ABSTRACT
BACKGROUND: No preferred first-line chemotherapy regimen exists for advanced esophagogastric adenocarcinoma. Addition of docetaxel to cisplatin and 5-fluorouracil (DCF) has been shown to improve survival but is associated with increased toxicity. In this randomized, non-comparative phase 2 trial, we tested carboplatin, docetaxel, and capecitabine (CTX), a potentially useful modification of DCF (NCT02177552). PATIENTS AND METHODS: Patients with advanced HER2-negative esophagogastric adenocarcinoma not previously treated in the first-line setting were randomized to intravenous docetaxel 60 mg/m2 and carboplatin AUC5 plus oral capecitabine 1000 mg/m2 bd days 1-14, q4w (CTX) or intravenous epirubicin 50 mg/m2 and oxaliplatin 130 mg/m2 on day 1 plus oral capecitabine 625 mg/m2 bd days 1-21, q3w (epirubicin, oxaliplatin and capecitabine [EOX]). Treatment continued until progression, intolerance or for a maximum of nine cycles. The primary endpoint was 1-year survival for patients treated with CTX. RESULTS: Between June 2014 and January 2019, a total of 98 eligible patients were randomized. The 1-year survival rate was 34.7% (95% CI 21.8 - 47.9) with CTX and 36.7% (95% CI 23.6 - 50.0) with EOX. Progression-free survival and overall survival were 6.1 months (95% CI 5.5 - 7.1) and 9.8 months (95% CI 8.2 - 11.0) with CTX and 5.1 months (95% CI 4.3 - 7.0) and 10.2 months (95% CI 8.0 - 11.9) with EOX, respectively. Related grade 3 or 4 treatment-emergent adverse events (AEs) occurred in 86% of patients on CTX and 69% on EOX. Febrile neutropenia occurred in 31.4% of patients on CTX and 13.7% on EOX. CONCLUSIONS: First-line CTX showed insufficient efficacy and caused a high rate of febrile neutropenia. CTX could not, therefore, be recommended for further study. This trial adds to current knowledge of docetaxel combined with platinum and 5-FU: that the combination is associated with increased toxicity and its use should be limited to fit patients in need of a response.
Subject(s)
Adenocarcinoma , Stomach Neoplasms , Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Capecitabine/therapeutic use , Carboplatin/therapeutic use , Docetaxel , Epirubicin , Fluorouracil/adverse effects , Humans , Oxaliplatin/therapeutic use , Stomach Neoplasms/drug therapy , Treatment OutcomeABSTRACT
BACKGROUND: Vitamin D deficiency and inflammation are associated with increased mortality. We investigated the relationship between pre-treatment serum vitamin D levels, inflammatory biomarkers (IL-6, YKL-40 and CRP) and overall survival (OS) in pancreatic ductal adenocarcinoma (PDAC) patients. METHODS: Pre-treatment serum vitamin D, IL-6, YKL-40 and CRP levels were determined in 1,267 patients with PDAC enrolled from July 2008 to September 2018 in the prospective BIOPAC study (NCT03311776). The patients were grouped according to vitamin D levels: sufficient >50 nmol/L, insufficient 25-50 nmol/L and deficient <25 nmol/L. RESULTS: Across all tumour stages, vitamin D-deficient patients had the highest median levels of IL-6 (8.3 pg/mL, range 0.7-91), YKL-40 (177 ng/ml, range 25-5279) and CRP (15.5 mg/L, range 0.8-384). The resected stage I and II patients with vitamin D deficiencies had a shorter median OS, 18.3 months (95% CI, 12.1-31.5 months) than those with sufficient levels, 29.7 months (95% CI, 22.3-36.1 months), and the hazard ratio for death was 1.55 (95% CI, 1.04-2.31; p = 0.03). In advanced PDAC, there was no significant difference in OS between the vitamin D groups. CONCLUSIONS: Vitamin D deficiency was associated with increased inflammatory biomarkers in all PDAC stages. The resected stage I and II patients with sufficient vitamin D levels had a higher OS than those with a vitamin D deficiency. However, there was no correlation between vitamin D levels and survival in advanced PDAC. Future studies need to investigate vitamin D supplementation effects on survival in PDAC.
