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1 Published Ahead of Print on August 15, 211 as 1.12/JCO The latest version is at JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T Carboplatin Plus Paclitaxel Versus Carboplatin Plus Pegylated Liposomal Doxorubicin As First-Line Treatment for Patients With Ovarian Cancer: The MITO-2 Randomized Phase III Trial Sandro Pignata, Giovanni Scambia, Gabriella Ferrandina, Antonella Savarese, Roberto Sorio, Enrico Breda, Vittorio Gebbia, Pietro Musso, Luigi Frigerio, Pietro Del Medico, Alessandra Vernaglia Lombardi, Antonio Febbraro, Paolo Scollo, Antonella Ferro, Stefano Tamberi, Alba Brandes, Alberto Ravaioli, Maria Rosaria Valerio, Enrico Aitini, Donato Natale, Laura Scaltriti, Stefano Greggi, Carmela Pisano, Domenica Lorusso, Vanda Salutari, Francesco Legge, Massimo Di Maio, Alessandro Morabito, Ciro Gallo, and Francesco Perrone Author affiliations appear at the end of this article. Submitted November 18, 21; accepted May 27, 211; published online ahead of print at on August 15, 211. Written on behalf of the Multicentre Italian Trials in Ovarian Cancer-2 (MITO-2) Investigators. Supported in part by Integrated Therapeutics Group (ITGI) and Schering- Plough Italy, which supplied the experimental drug, and by the nonprofit Italian Association for Cancer Research. Presented in part at the 45th Annual Meeting of the American Society of Clinical Oncology, May 29-June 2, 29, Orlando, FL; the 46th Annual Meeting of the American Society of Clinical Oncology, June 4-8, 21, Chicago, IL; and the 35th Congress of the European Society of Medical Oncology, October 8-12, 21, Milan, Italy. ITGI and Schering-Plough Italy had no role in trial design and data interpretation. Authors disclosures of potential conflicts of interest and author contributions are found at the end of this article. Clinical Trials repository link available on JCO.org. Corresponding author: Sandro Pignata, MD, PhD, Istituto Nazionale Tumori, via Mariano Semmola, 8131 Napoli, Italy; by American Society of Clinical Oncology X/11/2999-1/$2. DOI: 1.12/JCO A B S T R A C T Purpose Carboplatin/paclitaxel is the standard first-line chemotherapy for patients with advanced ovarian cancer. Multicentre Italian Trials in Ovarian Cancer-2 (MITO-2), an academic multicenter phase III trial, tested whether carboplatin/pegylated liposomal doxorubicin (PLD) was more effective than standard chemotherapy. Patients and Methods Chemotherapy-naive patients with stage IC to IV ovarian cancer (age 75 years; Eastern Cooperative Oncology Group performance status 2) were randomly assigned to carboplatin area under the curve (AUC) 5 plus paclitaxel 175 mg/m 2 or to carboplatin AUC 5 plus PLD 3 mg/m 2, every 3 weeks for six cycles. Primary end point was progression-free survival (PFS). With 632 events in 82 enrolled patients, the study would have 8% power to detect a.8 hazard ratio (HR) of PFS. Results Eight hundred twenty patients were randomly assigned. Disease stages III and IV were prevalent. Occurrence of PFS events substantially slowed before obtaining the planned number. Therefore, in concert with the Independent Data Monitoring Committee, final analysis was performed with 556 events, after a median follow-up of 4 months. Median PFS times were 19. and 16.8 months with carboplatin/pld and carboplatin/paclitaxel, respectively (HR,.95; 95% CI,.81 to 1.13; P.58). Median overall survival times were 61.6 and 53.2 months with carboplatin/pld and carboplatin/paclitaxel, respectively (HR,.89; 95% CI,.72 to 1.12; P.32). Carboplatin/PLD produced a similar response rate but different toxicity (less neurotoxicity and alopecia but more hematologic adverse effects). There was no relevant difference in global quality of life after three and six cycles. Conclusion Carboplatin/PLD was not superior to carboplatin/paclitaxel, which remains the standard first-line chemotherapy for advanced ovarian cancer. However, given the observed CIs and the different toxicity, carboplatin/pld could be considered an alternative to standard therapy. J Clin Oncol by American Society of Clinical Oncology INTRODUCTION Ovarian cancer is the fourth leading cause of cancerrelated death in women. 1 Intensive surgical staging and cytoreduction, followed by chemotherapy with carboplatin/paclitaxel, represent the standard treatment approach. 2-6 However, even after optimal debulking surgery and response to systemic therapy, the risk of recurrence is high, and long-term survival remains poor. Furthermore, standard medical treatment of ovarian cancer negatively impacts on quality of life (QoL) as a result of frequent toxicity, such as alopecia, neurotoxicity, and fatigue. Anthracyclines were used in the first-line treatment of advanced ovarian cancer before the introduction of taxanes, with data from meta-analyses 211 by American Society of Clinical Oncology 1 Copyright 211 by American Society of Clinical Oncology
2 Pignata et al suggesting that their addition to the platinum-based treatment might be advantageous. 7 Pegylated liposomal doxorubicin (PLD) is a formulation of doxorubicin encapsulated in liposomes that are coated with methoxypolyethylene glycol, promoting the prolongation of circulation of the drug in the blood and its concentration in the tumor. This formulation results in a different pharmacokinetic and toxicity profile, as compared with conventional anthracyclines, with less myelotoxicity, alopecia, nausea, vomiting, and cardiotoxicity, but more skin and mucosal toxicity, namely palmer-plantar erythrodysesthesia and stomatitis. 8 In a randomized phase III trial, compared with standard topotecan in second-line treatment, PLD produced better overall survival (OS) in platinum-sensitive patients and was characterized by a favorable tolerability profile, with less severe hematologic toxicity. 9 On this basis, PLD is considered a treatment of choice for relapsed ovarian cancer. PLD was also compared to paclitaxel in the treatment of relapsed ovarian cancer. 1 No significant efficacy difference was found between the two drugs, but PLD caused significantly less alopecia and neurotoxicity. This evidence encouraged the use of PLD in combination with carboplatin. Several phase I and II studies showed the possibility of easily combining PLD with standard doses and schedules of carboplatin. 11,12 A Group d Investigateurs Nationaux pour l Etude des Cancers Ovariens phase II study 13 in patients with relapsed platinum-sensitive ovarian cancer demonstrated that the combination of carboplatin at area under the curve (AUC) 5 with PLD 3 mg/m 2, given every 4 weeks, was active, with a 63% response rate and median progression-free survival (PFS) and OS times of 9.4 and 32 months, respectively. The combination was well tolerated; although nearly half of the patients experienced severe neutropenia, it was complicated by fever in only 3% of patients, and there was only mild to moderate nonhematologic toxicity, including palmer-plantar erythrodysesthesia (32%) and neuropathy (28%). Therefore, we planned a randomized phase III clinical trial, Multicentre Italian Trials in Ovarian Cancer-2 (MITO-2), to evaluate whether carboplatin/pld is superior in terms of PFS to the standard carboplatin/paclitaxel as first-line therapy of patients with advanced ovarian cancer. To plan the same dose-intensity of carboplatin in both arms, we chose an every-3-week schedule of carboplatin and PLD. PATIENTS AND METHODS Study Design MITO-2 was an open-label, randomized, phase III study (Clinicaltrials. gov identifier: NCT326456). The primary end point was PFS. Secondary end points included OS, treatment activity, toxicity, and QoL. Overall, 82 patients were planned to be enrolled, and 632 events were needed to have 8% power of detecting a.8 hazard ratio (HR) of progression, with two-tailed.5 (East Software; Cytel, Cambridge, MA). This would represent an