Phase I study of paclitaxel and uracil plus tegafur combination in patients with pretreated metastatic breast cancer: drug sequencing based on preclinical modelling studies.

OBJECTIVE: Taxanes and fluoropyrimidines are active in metastatic breast cancer (MBC), and their combination has proven effective in anthracycline-refractory patients. We conducted a phase I study to determine the maximum tolerated dose (MTD) of uracil plus tegafur (UFT) given in combination with leucovorin (LV) and paclitaxel (Pacl) in patients with refractory MBC. METHODS: Pacl was infused at a fixed dose of 150 mg/m2 on day 1. UFT, at doses escalated by 50 mg/m2 starting from 200 mg/m2 . day, and LV, at a fixed dose of 90 mg/day, were given orally every 8 h for 11 days (days 3-13). Cohorts of at least 3 patients were treated at each dose level, and if 1 experienced dose-limiting toxicity (DLT), a maximum of 3 additional patients were added at the same dose level. MTD was reached if 2 out of the 6 patients experienced DLT. RESULTS: Sixteen patients were enrolled in the study. The most important toxicity observed was hematological. Nonhematological toxicities were paresthesia and myalgia, asthenia, nausea, and mucositis. DLT occurred in only 1 patient (grade 3 hepatic toxicity). CONCLUSIONS: The recommended dose for a subsequent phase II trial is Pacl 150 mg/m2 on day 1, and UFT 300 mg/m2 and LV 90 mg on days 3-13, every 2 weeks.

Incidence of second primary cancers in three Italian population-based cancer registries.

This is the first population-based study carried out in a southern European region to evaluate the risk of a cohort of cancer patients for developing further cancers. The Tuscany Tumour Registry, the Ragusa Cancer Registry and the Cancer Registry of Romagna, three of the 14 population-based cancer registries active in Italy, were involved in the present study. Overall, 19,252 incident cases of cancer of the female breast, and of the colon, rectum, lung and stomach were followed-up for 48 358.3 person-years. Only second metachronous cancers were considered. Controlateral breast cancers were analysed separately. Multiple primaries (MPs) were defined according to the IACR-IACR rules. The observed (O) numbers of MPs were compared with those expected (E) from age-, sex- and registry-specific incidence rates. Overall, 463 MPs were diagnosed (O/E = 0.87, P < 0.001). The O/E ratios for cancers of the colon (O/E = 0.66), rectum (O/E = 0.72) and all sites combined (O/E = 0.78) in males were significantly lower than expected. The deficit of observed MPs was significant during the first period (2-12 months) and increased over time. Patients over 65 years of age had a significant lower risk of MP, whereas young cancer patients had significantly higher risks for all cancers and for female breast cancer. Male lung cancer patients had a significantly reduced O/E ratio for stomach cancer (O/E = 0.21). Rectal cancer patients had reduced risks of developing stomach cancer and tumours of all sites combined and a 3-fold increased risk of kidney cancers. Colon cancer patients had an overall reduction in risk of MPs, but female colon cancer patients had a significantly increased risk for tumours of the ovary and small intestine; no significant results were found for primary stomach cancers. Female breast cancer patients had a significantly increased risk of rectal cancer (O/E = 1.97), and when synchronous and bilateral breast cancers were considered, significant overall increases in risk were seen for all cancer sites (O/E = 1.6) and for rectal (O/E = 2), and especially for breast cancers (O/E = 3). The cohort analysed had a lower risk of developing further independent tumours than the general population. Several artefacts may have biased these results: the exclusion of synchronous cancers greatly reduced the overall MP risk, and the age-related differences may have been due to reduced medical surveillance and diagnostic aggressiveness. We have confirmed the increased risk for kidney cancers in rectal cancer patients and the association between cancers of the colon and ovary. The significantly increased risk for rectal cancer in female breast cancer patients is probably due to hormonal and dietary factors. For female breast cancer patients, controlateral breast cancer represented the highest risk. The increased risk of cancer of the small intestine in patients with colon cancer may be due to overdiagnosis within increased medical surveillance.

Paclitaxel plus doxorubicin in breast cancer: an Italian experience.

