Time Of Disease Progression Research Articles

877 - A Review of Radiological Assessment Response in Metastatic Renal Cell Carcinoma Treated with Antiangiogenic Therapy- are we Hitting the Target?

ABSTRACT Background Targeted therapy has changed the treatment landsacpe of metastatic renal cell carcinoma (RCC) in the last years. However, despite the positive results with antiangiogenic drugs in the treatment of metastatic RCC, the evaluation of response to these therapies remains undefined. This study aimed to review different proposed radiologic methods used for response evaluation with antiangiogenic agents in RCC. Methods A no systematic literature review using electronic databases PubMed/MEDLINE, EMBASE, Cochrane Library and LILACS with the terms “renal cell carcinoma”, “response criteria” and “targeted therapy” and its variables. Results A total of 53 articles were identified, of which 12 were selected and 41 excluded. After evaluation of the references of the 12 selected studies, two new studies were included. The 14 studies were published from August 2009 to October 2011, 11 of them using computed tomography as a method of response evaluation, one with doppler ultrasound and two others with positron emission tomography. A total of 927 patients were studied. The drugs used for analysis in the different studies were sunitinib, sorafenib, cediranibe, bevacizumab and interferon alpha; but sunitinib and sorafenib are variously present in all studies. The retrospective design was the basis for most of the analysis (71%) and endpoints analysed for method comparison were time to disease progression (TTP) or progression-free survival (PFS). All studies had RECIST as the assessment parameters (control). Proposed new methods of radiographic response criteria in this context were present in 11 studies (78%). In 3 studies (21%) only one radiologist reviewed the images, in the other at least 2 radiologists participated in the evaluation. Most studies evaluated a small number of patients and 8 studies (57%) included more than one antiangiogenic drugs in its analysis. Conclusion Antiangiogenic drugs are considered standard therapy in the treatment of metastatic RCC. Phase III trials are needed to validate the best radiological response criteria in this context, new proposed methods should be incorporated as secondary end-points in future prospective trials. Disclosure All authors have declared no conflicts of interest.

782TiP - Review of the Management of advanced Gastric Cancer; an Experience from a Low Resource Setting

ABSTRACT Purpose Adjuvant treatment combines Epirubicin, Cisplatin and 5-FU (ECF). Replacement of 5FU and Cisplatin with Capecitabine (X) and Oxaliplatin (O) has shown an efficacy similar to ECF, with improved tolerability and safety. The outcome of management of advanced gastric cancer at the Oncology Unit was assessed, with emphasis on the use of Capecitabine alone or in combination. Patients & methods 27 patients adenocarcinoma of the stomach between 2004 and 2008 were eligible. Time to disease progression (TTP) as well as tolerability of treatment was assessed retrospectively. Results Median follow up was 12 months (1 to 60 months). No adjuvant treatment was given in 36%. 26% received concurrent chemoradiation with Capecitabine. 11.1% received palliative radiotherapy only. One patient did not complete radiotherapy due to side effects. 26.6% received Capecitabine alone and combined with Oxaliplatin in 11.1% Grade 3/4 diarrhoea was reported in 7.4%; neuropathy and neutropenia were seen in 3.7%. Median time to progression in patients who had adjuvant treatment was 6.4 months (2 to 13 months). Conclusion There is a favorable tolerability of Capecitabine used alone or in combination with radiotherapy or other chemotherapy drugs. Disclosure All authors have declared no conflicts of interest.

First-Line Bevacizumab-Based Therapy in Advanced Non-Squamous Non-Small-Cell Lung Cancer

First-line bevacizumab-based therapy has been shown to improve outcomes in patients with advanced non-squamous non-small-cell lung cancer (NSCLC). The recent international phase IV SAiL study (a Study of Avastin [bevacizumab] in combination with platinum-containing chemotherapy in patients with advanced or recurrent non-squamous cell Lung cancer) evaluated the safety and efficacy of bevacizumab combined with standard chemotherapy regimens in routine clinical practice. Here we report the results of a subanalysis of baseline characteristics and efficacy data for Italian patients enrolled in SAiL. In the SAiL study, patients with untreated locally advanced, metastatic or recurrent non-squamous NSCLC received bevacizumab (7.5 or 15 mg/kg) every 3 weeks plus chemotherapy for up to six cycles, followed by single-agent bevacizumab until disease progression. Efficacy was assessed in terms of time to disease progression (TTP) and overall survival (OS). The Italian intent-to-treat population comprised 215 patients from a SAiL population of 2212 patients. At baseline, Italian patients tended to have less advanced disease than the overall population. Thus, the proportion of patients at enrollment with tumour stage IIIb and IV was 23.7 and 76.3 %, respectively, for the Italian population versus 19.7 and 80.3 % for the whole SAiL population. In addition, a higher proportion of Italian patients had an Eastern Cooperative Oncology Group performance status of 0 (72.6 vs. 37.2 %) and the prevalence of co-morbid conditions was lower in Italian patients (59.5 % of Italian patients reported a co-morbid condition and 60.0 % were receiving non-oncological treatment compared with 73.3 and 73.4 %, respectively, of SAiL patients overall). The mean exposures to bevacizumab and to chemotherapy were comparable between the Italian patient group and overall patient population, although cisplatin doublets were more commonly employed in Italian patients whereas carboplatin doublets were more commonly employed in the overall SAiL population. The median TTP and OS times for Italian and SAiL populations were comparable (TTP, 7.8 months vs. 7.8 months; OS, 14.8 months vs. 14.6 months). The results of this subanalysis of the SAiL study of bevacizumab treatment in routine clinical practice suggest that Italian oncologists tend to prescribe bevacizumab to a selected population of patients with less advanced disease than is the case in the overall population. Nevertheless, the first-line use of bevacizumab in combination with chemotherapy offers clinical benefits to Italian patients with advanced or recurrent non-squamous NSCLC.

