Search

Purpose: To evaluate the clinical patterns of utilization of OncotypeDX Recurrence Score (RS) in early-stage, hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer (BC) at an academic center with previously established internal reflex testing guidelines., Methods: RS testing in accordance with preexisting reflex criteria and predictors of utilization outside of reflex criteria were retrospectively analyzed for the years 2019-2021 in a quality improvement evaluation. Patients were grouped according to OncotypeDX testing within (cohort A) or outside (cohort B) of predefined criteria which included a cap at age older than 65 years., Results: Of 1,687 patients whose tumors had RS testing, 1,087 were in cohort A and 600 in cohort B. In cohort B, nearly half of patients were older than 65 years (n = 279; IQR, 67-72 years). For patients older than 65 years, those with RS testing were younger (median age: 69 v 73 years), with higher grade cancers (G2-3: 84.9% v 54.7%) and were more likely to be treated with chemotherapy (15.4% v 4.1%). Issues for implementation of RS testing in older patients were identified, including potential structural barriers related to the current policy on the reimbursements of genomic tests., Conclusion: Internal guidelines may facilitate standardized utilization of the RS in early-BC. Our data suggest that clinicians preferred broader utilization of RS across the age spectrum, with therapeutically important consequences. Modifying the current policy for reimbursement of RS testing and in internal reflexive testing criteria for those older than 65 years is warranted.

Clinical pathways have the potential to improve complex clinical decision-making in cancer care. The authors implemented pathways with customized content to assist oncologists to select treatments, aiming for an on-pathway rate of 70%-85%. Treatment decisions were captured as on or off pathway, and metrics were shared monthly with users. Oncologists were categorized into quintiles based on on-pathway performance during the first 90 days of use. On-pathway rates were then calculated for days 91-360 (N = 121). Median on-pathway quintile rates varied from 50% to 100% in the initial 90-day period. During follow-up, median on-pathway rates shifted into the prespecified goal range for all groups. Clinical pathways resulted in greater uniformity in medical oncology practice. Monthly feedback about usage, familiarity with the electronic platform, and regular content updates are some factors that may influence on-pathway rates. Clinical pathways hold promise to manage unwarranted variation in cancer care., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Preclinical studies support the JAK2-STAT3 signaling pathway as a key driver in CD44+ CD24- "stem-cell-like" breast cancer cells. Ruxolitinib is an orally bioavailable JAK1/2 inhibitor. We aimed to identify the recommended phase 2 dose (RP2D) of ruxolitinib in combination with paclitaxel in patients with HER2-negative metastatic breast cancer (MBC)., Methods: Eligible patients had HER2-negative MBC and had received ≤ 3 chemotherapy regimens for advanced disease. Patients received oral ruxolitinib (10-25 mg bid) in a 3 + 3 dose escalation design in combination with weekly paclitaxel 80 mg/m 2 in a 3-week cycle. The primary objective was to determine the maximum tolerated dose (MTD) and the RP2D., Results: Nineteen patients received protocol therapy (mean age 52 years). Eight (42%) had triple-negative breast cancer and 11 (58%) had hormone receptor-positive disease; 12 (63%) had visceral disease. Ten (53%) patients had not received prior treatment for advanced disease. Patients received a median number of 5 cycles of combination therapy (range 1-12) and five patients continued single-agent ruxolitinib. The MTD of ruxolitinib was 25 mg bid when combined with paclitaxel, and the RP2D for the combination was 15 mg bid. Thirteen (68%) patients required dose reductions or holds. Most frequent toxicities reported of any grade were neutropenia (50%) and anemia (33%). There were no grade 4/5 toxicities attributed to study drug. Four (21%) patients had PR, 12 (63%) had SD and three (16%) had PD as their best response., Conclusion: The combination of ruxolitinib and weekly paclitaxel was well tolerated with evidence of clinical activity. Further analysis of this combination is ongoing (NCT02041429)., Trial Registration: NCT02041429. Date of registration: January 22, 2014.

Purpose: To assess the incidence and clinical significance of discrepancy in subspecialty interpretation of outside breast imaging examinations for newly diagnosed breast cancer patients presenting to a tertiary cancer center., Materials and Methods: This Institutional Review Board-approved retrospective study included patients presenting from July 2016 to March 2017 to a National Cancer Institute-designated comprehensive cancer center for second opinion after breast cancer diagnosis. Outside and second opinion radiology reports of 252 randomly selected patients were compared by two subspecialty breast radiologists to consensus. A peer review score was assigned, modeled after ACR's RADPEER TM peer review metric: 1-agree; 2-minor discrepancy (unlikely clinically significant); 3-moderate discrepancy (may be clinically significant); 4-major discrepancy (likely clinically significant). Among cases with clinically significant discrepancies, rates of clinical management change (management alterations including change in follow-up, neoadjuvant therapy use, and surgical management as a direct result of image review), and detection of additional malignancy were assessed through electronic medical record review., Results: A significant difference in interpretation (scores = 3 or 4) was seen in 41 of 252 cases (16%, 95% confidence interval [CI], 11.7%-20.8%). The difference led to additional workup in 38 of 252 cases (15%, 95% CI 10.6%-19.5%) and change in clinical management in 18 of 252 cases (7.1%, 95% CI 4.0%-10.2%), including 15 of 252 with change in surgical management (6.0%, 95% CI, 3.0%-8.9%). An additional malignancy or larger area of disease was identified in 11 of 252 cases (4.4%, 95% CI, 1.8%-6.9%)., Conclusion: Discrepancy between outside and second-opinion breast imaging subspecialists frequently results in additional workup for breast cancer patients, changes in treatment plan, and identification of new malignancies., (Copyright © 2018 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Background: For clinically appropriate early-stage breast cancer patients, reflex criteria for Oncotype DX ordering ("the intervention") were implemented at our comprehensive cancer center, which reduced time-to-adjuvant chemotherapy initiation. Our objective was to evaluate Oncotype DX ordering practices and chemotherapy use before and after implementation of the intervention., Materials and Methods: We examined medical records for 498 patients who had definitive breast cancer surgery at our center. The post-intervention cohort consisted of 232 consecutive patients who had Oncotype DX testing after reflex criteria implementation. This group was compared to a retrospective cohort of 266 patients who were diagnosed and treated prior to reflex criteria implementation, including patients who did and did not have Oncotype DX ordered. Factors associated with Oncotype DX ordering pre- and post-intervention were examined. We used multivariate logistic regression to evaluate factors associated with chemotherapy receipt among patients with Oncotype DX testing., Results: The distribution of Oncotype DX scores, the proportion of those having Oncotype DX testing (28.9% vs. 34.1%) and those receiving chemotherapy (14.3% vs. 19.4%), did not significantly change between pre- and post-intervention groups. Age ≤65 years, stage II, grade 2, 1-3+ nodes, and tumor size >2 cm were associated with higher odds of Oncotype DX testing. Among patients having Oncotype DX testing, node status and Oncotype DX scores were significantly associated with chemotherapy receipt., Conclusion: Our criteria for reflex Oncotype DX ordering appropriately targeted patients for whom Oncotype DX would typically be ordered by providers. No significant change in the rate of Oncotype DX ordering or chemotherapy use was observed after reflex testing implementation., Implications for Practice: This study demonstrates that implementing multidisciplinary consensus reflex criteria for Oncotype DX ordering maintains a stable Oncotype DX ordering rate and chemotherapy rate, mirroring what was observed in a specific clinical practice, while decreasing treatment delays due to additional testing. These reflex criteria appropriately capture patients who would likely have had Oncotype DX ordered by their providers and for whom the test results are predicted to influence management. This intervention serves as a potential model for other large integrated, multidisciplinary oncology centers to institute processes targeting patient populations most likely to benefit from genomic assay testing, while mitigating treatment delays., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2018.)

