Combined irinotecan and oxaliplatin in patients with advanced pre-treated pancreatic cancer.

OBJECTIVES: This study evaluated the clinical activity and toxicity of combination chemotherapy with irinotecan and oxaliplatin in patients with advanced pancreatic cancer that had progressed despite > or =1 course of a gemcitabine-containing regimen. METHODS: Thirty patients with metastatic pancreatic cancer and Karnofsky performance status > or =70 received oxaliplatin 60 mg/m2 on days 1 + 15 and irinotecan 60 mg/m2 on days 1 + 8 + 15 every 4 weeks. Patients were assessed on the basis of clinical benefit response, changes in serum tumour marker CA 19-9, objective tumour response, time to progressive disease (TTP), and survival. RESULTS: Six patients (20%) had clinical benefit response (median duration of 7.2 months). CA 19-9 levels were reduced > or =50% from baseline in 8 patients (26%) and remained stable in 8 patients. CT scans revealed that 3 patients (10%) had a partial response and 7 (23%) had stable disease. Two patients (7%) were down-staged and underwent surgery. Median TTP was 4.1 months, median survival was 5.9 months and the 1-year survival rate was 23.3%. The most serious adverse events were grade 3-4 leukopenia in 2 patients (6%), grade 3 neuropathy in 2 (6%) and grade 3 diarrhoea in 1 (3%). CONCLUSION: Chemotherapy with irinotecan and oxaliplatin is an active and well-tolerated combination in patients with advanced pre-treated pancreatic cancer.

Gemcitabine versus FLEC regimen given intra-arterially to patients with unresectable pancreatic cancer: a prospective, randomized phase III trial of the Italian Society for Integrated Locoregional Therapy in Oncology.

Gemcitabine is considered the gold standard treatment for unresectable pancreatic adenocarcinoma. Intra-arterial drug administration had shown some interesting results in small phase II studies. In this study, patients were randomly assigned to receive gemcitabine at a dose of 1,000 mg/m2 over 30 minutes intravenously weekly for 7 weeks, followed by 1 week of rest, then weekly for 3 weeks every 4 weeks or FLEC: 5-fluoruracil 1,000 mg/m2, leucovorin 100 mg/m2, epirubicin 60 mg/m2, carboplatin 300 mg/m2 infused bolus intra-arterially into celiac axis at a 3-week interval 3 times or 5-fluorouracil 400 mg/m2 plus folinic acid 20 mg/m2 for 5 days every 4 weeks for 6 cycles. The primary endpoint was overall survival, while time to treatment failure, response rate, clinical benefit response were secondary endpoints. Sixty-seven patients were randomly allocated gemcitabine and 71 were allocated FLEC intra-arterially. Patients treated with FLEC lived for significantly longer than patients on gemcitabine (p=0.036). Survival at 1 year increased from 21% in the gemcitabine group to 35% in the FLEC group. Median survival was 7.9 months in the FLEC group and 5.8 months in the gemcitabine group. Median time to treatment failure was longer with FLEC (5.3 vs 4.2 months for FLEC vs gemcitabine respectively; p=0.013). Clinical benefit was similar in both groups (17.9% for gemcitabine and 26.7% for FLEC; p=NS). CT-scan partial response was similar in both groups (5.9% for gemcitabine and 14% for FLEC; p=NS). Toxicity profiles were different. Compared with gemcitabine, the FLEC regimen given intra-arterially improved survival in patients with unresectable pancreatic adenocarcinoma.

Intra-arterial chemiotherapy for invasive bladder cancer.

Standard treatment for transitional cell carcinoma confined to the bladder is radical cystectomy that allow to obtain an overall 5-year disease-free survival rate only of 50-70%. It has been demonstrated that intra-arterial chemotherapy produces the same survival outcomes as radical cystectomy. This study aimed to evaluate the activity and toxicity of a bladder-sparing loco-regional treatment. Five patients with transitional cell carcinoma of the bladder (4 locally advanced and 1 pelvic relapse) were treated with doxorubycin 25 mg/m2, cisplatin 40 mg/m2 and methotrexate 50 mg/m2, all infused bolus via internal iliac arteries on day 1, every three weeks. We obtained 3 complete responses, 1 stable disease and 1 progression of disease. The treatment was well tolerated with a minimal hematological toxicity and no others major toxicity. Median disease free survival was 8 months (1-17), median overall survival was 22 months (2-55). This loco-regional regimen of chemotherapy is active and safe in locally advanced bladder cancer patients and permits a prolonged good quality of life regarding the maintenance of the physiological functions of the lower urinary tract.

