Postoperative chemoradiotherapy in gastric cancer--a phase I-II study of radiotherapy with dose escalation of weekly cisplatin and daily capecitabine chemotherapy.

BACKGROUND: Postoperative chemoradiotherapy with concurrent 5-fluorouracil improves gastric cancer outcome. We previously demonstrated that chemoradiotherapy with a more intensified--and therefore potentially more effective--schedule with daily cisplatin and oral capecitabine is feasible. Because such an intensive schedule requires an extensive logistic infrastructure which is not available in every hospital, we additionally investigated the tolerability of this combined regimen with weekly instead of daily cisplatin in a dose-escalation study. PATIENTS AND METHODS: After R0 or R1 resection, treatment initiated with capecitabine 1000 mg/m(2) b.i.d. for 2 weeks and 1-week rest. Subsequently, patients received capecitabine (575-650 mg/m(2) orally b.i.d., 5 days/week) and cisplatin (20-25 mg/m(2) i.v., once weekly) according to a predefined dose-escalation schedule concurrent with radiation. Radiotherapy was given to a fixed total dose of 45 Gy in 25 fractions. RESULTS: Thirty-one patients were eligible and started treatment. During chemoradiotherapy, seven patients developed 10 items of grade III and one episode of grade IV (mainly hematological) toxicity (National Cancer Institute-Common Toxicity Criteria version 3.0). The maximum tolerable dose was determined to be for cisplatin 20 mg/m(2) i.v. weekly and for capecitabine 575 mg/m(2) b.i.d. orally. CONCLUSIONS: This phase I-II study demonstrated that postoperative chemoradiotherapy with weekly cisplatin and daily capecitabine is feasible in gastric cancer at the defined dose level. This schedule is currently being tested as the experimental arm in a phase III multicenter study (CRITICS: chemoradiotherapy after induction chemotherapy in cancer of the stomach; Clinicaltrials.gov NCT 00407186).

Monitoring of interaction products of cis-diamminedichloroplatinum(II) and cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II) with DNA in cells from platinum-treated cancer patients.

The formation and stability of interaction products between the anti-cancer drug cis-diamminedichloroplatinum(II) (cis-DDP) and DNA were studied in buccal epithelial and urinary cells from ten cancer patients who received cis-DDP-based therapy. Buccal cells were collected 1 h before and 1-2 h after i.v. infusions with cis-DDP. The interaction products were visualized in an immunocytochemical peroxidase assay, using an antiserum against cis-DDP-modified calf thymus DNA. The nuclear staining density was measured by microdensitometry. Nuclear staining densities in buccal cells after infusions of greater than or equal to 20 mg/m2 cis-DDP were always higher than pretreatment values. Repeated sampling from individual patients treated for 2-5 consecutive days with daily doses of 20-70 mg/m2 cis-DDP indicated that cis-DDP-DNA binding in buccal cells increased in proportion to the cumulative total dose of cis-DDP. The variation in dose-density response between patients was 17%. Apparent adduct loss in buccal cells from four patients, as measured 8-17 days after the last infusion, amounted to 67-86%. Platinum-induced DNA modifications could also be detected in buccal cells from two cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II)-treated patients. In vitro experiments with human buccal cells and lymphocytes indicated linear relationships between DNA modification and either cis-DDP concentration or incubation time. Nuclear staining densities in pretreatment buccal cells from ten cancer patients treated in vitro with 33 microM cis-DDP for 1 h revealed that interpatient variation in in vitro DNA modification by cis-DDP was low. No quantitative correlation was found between in situ and in vitro DNA modification.

Telephone-based nursing intervention improves the effectiveness of the informed consent process in cancer clinical trials.

PURPOSE: Here we report the results of a randomized study undertaken to test the efficacy of a supplementary, telephone-based nursing intervention in increasing patients' awareness and understanding of the clinical trials in which they are asked to participate. METHODS: During a 12-month period, 180 cancer patients who were approached to participate in a phase II or III clinical trial were randomized to undergo either of the following: (1) standard informed consent procedures based on verbal explanations from the treating physician plus written information (controls); or (2) standard informed consent procedures plus a supplementary, telephone-based contact with an oncology nurse (intervention). For purposes of evaluation, face-to-face interviews were conducted with all patients approximately 1 week after the informed consent process had been completed. RESULTS: The two groups were comparable with regard to sociodemographic and clinical variables. Both groups had a high level of awareness of the diagnosis and of the nature and objectives of the proposed treatments. The intervention group was significantly (P < .01) better informed about the following: (1) the risks and side effects of treatment; (2) the clinical trial context of the treatment; (3) the objectives of the clinical trial; (4) where relevant, the use of randomization in allocating treatment; (5) the availability of alternative treatments; (6) the voluntary nature of participation; and (7) the right to withdraw from the clinical trial. The intervention did not have any significant effect on patients' anxiety levels or on rates of clinical trial participation. Patients reported high levels of satisfaction with the intervention. CONCLUSION: The use of a supplementary, telephone-based nursing intervention is a feasible and effective means to increase cancer patients' awareness and understanding of the salient issues that surround the clinical trials in which they are asked to participate.

