Mitoxantrone and ifosfamide as second-line therapy of epithelial ovarian cancer. A pilot study by the I.T.M.O. Group.
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Adult↗
Biomedical subjects
E Bajetta
Publications and source records attributed to E Bajetta.
Etoposide, doxorubicin and cisplatin (EAP) treatment in advanced gastric carcinoma: a multicentre study of the Italian Trials in Medical Oncology (I.T.M.O.) Group.
Various reports have documented the efficacy of the combination of etoposide, doxorubicin and cisplatin (EAP) in the treatment of advanced gastric cancer, although other studies have not confirmed such results. This multicentre phase II study was designed to try to define the efficacy and tolerability of the original EAP regimen. From January 1990 to May 1992, 96 patients with locally advanced or metastatic gastric cancer were treated every 3 weeks with etoposide (120 mg/m2) on days 4, 5 and 6, doxorubicin (20 mg/m2) on days 1 and 7, and cisplatin (40 mg/m2) on days 2 and 8. All of the patients had measurable lesions, and were to receive a maximum of six cycles. A total of 416 courses was given (median four/patient), 27% with a delay of > or = 2 weeks. Objective responses were achieved in 34 of the 91 evaluable patients (37%: confidence interval 27-47%), with complete response (CR) in 11 (12%) and partial response (PR) in 23 (25%). The median duration of response was 6 months (range 1-19), and the median survival of the 96 eligible patients was 9 months. Side-effects (WHO grade 3-4) were leucopenia (30%), thrombocytopenia (9%) and mucositis (10%). We conclude that the EAP regimen is active in inducing major objective responses (12% of CR), and that treatment is feasible in patients with good performance status.
Adult↗
Treatment of relapse of breast cancer after adjuvant systemic therapy--review and guidelines for future research.
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Antineoplastic Combined Chemotherapy Protocols↗
The intramuscular administration of granulocyte colony-stimulating factor as an adjunct to chemotherapy in pretreated ovarian cancer patients: an Italian Trials in Medical Oncology (ITMO) Group pilot study.
No published data are available concerning the activity and tolerability of intramuscularly administered granulocyte colony-stimulating factor (G-CSF) in humans. To fill this gap, 19 patients with advanced ovarian cancer previously treated with at least one first-line chemotherapy cycle received the following myelosuppressive regimen: mitoxantrone (DHAD) 12 mg m-2 i.v. on day 1; ifosfamide (IFO) 4 g m-2 i.v. on days 1 and 2; mesna 800 mg m-2 i.v. t.i.d. on days 1 and 2. G-CSF (Filgrastim) was given at a dose of 5 micrograms/kg/day i.m. from day 6 to day 19, its pharmacokinetics being assessed in five patients. The neutrophil nadir was observed after a mean period of 8 days, and the neutrophil count was < 1.0 x 10(3) mm-3 for a mean of 6 days during the cycle of chemotherapy. The neutrophil count fell after the withdrawal of G-CSF on the 19th day of treatment. The difference in absolute neutrophil count between day 19 and day 21 was statistically significant (P = 0.0001); nevertheless, at day 21 no WHO grade 3-4 neutropenia was reported. DHAD and IFO were respectively given at 95% and 93% of the planned dose. The pharmacokinetics of G-CSF i.m. seems to be similar to that of the drug given subcutaneously. No evidence of cumulative myelosuppression was observed. G-CSF was well tolerated and no complications were observed at the injection sites. In conclusion, if the results obtained in this pilot study regarding the activity of i.m. G-CSF are confirmed by a randomised trial, the intramuscular administration of G-CSF could become a valid alternative for patients who dislike the subcutaneous route and who are being treated with chemotherapy that does not induce profound thrombocytopenia.
Antineoplastic Combined Chemotherapy Protocols↗
Endocrinological and clinical evaluation of two doses of formestane in advanced breast cancer.
Formestane is a selective inhibitor of oestrogen synthesis by aromatase enzymes and induces disease regression in breast cancer patients. This phase II randomised study was carried out to determine whether there were any differences in the effects of two different doses of formestane on oestradiol (E2) serum levels and to evaluate the corresponding clinical activity in post-menopausal patients with positive or unknown oestrogen receptor status pretreated or not for advanced disease. Furthermore, possible drug interference with adrenal steroidogenesis was assessed by measuring 17-hydroxycorticosteroid (17-OHCS) urinary levels. A total of 143 patients entered the study and were randomly assigned to receive formestane 250 mg (72 patients) or formestane 500 mg (71 patients), both given i.m. every 2 weeks. In comparison with baseline, E2 serum levels decreased by an average of 40% after only 15 days and remained unchanged thereafter, with no difference being observed between the two doses. The values of 17-OHCS remained unchanged during treatment in both groups. Objective responses were 28% (19/69) in the 250 mg and 46% (31/68) in the 500 mg group. In conclusion, the two formestane doses were equally effective in reducing E2 levels without affecting adrenal function, and in inducing a considerable percentage of clinical responses.