increase in median PFS from 18 to 22.5 months. No interim analyses were planned. Patients were randomly assigned 1:1 to the standard or experimental arm. Telephone random assignment was performed centrally (Clinical Trials Unit, National Cancer Institute, Napoli, Italy) by a computer-driven minimization procedure. Stratification variables were center, residual disease after surgery (absent, 1 cm, 1 cm, or no primary surgery), stage (IC, II, III, or IV), Eastern Cooperative Oncology Group performance status ( to 1 or 2). Random assignment (N = 82) Allocation to carboplatin + paclitaxel (n = 41) Missing information on treatment started (n = 2) Did not start treatment (n = 4) Started assigned treatment (n = 44) Allocation to carboplatin + pegylated liposomal doxorubicin (n = 41) Missing information on treatment started (n = 4) Received carboplatin + paclitaxel (violation) (n = 3) Did not start treatment (n = 6) Started assigned treatment (n = 397) Follow-up Primary end point (282 events) Progressed (n = 267) Died without documented progression (n = 15) Alive and without progression (n = 128) Observed for 18 months (n = 2) Observed for months (n = 51) Observed for > 36 months (n = 75) Follow-up Primary end point (274 events) Progressed (n = 264) Died without documented progression (n = 1) Alive and without progression (n = 136) Observed for 18 months (n = 2) Observed for months (n = 51) Observed for > 36 months (n = 83) Fig 1. Flow of study procedures and data collection according to CONSORT diagram. QoL, quality of life; RECIST, Response Evaluation Criteria in Solid Tumors. Analysis Progression-free survival (intention to treat) (n = 41) Overall survival (intention to treat) (n = 41) Objective response (eligible for RECIST) (n = 16) Available for toxicity (n = 44) Available for QoL Baseline v after 3 cycles (n = 165) Baseline v after 6 cycles (n = 13) Analysis Progression-free survival (intention to treat) (n = 41) Overall survival (intention to treat) (n = 41) Objective response (eligible for RECIST) (n = 137) Available for toxicity (n = 396) Available for QoL Baseline v after 3 cycles (n = 171) Baseline v after 6 cycles (n = 117) by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
3 Carboplatin/PLD for Patients With Advanced Ovarian Cancer Study Population Women younger than age 75 years, with a cytologic or histologic diagnosis of epithelial ovarian cancer (stage IC to IV according to International Federation of Gynecology and Obstetrics staging system), an Eastern Cooperative Oncology Group performance status 2, and a life expectancy of 3 months were eligible. Patients were excluded if they had received previous chemotherapy. Patients with a history of clinically relevant heart disease, with other concomitant diseases representing contraindication to treatment drugs, or with previous or concomitant other malignancy (except nonmelanoma skin cancer or carcinoma in situ of the uterine cervix) were not eligible. Adequate bone marrow, kidney, and liver functions were required. The study was approved by local ethics committees of each participating institution, and all patients gave written informed consent. Study Treatment Patients in the standard arm received carboplatin AUC 5 (dosed according to the Calvert formula, with creatinine clearance estimated according to the Cockcroft formula) and paclitaxel 175 mg/m 2. Patients randomly assigned to the experimental arm received carboplatin AUC 5 and PLD (Caelyx; Schering-Plough, Kenilworth, NJ) 3 mg/m 2. In both arms, chemotherapy was given intravenously on day 1 every 3 weeks. Carboplatin was diluted in 25 ml of glucose 5% and infused over 3 minutes. Paclitaxel was diluted in 25 ml of physiologic saline and infused over 3 hours. PLDwasdilutedin25mLof glucose 5% and infused over 6 minutes, following completion of carboplatin infusion. Treatment was initially administered for three cycles, and patients with stable or responding disease continued treatment for further a three cycles. Conditions required for re-treatment were leukocytes more than 3,/ L, neutrophils more than 1,5/ L, platelets 1,/ L, and absence of organ toxicity (excluding alopecia) grade 2. Treatment was discontinued as a result of prolonged toxicity in patients requiring a treatment delay of 2 weeks. A 2% dose reduction for all drugs was planned in patients with neutrophils less than 5/ L or platelets less than 5,/ L for more than 7 days. Carboplatin dose was reduced to AUC 4 in patients with creatinine clearance less than 6 ml. In the event of grade 2 skin toxicity, PLD was delayed for up to 2 weeks or until toxicity resolved to grade 1; otherwise, PLD was interrupted. Subsequent doses were reduced by 25% if grade 3 or 4 skin toxicity cleared within 2 weeks. In the standard arm, doses of carboplatin and paclitaxel were reduced by 2% in presence of neuropathy. Patient Evaluation Computed tomography scan or nuclear magnetic resonance of the abdomen and pelvis and any other tests that gave positive results during staging were performed after three and six cycles of chemotherapy. Response evaluation was in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) version During the follow-up, the first among the following events defined progression: increase of more than 2% in the sum of largest diameters of known lesions; appearance of a new lesion; confirmed increase of more than 25% in CA-125; or death without clinical or instrumental signs of disease progression. QoL was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C3 (QLQ- C3). 15 Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria (version 2.). Statistical Analysis Efficacy analyses were performed on an intent-to-treat basis. PFS was defined as the time interval between random assignment and progression or death, whichever occurred first, or last follow-up for patients alive without progression. OS was defined as the time interval between random assignment and death or date of last follow-up for patients still alive. Median follow-up was calculated according to the inverted Kaplan-Meier method. 16 PFS and OS curves were estimated using the Kaplan-Meier product-limit method 17 and compared using the log-rank test. 18 ForPFS,theCoxproportionalhazardsmodel 19 wasusedtoassesstreatment effect adjusted by baseline prognostic variables. A preplanned early activity analysis was performed in 26, using data from the first 5 patients eligible for response assessment in the experimental arm. 2 For the final analysis, objective response rate (ORR) was defined as the proportion of complete and partial responses among patients with at least one target lesion. Patients who died or stopped treatment because of toxicity or refusal before restaging were conservatively defined as nonresponders. The statistical significance of the difference in ORR between arms was assessed using the 2 test. Activity was also described in women with nontarget lesions only and in women without any tumor lesion but with elevated CA-125 levels before starting treatment. A preplanned toxicity analysis of the experimental combination was performed in 24, based on the first 5 patients receiving experimental treatment. 21 For the final toxicity analysis, all patients who received chemotherapy at least once were eligible. The worst grade of toxicity experienced was computed for each patient. For each toxicity, two statistical tests were performed to compare study arms; patterns of toxicity (considering all grades) were compared using an exact linear rank test, whereas rates of severe toxicity (grade 3 v grade to 2) were compared using 2 or Fisher s exact tests as appropriate. QoL analysis was performed according to the EORTC manual. 22 Multiitem scales were computed by calculating the mean raw scores and transforming them linearly, in scales ranging from to 1. For single items, only linear transformation was performed. Changes from baseline after three and six cycles were calculated for each domain and compared between arms by a linear model, using baseline values as a covariate. Statistical analyses were performed using S-Plus version 6.1 (Insightful, Seattle, WA). Exact tests were performed using StatXact 7 (Cytel). RESULTS Patient Characteristics Between January 23 and November 27, 82 patients were randomly assigned, as planned (Fig 1). Baseline characteristics were Table 1. Baseline Clinical Characteristics of Patients by Treatment Arm Characteristic Standard Arm (n 41) No. of Patients % Experimental Arm (n 41) No. of Patients % Total (N 82) No. of Patients % Age, years Median Range FIGO stage Ic II III IV Tumor histology Serous Endometrioid Clear cell Mucinous Undifferentiated Mixed or other Missing information ECOG performance status Residual disease None cm cm No surgery Abbreviations: ECOG, Eastern Cooperative Oncology Group; FIGO, International Federation of Gynecology and Obstetrics by American Society of Clinical Oncology 3
