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Biomedical subjects

E Cvitkovic

Publications and source records attributed to E Cvitkovic.

At least 73 records · Page 4Linked to original sources
PubMed1998

Phase III trial of modulation of cisplatin/fluorouracil chemotherapy by interferon alfa-2b in patients with recurrent or metastatic head and neck cancer. Head and Neck Interferon Cooperative Study Group.

PURPOSE: In preclinical experiments, interferon alfa modulates the anticancer activity of fluorouracil (5-FU) and cisplatin (CDDP). To test this effect clinically in patients with recurrent or metastatic head and neck cancer (RMHNC), a multicenter randomized controlled trial with CDDP and 5-FU with or without interferon alfa-2b (IFNalpha) was performed. PATIENTS AND METHODS: Eligible patients had histologically confirmed RMHNC; a good performance status; measurable disease; adequate bone marrow, hepatic, and renal function; no prior chemotherapy for recurrent or metastatic disease; only one chemotherapy regimen administered with previous local therapy; and a treatment-free interval of at least 3 months following previous local therapy. Patients were randomized and stratified according to treatment center, and prior radiotherapy and chemotherapy. The treatment regimen consisted of CDDP 100 mg/m2 on day 1 and 5-FU 1,000 mg/m2/d by continuous infusion for 96 hours (days 1 to 4), without (arm A) or with (arm B) IFNg alpha 3 x 10(6) U/d subcutaneously on days 1 to 5. Cycles were repeated every 21 days. RESULTS: One hundred twenty-two patients were entered on each arm. The response rate (RR) was similar in both arms (arm A: complete response [CR] 10.7%, partial response [PR] 36.4%; arm B: CR 6.8%, PR 31.6%) (.70 < P < .50). There was no difference in median survival between the two arms (arm A 6.3 months v arm B 6.0 months; P = .49). Anorexia, fever, leukopenia, and thrombocytopenia grade III to IV were significantly more frequent in the IFNalpha arm. CONCLUSION: Modulation of CDDP and 5-FU with IFNalpha as used in this study does not improve the RR or the median survival in patients with RMHNC. Patients on both study arms had a poor prognosis, which indicates the need for novel therapies.

Adult↗
PubMed1998

Pathophysiology and therapy of irinotecan-induced delayed-onset diarrhea in patients with advanced colorectal cancer: a prospective assessment.

PURPOSE: Irinotecan (CPT-11), a camptothecin derivative, has shown efficacy against colorectal cancer. Delayed-onset diarrhea is its main limiting toxicity. The aim of this study was to determine the pathophysiology of CPT-11-induced delayed-onset diarrhea and assess the efficacy of combined antidiarrheal medication in a phase II, prospective, successive-cohorts, open study. PATIENTS AND METHODS: Twenty-eight patients with advanced colorectal cancer refractory to fluorouracil (5-FU) therapy received CPT-11 350 mg/m2 every 3 weeks. The first cohort of 14 consecutive patients explored for the mechanism of diarrhea received acetorphan (a new enkephalinase inhibitor) 100 mg three times daily; the second 14-patient cohort received, in addition to acetorphan, loperamide 4 mg three times daily. Before treatment, and if late diarrhea occurred, patients underwent colon mucosal biopsies for CPT-11 and topoisomerase I levels; intestinal transit time; fecalogram; fat and protein excretion; alpha1-antitrypsin clearance; D-xylose test; blood levels for vasoactive intestinal polypeptide, glucagon, gastrin, somatostatin, prostaglandin E2, and carboxylesterase; CPT-11/SN-38 and SN-38 glucuronide pharmacokinetics; and stool cultures. RESULTS: Delayed-onset diarrhea occurred during the first three treatment cycles in 23 patients (82%). Electrolyte fecal measurements showed a negative or small osmotic gap in nine of nine patients and an increased alpha1-antitrypsin clearance in six of six patients. There were no modifications in stool cultures or hormonal dysfunction. Four of 11 patients (36%) with delayed-onset diarrhea in the first cohort responded to acetorphan, whereas nine of 10 patients (90%) responded to the combination of acetorphan and loperamide (P < .02). CONCLUSION: CPT-11-induced delayed-onset diarrhea is caused by a secretory mechanism with an exudative component. Early combined treatment with loperamide and acetorphan seems effective in controlling the diarrheal episodes.

