A phase II study of 5-fluorouracil and high-dose folinic acid in combination with cyclophosphamide and mitoxantrone for advanced breast cancer.

38 patients with advanced breast adenocarcinoma were treated in a phase II study with 5-fluorouracil and high-dose folinic acid combined with cyclophosphamide and mitoxantrone. 6 patients had received prior chemotherapy for advanced disease, all with an anthracycline-containing regimen. Treatment was generally well tolerated. The most common side-effect was myelosuppression, with 1 toxic death due to leukopenia-related sepsis. 1 patient developed severe congestive heart failure 12 months from the end of therapy. 36 patients were evaluable for response. The overall response rate was 55%. Median duration of response was 8 months and median survival time was 16 months. This regimen warrants further investigations.

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.

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.

Breast metastasis from gastric signet ring cell carcinoma, mimicking inflammatory carcinoma. A case report.

We report a case of breast metastasis of signet ring cell gastric cancer clinically presented as a primary inflammatory carcinoma. Metastases to the breast are uncommon; review of the literature demonstrated only 300 cases. The clinical and radiographic features of the metastatic lesion were unlike those reported in the literature. Although a primary signet ring cell breast carcinoma were described, the pathologic patterns of the breast lesion, here reported, lead us to conclude this was a metastasis and not another primary tumor.

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.

Intra-arterial hepatic carboplatin-based chemotherapy for ocular melanoma metastatic to the liver. Report of a phase II study.

AIMS AND BACKGROUND: ocular melanoma tends to metastasize to the liver, sparing for a long time the rest of the organism. Therefore, a regional treatment is especially indicated. METHODS: eight patients with ocular melanoma metastatic to the liver were treated with intra-arterial hepatic carboplatin-based chemotherapy at the dose of 300 mg/m2 once every two weeks at an out-patient clinic. All the patients were submitted to laparotomy with surgical implantation of an arterial port device through the gastroduodenal artery. RESULTS: the overall response rate was 38% with a median survival time of 15 months. The regimen was well tolerated and the principle toxicity was myelosuppression; any instance of hepatic and/or cholangitic damage was reported. CONCLUSIONS: Carboplatin seems suitable for intra-arterial hepatic chemotherapy and active in ocular melanoma metastatic to the liver.

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.

[Pulmonary metastasis from an eccrine carcinoma: thoracic perfusion with the aorto-caval stop-flow technique. Description of a clinical case]. / Metastasi polmonari da carcinoma eccrino: perfusione toracica con tecnica dello stop-flow aorto-cavale. Descrizione di un caso clinico.

A case of a 64-year-old man with eccrine carcinoma arising from hand skin is reported. At the time of diagnosis he showed bilateral pneumonic metastases. Although the patient underwent two systemic chemotherapy lines, he showed further progressive disease of the lung. For this reason a third chemotherapy line was started through thoracic stop-flow infusion. In this way, a five month stable disease had been achieved. The patient died 7 months later for progressive disease. The rarity of this disease, the uncertain treatment, the feasibility and efficacy of thoracic stop-flow infusion are underlined and further studies are suggested.

[Current approaches in the medical treatment of advanced ovarian carcinoma]. / Attuali orientamenti nella terapia medica del carcinoma ovarico in fase avanzata.

Ovarian cancer is most frequently diagnosed at an advanced stage. In recent years there has been intense interest in the chemotherapy of this disease. About cisplatin, the most active agent in the treatment of advanced ovarian cancer, some questions are only partially answered, as the optimal dose, the duration of treatment, the role of ciplatin-based two-, three-, or four-drug regimens, the role of intraperitoneal therapy, the use of old and new drugs in cisplatin-resistant patients. Carboplatin is currently the most important cisplatin analogue with a toxicity pattern very different from that of the parent compound, but, up to date, the combination of these two drugs does not seem to be any better than standard chemotherapy. Among new drugs, three deserve particular attention: taxol, a natural produce from the bark of the Pacific yew Taxus brevifolia, taxotere, a taxoid obtained by semisynthesis from the needles of the European yew Taxus baccata and gemcitabine, a cytostatic agent with a close resemblance to cytosine-arabinoside. Anyway, new approaches must continue to be sought too: among these, probably gene therapy may offer the best mechanism to overcome both intrinsic and acquired drug resistance.

[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.

[Oropharyngeal and rhinopharyngeal carcinomas in patients treated for non-Hodgkin's lymphoma]. / Carcinoma dell'oro- e del rinofaringe in pazienti trattati per linfoma non-Hodgkin.

The authors describe two cases of nasopharynx and oropharynx carcinomas in treated non-Hodgkin lymphoma's patients. They evaluate pathogenetic hypotheses related to lymphoma, its treatment and some exogenous factors like smoke, alcohol, Epstein-Barr virus.

[Lymphoma of the bladder. Description of 2 cases and review of the literature]. / Linfomi a localizzazione vescicale. Descrizione di due casi e revisione della letteratura.

Two case reports and review of the literature. The authors describe one case of primary lymphoma and one case of secondary lymphoma of the bladder. They evaluate the differences, underline the rarity of the primitive type and make a review of the literature.

