Adjuvant chemotherapy in gastric cancer: 5-year results of a randomised study by the Italian Trials in Medical Oncology (ITMO) Group.

BACKGROUND: The aim of this study was to determine the efficacy of the EAP regimen (etoposide, adriamycin and cisplatin) followed by the Machover schedule (fluorouracil and folinic acid) given as adjuvant treatment to patients with poor prognostic factors (N+ or T3/4). PATIENTS AND METHODS: Before randomisation, the subjects were stratified on the basis of node involvement (N+ or N-) and the time from surgery to randomisation (< or = 21 days or > 22 days). The surgical procedures for sub-total or total gastrectomy with D2 dissection were standardised among the participating centres. RESULTS: Between December 1992 and December 1997, 274 patients were enrolled: 137 in the treatment arm and 137 in the control arm. The majority of the patients (90%) were N+. After a median follow up of 66 months (range 2-83), the 5-year overall survival (OS) was 52% in the treatment arm and 48% in the control arm [hazard ratio (HR) 0.93; 95% confidence interval (CI) 0.65-1.34]; the 5-year disease-free survival (DFS) was 49% and 44%, respectively (HR: 0.83; 95% CI 0.59-1.17). Among the patients with N-/N+ (1-6), the 5-year OS was 61% in the treatment group and 60% in the control group; in those with N+ (1-6), it was 42% and 22%. The treatment was completed by 87% of patients. Drug-related grade 3/4 WHO toxicities included leukopenia (21%), nausea and vomiting (14%), mucositis (9%), neutropenia (3%) and thrombocytopenia (2%). There were two deaths due to sepsis. CONCLUSIONS: Although our results are not statistically significant, there was a limited relative risk reduction in the patients receiving adjuvant therapy (17% in DFS and 7% in OS). The data suggest that D2 surgery may have a favourable impact on OS.

Sequential tamoxifen and aminoglutethimide versus tamoxifen alone in the adjuvant treatment of postmenopausal breast cancer patients: results of an Italian cooperative study.

PURPOSE: To determine whether switching patients from tamoxifen to antiaromatase treatment would prevent some of the relapses or deaths that we assume would occur if tamoxifen were continued. PATIENTS AND METHODS: Three hundred eighty postmenopausal breast cancer patients receiving adjuvant tamoxifen treatment for 3 years were randomized to either continue tamoxifen for 2 more years or to switch to low-dose aminoglutethimide (250 mg daily) for 2 years. RESULTS: At a median follow-up of 61 months (range, 5 to 94 months), 59 events occurred in the tamoxifen group, and 55 occurred in the aminoglutethimide group. More treatment failures at distant sites, such as viscera (P =.02), were observed in the tamoxifen group. Although no differences in disease-free survival between the two groups have emerged so far, a significant trend favors aminoglutethimide in overall survival (P =.005) and breast cancer-specific survival (P =.06). Even if more patients in the antiaromatase group complained of drug-related side effects and more of them discontinued treatment (P =.0001), the number of cardiovascular events and, in general, of life-threatening adverse events was higher in the tamoxifen arm. CONCLUSION: Switching patients from tamoxifen to aminoglutethimide treatment resulted in comparable event-free survival, but longer overall survival was achieved in patients who were switched to aminoglutethimide as compared with those who continued to receive tamoxifen. Should these preliminary results be confirmed by larger studies with a similar design, which are now testing the effectiveness of the new, more active, and tolerable aromatase inhibitors, sequencing tamoxifen with an aromatase inhibitor could become a preferable alternative to tamoxifen alone in early breast cancer patients.

FEP regimen (epidoxorubicin, etoposide and cisplatin) in advanced gastric cancer, with or without low-dose GM-CSF: an Italian Trial in Medical Oncology (ITMO) study.