Subject(s)
Biomarkers, Tumor/blood , Carcinoma, Pancreatic Ductal/mortality , Inflammation/mortality , Pancreatic Neoplasms/mortality , Vitamin D Deficiency/complications , Vitamin D/blood , Adult , Aged , Aged, 80 and over , Carcinoma, Pancreatic Ductal/blood , Carcinoma, Pancreatic Ductal/etiology , Carcinoma, Pancreatic Ductal/pathology , Female , Follow-Up Studies , Humans , Inflammation/blood , Inflammation/etiology , Inflammation/pathology , Male , Middle Aged , Pancreatic Neoplasms/blood , Pancreatic Neoplasms/etiology , Pancreatic Neoplasms/pathology , Prognosis , Prospective Studies , Survival Rate , Vitamins/bloodABSTRACT
OBJECTIVES: Few studies have evaluated the impact of risk factors and comorbidity on overall survival (OS) in patients with pancreatic ductal adenocarcinoma (PDAC). The aim was to investigate the prognostic importance of Charlson's age-comorbidity index (CACI) and other risk factors on prognosis in a clinical real-world cohort of PDAC patients. METHODS: A total of 1,159 patients with PDAC who had received at least one cycle of adjuvant or palliative chemotherapy were included from the Danish BIOPAC study. We analysed OS according to CACI, tobacco smoking, alcohol intake, performance status (PS), BMI and diabetes. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for OS using Cox proportional hazards regression. RESULTS: At the end of follow-up, 994 (86%) patients had died. The median OS was 298 days for all patients (range 3-3010) and shortest in patients with stage IV. No association with short OS was seen for CACI > 2, diabetes, alcohol abuse, tobacco smoking, hypertension, and high BMI. Multivariate analysis showed that stage (IV vs. I: HR = 9.05, 95% CI 5.17-15.84), PS (2 vs. 0: HR = 3.67, 2.92-4.61) and treatment with angiotensin-converting enzyme inhibitors (yes vs. no: HR = 1.31, 1.06-1.61) were independent negative prognostic factors. CONCLUSIONS: We found that CACI, diabetes, tobacco smoking, alcohol abuse, hypertension, and high BMI were not associated with OS in a real-world cohort of patients with PDAC treated with chemotherapy. Only stage and PS were prognostic parameters.
Subject(s)
Carcinoma, Pancreatic Ductal/epidemiology , Pancreatic Neoplasms/epidemiology , Adult , Age Factors , Aged , Aged, 80 and over , Alcohol Drinking/epidemiology , Alcoholism/epidemiology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Body Mass Index , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Pancreatic Ductal/physiopathology , Comorbidity , Denmark/epidemiology , Diabetes Mellitus/epidemiology , Female , Functional Status , Humans , Hypertension/epidemiology , Male , Middle Aged , Neoplasm Staging , Obesity/epidemiology , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/physiopathology , Prognosis , Proportional Hazards Models , Risk Factors , Survival Rate , Tobacco Smoking/epidemiologyABSTRACT
BACKGROUND: IL6 and YKL-40 (also known as chitinase 3-like 1 protein, CHI3L1) are produced by pancreatic cancer cells and macrophages and activate inflammation. C-reactive protein (CRP) is synthesized mainly in hepatic cells and primarily stimulated by IL6. The aim of this study was to determine the prognostic value of combined detection of serum IL6, YKL-40, and CRP in patients with pancreatic cancer receiving palliative chemotherapy. METHODS: In all, 592 patients with unresectable pancreatic cancer from five hospitals in Denmark were included in the BIOPAC biomarker study between 2008 and 2017. Pretreatment and longitudinal serum values of IL6 and YKL-40 were determined. Baseline CRP and CA19-9 values were available for the whole cohort. Patients were dichotomized as low versus high using cutoffs for IL6 of >4.92 pg/mL, YKL-40 of >95% age-corrected percentile, and CRP of >10 mg/L. The main outcome was overall survival. RESULTS: Combined elevations of serum IL6, YKL-40, and CRP were associated with worse survival in contrast to an isolated high concentration of a single marker. Serum IL6, YKL-40, and CRP were higher in patients with advanced stage disease and in patients with poor performance status. Higher IL6 and YKL-40 levels at the time of tumor progression and serum IL6 measured over time were associated with shorter overall survival. CONCLUSIONS: Combined high baseline serum levels of IL6, YKL-40, and CRP are associated with poor survival. IMPACT: Assessment of systemic inflammation via measurements of IL6, YKL-40, and CRP may be important for pancreatic cancer prognostication.