Prognostic significance of del 17p, ZAP-70 and CD38 as independent indicators for B-CLL: correlation to response to treatment and disease outcome

Prognostic markers as CD38 and ZAP-70 and specific chromosomal abnormalities as del 17p have now been developed to refine the risk of progressive disease in chronic lymphocytic leukemia (CLL). This study analyzed 40 recently diagnosed, untreated B-CLL patients for CD38 and ZAP-70 expression by flow cytometry and for del 17p by conventional cytogenetics (CCG) and by fluorescence in situ hybridization (FISH) technique to evaluate their effect on the clinical course of CLL and as risk factors for disease progression in addition to their impact on response to treatment and disease outcome. Twenty healthy age- and sex-matched subjects were included as a control. The results revealed that CD38 and ZAP-70 expression were detected in 42.5% and 47.5% of cases, respectively. They were associated with an unfavorable clinical course. Higher levels were significantly associated with increased risk of unfavorable response to treatment (P=0.003), with poor clinical outcome (P=0.0001). Del 17p was detected in 35% of cases by FISH technique and in 7.5% by CCG. The deletion was significantly associated with progressive clinical course; poor response to treatment (P=0.007) but not with disease outcome (P=0.103).Combined analysis of ZAP-70 and CD38 yielded concordantly negative results in 50% of patients and concordantly positive results in 40% of patients, while 10% were discordant. CD38+/ZAP-70+ patients were significantly associated with progressive disease (P<0.05) and with del 17p than CD38−/ZAP-70- patients (P=0.008).Time to disease progression (TDP) was 6months among CD38+/ZAP-70+ patients as compared to 16months in CD38−/ZAP-70− patients. In patients with discordant results, the TDP was 9months. Over-representation of the three parameters (CD38, ZAP-70 and del 17p) was detected in 22.5% of cases, and pointed towards even shorter TDP (4.5months), more aggressive disease; more resistance to chemotherapy and poor outcome thus providing a precise tool for identifying high-risk patients.In conclusion, the combined expression of CD38 and ZAP-70 together with del 17p in CLL is a precise diagnostic tool for identifying high-risk patients and convey rapid progression; they are accurate predictors of clinical outcome thus could be used to indicate when more novel chemotherapeutic approaches are needed and provided help in guiding individual patient treatment.

Hormonal therapy for recurrent low-grade serous carcinoma of the ovary or peritoneum

ObjectiveTo determine whether hormonal therapies have efficacy in patients with recurrent low-grade serous carcinoma of the ovary or peritoneum. MethodsWe searched departmental databases for patients with histologically-confirmed, evaluable, recurrent low-grade serous ovarian or peritoneal carcinoma who received hormonal therapy at our institution between 1989 and 2009. We retrospectively reviewed patients' medical records for demographic, disease, hormonal therapy, and estrogen receptor and progesterone receptor expression data. We used the Response Evaluation Criteria in Solid Tumors version 1.1 to determine patients' responses to hormonal therapy. Because patients could have received more than one evaluable hormonal therapy regimen, we chose to define the outcome metric as “patient-regimens.” Median time to disease progression (TTP) and overall survival (OS) were also calculated. Regression analysis was also performed. ResultsWe identified 64 patients with recurrent low-grade serous carcinoma of the ovary or peritoneum. Patients' median TTP and median OS were 7.4 and 78.2months, respectively. Patients received 89 separate hormonal patient-regimens, which produced an overall response rate of 9% (6 complete responses and 2 partial responses). Sixty-one percent of the patient-regimens resulted in a progression-free survival duration of at least 6months. Patient-regimens involving ER+/PR+ disease produced a longer median TTP (8.9months) than patient-regimens involving ER+/PR− disease did (6.2months; p=0.053). This difference approached but did not reach statistical significance. ConclusionsHormonal therapies have moderate anti-tumor activity in patients with recurrent low-grade serous carcinoma of the ovary or peritoneum. Further study to determine whether ER/PR expression status is a predictive biomarker for this rare cancer subtype is warranted.

