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1.
Eur Rev Med Pharmacol Sci ; 24(6): 2994-3003, 2020 03.
Article in English | MEDLINE | ID: mdl-32271417

ABSTRACT

OBJECTIVE: To profile and correlate KRAS mutations with outcome in stage III colon cancer (CC) patients who underwent adjuvant chemotherapy following curative resection surgery. PATIENTS AND METHODS: In this retrospective study, eligible patients were those with resected stage III CC who underwent 6-months adjuvant chemotherapy, either with fluoropyrimidine monotherapy (FP) or with oxaliplatin-based regimens (O-FP). Disease-free survival (DFS) and overall survival (OS) were analyzed and computed using the Kaplan-Meier method and the log-rank test. RESULTS: The study population included 148 patients (n=65 FP and n=83 O-FP). We identified KRAS mutations in 41/148 (27%) patients, of which 18 (44%) received FP and 23 (56%) O-FP. Five-year DFS and OS were significantly higher in patients with KRAS wild-type vs. mutant [DFS: 78 vs. 56%, HR: 0.47 (95% CI: 0.25; 0.87), p=0.01; OS: 73 vs. 68%, HR: 0.44 (95% CI: 0.21; 0.88), p=0.01]. In patients treated with FP, the 5-year DFS and OS was significantly improved in the KRAS wild-type vs. mutant group, respectively [DFS: 80 vs. 43%, HR: 2.88 (95% CI: 0.67; 3.76), p=0.014; OS: 85 vs. 68%, HR: 0.27 (95% CI: 0.10; 0.73), p=0.005]. Conversely, 5-year DFS and OS were not statistically different for patients with KRAS wild-type vs. mutations treated with O-FP, respectively [DFS: 78 vs. 65%, HR: 1.59 (95% CI: 0.67; 3.76), p=0.281; OS: 80 vs. 75%, HR: 0.73 (95% CI: 0.55; 2.12), p=0.57)]. CONCLUSIONS: Our results suggest that curatively resected stage III CC patients exhibiting wild-type KRAS status might benefit from FP alone. Conversely, an oxaliplatin-containing regimen should be recommended in KRAS mutated patients.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colonic Neoplasms/therapy , Proto-Oncogene Proteins p21(ras)/genetics , Adult , Aged , Aged, 80 and over , Chemotherapy, Adjuvant , Colonic Neoplasms/diagnosis , Colonic Neoplasms/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Endonucleases/genetics , Endonucleases/metabolism , Female , Humans , Male , Middle Aged , Mutation , Neoplasm Staging , Proto-Oncogene Proteins p21(ras)/metabolism , Retrospective Studies
3.
Ann Oncol ; 27(5): 856-61, 2016 05.
Article in English | MEDLINE | ID: mdl-26884590

ABSTRACT

BACKGROUND: Sorafenib (S), a multitargeted tyrosine kinase inhibitor, is the standard of care for first-line systemic treatment of advanced hepatocellular carcinoma (HCC). Everolimus (E) is a potent inhibitor of mTOR, a pathway frequently activated in HCC. Preclinical data suggest that the combination S + E has additive effects compared with single-agent S. PATIENTS AND METHODS: Patients with unresectable or metastatic HCC and Child-Pugh ≤7 liver dysfunction were randomized to receive daily S 800 mg alone or with E 5 mg until progression or unacceptable toxicity. The primary end point was progression-free survival at 12 weeks (PFS12). The secondary end points included response rate, PFS, time to progression (TTP), overall survival (OS), duration of disease stabilization (DDS), safety, and quality-of-life (QoL) assessments. RESULTS: A total of 106 patients were randomized: 46 patients received S and 60 patients received S + E. Ninety-three patients were assessable for the primary end point and 105 patients for the safety analysis. The PFS12 rate was 70% [95% confidence interval (CI) 54-83] and 68% (95% CI 53-81) in patients randomized to S and S + E, respectively. The RECIST (mRECIST) response rate was 0% (23%) in the S arm and 10% (35%) in the S + E arm. Median PFS (6.6 versus 5.7 months), TTP (7.6 versus 6.3 months), DDS (6.7 versus 6.7 months), and OS (10 versus 12 months) were similar in the S and S + E arms, respectively. Grade 3/4 adverse events occurred in 72% and 86% of patients in arm S and arm S + E, respectively. Patients had similar QoL scores over time, except for a greater worsening in physical well-being and mood in the arm S + E. CONCLUSIONS: No evidence was found that S + E improves the efficacy compared with S alone. Combining 5 mg E with full-dose S is feasible, but more toxic than S alone. Further testing of this drug combination in molecularly unselected HCCs appears unwarranted. CLINICALTRIALSGOV: NCT01005199.


