J.B. Vermorken

Humoral immune response to polymorphic epithelial mucin (MUC-1) in patients with benign and malignant breast tumours

To investigate the clinical significance of an immune response to the MUC-1 encoded polymorphic epithelial mucin (PEM) breast cancer, circulating immune complexes containing PEM (PEM.CIC) were measured in sera from 96 healthy women, in pretreatment serum samples from 40 patients with benign breast tumours and from 140 patients with breast cancer and in serum samples from 61 breast cancer patients with recurrent or progressive disease. PEM.CIC were measured using a sandwich enzyme-linked immunoassay, and PEM serum levels were measured with CA 15.3 IRMA (Centocor Inc., Malvern, Pennsylvania, U.S.A.). Cut-off levels used for PEM.CIC and CA 15.3 were 120 Optical Density Units (O.D.) x 10(3) and 30 U/ml, respectively. In benign tumours, positivity for PEM.CIC was 37.5% (15/40). 36 of the 140 patients (25.7%) in the breast cancer pretreatment group had elevated PEM.CIC values. In patients with advanced metastatic disease, positivity for PEM.CIC was 18% (11/61). PEM.CIC was elevated in 32% (24/74) of node-negative patients, but only in 20% (12/59) of node-positive patients and absolute values were higher in node-negative patients (Mann-Whitney U test, two-tailed P = 0.0168). There was an inverse correlation between positivity for PEM.CIC and extent of disease: while 3 of the 6 patients with a carcinoma in situ were positive, only 1 of the 15 patients with more than five nodes involved had elevated levels of PEM.CIC. All 7 patients with distant metastases at first diagnosis were PEM.CIC negative. 28 out of 133 patients had a recurrence during the observation period (median 55 months, range 27-84 months). 23 of these 28 patients (82%) were PEM.CIC negative at the moment of first diagnosis. None of the patients with pretreatment elevation of both PEM.CIC and CA 15.3 (n = 13) relapsed. Our preliminary clinical results suggest that a humoral immune response to PEM protects against disease progression, and further support the idea of using synthetic peptides or glycopeptides containing the immunogenic core of the mucin as cancer vaccines.

Initial experience with conservative treatment in cancer patients with osteonecrosis of the jaw (ONJ) and predictors of outcome

BACKGROUNDnOverall survival (OS) and outcome of cancer patients with bisphosphonate-associated osteonecrosis of the jaw (ONJ) using conservative treatment (chlorhexidine 0.12% rinse, intermittent antibiotics, and careful sequestrectomy) are unknown.nnnDESIGNnIn all, 33 ONJ patients were studied for OS and ONJ outcome.nnnRESULTSnMedian duration of bisphosphonate treatment was 27 months (range 4-115) and was stopped in 25 (76%) patients. Nine (27%) cases presented with stage 1, 21 (64%) with stage 2, and 3 (9%) with stage 3 disease. During median follow-up of 23 months, 11 patients (33%) died (median survival 39 months), with no ONJ-related fatalities. Out of 30 assessable patients, 53% no longer had exposed bone, 37% had stable lesions, and 10% showed progressive necrosis. The hazard ratio for healing with doubling of bisphosphonate exposure was 0.419 [95% confidence interval (CI) 0.178-0.982; P = 0.045], stage 2 versus stage 1 disease 0.216 (95% CI 0.063-0.738; P = 0.015), and stage 3 versus stage 1 disease 0.084 (95% CI 0.008-0.913; P = 0.042). Cessation of bisphosphonate treatment did not influence outcome.nnnCONCLUSIONSnConservative treatment of ONJ leads to mucosal closure in 53% of patients. Doubling the exposure time to bisphosphonates and higher stages of ONJ significantly reduce ONJ healing rates.

