Weekly high-dose 5-fluorouracil and folinic acid in metastatic pancreatic carcinoma: a phase II study of the EORTC GastroIntestinal Tract Cancer Cooperative Group.

The aim of the study was to assess the response rate and toxicity of high-dose 24 h infusion of 5-fluorouracil (5FU) in metastatic adenocarcinoma of the pancreas. Patients with measurable disease, performance status 0-2, and no prior chemotherapy were registered to receive cycles of leucovorin (LV) 500 mg/m2 (or l-LV 250 mg/m2 over 1 h followed by 5FU 2.6 g/m2 over 24 h, weekly for 6 weeks, followed by a 2-week rest. The main endpoints were the response rate and toxicity. From 37 patients, 36 were the analysed for toxicity, and 33 were eligible and analysed for response. The median age was 59 years (range 28-74 years), and the median performance status was 1. Partial response was observed in three patients (9%) (95% Confidential Interval (CI): [2-24]%). Main grade 3/4 National Cancer Institute (NCI) common toxicity criteria toxicities (patients) were diarrhoea (n = 3), vomiting (n = 2) and hand-foot syndrome (n = 5). Median time to progression was 7 weeks (95% CI: [6.4-11.7] weeks) and median survival 19 weeks (95% CI: [12-35] weeks). In conclusion, high-dose 5FU and folinic acid is well tolerated, but has only modest activity in pancreatic cancer.

Cisplatin, doxorubicin and ifosfamide in carcinosarcoma of the female genital tract. A phase II study of the European Organization for Research and Treatment of Cancer Gynaecological Cancer Group (EORTC 55923).

Carcinosarcomas of the female genital tract are highly malignant tumours composed of carcinomatous and sarcomatous elements. In the past, these tumours were frequently treated as sarcomas. However, a number of arguments, including the sensitivity of these tumours to platinum-based chemotherapy, suggest that these tumours behave more like poorly differentiated carcinomas. The European Organization for Research and Treatment of Cancer (EORTC) Gynaecological Cancer Group therefore decided to perform a prospective phase II study in patients with advanced or metastatic carcinosarcoma with an approach such as that used in gynaecological carcinomas. Eligible patients could have primary or recurrent disease, but prior radiotherapy or chemotherapy was not allowed. The treatment plan recommended upfront debulking, followed by chemotherapy with cisplatin, ifosfamide and doxorubicin. Patients who could be debulked to non-measurable disease remained eligible for the study, but the response assessment was restricted to patients who had measurable disease before the start of chemotherapy. A total of 48 patients (39 primary disease, 9 recurrent disease) were registered, 41 of them being eligible. In 9 patients, all macroscopic lesions could be removed, 32 patients were left with residual disease and were assessable for response. The overall response rate was 56%: a complete response (CR) was observed in 11 (34%) patients and partial response (PR) in 7 (22%) patients. No change occurred in 5 patients and progression in 2 patients. In 7 patients, response could not be assessed. Median survival for all of the 41 eligible patients was 26 months. Severe leucopenia and thrombocytopenia were common and necessitated dose reductions or delays in 60% of patients. From a clinical point of view, the most severe non-haematological toxicity was renal dysfunction, and one patient died of this complication in the absence of disease progression. The results of this study are in-line with the hypothesis that carcinosarcomas are chemosensitive, in particular for the currently investigated regimen. The treatment also included upfront cytoreduction when feasible. Considering the observed toxicities, alternative platinum-based regimens with more favourable toxicity profiles should be explored.

Modulation of the cytochrome P450-mediated metabolism of ifosfamide by ketoconazole and rifampin.