Molecular therapy: clinical applications. intra-arterial adenoviruses administration.

Gene therapy involves the introduction of foreign DNA into somatic cells to produce a therapeutic effect. The therapeutic gene is transferred into the tumor cells using a vector. Transfer may either be in vivo in which the DNA and vector are directly introduced into the body, or ex vivo, in which cells are removed from the body, transfected with DNA and then reintroduced into the patients. The mode of gene transfer can be classified into chemical, physical and viral (1). Viruses are the most popular vectors in clinical trials because they invade cells and manipulate the cell's machinery to make viral protein; but the immune response they provoke can rapidly destroy the viral vector or the infected cells, blocking production of the useful protein. Most nonviral vector fly under the radar of immune system, but most of them have not been as efficient as viruses in shuttling genes into cells and the genes that were delivered didn't remain active for long. Intra-arterial administration can have advantages over intravenous, and intralesion routes.

Regional combined with systemic chemotherapy in unresectable biliary tract cancers: a phase II study.

Unresectable biliary tract cancers have a very poor prognosis. No good systemic chemotherapeutic regimen is available. This study aimed to evaluated the activity and toxicity of a novel approach of combined loco-regional and systemic chemotherapy. Twenty four patients with advanced or metastatic biliary tumors were treated with epiadriamycin 50 mg/m2 and cisplatin 60 mg/m2 administered bolus in proper hepatic artery on day 1, combined with systemic continuous infusion of 5-fluorouracil 200 mg/m2/day, from day 1 to day 14, every 3 weeks. The overall response rate was 8/24 (33%), including one complete response and 7 partial responses (stable disease 46%, progression 21%). The treatment was well tolerated with a minimal hematological toxicity; the major clinical problem was the deep venous thrombosis related to central venous catheter, that occurred in 5 patients (21%). Median overall survival was 14,6 months and 1-year and 2-year survival were 54% and 38% respectively. Performance status improved in 33% of patients and weight gain more than 7% was observed in 17%. This novel combined loco-regional and systemic chemotherapeutic regimen is active and safe for advanced biliary tract cancer patients.

Randomised trial of gemcitabine versus flec regimen given intra-arterially for patients with unresectable pancreatic cancer.

Gemcitabine is considered the golden standard treatment for unresectable pancreatic adenocarcinoma. Intra-arte-rial drug administration had shown a deep rationale with some interesting results. In a multicenter phase III trial, we compared gemcitabine given weekly with a combination of 5-fluoruracil, leucovorin, epirubicin, carboplatin (FLEC) administered intra-arteriously as first-line therapy in unresectable pancreatic adenocarcinoma. Patients were randomly assigned to receive gemcitabine at a dose of 1,000 mg/m2 over 30 minutes intravenously weekly for 7 weeks, followed by 1 week of rest, then weekly for 3 weeks every 4 weeks or 5-fluoruracil 1,000 mg/m2, leucovorin 100 mg/m2, epirubicin 60 mg/m2, carboplatin 300 mg/m2 infused bolus intra-arteriously at three-weekly interval for 3 times. The primary end point was overall survival, while time to treatment failure, response rate, clinical benefit response were secondary endpoints. Sixty-seven patients were randomly allocated gemcitabine and 71 were allocated FLEC intra-arterially. Patients treated with FLEC lived for significantly longer than patients on gemcitabine (p=.036). Survival at 1 year was increased from 21% in the gemcitabine group to 35% in the FLEC group. Median survival was 7.9 months in the FLEC group and 5.8 months in the gemcitabine group. Median time to treatment failure was longer with FLEC (5.3 vs 4.2 months for FLEC vs gemcitabine respectively; p=.013). Clinical benefit was similar in both groups (17.9% for gemcitabine and 26.7% for FLEC; p=NS). CT-scan partial response was similar in both group (5.9% for gemcitabine and 14% for FLEC; p=NS). Toxicity profiles were different. Compared with gemcitabine, FLEC regimen given intra-arteriously, improved survival in patient with unresectable pancreatic adenocarcinoma.

Epirubicin, cisplatin and continuous infusion 5-fluorouracil (ECF) in locally advanced or metastatic gastric cancer: a single institution experience.

