Lenalidomide is a novel therapeutic agent with uncertain mechanism of action that is clinically active in myelodysplastic syndrome (MDS) and multiple myeloma (MM). Application of high (MM) and low (MDS) doses of lenalidomide has been reported to have clinical activity in CLL. Herein, we highlight life-threatening tumor flare when higher doses of lenalidomide are administered to patients with CLL and provide a potential mechanism for its occurrence.
Patients and Methods
Four patients with relapsed CLL were treated with lenalidomide (25 mg/d for 21 days of a 28-day cycle). Serious adverse events including tumor flare and tumor lysis are summarized. In vitro studies examining drug-induced apoptosis and activation of CLL cells were also performed.
Four consecutive patients were treated with lenalidomide; all had serious adverse events. Tumor flare was observed in three patients and was characterized by dramatic and painful lymph node enlargement resulting in hospitalization of two patients, with one fatal outcome. Another patient developed sepsis and renal failure. In vitro studies demonstrated lenalidomide-induced B-cell activation (upregulation of CD40 and CD86) corresponding to degree of tumor flare, possibly explaining the tumor flare observation.
Lenalidomide administered at 25 mg/d in relapsed CLL is associated with unacceptable toxicity; the rapid onset and adverse clinical effects of tumor flare represent a significant limitation of lenalidomide use in CLL at this dose. Drug-associated B-cell activation may contribute to this adverse event. Future studies with lenalidomide in CLL should focus on understanding this toxicity, investigating patients at risk, and investigating alternative safer dosing schedules.
Elucidation of the CSF proteome may yield insights into the pathogenesis of CNS disease. We tested the hypothesis that individual CSF proteins distinguish CNS lymphoma from benign focal brain lesions.
We used a liquid chromatography/mass spectrometry–based method to differentially quantify and identify several hundred CSF proteins in CNS lymphoma and control patients. We used enzyme-linked immunosorbent assay (ELISA) to confirm one of these markers in an additional validation set of 101 cases.
Approximately 80 CSF proteins were identified and found to be present at significantly different concentrations, both higher and lower, in training and test studies, which were highly concordant. To further validate these observations, we defined in detail the expression of one of these candidate biomarkers, antithrombin III (ATIII). ATIII RNA transcripts were identified within CNS lymphomas, and ATIII protein was localized selectively to tumor neovasculature. Determination of ATIII concentration by ELISA was significantly more accurate (> 75% sensitivity; >98% specificity) than cytology in the identification of cancer. Measurement of CSF ATIII levels was found to potentially enhance the ability to diagnose and predict outcome.
Our findings demonstrate for the first time that proteomic analysis of CSF yields individual biomarkers with greater sensitivity in the identification of cancer than does CSF cytology. We propose that the discovery of CSF protein biomarkers will facilitate early and noninvasive diagnosis in patients with lesions not amenable to brain biopsy, as well as provide improved surrogates of prognosis and treatment response in CNS lymphoma and brain metastasis.
We aimed to describe disease-free survival (DFS) and overall survival (OS) in men with localized or locally advanced prostate cancer receiving immediate hormone therapy as adjunct to radiation therapy, adjunct to radical prostatectomy, or stand-alone therapy.
Materials and Methods
A systematic literature search of MEDLINE, EMBASE, CancerLit, the Cochrane Library, and Current Contents (from 1986 to September 2006) yielded 35 high-quality clinical trials (n = 11,105 patients) which formed the evidence base. Selected studies were required to address early hormone therapy in nonmetastatic prostate cancer only. Data on DFS and OS were extracted from individual trials, summarized statistically, and displayed in graphic form.
Survival probabilities were extracted from 16 trials (n = 5,987 patients) addressing hormone therapy as an adjunct to radiation therapy, 11 trials (n = 1,885 patients) investigating hormone therapy as an adjunct to prostatectomy, and 10 trials (n = 3,233 patients) evaluating hormone therapy alone. In men receiving hormones and radiation, estimated 5-year DFS and OS were 52% and 82%, whereas median DFS and OS were 5.4 years and more than 7 years, respectively. In men receiving hormones and surgery, 5-year DFS and OS were 64% and 90%, whereas median DFS and OS were more than 6 years and more than 7 years, respectively. In men receiving hormones alone, 5-year DFS and OS were 57% and 70%, whereas median DFS and OS were 6.0 years and more than 7 years, respectively.
