ABSTRACT
BACKGROUND: Prior trials validated triplet chemotherapy (Tri-CT) with bevacizumab as first line treatment for metastatic colorectal cancer (mCRC) but real-world data are scarce and practices remain heterogeneous. AIMS: To evaluate Tri-CT +/- bevacizumab efficacy and safety, and to identify factors influencing treatment decisions. METHODS: The COLOTRIP retrospective study enrolled mCRC patients treated from 2014 to 2019 in 14 French centers. RESULTS: Of 299 patients (81% PS 0-1, 58% RAS-mutated and 19% BRAF-mutated), 51% received Tri-CT and 49% Tri-CT + bevacizumab. Metastatic disease was classified as resectable (6.5%), potentially resectable (40%), and unresectable (54%). Bevacizumab use was associated with primary tumor location, mutational status and number of metastases. Median overall survival was 33.5 months in the Tri-CT group and 23.9 months in the Tri-CT + bevacizumab group, with median progression-free survival being 14.5 and 11.4 months. After adjusting for initial characteristics, no difference in survival was noted. Around 30% of patients experienced grade ≥3 adverse events. CONCLUSIONS: This study highlights several factors influencing Tri-CT use +/- bevacizumab decision and confirms the real-world good oncological outcomes and tolerability of these regimens in mCRC patients. Our results suggest that Tri-CT alone may by an appropriate option for specific subgroups of patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Bevacizumab , Colorectal Neoplasms , Humans , Bevacizumab/administration & dosage , Bevacizumab/therapeutic use , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Colorectal Neoplasms/genetics , Colorectal Neoplasms/mortality , Male , Female , Retrospective Studies , Aged , Middle Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , France , Antineoplastic Agents, Immunological/therapeutic use , Antineoplastic Agents, Immunological/administration & dosage , Progression-Free Survival , Adult , Aged, 80 and overABSTRACT
BACKGROUND: Histological characteristics at the invasive front may reflect tumor aggressiveness; specifically, tumor budding (Bd) is an emerging prognostic biomarker in colon cancer (CC). We explored further the significance of Bd for risk stratification by evaluating survival of stage III CC patients included in the IDEA-France phase III trial. PATIENTS AND METHODS: This post-hoc study was conducted on tissue slides from 1048 stage III CC patients. Bd was scored by central review by the Bd criteria of the 2016 International Tumor Budding Consensus Conference (ITBCC 2016) and classified as Bd1 (0-4 buds/0.785 mm2), Bd2 (5-9 buds), and Bd3 (≥10 buds) categories. Disease-free survival (DFS) and overall survival (OS) were analyzed by the log-rank test. Clinicopathological features and Immunoscore® were correlated with Bd. RESULTS: Overall, Bd1, Bd2, and Bd3 were observed in 39%, 28%, and 33% of CC, respectively. Bd2 and Bd3 were associated with vascular (P = 0.002) and perineural invasions (P = 0.0009). The 3-year DFS and the 5-year OS rates for Bd (1 versus 2-3) were 79.4% versus 67.2% (P = 0.001) and 89.2% versus 80.8% (P = 0.001), respectively. This was confirmed after adjustment for relevant clinicopathological features for DFS [hazard ratio (HR) 1.41, 95% confidence interval (CI) 1.12-1.77, P = 0.003] and OS (HR 1.65, 95% CI 1.22-2.22, P = 0.001). When combined with pTN stage and Immunoscore® subgroups, Bd significantly improved disease prognostication. CONCLUSIONS: Bd demonstrated its independent prognostic value for DFS and OS. Given these findings, Bd as per the ITBCC 2016 should be mandatory in every pathology report in stage III CC patients. Bd and Immunoscore® could play a complementary role in personalized health care in this setting.
