bluuebunny/crossref_metadata_2025 huggingface dataset:
A new design of clinical trial – use of nomograms – illustration with local treatment of T2 tumors in the SEER database.
Authors: Rouzier R , Lesieur B , Coutant C , Uzan S
Published: December 2010

Abstract #4079

Background: Nomograms are more and more used as models in which known prognostic factors are combined and used to predict individuals outcomes. Their use as pivotal tools for conducting clinical trial without randomizing treatment allocation has never been reported. We sought to investigate if the use of a nomogram could mimic a randomized trial. In this report, we designed a study based on the use of nomograms to investigate the prognosis of patients with tumors measuring 2.1 to 5 cm according to local treatment.  Methods: The SEER registry provided data from 17 registries. A survival difference is observed according to surgical treatment (p=0.01) in this database. This difference may account for patient and tumor characteristics leading to the choice of local treatment and not to the local treatment itself. To investigate this hypothesis, we developed a nomogram to predict cause-specific survival in patients with T2 tumors treated with breast conservation therapy (BCT). To provide a more flexible model, we represented continuous variables using restricted cubic splines. We then applied this nomogram to patients treated with mastectomy. In this particular application, a nomogram can provide individual predictions of cause-specific survival taking into account several variables and their interaction. Patients treated with mastectomy were then grouped in deciles and predicted survivals for these subgroups were plotted against observed proportions of patients alive (calibration curve).  Results: The study population comprised 128,454 patients. The nomogram for predicting cause-specific survival included number of metastatic nodes, tumor size, age, grade, estrogen receptor status of the tumor, and use of radiation. This nomogram was perfectly well calibrated in an internal validation (bootstrap). In patients treated with mastectomy, the calibration curve was almost perfect with a maximal difference of 0.6% between predicted probabilities and observed proportions (figure). Discrimination was very good (area under the ROC curve = 0.73). This result suggests that the apparent survival difference between T2 patients treated with breast conservation and those treated with mastectomy in the SEER database, is related to tumor characteristics leading to the choice of local treatment and not to the local treatment itself.  Conclusion: Nomograms may be useful to test a new treatment or therapeutic strategy without randomization. They can provide theoretical individualized outcome with a reference treatment (taking into account multiple variables, and interaction) for patients receiving an alternative treatment. Any difference between predicted probability and observed proportion reflects that alternative treatment modifies outcome.   

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4079.
Urinary estrogen metabolites in patients at high risk for breast cancer.
Authors: Im A , Vogel V , Ahrendt G , Lloyd S , Garte S , Ragin C , Taioli E
Published: December 2010

Abstract #4080

Background:  Variations in estrogen metabolism may be associated with increased breast cancer risk. Women who have preferential metabolism via 16α-hydroxylation are reported to have a higher risk of developing breast cancer compared to women who have preferential metabolism via 2α-hydroxylation. Profiling estrogen metabolites may identify women who are more likely to develop breast cancer within a population of women with known risk factors. Our aim was to evaluate estrogen metabolism in a group of high risk women.  Methods:  Women were recruited from the Magee-Women's Hospital High Risk Breast Cancer program. Risk factors included first degree family history, atypia, fibrocystic breast disease, BRCA1/2, Ashkenazi Jewish descent. Urine 2:16 OHE ratios were compared among the high risk group, an average risk control group, and a group of women with breast cancer. We also evaluated the relationship between urine 2:16 OHE ratios and epidemiological risk factors including BMI, alcohol use, smoking history and first degree family history.  Results:  There were 65 high risk patients, 30 breast cancer patients, and 41 controls. The Kruskaul-Wallis rank test and Wilcoxon rank-sum test were used for analysis. There was a significant difference in 2:16 OHE ratios among all three groups, p=0.0001. Urine 2:16 OHE ratios were lower in the high risk group (median 1.15) compared to the control group (2.22), p=0.00, and were lower in the breast cancer group (1.09) compared to the controls, p=0.00. There was a difference in BMI among all three groups, p=0.002. Overall, the 2:16 OHE ratio was positively associated with BMI, p=0.0006, and with alcohol use, p=0.02. Smoking history did not differ among all groups, and there was no association between smoking history and 2:16 OHE ratio. Within the high risk group, family history was not associated with 2:16 OHE ratio.  Conclusions:  Our research suggests that there is an association between lower urine 2:16 OHE ratios and high risk breast cancer. This association may be linked to specific risk factors such as BMI and alcohol use. This information may help to further elucidate the clinical relevance of using urinary 2:16 OHE ratios as clinical markers and prognostic indicators in this population.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4080.
Mammographic density and breast cancer risk in Chinese women.
Authors: Gao J , Zhao W , Lian R , Liang X
Published: December 2010

