Birthe Lund

Single-agent activity of weekly gemcitabine in advanced non-small-cell lung cancer: a phase II study.

PURPOSE To evaluate the efficacy and safety of gemcitabine, a pyrimidine antimetabolite with activity against solid tumours. PATIENTS AND METHODS Eighty-two patients with unresectable stage IIIa to IV non-small-cell lung cancer (NSCLC) were entered. The first 54 patients received gemcitabine 800 mg/m2, and subsequent patients 1,000 mg/m2, as a 30-minute intravenous infusion on days 0, 7, and 14. Courses of therapy were repeated every 28 days. Twenty percent dosage escalation was permitted after course no.1 if World Health Organization (WHO) toxicity was < or = 1. RESULTS Sixteen (20%; 95% confidence interval [CI], 12% to 31%) of 79 patients assessable for response had independently validated partial responses, with a median duration of 7 months. The overall median survival duration was 7 months. Gemcitabine improved disease-related symptoms (70% patients) and increased WHO performance status (44%). Toxicity was generally mild and reversible. Patients experienced little WHO grade 3 and 4 toxicity, with anemia in four (5%), thrombocytopenia in one (1%), leukopenia in six (7%), and neutropenia in 18 (22%). Infection occurred in nine patients (12%) during the study (four were neutropenic), but there were no episodes of WHO grade 3 or 4 infection. WHO grade 3 and 4 biochemical toxicity occurred with transient elevations of transaminases in 10 patients (12%). Two patients had transient WHO grade 3 elevation of serum creatinine levels, and two developed acute renal failure 4 and 6 weeks after the last dose of gemcitabine. There was no WHO grade 4 symptomatic toxicity. WHO grade 3 vomiting occurred in 31 patients (38%) and grade 3 alopecia in one (1%). Flu-like symptoms were associated with gemcitabine administration in 36 patients (44%). Twenty-six patients (32%) experienced fever (1% WHO grade 3), 33 (40%) ankle edema not associated with cardiac failure, 31 (38%) lethargy, and 11 (13%) dyspnea. CONCLUSION Gemcitabine is an active new agent in the treatment of NSCLC. This schedule was associated with little alopecia or myelosuppression. Gemcitabine warrants further investigation in other malignancies and in combination with other agents.

Phase II study of gemcitabine in previously platinum-treated ovarian cancer patients.

Fifty-one patients with histologically confirmed epithelial stage III or IV ovarian cancer were entered into a study in which gemcitabine 800 mg/m2 was given as a 30 min intravenous infusion in a cycle once a week for 3 weeks followed by a week of rest. Patients were aged 58 years (range 23-70 years) with WHO performance status 0-2, and had received up to two different chemotherapy regimens. Thirty-eight patients had received only one prior platinum-containing chemotherapy regimen whereas 9 had received a first-line regimen on more than one occasion. A further 3 patients had received two different regimens. Of 42 patients evaluable for response, 8 (19%; 95% Cl: 9%34%) were partial responders. Seven of the 8 responders were resistant to first-line platinum-based therapy. Median duration of response was 8.1 months (range 4.4-12.5 months). Median progressionfree survival was 2.8 months (range 0.2-12.5 months). Haematological toxicity with gemcitabine was modest, with grade 3 leukopenia (11 patients) and grades 3 and 4 thrombocytopenia (6 patients). Grade 3 non-haematological toxicity included nausea/vomiting (6 patients) and elevated AST/ ALT (1 patient), while dose-limiting non-haematologic toxicity consisted of flu-like symptoms (2 patients), peripheral oedema (1 patient) and lethargy (1 patient). The activity and modest haematological and non-haematological toxicity seen with gemcitabine suggest that this agent should be further evaluated in the treatment of patients with ovarian cancer and in combination chemotherapy regimens, primarily in combination with platinum.

Correlation of abdominal ultrasound and computed tomography scans with second- or third-look laparotomy in patients with ovarian carcinoma

Abstract To determine the best noninvasive means of evaluating response in patients with advanced ovarian carcinoma, 50 abdominal ultrasound (US) and computed tomography (CT) scans were performed in clinically disease-free ovarian cancer patients. The scans were correlated with the results obtained at a subsequent second- or third-look laparotomy. CT and US were not complementary, and only metastases larger than 2 cm were detected. The overall positive predictive value of nonconcordant scans was 57% compared with 100% for concordant CT and US (95% confidence limits: 18.4–90.1 and 29.2–100%, respectively). The corresponding negative predictive values were 45 and 47% (30.2–59.9 and 30.4–61.2%, respectively), if undetected microscopic disease was classified as a false-negative result. The negative predictive value of US and CT increased only to 60% in both cases, if undetected microscopic disease was registered as a true-negative result. Compared with the pelvic examination CT and US added positive information for 4 of 22 (18%) patients with macroscopic residual disease. In this study neither CT nor US was sensitive enough to preclude second-look laparotomy.

