taxane and Adenocarcinoma

Neoadjuvant chemotherapy (NAC) for locally advanced gastric and gastroesophageal junction adenocarcinoma (LAGC) has been recommended in several guidelines. However, there is no global consensus about the optimum of NAC regimens. We aimed to determine the optimal NAC regimen for LAGC.. A systematic review and Bayesian network meta-analysis was performed. The literature search was conducted from inception to June 2022. The odds ratio (OR) value and 95% confidence interval (95% CI) were used for assessment of R0 resection rate and pathological complete response rate (pCR) as primary outcomes. The hazard ratio (HR) value and 95% CI were interpreted for the assessment of overall survival (OS) and disease-free survival (DFS) as second outcomes. The risk ratio (RR) value and 95% CI were used for safety assessment.. Twelve randomized controlled trials were identified with 3846 eligible participants. The network plots for R0 resectability, OS, and DFS constituted closed loops. The regimens of TPF (taxane and platinum plus fluoropyrimidine), ECF (epirubicin and cisplatin plus fluorouracil), and PF (platinum plus fluoropyrimidine) showed a meaningful improvement of R0 resectability, as well as OS and/or DFS, compared with surgery (including surgery-alone and surgery plus postoperative adjuvant chemotherapy). Importantly, among these regimens, TPF regimen showed significant superiority in R0 resection rate (versus ECF regimen), OS (versus ECF regimen), DFS (versus PF and ECF regimens), and pCR (versus PF regimen).. The taxane-based triplet regimen of TPF is likely the optimal neoadjuvant chemotherapy regimen for LAGC patients.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Bayes Theorem; Chemotherapy, Adjuvant; Esophagogastric Junction; Fluorouracil; Humans; Neoadjuvant Therapy; Network Meta-Analysis; Platinum; Stomach Neoplasms; Taxoids

Gemcitabine monotherapy is the cornerstone of treatment for advanced pancreatic cancer. To date, no clear survival benefit has been found when combination chemotherapy has been compared with gemcitabine alone, except in a few studies. This meta-analysis compared the efficacy of polychemotherapy with gemcitabine alone in advanced pancreatic cancer.. Randomised trials comparing combination chemotherapy with gemcitabine alone were identified through electronic searches of PubMed, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials. Overall survival, reported as the hazard ratio at the 95% confidence interval, was the primary outcome measure.. 29 trials (19 phase III and 10 small randomised trials) that included 8421 patients were identified. Overall, polychemotherapy significantly improved overall survival (hazard ratio=0.87; 95% CI, 0.81-0.93; P<0.0001), progression-free survival (hazard ratio=0.77; 95% CI, 0.70-0.84; P<0.00001), and response rate (risk ratio=1.71; 95% CI, 1.42-2.07; P<0.00001) compared with gemcitabine alone.. Compared with gemcitabine monotherapy, combinations of two or more drugs (particularly those with novel agents or associated with >20% response rates and triplets) improved outcomes and response rate in advanced pancreatic cancer, and they could be considered a new standard of care in advanced settings.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Deoxycytidine; Disease-Free Survival; Fluorouracil; Gemcitabine; Humans; Pancreatic Neoplasms; Platinum Compounds; Randomized Controlled Trials as Topic; Survival Rate; Taxoids

To investigate the safety and efficacy of acitinib mesylate combined with chemotherapy in the treatment of patients with gastroesophageal junction adenocarcinoma.. A total of 119 patients with gastroesophageal junction adenocarcinoma were enrolled and randomized into an experimental group (n = 60) and a control group (n = 59). Both groups were treated with a combination of taxane, irinotecan and fluorouracil, while the experimental group also received acitinib mesylate. The clinical efficacy, survival time and adverse reactions of patients in two groups were recorded and analyzed.. The total remission rate in the experimental group and the control group was 15.79% and 3.23%, respectively; the disease control rate was 73.68% and 54.84%, respectively; and progression-free survival was 3.72 months (1-13.5 months) and 3.04 months (1-6 months), respectively. Overall survival was 13.66 months (5-24 months) and 10.08 months (6.5-19.5 months), in the experimental group and the control group, respectively. In addition, the incidence of adverse events in the experimental group was significantly lower than that in the control group.. Apatinib mesylate combined with chemotherapy for the treatment of patients with gastroesophageal junction adenocarcinoma was safe and effective, with improved survival benefit compared with control.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carcinoma, Squamous Cell; Case-Control Studies; Cisplatin; Esophageal Neoplasms; Esophagogastric Junction; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Male; Middle Aged; Prognosis; Pyridines; Stomach Neoplasms; Survival Rate; Taxoids

Eribulin mesylate (E7389) is an analog of halichondrin B with a unique mechanism of microtubule binding. The activity and toxicity of eribulin were assessed in patients with advanced non-small cell lung cancer (NSCLC) previously treated with a taxane.. An open-label phase II study included patients with NSCLC previously treated with platinum and taxane-based therapy, with up to two prior cytotoxic regimens, given for metastatic disease or as adjuvant therapy. Patients were stratified by taxane-sensitivity: taxane-sensitive (TS, progression >90 days after taxane) or taxane-resistant (TR, progression ≤90 days after taxane). Patients received an intravenous infusion of eribulin at 1.4 mg/m on days 1 and 8 every 21 days. The primary end point was objective response rate and secondary end points included progression-free survival and overall survival.. Sixty-six patients were accrued. The objective response rate was 5% with a median duration of response of 7.8 months. In the TS arm, 3 of 45 patients (7%) achieved a partial response and another 11 of 45 (24%) achieved stable disease for at least 3 months, whereas in the TR arm, no patients achieved a partial response and 4 of 21 (19%) achieved stable disease for at least 3 months. Median progression-free survival was 2.9 months in the TS subgroup and 1.2 months in the TR subgroup. The median overall survival was 12.6 months in the TS subgroup and 8.9 months in the TR subgroup. Toxicities were primarily hematologic; only two patients developed grade 3 neuropathy.. Eribulin mesylate is well tolerated and demonstrates activity in pretreated, TS NSCLC.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Ethers, Cyclic; Female; Follow-Up Studies; Furans; Humans; Ketones; Lung Neoplasms; Macrolides; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Platinum; Salvage Therapy; Survival Rate; Taxoids; Treatment Outcome