This systematic review provides a new baseline for expected DFS and OS in patients treated with hormone therapy for nonmetastatic prostate cancer. Survival in these men may be longer than estimated previously.
Prognostic factor analyses have proven useful in predicting outcome in patients with newly diagnosed malignant glioma. Similar analyses in patients with recurrent glioma could substantially affect the design and conduct of clinical trials.
Patients and Methods
Between 1995 and 2002, 333 adults with recurrent gliomas were enrolled on 10 phase I or II trials of systemic or local therapy. The studies had similar inclusion criteria and were conducted within the NABTT CNS Consortium. Ninety-three percent of the patients have died. Cox proportional hazards (PH) regression and recursive partitioning analysis (RPA) were performed to identify prognostic factors.
Factors associated with an increased risk of death were increased age, lower Karnofsky performance status (KPS), initial and on-study histologies of glioblastoma multiforme (GBM), corticosteroid use, shorter time from original diagnosis to recurrence, and tumor outside frontal lobe. The final PH model included initial histology of GBM (relative risk (RR)=2.01), 10 year increase in age (RR=1.23), KPS<80 (RR=1.54), and corticosteroid use (RR=1.49). RPA resulted in 7 classes. Median survival time was poorest in non-GBM patients with KPS<80 or GBM patients, age≥50, taking corticosteroids (4.4 mo; 95% confidence interval (CI)=3.6-5.4), best in patients with initial histology other than GBM with KPS≥80 and tumor confined to the frontal lobe (25.7 mo; 95% CI=18.7-52.5), and was 7.0 mo (95% CI=6.2-8.0) for all patients.
Initial histology, age, KPS, and corticosteroid use are prognostic for survival in recurrent glioma patients. To allow comparisons across Phase II trials, enrollment criteria may need to be restricted.
Magnetic resonance imaging (MRI) is an important tool for characterizing invasive breast cancer but has proven to be more challenging in the setting of ductal carcinoma in situ (DCIS). We investigated whether MRI features of DCIS reflect differences in biology and pathology.
Patients and Methods
Forty five of 100 patients with biopsy-proven DCIS who underwent MRI and had sufficient tissue to be characterized by pathologic (nuclear grade, presence of comedo necrosis, size, and density of disease) and immunohistochemical (IHC) findings (proliferation, Ki67; angiogenesis, CD34; and inflammation, CD68). Pathology and MRI features (enhancement patterns, distribution, size, and density) were analyzed using pairwise and canonical correlations.
Histopathologic and IHC variables correlated with MRI features (r = 0.73). The correlation was largely due to size, density (by either MRI or pathology), and inflammation (P < .05). Most small focal masses were estrogen receptor-positive. MRI enhancement patterns that were clumped were more likely than heterogeneous patterns to be high-grade lesions. Homogenous lesions were large, high grade, and rich in macrophages. Presence of comedo necrosis and size could be distinguished on MRI (P < .05). MRI was most likely to over-represent the size of less dense, diffuse DCIS lesions.
The heterogeneous presentation of DCIS on MRI reflects underlying histopathologic differences.
To assess cardiac safety and potential cardiac risk factors associated with trastuzumab in the NCCTG N9831 Intergroup adjuvant breast cancer trial.
Patients and Methods
Patients with HER2-positive operable early breast cancer were randomized to 1 of 3 treatment arms: doxorubicin plus cyclophosphamide (AC) followed by either weekly paclitaxel (Arm A); paclitaxel then trastuzumab (Arm B); or paclitaxel plus trastuzumab then trastuzumab alone (Arm C). Left ventricular ejection fraction (LVEF) was evaluated at registration and 3, 6, 9, and 18–21 months post-registration.
A total of 1944 patients completed AC with a satisfactory LVEF and proceeded to post-AC therapy. Post-AC cardiac events (congestive heart failure [CHF] or cardiac death [CD]) were: Arm A, n=3 (2 CHF, 1 CD); Arm B, n=19 (18 CHF, 1 CD); Arm C, n=19 (all CHF); 3-year cumulative incidence was 0.3%, 2.8%, and 3.3%, respectively. Cardiac function improved in most CHF cases following trastuzumab discontinuation and cardiac medication. Factors associated with increased risk of a cardiac event after AC in Arms B and C were older age (P<.003), prior/current antihypertensive agents (P=.005), and lower registration LVEF (P=.033). Incidence of asymptomatic LVEF decreases requiring trastuzumab to be held was 8–10%; LVEF recovered and trastuzumab was restarted in approximately 50% of these patients.
