Comparing and Validating Simple Measures of Patient-Reported Peripheral Neuropathy for Oncology Clinical Trials: NCCTG N0897 (Alliance) A Pooled Analysis of 2440 Patients.

INTRODUCTION: Current standard evaluation of Peripheral Neuropathy (PN) is based on an investigator-reported classification system that is commonly unable to correctly reflect the subjective symptoms for patients. Thus more reliable methods to assess PN are needed. This study assessed alternative methods of assessing patient-reported PN in 5 North Central Cancer Treatment Group (NCCTG) clinical trials. METHOD: Two single-item assessments relating to numbness and tingling were used to measure PN. Patients' Quality Of Life (QOL) was also assessed using the Uniscale, Symptom Distress Scale (SDS), Profile of Mood States (POMS), Brief Pain Inventory (BPI) and Subject Global Impression of Change (SGIC). Wilcoxon tests compared QOL scores between patients with PN (score > 50) vs. no PN (score ≤ 50). Changes from baseline in QOL were compared by Wilcoxon rank sum test with a 20-point change in PN defined as clinically meaningful. Both distribution-based and anchor-based approaches were used to derive estimates of Minimal Important Differences (MID). Standardized Response Means (SRM), Effect Sizes (ES) and Guyatt's responsiveness statistic were used to measure responsiveness. RESULTS: The proportion of patients reporting numbness (tingling) at baseline was 10.7% (10.0%) and 18.4% (17.8%) at last assessment. The correlation between numbness and tingling at baseline was 0.81, and at last assessment was 0.83. Patients with substantial PN reported an average of 10 points lower overall QOL, mood and worse symptom distress and 20 points lower in the BPI interference items. Patients having a ≤ 20 point worsening in PN score reported significantly worse in symptom distress and BPI worst pain, but not in POMS or overall QOL. The MID estimates were similar between numbness and tingling items but varied depending on the approach used. Responsiveness statistics indicated that the two PN assessments are sensitive and responsive instruments for cancer patients with PN. CONCLUSIONS: The two PN items for numbness and tingling were redundant. Evidence of criterion validity and responsiveness indicates that these simple measures of PN can be used successfully in cancer clinical trials.

Glycogen Synthase Kinase 3 Beta Predicts Survival in Resected Adenocarcinoma of the Pancreas.

PURPOSE: GSK3ß is a protein kinase that can suppress a number of key oncoproteins. We have previously shown in preclinical models of pancreatic ductal adenocarcinoma (PDAC) that inhibition of GSK3ß causes stabilization and nuclear translocation of ß-catenin, poor differentiation, proliferation, and resistance to radiation. The objective of this study was to determine its utility as a biomarker of clinical outcomes. EXPERIMENTAL DESIGN: Automated Quantitative Immunofluorescence Analysis (AQUA) of GSK3ß was performed on a tissue microarray with samples from 163 patients treated on RTOG 9704. On the basis of findings in an exploratory cohort, GSK3ß was analyzed as a categorical variable using its upper quartile (>Q3) as a cut point. Overall survival (OS) and disease-free survival (DFS) were estimated with the Kaplan-Meier method, and GSK3ß groupings were compared using the log-rank test. Univariable and multivariable Cox proportional hazards models were used to determine associations between GSK3ß and OS/DFS. RESULTS: The 3-year OS rates for GSK3ß≤Q3 versus GSK3ß >Q3 were 16% (95% confidence intervals; CI, 10%-23%) and 30% (95% CI, 17%-44%), respectively, P = 0.0082. The 3-year DFS rates were 9% (95% CI, 5%-15%) and 20% (95% CI, 9%-33%) respectively, P value = 0.0081. On multivariable analysis, GSK3ß was a significant predictor of OS. Patients with GSK3ß >Q3 had a 46% reduced risk of dying of pancreatic cancer (HR, 0.54; 95% CI, 0.31-0.96, P value = 0.034). The HR for DFS was 0.65 (95% CI, 0.39-1.07; P value = 0.092). CONCLUSIONS: GSK3ß expression is a strong prognosticator in PDAC, independent of other known factors such as tumor (T) stage, nodal status, surgical margins and CA19-9. Clin Cancer Res; 21(24); 5612-8. ©2015 AACR.

The Complementary Nature of Patient-Reported Outcomes and Adverse Event Reporting in Cooperative Group Oncology Clinical Trials: A Pooled Analysis (NCCTG N0591).