In first-line treatment of metastatic breast cancer, the best use of the available therapeutic agents is unclear. This study evaluated the efficacy and safety of combined therapy with bevacizumab and gemcitabine.. Women who were to undergo first-line treatment for locoregionally recurrent or metastatic breast cancer were eligible. Patients must have received a taxane-containing regimen in the neoadjuvant and/or adjuvant setting with a ≥ 12-month disease-free interval.. This was a single-arm, phase II trial. On day 1 of each 14-day cycle, patients received gemcitabine (2500 mg/m(2)) followed by bevacizumab (10 mg/kg). Patients were treated until complete response, progressive disease (PD), or intolerable toxicity. The primary endpoint was progression-free survival (PFS).. Fifty-two women were enrolled and treated. The median PFS was 4.8 months (95% confidence interval [CI], 3.4-7.6), the 1-year overall survival rate was 68.7% (95% CI, 54.1%-79.5%), and the response rate was 21.4% (95% CI, 10.3%-36.8%). The clinical benefit rate was 35.7%. The median PFS in the triple-negative (n = 19) and non-triple-negative (n = 33) subsets was 3.9 months (95% CI, 2.7-11.7) and 4.9 months (95% CI, 3.4-8.1), respectively. The most common (all grades) drug-related adverse events (AEs) were nausea (51.9%), fatigue (46.2%), decreased appetite (25.0%), and anemia (25.0%). The most common grade 3 or grade 4 drug-related AEs were neutropenia (13.5%), leukopenia (11.5%), and hypertension (7.7%).. Although the gemcitabine-bevacizumab doublet appears active, the median PFS was lower than expected. There were no unexpected safety signals at this dose and schedule of this combination.

Topics: Adenocarcinoma; Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Breast Neoplasms; Bridged-Ring Compounds; Deoxycytidine; Female; Gemcitabine; Humans; Immunoenzyme Techniques; In Situ Hybridization, Fluorescence; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Receptor, ErbB-2; Survival Rate; Taxoids

Angiogenesis is an established target for the treatment of MBC. Aflibercept (VEGF-Trap) is a humanized fusion protein, which binds VEGF-A, VEGF-B, and PIGF-1 and -2.. A 2-stage phase II study with primary end points of confirmed tumor response and 6-month progression-free survival (PFS). If either end point was promising after the initial 21 patients, an additional 20 patients would be enrolled. Measurable disease, <2 previous chemotherapy treatments, previous anthracycline or taxane therapy, and Eastern Cooperative Oncology Group performance status of 0 or 1 were required. Aflibercept was given at a dose of 4 mg/kg intravenous every 14 days.. Twenty-one patients were enrolled; 71% had visceral disease, 57% were estrogen receptor negative, 19% had HER2(+) disease with previous trastuzumab treatment, and 33% had 2 previous chemotherapy regimens. Partial response rate was 4.8% (95% confidence interval [CI], 0.1%-23.8%) and 6-month PFS was 9.5% (95% CI, 1.2%-30.4%). Neither primary end point met efficacy goals and the study was terminated. A median of 3 cycles was given. Median PFS was 2.4 months. Common grade 3 or 4 adverse events were hypertension (33%), fatigue (19%), dyspnea (14%), and headache (14%). Two cases of severe left ventricular dysfunction were noted.. Aflibercept did not meet efficacy goals in patients previously treated with MBC. Toxicity was as expected for anti-VEGF therapy.

Topics: Adenocarcinoma; Adult; Aged; Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Drug Resistance, Neoplasm; Female; Humans; Medical Oncology; Middle Aged; Neoplasm Metastasis; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Societies, Medical; Survival Analysis; Taxoids; United States

To evaluate the efficacy and safety of the combination chemotherapy regimen of irinotecan plus oral etoposide for the treatment of patients with recurrent ovarian cancer after previous treatment with platinum and taxane agents.. A total of 42 patients with recurrent ovarian cancer who had an evaluable lesion and provided informed consent for participation in the present study were analyzed. Irinotecan was administered intravenously at a dose of 60 mg/m on days 1 and 15. Etoposide was administered orally at a daily dose of 50 mg/body weight from days 1 to 21. A 28-day period comprised one cycle. The tumor response, adverse events, progression-free survival, and overall survival were examined. Tumor response was evaluated based on the Response Evaluation Criteria in Solid Tumors and the serum CA125 levels (Gynecologic Cancer Intergroup criteria). Adverse events were assessed according to the NCI-CTCAE (version 3.0).. Partial response was observed in 21 patients, stable disease in 14 patients, and progressive disease in 7 patients. The response rate was 50.0%, and the clinical benefit (partial response + stable disease) rate was 83.3%. Hematological toxicities of at least grade 3 severity included leukopenia in 21 patients (50.0%), neutropenia in 22 patients (52.4%), thrombocytopenia in 1 patient (2.4%), anemia in 9 patients (21.4%), and febrile neutropenia in 3 patients (7.1%). Nonhematological toxicities of at least grade 3 severity included queasy feeling in 5 patients (11.9%), vomiting in 3 patients (7.1%), and diarrhea in 2 patients (4.8%). Acute myeloid leukemia occurred in one patient (2.4%).. It is suggested that combination chemotherapy with irinotecan plus oral etoposide offers significant clinical benefit to patients with recurrent ovarian cancer previously treated with platinum and taxane agents.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Camptothecin; Disease-Free Survival; Drug Resistance, Neoplasm; Etoposide; Female; Humans; Irinotecan; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Ovarian Neoplasms; Survival Rate; Taxoids; Treatment Outcome

The primary objective of this study was to determine the rate of pathological response after preoperative celecoxib and concurrent taxane-based chemotherapy in patients with cancer of the esophagus and gastroesophageal junction.. Thirty-nine patients were enrolled in this single-arm, phase II clinical trial. Patients were administered daily celecoxib in combination with two to three cycles of carboplatin and paclitaxel with preoperative intent. Levels of cyclooxygenase (COX)-2 expression in resected tumors were analyzed by immunohistochemistry and correlated with clinical outcome measures. Postoperatively, patients were administered daily celecoxib for 1 year or until documented tumor recurrence.. All patients received two to three cycles of chemotherapy plus celecoxib 800 mg/d. Toxicities were as expected. A major clinical response (complete response + partial response) was noted in 22 patients (56%); six patients (15%) had a complete clinical response. Thirty-seven patients underwent esophagectomy. Five patients had a major pathological response (12.8%). Four-year overall and disease-free survivals were 40.9% and 30.3%, respectively. Patients with tumors expressing COX-2 demonstrated a higher likelihood of a major clinical response response (62% versus 50%) and an improved overall survival, compared with patients with COX-2-negative tumors.. Preoperative celecoxib with concurrent chemotherapy demonstrated sufficient effect on pathologic response to warrant further study. Patients with tumors expressing COX-2 demonstrated trends toward improved response to preoperative therapy and improved overall survival compared with nonexpressors.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carcinoma, Squamous Cell; Celecoxib; Cyclooxygenase 2; Esophageal Neoplasms; Esophagogastric Junction; Female; Humans; Male; Middle Aged; Preoperative Care; Pyrazoles; Sulfonamides; Survival Analysis; Taxoids; Treatment Outcome