Abstract #4081

Introduction: Mammographic density has been widely accepted as an important breast cancer risk factor. Women with high mammographic density are believed to have an elevated risk of breast cancer. However, no such association has been shown in native Chinese women so far. We carried out a matched case-control study to evaluate the relationship between mammographic density and the risk of breast cancer among Chinese women in a province of Northern China.  Method: Cases included 220 women histologically confirmed with breast cancer at a cancer hospital in Northern China between 2005 and 2007. Each case was matched to a control subject with the similar age (within two years old) who attended the same hospital in the same year and diagnosed as benign breast disease or normal breast. Mammograms were the films used for diagnosis. Breast density was evaluated according to Wolf parenchyma patterns through digitalized normal Medio-Lateral Oblique (MLO) mammography view without knowledge of diagnosis. Risk factor information was obtained from archival database of patient-provided information.  Results: Compared to women with low-risk (N1 and P1) mammographic parenchymal patterns, those with high-risk patterns (P2 and DY) had an increased risk of breast cancer (odds ratio = 1.9; 95% confidence interval: 1.1 - 3.2) after adjustment for body mass index, age at menarche, and number of full-term pregnancies. There was no statistically significant difference in this association between premenopausal and postmenopausal women.  Conclusion: These results indicate that high mammographic density is associated with the risk of breast cancer in native Chinese women. A larger scale study with the validated computer-assisted mammographic density measurement method is being carried out to further confirm this association.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4081.
Mammographic density and breast cancer risk factors in Chinese women.
Authors: Gao J , Zhao W , Lian R , Liang X
Published: December 2010

Abstract #4082

Background: Past studies have indicated that mammographic density is associated with not only breast cancer risk but also breast cancer risk factors in women living in western nations. However, to data, no such association has been shown among native Chinese women. The aim of this cross-sectional study was to investigate the effects of age, body mass index (BMI), age at menarche, parity, and menopausal status on mammographic patterns in women from a province of Northern China.  Methods: Seven hundred and two women's mammograms and information of the breast cancer risk factors were obtained from Shanxi province cancer hospital in Northern China. Mammograms were assessed according to the Wolfe classification.  Results: Age, BMI, parity, and menopause were inversely and independently related to high-risk mammographic parenchymal patterns. However, there was no statistically significant association between age at menarche and high mammographic density. Relative to subjects aged less than or equal to 35 years, subjects aged greater than 55 years had reduced 62% (OR = 0.38, 95% CI: 0.14 – 1.00) odds of having a high-risk pattern. In comparison to women whose BMI was less than or equal to 25, there was a 51% and 72% reduction in the odds of having high-risk mammographic patterns for those with BMI 25 to 30 and larger than or equal to 30 respectively (OR = 0.49, 95% CI: 0.32 - 0.74; OR = 0.28, 95% CI: 0.12 - 0.68 respectively). Women with more than three children had decreased 68% risk to have high mammographic density compared to those who were nulliparous (OR = 0.32, 95% CI: 0.1 – 1.0). Premenopausal women were more than four times likely to have a high-risk pattern than postmenopausal women (OR = 4.12, 95% CI: 2.17 – 7.87).  Conclusion: Our findings demonstrated that mammographic parenchymal patterns are also associated with some risk factors of breast cancer in native Chinese women. This is consistent with most studies carried out in Western countries. Further studies are needed to determine the relationship between quantitative percentage density and breast cancer risk factors.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4082.
Seroma formation after breast cancer surgery and its risk factors.
Authors: Lin Y , Yin W , Zhou L , Lu J , Di G , Wu J , Shen Z , Shao Z
Published: December 2010

Abstract #4085

Background:. Seroma formation is one of the most common complications after breast cancer surgery including modified radical mastectomy and breast conservative surgery. Our study aims to investigate the risk factors of postoperative seroma in Chinese breast cancer patients.  Methods: Clinical data of 158 women who underwent surgerical therapy for breast cancer in our hospital were collected prospectively and all patients were followed up. The risk factors for seroma occurrence were compared between the seroma group and control group using X 2 test or t test, as well as the logistic regression was used as multivariate analysis.  Results: Univariate analysis showed that the average age of the seroma group was significantly higher than those without seroma formation(58.71vs51.00, P=0.0019), but the total serum protein and albumin content were lower (68.47g/L vs 72.53g/L, P=0.009 and 40.75g/L vs 42.52g/L,P=0.020, respectively). In seroma group, the drainage volume of the first three days, the total and daily drainage volume were all higher (all p values less than 0.01), as well as drainage duration and hospital stay were longer(8.3d vs 14.4d, P=0.000 and 11.5d vs 23.7d, P=0.000, respectively). Logistic regression showed that older patients (OR=1.080, 95%CI 1.016∼1.148, P=0.013), lower total serum protein content(OR=0.814, 95%CI 0.705∼0.940, P=0.005)and higher drainage volume in d1(OR=1.009, 95%CI 1.001∼1.016, P=0.022) and d3 (OR=1.017, 95%CI 1.005∼1.029, P=0.005) were all independent risk factors for subcutaneous seroma. The daily average drainage curve showed a gradually decreasing trend with a highest collections in the first three days. The seroma group had significantly higher average daily drainage volume( P=0.034) and longer duration (P=0.000).  Conclusion:The risk factors of seroma formation after breast cancer surgery are complicated. However in order to prevent its occurrence effectively, the factors including age, nutrition status and daily drainage volume should be taken into consideration.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4085.
Comparison of palonosetron (PALO) plus dexamethasone on day 1, with or without dexamethasone on days 2 and 3, in the prevention of chemotherapy induced nausea and vomiting (CINV) in breast cancer patients treated with anthracycline/cyclophosphamide regimens.
Authors: Fabi A , Nole' F , Roila F , Medici M , Steger G , Bachmann C , Roncoroni S , Ballinari G
Published: December 2010