CT-guided radiofrequency ablation after with transarterial chemoembolization in treating unresectable hepatocellular carcinoma with long overall survival improvement

PurposeTo assess the time to disease progression (TTP), long-term survival benefit and safety of patients with unresectable hepatocellular carcinoma (HCC) treated with computed tomography (CT)-guided radiofrequency ablation (RFA) with transarterial chemoembolization chemoembolization (TACE). MethodsThis study was approved by the institutional review board. We reviewed the records of patients with intermediate and advanced HCC treated with CT-guided RFA with TACE between January 2000 and December 2009. Median TTP, overall survival (OS) and hepatic function were analyzed with the Kaplan–Meier method and log-rank tests. ResultsOne hundred and twenty-two patients (112 men and 10 women, mean age 53 years, range 18–86 years) were included in the study. The median follow-up time was 42 months (range 6–89 months), TTP was 6.8 months, the median OS was 31 months, and the 1-, 3-, and 5-year OS were 88.5%, 41.0%, and 10.7%. The results of the univariate analysis revealed that intrahepatic lesion, AJCC stage, and Child-Pugh stage were predictors of OS (P<0.01). In the multivariate analysis, the AJCC stage system showed a statistically significant difference for prognosis. Procedure-related death was 0.21% (1/470) within 1 month, and a statistical difference was found between the TACE and RFA of liver decompensation and Child-Pugh stage (P<0.05). ConclusionsThe survival probabilities of OS increased with CT-guided RFA with TACE, as observed in randomized studies from Europe and Asia. The longest TTP was observed for the intermediate stage HCC. The procedures were well tolerated with acceptable minor and major complications in unresectable HCC patients.

Safety and Efficacy of First-Line Bevacizumab Plus Chemotherapy in Elderly Patients with Advanced or Recurrent Nonsquamous Non-small Cell Lung Cancer: Safety of Avastin in Lung trial (MO19390)

Safety of Avastin in Lung (MO19390) was an international, open-label, single-arm study, which assessed the safety and efficacy of first-line bevacizumab (Avastin®) in combination with standard chemotherapy in patients (n = 2212) with advanced or recurrent non-small cell lung cancer (NSCLC). A preplanned subgroup analysis was performed to examine these outcomes in elderly patients older than 65 years. Eligible patients with nonsquamous NSCLC received up to six cycles of bevacizumab (7.5 or 15 mg/kg) plus any standard of care chemotherapy. Patients who did not experience disease progression after induction therapy continued bevacizumab therapy until disease progression or unacceptable toxicity. The primary end point was safety; secondary end points included time to disease progression (TTP) and overall survival (OS). Data were evaluated for 623 patients older than 65 years (mean age 70.6). The majority were Whites (86.2%) with stage IV disease (79.7%) and had adenocarcinoma (83.5%). The incidence of adverse events (AEs) of special interest was similar for elderly and younger patients (any grade bleeding 38.2% versus 38.3%; any grade hypertension 33.1% versus 30.6%; any grade proteinuria 33.4% versus 29.3%). Most AEs were grade less than or equal to 2. Serious AEs were reported in 45.3 and 34.7% of elderly and younger patients, respectively. Median OS was similar in elderly and younger patients (14.6 months in both age groups), as were TTP (8.2 versus 7.6 months), response rate (49.3% versus 52.4%), and disease control rate (89.3% versus 88.4%). Similar results were seen in a post hoc comparison of the older than 70 years and 70 years or younger subgroups: TTP was 8.6 months versus 7.7 months, respectively; OS was 14.6 months in both subgroups; response rate was 49% and 52%, respectively; incidence of AEs of special interest was comparable. Patients older than 65 years with nonsquamous NSCLC derive a similar clinical benefit from first-line bevacizumab-based therapy as their younger counterparts and do not experience increased toxicity.

P5-22-01: Feasibility and Patient Safety of Serial Biopsies (bx) in Metastatic HER2−Positive Breast Cancer (BC) To Evaluate Alterations in Molecular Biomarkers (BM): Preliminary Results of SHERsig (Study of HER2 Signature in Metastatic Breast Cancer) a Prospective Phase II Study.