Ixabepilone is a semisynthetic epothilone B analogue that is active in taxane-resistant cell lines and has shown activity in patients with refractory breast and ovarian cancer. We carried out a phase I trial of ixabepilone plus pegylated liposomal doxorubicin (PLD) in patients with advanced taxane-pretreated ovarian and breast cancer.. Patients with recurrent ovarian or breast carcinoma received PLD every 3 or 4 weeks plus five different dose schemas of ixabepilone in cohorts of three to six patients.. Thirty patients received a total of 142 treatment cycles of the PLD-ixabepilone combination. The recommended phase II dose and schedule of ixabepilone was 16 mg/m(2) on days 1, 8, and 15 plus PLD 30 mg/m(2) given on day 1, repeated every 4 weeks. Hand-foot syndrome and mucositis were dose limiting when both ixabepilone and PLD were given every 3 or 4 weeks. Objective responses were observed in 3 of 13 patients (23%) with breast cancer and 5 of 17 patients (29%) with ovarian cancer.. Ixabepilone may be safely combined with PLD, but tolerability is highly dependent upon the scheduling of both agents. This combination demonstrated efficacy in patients with breast and ovarian cancer and merits further evaluation in these settings.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Bridged-Ring Compounds; Doxorubicin; Epothilones; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Polyethylene Glycols; Survival Rate; Taxoids; Treatment Outcome

XRP6258 is a novel taxoid with a low affinity for P-glycoprotein. This multicenter phase II study assessed the activity of XRP6258 in the treatment of taxane-resistant metastatic breast cancer (MBC).. XRP6258 was administered as a 1-h i.v. infusion every 3 weeks at 20 mg/m(2) (then, in the absence of severe toxicity, at 25 mg/m(2) from cycle 2). The primary end point was the objective response rate (ORR) assessed according to response evaluation criteria in solid tumours (RECIST) guidelines.. Seventy-one patients were enrolled. The median relative dose intensity was 0.98. The ORR was 14% (two complete, eight partial responses). Eighteen patients (25%) had stable disease of >3 months duration. At a median follow-up of 20.0 months, the median time to progression was 2.7 months, and the median overall survival 12.3 months. The most common grade 3/4 adverse events (AEs) were neutropenia (73%) and leucopenia (55%), with a low febrile neutropenia rate (3%) and infrequent grade 3/4, treatment-related, non-hematological AEs (<5% patients for any AE). Two deaths were reported, one related to study drug and one to unknown cause.. XRP6258 was active and well tolerated in this group of MBC patients with taxane-resistant disease. These results support the further clinical development of this agent.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Confidence Intervals; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Humans; Infusions, Intravenous; Kaplan-Meier Estimate; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Prognosis; Risk Assessment; Survival Analysis; Taxoids; Treatment Outcome

To assess the reproducibility of intrinsic relaxivity and both relaxivity- and susceptibility-based dynamic contrast enhanced (DCE) MRI in pelvic tumors; to correlate kinetic parameters obtained and to assess whether acute antivascular effects are seen in response to cisplatin- or taxane-based chemotherapy.. T1-weighted and T2*-weighted DCE-MRI and basal R2* measurements were performed on three consecutive days in women with gynecological tumors. The third scan was 21.0 (range 17.3-23.5) hours after the first cycle of chemotherapy. Kinetic parameter estimates were obtained and correlated between techniques. Test-retest reproducibility and response to treatment were assessed.. Relative blood volume (rBV) and relative blood flow (rBF) correlated strongly with transfer constant (Ktrans), kep, and the initial area under the gadopentetate dimeglumine (Gd-DTPA) concentration-time curve (IAUGC) (all P<0.01). The group 95% confidence interval (CI) for change was -10.8 to +12.1%; +/-5.1%; -9.5 to +10.5%; +/-7.5%; for Ktrans, ve, kep, and IAUGC, respectively, and +/-13.6%, +/-2.4%, +/-11.6%, and +/-11.0%, for rBV, mean transit time (MTT), rBF, and R2*, respectively. There were no significant acute changes in kinetic parameter estimates in response to treatment on group analysis, apart from a small decrease in ve.. The results confirm the dominant influence of flow on Ktrans in untreated gynecological tumors. There is no evidence of an acute, large magnitude antivascular effect caused by cisplatin- or taxane-based chemotherapy.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Bridged-Ring Compounds; Female; Genital Neoplasms, Female; Humans; Magnetic Resonance Imaging; Middle Aged; Pelvic Neoplasms; Platinum; Regional Blood Flow; Reproducibility of Results; Taxoids

Ixabepilone is one of the epothilones, a new class of cytotoxics, that function as microtubule-stabilizing agents. With the primary endpoint of assessing ixabepilone's response rate against metastatic gastric cancer previously treated with a taxane, we performed a multi-center phase II trial.. Patients with histologically documented metastatic gastric or gastroesophageal adenocarcinoma, who had previously received a taxane, were eligible. Patients were required to have near normal organ function, > or =18 years of age, ECOG performance status of 0 or 1. A written informed consent was obtained from all patients. Ixabepilone was administered over one hour intravenously at a dose of 50 mg/m2 every 21 days (23 patients; cohort A) and 24 subsequent patients were treated with an amended protocol schedule to receive 6 mg/m2 intravenously on days 1-5 every 21 days (cohort B).. A total of 47 patients were treated. Most patients were men with a median performance status of 1. Two of 23 patients in cohort A achieved a confirmed partial response (9%, 95% CI 1.1-28%) but none of the 24 patients in cohort B achieved a response. A higher proportion of patients in cohort A experienced Grade 3/4 toxicities compared with those in cohort B.. Ixabepilone, on a once every 21-day schedule, is modestly active against metastatic gastric cancer previously treated with a taxane. The days 1-5 every 21 days schedule had a more favorable safety profile but no activity. The results of this study suggest that once every 21-day ixabepilone schedule should be pursued further in untreated gastric or gastroesophageal adenocarcinoma patients.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Bridged-Ring Compounds; Disease Progression; Epothilones; Female; Humans; Male; Middle Aged; Multicenter Studies as Topic; Peripheral Nervous System Diseases; Stomach Neoplasms; Taxoids

