Frequent intragenic rearrangements of DPYD in colorectal tumours.

Dihydropyrimidine dehydrogenase is a crucial enzyme for the degradation of 5-fluorouracil (5FU). DPYD, which encodes dihydropyrimidine dehydrogenase, is prone to acquire genomic rearrangements because of the presence of an intragenic fragile site FRA1E. We evaluated DPYD copy number variations (CNVs) in a prospective series of 242 stage I-III colorectal tumours (including 87 patients receiving 5FU-based treatment). CNVs in one or more exons of DPYD were detected in 27% of tumours (deletions or amplifications of one or more DPYD exons observed in 17% and 10% of cases, respectively). A significant relationship was observed between the DPYD intragenic rearrangement status and dihydropyrimidine dehydrogenase (DPD) mRNA levels (both at the tumour level). The presence of somatic DPYD aberrations was not associated with known prognostic or predictive biomarkers, except for LOH of chromosome 8p. No association was observed between DPYD aberrations and patient survival, suggesting that assessment of somatic DPYD intragenic rearrangement status is not a powerful biomarker to predict the outcome of 5FU-based chemotherapy in patients with colorectal cancer.

Molecular patterns in deficient mismatch repair colorectal tumours: results from a French prospective multicentric biological and genetic study.

BACKGROUND: To test the prognostic value of tumour protein and genetic markers in colorectal cancer (CRC) and examine whether deficient mismatch repair (dMMR) tumours had a distinct profile relative to proficient mismatch repair (pMMR) tumours. METHODS: This prospective multicentric study involved 251 stage I-III CRC patients. Analysed biomarkers were EGFR (binding assay), VEGFA, thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) expressions, MMR status, mutations of KRAS (codons 12-13), BRAF (V600E), PIK3CA (exons 9 and 20), APC (exon 15) and P53 (exons 4-9), CpG island methylation phenotype status, ploidy, S-phase, LOH. RESULTS: The only significant predictor of relapse-free survival (RFS) was tumour staging. Analyses restricted to stage III showed a trend towards a shorter RFS in KRAS-mutated (P=0.005), BRAF wt (P=0.009) and pMMR tumours (P=0.036). Deficient mismatch repair tumours significantly demonstrated higher TS (median 3.1 vs 1.4) and TP (median 5.8 vs 3.5) expression relative to pMMR (P<0.001) and show higher DPD expression (median 14.9 vs 7.9, P=0.027) and EGFR content (median 69 vs 38, P=0.037) relative to pMMR. CONCLUSIONS: Present data suggesting that both TS and DPD are overexpressed in dMMR tumours as compared with pMMR tumours provide a strong rationale that may explain the resistance of dMMR tumours to 5FU-based therapy.

Malignant peritoneal mesothelioma treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: is GLUT1 expression a major prognostic factor? A preliminary study.

PURPOSE: Diffuse malignant peritoneal mesothelioma (DMPM) is a rare primary peritoneal malignancy. Its prognosis has been improved by an aggressive locoregional treatment combining extensive cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Prognostic factors are currently poorly defined for this disease but are essential if treatment is to be standardized. METHODS: Twenty-eight patients with DMPM, who were considered preoperatively to be candidates for CRS and HIPEC between June 1998 and August 2010 at our institution, were selected for this study. Medical records and histopathological features were retrospectively reviewed and 24 clinical, histological, and immunohistochemical parameters were assessed for their association with overall survival by univariate and multivariate analyses. RESULTS: The following factors were significantly associated with overall survival by univariate analysis: predominant histological growth pattern in the epithelioid areas, nuclear grooves in the epithelioid areas, atypical mitoses, and calretinin and GLUT1 expression by immunohistochemistry in the epithelioid areas. Expression of the facilitative glucose transporter protein GLUT1 in the epithelioid areas was the only factor independently associated with overall survival by multivariate analysis. CONCLUSIONS: GLUT1 expression appears to be an indicator of poor prognosis in DMPM. Standard histological classification of DMPM may not be adequate to select patients for aggressive locoregional treatments, such as CRS and HIPEC. Multicenter validation of the prognostic factors identified in this preliminary study is needed to refine patient selection for potential cure.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for persistent and recurrent advanced ovarian carcinoma: a multicenter, prospective study of 246 patients.

