Emmanuel Guardiola

Palliative 5-fluorouracil-based chemotherapy for advanced colorectal cancer in the elderly: Results of a 10-year experience

The aim of this study was to evaluate the objective tumor response rates and toxicities in elderly patients (older than 70 years) with advanced colorectal cancer treated with 5-fluorouracil (5-FU) as a first-line palliative chemotherapy regimen. Eighty-six consecutive patients were enrolled onto a retrospective study between January 1990 and February 1998. Patients were divided into two groups; group 1 consisted of patients who were 70 to 74 years old, and group 2 consisted of patients who were age 75 years and older. Four types of 5-FU-based chemotherapy were administered. First-line chemotherapy was continued until disease progression, unacceptable toxicity, or patient refusal. Primary tumor sites were the colon (n = 44), rectum (n = 29), and colorectal (n = 13). There was no difference in response (complete/partial) rates according to age groups (group 1: 21%, group 2: 26%). Median overall survival was 17 months for group 1 and 14 months for group 2, with 1-year survival at 63% and 55%, respectively (not statistically significant). Median time to progression was 6 months for both age groups. Chemotherapy in both groups increased performance status, and weight in 26% and 31%, respectively. No toxic death was reported. There was no difference in overall or severe toxicity between the two age groups, and all adverse events were manageable. Toxicity (grade III/IV) occurred in 25% of patients. Based on these findings, palliative first-line chemotherapy for colorectal cancer can be performed in selected elderly patients without increasing either morbidity or mortality, while obtaining response rates and side effects comparable to those in younger patients.

Intra-operative intra-peritoneal chemotherapy with cisplatin in patients with peritoneal carcinomatosis of ovarian cancer.

BackgroundIntra-peritoneal (i.p.) chemotherapy is an encouraging treatment option for ovarian cancer with peritoneum involvement in addition with intravenous (i.v.) chemotherapy. Intra-operative i.p. chemotherapy is an interesting method of administration by enhancing the diffusion of chemotherapy. This study had assessed the feasibility of intra-operative i.p. chemotherapy in patients with peritoneal carcinoma of ovarian cancer.MethodsFrom January 2003 to February 2006, 47 patients with stage III ovarian cancer were treated with standard paclitaxel carboplatin intravenous chemotherapy and debulking surgery with intra-operative i.p. chemotherapy. After optimal cytoreductive surgery, defined by no unresectable residual disease > 1 cm, i.p. chemotherapy was performed during surgery. The peritoneal cavity was filled by 3 litres of isotonic saline pre-heated at 37 degrees and 90 mg of cisplatin. The sequence was repeated twice during 2 hours based on previous published studies which optimized the cisplatin dosage and exposure duration. Optimal diffusion was obtained by stirring by hands during the 2 hours.ResultsMedian age was 59.6 years. No severe haematological or non-haematological toxicity induced by intra operative i.p. chemotherapy was reported. No patient died due to the complications of surgery or the i.p. chemotherapy. No neurotoxicity occurred, and one patients had renal impairment.ConclusionThis study demonstrates the feasibility of intra-operative i.p. chemotherapy with cisplatin after optimal resection of peritoneal tumor nodules. Further randomized trials are planned to investigate the clinical benefit of this therapeutic modality.

Is there still a role for triple endoscopy as part of staging for head and neck cancer

Purpose of reviewRecently, there has been increased interest in bacterial biofilms as a major factor in chronic infections. Chronic rhinosinusitis is one of the most common chronic infections seen by physicians. The purpose of this review is to summarize the literature available on chronic rhinosinusitis and biofilms. Recent findingsOnly very few articles are available about the relationship between biofilms and chronic rhinosinusitis. Three separate authors reported on finding biofilms in samples obtained from patients with chronic rhinosinusitis. One article demonstrated biofilms on samples obtained from animals that were inoculated with bacteria. The major breakthrough was noted when the majority of samples from patients with chronic rhinosinusitis had biofilms in them but none were found on similar samples obtained on controls. SummaryEven though only a few reports are available about the role of biofilms and chronic rhinosinusitis, the evidence seems to be convincing that such a role exists. We still have a long way to go, however, before we know the exact relationship of biofilms and chronic rhinosinusitis. Why do some patients form biofilms, what triggers biofilm formation and how can we prevent them from forming are questions that need to be answered.

