Postoperative irinotecan in resected stage II-III rectal cancer: final analysis of the French R98 Intergroup trial†.

BACKGROUD: The R98 trial explores the addition of irinotecan to a 5-fluorouracil (5-FU) plus leucovorin (5-FU/LV) adjuvant regimen in optimally resected stages II-III rectal cancers. We report the updated long-term results. Disease-free survival (DFS) was the primary end point. PATIENST AND METHODS: Between March 1999 and December 2005, 357 patients were randomized: 178 in 5-FU/LV and 179 in LV5-FU2 + irinotecan arm. The trial was stratified by control arm: Mayo Clinic regimen or LV5-FU2 regimen. RESULTS: Three hundred and fifty-seven randomized patients were evaluable for efficacy. With a follow-up of 156 months, the DFS was in favour of experimental arm but did not reach statistical significance [hazard ratio (HR) = 0.80, P = 0.154]. The same was observed for overall survival (OS) (HR = 0.87, P = 0.433). The 5-year DFS was 58% in the control arm and 63% in the experimental arm. The 5-year OS was 74% in the control arm and 75% in the experimental arm. Patients allocated to the experimental arm had more grade 3-4 neutropenia when compared with the LV5-FU2 arm (33% versus 6%, P = 0.03), but not when compared with the Mayo Clinic arm (33% versus 36%, P = 0.84). Grade 3-4 diarrhoea tended to be higher in the experimental arm, but analyses stratified by control arm or by radiotherapy failed to show significant differences across strata (test for interaction P = 0.44). CONCLUSION: Even though a benefit of irinotecan in subgroups of patients cannot be excluded, due to early termination and lack of power, the study does not support the addition of irinotecan to 5-FU/LV in routine in patients with resected stage II-III rectal cancer.

Prognostic value of EndoPredict test in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative primary breast cancer screened for the randomized, double-blind, phase III UNIRAD trial.

BACKGROUND: The purpose of this study was to evaluate the prognostic value of the multigene EndoPredict test in prospectively collected data of patients screened for the randomized, double-blind, phase III UNIRAD trial, which evaluated the addition of everolimus to adjuvant endocrine therapy in high-risk, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer. PATIENTS AND METHODS: Patients were classified into low or high risk according to the EPclin score, consisting of a 12-gene molecular score combined with tumor size and nodal status. Association of the EPclin score with disease-free survival (DFS) and distant metastasis-free survival (DMFS) was evaluated using Kaplan-Meier estimates. The independent prognostic added value of EPclin score was tested in a multivariate Cox model after adjusting on tumor characteristics. RESULTS: EndoPredict test results were available for 768 patients: 663 patients classified as EPclin high risk (EPCH) and 105 patients as EPclin low risk (EPCL). Median follow-up was 70 months (range 1-172 months). For the 429 EPCH randomized patients, there was no significant difference in DFS between treatment arms. The 60-month relapse rate for patients in the EPCL and EPCH groups was 0% and 7%, respectively. Hazard ratio (HR) supposing continuous EPclin score was 1.87 [95% confidence interval (CI) 1.4-2.5, P < 0.0001]. This prognostic effect remained significant when assessed in a Cox model adjusting on tumor size, number of positive nodes and tumor grade (HR 1.52, 95% CI 1.09-2.13, P = 0.0141). The 60-month DMFS for patients in the EPCL and EPCH groups was 100% and 94%, respectively (adjusted HR 8.10, 95% CI 1.1-59.1, P < 0.0001). CONCLUSIONS: The results confirm the value of EPclin score as an independent prognostic parameter in node-positive, hormone receptor-positive, HER2-negative early breast cancer patients receiving standard adjuvant treatment. EPclin score can be used to identify patients at higher risk of recurrence who may warrant additional systemic treatments.

Combined first-stage hepatectomy and colorectal resection in a two-stage hepatectomy strategy for bilobar synchronous liver metastases.