AIMS AND BACKGROUND: The role of chemotherapy in locally advanced or metastatic gastric cancer has been controversial, but chemotherapy has recently been shown to relieve tumor-related symptoms, improve quality of life and prolong survival when compared with best supportive care. Furthermore, palliative chemotherapy is also cost-effective. "Second-generation" combination chemotherapy regimens were developed in the 1980s with high activity in advanced or metastatic gastric cancer (EAP, FAMTX, PELF, ECF). In randomized studies, EAP demonstrated no difference in activity but a significantly higher overall toxicity and toxic death rate than FAMTX, and the ECF (epirubicin, cisplatin, 5-fluorouracil) regimen gave a survival and response advantage, tolerable toxicity, better quality of life and was more cost-effective than FAMTX. METHODS: Sixty patients with locally advanced or metastatic gastric cancer were treated with the ECF regimen (21 weeks of 5-fluorouracil given by continuous infusion through a central line at 200 mg/m2 for 24-hr combined with cisplatin at 60 mg/M2 iv and epirubicin at 50 mg/M2 iv beginning on day 1 and repeated every 3 weeks for 8 courses). There were 42 males and 18 females, with a median age of 64 years (range, 40-74). The median performance status was 1. The histologic type was adenocarcinoma in 44 patients and undifferentiated carcinoma in 16 (27%). Three patients had locally advanced disease (5%) and 57 had metastatic disease (95%). Seven patients (12%) had received prior chemotherapy for advanced disease. RESULTS: All patients were assessable for toxicity and 55 for response (5 had insufficient treatment). Toxicity was mild or moderate, and there was no toxic death. Incidence of WHO toxicity > or = 2 was nausea and vomiting in 3%, mucositis in 3%, leukopenia in 7%, anemia in 3%, and thrombocytopenia in 2%. Port-a-Cath toxicity was thrombosis in 4, dislocation in 2 and infection in 3 patients. Seven complete responses and 13 partial responses (overall response rate, 36%) were achieved, with a response rate of 39% in untreated and 17% in pretreated patients. Nine patients (16%) had stable disease and 26 (47%) progressive disease. Most patients felt symptomatically improved on ECF. CONCLUSIONS: Our study confirms that the ECF regimen has a favorable pattern of toxicity and is feasible on an outpatient basis. However, it did not confirm the high response rate reported in other phase II trials.

Four years experience of primary intra-arterial chemotherapy (PIAC) for locally advanced and recurrent breast cancer.

AIMS: To find a means of achieving operability very quickly without the additional discomfort of prolonging systemic chemotherapy. To improve the patient's quality of life by obtaining quick tumor reduction and decreasing systemic toxicity. MATERIALS AND METHODS: From January 1991 to January 1995, 13 patients with locally advanced breast cancer (LABC) and 8 patients with recurrent breast cancer (RBC), were treated by transfemoral Seldinger technique, with the catheter tip placed into the subclavian artery at the basis of the internal mammary artery. The patients received 5-fluorouracil (5FU) 1000 mg, epirubicin (EPI) 30 mg/m2, mitomycin (MMC) 7 mg/m2 over an infusion for 30 minutes. The cycle was repeated every two weeks for three times. RESULTS: The overall response rate was 62%. Stage IIIb and RBC patients had a response rate of 100% and 25% respectively. In respondent patients a measurable response was seen after the first cycle. Ten patients were radically operated. After a media follow-up of 21 months, the overall survival is 52% at 48 months (68% at 48 months and 65% at 34 months for stage IIIb and RBC patients respectively). CONCLUSIONS: PIAC is feasible and effective. In LABC patients it reaches 100% of response rate. Systemic toxicity was absent and the local one was mild. The interval between the starting of PIAC and operation is short. There was an optimal compliance of the patients.

[Combined intra-arterial locoregional and systemic treatment of nonresectable hepatic metastases of colorectal carcinoma]. / Trattamento combinato locoregionale intra-arterioso e sistemico delle metastasi epatiche non resecabili da carcinoma del colon-retto.