Phase I study and pharmacokinetics of intraperitoneal carboplatin.

In the early stages of this phase I study the tolerance of carboplatin intraperitoneally was good. Pharmacokinetic profiles suggest a possible therapeutic advantage for giving the drug intraperitoneally for the treatment of tumour nodules situated in the peritoneum. The extent of penetration of carboplatin through tumour nodules has not yet been assessed but tumour nodules are being processed for nuclear activation analysis.

Age-dependent vitamin D status and vertebral condition of white women living in Curaçao (The Netherlands Antilles) as compared with their counterparts in The Netherlands.

Plasma vitamin D metabolites and parathyroid hormone concentrations of two groups of white women, aged 26-46 and 63-83 y, in Curaçao were studied to evaluate the effect of yearlong abundant sunlight on frequency of vertebral compression fractures in elderly women. 25-Hydroxyvitamin D of the younger group (median, 116 nmol/L) was higher than that of the older group (75 nmol/L). Both groups had higher 25-hydroxyvitamin D compared with approximately age-matched counterparts in The Netherlands during autumn and winter (50 and 25 nmol/L, respectively). Similar differences were found for 1,25-dihydroxyvitamin D, although to a lesser extent. Parathyroid hormone concentrations of older women in Curaçao (4.3 pmol/L) were higher than those of the younger women (2.3 pmol/L). Roentgenographic analyses of the spines of the older women did not show vertebral compression fractures commonly encountered in women living at higher latitudes. Uninterrupted high plasma concentrations of vitamin D metabolites may reduce vertebral compression fractures in postmenopausal white women.

Docetaxel alternating with epirubicin and cyclophosphamide: a feasibility study in breast cancer patients.

Docetaxel is one of the most active drugs used in the treatment of breast cancer. However, its major side-effect, myelosuppression, hampers full-dose combination chemotherapy. We have, therefore, developed an alternating schedule of docetaxel with epirubicin and cyclophosphamide, together with granulocyte colony-stimulating factor, to ameliorate neutropenia. We studied the feasibility of such a strategy, decreasing the treatment interval from 21 days to 14 days, thus further increasing the dose intensity. As expected, myelosuppression was common, complicated by neutropenic fever, which did not exceed preset criteria. Other side-effects were also as expected: alopecia, malaise, nausea and vomiting. After two alternating courses of chemotherapy, a partial response was documented in 15 of 17 patients. We conclude that this alternating schedule is very active against breast cancer and warrants further phase II studies.

Phase I and pharmacological study of daily oral administration of perifosine (D-21266) in patients with advanced solid tumours.

Alkylphosphocholines are a novel class of antitumour agents structurally related to ether lipids that interact with the cell membrane and influence intracellular growth signal transduction pathways. We performed a phase I trial with an analogue of miltefosine, perifosine (D-21266), which was expected to induce less gastrointestinal toxicity. Objectives of the trial were: to determine the maximum-tolerated dose (MTD) for daily administration, to identify the dose-limiting toxicity (DLT) of this schedule, to assess drug accumulation and to determine the relevant pharmacokinetic parameters. 22 patients with advanced solid tumours were treated at doses ranging from 50 to 350 mg/day for 3 weeks, followed by 1 week of rest. Toxicity consisted mainly of gastrointestinal side-effects: nausea was reported by 11 patients (52%, 10 patients Common Toxicity Criteria (CTC) grades 1-2 and 1 patient CTC grade 3), vomiting by 8 (38%, all CTC grades 1-2), and diarrhoea by 9 (43%, 8 patients CTC grades 1-2 and 1 patient CTC grade 3). The severity of these side effects appeared to increase with increasing doses. Another common side-effect was fatigue, occurring in 9 patients (43%). No haematology toxicity was observed. Dose-limiting toxicity (DLT) was not reached, but gastrointestinal complaints led to an early treatment discontinuation in an increasing number of patients at the higher dose levels. Therefore, MTD was established at 200 mg/day. The pharmacokinetic studies suggested dose proportionality.

