Prediction of response to immune checkpoint blockade in patients with metastatic colorectal cancer with microsatellite instability.

BACKGROUND: Mismatch repair-deficient (dMMR) tumors displaying microsatellite instability (MSI) represent a paradigm for the success of immune checkpoint inhibitor (ICI)-based immunotherapy, particularly in patients with metastatic colorectal cancer (mCRC). However, a proportion of patients with dMMR/MSI mCRC exhibit resistance to ICI. Identification of tools predicting MSI mCRC patient response to ICI is required for the design of future strategies further improving this therapy. PATIENTS AND METHODS: We combined high-throughput DNA and RNA sequencing of tumors from 116 patients with MSI mCRC treated with anti-programmed cell death protein 1 ± anti-cytotoxic T-lymphocyte-associated protein 4 of the NIPICOL phase II trial (C1, NCT03350126, discovery set) and the ImmunoMSI prospective cohort (C2, validation set). The DNA/RNA predictors whose status was significantly associated with ICI status of response in C1 were subsequently validated in C2. Primary endpoint was progression-free survival by immune RECIST (iRECIST) (iPFS). RESULTS: Analyses showed no impact of previously suggested DNA/RNA indicators of resistance to ICI, e.g. MSIsensor score, tumor mutational burden, or specific cellular and molecular tumoral contingents. By contrast, iPFS under ICI was shown in C1 and C2 to depend both on a multiplex MSI signature involving the mutations of 19 microsatellites hazard ratio cohort C2 (HRC2) = 3.63; 95% confidence interval (CI) 1.65-7.99; P = 1.4 × 10-3] and the expression of a set of 182 RNA markers with a non-epithelial transforming growth factor beta (TGFB)-related desmoplastic orientation (HRC2 = 1.75; 95% CI 1.03-2.98; P = 0.035). Both DNA and RNA signatures were independently predictive of iPFS. CONCLUSIONS: iPFS in patients with MSI mCRC can be predicted by simply analyzing the mutational status of DNA microsatellite-containing genes in epithelial tumor cells together with non-epithelial TGFB-related desmoplastic RNA markers.

Colorectal cancer (CRC) monitoring by 6-monthly 18FDG-PET/CT: an open-label multicentre randomised trial.

Background: [18F]2-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (18FDG-PET/CT) has high sensitivity for detecting recurrences of colorectal cancer (CRC). Our objective was to determine whether adding routine 6-monthly 18FDG-PET/CT to our usual monitoring strategy improved patient outcomes and to assess the effect on costs. Patients and methods: In this open-label multicentre trial, patients in remission of CRC (stage II perforated, stage III, or stage IV) after curative surgery were randomly assigned (1 : 1) to usual monitoring alone (3-monthly physical and tumour marker assays, 6-monthly liver ultrasound and chest radiograph, and 6-monthly whole-body computed tomography) or with 6-monthly 18FDG-PET/CT, for 3 years. A multidisciplinary committee reviewed each patient's data every 3 months and classified the recurrence status as yes/no/doubtful. Recurrences were treated with curative surgery alone if feasible and with chemotherapy otherwise. The primary end point was treatment failure defined as unresectable recurrence or death. Relative risks were estimated, and survival was analysed using the Kaplan-Meier method, log-rank test, and Cox models. Direct costs were compared. Results: Of the 239 enrolled patients, 120 were in the intervention arm and 119 in the control arm. The failure rate was 29.2% (31 unresectable recurrences and 4 deaths) in the intervention group and 23.7% (27 unresectable recurrences and 1 death) in the control group (relative risk = 1.23; 95% confidence interval, 0.80-1.88; P = 0.34). The multivariate analysis also showed no significant difference (hazards ratio, 1.33; 95% confidence interval, 0.8-2.19; P = 0.27). Median time to diagnosis of unresectable recurrence (months) was significantly shorter in the intervention group [7 (3-20) versus 14.3 (7.3-27), P = 0.016]. Mean cost/patient was higher in the intervention group (18 192 ± 27 679 € versus 11 131 ± 13 €, P < 0.033). Conclusion: 18FDG-PET/CT, when added every 6 months, increased costs without decreasing treatment failure rates in patients in remission of CRC. The control group had very close follow-up, and any additional improvement (if present) would be small and hard to detect. ClinicalTrials.gov identifier: NCT00624260.