The new regimens developed over the last few years have led to an improvement in the treatment of advanced gastric cancer, and our previous experience confirmed the fact that the combination of etoposide, doxorubicin and cisplatin (EAP regimen) is an active treatment that leads to interesting complete remission rates. The primary end point of the present multicentre, randomized, parallel-group phase II study was to determine the activity of the simplified 2-day EAP schedule in patients with locally advanced or metastatic gastric cancer, and to verify whether the addition of low doses of granulocyte-macrophage colony-stimulating factor (GM-CSF) made it possible to increase dose intensity. Of the 62 enrolled patients, 30 were randomized to receive epirubicin 35 mg m(-2), etoposide 120 mg m(-2) and cisplatin 45 mg m(-2) (FEP) on days 1 and 2 every 28 days and 32 to receive the same schedule plus subcutaneous GM-CSF (molgramostin) 150 microg day(-1) on days 5-14 every 21 days. The patients were stratified by age and the number of disease sites. The characteristics of the patients were well balanced between the two groups. The objective response rate of the patients as a whole was 34% (21 out of 62; 95% confidence interval 22-46), with only one complete remission. The median response duration was 4.5 months (range 1-24 months). The median time to treatment failure was 5 months (range 1-14 months), without any difference between the two groups. The median survival of the patients as a whole was 9 months. Full doses were administered in 92% and 94% of the cycles in the control and GM-CSF arms respectively. The average dose intensity calculated for all drugs was 0.96% in the control and 1.27% in the GM-CSF group. CTC-NCI grade 3-4 neutropenia was reported in 39% vs 45% of patients, thrombocytopenia in 11% vs 35% (P = 0.020) and anaemia in 7% vs 35% (P = 0.014). The FEP combination is as active (OR: 34%) in the treatment of patients with advanced gastric cancer as the EAP regimen, although it leads to fewer complete remissions. The patients randomized to receive low-dose GM-CSF achieved a significantly higher dose intensity than controls (P = 0.0001).

Italian Breast Cancer Adjuvant Chemo-Hormone Therapy Cooperative Group Trials. GROCTA Trials.

The first GROCTA trial compared 5-year tamoxifen treatment to ten chemotherapy cycles in a group of 504 pre-/post-menopausal, node-positive, ER-positive breast cancer patients. This study also included an arm combining tamoxifen with chemotherapy. Fifteen-year results showed no difference between tamoxifen and tamoxifen plus chemotherapy, while both treatments were significantly superior to chemotherapy alone. A confirmatory study (GROCTA 02) was performed in 244 pre-/perimenopausal patients by comparing 5 years of tamoxifen treatment (plus 2 years of goserelin) to six CMF cycles. No difference has emerged so far between the tamoxifen and CMF arms at a median follow-up time of 62 months. Post-menopausal women were scheduled to receive 3 years of tamoxifen treatment and then to be randomly allocated to further 2 years of tamoxifen or to 2 years of low-dose aminoglutethimide (GROCTA 04B). So far 662 patients have been entered, 375 of whom have been randomized to tamoxifen (n = 188) or aminoglutethimide (n = 187). Preliminary results (median follow-up time 32 months) show no major difference in patients' outcome. A new trial (ITA trial) with a similar design but employing anastrozole in place of aminoglutethimide has been activated in 1998. The GROCTA 03 study investigated the potential superiority of alternating adjuvant chemotherapy over standard CMF. This study, which included 107 node-positive ER-negative pre-menopausal women, was prematurely closed because more patients allocated to the triple alternated chemotherapy appeared to have relapsed and died at the first interim analysis. The use of high-dose chemotherapy (HDC) was explored by the GROCTA 06 trial which included 53 patients with ten or more involved nodes and a maximum age of 55 years. These patients were scheduled to receive three standard CEF cycles followed by one cycle of HDC (cyclophosphamide 5 g/m2; etoposide 1.5 g/m2; cisplatin 150 mg/m2) without any form of bone marrow rescue. This HDC program proved to be feasible but was not superior to CMF-based chemotherapy we had previously employed in a comparable group of patients in previous GROCTA trials. These findings prompted us to explore new HDC programmes with the use of peripheral stem cell support and in addition the possible value of new drugs such as Taxol and vinorelbine. New-generation trials will also explore the value of new prognostic indicators such as tumor proliferative activity, which are prospectively used to allocate patients to different treatment options.