Based on preclinical data, phase I/II clinical trials were performed at Istituto Oncologico Romagnolo (IOR) Operative Units (Medical Oncology Departments of Forlì, Rimini, and Ravenna, Italy) to determine the efficacy and toxicity of sequential administration of doxorubicin followed by paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in the treatment of patients with advanced breast cancer that either had been previously untreated or that had relapsed after adjuvant therapy. In the phase I trial, 19 patients received bolus doxorubicin (50 mg/m2) followed after a 16-hour interval by paclitaxel (given at dose levels ranging from 130 to 250 mg/m2) by 3-hour infusion every 3 weeks, for a maximum of eight cycles. Paclitaxel doses were escalated in 30-mg/m2 increments if the maximum tolerated dose had not been reached in the previous dose level. Analysis of the 128 cycles assessable for toxicity demonstrated neutropenia (<500/microL) in 26 courses (20.3%), with no significant clinical events. No relevant clinical cardiotoxicity was observed. The paclitaxel maximum tolerated dose was not reached at the 250-mg/m2 dose level (no grade 3 or 4 extramedullary toxicity). In the IOR phase II trial, 13 patients were treated with fixed doses of both drugs (doxorubicin 50 mg/m2 and paclitaxel 220 mg/m2). Grade 4 neutropenia occurred in 39 of the 95 cycles, but was complicated by fever in only eight cycles (8.4%); three cycles required granulocyte colony-stimulating factor support. Peripheral neurotoxicity was the most common extramedullary side effect noted. Overall clinical responses in the IOR trials included 10 complete responses (31.3%) and 15 partial responses (46.9%), with an objective response rate of 78.1%. Comparison of these results with those obtained from a phase I trial using the opposite drug sequence showed comparable overall response rates, but IOR's sequence was associated with a higher complete response rate, as well as less frequent and less severe nonhematologic toxicity.

A phase I/II study of sequential doxorubicin and paclitaxel in the treatment of advanced breast cancer.

Based on preclinical data, we designed a phase I/II clinical trial to determine the efficacy and toxicity of doxorubicin followed by paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in the treatment of patients with advanced breast cancer (either untreated or relapsed after adjuvant therapy). In the phase I study, 19 enrolled patients received bolus doxorubicin (50 mg/m2) and, after a 16-hour interval, escalating doses of paclitaxel (from 130 to 250 mg/m2 in 30-mg/ m2 increments) by 3-hour infusion every 3 weeks for a maximum of eight cycles. Paclitaxel doses were increased if the maximum tolerated dose (MTD; defined by dose-limiting toxicities) had not been reached. Analysis of the 128 cycles assessable for toxicity demonstrated neutropenia (< 500/microL) in 20% of cycles with no significant clinical events. No relevant clinical cardiotoxicity was observed. Other toxicities included mild peripheral neuropathy and mild myalgia/arthralgia (In 37.5% and 30.4% of cycles, respectively). The maximum tolerated paclitaxel dose was not reached at the 250 mg/m2 dose level. In the second phase, 13 patients were treated with fixed doses of both drugs (doxorubicin 50 mg/m2 and paclitaxel 220 mg/m2, the dose level immediately preceding the highest paclitaxel dose used in phase I). Grade 4 neutropenia occurred in 36 of the 87 cycles but was complicated by fever in only eight cycles (9%); three patients needed granulocyte colony-stimulating factor. Peripheral neuropathy (grades 1 and 2 in 41.3% and 5.7% of cycles, respectively) and a myalgic syndrome (grades 1 and 2 in 24.1% and 17.2% of cycles, respectively) were observed. No significant clinical cardiotoxicity was observed in 12 of the 13 patients. One patient experienced a decrease in left ventricular ejection fraction (from 60% to 43%) at a cumulative doxorubicin dose of 400 mg/m2. Antitumor efficacy was evaluated in both phase I and phase II. Overall clinical responses included 10 complete (31.3%) and 15 partial (46.9%) responses, for an objective response rate of 78.1%. Six patients (18.8%) had stable disease. The median durations of objective and complete response were 9 and 7 months, respectively. The 78.9% objective response rate in the phase I trial (31.6% complete and 47.3% partial responses) suggests a dose response relationship: at paclitaxel dose > or = 190 mg/m2, all patients had an objective response (six complete and nine partial responses). These results confirm that doxorubicin followed by paclitaxel is active and should be tested as adjuvant treatment and in patients treated previously with anthracyclines.

The sequential administration of combined doxorubicin and paclitaxel in the treatment of advanced breast cancer.