Use of chemotherapy near the end of life: what factors matter?

Background: Use of chemotherapy near the end of life in patients with metastatic cancer is often ineffective and toxic. Data about the factors associated with its use remain scarce, especially in Europe. Methods: Nationwide, register-based study including all hospitalized patients aged ≥20 years who died from metastatic solid tumors in France between 2010 and 2013. Results: A total of 279 846 hospitalized patients who died from metastatic cancer were included. During the last month before death, 19.5% received chemotherapy (including 11.3% during the last 2 weeks). Female sex (OR= 0.96, 95% CI= 0.93-0.98), older age (OR= 0.70, 95% CI= 0.69-0.71 for each 10-year increase) and higher number of chronic comorbidities (OR= 0.83, 95% CI= 0.82-0.84) were independently associated with lower rates of chemotherapy. Although patients with chemosensitive tumors were statistically more likely to receive chemotherapy during the last month before death (OR= 1.21, 1.18-1.25), this association was mostly fueled by testis and ovary tumors and we found no obvious pattern between the expected chemosensitivity of different cancers and the rates of chemotherapy use close to death. Compared with university hospitals, patients who died in for-profit clinics/hospital (OR= 1.40, 95% CI= 1.34-1.45), or comprehensive cancer centers (OR= 1.43, 95% CI= 1.36-1.50) were more likely to receive chemotherapy. Finally, high-volume centers and hospitals without palliative care units reported greater-than-average rates of chemotherapy near the end of life. Conclusion: among hospitalized patients with cancer, young individuals, treated in comprehensive cancer centers or in high-volume centers without palliative care units were the most likely to receive chemotherapy near the end of life. We found no evident pattern between the expected chemosensitivity of different cancers and the probability for patients to receive chemotherapy close to death.

How health-related quality of life assessment should be used in advanced colorectal cancer clinical trials.

Traditionally, the efficacy of cancer treatment in patients with advance or metastatic disease in clinical studies has been studied using overall survival and more recently tumor-based end points such as progression-free survival, measurements of response to treatment. However, these seem not to be the relevant clinical end points in current situation if such end points were no validated as surrogate of overall survival to demonstrate the clinical efficacy. Appropriate, meaningful, primary patient-oriented and patient-reported end points that adequately measure the effects of new therapeutic interventions are then crucial for the advancement of clinical research in metastatic colorectal cancer to complement the results of tumor-based end points. Health-related quality of life (HRQoL) is effectively an evaluation of quality of life and its relationship with health over time. HRQoL includes the patient report at least of the way a disease or its treatment affects its physical, emotional and social well-being. Over the past few years, several phase III trials in a variety of solid cancers have assessed the incremental value of HRQoL in addition to the traditional end points of tumor response and survival results. HRQoL could provide not only complementary clinical data to the primary outcomes, but also more precise predictive and prognostic value. This end point is useful for both clinicians and patients in order to achieve the dogma of precision medicine. The present article examines the use of HRQoL in phase III metastatic colorectal cancer clinical trials, outlines the importance of HRQoL assessment methods, analysis, and results presentation. Moreover, it discusses the relevance of including HRQoL as a primary/co-primary end point to support the progression-free survival results and to assess efficacy of treatment in the advanced disease setting.

End-of-life care for hospitalized patients with metastatic melanoma in France: a nationwide, register-based study.