Abstract Background The use of trastuzumab (H)-based therapy for HER2−positive BC has significantly altered outcomes. Yet up to 64% of metastatic patients (pts) fail to respond (Robert JCO 2006) and most pts will progress within 24–42 months (m) following an initial response for metastatic disease. Preclinical data suggest several in vitro resistance mechanisms but confirmatory in vivo data are lacking, preventing optimal personalized care. This ongoing proof-of-concept study examines serial bx in pts with HER2−positive metastatic BC in order to assess BM profiles across multiple lines of treatment. Methods: Key eligibility criteria include: centrally confirmed HER2 status, minimum of 1 disease site considered suitable for serial bx, normal coagulation profile and cardiac function, prior adjuvant/neoadjuvant taxane and H completed ≥12 m and ≥6 m respectively, ECOG ≤2. Pts receive q3wk H with clinician choice of taxane (docetaxel 75–100 mg/m2 q21, paclitaxel 80 mg/m2 weekly or 175 mg/m2 q21 [TH]). At the time of progressive disease, pts receive capecitabine (X) and H. Two core bx and 1 optional fine needle aspirate are performed at the following times: baseline (after 3 weeks [w] of TH), at 6 w, at time of first progression prior to XH, and at the time of progression on XH. Tumor assessments are performed at 6 w, then 9 w intervals, with cardiac assessment every 6 m. Primary endpoint aims to explore and potentially define BM signatures that could alter during HER2−targeted therapy and predict for decreased or increased sensitivity to H-based treatment. Secondary endpoints include bx safety, ORR and TTP. At time of baseline bx, pts have the option to complete a pt satisfaction questionnaire. Results: Between August 2009 and June 2011, 58 pts were screened; 29 enrolled. The other 29 pts were screen failures, with 3 pts (5%) specifically declining entry due to the requirement for serial bx. Median age is 53 y (range 37–86), with 9 and 20 pts having recurrent or de novo metastatic disease. Eight pts received adjuvant systemic treatment, including H in 4 pts. Baseline bx performed in the breast, n (%): 15 (52), bone: 6 (21), liver: 4 (14), and lymph nodes: 4 (14); 14 and 27 pts underwent bx at 3 and 6 w respectively. After a median of 34 w of treatment 11 pts progressed on TH and 7 pts underwent planned bx. There were 12 SAEs, none related to bx. Most AEs were grade 1/2 (95%) with 3% grade 3 and 1 death due to intercurrent illness. From a total of 43 bx, 12 (27%) grade 1/2 AEs (hematoma 2, transient hypotension 2, mild pain 8) were reported, with resolution in all instances. Fifteen pts consented to the pt satisfaction substudy. Conclusions: Preliminary results of the first reported serial bx study in metastatic BC demonstrated 95% pt acceptance of this approach. Evaluation of BM profiles will be conducted following planned recruitment of 50 pts. To date, the feasibility and safety of obtaining serial bx in metastatic BC is supported by the current safety profile and patient uptake. Updated recruitment data will be presented. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-22-01.

OT3-01-06: A Phase 2 Study Investigating the Safety, Efficacy and Surrogate Biomarkers of Response of 5-Azacitidine (5-AZA) and Entinostat (MS-275) in Patients with Advanced Breast Cancer.

Abstract Background: Epigenetic alterations in the genome, including abnormal DNA methylation and histone hypoacetylation, initiate and promote cancerous changes via several mechanisms, including inactivation of tumor suppressor genes. Preclinical investigations in breast cancer suggest that use of epigenetic modifiers results in re-expression of aberrantly silenced genes and proteins that represent important therapeutic targets (e.g. estrogen receptor alpha, ER). Combination therapy with a DNA methyltransferase inhibitor (DNMTI) and a histone deacetylase inhibitor (HDACI) has yielded superior ER reexpression and greater restoration of tamoxifen responsiveness than with HDACI alone. We hypothesize that clinically tolerable doses of the DNMTI 5-azacitidine (5-AZA) and the HDACI entinostat may not only effect changes in DNA methylation and gene expression, but also yield objective disease responses in women with advanced breast cancer. Trial design: This multicenter phase II study (NCT01349959) is enrolling patients with advanced human epidermal growth factor receptor 2 (HER2)-negative breast cancer with triple negative (ER/progesterone receptor [PR]/HER2−negative, Cohort A) or hormone-resistant (Cohort B) disease. Patients will receive 5-AZA 40 mg/m2 subcutaneously days 1–5 and 8–10 and entinostat 7 mg orally days 3 and 10 every 28 days. Because of the potential for re-expression of the ER with epigenetic agents, patients will be offered continuation of 5-AZA and entinostat at progression with the addition of hormonal therapy (investigator discretion). Mandatory tumor biopsies will be performed at baseline and after 8 weeks of therapy to evaluate correlative biomarkers. Eligibility Criteria: Eligible patients must be ≥ 18 years, have measurable locally advanced/metastatic triple-negative (at least one prior chemotherapy received adjuvant/metastatic setting) or hormone-resistant (must have received two prior hormonal agents and one prior chemotherapy) disease, adequate organ function and ECOG PS ≤ 2. Specific Aims: 1. Objective response rate (ORR) by RECIST 1.1 criteria. 2. Safety and tolerability 3. Progression-free survival, overall survival and clinical benefit rate. 4. Safety and toxicity data, feasibility and response rate where hormonal therapy is added to the combination under investigation at the time of progressive disease. 5. Pharmacokinetics, cytidine deaminase, changes from baseline of candidate gene methylation and expression in circulating deoxyribonucleic acid (DNA) and malignant tissue. Statistical Methods: Using a two-stage three-outcome design to assess the efficacy of the combination, a maximum of 30 patients (requiring 27 evaluable) will be accrued to each cohort unless undue toxicity is encountered for a maximum sample size of 60 patients. The study design tests the null hypothesis that the ORR is at most 5% against the alternative hypothesis that it is at least 20% with a type I error of 4% and power of 90%. Present and Targeted Accrual: This study has just opened to patient enrollment. We anticipate a rapid accrual of 60 patients within 1 year.br](Funding from Stand Up to Cancer and CTEP). Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT3-01-06.