Experimental and clinical results with intraperitoneal cisplatin.

Up to 30% of ovarian cancer patients with minimal residual disease may achieve a complete remission with intraperitoneal cisplatin therapy. This mode of therapy, however, is toxic and cumbersome. Sodium thiosulfate was shown to protect renal function, as well as lessen hematologic complications of cisplatin therapy. A major problem with cisplatin in terms of achieving maximal therapeutic dosages is neurotoxicity. Different platinum chemotherapeutic agents, pharmacodynamics, and pharmacokinetics of intraperitoneal administration, and rescue agents other than sodium thiosulfate are presently being investigated by The Netherlands Cancer Institute.

Dose-finding studies with carboplatin, ifosfamide, etoposide, and mesna in non-small cell lung cancer.

Carboplatin, a clinically active analogue of cisplatin, was added to a regimen containing ifosfamide and etoposide, two agents with proven activity in non-small cell lung cancer (NSCLC). From August 1986 until November 1988, 43 consecutive patients (29 men and 14 women), mean age 57 years, performance status of 2 or less, with symptomatic, inoperable NSCLC were accrued and received carboplatin 100 mg/m2 on days 1, 3, and 5, or 300 or 350 mg/m2 on day 1; ifosfamide 1,500 mg/m2 and etoposide 60 or 100 mg/m2 every 4 weeks. Thirty-four patients were previously untreated, nine had been irradiated before, and two had also received previous chemotherapy. So far, 154 courses have been administered; 19 patients have received four or more courses. With the combination of 350 mg/m2 carboplatin and 100 mg/m2 etoposide, myelosuppression was dose-limiting; nephrotoxicity and neurotoxicity did not occur. Evaluation of response after two or four courses in 40 patients showed an objective response in 40%, whereas 30% progressed during therapy. Carboplatin added to etoposide and ifosfamide is a feasible combination that warrants further study in a randomized fashion.

Carboplatin and paclitaxel in patients with advanced ovarian cancer: a dose-finding study.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) combined with cisplatin seems the new standard of care for ovarian cancer patients. Since carboplatin lacks the neurotoxicity of cisplatin with an equal antitumor activity against ovarian cancer, it was chosen as the next logical step for combination chemotherapy with paclitaxel. In 46 patients an alternating dose-escalation trial has been performed. The maximum tolerated doses are carboplatin 500 mg (area under the concentration-time curve of 9) and paclitaxel 200 mg/m2 given every 3 weeks. The dose-limiting toxicity is thrombocytopenia, which emerges in the later stages of the treatment. A true platelet-sparing effect of the combination seems highly probable. The antitumor activity of the combination equals that reported for the new standard paclitaxel/cisplatin treatment. Further phase III studies are warranted.

Replacement of cisplatin with carboplatin in combination chemotherapy against ovarian cancer: long-term treatment results of a study of the Gynaecological Cancer Cooperative Group of the EORTC and experience at The Netherlands Cancer Institute.

Carboplatin-based chemotherapy has been evaluated in three studies of ovarian cancer patients. In the first, combination cisplatin and carboplatin plus doxorubicin/hexamethylmelamine/cyclophosphamide were compared as first-line treatment of ovarian cancer in 341 women with stage IIB to IV disease. There were no observed differences in results between the two treatment groups. In the second study, conventional doses of intravenous carboplatin (350 mg/m2, given on day 1) plus oral cyclophosphamide (100 mg/m2 days 2 to 6) were given to late-relapsing patients (12 to 72 months) previously treated with cisplatin. Mature data showed a 55% overall response rate, acceptable toxicity, and an absence of additive neurotoxicity. Finally, 65 patients with refractory disease or in early relapse after cisplatin therapy (within 12 months) were treated with high-dose carboplatin (800 mg/m2). Toxicity was severe, but the 45% combined response rate was considered encouraging and worthy of further evaluation. It was concluded that carboplatin is an appropriate replacement for cisplatin in the treatment of ovarian cancer.

Phase I study of mitozolomide on a once daily for 5 days schedule.

