Temsirolimus in combination with carboplatin and paclitaxel in patients with advanced solid tumors: a NCIC-CTG, phase I, open-label dose-escalation study (IND 179).

BACKGROUND: The purpose of the study was to assess the safety, tolerability, recommended phase II dose (RPTD), and preliminary antitumor activity of the combination of carboplatin-paclitaxel (Taxol)-temsirolimus. MATERIALS AND METHODS: Patients with solid malignancies suitable for carboplatin-paclitaxel (CP) chemotherapy and two or less prior lines of chemotherapy received 15, 20, or 25 mg of temsirolimus per week with CP given every 21 days. Thirty-eight eligible patients were entered into six dose levels with the first two levels administering temsirolimus on days 8 and 15 and the subsequent four dose levels switching to days 1 and 8 temsirolimus administration. RESULTS: Days 8 and 15 administration of temsirolimus was not feasible due to myelosuppression on day 15. CP on day 1 with temsirolimus on days 1 and 8 was well tolerated. Dose-limiting toxicity (DLT) was grade 4 thrombocytopenia (n=2) and grade 3 fatigue (n=1). Relative dose intensities for carboplatin, paclitaxel, and temsirolimus at the RPTD were 92%, 82%, and 56%, respectively. Non-DLT treatment-related adverse events occurring in >20% of patients included fatigue, mucositis, alopecia, neuropathy, nausea, neutropenia, thrombocytopenia, and infection. Grade 3/4 non-hematological toxicity was rare. Partial responses (PRs) and disease stabilization were seen in 46% and 49% of patients, respectively. Nine of 11 (82%) endometrial cancer patients had objective PRs. CONCLUSION: Carboplatin-paclitaxel-temsirolimus is well tolerated and the RPTD is carboplatin area under the curve 5 mg/ml/min, paclitaxel 175 mg/m2, both given on day 1 with temsirolimus 25 mg on days 1 and 8.

Desmoplastic small round cell tumor presenting in the ovaries: report of a case and review of the literature.

Desmoplastic small round cell tumor is a recently recognized clinical entity with specific morphologic, immunocytochemical, and genetic features. Though this tumor is mostly described to involve serosal surfaces, we report a case with ovarian involvement. The clinical presentation and differential diagnoses as well as the treatment including aggressive surgical debulking and multiagent chemotherapy are discussed.

Weekly intravenous methotrexate with folinic acid for nonmetastatic gestational trophoblastic neoplasia.

OBJECTIVE: The objective of this study was to determine the complete response rate to weekly intravenous methotrexate at 100 mg/m(2) with folinic acid for patients with nonmetastatic gestational trophoblastic neoplasia. METHODS: From 1988 to 1999, 22 women with nonmetastatic gestational trophoblastic neoplasia were treated with weekly intravenous methotrexate with folinic acid at the Hamilton Regional Cancer Centre. Complete response was defined as the attainment of a serum beta-hCG level <5 IU/L for 3 consecutive weeks. Toxicity was graded according to the National Cancer Institute of Canada-Clinical Trials Group criteria for chemotherapy toxicity. RESULTS: There were 10 women who achieved complete response with weekly intravenous methotrexate alone (45.5%). Of the 12 who did not achieve complete response with methotrexate, 10 received actinomycin D and 2 received EMA as second-line chemotherapy. Patients successfully treated with methotrexate required a median of 6.5 cycles (including 2 cycles for consolidation) to achieve complete response. The only significant prognostic factor for failure with methotrexate was pretreatment beta-hCG (P = 0.01). CONCLUSIONS: Only a select group of patients with low pretreatment beta-hCG titers would be expected to achieve complete response with this regimen. Large randomized studies are required to determine the optimal treatment for nonmetastatic gestational trophoblastic neoplasia.

Reversal of suppression of lymphokine-activated killer cells by transforming growth factor-beta in ovarian carcinoma ascitic fluid requires interleukin-2 combined with anti-CD3 antibody.

Ascitic fluid from human ovarian carcinoma (AF) has been shown to inhibit IL-2-induced lymphokine-activated killer (LAK) cell generation from peripheral blood mononuclear cells (PBMC) resulting from the presence of biologically active transforming growth factor-beta (TGF-beta). A 50% concentration of AF completely suppressed the LAK response to 100 units IL-2/ml and only partial reversal (less than 50%) could be achieved by increasing the IL-2 concentration to 1000 units/ml. We evaluated the ability of tumor necrosis factor-alpha (TNF-alpha, 1-1000 ng/ml) and anti-CD3 antibody (alpha-CD3, 1-100 ng/ml) to reverse AF-mediated suppression of IL-2-stimulated LAK generation. TNF-alpha alone did not generate significant LAK activity, but in the presence of suboptimal concentrations of IL-2 (10 and 100 units/ml), TNF-alpha significantly boosted the generation of LAK, but was unable to significantly reverse AF-mediated suppression of the IL-2 response (even at 1000 units/ml). In contrast, alpha-CD3 alone generated LAK activity at concentrations as low as 1 ng/ml and markedly enhanced generation of LAK activity when added to suboptimal concentrations of IL-2. alpha-CD3 combined with IL-2 significantly reversed AF suppression at 100 units IL-2/ml and at 1000 units/ml completely reversed suppression by two of three highly suppressive samples of AF. Significant reversal occurred with the third AF sample. It may be possible to overcome TGF-beta-mediated suppression by measures other than by increasing the IL-2 concentration.

