Pierre Dubé

Peritoneal Colorectal Carcinomatosis Treated With Surgery and Perioperative Intraperitoneal Chemotherapy: Retrospective Analysis of 523 Patients From a Multicentric French Study

PURPOSE Peritoneal carcinomatosis (PC) from colorectal cancer traditionally is considered a terminal condition. Approaches that combine cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy (PIC) have been developed recently. The purpose of this study was to assess early and long-term survival in patients treated with that strategy. PATIENTS AND METHODS A retrospective-cohort, multicentric study from French-speaking countries was performed. All consecutive patients with PC from colorectal cancer who were treated with CRS and PIC (with or without hyperthermia) were included. Patients with PC of appendiceal origin were excluded. Results The study included 523 patients from 23 centers in four French-speaking countries who underwent operation between 1990 and 2007. The median follow-up was 45 months. Mortality and grades 3 to 4 morbidity at 30 days were 3% and 31%, respectively. Overall median survival was 30.1 months. Five-year overall survival was 27%, and five-year disease-free survival was 10%. Complete CRS was performed in 84% of the patients, and median survival was 33 months. Positive independent prognostic factors identified in the multivariate analysis were complete CRS, PC that was limited in extent, no invaded lymph nodes, and the use of adjuvant chemotherapy. Neither the grade of disease nor the presence of liver metastases had a significant prognostic impact. CONCLUSION This combined treatment approach against PC achieved low postoperative morbidity and mortality, and it provided good long-term survival in patients with peritoneal scores lower than 20. These results should improve in the future, because the different teams involved will gain experience. This approach, when feasible, is now considered the gold standard in the French guidelines.

Downregulation of Intestinal Cytochrome P450 in Chronic Renal Failure

Chronic renal failure (CRF) is associated with a decrease in intestinal drug metabolism. The mechanisms remain poorly understood, but one hypothesis involves a reduction in cytochrome P450 levels. This study aimed to investigate the effects of CRF on intestinal cytochrome P450. Two groups of rats were defined, i.e., rats with CRF (induced by 5/6 nephrectomy) and control pair-fed rats. Total cytochrome P450 levels and protein and mRNA expression of cytochrome P450 isoforms, as well as in vitro N-demethylation of erythromycin (a probe for CYP3A activity) and 7-ethoxyresorufin o-deethylase activity (a probe for CYP1A), were assessed in intestinal microsomes. Body weights were similar in the two groups. Creatinine clearance was reduced by 77% (P < 0.001) in CRF rats, compared with control pair-fed animals. Total intestinal cytochrome P450 activity was reduced by 32% (P < 0.001) in CRF rats. CYP1A1 and CYP3A2 protein expression was considerably reduced (>40%, P < 0.001) in rats with CRF. CYP2B1, CYP2C6, and CYP2C11 levels were the same in the two groups. RT-PCR assays revealed marked downregulation of CYP1A1 and CYP3A2 gene expression in CRF rats (P < 0.001). Although intestinal cytochrome P450 levels were reduced in CRF, induction by dexamethasone was present. N-Demethylation of erythromycin and 7-ethoxyresorufin o-deethylase activity were decreased by 25% (P < 0.05) in CRF rats, compared with control rats. In conclusion, CRF in rats is associated with decreases in intestinal cytochrome P450 activity (mainly CYP1A1 and CYP3A2) secondary to reduced gene expression.

Antitumor Effects of Somatostatin Analogs in Neuroendocrine Tumors

BACKGROUND For decades, somatostatin analogs (including octreotide and lanreotide) have been indicated for relief of the symptoms of flushing, diarrhea, and wheezing associated with secretory neuroendocrine tumors (NETs). Recently, it has been suggested that somatostatin analogs may provide direct and indirect antitumor effects in secretory and nonsecretory NETs in addition to symptom control in secretory NETs. METHODS A systematic review of MEDLINE was conducted to identify studies that investigated the antitumor effects of octreotide or lanreotide for patients with NETs. Additional studies not published in the peer-reviewed literature were identified by searching online abstracts. Results. In all, 17 octreotide trials and 11 lanreotide trials that included antitumor effects were identified. Partial response rates were between 0% and 31%, and stable disease rates were between 15% and 89%. Octreotide was the only somatostatin analog for which results of a phase III, randomized, placebo-controlled clinical trial that investigated antitumor effects were published. After 6 months of treatment in this randomized phase III trial, stable disease was observed in 67% of patients (hazard ratio for time to disease progression: 0.34; 95% confidence interval: 0.20-0.59; p = .000072). CONCLUSIONS In addition to symptom control for NETs, the data support an antitumor effect of somatostatin analogs and suggest that they may slow tumor growth. Long-acting repeatable octreotide has been shown to have an antitumor effect in a randomized phase III trial in midgut NETs, whereas results are pending in a corresponding controlled trial with lanreotide for patients with intestinal and pancreatic primary NETs.