BACKGROUND: Epithelial ovarian carcinoma is the main cause of death from gynaecological cancers in the western world. The initial response rate to the frontline therapy is high. However, the prognosis of persistent and recurrent disease remains poor. During the two past decades, a new therapeutic approach to peritoneal carcinomatosis has been developed, combining maximal cytoreductive effort with hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: A retrospective, multicentric study of 246 patients with recurrent or persistent ovarian cancer, treated by cytoreductive surgery and HIPEC in two French centers between 1991 and 2008, was performed. RESULTS: An optimal cytoreductive surgery was possible in 92.2 % of patients. Mortality and morbidity rates were 0.37 % and 11.6 %, respectively. The overall median survival was 48.9 months. There was no significant difference in overall survival in patients with persistent or recurrent disease. In multivariate analysis, performance status was a significant prognostic factor in patients with extensive peritoneal carcinomatosis (peritoneal cancer index >10). CONCLUSIONS: Salvage therapy combining optimal cytoreductive surgery and HIPEC is feasible and may achieve long-term survival in highly selected patients with recurrent ovarian carcinoma, including those with platinum resistant disease, with acceptable morbidity.

Intraperitoneal free cancer cells in non-gynaecological adenocarcinomas: a reproducibility study.

OBJECTIVE: In recent years, therapeutic approaches including cytoreductive surgery followed by intraperitoneal chemotherapy have proven effective in peritoneal carcinomatosis of colorectal origin. If cytology is to be used to include patients in aggressive treatment regimens, it is necessary to evaluate its performance, particularly in terms of specificity. The aim of this study was to assess interobserver agreement for the detection of intraperitoneal free cancer cells (IFCCs) in patients with non-gynaecological adenocarcinomas. METHODS: Over a 5-year period, 1223 patients were recruited in 19 French surgery departments. Peritoneal samples were examined in 14 dispersed pathology laboratories. Giemsa-stained slides were sent to a control reader blind to the previous diagnosis. Discordant cases, concordant positive results and a random selection of negative concordant cases were reviewed by a panel of seven cytopathologists. The 'final diagnosis' was that of the consensus meetings but took into account locally-processed slides. RESULTS: Gathering dubious cases with negative results, a 95.6% concordance was achieved between local readers and the control reader. IFCCs were ascertained by the panel in 85 cases (7.0%). Eight of 873 colorectal cancers cases viewed locally were falsely positive (0.9%). Radiotherapy and neoadjuvant therapy had no impact on the false-positive rate as assessed by final validation by the panel (P > 0.05). Samples initially considered as dubious were reclassified as negative by the panel in 24 of 25 cases (96.0%). CONCLUSIONS: The panel consensus allowed reclassification of most dubious/equivocal peritoneal cytology cases, whereas clearcut distinction between benign and malignant cases was correctly achieved in almost all cases.

Epidermal growth factor receptor (EGFR) status and K-Ras mutations in colorectal cancer.

BACKGROUND: In advanced colorectal cancer, K-Ras somatic mutations predict resistance to mAbs targeting epidermal growth factor receptor (EGFR). Relationships between K-Ras mutations and EGFR status have not been examined so far. We analyzed relationships between K-Ras mutations and EGFR tumoral status based on EGFR germinal polymorphisms, gene copy number and expression. METHODS: Eighty colorectal tumors (stage 0-IV) and 39 normal mucosas were analyzed. K-Ras mutations at codons 12 and 13 were detected by a sensitive enrichment double PCR-restriction fragment length polymorphism (RFLP) assay. EGFR gene polymorphisms at positions -216G>T, -191C>A and 497Arg>Lys were analyzed (PCR-RFLP), along with CA repeat polymorphism in intron 1 (fluorescent genotyping) and EGFR gene copy number (PCR amplification). EGFR expression was quantified by Scatchard binding assay. RESULTS: The number of EGFR high-affinity sites, dissociation constant (Kd), gene copy number, intron 1, -216G>T, -191C>A or 497Lys>Arg genotypes was not different between K-Ras-mutated or K-Ras-non-mutated tumors. No relationship was observed between any of the analyzed EGFR genotypes and EGFR expression. EGFR expression was not related to gene copy number. EGFR gene copy number in tumor and normal tissue was not correlated. The mean value of the tumor/normal mucosa gene copy number ratio was 1.16. CONCLUSIONS: Present data clearly show that EGFR status is independent of K-Ras mutations in colorectal tumors.

