Docetaxel in patients with anthracycline-resistant advanced breast cancer.

OBJECTIVE: To better determine docetaxel activity in patients with well-defined anthracycline-resistant breast cancer. METHODS: From October 1996, we carried out a phase II trial in 69 heavily pretreated patients with advanced breast cancer with docetaxel 100 mg/m(2) by a 1-hour infusion on day 1, with cycles repeated every 3 weeks. Patients were classified as having primary anthracycline resistance (n = 32), secondary anthracycline resistance (n = 7), anthracycline pretreatment (n = 22) or no anthracycline pretreatment (n = 8). RESULTS: Among 68 evaluable patients, we observed 6 (9%) complete responses and 27 (40%) partial responses, for an overall response rate of 49% (95% confidence interval 37-61%); the disease remained stable in 17 patients (25%). Responses according to the above subgroups were as follows: primary anthracycline resistance 41%, secondary anthracycline resistance 43%, anthracycline pretreatment 64% and no anthracycline pretreatment 43%. The median time to response, median time to progression and median overall survival were 2, 7 and 10 months, respectively. Myelosuppression was the dose-limiting toxicity, with grade 4 neutropenia occurring in 47% of the patients and neutropenic fever in 12%. G-CSF was added in the case of grade 4 febrile neutropenia; a 25% reduction in the dose of docetaxel was required in 4 patients. Other side effects were mild. CONCLUSIONS: The results of the present trial confirm the high activity of docetaxel in heavily pretreated patients with advanced breast cancer, including those with strictly defined anthracycline resistance.

First-line chemotherapy with vinorelbine and paclitaxel as simultaneous infusion in advanced breast cancer.

Based on preclinical data showing a synergistic activity of simultaneous administration of vinorelbine and paclitaxel, we carried out a phase II trial in previously untreated advanced breast cancer patients. Treatment consisted of vinorelbine 25 mg/m(2) and paclitaxel 150 mg/m(2), both drugs given by intravenous infusion over 3 h on day 1, with cycles repeated every 3 weeks. Granulocyte colony-stimulating factor, 300 microg subcutaneously, was given on days 7-12 to the first 10 patients. From October 1995 to January 1997, 43 patients with advanced breast cancer entered the study, and 41 were evaluable for response. We obtained 2 complete responses (5%) and 18 partial responses (44%), for an overall response rate of 49% (95% CI 34-64%). Median time to response, time to progression and survival were 2, 7 and 22 months, respectively. Myelosuppression was the dose-limiting toxicity, with G4 neutropenia in 21% and neutropenic fever in 7% of the patients. Other toxicities were mild. Simultaneous infusion of vinorelbine and paclitaxel is a well-tolerated and active regimen in metastatic breast cancer, with overall results similar to those reported with more toxic regimens; furthermore, it may be a good option in patients with anthracycline contraindications.

[Gemcitabine in advanced stage soft tissue sarcoma: a phase II study]. / Gemcitabina nei sarcomi dei tessuti molli in fase avanzata: studio di fase II.

PURPOSE: To assess the activity and toxicity of gemcitabine in locally advanced or metastatic soft tissue sarcoma patients (pts). PATIENTS AND METHODS: Gemcitabine was administered on days 1, 8, 15 every 4 weeks at a dose of 1.000/1.250 mg/m2, respectively, in pretreated or not pretreated pts. RESULTS: Eighteen pts entered this phase II trial; sixteen had been previously treated with anthracyclines and ifosfamide. A partial response was observed in a woman with fibrous malignant istocytoma, whereas in 7 pts the disease remained stable. Median time to progression was 4 months. The treatment was well tolerated. Grade 4 toxicity was not observed. CONCLUSIONS: These results do not suggest that gemcitabine, in the dose and schedule used in this trial, may be of value in the treatment of soft tissue sarcomas.