4 Pignata et al balanced between the two arms (Table 1). Median age was 57 years (range, 21 to 77 years), and 97% of the patients had a performance status of to 1. The majority of patients had advanced disease (6% with stage III and 21% with stage IV), and 45% of patients were enrolled after suboptimal surgical debulking. Treatment Compliance Information on treatment received was not available in six patients. Of the remaining 814 patients, 1 patients did not start treatment (Table 2). Eighty-six percent and 81.1% of the patients completed six cycles in the standard and experimental arms, respectively. The proportion of patients delaying treatment because of toxicity, usually hematologic, was higher in the experimental arm at all cycles. Overall, 11.5% and 34.5% of cycles were delayed as a result of toxicity in the standard and experimental arms, respectively. Considering patients receiving six cycles, median times between first and last administration of chemotherapy were 16.3 and 18.1 weeks in the standard and experimental arms, respectively. Treatment Table 2. Compliance With Chemotherapy Standard Arm (n 48/41 ) No. of Patients % Experimental Arm (n 43/ 41 ) No. of Patients % No. of cycles administered (did not start treatment) Started treatment, but incomplete data on No. of cycles Cause of treatment interruption Missing information Progression/death Toxicity/refusal Violation/other Cycle delayed because of toxicity Second cycle 34/ / Third cycle 49/ / Fourth cycle 39/ / Fifth cycle 36/ / Sixth cycle 55/ / Two patients were excluded because they were missing all information on treatment received. Seven patients were excluded (four patients were missing all information on treatment received, and three patients actually received carboplatin/paclitaxel). No. of patients/total No. of patients who received cycle. Efficacy All randomly assigned patients were included in the intent-totreat efficacy analysis. By the end of 29, the PFS curve of the whole study population (not scattered by arm) showed that event occurrence substantially slowed before the required number of events was attained. More than half of the patients had optimal debulking, and more than one third did not have residual disease at all. This was a result of the significant proportion of patients with early-stage disease. The better prognosis of these subgroups of patients clearly conditioned the overall event rate (Appendix Fig A1, online only) and the time required to attain the planned events. Therefore, in concert with the Independent Data Monitoring Committee, the final analysis was anticipated at 556 events as of December 31, 29. This number of events still allowed the detection of an HR for PFS of.79 with 8% power. With a median follow-up time of 4 months, 282 events (68.8%) were recorded in the standard arm, and 274 events (66.8%) were recorded in the experimental arm. Median PFS was 16.8 months (95% CI, 15.2 to 19.4 months) in the standard arm and 19. months (95% CI, 16.3 to 24. months) in the experimental arm (HR,.95; 95% CI,.81 to 1.13; log-rank test, P.58). PFS curves are shown in Figure 2A. In multivariable analysis adjusted by stage, performance status, residual disease, age, and size of the institution, the difference between treatments remained not significant (HR,.97; 95% CI,.82 to 1.14; A Median 1. Progression-Free Survival (probability) n Events (months) 95% CI Standard to 19.4 Experimental to 24. HR,.95; 95% CI,.81 to 1.13 Log-rank P = Time (months) No. at risk Standard Experimental B Median 1. n Events (months) 95% CI Standard to NA Experimental to NA.8 Overall Survival (probability) HR,.89; 95% CI,.72 to 1.12 Log-rank P = Time (months) No. at risk Standard Experimental Fig 2. (A) Progression-free survival and (B) overall survival curves by treatment arm. HR, hazard ratio; NA, not available by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
5 Carboplatin/PLD for Patients With Advanced Ovarian Cancer Table 3. Cox Proportional Hazard Model for Progression-Free Survival Factor Hazard Ratio 95% CI P Treatment (experimental v standard) to Stage (III-IV v IC-II) to ECOG PS (2 v -1) to Residual disease after surgery.1 1cmv absent to cmv absent to 3.51 No surgery v absent to 4.86 Age ( v 7 years) to Size of institution.38 Intermediate (2-99 patients) v large ( 1 patients) to 1.15 Small ( 2 patients) v large ( 1 patients) to 1.24 Abbreviation: ECOG PS, Eastern Cooperative Oncology Group performance status. P.7), whereas residual disease and stage were independent predictors of PFS (Table 3). Exploratory analysis by subgroups according to International Federation of Gynecology and Obstetrics stage, performance status, age category, residual disease after surgery, and tumor histology showed no heterogeneity of treatment effect (Fig 3). With 313 deaths (38.2%) recorded, the median OS (Fig 2B) was 53.2 months (95% CI, 42.3 months to not available) in the standard arm compared with 61.6 months (95% CI, 5.4 months to not available) in the experimental arm (HR,.89; 95% CI,.72 to 1.12; log-rank test, P.32). Two-hundred ninety-seven patients (36.2%) were eligible for response analysis according to RECIST criteria ( one target lesion), 16 patients (39.%) in the standard and 137 patients (33.4%) in the experimental arm. ORR was 59% in the standard arm (24 complete responses and 71 partial responses) and 57% in the experimental arm (23 complete responses and 55 partial responses; P.76). In 184 patients with nontarget lesions only, complete response was 33% and 29% in the standard and experimental arms, respectively (P.69). In 173 patients with elevated CA-125 only, CA-125 normalization was obtained in 82% and 86% of patients in the standard and experimental arms, respectively (P.7; Appendix Table A1, online only). Toxicity All patients who received at least one dose were eligible for toxicity analysis (n 83). Worst toxicities by treatment arm are listed in Table 4. There were six potentially treatment-related deaths four in the standard arm (allergy during paclitaxel infusion followed by sudden death at home, n 1; febrile neutropenia, n 1; nonneutropenic fever, n 1; intestinal necrosis with septic shock, n 1) and two in the experimental arm (bleeding, n 1; disseminated intravascular coagulation, n 1). Thrombocytopenia and anemia were significantly more frequent and severe in the experimental arm; RBC transfusions were more frequently required in the experimental arm than the standard arm (6% v 2%, respectively; P.1). There were no significant differences in leukopenia, neutropenia, febrile neutropenia, infections, platelet transfusions, and bleeding. The nonhematologic adverse effects profile was significantly different between the arms. Hair loss, diarrhea, and neuropathy were significantly worse in the standard Overall (N = 82) ECOG PS -1 (n = 795) 2 (n = 25) Age, years < 7 (n = 721) 7 (n = 99) Stage IC II (n = 153) III IV (n = 667) Residual disease Absent (n = 298) 1 cm (n = 149) > 1 cm (n = 227) No primary surgery (n = 146) Tumor histology Serous (n = 53) Endometroid (n = 98) Clear cell (n = 27) Mucinous (n = 25) Undifferentiated (n = 6) Mixed or other (n = 44) Missing (n = 36) Fig 3. Treatment effect on progressionfree survival within major patient subgroups. Vertical dotted line represents hazard ratio (experimental arm v standard arm) in the overall study population. ECOG PS, Eastern Cooperative Oncology Group performance status Standard worse Experimental worse Hazard Ratio 211 by American Society of Clinical Oncology 5