[Hyperthermic intraperitoneal chemotherapy for the treatment of peritoneal carcinomatosis arising from gastric cancer]. / Chimiohyperthermie intrapéritonéale dans le traitement des carcinoses péritonéales d'origine gastrique.

Since 20 years, treatment of peritoneal carcinomatosis has been developed in expert centers. Cytoreductive surgery and perioperative intraperitoneal chemotherapy, especially hyperthermic intraperitoneal chemotherapy, was assessed by many nonrandomised studies for the treatment of peritoneal carcinomatosis arising from gastric cancer. Results described increased survival, especially for the most favourable cases: limited carcinomatosis and complete cytoreductive surgery. A strict selection of the patients is necessary because of the important morbidity of those treatments. Only patients with good general health, able to tolerate a threatening treatment, with possible complete cytoreduction, may benefit from those treatments. Many japanese studies had demonstrated the efficacy of hyperthermic intraperitoneal chemotherapy for the prophylactic treatment of carcinomatosis in advanced-gastric cancers. These results have to be confirmed by european randomised studies.

[Peritoneal mesothelioma: treatment with cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy]. / Mésothéliome péritonéal: traitement par l'association chirurgie de cytoréduction et chimiothérapie hyperthermique intrapéritonéale.

UNLABELLED: Diffuse malignant peritoneal mesothelioma is a rare and lethal disease. Locoregional treatments combining cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) seem to improve prognosis. METHODS: Cytoreductive surgery and HIPEC was performed in 22 patients at the Centre Hospitalier-Lyon Sud between 1989 and 2006. A retrospective analysis of survival was carried out to assess clinical and histological prognostic factors. RESULTS: Nineteen patients with diffuse malignant peritoneal mesothelioma were included (16 epithelial, 3 biphasic and 3 multicystic forms). Sixteen patients presented stage 3 or 4 peritoneal mesothelioma according to the Gilly classification. Optimal cytoreductive surgery was performed for 11 patients (complete macroscopic resection or residual tumor nodules less than 2.5mm). No post-operative deaths occurred but 9 patients (47%) presented grade III or IV post-operative complications. The overall median survival was 36.9 months; completeness of cytoreduction was the only significant prognostic factor. CONCLUSION: Cytoreductive surgery combined with HIPEC may improve the length of survival for patients with diffuse malignant peritoneal mesothelioma; such patients should be treated in specialized centers.

The RENAPE observational registry: rationale and framework of the rare peritoneal tumors French patient registry.

BACKGROUND: Rare peritoneal cancers represent complex clinical situations requiring a specific and multidisciplinary management. Because of their rarity, lack of awareness and knowledge often leads to diagnostic delays and misdiagnosis. And patients are not systematically referred to expert centers as they should be. Clinicians and researchers also face unique challenges with these rare cancers, because it is hard to conduct adequately powered, controlled trials in such small patient population. This is how an observational patient registry constitutes a key instrument for the development of epidemiological and clinical research in the field of these rare cancers. It is the appropriate tool to pool scarce data for epidemiological research and to assess the impact of diagnostic and therapeutic strategies. We aimed to provide the outlines and the framework of the RENAPE observational registry and share our experience in the establishment of a national patient registry. RESULTS: The RENAPE observational registry has been launched in 2010 thanks to institutional supports. It concerns only patients with a histological diagnosis confirming a peritoneal surface malignancy. A web secured clinical database has been implemented based on data management procedures according to the principles of international recommendations and regulatory statements. A virtual tumor bank is linked in order to the conduct translational studies. Specialized working groups have been established to continuously upgrade and evolve the common clinical and histological data elements following the last classifications and clinical practices. They contribute also to standardize clinical assessment and homogenize practices. CONCLUSIONS: The RENAPE Registry may improve awareness and understanding of the rare peritoneal tumors into the incidence, prevalence, recurrence, survival and mortality rates, as well as treatment practices thereby enabling therapeutic intervention to be evaluated and ultimately optimized. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02834169.