17-Hydroxycorticosteroids↗
Multicenter randomized trial of dacarbazine alone or in combination with two different doses and schedules of interferon alfa-2a in the treatment of advanced melanoma.
PURPOSE: Some phase II studies have suggested that the combination of interferons (IFNs) with dacarbazine (DTIC) in the treatment of malignant melanoma (MM) increases the antitumor activity of DTIC alone. In an attempt to confirm this hypothesis, a randomized study was performed with the further intent of observing whether low doses of recombinant interferon alfa-2a (rIFN alpha 2a) could be as effective as intermediate doses. PATIENTS AND METHODS: Two hundred sixty-six patients were randomized onto three different treatment arms: DTIC 800 mg/m2 intravenously (IV) days 1 and 21; DTIC plus rIFN alpha 2a 9 mIU intramuscularly (IM) daily; and DTIC plus rIFN alpha 2a 3 mIU IM three times per week. Major prognostic factors were well balanced among the three arms. Chemotherapy was administered for a maximum of eight cycles. After 6 months of therapy, rIFN alpha 2a was continued until disease progression at 3 mIU three times per week in responding patients who had received the combined treatment. RESULTS: The percentage of objective responses did not differ among the three groups (20%, 28%, and 23%, respectively), although a significant prolongation of response duration was observed when rIFN alpha 2a was added to DTIC (2.6 v 8.4 v 5.5 months, respectively). However, this improvement in response duration did not translate into an amelioration of overall survival. The addition of rIFN alpha 2a led to the onset of flu-like syndrome, but in no case was it necessary to withdraw the treatment program and no toxic deaths or life-threatening toxicities were reported. CONCLUSION: In this study, rIFN alpha 2a significantly prolonged response duration, whereas no effects on response rate and survival were observed; rIFN alpha 2a 3 mIU appeared to be equally effective and better tolerated than 9 mIU.
Adult↗
Results of a salvage regimen in refractory or relapsed non-Hodgkin's lymphoma.
After therapy with adriamycin-containing regimens, relapsed or refractory non-Hodgkin's lymphomas (NHL) have a very poor prognosis. Although high dose chemotherapies are widely employed, their related costs and the controversial results achieved justify the development of new second-line conventional therapies. Forty-three patients with relapsed or refractory NHL were consequently treated with an outpatient polychemotherapy schedule including ifosfamide, mitoxantrone and etoposide on day 1, and vindesine, cisplatinum and cytosine arabinoside on day 15. The courses were repeated on day 29. All of the patients were pretreated with at least one chemotherapy regimen. Twenty-two patients had diffuse large cell lymphoma, 8 had bone marrow involvement, and 17 altered baseline lactate dehydrogenase (LDH) values. After a median number of 4 cycles (range 2-8), we registered 20 complete (46%) and 4 partial remissions, for an overall remission rate of 56% (95% confidence interval: 40-71%). All of the responses occurred in patients who had achieved at least partial remission during first-line therapy. Four patients are long term responders after 31, 39, 49 and 52 months, and are possibly cured. Univariate analysis of prognostic factors showed that baseline LDH values and response to front-line therapy significantly affected both time to disease progression and survival, whereas the number of previous treatments given, significantly affected only the time to progression. Therapy was administered in an out-patient setting and no life-threatening toxicity was observed. Side effects consisted of nausea/vomiting, alopecia and reversible myelosuppression. The results suggest that different treatment strategies for relapsed and refractory patients should be considered on the basis of prognostic factors.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Formestane: effective therapy in postmenopausal women with advanced breast cancer.
