Adjuvant chemotherapy with cisplatin and gemcitabine versus chemotherapy at relapse in patients with muscle-invasive bladder cancer submitted to radical cystectomy: an Italian, multicenter, randomized phase III trial.

BACKGROUND: The purpose of the study was to evaluate the benefit of adjuvant chemotherapy (AC) versus surgery alone in patients with muscle-invasive bladder cancer (MIBC). PATIENTS AND METHODS: One hundred and ninety-four patients with pT2G3, pT3-4, N0-2 transitional cell bladder carcinoma were randomly allocated to control (92 patients) or to four courses of AC (102 patients). These latter patients were further randomly assigned to receive gemcitabine 1000 mg/m(2) days 1, 8 and 15 and cisplatin 70 mg/m(2) day 2 or gemcitabine as above plus cisplatin 70 mg/m(2) day 15, every 28 days. RESULTS: At a median follow-up of 35 months, the 5-year overall survival (OS) was 48.5%, with no difference between the two arms [P = 0.24, hazard ratio (HR) 1.29, 95% confidence interval (CI) 0.84-1.99]. Mortality hazard was significantly correlated with Nodes (N) and Tumor (T) stage. The control and AC arms had comparable disease-free survival (42.3% and 37.2%, respectively; P = 0.70, HR 1.08, 95% CI 0.73-1.59). Only 62% of patients received the planned cycles. A significant higher incidence of thrombocytopenia was observed in patients receiving cisplatin on day 2 (P = 0.006). A similar global quality of life was observed in the two arms. CONCLUSION: The study was underpowered to demonstrate that AC with cisplatin and gemcitabine improves OS and disease-free survival in patients with MIBC.

Intraperitoneal recombinant alpha-2-interferon alternating with cisplatin as salvage therapy for minimal residual-disease ovarian cancer: a phase II study.

A phase II study was initiated in March 1987 at the Regina Elena National Cancer Institute of Rome to evaluate the efficacy of alternating intraperitoneal (IP) recombinant alpha-2-interferon (r-alpha 2-IFN) and cisplatin (DDP) as salvage therapy for less than or equal to 5 mm residual-disease (RD) ovarian carcinoma. Fourteen assessable patients entered the study. All had received prior chemotherapy (11 with DDP-based regimens); five patients had macroscopic RD (less than or equal to 5 mm), and nine had microscopic RD (histologically positive random biopsies and/or positive cytology and immunocytochemical tests). The response to IP immunochemotherapy was evaluated by laparotomy. Pathologic complete remissions (PCRs) were achieved in seven patients (50%) who have remained free of disease with a median follow-up of 22+ months (range, 11+ to 30+ months). Six patients achieved a stable disease and one presented disease progression. With the exception of chemical peritonitis-induced adhesions, no limiting toxicity was observed. The results obtained in this small, highly selected series demonstrate that a high PCR rate may be obtained with IP immunochemotherapy with DDP and r-alpha 2-IFN as salvage therapy in residual ovarian carcinoma less than or equal to 5 mm after first-line chemotherapy also including intravenous (IV) DDP. Larger comparative studies must be conducted to establish the potential role of IP DDP and r-alpha 2-IFN as compared with either of the single treatments.

A partial response in anaplastic carcinoma of the thyroid with liposomal doxorubicin.

Anaplastic thyroid carcinoma is a rare disease with a poor prognosis. Surgery represents the curative treatment for limiting the disease. In the presence of locoregional disease, not suitable for surgery, and for metastastic disease, chemotherapy represents the treatment option. Single agents chemotherapy can produce some responses; doxorubicin is an active drug with a rate of partial response lower than 20%. Association with cisplatin seems to be more active producing a higher rate of complete responses. Liposomal doxorubicin is a new class of anthracyclines, derived from a structural modification of doxorubicin, representing a new form of an old drug with pharmacological characteristics that facilitate a more easy elusion from immune system, a longer half-life, an increased tumor cell uptake and a reduced toxicity if compared with parental drug. Herein we report the first case of an anaplastic thyroid carcinoma treated with the use of liposomal doxorubicin. The encouraging response observed with single agent liposomal doxorubicin (70% according to RECIST criteria) deserves further investigations.