In a phase I study mitozolomide was given on a once daily for 5 days schedule to 18 patients with a variety of malignancies. Non-hematological toxicity was negligible. Significant myelosuppression occurred at a total dose as low as 62.5 mg/m2 per course. In particular, thrombocytopenia, which was unpredictable, precluded dose increments beyond 15 mg/m2 per day (or a total of 75 mg/m2). Antitumor effects were not observed. The 5-day schedule of mitozolomide appears to have no advantage over administration once every 3-4 weeks, and may even be more dangerous than the latter schedule.

Clinical pharmacokinetics of mitoxantrone after intraperitoneal administration.

The pharmacokinetics of intraperitoneally (i.p.) injected mitoxantrone was determined in plasma and peritoneal dialysate taken from five patients presenting with cancer confined to the peritoneal cavity over a sampling period of 1 week. The drug was given through a Tenckhoff catheter as a 15-min infusion and the peritoneal dialysate was removed after a dwell time of 4 h; the doses delivered varied between 20 and 50 mg/m2. Dose-limiting local toxicity was moderate. The HPLC technique used for mitoxantrone determinations proved to be sensitive within the range of 0.3-4,000 ng/ml. Median values obtained for the pharmacokinetic parameters of mitoxantrone in peritoneal dialysate were: t1/2 beta (distribution), 56.4 min (range, 16.8-235.8 min); t1/2 gamma (elimination), 128 h (range, 28.3-171.0 h); Vdss (volume of distribution at steady state), 24.8 l (range, 17.0-232.5 l); delta'ss (volume of distribution at steady state corrected for the body surface area in square meters), 14.4 l/m2 (range, 10.6-129.2 l/m2); and clearance, 0.25 l/h (range, 0.16-0.59 l/h). For plasma the median values were: t1/2 alpha (absorption), 58.8 min (range, 45.6-87.0 min); t1/2 beta (distribution), 2.5 h (range, 1.4-6.3 h); t1/2 gamma (elimination), 44.1 h (range, 9.1-91 h); Vdss, 2,152 l (range, 352-19,733 l); delta'ss, 1,345 l/m2 (range, 220-11,606 l/m2); and clearance, 117 l/h (range, 51-1,609 l/h). After 168 h the median plasma concentration was 1 ng/ml. The median peak concentration in peritoneal dialysate was 490 ng/ml. Considering the moderate toxicity observed and the concentrations achieved in the peritoneal dialysate, removal of the dialysate after certain dwell times seems reasonable to be a reasonable approach for the optimization of i.p. treatment with mitoxantrone.

Feasibility and pharmacokinetics of intraperitoneal suramin in advanced malignancy.

PURPOSE: Bioactive lipids have been causally linked to intraabdominal malignancies such as ovarian cancer. In advanced tumors confined to the peritoneal cavity. inhibition of lipid growth factors present in ascites might induce tumor remissions. The systemic toxicity of the growth factor inhibitor suramin has so far hampered its use in standard oncologic practice, but this could be alleviated by intraperitoneal administration. In this study the feasibility, toxicity and pharmacokinetics of intraperitoneal suramin administration are described. METHODS: Patients with histologically verified cancer confined to the abdominal cavity, for which no effective therapy was available, were treated with intraperitoneal suramin through a Tenckhoff catheter. Patients with ascites were treated with low-volume continuous i.p. infusions of 500 mg/24 h, and patients without ascites were treated with intermittent large-volume i.p. infusions of 1000 mg three times a week. Regular pharmacokinetic sampling of plasma and ascites fluid was carried out. Patients were treated for 6 weeks or until development of progressive disease or until plasma suramin levels exceeded 250 mg/l. RESULTS: Nine patients were treated in ten periods, three with intermittent i.p. suramin, and seven with continuous i.p. suramin, for a median of 28.5 days (16-42 days), with a median suramin dose of 12 g (range 9 21 g ). Treatment was discontinued because of high systemic suramin levels in three patients (all in the intermittent schedule), progressive disease (five patients) or completion of planned treatment (one patient). Toxicity was mild, without any of the systemic side effects commonly associated with suramin. Intraperitoneal suramin levels were consistently higher than plasma levels in all patients, but this effect was most marked in the continuous infusion schedule. CONCLUSIONS: Intraperitoneal suramin infusion in patients with advanced peritoneal cancers is feasible and well-tolerated. Continuous low volume i.p. infusion in patients with ascites confers the largest pharmacokinetic advantage.

Pharmacokinetics of carboplatin after intraperitoneal administration.