BACKGROUND: This study assessed the feasibility and outcomes of combined colorectal and hepatic resection as the first step of two-stage hepatectomy in patients with bilobar synchronous colorectal liver metastases. METHODS: All patients with bilobar synchronous colorectal liver metastases who were considered for two-stage hepatectomy, combining resection of the primary tumour with the first stage of hepatectomy, between 2000 and 2008 were selected from a prospectively collected database at two institutions. Data were analysed retrospectively on an intention-to-treat basis. RESULTS: Thirty-three patients were studied. Twenty patients received neoadjuvant chemotherapy. Combined colorectal resection and clearance of left-sided liver metastases was the first-stage procedure in all but one patient, in whom right clearance was performed. In 17 patients right portal vein ligation was undertaken at the same time. No patient died. Two patients had anastomotic leakage. Interval chemotherapy was given to 25 patients, five of whom also had percutaneous portal vein embolization. Twenty-five patients had the second-stage hepatectomy, but not eight patients with disease progression. There was one postoperative death after the second stage, and eight patients experienced morbidity. Median follow-up from the first stage was 28.7 months. Overall and disease-free survival rates for patients who completed the procedure were 80 and 44 per cent respectively at 3 years, and 48 and 22 per cent at 5 years. CONCLUSION: In patients with bilobar synchronous colorectal liver metastases who are candidates for two-stage hepatectomy, combined resection of the primary tumour and first-stage hepatectomy reduces the number of procedures, optimizes chemotherapy administration and may improve outcome.

[Specificities of chemotherapy in elderly cancer patients]. / Spécificités de la prise en charge par chimiothérapie chez le sujet âgé.

The management of cancer in the elderly patients is becoming a major problem of public health. The population is becoming older, the risk of cancer is increasing with age and therapeutic tools are improving. The numerous pharmacological changes of age might influence the pharmacokinetic and pharmacodynamic variables of many drugs, in particular the agents of chemotherapy. The development of news drugs, with less toxicity, administrated weekly or orally, and of supportive care (hematological growth factors, nutritional support) allows proposing specific treatment to elderly patients with cancer. However, evidence-based medicine data are lacking to define optimal schedules in this population due to low inclusion rates in clinical trials. This paper explores the specificities of chemotherapy in elderly patients with cancer.

Chemotherapy has also an effect on primary tumor in colon carcinoma.

BACKGROUND: This study characterizes the histological effect of chemotherapy (CT) on primary colonic tumors. METHODS: Between 2000 and 2006, 38 patients with stage IV colon cancer underwent resection of the primary, after chemotherapy (CT group, n = 16) or without preoperative CT (control group, n = 22). For all primary tumors, histological analysis included: fibrosis, acellular necrosis, acellular mucin pools, lymphoplasmacytic infiltration, and changes at tumor surface. Tumor regression grade (TRG) was determined by the amount of residual tumor cells and was graded from 1 to 5. RESULTS: No patient had complete histological response. Major histological tumor regression (TRG2) was observed in 70% of patients treated by CT and none of the not treated patients (P < 0.0001). Fibrosis, acellular necrosis, and surface changes were significantly increased in the CT group. TRG in the primary was comparable to the TRG in the corresponding liver metastases for 7/9 patients who underwent both colonic and hepatic resection after CT. CONCLUSION: CT induces major histological response in 70% of colon cancers. Response to CT in the primary and the corresponding liver metastases are correlated. These results support a policy of initial CT management for stage IV colon cancer and may warrant future studies of neoadjuvant CT in locally advanced colon carcinomas.

Plasmin-catalyzed proteolysis in colorectal neoplasia.

The expression of different components of the plasminogen activator (PA)/plasmin system was explored in a series of colorectal neoplasia. We have found that urokinase (uPA) and urokinase receptor (uPA-R) gene expression is upregulated in adenomas and carcinomas, and that uPA/uPA-R production is confined to stromal cells in the proximity of epithelial proliferations. In addition, in adenomas, the focal increase in uPA mRNA is not systematically coupled to detectable enzymatic activity, whereas in carcinomas, uPA mRNA accumulation is consistently associated with detectable but variable levels of enzymatic activity. In contrast, in the tumor vasculature, tissue-type plasminogen activator-mediated proteolysis is considerably reduced when compared to normal mucosal and submucosal vessels; this reduction in plasmin formation appears to result from the highly increased production of plasminogen activator inhibitor type 1 by endothelial cells. Our observations demonstrate that colorectal neoplasia are associated with marked alterations in the extracellular proteolytic balance controlled by the PA/plasmin system. They show that contrasting disturbances in plasmin formation take place in distinct stromal compartments but not in epithelial cells, and that these disturbances are maximal during invasive neoplasia. Altogether, our results raise the possibility that alterations in plasmin formation should not be exclusively regarded as promoters of cancer cell invasiveness.

Plasminogen activation in melanocytic neoplasia.