Subject(s)
Carcinoma, Hepatocellular/drug therapy , Everolimus/administration & dosage , Liver Neoplasms/drug therapy , Niacinamide/analogs & derivatives , Phenylurea Compounds/administration & dosage , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Carcinoma, Hepatocellular/pathology , Disease-Free Survival , Drug-Related Side Effects and Adverse Reactions/classification , Drug-Related Side Effects and Adverse Reactions/pathology , Female , Humans , Liver Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Niacinamide/administration & dosage , Sorafenib
4.
Ann Oncol ; 26(4): 709-714, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25605741

ABSTRACT

BACKGROUND: Chemotherapy plus bevacizumab is a standard option for first-line treatment in metastatic colorectal cancer (mCRC) patients. We assessed whether no continuation is non-inferior to continuation of bevacizumab after completing first-line chemotherapy. PATIENTS AND METHODS: In an open-label, phase III multicentre trial, patients with mCRC without disease progression after 4-6 months of standard first-line chemotherapy plus bevacizumab were randomly assigned to continuing bevacizumab at a standard dose or no treatment. CT scans were done every 6 weeks until disease progression. The primary end point was time to progression (TTP). A non-inferiority limit for hazard ratio (HR) of 0.727 was chosen to detect a difference in TTP of 6 weeks or less, with a one-sided significance level of 10% and a statistical power of 85%. RESULTS: The intention-to-treat population comprised 262 patients: median follow-up was 36.7 months. The median TTP was 4.1 [95% confidence interval (CI) 3.1-5.4] months for bevacizumab continuation versus 2.9 (95% CI 2.8-3.8) months for no continuation; HR 0.74 (95% CI 0.58-0.96). Non-inferiority could not be demonstrated. The median overall survival was 25.4 months for bevacizumab continuation versus 23.8 months (HR 0.83; 95% CI 0.63-1.1; P = 0.2) for no continuation. Severe adverse events were uncommon in the bevacizumab continuation arm. Costs for bevacizumab continuation were estimated to be ∼30,000 USD per patient. CONCLUSIONS: Non-inferiority could not be demonstrated for treatment holidays versus continuing bevacizumab monotheray, after 4-6 months of standard first-line chemotherapy plus bevacizumab. Based on no impact on overall survival and increased treatment costs, bevacizumab as a single agent is of no meaningful therapeutic value. More efficient treatment approaches are needed to maintain control of stabilized disease following induction therapy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, number NCT00544700.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Liver Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Bevacizumab/administration & dosage , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , Female , Fluorouracil/administration & dosage , Follow-Up Studies , Humans , Irinotecan , Leucovorin/administration & dosage , Liver Neoplasms/mortality , Liver Neoplasms/secondary , Male , Middle Aged , Neoplasm Staging , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Prognosis , Prospective Studies , Survival Rate , Young Adult
5.
Br J Cancer ; 108(3): 668-75, 2013 Feb 19.
Article in English | MEDLINE | ID: mdl-23348520

ABSTRACT

BACKGROUND: In metastatic colorectal cancer (mCRC), KRAS is the only validated biomarker used to select patients for administration of epidermal growth factor receptor (EGFR)-targeted therapies. To identify additional predictive markers, we investigated the importance of HER2, the primary EGFR dimerisation partner, in this particular disease. METHODS: We evaluated the HER2 gene status by fluorescence in situ hybridisation (FISH) in 170 KRAS wild-type mCRC patients treated with cetuximab or panitumumab. RESULTS: Depending on HER2 gene copy number status, patients showed three distinct cytogenetic profiles: 4% of patients had HER2 gene amplification (R:HER2/CEP17 ≥ 2) in all neoplastic cells (HER2-all-A), 61% of patients had HER2 gain due to polysomy or to gene amplification in minor clones (HER2-FISH+*), and 35% of patients had no or slight HER2 gain (HER2-FISH-). These subgroups were significantly correlated with different clinical behaviours, in terms of response rate (RR; P=0.0006), progression-free survival (PFS; P<0.0001) and overall survival (OS; P<0.0001). Patients with HER2-all-A profile experienced the worst outcome, patients with HER2-FISH- profile showed an intermediate behaviour and patients with HER2-FISH+* profile were related to the highest survival probability (median PFS in months: 2.5 vs 3.9 vs 7.6, respectively; median OS in months: 4.2 vs 9.7 vs 13, respectively). CONCLUSION: HER2 gene copy number status may influence the clinical response to anti-EGFR-targeted therapy in mCRC patients.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Gene Dosage , Receptor, ErbB-2/genetics , Adenocarcinoma/genetics , Adenocarcinoma/mortality , Adenocarcinoma/secondary , Adult , Aged , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Humanized , Cetuximab , Colorectal Neoplasms/genetics , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , Female , Follow-Up Studies , Gene Amplification , Gene Expression Regulation, Neoplastic , Humans , In Situ Hybridization, Fluorescence , Male , Middle Aged , Mutation/genetics , Panitumumab , Prognosis , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins p21(ras) , Retrospective Studies , Survival Rate , ras Proteins/genetics
6.
Support Care Cancer ; 21(1): 157-63, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22648205