Adult↗
PubMed1998

Oxaliplatin for the treatment of advanced colorectal cancer: future directions.

The introduction of oxaliplatin into the colorectal cancer setting represents a significant advancement in the treatment of the disease. Synergistic effects with traditional therapy 5-fluorouracil/folinic acid have increased response rates significantly, improved time-sensitive response parameters, and facilitated the removal of previously unresectable hepatic metastases, thus changing the natural history of the disease. Ongoing and planned trials are identifying various issues that need to be addressed to fully realize the potential of oxaliplatin. These include optimization of dosing and schedule of administration, determination of the most effective oxaliplatin-5-fluorouracil/folinic acid combination, definition of the role of new thymidylate synthase inhibitors with respect to oxaliplatin therapy, and identification of the most effective combinations of oxaliplatin with the new anticancer agents that have been recently introduced. Providing the answers to these questions will contribute to changing the attitude of the clinical oncologist regarding what strategy to adopt in treating colorectal cancer in the coming years.

Antineoplastic Agents↗
PubMed1997

Palliative treatment with low-dose continuous infusion 5-fluorouracil in recurrent and/or metastatic undifferentiated nasopharyngeal carcinoma type.

BACKGROUND: Low-dose protracted continuous infusion (CI) 5-fluorouracil (5-FU), as proposed by Lokich et al, has been reported to be active and well tolerated in colorectal and breast cancers. We initiated a phase II trial with CI 5-FU in heavily pretreated undifferentiated carcinoma of the nasopharyngeal type (UCNT) patients in February 1989. METHODS: Twenty-one UCNT patients with recurrent and/or metastatic disease were treated with CI 5-FU (300 mg/m2) for 6 consecutive weeks. Treatment was to be continued until disease progression. RESULTS: Toxicity was mild. Diarrhea and mucositis (WHO grade 2 or greater) were seen in 4 (20%) and 6 patients (30%), respectively. Myelosuppression was infrequent, with only one patient with bone marrow invasion, experiencing grade 3 leukopenia. Two complete and 3 partial responses were obtained in 20 evaluable patients (ORR:25%). The median time to progression was 4 months (range 2-14); The median survival for the whole population was 10 months (avg 2-41). CONCLUSION: This appears to be a useful palliative treatment for heavily pretreated UCNT patients.

Adolescent↗
PubMed1997

6-Day continuous infusion of high-dose ifosfamide with bone marrow growth factors in advanced refractory malignancies.

Ifosfamide is an analogue of cyclophosphamide active in the treatment of numerous tumours. Although its use by continuous infusion seems to be responsible for less toxicity, differences of efficacy and toxicity, observed according to its doses and schedules of administration, still remain debated. The objective of this study was to assess the toxicity of high-dose ifosfamide given by continuous infusion over 6 days and its therapeutic activity in various advanced tumours. Twenty-six patients were treated with 14 g/m2 ifosfamide, an equal dose of MESNA, and routine granulocyte- or granulocyte/macrophage-colony-stimulating factor during the intercycle. Courses were repeated every 3 weeks until disease progression or unacceptable toxicity occurred; 75 cycles were administered. The mean number of cycles per patient was 3 (range 1-11). Extrahaematological toxicity was manageable in most patients, WHO grade II or more neurological (5 patients) and renal (5 patients) toxicities occurring in those heavily pretreated with platinum compounds and presenting peritoneal disease. WHO grade III or more neutropenia occurred in 60% of cycles, while grade III-IV thrombocytopenia and anaemia were observed in 19% of them. Three partial responses (germ-cell tumour, chondrosarcoma, soft-tissue sarcoma) and one complete response (metastatic osteosarcoma) were assessed, all in patients with tumours refractory or resistant to standard-dose ifosfamide, which underlines the possibility of circumventing the resistance to ifosfamide given in conventional schedules. The present results confirm previous reports of changes in the therapeutic index of ifosfamide according to its dose and administration schedule.