Gemcitabine and cisplatin in the treatment of elderly patients with advanced non-small cell lung cancer: impact of comorbidities on safety and efficacy outcome.

The aim of the study was to describe in detail the impact of aging and comorbidities on safety and efficacy of gemcitabine-cisplatin in the subset of elderly with advanced NSCLC. We report the results of our study which enrolled patients aged over 65 years or older. This study included 46 patients consecutively admitted to our Department. Treatment consisted of gemcitabine 1250 mg/m2 on days 1 and 8, and cisplatin 75 mg/m2 on day 2, of a 21-day cycle. The Charlson score method was chosen to evaluate the conditions of comorbidity. All patients were evaluable for toxicity and 44 for activity. A total of 128 courses were administered, with a median of 3 courses per patient and a dose-intensity of 93% and 88% for gemcitabine and cisplatin, respectively. Grade 3-4 neutropenia (22% of patients) and grade 3 asthenia (4.5%), emesis (4.5%) and nephrotoxicity (4.5%) were the most severe adverse events. Univariate analysis of toxicity did not show any significant difference among all groups. The overall response rate was 45.6% (95% CI, 31.3-60). At a median follow up of 13 months, the median and progression-free survival were 15 and 8 months, respectively. The multivariate analysis resulted in objective response and disease control being predictive of longer survival. The combination of gemcitabine and cisplatin appears to be an effective and tolerated regimen for elderly patients with advanced NSCLC, regardless of aging and condition of comorbidities. Prospective randomized trials based on specific geriatric assessment are required to obtain compelling information for the optimal management of elderly patients with advanced NSCLC.

A phase II study of gemcitabine in patients with transitional cell carcinoma of the urinary tract previously treated with platinum. Italian Co-operative Group on Bladder Cancer.

The aim of this study was to evaluate the efficacy and safety of gemcitabine, a pyrimidine antimetabolite, in the treatment of advanced transitional cell carcinoma of the urinary tract. 35 patients with unresectable or metastatic transitional cell carcinoma of the urinary tract previously treated with a platinum-based regimen were studied. Gemcitabine was administered at a dosage of 1200 mg/m2 as a 30-min intravenous infusion on days 1, 8 and 15, repeated every 28 days. 31 patients were evaluable for efficacy. 4 patients achieved a complete response (12.9%), 3 a partial response (9.6%) and 13 (42%) were stable for at least 4 weeks (overall response 22.5%; 95% confidence interval 8-37%). The median response duration was 11.8 months (range 3.6-17.7 + months) and median survival for all patients entered was 5 months (range 2-21 + months). 2 patients with complete response are still alive with no evidence of disease after 14 and 21 months. Gemcitabine also provided subjective symptomatic relief from pain, cystitis, dysuria, haematuria and peripheral oedema. Patients experienced little WHO grade 3-4 toxicity, with anaemia in 8 patients (23%), thrombocytopenia in 5 (14.2%), leucopenia in 4 (11.4%) and neutropenia in 7 (20%). WHO grade 3-4 hepatic toxicity occurred in 4 patients (11.4%) and transient elevations of transaminase was noted in 3 (8.6%). No patient had WHO grade 3-4 elevation of serum creatinine level. There was no WHO grade 4 symptomatic toxicity and no alopecia was noted. Transient influenza symptoms with gemcitabine occurred in 18 patients (51.4%) with 13 patients (37.1%) experiencing fever (2.9% WHO grade 3). In conclusion, gemcitabine is an new active agent for the treatment of transitional cell carcinoma of the urinary bladder with a mild toxicity profile; it warrants further investigation in combination with cisplatin in chemotherapy naive patients.