[Simultaneous infusion of vinorelbin and taxol as first-line chemotherapy in metastasized breast cancer]. / Infusione simultanea di vinorelbina e taxolo come chemioterapia di prima linea nel trattamento del carcinoma mammario metastatizzato.

PURPOSE: To evaluate the activity and toxicity of simultaneous infusion of vinorelbine (VNB) and paclitaxel (T) as first line chemotherapy in advanced breast cancer patients (pts). PATIENTS AND METHODS: 33 pts with histologically proven advanced breast cancer were treated with VNB 25 mg/m2 and T 150 mg/m2, both drugs given by i.v. infusion over 3 hours, with cycles repeated every 3 weeks. Granulocyte-colony-stimulating factor (G-CSF), 300 micrograms subcutaneously, was given on days 7 to 12 of each cycle in the first 10 patients. RESULTS: From October 1995 to July 1996, 33 untreated pts entered the study. Characteristics of the pts were the following: median age 53 years (29-71); median WHO performance status 1 (0-3); pre/postmenopausal 8/25; prior adjuvant chemotherapy 16; prior radiotherapy 8; dominant disease sites: soft tissue in 6; bone in 7, viscera in 19; number of metastatic sites: 1 in 18, 2 in 9, 3 in 6 pts. In 31 evaluable pts we observed: 1 CR (3%) and 14 PR (45%), for an overall response rate of 48%. Median time to response was 2 months; median time to progression and median survival were 7 and 22+ months, respectively. Median number of cycles was 6. Myelosuppression was the dose-limiting toxicity, with G 4 neutropenia occurring in 22% of the pts and neutropenic fever in 6% of the pts. Other toxicities were generally mild with nausea in 52% of the pts; mucositis in 15%; constipation in 12%; peripheral neuropathy in 46.5%. Alopecia was universal. CONCLUSIONS: Simultaneous infusion of VNB and T is well tolerated and active in untreated patients with advanced breast cancer. Median survival (22+ months) is similar to that reported with anthracycline-containing regimens, although response rate appears to be lower. It is likely that higher response rates may be achieved with a higher dose-intensity.

[Sequential therapy with methotrexate and 5-fluorouracil in patients with advanced colorectal cancer pretreated with 5-fluorouracil plus folinic acid]. / Terapia sequenziale con methotrexate e 5-fluorouracile in pazienti affetti da carcinoma colorettale avanzato pretrattati con 5-fluorouracile + acido folinico.

PURPOSE: To evaluate the efficacy and toxicity of a sequential low-dose methotrexate (MTX) and 5-fluorouracil (5FU) regimen in the palliative treatment of patients with advanced colorectal cancer. PATIENTS AND METHODS: Enrolled in the study were patients with advanced colorectal cancer, refractory to 5FU + FA. Patients were treated with MTX 40 mg/m2 i.v. bolus d 1 and 8, 5FU 700 mg/m2 i.v. bolus d 2 and 9 (24 hours after MTX bolus). The cycle was repeated every 4 weeks. RESULTS: 48 patients entered the study, and 45 are evaluable. The overall response rate was 15% with 1 complete response and 6 partial responses. Eight patients obtained disease stabilization. Median time to progression was 9 months. Toxicity was mild. Grade 3 stomatitis was observed in 7 (15%) patients. CONCLUSIONS: Sequential MTX/5FU is a well tolerated regimen with mild antitumor activity in refractory advanced colorectal patients.

[Phase II study of docetaxel in patients with advanced stage soft tissue sarcoma]. / Studio di fase II con docetaxel in pazienti con sarcoma dei tessuti molli in fase avanzata.