6 Pignata et al Toxicity Table 4. Worst Grade (according to NCI-CTC) of Toxicity According to Treatment Arm Carboplatin Paclitaxel (n 47 ) Carboplatin Pegylated Liposomal Doxorubicin (n 396) Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 No. % No. % No. % No. % No. % No. % No. % No. % No. % No. % P P Anemia Leukopenia Neutropenia Febrile neutropenia Neutropenic infection Non-neutropenic infection Thrombocytopenia Bleeding Allergy Kidney Heart, rhythm Heart, general Pulmonary Fatigue Fever Weight loss Hair loss Skin Anorexia Constipation Diarrhea Nausea Vomiting Stomatitis Liver Neuropathy Other Abbreviation: NCI-CTC, National Cancer Institute Common Toxicity Criteria. Including three patients assigned to the experimental arm who received carboplatin plus paclitaxel. Any grade (test for trend). Severe toxicity (grade 3). Death as a result of intestinal necrosis and septic shock. Grade 4 hypocalcemia. Death as a result of disseminated intravascular coagulation. arm, whereas skin toxicity and stomatitis were significantly worse in the experimental arm. QoL Overall, 62 patients (76%; 39 patients in the standard arm v 311 patients in the experimental arm) completed the valid baseline QoL questionnaire. Of these, 336 patients completed the questionnaire after three cycles (165 patients in the standard arm v 171 patients in the experimental arm), and 247 patients completed the questionnaire after six cycles (13 patients in the standard arm v 117 patients in the experimental arm). Mean difference from baseline in global QoL (EORTC QLQ-C3 items 29 and 3) was 3.7 in the standard arm versus 4.9 in the experimental arm after three cycles, and 8.7 in the standard arm versus 1.56 in the experimental arm after six cycles. Both comparisons were not statistically significant. No relevant differences were observed in all functional domains and in most symptom scales. Statistically significant differences were reported in loss of appetite after three cycles, favoring the standard treatment, and in diarrhea after three cycles, favoring the experimental arm (Appendix Fig A2, online only). DISCUSSION The MITO-2 trial compared an experimental regimen of carboplatin/pld versus standard carboplatin/paclitaxel as first-line treatment of patients with advanced ovarian cancer. The experimental treatment did not significantly prolong PFS, the primary end point of the trial, and no differences were apparent in OS, ORR, and QoL. Nonhematologic toxicity significantly differed between the arms, with hair loss and neurotoxicity being drastically less frequent in the experimental arm, but with this arm having more skin toxicity and stomatitis. Hematologic toxicity was also worse with experimental treatment but within acceptable limits for clinical practice. Overall, given these results and considering that CIs of both PFS and OS completely lie within limits typically considered acceptable for noninferiority, the experimental treatment might be considered as an alternative to the standard treatment. This choice, of course, should take into account patient s will and consider limitations as a result of the lack of regulatory approval of PLD for first-line treatment and its cost by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
7 Carboplatin/PLD for Patients With Advanced Ovarian Cancer The dramatic reduction of hair loss and neurotoxicity seen with the experimental treatment is extremely important. Approximately three fourths of patients experience some degree of peripheral neuropathy while on carboplatin/paclitaxel, and 7% have grade 3 peripheral neuropathy. 5 We previously showed that residual neurotoxicity occurs frequently in patients after completion of carboplatin/paclitaxel, with a long-lasting pattern of recovery and 14% of patients still suffering residual neuropathy 1 year after treatment. 23 In addition, such toxicity may still persist in a significant proportion of patients who experience relapse and, therefore, affects second-line treatment choice. However, in the MITO-2 trial, differences in toxicity pattern did not translate into relevant QoL differences. This might eventually depend on the fact that we limited QoL data collection to the treatment period, therefore missing late neurotoxicity. Furthermore, we only used the EORTC QLQ-C3 general questionnaire and not a more specific QoL questionnaire (eg, EORTC QLQ Ovarian Cancer Module). The MITO-2 study, which studied the substitution of paclitaxel with PLD in combination with carboplatin, adds important evidence about the role of anthracyclines in first-line treatment of ovarian cancer. Meta-analysis of trials performed before the introduction of taxanes showed that the addition of doxorubicin prolonged survival 7 ; however, on the contrary, in the taxane era, the addition of epirubicin to carboplatin/paclitaxel did not prolong OS and PFS in two phase III trials. 24,25 In a recent phase III trial 26 comparing carboplatin/pld with carboplatin/paclitaxel in platinum-sensitive recurrent ovarian cancer, a statistically significant advantage in PFS in favor of carboplatin/pld was found (HR of PFS,.821; P.5; median PFS, 11.3 v 9.4 months, respectively). Carboplatin/PLD was associated with less alopecia and neurotoxicity. To our knowledge, the only study testing PLD in first-line treatment of ovarian cancer is a phase III trial performed by the Gynecology Oncology Group comparing standard carboplatin/paclitaxel with two triplet regimens (standard carboplatin/paclitaxel plus gemcitabine or PLD) and two sequential doublet regimens (carboplatin plus topotecan or gemcitabine, both followed by carboplatin/paclitaxel). 27 Although efficacy was similar across the five arms, hematologic toxicity increased with three-drug combinations. However, the information regarding PLD efficacy in this trial is limited because PLD was given in association with carboplatin/paclitaxel every other cycle, and the overall dose-intensity was 5 mg/m 2 /wk, much lower than that considered optimal. Final MITO-2 analysis was performed with fewer events than planned (556 instead of 632 events), but it is unlikely that this affected the results. The reason was a dramatic decrease in the incidence of PFS events, which was not a result of flaws in follow-up procedures, consistent with plans, but rather a result of the favorable prognostic characteristics of the enrolled patients (significant proportion of patients with early-stage disease and of patients without residual disease after surgery). Therefore, an extremely longer time would have been required to get the planned number of events, and non ovarian cancer deaths might dilute PFS differences. The Independent Data Monitoring Committee blindly advised to perform final analysis with the available events, considering that statistical power was reduced just to 75% and that there was still 8% power in detecting an HR for PFS of.79. In conclusion, the MITO-2 trial shows that the combination of carboplatin/pld does not prolong PFS compared with standard carboplatin/paclitaxel. However, given the observed difference in toxicity, it can be considered as a reasonable alternative for first-line treatment of advanced ovarian cancer, particularly in patients at high risk of neurotoxicity