To assess the efficacy and tolerance of the vinorelbine/cisplatin combination in non-small cell lung cancer patients pre-treated with a taxane-based regimen.. Among the 32 enrolled patients, 28 (87.5%) had a PS (WHO) of 0-1 and 13 (40.6%) have previously received both platinum compounds and taxanes. Vinorelbine (25 mg/m2 on days 1 and 8) was given by a rapid i.v. infusion and cisplatin (80 mg/m2 on day 8) after appropriate hydration. The treatment was repeated every 3 weeks.. A partial response was achieved in six patients (ORR=18.8%; 95% confidence interval: 5.23-32.27); 13 (44.8%) and 10 (34.5%) patients had stable and progressive disease, respectively (intention-to-treat analysis). Four partial responses were observed in patients who were previously treated with taxanes/platinum-containing regimens. The median time to tumor progression was 4.7 months (range, 1.3-15.4). After a median follow-up period of 6.3 months (range, 1.3-15.4) the median overall survival was 7.6 months and the 1-year survival rate 17.7%. Grade 3 and 4 granulocytopenia was observed in 11 (34.4%) patients and grade 4 thrombocytopenia in one (3.1%). Eleven (34.4%) patients presented grade 2 and 3 anemia. Febrile neutropenia occurred in one (3.1%) patient. Grade 3 and 4 nausea/vomiting was reported in one (9.3%) patient each and grade 2 fatigue in four (12.5%).. The combination of vinorelbine and cisplatin is an active and well tolerated salvage regimen in NSCLC patients pre-treated with taxane-based chemotherapy.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cisplatin; Female; Humans; Lung Neoplasms; Male; Middle Aged; Survival Rate; Taxoids; Treatment Outcome; Vinblastine; Vinorelbine

This is a phase I/II trial of thalidomide with estramustine and paclitaxel in men with androgen-independent prostate cancer (AIPC) who underwent previous chemotherapy.. Men with progressive AIPC were treated with oral thalidomide (200 mg, 400 mg, or 600 mg daily), intravenous paclitaxel (100 mg/m2 over 3 hours on days 3 and 10), and oral estramustine (140 mg 3 times daily on days 1-5 and days 8-12) every 21 days.. Phase I: first cycle dose-limiting toxicity occurred in 0 of 3 patients at 200 mg thalidomide daily, 0 of 3 at 400 mg daily, and 1 of 3 at 600 mg daily (the designated maximum tolerated dose). Phase II: twenty-nine of 38 evaluable patients (76%; 95% confidence interval, 67%-87%) experienced a 50% decrease in prostate-specific antigen level. Five of 18 patients (28%) with measurable disease exhibited an objective response. Nine of 14 patients (64%) with disease refractory to previous taxane therapy had 50% decreases in prostate-specific antigen level. Grade 3/4 adverse events included neutropenia (9 of 39 [23%]), fatigue (9 of 39 [23%]), dyspnea (8 of 39 [21%]), and thromboembolic events (7 of 39 [18%]). Cumulative dose-limiting toxicity rates were minimal (13%) with thalidomide at 200 mg daily.. The profile of activity of thalidomide/paclitaxel/estramustine in taxane-refractory AIPC warrants further investigation.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Disease Progression; Estramustine; Humans; Male; Middle Aged; Neoplasms, Hormone-Dependent; Paclitaxel; Prostate-Specific Antigen; Prostatic Neoplasms; Survival Rate; Taxoids; Thalidomide; Time Factors; Treatment Outcome

Beyond first-line palliative systemic treatment can be beneficial to selected oesophagogastric cancer patients, but experience with its administration may be limited and vary among hospitals. In a population-based study, we analysed the association between hospital systemic treatment volume and administration of beyond first-line treatment in oesophagogastric adenocarcinoma, as well as the effect on overall survival (OS).. Synchronous metastatic oesophagogastric adenocarcinoma patients (2010-2017) were selected from the Netherlands Cancer Registry. Hospitals were categorised in volumes quartiles. The association between hospital systemic treatment volume and the use of beyond first-line treatment was assessed using trend and multivariable logistic regression analyses. OS was compared between hospitals with high and low beyond first-line treatment administration and treatment strategies using Kaplan-Meier curves with log-rank test and multivariable Cox proportional hazard regression.. Beyond first-line treatment was administered in 606 of 2,466 patients who received first-line treatment, and increased from 20% to 31% between 2010 and 2017 (P < 0.001). The lowest hospital volumes were independently associated with lower beyond first-line treatment administration compared to the highest volume (OR 0.62, 95% CI 0.39-0.99; OR 0.67, 95% CI 0.48-0.95). Median OS was higher in all patients treated in hospitals with a high versus low beyond first-line treatment administration (7.9 versus 6.2 months, P < 0.001). Second-line paclitaxel/ramucirumab was administered most frequently and independently associated with longer OS compared to taxane monotherapy (HR 0.74, 95% CI 0.59-0.92).. Higher hospital volume was associated with increased beyond first-line treatment administration in oesophagogastric adenocarcinoma. Second-line paclitaxel/ramucirumab resulted in longer survival compared to taxane monotherapy.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Esophageal Neoplasms; Esophagogastric Junction; Female; Hospitalization; Hospitals, High-Volume; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Netherlands; Paclitaxel; Palliative Care; Ramucirumab; Stomach Neoplasms; Taxoids

We present a rare case of taxane-pretreated metastatic gastric cancer with an excellent response to nab-paclitaxel. A 66- year-old woman was diagnosed with Stage Ⅳ gastric adenocarcinoma (T4aN3M1[LYM, OTH]P1CY1). She failed to respond to multiple chemotherapeutic regimens including S-1, capecitabine, cisplatin, L-OHP, paclitaxel, docetaxel, and CPT- 11. Finally, 6th line chemotherapy with nab-paclitaxel was tried. After 4 courses of nab-paclitaxel, a CT scan revealed decreasing ascites and a reduction in the size of the ovary metastasis. She experienced a clinical response for about 4 months. The adverse events were only Grade 1 peripheral sensory neuropathy and joint pain, and her performance status improved during the treatment period.