The cumulative incidence of post-AC cardiac events at 3 years was higher in the trastuzumab-containing arms versus control arm but by <4%. Older age, lower registration LVEF, and antihypertensive medications increase the risk of cardiac dysfunction in patients receiving trastuzumab following AC.
HER2; trastuzumab; adjuvant; breast cancer; doxorubicin; cyclophosphamide; paclitaxel; cardiac safety
Vertebral fractures due to osteoporosis are a potential complication of childhood acute lymphoblastic leukemia (ALL). To date, the incidence of vertebral fractures during ALL treatment has not been reported.
Patient and Methods
We prospectively evaluated 155 children with ALL during the first 12 months of leukemia therapy. Lateral thoracolumbar spine radiographs were obtained at baseline and 12 months. Vertebral bodies were assessed for incident vertebral fractures using the Genant semi-quantitative method, and relevant clinical indices such as spine bone mineral density (BMD), back pain and the presence of vertebral fractures at baseline were analyzed for association with incident vertebral fractures.
Of the 155 children, 25 (16%, 95% Confidence Interval (CI) 11% to 23%) had a total of 61 incident vertebral fractures, of which 32 (52%) were moderate or severe. Thirteen of the 25 children with incident vertebral fractures (52%) also had fractures at baseline. Vertebral fractures at baseline increased the odds of an incident fracture at 12 months by an odds ratio of 7.3 (95% CI 2.3 to 23.1, p = 0.001). In addition, for every one standard deviation reduction in spine BMD Z-score at baseline, there was 1.8-fold increased odds of incident vertebral fracture at 12 months (95% CI 1.2 to 2.7, p = 0.006).
Children with ALL have a high incidence of vertebral fractures after 12 months of chemotherapy, and the presence of vertebral fractures and reductions in spine BMD Z-scores at baseline are highly associated clinical features.
PMID: 22734031 CAMSID: cams4400
acute lymphoblastic leukemia; children; osteoporosis; vertebral fractures
To update eligibility and outcome measures in trials that evaluate systemic treatment for patients with progressive prostate cancer and castrate levels of testosterone.
A committee of investigators experienced in conducting trials for prostate cancer defined new consensus criteria by reviewing previous criteria, Response Evaluation Criteria in Solid Tumors (RECIST), and emerging trial data.
The Prostate Cancer Clinical Trials Working Group (PCWG2) recommends a two-objective paradigm: (1) controlling, relieving, or eliminating disease manifestations that are present when treatment is initiated and (2) preventing or delaying disease manifestations expected to occur. Prostate cancers progressing despite castrate levels of testosterone are considered castration resistant and not hormone refractory. Eligibility is defined using standard disease assessments to authenticate disease progression, prior treatment, distinct clinical subtypes, and predictive models. Outcomes are reported independently for prostate-specific antigen (PSA), imaging, and clinical measures, avoiding grouped categorizations such as complete or partial response. In most trials, early changes in PSA and/or pain are not acted on without other evidence of disease progression, and treatment should be continued for at least 12 weeks to ensure adequate drug exposure. Bone scans are reported as “new lesions” or “no new lesions,” changes in soft-tissue disease assessed by RECIST, and pain using validated scales. Defining eligibility for prevent/delay end points requires attention to estimated event frequency and/or random assignment to a control group.
PCWG2 recommends increasing emphasis on time-to-event end points (ie, failure to progress) as decision aids in proceeding from phase II to phase III trials. Recommendations will evolve as data are generated on the utility of intermediate end points to predict clinical benefit.
Limited data are available on the efficacy of oral bisphosphonate therapy in breast cancer survivors. Our goal was to examine prevention of breast cancer–related bone loss in this cohort.
Patients and Methods
Eighty-seven postmenopausal women after chemotherapy for breast cancer were randomly assigned to once-weekly risedronate 35 mg or placebo for 24 months. Outcomes included bone mineral density (BMD) and turnover markers.
