Gaetan Des Guetz

Comparison of FDG-PET/CT and MR with diffusion-weighted imaging for assessing peritoneal carcinomatosis from gastrointestinal malignancy

ObjectivesTo assess the accuracy of FDG-PET/CT and MR with diffusion-weighted imaging (MR-DWI) for diagnosing peritoneal carcinomatosis (PC) from gastrointestinal malignancies.MethodsThirty consecutive patients referred for staging of gastrointestinal malignancy underwent FDG-PET/CT and MR-DWI in this retrospective study. Extent of PC was characterised by dividing the peritoneal cavity into three sites in each patient: right and left supramesocolic areas and inframesocolic level (total 90 sites). Presence of PC was confirmed either by surgery (18/30) or by follow-up (12/30).ResultsPC was confirmed in 19 patients (19/30). At a total of 90 sites, 27 showed proven PC. On a patient-based analysis, sensitivity, specificity, PPV, NPV and accuracy were respectively 84%, 73%, 84%, 73% and 80% for PET/CT and 84%, 82%, 89%, 75% and 83% for MR-DWI. On a site-based analysis, overall sensitivity and specificity of PET/CT (63%, 90%) and MR-DWI (74%, 97%) were not statistically different (Pu2009=u20090.27). In the supramesocolic area, MR-DWI detected more sites involved than PET/CT (7/9 vs. 4/9). The sensitivities of PET and MR were lower for subcentimetre tumour implants (42%, 50%). Interobserver agreement was very good for PET/CT and good for MR-DWI.ConclusionsFDG-PET/CT and MR-DWI showed similar high accuracy in diagnosing PC. Both techniques underestimated the real extent of PC because of decreased sensitivity for subcentimetre lesions.Key Points• FDG-PET/CT and MR-DWI showed similar high accuracy for diagnosing peritoneal carcinomatosis.• In the supramesocolic area, MR-DWI could be more sensitive than PET/CT.• Both techniques showed lower sensitivity for subcentimetre lesions.• Interobserver agreement was very good for PET/CT and good for MR-DWI.

Effets vasculaires et rénaux des médicaments anti-angiogéniques : recommandations françaises pour la pratique (SN, SFHTA, APNET, FFCD)

Angiogenesis inhibitor drugs (bevacizumab, sunitinib, sorafénib...) are now widely used for treatment of cancers, including colorectal, advanced renal cell and hepatocellular carcinomas, breast cancer). Vascular and renal side-effects of these drugs are not well known. Hypertension is one of the most common side effects. Incidence of hypertension may be different among angiogenis inhibitors and seems dose-depend. Arterial pressure can usually be controlled with anti-hypertensive medications, and treatment with angiogenesis inhibitors can be continued in most cases; however, serious hypertension-induced side effects were reported included malignant hypertension, stroke and reversible posterior leucoencephalopathy. Renal damage is infrequently reported: usually reversible mild or moderate proteinuria and in some rare cases nephritic syndrome, acute renal dysfunction, proliferative or collapsing glomerulonephritis, interstitial nephritis and thrombotic microangiopathy. Prolongation of the QT interval, congestive heart failure and left ventricular dysfunction have been reported in patients using tinibs. In the present guidelines, we recommend: (1) before the first administration of angiogenesis inhibitors: acute IV or oral antihypertensive medications should not be administered in a patient regardless of arterial pressure levels with postponing the administration because of hypertension is not recommended; (2) initial work-up should include ambulatory measurement of arterial pressure (by the general practitioner or by the patient using home blood pressure (three times in the morning and in the evening during three consecutive days) with a validated (cf: http://afssaps.sante.fr/) upper arm device: ideally, this device should be financed and provided by the pharmaceutical companies marketing the angiogenesis inhibitor drugs. Using 24-hour ambulatory blood pressure measurement is optional; (3) urine dipstick (and quantification if positive) and estimated glomerular filtration rate (using abbreviated MDRD rather than Cockcroft-Gault formula) must be performed before treatment and regularly during follow-up; (4) therapeutic management must be done in accordance with national or international guidelines (in France: http://www.has-sante.fr/); (5) optimal care is best achieved within a network of professionals including general practitioners, oncologists, cardiologists and nephrologists.