Aromatase inhibitors are a useful therapeutic option in the management of endocrine-dependent advanced breast cancer. Formestane (Lentaron) is the first irreversible aromatase inhibitor to be extensively investigated. In a phase II study to determine the effects of formestane on serum estradiol and urinary 17-hydroxycorticosteroid (17-OHCS) levels and to evaluate its clinical activity, 72 postmenopausal patients with advanced breast cancer were given formestane 250 mg intramuscularly every 2 weeks. Of 66 patients fully evaluable, 56 were estrogen receptor (ER) positive, and 43 had a disease-free interval > or = 2 years. Metastases were assessable in soft tissue (53%), bone (53%) and viscera (47%); 34 patients had 1, 32 had > or = 2 metastatic lesions. Serum estradiol levels fell significantly (p < 0.01) after 2 weeks and remained unchanged thereafter, whereas urinary 17-OHCS levels did not change during treatment. Objective responses were obtained in 19 patients (29%), of whom 8 had complete response. In relation to disease sites, similar responses were obtained in soft tissue (33%) and viscera (30%), whereas response in bone was 18%. The overall tolerability of formestane was satisfactory, and only two patients complained of local side effects. We conclude that formestane is an effective aromatase inhibitor in postmenopausal patients with hormone-dependent breast cancer, and does not interfere with adrenal steroidogenesis.
17-Hydroxycorticosteroids↗
Medical treatment of neuroendocrine tumors.
BACKGROUND: Tumors of the neuroendocrine system are characterized by amine precursor uptake and decarboxylation, and they represent a heterogeneous group of carcinomas including carcinoids, islet cell carcinomas of the pancreas, medullary thyroid carcinomas and Merkel cell carcinomas. Their similar cytochemical and ultrastructural properties sustain the hypothesis of a common embryologic origin within the neural crest. Many of these tumors grow slowly, and reducing tumor burden represents the treatment of choice. However, when surgery is not feasible, medical treatment has to be considered. Therapeutic approaches in metastatic disease often do not consider the different biologic behaviors of these neoplasms. Moreover, efficacy of the treatment is associated with lack of a clear definition of the type of response: objective, symptomatic or biochemical. METHODS: In this review we have analyzed the different medical approaches used in the treatment of neuroendocrine tumors in an attempt to define their precise role in the different neoplasms. RESULTS: In carcinoid tumors, immunotherapy and the somatostatin analogue can be efficaciously used for the control of carcinoid syndrome. For inhibition of tumor growth, chemotherapy should be used only in patients with rapidly progressive disease, and the results are still unsatisfactory. CONCLUSIONS: Although all these tumors appear to have similar cytochemical properties, the responsiveness of the various neoplasms is very different. In the future, a specific treatment modality and a clear definition of the type of response (objective, symptomatic or biochemical) need to be defined for each type of neuroendocrine tumor.
Antineoplastic Combined Chemotherapy Protocols↗
A phase II study of mitoxantrone combined with beta-interferon in unresectable hepatocellular carcinoma.
BACKGROUND: Chemoimmunotherapy is being evaluated in the most common gastrointestinal tumors, but little data are available on hepatocellular carcinoma (HCC). Considering the encouraging objective response rates and the absence of important side effects obtained with mitoxantrone in HCC, we tested the activity and feasibility of a schedule combining beta-interferon (beta-IFN) and mitoxantrone. METHODS: Forty patients (ECOG Performance Status 0-1) with unresectable HCC received mitoxantrone (12 mg/m2 intravenously every 3 weeks) plus beta-IFN (3 x 10(6) U on days 1, 2, and 3; 6 x 10(6) from day 4 to day 60; and then 6 x 10(6) U three times a week for 10 months). RESULTS: Thirty-eight patients were evaluable for response and toxicity with a median of four administered cycles (range, 2-10 cycles). Nine patients achieved a partial response (23%) (95% confidence interval, 11-40%) with a median duration of response of 4 months. In 15 cases, the disease was stable for at least 2 months; 14 patients had disease progression. The median survival time of the group as a whole was 8 months. Patients who were alpha-fetoprotein positive had a median survival time of 7 months; those who were alpha-fetoprotein negative had a median survival time of 9 months. The most common side effects were hematologic (World Health Organization Grade 3, 15 patients; Grade 4, 3 patients). Mild or moderate flu-like syndrome was present in 50% of treated patients, whereas 10 patients experienced mild or moderate nausea. CONCLUSIONS: The schedule was active on advanced tumors with high alpha-fetoprotein values, and side effects were manageable. However, the addition of beta-IFN did not seem to improve significantly the response rate in HCC.
Adult↗
Treatment of metastatic carcinoids and other neuroendocrine tumors with recombinant interferon-alpha-2a. A study by the Italian Trials in Medical Oncology Group.