Subject(s)
Colonic Neoplasms , Colonic Neoplasms/pathology , Disease-Free Survival , France/epidemiology , Humans , Neoplasm Staging , Prognosis , Proportional Hazards ModelsABSTRACT
BACKGROUND: BRAF mutation is associated with a poor prognosis in patients with metastatic colorectal cancer. For patients with resectable colorectal liver metastases (CRLMs), the prognostic impact of BRAF mutation is unknown and the benefit of surgery debated. This nationwide intergroup (ACHBT, FRENCH, AGEO) study aimed to evaluate the oncological outcome of patients undergoing liver resection for BRAF-mutated CRLMs. METHODS: The study included patients who underwent resection for BRAF-mutated CRLMs in 24 centres between 2012 and 2016. A case-matched comparison was made with 183 patients who underwent resection of CRLMs with wild-type BRAF during the same interval. RESULTS: Sixty-six patients who underwent resection for BRAF-mutated CRLMs in 24 centres were compared with 183 patients with wild-type BRAF. The 1- and 3-year disease-free survival (DFS) rates were 46 and 19 per cent for the BRAF-mutated group, and 55·4 and 27·8 per cent for the group with wild-type BRAF (P = 0·430). In multivariable analysis, BRAF mutation was not associated with worse DFS (hazard ratio 1·16, 95 per cent c.i. 0·72 to 1·85; P = 0·547). The 1- and 3-year overall survival rates after surgery were 94 and 54 per cent respectively among patients with BRAF mutation, and 95·8 and 82·9 per cent in those with wild-type BRAF (P = 0·004). Median survival after disease progression was 23·0 (95 per cent c.i. 11·0 to 35·0) months among patients with mutated BRAF and 44·3 (35·9 to 52·6) months in those with wild-type BRAF (P = 0·050). Multisite disease progression was more common in the BRAF-mutated group (48 versus 29·8 per cent; P = 0·034). CONCLUSION: These results support surgical treatment for resectable BRAF-mutated CRLM, as BRAF mutation by itself does not increase the risk of relapse after resection. BRAF mutation is associated with worse survival in patients whose disease relapses after resection of CRLM, as for non-metastatic colorectal cancer.
Subject(s)
Colorectal Neoplasms/genetics , Liver Neoplasms/secondary , Neoplasm Recurrence, Local/genetics , Proto-Oncogene Proteins B-raf/genetics , Aged , Case-Control Studies , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , Colorectal Neoplasms/surgery , Disease-Free Survival , Female , Hepatectomy , Humans , Liver Neoplasms/genetics , Liver Neoplasms/mortality , Liver Neoplasms/surgery , Male , Middle Aged , Mutation/genetics , Survival AnalysisABSTRACT
Background: RAS mutations are currently sought for in tumor samples, which takes a median of almost 3 weeks in western European countries. This creates problems in clinical situations that require urgent treatment and for inclusion in therapeutic trials that need RAS status for randomization. Analysis of circulating tumor DNA might help to shorten the time required to determine RAS mutational status before anti-epidermal growth factor receptor antibody therapy for metastatic colorectal cancer. Here we compared plasma with tissue RAS analysis in a large prospective multicenter cohort. Patients and methods: Plasma samples were collected prospectively from chemotherapy-naive patients and analyzed centrally by next-generation sequencing (NGS) with the colon lung cancer V2 Ampliseq panel and by methylation digital PCR (WIF1 and NPY genes). Tumoral RAS status was determined locally, in parallel, according to routine practice. For a minimal κ coefficient of 0.7, reflecting acceptable concordance (precision ± 0.07), with an estimated 5% of non-exploitable data, 425 subjects were necessary. Results: From July 2015 to December 2016, 425 patients were enrolled. For the 412 patients with available paired plasma and tumor samples, the κ coefficient was 0.71 [95% confidence interval (CI), 0.64-0.77] and accuracy was 85.2% (95% CI, 81.4% to 88.5%). In the 329 patients with detectable ctDNA (at least one mutation or one methylated biomarker), the κ coefficient was 0.89 (95% CI, 0.84-0.94) and accuracy was 94.8% (95% CI, 91.9% to 97.0%). The absence of liver metastases was the main clinical factor associated with inconclusive circulating tumor DNA results [odds ratio = 0.11 (95% CI, 0.06-0.21)]. In patients with liver metastases, accuracy was 93.5% with NGS alone and 97% with NGS plus the methylated biomarkers. Conclusion: This prospective trial demonstrates excellent concordance between RAS status in plasma and tumor tissue from patients with colorectal cancer and liver metastases, thus validating plasma testing for routine RAS mutation analysis in these patients. Clinical Trial registration: Clinicaltrials.gov, NCT02502656.
