SALTO: a randomized, multicenter study assessing octreotide LAR in inoperable bowel obstruction.

This phase II, multicenter, randomized, double-blind, non-comparative study assessed the efficacy and safety of immediate-release octreotide and octreotide LAR, in combination with corticosteroids and standard medical care, on the symptoms of inoperable malignant bowel obstruction (MBO) due to peritoneal carcinomatosis. The primary efficacy endpoint was "success" at day 14 defined as a composite endpoint including the absence of a nasogastric tube, and vomiting less than twice per day and no use of anticholinergic agents. Patients in the octreotide arm received octreotide LAR 30 mg intramuscular (im) on days 1, 29 and 57, as well as daily immediate-release octreotide 600 µg per day plus methylprednisolone on days 1 to 6. Placebo-treated patients received methylprednisolone and matched placebo instead of octreotide. Difficulties associated with enrolling patients at palliative-care stage meant only 64 patients (instead of the planned 102 patients) were randomized, 32 to octreotide and 32 to placebo. Despite randomization, more patients in the octreotide arm (46.4%) than in the placebo arm (21.9%) had a baseline Karnofsky score less than 50. An intention-to-treat analysis showed that in the octreotide and placebo arms, 12 (38%) and nine (28%), respectively, patients were successfully treated at day 14, which increased to 9/15 (60%) and 7/25 (28%), respectively, among patients with a baseline Karnofsky score greater or equal to 50. Octreotide-treated patients reported three drug-related adverse events (AEs), and no drug-related serious AEs or deaths. Octreotide LAR may have a key role in treating patients with a MBO due to peritoneal carcinomatosis, particularly in those with moderately severe disease.

Evaluation of pelvic posterior exenteration in the management of advanced-stage ovarian cancer.

PURPOSE: The main aim of this study was to show the interest of pelvic posterior exenteration to obtain complete resection of the tumor in case of invasion of the rectum by contiguity in advanced-stage ovarian cancer. The secondary aim was to determine the morbidity of this surgery. METHODS: It is a multicentric, retrospective study of a series of 41 patients, who underwent posterior pelvectomy for advanced-stage ovarian cancer, over a period of 18 years, from July 1989 to July 2007. RESULTS: The surgery resulted in macroscopically complete resection in 19 patients (46.34%), a residual tumor <2 cm in 19 patients (46.34%) and >2 cm in 3 patients (7.32%). In 34 patients (34/41), digestive continuity with satisfactory anal sphincter function was restored immediately or in the short term. The mean delay to the start of complementary treatment was 36 days. Median overall survival was 33 months. CONCLUSION: The main aim of surgery for ovarian peritoneal carcinomatosis is to obtain a complete resection. In the case of direct invasion of the rectum by contiguity, when there is no cleavage plane between the uterus and the rectum, pelvic posterior exenteration is an effective method to achieve this objective. Morbidity is relatively high, but acceptable given the poor prognosis of this disease, the improved survival after surgery, and improvements in post-operative quality of life and functions.

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

BACKGROUND: Intraperitoneal (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. METHODS: To 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 degrees C. RESULTS: No 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. CONCLUSION: The 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.

Pegylated liposomal doxorubicin and carboplatin in late-relapsing ovarian cancer: a GINECO group phase II trial.

BACKGROUND: The GINECO group previously demonstrated that pegylated liposomal doxorubicin (PLD)-carboplatin combination was an effective and well-tolerated treatment for advanced ovarian cancer (AOC) patients in late relapse. The purpose of the present analysis was to confirm these results in a prospective cohort of late-relapsing AOC patients. PATIENTS AND METHODS: Eighty-one consecutive patients received PLD 30 mg/m(2), followed by carboplatin (area under the curve) 5 mg min/ml, every 28 days for 6 courses or until progression. RESULTS: The objective response (OR) rate was 65.4%. The median progression-free survival (PFS) and overall survival (OS) were 13.6 months and 38.9 months, respectively. Haematological toxicities were more common than non-haematological toxicities. Non-hematologic adverse reactions were moderate and grade 3 palmar-plantar erythrodysesthesia was limited to one patient. No cardiotoxicity was observed and no toxic death occurred. CONCLUSION: These data support the clinical efficacy and tolerability of PLD in combination with carboplatin as second-line therapy for AOC patients in late relapse.

Results of a phase I trial of intravenous vinorelbine plus oral capecitabine as first-line chemotherapy of metastatic breast cancer.