ABSTRACT

PURPOSE: We evaluated the attitude in using chemotherapy near the end of life in advanced pancreatic adenocarcinoma (PAC). Clinical and laboratory parameters recorded at last chemotherapy administration were analyzed, in order to identify risk factors for imminent death. METHODS: Retrospective analysis of patients who underwent at least one line of palliative chemotherapy was made. Data concerning chemotherapy (regimens, lines, and date of last administration) were collected. Clinical and laboratory factors recorded at last chemotherapy administration were: performance status, presence of ascites, hemoglobin, white blood cell (WBC), platelets, total bilirubin, albumin, LDH, C-reactive protein (C-rp), and Ca 19.9. RESULTS: We analyzed 231 patients: males/females, 53/47 %; metastatic/locally advanced disease, 80/20 %; and median age, 66 years (range 32-85). All patients died due to disease progression. Median overall survival was 6.1 months (95 % CI 5.1-7.2). At the last chemotherapy delivery, performance status was 0-1 in 37 % and 2 in 63 %. Fifty-nine percent of patients received one chemotherapy line, while 32, 8, and 1 % had second-, third-, and fourth line, respectively. The interval between last chemotherapy administration and death was <4 weeks in 24 %, ≥4-12 in 47 %, and >12 in 29 %. Median survival from last chemotherapy to death was 7.5 weeks (95 % CI 6.7-8.4). In a univariate analysis, ascites, elevated WBC, bilirubin, LDH, C-rp and Ca 19.9, and reduced albumin were found to predict shorter survival; however, none of them remained significant in a multivariate analysis. CONCLUSIONS: A significant proportion of patients with advanced PAC received chemotherapy within the last month of life. The clinical and laboratory parameters recorded at last chemotherapy delivery did not predict shorter survival.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents , Inappropriate Prescribing , Palliative Care , Pancreatic Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Disease Progression , Drug Utilization , Female , Humans , Male , Middle Aged , Multivariate Analysis , Practice Patterns, Physicians' , Retrospective Studies , Survival Analysis , Switzerland
7.
Ann Oncol ; 24(3): 718-25, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23139259

ABSTRACT

BACKGROUND: We conducted a randomized, phase II, multicenter study to evaluate the anti-epidermal growth factor receptor (EGFR) mAb panitumumab (P) in combination with chemoradiotherapy (CRT) with standard-dose capecitabine as neoadjuvant treatment for wild-type KRAS locally advanced rectal cancer (LARC). PATIENTS AND METHODS: Patients with wild-type KRAS, T3-4 and/or N+ LARC were randomly assigned to receive CRT with or without P (6 mg/kg). The primary end-point was pathological near-complete or complete tumor response (pNC/CR), defined as grade 3 (pNCR) or 4 (pCR) histological regression by Dworak classification (DC). RESULTS: Forty of 68 patients were randomly assigned to P + CRT and 28 to CRT. pNC/CR was achieved in 21 patients (53%) treated with P + CRT [95% confidence interval (CI) 36%-69%] versus 9 patients (32%) treated with CRT alone (95% CI: 16%-52%). pCR was achieved in 4 (10%) and 5 (18%) patients, and pNCR in 17 (43%) and 4 (14%) patients. In immunohistochemical analysis, most DC 3 cells were not apoptotic. The most common grade ≥3 toxic effects in the P + CRT/CRT arm were diarrhea (10%/6%) and anastomotic leakage (15%/4%). CONCLUSIONS: The addition of panitumumab to neoadjuvant CRT in patients with KRAS wild-type LARC resulted in a high pNC/CR rate, mostly grade 3 DC. The results of both treatment arms exceeded prespecified thresholds. The addition of panitumumab increased toxicity.


Subject(s)
Adenocarcinoma/therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Rectal Neoplasms/therapy , Adenocarcinoma/genetics , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Capecitabine , Chemoradiotherapy , DNA Mutational Analysis , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Diarrhea/chemically induced , Female , Fluorouracil/administration & dosage , Fluorouracil/analogs & derivatives , Humans , Male , Middle Aged , Neoadjuvant Therapy , Neoplasm Staging , Panitumumab , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins p21(ras) , Rectal Neoplasms/genetics , Rectal Neoplasms/mortality , Rectal Neoplasms/pathology , Treatment Outcome , ras Proteins/genetics
8.
Anticancer Res ; 30(10): 4289-95, 2010 Oct.
Article in English | MEDLINE | ID: mdl-21036754