Phase I study of single, escalating doses of a superantigen-antibody fusion protein (PNU-214565) in patients with advanced colorectal or pancreatic carcinoma.

To develop a T-cell-based therapy for carcinomas, the superantigen staphylococcal enterotoxin A (SEA) was supplied with tumor specificity by means of a recombinant fusion of the Fab fragment of the monoclonal antibody C242 recognizing human colorectal (CRC) and pancreatic carcinomas (PC). Using this Fab-SEA fusion protein (PNU-214565), potent cytotoxicity by activation of T cells can be obtained in the targeted area. Twenty-one patients with CRC and 3 with PC were treated with single, escalating doses of PNU-214565 to establish the maximum tolerated dose (MTD) and to define toxicities. The doses ranged from 0.01 ng/kg to 4.0 ng/kg with three patients at each dose level, except for the dose of 1.5 ng/kg with which six patients were treated because of dose-limiting toxicity. Adverse events (AE) were transient: 13 patients experienced mild to moderate fever. In one patient, a grade 3 fever was followed by a grade 2 hypotension. Other mild or moderate AEs were fatigue, nausea, vomiting, diarrhea, and abdominal pain. No significant hematological toxicity occurred. Immune activation was highly variable with strong activity in peripheral blood seen only in two patients at the dosage level 1.5 ng/kg. They showed pronounced elevations of interleukin-2 (IL-2), IL-6, tumor necrosis factor-alpha, and interferon-gamma, 3-5 hours after the start of infusion. In one patient, IL-2 and IL-6 increased substantially (2,925 U/mL and 32,000 U/mL) concomitantly with grade 3 fever and transient grade 2 neutropenia, grade 2 lymphopenia, and grade 2 monocytopenia. In conclusion, a single 3-hour infusion of PNU-214565 could be safely administered up to 4 ng/kg. MTD was not determined. Instead, a repeat-dose trial was initiated starting at 0.5 ng/kg, considered safe in this trial, with the objective of defining the MTD.

Safety profile of gemcitabine, a novel anticancer agent, in non-small cell lung cancer

Gemcitabine is a novel anticancer agent showing activity with relatively mild toxicity across a range of solid tumors including non-small cell lung cancer (NSCLC). In studies using similar doses and schedules, consistent response rates of around 20% were recorded in NSCLC. In an integrated safety study using data from 360 patients with NSCLC, gemcitabine exhibits a mild safety profile for such an active drug. Hematological toxicity is mild and short lasting, and the level of infection associated with this degree of myelosuppression was low. Mild transaminase elevations occurred frequently but were not progressive or dose limiting. There was no evidence of cumulative hepatic or renal toxicity. Nausea and vomiting were mild, rarely dose limiting and generally well controlled with standard antiemetics. Mild flu-like symptoms were experienced in a small proportion of patients and rarely resulted in discontinuation. Where edema or peripheral edema were experienced, there was no evidence of any association with cardiac, hepatic or renal failure. Hair loss was rare and there was no grade 4 alopecia. In conclusion, gemcitabine is a promising new agent in the treatment of NSCLC. Its mild toxicity which is non-overlapping with other cytotoxics has prompted investigation into its use in combination with other chemotherapy regimens.

Gemcitabine: once-weekly schedule active and better tolerated than twice-weekly schedule.

This paper reviews the toxiclty profile of gemcitabine, a novel anticancer drug. Gemcitabine has been administered using two different treatment schedules: once weekly or twice weekly for 3 weeks followed by a week of rest (one cycle). It was well tolerated and alopecia was not a problem. Toxlcity was greater in the twice-weekly schedule. Comparing the once-weekly with the twice-weekly schedule, WHO grade 3 or 4 thrombocytopenia was reported in 4.7 and 25.6% of patients, respectively. Other hematological toxicity was minimal. Transient WHO grade 3 or 4 elevations of ALT and AST occurred in 9.2 and 7.1% of patients, respectively, in the once-weekly schedule. For the twice-weekly schedule the corresponding percentages were 12.2 and 13.8%. Symptomatic toxicity was greater in patients who received twice-weekly gemcitabine. Nausea and vomiting was mild and generally well controlled without 5HT3 antagonists. However, there was a greater incidence of nausea and vomiting on the twice-weekly schedule. Flu-like symptoms were documented in 19.8% of patients receiving once-weekly and 63.3% of patients receiving twice-weekly gemcitabine. Peripheral edema, not related to cardiac, hepatic or renal failure, was seen more often in patients on twice-weekly treatment. As the efficacy of gemcitabine in non-small cell lung cancer was equivalent when using both regimens, the better tolerated and more easily administered once-weekly schedule is recommended.