BACKGROUND: Using a wide range of interferon (IFN) doses and schedules, a number of authors have found them to be active against neuroendocrine tumors. METHODS: To verify the clinical activity of IFN, 49 evaluable patients with advanced stage low- and intermediate-grade neuroendocrine tumors were treated with recombinant IFN-alpha-2a at a daily dose of 6 x 10(6) IU intramuscularly for 8 weeks, and 3 times weekly thereafter. The predominant histotype was carcinoid, although a few cases had malignant islet cell tumors, medullary thyroid carcinoma, Merkel cell carcinoma, or other neuroendocrine tumors. All of the patients had measurable lesions and most had multiple sites. Carcinoid syndrome was present in 14 cases. RESULTS: After a median treatment duration of 6 months, complete regression was achieved in 1 of the 7 cases of medullary thyroid carcinoma, and partial response was observed in 4 of 34 carcinoids. Response duration ranged from 1-11 months. Control of the syndrome was obtained in nine patients and a greater than or equal to 50% reduction of 5-hydroxyindoleacetic acid in eight patients. The treatment was well-tolerated. The most frequently observed side effects were fever, flu-like syndrome, and leukopenia. After 12 months of recombinant IFN-alpha-2a, 15 cases in progression and 4 with stable disease or partial response received another treatment (either radiometabolic therapy with I131 metaiodobenzylguanidine or polychemotherapy with streptozotocin plus epirubicin). CONCLUSIONS: The use of recombinant IFN-alpha-2a at these doses is well-tolerated and effective in controlling carcinoid syndrome (complete remission plus partial remission, 64%), although it has limited activity on tumor growth inhibition. No definitive data can be given for the other protocol treatments.
Adult↗
Disodium pamidronate in the treatment of bone metastases from breast cancer.
AIMS AND BACKGROUND: Symptomatic relief of bone metastases with biphosphonates has been previously reported, but limited data are available on the possibility of the induction of sclerosis in osteolytic lesions. METHODS: We therefore initiated an open study with disodium pamidronate (45 mg infused over 1 h and repeated every 21 days) in patients with bone metastases from breast cancer pretreated with chemotherapy and/or hormonetherapy. Fourteen patients with measurable lytic or mixed bone disease entereted the study. No other systemic therapy for breast cancer was allowed after their inclusion in the study. RESULTS: No radiologic evidence of bone sclerosis of lytic disease was seen. After 2 months of therapy, 9 patients had progressed and 5 had stable disease. The median time to progression of bone disease was 1.6 months (range, 1-9). No significant improvement in terms of symptomatic status or analgesic consumption was recorded. The treatment was well tolerated, and no significant local or systemic toxicity was observed. CONCLUSIONS: Disodium pamidronate at a dose of 45 mg every 3 weeks is not capable of inducing sclerosis of lytic lesions from pretreated breast cancer. Further trials concentrating on higher dosages of disodium pamidronate are warranted.
Adult↗
Subcutaneous low-dose interleukin-2 plus alpha interferon in advanced malignant melanoma.
AIMS AND BACKGROUND: Interferon (IFN) and interleukin-2 (IL-2) have been proven to be active agents in the treatment of malignant melanoma, but the most effective doses of these cytokines were often associated to important side effects and poor patient compliance. Recently, the subcutaneous administration of low-dose IL-2 was found to be a well-tolerated and effective treatment for renal cancer. Since the combination of low doses of IL-2 and IFN has been hypothesized to have synergistic biologic and cytotoxic effects, we evaluated feasibility and patient compliance of a scheme that combined recombinant IFN-alpha (rIFN-alpha) (3 million units by intramuscular injection, 3 times a week) plus low-dose IL-2 (9 million IU, 3 to 5 times a week) administered subcutaneously for 2 weeks every 28 days. RESULTS: Fifteen patients with disseminated malignant melanoma previously treated with chemotherapy entered the study. All but the first 2 self-administered the therapy at home and were followed in an out-patient setting. None of them required in-patient care for toxicity. No WHO grade 4 side effects were detected; the only grade 3 side effects were fever and asthenia in 5% of the cycles. Mild hematologic toxicity (grade 2) was observed at the highest weekly dose of IL-2. No major responses were observed in this subset of heavily pretreated patients. CONCLUSIONS: We conclude that the regimen studied is feasible and well tolerated in an out-patient setting, but it is unlikely to be effective. The good patient compliance makes this schedule eligible to evaluate whether IL-2 plus rIFN-alpha can enhance the results of chemotherapy in this disease.
Adult↗
Fluorouracil plus folinic acid in metastatic adenocarcinoma of unknown primary site suggestive of a gastrointestinal primary.