Combination of cisplatin-doxorubicin-cyclophosphamide in adenocarcinoma of unknown primary site: a phase II trial.

&NA; The purpose of this report is to evaluate toxicity, response, and survival of the cyclophosphamide‐doxorubicin‐cisplatin (CAP) chemotherapy regimen in patients with adenocarcinoma of unknown primary site (ACUP). Twenty‐two patients with ACUP were eligible for this study between June 1992 and April 1999. There were 13 men (59%) and 9 women (41%) with a median age of 53.5 years (range: 29–78 years). Lung (seven), liver (six), vertebral bone site (six), and abdominal nodes (six) were the most common metastatic sites. Treatment consisted of doxorubicin 50 mg/m2, cyclophosphamide 1,000 mg/m2, and cisplatin 100 mg/m2 (CAP), administered every 3 weeks; a total of six courses were planned. Twenty‐two patients were assessable for toxicity and 20 patients were assessable for response. Grade III to IV neutropenia was observed in 14 patients (64%); febrile neutropenia occurred in 6 patients (27%) and in 10 cycles (12.5%). Grade III to IV anemia and thrombocytopenia were found in 12 (54.5%) and 9 patients (41%), respectively. Grade III to IV nausea and vomiting was observed in 9 patients (41%). Ten patients, 50% of the assessable population, obtained an objective response, including 3 complete (15%) and 7 partial (35%) responses. The median response duration was 3.9 months (range: 0.5–13.3 months). One patient (5%) had stable disease and 5 patients (25%) had progressive disease. The median overall survival and the median time to progression were 10.7 months (range: 0.4–56.9 months) and 8.8 months (range: 6.6–16.5 months), respectively. The CAP regimen in patients with ACUP had significant activity. This chemotherapy regimen induced a high level of grade III to IV toxicities and could not be considered as a treatment of reference. However, the emergence of long‐term survivors among responder patients highlighted the need to search for an active treatment for patients with ACUP.

Intraoperative chemotherapy with cisplatin and epinephrine after cytoreductive surgery in patients with recurrent ovarian cancer: a phase I study.

BackgroundIntraperitoneal (i.p.) epinephrine was shown to increase the accumulation of i.p. cisplatin in tumours, and thus its antitumour effect in a model of peritoneal carcinomatosis in rats. MethodsTo determine the tolerance to i.p. epinephrine with cisplatin, 18 patients with recurrent ovarian carcinoma were intraoperatively treated in this phase 1 study. After maximal cytoreductive surgery, the peritoneal cavity was filled twice for 1 h with 30 mg/l of cisplatin and increasing concentrations of epinephrine (0, 1, 2, 3 mg/l) in 3 l of saline solution at 37°C. ResultsNo deaths occurred. Three patients were treated at each of the 0, 1 and 2 mg/l epinephrine levels without adverse events. Two of the three patients who received 3 mg/l epinephrine experienced cardiac intolerance. Six additional patients received 2 mg/l of epinephrine without toxicity. A relationship between the serum concentration of epinephrine and occurrence of cardiac toxicity was established. A 60% decrease in serum area under the curve of platinum was calculated in patients receiving i.p. epinephrine compared with i.p. cisplatin alone. Renal toxicity from cisplatin was not increased by epinephrine. No haematological or neurological toxicity was recorded. The other grade 3–4 adverse events [thromboembolism (5), peritonitis (1), abdominal bleeding (1), bowel fistula (1)] occurred as often as usually reported for this heavy surgical procedure. ConclusionThe combination of i.p. epinephrine with cisplatin as intraoperative chemotherapy after optimal cytoreductive surgery is feasible. The recommended concentration for further studies is 2 mg/l for i.p. epinephrine.