Phase II study of 1,2,4-triglycidylurazol (TGU) previously untreated and treated patients with small cell lung cancer

Six previously untreated poor prognosis patients and eight previously treated patients with small cell lung cancer (SCC) were treated with 1,2,4-triglycidylurazol (TGU, NSC-332488) 800 and 650 mg/m2 every 4 weeks, respectively. No responses were observed. The survival time of the previously untreated patients was short, a median of 7 weeks (range 5-10 weeks). Myelosuppression was severe and prolonged with white blood count, WHO grade 3-4, in four previously untreated patients and in two previously patients, and with platelets, WHO grade 3-4, in both four previously untreated and in four previously treated patients. Gastrointestinal toxicity was mild to moderate. It is concluded that TGU is inactive in SCC.

Phase-I study of ?-1,3,5-Triglycidyl-s-triazinetrione (NSC 296934)

Summaryα-1,3,5-Triglycidyl-s-triazinetrione (TGT) is a triepoxide derivative with alkylating properties discovered by random screening. TGT has been found to be active against a wide variety of murine tumors, including a P388 subline resistant to cyclophosphamide.The starting dose in this phase-I study was 30 mg/m2 as a single dose IV, repeated every 3–4 weeks, increasing up to 2,700 mg/m2. Severe dose-limiting toxicity took the form of phlebitis becoming apparent a few days after treatment. This was initially seen at the 480 mg/m2 dose level, and was observed with increasing frequency and intensity at higher dose levels. Leukopenia occurred regularly at dose levels above 1,800 mg/m2 and resulted in life-threatening leukopenia in one patient, and in a toxic death at 2,700 mg/m2 in another patient. Other toxic side-effects included moderate reversible thrombocytopenia, nausea, and vomiting.It is recommended that further trials with TGT await the development of more water-soluble formulations or of other triepoxide derivatives.

CA 125, placental alkaline phosphatase, and tissue polypeptide antigen in the monitoring of ovarian carcinoma : a comparative study of three different tumor markers

Three different tumor markers, placental alkaline phosphatase (PLAP), tissue polypeptide antigen (TPA), and cancer antigen 125 (CA 125), were measured in serum samples obtained during chemotherapy in 57 ovarian carcinoma patients. At the start of chemotherapy, 37, 63, and 77% had elevated serum values of PLAP, TPA, and CA 125, respectively. During chemotherapy, changing PLAP serum levels reflected disease regression and, later, progression in only 2 patients. TPA serum levels reflected the disease course in 15 patients and CA 125 in 28 patients. Rising CA 125 values predicted disease progression in 12 patients for a median of 2 months. At second-look laparotomy, all 11 patients with pathological complete response were marker negative. In the remaining 46 patients with residual or progressive disease, 27, 50, and 61% had elevated serum levels of PLAP, TPA, and CA 125, respectively. None of the markers reflected microscopic disease or pure carcinomatosis. For management decisions, CA 125 was clearly the most useful of the markers. In this study no further information was gained from the other two markers.

cis-dichlorodiammineplatinum (II) and hexamethylmelamine in advanced ovarian carcinoma: A phase II study

Thirty-eight previously treated patients with ovarian carcinoma received a combination of cis-dichlorodiammineplatinum (II) (CDDP) and hexamethylmelamine (HMM). The schedule was CDDP 75 mg/m2 i.v. with forced diuresis on day 1, followed by HMM 200 mg/m2 p.o. on days 8-21, repeated every 4 weeks. In 29 evaluable patients an overall response rate (CR + PR) of 35% with a median response duration of 4.5 months was observed. The performance status seemed to be an important prognostic factor. The gastrointestinal- and neurotoxicities were severe and resulted in dose modification and/or drug discontinuation in half of the patients. In conclusion, CDDP and HMM is an active drug combination in advanced ovarian carcinoma resistant to conventional chemotherapy. A possible superiority of this combination compared with CDDP or HMM alone has to await randomized trials.