Despite a growing number of clinical trials and supportive care programs for cancer survivors, recruitment of patients for these opportunities during the survivorship phase of care is challenging. We piloted a novel process to systematically educate patients about available research studies and supportive care programs as part of a survivorship care visit. Between 3/2015 and 8/2015, patients seen in the Adult Survivorship Program who had not previously received a treatment summary and survivorship care plan (TS/SCP) were provided with one accompanied by a list of survivorship research studies and care programs tailored to their diagnosis. Survivorship providers discussed the opportunities and recorded whether the patient was interested in relevant studies and placed referrals to study staff. Following the visit, we tracked study enrollment and surveyed patients about their experience. Fifty of 56 (89%) pilot participants completed the survey. Almost all (98%) reported that the TS/SCP visit and document helped with knowledge of research opportunities and supportive care interventions. Following receipt of the TS/SCP, 44% were interested in at least one study and in further follow-up with research staff. Of the 30 survivors eligible for at least one study, 6 (20%) have enrolled in at least one study to date. This pilot program demonstrates that the systematic sharing of available clinical studies and supportive care programming as part of a survivorship care plan visit is feasible and well received by cancer survivors and may facilitate and enhance accrual to clinical trials in the survivorship phase of care.

Purpose: Delays to adjuvant chemotherapy initiation in breast cancer may adversely affect clinical outcomes and patient satisfaction. We previously identified an association between genomic testing (Onco type DX) and delayed chemotherapy initiation. We sought to reduce the interval between surgery and adjuvant chemotherapy initiation by developing standardized criteria and workflows for Onco type DX testing., Methods: Criteria for surgeon-initiated reflex Onco type DX testing, workflows for communication between surgeons and medical oncologists, and a streamlined process for receiving and processing Onco type DX requests in pathology were established by multidisciplinary consensus. Criteria for surgeon-initiated testing included patients ≤ 65 years old with T1cN0 (grade 2 or 3), T2N0 (grade 1 or 2), or T1/T2N1 (grade 1 or 2) breast cancer on final surgical pathology. Medical oncologists could elect to initiate Onco type testing for cases falling outside the criteria. We then examined 720 consecutive patients with breast cancer who underwent Onco type DX testing postoperatively between January 1, 2014 and November 28, 2016 and measured intervals between date of surgery, Onco type DX order date, result received date, and chemotherapy initiation date (if applicable) before and after intervention implementation., Results: The introduction of standardized criteria and workflows reduced time between surgery and Onco type DX ordering, and time from surgery to receipt of result, by 7.3 days ( P < .001) and 6.3 days ( P < .001), respectively. The mean number of days between surgery and initiation of chemotherapy was also reduced by 6.4 days ( P = .004)., Conclusion: Developing consensus on Onco type DX testing criteria and implementing streamlined workflows has led to clinically significant reductions in wait times to chemotherapy decision making and initiation.

Background: National guidelines endorse time-dependent quality metrics for breast cancer care. We examined factors associated with delays in chemotherapy initiation at an NCI-Designated Comprehensive Cancer Center., Patients and Methods: We identified 523 patients who received postoperative adjuvant chemotherapy between January 2011 and December 2013 at our center. We defined 28 days from last definitive surgery (LDS) to chemotherapy as the target time frame, and an unacceptable delay in chemotherapy initiation (UCD) as greater than 42 days from LDS. Multivariate regression models were used to identify factors associated with UCD and the impact of Oncotype DX testing in patients with hormone receptor (HR)-positive breast cancer., Results: Median days between LDS and chemotherapy initiation was 34 (interquartile range, 15), with 30% of patients starting within 28 days of LDS and 26.9% having UCD. Tumor characteristics such as subtype and stage affected UCD; patients with HR-positive or HER2-positive tumors were more likely to be delayed compared with those with triple-negative breast cancer. Patients with stage I disease, those undergoing mastectomy with or without immediate reconstruction, and those whose pathology sign-out was greater than 10 days postoperatively were more likely to be delayed. A higher proportion of UCD was found in HR-positive patients (31%) for whom Oncotype DX testing was ordered compared with those in whom it was not ordered (20%)., Conclusions: This study provides insight into subpopulations that may be at risk to experience delays in chemotherapy initiation, directing interventions to improve the timeliness of care., (Copyright © 2016 by the National Comprehensive Cancer Network.)

