Publications by authors named "Craig A Bunnell"

26 Publications

  • Page 1 of 1

Phase I study of JAK1/2 inhibitor ruxolitinib with weekly paclitaxel for the treatment of HER2-negative metastatic breast cancer.

Cancer Chemother Pharmacol 2021 Feb 14. Epub 2021 Feb 14.

Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA.

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 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.
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http://dx.doi.org/10.1007/s00280-021-04245-xDOI Listing
February 2021

Clinical Impact of Second Opinion Radiology Consultation for Patients With Breast Cancer.

J Am Coll Radiol 2019 Jun 20;16(6):814-823. Epub 2018 Dec 20.

Center for Evidence-Based Imaging and Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.

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 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.
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http://dx.doi.org/10.1016/j.jacr.2018.10.010DOI Listing
June 2019

Impact of Genomic Assay Testing and Clinical Factors on Chemotherapy Use After Implementation of Standardized Testing Criteria.

Oncologist 2019 05 3;24(5):595-602. Epub 2018 Aug 3.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

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.
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http://dx.doi.org/10.1634/theoncologist.2018-0154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516114PMC
May 2019

Developing a Novel Model to Improve Research and care for Cancer Survivors: a Feasibility Study.

J Cancer Educ 2019 04;34(2):229-233

Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA.

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.
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http://dx.doi.org/10.1007/s13187-017-1291-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910291PMC
April 2019

Implementation of Surgeon-Initiated Gene Expression Profile Testing (Onco type DX) Among Patients With Early-Stage Breast Cancer to Reduce Delays in Chemotherapy Initiation.

J Oncol Pract 2017 09 31;13(9):e815-e820. Epub 2017 Aug 31.

Dana-Farber Cancer Institute; Dana-Farber/Brigham and Women's Cancer Center; Brigham and Women's Hospital; and Harvard Medical School, Boston, MA.

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.
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http://dx.doi.org/10.1200/JOP.2017.023788DOI Listing
September 2017

Factors Associated With Delays in Chemotherapy Initiation Among Patients With Breast Cancer at a Comprehensive Cancer Center.

J Natl Compr Canc Netw 2016 12;14(12):1519-1526

From Department of Medical Oncology and Quality and Patient Safety, Dana-Farber Cancer Institute, Boston, Massachusetts; Oncoclinicas, Sao Paulo, Brazil; Department of General Surgery, Istanbul Medical School, Istanbul, Turkey; and Department of Surgery, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts.

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.
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http://dx.doi.org/10.6004/jnccn.2016.0163DOI Listing
December 2016

Variation in the use of granulocyte-colony stimulating factor for dose dense paclitaxel: A single institution retrospective study.

Breast 2016 Dec 6;30:136-140. Epub 2016 Oct 6.

Department of Medical Oncology, Dana Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.breast.2016.09.013DOI Listing
December 2016

Teamwork and Electronic Health Record Implementation: A Case Study of Preserving Effective Communication and Mutual Trust in a Changing Environment.

J Oncol Pract 2016 11 31;12(11):1075-1083. Epub 2016 Oct 31.

Dana-Farber Cancer Institute, Boston, MA.

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.
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http://dx.doi.org/10.1200/JOP.2016.013649DOI Listing
November 2016

Implementation of a Breast/Reconstruction Surgery Coordinator to Reduce Preoperative Delays for Patients Undergoing Mastectomy With Immediate Reconstruction.

J Oncol Pract 2016 Mar 16;12(3):e338-43. Epub 2016 Feb 16.

Brigham and Women's Hospital; and Dana-Farber Cancer Institute, Boston, MA.

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.
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http://dx.doi.org/10.1200/JOP.2015.008672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4960471PMC
March 2016

Variation in Additional Breast Imaging Orders and Impact on Surgical Wait Times at a Comprehensive Cancer Center.