or wishing to avoid alopecia. AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a U are those for which no compensation was received; those relationships marked with a C were compensated. For a detailed description of the disclosure categories, or for more information about ASCO s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Alba Brandes, Schering-Plough (C) Stock Ownership: None Honoraria: Sandro Pignata, Schering-Plough; Roberto Sorio, Schering-Plough; Alba Brandes, Schering-Plough, Roche; Francesco Perrone, Schering-Plough Research Funding: Sandro Pignata, Schering-Plough; Francesco Perrone, Schering-Plough Expert Testimony: None Other Remuneration: None AUTHOR CONTRIBUTIONS Conception and design: Sandro Pignata, Giovanni Scambia, Ciro Gallo, Francesco Perrone Collection and assembly of data: Sandro Pignata, Giovanni Scambia, Gabriella Ferrandina, Antonella Savarese, Roberto Sorio, Enrico Breda, Vittorio Gebbia, Pietro Musso, Luigi Frigerio, Pietro Del Medico, Alessandra Vernaglia Lombardi, Antonio Febbraro, Paolo Scollo, Antonella Ferro, Stefano Tamberi, Alba Brandes, Alberto Ravaioli, Maria Rosaria Valerio, Enrico Aitini, Donato Natale, Laura Scaltriti, Stefano Greggi, Carmela Pisano, Domenica Lorusso, Vanda Salutari, Francesco Legge, Massimo Di Maio, Alessandro Morabito, Francesco Perrone Data analysis and interpretation: Sandro Pignata, Massimo Di Maio, Alessandro Morabito, Ciro Gallo, Francesco Perrone Manuscript writing: All authors Final approval of manuscript: All authors REFERENCES 1. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 27. CA Cancer J Clin 57:43-66, McGuire WP, Hoskins WJ, Brady MF, et al: Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 334:1-6, Piccart MJ, Bertelsen K, James K, et al: Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: Three-year results. J Natl Cancer Inst 92:699-78, 2 4. Neijt JP, Engelholm SA, Tuxen MK, et al: Exploratory phase III study of paclitaxel and cisplatin versus paclitaxel and carboplatin in advanced ovarian cancer. J Clin Oncol 18: , 2 5. du Bois A, Lück HJ, Meier W, et al: A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. 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8 Pignata et al ovarian cancer: Antitumor activity and toxicity modification by liposomal encapsulation. J Clin Oncol 15: , Gordon AN, Tonda M, Sun S, et al: Long-term survival advantage for women treated with pegylated liposomal doxorubicin compared with topotecan in a phase 3 randomized study of recurrent and refractory epithelial ovarian cancer. Gynecol Oncol 95:1-8, O Byrne KJ, Bliss P, Graham JD, et al: A phase III study of Doxil/Caelyx versus paclitaxel in platinum-treated, taxane-naïve relapsed ovarian cancer. Proc Am Soc Clin Oncol 21:23a, 22 (abstr 88) 11. Braud A, Goncalves A, Genre D, et al: Phase I study of liposomal doxorubicin (Caelyx) in combination with carboplatin (CBDCA) in patients with advanced or metastatic solid tumors. Proc Am Soc Clin Oncol 2:91b, 21 (abstr 2113) 12. Verschraegen CF, Kavanagh JJ, Loyer E, et al: Phase II study of carboplatin and liposomal doxorubicin in patients with recurrent squamous cell carcinoma of the cervix. Cancer 92: , Ferrero JM, Weber B, Geay JF, et al: Secondline chemotherapy with pegylated liposomal doxorubicin and carboplatin is highly effective in patients with advanced ovarian cancer in late relapse: A GINECO phase II trial. Ann Oncol 18: , Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:25-216, Aaronson NK, Ahmedzai S, Bergman B, et al: The European Organization for Research and Treatment of Cancer QLQ-C3: A quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85: , Schemper M, Smith TL: A note on quantifying follow-up in studies of failure time. Control Clin Trials 17: , Kaplan EL, Meier P: Nonparametric estimation from incomplete observation. J Am Stat Assoc 53: , Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 5:163-17, Cox DR: Regression models and life tables. J R Stat Soc B 34:187-22, Pignata S, Scambia G, Savarese A, et al: Carboplatin and pegylated liposomal doxorubicin for advanced ovarian cancer: Preliminary activity results of the MITO-2 phase III trial. Oncology 76:49-54, Pignata S, Scambia G, Savarese A, et al: Safety of a 3-weekly schedule of carboplatin plus pegylated liposomal doxorubicin as first line chemotherapy in patients with ovarian cancer: Preliminary results of the MITO-2 randomized trial. BMC Cancer 6:22, Fayers PM, Aaronson NK, Bjordal K, et al: EORTC QLQ-C3 Scoring Manual (ed 3). Brussels, Belgium, European Organisation for Research and Treatment of Cancer, Pignata S, De Placido S, Biamonte R, et al: Residual neurotoxicity in ovarian cancer patients in clinical remission after first line chemotherapy with carboplatin and paclitaxel: The Multicenter Italian Trial in Ovarian cancer (MITO-4) retrospective study. BMC Cancer 6:5, du Bois A, Weber G, Rochon J, et al: Addition of epirubicin as a third drug to carboplatin-paclitaxel in first-line treatment of advanced ovarian cancer: A prospectively randomized gynecologic cancer intergroup trial by the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group and the Groupe d Investigateurs Nationaux pour l Etude des Cancers Ovariens. J Clin Oncol 24: , Kristensen GB, Vergote I, Eisenhauer E, et al: First line treatment of ovarian/tubal/peritoneal cancer FIGO stage IIb-IV with paclitaxel/carboplatin with or without epirubicin (TEC vs TC): A Gynecologic Cancer Intergroup study of the NSGO, EORTC GCG, and NCIC CTG Results on progression free survival. J Clin Oncol 23:448, 24 (suppl; abstr 53) 26. Pujade-Lauraine E, Wagner U, Aavall- Lundqvist E, et al: Pegylated liposomal doxorubicin and carboplatin compared with paclitaxel and carboplatin for patients with platinum-sensitive ovarian cancer in late relapse. J Clin Oncol 28: , Bookman MA, Brady MF, McGuire WP, et al: Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer: A phase III trial of the Gynecologic Cancer Intergroup. J Clin Oncol 27: , 29 Affiliations SandroPignata, StefanoGreggi, CarmelaPisano, MassimoDiMaio, AlessandroMorabito, andfrancescoperrone, IstitutoNazionaleTumori; Ciro Gallo, Seconda Università di Napoli, Napoli; Giovanni Scambia, Domenica Lorusso, and Vanda Salutari, Policlinico Gemelli, Università Cattolica del SacroCuore; AntonellaSavarese, IstitutoNazionaleTumoriReginaElena; EnricoBreda, OspedaleS. GiovanniCalibitaFatebenefratelli, Roma; Gabriella FerrandinaandFrancescoLegge, UniversitàCattolicadelSacroCuore, Campobasso; RobertoSorio, CentrodiRiferimentoOncologico, Aviano; Vittorio Gebbia, Casa di Cura La Maddalena; Pietro Musso, Azienda Ospedaliera di Rilievo Nazionale e di Alta Specializzazione Civico Di Cristina Benfratelli; Maria Rosaria Valerio, Policlinico Giaccone, Università, Palermo; Luigi Frigerio, Ospedali Riuniti, Bergamo; Pietro Del Medico, Ospedale Bianchi Melacrino Morelli, Reggio Calabria; Alessandra Vernaglia Lombardi, Casa di Cura Malzoni Villa dei Platani, Avellino; Antonio Febbraro, Ospedale Fatebenefratelli, Benevento; PaoloScollo, OspedaleCannizzaro, Catania; AntonellaFerro, OspedaleS. Chiara, Trento; StefanoTamberi, OspedaleCivile, Faenza; Alba Brandes, Ospedale Bellaria, Bologna; Alberto Ravaioli, Ospedale degli Infermi, Rimini; Enrico Aitini, Ospedale Carlo Poma, Mantova; Donato Natale, Ospedale S. Massimo, Penne; and Laura Scaltriti, Ospedale Ramazzini, Carpi, Italy. Appendix MITO-2 Investigators Sandro Pignata, Carmela Pisano, Gaetano Facchini, Giovanni Salvatore Bruni, Lucia Cannella, Davide Leopardo, Stefano Greggi, Francesco Iodice, Gennaro Casella (Dipartimento Uro-Ginecologico, Istituto Nazionale Tumori, Napoli); Giovanni Scambia, Domenica Lorusso, Vanda Salutari, Antonia Testa, Rosa De Vincenzo, Alessia di Legge, Claudia Masi, Valeria Masciullo, Mirella Di Stefano (Policlinico Universitario Gemelli, UniversitàCattolicadelSacroCuore, Roma); GabriellaFerrandina, FrancescoLegge, GiacomoCorrado, MarcoPetrillo, AidaDistefano, Manuela