Rationale for heating oxaliplatin for the intraperitoneal treatment of peritoneal carcinomatosis: a study of the effect of heat on intraperitoneal oxaliplatin using a murine model.

Objective:To study the effect of heat on the absorption of intraperitoneal (IP) oxaliplatin using a murine model. Background:Because of its efficiency in the systemic treatment of colorectal cancer, oxaliplatin is currently used in hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis. However, its properties when administered by the IP route have not been well characterized by preclinical studies. Methods:Under general anesthesia, 35 Sprague–Dawley rats were submitted to 3 different doses of IP oxaliplatin (460, 920, and 1840 mg/m2) at 3 different perfusion temperatures (37, 40, and 43°C) during 25 minutes. At the end of perfusion, samples in different compartments (peritoneum, portal blood, and systemic blood) were harvested and the concentrations of oxaliplatin were measured by high performance liquid chromatography. Results:As the dose of IP oxaliplatin was increased, higher concentrations were observed in every compartment. When the temperature of IP oxaliplatin was increased, it resulted in an increase of its peritoneal concentration (linear regression 0.38; 95% CI: 0.28–0.47) and in a decrease of its systemic blood (linear regression −1, 02; 95% CI: −1.45 to −0.60) and portal blood (linear regression −1.08; 95% CI: −1.70 to −0.47) concentrations. Conclusion:Proportionally to the dose administered, IP oxaliplatin leads to high concentration of drug in peritoneal tissues. Furthermore, heat enhances peritoneal tissue concentration of Oxaliplatin while reducing its systemic absorption. This last effect may possibly lead to decreased systemic toxicity. These observations support the use of oxaliplatin for HIPEC.

Surgical margins in breast-conservation operations for invasive carcinoma: does neoadjuvant chemotherapy have an impact?

BACKGROUND Regression of breast tumors in response to neoadjuvant chemotherapy is variable. The goal of breast-conservation operation after neoadjuvant chemotherapy is generally to resect any residual tumor with negative margins. There are limited data about the success of achieving negative resection margins in these patients. The purpose of this study was to compare surgical margin involvement of breast-conservation resection specimens from patients treated initially with operation with those from patients receiving neoadjuvant chemotherapy. METHODS Between January 2003 and June 2006, 478 breast-conservation operations were performed for invasive breast cancer at our institution. Seventy-six patients received neoadjuvant chemotherapy. Data collected included age, tumor size, nodal status, hormonal receptors and Her-2-neu status, lymphovascular invasion, histologic grade and type, use of guidewire, preoperative chemotherapy regimens, and microscopic evaluation of surgical margins. Univariate analyses and a regression model were used to identify factors associated with margin involvement. RESULTS No statistical difference was observed for margin involvement between patients treated with neoadjuvant chemotherapy and those treated initially with operation (21% versus 18%; p = 0.52). Variables associated with positive margins in a logistic regression model were carcinoma type (43% of all lobular carcinomas had positive margins versus 16% in ductal carcinomas; p = 0.002) and hormonal receptor status (margin involvement was present in 20% of tumors that exhibited hormonal receptors versus 10% in negative receptors tumors; p = 0.014). CONCLUSIONS Breast conservation after neoadjuvant systemic therapy yields no higher incidence of positive margins than primary surgical treatment. Special consideration should be accorded to lobular carcinoma, because our findings, consistent with previous studies, demonstrate an association with margin involvement.

