Dose finding of ifosfamide administered with a chronic two-week continuous infusion.

PURPOSE: Ifosfamide (IFO) is an active drug in several malignancies. A short-term 3- to 7-day (A) continuous infusion (c.i.) has been used in different tumor types. The 14-day c.i. (B) has been investigated in advanced breast cancer and in soft tissue sarcoma patients at a fixed daily dose. The tolerance and response rate (RR) of therapies A and B has been considered encouraging. AIM: To study the 14-day c.i. IFO schedule, every 28 days, with a dose-finding approach. METHODS: From January 1998 to December 2001, 34 pretreated patients with advanced malignancy and disease progression were treated with c.i. IFO (and the same dose of mesna) from 400 to 1,000 mg/m(2)/24 h for 2 consecutive weeks every 28 days. An elastomeric pumping device via an Infuse-a-Port((R)) or a Groshong((R)) catheter was used. RESULTS: A total of 159 cycles were evaluable for toxicity and results. No toxic deaths occurred. Three patients (8.8%) had a severe acute allergic cutaneous reaction with various grade 3-4 toxicities requiring hospitalization and therapy was stopped at day 6 of the first cycle, 7 and 12 of the second cycle respectively. In the other 31 patients, grade 4 neutropenia occurred in 6 (19.3%) and it represented the main toxicity. There was a positive relationship between the IFO dose step and neutropenia (p = 0.001). A positive relationship was observed between the RR and the received total IFO dose (g) (p < 0.004). Twelve patients out of 31 had progressive disease (PD) (38.7%), 8 had partial remission (PR) (25.8%), and 11 maintained a steady state (35.5%). Six of the 12 patients (50%) with PD and 2 of the 8 PRs (25%) had bone metastases. CONCLUSIONS: IFO c.i. is generally well tolerated, but acute untoward allergic reactions can occur. In chemotherapy-pretreated patients the recommended daily dose of continuously infused IFO for 14 days every 4 weeks is 900 mg/m(2)/day, together with mesna at the same dose schedule.

Mitomycin C, cisplatin, and 5-fluorouracil for advanced and/or recurrent head and neck squamous cell carcinomas.

The combination of cisplatin (CDDP 100 mg/m2 on day 1) and 5-fluorouracil (5-FU 1,000 mg/m2 continuous intravenous (i.v.) infusion days 1-5) is the most widely used chemotherapy regimen for the treatment of advanced head and neck carcinomas, with a response rate of 70-90% but with a survival and a duration of response which are not impressive. Most patients relapse in < or = 2 years and die of cancer. We evaluated the activity of a CDDP (90 mg/m2 on day 1), 5-FU (900 mg/m2/120 h continuous i.v. infusion from day 1), and mitomycin C (MMC 6 mg/m2 on day 1) regimen in advanced or recurrent head and neck squamous cell carcinoma (HNSCC). Fifty-six patients were treated and evaluated for response and toxicity: 5 (9%) complete responses (CR) and 36 (64%) partial responses, (PR) were observed (response rate 73%). The median duration of response was 12 months, and median survival was 15 months. At a median follow-up of 14 months, the estimated overall survival at 1 year was 65%; at 2 years, it was 35%. Grade 3-4 toxicity was noted in 14 patients, mostly hematologic; overall toxicity required a dose-intensity decrease in 20.2% of all cycles. No treatment-related deaths occurred. The regimen showed a good response rate and an encouraging median duration of response with a good tolerability profile.

Synthetic thymic fraction 5: effects of high dose administration on circulating lymphocytes in patients.

The synthetic pentapeptide (Arg-Lys-Asp-Val-Tyr; TP-5) corresponding to the active site of the hormone thymopoietin, was given at the dose of 300 mg/m2/day (1 day), higher than the usually administered, to a group of 27 immunodepressed patients in order to determine the tolerability and the immunomodulatory activity. The examination of a series of hematological parameters including counts of differential clustering of lymphocytes by cytofluorimetric analysis was performed 24 hr and 48 hr after treatment, and repeated at different intervals up to 14 days after treatment. TP-5 caused a significant increase of circulating lymphocytes and particularly of CD3+CD4+ and CD3+CD8+ subtypes, peaking at 48 hr and maintaining the increased values up to the last examination on day 14 from treatment. A faster increase (zenith at 24 hr) was observed for CD4+ cells, in comparison with CD8+ cells (zenith at 48 hr). The number of patients that increased total lymphocytes or lymphocyte subset after treatment ranged between 52.6 (CD4+ cells) and 69.2% (NK cells), whereas about 7.7% (NK cells) to 36.9% (CD4+ cells) remained unchanged and a smaller amount of 10.5% (CD4+ and CD8+ cells) or 23.1% (NK cells) showed a decrease greater than 10% of their respective basal value. No significant relationship between responders and non-responders can be found on the basis of previous treatments, cancer type, sex or age.

Reduced lymphocyte subpopulations in patients with advanced or disseminated melanoma.