A multicentre, randomized, pharmacokinetic, endocrine and clinical study to evaluate formestane in breast cancer patients at first relapse: endocrine and clinical results. The Italian Trials in Medical Oncology (I.T.M.O.) group.

BACKGROUND: In postmenopausal breast cancer (BC) patients, tamoxifen (TAM) is frequently used in first-line therapy, and for those relapsing under TAM, aromatase inhibitors would be the drug of choice. Formestane, a new aromatase inhibitor, has been demonstrated to be as effective as TAM in first-line therapy. This trial was carried out to investigate the pharmacokinetics and antitumor activity of two formestane doses in BC patients at first relapse, as well as their effects on estrogen levels, evaluated by means of a new analytical method. PATIENTS AND METHODS: One hundred fifty-two postmenopausal BC patients were randomly given formestane 250 mg or 500 mg intramuscularly every two weeks. The blood samples for estrogen measurements were taken on the first day of therapy, at 4 and 10 weeks, and every 12 weeks thereafter. Tumor response was first evaluated after 2.5 months, and then every three months. RESULTS: Seventy-three patients received formestane 250 mg and 79 received 500 mg. After four weeks, plasma estrone, estradiol and estrone sulphate levels were significantly (P < 0.001) suppressed in both groups. The overall response rates were 30% and 40% on 250 mg and 500 mg, respectively. CONCLUSIONS: Both of the formestane doses are effective in reducing plasma estrogen levels in BC patients at first relapse, and the new analytical method improved the quality of results. The antitumor response was highly satisfactory.

Recovery of response to adriamycin and cyclophosphamide by lonidamine in previously treated metastatic breast-cancer patients.

Thirty-one patients with metastatic breast cancer not responding or progressing after initial response to adriamycin + cyclophosphamide (AC) treatment entered a phase 11 study with oral lonidamine in association to AC. Objective clinical responses were observed in 10 patients (32%) and consisted of 1 complete + 9 partial remissions. Disease stability and progression were observed in 8 and 13 cases, respectively. These results were obtained with a marginal toxicity in addition to that already reported for AC therapy, the main additional side effect being myalgia, which was easily manageable in most cases.

[Chronic eosinophilic pulmonitis with eosinophilic pleurisy. A report on 2 clinical cases seen by the authors]. / Polmonite cronica eosinofila con pleurite eosinofila. Descrizione di due casi clinici di nostra osservazione.

We discuss the cases of two patients affected with chronic eosinophilic pneumonia (CEP) pleurisy and eosinophilia in pleural effusion, not previously mentioned in the literature, to point out their peculiarity, to consider differential diagnosis and the effect of steroid therapy. Both patients, a 57-year-old man and a 55-year-old woman, were atopic: they had been suffering from allergic rhinitis and asthma for several years when they suffered sudden onset of cough, dyspnea and thoracic pain. This symptomatology persisted for more than 6 weeks. Chest radiography highlighted pulmonary infiltrates, not fixed in the first case, fixed in the second. The laboratory features revealed eosinophilia in peripheral blood and in pleural effusion. These data conformed to the criteria suggested by Jederlinic et al. for the diagnosis of chronic eosinophilic pneumonia. Tuberculosis had been present in the remote history of the second case; the repeated research for mycobacteria was negative, and no improvement was seen after antitubercular chemotherapy for one month. We excluded the diagnosis of allergic bronchopulmonary aspergillosis because of the absence of both precipitating antibodies against Aspergillus fumigatus and bronchiectasis. Neither vasculitis nor autoantibodies were found; possible drug-related correlations were excluded; culture data and serological researches for infections were negative in both cases; no involvement of other districts correlated to hypereosinophilia was evidenced. Clinical and radiological remission was obtained in both cases after steroid therapy for a month at the dosage of 1-2 mg/kg daily. No clinical recurrence was seen during a follow-up period of 6 months. Pleural effusion has already been reported in patients with CEP, while we have not found any references to pleural fluid eosinophilia in this disease; this finding has instead been already reported in patients affected with acute eosinophilic pneumonia or hypereosinophilic syndrome.