Subject(s)
Biomarkers, Tumor/blood , C-Reactive Protein/analysis , Chitinase-3-Like Protein 1/blood , Inflammation/diagnosis , Interleukin-6/blood , Pancreatic Neoplasms/mortality , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Denmark/epidemiology , Disease Progression , Female , Follow-Up Studies , Humans , Inflammation/blood , Inflammation/immunology , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasm Staging , Palliative Care/methods , Pancreatic Neoplasms/blood , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/immunology , Prognosis , Prospective Studies , Time FactorsABSTRACT
BACKGROUND: Docetaxel in combination with cisplatin and 5-fluorouracil (5-FU) is one of several standard chemotherapy regimens for patients with advanced gastro-esophageal adenocarcinoma (aGEA) in Europe. To enable outpatient treatment, we evaluated the maximum tolerated dose (MTD), recommended dose (RD), dose limiting toxicity (DLT) and safety of docetaxel in combination with oxaliplatin (O) and S-1 (DOS) in Caucasian patients with aGEA. METHODS: We present final results of two parallel phase 1/2a studies (3 + 3 design). Escalating doses of docetaxel and S-1 with fixed dose O were given for 18 weeks every second week (DOS2w) or every third week (DOS3w) followed by S-1 maintenance therapy. RESULTS: Thirty-four patients (18 in DOS2w and 16 in DOS3w) were enrolled between October 2013 and June 2015. Median age was 65 years (range 49-78). DLT was most often febrile neutropenia. Most common severe non-hematological adverse events were diarrhea (9%) and fatigue (6%). The RD of DOS3w was: docetaxel 50 mg/m2, O 100 mg/m2 and S-1 25 mg/m2 twice daily and of DOS2w was: docetaxel 40 mg/m2, O 70 mg/m2 and S-1 35 mg/m2 twice daily. Overall, response rate was 56%; median progression-free survival was 9.1 months; and median overall survival was 13.2 months in 34 patients. CONCLUSIONS: At the RD, DOS2w and DOS3w showed an acceptable safety profile in patients with aGEA. Clinical trials ID: NCT-01928524 and EudraCT 2012-005187-10.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Esophageal Neoplasms/drug therapy , Stomach Neoplasms/drug therapy , Adenocarcinoma/pathology , Aged , Docetaxel , Drug Combinations , Esophageal Neoplasms/pathology , Female , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasm Staging , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Oxonic Acid/administration & dosage , Prognosis , Stomach Neoplasms/pathology , Survival Rate , Taxoids/administration & dosage , Tegafur/administration & dosageABSTRACT
BACKGROUND: Multidisciplinary team (MDT) conferences have been introduced into standard cancer care, though evidence that it benefits the patient is weak. We used the national Swedish Rectal Cancer Register to evaluate predictors for case discussion at a MDT conference and its impact on treatment. MATERIAL AND METHODS: Of the 6760 patients diagnosed with rectal cancer in Sweden between 2007 and 2010, 78% were evaluated at a MDT. Factors that influenced whether a patient was discussed at a preoperative MDT conference were evaluated in 4883 patients, and the impact of MDT evaluation on the implementation of preoperative radiotherapy was evaluated in 1043 patients with pT3c-pT4 M0 tumours, and in 1991 patients with pN+ M0 tumours. RESULTS: Hospital volume, i.e. the number of rectal cancer surgical procedures performed per year, was the major predictor for MDT evaluation. Patients treated at hospitals with < 29 procedures per year had an odds ratio (OR) for MDT evaluation of 0.15. Age and tumour stage also influenced the chance of MDT evaluation. MDT evaluation significantly predicted the likelihood of being treated with preoperative radiotherapy in patients with pT3c-pT4 M0 tumours (OR 5.06, 95% CI 3.08-8.34), and pN+ M0 (OR 3.55, 95% CI 2.60-4.85), even when corrected for co-morbidity and age. CONCLUSION: Patients with rectal cancer treated at high-volume hospitals are more likely to be discussed at a MDT conference, and that is an independent predictor of the use of adjuvant radiotherapy. These results indirectly support the introduction into clinical practice of discussing all rectal cancer patients at MDT conferences, not least those being treated at low-volume hospitals.