BACKGROUND: Studies have revealed many features of lymphocyte behavior in patients with malignant melanoma, but there are conflicting results. OBJECTIVE: The aim of this study was to measure with easily reproducible assays the circulating lymphocytes and other immunologic aspects in 33 patients with advanced or disseminated malignant melanoma (MM). METHODS: The following variables were measured: circulating monocytes; total lymphocytes; B (CD19) and T-cell subpopulations; CD3, CD4, and CD8, natural killer cells (anti-Leu-7+ or CD57 and anti-Leu-11+ or CD16) (cytofluorimetry); plasma levels of IgG, IgA, IgM, and IgE; complement fractions 3, 4, and 1Q; antibodies against foreign microorganisms (AaM) (adeno, herpes simplex, herpes zoster, measles, parotitis, cytomegalo, Epstein-Barr, and rubella viruses) and Toxoplasma; and cutaneous delayed hypersensitivity (CDH) to recall antigens (tetanus, diphtheria, Streptococcus, tuberculin, Proteus, Trichophyton, and Candida). We also studied 96 healthy persons, matched for age and geographic location, who were tested on the same days as the patients. RESULTS: In MM the number of total lymphocytes and subsets CD19, CD3, CD4, and CD8 was decreased from 25% to 40% (p < 0.001). The CD4/CD8 ratio increased (22%, p < 0.005) because of the relatively greater decrease of CD8. The CD57 and CD16 cells (expression of natural killer lymphocytes) were consistently reduced (30%; p < 0.002 to p < 0.003). C3 serum level was increased (30%; p < 0.001). Immunoglobulins, CDH, AaM, and all other tests were the same in the two groups. CONCLUSION: The single most important result seems to be a reduction of CD57 and CD16 cells in patients with advanced MM.

Carboplatino (JM8) en el tratamiento del cáncer metastásico: estudio preliminar sobre toxicidad, tolerabilidad y eficacia / Carboplatinum (JM8) in the treatment of metastatic cancer: preliminary study over toxicity, tolerability and efficacy

Los autores han tratado 31 pacientes afectados con cáncer metastásico (13 cánceres de mama; cuatro de testículo; 14 misceláneos) y parcialmente ya tratados (17 con quimioterapia; cuatro también con radioterapia y cuatro también con hormonoterapia), con un derivado del platino, el carboplatino, solo (400 mg/m* cada 21 días) o en asociación (300 mg/m*) con otros antineoplásicos. Fueron suministrados en total 104 ciclos y la evaluación fue hecha después de por lo menos dos ciclos. En los 31 pacientes tuvimos cinco remisiones completas y siete parciales. En los 13 pacientes con cáncer de mama obtuvimos 46 porciento de remisiones parciales. Recordemos que después de dos ciclos no se evaluaron respuestas a nivel óseo. La mielosupresión fue la toxicidad más alta y frecuente (leucopenia en 54.8 porciento; plaquetopenia 9.6 porciento; anemia 22.5 porciento). La náusea y el vómito fueron bien controlados con los antieméticos usuales. Dos casos de presuntas reacciones alérgicas se resolvieron con el uso oportuno de cortisona y antihistamímicos. Dado que el carboplatino no demostró ser nefrotóxico y no necesitó de terapia hidratante, puede ser usado en pacientes ambulatorios. El estudio se encuentra aún abierto.

Evaluation of the circulating glycoprotein CA549 in mammary cancer and other malignancies.

A prospective study was carried out on a recent marker for breast cancer, CA549, a mucine-like acid glycoprotein present in the fat membranes of human milk. Fifty healthy control subjects and 91 with benign conditions, 103 mammary cancer patients and 256 patients with other types of malignancy were studied. For comparison, CEA and CA15-3 were also investigated. The CA549 cutoff was 11 U/ml. In breast cancer the marker was below the cutoff in 9 cases (92.8%); in malignancies other than breast cancer it was above the cutoff in 5 to 50% of patients. In breast cancer it was raised in 83.3% of cases (CA15-3 showed 82.9% and CEA 50%). In breast cancer after radical surgery, CA549 was normal in patients who were in TNM stage I but above the cutoff in 57.1% of those at more advanced stages. The follow-up study is ongoing among these patients. In all the study conditions, CA549 favorably compared to CA15-3 values, with sensitivity and specificity greater than CEA.

Effectiveness and toxicity of "BELD" polychemotherapy in advanced malignant melanoma.

From January 1985 to December 1987, 17 patients with advanced malignant melanoma were treated with the polychemotherapy regimen BELD (bleomycin, 15 mg subcutaneously on day 1 and 4, vindesine 3 mg/m2 intravenously on day 1 and 5, CCNU 80 mg/m2 orally on day 1 and DTIC 200 mg/m2 intravenously on day 1 through 5) proposed as effective (CR + PR 45%) and tolerable. All patients were evaluable for toxicity and 14/17 also for response after 2 BELD cycles (total n. of cycles was 54). Criteria for response were just the same as those used by Young et al. A complete remission and a partial remission (2/14) have been observed at lymph nodal level, the unique sites of the disease in these two patients. Remission lasted 6 and 4 months, respectively. Two other patients showed a minimal response of 2 and 3 months duration (lymphonodal and cutis, respectively); 9 patients had stabilized disease of 5 months median duration. One case of progression of disease was observed. However, toxicity was relevant because of 2 early deaths after the first cycle, most probably therapy related, nausea and vomiting (82%), leukopenia (17%) and muscle rigors (11%).

A phase II study of mitoxantrone.

Thirty pretreated patients with progressive and measurable solid tumors (24/30 patients) or myeloproliferative diseases (6/30 patients) were given mitoxantrone at the dose of 5 mg/m2/day in 250 ml normal saline over 30 minutes infusion for 3 consecutive days every 3 weeks. A total of 104 cycles were administered, median 3 for each patient. 39/104 cycles were delayed for a median of 9 days (from 2 to 59 days) because of myelodepression grade I to III (median I); no infection or bleeding was observed. Grade I to II alopecia was recorded in 16 patients. Chronic cardiac toxicity was observed in one patient previously treated with adriamycin. Mitoxantrone at the studied dose schedule in heavily pretreated subjects was well tolerated every 3 to 4 weeks. In 25/30 patients evaluable for response, one patient had a PR, another had 25% reduction (both patients previously treated) and eleven patients obtained disease stability. This effectiveness, 1 PR, 1 MR, 11 disease stability, is not negligible when it is considered that mitoxantrone was the seventh median line of therapy and the fifth median antiblastic drug.