CONTEXT: Clinical trials use clinician-graded adverse events (AEs) and patient-reported outcomes (PROs) to describe symptoms. OBJECTIVES: The aim of the study was to examine the agreement between PROs and AEs in the clinical trial setting. METHODS: Patient-level data were pooled from seven North Central Cancer Treatment Group, two Southwest Oncology Group, and three Radiation Therapy Oncology Group lung studies that included both PROs and AE data. Ten-point changes (on a 0-100 scale) in PRO scores were considered clinically significant differences (CSDs). PRO score changes were compared to AE grade (Gr) categories (2+ yes vs. no and 3+ yes vs. no) using Wilcoxon rank-sum or two-sample t-tests between Gr categories. Incidence rates and concordance of CSD in PRO scores and AE Gr categories were compiled. Spearman correlations were computed between PRO scores and AE severity. RESULTS: PROs completed by patients (n = 1013) were the Uniscale, Lung Cancer Symptom Scale (LCSS), Functional Assessment of Cancer Therapy-Lung (FACT-L), Symptom Distress Scale, and/or Functional Living Index-Cancer. Significantly worse PRO score changes were found for the FACT-L in patients with Gr 2+ AEs. Worse scores were seen for the Uniscale for patients with Gr 2+ AEs (P = 0.07) and LCSS for patients with Gr 3+ AEs (P = 0.09). Agreement between incidence of any Gr 2+ (Gr 3+) AE and a CSD in PROs ranged from 27% to 67% (36%-61%). Correlations between PRO scores and AE severity were low: -0.06 Uniscale, -0.03 LCSS, 0.10 FACT-L, -0.11 Symptom Distress Scale, and -0.51 Functional Living Index-Cancer. CONCLUSION: These results support previous work and an a priori hypothesis that AEs and PROs measure differing aspects of the disease experience and are complementary.

Aspirin and COX-2 inhibitor use in patients with stage III colon cancer.

We conducted a prospective, observational study of aspirin and COX-2 inhibitor use and survival in stage III colon cancer patients enrolled in an adjuvant chemotherapy trial. Among 799 eligible patients, aspirin use was associated with improved recurrence-free survival (RFS) (multivariable hazard ratio [HR] = 0.51, 95% confidence interval [CI] = 0.28 to 0.95), disease-free survival (DFS) (HR = 0.68, 95% CI = 0.42 to 1.11), and overall survival (OS) (HR = 0.63, 95% CI = 0.35 to 1.12). Adjusted HRs for DFS and OS censored at five years (in an attempt to minimize misclassification from noncancer death) were 0.61 (95% CI = 0.36 to 1.04) and 0.48 (95% CI = 0.23 to 0.99). Among 843 eligible patients, those who used COX-2 inhibitors had multivariable HRs for RFS, DFS, and OS of 0.53 (95% CI = 0.27 to 1.04), 0.60 (95% CI = 0.33 to 1.08), and 0.50 (95% CI = 0.23 to 1.07), and HRs of 0.47 (95% CI = 0.24 to 0.91) and 0.26 (95% CI = 0.08 to 0.81) for DFS and OS censored at five years. Aspirin and COX-2 inhibitor use may be associated with improved outcomes in stage III colon cancer patients.

Relationship between statin use and colon cancer recurrence and survival: results from CALGB 89803.

BACKGROUND: Although preclinical and epidemiological data suggest that statins may have antineoplastic properties, the impact of statin use on patient survival after a curative resection of stage III colon cancer is unknown. METHODS: We conducted a prospective observational study of 842 patients with stage III colon cancer enrolled in a randomized adjuvant chemotherapy trial from April 1999 to May 2001 to investigate the relationship between statin use and survival. Disease-free survival (DFS), recurrence-free survival (RFS), and overall survival (OS) were investigated by Kaplan-Meier curves and log-rank tests in the overall study population and in a subset of patients stratified by KRAS mutation status (n = 394), and Cox proportional hazards regression was used to assess the simultaneous impact of confounding variables. All statistical tests were two-sided. RESULTS: Among 842 patients, 134 (15.9%) reported statin use after completing adjuvant chemotherapy. DFS among statin users and nonusers was similar (hazard ratio [HR] of cancer recurrence or death = 1.04, 95% confidence interval [CI] = 0.73 to 1.49). RFS and OS were also similar between statin users and nonusers (adjusted HR of cancer recurrence = 1.14, 95% CI = 0.77 to 1.69; adjusted HR of death = 1.15, 95% CI = 0.77 to 1.71). Survival outcomes were similar regardless of increasing duration of statin use before cancer diagnosis (P(trend) = .63, .63, and .59 for DFS, RFS, and OS, respectively). The impact of statin use did not differ by tumor KRAS mutation status, with similar DFS, RFS, and OS for statin use among mutant and wild-type subgroups (P(interaction) = .84, .67, and .98 for DFS, RFS, and OS, respectively). CONCLUSION: Statin use during and after adjuvant chemotherapy was not associated with improved DFS, RFS, or OS in patients with stage III colon cancer, regardless of KRAS mutation status.