BACKGROUND: Although the aggressiveness of end-of-life cancer care has come under great scrutiny over the past two decades, little is known about the intensity of care and treatments in the last months of life of patients with metastatic melanoma. OBJECTIVES: To measure the prevalence of aggressive cancer care use, and to assess the frequency of palliative care referral over the course of the last 3 months of life of hospitalized patients who died from metastatic melanoma. METHODS: A nationwide register-based study in France was carried out, including all hospitalized adults aged ≥ 20 years who died from metastatic melanoma in metropolitan France between 2010 and 2013. RESULTS: Of 3889 patients who died from metastatic melanoma, 51·9% received chemotherapy in the last 3 months before death, 25·9% in the last month, 12·9% in the last 2 weeks and 7·6% in the last week. On average, patients were hospitalized for 31·7 days over the course of their last 3 months of life. During the final month before death, 12·0% of patients received radiation therapy, 14·0% received blood transfusion, 12·1% were transferred into an intensive care unit and 19·7% remained hospitalized continuously. Palliative care needs were identified in 78·4% of patients, with variations according to the type of facility. In total 17% of all patients died in palliative care inpatient units. CONCLUSIONS: Treatment intensity near the end of life of patients with metastatic melanoma raises concerns for the quality of care. There is a need for clinical guidelines and adequate support to facilitate patient-physician communication and to improve access to palliative care services.

Clinical relevance of reports on early access programs for checkpoint inhibitors in cancer patients: a French retrospective nationwide cohort study.

BACKGROUND: To accelerate access to new drugs, France operated an early access program known as Temporary Authorizations for Use (ATUs) until 2021. We analyzed clinical reports submitted under ATUs for immune checkpoint inhibitors (ICIs) and assessed their clinical relevance regarding the approval of ICIs in oncology. METHODS: We included all ICIs granted an ATU by the French drug safety agency, Agence nationale de sécurité du médicament et des produits de santé (ANSM; French National Agency for the Safety of Medicines and Health Products), for patients with cancer between 1 January 2010 and 31 December 2020. We collected patients' clinical and pharmacovigilance data from ATU reports submitted by pharmaceutical companies and compared these data with those from corresponding pivotal clinical trials (CTs). RESULTS: The ATUs provided early access to 5807 patients with seven ICIs across 11 cancer indications, 1 of which had no corresponding ATU report. Of the 10 available ATU reports, only 1 included all required data. Clinical follow-up forms were available for 40.5% of patients. Differences in data reporting prevented us from comparing serious adverse events between the CTs and ATU reports. Clinicians and pharmaceutical companies often disagreed on whether ICIs caused 163 permanent treatment discontinuations, with Cohen's bias- and prevalence-adjusted κ = 0.52, 95% CI 0.33-0.68. Although agreement was almost perfect for 93 nonprogressive tumor deaths (κ = 0.88, 95% CI 0.66-0.97), 29% of ATU patient deaths remained unexplained and were reported as unrelated to treatment by the pharmaceutical companies. CONCLUSION: French ATUs facilitated early access to new ICIs for many patients with cancer. However, data attrition hindered effective real-world monitoring.

Combined HER2 analysis of biopsies and surgical specimens to optimize detection of trastuzumab-eligible patients in eso-gastric adenocarcinoma: a GERCOR study.

BACKGROUND: HER2 is overexpressed in 10 to 20% of gastro-esophageal adenocarcinoma (GE-ADK), and is a target for trastuzumab in metastatic patients. We conducted a study to compare HER2 expression between diagnostic biopsies (DBs) and surgical specimens (SSs) of GE-ADK, and to determine the influence of non-trastuzumab containing neoadjuvant chemotherapy (NAC) on this expression. PATIENTS AND METHODS: Pathological specimens from biopsies of 228 patients operated on between 2004 and 2011 were collected. Two cohorts treated (n = 141) or not (n = 87) with a NAC were constituted. Two blind independent pathological HER2 analyses on DB and on SS were carried out using immunohistochemistry (IHC) and colorimetric in situ hybridization (CISH). HER-2 overexpression (HER2+) was defined by a score 3+ in IHC, or 2+ with a positive CISH test, according to the specific HER2 scoring guidelines for GE-ADK. RESULTS: Paired HER2 status could be determined for 218 out of the 228 patients (95.6%). HER2+ rates were 13.3% on DB (29/218) and 14.7% on SS (32/218). HER2+ tumors were mainly cardial or esophageal adenocarcinomas, with a well-differentiated, intestinal histological type. HER2 status differed between DB and SS in 6% of cases. When DB analyses were added to SS analyses, the relative increase in HER2+ cases was 13.5% (17.1% for patients with NAC and 23.5% for patients with histological response to NAC, versus 7.1% for patients without NAC, P = 0.4, NS). Differences between DB and SS HER2 expression could be explained by intratumoral heterogeneity and by a HER2 expression decrease in SS after NAC in responding patients possibly due to a higher chemosensitivity of HER2-positive clones. CONCLUSION: The determination of HER2 status on DB provides results that complete those obtained with SS. Combining the analysis of DB and of SS enables to optimize the selection of trastuzumab-eligible patients in case of metastatic relapse, and particularly in previously NAC-responding patients.