Subject(s)
Hospitals, High-Volume/statistics & numerical data , Hospitals, Low-Volume/statistics & numerical data , Interdisciplinary Communication , Rectal Neoplasms/radiotherapy , Rectal Neoplasms/surgery , Age Factors , Aged , Congresses as Topic/statistics & numerical data , Female , Humans , Male , Odds Ratio , Practice Guidelines as Topic , Preoperative Care , Rectal Neoplasms/pathology , Registries , SwedenABSTRACT
IMPORTANCE: Biomarkers for the early diagnosis of patients with pancreatic cancer are needed to improve prognosis. OBJECTIVES: To describe differences in microRNA expression in whole blood between patients with pancreatic cancer, chronic pancreatitis, and healthy participants and to identify panels of microRNAs for use in diagnosis of pancreatic cancer compared with the cancer antigen 19-9 (CA19-9). DESIGN, SETTING, AND PARTICIPANTS: A case-control study that included 409 patients with pancreatic cancer and 25 with chronic pancreatitis who had been included prospectively in the Danish BIOPAC (Biomarkers in Patients with Pancreatic Cancer) study (July 2008-October 2012) plus 312 blood donors as healthy participants. The microRNA expressions in pretreatment whole blood RNA samples were collected and analyzed in 3 randomly determined subcohorts: discovery cohort (143 patients with pancreatic cancer, 18 patients with chronic pancreatitis, and 69 healthy participants), training cohort (180 patients with pancreatic cancer, 1 patient with chronic pancreatitis, and 199 healthy participants), and validation cohort (86 patients with pancreatic cancer, 7 patients with chronic pancreatitis, and 44 healthy participants); 754 microRNAs were screened in the discovery cohort and 38 microRNAs in the training cohort and 13 microRNAs in the validation cohort. MAIN OUTCOMES AND MEASURES: Identification of microRNA panels (classifiers) for diagnosing pancreatic cancer. RESULTS: The discovery cohort demonstrated that 38 microRNAs in whole blood were significantly dysregulated in patients with pancreatic cancer compared with controls. These microRNAs were tested in the training cohort and 2 diagnostic panels were constructed comprising 4 microRNAs in index I (miR-145, miR-150, miR-223, miR-636) and 10 in index II (miR-26b, miR-34a, miR-122, miR-126*, miR-145, miR-150, miR-223, miR-505, miR-636, miR-885.5p). The test characteristics for the training cohort were index I area under the curve (AUC) of 0.86 (95% CI, 0.82-0.90), sensitivity of 0.85 (95% CI, 0.79-0.90), and specificity of 0.64 (95% CI, 0.57-0.71); index II AUC of 0.93 (95% CI, 0.90-0.96), sensitivity of 0.85 (95% CI, 0.79-0.90), and specificity of 0.85 (95% CI, 0.80-0.85); and CA19-9 AUC of 0.90 (95% CI, 0.87-0.94), sensitivity of 0.86 (95% CI, 0.80-0.90), and specificity of 0.99 (95% CI, 0.96-1.00). Performances were strengthened in the validation cohort by combining panels and CA19-9 (index I AUC of 0.94 [95% CI, 0.90-0.98] and index II AUC of 0.93 [95% CI, 0.89-0.97]). Compared with CA19-9 alone, the AUC for the combination of index I and CA19-9 was significantly higher (P = .01). The performance of the panels in patients with stage IA-IIB pancreatic cancer was index I AUC of 0.80 (95% CI, 0.73-0.87); index I and CA19-9 AUC of 0.83 (95% CI, 0.76-0.90); index II AUC of 0.91 (95% CI, 0.87-0.94); and index II and CA19-9 AUC of 0.91 (95% CI, 0.86-0.95). CONCLUSIONS AND RELEVANCE: This study identified 2 diagnostic panels based on microRNA expression in whole blood with the potential to distinguish patients with pancreatic cancer from healthy controls. Further research is necessary to understand whether these have clinical implications for early detection of pancreatic cancer and how much this information adds to serum CA19-9.
