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Abstract: Purpose: Fluid retention, which includes peripheral edema, ascites, pleural or pericardial effusion, or a combination of these that is sometimes associated with significant weight gain, is one of the most troublesome cumulative side effects of docetaxel. A suggestive observation from the data base available at the manufacturer (Rhone-Poulenc Rorer) was that patients who received venotonic drugs appeared to tolerate more courses of docetaxel. This prompted a comparative study to investigate whether the venotonic drug hydroxyethylrutosiden could reduce or delay docetaxel-related fluid retention. Methods: A total of 85 patients with metastatic breast cancer who were treated with docetaxel at a dose of 100 mg/m2 with corticoid comedication were allocated to receive either 300 mg hydroxyethylrutosiden given orally four times daily (group A) or no hydroxyethylrutosiden (group B). The end point for analysis was the development of fluid retention of ≥grade 2. Results: Fluid retention of ≥grade 2 was reported in 14 of 42 patients (33%) in group A and in 15 of 43 patients (35%) in group B and occurred after a median of 4 cycles of docetaxel in both groups. Weight gain was similar in groups A and B. Conclusion: We conclude that hydroxyethylrutosiden does not reduce or delay the incidence and severity of docetaxel-related fluid retention.

Topoisomerase I inhibitors are interesting anti-cancer agents with a novel mechanism of action. We performed a phase I study with intravenous GI147211, a new semisynthetic camptothecin analogue, using a daily x 5 schedule administered every 3 weeks, to evaluate the side-effects and pharmacokinetics of the agent. Patients with a histologically confirmed diagnosis of a solid tumour refractory to standard froms of therapy were eligible for the study. GI147211 was given as a 30 min intravenous infusion daily for 5 consecutive days, repeated every 3 weeks. In subsequent patient cohorts the dose was escalated from 0.3 to 1.5 mg m-2 day-1. Pharmacokinetics analysis was performed on days 1 and 4 of the first course using a validated high-performance liquid chromatographic assay and non-compartmental methods. A total of 19 patients were entered into the study, one patient was not evaluable for toxicity because only one drug administration was given. Eighteen patients received a total of 67 courses through four dose levels. The dose-limiting toxicities were neutropenia and thrombocytopenia at the dose of 1.5 mg m-2 day-1. Nadirs occurred on day 15 and day 15 respectively. Other toxicities were mild and infrequent and included nausea/vomiting, headache and alopecia. The maximal tolerated dose was 1.2 mg m-2 day-1. One partial response was observed in a patient with colorectal cancer. The total plasma clearance was 999+/-184 ml min-1 (range 640-1329). The volume of distribution was 190+/-461 m-2 and the terminal half-life was 3.7+/-1.2 h. The AUC increased linearly with the administered dose. A steep and significant sigmoid relationship was established between the AUC and the percent decrease of ANC. GI147211 is a new topoisomerase I inhibitor that induced dose-limiting neutropenia and thrombocytopenia in this phase I study. The recommended dose for phase II studies with this schedule is 1.2 mg m-2 x 5 every 3 weeks.

We investigated the pharmacokinetic profile and the efficacy of ondansetron (day 1) given as 16 mg suppository once a day, as compared with ondansetron 8 mg tablets twice daily, in patients receiving moderately emetogenic chemotherapy. The study was primarily aimed at investigating the pharmacokinetics and was part of a large multinational, randomised, double-blind, double-dummy efficacy trial. Pharmacokinetic data were obtained in a total of 20 patients, 11 of whom had received a suppository containing ondansetron, and nine patients had received the oral formulation. The median area under the plasma concentration curve (AUC) obtained with the oral formulation was 226 ng ml-1h-1 (range 91-750), and the median maximum plasma level (Cmax) was 50.5 ng ml-1 (range 24.7-199.6) after a dose of 8 mg. For the ondansetron suppository the median AUC was 140 ng ml-1h-1 range (77-405) and the median Cmax was 17.1 ng ml-1 (range 13-48.3) after a dose of 16 mg. The systemic exposure after correction for the dose difference after the suppository was on average 70% lower than after the tablet. The median time to reach the maximum level (Tmax) was 60 min (range 28-120) with the oral formulation and 209 min (range 90-420) with the suppository. For both the tablet and suppository, there was no apparent relationship between either Cmax or AUC, and efficacy. Although the patient numbers were too small for a formal exposure-response relationship to be derived, the slightly poorer pharmacokinetic performance of the suppository did not appear to be associated with a lessening of control of emesis following chemotherapy. The study demonstrates that the pharmacokinetic analysis of a once-daily 16 mg ondansetron suppository results in appropriate plasma concentrations and AUC, and that this rectal formulation is effective in the protection against nausea and vomiting associated with cyclophosphamide chemotherapy. This formulation will provide a useful alternative to the currently available oral formulation.