BACKGROUND: The autoinducible metabolic transformation of the anticancer agent ifosfamide involves activation through 4-hydroxyifosfamide to the ultimate cytotoxic ifosforamide mustard and deactivation to 2- and 3-dechloroethylifosfamide with concomitant release of the neurotoxic chloroacetaldehyde. Activation is mediated by cytochrome P450 (CYP) 3A4 and deactivation by CYP3A4 and CYP2B6. The aim of this study was to investigate modulation of the CYP-mediated metabolism of ifosfamide with ketoconazole, a potent inhibitor of CYP3A4, and rifampin (INN, rifampicin), an inducer of CYP3A4/CYP2B6. METHODS: In a double-randomized, 2-way crossover study a total of 16 patients received ifosfamide 3 g/m(2) per 24 hours intravenously, either alone or in combination with 200 mg ketoconazole twice daily (1 day before treatment and 3 days of concomitant administration) or 300 mg rifampin twice daily (3 days before treatment and 3 days of concomitant administration). Plasma pharmacokinetics and urinary excretion of ifosfamide, 2- and 3-dechloroethylifosfamide, and 4-hydroxyifosfamide were assessed in both courses. Data analysis was performed with a population pharmacokinetic model with a description of autoinduction of ifosfamide. RESULTS: Rifampin increased the clearance of ifosfamide at the start of therapy at 102%. The fraction of ifosfamide metabolized to the dechloroethylated metabolites was increased, whereas exposure to the metabolites was decreased as a result of increased elimination. The fraction metabolized and the exposure to 4-hydroxyifosfamide were not significantly influenced. Ketoconazole did not affect the fraction metabolized or the exposure to the dechloroethylated metabolites, whereas both parameters were reduced with 4-hydroxyifosfamide. CONCLUSIONS: Coadministration of ifosfamide with ketoconazole or rifampin did not produce changes in the pharmacokinetics of the parent or metabolites that may result in an increased benefit of ifosfamide therapy.

Drug therapy for gynaecological cancer in older women.

A substantial proportion of all women dying from gynaecological malignancies are aged >75 years. Many reports have indicated that the survival of these patients is decreased compared with younger patients. Differences in biological behaviour, stage of the disease at presentation, and reluctance to undergo aggressive treatment with its associated morbidity are among the factors thought to be responsible for this difference in outcomes. However, investigations also indicate that elderly patients may receive less surgical and chemotherapeutic treatment without obvious clinical rationale. This overview is aimed at providing a guideline of chemotherapy appropriate for patients with epithelial ovarian, uterine (corpus and cervix), and vulvar cancer, aged 70 to 75 years and over. Platinum-based chemotherapy is the cornerstone of drug treatment in patients with ovarian cancer. Patients aged between 70 and 75 years with a good performance status can be treated with cisplatin- or carboplatin-based chemotherapy. Carboplatin, either in combination or as a single-agent, may offer advantages in patients aged >75 years and in those with a poor performance status. For patients with early recurrence there is no standard treatment, but several cytostatic and hormonal agents can be used with palliative intent. Patients with a late recurrence are probably best retreated with a platinum-based regimen. In metastatic endometrial cancer, hormonal therapy is the first choice in tumours expressing a progesterone receptor. Poorly differentiated tumours infrequently respond to endocrine therapy. In this situation, and for patients with tumours that have become resistant to hormonal manipulation, platinum-based chemotherapy may be used. The use of carboplatin-based regimens seems preferable in elderly patients, particularly in those with a decreased performance status. The usefulness of chemotherapy in elderly patients with cervical cancer is limited. In case of recurrent or metastatic disease, the use of single agent (low-dose) cisplatin should be balanced against best supportive care. Although overall chemoradiation seems superior than radiotherapy alone in patients with locally advanced cervical cancer, the feasibility of this approach in elderly patients needs further investigation. Chemoradiation might also be considered in patients with locally advanced vulvar cancer. However, treatment-related morbidity can be considerable and randomised studies are lacking to prove a survival benefit. Our understanding of the tolerance and effectiveness of chemotherapy in elderly patients is still incomplete due to a paucity of trials that specifically focus on this subset of patients. However, there appears no argument to withhold chemotherapy based purely on age.

Experience with intraperitoneal cisplatin and etoposide and i.v. sodium thiosulphate protection in ovarian cancer patients with either pathologically complete response or minimal residual disease.