At study initiation, 13% of patients were on an aromatase inhibitor (AI). After 24 months, there were differences of 1.6 to 2.5% (P < .05) at the spine and hip BMD between the placebo and risedronate groups. At study completion, 44% were on an AI. Adjusting for an AI, women on placebo plus AI had a decrease in BMD of (mean ± SE) 4.8% ± 0.8% at the spine and 2.8% ± 0.5% at the total hip (both P < .001). In women on risedronate + AI, the spine decreased by 2.4% ± 1.1% (P < .05) and was stable at the hip. Women in the placebo group not on an AI, maintained BMD at the spine, and had a 1.2% ± 0.5% loss at the total hip (P < .05). Women who received risedronate but no AI had the greatest improvement in BMD of 2.2% ± 0.9% (P < .05) at the total hip. Bone turnover was reduced with risedronate. There were no differences in adverse events between the groups.
We conclude that in postmenopausal women with breast cancer with or without AI therapy, once-weekly oral risedronate was beneficial for spine and hip BMD, reduced bone turnover, and was well tolerated.
Although previous studies have demonstrated an inverse relationship between folate intake and colorectal cancer risk, a recent trial suggests that supplemental folic acid may accelerate tumorigenesis among patients with a history of colorectal adenoma. Therefore, high priority has been given to research investigating the influence of folate on cancer progression in patients with colorectal cancer.
To investigate whether prediagnostic levels of plasma folate are associated with colorectal cancer-specific and overall mortality, we performed a prospective, nested observational study within two large U.S. cohorts, the Nurses’ Health Study and Health Professionals Follow-up Study. We measured folate levels among 301 participants who developed colorectal cancer 2 or more years after their plasma was collected and compared participants using Cox proportional hazards models by quintile of plasma folate.
Higher levels of plasma folate were not associated with an increased risk of colorectal cancer-specific or overall mortality. Compared with participants in the lowest quintile of plasma folate, those in the highest quintile experienced a multivariable-adjusted hazard ratio for colorectal-cancer-specific mortality of 0.42 (95% CI, 0.20–0.88) and overall mortality of 0.46 (95% CI, 0.24–0.88). When the analysis was limited to participants whose plasma was collected within 5 years of cancer diagnosis, no detrimental effect of high plasma folate was noted. In subgroup analyses, no subgroup demonstrated worse survival among participants with higher plasma folate levels.
In two large prospective cohorts, higher prediagnostic levels of plasma folate were not associated with an increased risk of colorectal cancer-specific or overall mortality.
Colorectal cancer; cancer-specific mortality; folate; prospective cohort study
The combination of a vascular endothelial growth factor (VEGF) -neutralizing antibody, bevaci-zumab, and irinotecan is associated with high radiographic response rates and improved survival outcomes in patients with recurrent malignant gliomas. The aim of these retrospective studies was to evaluate tumor vascularity and expression of components of the VEGF pathway and hypoxic responses as predictive markers for radiographic response and survival benefit from the bevacizumab and irinotecan therapy.
Patients and Methods
In a phase II trial, 60 patients with recurrent malignant astrocytomas were treated with bevacizumab and irinotecan. Tumor specimens collected at the time of diagnosis were available for further pathologic studies in 45 patients (75%). VEGF, VEGF receptor-2, CD31, hypoxia-nducible carbonic anhydrase 9 (CA9), and hypoxia-inducible factor-2α were semiquantitatively assessed by immunohistochemistry. Radiographic response and survival outcomes were correlated with these angiogenic and hypoxic markers
Of 45 patients, 27 patients had glioblastoma multiforme, and 18 patients had anaplastic astrocytoma. Twenty-six patients (58%) had at least partial radiographic response. High VEGF expression was associated with increased likelihood of radiographic response (P = .024) but not survival benefit. Survival analysis revealed that high CA9 expression was associated with poor survival outcome (P = .016)
In this patient cohort, tumor expression levels of VEGF, the moleculartarget of bevacizumab, were associated with radiographic response, and the upstream promoter of angiogenesis, hypoxia, determined survival outcome, as measured from treatment initiation. Validation in a larger clinical trial is warranted
The long-term impact of thalidomide plus dexamethasone (thal/dex) as primary therapy for newly diagnosed multiple myeloma (MM) is unknown. The goal of this study was to compare thalidomide plus dexamethasone versus placebo plus dexamethasone (placebo/dex)as primary therapy for newly diagnosed MM.