Neoadjuvant Chemotherapy in Invasive Breast Cancer Results in a Lower Axillary Lymph Node Count

BACKGROUND It is essential to have the highest level of confidence in axillary staging assessment. Many surgeons and pathologists believe that fewer lymph nodes are present in axillary dissection specimens of women treated by neoadjuvant chemotherapy. Consequently, the purpose of this study was to compare the lymph node counts of axillary dissection specimens from patients having received neoadjuvant chemotherapy with those of patients treated with primary operation. STUDY DESIGN A retrospective analysis of a prospective database from our institution identified 283 women with invasive breast cancer who underwent level I and II axillary lymph node dissections. Women from the neoadjuvant chemotherapy group (n=107) were compared with those from the primary surgery group (n=176). The total number of lymph nodes harvested was considered as a continuous variable, but also dichotomized into two categories (< 10 and >or=10). Its correlation with the different variables was analyzed. RESULTS The median number of lymph nodes retrieved in the neoadjuvant chemotherapy group was 10.0 (range 0 to 38) compared with 12.5 (range 0 to 30) in the control group (p=0.002). There were also significantly more patients with fewer than 10 lymph nodes recovered in the neoadjuvant group (45 versus 28%, p=0.007). Logistic regression showed that neoadjuvant chemotherapy was the only factor associated with retrieval of fewer than 10 lymph nodes. CONCLUSIONS This study suggests that administration of neoadjuvant chemotherapy to breast cancer patients results in a reduced number of lymph nodes retrieved in the axillary dissection specimens.

Analysis of Clinical Applicability of the Breast Cancer Nomogram for Positive Sentinel Lymph Node: The Canadian Experience

A Breast Cancer Nomogram (BCN) for predicting nonsentinel lymph node (NSLN) involvement has been developed and prospectively tested in several series. However, its clinical applicability has never been tested among surgeons. The BCN was applied to 209 SLN-positive patients. Its performance was assessed by the area under the receiver–operating characteristic (ROC) curve. Surgeons in Quebec were surveyed to determine the predicted NSLN positivity below which they would not dissect the axilla. The accuracy of the BCN was determined in this clinically relevant range. The predictive accuracy of the BCN had an area under the ROC curve of 0.687. Almost half of interviewed surgeons treat over 20 breast cancer per year. Fourteen out of 82 surgeons questioned would never leave the patient without a completion axillary dissection after a positive SLN, regardless of the BCN result. Seventy one percent of them would not complete axillary dissection if the prediction of a positive NSLN was ≤10%. Only 37 of the 209 patients were in this 10% or less category, with a mean observed rate of positive NSLN of 13% (95% confidence interval [CI], 2–24%). The global performance of the BCN was fair. A majority of surgeons in Quebec would omit an axillary lymph node dissection (ALND) if the predicted probability of positive NSLN is 10% or less. Although useful, the BCN data should be used with caution at the low end of the scale. Because of some limitations in the performance in this category, other clinical factors and judgment must accompany its use.BackgroundA Breast Cancer Nomogram (BCN) for predicting nonsentinel lymph node (NSLN) involvement has been developed and prospectively tested in several series. However, its clinical applicability has never been tested among surgeons.MethodsThe BCN was applied to 209 SLN-positive patients. Its performance was assessed by the area under the receiver–operating characteristic (ROC) curve. Surgeons in Quebec were surveyed to determine the predicted NSLN positivity below which they would not dissect the axilla. The accuracy of the BCN was determined in this clinically relevant range.ResultsThe predictive accuracy of the BCN had an area under the ROC curve of 0.687. Almost half of interviewed surgeons treat over 20 breast cancer per year. Fourteen out of 82 surgeons questioned would never leave the patient without a completion axillary dissection after a positive SLN, regardless of the BCN result. Seventy one percent of them would not complete axillary dissection if the prediction of a positive NSLN was ≤10%. Only 37 of the 209 patients were in this 10% or less category, with a mean observed rate of positive NSLN of 13% (95% confidence interval [CI], 2–24%).ConclusionThe global performance of the BCN was fair. A majority of surgeons in Quebec would omit an axillary lymph node dissection (ALND) if the predicted probability of positive NSLN is 10% or less. Although useful, the BCN data should be used with caution at the low end of the scale. Because of some limitations in the performance in this category, other clinical factors and judgment must accompany its use.