BACKGROUND: High-dose platinum-based regimens can produce responses in patients not responding to standard chemotherapy. As in many ovarian cancer patients the disease remains confined to the peritoneal cavity, intraperitoneal (i.p.) chemotherapy has been applied as an alternative approach to increase drug exposure. The delivery of cytotoxic agents to the peritoneal cavity can lead to high drug concentrations intraperitoneally with less systemic toxicity. This study aimed at evaluating the efficacy and toxicity of high-dose i.p. cisplatin plus etoposide and intravenous sodium thiosulphate protection in ovarian cancer. PATIENTS AND METHODS: Patients with either a pathologically complete response (pCR) after first-line treatment or with persistent disease after first-line platinum-based chemotherapy or abdominal recurrences were eligible. All intraabdominal lesions had to be < 2 cm at the start of i.p. treatment. The treatment consisted of etoposide 350 mg/m2 i.p. followed by cisplatin 200 mg/m2 i.p. with intravenous sodium thiosulphate (4 g/m2 bolus, followed by 12 g/m2 over six hours) protection. Four courses of i.p. treatment were administered in case of pCR and 6 courses otherwise, at four-weekly intervals. RESULTS: The study comprised 29 patients, six patients with pCR, 17 patients with persistent disease and six patients with abdominal recurrences. They received a total of 105 courses of treatment (65% of the scheduled number of courses). Twelve patients completed scheduled treatment, illustrating its feasibility. In 17 patients treatment had to be prematurely stopped because of inflow obstruction (seven patients), bowel perforation (two patients), renal toxicity (two patients), neurotoxicity (two patients), or malaise and vomiting (four patients). One patient with bowel perforation died of this complication. Severe nausea and vomiting occurred in 51% of cycles. Leukopenia and thrombopenia grade 3 and 4 occurred in 30% and 6% of cycles, respectively. Ototoxicity of cisplatin was measured by serial tone audiography in 23 patients: only eight patients (35%) showed significant audiographic changes, although none of them developed clinical hearing loss. Fifteen patients were evaluable for response: four pCR, five PR, two SD, four PD. The median duration of freedom from progression was 616 days and the median overall survival 1065 days from the start of treatment. CONCLUSIONS: High-dose i.p. treatment with cisplatin and etoposide can be associated with significant toxicities. Major clinical problems are nausea, vomiting, and the formation of intraabdominal adhesions. Intravenous sodium thiosulphate effectively reduces the systemic toxicity of high-dose cisplatin. The value of high-dose i.p. treatment is uncertain and its routine use cannot be recommended.

Effect of suramin on adenylate cyclase and protein kinase C.

The trypanocidal drug, suramin, has been shown to possess antitumour activity, both in vitro and in vivo. Its mechanism of action, however, remains unclear although an effect on signal transduction has been proposed. We therefore studied the in vitro effect of suramin on protein kinase C (PKC), on adenylate cyclase and on the intracellular calcium concentrations [Ca2+]i in human cancer cell lines. Ca(2+)- and phospholipid-dependent PKC was isolated from a normal rat spleen, and compared with that of the human cancer cell lines MCF-7 (breast cancer) and PC3 (prostate cancer). PKC was inhibited by 50% at 55, 40 and 27 microM suramin in the three PKC sources, respectively, while 300 microM of suramin gave 97, 95 and 99% inhibition. With 50 nM staurosporine, a known PKC inhibitor, we observed 80, 99 and 96% inhibition in these three different sources of PKC. Six day exposure of these cell lines to suramin, causing 50% growth inhibition, decreased the Ca(2+)- and phospholipid-dependent PKC activity in MCF-7 cells to 52% of the control and in PC3 cells to 48% at equitoxic concentrations (45 and 150 microM suramin, respectively). These concentrations of suramin slightly increased (approximately 2-fold) the adenylate cyclase activity in MCF-7 cells, but not in PC3 cells. In MCF-7 and PC3 cells, we measured the [Ca2+]i using Fura-2 fluorescence and observed a decrease in MCF-7 cells from 126 to 99 nM when the cells were exposed for 6 days to 45 microM suramin. In PC3 cells, [C2+]i decreased from 131 to 117 nM after exposure to 150 microM suramin. In conclusion, suramin inhibited the Ca(2+)- and phospholipid-dependent PKC activity in both cell lines in a dose-dependent manner. Only in the more sensitive MCF-7 cell line was a significant effect of suramin on intracellular Ca2+ and adenylate cyclase observed, indicating that one of the mechanisms of action of suramin could be mediated by perturbations of intracellular signalling pathways.