Patients and Methods
In this double-blind, placebo-controlled trial, patients with untreated symptomatic MM were randomized to thal/dex (arm A) or to placebo plus dexamethasone (dex) (arm B). Patients in arm A received oral thalidomide 50 mg daily, escalated to 100 mg on day 15, and to 200 mg from day 1 of cycle 2 (28-day cycles). Oral dex 40 mg was administered on days 1 through 4, 9 through 12, and 17 through 20 during cycles 1 through 4 and on days 1 through 4 only from cycle 5 onwards. Patients in arm B received placebo and dex, administered as in arm A. The primary end point of the study was time to progression. This study is registered at http://ClinicalTrials.gov (NCT00057564).
A total of 470 patients were enrolled (235 randomly assigned to thal/dex and 235 to placebo/dex). The overall response rate was significantly higher with thal/dex compared with placebo/dex (63% v 46%), P < .001. Time to progression (TTP) was significantly longer with thal/dex compared with placebo/dex (median, 22.6 v 6.5 months, P < .001). Grade 4 adverse events were more frequent with thal/dex than with placebo/dex (30.3% v 22.8%).
Thal/dex results in significantly higher response rates and significantly prolongs TTP compared with dexamethasone alone in patients with newly diagnosed MM.
Nomograms are statistically based tools that provide the overall probability of a specific outcome. They have shown better individual discrimination than the current TNM staging system in numerous patient tumor models. The pancreatic nomogram combines individual clinicopathologic and operative data to predict disease-specific survival at 1, 2, and 3 years from initial resection. A single US institution database was used to test the validity of the pancreatic adenocarcinoma nomogram established at Memorial Sloan-Kettering Cancer Center.
Patients and Methods
The nomogram was created from a prospective pancreatic adenocarcinoma database that included 555 consecutive patients between October 1983 and April 2000. The nomogram was validated by an external patient cohort from a retrospective pancreatic adenocarcinoma database at Massachusetts General Hospital that included 424 consecutive patients between January 1985 and December 2003.
Of the 424 patients, 375 had all variables documented. At last follow-up, 99 patients were alive, with a median follow-up time of 27 months (range, 2 to 151 months). The 1-, 2-, and 3-year disease-specific survival rates were 68% (95% CI, 63% to 72%), 39% (95% CI, 34% to 44%), and 27% (95% CI, 23% to 32%), respectively. The nomogram concordance index was 0.62 compared with 0.59 with the American Joint Committee on Cancer (AJCC) stage (P = .004). This suggests that the nomogram discriminates disease-specific survival better than the AJCC staging system.
The pancreatic cancer nomogram provides more accurate survival predictions than the AJCC staging system when applied to an external patient cohort. The nomogram may aid in more accurately counseling patients and in better stratifying patients for clinical trials and molecular tumor analysis.
To determine the outcomes, with particular attention to toxicity, of children with Down syndrome (DS) and acute myeloid leukemia (AML) treated on Pediatric Oncology Group (POG) protocol 9421.
Patients and Methods
Children with DS and newly diagnosed AML (n = 57) were prospectively enrolled onto the standard-therapy arm of POG 9421 and were administered five cycles of chemotherapy, which included daunorubicin 135 mg/m2 and mitoxantrone 80 mg/m2. Outcomes and toxicity were evaluated prospectively and were compared with the non-DS–AML cohort (n = 565). A retrospective chart review was performed to identify adverse cardiac events.
In the DS-AML group, 54 patients (94.7%) entered remission. One experienced induction failure and two died. Of the 54 who entered remission, three relapsed and six died as a result of other causes. The remission induction rate was similar in the non-DS–French-American-British (FAB) M7 (91.7%) and non-DS–non-M7 (89.3%) groups. The 5-year overall survival was significantly better in the DS-AML group (78.6%) than in the non-DS–M7 (36.3%) or the non-DS-non-M7 (51.8%) groups (P < .001). No age-related difference in 5-year, event-free survival was seen between patients younger than 2 years (75.8%) and those aged 2 to 4 years (78.3%). Symptomatic cardiomyopathy developed in 10 patients (17.5%) with DS-AML during or soon after completion of treatment; three died as a result of congestive heart failure.