Subject(s)
MicroRNAs/blood , Pancreatic Neoplasms/diagnosis , Pancreatitis, Chronic/diagnosis , Adult , Aged , Biomarkers, Tumor/blood , CA-19-9 Antigen/blood , Case-Control Studies , Diagnosis, Differential , Female , Humans , Male , MicroRNAs/metabolism , Middle Aged , Pancreatic Neoplasms/blood , Pancreatitis, Chronic/blood , Sensitivity and SpecificityABSTRACT
PURPOSE: The purpose was to examine characteristics, treatment and outcome in an unselected, prospectively registered complete population of patients with gastro-oesophageal adenocarcinoma cancer (GEA). METHODS: All cases diagnosed with GEA between 2008 and 2009 in the Region of Southern Denmark (pop: 1,200,000) were registered. Patient characteristics, including performance status, stage and therapy, were retrieved from patient charts and used to compare sub-groups of patients. RESULTS: Three hundred and thirty patients were registered as having GEA. Patients were divided into three clinical subgroups based on initial treatment option: group 1: patients with resectable GEA (n = 113); group 2: patients receiving first-line therapy (n = 107); group 3: patients receiving no tumour-directed therapy (n = 110). Median overall survival (95% CI) in the three groups was 36 months (25-not reached), 7.1 months (7-9) and 2.4 months (2-3), respectively. Seven percent of patients participated in clinical trials. CONCLUSION: Among patients not amendable to resection, around 30% are candidates for three-drug combination chemotherapy. Age > 65 years was found not to be a poor prognostic factor for survival, giving the possibility of treating elderly patients in the future. Many patients (approx. 30%), however, never received cancer-directed therapy. In order to improve survival in the entire population, it is important that future trials also focus on this group of patients.
Subject(s)
Adenocarcinoma/mortality , Adenocarcinoma/therapy , Esophageal Neoplasms/mortality , Esophageal Neoplasms/therapy , Stomach Neoplasms/mortality , Stomach Neoplasms/therapy , Adenocarcinoma/surgery , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cohort Studies , Denmark , Esophageal Neoplasms/surgery , Humans , Male , Middle Aged , Prospective Studies , Registries , Stomach Neoplasms/surgery , Treatment OutcomeABSTRACT
PURPOSE: We tested the hypothesis that high plasma YKL-40 and IL-6 associate with pancreatic cancer and short overall survival. PATIENTS AND METHODS: In all, 559 patients with pancreatic cancer from prospective biomarker studies from Denmark (nâ=â448) and Germany (nâ=â111) were studied. Plasma YKL-40 and IL-6 were determined by ELISAs and serum CA 19.9 by chemiluminescent immunometric assay. RESULTS: Odds ratios (ORs) for prediction of pancreatic cancer were significant for all biomarkers, with CA 19.9 having the highest AUC (CA 19.9: ORâ=â2.28, 95% CI 1.97 to 2.68, p<0.0001, AUCâ=â0.94; YKL-40: ORâ=â4.50, 3.99 to 5.08, p<0.0001, AUCâ=â0.87; IL-6: ORâ=â3.68, 3.08 to 4.44, p<0.0001, AUCâ=â0.87). Multivariate Cox analysis (YKL-40, IL-6, CA 19.9, age, stage, gender) in patients operated on showed that high preoperative IL-6 and CA 19.9 (dichotomized according to normal values) were independently associated with short overall survival (CA 19.9: HRâ=â2.51, 1.22-5.15, pâ=â0.013; IL-6: HRâ=â2.03, 1.11 to 3.70, pâ=â0.021). Multivariate Cox analysis of non-operable patients (Stage IIB-IV) showed that high pre-treatment levels of each biomarker were independently associated with short overall