A randomized trial comparing alizapride alone or with dexamethasone vs a metoclopramide-dexamethasone combination for emesis induced by moderate-dose cisplatin.

To evaluate the antiemetic effectiveness and toxicity of a novel congener of metoclopramide (MCP), alizapride (AZP), 29 patients receiving cisplatin (50 mg/m2) alone or with adriamycin (40 mg/m2) were entered into a randomized cross-over trial comparing moderate-dose AZP (2 mg/kg for 4 doses) administered alone or with dexamethasone (DXM) (8 mg for five doses) vs a standard combination of MCP (1 mg/kg for four doses) and DXM (as above). With the dosage and schedule used, AZP provided only limited antiemetic protection, with less than 10% of the patients free of emesis. The AZP-DXM combination was significantly more effective than AZP alone in reducing the intensity of the emesis (P less than 0.03). The incidence, however, was statistically unaffected. The additional toxicity of DXM was negligible. Except for the patients' preference for MCP-DXM (P less than 0.01), no differences could be found between the DXM-based regimens, although a trend towards a better antiemetic effect with the MCP combination was evident. The benzamide-related dystonic reactions were equally distributed. Among the 11 patients affected there were 6 who required specific treatments. Unfavourable prognostic factors in the patient population could provide a reasonable explanation for the disappointing antiemetic protection obtained with all the regimens evaluated in this study.

Very high-dose cisplatin-induced ototoxicity: a preliminary report on early and long-term effects.

Acute and subacute audiometric hearing changes were evaluated in 12 patients receiving 35 courses of very high-dose (vhd) cisplatin (200 mg/m2 per course) in hypertonic saline at 4 or 8-week intervals. Audiogical evaluations were performed both before and immediately after each course of chemotherapy, and again after the discontinuation of treatment. A significant drop of the mean hearing threshold (P less than 0.01) at high frequencies was observed even within 48 h from the end of the first course of therapy, with 50% of the patients presenting a hearing loss of more than 15 dB. At the same total dose (200 mg/m2), one course of this regimen provided an incidence of hearing loss of more than 15 dB, which was four times greater than that reported with two courses of standard-dose regimens. The incidence and severity of the hearing impairment progressed further with subsequent courses of chemotherapy. Compared with baseline levels, most patients (75%) receiving at least two courses had a moderate to severe hearing loss, especially involving 4 and 8 kHz. At the end of treatment, 33% of the patients complained of a nondisabling functional hearing impairment. No recovery occurred after chemotherapy had been discontinued for 9-28 weeks. At this dose level cisplatin is markedly ototoxic. The use of hypertonic saline and vigorous hydration are effective means of minimizing the risk of nephrotoxicity, but seem to have no effect on cisplatin-related ototoxicity.

Improved control of cisplatin-induced emesis with a metoclopramide-dexamethasone combination.

Twenty-four patients receiving combination chemotherapy including cisplatin at a dosage of 50 mg/m2 were entered on this antiemetic randomized open cross-over study. High-dose dexamethasone (DXM) (regimen A) was compared with the combination of DXM and high doses of metoclopramide (MCP) (regimen B). Five patients (20%) treated with regimen A and 13 (54%) treated with regimen B suffered neither nausea nor vomiting (P less than 0.05). Regimen B was found to be significantly more effective than regimen A for all the parameters of evaluation considered. No severe side-effects were observed.

Changes in serum iron levels following very high-dose cisplatin.

A four-fold (P less than 0.001) mean increase in iron levels was found in 18 patients (a total of 36 courses of therapy) with ovarian cancer at the end of a 5-day course of cisplatin (40 mg/m2 per day every 4-5 weeks). The kinetics of these modifications began very early (24-48 h after initiation of therapy): they reached their maximum on the 4th-5th day, coinciding with the last drug administration, and basal levels were recovered after the 10th day. A subsequent eight-fold average increase (P less than 0.001) in ferritin serum levels, beginning 2 days after the iron changes, was observed, but showed a slower regression (after the 15th day). Reticulocyte counts were lowered (P less than 0.001) with the same time-course of the iron increases, but returned to pretreatment levels within 2 weeks. Total bilirubin and serum glutamate-pyruvate transaminase showed significantly delayed increases compared with iron. The results are in keeping with a reduced iron utilization by the erythroid precursors, but other mechanisms cannot be excluded. There is no statistical correlation between the early iron increases and the subsequent hemoglobin nadir values.