Abstract #4088

BACKGROUND PALO is a selective and potent serotonin antagonist, with a pharmacologically different structure and binding affinity compared to older 5-HT3 receptors antagonists. Multiple studies with PALO have demonstrated better efficacy in preventing emesis throughout the 5 days after moderately and highly emetogenic chemotherapy (CT) compared to ondansetron, dolasetron or granisetron.  METHODS This was a phase 4, double-blind, randomized, multicenter, parallel study, in 300 CT naïve patients with breast cancer receiving cyclophosphamide <1500 mg/m2 or anthracycline (epirubicin or doxorubicin) alone or in combination. The study aimed to determine whether the efficacy during the 0-120 hr (overall) period after CT, of a PALO single-dose 0.25mg IV administered 30 minutes before CT plus dexamethasone 8 mg IV approximately 1 hr before CT on day 1 (PALO/DEX/Placebo), was non-inferior to the same day 1 regimen followed by DEX 4 mg orally twice daily on days 2 and 3 (PALO/DEX/DEX). The primary endpoint was complete response (CR), defined as no emesis and no rescue therapy, in the overall phase. Emesis, nausea, use of rescue antiemetics, and functional impact were secondary endpoints. Adverse events (AEs) were documented to monitor safety.  RESULTS This study showed non-inferiority in CR rates between the two groups in the overall phase, and in the acute and delayed phases (Table I).    There were no significant differences between groups for no emesis and no nausea rates. Rates of AEs were similar in the two groups, with no serious drug-related AEs reported.  CONCLUSIONS The comparable results between the two groups support the efficacy of PALO plus DEX administration on day 1 only, with no benefit shown for additional doses of dexamethasone.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4088.
A quality-adjusted time without symptoms or toxicity (Q-TWiST) analysis comparing lapatinib plus paclitaxel versus paclitaxel alone for first line metastatic breast cancer (MBC) in HER2+ patients.
Authors: Sherrill B , Dileo A , Amonkar M , Koehler M , Arbushites M
Published: December 2010

Abstract #4090

Background: Women with MBC received first line treatment with lapatinib and paclitaxel (L+P) or paclitaxel alone (P) in a phase III randomized, multicenter, double-blind, placebo-controlled study. In a sub-group analysis of HER2+ (ErbB2+) patients, time to tumor progression for L+P was significantly improved, with an emerging trend for survival benefit. The Q-TWiST method was used to examine overall quality-of-life adjusted survival experience comparing the trade-off between treatment toxicities and delayed progression in a subset of the randomized ITT population that overexpressed HER2.  Methods: Survival curves for each treatment arm were partitioned into 3 health states: TOX (toxicity) - time with grade 3/4 adverse events (AEs) during progression-free survival time; TWiST (time without toxicity or disease progression) - remaining time prior to progression in which no serious AEs were experienced; REL (relapse) - time until death or end of follow-up following disease progression. The utility-weighted sum of the mean health state durations was derived to calculate a Q-TWiST score and treatment comparisons were made at varying combinations of the utility weights using a threshold utility analysis.  Results: The ITT population included 579 subjects ages 23-87 of which 91 were HER2+ (n = 52 L+P, n = 39 P) based on FISH+ or IHC3+ irrespective of FISH (86 patients based on FISH+ or IHC3+ if FISH unknown; n = 49 L+P, n = 37 P). Overall median survival was 96 weeks after randomization based on data through 5FEB07. For the 91 patient cohort, using utility weights of 0.5 for both TOX and REL, i.e. counting 2 days of TOX or REL as 1 day of TWiST, resulted in a 9.4 week difference (p = 0.0459) in quality-adjusted survival favoring L+P. For the 86 patient cohort the difference was 8.5 weeks still favoring L+P (p = 0.1005). Q-TWiST differences between the arms (for 91 patient cohort) ranged from 5-13 weeks across utility weight combinations, with most tests providing a statistically significant advantage of L+P over P alone. Results from the sensitivity analysis using all grade AEs in the TOX state gave similar results.  Conclusions: Among HER2+ patients, treatment with L+P resulted in more quality-adjusted survival than with P monotherapy. When utilities for periods of toxicity and relapse were valued at half the utility of TWiST, the Q-TWIST difference was around 9 weeks, approximately 10% of the 96 weeks median overall survival. These findings represent clinically important differences between treatment groups in quality-adjusted survival.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4090.
Response vs. nonresponse to treatment with erythropoiesis stimulating agents among breast cancer patients with anemia: findings from the European anemia cancer treatment study.
Authors: Aapro M , Ludwig H , Bokemeyer C , Soubeyran P , MacDonald K , Albrecht T , Abraham I
Published: December 2010