A large body of experimental evidence suggests that plasminogen activators provide tumoral cells with efficient means to degrade extracellular matrix constituents and thereby facilitate their dissemination to distant sites. Melanocytic neoplasia encompass a spectrum of lesions exhibiting diverse clinical behavior that remain difficult to predict with current histopathological evaluations. Little information concerning the contribution of plasminogen activation in diagnostic specimens of human melanocytic tumors is presently available. We thus analyzed biopsy specimens of pigmented skin lesions by histological techniques that identify the cellular sites of synthesis of plasminogen activators and of their inhibitors and that localize the sites of plasminogen activators-catalyzed enzymatic activities. We found that urokinase-type plasminogen activators (uPA) and plasminogen activator inhibitor type 1 mRNAs accumulate in atypical nevocytes and in melanoma cells, but not in benign nevocytes. However, uPA-catalyzed proteolytic activity was detected exclusively in melanomas. These observations suggest that up-regulation of the uPA gene is an early feature of melanocyte transformation and that unbalanced enzyme/inhibitor activity is associated with the malignant phenotype. By supporting a role for uPA in melanoma invasiveness, they provide a novel tool for the evaluation of atypia in nevi.

Bullous pemphigoid associated with acute graft-versus-host disease after allogeneic bone marrow transplantation.

A 47-year-old patient was treated with allogeneic bone marrow transplantation (BMT) for chronic myelogenous leukaemia in blast crisis. Three months after the procedure he developed bullous pemphigoid (BP) and symptoms suggestive of BP oesophageal involvement, associated with skin and liver acute graft-versus-host disease. The occurrence of BP is exceptional after BMT.

[Epidermal growth factor inhibitors]. / Les inhibiteurs des récepteurs de l'Epidermal Growth Factor (EGF).

PURPOSE: Tyrosine kinases are implicated in the normal cellular proliferation and in malignant transformation. Among the tyrosine kinase receptors, one of best described is the Epidermal Growth Factor Receptor (EGFR), which is widely expressed in particular in epithelial cells and in many human carcinomas. CURRENT KNOWLEDGE AND KEY POINTS: Compounds have been developed that target either the extracellular ligand-binding region of EGFR (Cetuximab) or the intracellular tyrosine kinase ATP-binding (Iressa), Tarceva. Phase I studies showed that these molecules have a favorable pharmacokinetic and pharmacodynamic profile, with excellent tolerance and easy administration. Phase II and III studies are currently testing their efficacy. FUTURE PROSPECTS AND PROJECTS: Preliminary results show interesting activity in different tumors, alone or in combination with either chemotherapy or radiotherapy. If these results are confirmed in larger trials including a high number of patients, these agents might be very useful in combination with chemotherapy, radiotherapy or other biological targeting agents such as cellular cycle inhibitors or antiangiogenics.

A phase III adjuvant randomised trial of 6 cycles of 5-fluorouracil-epirubicine-cyclophosphamide (FEC100) versus 4 FEC 100 followed by 4 Taxol (FEC-T) in node positive breast cancer patients (Trial B2000).

BACKGROUND: Standard adjuvant chemotherapy regimens for patients with node positive (N+) breast cancer consisted of anthracycline followed by taxane. The European Association for Research in Oncology embarked in 2000 on a phase III trial comparing 6 cycles of FEC100 versus 4 FEC100 followed by 4 Taxol. Primary end-point was disease free survival. Secondary end-points were overall survival, local recurrence free interval, metastases free interval and safety. PATIENTS AND METHODS: Between March 2000 and December 2002, 837 patients were randomised between 6FEC100 for 6 cycles (417patients) or FEC100 for 4 cycles then Taxol 175mg/m(2)/3 weeks for 4 cycles (4FEC100-4T) (420 patients). One thousand patients had been planned initially but the trial was closed earlier due to slow accrual. RESULTS: Hazard ratios (HRs) were 0.99 for disease-free survival (DFS) (95%CI: 0.77-1.26; p=0.91), and 0.85 for overall survival (OS) (95%CI: 0.62-1.15; p=0.29). Nine-year DFS were 62.9% versus 62.5% for 6FEC100 and 4FEC100-4T, respectively. Nine-year OS were 73.9% versus 77% for 6FEC100 and 4FEC100-4T, respectively. Toxicity analyses based on 803 evaluable patients showed that overall grade 3-4 toxicities were similar in both arms (63% versus 58% for 6FEC100 arm and 4FEC100-4T arm, respectively; p=0.16). CONCLUSION: In this trial replacing the last 2 FEC100 cycles of 6FEC100 regimen by 4 Taxol does not lead to a discernable DFS or OS advantage. The lack of a significant difference between the randomised treatment arms may however be due to a lack of power of this trial to detect small, yet clinically worthwhile, treatment benefits.