Efficacy of Adjuvant Chemotherapy in Colon Cancer With Microsatellite Instability: A Large Multicenter AGEO Study

BACKGROUNDnDeficient mismatch repair (dMMR) colon cancer (CC) is reportedly resistant to 5-fluorouracil (5FU) adjuvant chemotherapy while preliminary data suggest chemosensitivity to oxaliplatin. We assessed the efficacy of fluoropyrimidine with and without oxaliplatin in a large cohort of dMMR CC patients.nnnMETHODSnThis retrospective multicenter study included all consecutive patients who underwent curative surgical resection for stage II or III dMMR CC between 2000 and 2011. Prognostic factors were analyzed using Cox models, and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. All statistical tests were two-sided.nnnRESULTSnA total of 433 dMMR CC patients were included (56.8% stage II, 43.2% stage III). Mean follow-up was 47.0 months. The patients received surgery alone (n = 263) or surgery plus adjuvant chemotherapy consisting of fluoropyrimidine with (n = 119) or without (n = 51) oxaliplatin. Adjuvant chemotherapy was administered to 16.7% of stage II and 69.0% of stage III CC patients. As compared with surgery alone, adjuvant oxaliplatin-based chemotherapy improved disease-free survival (DFS) in multivariable analysis (HR = 0.35, 95% CI = 0.19 to 0.65, P < .001), contrary to adjuvant fluoropyrimidine alone (HR = 0.73, 95% CI = 0.36 to 1.49, P = .38). In the subgroup analysis, the DFS benefit of oxaliplatin-based chemotherapy was statistically significant in multivariable analysis only in stage III (HR = 0.41, 95% CI = 0.19 to 0.87, P = .02).nnnCONCLUSIONnThis study supports the use of adjuvant chemotherapy with fluoropyrimidine plus oxaliplatin in stage III dMMR CC.

Deficient mismatch repair phenotype is a prognostic factor for colorectal cancer in elderly patients

OBJECTIVEnAbout 15% of colorectal adenocarcinomas have a deficient DNA mismatch repair phenotype. The frequency of deficient DNA mismatch repair tumours increases with age due to the hypermethylation of hMLH1 promoter. The study aimed to determine the prognostic value of deficient DNA mismatch repair phenotype in elderly patients.nnnDESIGNnMismatch repair phenotype was retrospectively determined by molecular analysis in consecutive resected colorectal adenocarcinoma specimens from patients over 75 years of age from 4 Oncology centres.nnnRESULTSn231 patients (median age: 81, range: 75-100) were enrolled from 2005 to 2008. Mean prevalence of deficient DNA mismatch repair phenotype was 22.5%, and 36% for patients over 85 years. Deficient DNA mismatch repair status was significantly associated with older age, female sex, proximal colon primary and high grade tumour. For stage II tumours no deficient DNA mismatch repair tumours had a recurrence at end of follow-up compared to 17% for tumours with proficient phenotype. The proficient phenotype status was significantly associated with worse age-adjusted overall survival [HR 2.60; 95% CI 1.05-6.44; p=0.039]. For stage III tumours a trend for less recurrence was observed for deficient DNA mismatch repair phenotype (16%) compared to proficient phenotype (36%).nnnCONCLUSIONndeficient DNA mismatch repair phenotype is a prognostic factor in stage II colorectal tumour in elderly patients. Our results suggest that mismatch repair phenotype should be taken in consideration for adjuvant chemotherapy decision in elderly patients.