A rapid and simple method for the purification of tumor cells from ascitic fluid of ovarian carcinoma.

Rapid isolation of tumor cells growing in clumps from the ascitic fluid of patients with ovarian carcinoma was achieved by harvesting cells from ascitic fluid and subsequently passing them over a 30-microns nylon mesh filter. Single cells and small cell aggregates passed through the mesh, and large cell clumps that had not passed through the filter were isolated by backwashing. Morphologically, the cells in the clumps consisted almost entirely of tumor cells. The clumps were analyzed by immunocytochemistry and only a small proportion of cells (3.1 +/- 0.5% to 8.3 +/- 0.8%) stained with anti-CD45 monoclonal antibody (a panleukocyte marker for cells of hematopoietic origin). Most of the cells in clumps stained positively (90.6 +/- 1.7% to 97.5 +/- 0.5%) with 2G3 (a monoclonal antibody binding to a high-molecular-weight carcinoma-associated antigen). Unfiltered cell populations, however, contained up to 34.4 +/- 2.1% contaminating CD45+ non-tumor cells. This method should be useful for rapidly and easily obtained highly enriched fresh ovarian carcinoma cells from ascitic fluid in a form in which they grow naturally.

Phase II study of mitomycin C and 5 fluorouracil in platinum resistant ovarian cancer.

Fourteen patients with relapsing ovarian cancer were treated with Mitomycin C (Mit C) and 5 Fluorouracil (5-FU). All but one patient (one responder) were defined as platinum resistant. The drug dosaging was Mit C 10 mg/m2 IV day 1 every 6 weeks, and 5-FU 500 mg/m2 IV days 1-3, every 3 weeks. Therapy was evaluated clinically and with ultrasound every 6 weeks. Toxicity was graded using the Gynecologic Oncology Group adverse criteria. All patients had been previously treated with platinum containing chemotherapeutic regimens with a mean cumulative total dose of 418 mg/m2 and 1308 mg/m2 of cisplatin and carboplatin, respectively. The mean time interval from completion of the last platinum containing regimen to entry in this study was 3.6 months. There were 4 responders, 1 complete, and 3 partial. The duration of the responses were 13 weeks for the complete responder, and 6, 6, and 12 weeks for the partial responders. No factor was identified which was predictive for response. Grade 3/4 granulocytopenia and thrombocytopenia were experienced by 43% and 21% of all patients respectively. Despite our documented response rate of 29%, the short duration of responses and high incidence of severe and life threatening hematologic toxicity preclude this regimen from being of any significant benefit to relapsing platinum resistant ovarian cancer patients.

Two phase I studies of carboplatin dose escalation in chemotherapy-naive ovarian cancer patients supported with granulocyte-macrophage colony-stimulating factor.

Recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF) may reduce myelosuppression and, thus, allow dose escalation of certain chemotherapeutic agents. We conducted two sequential phase I trials of escalating doses of carboplatin and a fixed dose and schedule of rHuGM-CSF in ovarian cancer patients who had not previously had chemotherapy, i.e., chemotherapy-naive patients. In the first trial, patients were assigned to regimens of increasing dose levels of carboplatin (starting at 400 mg/m2) and fixed doses and schedules of cyclophosphamide (600 mg/m2) and rHuGM-CSF (10 micrograms/kg given subcutaneously once daily on days 2-11). Chemotherapy was given every 3 weeks (regimen A). In the subsequent trial, the design was the same except that cyclophosphamide was omitted (regimen B). Fifteen patients received regimen A, and seven patients received regimen B. In regimen A, all three patients treated at the first dose level tolerated five cycles at full doses. Hematologic toxicity was dose limiting at the 600-mg/m2 dose level. When 500 mg/m2 carboplatin was given, six of eight patients tolerated three or four cycles at full doses before requiring dose reductions or treatment delays. In regimen B, doses could not be escalated above the first dose level (600 mg/m2) because of severe hematological toxicity. Nonhematological toxicity was tolerable and managed with acetaminophen, antihistamines, and/or nonsteroidal, anti-inflammatory medication. Compliance was excellent. We conclude that (a) rHuGM-CSF can be given safely and reliably to chemotherapy-naive ovarian cancer patients receiving these treatment regimens, (b) early and severe thrombocytopenia was a major problem with or without cyclophosphamide with doses of carboplatin at or above 600 mg/m2, and (c) 500 mg/m2 carboplatin administered every 3 weeks is the highest dose in regimen A that can be given safely in the outpatient setting.

Prognostic significance of positive peritoneal cytology in endometrial carcinoma.

A retrospective review of 280 patients with endometrial carcinoma who had peritoneal cytologic examination done at the time of laparotomy was undertaken. A positive cytologic finding was the only manifestation of extrauterine disease in 16 patients (6%). Four (25%) of these patients had a recurrence. Only 13 (5%) of 237 patients with negative cytologic findings had a recurrence. Positive peritoneal cytology is a marker for potential recurrence.