Neutrophil function during cyclic chemotherapy for cancer disease.

A study of some aspects of granulocyte function was carried out before, during, and after cyclic chemotherapy in 9 patients surgically treated for carcinoma and in 6 patients with very advanced and inoperable cancer. In most patients, total leukocyte mobilization, Candida-stimulated nitroblue tetrazolium dye reduction, and phagocytosis increased after chemotherapy. Furthermore, delayed hypersensitivity skin reactions to PPD and above all to Varidase increased in the same cases. A significant correlation between accumulation of polymorphonuclear leukocytes into skin chambers and skin tests was found in both groups of patients (p less than 0.001). In some instances, fluctuations in the levels of circulating immune complexes without a distinct correlation between these complexes and granulocyte function were found. The data support the hypothesis that depressed granulocyte function may contribute to an increased susceptibility to infections and may be considered an additional factor that favors tumor dissemination. Chemotherapy seems to restore polymorphonuclear function and delayed hypersensitivity skin reactions.

Clinical staging and therapeutic results in multiple myeloma.

The validity of the Durie and Salmon's clinical staging system for multiple myeloma has been tested in 81 consecutive patients studied at the Istituto Nazionale Tumori of Milan from January 1970 to June 1982. Median survival from diagnosis was 48 months for stage I, 41 months for stage II and 23 months for stage III (P = 0.02). Median survival of patients with normal renal function (A) was 35 months and of those with abnormal kidney function (B) 7 months. Almost all early deaths were observed in patients with stage III disease associated with renal failure. No statistically significant difference was found in the median survival in patients with kappa and those with lambda light chains. The analysis of survival according to the three main combinations of chemotherapy used in this study (melphalan-prednisone vs melphalan-procarbazine-prednisone vs adriamycin-prednisone) could not disclose any significant difference. Prognosis was, however, closely related to the response to combination chemotherapy: median survival was 72 months in responders, 36 months in patients with improvement and 25 months in non-responders (P less than 0.01). A lower incidence of response was obtained in patients with stage III myeloma compared to patients with stage I-II. The myeloma staging system used in this study is simple to employ and allows identification of truly comparable patient groups in the evaluation of therapeutic results. Our therapeutic results confirm the effectiveness of melphalan plus prednisone and fail to demonstrate any advantage in the administration of adriamycin as first-line therapy.

Defective function of granulocytes in patients with cancer.

Mobilization of granulocytes into a serum-filled chamber, histochemical nitroblue tetrazolium (NBT) reduction tests, and phagocytosis were performed in 11 patients with solid tumors treated with surgical excision and chemotherapy and in 22 untreated or surgically treated patients. The results revealed a decreased mobilization (p less than 0.001) and an impaired capability of neutrophils to reduce NBT after stimulation (p less than 0.05) in both groups of patients. The decrease in the values in the stimulated reduction of NBT was more pronounced in untreated patients than in treated ones. At the same time the phagocytic activity of neutrophils on Candida albicans, which was decreased (p less than 0.01) in untreated patients, was normal in those who had been treated with chemotherapy. There were no distinctive correlations between circulating immune complexes and granulocyte function. We propose that this newly demonstrated defect in neutrophil mobilization and low median C. albicans-stimulated NBT reduction contributes more in the evolution of the tumor than in the pathogenesis of infections and that chemotherapy seems to restore a better granulocyte function.

Plasma exchange for a hemolytic crisis due to autoimmune hemolytic anemia of the IgG warm type.

A patient with a hyperacute hemolytic crisis due to AIHA of the IgG type was treated by combined plasmapheresis and exchange transfusion. A discontinuous flow centrifuge was used. Immediately after the exchange the hemoglobin level rose from 2.6 to 9.8 g/dl. The D. A. T. became weakly positive and the hemolytic crisis subsided. During the days following the exchange the autoantibodies responsible for the hemolytic crisis, switched from IgG1 and IgG3 to IgG2 and IgG4. The clinical and laboratory picture stabilized thereafter.