Systemic toxicities of trastuzumab-emtansine predict tumor response in HER2+ metastatic breast cancer.

The mechanism by which trastuzumab-emtansine (T-DM1) causes systemic toxicities apart from trastuzumab alone is currently unknown. We hypothesized that the systemic toxicities from T-DM1 may have been caused by the free and active maytansine released from the lysed HER2+ tumor cells, and if so, they may correlate with the response to treatment and eventually disease-free survival or patient outcome. In a retrospective, observational study, we evaluated 73 patients from three centers in the United States and Canada with advanced HER2+ breast cancer that received at least one dose of T-DM1. Toxicity grades were summed to create a corresponding toxicity sum score (TSS), and its association with clinical outcomes was analyzed. A higher TSS was significantly associated with longer progression-free survival with an HR = 0.66 [95% confidence interval [CI]: 0.47-0.92], P = .014, for each 1-point increase in the TSS score. Adjusted for baseline platelet count, aspartate transaminase and alanine transaminase, higher TSS remains significantly associated with longer progression-free survival with adjusted HR = 0.67 [95% CI: 0.47-0.93], P = .020. The analysis suggests that the systemic toxicities of T-DM1 were significantly correlated with its clinical efficacy. This is the first report to correlate the systemic toxicities of T-DM1 with clinical outcome. Further, this suggests that systemic toxicities of antibody-drug conjugates (ADCs) may serve as a predictive biomarker, particularly if noncleavable linkers are used. If confirmed in larger prospective studies, the present finding is significant because most ADCs do not have a biomarker predictive of clinical outcome other than the presence or absence of the antibody target.

The Will Rogers phenomenon, breast cancer and race.

BACKGROUND: The Will Rogers phenomenon [WRP] describes an apparent improvement in outcome for patients' group due to tumor grade reclassification. Staging of cancers is important to select appropriate treatment and to estimate prognosis. The WRP has been described as one of the most important biases limiting the use of historical cohorts when comparing survival or treatment. The main purpose of this study is to assess whether the WRP exists with the move from the AJCC 7th to AJCC 8th edition in breast cancer [BC] staging, and if racial differences are manifested in the expression of the WRP. METHODS: This is a retrospective analysis of 300 BC women (2007-2017) at an academic medical center. Overall survival [OS] and disease-free survival [DFS] was estimated by Kaplan-Meier analysis. Bi and multi-variate Cox regression analyses was used to identify racial factors associated with outcomes. RESULTS: Our patient cohort included 30.3% Caucasians [Whites] and 69.7% African-Americans [Blacks]. Stages I, II, III, and IV were 46.2, 26.3, 23.1, and 4.4% of Whites; 28.7, 43.1, 24.4, and 3.8% of Blacks respectively, in anatomic staging (p = 0.043). In prognostic staging, 52.8, 18.7, 23, and 5.5% were Whites while 35, 17.2, 43.5, and 4.3% were Blacks, respectively (p = 0.011). A total of Whites (45.05% vs. 47.85%) Blacks, upstaged. Whites (16.49% vs. 14.35%) Blacks, downstaged. The remaining, 38.46 and 37.79% patients had their stages unchanged. With a median follow-up of 54 months, the Black patients showed better stage-by-stage 5-year OS rates using 8th edition compared to the 7th edition (p = 0.000). Among the Whites, those who were stage IIIA in the 7th but became stage IB in the 8th had a better prognosis than stages IIA and IIB in the 8th (p = 0.000). The 8th showed complex results (p = 0.176) compared to DFS estimated using the 7th edition (p = 0.004). CONCLUSION: The WRP exists with significant variability in the move from the AJCC 7th to the 8th edition in BC staging (both White and Black patients). We suggest that caution needs to be exercised when results are compared across staging systems to account for the WRP in the interpretation of the data.

Development of a Nostalgic Remembering Intervention: Feeling Safe in Dyads Receiving Palliative Care for Advanced Heart Failure.

BACKGROUND: Dyads receiving palliative care for advanced heart failure are at risk for the loss of feeling safe, experienced as a fractured sense of coherence, discontinuity in sense of self and relationships, and strained social connections and altered roles. However, few theory-based interventions have addressed feeling safe in this vulnerable population. PURPOSE: The purpose of this article is to describe the development of the Nostalgic Remembering Intervention to strengthen feeling safe and promote adaptive physiological and psychological regulation in dyads receiving palliative care for heart failure. CONCLUSIONS: Systematic intervention development is essential to understand what, for whom, why, and how an intervention works in producing outcomes. Program theory provided a systematic approach to the development of the Nostalgic Remembering Intervention, including conceptualization of the problem targeted by the intervention, specification of critical inputs and conditions that operationalize the intervention, and understanding the mediating processes leading to expected outcomes. CLINICAL IMPLICATIONS: Creating a foundation for cardiovascular nursing research and practice requires continued, systematic development of theory-based interventions to best meet the needs of dyads receiving palliative care for heart failure. The development of the Nostalgic Remembering Intervention to strengthen feeling safe in dyads provides a novel and relevant approach.