Prophylactic tetracycline does not diminish the severity of epidermal growth factor receptor (EGFR) inhibitor-induced rash: results from the North Central Cancer Treatment Group (Supplementary N03CB).

PURPOSE: Previous studies suggest tetracycline and other antibiotics lessen the severity of epidermal growth factor receptor (EGFR) inhibitor-induced rash. This study sought to confirm such findings. METHODS: Patients starting an EGFR inhibitor were eligible for this randomized, double-blinded, placebo-controlled study and had to be rash-free. They were then randomly assigned to tetracycline 500 mg orally twice a day for 28 days versus a placebo. Rash development and severity (monthly physician assessment and weekly patient-reported questionnaires), quality of life (SKINDEX-16), and adverse events were monitored during the 4-week intervention and then for an additional 4 weeks. The primary objective was to compare the incidence of grade 2 or worse rash between study arms; 32 patients per group provided a 90% probability of detecting a 40% difference in incidence with a type I error rate of 0.05 (two-sided). RESULTS: Sixty-five patients were enrolled, and groups were balanced on baseline characteristics. During the first 4 weeks, healthcare provider-reported data found that 27 tetracycline-treated patients (82%) and 24 placebo-exposed patients (75%) developed a rash. This rash was a grade 2+ in 17 (52%) and 14 (44%), respectively (p = 0.62). Comparable grade 2+ rash rates were observed during weeks 5 through 8 as well as with patient-reported rash data throughout the study period. Quality of life was comparable across study arms, and tetracycline was well tolerated. CONCLUSION: Although previous studies suggest otherwise, this randomized, double-blinded, placebo-controlled study did not find that tetracycline lessened rash incidence or severity in patients who were taking EGFR inhibitors.

Phase II evaluation of gefitinib in patients with newly diagnosed Grade 4 astrocytoma: Mayo/North Central Cancer Treatment Group Study N0074.

PURPOSE: Amplification of the epidermal growth factor receptor (EGFR) gene represents one of the most frequent gene alterations in glioblastoma (GBM). In the current study, we evaluated gefitinib, a potent EGFR inhibitor, in the treatment of adults with newly diagnosed GBM. METHODS AND MATERIALS: Ninety-eight patients (96 evaluable) were accrued between May 18, 2001, and August 2, 2002. All were newly diagnosed GBM patients who were clinically and radiographically stable/improved after radiation treatment (enrollment within 5 weeks of radiation completion). No prior chemotherapy was permitted. EGFR amplification/mutation, as assessed by fluorescence in situ hybridization and immunohistochemistry, was not required for treatment with gefitinib but was studied when tissues were available. Gefitinib was administered at 500 mg each day; for patients receiving dexamethasone or enzyme-inducing (CYP3A4) agents, dose was escalated to a maximum of 1,000 mg QD. Treatment cycles were repeated at 4-week intervals with brain magnetic resonance imaging at 8-week intervals. RESULTS: Overall survival (OS; calculated from time of initial surgery) at 1 year (primary end point) with gefitinib was 54.2%, which was not statistically different compared with that of historical control population (48.9%, data from three previous Phase III North Central Cancer Treatment Group studies of newly diagnosed GBM patients). Progression-free survival (PFS) at 1 year post-RT (16.7%) was also not significantly different to that of historical controls (30.3%). Clinical outcome was not affected by EGFR status (amplification or vIII mutation). Fatigue (41%), rash (62%), and loose stools (58%) constituted the most frequent adverse events, the majority of these being limited to Grade 1/2. Of note, the occurrence of drug-related adverse effects, such as loose stools was associated with improved OS. CONCLUSIONS: In our evaluation of nearly 100 patients with newly diagnosed GBM, treatment with adjuvant gefitinib post-radiation was not associated with significant improvement in OS or PFS. However, patients who experienced gefitinib-associated adverse effects (rash/diarrhea) did demonstrate improved OS.