The pharmacokinetics of carboplatin, ultrafilterable platinum, and total platinum after intraperitoneal (i.p.) administration were studied in peritoneal fluid, plasma, red blood cells (RBCs), and urine during a phase-I trial in patients with minimal, residual ovarian cancer. Samples were collected from 7 patients who had received carboplatin (200-500 mg/m2) in 21 dialysis fluid. The fluid was withdrawn after a 4-h dwell. Platinum concentrations were measured by flameless atomic absorption spectrometry, and intact carboplatin was determined by HPLC with electrochemical detection. Peak concentrations of carboplatin in plasma were obtained 2 h after the end of instillation. The mean ratio of peak concentrations of carboplatin in instilled fluid and plasma was 24 +/- 11. The peritoneal clearance of carboplatin was 8 +/- 3 ml/min, which was 12 times less than the plasma clearance (93 +/- 32 ml/min). Due to this clearance ratio, the AUCs for the peritoneal cavity were about 10 times higher than those for plasma. On average, 34% +/- 14% of the dose was still present in the instillation fluid that had been withdrawn after a dwell time of 4 h. In plasma, the mean value of AUC/Dnet (Dnet = Dose - amount recovered from the peritoneal cavity) after i.p. administration was comparable with that of AUC/D after i.v. administration. This means that unrecovered carboplatin (66%) was completely absorbed from the peritoneal cavity. It may be expected from this bioavailability that the maximum tolerated dose (MTD) of i.p.-administered carboplatin with a 4-h dwell is around 1.5 times higher than that after i.v. administration. Overall pharmacokinetic parameters of carboplatin and platinum in plasma were comparable after i.p. and i.v. administration.

Treatment of patients with IVCS and gross oedema and ascites with diuretic combination and ACE-inhibitors: relation to baseline PRA and PAC.

OBJECTIVE: (1) To assess plasma renin activity (PRA) and plasma aldosterone concentration (PAC) in patients with inferior vena cava syndrome (IVCS). (2) To study in an open fashion the efficacy of loop diuretic treatment, single, or in combination with an ACE-inhibitor or with spironolactone. METHODS: In 13 patients PRA and PAC were measured and related to urinary sodium excretion (UNa). RESULTS: Highly elevated PRA and PAC were found in recently developed IVCS. The correlation coefficient between PAC and UNa was -0.61, p < 0.05. In 10 patients the influence of captopril (C)] at maximum tolerable doses with or without furosemide (F) was evaluated. Mean tolerated dose of C amounted to 8.8 mg t.i.d. (range 2-25), achieving a PAC reduction of 26%. Efficacy of F was severely blunted when PAC exceeded the low-normal range. Spironolactone addition at 100 mg/day in non-responders to F or to F and C, induced immediate natriuretic responses except in a patient with 7-70 fold increase in PAC. CONCLUSIONS: (1) In IVCS loop diuretic efficacy is attenuated by aldosterone activation; (2) complete aldosterone suppression with captopril is difficult to achieve due to dose restriction; (3) spironolactone is favoured for a synergistic response.

Postoperative chemoradiotherapy in gastric cancer -- a Phase I/II dose-finding study of radiotherapy with dose escalation of cisplatin and capecitabine chemotherapy.

We hypothesised that gastric cancer outcome could be improved with more effective and intensified postoperative chemoradiotherapy. This phase I/II study was performed to determine the maximal tolerated dose (MTD) and toxicity profile of postoperative radiotherapy with concurrent daily cisplatin and capecitabine. Patients were treated with capecitabine 1000 mg m(-2) twice a day (b.i.d.) for 2 weeks. Subsequently, patients received capecitabine (250-650 mg m(-2) orally b.i.d., 5 days week(-1)) and cisplatin (3-6 mg m(-2) i.v., 5 days week(-1)) according to an alternating dose-escalation schedule. Radiotherapy was given to a total dose of 45 Gy in 25 fractions. Thirty-one patients completed treatment. During chemoradiotherapy, eight patients developed nine items of grade III and one episode of grade IV (mainly haematological) toxicity. The MTD was determined to be cisplatin 5 mg m(-2) i.v. and capecitabine 650 mg m(-2) b.i.d. orally. This phase I/II study demonstrated that chemoradiotherapy with daily cisplatin and capecitabine is feasible in postoperative gastric cancer at the defined dose level and is currently being tested in a phase III multicenter study.