Postirradiation Sarcoma: Clinicopathologic Features and Role of Chemotherapy in the Treatment Strategy

Purpose. An analysis of the clinicopathologic features and treatment of patients was performed to guide evaluation and management of postirradiation sarcoma. Patients and Methods. Between 1994 and 2001, 25 patients with postirradiation sarcoma were treated in one center with different chemotherapy, mainly in neoadjuvant setting (19). Tumors for which these patients received radiotherapy initially were mainly breast carcinoma (for 15 patients). The postirradiation sarcomas were of different histopathologic forms, most frequently osteosarcoma, leiomyosarcoma, and angiosarcoma. Results. Of the 25 patients, 19 were initially treated with chemotherapy. Nine of 19 pretreated patients achieved clinical partial response (RP = 47%). Leiomyosarcomas were good responders (3/4) and undifferentiated sarcoma (3/5). Responders were more often treated with MAID (6/8). Eight of the 9 responders underwent surgery. Two patients achieved complete histological response. Seven of the 9 good responders are alive with a median follow up of 24 months. For all treated patients, median follow up 24 months (6–84 months), overall survival and disease free survival were, respectively, 17/25 (68%), and 14/25 (56%). Conclusion. From our data, postirradiation sarcoma should not be managed differently from primary sarcoma. Chemotherapy has to be included in the treatment plan of postirradiation sarcoma, in future studies.

Doublet chemotherapy vs. single-agent therapy with 5FU in elderly patients with metastatic colorectal cancer. a meta-analysis

BackgroundThe clinical benefit of first-line doublet chemotherapy (including oxaliplatin or irinotecan) compared to single-drug therapy (5FU) in elderly patients (>70 or >75xa0years old) with metastatic colorectal cancer (MCRC) is controversial. Therefore, we undertook a meta-analysis of all published phase III studies.Material and methodsWe performed a PubMed search using keywords metastatic colorectal cancer, phase III studies, oxaliplatin, irinotecan, survival. We also screened Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) proceedings. Few studies have been published corresponding to our inclusion criteria. The efficacy outcomes were overall survival (OS) and progression-free survival (PFS). Toxicity was also examined when available. Hazard ratios (HRs) with their 95xa0% confidence intervals (CI) were collected from the studies and pooled. By convention, HRs <1 corresponded to a better outcome for doublets. p values <0.05 were considered statistically significant. A fixed-effect model was used. We used Comprehensive Meta-Analysis Software (Biostat, Englewood, NJ, USA).ResultsThis meta-analysis (MA) included five original studies (Mitry and Venderbosch for CAIRO both assessing irinotecan, De Gramont and Seymour for FOCUS2 and Ducreux assessing oxaliplatin) and an already published MA (Folprecht) of four trials comparing FOLFIRI with 5FU (Saltz, Douillard, Köhne and Seymour). Our MA included 1225 patients (70xa0% men). For age, we chose a cut-off of 70xa0years for oxaliplatin and a cut-off of 75xa0years for irinotecan. The performance status (PS) score was 0–1 in about 90xa0% of patients except for the studies by Mitry and Seymour FOCUS2 which both included 30xa0% of PS2 patients. Overall, doublet chemotherapy, compared to 5FU alone, did not improve OS (HRu2009=u20091.00; CI: 0.89–1.13) but significantly improved PFS (HRu2009=u20090.82; CI: 0.72–0.93). When assessed separately, FOLFIRI and FOLFOX both significantly improved PFS (HRu2009=u20090.83; 0.68–1.00 and HRu2009=u20090.81; 0.68–0.97, respectively). The main grade 3–4 toxicities for FOLFIRI were diarrhoea, nausea, vomiting and neutropenia, which occurred significantly more often than with 5FU alone.ConclusionAddition of oxaliplatin or irinotecan to 5FU in metastatic CRC significantly improved PFS in elderly patients more than 70xa0years old but was associated with an increased risk of toxicity as shown for irinotecan.

Chronological Age and Risk of Chemotherapy Nonfeasibility: A Real-Life Cohort Study of 153 Stage II or III Colorectal Cancer Patients Given Adjuvant-modified FOLFOX6.