Subject(s)
Biomarkers, Tumor/blood , Circulating Tumor DNA/genetics , Colorectal Neoplasms/blood , Liver Neoplasms/blood , ras Proteins/genetics , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , DNA Mutational Analysis/methods , Female , Humans , Liver Neoplasms/genetics , Liver Neoplasms/secondary , Male , Middle Aged , Patient Selection , Predictive Value of Tests , Prospective Studies , Randomized Controlled Trials as Topic , Young AdultABSTRACT
BACKGROUND: While tumor-tissue remains the 'gold standard' for genetic analysis in cancer patients, it is challenged with the advent of circulating cell-free tumor DNA (ctDNA) analysis from blood samples. Here, we broaden our previous study on the clinical validation of plasma DNA in metastatic colorectal cancer patients, by evaluating its clinical utility under standard management care. PATIENTS AND METHODS: Concordance and data turnaround-time of ctDNA when compared with tumor-tissue analysis were studied in a real-time blinded prospective multicenter clinical study (n = 140 metastatic colorectal patients). Results are presented according to STARD criteria and were discussed in regard with clinical outcomes of patients. RESULTS: Much more mutations were found by ctDNA analysis: 59%, 11.8% and 14.4% of the patients were found KRAS, NRAS and BRAF mutant by ctDNA analysis instead of 44%, 8.8% and 7.2% by tumor-tissue analysis. Median tumor-tissue data turnaround-time was 16 days while 2 days for ctDNA analysis. Discordant samples analysis revealed that use of biopsy, long delay between tumor-tissue and blood collection and resection of the tumor at time of blood draw, tumor site, or type of tissue analyzed seem to affect concordance. Altogether, the clinical data with respect to the anti-epidermal growth factor receptor response (RAS status) and the prognosis (BRAF status) of those discordant patients do not appear contradictory to the mutational status as determined by plasma analysis. Lastly, we present the first distribution profile of the RAS and BRAF hotspot mutations as determined by ctDNA analysis (n = 119), revealing a high proportion of patients with multiple mutations (45% of the population and up to 5 mutations) and only 24% of WT scored patients for both genes. Mutation profile as determined from ctDNA analysis with using various detection thresholds highlights the importance of the test sensitivity. CONCLUSION: Our study showed that ctDNA could replace tumor-tissue analysis, and also clinical utility of ctDNA analysis by considerably reducing data turnaround time.
Subject(s)
Antineoplastic Agents/therapeutic use , Colorectal Neoplasms/genetics , DNA, Neoplasm/blood , ErbB Receptors/antagonists & inhibitors , Neoplasm Metastasis/genetics , Point Mutation , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/pharmacology , Colorectal Neoplasms/blood , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Female , Genes, ras , Humans , Male , Middle Aged , Prospective Studies , Proto-Oncogene Proteins B-raf/genetics , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: A microsatellite instability (MSI) phenotype is found in about 12% of colorectal cancers (CRCs) and is associated with a low recurrence rate after curative surgery. Several studies have identified clinical and pathological factors predictive of recurrence in resected CRC, but not in the MSI subgroup. PATIENTS AND METHODS: This multicentre retrospective study included patients with stage I, II or III MSI CRCs. Disease-free survival (DFS) was calculated with the Kaplan-Meier method. Factors associated with DFS were identified in univariate and multivariate Cox analyses. RESULTS: We studied 521 patients with MSI CRC. Respectively 11%, 51% and 38% of patients were at stage I, II and III. Mean age was 68.7years and 36% of the patients received adjuvant chemotherapy. Median follow-up was 32.8months. The disease recurrence rates were 6% and 21% in stage II and III patients, respectively. The 3-year DFS rate was 77%. In univariate analysis, age, bowel obstruction, lymph node invasion, stage T4, vascular emboli, lymphatic invasion and perinervous invasion were associated with poorer DFS (P<0.05). Three relevant independent predictors of poor DFS were identified in multivariate analysis, namely bowel obstruction (HR=2.46; 95%CI 1.31-4.62, P=0.005), vascular emboli (HR=2.79; 95%CI 1.74-4.47, P<0.001) and stage T4 (HR=2.16; 95%CI 1.31-3.56, P=0.002). CONCLUSIONS: Bowel obstruction, vascular emboli and stage T4 are independently associated with MSI CRC recurrence, suggesting that screening for vascular emboli in routine clinical practice may assist with adjuvant chemotherapy decision-making.
Subject(s)
Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/genetics , Microsatellite Instability , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , Chemotherapy, Adjuvant , Colorectal Neoplasms/therapy , Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/therapy , Digestive System Surgical Procedures , Disease-Free Survival , Female , Humans , Male , Middle Aged , Prognosis , Retrospective StudiesABSTRACT
BACKGROUND: Pancreatic carcinoma is one of the leading causes of cancer-related mortality. At the time of diagnosis, 30% of patients present with a locally advanced pancreatic carcinoma (LAPC). As circulating tumor cells (CTCs) count may be a surrogate of the cancer metastatic abilities, CTC detection rates and prognostic value were studied in a prospective cohort of LAPC patients. PATIENTS AND METHODS: An LAP07 international multicenter randomized study assesses in patients whose LAPC is controlled after 4 months of chemotherapy whether chemoradiotherapy could increase survival versus continuation of chemotherapy. A subgroup of patients included in the LAP07 trial was screened for CTCs (CellSearch®) before the start of the chemotherapy and after 2 months of treatment. Patient characteristics and survival were obtained prospectively and were correlated with CTC detection. RESULTS: Seventy-nine patients were included. One or more CTCs/7.5 ml were detected in 5% of patients before treatment and in 9% of patients after 2 months of treatment (overall detection rate: 11% of patients). CTC positivity was associated with poor tumor differentiation (P = 0.04), and with shorter overall survival (OS) in multivariable analysis (RR = 2.5, P = 0.01), together with anemia. CONCLUSIONS: The evaluation of micrometastatic disease using CTC detection appears as a promising prognostic tool in LAPC patients.