In phase I and II studies we administered fixed doses of doxorubicin by intravenous bolus 16 hours before escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) for the treatment of patients with advanced breast cancer who had received no prior treatment or who had relapsed after adjuvant therapy. Nineteen patients were entered in the study from April 1994 to February 1995. The median age of participants was 54 years; the median disease-free interval was 328 days. Eleven patients had undergone prior adjuvant chemotherapy, seven had undergone prior hormonal therapy, and six had undergone chest radiotherapy. A total of 128 courses of fixed-dose doxorubicin 50 mg/m2 by intravenous bolus and paclitaxel (doses escalated from 130 to 250 mg/m2, through dose escalations of 30 mg/m2 if maximum tolerated dose was not reached) were repeated every 21 days for a median of seven cycles per patient. Toxicities encountered in this trial included grade 4 neutropenia (20% of courses) and grade 4 thrombocytopenia (3% of courses). No grade 3 or 4 nonhematologic toxicities were observed (World Health Organization grade I peripheral neuropathies and mild myalgias in 37.5% and 30% of courses, respectively). No cardiac toxicity was observed. Responses included six complete responses (31.6%), nine partial responses (47.2%), and three stable disease (15.8%), for an overall response rate of 78.8%. Median duration of overall and complete response was 8+ months and 7+ months, respectively. At dose levels > or = 190 mg/m2, all patients had achieved a response (six complete responses and six partial responses). A phase II trial using fixed doses of doxorubicin (50 mg/m2) and paclitaxel (220 mg/m2) is ongoing. Preliminary data on 71 courses report no cardiac toxicity. Treatment with paclitaxel has been well tolerated at each dose level. The maximum tolerated dose was not reached at 250 mg/m2. No cardiac toxicity was reported. The dosing sequence of doxorubicin followed by paclitaxel is a highly active regimen and needs to be tested in anthracycline patients and in an adjuvant setting.

Vascular complications in patients receiving chemotherapy - what role do 3rd-generation antiemetics play.

Vascular diseases in oncology are often attributed to several factors (hospitalisation, paraneoplastic syndrome, probable damaging effect on epithelium by chemotherapeutic agents) however they are reasonably infrequent events. From 7/10/1993 to 21/3/1994 we observed 8 cases of vascular diseases (venous and arterial) of varying intensity in patients receiving anticancer chemotherapy in association with third generation antiemetics. On the basis of similar experiences reported in the literature of patients undergoing chemotherapy and serotonin-antagonist antiemetics, we performed a detailed analysis of these 8 cases. Few-cases of vascular diseases have been observed in phase II and III studies inpatients treated with ondansetron but the physiopathological mechanism is still not well understood. Of our 8 patients, 5 were female and 3 male, with ages ranging from 36 to 73 years. All cases had different types of solid tumors and had been treated with different chemotherapeutic schemes (two containing cisplatin). All the patients had received varying doses (from 16 to 96 mg for 5 days) of ondansetron. Vascular complications occurred 1 to 3 weeks after treatment and 3 cases are still receiving therapy. It can be noted that two patients who had previously been treated with ondansetron did not develop vascular problems. This drug has been in use in our department since May 1991, but problems of a vascular nature only arose in October 1993. At present a final conclusion cannot be reached as to the link between ondansetron and vascular complications.

Topical prostaglandin E2 and chemo- and radio-induced oral mucositis.

Oral mucositis is a frequent complication of specific antineoplastic treatments. Mouth lesions have a great impact on the quality of life of cancer patients. Current topical and systemic therapies have not yet achieved completely satisfactory results. We studied the effect of topical use of prostaglandin E2 (PGE2) 2.25 mg/day on oral mucositis of 15 chemo- or radio-treated cancer patients. Absolute mean VAS value on mouth pain decreased from 71.2 at TO, to 34.1 at T3 (p<0.001) and to 14.1 at T6 (p<0.001). Objective evaluation according to Miller scale showed significant improvement at day 3 and 6, as well. We suggest that PGE2 could be a useful additional therapeutic agent to palliate oral symptoms.

Doxorubicin and paclitaxel (sequential combination) in the treatment of advanced breast cancer.