Introduction: The necessity of using granulocyte-colony stimulating factor (G-CSF) during dose-dense (DD) paclitaxel (T) after doxorubicin and cyclophosphamide (AC) is unclear., Methods: This was a retrospective cohort study including patients with stage I-III breast cancer treated at Dana-Farber Cancer Institute with adjuvant DD-ACT between January 2011 and December 2013. Descriptive analyses evaluating patterns of G-CSF utilization during T were performed., Results: Overall, 156 patients were treated with DD-ACT by 26 providers. The majority of patients (135, 87%) received at least one dose of G-CSF during T (group 1), 17% of these patients received it in only one cycle and 48% received it in all four cycles. Reasons for omitting G-CSF included high baseline absolute neutrophil count and pain. Twenty-one (13%) patients did not receive any G-CSF during T (group 2). Respectively, 94% and 90% of patients completed the treatment in groups 1 and 2. There were no cases of treatment cessation due to neutropenia. Six percent of patients in group 1 had at least one treatment delay. There were no treatment delays reported in group 2. Variation in the use of G-CSF by provider and by patient was found, with 11 providers choosing not to use G-CSF in at least one patient., Conclusions: We identified substantial variation in the use of G-CSF within the practice. However, omission of G-CSF was not associated with treatment delays or adverse events. Prospective studies are warranted to formally test whether routine G-CSF is necessary during dose-dense T therapy., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

This article describes how trust among team members and in the technology supporting them was eroded during implementation of an electronic health record (EHR) in an adult outpatient oncology practice at a comprehensive cancer center. Delays in care of a 38-year-old woman with high-risk breast cancer occurred because of ineffective team communication and are illustrated in a case study. The case explores how the patient's trust and mutual trust between team members were disrupted because of inaccurate assumptions about the functionality of the EHR's communication tool, resultant miscommunications between team members and the patient, and the eventual recognition that care was not being effectively coordinated, as it had been previously. Despite a well-established, team-based culture and significant preparation for the EHR implementation, the challenges that occurred point to underlying human and system failures from which other organizations going through a similar process may learn. Through an analysis and evaluation of events that transpired before and during the EHR rollout, suggested interventions for preventing this experience are offered, which include: a thorough crosswalk between old and new communication mechanisms before implementation; understanding and mitigation of gaps in the communication tool's functionality; more robust training for staff, clinicians, and patients; greater consideration given to the pace of change expected of individuals; and development of models of collaboration between EHR users and vendors in developing products that support high-quality, team-based care in the oncology setting. These interventions are transferable to any organizational or system change that threatens mutual trust and effective communication.

Purpose: Mastectomy with immediate reconstruction (MIR) requires coordination between breast and reconstructive surgical teams, leading to increased preoperative delays that may adversely impact patient outcomes and satisfaction. Our cancer center established a target of 28 days from initial consultation with the breast surgeon to MIR. We sought to determine if a centralized breast/reconstructive surgical coordinator (BRC) could reduce care delays., Methods: A 60-day pilot to evaluate the impact of a BRC on timeliness of care was initiated at our cancer center. All reconstructive surgery candidates were referred to the BRC, who had access to surgical clinic and operating room schedules. The BRC worked with both surgical services to identify the earliest surgery dates and facilitated operative bookings. The median time to MIR and the proportion of MIR cases that met the time-to-treatment goal was determined. These results were compared with a baseline cohort of patients undergoing MIR during the same time period (January to March) in 2013 and 2014., Results: A total of 99 patients were referred to the BRC (62% cancer, 21% neoadjuvant, 17% prophylactic) during the pilot period. Focusing exclusively on patients with a cancer diagnosis, an 18.5% increase in the percentage of cases meeting the target (P = .04) and a 7-day reduction to MIR (P = .02) were observed., Conclusion: A significant reduction in time to MIR was achieved through the implementation of the BRC. Further research is warranted to validate these findings and assess the impact the BRC has on operational efficiency and workflows., (Copyright © 2016 by American Society of Clinical Oncology.)

Background: In the multidisciplinary care model, breast imagers frequently provide second-opinion reviews of imaging studies performed at outside institutions. However, the need for additional imaging and timeliness of obtaining these studies has yet to be established. We sought to evaluate the frequency of additional imaging orders by breast surgeons and to evaluate the impact of this supplementary imaging on timeliness of surgery., Methods: We identified 2489 consecutive women with breast cancer who underwent first definitive surgery (FDS) at our comprehensive cancer center between 2011 and 2013. The number of breast-specific imaging studies performed for each patient between initial consultation and FDS was obtained. χ (2) tests were used to quantify the proportion of patients undergoing additional imaging by surgeon. Interval time between initial consultation and additional imaging and/or biopsy was calculated. The delay of additional imaging on time to FDS was assessed by t test., Results: Of 2489 patients, 615 (24.7 %) had at least one additional breast-specific imaging study performed between initial consultation and FDS, with 222 patients undergoing additional biopsies (8.9 %). The proportion of patients receiving imaging tests by breast surgeon ranged from 15 to 39 % (p < 0.0001). Patients receiving additional imaging had statistically longer wait times to FDS for BCT (21.4-28.5 days, p < 0.0001)., Conclusions: Substantial variability exists in the utilization of additional breast-specific imaging and in the timeliness of obtaining these tests among breast surgeons. Further research is warranted to assess the sources and impact of this variation on patient care, cost, and outcomes.

The authors sought to measure the timeliness of care for patients with breast cancer at Dana-Farber/Brigham and Women's Cancer Center throughout the treatment continuum, and to identify sources of variation that may serve as targets for improving care delivery. This report describes the methods that were developed to measure and analyze baseline performance.