Topics: Adenocarcinoma; Aged; Albumins; Antineoplastic Agents, Phytogenic; Bridged-Ring Compounds; Drug Resistance, Neoplasm; Female; Humans; Ovarian Neoplasms; Paclitaxel; Stomach Neoplasms; Taxoids

Lung adenocarcinoma (ADC) is the most common lung cancer subtype and presents a high mortality rate. Clinical recurrence is often associated with the emergence of metastasis and treatment resistance. The purpose of this study was to identify genes with high prometastatic activity which could potentially account for treatment resistance. Global transcriptomic profiling was performed by robust microarray analysis in highly metastatic subpopulations. Extensive in vitro and in vivo functional studies were achieved by overexpression and by silencing gene expression. We identified the small GTPase RHOB as a gene that promotes early and late stages of metastasis in ADC. Gene silencing of RHOB prevented metastatic activity in a systemic murine model of bone metastasis. These effects were highly dependent on tumor-host interactions. Clinical analysis revealed a marked association between high RHOB levels and poor survival. Consistently, high RHOB levels promote metastasis progression, taxane-chemoresistance, and contribute to the survival advantage to γ-irradiation. We postulate that RHOB belongs to a novel class of "genes of recurrence" that have a dual role in metastasis and treatment resistance.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Bone Neoplasms; Bridged-Ring Compounds; Cell Line, Tumor; Drug Resistance, Neoplasm; Heterografts; Humans; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Proteins; Neoplasm Transplantation; rhoB GTP-Binding Protein; Taxoids

Taxanes, such as docetaxel and taxol, have been used as firstline chemotherapies in advanced lung adenocarcinoma (LAD), but limited responses to chemotherapy remain a major impediment in the clinic. Treatment with 5-azacytidine increases the sensitivity of SPC-A1/DTX cell line to taxanes. The results of DNA methylation microarray and cDNA array analysis indicate that DNA methylation contributes to the downregulation of secreted frizzled related protein 1 (SFRP1) in SPC-A1/DTX cells. Overexpression of SFRP1 reverses the chemoresistance of taxane-resistant LAD cell lines and enhances the in vivo sensitivity of taxane-resistant LAD cells to taxanes. Meanwhile, short hairpin RNA (shRNA)-mediated SFRP1 knockdown decreases the sensitivity of parental LAD cell lines to taxanes. Furthermore, FH535, a reversible Wnt signaling inhibitor, enhances the sensitivity of taxane-resistant LAD cells to taxanes. The level of SFRP1 in tumors of nonresponding patients is significantly lower than that in tumors of responders. Taken together, our results provide the direct evidence that SFRP1 is a clinically important determinant of taxanes resistance in human LAD cells, suggesting that SFRP1 might be a novel therapeutic target for the treatment of taxane-resistant LAD patients.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Animals; Antineoplastic Agents; Azacitidine; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; DNA Methylation; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Intercellular Signaling Peptides and Proteins; Lung Neoplasms; Male; Membrane Proteins; Mice, Inbred BALB C; Oligonucleotide Array Sequence Analysis; Sulfonamides; Taxoids; Wnt Signaling Pathway; Xenograft Model Antitumor Assays

Taxane and platinum-based chemotherapy regimens are standard treatment for advanced ovarian carcinoma. Expression levels of putative markers of taxane resistance in carcinoma tissues and paired peritoneal samples (n=55) and in 16 samples of ovaries without signs of carcinoma were compared with clinical data and the patients' time to progression. KIF14, PRC1, CIT and ABCC1 genes were significantly overexpressed in carcinomas when compared with normal ovarian tissues, while ABCB1 and CASP9 expression was decreased. Associations of protein expression of the proliferation marker Ki-67 with KIF14, PRC1, ABCB1 and CASP2 were found. Lastly, it was discovered that ABCB1 and CASP2 levels associated with FIGO stage and that the CIT level associated with the time to progression of ovarian carcinoma patients (P<0.0001). In conclusion, ABCB1, CASP2, KIF14, PRC1 and CIT genes seem to associate with surrogate markers of ovarian carcinoma progression and CIT gene associates with therapy outcome.

Topics: Adenocarcinoma; Antineoplastic Agents; ATP-Binding Cassette Transporters; Bridged-Ring Compounds; Caspases; Cell Cycle Proteins; Disease Progression; Drug Resistance, Neoplasm; Female; Genetic Association Studies; Humans; Intracellular Signaling Peptides and Proteins; Kinesins; Middle Aged; Oncogene Proteins; Ovarian Neoplasms; Ovary; Peritoneum; Protein Serine-Threonine Kinases; Taxoids; Treatment Outcome

It is unclear whether patients undergoing trimodality therapy (TMT) should be screened or surveyed for brain metastases.. We retrospectively analyzed esophageal cancer (EC) patients who underwent TMT between the years 2000 and 2010. All were systematically staged and surveyed but none had screening or surveillance brain imaging.. The median follow-up time for 518 patients was 29.3 months (range 1-149.2); all patients had adenocarcinoma of the esophagus. Of 188 (36.3%) patients who developed distant metastases, 20 (10.6% of 188 patients or 3.9% of 518 patients) had brain metastases. A higher baseline clinical stage (stage III or IVa) was associated with brain metastases. Most (90%) patients with brain metastases were diagnosed within 24 months of surgery. Sixteen patients had central nervous system symptoms at diagnosis. Twelve (60%) patients had solitary metastasis and 8 (40%) patients had multiple metastases. Although 17 patients received therapy for brain metastases, the median overall survival time of 20 patients was only 10.5 months (95% CI 6.6-14.0).. After TMT, 3.9% of EC patients developed brain metastases and their prognosis was poor. Our data suggest that screening and/or surveillance for brain metastases in the EC population undergoing TMT is not warranted.

Topics: Adenocarcinoma; Adult; Aged; Brain Neoplasms; Bridged-Ring Compounds; Chemoradiotherapy; Combined Modality Therapy; Dose Fractionation, Radiation; Early Detection of Cancer; Esophageal Neoplasms; Esophagectomy; Female; Fluorouracil; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Platinum Compounds; Retrospective Studies; Survival Rate; Taxoids; Young Adult