Immunohistochemical evaluation of two antibodies against PD-L1 and prognostic significance of PD-L1 expression in epithelioid peritoneal malignant mesothelioma: A RENAPE study.

BACKGROUND: Epithelioid peritoneal malignant mesothelioma (EPMM) is the most common subtype of this aggressive tumor. We compared two antibodies against PD-L1, a recent theranostic biomarker, and evaluated the prognostic value of PD-L1 expression by mesothelial and immune cells in EPMM. METHODS: Immunohistochemistry was performed on 45 EPMM. Clinical and pathological data were extracted from the RENAPE database. Using E1L3N and SP142 clones, inter-observer agreement, PD-L1 expression by mesothelial and immune cells and inter-antibody agreement were evaluated. The prognostic relevance of PD-L1 expression was evaluated in 39 EPMM by univariate and multivariate analysis of overall survival (OS) and progression-free survival (PFS). RESULTS: Inter-observer agreement on E1L3N immunostaining was moderate for mesothelial and immune cells, and fair for mesothelial and poor for immune cells using SP142. Using E1L3N, 31.1% of mesothelial and 15.6% of immune cells expressed PD-L1, and 22.2% of mesothelial and 26.7% of immune cells using SP142. Inter-antibody agreement was moderate. In most positive cases, 1-5% of tumor cells were positive. Using E1L3N, PD-L1 expression by lymphocytes was associated with better OS and PFS by both univariate and multivariate analysis. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy predicted better prognosis than other treatments. Solid subtype was an independent prognostic factor for worse OS. CONCLUSION: E1L3N appeared easier to use than SP142 to evaluate PD-L1 expression. A minority of EPMM expressed PD-L1, and only a few cells were positive. PD-L1 expression by immune cells evaluated with E1L3N was an independent prognostic factor in EPMM.

Phase II studies: International registry of colorectal carcinomatosis.

Peritoneal carcinomatosis (PC) is a common manifestation of colorectal cancer and has traditionally been regarded as a terminal disease with a short median survival. Over the last decade, a new local-regional therapeutic approach combining cytoreductive surgery with perioperative intraperitoneal chemotherapy has evolved and promising survival results were reported in large phase II studies. A retrospective multicentric study of 506 patients from 28 institutions was performed to evaluate the international experience with this combined treatment and to identify the principal prognostic indicators. All patients had cytoreductive surgery and perioperative intraperitoneal chemotherapy (intraperitoneal chemohyperthermia and/or immediate postoperative intraperitoneal chemotherapy) within the 7 days following surgery. The morbidity and mortality rates were 22.9% and 4%, respectively. Patients in whom cytoreductive surgery was complete had a median survival of 32.4 months compared to 8.4 months for patients in whom complete cytoreductive surgery was not possible (p < 0.001). Positive independent prognostic indicators by multivariate analysis were complete cytoreduction, treatment by a second procedure, limited extent of PC, age less than 65 years, and use of adjuvant chemotherapy. The use of neoadjuvant chemotherapy, lymph node involvement, presence of liver metastasis and poor histological differentiation were negative independent prognostic indicators. The therapeutic approach combining cytoreductive surgery with perioperative intraperitoneal chemotherapy achieved long-term survival in carefully selected group of patients with PC from colorectal origin and offer a chance for cure or palliation in this condition. Further collaboration between peritoneal surface malignancy treatment centres are needed in order to standardize indications, intraperitoneal chemotherapy and peritonectomy techniques.

Quantitative prognostic indices in peritoneal carcinomatosis.