A Partnership in Health-Related Social Media for Young Breast Cancer Survivors.

In the United States, about 11% (26,393) of those diagnosed with breast cancer in 2016 will be young or less than 45 years old. Young breast cancer survivors, compared to older cancer survivors, are a disparate group that experience higher incidence of advanced disease, greater mortality, and poorer quality of life, and are often faced with difficulty locating support that meet the unique needs of young women. The Gulf States Young Breast Cancer Survivor Network, composed of three sister networks, formed a partnership aimed at harnessing the power of social media to reach and impact the lives of young women with breast cancer. The collaborative partnership framework and the power of synergy are shown in merging two existing programs and incorporating a third new program.

BRCA1-IRIS inactivation overcomes paclitaxel resistance in triple negative breast cancers.

INTRODUCTION: Intrinsic or acquired chemoresistance is a major problem in oncology. Although highly responsive to chemotherapies such as paclitaxel, most triple negative breast cancer (TNBC) patients develop chemoresistance. Here we investigate the role of BRCA1-IRIS as a novel treatment target for TNBCs and their paclitaxel-resistant recurrences. METHODS: We analyzed the response of BRCA1-IRIS overexpressing normal mammary cells or established TNBC cells silenced from BRCA1-IRIS to paclitaxel in vitro and in vivo. We analyzed BRCA1-IRIS downstream signaling pathways in relation to paclitaxel treatment. We also analyzed a large cohort of breast tumor samples for BRCA1-IRIS, Forkhead box class O3a (FOXO3a) and survivin expression. Finally, we analyzed the effect of BRCA1-IRIS silencing or inactivation on TNBCs formation, maintenance and response to paclitaxel in an orthotopic model. RESULTS: We show that low concentrations of paclitaxel triggers BRCA1-IRIS expression in vitro and in vivo, and that BRCA1-IRIS activates two autocrine signaling loops (epidermal growth factor (EGF)/EGF receptor 1 (EGFR)-EGF receptor 2 (ErbB2) and neurogulin 1 (NRG1)/ErbB2-EGF receptor 3 (ErbB3), which enhances protein kinase B (AKT) and thus survivin expression/activation through promoting FOXO3a degradation. This signaling pathway is intact in TNBCs endogenously overexpressing BRCA1-IRIS. These events trigger the intrinsic and acquired paclitaxel resistance phenotype known for BRCA1-IRIS-overexpressing TNBCs. Inactivating BRCA1-IRIS signaling using a novel inhibitory mimetic peptide inactivates these autocrine loops, AKT and survivin activity/expression, in part by restoring FOXO3a expression, and sensitizes TNBC cells to low paclitaxel concentrations in vitro and in vivo. Finally, we show BRCA1-IRIS and survivin overexpression is correlated with lack of FOXO3a expression in a large cohort of primary tumor samples, and that BRCA1-IRIS overexpression-induced signature is associated with decreased disease free survival in heavily treated estrogen receptor alpha-negative patients. CONCLUSIONS: In addition to driving TNBC tumor formation, BRCA1-IRIS overexpression drives their intrinsic and acquired paclitaxel resistance, partly by activating autocrine signaling loops EGF/EGFR-ErbB2 and NRG1/ErbB2-ErbB3. These loops activate AKT, causing FOXO3a degradation and survivin overexpression. Taken together, this underscores the need for BRCA1-IRIS-specific therapy and strongly suggests that BRCA1-IRIS and/or signaling loops activated by it could be rational therapeutic targets for advanced TNBCs.

Hormone receptor-independent CXCL10 production is associated with the regulation of cellular factors linked to breast cancer progression and metastasis.