Topoisomerase I inhibitors are new compounds of interest for cancer chemotherapy. We performed a study with GI147211, a new semisynthetic camptothecin analogue, to determine the absolute bioavailability of the drug given orally. Patients with a histologically confirmed diagnosis of a solid tumour refractory to standard forms of therapy were eligible for the study. GI147211 was given orally on day 1 and as a 30-min infusion daily on days 2-5. The treatment course was repeated every 3 weeks. In subsequent patient cohorts, the dose of the oral formulation was escalated from 1.5 mg m(-2) to 6.0 mg m(-2); the dose for i.v. administration was fixed at 1.2 mg m(-2). Plasma pharmacokinetics was performed on day 1 and 2 of the first course and on day 1 of the second course using a validated high-performance liquid chromatographic assay. Nineteen patients were entered into the study; one patient was not evaluable because the treatment course was stopped prematurely. Eighteen patients received a total of 47 treatment courses. The absolute bioavailability of GI147211 averaged 1.3 +/- 5.2%. Drug appeared quickly in plasma with a median Tmax at 0.5 h. Fasting or fed state had no significant influence on the bioavailability of GI147211. The terminal half-life after administration of oral GI147211 was 6.85 +/- 3.13 h, similar to the half-life after intravenous administration. The major toxicities were neutropenia and thrombocytopenia. Nadirs for neutropenia and thrombocytopenia occurred on day 8 and day 15 respectively. Other toxicities predominantly consisted of mild and infrequent nausea and vomiting, and fatigue. The oral administration of the drug is well tolerated. Oral administration of topoisomerase I inhibitor GI147211 results in a low bioavailability with relatively wide interpatient variation. The intravenous route of administration is advised for further development of this promising topoisomerase I inhibitor.

DNA adduct levels were measured with atomic spectroscopy in white blood cells (WBCs) from patients with solid tumours who were treated with six weekly courses of cisplatin. In 21 patients (I) the WBCs were collected after thawing frozen whole-blood samples according to a previously described method. In 32 other patients (II) WBCs were collected immediately after blood sample collection. The two methods for WBC collection were also compared in vitro. The maximal DNA adduct levels in vivo after the first course were in I 2.48 +/- 1.14 and in II 1.28 +/- 0.40 pg of platinum per microgram of DNA (P < 0.0001). The DNA 'repair' in the first course (DNA adduct level at the end of the infusion minus the level 15 h post infusion) was in I 40% +/- 29% and in II 18% +/- 29% (P = 0.009). These differences were consistent in all measured courses. In vitro, the DNA adduct levels in the freshly prepared WBCs were significantly lower at 0, 1 and 4, but not 24 h, after start of the incubation with cisplatin than in the WBCs collected after freezing and thawing the blood sample. The same experiment with carboplatin in vitro also resulted in significantly lower adducts in freshly isolated WBCs. The higher DNA adduct levels and DNA 'repair' in I are caused by remaining unbound cisplatin in the sample tubes, which can form DNA adducts ex vivo. The same results in vivo can be anticipated when carboplatin is used.