Ludovisi (Centro di Ricerca e Formazione ad Alta Tecnologia nelle Scienze Biomediche, Università Cattolica del Sacro Cuore, Campobasso); Antonella Savarese, Francesco Cognetti, Gianluigi Ferretti, Enrico Vizza, Emanuela Mancini (Istituto Nazionale Tumori Regina Elena, Roma); Roberto Sorio, Simona Scalone, Giorgio Giorda, Elio Campagnutta (Centro di Riferimento Oncologico, Aviano [PN]); Enrico Breda, Antonella Mecozzi, Emanuela Proietti, Loredana Rossi, Angelo Fedele Scinto (Ospedale S. Giovanni Calibita Fatebenefratelli, Roma); Vittorio Gebbia, Eugenia Baiardi, Carlo Arcara, Antonio Testa (Casa di Cura La Maddalena, Palermo); Pietro Musso, Rosa Demma, Francesco MariaRe(AziendaOspedalieradiRilievoNazionaleediAltaSpecializzazioneCivicoDiCristinaBenfratelli, Palermo); LuigiFrigerio, LuisaBusci, Antonella Villa (present address, Clinica Mangiagalli, Milano), Laura Carlini (present address, Ospedale Bolognini, Segrate [BG]) (Ospedali Riuniti, Bergamo); Pietro Del Medico, Mario Nardi, Mario Raffaele, Domenico Azzarello (Ospedale Bianchi Melacrino Morelli, Reggio Calabria); Alessandra Vernaglia Lombardi, Carmine Malzoni, Mario Malzoni, Giuseppina Farnetano (Casa di Cura Malzoni Villa dei Platani, Avellino); Antonio Febbraro, Claudia Corbo, Ilaria Spagnoletti (Ospedale Fatebenefratelli, Benevento); Paolo Scollo, Giuseppe Scibilia, Gabriella D Agate (Ospedale Cannizzaro, Catania); Enzo Galligioni, Antonella Ferro, Viviana Murgia (Ospedale S. Chiara, Trento); Stefano Tamberi, Laura Amaducci, Carmelo Bucolo (Ospedale Civile, Faenza); Alba Brandes, Simonetta Rimondini, Stefania Bartolini (Ospedale Bellaria, by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
9 Carboplatin/PLD for Patients With Advanced Ovarian Cancer Bologna); Alberto Ravaioli, Giovanni Oliverio, Enzo Pasquini(Ospedale degli Infermi, Rimini, Ospedale Cervesi, Cattolica[RN]); Maria Rosaria Valerio, Mario Lomauro, Nicola Gebbia (Policlinico Giaccone, Università, Palermo); Enrico Aitini, Giovanna Cavazzini, Francesca Adami (Ospedale Carlo Poma, Mantova); Donato Natale, Bruna Fornarini, Dante Orlando (Ospedale S. Massimo, Penne [PE]); Fabrizio Artioli, Laura Scaltriti, Lorenzo Aguzzoli (Ospedale Ramazzini, Carpi [MO]); Emanuele Naglieri, Agnese Latorre, Sabina Delcuratolo (Istituto Tumori Giovanni Paolo II, Bari); Cesare Gridelli, Filomena Del Gaizo (Ospedale S.Giuseppe Moscati, Avellino); Alfonso M. D Arco, Antonietta Fabbrocini (Ospedale Civile Umberto I, Nocera Inferiore [SA]); Isabel Henriques, Ondina Campos (CHC Maternidade Bissaya-Barreto, Coimbra, Portugal); Bruno Massidda, Valeria Pusceddu (Policlinico Universitario Monserrato, Cagliari); Rossella Lauria, Valeria Forestieri (Università Federico II, Napoli); Marina Marzola, Pamela Pizzutilo (Arcispedale Sant Anna, Ferrara); Rocco De Vivo (Ospedale S. Bortolo ULSS 6, Vicenza); Giovanni Lore (Ospedale S. Maria degli Angeli, Pordenone); Saverio Danese (Ospedale S. Anna, Torino); Nada Riva (Istituto Romagnolo per lo Studio e la Cura dei Tumori, Meldola [FC]); Vito Lorusso (Ospedale Vito Fazzi, Lecce); Gabriella Landi (Oncologia Medica Senologica, Istituto Nazionale Tumori, Napoli); Giuseppe Nettis (Ospedale Miulli, Acquaviva delle Fonti [BA]); Filomena Narducci (Ospedale SS. Trinità Sora [FR]); Rosalbino Biamonte (Ospedale Mariano Santo, Cosenza); Vincenzo Montesarchio (Ospedale Cotugno, Napoli); Giancarlo Balbi (Clinica Ostetrica e Ginecologica, Seconda Università, Napoli); Cosimo Sacco (Azienda Ospedaliero Universitaria, Udine); Vincenzo Arigliano (Ospedale di Bentivoglio [BO]); Simona Losito (Anatomia Patologica, Istituto Nazionale Tumori, Napoli); Ciro Gallo, Simona Signoriello, Paolo Chiodini, Giuseppe Signoriello (Statistica Medica, Seconda Università, Napoli); Francesco Perrone, Aldo Vecchione, Massimo Di Maio, Alessandro Morabito, Maria Carmela Piccirillo, Ermelinda De Maio (present address, Ospedali Riuniti, Livorno), Antonia Del Giudice, Fabiano Falasconi, Jane Bryce, Gianfranco De Feo, Giuliana Canzanella, Alfonso Savio (Unità Sperimentazioni Cliniche, Istituto Nazionale Tumori, Napoli, Italy). Data Monitoring Committee Nicoletta Colombo (Istituto Europeo di Oncologia, Milano); Paolo Bruzzi (Istituto Nazionale per la Ricerca sul Cancro, Genova); Roldano Fossati (Istituto di Ricerche Farmacologiche Mario Negri, Milano), Italy. Data Managers Giuliana Canzanella, Federika Crudele, Manuela Florio, Fiorella Romano, Giovanni de Matteis, Balbina Apice, Rosa Nunziata (Napoli); AgneseProvenziani(Roma); GiannaTabaro(Aviano[PN]); PaoloRusso(Palermo); AntonellaFalzea(ReggioCalabria); AlessandraPiancastelli, EmanuelaMontanari(Faenza[RA]); GiulianaDrudi, BarbaraVenturini(Rimini, Cattolica[RN]); PatriziaMorselli, BeatriceVivorio(Mantova); Roberta Guerzoni, Giorgia Razzini (Carpi [MO]); Valentina Barbato, Rita Ambrosio (Avellino); Sabrina Prisco (Nocera Inferiore [SA]); Elena Raisi (Ferrara); Bruna Stupar (Vicenza); Michela Ballardini (Meldola [FC]); Luciana Petrucelli (Lecce); and Marica Gaiardo (Udine), Italy. Research Nurses Jane Bryce, Marzia Falanga, Immacolata Gargiulo (Napoli); Ilaria Orsini, Tonia Marra, Chiara Frediani, Alessandra Focaccetti (Roma); Annamaria Colussi, Sara Rosalen (Aviano [PN]); Michela Pilati (Rimini, Cattolica [RN]); Paola Costantini (Udine), Italy. Table A1. Intent-to-Treat Analysis of Treatment Activity Standard Arm (n 41) Experimental Arm (n 41) Response No. of Patients % No. of Patients % Missing information 2 6 Patients with at least one target lesion Objective response Complete response Partial response No response Stable disease Progressive disease Not evaluated Patients with nontarget lesions only Complete response No complete response/no progression Progressive disease Not evaluated Patients with elevated CA-125 only 9 83 CA-125 normalized CA-125 not normalized Not evaluated No lesions, normal CA According to Response Evaluation Criteria in Solid Tumors (RECIST) by American Society of Clinical Oncology 9
10 Pignata et al A Progression-Free Survival (probability) Absent residual Residual 1 cm Residual > 1 cm No surgery B Progression-Free Survival (probability) Stage I Stage II Stage III Stage IV Time (months) Time (months) Fig A1. Progression-free survival curves of patients enrolled onto the trial by (A) residual disease after surgery and (B) tumor stage by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
11 Carboplatin/PLD for Patients With Advanced Ovarian Cancer A Better 2 General QoL 2 Physical Functioning 2 Role Functioning Mean Change From Baseline Worse After 3 Cycles After 6 Cycles After 3 Cycles After 6 Cycles After 3 Cycles After 6 Cycles Better 2 Emotional Functioning 2 Cognitive Functioning 2 Social Functioning Mean Change From Baseline Worse After 3 Cycles After 6 Cycles After 3 Cycles After 6 Cycles After 3 Cycles After 6 Cycles B Worse Mean Change From Baseline Pain Loss of Appetite * Constipation Better After 3 Cycles After 6 Cycles After 3 Cycles After 6 Cycles After 3 Cycles After 6 Cycles Worse Mean Change From Baseline Better Fatigue Vomiting Sleep Disturbance After 3 Cycles After 6 Cycles After 3 Cycles After 6 Cycles After 3 Cycles After 6 Cycles Worse Mean Change From Baseline Better Diarrhea Dyspnea Financial * After 3 Cycles After 6 Cycles After 3 Cycles After 6 Cycles After 3 Cycles After 6 Cycles Fig A2. Quality-of-life (QoL) analysis for standard (blue bars) versus experimental (gold bars) arms. Bars correspond to mean changes from baseline after three and after six cycles. (A) For global QoL and functional domains, improvement is indicated by positive changes. (B) For symptoms, improvement is indicated by negative changes. (*) Statistically significant difference between arms, P by American Society of Clinical Oncology 11
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text:
|Problems? Is your data what you think it is?