Subject(s)
Adenocarcinoma/pathology , Neoplasm Metastasis/diagnosis , Neoplastic Cells, Circulating , Pancreatic Neoplasms/pathology , Adenocarcinoma/drug therapy , Adenocarcinoma/radiotherapy , Adult , Antimetabolites, Antineoplastic/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor , Chemoradiotherapy , Cohort Studies , Deoxycytidine/analogs & derivatives , Deoxycytidine/therapeutic use , Disease-Free Survival , Female , Humans , Male , Middle Aged , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/radiotherapy , Prospective Studies , Survival , Young Adult , GemcitabineABSTRACT
BACKGROUND: The detection of KRAS mutations is mandatory to initiate an anti-epidermal growth factor receptor (EGFR) antibody in the treatment of metastatic colorectal carcinoma (mCRC). PATIENTS AND METHODS: This observational retrospective study was performed in 160 French centres during a 2-week period in 2011. Its main objective was to evaluate the rate of KRAS testing in patients with mCRC having initiated their first-line therapy. Secondary objectives included time of process, techniques used and reasons for non-prescription. RESULTS: Five hundred and thirty eight mCRC patients (67.1 ± 11.3 years, synchronous metastases: 69.9%) were enrolled in the study. KRAS testing was prescribed in 81.1% of patients, in a median of 15 days after the diagnosis of metastases, and of 15 days prior to the initiation of the first-line metastatic chemotherapy. KRAS status was available for 87% of patients, after 23.6 ± 28.2 days, but after the choice of the first-line therapy in 56.6% of patients. Heterogeneity of reception time was noteworthy within regions (8.3 ± 7 days to 38.8 ± 101 days). KRAS testing was not prescribed mainly due to the planned non-prescription of an anti-EGFR antibody. CONCLUSION: This study confirmed that KRAS testing is definitely part of the management of most of mCRC patients, despite discrepancies observed in the rate of prescription and the time of results.
Subject(s)
Colonic Neoplasms/genetics , Genes, ras/genetics , Mutation/genetics , Rectal Neoplasms/genetics , Adult , Aged , Antineoplastic Agents/therapeutic use , Colonic Neoplasms/drug therapy , DNA Mutational Analysis/statistics & numerical data , ErbB Receptors/antagonists & inhibitors , Female , France , Genetic Testing/statistics & numerical data , Genotype , Humans , Male , Middle Aged , Neoplasm Metastasis , Practice Patterns, Physicians'/statistics & numerical data , Rectal Neoplasms/drug therapy , Referral and Consultation/statistics & numerical data , Retrospective Studies , Time FactorsABSTRACT
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.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Camptothecin/analogs & derivatives , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Proto-Oncogene Proteins/genetics , ras Proteins/genetics , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/adverse effects , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Camptothecin/adverse effects , Camptothecin/therapeutic use , Colorectal Neoplasms/pathology , Drug Resistance, Neoplasm , ErbB Receptors/genetics , Female , GTP Phosphohydrolases/genetics , Humans , Irinotecan , Male , Membrane Proteins/genetics , Middle Aged , Neoplasm Metastasis/drug therapy , Panitumumab , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins p21(ras)ABSTRACT
PURPOSE: Cutaneous adverse events induced by epidermal growth factor receptor (EGFR) inhibitors can hamper the patients' quality of life. The aim of our work was to draft an algorithm for the optimised management of this skin toxicity. METHODS: This algorithm was built in three steps under the responsibility of a steering committee. Step I: a systematic literature analysis (SLA) has been performed. Step II: the collection of information about practices was performed through a questionnaire.These questions were asked during regional meetings to which oncologists, gastro-enterologists, radiotherapists, and dermatologists were invited. Step III: a final meeting was organised involving the bibliography group and the steering committee and regional scientific committees for proposing a final algorithm. RESULTS: Step I: 14 publications were selected to evaluate the use of cyclines as curative or prophylactic treatment of the folliculitis induced by EGFR inhibitors. Nineteen publications were retained for the topical treatment of the folliculitis. Forty-six articles were selected for the management of the cutaneous lesions in link with appendages and 12 for xerosis and pruritus. Step II: 96 delegates attended the seven regional meetings and 67 questionnaires were analysed. Step III: a final algorithm was proposed on the basis of the conclusions of the first two steps and expert opinions present at this final meeting. The different propositions were unanimously approved by the 14 experts who voted. CONCLUSIONS: This multidisciplinary study summarising published data and current practices produced a therapeutic algorithm, which should facilitate the standardised, optimised management of skin toxicity associated with EGFR inhibitors in France.