Subcellular proteomic analysis of Tetrazanbigen on human hepatocellular carcinoma cell line QGY-7701

To investigate the clinical efficacy of cryotherapy ablation treatment for advanced hepatocellular carcinoma, and to analyse the predictive factors of cryotherapy ablation treatment. 190 patients of hepatitis B-related advanced HCC from 2005 to 2008 in our hospital underwent curative cryoablation. We used clinical cohort method to analyze cryoablation group (147 cases) and control group (43 cases). The median OS (over survival time) and TTP (time to disease progression) were compared. We also evaluated the clinical significance of age, gender, location of portal vein tumor thrombus, HBeAg, tumor histological grade, Child-Pugh classification, end-stage liver disease (MELD) score, advanced liver cancer prediction system (ALCPS) score and the Eastern Cooperative Oncology Group performance status (ECOG PS) score for predicting the efficacy of cryoablation. Two Groups were compared with the x² test. Survival rates were estimated by the Kaplan-Meier method and compared by the log rank test. The Cox proportional hazards model was used to determine the independent factors on survival based on the variables selected in univariate analysis. Median survival time of cryoablation group and Control group were 7.5 (4.2 to 14.6) months and 3.2 (1.2 to 8.6) months, median TTP were 3.5 (2.5 to 4.5) months and 1.5 (1.0 to 3.5 months), the differences between were statistically significant (P < 0.05). Median OS and TTP of advanced HCC patients who had Well-differentiated tumor, Child-pugh A-class and low score of MELD score, ALCPS score; ECOG PS score were significantly longer than that of the poorly differentiated tumor, Child-pugh B-class and the high those scores (P < 0.05). ECOG PS (P less than 0.05, 95% CI 1.074 - 2.143) and ALCPS (P < 0.05, 95% CI 1.005-2.121) were independent predictors for OS of advanced HCC. Cryoablation treatment can prolong median OS and TTP of advanced HCC. ECOG PS and ALCPS are important predictors for survival time of advanced HCC.

Randomized phase II trial of capecitabine (X) versus X plus erlotinib (E) in patients (pts) with metastatic colorectal cancer (mCRC): Differential impact of KRAS.

e14031^ Background: Palliative X monotherapy of mCRC is generally tolerated by elderly, and/or medically unfit pts. Epidermal growth factor receptor (EGFR) inhibitors improve efficacy when added to combination chemotherapy for mCRC. It is unknown whether biologic agents add benefit to alone in pts who either opt against, or are not candidate for, combination chemotherapy. We conducted a randomized phase II trial to investigate the novel “all-oral” combination of low-dose X and E in this pt population. Methods: Eligible pts with mCRC were either deemed unfit for, or chose against, 1st-line combination chemotherapy. Pts were randomized to X (1000 mg/m2 PO BID x 14 days) alone or in combination with E (150 mg PO OD) on a 3-week schedule. A 3rd arm (E alone) was ineffective, and discontinued after a preplanned interim analysis. Imaging was performed every 9 weeks until progression. Primary endpoint was time to disease progression (TTP); secondary endpoints included: objective response rate (ORR), overall survival (OS), safety and quality of life. Results: From June 2004 to June 2008, 95 pts [median age: 67; range 40-84; ECOG PS: 0 (45pts), 1 (38 pts), or 2 (22 pts)] were randomized to X alone (40 pts), XE (42 pts), or E alone (13 pts). KRAS status, where possible, was analyzed for pts in the first 2 arms only. As compared to X alone, XE was associated with significantly more Gr 3+ toxicity: (diarrhea: 29% vs 5%; fatigue: 12% vs 0%; anorexia 7% vs 0%; stomatitis 7% vs 0%). One pt discontinued treatment in the X arm vs 2 in XE. There was 1 toxic death in XE. TTP was not different for the whole trial (X=7.9 m, XE=9.2 m; p=0.8897), but exploratory subgroup differences emerged (below). Conclusions: The addition of E to X is associated with additional toxicity. E may benefit pts with KRAS-wild-type CRC and may harm those with KRAS-mutated CRC. Further study of XE in elderly/unfit pts with KRAS-wild-type CRC is warranted. Supported by grant from Roche. Median TTP (m) X XE p All pts (n = 40 / 42) 7.9 9.2 0.8897 KRAS wt (n =18 / 24) 8.4 11.7 * KRAS mut (n = 18 / 12) 7.4 1.9 * *Cox regression p=0.0236 for interaction of study arm by Kras status.