Mometasone furoate effect on acute skin toxicity in breast cancer patients receiving radiotherapy: a phase III double-blind, randomized trial from the North Central Cancer Treatment Group N06C4.

PURPOSE: A two-arm, double-blind, randomized trial was performed to evaluate the effect of 0.1% mometasone furoate (MMF) on acute skin-related toxicity in patients undergoing breast or chest wall radiotherapy. METHODS AND MATERIALS: Patients with ductal carcinoma in situ or invasive breast carcinoma who were undergoing external beam radiotherapy to the breast or chest wall were randomly assigned to apply 0.1% MMF or placebo cream daily. The primary study endpoint was the provider-assessed maximal grade of Common Terminology Criteria for Adverse Events, version 3.0, radiation dermatitis. The secondary endpoints included provider-assessed Common Terminology Criteria for Adverse Events Grade 3 or greater radiation dermatitis and adverse event monitoring. The patient-reported outcome measures included the Skindex-16, the Skin Toxicity Assessment Tool, a Symptom Experience Diary, and a quality-of-life self-assessment. An assessment was performed at baseline, weekly during radiotherapy, and for 2 weeks after radiotherapy. RESULTS: A total of 176 patients were enrolled between September 21, 2007, and December 7, 2007. The provider-assessed primary endpoint showed no difference in the mean maximum grade of radiation dermatitis by treatment arm (1.2 for MMF vs. 1.3 for placebo; p = .18). Common Terminology Criteria for Adverse Events toxicity was greater in the placebo group (p = .04), primarily from pruritus. For the patient-reported outcome measures, the maximum Skindex-16 score for the MMF group showed less itching (p = .008), less irritation (p = .01), less symptom persistence or recurrence (p = .02), and less annoyance with skin problems (p = .04). The group's maximal Skin Toxicity Assessment Tool score showed less burning sensation (p = .02) and less itching (p = .002). CONCLUSION: Patients receiving daily MMF during radiotherapy might experience reduced acute skin toxicity compared with patients receiving placebo.

Multivitamin use is not associated with cancer recurrence or survival in patients with stage III colon cancer: findings from CALGB 89803.

PURPOSE: Multivitamin use is widespread in the United States, especially among patients with cancer. However, the influence of multivitamin supplementation on cancer recurrence and death after a curative resection of colon cancer is unknown. PATIENTS AND METHODS: We conducted a prospective, observational study of 1,038 patients with stage III colon cancer enrolled in a randomized adjuvant chemotherapy trial. Patients reported on multivitamin use during and 6 months after adjuvant chemotherapy. Patients were observed until March 2009 for disease recurrence and death. To minimize bias by occult recurrence, we excluded patients who recurred or died within 90 days of their multivitamin assessment. RESULTS: Among 1,038 patients, 518 (49.9%) reported multivitamin use during adjuvant chemotherapy. Compared with nonusers, the multivariate hazard ratio (HR) for disease-free survival was 0.94 (95% CI, 0.77 to 1.15) for patients who used multivitamins. Similarly, multivitamin use during adjuvant chemotherapy was not significantly associated with recurrence-free survival (multivariate HR, 0.93; 95% CI, 0.75 to 1.15) or overall survival (multivariate HR 0.92; 95% CI, 0.74 to 1.16). Multivitamin use reported 6 months after completion of adjuvant chemotherapy was also not associated with improved patient outcome, and consistent use both during and following adjuvant therapy conferred no benefit. Neither an increasing number of tablets nor increasing duration of use before cancer diagnosis was associated with cancer recurrence or mortality. Multivitamin use also did not improve the rates of grade 3 and higher GI toxicity. CONCLUSION: Multivitamin use during and after adjuvant chemotherapy was not significantly associated with improved outcomes in patients with stage III colon cancer.

Gabapentin for the management of hot flashes in prostate cancer survivors: a longitudinal continuation Study-NCCTG Trial N00CB.