PURPOSE: To evaluate the activity and toxicity of docetaxel (TXT) as second line therapy in advanced soft-tissue sarcoma. PATIENTS AND METHODS: Adult patients (pts) with histologically proven locally advanced or metastatic soft tissue sarcoma, were treated with TXT at a dose of 100 mg/m2 in a 1-hour i.v. infusion every 21 days and steroid premedication with oral prednisone 50 mg twice a day for five days starting 24 hours prior to TXT. RESULTS: From November 1995 to May 1997, 19 pretreated pts entered the trial. Characteristics of the pts: males/females 11/8, median age 58 years (30-74), median WHO performance status 1 (0-2); histotypes: leiomyosarcoma 6 pts, malignant fibrous histiocytoma 6 pts, fibrosarcoma 2 pts, others 5 pts. No objective responses were seen. The disease remained stable in 8 pts (42%). Median time to progression was 3.5 months (range, 2-8), median survival 6 months (range, 2-20). The treatment was well-tolerated: the main side effect was hematological toxicity with G3/4 leukopenia and neutropenia in 58% of the pts; G3 anemia and thrombocytopenia occurred only in 1 case. Other toxicities were alopecia that was universal, G3 emesis in 1 pt, G3 diarrhea in 2 pts, G3 stomatitis in 1 pt. Mild fluid retention was recorded only in 2 pts. CONCLUSIONS: The results of this study do not suggest the use of TXT at this dosage and schedule in advanced soft tissue sarcoma.

Single-agent ifosfamide in the treatment of anthracycline-refractory adult sarcomas.

OBJECTIVE: The objective of this trial was to assess the therapeutic activity and toxicity of ifosfamide (IFO) with mesna uroprotection as salvage therapy in patients (pts) with soft tissue sarcomas (STS) who had failed high-dose epirubicin treatment. PATIENTS AND METHODS: IFO was administered at a dose of 2.0 g/m2 daily for 5 consecutive days by a 2-h i.v. infusion every 3 weeks. RESULTS: Partial responses were observed in 5/31 (16%) evaluable patients, whereas in other 5 pts the disease remained stable. The median duration of response was 8 months. The median overall survival was 6.5 months. The most common toxicity was hematologic with grade 3 or 4 neutropenia occurring in 47% of the pts. Neurologic toxicity was infrequent, but in 1 patient treatment discontinuation was needed because of severe mental confusion and disorientation. CONCLUSIONS: Although IFO can be of value in a minority of pts with anthracycline-refractory STS, more active agents and new salvage cytotoxic regimens should be investigated in this disease.

Triple combination antimicrobial regimen in the treatment of infections of neutropenic cancer patients.

Twenty-six cancer patients (pts) with chemotherapy-related neutropenic fever were treated with vancomycin 30 mg/m2/day i.v. every 12 hrs, imipenem 1500 mg/day i.v. every 8 hrs, and pefloxacin 800 mg/day i.v. every 12 hrs. Twelve fevers of unknown origin (FUO), 10 gram-positive, 3 gram-negative and 1 mycoplasma were also treated. Globally, cure was observed in 22 pts (84%) and failure in 4 pts (16%); in gram-positive infections alone, cure was observed in 10 pts (80%) and failure in 4 pts (20%). Defervescence was obtained within 3 days in 77% pts. No relevant side effects were observed.

Paclitaxel activity in anthracycline refractory breast cancer patients.

AIMS AND BACKGROUND: We investigated the efficacy and tolerability of two doses of paclitaxel, 175 mg/m2 and 135 mg/m2, over a 3-hr infusion, without prophylactic G-CSF, in heavily pretreated patients with anthracycline-resistant breast cancer. Although paclitaxel may share with anthracyclines a common mechanism of drug resistance, there is evidence that the two drugs are not completely cross resistant. METHODS: From July 1994 to January 1996, 42 patients were treated every 3 weeks, for a maximum of 6 cycles; paclitaxel dose was established according to pretreatment extension. RESULTS: In 41 assessable patients we observed 9 partial responses, for an overall response rate of 22% (95% CI, 10-34%). There was no difference in response rate between the two dose levels. Median duration of response was 9 months, median time to progression 5 months, and median survival 9 months. The dose-limiting toxicity was neutropenia, which was grade 3-4 in 40% (135 mg/m2) and 62% (175 mg/m2) of the patients (P = 0.28); neutropenic fever occurred in 24% of the patients, without significant differences between the two dose levels. Other toxicity was mild to moderate. CONCLUSIONS: Paclitaxel at doses of 175 mg/m2 or 135 mg/m2 is active and well tolerated in advanced breast cancer patients resistant to anthracyclines. The prophylactic use of colony-stimulating factors seems appropriate in heavily pretreated patients given the higher dose level.