A combination of ifosfamide and mitoxantrone as salvage therapy in patients with advanced ovarian cancer.

Ifosfamide (IFX) and mitoxantrone (MXN) have been found to be effective against advanced epithelial ovarian cancer. The combination of these two agents has not yet been tested in this setting but seems to be rational, given the different action mechanisms of these drugs and their not completely overlapping side effects. Between June 1987 and November 1991, 37 patients with advanced ovarian carcinoma recurrent or refractory to primary cisplatin-based chemotherapy entered the study. Therapy consisted of MXN, given i.v. at 10 mg/m2 on day 1 and IFX given i.v. at 2,000 mg/m2 per day on days 1-3 with mesna. The cycles were repeated every 3 weeks. Four patients achieved a complete remission and three achieved a partial remission, for response rates of 18.9% [95% confidence interval (CI) 6.3-31.5%] in the whole sample and 38.8% (95% CI 16.3-61.3%) in the subset of 18 patients responding to first-line cisplatin. No response was obtained in the remaining patients, whose disease was refractory to primary platinum-based chemotherapy. Clinically significant toxicity (WHO grades 3-4) included leukopenia in 46% of the patients and anemia in 32.5%. The non-hematologic toxicity was mild, except for reversible alopecia (57%) and nausea and vomiting (48.5%). This regimen seems attractive for patients who have either failed or not received platinum retreatment, especially when limiting neurotoxicity occurs. Further studies are warranted to establish the relative impact of both of these agents.

Effective control of CMF-related emesis with high-dose dexamethasone: results of a double-blind crossover trial with metoclopramide and placebo.

To establish the antiemetic activity of both dexamethasone (DXM) and metoclopramide (MCP) in patients receiving i.v. cyclophosphamide, methotrexate, and 5-fluorouracil (CMF), 25 women with stage II breast cancer were entered into this study. A randomized, double-blind, crossover design was employed to evaluate DXM (24 mg in 5 doses) versus MCP (1 mg/kg as a single dose) versus a combination of both drugs (as above) or placebo (PLC). The patients were requested to complete a questionnaire evaluating the antiemetic effect. All but one patient completed the planned antiemetic program during the first four CMF courses. As compared to PLC, both the DXM-MCP combination and DXM alone provided a higher complete antiemetic protection rate (p = 0.01 and p = 0.006, respectively). The DXM regimens were more effective than both PLC (p = 0.004 and p = 0.01) and MCP (p = 0.002 and p = 0.006) in reducing the prevalence of severe vomiting. As compared to MCP, the DXM regimens provided a better control of the nausea (p less than 0.04 and p less than 0.01) and reduced both the episodes and the duration of vomiting (p less than 0.02 and p less than 0.05). The DXM regimens were also associated with a better patient opinion than the PLC (p less than 0.002 and p less than 0.0002). No significant differences were found between MCP and PLC, nor between the DXM regimens. Except for two dystonic reactions, MCP-related toxicity was mild, whereas that induced by DXM was negligible in patients with no contraindications to corticosteroids. As employed in this study, DXM provided safe and effective antiemetic protection for patients receiving adjuvant i.v. CMF. Data available do not support the use of a short-course MCP, either alone or in combination with DXM. The search for better antiemetic treatments is mandatory, especially for patients receiving adjuvant chemotherapy. To date, we recommend the use of DXM as a standard regimen and as a control for further studies.

Gemcitabine: safety profile unaffected by starting dose.