Adolescent↗
PubMed1997

A call for change in anticancer drug evaluation.

In the evaluation of anticancer agents, the present emphasis on the use of measurements determining the drug's capacity for cytoxicity and tumour shrinking prevents oncologists from defining efficacy measures which may be more relevant to clinical reality. In addition, oncologists are not yet making adequate or appropriate use of the advanced technologies available, and the use of standardised response criteria does not ensure that results are clinically meaningful. There is a strong need for flexibility in the choice of the endpoint to be measured according to the type of cancer. It is important that faster, smaller-scale trial designs must be developed so that promising, new anticancer agents are made available as quickly as possible.

Antineoplastic Agents↗
PubMed1997

Oxaliplatin/cisplatin (L-OHP/CDDP) combination in heavily pretreated ovarian cancer.

The aim of this study was to evaluate the toxicity and the activity of two non-cross-resistant platinum compounds: oxaliplatin (L-OHP) and cisplatin (CDDP) in platinum pretreated ovarian cancer patients. Chemotherapy consisted of L-OHP and CDDP given sequentially as 2 h infusions on day 1 at their standard recommended dose (130 mg/m2 for oxaliplatin, 100 mg/m2 for cisplatin) every 3 weeks. Dose reductions (20-35%) were planned according to baseline haematological and renal status, but the dose ratio between L-OHP and CDDP was always maintained at 1.3. Cycles were repeated until progression or treatment limiting toxicities. From September 1992 to November 1994, 25 patients with pretreated ovarian cancer entered this salvage programme. They had received a median number of three previous chemotherapy lines (1-7), one at least platinum based. Previously cisplatin had been given to 22 patients at a median total dose of 600 mg/m2 (170-1175), while 18 had received carboplatin to a median total dose of 1135 mg/m2 (200-2450). 9 patients had also received and were resistant to taxanes (paclitaxel, 6 patients, docetaxel, 3 patients), while the rest were considered ineligible for simultaneously ongoing single-agent taxane phase II trials. 13 and 12 patients, respectively, were considered to have platinum refractory and potentially sensitive disease, according to Markman's criteria. 77 cycles of L-OHP/CDDP were given, with a median of three cycles/patient (range 1-6) and were evaluable for toxicity. The limiting toxicity of the L-OHP/CDDP combination was a cumulative, sensory peripheral neuropathy, severe (> or = grade 3 CTC) after more than three cycles, but reversible within a few months of its discontinuation. Grade 3-4 (WHO scale) neutropenia and thrombopenia were seen in 35-40% of cycles, with one neutropenic treatment-related death (septic shock). 22 patients with measurable/evaluable disease were assessable for antitumoral activity. Two complete responses (CR) (8%) (one proven histologically at laparotomy (pCR)) and 8 partial responses (PR) (32%) for an overall objective response rate (ORR) of 40% (95% CI, 21-61%) (intent to treat). The median duration of response was 4 months. Seven responses were seen among 12 potentially platinum-sensitive tumours (58%, CI 95% 28-85%), while 3/13 platinum refractory patients (23%, CI 95% 5-54%) had an objective response. These encouraging results are the basis for new first- and second-line combination treatment programmes in ovarian carcinoma.

Adult↗
PubMed1997

Higher doses of alpha-interferon do not increase the activity of the weekly cisplatin-interferon combination in advanced malignant mesothelioma.

Management of advanced malignant mesothelioma (MM) still requires innovative systemic therapy as its prognosis is poorly affected by currently available chemotherapy. The combination cisplatin and alpha-interferon (alpha-INF) has synergistic antitumoral activity in preclinical models and interesting activity in phase I-II clinical trials. Weekly CDDP (60 mg/m2) and alpha-IFN (3 MUI/d: d1-d4) in combination was tested in a previous phase I-II study in 23 MM patients, with a 36% objective response rate (ORR). A trial with higher doses of alpha-IFN in the same combination schedule was conducted to explore an incrementalist hypothesis. Thirty patients with MM received the same CDDP dose (60 mg/m2/w) and doubled doses of alpha-IFN (6 MUI/d: d1-d4). The treatment protocol consisted of two cycles of 4 weeks on/4 weeks off followed by two shorter cycles of 3 weeks on/3 weeks off, in the absence of life-threatening toxicity or progressive disease. All patients were evaluable for toxicity. The main treatment-limiting side-effects were digestive intolerance (nausea, vomiting) and severe asthenia. Antitumoral efficacy was not increased (ORR = 27%). Haematological and neurological toxicities were moderate and manageable. The antitumoral activity of the CDDP-alpha-IFN combination with higher doses of the latter is similar to our previous experience, but tolerance issues make it a poorer choice for eventual comparative trials, or as a standard therapeutic indication.