survival (YKL-40: HRâ=â1.30, 1.03 to 1.64, pâ=â0.029; IL-6: HRâ=â1.71, 1.33 to 2.20, p<0.0001; CA 19.9: HRâ=â1.54, 1.06 to 2.24, pâ=â0.022). Patients with preoperative elevation of both IL-6 and CA 19.9 had shorter overall survival (p<0.005) compared to patients with normal levels of both biomarkers (45% vs. 92% alive after 12 months). CONCLUSIONS: Plasma YKL-40 and IL-6 had less diagnostic impact than CA 19.9. Combination of pretreatment YKL-40, IL-6, and CA 19.9 may have clinical value to identify pancreatic cancer patients with the poorest prognosis.
Subject(s)
CA-19-9 Antigen/blood , Chitinase-3-Like Protein 1/blood , Interleukin-6/blood , Pancreatic Neoplasms/blood , Pancreatic Neoplasms/diagnosis , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/blood , Female , Humans , Male , Middle Aged , Pancreatic Neoplasms/surgery , Pancreatitis/blood , Prognosis , Risk , Survival AnalysisABSTRACT
Improving the prognosis for patients with cancer from the exocrine pancreas (PC) represents a challenge for health-care systems in the Western world. Vague and non-specific symptoms combined with rapid deterioration of the patients' condition often make diagnosis difficult. Multimodality therapy with a combination of surgery followed by adjuvant chemotherapy has improved the long-term survival of patients. Recent data suggest improved efficacy of aggressive chemotherapy. Multidisciplinary team management and research are essential in order to further improve the outcome of patients with PC.
Subject(s)
Pancreatic Neoplasms , Adenocarcinoma/diagnosis , Adenocarcinoma/drug therapy , Adenocarcinoma/pathology , Adenocarcinoma/surgery , Algorithms , Humans , Palliative Care , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/surgery , Risk FactorsABSTRACT
BACKGROUND AND PURPOSE: Controversies regarding the optimal therapy for patients with locally advanced pancreatic cancer (LAPC) exist. Although the prognosis as a whole remains dismal, subgroups are known to benefit from intensive therapy, including chemoradiotherapy (CRT). We describe the results in 178 patients treated from 2001 to 2010 and have developed a prognostic model for both survival and the possibility of a subsequent resection in these patients. METHODS AND MATERIALS: From 2001 until 2010, 178 consecutive patients with LAPC were treated and included in the present study, with CRT consisting of 50 Gy in 27 fractions combined with tegafur-uracil(UFT)/folinic acid(FA). RESULTS: The median survival from diagnosis was 11.5 months. Adverse events of Grade 3 or above were seen in 36% of the patients. Ninety-three percent of the patients completed all fractions. A Cox regression model for survival demonstrated resection (hazard ratio [HR] 0.12; 95% confidence interval [CI], 0.1-0.3) and pre-CRT gemcitabine-based therapy (HR 0.57; 95% CI, 0.4-0.9) as being associated with a favorable outcome, increasing gross tumor volume (HR 1.14; 95% CI, 1.0-1.3) was associated with shorter survival. A logistic regression model showed Stage III disease (odds ratio [OR] 0.16; 95% CI, 0.0-1.1) and abnormal hemoglobin (OR 0.26; 95% CI, 0.0-1.2) as being associated with lower odds of resection. CONCLUSION: This study confirms the favorable prognosis for patients receiving gemcitabine therapy before CRT and the poor prognosis associated with increasing tumor volume. In addition, CRT in patients with abnormal hemoglobin and Stage III disease rarely induced tumor shrinkage allowing subsequent resection.
