Sarah R. Haile

Background: The purpose of this study was to evaluate the impact of 2-[fluorine-18]fluoro-2-deoxy-D-glucose–positron emission tomography/computed tomography (FDG-PET/CT) during follow-up of patients with diffuse large B-cell lymphoma (DLBCL) being in complete remission or unconfirmed complete remission after first-line therapy. Patients and methods: DLBCL patients receiving FDG-PET/CT during follow-up were analyzed retrospectively. Confirmatory biopsy was mandatory in cases of suspected disease recurrence. Results: Seventy-five patients were analyzed and 23 (30%) had disease recurrence. The positive predictive value (PPV) of FDG-PET/CT was 0.85. Patients >60 years [P = 0.036, hazard ratio (HR) = 3.82, 95% confidence interval (CI) 1.02-7.77] and patients with symptoms indicative of a relapse (P = 0.015; HR = 4.1; 95% CI 1.20-14.03) had a significantly higher risk for relapse. A risk score on the basis of signs of relapse, age >60 years, or a combination of these factors identified patients at high risk for recurrence (P = 0.041). Conclusions: FDG-PET/CT detects recurrent DLBCL after first-line therapy with high PPV. However, it should not be used routinely and if only in selected high-risk patients to reduce radiation burden and costs. On the basis of our retrospective data, FDG-PET/CT during follow-up is indicated for patients <60 years with clinical signs of relapse and in patients >60 years with and without clinical signs of relapse.

Preclinical data indicated a detrimental effect of statins on the anti-lymphoma activity of rituximab. We evaluated the impact of concomitant statin medication on the response and survival of patients with diffuse large B cell lymphoma (DLBCL) receiving rituximab-cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) as first-line therapy. Medical histories of patients with DLBCL who were treated with R-CHOP as first-line therapy were assessed for concomitant statin use, response after completion of chemotherapy, event-free survival (EFS), and overall survival (OS). Furthermore, 2-[(18)F]fluor-2-deoxyglucose (FDG)-PET/CT results after completion of first-line therapy were compared between the groups. Overall, 145 patients with DLBCL treated with R-CHOP from January 2001 to December 2009 were analyzed. Twenty-one (15 was 67.3 receiving statins during R-CHOP (HR, 0.47; 95 p = 0.2). Five-year OS was 81.4 with 93.3 p = 0.6). There were no statistically significant differences in the rates of complete remissions between the two groups (75 non-statin group versus 86 toward a lower rate of complete metabolic responses in FDG-PET/CT after chemotherapy was seen in patients without statin medication compared with the patients taking statins (84 Concomitant statin use had no adverse impact on response to chemotherapy, EFS, and OS in patients treated with R-CHOP for DLBCL.

Intravenous immunoglobulin (IVIG) is used for many indications beyond the original substitution in primary antibody deficiency. Whereas many reports mention adverse reactions, no comparative data exist concerning the incidence of side-effects among the different brands of IVIG. We describe here our experience with the use of different IVIG formulations and their tolerability in a select cohort of 40 patients. The IVIG dose ranged from 0.4 to 3 g/kg/day and was given for 1–2742 days. Fourteen patients (35%) experienced mild to severe adverse reactions during or within 48 h of administration of standard IVIG preparation, which did not recur after switching to an alternative preparation. Adverse reactions included headache, fever, chills, nausea, emesis, hypotension and muscle cramps. One patient experienced a severe adverse reaction; he had a 3-day headache following IVIG infusion. Among the 16 patients who received alternative preparation initially, none experienced adverse reactions. In conclusion, this study shows that IVIG preparations are not all equally well tolerated in patients. The data suggest that, perhaps to a comparable extent to the preparation itself, the infusion rate has a major effect. If a reduction in the infusion rate does not minimize sideeffects, one should consider switching the IVIG formulation.

Keywords: intravenous immunoglobulin; adverse drug reaction; prevention; toxic epidermal necrolysis; hypogammaglobulinaemia; lung transplantation.

To reduce the duration of neutropenia after conditioning chemotherapy and autologous peripheral blood stem cell transplantation (APBSCT), granulocyte-colony stimulating factors (G-CSF) are commonly administered. We retrospectively evaluated the impact of pegfilgrastim compared to filgrastim on neutrophil engraftment, hospital stay, and supportive measures in patients with multiple myeloma after conditioning with Melphalan 200 (Mel200) followed by APBSCT. Ninety-two APBSCT after Mel200 treatment were performed in 72 patients between January 2006 and December 2009 at our institution. Patients received either single-dose pegfilgrastim (n=46; 50%), or daily filgrastim (n=46; 50%) after APBSCT (median duration of filgrastim use, 9 days; range, 3-14 days). Duration of neutropenia grade IV was shorter with pegfilgrastim compared with filgrastim (median, 5 days (range, 3-14 days) versus 6 days (range, 3-9 days), p=0.0079). The length of hospitalization differed significantly (pegfilgrastim (median, 14.5 days; range, 11-47 days) versus filgrastim (median, 15.5 days; range, 12-64 days), p=0.024). Pegfilgrastim treated patients had less red blood cell transfusions (median, 0 transfusions (range, 0-10 versus 0.5 transfusions (range, 0-9), p=0.00065). Pegfilgrastim was associated with reduced cost of the treatment procedure compared with filgrastim (p= 0.031). Pegfilgrastim appears to be at least equivalent to filgrastim without additional expenditure in myeloma patients treated with Mel200 and APBSCT.