Adult↗
PubMed1997

Severe CPT-11 toxicity in patients with Gilbert's syndrome: two case reports.

BACKGROUND: CPT-11 is hydrolyzed to its active metabolite SN-38, which is mainly eliminated through conjugation by hepatic uridine diphosphate glucuronosyl transferases (UGTs) to the glucuronide (SN-38G) derivative. Preclinical studies showed that UGT*1.1 is the isozyme responsible for SN-38 glucuronidation. Patients with Gilbert's syndrome have deficient UGT*1.1 activity, therefore may have an increased risk for related CPT-11 toxicity. PATIENTS AND METHODS: Two patients with metastatic colon cancer and Gilbert's syndrome were treated with CPT-11 based chemotherapy. CPT-11, SN-38 and SN-38G pharmacokinetics parameters were obtained. Serum bilirubin was analysed by alkaline methanolysis and HPLC. RESULTS: Both patients presented grade 4 neutropenia and/or diarrhea (NCI-CTC) in every treatment cycle. Biliary index (after Gupta et al) values were well above 4000. CONCLUSION: We present the first clinical evidence linking bilirubin glucuronidation status and CPT-11 related toxicity. The severe toxicity experienced by the two patients with Gilbert's syndrome treated with CPT-11 based chemotherapy has a genetic basis. Individuals with Gilbert's syndrome have an enhanced risk for CPT-11 toxicity. Unconjugated serum bilirubin could be predictive parameter of CPT-11 toxicity.

Bilirubin↗
PubMed1997

Long-term prognostic and predictive factors in 107 stage II/III breast cancer patients treated with anthracycline-based neoadjuvant chemotherapy.

The heterogeneity of therapeutic modalities and eligibility criteria and the lack of long-term follow-up in most reports of neoadjuvant chemotherapy for breast cancer preclude us from drawing conclusions about its value in clinically relevant patient subgroups. The present study aims to identify predictive and prognostic factors in 107 non-inflammatory stage II/III breast cancer patients treated between November 1980 and October 1991 with an anthracycline-based induction regimen before locoregional surgery. Preoperative chemotherapy comprised 3-6 cycles of doxorubicin (pirarubicin after 1986), vindesine, cyclophosphamide and 5-fluorouracil. Type of subsequent surgery and adjuvant treatment were decided individually. In analysis of outcome, univariate comparisons of end points were made using the log-rank test, and significant (P < or = 0.05) pre- and post-therapeutic factors were incorporated in a Cox multivariate analysis. With a median follow-up of 81 months (range 32-164+ months), the median disease-free survival (DFS) is 90.5 months while median overall survival has not yet been reached. Cytoprognostic grade and histopathological response in both the primary and lymph nodes were independent covariates associated with locoregional relapse with or without DFS and overall survival. Eleven patients with pathological complete response remain free of disease with a 68-month median follow-up, while the 18 with residual microscopic disease on the specimen showed a 60% cumulative incidence of locoregional recurrence. Despite encouraging response rates based on clinical or radiological evaluation (87% or 70%), neither method showed any significant correlation with pathological response and failed to contribute prognostic information on patients' outcome. Pathological evaluation of antitumoral activity of primary chemotherapy remains a major source of prognostic information and might be used to select patients in need of additional adjuvant treatment.

Adult↗
PubMed1997

Role of vindesine as neoadjuvant chemotherapy for non-small cell lung and head and neck cancers.