To investigate the clinical value of the expression of glucose regulated protein 78 (GRP78) for assessment of severity, chemoresistance and prognosis in patients with gastric adenocarcinoma ( GC) .. A cohort of 237 patients with gastric cancer was included in this study. 160 patients of them were treated by D2 radical gastrectomy and adjuvant chemotherapy. The GRP78 expression was detected by immunohistochemistry and 80 patients of them were tested in vitro for cancer chemosensitivity by ATP-tumor chemosensitivity assay (ATP-TCA). In addition, the relationships were analyzed between GRP78 and age, gender, tumor differentiation, invasion, disease stage, lymph node metastasis and chemoresistance as well as disease-free survival (DFS).. The positive rate of GRP78 expression in the gastric adenocarcinoma was 68.8% before the initiation of chemotherapy. The positive GRP78 expression was significantly correlated with tumor invasion depth, poor differentiation, TNM stages, and lymph node metastasis (all P < 0.05), not correlated with gender and age, and high GRP78 expression was associated with the chemoresistance of the gastric cancer cells to chemotherapeutic agents. Negative GRP78 expression was associated with higher sensitivity to both drugs and regimens. The DFS of GRP78-positive group and GRP78-negative group was (53.6 ± 0.9) months and (38.3 ± 0.8) months, respectively (P = 0.041). Interestingly, subgroup analysis revealed that the DFS in GRP78-negative and-positive patients treated with taxane-containing chemotherapy was (58.6 ± 2.6) months and (49.1 ± 2.7) months, respectively, but the difference was statistically not significant (P = 0.111). In contrast, in the subset of GRP78-negative and- positive patients treated with taxane-containing regimens, the DFS was (45.5 ± 1.9) months and (35.1 ± 2.2) months, respectively, showing a significant difference (P = 0.038). In the group of patients with positive GRP78 expression, the patients treated with taxane-containing chemotherapy had a longer DFS [(49.1 ± 2.7) months] than those without that treatment [(35.1 ± 2.2) months], showing a significant difference (P = 0.017). Univariate analysis revealed that DFS was correlated with histological grade, GRP78 expression and lymph node metastasis (all P < 0.05). Multivariate analysis showed that GRP78 expression and TNM staging were independent influencing factors for gastric cancer (both P < 0.05).. The results of our study suggest that GRP78 may be a novel biomarker for assessment of malignant degree and prediction of chemoresistance in gastric cancer, and may be helpful to chemotherapy planning and prognosis prediction in patients with gastric cancer.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bridged-Ring Compounds; Chemotherapy, Adjuvant; Disease-Free Survival; Drug Resistance, Neoplasm; Endoplasmic Reticulum Chaperone BiP; Female; Gastrectomy; Heat-Shock Proteins; Humans; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Grading; Neoplasm Invasiveness; Neoplasm Staging; Stomach Neoplasms; Taxoids

The aim of this study was to evaluate the activity and safety of the combination chemotherapy of 5-fluorouracil (5-FU), leucovorin, and irinotecan (FOLFIRI regimen) after failure of fluoropyrimidine, platinum, and taxane in gastric cancer (GC) and to evaluate the prognostic factors for survival.. Patients received biweekly FOLFIRI chemotherapy as third-line treatment. The FOLFIRI-1 consisted of irinotecan (180 mg/m(2) in a 2-h infusion) on day 1, and then leucovorin (200 mg/m(2) in a 2-h infusion) and 5-FU (a 400 mg/m(2) bolus, followed by 600 mg/m(2) in a 22-h continuous infusion) on days 1 and 2. FOLFIRI-2 consisted of irinotecan (180 mg/m(2) in a 2-h infusion) on day 1, and then leucovorin (400 mg/m(2) in a 2-h infusion) and 5-FU (a 400 mg/m(2) bolus, followed by 2400 mg/m(2) in a 46-h continuous infusion) on day 1.. A total of 158 patients were included. The overall response rate was 9.6 % in patients with measurable lesions. The median progression-free survival (PFS) and overall survival (OS) were 2.1 months [95 % confidence interval (CI), 1.7-2.5] and 5.6 months (95 % CI, 4.7-6.5), respectively. The major grade 3/4 toxicity was myelosuppression (36.7 %). Good performance status (PS), fewer metastatic sites, and longer duration from the first-line to third-line chemotherapy were independent prognostic factors affecting both PFS and OS.. The FOLFIRI regimen showed antitumor activity and tolerable toxicity profiles against advanced GC in the third-line setting. Patients with good PS, fewer metastatic sites and longer previous treatment duration might have the maximal benefit from third-line chemotherapy.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Camptothecin; Carcinoma, Signet Ring Cell; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Platinum; Retrospective Studies; Salvage Therapy; Stomach Neoplasms; Survival Rate; Taxoids; Treatment Outcome

To evaluate the management of patients with prostate cancer in Senegal.. We performed a retrospective descriptive study, based on the medical records of patients managed for prostate cancer during a period of six years and a half from January 1, 2004, to June 30, 2010. All records of inpatients and outpatients managed for prostate cancer were collected. Data collection was performed through a standardized survey form, and included the following parameters: age, presence or absence of known history of prostate cancer in siblings, circumstances of discovery, clinical and paraclinical examination, histology and therapeutic modalities.. We studied the records of 164 patients with prostate cancer. The mean age of our patients was 65years, ranging from 43 to 96years. The circumstances of diagnosis were mostly due to lower urinary tract symptoms. Digital rectal examination was suggestive in 87% of cases, and PSA levels were high in 100% of cases, ranging from 5.88ng/ml to 21,660ng/ml, with a mean of 1447.57ng/ml. Half of the patients had PSA levels greater than or equal to 100ng/ml. The most common histological type was adenocarcinoma. During the study period, 49 radical prostatectomies were performed. The mean PSA levels of patients who underwent a prostatectomy were 23.4ng/ml. Radical retropubic prostatectomy was performed in 35 patients, and radical perineal prostatectomy was performed in 10 cases. Pulpectomy was the method most commonly used in metastatic prostate cancer; it was performed in 48 patients. After resistance to castration, antiandrogens were reintroduced in 13 patients, and diethylstilbestrol in four patients. Only two patients underwent a taxane-based chemotherapy regimen.. The diagnosis of prostate cancer was usually tardive in Senegal. Treatment often involves surgical castration. Prostatectomy was only very seldom indicated.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents; Biomarkers, Tumor; Bridged-Ring Compounds; Delayed Diagnosis; Diethylstilbestrol; Digital Rectal Examination; Estrogens, Non-Steroidal; Health Care Surveys; Humans; Male; Medical Records Systems, Computerized; Middle Aged; Orchiectomy; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Retrospective Studies; Senegal; Taxoids; Treatment Outcome

This study's objectives were to determine whether tumor response measured by computed tomography (CT) and evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) correlated with overall survival (OS) in patients with non-small-cell lung cancer (NSCLC) after neoadjuvant chemotherapy and surgical resection.. We measured primary tumor size on CT before and after neoadjuvant chemotherapy in 160 NSCLC patients who underwent surgical resection. The relationship between CT-measured response (RECIST) and histopathologic response (≤ 10% viable tumor) and OS were assessed by Kaplan-Meier survival, univariable, and multivariable Cox proportional hazards regression.. There was a statistically significant association between CT-measured response (RECIST) and OS (p = 0.03). However, histopathologic response was a stronger predictor of OS (p = 0.002), with a more pronounced separation of the survival curves when compared with CT-measured response. In multivariable Cox regression analysis, only pathologic stage and histopathologic response were significant predictors of OS. A 41% overall discordance rate was noted between CT RECIST response and histopathologic response. CT RECIST classified as nonresponders a subset of patients with histopathologic response (8 out of 30 points, 27%) who demonstrated prolonged survival after neoadjuvant chemotherapy.. We were unable to show that CT RECIST is a reliable predictor of OS in patients with NSCLC undergoing surgical resection after neoadjuvant chemotherapy. The failure of CT RECIST to predict long-term outcome may be because of the inability of CT imaging to consistently identify patients with histopathologic response. CT RECIST may have only a limited role as an efficacy endpoint after neoadjuvant chemotherapy in patients with resectable NSCLC.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Platinum; Prognosis; Retrospective Studies; Survival Rate; Taxoids; Tomography, X-Ray Computed