Keywords: APBSCT, Filgrastim, Pegfilgrastim, Engraftment, Mel200

Background: Since traditional non-steroidal anti-inflammatory drugs are associated with increased risk for acute cardiovascular events, current guidelines recommend acetaminophen as the first-line analgesic of choice on the assumption of its greater cardiovascular safety. Data from randomized clinical trials prospectively addressing cardiovascular safety of acetaminophen, however, are still lacking, in particular in patients at increased cardiovascular risk. Hence, it was the aim of this study to evaluate the safety of acetaminophen in patients with coronary artery disease. Methods and Results: 33 patients with coronary artery disease were included in this randomized, double-blind, placebo-controlled, crossover study and received acetaminophen (1g TID) on top of standard cardiovascular therapy for 2 weeks. Ambulatory blood pressure, heart rate, endothelium-dependent and -independent vasodilatation, platelet function, endothelial progenitor cells, markers of the renin-angiotensin-system, inflammation and oxidative-stress were determined at baseline and after each treatment period. Treatment with acetaminophen resulted in a significant increase of mean systolic (from 122.4±11.9 to 125.3±12.0 mmHg, p=0.007 vs placebo) and diastolic (from 73.2±6.9 to 75.4±7.9 mmHg, p=0.015 vs. BL, p=0.008 vs. placebo) ambulatory blood pressure. On the other hand, heart rate, endothelial function, early endothelial progenitor cells and platelet function did not change. Conclusions: As this study for the first time demonstrates that acetaminophen induces a significant increase in ambulatory blood pressure in patients with coronary artery disease, the use of acetaminophen should be as rigorously evaluated as traditional NSAIDs and COX-2 inhibitors, in patients at increased cardiovascular risk in particular. Trial Registration: ClinicalTrials.gov Identifier: NCT00534651

Background: NSABP B-32, a phase III randomized trial of SN resection vs SN resection followed by AD (SNAD) in early stage breast cancer, provided a unique opportunity to compare patient-reported outcomes (PROs) arm function, symptoms, and quality of life (QOL). We report the final treatment (TX) comparison of PROs. Methods: Women with operable invasive breast cancer were eligible for B-32; those whose SNs were negative were eligible for the PRO questionnaire sub-study. Symptoms, arm-related disabilities, and QOL were assessed at baseline, 1 week after surgery (post-op), 2-3 weeks post-op, and 6, 12, 18, 24, 30, 36 months (mos). The primary endpoint, a multi- item ipsilateral surgery symptom scale, was compared between TX at 6 and 12 mos using two-sided, two-sample t-tests, with Bonferroni correction. An anticipated accrual of 819 patients (pts) was calculated to yield 87 the primary comparisons. We compared each PRO item by TX with repeated measures analysis. We analyzed separately pts who received lumpectomy vs mastectomy, and accounted for breast reconstruction and dominant hand. Results: 749 pts enrolled in the PRO sub-study before B-32 completed accrual (358 SNAD, 391 SN). Arm symptoms were greater for SNAD pts (effect size 0.4, p<0.0001 at 6 mos; effect size 0.25, p=0.006 at 12 mos). Over the complete time on study, SNAD pts had more difficulty pushing large objects, lifting objects, reaching, and conducting social and work activity (p<0.001). They were more likely to avoid arm use and to experience symptoms (p=0.002 breast tenderness; p<0.001 all other items). The treatment difference persisted over time for avoidance of arm use; arm or breast tenderness or swelling; and breast pain, numbness, skin sensitivity, or tightness. Overall QOL was better among SN pts (p<0.001) and improved over time (p<0.001). In both groups, treatment was well tolerated by 6 mos: only 10 restriction of social/recreational activity, and overall QOL averaged 8 (scale 0-10). Conclusions: SN pts experienced significantly fewer symptoms and activity limitations. However, long-term levels of symptoms and limitations were low, and QOL was high, for both groups.

While nonparametric methods have been well established for inference on competing risks data, parametric methods for such data have not been developed as much. Because the cumulative incidence functions are improper by their nature, flexible distribution families accommodating improperness are needed for modeling competing data more accurately. Additionally, different types of events present in a competing risks setting may be correlated, yet current inference methods do not permit inferring such data taking into account the correlation between failure time distributions. This work first presents two new distributions which are well-suited for modeling competing risks data. In existing inference procedures for competing risks data, it appears that the correlation between failure time distributions of competing events are fixed as a constant. In the second part of this dissertation, a novel approach is proposed which allows researchers to model competing risks data by taking the correlation into account by estimating it. The methods are illustrated by analyzing survival data from a breast cancer trial of the National Surgical Adjuvant Breast and Bowel Project. Simulation studies are also presented for each of the proposed new distributions. Public Health Significance: Competing risks occur often in many clinical studies, and must be accounted for whenever researchers are interested in only one type of event. For example, researchers may be interested in investigating only local recurrences of breast cancer, but must also take into account all other possible types of events as competing. Parametric methods are not currently as well established as other methods for competing risks data. Development of flexible parametric inference procedures suitable for modeling competing risks data would provide more accurate information, which will serve to improve patient care in clinical settings.