Objectives: To assess nonfeasibility of adjuvant-modified FOLFOX6 chemotherapy in patients with stage II or III colorectal cancer. Methods: Consecutive patients managed between 2009 and 2013 in 2 teaching hospitals in the Paris urban area were included in the CORSAGE (COlorectal canceR, AGe, and chemotherapy fEasability study) cohort study. Nonfeasibility was defined by the frequencies of empirical first-cycle dose reduction (>15%), early discontinuation (<12 cycles), and low relative dose intensity (RDI) (<0.85). Risk factors for chemotherapy nonfeasibility were identified using multivariate logistic regression. Results: Among 153 patients, 56.2% were male (median age, 65.6 y; 35.3%≥70 y; 7.3% with performance status [PS]≥2). For 5-fluorouracil (5-FU), 20.9% of patients had first-cycle dose reduction and 28.1% early discontinuation; RDI was 0.91 (25th to 75th percentiles, 0.68 to 0.99). Factors independently associated with first-cycle 5-FU dose reduction were aged 65 to 69 years versus those younger than 65 years (adjusted odds ratio [aOR], 5.5; 95% confidence interval [CI], 1.5-19.9) but not age 70 years and older, PS≥2 (aOR, 6.02; 95% CI, 1.15-31.4), higher Charlson Comorbidity Index (aOR1-point increase, 1.4; 95% CI, 1.05-1.82), or larger number of medications (aOR 1-medication increase, 1.19; 95% CI, 1.00-1.42). Oxaliplatin dose reduction occurred in 52.3% of patients and early discontinuation in 62.7%; the latter was more common in the 70 years and older group (92.6% vs. 74.6% in the <65-y group; P=0.01); RDI was 0.7 (95% CI, 0.55-0.88). Conclusions: In the real-world setting, compared with their younger and older counterparts, patients aged 65 to 69 years given modified FOLFOX6 for stage II or III colorectal cancer had higher frequencies of 5-FU nonfeasibility defined based on first-cycle dose reduction, early discontinuation, and RDI; and these differences were independent from PS, comorbidities, and number of medications.

Perioperative chemotherapy with FOLFOX in resectable gastroesophageal adenocarcinoma in real life practice: An AGEO multicenter retrospective study

PURPOSEnPerioperative chemotherapy with 5-fluorouracil and cisplatin, with or without epirubicin, improves overall survival in resectable gastroesophageal junction and gastric adenocarcinoma. The aim of this retrospective multicenter study was to evaluate the safety and efficacy of perioperative chemotherapy with a FOLFOX-based regimen.nnnPATIENTS AND METHODSnWe enrolled patients with resectable gastric or gastroesophageal adenocarcinoma, who had at least 3 cycles of a pre-operative FOLFOX-based regimen. The primary end point was the feasibility of the peri-operative chemotherapy.nnnRESULTSnWe enrolled 109 patients from 2007 to 2012 in 12 centres. Their median age was 66, 67% were men and 73% had gastric tumours. The median number of chemotherapy courses was 6 with a median of 4 pre-operative cycles and 2 post-operative cycles. Twenty-three patients received at least 8 cycles of chemotherapy. In univariate analysis, the Karnofsky index at inclusion was the only factor associated with 8 cycles of chemotherapy. An R0 resection was achieved in 100 patients (95.2%).nnnCONCLUSIONnThe FOLFOX-based perioperative regimen achieves favourable results in real life practice. The optimal number of chemotherapy cycle remains to be determined. FOLFOX regimen may be used as an alternative treatment option to a cisplatin-based regimen in resectable gastroesophageal adenocarcinoma. A prospective randomized trial is needed to confirm these results.