Subject(s)
Chemoradiotherapy/methods , Pancreatic Neoplasms/therapy , Adult , Aged , Aged, 80 and over , Antimetabolites, Antineoplastic/therapeutic use , Chemoradiotherapy/adverse effects , Deoxycytidine/analogs & derivatives , Deoxycytidine/therapeutic use , Dose Fractionation, Radiation , Female , Humans , Leucovorin/therapeutic use , Logistic Models , Male , Middle Aged , Pancreatic Neoplasms/blood , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/pathology , Prognosis , Retrospective Studies , Tegafur/therapeutic use , Tumor Burden , Uracil/therapeutic use , GemcitabineSubject(s)
Fluorodeoxyglucose F18 , Pancreatic Neoplasms/diagnostic imaging , Pancreatic Neoplasms/therapy , Radiopharmaceuticals , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Combined Modality Therapy , Fluorodeoxyglucose F18/pharmacokinetics , Humans , Leucovorin/administration & dosage , Pancreatic Neoplasms/metabolism , Positron-Emission Tomography/methods , Radiopharmaceuticals/pharmacokinetics , Tegafur/therapeutic use , Tomography, X-Ray Computed , Uracil/therapeutic useABSTRACT
BACKGROUND: The efficacy and safety of concurrent administration of irinotecan with the two monoclonal antibodies cetuximab and bevacizumab as fourth line therapy in heavily pretreated patients with metastatic colorectal cancer were evaluated. PATIENTS AND METHODS: Patients with metastatic colorectal cancer who had progressed on therapy with 5-FU, oxaliplatin and irinotecan in the first and second line setting and on the combination of irinotecan and cetuximab in third line setting independent of their KRAS mutation status, were treated with irinotecan and cetuximab combined with bevacizumab in a dosage of 5 mg/kg. All drugs were administered every second week. RESULTS: From January 2007 to November 2008 27 patients were treated with cetuximab, irinotecan and bevacizumab. The triple-combination was well tolerated. Progression free survival (PFS) was 8.3 months and median overall survival (mOS) was 12.0 months. Two patients without KRAS mutation (7%) obtained a partial response and 17 (63%) had stable disease for at least two months. A retrospective KRAS mutation analysis revealed that there was a trend toward longer PFS and mOS in patients without KRAS mutations compared to patients with KRAS mutations with a PFS of 8.9 vs. 5.1 months and a mOS of 12.7 vs. 9.0 months. CONCLUSION: Bevacizumab is safe to add to irinotecan and cetuximab with a toxicity profile that seems to be similar to what would be expected from the agents alone. The results indicate that adding bevacizumab to irinotecan and cetuximab in a fourth line setting may induce a high rate of disease control in heavily pretreated patients with metastatic colorectal cancer.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Liver Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Humanized , Bevacizumab , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Cetuximab , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Female , Humans , Irinotecan , Liver Neoplasms/genetics , Liver Neoplasms/secondary , Male , Middle Aged , Mutation/genetics , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins p21(ras) , Retrospective Studies , Survival Rate , Treatment Outcome , ras Proteins/geneticsABSTRACT
BACKGROUND: Until recently there has been no proven second-line therapy for patients with advanced gastro-esophageal cancer (GEC). Since 2004, Denmark has had a national health program where non-proven therapy can be offered to patients with advanced cancer, after approval by an expert panel appointed by the National Board of Health. This program has accelerated the introduction and implementation of new therapies in Denmark. Inspired by therapy in metastatic colorectal cancer, a combination of cetuximab and irinotecan (Cetiri) was chosen for second-line therapy in GEC patients. We report our experience with Cetiri as second-line therapy in patients with GEC. METHODS: All patients had histologically confirmed GEC and all patients had progressive disease during or after first-line platinum-containing chemotherapy. The patients received cetuximab 500 mg/m(2) on day 1 and irinotecan 180 mg/m(2) on day 1 every 2nd week until progression or