Abstract #4095

Background. More cancer patients (pts) with anemia are being treated with erythropoiesis stimulating agents (ESA) in Europe than 7 years ago, but treatment response patterns remain poorly documented. The use of ESAs in breast cancer (BCA) is under debate and knowledge about response rates may benefit clinical risk-benefit analysis. We conducted a subgroup analysis of the A.C.T. study to estimate the proportions of responders vs. nonresponders to ESA treatment (Rx) among breast cancer pts with anemia (Hb≤11g/dL) using five commonly used measures of treatment response.  Methods. Multicenter, longitudinal retrospective study with at least 3 time points at approximately 1 month intervals, with visit 1 coinciding with start of ESA Rx. 148 centers in 12 European countries contributed 415 BCA pts who were on chemotherapy, anemic, and treated with an ESA (18.9% of total study sample). Patient demographics, clinical status, treatment patterns, and hemoglobin (Hb) and performance outcomes are reported by Aapro et al. (2008 SABCS). Five measures of treatment response were estimated: Hb rise ≥1g/dL, Hb rise ≥1g/dL within 8 weeks, hematopoietic response (Hb rise ≥2g/dL or Hb≥12g/dL achieved), Hb rise ≥2g/dL, and Hb target range of 12.0-12.9g/dL achieved by visit 3.  Results. Types of ESA prescribed included epoetin alfa (22.9%), epoetin beta (39.3%), darbepoetin (37.6%), and other (0.2%) at a median standardized dose of 30000 IU/wk. 33.0% of patients received iron supplementation; of these 11.9% received IV iron. Mean Hb increased from 9.9±0.8g/dL to 11.1±1.3g/dL from visits 1 to 3, indicating a positive treatment response across all patients. Table 1 presents the percentages of responders versus nonresponders according to the 5 measures.    Conclusions. An increase in Hb of ≥1g/dL over the course of treatment is an attainable goal in approximately three-quarters of BCA pts with anemia. Adding time constraints, increasing the threshold level to ≥2g/dL, and/or setting an evidence-based target range of 12-12.9g/dL is associated with lower response rates. In BCA pts, the therapeutic Hb goal to be achieved may need to be determined under consideration of multiple factors, however the general effectiveness of ESAs in this population is evident.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4095.
Functional assessment of the arm following breast cancer treatment using the DASH survey.
Authors: Jacobs LK , Kelley KA , Detrani ME , Tsangaris TN , Chang DC
Published: December 2010

Abstract #4096

Treatment of the axilla with surgery and radiation therapy (RT) has a risk of lymphedema and diminished function of the arm. The purpose of this study is to evaluate the Disability of the Arm, Shoulder and Hand survey (DASH) as a potential functional assessment tool post breast cancer treatment by comparing it to the Lymphedema and Breast Cancer Questionnaire (LBCQ), a lymphedema-specific questionnaire, the SF12, and functional arm measurements.  A series of patients presenting to the Johns Hopkins Hospital Avon Foundation Breast Center for follow-up of breast cancer were collected. Inclusion criteria are patients > eighteen years receiving either a sentinel lymph node biopsy (SLNB) or axillary node dissection (ALND) at Johns Hopkins Hospital. Exclusion criteria were individuals who reported mental illness, prior deficits of the arm, or any bilateral procedure for treatment of breast cancer. Dependent variables are the DASH, LBCQ, and SF12 scores. Independent measures are arm circumferences and range-of-motion measurements of both arms.  The study population included 41 female individuals presenting either prior to or following surgical procedures in the axilla. See Table 1 for demographics. Of those undergoing lumpectomy, 95.24% had RT, none received axillary RT, and 31.58% of the mastectomy patients had RT to the axillary basin. Subjects receiving RT (65.85%) either had whole breast RT (74.07%) or axillary RT (25.93%), others received chemotherapy (53.66%), and a small percentage received herceptin (7.32%).  Internal validation of the quality of life surveys were highly correlated to each other. (Table 2). External validity was determined by comparing the quality of life surveys to the physiologic measures. The physical component of the SF-12 was significantly correlated to moderate lymphedema (p=0.019), which is defined as a difference in arm circumference of 2.0 to 3.0 cm. The patient sample included 11 patients with lymphedema, therefore the sample size was insufficient to assess the correlations between arm circumference and range of motion with the DASH and LBCQ.  The DASH, LBCQ, and SF-12 are appropriate and valid measures of post-operative quality of life in the patient population post breast cancer treatment. Further patient recruitment is necessary to adequately determine the external validity of the DASH as a measure of the quality of life of patients with lymphedema.       

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4096.
Lapatinib monotherapy in HER2+ relapsed or refractory inflammatory breast cancer (IBC): quality of life (QOL) assessment.
Authors: Kaufman B , Bachelot T , Wu Y , Amonkar M , Zaks T , Salazar V , Viens P , Johnston S
Published: December 2010

Abstract #4097

Background: IBC is a rare, clinically distinct and aggressive form of breast cancer characterized by severe pain and a poor prognosis. EGF103009 was a phase II, open-label, multicenter study that showed lapatinib monotherapy is clinically active in women with relapsed/refractory HER2+ IBC that progressed on prior therapy with anthracylines, taxanes, and trastuzumab. This analysis focuses on the impact of lapatinib on QOL and pain symptoms (endpoints added during a study amendment) in these patients.  Methods: QOL was assessed using the EORTC QLQ C-30, a 30-item instrument that assesses 15 domains consisting of 5 functional scales (physical, role, emotional, cognitive, social) and 9 symptom scales (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, financial difficulties) and a global QOL item. A high score for a functional scale/global QOL indicates a high and healthy level of functioning/QOL whereas a high score for a symptom scale indicates a high level of symptoms/problems. Pain was specifically assessed using the Brief Pain Inventory-Short Form (BPI-SF), which includes 4 severity items and 7 items assessing pain interference with general activity, mood, work, walking ability, relations, sleep, and enjoyment of life. Scoring produces 4 scores: pain severity, overall pain interference, activity-related pain interference and mood-related pain interference. Higher scores indicate greater pain severity or pain interference. Both questionnaires were completed at baseline and every 4 weeks thereafter. Mean change in scores from baseline (with 95% CI) were provided by visit.  Results: Because QOL/pain scales were added late in the study, only 33 of 126 patients in the HER2+ cohort completed at least one question in the health outcome questionnaires at baseline. At week 8, 64% (n=21) of patients completed assessments, and the results showed moderate improvement (10-20 points) in average EORTC QLC scores for global QOL, role functioning and social subscales. The physical function subscale also showed improvement (9 points). All symptom scales (except diarrhea) were lower than baseline at most scheduled visits indicating improvement in symptoms. Scores for all 4 summary pain scores of the BPI-SF at week 8 were also lower than baseline values suggesting improvement in pain severity and pain interference (decrease ranged from 1.3 to 2.7 points). Sixteen of the 33 patients (48%) had partial response to treatment and 9 had stable disease.  Conclusions: Results suggest that lapatinib monotherapy may improve level of functioning/QOL and provide relief from most symptoms, including pain, in the short term. These QOL benefits add to the clinical improvement associated with lapatinib therapy in these heavily pre-treated patients with an aggressive form of breast cancer.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4097.
Quality of life evaluation and decision-making after mastectomy for breast reconstruction of breast cancer patients.
Authors: Kalder M , Eibisch T , Hadji P , Wagner U , Albert U
Published: December 2010