Quality of Life in MAP.3 (Mammary Prevention 3): A Randomized, Placebo-Controlled Trial Evaluating Exemestane for Prevention of Breast Cancer

PURPOSE Exemestane, a steroidal aromatase inhibitor, reduced invasive breast cancer incidence by 65% among 4,560 postmenopausal women randomly assigned to exemestane (25 mg per day) compared with placebo in the National Cancer Institute of Canada (NCIC) Clinical Trials Group MAP.3 (Mammary Prevention 3) trial, but effects on quality of life (QOL) were not fully described. PATIENTS AND METHODS Menopause-specific and health-related QOL were assessed by using the four Menopause-Specific Quality of Life Questionnaire (MENQOL) domains and the eight Medical Outcomes Study Short Form Health Survey (SF-36) scales at baseline, 6 months, and yearly thereafter. MENQOL questionnaire completion was high (88% to 98%) in both groups at each follow-up visit. Change scores for each MENQOL and SF-36 scale, calculated at each assessment time relative to baseline, were compared by using the Wilcoxon rank-sum test. Clinically important worsened QOL was defined as a MENQOL change score increase of more than 0.5 (of 8) points and an SF-36 change score decrease of more than 5 (of 100) points from baseline. RESULTS Exemestane had small negative effects on womens self-reported vasomotor symptoms, sexual symptoms, and pain, which occurred mainly in the first 6 months to 2 years after random assignment. However, these changes represented only a small excess number of women being given exemestane with clinically important worsening of QOL at one time or another; specifically, 8% more in the vasomotor domain and 4% more each in the sexual domain and for pain. No other between-group differences were observed. Overall, slightly more women in the exemestane arm (32%) than in the placebo arm (28%) discontinued assigned treatment. CONCLUSION Exemestane given for prevention has limited negative impact on menopause-specific and health-related QOL in healthy postmenopausal women at risk for breast cancer.

Prolonged Therapy with Imatinib Mesylate before Surgery for Advanced Gastrointestinal Stromal Tumor Results of a Phase II Trial

Purpose. Proven efficacy of imatinib mesylate in gastrointestinal stromal tumour (GIST) has led to its use in advanced disease and, more recently, in adjuvant and neoadjuvant settings. The purpose of this study was to evaluate the optimal neoadjuvant imatinib duration to reduce the morbidity of surgery and increase the possibility of resection completeness in advanced tumours. Patients and Method. Patients with advanced GIST were enrolled into a registered open-label multicenter trial and received imatinib daily for a maximum of 12 months, followed by en bloc resection. Data were prospectively collected regarding tumour assessment, response rate, surgical characteristics, recurrence, and survival. Results. Fourteen patients with advanced GIST were enrolled. According to RECIST criteria, 6 patients had partial response and 8 had stable disease. The overall tumour size reduction was 25% (0–62.5%), and there was no tumour progression. Eleven patients underwent tumour resection, and all had R0 resection. After a median followup of 48 months, 4-year OS and DFS were 100% and 64%, respectively. Conclusion. This prospective trial showed that one year of neoadjuvant imatinib in advanced GIST is safe and associated with high rate of complete microscopic resection. It is not associated with increased resistance, progression, or complication rates.

Malignant paraganglioma of the mesentery: a case report and review of literature.

Paragangliomas represent only 10% of chromaffin tissue tumors and those arising from the mesentery seem to be a rare occurrence. We report a case of a 55 year old man in whom an abdominal mass was discovered fortuitously by ultrasonography during a routine health exam. He presented occasional heart palpitations and diaphoresis as well as a well-demarcated mass upon abdominal physical examination. CT scan revealed a solid polylobulated mass in the right lower quadrant. Exploration laparotomy revealed a voluminous multi-nodular tumoral mass, which contained hemorrhagic spots. Histopathological studies confirmed the presence of a paraganglioma. The excision of the mass as well as the surrounding intestine and mesentery also revealed two lymphatic metastases, the first among 14 documented cases to be described concerning mesenteric paragangliomas. One year follow up and CT scan revealed neither recurrence nor the presence of distant metastases.