Evaluating the impact of Relative Total Dose Intensity (RTDI) on patients' short and long-term outcome in taxane- and anthracycline-based chemotherapy of metastatic breast cancer- a pooled analysis

BackgroundChemotherapy dose delay and/or reduction lower relative total dose intensity (RTDI) and may affect short- and long-term outcome of metastatic breast cancer (MBC) patients.MethodsBased on 933 individual patients' data of from 3 randomized MBC trials using an anthracycline and taxane we examined the impact of RTDI on efficacy and determined the lowest optimal RTDI for MBC patients.ResultsMedian time to disease progression (TTDP) and overall survival (OS) of all patients were 39 and 98 weeks. Overall higher RTDI was correlated with a shorter TTDP (log-rank p = 0.0525 for 85% RTDI cut-off). Proportional hazards assumption was violated, there was an early drop in the TTDP-curve for the high RTDI group. It was explained by the fact that patients with primary disease progression (PDP) do have a high RTDI per definition. Excluding those 114 patients with PDP the negative correlation between RTDI and TTDP vanished. However, non-PDP patients with RTDI-cut-off levels <85% showed a shorter OS than patients with higher RTDI levels (p = 0.0086).ConclusionsOptimizing RTDI above 85% appears to improve long-term outcome of MBC patients receiving first-line chemotherapy. Lowering RTDI had no negative influence on short term outcome like OR and TTDP.

Glioma-Associated Oncogene Family Zinc Finger 1 Expression and Metastasis in Patients With Head and Neck Squamous Cell Carcinoma Treated With Radiation Therapy (RTOG 9003)

Glioma-associated oncogene family zinc finger 1 (GLI1) expression was assessed to determine a potential role of hedgehog (Hh) signaling in head and neck squamous cell carcinoma (HNSCC). Additional proteins known to be modulated by Hh signaling, including beta-catenin (CTNNB1) and epidermal growth factor receptor (EGFR), were also assessed to determine the correlation among these distinct signaling pathways. Nuclear GLI1 and CTNNB1 expression levels were determined in tumors from patients enrolled on Radiation Therapy Oncology Group (RTOG) 9003, a radiation fractionation trial. The results were also correlated with previously determined EGFR expression. The expression levels were evaluated in relation to three end points: time to metastasis (TTM), time to disease progression (TDP), and overall survival (OS). Among 1,068 eligible patients, data on GLI1, CTNNB1, and EGFR were available in 339, 164, and 300 patients, respectively. Although CTNNB1 expression did not differentiate prognosis, GLI1 was associated with poorer outcomes, adjusted for age, TNM stages, and Karnofsky performance score, and the significant influence persisted in a multivariable analysis (quartile 4 [Q4] v Q1 to Q3: TTM hazard ratio [HR], 2.7; 95% CI, 1.5 to 4.9; TDP HR, 1.6; 95% CI, 1.1 to 2.5; OS HR, 1.9; 95% CI, 1.4 to 2.7). The significance of GLI1 persisted in a multivariable analysis that included EGFR expression levels. These data suggest that Hh signaling may play an important role in metastasis and that GLI1 could serve as a marker in HNSCC, but the regulatory mechanisms and oncogenic significance need further investigation. Risk classification based on this analysis needs a validation in independent cohorts.

Weekly combination of non-pegylated liposomal doxorubicin and taxane in first-line breast cancer: wALT trial (phase I–II)

BackgroundThrough different pharmacodynamic–kinetic interactions, weekly administration of proved efficacy agents can overcome resistance with lower toxicity and greater benefit. Based on this assumption, we designed a phase I–II trial with weekly non-pegylated liposomal anthracycline and taxane in first-line breast cancer patients. Patients and methodsWe enrolled 56 previously untreated metastatic breast cancer patients; they were randomly assigned to receive paclitaxel (Taxol) (50 mg/mq) or docetaxel (Taxotere) (30 mg/mq) combined with non-pegylated liposomal anthracycline (25 mg/mq) on days 1, 8 and 15 every 4 weeks. The primary end points were the clinical benefit and treatment-related toxic effects assessment. Secondary end points were time-to-disease progression (TTP) and overall survival (OS). ResultsThe overall clinical benefit was 87.04%. World Health Organization G3–4 toxic effects included neutropenia (45%), anemia (44%), complete alopecia (83%), severe onycholysis and neuropathy. The 24% of patients developed left ventricular ejection fraction reduction but none >10% with recover after treatment completion. The median absolute decrease from baseline was 1%. Median TTP was 11 months and median OS was 23 months. ConclusionsCombined weekly administration of taxane and non-pegylated liposomal anthracycline is well tolerated and clinical benefit data encourage phase III study design.