Twenty-five patients with advanced solid tumours were entered in a phase I/II study of six, weekly cycles of cisplatin. Nineteen patients were chemonaive and six were previously treated. The starting dose was 50 mg m-2 week-1. This dose could be escalated without major toxicity to 70 mg m-2 week-1. At a dose of 80 mg m-2 myelosuppression grade 3 occurred as well as grade 1 nephro- and neurotoxicity. The maximum tolerated dose was 85 mg m-2 with dose limiting thrombocytopenia. Hypertonic saline was effective in preventing nephrotoxicity. Ondansetron was a very effective antiemetic in the first weeks of treatment but its efficacy waned later on. Responses were observed in head and neck cancer, melanoma and mesothelioma. At the dose level of 80 mg m-2 the optimal dose intensity was reached. This schedule will be tested further in phase II studies.

The results of preclinical and clinical studies indicate enhanced antineoplastic activity of topotecan (SKF 104864-A) when administered as a chronic treatment. We determined the apparent bioavailability and pharmacokinetics of topotecan administered orally to 12 patients with solid tumours in a two-part crossover study. The oral dose of 1.5 mg m-2 was administered as a drinking solution of 200 ml on day 1. The i.v. dose of 1.5 mg m-2 was administered as a 30 min continuous infusion on day 2. The bioavailability was calculated as the ratio of the oral to i.v. area under the curve (AUC) calculated up to the last measured time point. The oral drinking solution was well tolerated. The bioavailability revealed moderate inter-patient variation and was 30% +/- 7.7% (range 21-45%). The time to maximum plasma concentration after oral administration (Tmax) was 0.78 h (median; range 0.33-2.5). Total i.v. plasma clearance of topotecan was 824 +/- 154 ml min-1 (range 535-1068 ml min(-1)). The AUC ratio of topotecan and the lactone ring-opened hydrolysis product (hydroxy acid) was of the same order after oral (0.34-1.13) and i.v. (0.47-0.98) administration. The bioavailability of topotecan after oral administration illustrates significant systemic exposure to the drug which may enable chronic oral treatment.

In 1983, Coates conducted a survey that ranked the side-effects perceived by patients receiving chemotherapy in the order of their severity. Vomiting and nausea were found to be the two most distressing side-effects. They have an impact on quality of life and compliance with treatment. The development of 5HT3 antagonists has been a major step forward in the prevention and treatment of chemotherapy-induced nausea and vomiting. Presently, these antiemetics are routinely used as concomitant therapy in emetogenic chemotherapy regimens. The purpose of this study was to evaluate the impact of 5HT3 antagonists on patient perceptions of the side-effects of chemotherapy. Coates' survey was replicated in patients who received 5HT3 antagonists for acute nausea and vomiting resulting from emetogenic chemotherapy. Patients received the survey to identify those physical and non-physical side-effects that they attributed to chemotherapy and were asked to rank the five most distressing side-effects. Of the 197 patients who consented to take part in the study, 181 were evaluable. Nausea, hair loss and vomiting were described as the three most distressing side-effects of chemotherapy. Eighty per cent of all the patients actually experienced nausea and 57% experienced vomiting. Hair loss appeared to be more distressing to women (P < 0.001) but, in other aspects, gender, age and marital status did not influence the ranking of the three most distressing side-effects. Constipation was ranked as 6th and was not identified as a distressing side-effect in 1983. Nausea and vomiting remain to be the first and third most distressing side-effects of chemotherapy, even though the incidence and severity of acute nausea and vomiting are now significantly reduced.

The study was designed to investigate possible relationships between tumour response and exposure to cisplatin (area under the curve of unbound cisplatin in plasma, AUC) and DNA-adduct formation in leucocytes (WBC) in patients with solid tumours. Patients were treated with six weekly courses of cisplatin at a dose of 70 or 80 mg m-2. The AUC was determined during the first course and DNA-adduct levels in WBC during all courses at baseline, 1 h (A(max)) and 15 h after a 3 h infusion of cisplatin. The area under the DNA-adduct-time curve (AUA) was calculated. The tumour response was determined after six courses. Forty-five evaluable patients received 237 courses of cisplatin. Sixteen patients with head and neck cancer received a dose of 80 mg m-2 and 29 with various other tumour types received 70 mg m-2 plus daily 50 mg oral etoposide. There were 20 responders (partial and complete) and 25 non-responders (stable and progressive disease). The AUC was highly variable (mean +/- s.d. = 2.48 +/- 0.51 micrograms h-1 ml-1; range 1.10-3.82) and was closely correlated with the AUA (r = 0.78, P < 0.0001) and A(max) (r = 0.73, P < 0.0001). The AUC, AUA and A(max) were significantly higher in responders than in non-responders in the total population (P < 0.0001) and in the two subgroups treated at 70 or 80 mg m-2. In logistic regression analysis AUC, AUA and A(max) were important predictors of response. The magnitude of exposure to cisplatin is, through DNA-adduct formation, the major determinant of the response rate in this population. Hence, individualised dosing of cisplatin using AUC or DNA-adducts should lead to increased response rates.