ABSTRACT

BACKGROUND: Increased knowledge about the treatment of pancreatic cancer has influenced the management of locally advanced and metastatic disease. Nonetheless, prognosis remains dismal (24%, 1-year survival). The impact on overall survival (OS) of second-line therapy has not been clarified and the use of platinum salts and/or fluoropyrimidines is hotly debated. It is the hope that future treatment can be tailored to predict chemosensitivity in order to improve outcomes in patients with locally advanced and metastatic pancreatic cancer. Since DNA-damaging agents could be one therapeutic option, a retrospective multicenter study was performed to evaluate the efficacy of salvage treatment with the hypothesis that levels of the DNA repair gene excision repair cross complementing 1 (ERCC1) could influence OS. PATIENTS AND METHODS: In a population of 160 patients treated with fluoropyrimidine-based second-line chemotherapy, expression levels of ERCC1 were determined by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). In 108 patients with locally advanced and metastatic pancreatic cancer treated with either fluoropyrimidines and platinum salts (group A=58) or fluoropyrimidines alone (group B=50), ERCC1 levels were correlated with OS, time to progression and response to chemotherapy. RESULTS: Median survival was significantly higher in group A with low ERCC1 levels [11.9 versus 9.9 months; p ≤ 0.05] (median follow-up 24 months). Moreover in the same group, a trend towards longer time to progression was observed. No differences in OS were observed when ERCC1 was studied (low versus high) in patients not treated with platinum salts. On multivariate analysis of pretreatment prognostic factors, ERCC1 emerged as an independent predictive factor for OS. CONCLUSION: The results of this study indicate that ERCC1 may predict survival in pancreatic cancer patients treated by platinum and fluoropyrimidine as second-line chemotherapy.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Pancreatic Neoplasms/drug therapy , Pyrimidines/therapeutic use , Adult , Aged , DNA-Binding Proteins/biosynthesis , DNA-Binding Proteins/genetics , Endonucleases/biosynthesis , Endonucleases/genetics , Female , Gene Expression , Humans , Immunohistochemistry , Male , Middle Aged , Organoplatinum Compounds/administration & dosage , Pancreatic Neoplasms/enzymology , Pancreatic Neoplasms/genetics , Pyrimidines/administration & dosage , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Retrospective Studies , Reverse Transcriptase Polymerase Chain Reaction , Salvage Therapy , Survival Rate
9.
Br J Cancer ; 102(1): 151-61, 2010 Jan 05.
Article in English | MEDLINE | ID: mdl-19935791

ABSTRACT

BACKGROUND: Our aim was to investigate the prognostic and predictive value of the oncogenic MAPKK-like protein T-cell-originated protein kinase (TOPK) stratified by KRAS and BRAF mutations in patients with sporadic, hereditary and metastatic colorectal cancer (CRC) treated with anti-EGFR therapy. METHODS: Immunohistochemistry (IHC) for TOPK was performed on four study groups. Group 1 included two subgroups of 543 and 501 sporadic CRC patients used to test the reliability of TOPK expression by IHC. In Group 2, representing an additional 222 sporadic CRCs, the prognostic effect of TOPK stratified by KRAS and BRAF was assessed. The prognostic effect of TOPK was further analysed in Group 3, representing 71 hereditary Lynch syndrome-associated CRC patients. In Group 4, the predictive and prognostic value of TOPK was analysed on 45 metastatic patients treated with cetuximab or panitumumab stratified by KRAS and BRAF gene status. RESULTS: In both sporadic CRC subgroups (Group 1), associations of diffuse TOPK expression with clinicopathological features were reproducible. Molecular analysis of sporadic CRCs in Group 2 showed that diffuse TOPK expression was associated with KRAS and BRAF mutations (p<0.001) and with poor outcome in patients with either mutation in univariate and multivariate analysis (P=0.017). In hereditary patients (Group 3), diffuse TOPK was linked to advanced pT stage. In metastatic patients treated with anti-EGFR therapy (Group 4), diffuse TOPK expression was linked to dismal outcome despite objective response to treatment (P=0.01). CONCLUSIONS: TOPK expression is an unfavourable prognostic indicator in sporadic patients with KRAS or BRAF mutations and also in patients with metastatic disease experiencing a response to anti-EGFR therapies. The inhibition of TOPK, which could benefit 30-40% of CRC patients, may represent a new avenue of investigation for targeted therapy.


