Marc Pocard

Résections hépatiques pour métastases de cancer du sein : résultats et facteurs pronostiques (65 cas)

Study aim: To report results of liver resections for breast cancer liver metastasis (BCLM) and to evaluate the rate of survival and the prognostic factors. Patients and method: Between 1988 and 1999, 69 patients were operated on for BCLM and 65 who had liver resection were analyzed. The selection criteria for surgery were: normal performance status and liver function test; radiological objective response to chemotherapy (and/or hormonotherapy); in cases of non-isolated BCLM, complete response of associated metastatic site (usually bone) and no brain metastases. The mean age of the 65 patients was 47 (30–70) years. BCLM was diagnosed an average of 60 (0–205) months after the initial cancer. The BCLM was more frequently solitary (n = 44). The mean diameter was 3.8 (0–12) cm. The mean number of cycles of chemotherapy before surgery was 7.5 (3–24). Liver resections included major hepatectomy (n = 31) : right n = 19, extended left n = 4, left n = 8, minor hepatectomy (n = 25) and limited resection (n = 9). Results: There was no postoperative mortality. The 18% morbidity rate included a majority of pleural effusions with two reoperations. The median follow-up was 41 months (6–100 months). The survival rate after surgery was 90% at 1 year, 71% at 3 and 46% at 4 years. Thirteen patients are alive at 4 years. The 36-month survival rate differed according to the time to onset of BCLM: 55% before versus 86% after 48 months (p = 0.01). The other studied factors were not statistically associated with survival. The recurrence rate in the remaining liver at 36 months differed according to the lymph node status of the initial breast cancer: 40% for N0-N1 versus 81% for N1b-N2 (p = 0.01) and according to the type of liver resection: 45% for minor liver resection versus 73% for major (p = 0.02). Conclusion: Adjuvant liver surgery should be included in multicenter treatment protocols for medically-controlled breast cancer liver metastasis.

Assessing the effectiveness of mesorectal excision in rectal cancer: Prognostic value of the number of lymph nodes found in resected specimens

PURPOSE: The aim of this study was to determine whether the number of involved or uninvolved lymph nodes in resected specimens can be used to predict the effectiveness of surgical resection for rectal cancer. METHODS: Local recurrence and survival rates for 118 patients undergoing curative resection for rectal carcinoma, without adjuvant therapy, were retrospectively studied. RESULTS: Mean follow-up was 62±37 months. Mean number of involved or uninvolved lymph nodes per resected specimen was 12±7. Overall local recurrence rate was 15.2 percent. In patients without involved lymph nodes (N0 patients) and with T1 or T2 tumors, the local recurrence rate ranged from 0 to 8 percent (not significant), depending on the number of lymph nodes on the specimen. In patients without involved lymph nodes and those with T3 tumors, the actuarial survival rate at ten years was significantly lower (P<0.05), and the local recurrence rate was higher (P<0.02) in patients with fewer than ten lymph nodes than in those with more than ten nodes. In patients with involved lymph nodes, the mean number of nodes on the resected specimen correlated closely with the mean number involved by the tumor. CONCLUSION: The assessment of the effectiveness of rectal excision for cancer is in part helped by the number of involved or uninvolved lymph nodes found on the resected specimen. This is of particular interest in patients without involved lymph nodes and those having infiltrating T3 tumors, for whom the long-term survival and local recurrence rates were significantly better when more than ten lymph nodes were present. On the other hand, when fewer than ten nodes were found, whatever the cause, adjuvant radiotherapy had to be considered, because of the high risk of local failure rate.

Single alteration of p53 or E-cadherin genes can alter the surgical resection benefit in an experimental model of colon cancer.

PURPOSE:p53 and E-cadherin mutations are associated with a high risk of metastatic potential and local recurrence after colorectal surgery. LoVo, a human colon cancer cell line expressing a wild-typep53 and a normal E-cadherin, was studied. Clone LoVo-XC17 was obtained from LoVo cells transfected with a vector bearing ap53 273his mutation. Clone LoVo-92R4 was obtained from LoVo by culture cells with an E-cadherin down-regulation. LoVo, LoVo-XC17, and LoVo-92R4 were studied forin vivo behavior in a surgical intracolonic graft model. METHODS: Ten nude mice were used per cell line. A colonic tumor was obtained by tumor implantation into the cecal wall. The cecal tumor was resected at Day 15; at this time the volumes of the different tumors were similar. RESULTS: Surgical resection of the LoVo tumor led to 100 percent disease-free animals at one month. Surgical resection of mice grafted with the LoVo-XC17 line did not cure any mice (0/10;P = 0.001). Mice had local recurrences (10/10), mesenteric lymph node metastases (9/10), liver metastases (2/10), and peritoneal carcinomatosis (8/10). Surgical resection of LoVo-92R4 tumors led to cures in 30 percent (3/10), whereas 70 percent had isolated mesenteric lymph node metastases (7/10;P = 0.003). CONCLUSION: In this model surgical tumor resection was consistently effective for colonic tumors with functionalp53 and E-cadherin, it was consistently ineffective with tumors displaying a mutatedp53, and it was partially effective with E-cadherin-deficient tumors. This study shows that the alteration of a single gene can be associated with a profound alteration of surgical resection benefit.