Abstract #4098

Background:  What is the level of information and the information needs of Breast Cancer patients after mastectomy regarding secondary breast reconstruction. Evaluation of the impact of a mastectomy regarding Quality of Life, satisfaction with the surgical result and personal job situation as well as the influence of a partnership according to the Quality of Life parameters.  Material and Methods:  From January 2000 until May 2003 a number of 282 women suffering from Breast Cancer underwent a mastectomy for various indications. During the routinely Breast Cancer follow-up Quality of Life was assessed using the EORTC QLQ-C30 questionnaire and the breast cancer specific module BR23 in patients at least one year after the mastectomy. 149 (52.8%) patients were excluded for the following reasons: Local recurrence (5%), pT4 stage cancer (3.5%), performed secondary breast reconstruction (22%) and an age of over 75 years (22.3%). 3.5% of the remaining 133 (47.2%) patients died, 3.5% moved with unknown address and 7.1% refused the questionnaire. All together 86 (30.5%) questionnaires could be evaluated.  Results:  93% of the patients were aware of the possibility to have a breast reconstruction.  Patients satisfied with the results of the surgical procedure comprised a higher level of content with their body image and reported higher overall Quality of Life compare to less satisfied patients.  Patients with a good body image had significantly less problems showing themselves nude to their partner (p < .0001) and accepted physical touch by them in the breast region significantly more frequently (p < .004) compared to those with a poor body image.  16% of the patients underwent secondary breast reconstruction between the last follow-up and the start of the questionnaire. 8% of the patients made the decision for breast reconstruction after filling in the questionnaire due to more information.  Discussion:  Although the majority of patients were well informed about the modalities of breast reconstruction, an additional 8% of the patients made a decision for breast reconstruction. In conclusion, due to our observation, additional information to patients about the possibility of secondary breast reconstruction even after one or more years, can lead to an unexpected high number of secondary breast reconstruction. We believe that this further information should be integrated into routine clinical practice.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4098.
Adjuvant chemotherapy with or without darbepoetin in node-positive breast cancer: a safety analysis from the phase III ARA plus trial.
Authors: Nitz U , Oberhoff C , Reimer T , Schumacher C , Hackmann J , Warm M , Uleer C , Runde V , Gluz O , Zuna I
Published: December 2010

Abstract #4100

Background: Modern adjuvant chemotherapy regimens may cause considerable anemia. Epoetins are currently used to reduce chemotherapy-associated anemia (CAA) rates in a variety of solid tumors. The discussion of potential effects on survival rates is highly controversial. The ARA Plus trial is a prospective randomized trial comparing adjuvant chemotherapy +- darbepoetin (ARA+ / ARA-) in node-positive breast cancer patients.  Methods: Inclusions criteria were: age of 18 to 65 years, positive lymph nodes (LN) after resection of >10 LN, free margins , M0 status confirmed by conventional staging. At the discretion of the investigating centre patients could receive 6 cycles T75A50C500 or 6 cycles F500E100C500) q3w. They were randomized to darbepoetin (ARA+) 500μg q3w until completion of radiotherapy or to standard supportive care. Darbepoetin was started at Hb level <13 g/dl (amendment 01/2008 at Hb <12g/dl) and stopped at 14 g/dl.  Event free survival (EFS) is the primary endpoint. Overall survival, toxicity, Hb-levels and quality of life are secondary endpoints.  Results: 1234 pts (616 ARA+/618 ARA-) from 70 centres in Germany were randomized from 01/04 to 05/08. 1130 received TAC and 104 FE100C. Baseline characteristics are well balanced in ARA+ and the ARA- patients: median age 53/53, median tumor size 2.4/2.4cm, median number of + LN is 3/3, HR+. 78%/ 75% , G3 36%/40%.  Deaths: There was 1 therapy-related death due to septic fever in the ARA+ group.  SAEs: in 1234 patients 279 serious adverse events (SAE) were reported (150 ARA+ vs. 129 ARA-). Most frequent SAEs were: leucopenia, febrile neutropenia (ARA+ 14 vs. ARA- 21)., infections and thrombosis. In ARA+ patients we observe a modest higher rate of thrombosis and cardiovascular events (ARA+ 24 vs. ARA- 13),  Toxicity: In 3429 documented cycles in 624 patients, there was significantly more anemia and diarrhea in ARA- patients and leucopenia, vomiting and nausea in ARA+ patients. In the ARA+ patients Hb-levels were stable over the whole treatment period (mean values from cycle 1-6: 12.9- 12.4g/dl, median of all cycles: 12.5 g/dl). In ARA- patients Hb-levels decreased during therapy (mean values from cycle 1-6 :13.0 -11.2g/dl, median of all cycles 11.6g/dl). Overstimulation in ARA+ patients were rare (highest reported Hb 15.8g/dl).  Conclusions: The ARA plus trial is the largest prospectively randomized trial ever done in early breast cancer exclusively focusing on the impact of adjuvant darbepoetin on outcome. The majority of the patients received 6 cycles TAC. In these patients overstimulation is an rare event. Short term toxicity and safety data are reassuring. Toxicity analysis and events on 1000 intensively monitored patients will be available in 11/08.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4100.
Cardiac safety of adjuvant bevacizumab (B) plus dose-dense doxorubicin/cyclophosphamide (AC) followed by nanoparticle albumin-bound paclitaxel (nab-P) in patients with early stage breast cancer.
Authors: McArthur HL , Rugo H , Nulsen B , Traina T , Patil S , Zhou Q , Steingart R , Dang C , Park J , Moasser M , Melisko M , Sugarman S , Norton L , Hudis C , Dickler MN
Published: December 2010