Phase I and pharmacokinetic study of Yondelis™ (Ecteinascidin-743; ET-743) administered as an infusion over 1 h or 3 h every 21 days in patients with solid tumours

Yondelis (ET-743) is a novel anticancer agent isolated from the marine ascidian Ecteinascidia turbinata. ET-743 possesses potent antitumour activity and a novel mechanism of action at the level of gene transcription. We conducted two sequential phase I dose escalation and pharmacokinetic studies of ET-743 given as a 1- or a 3-h intravenous (i.v.) infusion. Seventy-two adults with metastatic or advanced solid tumours received ET-743 in escalating doses between 50 and 1100 microg/m(2), initially as a 1-h infusion, and later at doses between 1000 and 1800 microg/m(2) as a 3-h infusion every 3 weeks. The maximum tolerated dose (MTD) of ET-743 was 1100 microg/m(2) for the 1-h infusion schedule and 1800 microg/m(2) when given as a 3-h infusion. Dose-limiting toxicities (DLTs) were fatigue, neutropenia and thrombocytopenia. Transient non-cumulatives grade 3-4 increase in transaminases (not considered DLT) and grades 3-4 nausea and vomiting were frequently observed. Other toxicities (maximum grade 3) included anaemia, increased lactate dehydrogenase (LDH), bilirubin and alkaline phosphatase serum levels, and phlebitis; there were no toxic deaths. One pCR (melanoma), CR (uterine leiomyosarcoma), one PR (colon stromal sarcoma) and a MR (37% tumour shrinkage, gastric stromal sarcoma) were observed. A further 9 patients with colorectal, mesothelioma, bile duct carcinoma and bladder cancer had SD which lasted for six or more treatment cycles. ET-743 pharmacokinetics were linear with the 3-h infusion schedule. The haematological and hepatic toxicities of ET-743 were dose-dependent and not cumulative. Based on the current trial, the recommended dose of ET-743 for phase II studies is 1650 microg/m(2) given as a 3-h infusion.

EORTC Early Clinical Studies Group early phase II trial of S-1 in patients with advanced or metastatic colorectal cancer

Cancer of the colon and rectum is one of the most frequent malignancies both in the US and Europe. Standard palliative therapy is based on 5-fluorouracil/folinic acid combinations, with or without oxaliplatin or irinotecan, given intravenously. Oral medication has the advantage of greater patient convenience and acceptance and potential cost savings. S-1 is a new oral fluorinated pyrimidine derivative. In a nonrandomised phase II study, patients with advanced/metastatic colorectal cancer were treated with S-1 at 40u2009mgu2009m−2 b.i.d. for 28 consecutive days, repeated every 5 weeks, but by amendment the dose was reduced to 35u2009mgu2009m−2 during the study because of a higher than expected number of severe adverse drug reactions. In total 47 patients with colorectal cancer were included. In the 37 evaluable patients there were nine partial responses (24%), 17 stable diseases (46%) and 11 patients had progressive disease (30%). Diarrhoea occurred frequently and was often severe: in the 40 and 35u2009mgu2009m−2 group, respectively, 38 and 35% of the patients experienced grade 3–4 diarrhoea. The other toxicities were limited and manageable. S-1 is active in advanced colorectal cancer, but in order to establish a safer dose the drug should be subject to further investigations.

A phase I study of bendamustine hydrochloride administered day 1+2 every 3 weeks in patients with solid tumours

The aim of the study was to determine the maximum tolerated dose (MTD), the dose limiting toxicity (DLT), and the pharmacokinetic profile (Pk) of bendamustine (BM) on a day 1 and 2 every 3 weeks schedule and to recommend a safe phase II dose for further testing. Patients with solid tumours beyond standard therapy were eligible. A 30-min intravenous infusion of BM was administered d1+d2 q 3 weeks. The starting dose was 120u2009mgu2009m−2 per day and dose increments of 20u2009mgu2009m−2 were used. Plasma and urine samples were analysed using validated high-performance liquid chromatography/fluorescence assays. Fifteen patients were enrolled. They received a median of two cycles (range 1–8). The MTD was reached at the fourth dose level. Thrombocytopaenia (grade 4) was dose limiting in two of three patients at 180u2009mgu2009m−2. One patient also experienced febrile neutropaenia. Lymphocytopaenia (grade 4) was present in every patient. Nonhaematologic toxicity including cardiac toxicity was not dose limiting with this schedule. Mean plasma Pk values of BM were tmax 35u2009min, t1/2 49.1u2009min, Vd 18.3u2009lu2009m−2, and clearance 265u2009mlu2009min−1u2009m−2. The mean total amount of BM and its metabolites recovered in the first micturition was 8.3% (range 2.7–26%). The MTD of BM in the present dose schedule was 180u2009mgu2009m−2 on day 1+2. Thrombocytopaenia was dose limiting. The recommended dose for future phase II trials with this schedule is 160u2009mgu2009m−2 per day.