Based on preclinical data, we designed a phase I/II clinical trial to determine the efficacy and toxicity of doxorubicin followed by paclitaxel in the treatment of advanced breast cancer (either untreated or relapsed after adjuvant therapy). In the phase I dose-finding study, 19 enrolled patients received bolus doxorubicin (50 mg/m2) and, after a 16-hour interval, a three-hour infusion of paclitaxel in escalating doses from 130 to 250 mg/m2, increased by 30-mg/m2 increments for each dose-level group. The first dose level group (paclitaxel 130 mg/m2) included three patients. The other dose level groups included four patients. Treatment was repeated every three weeks for a maximum of eight cycles. The paclitaxel dose was escalated to 250 mg/m2 without reaching the maximum tolerated dose. In the 128 cycles assessable for toxicity, there were no relevant clinical signs or symptoms of cardiotoxicity. This absence of significant cardiotoxicity required confirmation in a phase II trial. Since a maximum tolerated dose of paclitaxel had not been reached during the first study and an increasing risk of neutropenia and peripheral neurotoxicity was feared if doses continued to escalate, a phase II confirmatory study was begun to evaluate treatment with fixed doses of doxorubicin (50 mg/m2) and paclitaxel (220 mg/m2), using the same schedule and interval as in phase I. The 13 patients enrolled in phase II received a total of 95 cycles of therapy; in 10 cycles (three patients) dose reductions were necessary because of toxicity. However, no significant clinical cardiotoxicity was observed in 12 of the 13 patients. One patient experienced an asymptomatic, transient decrease in left ventricular ejection fraction at a cumulative doxorubicin dose of 400 mg/m2. Overall clinical responses included 10 complete remissions (31.3%) and 15 partial remissions (46.9%) for an objective response rate of 78.1%. At 16 months' median follow-up, the median time to progression for all patients is nine months. The high response rate obtained in the phase I/II studies and, in particular, the absence of significant cardiotoxicity require confirmation in further clinical trials. To date, two confirmatory phase II trials are ongoing in our institutions.

Potentiation of antiproliferative drug activity by lonidamine in hepatocellular carcinoma cells.

The ability of lonidamine (LND), a derivative of indazole-carboxylic acid, to modulate the cytotoxic activity of anticancer drugs was investigated in two human hepatocarcinoma (HCC) cell lines. The cytotoxicity of drugs used singly, in association or in sequence was evaluated using the Sulforhodamine B (SRB) assay. LND did not appreciably potentiate the effect of antitumor drugs when given before or simultaneously, in either cell line. Conversely, a synergistic interaction was observed in both cell lines when LND was given after conventional drugs. LND produced a moderate decrease in S-phase cell fraction and did not induce apoptosis. Conversely, paclitaxel (TAX) induced an important block in G2 and an increase in apoptosis. Following a 48-h TAX wash out, a progressive passage of cells from G2 to M phase was observed with a corresponding increase in apoptotic cells. Post-treatment with LND increased the cytotoxicity of some antitumor drugs, especially TAX, in hepatocarcinoma cells, possibly by preventing, as an energolytic drug, cell damage repair or by producing an additional effect on microtubule stabilization.

A phase II study of advanced colorectal cancer patients treated with combination 5-fluorouracil plus leucovorin and subcutaneous interleukin-2 plus alpha interferon.

Twenty-one patients with advanced, pretreated colorectal cancer in disease progression were entered in a phase II study to investigate the use of 5-fluorouracil (5FU) + leucovorin with subcutaneous Interleukin-2 + alpha interferon (alpha-IFN). Eighteen of these patients were evaluable for response to treatment: 1 partial response (PR) (duration 8 months), 9 stable disease (SD) (median duration of 6.5 months, range 2-15) and 8 progressive disease (PD). The PR patient survived for 15 months, the SD patients for a median of 11 months and 8 months for PD patients. Toxicity evaluated in the 21 patients reached grade 4 for mucositis in two cases. Grade 3 toxicity was observed more frequently for fever (52.3%) and diarrhea (33.3%) and was most probably the result of the combined side-effect of chemotherapy and the biological response modifiers (BRMs). Treatment was, for the most part, carried out on an out-patient basis as originally planned. In 15 patients tests were carried out to verify whether any immuno-activation had taken place. Significant increases were found during the course of therapy regarding cluster of differentiation activation (HLA-DR, CD71, CS25). Different curves were observed during the course of treatment with respect to the CD8 value, which proved higher in SD patients than in PD patients. Our study would seem to suggest that the addition of BRMs to 5FU + leucovorin could increase survival. The next step, however, must be to determine lower doses of IL-2 for subcutaneous administration in order to reduce toxicity but maintain the same immunostimulation.