[Phyllodes tumors and breast sarcomas: a review]. / Tumeurs phyllodes et sarcomes du sein: mise au point.

Phyllodes tumors and sarcomas of the breast are non-epithelial tumors of the breast. Phyllodes tumors are benign tumors, tumors of intermediate malignancy or malignant tumors. The differential diagnosis with a very proliferant fibroadenoma may be difficult. Histological sub-type, type of surgery (definitive or not) and stromal proliferation determine the prognosis. There is a risk of local relapse and distant metastases, in particular to the lung. Surgery (often radical) is the standard treatment. Radiotherapy is recommended in case of high-grade tumor and after conservativetreatment. Breast sarcomas are even rarer. All histological types exist with a predominance of histiofibrocytome type tumors. Grade, involved margins and sometimes tumor necrosis are major prognostics factors. Among the various sub-types, angiosarcoma is characterized by a high risk of occurrence in irradiated fields and by a poor prognosis with a high risk of lung metastases. The treatment is mostly based on mastectomy without lymph node dissection given the exceptional flooding axillary. In some situations, a conservative treatment can be discussed, based on tumor size, grade and volume of the breast. Locoregional radiotherapy is often proposed for tumors over 5 cm and/or of high grade. Systemic chemotherapy is not a standard but should be discussed in the forms at high risk of relapse (like angiosarcoma).

Primary chemotherapy with or without colonic stent for management of irresectable stage IV colorectal cancer.

AIM: Management of patients with irresectable stage IV colorectal cancer is controversial. Since 2000, we have favoured primary chemotherapy with stent insertion in case of obstructive tumor. Our aim was to report the results of this strategy in an unselected consecutive series of patients. PATIENTS AND METHODS: From 2000 to 2007, 68 of 115 consecutive patients admitted with stage IV colorectal cancer were considered irresectable. Data were collected prospectively. Feasibility and outcomes were analysed in an intention to treat basis. RESULTS: Of 68 patients, 37 received the intended primary chemotherapy, with stent insertion in 19, 13 required surgery as initial management and 18 patients received supportive care only. Twelve patients in the primary chemotherapy group developed local complication, including bowel obstruction in 9, successfully managed by stent in 6 of them. In patients requiring surgery at presentation, mortality and morbidity were 31% and 77%, respectively. Overall, 41 patients received chemotherapy, of whom, 6 were downstaged to undergo curative resection. Median survival was 6.7 and 15.4 months for the whole series and patients treated by primary chemotherapy, respectively (p<0.0001). On multivariate analysis, age, CEA level, primary chemotherapy and secondary curative resection were independently associated with survival. CONCLUSION: In unselected patients with irresectable stage IV colorectal cancer, primary chemotherapy with or without stent is feasible in more than 50% of cases and is associated with a low rate of secondary surgery for complicated primary tumor. This strategy may represent the best palliation in these patients for both duration and quality of survival.

Early detection of recurrence by 18FDG-PET in the follow-up of patients with colorectal cancer.

We assessed the potential benefits of including systematic 18fluorodeoxyglucose positron emission tomography (FDG-PET) for detecting tumour recurrence in a prospective randomised trial. Patients (N=130) who had undergone curative therapy were randomised to undergo either conventional (Con) or FDG-PET procedures during follow-up. The two groups were matched at baseline. Recurrence was confirmed histologically. 'Intention-to-treat' analysis revealed a recurrence in 46 patients (25 in the FDG-PET group, and 21 in the Con group; P=0.50), whereas per protocol analysis revealed a recurrence in 44 out of 125 patients (23 and 21, respectively; P=0.60). In another three cases, PET revealed unexpected tumours (one gastric GIST, two primary pulmonary cancers). Three false-positive cases of FDG-PET led to no beneficial procedures (two laparoscopies and one liver MRI that were normal). We failed to identify peritoneal carcinomatosis in two of the patients undergoing FDG-PET. The overall time in detecting a recurrence from the baseline was not significantly different in the two groups. However, recurrences were detected after a shorter time (12.1 vs 15.4 months; P=0.01) in the PET group, in which recurrences were also more frequently (10 vs two patients) cured by surgery (R0). Regular FDG-PET monitoring in the follow up of colorectal cancer patients may permit the earlier detection of recurrence, and influence therapy strategies.