Intra-arterial hepatic chemotherapy (LAHC) results in significantly higher response rate than the best systemic treatment of liver metastases from colorectal cancer, but no survival advantage has to date shown because of extra-hepatic progression. From June 1991 to December 1994, twenty patients with hepatic metastases from colorectal cancer were enrolled. All patients underwent laparotomy for the placement of an intra-arterial catheter into the gastroduodenal artery connected with a subcutaneous port. All patients underwent cholecystectomy and biopsy of liver lesion to confirm metastatic disease. Locoregional schedule was: 5-fluorouracil (5FU) 500 mg/sqm, epirubicin (EPI) 13 mg/sqm, mitomycin-C (MMC) 7 mg/sqm, in bolus every 3 weeks. Systemic therapy consisted of leucovorin 500 mg/sqm, over 2 hours and 5FU 600 mg/sqm in bolus every week. Treatment was planned over a six month period. The complete response (CR) plus partial response (PR) rate was 50% of the entire group. The median survival was 18 months and 1- and 2- and 3-year survival rates were 71%, 38% and 20% respectively. Prior to chemotherapy, LDH value and % of liver involvement were the only significant prognostic parameters. Toxicity was absent or mild and no patient stopped treatment because of side effects. Combined systemic and IAHC is an effective treatment for liver metastases from colorectal cancer, with a mild or moderate toxicity. However, more trials are needed, to improve the control of the extrahepatic disease.

[Prognostic factors in breast carcinoma with negative axillary lymph nodes]. / Fattori prognostici nel carcinoma mammario con linfonodi ascellari negativi.

Conventionally, tumor size, axillary lymph nodes status, histologic type and grading, proliferative activity, steroid receptors have been used to predict the natural history of breast cancer. In node-negative patients with breast cancer it is most important to identify biological markers that can predict the risk of systemic relapse. These features have been used to allow selection of the best treatment. In this paper we describe the prognostic significance of new tumoral markers in breast cancer patients without axillary involvement. We analyze the prognostic role and the correlation with response to treatment of these parameters: ploidy, oncogenes, p53, epidermal growth factor receptor and cathepsin D.

Stomach preservation in low- and high-grade primary gastric lymphomas: preliminary results.

BACKGROUND: The optimal management of primary gastric lymphomas has yet to be defined. In the past surgery was advocated as the optimal first step for patients with PGL. Recently, an increasing number of studies suggest that chemotherapy is as effective as surgery. METHODS: Fourteen patients with PGL were treated with chemotherapy alone. For patients with low-grade lymphoma, chemotherapy consisted of mitoxantrone 5 mg/sqm on days 1 to 3. Treatment courses were administered every 3 weeks up to a maximum of 6 cycles. Patients with high-grade lymphoma received chemotherapy according to the CHOP schedule every 4 weeks up to a maximum of 6 cycles. Two patients with high-grade lymphoma were treated as low-grade lymphoma patients (one because of age and poor performance status, the other because she refused chemotherapy that would cause hair loss). Two patients with low-grade lymphomas who did not respond to mitoxantrone were crossed over to CHOP. RESULTS: All patients were evaluable for toxicity, 13 for response to therapy and survival. Toxicity was mild or moderate. Neither perforation nor hemorrhage was observed. Eleven patients achieved a complete remission (85%), 1 a partial remission (7.5%) and 1 underwent disease progression (7.5%). At a median follow-up of 12 months (range 4-44 months) all complete responders are alive and disease free. CONCLUSIONS: Although the number of evaluable patients is too small to draw any final conclusions, chemotherapy seems to be as effective as surgery in PGL, and stomach preservation improves the quality of life of the patients.

Carboplatin and etoposide in an out-patient schedule for the palliation of advanced non-small-cell lung cancer.

AIMS AND BACKGROUND: In Western countries, non-small-cell lung cancer is the most important cause of cancer-related death. To date, medical treatment for advanced stages remains of a palliative nature. METHODS: Forty-four patients with advanced non-small-cell lung cancer were treated in a phase II study with carboplatin and etoposide (each at 60 mg/m2 daily) in a 5-day schedule. Among 44 patients, 18 (40%) had stage IIIB disease and 26 (60%) had stage IV disease. RESULTS: Treatment was well tolerated, and the only significant side effect was alopecia. The overall response rate was 27% with 2 complete remissions; median survival time was 10.4 months. One of the 2 patients achieving a complete remission was still alive and disease free at 36 months from the start of therapy. An improvement of performance status was observed in 22 patients (50%). CONCLUSIONS: The combinations of carboplatin and etoposide using this schedule appears to be well tolerated and has some activity in the palliation of advanced non-small-cell lung cancer.