The synergistic and antagonistic effects of cytotoxic and biological agents on the in vitro antitumour effects of suramin.

Suramin has shown antitumour activity in vitro and in vivo. At plasma levels higher than 200 microM there is, however, excessive toxicity. We have, therefore, attempted to improve the antitumour effects of suramin in vitro by combining it with several other antitumour agents. The MCF-7 mammary carcinoma and PC3 prostate cancer cell lines were exposed continuously to suramin and the other agents for 6 days. The sulphorhodamine B (SRB) assay was used for the assessment of growth inhibition. The dose-response interactions were evaluated using the median-effect analysis with the Chou and Talalay computer programme. In the MCF-7 cell line, the combination of suramin plus doxorubicin (DXR), cisplatin (CDDP), 5-fluorouracil (5-FU) or tumour necrosis factor (TNF) resulted in synergistic growth inhibition, whilst its combination with miltefosine (HPC) was antagonistic. In the PC-3 cell line, suramin plus CDDP or TNF was synergistic, whilst its combination with DXR, 5-FU and HPC was antagonistic. All tested combinations with interferon-alpha (IFN-alpha), interferon-gamma (IFN-gamma) and with the combination of both IFN-alpha+IFN-gamma were not synergistic. The synergistic effect of suramin with DXR was schedule dependent. Pretreatment (addition of DXR on day 1 and suramin on days 2-5) was additive at the IC50 level, in both cell lines. Addition of DXR at day 5 was more effective than simultaneous exposure. We found a synergistic effect for the combination of suramin with CDDP and TNF in both cell lines. In addition the combination with DXR and 5-FU was synergistic in MCF-7. Sequential administration of DXR-suramin or suramin-DXR increased the growth inhibition.

The effect of chemotherapy on the different components of advanced carcinosarcomas (malignant mixed mesodermal tumors) of the female genital tract.

The effect of chemotherapy on the different components of uterine and ovarian carcinosarcoma is largely unknown. This report describes six patients with advanced carcinosarcoma, five of whom received 4 cycles of doxorubicin and ifosfamide (AI) directed at the sarcomatous component of the tumor. Responses in these five patients at second-look laparotomy were: one complete response, two partial responses (persistence of only the carcinomatous component), one stable disease, and one progressive disease (both components still present in both cases). Thereafter 4 cycles of a cisplatin-based regimen were scheduled. Response to the cisplatin-containing regimen was only evaluated clinically. The sixth patient (with no macroscopic disease left after initial surgery) received 6 cycles of a cisplatin-based chemotherapy from the onset and was found to be in complete response at relaparotomy. Median progression-free survival for all patients was 15 months and median survival 21 months. A literature survey showed that carcinosarcoma differs from adult soft tissue sarcomas with respect to responsiveness to chemotherapy. Cisplatin and ifosfamide are active as single agents, whereas the response to single-agent doxorubicin seems to be lower. The data suggest, however, that superior response rates and increased survival times are achieved with cisplatin/doxorubicin-based chemotherapy. The sensitivity of carcinosarcoma to cisplatin supports the recent view that carcinosarcoma of the female genital tract is possibly a high grade carcinoma with metaplastic sarcomatous elements.

A double-blind randomized crossover study to compare the antiemetic efficacy of 250 mg with 500 mg methylprednisolone succinate (Solu-Medrol) as a single intravenous dose in patients treated with noncisplatin chemotherapy.