Hot flashes are a complication of androgen deprivation therapy for prostate cancer. A phase III study showed that use of low-dose gabapentin was well tolerated and moderately decreased the frequency of hot flashes due to androgen deprivation therapy when taken for 4 weeks. The current study, an open-label continuation of the randomized study, examined the efficacy and toxicity of gabapentin when taken for (an additional) 8 weeks. Patients were allowed to start, or continue, gabapentin and to titrate the dose to maximum efficacy, up to 900 mg/d. They were asked to complete a hot flash diary daily and keep weekly logs of toxicity, satisfaction with hot flash control, and quality of life. The moderate reduction in hot flash frequency and severity in the randomized phase of the study appeared to be maintained during this continuation phase. Men originally receiving the placebo or lowest dose of gabapentin (300 mg/d) had improved hot flash control relative to that at the end of the randomized phase. Minimal adverse effects were reported. These findings suggest that low-dose gabapentin is moderately efficacious for at least 12 weeks of hot flash treatment in men undergoing androgen deprivation therapy for prostate cancer and seems to be well tolerated. (NCT00028572)

Immediate versus delayed zoledronic acid for prevention of bone loss in postmenopausal women with breast cancer starting letrozole after tamoxifen-N03CC.

Postmenopausal women with breast cancer (BC) are at increased risk for bone loss. Bisphosphonates improve bone mineral density (BMD) in normal postmenopausal women. The purpose of this study was to determine if immediate treatment with zoledronic acid preserves BMD in postmenopausal women with BC starting letrozole after tamoxifen. Postmenopausal women with BC completing tamoxifen were treated with daily letrozole 2.5 mg/vitamin D 400 I.U., calcium 500 mg twice daily and were randomized to upfront or delayed zoledronic acid 4 mg every 6 months. Patients in the delayed arm were only given zoledronic acid if they developed a post-baseline BMD T score <-2.0 or had a fracture. The primary endpoint was the mean percent change in lumbar spine (LS) BMD at 1 year. About 558 women enrolled; 395 provided 1 year BMD data. The upfront arm experienced a mean change of +3.66% in LS BMD versus -1.66% for the delayed group (P < 0.001). Changes at the femoral neck/total hip were also greater for the upfront versus delayed arms (P < 0.001; P < 0.001) with differences persisting at 2 years. Patients in the delayed arm were more likely to experience a clinically meaningful 5% loss of BMD at all sites versus the upfront zoledronate group. Patients in the upfront arm were slightly more likely to report limb edema, fatigue, fever, nausea and jaw osteonecrosis(1%). Upfront zoledronic acid prevents bone loss in postmenopausal women with BC starting letrozole after tamoxifen.

Use of a lidocaine patch in the management of postsurgical neuropathic pain in patients with cancer: a phase III double-blind crossover study (N01CB).

OBJECTIVE: Current therapies often have limited efficacy and untenable side effects when used to treat persistent incisional pain following cancer-related surgery. Lidocaine patches reduce neuropathic pain from herpes zoster but their benefits for persistent cancer-related postsurgical incisional pain remain unclear. STUDY DESIGN: Multicenter, double-blind, randomized, two-period crossover trial. MATERIALS AND METHODS: Twenty-eight cancer patients with postsurgical incisional pain were randomly assigned to receive either lidocaine patches followed by placebo patches or the reverse. Each study period lasted 4 weeks. Patches were applied daily upon waking and left in place for a maximum of 18 h. The primary outcome measure, an 11-point pain intensity rating scale, was administered weekly. Secondary outcomes were administered weekly (Brief Pain Inventory-Short Form(BPI-SF), Subject Global Impression of Change) and at the end of each study period (Short Form-Magill Pain Questionnaire, Linear Analogue Self Assessment Scale, Neuropathy Pain Scale, Pain Catastrophizing Scale, Profile of Mood States Short Form). RESULTS: Twenty-one patients completed the first period and 18 completed their crossover second phase. No significant intergroup differences were detected in pain intensity ratings. Few secondary end points were significantly different when subjects used the lidocaine versus placebo patches. BPI-SF interference scores were lower in patients using the lidocaine patch during the first study period, including several scores that achieved statistical significance, general activity (p = 0.02), work (p = 0.04), and relations with others (p = 0.02). CONCLUSION: Lidocaine patch use did not significantly reduce pain intensity ratings or the majority of related secondary end points in cancer patients with persistent incisional pain.

Tetracycline to prevent epidermal growth factor receptor inhibitor-induced skin rashes: results of a placebo-controlled trial from the North Central Cancer Treatment Group (N03CB).