Induction of invasion in vivo of α-catenin-positive HCT-8 human colon-cancer cells

Variants from the HCT‐8 colon‐cancer cell line were implanted s.c. and orthotopically into nude mice. Well‐differentiated HCT‐8/E11 and HCT‐8/E41 cells have a functional E‐cadherin–catenin complex and are non‐invasive into pre‐cultured chick heart fragments in vitro, whereas poorly differentiated HCT‐8/E11R1 cells are deficient in α‐catenin protein and invasive in heart fragments. We investigated whether these differences were maintained in vivo. In contrast with in vitro observations, in vivo the 3 HCT‐8 variants behaved very similarly and all formed undifferentiated tumors. The in vivo invasive behavior of HCT‐8 cells was site‐dependently modulated: HCT‐8 cells invaded when injected into the cecum but not when injected s.c. Metastases to the liver or lungs were not observed. The composition and expression of the E‐cadherin–catenin complex in nude mouse HCT‐8 tumors was the same as in HCT‐8 cells in culture on solid substrate. We conclude that the in vivo invasive behavior of HCT‐8 cells is not determined by whether α‐catenin is expressed or not but by as yet unidentified host factors. Int. J. Cancer 88:751–758, 2000.

Functional and molecular characterization of the epithelioid to round transition in human colorectal cancer LoVo cells

In subclones of the human colon cancer LoVo cell line, there is a reproducible spontaneous transition from an epithelioid (E) to a round (R) morphotype. The E to R transition is associated with increased cell growth, absence of E-cadherin-dependent compaction in a slow aggregation assay, loss of contact inhibition of motility and directional migration in a wound filling motility assay. Furthermore, none of the E subclones from LoVo was invasive into chick heart fragments. This is in contrast to the R subclones that were either nonadherent or adherent and invasive. Macroarray analysis demonstrated transcriptional downregulation of plakoglobin in R type LoVo cells and this was confirmed at the level of the mRNA by quantitative RT–PCR. Western blotting showed lower expression of all components of the E-cadherin/catenin complex in R subclones. Interestingly, treatment of R subclones with the demethylating agent 5-aza-2′-deoxycytidine resulted in restoration of the E morphotype, higher expression of E-cadherin, but not plakoglobin mRNA, and higher expression of E-cadherin and plakoglobin at the protein level.

Experimental pharmacokinetics evaluation of chemotherapy delivery by PIPAC for colon cancer: first evidence for efficacy

Abstract Background Pressurised intraperitoneal aerosol chemotherapy (PIPAC) is a novel technique of intraperitoneal chemotherapy devoted to unresectable peritoneal metastasis (PM). The first results obtained with PIPAC in preclinical models of colon cancer are presented here. Methods In vitro, PIPAC (normotherm oxaliplatin at 0.028 mg/mL for 10 min at 1.6 bars) and HIPEC (hyperthermic oxaliplatin at 0.14 mg/mL for 30 min) were compared using the apoptosis and proliferation assay on two colon cancer cell lines (LS 174 and CT 26); ex vivo tumours from an orthotopic mouse model of PM and non-tumour peritoneum from a patient treated according to the two modalities were assessed, investigating the percentage of penetration of oxaliplatin in the tumour and oxaliplatin concentration below the peritoneum. In vivo, a mouse model of colon (CT 26) PM was used to create a PIPAC model (same modalities) for the comparison of IV oxaliplatin (at 5 mg/mL). Results In vitro, the rate of apoptotic and proliferative cells as well as the level of oxaliplatin penetration in tumour nodes was higher in PIPAC groups with less systemic passage through the peritoneum. In vivo, in the colon PM mouse model, the peritoneal cancer index (PCI) was decreased to the same level using PIPAC or IV oxaliplatin. Systemic passage was lower in the PIPAC group. Conclusions PIPAC with low-dose oxaliplatin is efficient in both in vitro and in vivo models of colon PM. Lower concentrations of chemotherapy are needed in PIPAC to achieve the same effect as IV chemotherapy on PCI. With a very low systemic oxaliplatin passage, this technique of drug delivery seems to be as effective as IV delivery for PM control.