A double-blind randomized crossover study was performed in 56 chemotherapy-naive patients, all receiving non-cisplatin-based chemotherapy, to compare the antiemetic effects of 2 doses of a single administration of methylprednisolone succinate (Solu-Medrol): 250 versus 500 mg. Among the 39 patients who satisfactorily completed both parts of the study, complete and major protection from emesis (0 and 1 emetic episode or only retching) was observed in 79% during the first course and in 69% during the second course. Treatment failure (> or = 6 episodes of vomiting) was observed in 18% during the first course and 21% during the second course. There was no significant difference between the two dose levels neither in terms of antiemetic protection nor in terms of the occurrence of side effects nor in patient preference. Most important side effects were facial flushing (45%), headache (22%) and facial edema (18%). It is concluded that, although a comparison with lower dosages cannot be made, within the dose range studied no clear dose-response relationship could be found.

The cellular composition in the peritoneal cavity and the cytotoxic function of the peritoneal cells from patients with ovarian cancer; effect of tumor necrosis factor-alpha treatment.

In patients with epithelial ovarian cancer (EOC), the cellular composition in the peritoneal cavity and the functional capacities of the peritoneal cells (PC) are unknown. Especially the peritoneal macrophages (m phi) could play an important role in defense against tumor cells. To study the cellular composition in the peritoneal cavity and the functional capacities of PC, these cells were obtained from three patients with EOC. The PC were immunophenotyped and tested functionally in vitro in a cytotoxicity assay. One of the patients was treated intraperitoneally (i.p.) with a single dose of 0.06 mg/m2 tumor necrosis factor-alpha (TNF-alpha). PC were obtained before the treatment, after 24 h and after 1 week. PC from healthy women undergoing laparoscopic sterilization served as controls. It appeared that patients with EOC have a lower percentage of macrophages (m phi) in the peritoneal cavity than healthy persons. These m phi of patients were also less capable of killing U 937 tumor cells as compared to the peritoneal m phi of control persons. However, in the patient treated i.p. with TNF-alpha the cytotoxic capacities of the peritoneal m phi were strongly improved. The percentage cytotoxicity at an effector to target ratio of 10, increased from 17% to 80%. Thus, the peritoneal m phi in this patient were activated in vivo to a tumoricidal state. These findings indicate that PC in patients with EOC differ from controls, but further investigation is necessary to define the contribution of the disease and/or prior chemotherapy to this defect.

Suramin: rapid loading and weekly maintenance regimens for cancer patients.

PURPOSE: Suramin is an anticancer agent with a narrow therapeutic window and a terminal half-life of 45 to 55 days. These characteristics make it necessary to control accurately the serum concentrations of the drug. Therefore, the aim of the present study was to develop a rapid loading regimen, followed by weekly administration of suramin to maintain serum concentrations of between 150 and 300 micrograms/mL for 8 weeks. PATIENTS AND METHODS: Eligible patients were treated with five different loading regimens. Initially, weekly maintenance doses were estimated manually by the treating physician. Subsequently, computer-assisted dosing that used Bayesian pharmacokinetic modeling was used. RESULTS: Thirty-eight courses of suramin that were administered to 35 patients were studied. The optimal loading regimen consisted of a continuous infusion of 600 mg/m2 during a 24-hour period, which resulted in a mean serum concentration of 319 micrograms/mL. Potentially toxic concentrations that were observed with shorter infusions were avoided. Maintenance treatment, which used the weekly administration of suramin during a 6-hour period, seemed to be able to maintain mean suramin serum trough concentrations of 150 micrograms/mL, while preventing mean peak concentrations of more than 300 micrograms/mL. The use of Bayesian pharmacokinetics was superior to manual estimation in tailoring the optimal dose to the therapeutic window. CONCLUSIONS: Continuous infusion is the optimal way of delivering suramin during the loading phase. To maintain trough levels and peak levels within a narrower therapeutic window, suramin will have to be administered more frequently than once a week. Bayesian modeling based on individual serum levels and population pharmacokinetics allows accurate dosing to maintain suramin levels within the therapeutic window.

The effect of schedule, protein binding and growth factors on the activity of suramin.