Subject(s)
Adenocarcinoma/chemistry , Colorectal Neoplasms/chemistry , Protein Serine-Threonine Kinases/analysis , Proto-Oncogene Proteins B-raf/genetics , Adenocarcinoma/drug therapy , Adenocarcinoma/epidemiology , Adenocarcinoma/genetics , Adenocarcinoma/secondary , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cetuximab , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Colorectal Neoplasms, Hereditary Nonpolyposis/chemistry , Colorectal Neoplasms, Hereditary Nonpolyposis/epidemiology , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/pathology , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/immunology , Female , Follow-Up Studies , Gene Expression Regulation, Neoplastic , Genes, ras , Humans , Male , Middle Aged , Mitogen-Activated Protein Kinase Kinases , Observer Variation , Panitumumab , Predictive Value of Tests , Prognosis , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Random Allocation , Reproducibility of Results , Signal Transduction/genetics
10.
Br J Cancer ; 100(7): 1087-94, 2009 Apr 07.
Article in English | MEDLINE | ID: mdl-19293803

ABSTRACT

Cetuximab and panitumumab efficacy in metastatic colorectal cancer (mCRC) may be influenced by EGFR gene status and/or deregulation of its downstream signalling proteins detected in primary tumour. However, metastasis might have different molecular patterns with respect to primary tumour, possibly affecting the prediction of EGFR-targeted therapy efficacy. We analysed primary tumour and metastasis in 38 mCRC patients. Twelve cases were cetuximab/panitumumab treated. EGFR gene status and protein expression were investigated through fluorescent in situ hybridisation and immunohistochemistry (IHC), K-Ras/BRAF mutations by sequencing and PTEN expression by IHC. We observed EGFR gene deregulation in 25 out of 36 primary tumours and 29 out of 36 metastases, K-Ras mutations in 16 out of 37 cancers and in 15 out of 37 metastases, BRAF mutations in 2 out of 36 cancers and 2 out of 36 metastases and PTEN loss in 8 out of 38 cancers and 12 out of 38 metastases. For the first time in literature, we show that primary colorectal cancer and paired metastasis may exhibit difference with respect to EGFR pathway deregulation mechanisms possibly implying a different response to cetuximab or panitumumab treatment. The investigation of treated patients confirms this hypothesis. We therefore suggest that the analysis of metastatic lesion should be considered in patient management as well as in designing future clinical trials aimed to investigate the effect of anti-EGFR monoclonal antibodies in the treatment of mCRC.


Subject(s)
Colorectal Neoplasms/genetics , ErbB Receptors/genetics , Aged , Aged, 80 and over , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Cetuximab , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , ErbB Receptors/analysis , ErbB Receptors/antagonists & inhibitors , Female , Genes, ras , Humans , Male , Middle Aged , Mutation , Neoplasm Metastasis , PTEN Phosphohydrolase/analysis , Panitumumab , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins p21(ras) , ras Proteins/genetics
11.
Cancer Treat Rev ; 35(2): 160-6, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19013023

ABSTRACT

Colon cancer is the second cause of death for cancer worldwide. In most cases it is diagnosed when it is still localized to the intestinal wall or in regional lymphnodes. Post-operative systemic therapy with 5-fluorouracil and folinic acid in combination with Oxaliplatin is the standard option for patients with radically resected stage III disease. In stage II, the value of a post-operative treatment remains controversial, but the identification of prognostic factors, histopathological and molecular, may allow the selection of patients who can benefit from adjuvant treatment. The inclusion of molecular targeted agents in combination regimens with cytotoxics, already proven effective in advanced disease, is the main field of development in the most recent protocols of adjuvant therapy.


Subject(s)
Antineoplastic Agents/therapeutic use , Chemotherapy, Adjuvant/trends , Colonic Neoplasms/drug therapy , Clinical Trials as Topic , Colonic Neoplasms/pathology , Drug Delivery Systems/methods , Humans , Neoplasm Staging
12.
Ann Oncol ; 19(7): 1288-1292, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18349029

ABSTRACT

BACKGROUND: To determine the activity and tolerability of adding cetuximab to the oxaliplatin and capecitabine (XELOX) combination in first-line treatment of metastatic colorectal cancer (MCC). PATIENTS AND METHODS: In a multicenter two-arm phase II trial, patients were randomized to receive oxaliplatin 130 mg/m(2) on day 1 and capecitabine 1000 mg/m(2) twice daily on days 1-14 every 3 weeks alone or in combination with standard dose cetuximab. Treatment was limited to a maximum of six cycles. RESULTS: Seventy-four patients with good performance status entered the trial. Objective partial response rates after external review and radiological confirmation were 14% and 41% in the XELOX and in the XELOX + Cetuximab arm, respectively. Stable disease has been observed in 62% and 35% of the patients, with 76% disease control in both arms. Cetuximab led to skin rash in 65% of the patients. The median overall survival was 16.5 months for arm A and 20.5 months for arm B. The median time to progression was 5.8 months for arm A and 7.2 months for arm B. CONCLUSION: Differences in response rates between the treatment arms indicate that cetuximab may improve outcome with XELOX. The correct place of the cetuximab, oxaliplatin and fluoropyrimidine combinations in first-line treatment of MCC has to be assessed in phase III trials.