Chromosomal aberrations +1q21 and del(17p13) predict survival in patients with recurrent multiple myeloma treated with lenalidomide and dexamethasone

In the era of novel agents such as lenalidomide and bortezomib, risk stratification by chromosomal abnormalities may enable a more rational selection of therapeutic approaches in patients with multiple myeloma (MM). The authors analyzed the prognostic value of deletion del(13q14), del(17p13), +1q21, translocation t(4;14), t(11;14), and t(14;16) by fluorescence in situ hybridization (FISH) in a series of 92 patients with recurrent MM who were treated with lenalidomide and dexamethasone (len/dex) at the study center. Patients carrying del(13q14) or t(14;16) were found to have a shorter median time to disease progression (TTP) of 5.1 months (vs 14.4 months; P = .009) and 2.0 months (vs 10.5 months; P <.001), respectively. However, no effect on TTP was observed in patients harboring del(13q14) as an exclusive chromosomal aberration without the concomitant presence of t(4;14) or del(17p13). The median overall survival (OS) for patients with del(17p13) or +1q21 was 6.7 months (P = .002) and 8.3 months (P < .001), respectively, whereas the median OS for patients carrying none of these abnormalities was not reached. Multivariate analysis revealed that the effects of del(17p13) and +1q21 on OS were independent of patient age as well as the type and number of regimens administered before len/dex. The results of the current study suggest that the prognostic significance of t(4;14) may be ameliorated or eliminated in patients treated with len/dex, whereas the presence of del(17p13) or +1q21 is still associated with a dismal OS. The presence of t(11;14) and del(13q14) as exclusive chromosomal aberrations indicates no impact on outcome. Because of its rarity in MM, a confirmation of the prognostic role of the t(14;16) aberration is still pending.

Randomized, Phase II Trial of Pemetrexed and Carboplatin with or without Enzastaurin versus Docetaxel and Carboplatin as First-Line Treatment of Patients with Stage IIIB/IV Non-small Cell Lung Cancer

Enzastaurin is an oral serine/threonine kinase inhibitor that targets protein kinase C-beta (PKC-β) and the phosphatidylinositol-3-kinase/AKT pathway. This trial assessed pemetrexed-carboplatin ± enzastaurin to docetaxel-carboplatin in advanced non-small cell lung cancer. Patients with stage IIIB (with pleural effusion) or IV non-small cell lung cancer and performance status 0 or 1 were randomized to one of the three arms: (A) pemetrexed 500 mg/m and carboplatin area under the curve 6 once every 3 weeks for up to 6 cycles with a loading dose of enzastaurin 1125 or 1200 mg followed by 500 mg daily until disease progression, (B) the same regimen of pemetrexed-carboplatin without enzastaurin, or (C) docetaxel 75 mg/m and carboplatin area under the curve 6 once every 3 weeks for up to six cycles. The primary end point was time to disease progression (TTP). Between March 2006 and May 2008, 218 patients were randomized. Median TTP was 4.6 months for pemetrexed-carboplatin-enzastaurin, 6.0 months for pemetrexed-carboplatin, and 4.1 months for docetaxel-carboplatin (differences not significant). Median survival was 7.2 months for pemetrexed-carboplatin-enzastaurin, 12.7 months for pemetrexed-carboplatin, and 9.2 months for docetaxel-carboplatin (log-rank p = 0.05). Compared with the other arms, docetaxel-carboplatin was associated with lower rates of grade 3 thrombocytopenia and anemia but a higher rate of grade 3 or 4 febrile neutropenia. There was no difference in TTP between the three arms, but survival was longer with pemetrexed-carboplatin compared with docetaxel-carboplatin. Enzastaurin did not add to the activity of pemetrexed-carboplatin.

Phase II Study of Bortezomib and Pegylated Liposomal Doxorubicin in the Treatment of Metastatic Breast Cancer

Background Based on preclinical studies and a phase I trial of the combination of bortezomib and pegylated liposomal doxorubicin (PLD), which both showed activity in breast cancer, we conducted a phase II study of this regimen in patients with metastatic breast cancer. Patients and Methods Patients received bortezomib 1.3 mg/m 2 on days 1, 4, 8, and 11 of an every-21-day cycle, along with PLD 30 mg/m 2 on day 4. The primary objective was to evaluate the response rate of this combination, while secondary objectives were to obtain further safety data about this combination, to evaluate the time to disease progression (TTP), and to evaluate response by the breast cancer subtype. Results One of 12 evaluable patients had a partial response (8%), while 3 (25%) had stable disease. At 26 months follow-up, the median overall survival was 4.3 months (95% CI, 1.2-26.2) and the median TTP was 1.3 months (95% CI, 0.8-14.0 months). The combination was well tolerated, with the most common events including low-grade nausea and vomiting, neutropenia, and neuropathy, and no cardiac toxicity was seen. Of the 7 tumors subtyped, no association was seen between intrinsic subtype or receptor status and response. Conclusion The combination of PLD and bortezomib was well tolerated but has minimal activity in heavily pretreated unselected metastatic breast cancer.