Abstract #4104

Background: Dose dense (dd) q2wk AC-paclitaxel (P) is superior to q3wk AC-P. Both regimens are associated with a <1% incidence of CHF. In MBC, q3wk nanoparticle albumin-bound paclitaxel (nab-P) is superior to q3wk P and bevacizumab (B) improves progression-free survival when added to P. Based on the MBC data, B may be more effective when targeting minimal residual disease in the adjuvant setting and nab-P may offer superior efficacy with reduced toxicity. However, it is uncertain whether AC plus B increases the risk of CHF. We evaluated the cardiac safety of ddAC-nab-P with concurrent B as adjuvant therapy for BC.  Methods: Based upon the accepted cardiac event (CE) rate of approximately 4% in trials with adjuvant trastuzumab, this study was designed with similar monitoring and tolerability thresholds. The primary endpoint is cardiac safety: symptomatic CHF or death from LV dysfunction. Secondary endpoints are toxicity, DFS, OS, and biomarkers for efficacy and toxicity. Eligible pts have resected HER2(-) BC and normal LVEF. B is administered concurrently (10 mg/kg IV q2wk x 8) with chemotherapy (AC at 60/600 mg/m2 q2wk x 4 then nab-P at 260 mg/m2 q2wk x 4) and continues at 15 mg/kg q3wk thereafter for a total one year of B therapy. Pegfilgrastim is administered Day 2 of each chemotherapy cycle. Radiation and endocrine therapy are administered per standard of care. MUGAs are obtained at baseline and mos 2, 6, 9 and 18. Although asymptomatic LVEF declines are not considered CEs, B may be held per protocol and long-term cardiac monitoring initiated. If 3 CEs or > 1 cardiac death from LV dysfunction occur, B + ddAC-nab-P will not be considered safe.  Results: The target accrual of 80 pts has been met. Median age is 47y (27-75). As of May 31, 2008, median follow-up is 14 mo (1-21) and 51 pts have completed 1y of planned therapy. No patients have developed symptomatic LV dysfunction at any point during study therapy. Sixteen pts have discontinued treatment due to toxicity: asymptomatic LVEF decline (N=3), hypertension (N=3), wound healing (N=3), headache (N=2), sensory neuropathy (N=2), pain (N=1), hypersensitivity reaction (N=1), and pneumonitis (N=1). Three pts had disease progression, and 8 pts withdrew consent.    Conclusions: At the time of this analysis, no symptomatic LV dysfunction has been observed with B + ddAC-nab-P. Follow-up is ongoing. Correlative studies, including analysis of troponin, renin, and circulating endothelial and tumor cells, are underway.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4104.
Toxicity analysis of a phase III study evaluating FEC-Doc vs. FEC-Doc in combination with gemcitabine as adjuvant treatment for breast cancer – the SUCCESS-trial.
Authors: Rack BK , Janni W , Genss E , Schneeweiss A , Rezai M , Hilfrich J , Lorenz R , Chatsiproios D , Schneider A , Sommer H , Lichtenegger W , Beckmann MW , Friese K
Published: December 2010

Abstract #4108

Background:  Taxane containing regimens have been established as standard of care for node-positive primary breast cancer patients and have shown superiority to mere anthracycline containing regimens. The SUCCESS-trial evaluates, whether adjuvant taxane based treatment can be further improved by the addition of Gemcitabine.  Methods:  The SUCCESS-Study is an open-label randomized controlled, Phase III study comparing the disease free survival after randomisation in patients treated with 3 cycles of Epirubicin(100 mg/m²)-Fluorouracil(500)-Cyclophosphamide(500, FEC)-chemotherapy, followed by 3 cycles of Docetaxel(100 mg/mg², D) versus 3 cycles of FEC, followed by 3 cycles of Gemcitabine(1,000mg/m² d1,8)-Docetaxel(75 mg/m²)(DG). Complete, monitored toxicity data of 2.691 pts were available for this analysis.  Results:  Dose reduction >20% (3.97% vs 2.90%) and postponement of treatment cycles >7die (22,85% vs 14.19%) was rare, but more frequent in the FEC-DG arm (both p< .001). Cytostatic treatment was prematurely stopped in 119 pts (4,4%) receiving FEC-DG and in 103 pts (3,8%) with FEC-D (p=0,21). G-CSF support was applied in 850 (29.2%) vs. 602 pts (20.7%, p< .001). Toxicities NCI grade > 2 which occurred with incidence > 1% or significantly different in the two arms are depicted in Table 1. Afebrile and febrile neutropenia and anemia did not differ between the two arms, but thrombocytopenia was more frequent in FEC-DG (1.7%, p= .007). Hand-foot syndrome and neuropathy was more frequent in the FEC-D arm (p= .09 and p= .02, respectively).  Conclusion:  No unexpected toxicities were observed and severe adverse effects were rare in both treatment arms. With the addition of gemcitabine to FEC-D adjuvant chemotherapy toxicity was moderately increased. Outcome data will have to be awaited to further interpret these findings.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4108.
Adjuvant chemotherapy for breast cancer – prognostic impact of relative dose-intensity.
Authors: Kahlert S , Rosenfeld J , Mair K , Sorokina Y , Engel J , Friese K
Published: December 2010