Ann Surg Oncol 2015 Dec 26;22 Suppl 3:S428-34. Epub 2015 Aug 26.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

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.
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http://dx.doi.org/10.1245/s10434-015-4834-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4688062PMC
December 2015

Use of potassium concentrations as a quality-of-service metric for phlebotomists detects systematic preanalytical biases and facilitates their correction.

Clin Chem 2014 Nov 26;60(11):1453-5. Epub 2014 Aug 26.

Department of Pathology, Brigham and Women's Hospital, Boston, MA; Harvard Medical School, Cambridge, MA; Dana Farber Cancer Institute, Boston, MA

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http://dx.doi.org/10.1373/clinchem.2014.227686DOI Listing
November 2014

Measuring opportunities to improve timeliness of breast cancer care at Dana-Farber/Brigham and Women's Cancer Center.

J Natl Compr Canc Netw 2014 Feb;12 Suppl 1:S5-9

From the aDepartment of Medical Oncology, and bDepartment of Quality and Patient Safety, Dana-Farber Cancer Institute; cDepartment of Surgery, Brigham and Women's Hospital; and dDepartment of Surgery, Dana-Farber Cancer Institute, Boston, Massachusetts.

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.
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http://dx.doi.org/10.6004/jnccn.2014.0215DOI Listing
February 2014

High performance teamwork training and systems redesign in outpatient oncology.

BMJ Qual Saf 2013 May 24;22(5):405-13. Epub 2013 Jan 24.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

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.
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http://dx.doi.org/10.1136/bmjqs-2012-000948DOI Listing
May 2013

Ixabepilone-associated peripheral neuropathy: data from across the phase II and III clinical trials.

Support Care Cancer 2012 Nov 2;20(11):2661-8. Epub 2012 Mar 2.

Weill Cornell Breast Center, Weill Cornell Medical College, New York, NY, USA.

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.
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http://dx.doi.org/10.1007/s00520-012-1384-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3461204PMC
November 2012

Models of multidisciplinary cancer care: physician and patient perceptions in a comprehensive cancer center.

J Oncol Pract 2010 Nov;6(6):283-8

Departments of Medical Oncology, Surgical Oncology, and Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital; Harvard Medical School, Boston, MA.

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.
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http://dx.doi.org/10.1200/JOP.2010.000138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2988660PMC
November 2010

Will we be able to care for cancer patients in the future?

Oncology (Williston Park) 2010 Dec;24(14):1343-8

Dana-Farber Cancer Institute, Boston, MA 02215, USA.

The number of cancer patients and cancer survivors continues to increase rapidly amid predictions of a shortfall in physicians to care for them. In addition, newer cancer therapies have become increasingly complex and resource-intensive, compounding the impending workforce shortage. Simultaneously, the growing understanding of the biologic heterogeneity of cancer and the development of pharmacogenomics have opened up the possibility of personalized approaches to cancer diagnosis and treatment. Such personalization has been promulgated as a means of decreasing the cost of drug development, improving the efficacy of treatments, and reducing treatment toxicity. Although there have been notable successes, the fulfillment of these promises has been inconsistent. Providing care for future cancer patients will require the development of innovative delivery models. Moreover, new approaches to clinical research design, to the assessment of therapeutic value, and to the approval of and reimbursement for diagnostics and treatments are needed.
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December 2010

Phase I trial of liposomal doxorubicin and ZD1839 in patients with refractory gynecological malignancies or metastatic breast cancer.

Int J Clin Oncol 2010 Aug 20;15(4):390-8. Epub 2010 Apr 20.

Department of Gynecology Oncology, Dana Farber Cancer Institute, 44 Binney Street, Boston, MA, USA.

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.
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http://dx.doi.org/10.1007/s10147-010-0073-6DOI Listing
August 2010

Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in patients with taxane-resistant metastatic breast cancer.

J Clin Oncol 2007 Aug 2;25(23):3399-406. Epub 2007 Jul 2.

The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.