The impact of tumor burden characteristics in patients with metastatic renal cell carcinoma treated with sunitinib

An important goal of noncurative therapy for metastatic renal cell carcinoma (mRCC) is tumor burden (TB) control. However, to the authors' knowledge, the impact of TB characteristics on clinical outcome has not been studied in patients with mRCC who were treated with vascular endothelial growth factor-targeted therapy. Patients with clear cell mRCC who were treated with sunitinib between June 2004 and October 2007 were retrospectively identified. Computed tomography scans were re-reviewed from baseline, at the time of maximal TB shrinkage (TS) while receiving sunitinib, and at the time of progressive disease (PD). Measurements were recorded as per Response Evaluation Criteria In Solid Tumors (RECIST). A total of 69 patients were identified. The majority (54%) were classified as being of favorable risk using Cleveland Clinic Foundation Tyrosine Kinase Inhibitor (CCF TKI) risk group criteria. All patients underwent prior nephrectomy and 77% received prior systemic therapy. There were a median of 8 metastatic deposits across all organs (range, 1-27 deposits). The median TB at the initiation of therapy was 14.0 cm (range, 3.0 cm-42.2 cm). On multivariable analysis, baseline characteristics of disease confined to above the diaphragm (P = .03) and a total TB <13 cm (P = .09) were found to be independent positive predictors of progression-free survival. A+ baseline, total number of metastases <10 (P < .001) and TB above the diaphragm <6.5 cm (P = .05) were found to be independent positive predictors of overall survival (OS). Increased TS while receiving sunitinib was found to be significantly associated with OS (P < .001). At the time of PD, tumor location and pattern of disease progression were not found to be associated with survival as measured from the date of PD. However, total TB (P = .003) and total number of metastatic deposits (≤12 vs >12; P < .001) were found to be significant predictors of survival after PD. The results of the current study indicate that TB characteristics are associated with clinical outcome in patients with mRCC who are treated with sunitinib.

Chemoembolization of colorectal liver metastases with cisplatin, doxorubicin, mitomycin C, ethiodol, and polyvinyl alcohol

Unresectable colorectal liver metastases have a 1- and 2-year survival of 55% and 33% with current systemic therapies. The authors evaluated response and survival after transarterial chemoembolization. Chemoembolization with cisplatin, doxorubicin, mitomycin C, ethiodized oil, and polyvinyl alcohol particles was performed at monthly intervals for 1 to 4 sessions. Cross-sectional imaging and clinical and laboratory evaluation were performed before treatment, 1 month after treatment, and then every 3 months. A second cycle was performed for intrahepatic recurrence. Toxicity was assessed using National Cancer Institute's Common Toxicity Criteria version 3.0. Response was evaluated using Response Evaluation Criteria in Solid Tumors criteria. Progression and survival were estimated with Kaplan-Meier analysis. A total of 245 treatments were performed over 141 cycles on 121 patients. Ninety-five of 141 treatment cycles were evaluable for response: 2 (2%) partial response, 39 (41%) stable disease, and 54 (57%) progression. Median time to disease progression (TTP) in the treated liver was 5 months, and median TTP anywhere was 3 months. Median survival was 33 months from diagnosis of the primary colon cancer, 27 months from development of liver metastases, and 9 months from chemoembolization. Survival was significantly better when chemoembolization was performed after first- or second-line systemic therapy (11-12 months) than after third- to fifth-line therapies (6 months) (P = .03). Presence of extrahepatic metastases did not adversely affect survival (P = .48). Chemoembolization provided local disease control of hepatic metastases after 43% of treatment cycles. Median survival was 27 months overall, and 11 months when initiated for salvage after failure of second-line systemic therapy.

Pegylated liposomal doxorubicin and gemcitabine in patients with advanced hepatocellular carcinoma

Over the years, doxorubicin and gemcitabine have been among the most widely used drugs for hepatocellular carcinoma (HCC), with relative efficacy. The authors report the results of a phase 2 study of the combination of gemcitabine plus pegylated liposomal doxorubicin. Patients with advanced HCC received combination chemotherapy with gemcitabine 1000 mg/m² on Days 1 and 8, followed by pegylated liposomal doxorubicin 30 mg/m² on Day 1. Treatment was repeated every 4 weeks to a maximum of 8 cycles. Primary endpoint was overall response rate, and secondary endpoints were time to disease progression (TTP), overall survival (OS), and toxicity. Forty-one patients were enrolled and were evaluable for response, toxicity, and survival. A total of 194 cycles of treatment were administered. Three (7%) patients had a complete response, and 1 of these patients underwent liver transplantation. Seven (17%) patients had a partial response and, among these patients, 1 patient underwent surgical resection. Among the 31 patients who had initial alpha-fetoprotein levels >400 ng/mL, 20 (64.5%) had a >20% decrease after 2 cycles of treatment. The median TTP and OS were 5.8 and 22.5 months, respectively. Hematologic toxicity was the most common side effect, including neutropenia (17%) and anemia (7%). The combination of gemcitabine plus pegylated liposomal doxorubicin was active and safe in advanced HCC. Moreover, this treatment induced some complete responses and converted some untreatable HCCs into lesions eligible for resection or transplantation.