Randomized controlled trials evaluating cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in prevention and therapy of peritoneal metastasis: a systematic review

Abstract Background Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is increasingly used to prevent or treat peritoneal metastases (PM) in selected indications. The objective of this article was to review published, recruiting or planned randomized controlled trials (RCTs) evaluating CRS and HIPEC versus standard of care. Comparator was systemic chemotherapy and/or CRS alone. Content Systematic review according to PRISMA guidelines. Electronic searches for published RCT using PubMed (from 1980 to November 2016) and for ongoing RCT in the United States and European clinical databases (until November 2016). Current update on ongoing trials from the 10th PSOGI meeting in November 2016 in Washington DC. Fourteen RCTs on CRS and HIPEC were excluded for various reasons. Summary Thirty-eight trials designed for randomizing 7,303 patients were identified: 11 in colorectal cancer (6 for prevention of PM, n=1,107 patients; 5 for therapy, n=781), 10 in ovarian cancer (5 in frontline therapy, n=438 patients; 5 for treating recurrence, n=1,062) and 17 in gastric cancer (14 for prevention of PM, n=3,659 patients; 3 for therapy, n=256). Results of 9 RCTs have been published: 1 in colorectal cancer (105 patients), 1 in ovarian cancer (130 patients) and 7 in gastric cancer (together 669 patients). Five RCTs have completed recruitment and follow-up is ongoing. There is a clear trend in recent trial design from therapeutic to preventive indications. Outlook The number of published RCT evaluating CRS and HIPEC in prevention or therapy of PM is relatively small. There is some evidence that CRS and HIPEC improve survival in recurrent colorectal origin, evidence in ovarian and gastric cancer remains debated. A large number of studies is ongoing that might deliver additional evidence. Trial design and interpretation of results remain difficult because of multiple methodological challenges.

PIPAC EstoK 01: Pressurized IntraPeritoneal Aerosol Chemotherapy with cisplatin and doxorubicin (PIPAC C/D) in gastric peritoneal metastasis: a randomized and multicenter phase II study

Abstract Background Peritoneal metastasis (PM) from gastric cancer often remains undiagnosed until it reaches an advanced stage. Despite curative management combining perioperative systemic chemotherapy, cytoreductive surgery (CRS), and hyperthermic intraperitoneal chemotherapy (HIPEC), treated patients’ 5 year survival rate remains under 20 % when patients are carefully selected. Palliative intravenous chemotherapy in patients with non-resectable cancer is frequently associated with poor long-term benefit and an estimated survival time below 1 year. Recently, two retrospectives studies reported that Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) improves patients’ overall survival without impairing their quality of life (QoL). This promising result needs however to be studied on large randomized clinical trial to validate the effect of PIPAC on survival and QoL of patients with gastric PM. Methods PIPAC EstoK 01 is a prospective, open, randomized multicenter phase II clinical study with two arms that aims at evaluating the effects of PIPAC with doxorubicin and cisplatin on patients with PM of gastric cancer with peritoneal cancer index (PCI)>8, treated with systemic chemotherapy between two PIPAC procedures. Patients were randomized at the end of explorative laparoscopy and after signing a written consent. Patients received in the first experimental arm a treatment associating PIPAC and systemic chemotherapy (1 PIPAC then 2 IV Chemo) and systemic chemotherapy only in the control arm. Primary endpoint was progression-free survival from the date of surgery to the date of death, or to the end of the 5 year follow-up. Secondary endpoint was 2 year overall survival, morbidity, QoL and secondary resectability rate. The number of patients randomized was calculated to be 94. Trial registration Retrospectively registered.

Actualités dans la prise en charge chirurgicale des cancers du côlon

La prise en charge des cancers du colon continue de progresser, la generalisation d’une vraie prise en charge multidisciplinaire constitue le progres le plus marquant, repondant aux objectifs du plan cancer. En chirurgie, si les grandes regles carcinologiques sont toujours indispensables (resection « en-bloc », resection R0, curage lymphatique, controle des hemorragies, la cœlioscopie actuellement validee comme voie d’abord, est devenue indiscutable pour les petites tumeurs. L’autre grande evolution, quoique moins perceptible est l’evaluation des pratiques et la determination de criteres de qualite qui a terme vont structurer la prise en charge chirurgicale de ces cancers.

Maladie de Crohn et cancer

Depuis plusieurs annees, il a ete demontre que la maladie de Crohn (MC) est associee a un risque eleve de cancer colorectal. De plus, d’autres tumeurs sont egalement plus frequentes en cas de MC, comme l’adenocarcinome de l’intestin grele ou la survenue de lymphome. Il n’existe pas actuellement d’argument pour lier ce surrisque de lymphome et le traitement medical de la MC. Le suivi endoscopique des patients est un element majeur pour diminuer la mortalite par cancer dans les MC. La carcinogenese est ici specifique et ne passe pas par les adenomes. A l’inverse, la dysplasie fait le lit du cancer et sa prise en charge doit etre active. Il existe des indications de colectomie en cas de dysplasie de haut grade, confirmee par une seconde endoscopie et une relecture par un second pathologiste. De la meme facon, les masses ou lesions associees a une dysplasie doivent conduire a la colectomie car leur exerese endoscopique laisse en place la dysplasie environnante. Il n’existe pas de chirurgie preventive ni prophylactique, mais apres 20 ans de colite diffuse, la probabilite de trouver une dysplasie de haut grade augmente de facon tres importante, d’autant que des stenoses interdisent de realiser des biopsies en amont. Le pronostic est identique a celui des adenocarcinomes sporadiques, tout comme les indications de traitement associe par radiotherapie et/ou chimiotherapie. Le suivi endoscopique en cas de colectomie segmentaire doit etre regulier.