Background: Oncology care is delivered largely in ambulatory settings by interdisciplinary teams. Treatments are often complex, extended in time, dispersed geographically and vulnerable to teamwork failures. To address this risk, we developed and piloted a team training initiative in the breast cancer programme at a comprehensive cancer centre., Methods: Based on clinic observations, interviews with key staff and analyses of incident reports, we developed interventions to address four high-risk areas: (1) miscommunication of chemotherapy order changes on the day of treatment; (2) missing orders on treatment days without concurrent physician appointments; (3) poor follow-up with team members about active patient issues; and (4) conflict between providers and staff. The project team developed protocols and agreements to address team members' roles, responsibilities and behaviours., Results: Using a train-the-trainer model, 92% of breast cancer staff completed training. The incidence of missing orders for unlinked visits decreased from 30% to 2% (p<0.001). Patient satisfaction scores regarding coordination of care improved from 93 to 97 (p=0.026). Providers, infusion nurses and support staff reported improvement in efficiency (75%, 86%, 90%), quality (82%, 93%, 93%) and safety (92%, 92%, 90%) of care, and more respectful behaviour (92%, 79%, 83%) and improved relationships among team members (91%, 85%, 92%). Although most clinicians reported a decrease in non-communicated changes, there was insufficient statistical power to detect a difference., Conclusions: Team training improved communication, task coordination and perceptions of efficiency, quality, safety and interactions among team members as well as patient perception of care coordination.

Purpose: Dose-limiting neuropathy is a major adverse event associated with most of the microtubule-stabilizing agent-based chemotherapy regimens. Ixabepilone, a semisynthetic analogue of the natural epothilone B, has activity against a wide range of tumor types. Peripheral neuropathy (PN), associated with ixabepilone treatment, is usually mild to moderate, predominantly sensory and cumulative. Preclinical studies demonstrate that ixabepilone and taxanes produce a similar neurotoxicity profile., Methods: We searched databases of phase II/III clinical trials involving patients receiving ixabepilone as a monotherapy or in combination with capecitabine for incidences of neuropathy. Potential risk factors for grade 3/4 PN were identified by a Cox regression analysis on a dataset of 1,540 patients with different tumor types across multiple studies., Results: Rates for incidence of ixabepilone-induced severe PN (Common Terminology Criteria for Adverse Events grade 3/4) ranged from 1% in early untreated breast cancer up to 24% in heavily pretreated metastatic breast cancer; grade 4 PN was rare (≤ 1%). Common symptoms included numbness, paresthesias, and sometimes dysesthesias. Cox regression analysis identified only preexisting neuropathy as a risk factor for increased ixabepilone-associated PN. The management of PN has been primarily through dose adjustments (dose delays and/or dose reduction). Patients had resolution of their neuropathy within a median time of 5 to 6 weeks., Conclusions: PN is a dose-limiting toxicity associated with ixabepilone treatment, is reversible in most patients, and can be managed with dose reduction and delays.

Purpose: Multidisciplinary clinics (MDCs) play a prominent role in coordinating complex cancer care delivered by multiple providers from different disciplines. The structure of such clinics and clinicians' perceptions of the advantages and disadvantages of practicing in MDCs have not been well characterized., Methods: We surveyed and interviewed medical providers who participate in cancer MDCs at our comprehensive cancer center about the structure of the MDCs in which they work, their satisfaction working in these clinics, and the perceived benefits and disadvantages. Press-Ganey patient satisfaction scores were also examined., Results: WE IDENTIFIED TWO CARE MODELS: one in which patients are seen sequentially by physicians from each discipline, and a second model in which patients are seen concurrently by physicians from each discipline. Of the 141 survey respondents from surgical oncology, medical oncology and radiation oncology, more than 90% of providers enjoyed working in an MDC and more than 75% preferred to see new patients in an MDC. Additionally, 90% believed that patients perceived the clinics to be valuable for comprehensive, coordinated, and appropriate care. However, one third of the phsyicians thought the clinics were not an efficient use of their time. Participants who practice in the concurrent model of care and surgical oncologists were more likely to express frustration with the inefficiency of MDCs. Patients seen in each clinic model uniformly expressed high satisfaction with the coordination of care., Conclusion: MDCs are valued by oncology patients and providers. Although they are personally and professionally satisfying for physicians, the use of this care model is perceived as inefficient by some caregivers.

Background: Pegylated liposomal doxorubicin has activity in both breast and ovarian cancer. Preclinical data noted that ZD1839 acts synergistically with chemotherapy. Given the lack of cross-resistance between these two agents, a phase I trial was initiated examining the safety and efficacy of the combination of liposomal doxorubicin and ZD1839 in patients with recurrent gynecologic or metastatic breast cancer., Methods: Dose-limiting toxicity (DLT) was defined within the first two cycles of treatment. Escalating doses of liposomal doxorubicin were administered every 4 weeks with ZD1839. Pharmacokinetic analysis and correlative studies were performed., Results: Thirty-five patients were enrolled in this study: six in each cohort. One DLT (febrile neutropenia) was observed in cohort 2. Dose level 3 was determined to be the maximum tolerated dose (MTD), and an additional ten patients were accrued. Serious adverse events (SAEs) included one patient with mental status changes believed secondary to disease progression and two central nervous system (CNS) bleeds believed to be unrelated to the combination of study agents. Toxicities were generally mild except for skin and gastrointestinal toxicity. No cardiac toxicity was observed. The best response to therapy included four partial responses and 20 patients with stable disease., Conclusions: Liposomal doxorubicin with ZD1839 is an active regimen but is associated with increased skin toxicity in patients with advanced breast and gynecologic cancer.