Hypersensitivity Reactions to the Taxanes Paclitaxel and Docetaxel

SummaryPaclitaxel and docetaxel are taxane derivatives with a significant antitumour activity. For both drugs, a high incidence of hypersensitivity reactions (HSRs) has been observed during the initial clinical development. However, current pretreatment regimens, consisting of corticosteroids and antihistamines, have led to a substantial decrease in major HSRs. In this study, we describe a case series of 9 out of a total of 415 patients from eight different taxane studies who received either paclitaxel or docetaxel and experienced severe HSRs, despite the use of premedication. Five of these 9 patients had allergies or atopy. We observed an increase in blood pressure during the HSR in 5 patients, whereas a decrease was anticipated. Retreatments, with additional corticosteroids, antihistamines and in some cases a lower infusion rate, were performed successfully in 7 patients. One of these patients was given, after two courses with HSR symptoms, sodium cromoglycate as prophylaxis, after which she received four successive courses without symptoms of HSR.In conclusion, premedication given before taxane infusions did not guarantee prevention of HSRs. We observed that these reactions did not resemble anaphylactic reactions in that there were unexpected increases in blood pressure. Retreatments were possible in most cases after appropriate measures were taken.

Combination chemotherapy studies with gemcitabine and etoposide in non-small cell lung and ovarian cancer cell lines

Gemcitabine (2,2-difluorodeoxycytidine, dFdC) and etoposide (4-demethylepipodo-phyllo-toxin-9-4,6-O-ethylidene-beta-D-g lucopyranoside, VP-16) are antineoplastic agents with clinical activity against various types of solid tumors. Because of the low toxicity profile of dFdC and the differences in mechanisms of cytotoxicity, combinations of both drugs were studied in vitro. For this purpose, we used the human ovarian cancer cell line A2780, its cis-diammine-dichloroplatinum-resistant and VP-16 cross-resistant variant ADDP, and two non-small cell lung cancer cell lines, Lewis Lung (LL, murine) and H322 (human). The interaction between the drugs was determined with the multiple drug effect analysis (fixed molar ratio) and with a variable drug ratio. In the LL cell line, the combination of dFdC and VP-16 at a constant molar ratio (dFdC:VP-16 = 1:4 or 1:0.125 after 4- or 24-hr exposure, respectively) was synergistic (combination index [CI], calculated at 50% growth inhibition = 0.7 and 0.8, respectively; CI <1 indicating synergism). After 24- and 72-hr exposure to both drugs at a constant ratio, additivity was found in the A2780, ADDP, and H322 cell lines (dFdC:VP-16 = 1:500 for both exposure times in these cell lines). When cells were exposed to a combination of dFdC and VP-16 for 24 or 72 hr, with VP-16 at its IC25 and dFdC in a concentration range, additivity was found in both the LL and H322 cells; synergism was observed in the A2780 and ADDP cells, which are the least sensitive to VP-16. Schedule dependency was found in the LL cell line; when cells were exposed to dFdC 4 hr prior to VP-16 (constant molar ratio, total exposure 24 hr), synergism was found (CI = 0.5), whereas additivity was found when cells were exposed to VP-16 prior to dFdC (CI = 1.6). The mechanism of interaction between the drugs was studied in more detail in the LL cell line; dFdCTP accumulation was 1.2-fold enhanced by co-incubation with VP-16, and was even more pronounced (1.4-fold) when cells were exposed to VP-16 prior to dFdC. dCTP levels were decreased by VP-16 alone as well as by the combination of both compounds, which may favor phosphorylation of dFdC, thereby increasing dFdCTP accumulation. DNA strand break (DSB) formation was increased for exposure to both compounds together compared to exposure to each compound separately, this effect being most pronounced when cells were exposed to VP-16 prior to dFdC (38% and 0% DSB for dFdC and VP-16 alone, respectively and 97% DSB for the combination). The potentiation in DSB formation might be a result of the inhibition of DNA repair by dFdC. Provided the right schedule is used, VP-16 is certainly a compound eligible for combination with dFdC.

Iproplatin and carboplatin induced toxicities: overview of phase II clinical trial conducted by the EORTC Early Clinical Trials Cooperative Group (ECTG).