Agreement estimate among three Italian cancer registries in the coding of multiple primary cancers.

AIMS: The aim of the study was to compare agreement on the coding of multiple primary cancers (MPs) between three italian cancer registries, the Ragusa Cancer Registry (RCR), the Cancer Registry of Romagna (RTRo), and the Tuscany Tumor Registry (RTT), that adhere to different rules for accepting MPs and to study whether coding according to common International rules (IARC-IACR) increased comparability. METHODS: One hundred cases were randomly extracted from the archives of each registry from those recorded as having more than one cancer. For each of the 300 patients, the number of independent cancers was attributed independently by one coder from each registry. The coders coded the series twice: once following the local registry rules and once according to the IARC-IACR rules. The agreement was estimated by couples of coders by means of Cohen's kappa statistics. RESULTS: The agreement on MP status between coders using local rules and definitions was good between the RTT and RCR (kappa = 0.77) and very good between the RTRo and RCR (kappa = 0.81) and the RTT and RTRo (kappa = 0.96). Exclusion of 23 expected discordant cases increased the agreement. The agreement reached with the use of the IARC-IACR rules was very good (RTRo vs RCR, 0.95; RTT vs RTR, 0.94; RTT vs RTRo, 0.95). CONCLUSIONS: The comparison among the RTT, RTRo and RCR confirmed that the number of tumors considered MPs may be modified depending on the rules adopted. There were minor differences between the RTT and the RTRo since their rules were very similar. Most differences in agreement were with the RCR since its classification was conceptually different from the other two. The result on agreement with IARC-IACR rules is encouraging from the point of view of conducting a cooperative study among different registries on the incidence of MPs.

[Combined treatment of inoperable liver metastases from colorectal cancer]. / Combined treatment of inoperable liver metastases from colorectal cancer.

AIMS: Liver resection improves survival in selected patients with colorectal liver metastases. However, the majority of patients with colorectal liver metastases have an inoperable oncological disease. The aim is to investigate whether intra-arterial infusion of chemotherapy, improves response to treatment and may convert a selected group of patients with irresectable liver metastases into an operable state. MATERIALS AND METHODS: Thirty-sex patients (pts) with inoperable hepatic metastases from colorectal cancer were treated with intra-arterial chemotherapy, by angiographic technique. All patients underwent a short 5-FU-based locoregional infusion and the 13 non pretreated patients also received systemic therapy. Evaluation of response was made by CT scan. RESULTS: Total cycles administered angiographically: 132 (range, 1-11). There were no complications associated with the angiographic procedure and no cases of > grade 2 toxicity. One heavily pretreated pt experienced moderate cholangitis and superficial gastric erosion. Thirty-one pts were assessable (20 pretreated and 11 not); there was 1 complete response (CR), 3 partial remissions (PR), 2 stabilizations (SD) among non-pretreated pts (6/11; CR + PR + SD = 55%) and 1 PR and 8 SD among pretreated pts (9/20; PR + SD = 45%). The remaining 16 pts progressed. Four pts became eligible for radical hepatic resection (1 refused surgery and 3 patients were operated on). There was no peri-operative deaths. Median survival of these 3 pts was 24, 28 and 39+ months. CONCLUSIONS: Our data, even if based on a relatively small case series, appear to confirm effective local disease control in this clinical setting. Regional chemotherapy used singly or in combination with systemic chemotherapy may convert a selected group of patients with irresectable liver metastases to an oncological disease that can benefit from surgical treatment.

[Locoregional chemotherapy of locally advanced breast cancer in a pre-treated patient: case report]. / Chemioterapia locoregionale nel carcinoma mammario localmente avanzato in paziente pre-trattata: case report.

We report of the use of intra-arterial chemotherapy in one case of locally advanced breast cancer, that had been systemically pre-treated. Locoregional chemotherapy was delivered via percutaneous access. The catheter tip was placed into the subclavian artery and into origin of the internal mammary artery; it was removed after every cycle of treatment. The schedule of chemotherapy was: epirubicin 30 mg/m2, mitomycin 7 mg/m2 and 5 fluouracil 1000 mg. Three cycles were administered, and the treatment was well tolerated. The patient responded to intra-arterial chemotherapy, and she subsequently underwent complete surgical resection. Intra-arterial chemotherapy for breast cancer in an uncommon approach to the treatment of locally advanced disease. Nevertheless, in selected cases, it could be a more effective therapeutic option for patients with systemic chemotherapy-resistant disease.