Five different descriptions quantitating peritoneal carcinomatosis are available: the Lyon staging system, the Peritoneal Cancer Index (PCI), the Japanese Research Society for Gastric Cancer carcinomatosis staging (JRSGS), the Dutch simplified peritoneal carcinomatosis assessment and the Completeness of Cytoreduction Score (CCR). These five staging systems are described and discussed. Combinations of these to achieve a complete description of peritoneal lesions prior to and following treatment assist in a correct prognostic assessment for these patients and in a selection of treatment options.

MRI evaluation of bulky tumor masses in the mesentery and bladder involvement in peritoneal carcinomatosis.

AIM: Peritonectomy procedures with intraperitoneal chemohyperthermia are an effective but costly treatment for peritoneal carcinomatosis (PC). Consequently a proper selection of patients is necessary. We evaluated the benefit of MRI prior to surgery, in the detection of two of the main surgery contraindications: bulky mesenteric tumors and bladder implants. METHODS: Three experts retrospectively reviewed abdominal and pelvic MRI from 19 cases of surgically proved PC (ovary: 7; colorectal: 7; gastric: 2; pseudomyxoma peritonei: 2; appendix: 1). RESULTS: Mesenteric tumors were always identified as hypersignal masses on axial and coronal fat suppression gadolinium-enhanced T1 images (n=3). Three out of five bladder implants were detected. The two cases of bladder implants that were not detected on MRI were missed because the bladder was not filled. The best sequence for the detection of bladder involvement was axial T2-weighted images with bladder filling. CONCLUSIONS: Evaluating the preoperative resectability of PC is crucial for patient management. MRI seems to reliably detect bulky mesenteric tumors and bladder implants on condition the bladder is filled and appropriate sequences are used.

Peritoneal carcinomatosis in digestive cancers: cytoreductive surgery combined with intraperitoneal chemohyperthermia. The experience in Centre Hospitalier et Universitaire Lyon Sud (CHLS).

Intraperitoneal chemohyperthermia (IPCH) with Cytoreductive surgery (CS) has been used in Centre Hospitalier et Universitaire Lyon Sud (CHLS) since 1989. Up to 2005, 420 patients were involved in different phase II studies for peritoneal carcinomatosis (PC) from colorectal, gastric or ovarian origin, as well as for pseudomyxoma peritonei and peritoneal mesothelioma. Encouraging results were achieved in case of optimal PC cytoreduction. The CHLS experience, as well as the Dutch randomized trial and the international registration, underline the advantage of such an aggressive combined therapy for selected patients in experienced multidisciplinary centers.

[Therapeutic innovations in the management of peritoneal carcinomatosis from digestive origin: cytoreductive surgery and intraperitoneal chemotherapy]. / Nouveautés thérapeutiques dans la prise en charge des carcinoses péritonéales d'origine digestive: chirurgie de cytoréduction et chimiothérapie intrapéritonéale.

PURPOSE: Peritoneal carcinomatosis and particularly those from digestive origin has long been considered as an automatically terminal disease in abdominal cancer patients. CURRENT KNOWLEDGE AND KEY POINTS: Over the past decade, new locoregional treatments combining cytoreductive surgery, peritonectomy procedures with perioperative intraperitoneal chemotherapy (with or without hyperthermia) have been developed by specialized teams. Because of its high but acceptable mortality and morbidity, this aggressive but comprehensive therapeutic strategy requires accurate and strict patient's selection into multidisciplinary and specialized teams. It may allow prolonged survival and cure for patients with pseudomyxoma peritonei, peritoneal mesothelioma, carcinomatosis from colorectal or gastric cancer. Qualitative and quantitative prognostic indicators are needed to assess a patient's eligibility, including tumor histopathology, assessment of carcinomatosis extent or completeness of cytoreduction which appears to be the most important. PERSPECTIVES: Combination of cytoreductive surgery with perioperative intraperitoneal chemotherapy appears to be an adapted therapeutic approach for patients strictly selected, with peritoneal carcinomatosis. Phase III studies are now needed for the validation and the evaluation of the type of intraperitoneal chemotherapy.

Diffuse malignant peritoneal mesothelioma: Evaluation of systemic chemotherapy with comprehensive treatment through the RENAPE Database: Multi-Institutional Retrospective Study.