BACKGROUND: Epidermal growth factor receptor (EGFR) inhibitors are effective cancer therapies, but they are reported to cause a rash in >50% of patients. In the current study, the authors examined the use of tetracycline for rash prevention. METHODS: This placebo-controlled, double-blinded trial enrolled patients who were starting cancer treatment with an EGFR inhibitor. Patients could not have had a rash at the time of enrollment. All patients were randomly assigned to receive either tetracycline at a dose of 500 mg orally twice a day for 28 days versus a placebo. Patients were monitored for rash (through monthly physician assessment and weekly patient-reported questionnaires), quality of life (using the SKINDEX-16, a skin-specific quality of life index), and adverse events. Monitoring occurred during the 4-week intervention and then for an additional 4 weeks. The primary objective of the current study was to compare the incidence of rash between the study arms, and the enrollment of 30 patients per arm provided a 90% probability of detecting a 40% difference in incidence with a P value of .05 (2-sided). RESULTS: A total of 61 evaluable patients were enrolled. The 2 treatment arms were well balanced with regard to baseline characteristics, dropout rates, and rates of discontinuation of the EGFR inhibitor. The incidence of rash was found to be comparable across treatment arms. Physicians reported that 16 patients treated with tetracycline (70%) and 22 patients treated with placebo (76%) developed a rash (P = .61). Tetracycline appears to have lessened the rash severity, although the high dropout rates invite caution when interpreting these findings. By Week 4, physician-reported grade 2 rash (using the National Cancer Institute's Common Terminology Criteria for Adverse Events [version 3.0]) occurred in 17% of tetracycline-treated patients (n = 4 patients) and in 55% of placebo-exposed patients (n = 16 patients) (P = .04). Patients treated with tetracycline reported better scores, as per the SKINDEX-16, on certain quality-of-life parameters such as skin burning or stinging, skin irritation, and being bothered by the persistence/recurrence of a skin condition. Adverse events were found to be comparable across treatment arms. CONCLUSIONS: In the current study, tetracycline was not found to prevent EGFR inhibitor-induced rashes and therefore cannot be clinically recommended for this purpose. However, preliminary observations of diminished rash severity and improved quality of life suggest this antibiotic merits further study.

Validation of single-item linear analog scale assessment of quality of life in neuro-oncology patients.

Assessment of patient quality of life (QOL) requires balancing the details provided by multi-item assessments with the reduced burden of single-item assessments. In this project, we investigated the psychometric properties of single-item Linear Analog Scale Assessments (LASAs) for patients with newly diagnosed high-grade gliomas. Measures included QOL LASAs (overall, physical, emotional, spiritual, intellectual), Symptom Distress Scale (SDS), Profile of Mood States (POMS; overall, confusion, fatigue), and Functional Assessment of Cancer Therapy-Brain (FACT-Br; overall, brain, physical, emotional). Associations of LASA measures with SDS, POMS, and FACT-Br domains and with Eastern Cooperative Oncology Group performance score (PS) and Mini-Mental State Examination (MMSE) were assessed. Repeated measures ANOVA models compared the change over time of LASAs and SDS, POMS, and FACT-Br. Two hundred five patients completed the assessments across three time points. To allow comparison across measures, all scores were converted to a scale of 0-100, with higher scores indicating better QOL. LASA mean scores ranged from 60 to 78; SDS, POMS, and FACT-Br ranged from 62 to 81. FACT-Br physical (P<0.001) and POMS fatigue subscale (P=0.005) decreased over time, as did LASA physical (P=0.08). LASA scales were strongly associated with corresponding scales on SDS, POMS, and FACT-Br (0.44

Gemcitabine, cisplatin, and radiotherapy for patients with locally advanced pancreatic adenocarcinoma: results of the North Central Cancer Treatment Group Phase II Study N9942.