Breast cancer (BC) is a major health problem for women around the world. Although advances in the field of molecular therapy have been achieved, the successful therapeutic management of BC, particularly metastatic disease, remains a challenge for patients and clinicians. One of the areas of current investigation is the circulating tumor cells (CTCs), which have a determinant role in the development of distant metastasis. At the present, many of the available treatment strategies for metastatic disease are of limited benefit. However, the elucidation of the mechanisms of tumor progression and metastasis may help to identify key molecules/components that may function as therapeutic targets in the future. In the present study, the functional analysis of CTCs revealed their ability to grow and proliferate to form colonies. Immunofluorescence staining of the CTCs' colonies exhibits elevated expression of cell growth and survival associated proteins such as, survivin, ERK and Akt1. More importantly, the functional screening of the chemokine profile in BC patients' sera revealed an HR-independent elevation of the chemokine CXCL10 when compared to healthy controls. The analysis of chemokines CXCL9 and CXCL11 demonstrated an HR-dependent production pattern. The levels of both CXCL9 and CXCL11 were markedly high in HR+ patients' sera when compared to HR- patients and healthy controls. The functional analysis of HR+ and HR- BC derived cell lines when cultivated in media supplemented with patients' sera demonstrated the alteration of tumor progression and metastasis related proteins. We noted the induction of survivin, ß-catenin, MKP-1, pERK, CXCR4 and MMP-1 both at the protein and mRNA levels. The induction of those proteins was in keeping with patients' sera induced cell proliferation as measured by the MTT assay. In conclusion, our data emphasizes the role of chemokines, especially CXCL10, in BC progression and metastasis via the induction of signaling pathways, which mainly involve survivin, ß-catenin, MKP-1 and MMP-1.

Toll-like receptor (TLR) expression of immune system cells from metastatic breast cancer patients with circulating tumor cells.

The risk posed by breast cancer represents a complex interaction among factors affecting tumor immunity of the host. Toll-like receptors (TLRs) are members of the innate immune system and generally function to attract host immune cells upon activation. However, the good intentions of TLRs are sometimes not transferred to positive long-term effects, due to their involvement in exacerbating inflammatory effects and even contributing to continued inflammation. Chronic inflammatory states are considered to favor an increased predisposition to cancer, with continuous activation of inflammatory cytokines and other hallmarks of inflammation exerting a deleterious effect. Circulating tumor cells (CTCs) are neoplastic cells present in the peripheral blood circulation that have been found to be an indicator of disease progression and long-term survival. In the present study, we examined the expression of TLRs on dendritic cells, which play a major role in eliciting anti-tumor immunity, in metastatic breast cancer patients with CTCs. Flow cytometric data showed significant differences between circulating tumor cell (CTC) positive patients and CTC negative patients in their expression of TLR2 by CD8 positive cytotoxic T cells and TLR2, TLR4, TLR3, and TLR8 by CD11c positive dendritic cells (p<0.05). Expression of TLR2, TLR4, and TLR8 was increased in CTC positive patients, whereas TLR3 expression was decreased in the dendritic cell population.

Comparative analysis of innate immune system function in metastatic breast, colorectal, and prostate cancer patients with circulating tumor cells.

In recent years, circulating tumor cells (CTCs) in metastatic cancer patients have been found to be a promising biomarker to predict overall survival and tumor progression in these patients. A relatively high number of CTCs has been correlated with disease progression and poorer prognosis. This study was designed to assess innate immune system function, known to be responsible for the immune defense against developing neoplasms, in metastatic cancer patients with CTCs. Our aim is to provide a link between indication of poorer prognosis, represented by the number of CTCs to the cytotoxic activity of natural killer cells, an important component of the innate immune system, and to represent a promising expanded approach to management of metastatic cancer patients with CTCs. Seventy-four patients, with metastatic breast, colorectal, or prostate cancer, were recruited for this study. Using a flow cytometric assay, we measured natural killer (NK) cell cytotoxicity against K562 target cells; and CTCs were enumerated using the CellSearch System. Toll-like receptors 2 and 4 expression was also determined by flow cytometry. We found that within each of our three metastatic cancer patient groups, NK cell cytotoxic activity was decreased in patients with a relatively high number of CTCs in peripheral blood compared to patients with a relatively low number of CTCs. In the breast and prostate cancer group, patients with CTCs greater than 5 had decreased NK cell cytotoxicity when compared to patients with less than 5 CTCs. In the colorectal cancer group, we found that 3 or more CTCs in the blood was the level at which NK cell cytotoxicity is diminished. Additionally, we found that the toll-like receptors 2 and 4 expression was decreased in intensity in all the metastatic cancer patients when compared to the healthy controls. Furthermore, within each cancer group, the expression of both toll-like receptors was decreased in the patients with relatively high number of CTCs, i.e. greater than 5 for the breast and prostate cancer group and greater than 3 for the colorectal cancer group, compared to the patients with relatively low number, i.e. less than 5 or 3, respectively. Treatment options to increase NK cell cytotoxic activity should be considered in patients with relatively high numbers of CTCs.