Two impurities found in both stressed and aged solid-state formulations of olanzapine have been identified as (Z)-1,3-dihydro-4-(4-methyl-1-piperazinyl)-2-(2-oxopropylidene)-2H-1,5-benzodiazepin-2-one (1) and (Z)-1-[1,2-dihydro-4-(4-methyl-1-piperazinyl)-2-thioxo-3H-1,5-benzodiazepin-3-ylidene]propan-2-one (2). The structures indicate that the two impurities are degradation products resulting from oxidation of the thiophene ring of olanzapine. The impurities were isolated by preparative HPLC from a thermally stressed formulation, and characterized by UV, IR, MS, and NMR. A synthetic preparation of compounds 1 and 2 by reaction of olanzapine with the singlet oxygen mimic 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) is presented. The structure of 2 was also determined by single-crystal X-ray diffraction analysis. A degradation pathway for the formation of 1 and 2 is proposed.

Purpose: To evaluate the safety and feasibility of concurrent radiation therapy and paclitaxel-based adjuvant chemotherapy, given either weekly or every 3 weeks, after adjuvant doxorubicin and cyclophosphamide (AC)., Methods and Materials: After definitive breast surgery and AC chemotherapy, 40 patients with operable Stage II or III breast cancer received protocol-based treatment with concurrent paclitaxel and radiation therapy. Paclitaxel was evaluated on 2 schedules, with treatment given either weeklyx12 weeks (60 mg/m2), or every 3 weeksx4 cycles (135-175 mg/m2). Radiation fields and schedules were determined by the patient's surgery and pathology. The tolerability of concurrent therapy was evaluated in cohorts of 8 patients as a phase I study., Results: Weekly paclitaxel treatment at 60 mg/m2 per week with concurrent radiation led to dose-limiting toxicity in 4 of 16 patients (25%), including 3 who developed pneumonitis (either Grade 2 [1 patient] or Grade 3 [2 patients]) requiring steroids. Efforts to eliminate this toxicity in combination with weekly paclitaxel through treatment scheduling and CT-based radiotherapy simulation were not successful. By contrast, dose-limiting toxicity was not encountered among patients receiving concurrent radiation with paclitaxel given every 3 weeks at 135-175 mg/m2. However, Grade 2 radiation pneumonitis not requiring steroid therapy was seen in 2 of 24 patients (8%) treated in such a fashion. Excessive radiation dermatitis was not observed with either paclitaxel schedule., Conclusions: Concurrent treatment with weekly paclitaxel and radiation therapy is not feasible after adjuvant AC chemotherapy for early-stage breast cancer. Concurrent treatment using a less frequent paclitaxel dosing schedule may be possible, but caution is warranted in light of the apparent possibility of pulmonary injury.

Purpose: Few studies have examined the influence of diet on survival and chemotherapy-associated toxicities in patients with cancer. Although several comprehensive dietary questionnaires have been validated and calibrated in healthy populations, similar studies have not been performed among cancer patients., Methods: Two hundred patients with colorectal, breast, or neuroendocrine cancer undergoing treatment with cytotoxic chemotherapy completed a self-administered, 131-item, semiquantitative food frequency questionnaire. Using the questionnaire, we calculated dietary intakes of carotenoids, tocopherols, and fatty acids, and correlated these values with relevant biomarkers measured in simultaneously collected plasma specimens., Results: The Pearson correlation coefficients for various carotenoids as measured by the questionnaire, with the corresponding measurements in plasma specimens, ranged from 0.33 to 0.44 (all P < .001), adjusted for total energy intake, body mass index, age, sex, smoking status, and total plasma cholesterol. Similarly, the adjusted correlation between self-reported total vitamin E intake and plasma alpha-tocopherol was 0.34 (P < .001). Correlations between questionnaire and plasma measurements of trans-fat, eicosapentaenoic acid, and docosahexaenoic acid were 0.55, 0.29, and 0.42 (all P < .001), respectively. These levels of correlation are consistent with those reported in similar studies of self-reported diet in otherwise healthy populations., Conclusion: Among patients with cancer receiving cytotoxic chemotherapy, questionnaire-based measurements of various micronutrients and dietary factors appeared to predict meaningful differences in the corresponding measurements in plasma specimens. This dietary questionnaire could offer an informative and practical means for assessing the influence of diet in cancer patients receiving chemotherapy.

Purpose: Dose-dense, every-2-week adjuvant chemotherapy using doxorubicin/cyclophosphamide (AC; 60/600 mg/m2 every 2 weeks x four cycles) followed by paclitaxel (175 mg/m2 every 2 weeks x four cycles), requiring filgrastim on days 3 through 10 of each cycle has been shown to improve survival compared with every-3-week treatment schedules but is associated with greater risk of RBC transfusion (13%). The role of long-acting hematopoietic growth factors in facilitating every-2-week chemotherapy and minimizing hematologic toxicity has not been established., Patients and Methods: Women with stage I to III breast cancer received dose-dense AC --> paclitaxel as neoadjuvant or adjuvant chemotherapy. Patients received pegfilgrastim 6 mg subcutaneous (SQ) on day 2 of each cycle. Darbepoetin alfa was initiated at 200 microg SQ every 2 weeks for hemoglobin < or = 12 g/dL, and administered thereafter, according to a preplanned algorithm. The primary end points were to evaluate the percentage of patients with febrile neutropenia and the percentage of patients requiring RBC transfusion., Results: Among 135 women treated on this single arm study, there were two cases of febrile neutropenia (incidence 1.5%). No patients received RBC transfusion. Darbepoetin alfa therapy was initiated in 92% of patients. The modest leukocytosis seen during paclitaxel cycles was attributable, in part, to corticosteroid premedication. Other toxicity and dose-delivery were similar to dose-dense AC --> paclitaxel in Cancer and Leukemia Group B 9741., Conclusion: Pegfilgrastim and darbepoetin alfa are effective and safe in facilitating every-2-week AC --> paclitaxel, minimizing rates of febrile neutropenia and RBC transfusion.