Abstract #4109

Introduction: Maintenance of adequate dose intensity (DI) is an important aim in the use of adjuvant chemotherapy for early breast cancer. Some studies report a decreased survival, if the DI is below 80% of the planned dose. We evaluated the rate of decreased DI and its prognostic impact for patients (pts.) treated in our institution between 1990 and 2004. During the long observation period a variety of regimens were used: CMF, normal dosed anthracycline (norA) based regimens (Epirubicin less than 35 mg/sqm*week) and higher dosed anthracyclines (hiA; Epirubicin doses of more than 45 mg/sqm*week).  Methods: All patient files were reviewed to calculate relative DI; cycles not applied were treated as a 100% dose reduction. Follow up-data were taken from our institutional prospective data base and the regional tumor registry. Excluded from the analysis were pts. with high dose chemotherapy with stem cell support, rare regimens (less than 10 cases / regimen), pts. switching institution during therapy and pts. progressing during chemotherapy.  Results: From 966 pts. receiving adjuvant chemotherapy, 887 matched the inclusion criteria. Mean follow up is 70 months with 260 distant progressions and 234 deaths. 193 pts. received CMF, 442 norA and 252 hiA, 302 pts. received taxanes. Preterm termination of chemotherapy occurred in 77 pts (8.7%), dose reductions in 36 pts. (4.1%). Pts. receiving hiA were at higher risk for dose reductions than with norA and CMF (7.5% vs. 2.9% vs. 2.1%, p=0.015). Mean dose delays were 12.7 days (CMF), 6.4 days (norA) and 5.7 (hiA) (p<0.01, Kruskal-Wallis-test). The mean rel. DI were 90% (CMF), 93% (norA) and 92% (hiA) and significantly different (p=0.01, Kruskal-Wallis-test).  In univariate analysis, 5 year-metastasis free survival (MFS, 74% vs. 55%, p=0.002) and overall survival (OAS, 80% vs. 65%, p=0.009) are significantly lower for pts. with a rel. DI of less than 80%. This effect seems more pronounced for norA (OAS 80% vs. 45%), than for CMF (OAS 74% vs. 74%) and hiA (OAS 85% vs. 77%). The adverse effect of low DI was independent of taxan-use. In a cox-regression analysis low DI was not identified as independent predictor for MFS and OAS.  Conclusions: Compared to DI reported from most prospective randomised trials the DI in this study seems lower, potentially reflecting patient selection. Dose reductions, delays and preterm termination are common findings, leading to impaired DI. In our study low DI is associated with adverse prognosis in univariate, but not in multivariate analysis. Nevertheless, unnecessary dose modifications should be avoided.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4109.
Incidence and impact of abnormal liver function in patients receiving adjuvant chemotherapy for early breast cancer.
Authors: Macpherson IR , Laskey J , Harden S , Canney P
Published: December 2010

Abstract #4112

Background: Abnormalities in liver function tests (LFTs) which complicate adjuvant polychemotherapy may prompt prescribers to institute a dose reduction or delay due to fears of altered pharmacokinetics and increased toxicity. However, inappropriate reduction in dose intensity is associated with reduced efficacy of adjuvant therapy. We wished to identify the incidence of abnormal liver function and its influence on decision-making and toxicity in patients (pts) receiving adjuvant chemotherapy for early breast cancer in the west of Scotland.  Methods: Data including baseline characteristics, LFTs (bilirubin, AST, ALT) on day 1 of each chemotherapy cycle, hematologic and grade 3/4 non-hematologic toxicity, dose delay or dose reduction were prospectively collected for 160 female pts commencing adjuvant chemotherapy at the Beatson West of Scotland Cancer Centre between August 2005 and February 2006. Association between LFT abnormality on day 1 of each chemotherapy cycle and toxicity occurring within that cycle was determined.  Results: The most common regimen administered was Epirubicin-CMF (n=128; epirubicin 100mg/m2 q3/52 x4; cyclophosphamide 600mg / m2, methotrexate 40mg/m2, 5-FU 600mg/m2 d1+8 q4/52 x 4) followed by AC (n=25; Doxorubicin 60mg/m2, Cyclophosphamide 600mg/m2 q3/52 x4), FEC (n=5) and CMF (n=3). Median age was 55 yrs. Febrile neutropenia or grade 3 /4 non-hematologic toxicity were recorded in 1.9% and 3.2% of cycles respectively. 8.5% of all cycles were delayed and 14% of pts (n=23) had a dose reduction. In only 1 patient was dose reduction due to abnormal LFTs. Grade 1, 2 or 3 hyperbilirubinemia occurred in 3%, 2% and 0% of pts respectively. Grade 1, 2 or 3 elevated ALT occurred in 39%, 9% and 3% of pts. Grade 1, 2 or 3 elevated AST occurred in 38%, 4%, and 1% of pts respectively. No episodes of grade 4 hyperbilirubinemia or elevated transaminases occurred. Despite receiving chemotherapy at full dose no patient with grade 2/3 elevated AST or ALT on day 1 of a chemotherapy cycle experienced either grade 3/4 non-hematologic toxicity or febrile neutropenia in that cycle.  Discussion: Although grade 1 elevation in transaminases was common, particularly in the context of the Epirubicin-CMF regimen, grade 2 or 3 abnormalities were infrequent. The absence of grade 3/4 chemotherapy-related toxicity in pts with grade 2/3 LFT abnormality supports maintenance of full dose anthracycline-based polychemotherapy in this population.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4112.
Immunotherapy with MUC1/CEA vaccine alone or combined with chemotherapy in patients with metastatic breast cancer.
Authors: Mohebtash M , Madan R , Arlen P , Jacquin J , Mary P , Oksook H , Myrna R , Jeffrey S , James G
Published: December 2010