The management of metastatic breast cancer becomes increasingly intricate, requiring new drugs and combinations. We present here the results of a phase I study evaluating the maximal tolerated dose of vinorelbine combined with capecitabine as first-line chemotherapy. Vinorelbine was administered intravenously on days 1 and 15, and capecitabine was given orally twice daily from day 1 to 14 (three cycles every 21 days). Three out of six patients receiving vinorelbine at 25mg/m2/day and capecitabine at 2000 mg/m2/day presented with a dose-limiting toxicity, consisting of protracted grade 3 neutropenia, hand-foot syndrome and/or liver test disturbances. Despite of a dose reduction in vinorelbine (20mg/m2/day), one patient among four developed a dose-limiting febrile neutropenia. This regimen cannot be recommended as first-line treatment of metastatic breast cancer. These findings are not in agreement with previous publications of this schedule, or with promising results using both drugs orally.

[Targeting ErbB receptors in breast cancer]. / Cancer du sein et ciblage des récepteurs ErbB (HER).

Because of the involvement of the receptors of the ErbB family in breast oncogenesis, numerous approaches aimed at targeting these receptors have been developed. A monoclonal antibody directed against the ErbB2 (HER2) receptor, trastuzumab (Herceptin), has shown a high activity in palliative, neo-adjuvant and, more recently, in adjuvant setting, and has been considered as bringing a "therapeutic revolution" in breast oncology. Other antibodies, directed against ErbB2 or EGFR, are being evaluated, especially lapatinib, which should be marketed in the next future. Combinations between targeted therapies and cytotoxic chemotherapy will certainly allow to take the greatest benefits from these new treatment approaches.

[Angiogenesis targeting in breast cancer]. / Le ciblage de l'angiogenèse dans les cancers du sein.

Several anti-angiogenic agents are under evaluation in breast cancer. Currently, only bevacizumab has shown its efficacy, in combination with paclitaxel, on relapse-free survival in the metastatic setting. The combination of targeted therapies (for instance, trastuzumab plus bevacizumab, lapatinib plus pazopanib, etc.) is certainly of utmost interest. However, the anti-angiogenic agents not always bring in phase III the expected effects on patient survival, and an increased toxicity of combinations versus chemotherapy only has been observed. Outside the privileged neo-adjuvant setting, it appears difficult, for technical and ethical reasons, to obtain tissue samples before and after treatment to study predictive factors of drug response and to establish surrogate makers.

Feasibility of using intraperitoneal epinephrine and cisplatin in patients with advanced peritoneal carcinomatosis.

Intraperitoneal epinephrine above 1 mg/l concentration has been shown to enhance the intratumoral accumulation and antitumor activity of intraperitoneal cisplatin in rats with advanced peritoneal carcinomatosis. The aim of this study was to determine the tolerance of intraperitoneal epinephrine combined with intraperitoneal cisplatin in patients with advanced peritoneal carcinomatosis (17 ovarian cancers, one peritoneal mesothelioma). Intraperitoneal epinephrine (1-5 mg/l) and cisplatin (50 mg/l; 100 mg total dose) were infused in 2 l of saline solution over 2 h. The maximal tolerated concentration of intraperitoneal epinephrine was not reached at 5 mg/l. Cardiovascular symptoms were infrequent and not strictly related to the epinephrine concentration. Tumor responses were obtained in some patients with disease resistant to intravenous platinum compounds. This work demonstrates for the first time that intraperitoneal epinephrine at sufficient concentration enhances the cisplatin effect and can be safely infused into the peritoneal cavity of patients with peritoneal carcinomatosis. The greatest limitation was abdominal pain and limited intraperitoneal distribution of the peritoneal fluid in this closed-abdomen procedure.

A multicenter phase II study of cisplatin and docetaxel (Taxotere) in the first-line treatment of advanced ovarian cancer: a GINECO study.

PURPOSE: A multicenter phase II study to evaluate the antitumor effect and safety of docetaxel in combination with cisplatin as first-line chemotherapy for advanced ovarian cancer. METHODS: Enrolled in the study were 45 patients who were to receive six courses of docetaxel 75 mg/m(2) plus cisplatin 75 mg/m(2) every 21 days with hydration and steroid prophylaxis after initial debulking surgery. Imaging techniques and radiography were used to assess clinical tumor response, and second-look surgery was required for patients with complete clinical responses and for those without clinically measurable disease. RESULTS: The overall clinical response rate in 29 patients with clinically measurable disease was 58% (41% complete response). A complete pathologic response was seen in 9 of 34 patients who underwent second-look laparotomy, while microscopic disease was found in 10 patients. The median time to progression was 14.4 months (95% CI 8.4-20.4 months), with a median overall survival of 43 months (95% CI 21.1-65.0 months). Patients received a median number of six cycles at a dose intensity of 98%. Grade 3-4 neutropenia was seen in 80% of patients, but was manageable. No patients withdrew because of fluid retention. CONCLUSIONS: The combination of docetaxel with cisplatin confers high clinical and pathologically verified tumor response rates and is well tolerated in the first-line management of advanced ovarian cancer.