PURPOSE: A phase II study was conducted to determine the efficacy and toxicity of radiotherapy with concomitant gemcitabine and cisplatin for patients with locally advanced pancreatic adenocarcinoma. PATIENTS AND METHODS: Forty-eight patients with locally advanced pancreatic adenocarcinoma received gemcitabine (30 mg/m2) and cisplatin (10 mg/m2) twice weekly during the first 3 weeks of radiotherapy. The radiation dose to the primary tumor and regional nodes was 45 Gy in 25 fractions, and the gross tumor volume received an additional 5.4 Gy in three fractions. Four weeks after radiotherapy, patients received gemcitabine (1,000 mg/m2) once weekly every 3 of 4 weeks for a 12-week period. The primary end point was survival at 12 months. Secondary end points were time to progression, toxicity, and quality of life. RESULTS: Survival at 1 year was 40% for 47 eligible patients. The median survival was 10.2 months. Confirmed responses were observed for 8.5% (two partial, two complete), and median time to progression was 7.3 months. Grade 4 or higher toxicity was observed for 31% and consisted primarily of hematologic and GI toxicity. There was a trend toward improved overall quality of life, measured by the Symptom Distress Scale (P = .06), with significant improvements in domains of insomnia, pain, and outlook. CONCLUSION: The combination of radiotherapy, gemcitabine, and cisplatin was well tolerated. Survival results were similar to those achieved with other treatment regimens for patients with locally advanced pancreatic cancer but did not meet our predefined criteria for additional evaluation of this regimen.

A pooled analysis of quality of life measures and adverse events data in north central cancer treatment group lung cancer clinical trials.

BACKGROUND: In this pooled analysis, the authors examined correlations between single-item and multiple-item quality of life (QOL) measures and assessed the agreement between clinically significant changes in QOL and patient-reported adverse events (AE). METHODS: Data from 6 lung cancer clinical trials that involved 358 patients were pooled. All trials incorporated the Uniscale and 1 of 3 multiple-item assessments: the Functional Assessment for Cancer Therapy-Lung, the Lung Cancer Symptom Scale, or the Symptom Distress Scale. Spearman rank correlations and a Bland-Altman approach were used to assess agreement. Time-to-event analysis was performed using the Kaplan-Meier method. RESULTS: Correlations between the Uniscale and multiple-item assessments were substantial (correlation coefficient = 0.49-0.66). At least 1 10-point decline was reported in the Uniscale and multiple-item assessments by 58% of patients and 39% of patients, respectively. At least 1 severe AE (grade >or=3) was reported in 35% of patients postbaseline. The percent agreement between experiencing a severe AE and a decline in QOL was 48% and 59% for the Uniscale and multiple-item assessments, respectively. The median time to the first 10-point decline in QOL for the Uniscale and multiple-item assessments was 67 days and 142 days, respectively, and the median time to the first occurrence of a severe AE was 304 days. CONCLUSIONS: Information gleaned from the single-item Uniscale assessment was comparable to that gleaned from multiple-item global measures. There was moderate agreement between QOL and AE. A 10-point decline in QOL occurred earlier than Common Toxicity Criteria AE reporting. This suggests the need for inclusion of a QOL instrument in lung cancer clinical trials.

Detrimental effects of tumor progression on cognitive function of patients with high-grade glioma.

PURPOSE: There is growing recognition that the primary cause of cognitive deficits in adult patients with primary brain tumors is the tumor itself and more significantly, tumor progression. To assess the cognitive performance of high-grade glioma patients, prospectively collected cognitive performance data were analyzed. PATIENTS AND METHODS: We studied 1,244 high-grade brain tumor patients entered onto eight consecutive North Central Cancer Treatment Group treatment trials that used radiation and nitrosourea-based chemotherapy. Imaging studies and Folstein Mini-Mental State Examination (MMSE) scores recorded at baseline, 6, 12, 18, and 24 months were analyzed to assess tumor status and cognitive function over time. RESULTS: The proportion of patients without tumor progression who experienced clinically significant cognitive deterioration compared with baseline was stable at 6, 12, 18, and 24 months (18%, 16%, 14%, and 13%, respectively). In patients without radiographic evidence of progression, clinically significant deterioration in MMSE scores was a strong predictor of a more rapid time to tumor progression and death. At evaluations preceding interval radiographic evidence of progression, there was significant deterioration in MMSE scores for patients who were to experience progression, whereas the scores remained stable for the patients who did not have tumor progression. CONCLUSION: The proportion of high-grade glioma patients with cognitive deterioration over time is stable, most consistent with the constant pressure of tumor progression over time. Although other factors may contribute to cognitive decline, the predominant cause of cognitive decline seems to be subclinical tumor progression that precedes radiographic changes.

Low-molecular-weight heparin in patients with advanced cancer: a phase 3 clinical trial.