Re: Associative arrayby Polyglot (Pilgrim)
|on Jul 13, 2009 at 06:29 UTC ( #779474=note: print w/replies, xml )
|Need Help??
It looks to me like you are trying to do two mutually exclusive things at the same time: print multiple values and print just one value. You have used a "for" loop as if you were going to print every value, but then only want to print the "correct" one.
Could it be that the "correct" value is not the first one in the list, and that the first value looked at (not necessarily a "correct" one) is uninitialized?
In Section Seekers of Perl Wisdom

subset: commoncrawl


text: Posted February 3, 2014 Couple things holding us back, fix these, and we will be good. 1: Overpriced RB's on this team, with no outside playmakers. 2: Average, at best OL. 3: Below average secondary. 4: Offensive Coordinator. 5: Depth The problem I see with us and the other two teams mentioned a lot in this thread....cheap QB's don't hang around very long. We will either have to break the bank with Cam's contract, or let him walk and start over at the QB position. The second part ain't happening. SF and Seattle both have to pay their QB's as well, and that's when the salary cap will start to bite us and them. The trick is shedding some really bad contracts (D Will and Stew), getting Cam to agree to a contract smaller than Matt Ryan, and drafting very very well, grooming your talent, and letting them walk after getting the most out of their rookie deals. Unless you have the very best QB's on your roster, (Brees, Rodgers, Manning, Brady) the high price of QB's makes being a consistent contender very tough. Share this post Link to post Share on other sites


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Commercial Photographers
Hey, thanks for stopping by. For those of you who haven't met me yet, I am from California & now live in the South Jersey area with a passion to shoot all types of photography, everything from single head shots to family portraits & commercial advertising. Ever since I was a child I loved cameras, I love freezing time, I loved the nostalgia of a single image moving you a year or even decades back in time with a simple blink of the eye.


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She was 39 when Jimmie Spratt yanked her off the street, threatened to kill her if she looked his way, and raped her.
It took a decade of pestering, she said, before New Orleans police finally got her rape exam kit tested, and eight years more before she found justice, with Spratt's 2012 conviction for raping her and two others over a span of less than six months in 1994. In the meantime, the serial rapist had gone on to assault several women in Tennessee.
"It seemed like they brought me to Charity (Hospital), and that was it," the woman, whose initials are S.M, said. "Right away I could tell the cops weren't doing anything. It's a universal problem of wanting rape victims to go away. You feel disposable."
So the woman, now 60, spent Saturday morning marching down Rampart Street and thrusting a sign high in the air: "NOPD: Do your job!"
More than 100 others marched with her, many of them wearing blue tape across their mouths as they headed silently for City Hall, to share stories of dismissive police responses to their rape allegations, and to demand more action amid the latest outcry over the New Orleans Police Department's handling of reported sexual assaults.
The signs bore messages such as: "How many more?," "New Orleans citizens deserve better," "If only the cops were as supportive as my bra" and "NOPD: Not Our Problem Dude."
The peaceful march from the 1st District police station came a month after New Orleans Inspector General Ed Quatrevaux's office released a scathing report on the work of five New Orleans police detectives who handled sex crime cases from 2011 to 2013. The five, who were among 16 detectives in the NOPD's Special Victims Section, relegated the majority of nearly 1,300 reported sex crimes to the "miscellaneous" bin, leaving no paper trail, according to the report.
Among the 450 cases in which the IG's Office investigators found an initial, cursory sketch of the allegation, files on 60 percent of them contained no supplemental reports detailing any additional investigative work.
Mayor Mitch Landrieu and new NOPD Superintendent Michael Harrison did not quibble with the findings of the IG's probe, and Landrieu pledged a complete overhaul of the Sex Crimes Unit.
All five detectives have been suspended pending the outcome of an internal investigation, and Harrison set up a task force to reinvestigate 271 cases flagged by Quatrevaux's office. Criminal charges could follow for the detectives and perhaps others, Harrison said.
But the sentiment among the crowd Saturday was that the city can't be trusted to fix its own mess. Many of the stories that demonstrators presented involved alleged sexual assaults and police responses that took place before or after the three-year time period the IG investigated, and that involved other detectives.
Among the group's most pointed demands was for an external probe of the NOPD's entire sex crimes caseload over the past five years.
"My case happened so long ago. I think about how many others, just since mine, how many unprosecuted, uninvestigated cases there were," said Aubrey Warren, who told the crowd of being raped by an employee after a night in 2003 at a bar on Magazine Street. Police, she said, never wrote up a report.
Perhaps the most disturbing aspect of Quatrevaux's report, according to organizers of Saturday's event, was the apparent disposal of 840 cases that were assigned to the five detectives and then coded "Signal 21," or miscellaneous. That meant they were never counted anywhere as reported crimes.
"It obviously means rape cases are being ignored, but the problem is that a lot of the advocacy groups rely on public funding based on the stats reported by police," said Laura Hope, an associate professor of theater at Loyola University who helped organize Saturday's event. "So when you underreport rapes, not only is it shoddy police work, but you're also taking money away from the very people who are there to help survivors."
Hope and a colleague, Erin Dupuis, said they were troubled by an earlier report by Quatrevaux's office, released in May, that sampled 90 reported rapes and found dozens were misclassified. That audit, which then-NOPD Superintendent Ronal Serpas vigorously challenged, pointed Quatrevaux's office toward the five detectives for a deeper look.
When the second report hit on Nov. 12, "we were just sort of beside ourselves," Hope said.
"It's not acceptable for the NOPD to investigate itself on these matters," Dupuis told the crowd.
A 2011 report by the U.S. Department of Justice detailed many of the same problems that Quatrevaux's office found. Among them were many cases of poorly documented "miscellaneous" classifications and detectives who seemed to dismiss victims' claims or to ask them accusatory questions — a criticism that echoed through Saturday's protest.
Also walking down Rampart Street on Saturday was Maria Treme, a Mid-City woman who has come forward to expose police missteps in handling her allegation of being drugged and raped this year by multiple men at the Country Club, a Bywater club that had a clothing-optional pool. Treme said she feels "some slight validation" from Quatrevaux's report.