Clinical and economic impact of epoetin in adjuvant-chemotherapy for breast cancer.

IntroductionAnaemia is a common toxicity in cancer patients and epoetins (EPOs) are now an established treatment. The economic profile of EPO treatment was assessed in patients with breast cancer treated by adjuvant-chemotherapy.Materials and methodsTwo strategies were compared: without treatment by EPO and with the possible use of treatment by EPO (epoetin alfa) when required. The clinical effectiveness criterion was time adjusted to quality of life and economic data included only direct medical costs.Main resultsOne hundred ninety-two patients were included. In the group with the strategy containing the possible use of EPO, 45.5% of patients effectively received EPO. A significant difference in the haemoglobin level profile over time was observed which provided a significant overall benefit of 0.0052 (p<10−4) quality-adjusted life year (QALY) associated with an extra cost of €1,615 (p<10−4). In the base case analysis, the cost per added QALY was estimated as €310,577 with the strategy containing the possible use of EPO.ConclusionThis robust result seems to be unacceptable, but the only relevant point of discussion might be the level of acceptable incremental cost-effectiveness ratio (ICER) for a patient.

Intraperitoneal clearance as a potential biomarker of cisplatin after intraperitoneal perioperative chemotherapy: a population pharmacokinetic study

Background:Intraperitoneal (IP) perioperative chemotherapy with cisplatin is an interesting option in ovarian cancer treatment. A combination of cisplatin with IP epinephrine (already shown to improve IP and decrease systemic platinum (Pt) exposure) was evaluated using a population pharmacokinetic analysis.Methods:Data from 55 patients treated with cisplatin-based IP perioperative chemotherapy with (n=26) or without (n=29) epinephrine were analysed using NONMEM.Results:Epinephrine halves clearance between peritoneum and serum (IPCL) and increases the Pt central volume of distribution, IP exposure and penetration in tissue. IPCL has a better predictive value than any other parameter with respect to renal toxicity.Conclusion:This confirms that IPCL could be useful in assessing renal toxicity. As IPCL is also linked to tissue penetration and IP exposure, it may be proposed as biomarker. In addition to a Bayesian estimation, we propose a single-sample calculation-way to assess it. Prospective studies are needed to validate IPCL as a biomarker in this context.

Population Pharmacokinetics and Dosing Recommendations for Cisplatin during Intraperitoneal Peroperative Administration

AbstractBackground: Ovarian cancer is the leading cause of gynaecological cancer-related death in Western countries. Intraperitoneal (IP) peroperative chemotherapy is an interesting therapeutic option. However, very few data are available regarding pharmacokinetics and especially population pharmacokinetics. Patients and methods: Thirty-one patients with advanced epithelial cancer classified as International Federation of Gynecology and Obstetrics stage IIIC were included in the study. Blood and IP samples were taken over a 24-hour period during and after IP treatment. Both total and ultrafiltered (Uf) platinum (Pt) concentrations were analysed using a population approach with nonlinear mixed-effects modelling (NONMEM®) software. Improvement of the model with covariates was performed as well as assessment of the model using bootstrap and posterior visual predictive methods. Results: Both IP fluid and serum pharmacokinetics were satisfactorily described with a three-compartment model for both Uf Pt and total Pt concentrations. The covariates were bodyweight for the IP volume of the total Pt model. A nomogram, based on the results of the Monte Carlo simulations, displays a dose recommendation regarding both the risk of renal toxicity and the potent efficacy of the treatment. A limited sampling strategy (LSS) allowing the estimation of potential risk of renal toxicity is also described. Conclusion: The pharmacokinetics of cisplatin during peroperative IP chemotherapy could be successfully fitted with the present model, which allowed a dosing strategy accompanied by an LSS to facilitate the follow-up of patients.