Purpose: Ixabepilone (BMS-247550) is an epothilone analog that optimizes the properties of naturally occurring epothilone B. Natural epothilones and their analogs promote tumor cell death by binding to tubulin and stabilizing microtubules, causing apoptosis. This international phase II trial assessed the activity of ixabepilone in patients with metastatic breast cancer (MBC) that was resistant to taxane therapy.

Patients And Methods: MBC patients, who had experienced disease progression while receiving or within 4 months of taxane therapy (6 months if adjuvant taxane only), and who had a taxane as their last regimen, received ixabepilone (1- or 3-hour infusion of 50 mg/m(2) or 3-hour infusion of 40 mg/m(2) every 3 weeks).

Results: Of 49 patients treated with 40 mg/m(2) ixabepilone during 3 hours, 35 (73%) had experienced disease progression within 1 month of their last taxane dose. The response rate was 12% (95% CI, 4.7% to 26.5%). All responses (n = 6) were partial; five of six patients had not responded to prior taxane therapy. In responders, the median response duration was 10.4 months. In 20 patients (41%), stable disease was the best outcome. Median time to progression was 2.2 months (95% CI, 1.4 to 3.2 months); median survival was 7.9 months. For treated patients across all cohorts (intent-to-treat population), the response rate was also 12% (eight of 66). Treatment-related adverse events in the study were manageable and primarily grade 1/2. Treatment-related neuropathy was mostly sensory and mild to moderate.

Conclusion: Ixabepilone (40 mg/m(2) as a 3-hour infusion every 3 weeks) demonstrates promising antitumor activity and an acceptable safety profile in patients with taxane-resistant MBC.
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http://dx.doi.org/10.1200/JCO.2006.08.9102DOI Listing
August 2007

Assessment of a dietary questionnaire in cancer patients receiving cytotoxic chemotherapy.

J Clin Oncol 2005 Nov;23(33):8453-60

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.

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.
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http://dx.doi.org/10.1200/JCO.2005.02.5460DOI Listing
November 2005

Efficacy of pegfilgrastim and darbepoetin alfa as hematopoietic support for dose-dense every-2-week adjuvant breast cancer chemotherapy.

J Clin Oncol 2005 Nov;23(33):8340-7

Dana-Farber Cancer Institute, Boston, MA 02115, USA.

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.
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http://dx.doi.org/10.1200/JCO.2005.02.8621DOI Listing
November 2005

Prospective evaluation of concurrent paclitaxel and radiation therapy after adjuvant doxorubicin and cyclophosphamide chemotherapy for Stage II or III breast cancer.

Int J Radiat Oncol Biol Phys 2006 Feb 21;64(2):496-504. Epub 2005 Oct 21.

Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham & Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA.

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.
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http://dx.doi.org/10.1016/j.ijrobp.2005.07.975DOI Listing
February 2006

Adjuvant ovarian suppression versus chemotherapy for premenopausal, hormone-responsive breast cancer: quality of life and efficacy tradeoffs.

Breast Cancer Res Treat 2005 Sep;93(1):25-34

Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 44, New York, NY 10021, USA.

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.
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http://dx.doi.org/10.1007/s10549-005-3380-2DOI Listing
September 2005

Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: multicenter phase II trial with clinical outcomes, analysis of serum tumor markers as predictive factors, and cardiac surveillance algorithm.

J Clin Oncol 2003 Aug;21(15):2889-95

Dana-Farber Cancer Institute, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

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.
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http://dx.doi.org/10.1200/JCO.2003.02.018DOI Listing
August 2003

Preoperative therapy with trastuzumab and paclitaxel followed by sequential adjuvant doxorubicin/cyclophosphamide for HER2 overexpressing stage II or III breast cancer: a pilot study.

J Clin Oncol 2003 Jan;21(1):46-53

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.

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.
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http://dx.doi.org/10.1200/JCO.2003.03.124DOI Listing
January 2003

Lumping versus splitting: the splitters take this round.

J Clin Oncol 2002 Sep;20(17):3576-7

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http://dx.doi.org/10.1200/JCO.2002.06.157DOI Listing
September 2002