In a phase I study of weekly administered cisplatin combined with oral etoposide, we observed a partial response in 4 out of 11 patients with metastatic colorectal cancer. Subsequently, we performed a phase II study to investigate the activity of this combination as first-line treatment in this disease. Fourteen patients with metastatic colorectal cancer were enrolled in this study. Treatment consisted of cisplatin, administered in 3% sodium chloride, at a dose of 70 mg m-2 on days 1, 8 and 15 and days 29, 36 and 43 combined with oral etoposide 50 mg absolute dose daily on days 1-15 of both courses. Patients with stable disease or better continued treatment with etoposide 50 mg m-2 orally on days 1-21 every 28 days. A partial response was observed in two patients with liver metastases (14%; 95% confidence limits 2-42%) for 30 and 32 weeks. Five patients had stable disease. Toxicity consisted mainly of anaemia, leucocytopenia, nausea and vomiting. Tinnitus was reported by six patients. The activity of the combination cisplatin-oral etoposide in the schedule is only minimal in metastatic colorectal cancer.

T is a watersoluble semisynthetic analog of camptothecin which exerts cytotoxicity during the S-phase of the cell cycle through specific inhibition of topoisomerase I. Preclinical data have indicated that T is more effective with prolonged exposure. The clinical feasibility of this concept was recently reported by Hochster et al. (J.C.O. 1009: 12; 553–559) using a 21-days continuous infusion (c.i.). We performed a phase II study with T 0.6mg/m2/d as a 21-days c.i. repeated every 28 days, in patients (pts) with metastatic colorectal cancer, not previously treated with chemotherapy. Dose reductions of 0.1mg/m2/d were performed if myelosuppression persisted beyond day 28. If no toxicity worse than grade 2 occurred dose increases by 0.1mg/m2/d were allowed. The starting dose was reduced to 0.5mg/m2/d after in 5/11 pts the second course was delayed. Response was evaluated every 2 courses according to the WHO criteria, toxicity was scored according to the CTC criteria. To date, 41 pts have entered the study. Patient characteristics included: 22 females, 19 males; median age 57 years (range 37–68); median WHO performance score 1 (range 0–2). Two pts were unevaluable; 39 pts assessable for toxicity up to now received a total of 94 courses, median 3 per pt (range 1–9). The main toxicity was myelosuppression, with neutropenia grade 3–4 occurring in 26% of courses, median nadir of ANC occurring on day 25 (range 8–35), and thrombocytopenia being, relatively mild with the nadir also on day 25. Despite this mild myelotoxicity treatment had to be delayed in 24 courses (26%) mainly because of prolonged myelosuppression. As prescribed by protocol treatment delays mandated dose-reduction in the subsequent course. As a result of this median dose intensity (mg/m2/wk) decreased in the successive courses 1–9 from 2.62–2.62–2.62–2.1–2.1–1.92–2.1 to 2.1. In addition, a marked inhibition of the erythropoiesis was observed. Non-haematological disease effects were mild, nausea grade 1–2 occurred in 25 courses (26%), vomiting in 15 courses (16%), and asthenia and fatigue in 32 courses (34%). Alopecia being grade 2, except in one, was seen in 8 pts (20%). Steady-state (Css) levels of T were determined by HPLC during the first 2 courses and varied widely: 0.65±0.15ng/ml (range 0.37–6.91, N=15). No significant correlation was found between Css and absolute dose. In the 30 pts presently evaluable for response 1 CR and 2 PRs were observed. In conclusion, this dosing schedule is relatively well tolerated but has only modest clinical activity in colorectal cancer.