Panitumumab combined with irinotecan for patients with KRAS wild-type metastatic colorectal cancer refractory to standard chemotherapy: a GERCOR efficacy, tolerance, and translational molecular study.

BACKGROUND: The purpose of this study was to evaluate the combination of panitumumab and irinotecan in patients with KRAS wild-type metastatic colorectal cancer refractory to standard chemotherapy (oxaliplatin, fluoropyrimidines-irinotecan and bevacizumab). PATIENTS AND METHODS: KRAS status was first determined locally but subsequent validation of KRAS status and additional screenings (rare KRAS, NRAS, BRAF mutations and EGFR copy number) were centrally assessed. Patients received panitumumab (6 mg/kg) and irinotecan (180 mg/m²) every 2 weeks. RESULTS: Sixty-five eligible patients were analyzed. The objective response rate (ORR) was 29.2% [95% confidence interval (95% CI) 18.2-40.3]. Median progression-free and overall survivals were 5.5 and 9.7 months, respectively. Most frequent grade 3/4 toxic effects were skin 32.3%, diarrhea 15.4% and neutropenia 12.3%. Tissue samples were available for 60 patients. For the confirmed KRAS wild-type population codon 12 or 13 mutation (n = 54), ORR was 35.2% (95% CI 22.4.1-47.9). Thirteen patients had a NRAS, a BRAF or a rare KRAS mutation, and no tumor response was observed in this subgroup when compared with 46.3% (95% CI 31.1-61.6) ORR in the subgroup of 41 patients with no identified mutation. CONCLUSION: Panitumumab and irinotecan is an active third-line regimen in a well-defined population based on biomarkers. ClinicalTrials.gov Identifier NCT00655499.

Immunogenicity and safety of the influenza A H1N1v 2009 vaccine in cancer patients treated with cytotoxic chemotherapy and/or targeted therapy: the VACANCE study.

BACKGROUND: Influenza vaccination is recommended to cancer patients undergoing chemotherapy, but vaccine coverage remains low. During the 2009 influenza pandemic, French recommendations were to vaccinate immunocompromised patients with two doses of adjuvanted vaccine. This study aimed to evaluate vaccine immunogenicity in cancer patients receiving chemotherapy. PATIENTS AND METHODS: VACANCE is a prospective open-label study that evaluated the immunogenicity and safety of two doses of AS03A-adjuvanted H1N1v vaccine in cancer patients receiving cytotoxic and/or targeted therapies. Serum haemagglutination-inhibited antibody titres against influenza A H1N1v were measured at days 1, 21, and 42, to estimate the proportion of participants with antibody titres ≥ 1 : 40 [seroprotection rate (SPR)], the efficacy of seroconversion, and factors that increased the geometric mean titre. RESULTS: Sixty-five patients were included. At baseline, 5% of patients had vaccine strain titres of specific haemagglutination inhibition antibodies that were ≥ 1 : 40. After one and two doses of vaccine, SPRs were 48% and 73%, respectively, and seroconversion rates were 44% and 73%, respectively. Vaccine-related adverse events were mild to moderate. CONCLUSIONS: A single dose of AS03-adjuvanted A/H1N1 vaccine triggered a low immune response in cancer patients on chemotherapy depending on their treatment type and frequency. Two doses are needed for these cancer patients.