[Adjuvant adoptive immunotherapy in patients with stage III and resected stage IV melanoma: a pilot study]. / Adjuvant adoptive immunotherapy in patients with stage III and resected stage IV melanoma: a pilot study.

Adoptive immunotherapy trials with tumor infiltrating lymphocytes (TIL) and interleukin-2 (IL-2) were carried out in the treatment of advanced melanoma with a 34% of overall responses (OR). However, theoretically it should be of greater benefit as adjuvant therapy, especially in high-risk stages (stage III and resected stage IV). In a pilot study, 22 patients (aged 23-72 years) with stage III-IV melanoma who underwent radical metastasectomy were reinfused with TIL cultivated and expanded in vitro with IL-2 from surgically removed metastases. IL-2 (starting dose 12 x 10(6) IU/m2) was co-administered as a continuous infusion according to West's scheme. A total of 8/22 (36.3%) patients were disease-free (DF) at a median follow-up of 5 years. DF survival (DFS) and overall survival (OS) in the remaining 14 patients were 44% and 37% and 52% and 45% at 2 and 3 years, respectively. The CNS was the only site of disease recurrence in 57% of patients who relapsed. DF patients received a higher median dose of IL-2 than those who progressed (total dose 110 x 10(6) vs 86 x 10(6) IU/m2, respectively). The progressive reduction in IL-2 dosage allowed all patients to complete treatment without permanent grade 4 toxicity. The effects of tumor immunosuppression in lymphocytes inside the tumor (TCR z and e chains, p56lck, FAS and FAS-ligand) confirmed that the potential function of TIL, immunodepressed at the time of metastasectomy, was significantly restored after in vitro, culture with IL-2. Adjuvant adoptive immunotherapy with TIL and IL-2 seems to improve DFS and OS, in comparison with literature data. Further studies are required to determine its role in the adjuvant treatment of patients with high-risk melanoma.

[Methodological issues and first results of a record linkage between AIDS and Cancer Registries in Italy]. / Incrocio tra i Registri Tumori italiani e il Registro nazionale AIDS: aspetti metodologici e primi risultati.Cancer and AIDS Registry Linkage Study.

We report herein, the first results of a record linkage between the Italian AIDS Registry and 13 population-based Cancer Registries (about 8-million population in 1991). An anonymous linkage process was carried out on about 339,000 cancer notifications and 6,067 AIDS ones reported between 1982 and 1994. Out of 243 Kaposi's sarcomas (KS) below age 50 years recorded at either type of registry, 90 (37%) were reported as such by both. Sixty-eight percent of individuals with KS at Cancer Registries could be identified at the AIDS Registry. Sixty-two percent of individuals with KS and 65% of individuals reported as having non-Hodgkin's lymphoma (NHL) at RAIDS could be also found at Cancer Registries. Among 6,067 persons with AIDS 15-69 years old, observed and expected numbers of cancer and age-standardised incidence ratios (SIR) on a total of 25,759 person-years were computed. Significantly increased SIR was found for Hodgkin's disease (8.9; 95% CI: 4.4-16.0), invasive carcinoma of the cervix uteri (15.5; 95% CI: 4.0-40.1), and non-melanomatous skin cancer (3.0, 95%, CI: 1.3-5.9). As in previous studies, KS and NHL were greatly increased (SIR = 1,300 and 59, respectively). The risk for all cancer types, after exclusion of KS and NHL, was approximately twice the risk of the general population. An increased SIR of Hodgkin's disease in persons with AIDS is thus confirmed, though many-fold smaller than for NHL. An association with invasive carcinoma of the cervix is also shown at a population level. These data indicate the potential of AIDS and Cancer Registries for improving cancer assessment in individuals with HIV/AIDS and elucidating the role of immune system on cancer onset.

Liver metastases from melanoma: hepatic intra-arterial chemotherapy. A retrospective study.