PURPOSE: This report describes interventions undertaken by the National Surgical Adjuvant Breast and Bowel Project (NSABP) to improve compliance with patient-reported outcome (PRO) assessments in the setting of multicenter cancer clinical trials. We describe the effectiveness of several interventions and of observational factors. METHODS: PRO submission rates were analyzed for the following three NSABP protocols: the Study of Raloxifene and Tamoxifen (STAR), B-32, and B-35. Institutions participating in protocol B-35 were randomly assigned to receive automated reminders of upcoming assessments or not. Compliance was analyzed with a logistic repeated measures mixed modeling. RESULTS: Compliance was high in the three protocols, with rates greater than 80% for nearly all time points. Institutions were a significant source of variability (P < .01). The largest institutions had the highest compliance in STAR (odds ratio [OR] = 0.68 for < 50 participants enrolled and OR = 0.82 for 50 to 99 participants enrolled v larger institutions; P < .001). Midsized institutions had highest compliance in B-32 (OR = 4.63 for 31 to 50 patients enrolled and OR = 3.12 for > 50 patients enrolled v small institutions; P = .007). Compliance increased with participant age in STAR (OR = 0.57, 0.89, and 1.01 for ages < 50, 50 to 60, and 60 to 70 years, respectively, v > 70 years; P < .001). Race was significant in B-32 (OR = 2.63 for white v nonwhite; P < .001) and in STAR (OR = 1.41 for white v nonwhite; P < .001). Treatment group was significant in B-32 (OR = 0.74; P = .006). The B-35 prospective reminder did not improve compliance significantly (P = .30), but in B-32, delinquency sanctions were significant (OR = 1.56; P = .007). CONCLUSION: Compliance in NSABP PRO studies is higher now than a decade ago. Results for compliance initiatives were mixed. Age and race are important factors, but institutional variation remains significant and largely unexplained.

BACKGROUND: We sought to identify the risk of axillary node involvement in patients with ductal carcinoma in situ (DCIS) and to determine whether axillary node assessment is necessary in these patients. Sentinel node biopsy (SNB) is replacing standard axillary lymph node dissection (ALND) for surgical staging of invasive breast cancer. Its use in patients with DCIS versus local excision (LE), observation, and/or breast irradiation remains in question. METHODS: We examined the records of 813 patients with localized DCIS and disease-negative margins after LE who were randomly assigned to no further therapy or to breast irradiation in National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-17 and 1799 patients randomized to receive placebo or tamoxifen after LE + radiotherapy in NSABP trial B-24. An ALND was performed in 253 patients in NSABP B-17 and in 162 in NSABP B-24. RESULTS: We found that in NSABP trial B-17, seven patients developed ipsilateral nodal recurrence (INR). Overall INR rate was 0.83/1000 patient-years. In NSABP B-24, overall INR rate was 0.36/1000 patient-years. INR can be considered a surrogate for axillary involvement at the time of DCIS diagnosis. CONCLUSIONS: INR in patients with DCIS treated conservatively is extremely rare. Our findings do not support the routine use of SNB in patients with conservatively treated, localized DCIS.

Background: The 3-year results of NSABP protocol C-03 published in 1993 (Wolmark, et al J Clin Oncol 11:1879-87, 1993) indicated significant improvement in DFS and OS for patients (pts) with stage II or III colon cancer treated with postoperative FL compared to pts treated with lomustine (MeCCNU), vincristine, and 5-FU (MOF). The present analysis reports long-term results. Methods: Pts with stage II or III (Dukes’ B or C) colon cancer who had undergone a potentially curative surgical resection were randomized postoperatively to receive adjuvant chemotherapy with either MOF or FL (given on the “Roswell Park schedule”) for approximately 1 year. Results: 1081 pts (1044 eligible-96.6 pts 986 (94.4 and 1022 (97.9 estimates, relative risks from a stratified Cox model, and stratified logrank p values (stratified for gender, # positive nodes [0, 1-4, 5+], and tumor location [right colon, non-right], as specified in the protocol) for DFS and OS are shown below. Tests for interactions of the stratification variables (gender, # positive nodes, and tumor location) with treatment were not significant (p>0.16). Conclusions: The 10-year results of NSABP C-03 confirm and extend the previously published analysis, and indicate a highly significant and clinically relevant improvement in DFS and OS for pts with stage II or III colon cancer treated with FL compared to MOF. These data serve as a standard for evaluation of new adjuvant regimens.