Incidence and evolution of oxaliplatin-induced peripheral sensory neuropathy in diabetic patients with colorectal cancer: a pooled analysis of three phase III studies.

BACKGROUND: The purpose of this study was to determine whether the presence of diabetes mellitus (DM) influences the incidence, severity, and/or course of peripheral sensory neuropathy (PSN) after oxaliplatin (FOLFOX) therapy in patients with colorectal cancer (CRC). METHODS: A retrospective pooled analysis incorporating three phase III studies was conducted: Multicenter International Study of Oxaliplatin, 5-Fluorouracil, and Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) (adjuvant treatment; stage II/III colon cancer), EFC4584 (second-line treatment; metastatic CRC), and EFC2962 (first-line treatment; metastatic CRC). Patients were ineligible for the studies if they had known PSN (EFC4584) or PSN grade > or =1 (MOSAIC and EFC2962) at baseline. The incidence of PSN was evaluated retrospectively in patient subgroups with or without DM at baseline that received FOLFOX. Kaplan-Meier curves were used to assess the probability of PSN with increasing cumulative oxaliplatin dose. RESULTS: Of 1587 patients enrolled across the three studies, 135 (8.5%) had DM at baseline. The incidence of PSN (non-DM/DM) was 45.0%/46.7% (grade 1), 28.6%/26.7% (grade 2), and 13.0%/12.6% (grade 3). The probability of PSN by cumulative dose of oxaliplatin was similar in DM and non-DM patients. CONCLUSIONS: This retrospective analysis indicates that oxaliplatin-based therapy does not influence the incidence, severity, or time to onset of PSN in asymptomatic DM patients with CRC who meet eligibility criteria for clinical trials.

FOLFOX in patients with metastatic colorectal cancer and high alkaline phosphatase level: an exploratory cohort of the GERCOR OPTIMOX1 study.

BACKGROUND: Alkaline phosphatase (ALP) is a strong prognostic factor in patients with metastatic colorectal cancer (MCRC). Patients with ALP more than three times the upper limit of normal (ULN) were excluded from our previous studies evaluating chemotherapy. An exploratory cohort of patients with ALP >3 ULN was included in the OPTIMOX1 study. PATIENTS AND METHODS: Previously untreated patients with MCRC were randomized to FOLFOX4 until progression (arm A) or FOLFOX7 for six cycles, maintenance without oxaliplatin for 12 cycles and reintroduction of FOLFOX7 (arm B). Patients were stratified according to ALP level

Efficacy of FOLFIRI-3 (irinotecan D1,D3 combined with LV5-FU) or other irinotecan-based regimens in oxaliplatin-pretreated metastatic colorectal cancer in the GERCOR OPTIMOX1 study.

BACKGROUND: Second-line irinotecan-based chemotherapy is commonly used in metastatic colorectal cancers after first-line oxaliplatin-based chemotherapy. No standard schedule of irinotecan has been established in this situation. PATIENTS AND METHODS: Metastatic colorectal cancer patients included in the OPTIMOX1 phase III study received first-line oxaliplatin-based chemotherapy (FOLFOX). No second line was defined in the protocol, but data concerning second line were prospectively registered. Inclusion criterion was patients receiving an irinotecan-based second-line chemotherapy. Second-line progression-free survival (PFS) and tumor response were evaluated according to type of irinotecan-based regimen administered. RESULTS: A total of 342 patients received irinotecan-based chemotherapy as second-line chemotherapy: FOLFIRI-3 [n = 109, irinotecan 100 mg/m(2) days 1 and 3 combined with leucovorin (LV) 400 mg/m(2) day 1 and 46-h continuous 5-fluorouracil (5-FU) 2000 mg/m(2)], FOLFIRI-1 (n = 112, irinotecan 180 mg/m(2) day 1 combined with LV 400 mg/m(2) day 1, 5-FU bolus 400 mg/m(2) and 46-h continuous 5-FU 2400 mg/m(2)) and other various irinotecan-based regimens (n = 121). Median second-line PFS was 3.0 months (FOLFIRI-3: 3.7 months; FOLFIRI-1: 3.0 months; other regimens: 2.3 months). In multivariate analysis, FOLFIRI-3 regimen (relative risk 0.43, 95% confidence interval 0.28-0.68, P = 0.0003) and lactate deshydrogenase level at inclusion (P = 0.0006) in OPTIMOX1 were associated with a longer second-line PFS. CONCLUSION: In unselected patients pretreated with oxaliplatin, PFS in second line appeared to be improved by FOLFIRI-3 regimen.