Neoadjuvant chemotherapy for adult soft tissue sarcoma: comparaison of systemic and intra-arterial chemotherapy

BackgroundThe introduction of a combined-modality approach, which added chemotherapy to local therapy (surgery and radiotherapy), has been controversial. We present our experience of the efficacy of neoadjuvant chemotherapy in patients with high-risk sarcomas and evaluate the benefit of intra-arterial (IA) chemotherapy.Patients and methodsForty patients with intermediate to high-grade soft tissue sarcomas (STS) were treated with neoadjuvant chemotherapy from 1994 to 2001 at the Institut Curie. Thirty-seven patients had localized tumours. Neoadjuvant intravenous (IV) chemotherapy consisted of 4–6 cycles of treatment (mainly CYVADIC, MAID). Sixteen patients (40%) received 2 cycles of IA chemotherapy with a combination of adriamycin and cisplatin. Radiotherapy was delivered in an adjuvant setting.ResultsAll patients underwent limb-sparing surgical resection after neoadjuvant therapy and pathologic assessment of tumour necrosis was performed on the resected specimens. Two groups of tumours were analysed: 1–95% (28 cases), and 95–100% (10 cases) of pathological necrosis, with a survival benefit in the group with more than 95% necrosis (pxa0=xa00.07). IA chemotherapy was superior to IV chemotherapy in terms of the necrosis rate (pxa0=xa00.045). With a median follow-up of 51xa0months, the 2-year overall survival rate was 90% for localized tumours.ConclusionNeoadjuvant chemotherapy can be considered to be effective in the treatment of STS. This study demonstrates the benefit of neoadjuvant therapy for patients with a high necrosis rate (very clear tendency) and the contribution of IA chemotherapy to the response rate, but with no survival advantage.

Impact of the addition of bevacizumab, oxaliplatin, or irinotecan to fluoropyrimidin in the first-line treatment of metastatic colorectal cancer in elderly patients

IntroductionThe clinical benefit of double-front-line therapy (including oxaliplatin or irinotecan or bevacizumab plus 5-fluorouracil (5FU) or capecitabine) compared to monotherapy (5FU or capecitabine) in elderly (>u200970xa0years) patients with metastatic colorectal cancer (MCRC) is controversial. We performed a meta-analysis of published randomized studies.Materials and methodsThe selection of the studies was carried out using PubMed with the following keywords: “metastatic colorectal cancer,” “elderly,” “oxaliplatin,” “irinotecan,” “bevacizumab,” “survival.” The efficacy endpoints were overall survival (OS) and progression-free survival (PFS). Hazard ratios (HRs) with their 95% confidence intervals (CIs) were collected from the studies and pooled. By convention, an HR <u20091 was a result in favor of biotherapy.ResultsThis meta-analysis (MA) included ten studies: three assessing irinotecan (FFCD 2001–02, CAIRO, and an already published MA by Folprecht), three assessing oxaliplatin (FOCUS2, FFCD 2000–05, and a published study by De Gramont), and four assessing bevacizumab (PRODIGE-20, AVEX, AGITG-MAX, and “AVF2192g” by Kabbinavar). Our MA included 1652 patients (62% of men). Concerning age, we chose a cut-off of 70xa0years or a cut-off of 75xa0years, corresponding to the available data for each study. The performance index (PS) was 0–1 for about 90% of patients, with the exception of FFCD 2001–02 and FOCUS2 which included 30% of patients with PS2. Overall, the addition of bevacizumab to fluoropyrimidin statistically improves both OS and PFS (HRu2009=u20090.78; CI 0.63–0.96 and HRu2009=u20090.55; CI 0.44–0.67, respectively). The addition of oxaliplatin did not statistically improve OS (=u20090.99; CI 0.85–1.17) but improves PFS (HRu2009=u20090.81; CI 0.67–0.97) as well as the addition of irinotecan (HRu2009=u20091.01; CI 0.84–1.22 and HRu2009=u20090.82; CI 0.68–1.00, respectively).ConclusionIn previously untreated elderly patients with MCRC, the addition of bevacizumab to fluoropyrimidin appears more effective in terms of OS or PFS than the addition of oxaliplatin or irinotecan.