The POG 9421 treatment regimen was highly effective in both remission induction and disease-free survival for patients with DS-AML. However, there was a high incidence of cardiomyopathy, which supports current strategies for dose reduction of anthracyclines in this patient population.
To investigate the association between physical activity, body mass
index (BMI) and mammographic density in an ethnically-diverse
population-based sample of 522 postmenopausal women diagnosed with stage
0–IIIA breast cancer and enrolled in the Health, Eating, Activity,
and Lifestyle Study.
We collected information on BMI and physical activity during a clinic
visit two to three years after diagnosis. Weight and height were measured in
a standard manner. Using an interview-administered questionnaire,
participants recalled the type, duration, and frequency of physical
activities in the past year. We estimated dense area and percent density as
a continuous measure using a computer-assisted software program from
mammograms imaged approximately one to two years after diagnosis. Analysis
of covariance methods were used to obtain mean density across World Health
Organization BMI categories and physical activity tertiles adjusted for
We observed a statistically significant decline in percent density (p
for trend = .0001), and mammographic dense area (p for trend = 0.0052), with
increasing level of BMI adjusted for potential covariates. We observed a
statistically significant decline in mammographic dense area (p for trend =
.036) with increasing level of sports/recreational physical activity in
women with a BMI ≥ 30 kg/m2. Conversely, in women with a
BMI < 25 kg/m2, we observed a nonstatistically significant
increase in mammographic dense area and percent density with increasing
level of sports/recreational physical activity.
Increasing physical activity among obese postmenopausal breast cancer
survivors may be a reasonable intervention approach to reduce mammographic
breast cancer; body fat; exercise; obesity; weight; breast tissue; breast density
Fenretinide induces apoptosis in malignant gliomas in vitro. This two-stage phase II trial was conducted to determine the efficacy of fenretinide in adults with recurrent malignant gliomas.
Patients and Methods
Twenty-two patients with anaplastic gliomas (AG) and 23 patients with glioblastoma (GBM) whose tumors had recurred after radiotherapy and no more than two chemotherapy regimens were enrolled. Fenretinide was given orally on days 1 to 7 and 22 to 28 in 6-week cycles in doses of 600 or 900 mg/m2 bid.
Six of 21 (29%) patients in the AG arm and two of 23 (9%) patients in the GBM arm had stable disease at 6 months. One patient with AG treated at 900 mg/m2 bid dosage had a partial radiologic response. Median progression-free survival (PFS) was 6 weeks for the AG arm and 6 weeks for the GBM arm. PFS at 6 months was 10% for the AG arm and 0% for the GBM arm. Grade 1 or 2 fatigue, dryness of skin, anemia, and hypoalbuminemia were the most frequent toxicities reported. The trial was closed after the first stage because of the inadequate activity at the fenretinide doses used. The first-administration mean plasma Cmax for fenretinide was 832 ± 360 ng/mL at the 600 mg/m2 bid dosage and 1,213 ± 261 ng/mL at the 900 mg/m2 bid dosage.
Fenretinide was inactive against recurrent malignant gliomas at the dosage used in this trial. However, additional studies using higher doses of the agent are warranted based on the tolerability of the agent and the potential for activity of a higher fenretinide dosage, as suggested in this trial.
Different prognostic factors stratify patients with pancreatic adenocarcinoma. The purpose of this study was to determine whether preoperative CA19-9 levels can predict stage of disease or survival and whether a change in preoperative to postoperative CA19-9 or the postoperative CA19-9 predicts overall survival.
Patients and Methods
Four hundred twenty-four consecutive patients with pancreatic adenocarcinoma underwent resection between January 1, 1985 and January 1, 2004. Of the patients with a bilirubin less than 2 mg/dL, 176 had preoperative CA19-9 values, and 111 had pre- and postoperative CA19-9 values. Survival was measured from the first postoperative CA19-9 level measured (median, 39 days) until death or last follow-up. A multivariate failure time model was fit using clinical, operative, pathologic, and adjuvant treatment characteristics, and a categorization was defined by the values and changes in CA19-9 before and after surgery.