Subject(s)
Antibodies, Monoclonal/adverse effects , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Aged , Aged, 80 and over , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Humanized , Antineoplastic Agents/administration & dosage , Cetuximab , Colorectal Neoplasms/diagnostic imaging , Colorectal Neoplasms/pathology , Drug Administration Schedule , Exanthema/chemically induced , Female , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasm Metastasis/diagnostic imaging , Neoplasm Metastasis/drug therapy , Neoplasm Metastasis/pathology , Organoplatinum Compounds/administration & dosage , Organoplatinum Compounds/adverse effects , Oxaliplatin , Radiography , Switzerland , Time Factors , Treatment Outcome
13.
Br J Cancer ; 97(8): 1139-45, 2007 Oct 22.
Article in English | MEDLINE | ID: mdl-17940504

ABSTRACT

To evaluate whether the epidermal growth factor receptor (EGFR), K-Ras and PTEN, all members of the EGFR signalling pathway, may affect the clinical response in cetuximab-treated metastatic colorectal cancer (mCRC) patients. Twenty-seven cetuximab-treated mCRC patients were evaluated for drug response and investigated for EGFR protein expression and gene status, K-Ras mutational status and PTEN protein expression. Ten patients achieved a partial response (PR) to cetuximab-based therapy. All 27 patients showed EGFR protein overexpression. Epidermal growth factor receptor gene amplification was observed in eight out of 27 (30%) and chromosome 7 marked polysomy in 16 (59%) patients. Partial response was observed in six out of eight patients with EGFR gene amplification, four out of 16 with marked polysomy and none out of three with eusomy (P<0.05). The K-Ras wild-type sequence was observed in 17 patients, and nine of them experienced a PR. Conversely, K-Ras was mutated in 10 cases, of which one patient experienced a PR (P<0.05). The PTEN protein was normally expressed in 16 patients, and 10 of them achieved a PR. In contrast, no benefit was documented in 11 patients with loss of PTEN activity (P<0.001). Patients with EGFR gene amplification or chromosome 7 marked polysomy respond to cetuximab. In addition to K-Ras mutations, we demonstrate for the first time that the loss of PTEN protein expression is associated with nonresponsiveness to cetuximab.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Colorectal Neoplasms/drug therapy , Drug Resistance, Neoplasm/genetics , PTEN Phosphohydrolase/metabolism , Adult , Aged , Algorithms , Antibodies, Monoclonal, Humanized , Biomarkers, Tumor/analysis , Biomarkers, Tumor/genetics , Cetuximab , Chromosomes, Human, Pair 7 , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , ErbB Receptors/genetics , ErbB Receptors/metabolism , Female , Gene Amplification , Gene Expression , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Male , Middle Aged , PTEN Phosphohydrolase/genetics , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins p21(ras) , ras Proteins/genetics
14.
Ann Oncol ; 16(2): 282-8, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15668285

ABSTRACT

BACKGROUND: To determine the efficacy, impact on quality-of-life (QoL) and tolerability of two different irinotecan administration schedules in combination with capecitabine as first-line treatment of metastatic colorectal cancer. PATIENTS AND METHODS: We carried out a randomized phase II trial to select one of the following treatment regimens for further investigation: weekly irinotecan at a dose of 70 mg/m(2) days 1, 8, 15, 22, 29 (arm A) or 3-weekly irinotecan at a dose of 300/240 mg/m(2) day 1 and days 22 (arm B) in combination with capecitabine 1000 mg/m(2) twice daily days 1-14 and days 22-35 every 6 weeks. RESULTS: Seventy-five patients with good performance status entered the trial. The two arms were well balanced for relevant patient and disease characteristics. The most frequent toxic effects were grade 3/4 diarrhea (arm A: 34%, B: 19%), grade 3/4 neutropenia (A: 5%, B: 19%) and grade 2/3 alopecia (A: 26%, B: 65%). Other grade 3/4 toxic effects were rare (<5%). Response rates were 34% [95% confidence interval (CI) 20% to 51%] in arm A and 35% (95% CI: 20% to 53%) in arm B. Median time to progression was 6.9 (4.6-10.1) and 9.2 (7.9-11.5) months and median overall survival was 17.4 (12.6-23.0+) and 24.7 (16.3-26.4+) months. Patients with an objective tumor response reported better physical well-being (P < 0.01), mood (P < 0.05), functional performance (P < 0.05) and less effort to cope (P < 0.05) compared with the non-responders and stable disease patients. CONCLUSIONS: The primary end point of this study was the objective response rate and based on the statistical design of the trial, the 3-weekly irinotecan schedule was selected over weekly irinotecan administration. The 3-weekly irinotecan schedule also seemed advantageous in terms of grade 3/4 diarrhea, time to progression, overall survival and patient convenience, but the study was not designed to detect differences in these parameters. In addition, tumor response was shown to have a beneficial effect on QoL indicators.


Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Antineoplastic Agents, Phytogenic/therapeutic use , Camptothecin/analogs & derivatives , Camptothecin/therapeutic use , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Deoxycytidine/analogs & derivatives , Deoxycytidine/therapeutic use , Adult , Aged , Antimetabolites, Antineoplastic/administration & dosage , Antimetabolites, Antineoplastic/adverse effects , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/adverse effects , Camptothecin/administration & dosage , Camptothecin/adverse effects , Capecitabine , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Drug Administration Schedule , Female , Fluorouracil/analogs & derivatives , Humans , Infusions, Intravenous , Irinotecan , Male , Middle Aged , Quality of Life , Treatment Outcome
16.
Br J Haematol ; 125(5): 584-9, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15147373

ABSTRACT

We retrospectively analysed toxicities and clinical results of 61 Hodgkin's lymphoma patients treated with chlorambucil, vinblastine, procarbazine, doxorubicin, bleomycin, vincristine and etoposide (ChlVPP/ABVVP), delivered in a weekly alternate schedule. Of 61 patients, 33 were in stages III-IV, 21 in stage IIB and seven in stage IIA with bulky disease or extranodal presentation. ChlVPP/ABVVP was administered for 6-8 cycles. Involved field radiotherapy (IFRT) (30-35 Gy) was delivered to 31 patients with residual disease after chemotherapy or bulky disease at diagnosis. Of 61 patients, 58 (95%) achieved complete clinical or radiological remission after chemotherapy and IFRT. With a median follow-up of 60 months, 5-year overall survival, relapse- and event-free survival were 78.8% (95% CI 68.2-91.1%), 81% (95% CI 70.6-92.2%) and 71.9% (95% CI 68.2-82.2%) respectively. Grades 3-4 neutropenia was the most relevant haematological toxicity and occurred in 82% of patients. Non-haematological toxicities were mild and reversible. No toxic deaths were recorded. One patient developed secondary acute myeloid leukaemia 1 year after ChlVPP/ABVVP. Due to the retrospective nature of this study, no definitive conclusions could be drawn about the clinical activity of ChlVPP/ABVVP. Nonetheless, clinical results seem better than those reported with standard regimens [ABVD (doxorubicin, bleomycin, vincristine, dacarbazine), MOPP (methotrexate, vincristine, procarbazine, prednisone), MOPP/ABVD] and as good as those reported using standard or escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone), with a lower degree of haematological and non-haematological toxicity. Long-term results of the ongoing randomized trial, comparing ABVD versus high-dose intensity weekly regimens will be useful to confirm our results.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Hodgkin Disease/drug therapy , Adolescent , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bleomycin/administration & dosage , Chlorambucil/administration & dosage , Disease-Free Survival , Doxorubicin/administration & dosage , Etoposide/administration & dosage , Female , Gastrointestinal Diseases/chemically induced , Hematologic Diseases/chemically induced , Humans , Male , Middle Aged , Neoplasms, Second Primary/therapy , Procarbazine/administration & dosage , Retrospective Studies , Survival Analysis , Treatment Outcome , Vinblastine/administration & dosage , Vincristine/administration & dosage
17.
Leuk Lymphoma ; 44(11): 1919-23, 2003 Nov.
Article in English | MEDLINE | ID: mdl-14738143

ABSTRACT

Vinblastine, bleomycin, methotrexate (VBM) combination chemotherapy (CT) with involved field radiotherapy (IFRT) was first described by the Stanford group as an active regimen in early stage Hodgkin's disease (HD). Here, we report our retrospective experience of a modified VBM schedule + IFRT in a similar group of patients. From 1988, 49 patients with stage I-IIA HD received vinblastine (VBL) 6 mg/m2, bleomycin (BLM) 10 IU/m2, methotrexate (MTX) 30 mg/m2 day 1,8 every four weeks for three cycles; IFRT was delivered four weeks later followed by three additional cycles of VBM with a dose reduction of BLM (6 IU/m2). The regimen was well tolerated, with grade 3-4 neutropenia occurring in 20 patients. No acute or late pulmonary toxicity was recorded in our series. Estimated Freedom from Progression (FFP) and Overall Survival (OS) at five years are 75% (95% CI, 60.1%-92.2%) and 85% (95% CI, 73.6%-98.1%), respectively. In this retrospective analysis, VBM + IFRT treatment with bleomycin dose reduction seems safe and active. Such combination could be considered as first line treatment for early stage HD patients with favorable prognosis and/or not suitable for anthracyclines-containing regimens.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bleomycin/therapeutic use , Hodgkin Disease/drug therapy , Hodgkin Disease/radiotherapy , Methotrexate/therapeutic use , Radiotherapy/methods , Vincristine/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bleomycin/adverse effects , Combined Modality Therapy , Female , Hodgkin Disease/pathology , Humans , Male , Methotrexate/adverse effects , Middle Aged , Neoplasm Staging , Retrospective Studies , Survival Rate , Treatment Outcome , Vincristine/administration & dosage , Vincristine/adverse effects
18.
Ann Oncol ; 12(2): 151-60, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11300317