Data of five phase II clinical trials on iproplatin and carboplatin, conducted by the ECTG, have been pooled in order to evaluate the extent of toxicities of these compounds. One hundred and seventy patients treated with iproplatin and 65 patients treated with carboplatin were evaluable. Most of them (81%) had been previously treated with chemotherapy. Doses ranged from 180 to 300 mg/m2 every 4 weeks for iproplatin, and from 350 to 450 mg/m2 every 5 weeks for carboplatin, according to the initial status of the patient. WHO criteria were used to grade toxic effects. Weekly blood counts were performed, and lowest observed counts were analysed by non-parametric methods. Censored data were analysed by actuarial methods. Thrombocytopenia was the dose-limiting toxicity and was dose related. Leucopenia was less severe. The risk of thrombocytopenia varied largely amongst patients, and could be predicted from the initial platelet count, the initial creatinine level and prior therapy with alkylating agents. The cumulative risk increased with the total dose, but with a decreasing hazard rate, and without additional delay to platelet recovery. Nausea, vomiting and diarrhoea were the most frequently observed non-haematological side-effects, and were more severe with iproplatin than with carboplatin. Peripheral neuropathy was observed in some cases, but could be due to prior treatments. Renal toxicity did not cause major problems. Our results confirm the findings of the phase I trials: thrombocytopenia is dose-limiting for both drugs, and renal side-effects are negligible. The risk model of thrombocytopenia, consistent with Egorins model for carboplatin, could serve as a basis for dose adjustment. The feasibility of the scheme could be insufficient for prolonged treatment.

Clinical phase II study and pharmacological evaluation of rubitecan in non-pretreated patients with metastatic colorectal cancer-significant effect of food intake on the bioavailability of the oral camptothecin analogue.

A randomised, open label phase II study was performed in patients with advanced colorectal cancer to evaluate the safety, toxicity and antineoplastic activity of the topoisomerase I-inhibitor rubitecan. A cross-over design was chosen to determine the intrapatient variation of the bioavailability and pharmacokinetics of the anticancer agent depending on the timing of food intake in relation to the oral drug administration. Patients with previously untreated metastatic disease received two single oral doses of rubitecan 1.5 mg/m2 for assessment of the pharmacokinetics. They were randomised to have the first administration either after an overnight fasting period or immediately after a high calorie breakfast, and crossed over to the alternative schedule after a one-week washout period. After completion of the pharmacokinetic sampling, treatment continued with rubitecan given orally at a dose of 1.5 mg/m2/day, to be increased up to 2.0 mg/m2/day, under fasting conditions for 5 consecutive days per week until disease progression. 19 patients entered the trial after informed consent was obtained. A total number of 35 treatment cycles (median 2, range 1-4) were administered. All patients were evaluable for safety. The toxicity profile of rubitecan was generally mild to moderate, with sporadic cases of grade 4 toxicities (Common Toxicity Criteria (CTC) version 2.0) diarrhoea, leucopenia and neutropenia. None of 15 evaluable patients achieved an objective response. The majority had early disease progression. 14 patients were evaluable for pharmacokinetic analysis. The bioavailability of rubitecan was found to be strongly dependent on the timing of food intake with a fasted-to-fed ratio for C(max) of 1.98 (two-tailed P<0.001; ANOVA), T(max) 0.49 (P<0.001), AUC(0-8 h) 2.52 (P<0.001) and AUC(0-24 h) 1.64 (P=0.003). Rubitecan is well tolerated, but clinically inactive in colorectal cancer at the currently recommended dose and schedule. The bioavailability is strongly dependent on the timing of food intake in relation to the oral administration of the drug. The topoisomerase I-inhibitor should be administered under fasting conditions to achieve adequate drug exposure in future prospective trials in other tumour types.

Clinical trials in patients with epithelial ovarian cancer : past, present and future

Combinations of surgery and chemotherapy are crucial in the treatment of ovarian cancer. This article reviews the conclusions of all recently performed trials and gives information on the now open randomized studies. The importance of radical surgery in combination with chemotherapy in early disease is clear, but uncertainties still exist in relation to timing and choice of chemotherapy. Many data from trials are helpful in outlining the indications for cytoreductive surgery, the timing of this procedure, second-look laparotomy in clinically complete remission, and secondary cytoreduction, but many details are yet to be addressed in future randomized studies. The place of new chemotherapeutic agents (in advanced disease and in adjuvant setting) is currently being investigated in many clinical trials.