Of the 176 patients, 128 (73%) had T3 lesions, and 99 (56%) had N1 disease; 138 patients (78%) underwent pancreaticoduodenectomy. Median preoperative CA19-9 levels were lower in N0 patients compared with patients with positive nodes (nine v 164 U/mL, respectively; nonparametric P = .06) and in T1/T2 patients versus T3 patients (41 v 162 U/mL, respectively; P = .03). Median follow-up time (n = 111) was 1.8 years (range, 1 to 12.9 years), with overall actuarial 1-, 3-, and 5-year survival rates of 70%, 36%, and 30%, respectively. Significant predictors of survival on multivariate analysis included a decrease in CA19-9 (P = .0005), negative lymph nodes (P = .001), lower T stage (P = .0008), and postoperative CA19-9 less than 200 U/mL (P = .0007).
In patients with pancreatic adenocarcinoma, preoperative CA19-9 correlates with stage of disease. Both a postoperative decrease in CA19-9 and a postoperative CA19-9 value of less than 200 U/mL are strong independent predictors of survival, even after adjusting for stage. CA19-9 levels should be included in a patient’s perioperative care and should be considered for prognostic nomograms.
This multi-institutional phase I trial was designed to determine the maximum tolerated dose (MTD) of cilengitide (EMD 121974) and evaluate the use of perfusion MRI in patients with recurrent malignant glioma.
Patients and Methods
Patients received cilengitide twice weekly on a continuous basis. A treatment cycle was defined as 4 weeks. Treatment related dose limiting toxicity was defined as any grade 3 or 4 non-hematological toxicity or grade 4 hematological toxicity of any duration.
A total of 51 patients were enrolled in cohorts of 6 patients to doses of 120, 240, 360, 480, 600, 1200, 1800, and 2400 mg/m2 administered as a twice weekly intravenous infusion. Three patients progressed early and were inevaluable for toxicity assessment. The dose limiting toxicities observed were: one thrombosis (120 mg/m2), one grade 4 joint and bone pain (480 mg/m2), one thrombocytopenia (600 mg/m2) and one anorexia, hypoglycemia, hyponatremia (800 mg/m2). The MTD was not reached. Two patients demonstrated complete response, three patients had partial response, and four patients had stable disease. Perfusion MRI revealed a significant relationship between the change in tumor relative cerebral blood flow (rCBF) from baseline and area under the plasma concentration versus time curve after 16 weeks of therapy.
1) Cilengitide is well tolerated to doses of 2400 mg/m2; 2) Durable complete and partial responses were seen in this phase I study; 3) Clinical response appears related to rCBF changes.
To investigate how communication among physicians, patients, and
family/companions influences patients’ decision making about
participation in clinical trials.
Patients and Methods
We video recorded 235 outpatient interactions occurring among
oncologists, patients, and family/companions (if present) at two
comprehensive cancer centers. We combined interaction analysis of the
real-time video-recorded observations (collected at Time 1) with patient
self-reports (Time 2) to determine how communication about trial offers
influenced accrual decisions.
Clinical trials were explicitly offered in 20% of the
interactions. When offers were made and patients perceived they were offered
a trial, 75% of patients assented. Observed messages (at Time 1)
directly related to patients’ self-reports regarding their decisions
(2 weeks later), and how they felt about their decisions and their
physicians. Specifically, messages that help build a sense of an alliance
(among all parties, including the family/companions), provide support
(tangible assistance and reassurance about managing adverse effects), and
provide medical content in language that patients and family/companions
understand are associated with the patient’s decision and
In two urban, National Cancer Institute–designated
comprehensive cancer centers, a large percentage of patients are not offered
trials. When offered a trial, most patients enroll. The quality and quantity
of communication occurring among the oncologist, patient, and
family/companion when trials are discussed matter in the patient’s
decision-making process. These findings can help increase physician
awareness of the ways that messages and communication behaviors can be
observed and evaluated to improve clinical practice and research.
The purpose of this article is to review the recent advances in the atomic-level understanding of the Epidermal Growth Factor Receptor Tyrosine Kinase (EGFR-TK). We aim to highlight the current and future importance of these studies for the understanding and treatment of malignancies where EGFR-TK is improperly activated.
The analysis was conducted on published crystal structures deposited in the Protein Data Bank (www.pdb.org) using the program O.