Gemcitabine, a novel anticancer agent, has been shown to be active in several human solid tumours, including non-small cell lung cancer and pancreatic cancer. In addition, gemcitabine has been noted to have a particularly mild safety profile for such an active agent and is lacking some of the classical toxicities of oncolytics, i.e. alopecia, severe nausea and vomiting, and mucositis. Therefore, the safety data from 790 patients in 18 completed clinical studies were integrated to study its toxicity profile in more detail. In all of these studies gemcitabine was administered as a 30-minute intravenous infusion every week for three weeks followed by a week of rest (one cycle). This integrated database confirmed that gemcitabine is well tolerated. Its haematological toxicity was mild and short lasting. The low incidence of infection was correspondingly low. Transaminase elevations occurred frequently, but they were usually mild and rarely dose-limiting. Mild proteinuria and haematuria were seen but were rarely clinically significant. 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. Flu-like symptoms were experienced in a proportion of patients but were short-lasting. Where oedema or peripheral oedema were experienced, there was no evidence of any association with cardiac, hepatic or renal failure. Hair loss was rare. The integrated database was also analysed according to starting dose (800, 1000 or 1250 mg/m2) in a subset of 665 chemonaive patients to see whether an increased dose resulted in increased toxicity. In general, only small, clinically insignificant differences in toxicity were seen between the three dose groups. Although segmented neutrophil count appeared to increase as starting dose increased (grade 3 or 4, 19.4%, 23.2%, 28.3% respectively), this was not associated with an increased incidence of infection. In some cases, toxicity decreased with increasing dose but this may have been because of imbalances between the patient groups. These findings indicate that not only is gemcitabine well tolerated, but it also has a broad therapeutic index and the use of higher doses may be possible.

Prognostic factors influencing cisplatin-induced emesis. Definition and validation of a predictive logistic model.

Data obtained from 209 patients who entered different prospective randomized antiemetic trials were analyzed to establish the prognostic value of some variables on the control of cisplatin-induced emesis. The antiemetic regimens evaluated included the following: metoclopramide (M) at 1, 2, and 4 mg/kg total dose and a combination of M (4 mg/kg) with dexamethasone (D) (40 mg). Vomiting lasting more than 1 hour (no protection [NP]) was the endpoint selected for the analysis. A logistic model carried out, first on the 110 subjects receiving the M + D regimen and then on the whole sample, selected sex (P = 0.0001), Eastern Cooperative Oncology Group performance status (PS) (P = 0.006), and age (P = 0.01) among the six factors considered. Since the prognostic value of these variables is mostly related to their interaction, three major risk classes were identified. The corresponding NP rates were 26.3%, 42.4%, and 70.8% for the low-risk, intermediate-risk, and high-risk groups, respectively (P = 0.000002). Except for the lowest M level, the observed NP rates were significantly associated to the risk classes, whereas the antiemetic regimen influenced the antiemetic outcome only in the low-risk class. Regardless of the regimen employed, certain patient characteristics, such as sex, PS, and age, significantly affect cisplatin-related emesis and should be carefully considered in planning further studies.

Effective control of moderate-dose cisplatin-induced emesis by a short-course regimen including metoclopramide, chlorpromazine and hydrocortisone: results of a randomized trial with metoclopramide alone.

To improve the antiemetic effectiveness of a previously selected short regimen of moderate-dose metoclopramide (MCP), 80 patients were randomized to receive MCP either alone (regimen A) or in combination with low-dose chlorpromazine (CLP) and high-dose hydrocortisone (HDC) (regimen B) with the first course of cisplatin (50 mg/m2). The antiemetic effect was assessed over a 24-hour period only by objective means (duration and volume of vomiting in overnight fasting patients). The response was classified as follows: no emesis (absence of vomiting), partial protection (up to 100 ml of vomiting) and antiemetic failure (more than 100 ml). For regimen A, this study confirms the results previously reported over a 6-hour period. Regimen B provided better emetic control, significantly reducing the prevalence (p = 0.03) and severity (p = 0.02) of emesis, as well as the median volume (p less than 0.006) and duration (p less than 0.02) of vomiting. Except for the higher incidence of sedation, neither limiting nor unexpected toxicities were observed with the multidrug regimen. The male sex and antiemetic regimen B were the only favorable independent prognostic factors recognized by means of a multivariate analysis using a logistic model. This study therefore shows the usefulness of combining a lower dose of MCP and CLP, together with a high-dose HDC in a short regimen, suitable for outpatients receiving moderate-dose cisplatin. The better emesis control in the highly resistant group of female patients warrants further studies and a more aggressive approach.