PURPOSE: Diffuse malignant peritoneal mesothelioma (DMPM) is a severe disease with mainly locoregional evolution. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is the reported treatment with the longest survival. The aim of this study was to evaluate the impact of perioperative systemic chemotherapy strategies on survival and postoperative outcomes in patients with DMPM treated with curative intent with CRS-HIPEC, using a multi-institutional database: the French RENAPE network. PATIENTS AND METHODS: From 1991 to 2014, 126 DMPM patients underwent CRS-HIPEC at 20 tertiary centres. The population was divided into four groups according to perioperative treatment: only neoadjuvant chemotherapy (NA), only adjuvant chemotherapy (ADJ), perioperative chemotherapy (PO) and no chemotherapy before or after CRS-HIPEC (NoC). RESULTS: All groups (NA: n = 42; ADJ: n = 16; PO: n = 16; NoC: n = 48) were comparable regarding clinicopathological data and main DMPM prognostic factors. After a median follow-up of 61 months, the 5-year overall survival (OS) was 40%, 67%, 62% and 56% in NA, ADJ, PO and NoC groups, respectively (P = 0.049). Major complications occurred for 41%, 45%, 35% and 41% of patients from NA, ADJ, PO and NoC groups, respectively (P = 0.299). In multivariate analysis, NA was independently associated with worse OS (hazard ratio, 2.30; 95% confidence interval, 1.07-4.94; P = 0.033). CONCLUSION: This retrospective study suggests that adjuvant chemotherapy may delay recurrence and improve survival and that NA may impact negatively the survival for patients with DMPM who underwent CRS-HIPEC with curative intent. Upfront CRS and HIPEC should be considered when achievable, waiting for stronger level of scientific evidence.

Surgery combined with peritonectomy procedures and intraperitoneal chemohyperthermia in abdominal cancers with peritoneal carcinomatosis: a phase II study.

PURPOSE: To evaluate the tolerance of peritonectomy procedures (PP) combined with intraperitoneal chemohyperthermia (IPCH) in patients with peritoneal carcinomatosis (PC), a phase II study was carried out from January 1998 to September 2001. PATIENTS AND METHODS: Fifty-six patients (35 females, mean age 49.3) were included for PC from colorectal cancer (26 patients), ovarian cancer (seven patients), gastric cancer (six patients), peritoneal mesothelioma (five patients), pseudomyxoma peritonei (seven patients), and miscellaneous reasons (five patients). Surgeries were performed mainly on advanced patients (40 patients stages 3 and 4 and 16 patients stages 2 and 1) and were synchronous in 36 patients. All patients underwent surgical resection of their primary tumor with PP and IPCH (with mitomycin C, cisplatinum, or both) with a closed sterile circuit and inflow temperatures ranging from 46 degrees to 48 degrees C. Three patients were included twice. RESULTS: A macroscopic complete resection was performed in 27 cases. The mortality and morbidity rates were one of 56 and 16 of 56, respectively. The 2-year survival rate was 79.0% for patients with macroscopic complete resection and 44.7% for patients without macroscopic complete resection (P =.001). For the patients included twice, two are alive without evidence of disease, 54 and 47 months after the first procedure. CONCLUSION: IPCH and PP are able to achieve unexpected long-term survival in patients with bulky PC. However, one must be careful when selecting the patients for such an aggressive treatment, as morbidity rate remains high even for an experienced team.

[Pseudomyxoma peritonei: new concept and new therapeutic approach]. / Pseudomyxome péritonéal ou maladie gélatineuse du péritoine: nouveaux concepts et nouvelle prise en charge thérapeutique.

Pseudomyxoma peritonei is a rare disease, usually diagnosed after the discover of "jelly belly" by laparotomy. With the progress of immunohistochemistry, most authors now acknowledge the appendix to be the principal origin of this disease. Pseudomyxoma peritonei need to considered as border line malignant disease because of its inevitable persistence and progression without adapted therapeutic approach: cytoreductive surgery combined with perioperative intraperitoneal chemotherapy (intraperitoneal chemohyperthermia and/or immediate postoperative intraperitoneal chemotherapy) into specialized centres. The principal prognostic factors are the prior surgical history, the completeness of cytoreduction and especially the histopathologic grade.