Age is associated with poor prognosis in ovarian cancer patients. Reasons could be increased comorbidity, more advanced stage, or nonoptimal surgery or chemotherapy. Objectives of this study were to evaluate the significance of comorbidity and age ≥70 years on receiving cytoreductive surgery, standard combination chemotherapy (TC), adherence to TC treatment, and prognosis.. A retrospective cohort study of all women registered in a nation-wide database with ovarian or peritoneal cancer in 2005-2006. Logistic regression was employed for determining the predictive value of age and comorbidity (ASA score) on receiving cytoreductive surgery and TC, and on adhering to TC. Kaplan-Meier method and Cox proportional hazards analysis were employed for survival analyses.. Of 961 patients, 348 (36.2%) were elderly. Age ≥70 years was independently predictive of not receiving surgery, OR 0.2(95% CI 0.1-0.5) and TC treatment, OR 0.03 (95% CI 0.01-0.1). Comorbidity was also independently predictive of not receiving standard treatment: OR for receiving surgery with ASA score of ≥3 was 0.2 (95% CI 0.1-0.5), and for receiving TC it was 0.03 (95% CI 0.01-0.1). Overall, age ≥70 was a poor prognostic factor in OS and PFS, but the effect of age ceased after 16 months. Comorbidity was a poor prognostic factor throughout the study period but with time-varying effect. For patients treated with TC, age was not a prognostic factor, whereas ASA score ≥3 was.. Elderly patients and patients with comorbidity less often receive optimal surgical and medical treatment. For those receiving optimal treatment, age ≥70 is not an independent poor prognostic factor, whereas severe comorbidity is.

Topics: Abdominal Cavity; Adenocarcinoma; Age Factors; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carboplatin; Chemotherapy, Adjuvant; Cohort Studies; Comorbidity; Denmark; Female; Guideline Adherence; Humans; Logistic Models; Middle Aged; Neoadjuvant Therapy; Ovarian Neoplasms; Ovariectomy; Practice Guidelines as Topic; Prognosis; Registries; Retrospective Studies; Survival Analysis; Taxoids

To determine whether genetic variations in CMPK1 or RRM1, which impact the pharmacodynamics of gemcitabine, differentially affect the outcomes of non-small cell lung cancer (NSCLC) patients treated with gemcitabine or taxane/cisplatinum.. We conducted retrospective study evaluating the associations between overall survival in 298 NSCLC patients at stages IIIA/IIIB (140) and IV (158), treated with gemcitabine (139) or taxane (159)/cisplatinum and 14 tagging single-nucleotide polymorphisms (tSNPs): 4 in CMPK1 and 10 in RRM1.. The wild-type genotypes of CMPK1 IVS1+1057 and IVS1-928 were associated with shorter overall survival in patients treated with the gemcitabine/cisplatinum (adjusted hazards ratio = 1.97 and 1.89; Cox pBonferroni = 0.008 and 0.020), whereas this effect was not observed in patients treated with taxane/cisplatinum. No associations were observed for the other 2 CMPK1 or 10 RRM1 tSNPs. Analysis of the interaction between the CMPK1 and RRM1 genes showed that the survival of patients with CMPK1 IVS1+1057 CC and RRM1 IVS1-2374 TT, IVS7+25 AA, IVS7-425 AA, or IVS8+287 TT was significantly shorter when they were treated with the gemcitabine/cisplatinum (adjusted hazards ratio = 3.00, 2.89, 3.14, and 3.00; Cox pBonferroni = 0.007, 0.012, 0.006, and 0.007). However, these effects were not observed in patients treated with taxane/cisplatinum.. These findings suggest that polymorphisms of CMPK1 and their combination with those of RRM1 are helpful in identifying patients who will benefit less from a gemcitabine/cisplatinum as the first-line regimen.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cisplatin; Cohort Studies; Deoxycytidine; DNA, Neoplasm; Female; Follow-Up Studies; Gemcitabine; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Nucleoside-Phosphate Kinase; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Retrospective Studies; Ribonucleoside Diphosphate Reductase; Survival Rate; Taxoids; Treatment Outcome; Tumor Suppressor Proteins

Multiple biologically relevant polymorphisms may have more accurate prediction of cancer prognosis compared with single polymorphism because of the modest effect. This study investigated whether the functional polymorphisms in P53 pathway genes, P53 Arg72Pro (rs1042522), P73 G4C14-to-A4T14 (rs2273953 and rs1801173), and MDM2 T309G (rs2279744), alone or in combination, affect survival in advanced non-small cell lung cancer (NSCLC) patients.. A total of 199 stage III-IV NSCLC patients with platinum-based chemotherapy were recruited between 2002 and 2004. Associations between genotypes and survival were assessed using Kaplan-Meier method. Cox proportional hazard models were performed to identify significant variables.. During the median 26.5 months of follow-up, the P53 Pro/Pro genotype was strongly associated with shorter overall survival compared with the Arg/Arg genotype (12.0 versus 20.0 months; log-rank p = 0.002; hazard ratio = 1.86; 95% confidence interval [CI], 1.15-3.02). Pairwise combination analysis showed that patients carrying the variant P53 Pro/Pro-P73 GC/GC or P53 Pro/Pro-MDM2 GG genotypes had survival time only half of that for those carrying the wild-type genotypes, with hazard ratio being 2.47 (95% CI, 1.20-5.10) and 2.00 (95% CI, 1.15-3.46), respectively. Furthermore, a combined effect was seen with survival time being gradually shorter with increasing number of unfavorable genotypes in these three genes (p(trend) = 0.039), indicating a gene-dose effect in association with survival.. These findings suggest that genetic polymorphisms in the P53 pathway may be promising biomarkers for individualized chemotherapy and prognosis of NSCLC patients.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carboplatin; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cisplatin; DNA-Binding Proteins; DNA, Neoplasm; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Middle Aged; Nuclear Proteins; Organoplatinum Compounds; Oxaliplatin; Polymerase Chain Reaction; Polymorphism, Genetic; Proto-Oncogene Proteins c-mdm2; Survival Rate; Taxoids; Treatment Outcome; Tumor Protein p73; Tumor Suppressor Protein p53; Tumor Suppressor Proteins; Vinblastine; Vinorelbine