[What are the new therapeutic strategies in metastatic colorectal cancer including biotherapies?]. / Quelles nouvelles stratégies dans le traitement du cancer colorectal métastatique avec les biothérapies?

Colorectal cancer remains one of the major causes of cancer death. Recent identification of new molecular targets led to the development of novel agents directed against growth factor receptors or key factors of angiogenesis. Recent phase III trials demonstrated a significant clinical benefit with bevacizumab, a VEGF inhibitor, and with EGFR-inhibitors, namely cetuximab and panitumumab. In this article we review the diverse treatment options combining cytotoxic and targeted therapies available for patients with metastatic colorectal cancer.

Oxaliplatin, 5-Fluorouracil and Nab-paclitaxel as perioperative regimen in patients with resectable gastric adenocarcinoma: A GERCOR phase II study (FOXAGAST).

BACKGROUND: 5-Fluorouracil (5-FU) and platinum-based perioperative chemotherapy is standard of care for resectable gastric adenocarcinoma (RGA). Nanoparticle albumin-bound (Nab-) paclitaxel is active in advanced disease but has never been evaluated in the perioperative setting. The objective was to evaluate the efficacy of Nab-paclitaxel in combination with FOLFOX for RGA patients. METHODS: We performed a non-randomised, open-label, phase II study. RGA patients were assigned to receive neoadjuvant Nab-paclitaxel (150 mg/m2) and FOLFOX q2w for six cycles. Six additional post-operative cycles were kept at the investigator's discretion. The primary end-point was complete pathological response (tumour regression grade [TRG1]) rate. According to Fleming design, 49 patients were required to test H0 (10% TRG1) and H1 (25% TRG1). To reject H0, TRG1 had to be achieved in 8 patients. RESULTS: Forty-nine patients were included. Median number of neoadjuvant chemotherapy cycles was 6 (range, 3-6). Median dose intensity for Nab-paclitaxel, oxaliplatin and 5-FU was 96% (38-103%), 97% (47-103%) and 99% (50-112%), respectively. Surgery could not be performed in 5 (10.2%) patients. Tumour resection was R0 for 42 of 44 (95.5%) patients. Pathological review classified tumours as TRG1 to TRG5 for 8 (16.3%), 11 (22.5%), 4 (8.2%), 18 (36.7%) and 3 (6.1%) patients, respectively. Grade 3 or worse toxicities during neoadjuvant chemotherapy were non-febrile neutropenia (20.4%), nausea (8.2%), diarrhoea (8.2%) and neuropathy (6.1%). Of 44 patients, 14 (31.8%) experienced surgery-related complications and three (6.8%) died of surgical complications. CONCLUSION: This regimen shows promising activity. Toxicity is manageable but a meaningful rate of surgical complications was observed. This strategy deserves investigation in phase III studies.

Bevacizumab improves survival in patients with synchronous colorectal liver metastases provided the primary tumor is resected first.

