive lymphnodes at surgery (66.6 pts group A and 75% group B), notwithstanding the good response to PCT of primary tumor. Therfore, the response to induction chemotherapy of primary tumor may be not sufficient to select the appropriate adjuvant treatment, which should be based on both the response of primary tumor and axillary lymphnodes. In this regard, new biologic parameters (gp 170, p53, bcl-2) will be analyzed. Nintynine pts with ≥ 3cm BC, 56 considered having a resectable tumor (group A, T2 > 3cm or T3, N0-1, M0) and 43 a locally advanced tumor (group B, T4 and/or N2, M0), were treated with PCT consisting of 3 cycles of CEF (CTX 400 mg/m2, EPI 50 mg/m2, 5-FU 500 mg/m2) iv on days 1 and 8, ± G-CSF 300 μg/day so every other day from day 5 to 17. The aims of the study were 1) to substitute conservative for mutilating surgery (group A) or to make resectable unreectable tumors (group B); 2) to improve disease free survial and overall survival (group A and B). Fiftysix pts in the group A and 41 in the group B are evaluable. There were 2 pCR and 46 pPR in group A (85.7%) and 1 pCR and 33 pPR in group B (82.9%). Only 1 pt in group A progressed during treatment. Myclosoppression was the most important side effect, with G3-G4 neutropenia in 42/58 pts (72.41%) treated with CEF plus G-CSF, and in 41/51 pts (80%) treated with CEF alone; the planned dose-intensity of CEF was maintained in 79.31% of the G-CSF pts, and in 31% of the no-G-CSF pts (p<0.0001). For this reason the study is continuing with G-CSF in all of the pts. Breast conserving surgery was carried out in 20/54 pts in group A (37%) and in 8/41 pts in group B(19.5%). The relative low percentage of quandrantectomy in group A was related to a particulary, unfavourable patient population with bifocal or multifocal residual malignancy, or with an extensive intraductal component, and central or retroareolar tumors. After surgery, responsive pts recieved 3 adjuvant cycles of the same CT; non responsive pts recieved 3 cycles of an alternative non-cross resistant adjuvant CT (Vinorelbine + Mitomycin C). Adjuvant CT was followed by RT in pts treated with quadrantectomy or with T4 and/or N2 tumors, and TAM in those with ER+tumors. With a median follow-up of 25 months (range 1–64), we have documented a new disease manifestation in 18 pts in group A (33%) and 16 pts in group B (37.2%). Among the 18 pts who relapsed in group A and the 16 who had a recurrence in group B, 16 and 15, respectively, had a response to PCT (88.8% and 93.7%). The majority of relapsed pts had axillary positive lymphnodes at surgery (66.6 pts group A and 75% group B), notwithstanding the good response to PCT of primary tumor. Therfore, the response to induction chemotherapy of primary tumor may be not sufficient to select the appropriate adjuvant treatment, which should be based on both the response of primary tumor and axillary lymphnodes. In this regard, new biologic parameters (gp 170, p53, bcl-2) will be analyzed.

The evidence of a dose-response effect to anthracyclines in advanced STS prompted us to begin a clinical trial with HD-EPI. We have already reported (Proc ASCO II:414, 1992) a 14% response rate with EPI 120 mg/m2 iv q 3 weeks in 36 sarcoma pts. Since April 1991,48 pts were treated with EPI 160 mg/m2 iv q 3 weeks. Clinical characteristics of pts are the following: M/F = 26/22, median age = 52 years (14–72), median (WHO) PS = 1 (0–2). Pre-treatment: surgery 34/48, chemotherapy 1/48, radiotherapy 15/48, stage of disease IIIB = 17%, IV = 83%. Median number of cycles (in 43 pts evaluable for response) = 6 (range 2–8), median cumulative EPI dose = 740 mg/m2 (range 290–1280 mg/m2). We observed 3 CR and 13 PR (37%) [95% CI, 23%-51%] 14 NC (33%); 13 PD (30%). Responses were observed in 6/IIIiposarcoma, 2/6 leiomyosarcoma, 1/5 MFH, 2(8 synovial sarcoma, 1/3 malignant schwannoma, 1/3 fibrosarcoma, 1/2 stromal sarcoma, 2/4 other types. Median duration of response was 10 months (range 4–38+). Median time to progression was 9 months (range 3–42+). Median overall survival was 14 months (range 3–42+) with a significant difference between responding (17 months) and progressive pts (6.5 months). The most important side effect was myelotoxicity with leukopenia occurring in all patients (G4 38%), thrombocytopenia in 36% (G1–G2 18%) and anemia in 72% (G1–G2 53%) of the pts. In 11/43 pts (26%) EPI dose was reduced because of myelotoxicity. Neutropenic fever occurred in 28% of the pts. Stomatitis was recorded in 36% of the pts and N/V (G3) in 6% of the pts. Cardiotoxicity was monitored in 24 pts by radionuclide angiography. Only 3/24 pts experienced a ≥20% decrease in left ventricular ejection fraction at cumulative doses of 880 mg/m2, 960 mg/m2 and 1280 mg/m2, Clinical cardiotoxicity was not observed. HD–EPI is an effective and reasonably well tolerated treatment in advanced STS. In comparison to our previous study a dose–response effect has been observed at EPI doses of 160 mg/m3. The accrual of pts continues to better define the effectiveness and the toxicity of this treatment.

A phase II study was performed to evaluate the clinical and immunological effects of a regimen of cisplatin (DDP) and etoposide (VP-16) combined with thymosin-alpha 1 (TA1) and low-dose interferon-alpha 2a (IFN) in the treatment of patients with advanced non-small cell lung cancer (NSCLC). Chemoimmunotherapy cycles were repeated every 3 weeks. There were 24 responses (two complete, 22 partial) among 56 assessable patients. Median survival was 12.6 months. Overall, treatment was well tolerated. Natural killer cell activity and lymphocyte subtypes were depressed by chemotherapy, but this effect was less prominent in patients receiving TA1 and IFN in comparison with a concomitant group of patients treated with DDP and VP-16 only. The combination of DDP and VP-16 and TA1 and IFN is effective in advanced NSCLC with acceptable toxicity. However, the results of this study need to be confirmed in a randomised trial.