Subject(s)
Antineoplastic Agents/adverse effects , ErbB Receptors/antagonists & inhibitors , Tetracyclines/therapeutic use , Algorithms , Antineoplastic Agents/therapeutic use , Drug Eruptions/etiology , Folliculitis/chemically induced , Folliculitis/drug therapy , France , Humans , Neoplasms/drug therapy , Practice Patterns, Physicians'/statistics & numerical data , Quality of Life , Surveys and QuestionnairesABSTRACT
Cetuximab was approved using a weekly schedule, alone or in combination with chemotherapy (CT). However, many CT regimens in metastatic colorectal cancer (CRC) are delivered every 2 weeks (q2wks). Preliminary data suggested that a simplified schedule using cetuximab q2wks, 500 mg/m² would be equivalent to the standard weekly administration. Medical data of all patients with advanced CRC who received cetuximab q2wks were retrospectively collected and checked for consistency by an independent monitor in 4 European centers. Ninety-one patients were treated between 2005 and 2007 when the K-RAS mutational status of tumors was not determined routinely. They received a median of 4 (0-5) previous drugs, including previous weekly cetuximab in 38.5% of patients. Cetuximab q2wks was associated with an irinotecan-based regimen in 85.7% of patients. The median number of cetuximab administrations was 6 (1-23). Skin toxicity was observed in 68.2% of evaluable patients (grade 3 in 15%). Only one grade 1 allergy was reported. In the 84 patients beyond first-line therapy, response rate was 29.3%. The median progression-free survival was 3.0 months (range 2.2-3.8), and median overall survival was 9.0 months (range 6.2-11.8). Cetuximab q2wks appears safe and effective in heavily pretreated patients and convenient in combination with q2wks CT schedules.
Subject(s)
Antibodies, Monoclonal/administration & dosage , Colorectal Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized , Cetuximab , Colorectal Neoplasms/pathology , Disease-Free Survival , Drug Administration Schedule , Feasibility Studies , Female , Follow-Up Studies , Humans , Male , Middle Aged , Retrospective StudiesABSTRACT
PURPOSE: To describe retrospectively the overall survival, the cancer specific survival and the tumor control in an homogeneous series of patients with epidermoid carcinoma of the anal canal treated with definitive radiotherapy; to assess the impact of brachytherapy, chemotherapy and pre-radiotherapy resection on the risk of recurrence. PATIENTS AND METHODS: From 1997 to 2007, 57 patients (pts) presenting with an epidermoid carcinoma of the anal canal (T1: 14, T2: 33, T3-4: 10, N0: 31, N1: 19, N2: 3, N3: 4, M0: 57) were treated with definitive radiotherapy by the same radiation oncologist. The treatment included an external beam irradiation (EBRT) given to the posterior pelvis (45Gy/25 fractions) and, six weeks later, a boost delivered with interstitial brachytherapy (37/57) or external beam irradiation (20/57). Twelve pts had undergone a surgical resection of the tumour before radiotherapy. A belly board was used for EBRT in 13 pts. A concurrent platinum based chemotherapy was done in 42 pts. The mean follow-up was 57 months. RESULTS: The overall survival rate at 5 years was 89% with a cause specific survival of 96%. Five patients recurred (5-year rate: 12%: four had local relapse (5-year rate: 8%), four had groin recurrence, and distant metastases were seen in two. In univariate analysis, the risk of relapse was higher in patients who had undergone a pre-radiation excision (p=0.018), in those who did not receive chemotherapy (p=0.076) and in those who were irradiated on a belly board (p=0.049). In multivariate analysis, a pre-radiotherapy resection (p=0.084) had an inverse impact on the tumour control reaching the level of statistical significance and the use of a belly board was of marginal influence (p=0.13). CONCLUSION: Radiotherapy and chemoradiation with cisplatine-based chemotherapy cure a vast majority of patients with epidermoid carcinoma of the anal canal. Therapeutic factors that may interfere with the definition of the target volume and the patients' repositioning may decrease the efficacy of radiotherapy. Pre-radiotherapy surgical resection should be avoided.