BACKGROUND: Multimodal strategy including chemotherapy and hepatectomy is advocated for the management of colorectal liver metastases (CRLM). The aim of this study was to evaluate the impact of neoadjuvant Bevacizumab-based chemotherapy on survival in patients with resected stage IVA colorectal cancer and liver metastases. METHODS: Data from 120 consecutive patients who received neoadjuvant chemotherapy and underwent curative-intent hepatectomy for synchronous CRLM were retrospectively reviewed. Overall survival (OS) was stratified according to administration of Bevacizumab before liver resection and surgical strategy, i.e., classical strategy (primary tumor resection first) versus reverse strategy (liver metastases resection first). RESULTS: Patients who received Bevacizumab (n = 37; 30%) had a higher number of CRLM (p = 0.003) and underwent more often reverse strategy (p = 0.005), as compared to those who did not (n = 83; 70%). Bevacizumab was associated with an improved OS compared with conventional chemotherapy (p = 0.04). After stratifying by the surgical strategy, Bevacizumab was associated with improved OS in patients who had classical strategy (p = 0.03). In contrast, Bevacizumab had no impact on OS among patients who had liver metastases resection first (p = 0.89). CONCLUSIONS: Neoadjuvant Bevacizumab-based chemotherapy was associated with improved OS in patients who underwent liver resection of synchronous CRLM, especially in those who underwent primary tumor resection first.

Differential roles of JNK and Smad2 signaling pathways in the inhibition of c-Myc-induced cell death by TGF-beta.

The transforming growth factor beta (TGF-beta) plays an important role in constraining cellular proliferation, but it is also a potent inducer of programmed cell death or apoptosis. Here, we demonstrate that TGF-beta can have an opposite effect, acting as a survival factor to prevent c-Myc-induced cell death in Rat-1 fibroblasts. However, in marked contrast to TGF-beta, Smad2, which is a critical intracellular mediator of the TGF-beta signaling pathway, functions as an antagonist to induce increased cell death. The protective activity of TGF-beta was associated with the activation of c-Jun N-terminal Kinase (JNK) and was not linked to the ability of TGF-beta to promote cell cycle progression. Expression of dominant-interfering forms of various components of the JNK signaling pathway, including Rac1, Cdc42, mitogen-activated protein kinase kinase 4 (MKK4), and c-Jun, abolished TGF-beta-mediated cell survival. Furthermore, overexpression of the constitutively activated mutant RacL61F37A, which selectively stimulates JNK cascade but not G1 cell cycle progression or actin polymerization, was sufficient to prevent apoptosis induced by c-Myc. These findings describe a differential effect of two separated signaling pathways of TGF-beta and indicate for the first time that Smad2 can act as antagonist to suppress TGF-beta-dependent cell survival. Oncogene (2000) 19, 1277 - 1287.

Influence of tamoxifen on carotid intima-media thickness in postmenopausal women.

BACKGROUND: Intima-media thickness of the common carotid artery (IMT-CCA) is an early marker of atherosclerosis. Tamoxifen is a selective estrogen-receptor modulator with estrogen-like effects on cardiovascular risk factors but as-yet unexplored effects on carotid artery structure. The goal of this study was to determine the influence of tamoxifen on IMT-CCA in menopausal women. METHODS AND RESULTS: With a predefined calculation of the sample size, 67 menopausal women with cancer who were treated with tamoxifen for > or =1 year and 37 menopausal women with cancer who were never treated with tamoxifen were enrolled. IMT-CCA, internal diameter, and pulse pressure were determined with a high-definition echotracking device and applanation tonometry in a central core laboratory that was blinded to treatment. Both groups were similar for clinical characteristics, including cardiovascular risk factors. IMT and internal diameter were significantly lower in the tamoxifen group (mean duration of treatment, 2.4+/-0.9 years) than in the control group (609+/-117 microm versus 662+/-147 microm, P=0.04, and 4.89+/-0.60 mm versus 5.12+/-0.58 mm, P=0.03, respectively). Pulse pressure was not influenced by the use of tamoxifen. After adjustment for age, cardiovascular risk factors, carotid pulse pressure, duration of menopause, and previous use of hormone replacement therapy, IMT remained significantly lower among tamoxifen users (P<0.00001), with an impact on IMT (-70 microm) equivalent to spontaneous evolution with 12 years of aging (5 microm/y). CONCLUSION: The use of tamoxifen was associated with a significantly lower carotid IMT in menopausal women with cancer. Randomized trials are needed to confirm the cardioprotective effect of selective estrogen-receptor modulators in terms of prevention of atherosclerosis.