AIMS AND BACKGROUND: The results of treatment strategies for carcinoma of an unknown primary location have been discouraging. Currently, no chemotherapeutic approach can be considered standard. METHODS: We therefore initiated a Phase II study in which fluorouracil (370 mg/m2, day 1 through 5) plus folinic acid (200 mg/m2 day 1 through 5) was administered in a subset of 17 patients (median age, 57 years) affected by histologically diagnosed adenocarcinoma of unknown primary location characterized by liver metastases and elevated CEA of CA 19.9. All of the patients had a performance status of 0-2 (ECOG Scale), and liver involvement was > 30% in 7 cases. RESULTS: No objective response was observed (4 cases of stabilization and 13 of disease progression). Median survival was 5 months. Toxicity was mild or moderate, and severe diarrhea was observed in only one case. CONCLUSIONS: The proposed regimen is inactive among this subset of patients and confirms that subdiaphragmatic metastases are related to a poor prognosis. Our results, in agreement with data published in the literature, suggest that patients affected by adenocarcinoma of an unknown primary origin metastatic to the liver and with a good performance status should be treated in an investigative setting.
Adenocarcinoma↗
Efficacy and tolerability of 4-hydroxyandrostenedione (4-OHA) as first-line treatment in postmenopausal patients with breast cancer after adjuvant therapy.
Aromatase inhibitors are known to be effective in the treatment of advanced postmenopausal breast cancer. To assess the efficacy of the aromatase inhibitor 4-hydroxyandrostenedione (4-OHA) as first-line treatment in patients who were either resistant to or had relapsed after adjuvant therapy, 50 eligible patients received intramuscular 4-OHA either 250 mg or 500 mg fortnightly until disease progression or severe adverse events. Of the 43 patients evaluable for clinical response (UICC criteria), 15 (36%) showed objective response (CR+PR), 6 (14%) stable disease (SD). In relation to disease site, objective responses were obtained in 55% of cases with soft tissue metastases (16/29); in 33% with visceral metastases (8/24), and in 24% with bone involvement (5/21). In relation to previous adjuvant treatment, there were eight objective responses among the 17 patients treated with chemotherapy (47%), and seven objective responses among the 24 treated with tamoxifen (29%). The treatment was well tolerated. These results support the hypothesis that adjuvant therapy, whether hormonal or chemotherapy, may make patients less responsive to subsequent treatment.
Aged↗
Carboplatin in patients with advanced colorectal cancer pretreated with fluoropyrimidines.
The activity of carboplatin (CBDCA) was tested in 21 consecutive patients with advanced colorectal cancer that had progressed during fluoropyrimidine therapy. CBDCA was chosen in view of the favourable results obtained in previous phase II studies. We were unable to find any activity of the agent which was given every 21 days at a dose of 400 mg/m2. The main toxicity was haematological. CBDCA is not recommended in pretreated patients with colorectal cancer.
Adenocarcinoma↗
Prospective randomised trial comparing fluorouracil versus doxifluridine for the treatment of advanced colorectal cancer.
Doxifluridine (dFUR) is a fluoropyrimidine derivative that has shown activity on a variety of solid tumours. The purpose of this study was to compare its therapeutic effect with a standard fluorouracil (FU) regimen in patients with locally advanced or metastatic colorectal cancer. 222 previously untreated patients were randomised to receive dFUR (4000 mg/m2) or FU (500 mg/m2) daily for 5 days every 28 days. The primary tumour originated in the colon in two-thirds of the cases in both groups; approximately 90% of patients had metastatic extension, and liver involvement was present in 69% of the patients in the dFUR and FU groups. A good performance status (ECOG 0-1) was recorded in 90% of cases in both arms. A median of five cycles was administered to the patients (range 1-12). Only one partial response among 110 patients in the FU arm and one complete response and five partial responses out of 112 evaluable patients in the dFUR group were observed. Time to progression was significantly longer in the dFUR group (P = 0.02); overall survival, while longer in the dFUR arm (48 weeks vs. 39 weeks), was not significantly so (P = 0.08). Toxicity was acceptable in both arms, although grade 3-4 neurological side-effects and leukopenia were more common after dFUR infusion. Despite the low response rate, our results indicate that dFUR may be a superior alternative to FU. The possibility of enhancing significantly the activity of dFUR with biochemical modulators should be further investigated.
Adult↗
Epirubicin, etoposide and cisplatin in advanced pancreatic carcinoma.
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Adenocarcinoma↗