OBJECTIVE: To prospectively assess whether low-molecular-weight heparin (LMWH) provides a survival benefit in patients with advanced cancer. PATIENTS AND METHODS: Between December 1998 and June 2001, we performed a randomized controlled study of patients with advanced cancer. Initially, the study was double blinded and placebo controlled, with the patients receiving daily injections of 5000 U of LMWH or saline. However, because of low accrual midway through the study, the placebo injection arm was eliminated, and the study became open labeled, with patients receiving either LMWH injections plus standard clinical care or standard clinical care alone. The primary study end point was overall survival. RESULTS: Of 141 patients randomized to this clinical trial, 3 dropped out, leaving 138 patients. The median survival time was 10.5 months (95% confidence interval, 7.6-12.2 months) for the combined standard care and placebo groups. The median survival time for the combined LMWH arms was 7.3 months (95% confidence interval, 4.8-12.2 months). These median survival times were not significantly different (log-rank P = .46). The median survival times for the blinded and unblinded LMWH groups were 6.2 months and 9.0 months, respectively. The median survival times were 10.3 months for the blinded placebo arm and 10.5 months for the standard care arm. The rate of severe or life-threatening venous thromboembolism was 6% in the LMWH arms and 7% in the control arms. The rate of severe or life-threatening bleeding was 3% in the LMWH arms and 7% in the control arms.

Results of a Phase I trial of concurrent chemotherapy and escalating doses of radiation for unresectable non-small-cell lung cancer.

PURPOSE: This trial was performed to determine the maximum tolerated dose (MTD) of radiation that can be administered with carboplatin and paclitaxel. METHODS AND MATERIALS: This trial included 15 patients with unresectable non-small-cell lung cancer. Paclitaxel (50 mg/m2) and carboplatin (area under the curve=2) were given weekly during radiation therapy (RT). The RT included 2 Gy daily to an initial dose of 70 Gy, and the dose was increased in 4 Gy increments until determining the MTD. The MTD was defined as the highest safely tolerated dose where at most 1 patient of 6 experienced dose-limiting toxicity (DLT) with the next higher dose having at least 2 of 6 patients experiencing DLT. Three-dimensional treatment planning techniques were used without prophylactic nodal RT. RESULTS: Two patients were not evaluable because they did not receive therapy according to the protocol. No DLTs occurred in the 3 patients who received 70 Gy, 1 DLT occurred in the 6 patients who received 74 Gy, and 2 DLTs occurred in the 4 patients who received 78 Gy. The DLTs included Grade 3 pneumonitis (n=2) and Grade 4 pneumonitis (n=1). There have been 3 deaths during follow-up ranging from 14 to 38 months (median, 28 months). CONCLUSIONS: The MTD of the RT was 74 Gy with weekly carboplatin and paclitaxel. The Phase II portion of this trial is currently under way. The goal is to improve local control and survival with higher doses of RT delivered with this combined modality approach.

Phase III study of two different dosing schedules of erythropoietin in anemic patients with cancer.

PURPOSE: To compare maintenance epoetin alfa administered once every 3 weeks with continued weekly epoetin alfa for patients with cancer-associated anemia. PATIENTS AND METHODS: Eligible patients were randomly assigned at enrollment to receive three weekly doses of epoetin alfa 40,000 U subcutaneously (SC), followed by either standard weekly epoetin alfa (40K arm) or 120,000 U of epoetin alfa (120K arm) SC every 3 weeks for 18 additional weeks. RESULTS: Three hundred sixty-five patients were enrolled. One hundred eighty-three patients were assigned to the 40K arm, and 182 were assigned to the 120K arm. There was no difference in the proportion of patients requiring transfusions during the study (23% in 40K arm and 18% in 120K arm, P = .22) or specifically during the maintenance phase (13% in 40K arm v 15% in 120K arm, P = .58). Patients randomly assigned to the 40K arm were more likely to have a > or = 2 or > or = 3 g/dL hemoglobin (Hb) increment, were more likely to have a drug dose held because of high Hb, and had higher mean end-of-study Hb levels. Toxicities, including thromboembolism, and overall survival were similar. Patients in the 40K arm had a higher global quality of life (QOL) at baseline for unclear reasons, whereas patients in the 120K arm had a greater global QOL improvement during the study, so end-of-study QOL was equivalent. CONCLUSION: After three weekly doses of epoetin alfa 40,000 U, a dose of 120,000 U can be administered safely once every 3 weeks without increasing transfusion needs or sacrificing QOL. The Hb increment is somewhat greater with continued weekly epoetin alfa. Lack of blinding as a result of different treatment schedules may have confounded results.