Purpose: Recent clinical trials suggest that adjuvant ovarian suppression may be an equally effective and less toxic alternative to systemic chemotherapy in premenopausal women with hormone-responsive breast cancer. We used a decision-analytic framework to evaluate tradeoffs between efficacy and quality of life in the choice between these treatments., Patients and Methods: We used a Markov state-transition model to simulate clinical practice in a cohort of 40-year-old premenopausal women with newly diagnosed, hormone-responsive early breast cancer. We assessed three adjuvant treatments: chemotherapy, surgical ovarian suppression, and medical ovarian suppression. Outcomes were recurrence-free, overall, and quality-adjusted survival. Quality-adjusted survival reflected effects of cancer, treatment-related side effects, and menopausal symptoms., Results: Assuming equal efficacy, ovarian suppression was superior to chemotherapy when the relative utility of chemotherapy side effects compared with ovarian suppression side effects was less than 0.95. Results were sensitive to assumptions about the likelihood, duration and consequences of treatment-induced menopause. Treatment choice was affected by a 7% proportional increase in the efficacy of one therapy relative to the others, independent of other factors., Conclusion: If adjuvant chemotherapy and ovarian suppression have similar efficacy, then there may be a subgroup of women for whom quality-of-life considerations dominate the choice of treatment. However, small differences in the relative efficacy of these therapies have a substantial impact on treatment choice, regardless of side effects and menopausal transitions.

SN biopsy (SNB) has evolved rapidly during the past decade and has now become a standard of surgical care for patients with breast cancer. The primary purpose of SNB is to minimize patient morbidity from axillary staging, but SNB also presents research opportunities to further understand the role of the sentinel node in the natural history of breast cancer. We have attempted to highlight several issues regarding SN and its biopsy in this review, including:(1) Investigation of the optimal particle size for radiotracers. The success of SNB is, in large part, attributed to the particle size of radiolabeled tracers. Electron microscopy demonstrated significant accumulation of the tracer (tin colloid) in harvested SN, of which particle sizes were in the range of 100-150 nm. Therefore, this appeared to be a suitable particle size for SN identification. (2) Invention of a new gamma probe. A cord-and boxless handheld gamma probe was invented, which was more sensitive to radioactivity and involved a background subtraction function based on defined criteria. (3) Characterization of the immunologic response against tumor antigens. Fluorescence-activated cell sorting (FACS) analyses were performed to determine the phenotypic characteristics of B cells and T cells in SN. They revealed an increase in B cells expressing co-stimulated molecules as antigen-presenting cells in SN, compared with non-SN. With respect to T cells, a heterogeneous pattern of naive and memory T cells (TCM) was demonstrated in SN, in contrast to homogeneous pattern with TCM in non-SN. These results may support the concept that B cells play a significant role in antigen presentation required for T cell activation. Studies are currently in progress to test these possibilities.

Purpose: Trastuzumab-based therapy improves survival for women with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer. We conducted a multicenter phase II study to evaluate the efficacy and safety of trastuzumab combined with vinorelbine, and to assess cardiac surveillance algorithms and tumor markers as prognostic tools., Patients and Methods: Patients with HER2-positive (immunohistochemistry [IHC] 3+-positive or fluorescence in situ hybridization [FISH]-positive) metastatic breast cancer received first-line chemotherapy with trastuzumab and vinorelbine to determine response rate. Eligibility criteria were measurable disease and baseline ejection fraction >or= 50%. Serial testing for HER2 extracellular domain (ECD) was performed., Results: Fifty-four women from 17 participating centers were entered onto the study. The overall response rate was 68% (95% confidence interval, 54% to 80%). Response rates were not affected by method of HER2 status determination (FISH v IHC) or by prior adjuvant chemotherapy. Median time to treatment failure was 5.6 months; 38% of patients were progression free after 1 year. Concurrent therapy was quite feasible with maintained dose-intensity. Patients received both chemotherapy and trastuzumab on 90% of scheduled treatment dates. Two patients experienced cardiotoxicity in excess of grade 1; one patient experienced symptomatic heart failure. A surveillance algorithm of screening left ventricular ejection fraction (LVEF) at 16 weeks successfully identified women at risk for experiencing cardiotoxicity. Other acute and chronic side effects were tolerable. Lack of decline in HER2 ECD during cycle 1 predicted tumor progression., Conclusion: Trastuzumab and vinorelbine constitute effective and well-tolerated first-line treatment for HER2-positive metastatic breast cancer. Patients with normal LVEF can be observed with surveillance of LVEF at 16 weeks to identify those at risk for cardiotoxicity.

Purpose: Trastuzumab combined with chemotherapy improves outcomes for women with human epidermal growth factor receptor 2 (HER2) overexpressing advanced breast cancer. We conducted a pilot study of preoperative trastuzumab and paclitaxel, followed by surgery and adjuvant doxorubicin and cyclophosphamide chemotherapy in earlier stage breast cancer., Patients and Methods: Patients with HER2-positive (2+ or 3+ by immunohistochemistry) stage II or III breast cancer received preoperative trastuzumab (4 mg/kg x 1, then 2 mg/kg/wk x 11) in combination with paclitaxel (175 mg/m(2) every 3 weeks x 4). Patients received adjuvant doxorubicin and cyclophosphamide chemotherapy following definitive breast surgery. Clinical and pathologic response rates were determined after preoperative therapy. Left ventricular ejection fraction and circulating levels of HER2 extracellular domain were measured serially., Results: Preoperative trastuzumab and paclitaxel achieved clinical response in 75% and complete pathologic response in 18% of the 40 women on study. HER2 3+ tumors were more likely to respond than 2+ tumors (84% v 38%). No unexpected treatment-related noncardiac toxicity was encountered. Four patients developed grade 2 cardiotoxicity (asymptomatic declines in left ventricular ejection fraction). Baseline HER2 extracellular domain was elevated in 24% of patients and declined with preoperative therapy. Immunohistochemical analyses of posttherapy tumor specimens indicated varying patterns of HER2 expression following trastuzumab-based treatment., Conclusion: Preoperative trastuzumab and paclitaxel is active against HER2 overexpressing early-stage breast cancer and may be feasible as part of a sequential treatment program including anthracyclines. The observed changes in cardiac function merit further investigation. Correlative analyses of HER2 status may facilitate understanding of tumor response and resistance to targeted therapy.