Intrapatient comparison of single-agent epirubicin with or without lonidamine in metastatic breast cancer.

The aim of this study was to determine if lonidamine (LND) supplementation to single-agent epirubicin (EPI) could reverse anthracycline resistance in patients with metastatic breast cancer. 45 patients with metastatic breast cancer were treated with EPI 120 mg/m2 by intravenous (i.v.) bolus every 3 weeks. Patients who progressed were given the same chemotherapy regimen on day 4 in combination with oral LND, 150 mg on day 1, 300 mg on day 2 and 450 mg on days 3-5. Among the 40 evaluable patients, 6 complete responses (CR) and 14 partial responses (PR) were achieved with EPI treatment alone for an overall response rate of 50%. The median duration of response was 6.5 months. Among the 25 patients treated with EPI+LND, 5 PR (21% of 24 evaluable patients) were observed with a median duration of response of 7 months. The median survival in patients receiving both treatments was 20 months. The survival for all patients was 18 months. The survival of patients receiving LND was not significantly longer than for the other patients. Myelotoxicity was the most common side-effect followed by alopecia, nausea and vomiting, and stomatitis. LND-related toxic effects were mild-to-moderate epigastralgia and myalgia. Anthracycline-related toxicity was the same in the two treatment groups. This study indicates that LND may circumvent clinical resistance to EPI without altering the pattern or severity of the toxicity of this anthracycline. Continued investigation of the clinical modulation of EPI resistance by LND in breast cancer is warranted, hopefully in patients with known multidrug resistance status.

Sequential subcutaneous thymopentin, interferon alpha-2a and interleukin-2 in metastatic renal cell cancer.

To determine the activity of sequential administration of thymopentin (TP-5), interferon alpha-2a (IFN) and interleukin-2 (IL-2) in metastatic renal cell cancer (RCC), 17 patients with RCC were treated with TP-5 50 mg/d on days 1 to 14, IFN 3 MIU/d on days 14, 15, 21, 22 and IL-2 18 MIU/d on days 16 to 20, and 23 to 27. Treatment was given subcutaneously and cycles were repeated every 6 weeks. All patients were assessed for toxicity and response. No objective responses were observed. Two patients had a short-lived disease stabilization. Median survival was 9 months. Toxicity was generally moderate. The most important side-effects were related to IL-2 administration. In view of the lack of antitumor activity, the combination of TP-5 + IFN + IL-2 in the doses and schedule used in this trial cannot be recommended. The investigation of chemotherapeutic and immunological agents that can effectively synergize with IFN or IL-2 is essential.

Thymopentin and interleukin-2 in combination with 5-fluorouracil and leucovorin in metastatic colorectal adenocarcinoma: preliminary results.

Thymic hormones have been shown to exhibit immunorestorative effects in vivo and in vitro, and to enhance the expression of high affinity interleukin-2 (IL-2) receptors on normal human lymphocytes stimulated with phytohemagglutinin. Based on these data, a clinical trial was initiated to determine the effects of the combination of 5-fluorouracil (5-FU) and folinic acid (FA) with thymopentin (TP-5) and interleukin-2 (IL-2) in patients with advanced colorectal carcinoma. Fifteen patients were treated with FA, 200 mg/m2/day by IV bolus, and 5-FU, 400 mg/m2/day as a 30-minute infusion, both given for 5 consecutive days every 28 days. TP-5, 50 mg/day, was administered subcutaneously on days 8-11, and IL-2, 9 million IU/m2 twice daily, was given subcutaneously on days 12-16. Of 8 patients evaluable for response, 4 achieved a response. Two patients had stable disease, and two progressed during treatment. There were no instances of life-threatening toxicity. Two patients developed grade III stomatitis and diarrhea followed by leukopenia and fever, requiring hospitalization. Other toxicities were moderate. These results are only preliminary, and a larger number of patients and longer follow-up are needed to draw meaningful conclusions about the merits of this new approach in cancer treatment.