Abstract #4123

Background: PANVAC is a recombinant pox viral vaccine that contains transgenes for the tumor-associated antigens (TAAs), MUC1 and CEA. PANVAC also contains three T-cell co-stimulatory molecules (B7.1, LFA-3, ICAM-1) to enhance immune response. Clinical studies with a similar vaccine have shown docetaxel does not diminish specific T-cell responses to the TAAs delivered in the pox viral vaccines. We are evaluating the use of PANVAC in two ongoing trials in patients with metastatic breast cancer.  Methods: The primary end point of these two phase II trials is progression-free survival (PFS). As secondary end point specific T-cell response is measured using ELISPOT assay in HLA-A2 patients. One study uses vaccine alone, given monthly by SC injections and is accompanied by 4 days of low dose GM-CSF. The other trial randomizes to either vaccine + docetaxel or docetaxel alone; giving the same V regimen (as the first study) on day 1 followed by docetaxel at 35 mg/m2 on days 2, 9, and 16 of each 28 day cycle. The chemotherapy alone arm uses the same docetaxel dosing.  Results: Twenty three patients have been accrued with a median age of 57.6 (31-75) years. Sixteen patietns had ER/PR+ tumors. The patients had a median of 4 (0-6) previous chemotherapy regimens; their median time since their last chemotherapy was 2 months with a 10th – 90th percentile of 1-8 months. Vaccine is well tolerated with few grade 3 and no grade 4 adverse events. Most of the grade 1-2 toxicities were self-limited site reactions and flu-like symptoms. Three of 13 patients on vaccine alone study have shown measurable clinical benefits. Two were on study for 6 months, of whom one had significant improvement in pain with reduction in vertebral lesions on MRI; another had a sustained >20% decrease in bulky liver metastases. A third patient on vaccine alone was on study for 9 months with reduction in her mediastinal lymphadenopathy. Of the 6 patients who received vaccine + docetaxel, 5 had measurable disease. One achieved PR by RECIST criteria and remained on study for 19 months; another had a 50% reduction in the diameter of a chest wall lesion. A third patient with bone only disease was on study for 12 months with significant improvements on her bone scan.  Conclusions: Vaccine given alone or in combination with docetaxel is shown to be safe in patient with metastatic breast cancer. There is preliminary evidence that there may be some clinical benefit from vaccine alone as well as its combination with chemotherapy. Confirmation of these results and PFS determination requires additional patient enrollment and follow up in both studies. Furthermore, immunologic studies including functional analysis of CD4 and CD8 T-cells will be performed to help elucidate the immune responses these regimens may elicit.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4123.
The role of systemic therapies in the development of lung sequelae after conformal radiotherapy in breast cancer patients.
Authors: Varga Z , Cserháti A , Boda K , Thurzó L , Kahán Z
Published: December 2010

Abstract #4125

Some data suggest that adjuvant systemic therapies like tamoxifen and paclitaxel play a role in the development of radiogenic lung toxicity.  Early and late radiogenic lung sequelae were prospectively studied in patients receiving sequential taxane-based chemotherapy (Tax), concomittant hormone therapy with tamoxifen (Tam) or aromatase inhibitor (AI), or no systemic therapy (C) according to the institutional guidelines. Clinical signs, radiologic abnormalities and the mean lung density changes measured at the level of the left heart ventricle (MDCLHV) and the head of the clavicle (MDCHC) of the irradiated lung on CT were evaluated according to Kahan et al., Int. J. Radiat. Oncol. Biol. Phys., 2007.  The incidence of pneumonitis grade I with or without clinical symptoms did not significantly differ between the 4 groups. None of the patients developed symptomatic radiogenic lung fibrosis one year after the radiotherapy, however, radiogenic CT changes were significantly more frequent in the group treated with Tam. No differences in the MDCLHV and MDCHC values according to systemic therapy were detected 3 months or 1 year after the radiotherapy (Table). Significant positive associations existed between radiogenic lung changes with or without clinical symptoms and the age of the patient, the ipsilateral mean lung dose (MLD), the volume of the ipsilateral lung receiving ≥20 Gy (V20 Gy) and the irradiation of the axillary and supraclavicular lymph nodes. Extended data and statistical analysis including multiple linear regression and multivariate logistic regression models will be presented.       

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4125.