ABSTRACT

Colorectal cancer (CRC) is a significant cause of mortality in Western populations. About 15% of CRC patients report a family history of the disease. Studies on individuals with a genetic predisposition to CRC have been responsible for significant advances in the understanding of this disease. Thus, although developments in molecular biology have been mainly restricted to a minority of individuals with a hereditary background, information obtained from this group may affect the diagnosis and therapy of sporadic CRCs as well. Deficiency in the DNA mismatch repair (MMR) system results in microsatellite instability (MSI). Individuals from hereditary non-polyposis colorectal cancer (HNPCC) kindreds with germline mutations in genes involved in MMR may benefit from clinical screening programs. The higher frequency of MSI in HNPCC than in sporadic tumours suggests that involvement of MMR genes in sporadic adenomas may be uncommon. Consequently


Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Colorectal Neoplasms/genetics , Microsatellite Repeats/genetics , Mutation , Adult , DNA Mutational Analysis , DNA Repair , Genetic Markers , Genotype , Humans , Middle Aged , Phenotype , Prognosis
19.
Leuk Lymphoma ; 33(3-4): 313-9, 1999 Apr.
Article in English | MEDLINE | ID: mdl-10221511

ABSTRACT

Prolonged remission can now be induced in the majority of patients with advanced Hodgkin's disease (HD) by the use of non-cross-resistant regimens. The aim of this retrospective analysis was to evaluate the efficacy and tolerability of a hybrid chemotherapy regimen (ChlVPP/ABV-VP16) in this unfavorable subset of patients. From 1982 to 1997 thirty-six previously untreated patients with advanced HD, Stages IIB to IV according to the Ann Arbor classification, were treated with the ChlVPP/ABV-VP16 regimen. The median age of the group was 29 years (range, 18 to 74), and 50% of them had bulky disease. Complete remission (CR) was induced in 31 patients (86%); 3 patients achieved partial responses and 2 had progressive disease. The median follow-up duration is 5.7 years, with a 5-year overall survival rate of 80%. At 5 years, the time to progression (TTP) and event-free survival (EFS) were 71% and 64%, respectively. Acute toxicity was quite acceptable, and there were no treatment-related deaths. A total of 3 second malignancies (8%) were documented. In conclusion, the ChlVPP/ABV-VP16 hybrid is an active regimen for use in advanced HD. Its overall survival, TTP and CR rates make this regimen an attractive alternative to MOPP/ABVD. However, the possibility of the development of second tumors is worrisome, although the relatively brief interval between the end of treatment and tumor detection may imply caution about the possible relationship.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Etoposide/administration & dosage , Hodgkin Disease/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bleomycin/administration & dosage , Bleomycin/adverse effects , Chlorambucil/administration & dosage , Chlorambucil/adverse effects , Disease Progression , Disease-Free Survival , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Etoposide/adverse effects , Female , Hodgkin Disease/mortality , Hodgkin Disease/pathology , Hodgkin Disease/radiotherapy , Humans , Male , Middle Aged , Neoplasm Staging , Prednisolone/administration & dosage , Prednisolone/adverse effects , Procarbazine/administration & dosage , Procarbazine/adverse effects , Retrospective Studies , Survival Analysis , Time Factors , Vinblastine/administration & dosage , Vinblastine/adverse effects
20.
Ann Hematol ; 78(2): 97-100, 1999 Feb.
Article in English | MEDLINE | ID: mdl-10089028

ABSTRACT

Systemic mastocytosis is a rare condition characterized clinically by the local consequences of vasoactive peptides released from infiltrating mast cells in the reticuloendothelial tissues. Mast cells originate from the pluripotent bone marrow stem cells; it is therefore not surprising that myeloproliferative and myelodysplastic disorders commonly coexist or terminate the clinical phase of mastocytosis. We report here, to our knowledge, the first case of Hodgkin's and Castleman's disease occurring in a patient with co-existent systemic mastocytosis, which remained unchanged after combination chemotherapy for Hodgkin's disease.


Subject(s)
Castleman Disease/complications , Hodgkin Disease/complications , Urticaria Pigmentosa/complications , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bleomycin/administration & dosage , Bone Marrow/pathology , Castleman Disease/pathology , Combined Modality Therapy , Hodgkin Disease/drug therapy , Hodgkin Disease/pathology , Hodgkin Disease/radiotherapy , Humans , Lymph Nodes/pathology , Male , Methotrexate/administration & dosage , Middle Aged , Neoplastic Stem Cells/pathology , Urticaria Pigmentosa/pathology , Vincristine/administration & dosage
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