Treatment of malignant pleural effusions with intracavitary Corynebacterium parvum.

Fifty-three cases of metastatic pleural effusion (30 haemorragic and 23 serofibrinous) were treated with 4 mg of Corynebacterium parvum (CP) injected weekly into the pleural cavity after total thoracentesis. Of the 53 effusions, 24 were metastases from lung cancer and 29 from breast cancer. Complete response (CR) was assessed as total resolution of pleural effusion after explorative thoracentesis. The results were as follows: 15 CR after two injections of CP, 30 CR after three, and 5 CR after the fourth administration. Three of 53 cases could not be evaluated because of early death. Of the 30 clearly haemorragic effusions, 25 turned into serofibrinosis after the first intrapleural injection of CP and the other five after the second. These findings indicate that intracavitary CP is the most adequate treatment for the control of neoplastic pleural effusion because it induces a significant clinical improvement with milder side effects with respect to other drugs and/or physical agents commonly used.

Amikacin plus ceftazidime versus amikacin plus piperacillin versus amikacin plus aztreonam in infections in neoplastic patients with granulocytopenia.

Sixty granulocytopenic patients (granulocytes less than 1000/mm3) affected with solid tumors, previously submitted to antiblastic therapy and with infections, were treated with three antibiotic combinations: amikacin + ceftazidime, amikacin + piperacillin or amikacin + aztreonam. In 68% of the cases the infections were due to gram-negative and in the remaining 32% to gram-positive microorganisms. The results obtained with the three treatments show a slight but significant statistical difference (p less than 0.05), due to the greater efficacy of the amikacin + ceftazidime combination on gram-positive and amikacin + aztreonam on gram-negative bacteria.

Immunologic monitoring during combined radiochemoimmunotherapy in inoperable lung cancer.

49 patients with advanced lung cancer underwent a combined treatment including radiochemoimmunotherapy. Before and at the end of the combined treatment, the immune status of the patients has been evaluated by testing the immunoreactivity to PPD in vivo and the phytohemagglutinin lymphocyte response and the rosette-forming cells in vitro. While the in vitro tests were not significantly modified by immunostimulation, as regards the immunoreactivity to PPD, we observed a positive conversion at the end of the treatment in 11 out of 25 patients who showed a negative reaction before therapy. All the patients who converted from negative to positive showed also a good response to therapy with regression or no progression of the tumor. Survival curves confirmed the prognostic value of PPD reactivity.

Short-term results of combined radioimmunotherapy in inoperable lung cancer.

Fifty-three inoperable lung cancer patients were treated with radiotherapy combined with immunostimulation with BCG. A good response was obtained in 30 patients (56%); the results were not significantly different than those obtained with a control group of 50 lung cancer patients matched by age, sex and stage of the disease (24 out of 50 equals 46%). These short-term results were compared with the immunologic "status" of patients evaluated before treatment by the parameters monitoring in vivo and in vitro delayed type hypersensitivity. The good response to therapy was documented in a higher percentage of patients with positive skin tests to recall and standard antigens and with normal values of lymphocyte transformation with PHA and Rosette E-forming cells, in comparison with patients with low levels of immunocompetence. An impairment of the cell-mediated immune response was found after combined therapy, presumably due to radiotherapy. BCG was not able to restore the patient's immunocompetence, no effect on host's immune reactivity was demonstrated. As regards humoral immunity, the patients with low levels of IgG before treatment (12/14) showed a good response.