Alizapride alone or alizapride-dexamethasone compared with metoclopramide-dexamethasone in patients at high risk of acute emesis after cisplatin. A randomized cross-over study.

Alizapride (ALZ) is a new benzamide derivative with promising antiemetic activity. In the present study, high-dose ALZ (16 mg/kg) alone or in combination with dexamethasone (DXM, 40 mg) was compared to a combination of DXM (40 mg) and metoclopramide (MCP, 4 mg/kg) in a randomized cross-over trial conducted on 21 out-patients at high emetic risk after moderate-dose cisplatin. All but 3 patients completed the planned cross-over trial for a total of 60 evaluable courses. The patients completed a self assessment questionnaire evaluating the severity and duration of both nausea and vomiting, the toxicity, as well as their subjective opinion of the antiemetic trial. At the dose and schedule employed, ALZ alone or in combination with DXM provided not only a significantly lower rate of complete protection against nausea and vomiting (0 and 4.8%) than MCP + DXM (28.6%) but was also less effective in reducing the number of vomiting episodes and the duration of the vomiting. In addition, the MCP - DXM regimen was the most frequently preferred. Except for one case of orthostatic hypotension following ALZ, benzamide-induced toxicity was mild, whereas that related to DXM was negligible. The results of this study suggest that high-dose ALZ gives no advantage compared to MCP in patients at high risk for emesis after moderate-dose cisplatin.

Weekly gemcitabine in advanced or metastatic solid tumors. A clinical phase I study.

Gemcitabine (GEM) is a novel deoxycytidine analogue which has shown promising antitumor activity in solid tumor models and a broad range of schedule-dependent MTDs (12-4560 mg/m2) in preliminary clinical studies. The present phase I trial evaluated escalating doses of weekly GEM using a 30-min infusion at a starting dose-level of 300 mg/m2/wk x 3 every 28 days. At least 3 patients entered each dose-level step and 3 more cases were treated when significant toxicity was seen. A total of 39 patients with various advanced solid tumors and prior chemotherapy entered this study. Six escalation steps (102 courses) were tested to define the MTD at 1,370 mg/m2/wk. No definite dose-effect relationships were observed for myelosuppression up to 1,095 mg/m2/wk. However, increased severity of leucopenia (dose-limiting) and greater non-hematologic toxicity as well as a higher number of toxic treatment delays, requiring subsequent dose attenuation in 6 out of 12 patients, were observed at 1,370 mg/m2/wk. In all, 6 out of 11 patients experiencing WHO grade > or = 3 toxicity (11/21 events recorded in 11/18 courses) were treated at the MTD. Clinically significant toxicity included (patients with WHO grade 2-3): leucopenia (44%), thrombocytopenia (26%), anemia (23%), fever (69%), emesis (38%) and AST/ALT rise (26%). Mild proteinuria, ankle edema, skin rash, hair loss and mucositis were seen in < or = 5%.(ABSTRACT TRUNCATED AT 250 WORDS)

Weekly gemcitabine in advanced bladder cancer: a preliminary report from a phase I study.