[Systemic mastocytosis. A review of current diagnostic and therapeutic approaches]. / La mastocitosi sistemica. Revisione degli attuali approcci diagnostico-terapeutici.

Mastocytosis is a heterogeneous group of disorders characterized by abnormal growth and accumulation of mast cells in skin, bone marrow, bone, gastrointestinal tract, liver, spleen and lymph nodes. Today, regarding its biological features, mastocytosis (with or without myeloid accompanying disorders) is considered to be a hematologic disease. The classification proposed by Metcalfe in 1991 is the most useful in caring for patients with mastocytosis. In this classification 4 groups are described: 1) indolent mastocytosis with or without extracutaneous involvement; 2) systemic mastocytosis with an associated hematologic disorder; 3) aggressive mastocytosis; 4) mast-cell leukemia. Cutaneous mastocytosis typically presents as urticaria pigmentosa or diffuse cutaneous mastocytosis and these patients usually have a benign course. On the contrary, systemic mastocytosis is a disease with an increased risk to develop an aggressive hematologic disorder. In these patients a second hematologic process, such as myeloproliferative or myelodysplastic syndrome or acute leukemia, may occur. These patients often present without skin involvement and they have a very poor prognosis. Mast cell is a medium-sized granulated cell releasing chemical mediators (histamine, heparin, protease and cytokines). Mast cells originate from pluripotent hemopoietic progenitor cells that express the CD34 antigen. Mast cells are present in the bone marrow and are distributed throughout the connective tissues. Recently a mast-cell growth factor (MGF) has been identified. Clinical symptoms occur from the release of chemical mediators and the pathologic infiltration of cells. Although no effective therapy for patients with Mastocytosis is known, some patients may benefit from corticosteroid and interferon alpha treatment. The present article gives an overview of current knowledge about the biology, heterogeneity and treatment of human mastocytosis.

[Primary non-Hodgkin's lymphoma of the bone. Description of 2 cases]. / Linfomi non Hodgkin primitivi dell'osso. Descrizione di due casi.

Primary bone non Hodgkin's lymphomas (PBL) are approximately 5% of extranodal lymphomas and 5% of all primary bone tumors. A standard treatment has not been codified yet. The most received only radiotherapy but recently it was introduced combined modality treatment with radiotherapy plus chemotherapy or chemotherapy alone. The authors describe two cases of high grade PBL that received combined treatment with chemotherapy (VACOP-B regimen and monochemotherapy with mitoxantrone respectively) and radiotherapy. The patients achieved complete remission and up to day are alive and disease free at 33 and 15 months from the diagnosis respectively.

[Testicular lymphomas. A clinico-pathological study of 5 cases and a review of the literature]. / I linfomi testicolari. Studio clinico patologico di 5 casi e revisione della letteratura.

The authors describe five consecutive patients with testicular non Hodgkin lymphoma, evaluate the clinical and histological characteristics and underline the importance of a chemotherapy approach both at diagnosis and at relapse. A review of the literature is carried on and particularly about the prognostic factors, the correlation with Ebstein Barr virus and the more recent integrated therapeutical approaches.

[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.

[Cisplatin and cytosine arabinoside (ARA-C) for the therapy of primary and secondary pleural neoplasms]. / Cisplatino e citosina arabinoside (ARA-C) nella terapia delle neoplasie pleuriche primitive e secondarie.

15 patients with primary or metastatic pleural effusion were studied: 2 had diagnosis of malignant mesothelioma and 13 of metastatic pleural disease. The treatment used was based on in vitro and in vivo studies which show a synergy between ARA-C and Cisplatin. These drugs were instilled in pleural cavity at the dose of 100 mg./m2 for Cisplatin and 100 mg. for ARA-C. The cavity was drained after 4 hours. The treatment was repeated weekly. All patients had not been previously treated with loco-regional therapy. The response rate was 93% with 10 loco-regional complete remissions (66%). The two patients with malignant mesothelioma achieved a complete remission. The overall toxicity was acceptable. We conclude that combination of Cisplatin and ARA-C is well-tolerated and produces a very high response rate in the treatment of malignant pleural effusions.

Treatment of primary or metastatic pleural effusion with intracavitary cytosine arabinoside and cisplatin. A phase II study.

Thirty-three patients with microscopically verified primary or metastatic malignant pleural effusion were studied: 7 had malignant mesothelioma and 26 metastatic pleural disease. The treatment was based on biochemical and clinical studies which show a synergy between cytosine-arabinoside (Ara-C) and cisplatin. These drugs were instilled in the pleural cavity at the dose of 100 mg for Ara-C and 100 mg/m2 for cisplatin. The cavity was drained after 4 h. If it was possible, the treatment was repeated weekly for 3 times and, after a 6-week rest, it could be started again with the same schedule. The overall response rate (complete plus partial remissions) was 74%. Toxicity was mild or moderate. We conclude that the combination of Ara-C and cisplatin is well tolerated and produces a high response rate in the treatment of malignant pleural effusions.

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.