Using a selection process designed to reflect clinically relevant conditions, a panel of taxane-selected variants were developed to study further the mechanisms of resistance in lung cancer. Unlike continuous or pulse exposure to high concentrations of chemotherapeutic drugs which yield high resistance and often cross resistance, most variants developed here displayed low level resistance to the selecting drug with slight cross-resistance. Pulsing with taxol resulted in more highly resistant clones (up to 51.4-fold). Analysis of taxol and taxotere in the four major lung cancer cell types showed the taxanes to be more effective against NSCLC (with the exception of SKMES-taxane selected variants) than against the SCLC. Comparison of taxol and taxotere shows that taxol induces higher levels of resistance than taxotere. Further, in taxotere-selected cell lines, the cells are more resistant to taxol than taxotere, suggesting that taxotere may be a superior taxane from a clinical view. Taxol treatment resulted in increased cross-resistance to 5-FU in all classes of lung cancer except DMS-53. The high levels of Pgp in the DMS-53 and selected variant suggests this mechanism is not related to Pgp expression. Analysis of the Pgp and MRP-1 status by combination inhibitory assays and Western blotting showed no consistent relationship between expression of the membrane pumps Pgp or MRP-1 and resistance. However, where high level resistance was seen, the parent cell line expressed Pgp or MRP-1 and was accompanied by increased levels in the variants. Overall we found that the clinically relevant models used here are useful for investigating mechanisms of taxane resistance.

Topics: Adenocarcinoma; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Bridged-Ring Compounds; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cell Survival; Docetaxel; Drug Combinations; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Lung Neoplasms; Taxoids

A relationship between inactivation of mitotic checkpoint genes and sensitivity of cancer cells to anticancer agents has been reported. We investigated the effect of epigenetic inactivation by aberrant hypermethylation of the mitotic checkpoint gene CHFR (checkpoint with forkhead and ring finger) on the sensitivity of cervical cancer cells to taxanes. Methylation-specific PCR (MSP) of cervical smears showed aberrant methylation of CHFR in 12.3% (2/14) of adenocarcinoma specimens. In contrast, aberrant DNA methylation was not detected in normal cervical cells or squamous cell carcinoma cells. Aberrant methylation of CHFR was also analyzed in 6 human cervical carcinoma-derived cell lines and was observed in SKG-IIIb and HeLa cells. These cell lines showed high sensitivity to taxanes, but became taxane-resistant upon treatment with 5-azacytidine. Furthermore, suppression of CHFR expression in siRNA-transfected SKG-IIIa cells caused increased sensitivity to taxanes. In conclusion, aberrant methylation of the CHFR gene may be useful as a molecular marker for selection of therapy for patients with cervical adenocarcinoma with a poor prognosis, and may also suggest a new therapeutic strategy of targeting CHFR in cervical cancer. To our knowledge, this study is the first to examine epigenetic inactivation by aberrant hypermethylation of CHFR in cervical cancer.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Antimetabolites, Antineoplastic; Antineoplastic Agents; Azacitidine; Bridged-Ring Compounds; Carcinoma, Squamous Cell; Cell Cycle Proteins; DNA Methylation; DNA, Neoplasm; Drug Tolerance; Epigenesis, Genetic; Female; Gene Expression Regulation, Neoplastic; Gene Silencing; Humans; Neoplasm Proteins; Poly-ADP-Ribose Binding Proteins; Promoter Regions, Genetic; RNA, Small Interfering; Taxoids; Tumor Cells, Cultured; Ubiquitin-Protein Ligases; Uterine Cervical Neoplasms

Carcinoma of unknown primary (CUP) is characterized by dismal patient survival. The outcome of patients with two favourable risk CUP subsets was studied. Eighty patients diagnosed with either midline lymph node metastases (n=33) or peritoneal carcinomatosis (n=47) were analysed retrospectively. The majority had poorly differentiated adenocarcinoma or undifferentiated carcinoma, treated with platinum-taxane based chemotherapy from 1996 till 2002. Females with peritoneal carcinomatosis also underwent surgical debulking. Objective tumour regression was present in 44% of patients (nodal group 30% versus peritoneal group 53%, p=0.066). Complete responses were seen more often in peritoneal carcinomatosis patients (nodal group 9%, peritoneal group 36%, p=0.008). At a median follow up of 60 months, median progression-free and overall survival were 5 and 10 months respectively in the nodal group, 7 and 15 months in the peritoneal group. Five-year survival was 7% (nodal group 0% vs. peritoneal group 10%, p=0.05). Complete responders fared better than non-CR patients. Fewer than four metastatic sites, elevated CA 125, and normal CA 19-9 levels were favourable prognostic factors for survival. Modern combination chemotherapy has satisfactory activity, with a minority of CUP patients enjoying long-term responses. Research efforts towards complete remission consolidation and molecular profiling are imperative.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers, Tumor; Bridged-Ring Compounds; Carcinoma; Female; Follow-Up Studies; Greece; Humans; Lymphatic Metastasis; Male; Middle Aged; Neoplasms, Unknown Primary; Peritoneal Neoplasms; Prognosis; Proportional Hazards Models; Survival Analysis; Taxoids; Treatment Outcome

Cancer of unknown primary site represents approximately 3% to 5% of all new cancer diagnoses. Adenocarcinomas account for 60% of all unknown primary cancers and poorly differentiated carcinomas or adenocarcinomas, for 30%. Historically, the prognosis for most patients with unknown primary tumors has been poor, with survival often less than 6 months from diagnosis. Recent advances in diagnostic techniques, including immunocytochemical and molecular genetic methods, have increased the probability of identifying a likely underlying tumor type. Based on clinical and pathologic features, approximately 40% of patients can be categorized within subsets for which specific treatment has been defined. Empiric therapy is an option for the remaining 60% of patients. In these patients, favorable prognostic factors for treatment response include tumor location in lymph nodes, fewer sites of metastases, younger age, and poorly differentiated carcinoma histology. Although experience remains limited, the incorporation of a taxane into empiric regimens appears to improve response rates and survival. A recent study of paclitaxel (Taxol), carboplatin (Paraplatin), and etoposide in 55 patients with cancer of unknown primary site reported an overall response rate of 47% and a median overall survival of 13.4 months. Investigations continue to explore new diagnostic techniques and novel therapeutic approaches.

Topics: Adenocarcinoma; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Carboplatin; Carcinoma; Etoposide; Evaluation Studies as Topic; Female; Humans; Male; Neoplasms, Unknown Primary; Paclitaxel; Prognosis; Survival Rate; Taxoids