unacceptable toxicity. Toxicity was prospectively evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0. RESULTS: From December 2007 to February 2009, 50 consecutive patients received Cetiri as second-line therapy. Median performance status (PS) was 1. The median number of courses was seven. Seven patients (14%) had a partial response. Median progression-free survival (PFS) was 3.3 months and overall survival (OS) was 5.5 months; two patients are still alive without progressive disease. Major toxicities were: diarrhea (8%), fatigue (10%), neutropenia (16%), and febrile neutropenia (2%). CONCLUSION: Cetiri every two weeks is a convenient and well-tolerated second-line regimen in GEC patients. A promising effect was seen in patients with PS 0-1 and in patients who developed a rash.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Esophageal Neoplasms/drug therapy , Organoplatinum Compounds/adverse effects , Salvage Therapy , Stomach Neoplasms/drug therapy , Adult , Aged , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Humanized , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Cetuximab , Esophageal Neoplasms/pathology , Female , Follow-Up Studies , Humans , Irinotecan , Male , Middle Aged , Neoplasm Metastasis , Stomach Neoplasms/pathology , Survival Rate , Treatment OutcomeABSTRACT
BACKGROUND: Definition and treatment options for locally advanced non-resectable pancreatic cancer (LAPC) vary. Treatment options range from palliative chemotherapy to chemoradiotherapy (CRT). Several studies have shown that a number of patients become resectable after complementary treatment prior to surgery. METHODS: From 2001 to 2005, 63 consecutive patients with unresectable LAPC received CRT. CRT was given at a dose of 50 Gy/27 fractions, combined with UFT (300 mg/m(2)/day) and folinic acid. Re-evaluation of resectability was planned 4-6 weeks after completion of CRT. RESULTS: Fifty-eight patients completed all 27 treatment fractions. Toxicity was generally mild, with 18 patients experiencing CTCAE grade 3 or worse acute reactions. One patient died following a treatment-related infection. Two patients developed grade 4 upper GI bleeding. Median survival was 10.6 (8-13) months. Eleven patients underwent resection, leading to a resection rate of 17%, and a median survival of 46 (23-nr) months. All 11 patients had a R0 resection. Median survival for the patients not resected was 8.8 (8-12) months. CONCLUSION: CRT with 50 Gy combined with UFT, is a well-tolerated and effective treatment for patients with LAPC. R0 resection was possible in 17% leading to a long median survival of 46 months in resected patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Pancreatic Neoplasms/therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Combined Modality Therapy , Female , Humans , Male , Middle Aged , Pancreatic Neoplasms/mortality , Tegafur/adverse effects , Tegafur/therapeutic use , Uracil/adverse effects , Uracil/therapeutic useABSTRACT
PURPOSE: Elderly cancer patients often have co-morbidities and other characteristics that make the selection of optimal treatment more complex. The introduction of targeted therapies in colorectal cancer has further complicated this problem. This review will focus on the role of the EGFR antibody cetuximab in elderly patients. METHODS: We have reviewed the available evidence in the literature to evaluate the results of therapy with cetuximab, alone or in combination with chemotherapy, with a focus on elderly patients with metastatic colorectal cancer (mCRC). RESULTS: In patients with mCRC, combination chemotherapy prolongs median survival to more than 18 months and even around 24 months in combination with cetuximab in selected patients. No prospective studies have evaluated cetuximab in elderly patients. However, subgroup analyses from randomized trials and retrospective analysis suggest that the efficacy of chemotherapy and cetuximab is maintained in fit elderly patients, but with slightly increased but acceptable toxicity. CONCLUSION: No prospective cetuximab studies have been conducted solely in a population of elderly patients. However, available data suggest that outcomes in the fit elderly mirror results observed in younger patients.