The liver is the primary site of metastases in most uveal melanoma patients. We retrospectively investigated intraarterial chemotherapy (IAC) as treatment for patients with hepatic melanoma metastases.Twenty-three patients (18 with uveal melanoma) received fotemustine (14 patients, 61.9%) or carboplatin (9 patients, 31.1%) via hepatic IAC delivery. The catheter was introduced through percutaneous access to the femoral artery with drugs delivered directly to the hepatic artery, and was removed at the end of each treatment cycle. A total of 3 cycles was planned, repeated every 21 days. However, patients with a clinical response could receive more than 3 cycles, provided that the toxic effects were acceptable.IAC was well tolerated and no catheter-related complications or grade 4 toxicities were reported. Considering only uveal melanoma patients, the overall response rate and disease control rate was 16.7% and 38.9%, respectively. Median time to progression was 6.2 months (95% CI 3.7-10.5) and median overall survival was 21 months (95% CI 8-39).IAC is well tolerated and is a valid choice for patients with a poor prognosis since median survival rates are among the longest reported.

A phase I/II trial of non-pegylated liposomal doxorubicin, docetaxel and trastuzumab as first-line treatment in HER-2-positive locally advanced or metastatic breast cancer.

AIM: To assess the activity and safety of non-pegylated liposomal doxorubicin (Myocet®) in combination with docetaxel and trastuzumab as first-line treatment of patients with HER-2/neu-positive metastatic breast cancer (MBC). PATIENTS AND METHODS: The maximum tolerated dose of the combination was defined in the phase I part of the study. In the phase II part, 45 HER-2/neu-positive MBC patients were enrolled to receive 6-8 cycles of Myocet® 50 mg/m2 (day 1), docetaxel 30 mg/m2 (days 2 and 9) plus trastuzumab (day 2, 4 mg/kg followed by 2 mg/kg/week) every 21 d until unacceptable toxicity or progression occurred. Objective response (primary end-point) and treatment tolerability were assessed according to World Health Organisation criteria. Cardiotoxicity was defined as signs and/or symptoms of congestive heart failure and/or a decrease in left ventricular ejection fraction (LVEF). RESULTS: The overall response rate was 55.6% (complete response 8.9%, partial response 46.7%), with a median time-to-progression of 10.9 months (C.I. 8.7-15.0). Median overall survival was not reached. The most frequent grade 3-4 adverse events were granulocytopaenia (60.0%), leukocytopenia (43.2%) and alopecia (35.6%). Grade 3-4 diarrhoea, pain, oral and skin toxicity (4.4%, each) and nausea/vomiting, thrombocytopenia and elevated alkaline phosphatase (2.2%, each) were also reported. In 2 patients LVEF fell to <50%, with a decrease from baseline>15%. LVEF median values remained stable from baseline to the end of the study (60%). CONCLUSIONS: The combination of Myocet®, docetaxel and trastuzumab is safe and shows promising activity as first-line treatment of HER-2-positive MBC.

In vitro and in vivo antitumor efficacy of docetaxel and sorafenib combination in human pancreatic cancer cells.

The response of pancreatic cancer to treatments remains unsatisfactory, highlighting the need for more effective therapeutic regimens. Sorafenib, an orally available multikinase inhibitor, is active against different tumors, including pancreatic cancer. We studied the antitumor efficacy of sorafenib in combination with different antitumor drugs currently used in clinical practice in in vitro and in vivo experimental models of human pancreatic cancer. The cytotoxic effect of sorafenib and conventional antitumor drug combinations was evaluated in vitro in human pancreatic cancer cell lines and the efficacy of the most active combination was tested on tumor-bearing mice. Flow cytometric, Western blot and immunohistochemistry analyses were performed to investigate the mechanisms involved in the activity of single drugs and in their interaction when used in combination. Sorafenib showed a strong sequence-dependent synergistic interaction in vitro with docetaxel, which was highly dependent on the drug sequence employed. In vivo, human pancreatic cancer-xenografted mice treated with docetaxel followed by sorafenib reduced and delayed tumor growth, with complete tumor regression observed in half of the mice. This marked antitumor effect resulted in an overall increase in mouse survival of about 70% and in a complete cure in 3 of the 8 treated mice. The strong activity was also accompanied by marked apoptosis induction, inhibition of tumor angiogenesis and downregulation of ERK signalling. Our results show that the docetaxel and sorafenib combination exerts high therapeutic efficacy in experimental models of human pancreatic cancer, indicating a promising antitumor strategy for clinical use.