BACKGROUND: Gemcitabine (2'2-difluorodeoxycytidine; GEM) is a novel deoxycytidine analogue with promising antitumor activity, currently under phase II investigation at doses > or = 800 mg/m2/week. PATIENTS AND METHODS: The present report summarizes the results obtained in a cohort of 15 patients with metastatic bladder cancer included in a larger phase I study, receiving GEM at therapeutically active doses (> or = 875 mg/m2/week x 3 every 28 days). Except for 1 chemotherapy-naive patient, all had received prior chemotherapy with the M-VAC regimen. RESULTS: All but 1 patient were given GEM doses exceeding 1,000 mg/m2 (1 case at 875, 3 at 1,095 and 11 at 1,370 mg/m2) for a total of 50 delivered courses. One complete and 2 partial remissions were seen among 14 previously treated patients. Furthermore, 1 additional partial remission was observed in the single case with no prior chemotherapy, for an overall response rate of 27% (90% C.I. 4.3%-49.1%). All responders had visceral sites of disease. Dose-limiting hematologic toxicity was found at 1,370 mg/m2/wk as underscored by the higher number of toxic treatment delays requiring subsequent dose attenuation in 6 of 11 patients. Toxicity was mild and easily managed. It included (patients with WHO grade 2-3): leukopenia (53%), thrombocytopenia (20%), anemia (53%), AST/ALT rise (27%) and (grade 2 only) fever (60%) and emesis (40%). CONCLUSIONS: The favourable tolerability and evidence of antitumor activity of GEM in patients with bladder cancer and prior M-VAC at doses > or = 875 mg/m2/wk are encouraging and deserve confirmation in larger phase II studies.

Prolonged infusion gemcitabine: a clinical phase I study at low- (300 mg/m2) and high-dose (875 mg/m2) levels.

Gemcitabine (GEM) is a novel nucleoside analogue with a unique mechanism of action. Preliminary studies have shown a mild, schedule-dependent toxic profile with a broad range of MTDs and promising antitumor activity in various solid tumors. This phase I study describes the infusion length-effect relationships of low- (300 mg/m2) and high-dose (875 mg/m2) GEM, administered on days 1, 8 and 15 at 4-week intervals in a step-wise escalation of duration (> or = 33%) at a starting level of 60 minutes. At least 3 patients entered each infusion-level step and 3 more cases were treated in the presence of significant toxicity. Conservative criteria for toxicity were employed, including treatment delay until recovery with infusion de-escalation in the subsequent course. Forty-seven patients (29 at low- and 18 at high-dose GEM levels) with various solid tumors, including 9 (taken as a reference) who had received the same dose levels over 30 min. entered the study. All but 9 patients (with pancreatic cancer) had been previously treated with chemotherapy and all had extensive visceral disease. A striking infusional-effect relationship was observed at both GEM dose levels. Four escalation steps were required to define the maximum tolerated infusion time (MTIT) at 6 hours for 300 mg/m2 GEM, with leucopenia being dose-limiting. At 875 mg/m2, although no limiting toxicity was observed (in spite of increased severity of leucopenia), no escalation was attempted following the 1-hour infusion, due to the limiting rate (58% of 12 patients) of toxic delay requiring shorter infusions. Toxicity was usually mild (no grade 4 event was recorded) showing the usual profile, although there was a trend towards increased non-hematologic toxicity (i.e. LFT abnormalities) as compared with the MTD previously defined using a 30-min. infusion schedule (1,370 mg/m2). Eight patients achieved a PR: 1 with NSCLC, 1 with gastric and 2 with bladder cancer at 300 mg/m2 (1 with a 3- and 3 with a 6-hour infusion) and 2 with pancreatic, 1 with cervical and another with bladder cancer at 875 mg/m2 (all but one with a 1-hour infusion). These data clearly suggest that the infusion duration is an important independent factor that influences the clinical effects of GEM. The present study not only defined the toxic profiles and the MTITs of the selected dose levels but demonstrated that GEM retained the antitumor activity at doses as small as 300 mg/m2 when given as a prolonged infusion. Further studies should clarify the underlying mechanism(s) responsible for the erratic dose-effect dose-effect relationships of GEM and establish the optimal dose-infusion level in the treatment of solid tumors.