Purpose: A phase I study of the antitumor antibiotic 7-cyanoquinocarcinol, DX-52-1, was conducted in patients with refractory solid malignancies. This study sought to determine the maximum tolerated dose and principal toxicities of this agent and to characterize its pharmacokinetic behavior., Methods: Patients were required to have adequate bone marrow, renal and hepatic function. DX-52-1 was administered by i.v. continuous infusion over a 6-h period each week for four consecutive weeks followed by a 2-week rest period, which constituted one cycle of treatment., Results: Initial dose levels were 3, 6, and 10 mg/m2. An intermediate dose level of 8 mg/m2 was added after acceptable toxicity was observed at the 6 mg/m2 dose level, but dose-limiting toxicities, including life-threatening ones, were seen at the 10 mg/m2 dose level in all three patients. The maximum tolerated dose (MTD) was subsequently determined to be 6 mg/m2. Because a clear pattern of toxicities was not initially evident, a larger than usual number of additional patients (16) were enrolled at the MTD to better distinguish toxicities due to the study drug from those secondary to the patients' underlying malignancies. Even at the MTD, the drug was poorly tolerated, with gastrointestinal toxicities (abdominal pain, nausea, vomiting and increased liver function tests) predominating and dose-limiting. Pharmacokinetic studies revealed that the mean maximum plasma concentration of DX-52-1 in patients evaluated at the MTD (138.8 +/- 59.3 ng/ml, n = 19) was considerably lower than the concentrations required for cytostatic or cytotoxic activity against sensitive human tumor cell lines in vitro. Further, the weekly dose intensity of the most efficacious treatment schedule identified during in vivo antitumor efficacy studies was 60 times greater than the 6 mg/m2 weekly dose tolerated by cancer patients. None of the 33 patients participating in this study, including the 22 patients evaluated at the MTD, had any response to treatment., Conclusion: Given the poor tolerability, the inability to achieve drug levels necessary to inhibit in vitro or in vivo tumor growth, and the lack of any responses in our study, DX-52-1, as given by this schedule, does not appear to warrant further investigation in phase II studies.

Cytotoxic chemotherapy is important for treatment of women with hormone-insensitive or hormone-refractory advanced breast cancer. A variety of agents are effective, alone or in combination. The clinical activity and side effects of many agents, as well as principles for use of chemotherapy, are reviewed. Recent advances in chemotherapy for breast cancer include important studies on the role of dose-intensity, modifications of available agents to reduce side effects, and the availability of oral chemotherapeutics. Finally, the combination of chemotherapy with novel biological agents may improve outcomes for women with certain types of breast cancer. The growing availability of such biological therapies given in combination with chemotherapy may mean better survival in the future for women with advanced breast cancer.

Purpose: To determine the response rate and toxicity profile of trastuzumab administered concurrently with weekly vinorelbine in women with HER2-overexpressing advanced breast cancer., Patients and Methods: Forty women with HER2-positive (+3 by immunohistochemistry, n = 30; +2 or positive, n = 10) breast cancer were enrolled onto a study of trastuzumab (4 mg/kg x 1, 2 mg/kg weekly thereafter) and vinorelbine (25 mg/m2 weekly, with dose adjusted each week for neutrophil count). Eighty-two percent of women had received prior chemotherapy as part of adjuvant (30%), metastatic (25%), or both (28%) treatment, including substantial portions of patients who had previously received either anthracyclines (20%), taxanes (15%), or both types (38%) of chemotherapy., Results: Responses were observed in 30 of 40 patients (overall response rate, 75%, conditional corrected 95% confidence interval, 57% to 89%). The response rate was 84% in patients treated with trastuzumab and vinorelbine as first-line therapy for metastatic disease, and 80% among HER2 +3 positive patients. High response rates were also seen in women treated with second- or third-line therapy, and among patients previously treated with anthracyclines and/or taxanes. Combination therapy was feasible; patients received concurrent trastuzumab and vinorelbine in 93% of treatment weeks. Neutropenia was the only grade 4 toxicity. No patients had symptomatic heart failure. Grade 2 cardiac toxicity was observed in three patients. Prior cumulative doxorubicin dose in excess of 240 mg/m2 and borderline pre-existing cardiac function were associated with grade 2 cardiac toxicity., Conclusion: Trastuzumab in combination with vinorelbine is highly active in women with HER2-overexpressing advanced breast cancer and is well tolerated.

High-dose chemotherapy with autologous stem cell support for the treatment of breast cancer can have a profound effect on patients' quality of life (QOL). This article reviews findings from studies assessing QOL before, during, and after high-dose chemotherapy. The impact of high-dose therapy on overall QOL and specific aspects of QOL including physical functioning, symptoms, psychosocial/emotional and cognitive functioning, sexual functioning, and role functioning is considered. High-dose chemotherapy with stem cell transplant results in largely transient impairment of overall QOL and physical functioning, with subsequent improvement to baseline or better over time. Despite these encouraging global QOL findings, many patients continue to suffer considerable symptoms and concerns attributable to their transplant long after completion of the therapy. Additional research in this area is needed to optimize QOL for patients receiving high-dose chemotherapy.