A review of GERCOD trials of bimonthly leucovorin plus 5-fluorouracil 48-h continuous infusion in advanced colorectal cancer: evolution of a regimen. Groupe d'Etude et de Recherche sur les Cancers de l'Ovaire et Digestifs (GERCOD).

The addition of leucovorin (LV) to 5-fluorouracil (5-FU) in advanced colorectal cancer has shown improved tumour response rates in many trials, but the optimal LV/5-FU regimen has yet to be determined. Seven studies carried out over the last 12 years to evaluate the safety and efficacy of various LV/5-FU regimens are reviewed. The initial bimonthly high-dose LV/5-FU regimen consisted of high-dose LV as a 2-h infusion followed by 5-FU as an intravenous (i.v.) bolus plus a 22-h continuous infusion (CI), repeated for two consecutive days every 2 weeks. A randomised comparison of this bimonthly high-dose LV/5-FU regimen and the NCCTG-Mayo Clinic regimen (LV [20 mg/m2/day] followed by 5-FU bolus [425 mg/m2/day] daily x 5, every 4 weeks) showed that the bimonthly high-dose LV/5-FU regimen was superior to the NCCTG-Mayo Clinic regimen in response rate and progression-free survival, but showed no difference in overall survival. In addition, toxicity was less with the bimonthly high-dose LV/5-FU regimen. These promising results led to a phase II trial of a simplified bimonthly high-dose LV/5-FU regimen consisting of LV (500 mg/m2/day) and a 48-h CI of 5-FU (1.5-2 g/m2/day) which has been administered alone or in combination. In summary, GERCOD-sponsored studies have further demonstrated that high doses of both LV and 5-FU given as a CI can improve response rates still more with acceptable toxicity. Further studies are focused on the effectiveness of combination with oxaliplatin or CPT-11 in metastatic disease and the use of high-dose LV/5-FU regimens for colorectal cancer in the adjuvant setting.

Oxaliplatin with high-dose leucovorin and 5-fluorouracil 48-hour continuous infusion in pretreated metastatic colorectal cancer.

Oxaliplatin has shown in vivo cytotoxic activity against colorectal cell lines. Preliminary studies suggest potentiation of fluorouracil (5-FU). To assess this issue, we performed a phase II study in pretreated patients with advanced colorectal cancer (CRC) resistant to leucovorin and 5-FU. The regimen (FOLFOX2) consisted of oxaliplatin 100 mg/m2 as a 2-h infusion on day 1; leucovorin 500 mg/m2 as a 2-h infusion, followed by 5-FU 24-h infusion 1.5-2 g/m2 for two consecutive days every 2 weeks. The initial 5-FU dose was 1.5 g/m2 for two cycles and increased to 2 g/m2 in case of no toxicity > grade 2. 46 patients were treated, all with disease progression on leucovorin and 5-FU therapy for metastatic disease, or relapse less than 6 months after the end of adjuvant therapy. One complete response (CR) and 20 partial responses (PRs) were observed for an overall response rate of 46%. 22 patients had prior documented progression while receiving the same schedule of leucovorin and 5-FU as the one used in the FOLFOX2 regimen, and among them, 10 had PRs (45%). From the start of FOLFOX2, median progression-free survival was 7 months and median survival 17 months. WHO toxicity > or = grade 3 per patient was: peripheral neuropathy 9%, nausea 4%, diarrhoea 9%, mucositis 13%, neutropenia 39%, thrombocytopenia 11%, alopecia 9%, and allergy 2%. Overall, 21 patients (46%) experienced grade 3-4 toxicity. This combination of leucovorin, 5-FU and oxaliplatin achieves a high response rate in pretreated patients with CRC resistant to leucovorin and 5-FU. Limiting toxicities are neutropenia and peripheral neuropathy.