Suramin has been shown to have antiproliferative activity, either by blocking the binding of growth factors to their receptors or by inhibiting critical cellular enzymes. In 6 different cell lines from 5 tumour types (MCF-7, MCF-7/ADRR, PC3, HT-29, UM-SCC-11B and SW-1573/IR500), we studied the effect of scheduling of suramin, of FCS and of human serum albumin (HSA), of epidermal growth factor (EGF) and of the addition of growth factors in serum-free medium on the activity of suramin. The concentration of suramin which gave 50% growth inhibition (IC50) varied from 45 microM in SW-1573/IR500 to 153 microM in PC3 cells grown in medium supplemented with 5% FCS, after 6 days of continuous exposure. Exposure for more than 4 days did not enhance the sensitivity to suramin, except in PC3. At exposure to suramin for 1 day followed by 5 days recovery, high IC50 values (greater than 0.5 mM) were observed in MCF-7 cells. In medium with 1% and 0.5% FCS these values were 3 to 8 and 14 to 26 times lower respectively. Addition of HSA increased the IC50 in PC3 and MCF-7 cells. Suramin binding to protein was dependent on the concentration of protein and of suramin. Excess of EGF in medium with different FCS concentrations did not change the IC50 values of suramin in PC3 and MCF-7 cells. Addition of EGF, fibroblast growth factor or platelet-derived growth factor in PC3 cells cultured in serum-free medium did not increase the IC50 values. Suramin was active against these 6 cell lines at clinically achievable concentrations. This activity varied depending on the cell line, exposure time and suramin concentration. The most significant factor interfering with sensitivity to suramin was the amount of protein present in the culture medium.

Dose intensity of MOPP chemotherapy and survival in Hodgkin's disease.

The association between dose intensity of chemotherapy with the rate of complete remission (CR), the duration of disease-free survival (DFS), and overall survival (OS) was separately analyzed for 67 patients initially treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP), and for 75 patients in relapse following radiotherapy who had received MOPP as a salvage regimen. In both groups of patients, the fraction of the total dose of mechlorethamine delivered in all cycles divided by the planned dose for six cycles was strongly associated with OS (P = .002 for patients receiving initial MOPP and P = .02 for the salvage group, respectively). B symptoms were independent of drug-derived variables associated with OS (corresponding P values .03 for initial MOPP and .004 for the salvage group). The predictive value of mechlorethamine dosage with regard to OS was retained in an analysis restricted to the patients receiving greater than or equal to six cycles of chemotherapy. In the initial chemotherapy group, mechlorethamine dosage was associated with attainment of CR but none of the variables tested was predictive of DFS. In the salvage chemotherapy group, mechlorethamine dosage was associated with attainment of CR and duration of DFS as well. The results emphasize that, besides tumor characteristics, optimal dosage of chemotherapy is of great importance for survival.

Major complications and causes of death in patients treated for Hodgkin's disease.

A total of 340 patients with Hodgkin's disease were evaluated for the occurrence of intercurrent fatalities after treatment with radiotherapy, chemotherapy, combined modality therapy, and salvage chemotherapy. Mean follow-up time was 76.6 months. Causes of death were compared with the expected risk, calculated from mortality statistics of the Netherlands' population. Sixty-seven patients died of progressive Hodgkin's disease, whereas 37 patients died of causes unrelated to advanced disease. Patients showed an increased risk of dying of leukemia and solid tumors (P less than .001), whereas the risk of dying of cardiovascular complications was not increased. The 10-year actuarial risk of dying of leukemia varied between 0% for patients treated with radiotherapy only and 5.7% for those needing salvage chemotherapy. The 10-year risk of dying of solid tumors was 0% for patients treated with chemotherapy and 6.5% for those receiving radiotherapy. Treatment-related fatalities were highest after combined modality therapy (P less than .025); the corresponding 10-year risk was 6.1%. Compared with younger ones, patients greater than or equal to 40 years had an increased risk of dying of causes unrelated to progressive Hodgkin's diseases. The actuarial risk of developing intercurrent fatalities at 10 years was 4.9% in patients less than 40 years, and 34.7% in those greater than or equal to 40 years (P less than .001). Compared with population based statistics, patients successfully treated for Hodgkin's disease still showed an increased risk of dying (P less than .001). Treatment modality, stage, and histologic subtype were not predictors of intercurrent death.