Subject(s)
Anal Canal/surgery , Anus Neoplasms/mortality , Anus Neoplasms/therapy , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/therapeutic use , Brachytherapy , Chemotherapy, Adjuvant , Cisplatin/therapeutic use , Dose Fractionation, Radiation , Female , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/epidemiology , Patient Positioning , Retrospective StudiesABSTRACT
PURPOSE: GemOx was defined as a D1-D2 schedule, based on preclinical data. In order to improve convenience for patients, we evaluated a simplified D1-D1 GemOx regimen (S-GemOx) in MPA. PATIENTS AND METHODS: Patients (pts) with MPA were 2:1 randomly assigned for first-line treatment to S-GemOx (gemcitabine 1,000 mg/m(2), 100-minute infusion D1 immediately followed by oxaliplatin 100 mg/m(2), 120-minute infusion) or to GemOx (Gem D1 and ox D2). Treatment was repeated in each arm every 2 weeks until disease progression. Stratification was performed on center and PS. RESULTS: Fifty-seven pts were enrolled, S-GemOx = 37 (PS 2: 22%), GemOx = 20 (PS 2: 20%). Populations were well balanced for age (64.9 vs 66.6 years); gender (57 vs 65% male), location of primary tumor (pancreas head: 49 vs 50%), and metastatic sites (liver 76 vs 85%; peritoneum 24 vs 20%; lung 16 vs 10%; lymph nodes 14 vs 15%; other 5 vs 5%). Tumor differentiation significantly differed between the 2 groups (S-GemOx: 8% poorly differentiated vs GemOx: 36%). Response rate was 27% (95% CI: 12-42) in arm S-GemOx and 10% (95% CI: 0-23) in GemOx. Median PFS was 4.0 and 2.5 months in S-GemOx and GemOx, respectively. Median OS was 7.6 and 3.2 months in S-GemOx and GemOx, respectively. Since more cycles were administered in S-GemOx (8.5 [1-29] vs 5.8 [2-12]), grade 3 oxaliplatin-induced neuropathy was higher in S-GemOx [21.6 vs 0%]). CONCLUSIONS: Activity and tolerance of S-GemOx are in the same range as compared to our previous experiences of classical GemOx in metastatic pancreatic cancer. The very bad outcome of patients randomized in GemOx arm could at least be in part explained by the high-rate of poorly differentiated tumors.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Pancreatic Neoplasms/drug therapy , Adenocarcinoma/pathology , Adenocarcinoma/secondary , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Deoxycytidine/analogs & derivatives , Drug Administration Schedule , Female , Humans , Male , Middle Aged , Organoplatinum Compounds/administration & dosage , Organoplatinum Compounds/adverse effects , Pancreatic Neoplasms/pathology , Remission InductionABSTRACT
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 Subject(s)
Alkaline Phosphatase/metabolism
, Antineoplastic Combined Chemotherapy Protocols/therapeutic use
, Colorectal Neoplasms/drug therapy
, Colorectal Neoplasms/enzymology
, Adult
, Aged
, Aged, 80 and over
, Antineoplastic Combined Chemotherapy Protocols/administration & dosage
, Antineoplastic Combined Chemotherapy Protocols/adverse effects
, Cohort Studies
, Colorectal Neoplasms/pathology
, Disease-Free Survival
, Female
, Fluorouracil/administration & dosage
, Fluorouracil/adverse effects
, Humans
, Leucovorin/administration & dosage
, Leucovorin/adverse effects
, Male
, Middle Aged
, Neoplasm Metastasis
, Organoplatinum Compounds/administration & dosage
, Organoplatinum Compounds/adverse effects
, Oxaliplatin
, Treatment Outcome
ABSTRACT
UNLABELLED: At the request of the National Thesaurus of Gastrointestinal Cancer (TNCD), the SOR program undertaken by the French federation of cancer centers and now led by the French National Cancer Institute, completed a systematic review to evaluate the value of perioperative chemotherapy in the management of resectable rectal adenocarcinoma in collaboration with clinician experts. METHODS: Results of a systematic literature search using Medline and Embase (from January 1996 to October 2007) were completed by a survey of Evidence- Based Medicine websites. All phase III randomized trials and systematic reviews comparing surgery (alone or associated with adjuvant therapy) to the same treatment plus chemotherapy, or comparing different perioperative chemotherapy modalities in patients with resectable rectal adenocarcinoma, were included in the study. The quality and clinical relevance of the trials were evaluated using validated checklists, allowing to associate each result with its level of evidence. Data synthesis was performed taking into account both efficacy and toxicity outcomes for each intervention. Finally, research recommendations were formulated. RESULTS: Of 29 studies meeting the selection criteria, 19 were included after critical methodological and clinical appraisal. As compared with preoperative radiotherapy, preoperative chemoradiotherapy with 5-fluorouracil and folinic acid does not improve overall or relapse-free survivals but decreases local recurrence rates. Postoperative chemotherapy with 5-fluorouracil and folinic acid does not improve overall or relapse-free survivals, whether the patients received preoperative radiotherapy or preoperative chemoradiotherapy, whereas it seems to decrease local recurrence rates after preoperative radiotherapy but not after preoperative chemoradiotherapy. As compared with postoperative chemoradiotherapy, preoperative chemoradiotherapy with continuous infusion of 5-fluorouracil does not improve overall or relapse-free survivals, but decreases local recurrence rates as well as acute and long-term toxicities. In the absence of preoperative radiotherapy, fluoropyrimidine-based postoperative chemotherapy improves both overall and relapse-free survivals and decreases local recurrence rates. CONCLUSIONS: Preoperative chemoradiotherapy reduces the risk of local recurrence as compared with preoperative radiotherapy or postoperative chemoradiotherapy.