Plasma estrone sulfate concentrations and genetic variation at the CYP19A1 locus in postmenopausal women with early breast cancer treated with letrozole.

Estrogen synthesis suppression induced by aromatase inhibitors in breast cancer (BC) patients may be affected by single nucleotide polymorphisms (SNPs) of the gene encoding aromatase enzyme, CYP19A1. We assessed the association between plasma estrone sulfate (ES), letrozole treatment, and four SNPs of CYP19A1 gene (rs10046 C>T, rs4646 G>T, rs749292 C>T, rs727479 T>G) which seem to be related to circulating estrogen levels. Patients were enrolled into a prospective, Italian multi-center clinical trial (Gruppo Italiano Mammella, GIM-5) testing the association of CYP19A1 SNPs with the efficacy of letrozole adjuvant therapy, in postmenopausal early BC patients. SNPs were identified from peripheral blood cell DNA. Plasma ES concentrations were evaluated by Radio Immuno Assay. Blood samples were obtained immediately before letrozole therapy (N = 204), at 6-weeks (N = 178), 6 (N = 152) and 12-months (N = 136) during treatment. Medians (IQR) of ES were 160 pg/mL (85-274) at baseline, 35 pg/mL (12-64) at 6-weeks, 29 pg/mL (17-48) at 6 months and 25 pg/mL (8-46) after 12 months treatment. No statistically significant association was evident between polymorphisms and ES circulating levels during letrozole therapy. Letrozole suppression of the aromatase enzyme function is not affected by polymorphisms of CYP19A1 gene in postmenopausal BC patients.

Timing of adjuvant chemotherapy and tamoxifen in women with breast cancer: findings from two consecutive trials of Gruppo Oncologico Nord-Ovest-Mammella Intergruppo (GONO-MIG) Group.

BACKGROUND: The timing of adjuvant chemotherapy and tamoxifen (TAM) has been investigated only in postmenopausal women with breast cancer. We analyzed the outcome of both pre- and postmenopausal women who entered two randomized trials (Gruppo Oncologico Nord-Ovest-Mammella Intergruppo studies) on adjuvant chemotherapy and received either concomitant or sequential TAM. PATIENTS AND METHODS: Patients who received anthracycline-based regimens and either concomitant or sequential TAM were eligible. The primary end point was overall survival (OS). Hazard ratios (HRs) of death or recurrence for treatment comparisons were estimated by Cox proportional hazards regression models. RESULTS: Among the 1096 eligible patients, 507 (46.3%) and 589 (53.7%) received concomitant and sequential TAM, respectively. The median follow-up time was 6.6 years. Ten-year OS was 83% [95% confidence interval (CI) 78-88%] and 80% (95% CI 74-86%) in the concomitant and sequential groups, respectively. Multivariate analyses confirmed no significant difference in the hazard of death (HR = 1.13; 95% CI 0.78-1.64; P = 0.534) and recurrence (HR = 1.03; 95% CI 0.80-1.33; P = 0.88) between the two groups. A decreasing trend (P = 0.015) in HR of death with increasing age was observed indicating, that concomitant therapy might be more effective than sequential therapy in young patients. CONCLUSIONS: We observed no outcome difference between sequential and concomitant chemo-endocrine therapy. The potential advantage of concomitant TAM in young patients needs to be further addressed in prospective trials.

HER2 expression and efficacy of dose-dense anthracycline-containing adjuvant chemotherapy in breast cancer patients.

No data are available on the role of HER2 overexpression in predicting the efficacy of dose-dense anthracycline-containing adjuvant chemotherapy in breast cancer patients. We retrospectively evaluated this role in patients enrolled in a phase III study comparing standard FEC21 (5-fluorouracil, epirubicin, and cyclophosphamide, administered every 3 weeks) vs dose-dense FEC14 (the same regimen repeated every 2 weeks). HER2 status was determined for 731 of 1214 patients. Statistical analyses were performed to test for interaction between treatment and HER2 status with respect to event-free survival (EFS) and overall survival (OS); EFS and OS were compared within each HER2 subgroup and within each treatment arm. Median follow-up was 6.7 years. Among FEC21-treated patients, both EFS (HR=2.07; 95% CI 1.27-3.38) and OS (HR=2.47; 95% CI 1.34-4.57) were significantly worse in HER2 + patients than in HER2 - patients. Among FEC14-treated patients, differences in either EFS (HR=1.21; 95% CI 0.65-2.24) or OS (HR=1.85; 95% CI 0.88-3.89) between HER2 + and HER2 - patients were not statistically significant. Interaction analysis suggested that the use of dose-dense FEC14 might remove the negative prognostic effect of HER2 overexpression on EFS and OS. Our data suggest a potential role of HER-2 overexpression in predicting the efficacy of dose-dense epirubicin-containing chemotherapy and the need to confirm this hypothesis in future prospective studies.

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.

[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.

[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.

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.

[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.

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.

Acute disseminated intravascular coagulation syndrome in cancer patients.

Hemostatic abnormalities are rather frequent in cancer patients either in hematological or in solid tumors. Acute disseminated intravascular coagulation (DIC) is a rare coagulopathy in cancer patients, but when it develops it becomes rapidly fatal. Between June 1988 and December 1992 we observed 8 cases of acute DIC occurring in gastric cancer (4 patients), breast cancer (3 patients) and high-grade non-Hodgkin lymphoma (1 patient). In 3 patients affected by gastric carcinoma, acute DIC was the first manifestation of the presence of the tumor, while in the other patients DIC occurred during the course of the disease. All the patients were treated with heparin, fresh frozen plasma and platelet support, but only in 1 patient was a short duration improvement of clinical conditions and coagulation tests recorded. Acute DIC can be the first manifestation of gastric tumors and the presence of the hemorrhagic syndrome associated with thrombocytopenia, hypofibrinogenemia and fibrin/fibrinogen degradation products should initiate a search for gastric carcinoma.

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.

[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.

[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.

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.

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.

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.

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.