Although surgery is the only therapeutic intervention with potential for cure of non-small cell lung cancer (NSCLC) and head and neck cancer, most patients present with tumors that are too far advanced for resection. For this reason, neoadjuvant chemotherapy is being increasingly used to down-stage primary tumor burden before surgery. The procedure offers the possibility of enhancing resectability and thereby improves the chances of achieving complete eradication. In NSCLC, the most successful results have been obtained in patients with disease that is localized to the thorax and in those achieving complete responses to chemotherapy. A number of different combination regimens have been studied with cisplatin as the key component. Response rates of up to 88% have been reported together with complete sections in up to 74% of patients. The impact on survival is still to be determined. Although there is ample data showing that combination regimens containing vindesine have a favorable effect on survival in patients with inoperable NSCLC, relatively few of the studies have evaluated these regimens for use as neoadjuvant therapy. New studies should focus on increasing the complete response rate above the 20% level that is currently attainable. The results using neoadjuvant chemotherapy in head and neck cancer are disappointing with no survival benefit demonstrated. However, neoadjuvant chemotherapy may help preserve organ function and thus improve quality of life of patients.

Antineoplastic Agents, Phytogenic↗
PubMed1997

Schedule-dependent paclitaxel tolerance/activity: data from a 7 day infusion phase I study with pharmacokinetics in paclitaxel refractory ovarian cancer.

Our objective was to determine the maximum tolerated dose (MTD) of paclitaxel when given as a 7 day continuous i.v. infusion, repeated every 3 weeks, and to evaluate the toxicity and the efficacy of such a schedule of administration as a salvage treatment in ovarian cancer patients pretreated and refractory to 3 or 24 h paclitaxel. Thirteen women were enrolled in this phase I trial. Four dose levels ranging from 105 to 157.5 mg/m2/cycle were explored. Two of four patients experienced dose-limiting febrile neutropenia at the dose of 157.5 mg/m2. No objective response was observed, although three patients experienced disease stabilization (five to six cycles), with regression of disease symptoms, two of them having sustained 50% or greater decrease in CA 125. We conclude that the MTD in this population was paclitaxel 140 mg/m2/7 days. Schedule-dependent mechanisms of resistance to paclitaxel could not be demonstrated in this clinical setting of heavily pretreated ovarian cancer patients.

Antineoplastic Agents, Phytogenic↗
PubMed1997

Antitumor activity of oxaliplatin in combination with 5-fluorouracil and the thymidylate synthase inhibitor AG337 in human colon, breast and ovarian cancers.

Oxaliplatin, classical [5-fluorouracil (5-FU)] and non-classical (AG337) thymidylate synthase inhibitors have shown promising activity in the treatment of cancer. This study investigates the cytotoxic effects of oxaliplatin in combination with 5-FU and AG337 in cultured human colon (HT29, CaCo2), breast (MCF-7, MDA-MB-231) and ovarian (2008) cancer cell lines, and their derived counterparts selected for their resistance to 5-FU (HT29-5-FU), doxorubicin (MCF-7mdr) or cisplatin (2008C13). Therapeutic experiments were conducted in mice bearing colon-HT29 xenografts and in the GR hormone-independent mammary carcinoma model. In vitro, oxaliplatin shows potent cytotoxic activity in colon (IC50 from 2.1 +/- 1.1 to 5.9 +/- 1.7 microM), ovarian (IC50 = 10 +/- 1.6 microM) and breast cancer cells (IC50 from 7.4 +/- 2.7 to 17.9 +/- 7.1 microM). Oxaliplatin was a potent inhibitor of DNA synthesis and bound to cellular DNA. Surprisingly, the overall amount of oxaliplatin DNA binding was significantly inferior to that induced by isocytotoxic concentrations of cisplatin in HT29 (p=0.026). In vitro, synergistic antiproliferative effects were observed when oxaliplatin was added to 5-FU and AG337. Those synergistic effects of combinations were maintained in colon HT29-5-FU cancer cells. In vivo, 5-FU increased significantly the antitumor activity of oxaliplatin in HT29 xenografts (p=0.0036), and similarly 5-FU and AG337 increased the activity of oxaliplatin in the GR tumor model (p=0.0012). These data may encourage further clinical investigation of oxaliplatin in combination with classical and non-classical thymidylate synthase inhibitors in the treatment of human cancers.