Purpose: To evaluate the safety and efficacy of weekly docetaxel in women with metastatic breast cancer., Patients and Methods: Twenty-nine women were enrolled onto a study of weekly docetaxel given at 40 mg/m(2)/wk. Each cycle consisted of 6 weeks of therapy followed by a 2-week treatment break, repeated until disease progression or removal from study for toxicity or patient preference. Fifty-two percent of patients had been previously treated with adjuvant chemotherapy; 21% had received prior chemotherapy for metastatic breast cancer, and 31% had previously received anthracyclines. All patients were assessable for toxicity; two patients were not assessable for response but are included in an intent-to-treat analysis., Results: Patients received a median of 18 infusions, with a median cumulative docetaxel dose of 720 mg/m(2). There were no complete responses. Twelve patients had partial responses (overall response rate, 41%; 95% confidence interval, 24% to 61%), all occurring within the first two cycles. Similar response rates were observed among subgroups of patients previously treated either with any prior chemotherapy or with anthracyclines. An additional 17% of patients had stable disease for at least 6 months. The regimen was generally well tolerated. There was no grade 4 toxicity. Only 28% of patients had any grade 3 toxicity, most commonly neutropenia and fatigue. Acute toxicity, including myelosuppression, was mild. Fatigue, fluid retention, and eye tearing/conjunctivitis became more common with repetitive dosing, although these side effects rarely exceeded grade 2. Dose reductions were made for eight of 29 patients, most often because of fatigue (n = 5)., Conclusion: Weekly docetaxel is active in treating patients with metastatic breast cancer, with a side effect profile that differs from every-3-weeks therapy.

Three oral 5-fluorouracil (5-FU) therapies have been approved by the US Food and Drug Administration or are in development for the treatment of patients with breast cancer: capecitabine, UFT, and 5-FU/eniluracil. Capecitabine has been approved for breast cancer patients whose disease is paclitaxel-resistant, and either anthracycline-resistant or for whom further anthracycline use is not indicated. A response rate of 20% was observed in an open-label phase II trial of capecitabine in heavily pretreated patients with metastatic breast cancer. Diarrhea and hand-foot syndrome were the most frequently reported toxicities. In a randomized phase II study of capecitabine vs paclitaxel in breast cancer patients who had failed anthracyclines, response rates were 36% for capecitabine vs 21% for paclitaxel. Several phase II trials of 5-FU/eniluracil in breast cancer are ongoing. Preliminary response data from one of these trials on 31 patients with anthracycline- and taxane-resistant advanced breast cancer showed a 16% partial response rate. Grade 3-4 treatment-related toxicities included diarrhea (8%), nausea (3%), and granulocytopenia (3%). In Japan, UFT is widely used for the treatment of breast cancer in both the adjuvant and metastatic settings, though studies in the United States are just getting under way. A phase II trial conducted in Madrid, Spain evaluated the combination of UFT, methotrexate, and leucovorin as salvage therapy for breast cancer patients. The overall response rate was 38% among 21 patients, and diarrhea was the most common toxicity. Many questions remain unanswered about the optimal use of oral 5-FU agents in breast cancer. There seems little question that these agents have substantial activity and will find a place in the therapeutic armamentarium.

Background: Ifosfamide and paclitaxel are antineoplastic agents with broad activity and with different mechanisms of action. A Phase I trial was conducted to determine the maximum tolerated dose and associated toxicities of these agents when used in combination., Methods: Patients with refractory, incurable solid tumors were entered on a 5-step Phase I trial of ifosfamide, given in doses of 2-3 g/m2 intravenous (i.v.) bolus for 3 days with mesna support, and paclitaxel, given in doses of 135-190 g/m2 i.v. by continuous infusion over 24 hours. Paclitaxel was given after the first dose of ifosfamide on Day 1., Results: Twenty-three patients were treated, and the maximum tolerated dose was the highest planned dose level of the trial: ifosfamide, 3 g/m2/day i.v. for 3 days, and paclitaxel, 190 mg/m2 i.v. over 24 hours. Hematologic toxicity was not dose-limiting, and although neutropenia occurred, it was brief (median, 2-4 days) and resulted in hospitalization for neutropenia and fever in only 7 of 111 courses of therapy. For patients treated at the highest dose level, only 1 of 50 courses of therapy resulted in hospitalization for neutropenia and fever. Nonhematologic toxicity also was not severe and no significant neuropathy occurred. Although patients entered into the study were heavily pretreated, responses were observed, particularly in patients with breast or ovarian carcinoma., Conclusions: Ifosfamide and paclitaxel can be administered safely in the doses used in this study and there are indications of significant antitumor effect. Further studies are necessary to explore the antineoplastic activity of this regimen, particularly for patients with breast and ovarian carcinoma.

Background: Systemic mastocytosis is characterized by mast cell infiltration of bone marrow and tissues in the absence of identified circulating bone marrow-derived progenitors. A 58-year-old man was first seen with aggressive systemic mastocytosis manifested by urticaria pigmentosa, hepatosplenomegaly, generalized bone lesions, anemia, thrombocytopenia, monoclonal gammopathy, and increased urine histamine levels., Objectives and Methods: A rapidly progressive anemia and thrombocytopenia dictated a splenectomy. We sought to identify the mast cell progenitors in the peripheral blood and to provide evidence of their maturation in tissues with immunohistochemical and ultrastructural analyses., Results: The peripheral blood contained 1% to 3% nonmetachromatic mononuclear cells with eccentric nuclei that expressed the mast cell proteases, tryptase and carboxypeptidase A, along with c-kit, stem cell factor (SCF), and high-affinity IgE receptor (Fc epsilon RI), but not chymase. Similar mononuclear cells colocalized in the spleen and lymph nodes with mature, metachromatic mast cells that expressed tryptase, chymase, carboxypeptidase A, c-kit, SCF, and Fc epsilon RI. Electron microscopy disclosed, at each site, a mature mast cell population with electron-dense, scroll-poor granules., Conclusions: The peripheral blood of a patient with aggressive systemic mastocytosis contained immature mononuclear cells of the mast cell lineage that express c-kit, SCF, tryptase, carboxypeptidase A, and Fc epsilon RI. These cells were also found in the skin, spleen, and lymph nodes where they presumably expand, differentiate, and mature, assuming the mast cell phenotype for those tissues characterized by metachromasia, expression of a full range of mast cell-related secretory granule proteases, and ultrastructural appearance. The presence of SCF on the surface membrane of the circulating, highly immature mast cells suggests an autocrine regulation of the c-kit-SCF interaction.