In this review we emphasize how recent EGFR kinase domain crystal structures can explain the mechanisms of activation for L858R and other EGFR-TK mutations, and compare these distinct activating mechanisms with those recently described for the wild-type EGFR. We suggest an atomic-level mechanism for the poor efficacy of lapatinib against tumors with activating EGFR kinase domain point mutations compared to the efficacy of gefitinib and erlotinib, and demonstrate how structural insights help our understanding of acquired resistance to these agents. We also highlight how these new molecular-level structural data are expected to affect the development of EGFR-TK targeted small molecule kinase inhibitors.
There are now more crystal structures published for the EGFR-TK domain than for any other tyrosine kinase. This wealth of crystallographic information is beginning to describe the mechanisms by which proper regulation of EGFR-TK is lost in disease. These crystal structures are beginning to show how small molecules inhibit EGFR-TK activity and will aid development of EGFR-TK mutant targeted therapies.
High-dose interleukin-2 (IL-2) induces responses in 15% to 20% of patients with advanced melanoma; 5% to 8% are durable complete responses (CRs). The HLA-A2–restricted, modified gp100 peptide (210M) induces T-cell immunity in vivo and has little antitumor activity but, combined with high-dose IL-2, reportedly has a 42% (13 of 31 patients) response rate (RR). We evaluated 210M with one of three different IL-2 schedules to determine whether a basis exists for a phase III trial.
Patients and Methods
In three separate phase II trials, patients with melanoma received 210M subcutaneously during weeks 1, 4, 7, and 10 and standard high-dose IL-2 during weeks 1 and 3 (trial 1), weeks 7 and 9 (trial 2), or weeks 1, 4, 7, and 10 (trial 3). Immune assays were performed on peripheral-blood mononuclear cells collected before and after treatment.
From 1998 to 2003, 131 patients with HLA-A2–positive were enrolled. With 60-month median follow-up time, the overall RR for 121 assessable patients was 16.5% (95% CI, 10% to 26%); the RRs were 23.8% in trial 1 (42 patients), 12.5% in trial 2 (40 patients), and 12.8% in trial 3 (39 patients). There were 11 CRs (9%) and nine partial responses (7%), with 11 patients (9%) progression free at ≥ 30 months. Immune studies including assays of CD3-ζ expression and numbers of CD4+/CD25+/FoxP3+ regulatory T cells, CD15+/CD11b+/CD14− immature myeloid-derived cells, and CD8+gp100 tetramer-positive cells in the blood did not correlate with clinical benefit.
The results again demonstrate efficacy of high-dose IL-2 in advanced melanoma but did not demonstrate the promising clinical activity reported with vaccine and high-dose IL-2 in any of three phase II trials.
To assess the efficacy and toxicity of carboplatin, etoposide, and the bcl-2 antisense oligonucleotide oblimersen as initial therapy for extensive-stage small-cell lung cancer (ES-SCLC). bcl-2 has been implicated as a key factor in SCLC oncogenesis and chemotherapeutic resistance.
Patients and Methods
A 3:1 randomized phase II study was performed to evaluate carboplatin and etoposide with (arm A) or without oblimersen (arm B) in 56 assessable patients with chemotherapy-naïve ES-SCLC. Outcome measures including toxicity, objective response rate, complete response rate, failure-free survival, overall survival, and 1-year survival rate.
Oblimersen was associated with slightly more grade 3 to 4 hematologic toxicity (88% v 60%; P = .05). Response rates were 61% (95% CI, 45% to 76%) for arm A and 60% (95% CI, 32% to 84%) for arm B. The percentage of patients alive at 1 year was 24% (95% CI, 12% to 40%) with oblimersen, and 47% (95% CI, 21% to 73%) without oblimersen. Hazard ratios for failure-free survival (1.79; P = .07) and overall survival (2.13; P = .02) suggested worse outcome for patients receiving oblimersen. These results hold when adjusted for other prognostic factors, such as weight loss, in multivariate regression analysis.
Despite extensive data supporting a critical role for Bcl-2 in chemoresistance in SCLC, addition of oblimersen to a standard regimen for this disease did not improve any clinical outcome measure. Emerging data from several groups suggest that this lack of efficacy may be due to insufficient suppression of Bcl-2 in vivo. Additional evaluation of this agent in SCLC is not warranted.