Antimetabolites, Antineoplastic↗
PubMed1997

[Oxaliplatin: the first DACH platinum in clinical practice].

Oxaliplatin is a new platinum analog of the DACH family. Recent preclinical data have confirmed its non overlapping spectrum of activity with cisplatin, including acquired and intrinsic platinum resistant cell lines (as KB-CP, A 2780, HT29, CaCo2 colon cancer). When combined with other cytotoxic agents (5FU, SN38, CDDP, carboplatin), oxaliplatin has additive and/or synergistic antitumoral effects on various in vitro and in vivo models (colon, breast, ovarian and epidermoid tumors). Phase II trials have confirmed a sensorial peripherical neuropathy as its limiting toxicity while neither ototoxicity nor renal toxicities and only limited myelotoxicity were noted. Available phase II studies have established its antitumoral activity as single agent in 5FU refractory colon carcinoma while preliminary results suggest efficacy in cisplatin resistant ovarian cancer, in non small cell lung cancer, non Hodgkin lymphoma. Antitumoral activity has been observed during phases 1 in melanoma, glioma, breast and oesophageal cancers. A high response rate (28-65%) with the triple association (FU/folinic acid/oxaliplatin) has been reported in advanced colon cancer treated in first and second line settings. The results of two randomized phase III studies (FU/folinic acid +/- oxaliplatin) are expected. The oxaliplatin/cisplatin combination as salvage regimen had produced significant antitumoral activity (response rate: 45%) in resistant/refractory ovarian cancer. Finally, recent experimental and clinical data have outlined the potential interest in the development of this new original platinum compound. New single agent phases II are expected in other tumor types as well as new oxaliplatin combinations are ongoing (phase I trials of oxaliplatin/CPT-11 and of oxaliplatin/carboplatin, phase II study of oxaliplatin-vinorelbine in lung cancer.

Antineoplastic Agents↗
PubMed1997

Cumulative pharmacokinetic study of oxaliplatin, administered every three weeks, combined with 5-fluorouracil in colorectal cancer patients.

The cumulative pharmacokinetic pattern of oxaliplatin, a new diamminecyclohexane platinum derivative, was studied in patients with metastatic colorectal cancer. Oxaliplatin was administered by i. v. infusion (130 mg/m2) over 2 h every 3 weeks, and 5-fluorouracil and leucovorin were administered weekly. A very sensitive method, inductively coupled plasma-mass spectrometry, allowed for the determination of total plasma and ultracentrifugable (UC) and RBC platinum levels on day 1, at 0, 2, and 5 h, and on days 8, 15, and 22. Sixteen patients underwent three or more courses, and six of them underwent six or more courses. The platinum concentration curves were quite similar from one course to another, with a high peak value 2 h after administration (day 1, Cmax = 3201 +/- 609 microgram/liter) and a rapid decrease (day 8, 443 +/- 99 microgram/liter). Cmax of both total and UC platinum levels in plasma remained unchanged throughout the treatment. The mean total platinum half-life in plasma was 9 days. We found residual levels of total platinum on day 22 (161 +/- 45 microgram/liter), but we observed no significant accumulation for the four first cycles (P = 0.57). In contrast, platinum accumulated significantly in RBCs after three courses (+91% at day 22 of the third cycle versus day 22 of the first cycle, P = 0.000018), and its half-life there was equivalent to that of RBCs. The patterns of UC and total platinum concentration curves were very similar and correlated significantly (P < 10(-6)) at all sampling times. The mean UC:total platinum ratio was 15% at day 1 and 5% at days 8, 15, and 22 in the 3-week treatment course. Unlike cisplatin, which rapidly accumulates in plasma as both free and bound platinum, oxaliplatin does not accumulate in plasma, but it does accumulate in RBCs, after repeated cycles at the currently recommended dose (130 mg/m2) and schedule of administration (every 3 weeks).

Adult↗