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents/therapeutic use , Rectal Neoplasms/drug therapy , Adenocarcinoma/radiotherapy , Adenocarcinoma/surgery , Clinical Trials, Phase III as Topic , Humans , Randomized Controlled Trials as Topic , Rectal Neoplasms/radiotherapy , Rectal Neoplasms/surgeryABSTRACT
This phase II trial was performed to evaluate the efficacy and tolerability of oral tegafur-uracil (UFT) with leucovorin (LV) combined with intravenous (i.v.) irinotecan every 3 weeks (TEGAFIRI) as first-line treatment for patients with metastatic colorectal cancer (mCRC). Patients received oral UFT 250 mg m(-2) day(-1) and LV 90 mg day(-1) in three divided daily doses for 14 days followed by a 1-week rest and i.v. irinotecan 250 mg m(-2) as a 90-min infusion every 3 weeks. Tumour responses, assessed every two cycles using RECIST criteria, were reviewed by an independent review committee. In 52 evaluable patients, the best overall response rate was 33% (95% confidence intervals (CI) 20-47%; 1 complete and 16 partial responses). The median time to progression was 5.4 months (95% CI 3.02-7.52 months) and median overall survival was 14.9 months (11.73-17.97 months). A total of 307 cycles were administered, with a median number of five cycles per patient (range: 1-10). The most common grade 3/4 toxicities were neutropenia (25% of patients), diarrhoea (22%), vomiting (11%) and anaemia (11%). The TEGAFIRI regimen is a feasible, well-tolerated and convenient treatment option for patients with non-resectable mCRC.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Colorectal Neoplasms/pathology , Female , Humans , Irinotecan , Leucovorin/administration & dosage , Male , Middle Aged , Neoplasm Metastasis , Tegafur/administration & dosage , Treatment Outcome , Uracil/administration & dosageABSTRACT
BACKGROUND: The purpose of the study was to prospectively evaluate the efficacy and tolerability of the FOLFIRI.3 regimen in patients with unresectable pancreatic adenocarcinoma. PATIENTS AND METHODS: Chemotherapy-naive patients with histologically proven advanced pancreatic adenocarcinoma were treated with the FOLFIRI.3 regimen, consisting of irinotecan 90 mg/m(2) as a 60-min infusion on day 1, leucovorin 400 mg/m(2) as a 2-h infusion on day 1, followed by 5-fluorouracil (5-FU) 2000 mg/m(2) as a 46-h infusion and irinotecan 90 mg/m(2), repeated on day 3, at the end of the 5-FU infusion, every 2 weeks. RESULTS: Forty patients were enrolled, of whom 29 (73%) had metastatic disease. A total of 441 cycles were delivered (1-53). Grade 3-4 neutropenia occurred in 35% of the patients, accompanied by fever in two cases. Other relevant grade 3-4 toxic effects were nausea-vomiting (27%) and diarrhea (25%). Grade 2 alopecia occurred in 48% of the patients. There were no treatment-related deaths. The confirmed response rate was 37.5%. Stable disease was observed in 27.5% of the patients. The median progression-free and overall survivals were 5.6 months and 12.1 months, respectively. The 1-year survival rate was 51%. CONCLUSION: The FOLFIRI.3 regimen seems to be active on advanced pancreatic cancer and to have a manageable toxicity profile. The lack of cross-resistance between FOLFIRI.3 and gemcitabine-based regimens allows efficient second-line therapies.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Pancreatic Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Disease-Free Survival , Female , Fluorouracil/administration & dosage , Humans , Irinotecan , Kaplan-Meier Estimate , Leucovorin/administration & dosage , Male , Middle Aged , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/pathology , Paris/epidemiology , Prospective Studies , Time Factors , Treatment OutcomeABSTRACT