"I definitely had my moments of feeling very alone in this situation. People were looking at it like I'm crazy and overreacted," Treme said. "I can look at this (report) and see how it's (messed) up. How did these people get away with not doing their jobs?"
Angel Bruno, a French Quarter bartender, marched with one arm over a crutch. She said she still has nightmares from a rape during a paid massage. She eventually dropped the case after she was told the chances of a successful prosecution were slim. She called the IG's findings appalling.
"This is a joke. It's ridiculous. There's so much sweeping under the rug," she said. "I'm glad we're doing things like this (protest), but there's no guarantee."
Saturday's march came with a police escort under the group's permit from the city.
Ali Duffey, who counsels local sexual assault victims, called it "heartbreaking" to think women she's helped got little or no attention from police. Still, Duffey sounded optimistic that the IG's report will prompt true reform.
"This is a great opportunity to turn things around," she said.
Follow John Simerman on Twitter, @johnsimerman.


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Clean, well presented and lovely bathroom. Very good breakfast. N/A
Hotel staff where very friendly and welcoming and great location for airport and ehibiton centre Room was very basic and i think the 4stars flatters the hotel for the services and ammenities available.
Exceptionally friendly and receptive staff. Breakfast served until 11.00am !! No obvious bedside lights switch!
Close to tram and Kaiserswerth
Beautiful and quiet surroundings no shuttle to the airport and the sauna is not free for guests
Very friendly staff Nice location of Dusseldorf Good breakfast None
Pleasant staff, good breakfast. good size rooms a pity there is no evening meal service
breakfast, dreindliness of staff I wonder whether the qulaifaction as a 4* hotel ist correct as far as the equipment of the hotel is concerned.
Clean, easy to find and extremely convenient for airport and city
Helpful staff speaking English. Internet access via Wi-Fi. Breakfast was good! Rooms clean and comfortable. Conveniently located for Dusseldorf and tram also airport. Wi-Fi reception in our room was poor, but excellent in the bar!
We were really impressed. It was where Florence Nightingale learned how to be a nurse. 5 minutes walk to the train stop and 7 euros to Dusseldorf Zoo, Nordpark, Aldstadt. Ideal place to stay if you like quiet and relaxation (no hotel bar, so no lager louts etc.) Breakfast was fantastic. All service was excellent. Nothing - it was perfect for us (we took a 3 year old and baby with us.
Interesting old historic building very well converted to a comfortable and modern hotel
Design of room. Very simple and effective but also a kind of chique. Loudlyness from the hall. No isolation on the door.
We meet with friends and did some sightseeing
Closeness to Kaiserswerth and Düsseldorf; pleasant walking to and along the Rhine River. Note correct author information: Eva, Oak Park, IL USA
Had a room under the roof. Was equipped with nice original furniture, wooden floor and new bathroom in minimalist style. A bit like a student room which gave me a cosy feeling after all these years from school. Everything felt in balance. Well done. The shores of the Rhein are within walking distance. Kaiserswerth is a nice village for a walk. No restaurant but there are a few in the neighboorhood.
Comfort like at home.
This is one of the most charming hotels ever stayed in.The friendliness and hospitality shown by the owner and staff, the very nice location with beautiful garden, super and TOP clean rooms,excellent breakfast.We will return one day!!!
Clean rooms and very good service
Everything. It was just perfect
clean room, confortable bed, newly refurbished bathroom.nice location for breakfast. very near to airport at very good price. poor or no isolation against noise (i could hear people chatting and walking along the aisle and stairs till late). poor supply of bathroom stuff (shampoo etc).breakfast buffet not so much.
The hotel is a short walk to the tram that will take you in 10-15 minutes to downtown Dusseldorf. They have free off street parking so it's cheaper to leave your car and take the tram then to pay for parking in the city. The staff while speaking very little english was accommodating and helpful. The owner, who speaks english, was away during our visit. Our room was small but off the street and parking so very quiet. Breakfast was basic but included eggs cooked to order which was nice. The hotel is only 10-15 minutes to the airport. The town of Kaiserworth has a nice main street with good non-smoking restaurants (the restaurants we saw in Dusseldorf all had smoking and so we came back to town to eat). They have free internet but it was not working during our time and the owner's staff did not know how to fix it. We booked a superior room but it you could hear both the parking lot and road noise. So we chose a smaller room which was quieter. I would not classify either room they offered as superior. The larger room actually had a tub show with now curtain so the entire bathroom gets wet when you shower (they said this was expected).
Wonderful welcome -I was given coffee and bread and cheese when I arrived - very welcome after a long hard cycle ride on a cold blustery day. Pleasant room and bathroom, good breakfast. Italian restaurant nearby,location very close to the centre of Kaiserswerth, a charming small Rheinside village. Well connected to Dusseldorf, on same side of town as the airport. No heating on, despite it being after mid-september; room was rather cold.
The rooms were excellent and the staff was very helpful and accomodating. Location was very good too, simply a few minutes to walk to the metro and restaurants.
Excellent location with good parking. Very friendly atmosphere and excellent service. Highly recommended
Meget rent, hyggeligt og velfungerende hotel. Fremragende service fra personalets side. Alt fungerede fra først til sidst. Nej, det er vanskeligt at forestille sif, at noget kan gøres bedre.
Hotellet er det tættest man kan komme på at have en følelse af at man er hjemme! Utrolig fleksibel service. Bedre plads i fælles rum så der evt var plads til et sofa arrangement.
Lille godt hotel, hvor personlet gjorde at man følte sig hjemme. Pæne rene værelse, lidt kunst på væggen. Et sted jeg komme igen - hvis vi vej går denne vej. Perfekt belligenhed i forhold til lufthavn og messe. Jeg derfor sagten undvære en central belligenhed i forhold til centrum når det er en eller to dage nej


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Who are the Herbivore Men?
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9 posts • Page 1 of 1
Who are the Herbivore Men?
And why don't they wanna have sex? How come there's no Herbivore women?
it´s not that they don´t want to sex but they don´t want to jump through the loops for sex. the ROI is simply not there for them. i think they are kind of mgtow. i don´t think they are against easy sex or prostitutes per se. - society wants to blame them for not working their ass for women. society wants them to put women on the pedestal so they have no other goal then to follow their wishes..
They become to civilized so they don´t have the primal urge to fight for women. probably low T too, but i am not shure if it´s the case with most of them.
Re: Who are the Herbivore Men?
There's plenty of sex being had there, so much so that they even have their own unique strains of STDs.
What's not being had at past rates are children.
There are lots of "host clubs" catering to women, they just don't get the scrutiny that the men get.
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"Even an American judge is unlikely to award child support for imputed children." - FredOnEverything
I don't understand this question. Why are you saying that plant eating men don't want sex? Who told you that? There are plenty of vegetarian women. Why do you say they aren't?
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"Even an American judge is unlikely to award child support for imputed children." - FredOnEverything
Winston, do you really not know what the "herbivore men" of Japan are? Or are you just trolling your own forum?
Ha ha, and you like to criticize Filipinos for allegedly not knowing what a vegetarian and/or vegan is. Funny thing is, a lot of my friends in the Phils. do know.
Before making a potentially embarrassing comment about something your not too sure about, do a 2 minute Google check:
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Desert Scorpions are a kind of Scorpion found in the Desert of Skulls in Allansia.
It is believed that the Caarth extract the poison from Desert Scorpions to use on their enemies and there have been rumours of the cruel Snake Men skinning their captives alive and offering their corpses to the Desert Scorpions.[1]
See AlsoEdit
- ↑ Titan - The Fighting Fantasy World - 86/194, 88/199