Intra-operative electron radiotherapy as a conservative treatment for infiltrating bladder cancer.

The intent of this feasibility study was to evaluate the use of intra-operative electron radiotherapy (IOERT), after transurethral resection (TUR), combined with external beam radiation with concurrent chemotherapy for the conservative treatment of infiltrating bladder cancer. From November 1988 to June 1998, 27 patients with histologically proven non-metastatic infiltrating bladder cancer were included in this protocol. The treatment consisted of: TUR, external beam irradiation (x18 MV:48 Grays (Gy)/24 fractions/5 weeks), with concurrent chemotherapy (cisplatin 30 mg/day for 3 days-two cycles during irradiation), followed by control cystoscopy and cystotomy with IOERT (e 9 MeV:15 Gy). 14 patients received two cycles of neoadjuvant methotrexate, vinblastine and cisplatin (MVC) and folinic acid chemotherapy. Patients were evaluated for toxicity, local control and survival. The 5-year overall and cystectomy-free survival rates were 53.3% +/-11.1% and 48.1%+/-11.4%, respectively. 4 patients developed infiltrating intravesicular recurrence (3 were treated by salvage cystectomy), and an additional patient developed a superficial recurrence. 2 patients subsequently developed regional recurrence in pelvic nodes and 10 patients were found to have distant metastases. The protocol was found to be feasible and associated with acceptable toxicity. Early and late toxicities consisted of 3 cases of bladder mucosal necrosis or ureteral stenosis which resolved with medical management. These preliminary results indicate that IOERT combined with TUR and neoadjuvant external beam radiation with concurrent chemotherapy is feasible. It could be considered as an alternative therapy for infiltrating carcinoma of the bladder, especially in patients unfit for radical surgery, and is well adapted to treat lesions of the fixed portion of the bladder.

Recurrences of rectal cancers: results of a multimodal approach with intraoperative radiation therapy. French Group of IORT. Intraoperative Radiation Therapy.

PURPOSE: Prognosis of recurrent rectal cancer remains poor, mainly because of the difficulties of achieving a satisfactory local control. Intraoperative radiation therapy (IORT) allows for the delivery of a complementary single dose to the tumor residues or to the tumor bed and could be useful jn a multimodal treatment. In an attempt to evaluate this interest, a retrospective analysis of patients treated with IORT in six French hospitals has been performed. METHODS AND MATERIALS: Data have been collected in 73 patients (41 men), with a mean age of 62 years, treated with IORT. Initial rectal tumors were large (mean diameter: 45 mm), partially or totally fixed to the contiguous structures in 39%, and with nodal involvement in 50% of the cases. Initial surgery had been a sphincter-sparing surgery in 67%; external radiation therapy had been delivered in 52%, and a chemotherapy had been given in 10% of the patients. Recurrences were isolated (without metastases) in 86%, and were posterior or posterolateral in 55% of the cases. Surgery allowed for a complete macroscopical resection in 57%, a partial resection with gross residual disease in 29%, and no resection in 14% of the recurrences. Intraoperative radiation therapy was delivered in a dose of 10 to 25 Gy (mean 18.5) through localizators of a mean diameter of 75 mm (60 to 110). External radiation therapy, either preoperative or postoperatively was given to 30 patients without prior radiation therapy. Ten patients received additional chemotherapy with 5-fluorouracil. RESULTS: Four postoperative deaths occurred. Postoperative morbidity occurred in 16 patients and some complications were probably related to the IORT procedure. Four long-term complications were observed. Overall actuarial survival occurred in 72.4% of the patients at 1 year, in 44.6% at 2 years, and in 30.6% at 3 years. Twenty-one local failures have been observed. Actuarial local control occurred in 71.3% of the patients at 1 year, 47.7% at 2 years, and 31.3% at 3 years. CONCLUSION: Intraoperative radiation therapy is a complementary treatment for recurrences of rectal cancer. It provides encouraging results, particularly in some selected situations, when patients have not previously been treated with external radiation therapy. Further studies of multimodal treatments are necessary.