In advanced colorectal cancer previously treated with oxaliplatin, efficacy of irinotecan-based chemotherapy is poor and the best regimen is not defined. We designed FOLFIRI-3 and conducted a phase II study to establish its efficacy and safety in advanced colorectal cancer patients previously treated with FOLFOX. FOLFIRI-3 consisted of irinotecan 100 mg m-2 as a 60-min infusion on day 1, running concurrently with leucovorin 200 mg m-2 as a 2-h infusion on day 1, followed by 46-h continuous infusion of 5-fluorouracil (5FU) 2000 mg m-2, and irinotecan 100 mg m-2 repeated on day 3, at the end of the 5FU infusion, every 2 weeks. Sixty-five patients entered the study. The intent-to-treat objective response rate was 23% (95% CI 13-33%). Disease was stable in 37% of patients, progressed in 26% and was not assessable in 14%. From the start of FOLFIRI-3, median progression-free survival was 4.7 months and median survival 10.5 months. Main toxicities (% of patients) were grade 3-4 diarrhoea 23% and grade 4 neutropenia 11%. FOLFIRI-3 is a promising regimen achieving high response rate and progression-free survival in patients previously treated with FOLFOX with a moderate toxicity.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Disease Progression , Female , Fluorouracil/administration & dosage , Humans , Infusions, Intravenous , Irinotecan , Leucovorin/administration & dosage , Male , Middle Aged , Organoplatinum Compounds/administration & dosage , Survival Analysis , Treatment OutcomeABSTRACT
UNLABELLED: Hemolytic uremic syndrome is a rare condition during gemcitabine therapy. METHODS: We report six new cases of hemolytic uremic syndrome related to gemcitabine, three issued from a retrospective study of 136 consecutive patients treated with gemcitabine for which a systematic screening of this side effect has been performed and 29 cases with clinical data available identified in the literature in order to better characterised frequency and clinical presentation of this side effect. RESULTS: In our series, frequency of HUS is 2.2% and is higher than this previously reported (0.015%) or estimated with the data of clinical trials analysed (0.072 %). For 35 cases with clinical data available, the patients were always treated for a local advanced and/or metastatic disease. For our cases and for literature cases, at the time of diagnosis of hemolytic uremic syndrome, mean number of doses received (mean+/-standard deviation. Minimum/maximum)) (personal cases: 26.5+/-6.6. 16/36, literature cases: 21+/-11. 8/54), cumulative dose received (g/m2) (personal cases : 24.5+/-6.3. 16/31.6, literature cases: 21.7+/-12.4. 2.4/54) and duration of treatment (months) (personal cases: 8.2+/-1.9. 5.6/11, literature cases: 8.5+/-4.0. 3/18) are very closed and high individual variations observed for these factors are not consistent with a time and/or dose dependant toxicity. New-onset hypertension or exacerbation of underlying hypertension is the most common clinical manifestation, with mild anemia; thrombocytopenia is inconstant. The degree of severity of renal failure is highly variable. The existence of subacute clinical form with progressive worsening of the symptoms and biological form at the time of diagnosis suggest the interest of a systematic clinical and biological screening of this side effect, before each injection of gemcitabine. Early prognosis is linked to the evolution of hemolytic uremic syndrome and after hemolytic uremic syndrome healing, cancer progression. Treatment include gemcitabine discontinuation, antihypertensive drugs and if necessary fresh frozen plasma. CONCLUSIONS: Systematic clinical and biological screening of hemolytic uremic syndrome during gemcitabine therapy should allow to better know this complication, to recognize and treat it earlier with a potential positive impact for patients.
Subject(s)
Antimetabolites, Antineoplastic/adverse effects , Antimetabolites, Antineoplastic/therapeutic use , Deoxycytidine/analogs & derivatives , Deoxycytidine/adverse effects , Deoxycytidine/therapeutic use , Hemolytic-Uremic Syndrome/chemically induced , Aged , Disease Progression , Female , Humans , Male , Middle Aged , Neoplasms/drug therapy , Prognosis , Retrospective Studies , GemcitabineABSTRACT
BACKGROUND: FOLFOX, a bimonthly combination of leucovorin, 5-fluorouracil and oxaliplatin, is active in metastatic colorectal cancer, but sometimes causes cumulative sensory neurotoxicity. This retrospective study investigated FOLFOX reintroduction after a break in treatment or following disease progression on another regimen. PATIENTS AND METHODS: FOLFOX was reintroduced in 29 patients. During their previous FOLFOX therapy, 24 had achieved a response, four were stable and one had progression. Median progression-free survival (PFS) was 33 weeks. Grade 3 neuropathy developed in nine and grade 2 neuropathy in eight patients. RESULTS: Following FOLFOX reintroduction, six patients (21%) showed a response, 15 (52%) were stable and eight (28%) had progression. Median PFS was 18 weeks. Grade 3 neuropathy developed in four patients and grade 2 neuropathy in 11. Two patients with previous grade 3 neuropathy had no recurrence of neuropathy after eight and 18 cycles, respectively. Among 13 patients who received no treatment between periods of FOLFOX therapy, four (31%) had a response and eight (62%) had stable disease. CONCLUSION: Reintroduction of oxaliplatin was feasible and achieved a response or stabilization in 73% of patients. These results support the concept of intensified, repeated short courses of FOLFOX, a strategy currently being evaluated prospectively in the OPTIMOX study.