A Tunneled Catheter Placement Program for Community Hospices.

CONTEXT: The symptoms associated with the excessive fluid accumulation of ascites or pleural effusions can be intractable to medical management and can have a significant negative impact on quality of life of hospice patients. Hospice of the Valley, a community-based, nonprofit hospice agency has historically referred patients to outpatient providers for paracentesis, thoracentesis, and placement of tunneled drainage catheters. OBJECTIVES: To describe an in-house pilot program of tunneled catheter placement to provide immediate and longer-term symptom relief for selected hospice patients. METHODS: The logistics and cost of the pilot program are described. Key data elements, including select demographics, patient eligibility screening, and incidence of procedure-related or late complications are reported. RESULTS: A total of 135 drainage procedures completed on 127 unique hospice patients over 27 months (2020-2023) were reviewed. The rate of procedure-related complications (<4%) and late complications (<3%) are low. The average cost per procedure ($1030) compares favorably with outpatient providers' fees. The program was well-accepted by the interdisciplinary hospice team, patients, and families. CONCLUSIONS: An in-house program of tunneled catheter placement is a feasible option for hospice providers with low-cost exposure and high potential for improved quality of life and symptom relief for selected patients.

Circulating tumor cells (CTCs) from metastatic breast cancer patients linked to decreased immune function and response to treatment.

We aimed to examine the use of circulating tumor cells (CTCs) as an effective measure of treatment efficacy and immune system function in metastatic breast cancer patients. CTCs are believed to be indicators of residual disease and thus pose an increased risk of metastasis and poorer outcomes to those patients who are CTC-positive. We obtained peripheral blood samples from 45 patients previously diagnosed with metastatic disease originating in the breast. Using TLR agonists that bind TLR ligands and upregulate immune effects versus unstimulated cells, we calculated a percent specific lysis using chromium-51 assay to illustrate the functional abilities of patient natural killer (NK) cells. We found those with greater than 5 CTCs per 7.5 mL blood had significantly decreased responses by their immune cells when compared with those patients who had 5 CTCs or less. We furthermore found a correlation between disease progression and CTC-positive patients, indicating that those who have a positive test should be closely monitored by their clinician. CTCs represent an exciting new clinical opportunity that will ideally utilize their low invasiveness and quick turnaround time to best benefit clinical scenarios.

Real World and Public Health Perspectives of Intraoperative Radiotherapy in Early-Stage Breast Cancer: A Multidisciplinary Analysis Beyond the Statistical Facts.

Breast conservation therapy (BCT) (usually a lumpectomy plus radiotherapy (RT)) has become a standard alternative to radical mastectomy in early-stage breast cancers with equal, if not higher, survival rates. The established standard of the RT component of the BCT had been about six weeks of Monday through Friday external beam RT to the whole breast (WBRT). Recent clinical trials have shown that partial breast radiation therapy (PBRT) to the region surrounding the lumpectomy cavity with shorter courses can result in equal local control, survival, and slightly improved cosmetic outcomes. Intraoperative RT (IORT) wherein RT is administered at the time of operation for BCT to the lumpectomy cavity as a single-fraction RT is also considered PBRT. The advantage of IORT is that weeks of RT are avoided. However, the role of IORT as part of BCT has been controversial. The extreme views go from "I will not recommend to anyone" to "I can recommend to all early-stage favorable patients." These divergent views are due to difficulty in interpreting the clinical trial results. There are two modalities of delivering IORT, namely, the use of low-energy 50 kV beams or electron beams. There are several retrospective, prospective, and two randomized clinical trials comparing IORT versus WBRT. Yet, the opinions are divided. In this paper, we try to bring clarity and consensus from a highly broad-based multidisciplinary team approach. The multidisciplinary team included breast surgeons, radiation oncologists, medical physicists, biostatisticians, public health experts, nurse practitioners, and medical oncologists. We show that there is a need to more carefully interpret and differentiate the data based on electron versus low-dose X-ray modalities; the randomized study results have to be extremely carefully dissected from biostatistical points of view; the importance of the involvement of patients and families in the decision making in a very transparent and informed manner needs to be emphasized; and the compromise some women may be willing to accept between 2-4% potential increase in local recurrence (as interpreted by some of the investigators in IORT randomized studies) versus mastectomy. We conclude that, ultimately, the choice should be that of women with detailed facts of the pros and cons of all options being presented to them from the angle of patient/family-focused care. Although the guidelines of various professional societies can be helpful, they are only guidelines. The participation of women in IORT clinical trials is still needed, and as genome-based and omics-based fine-tuning of prognostic fingerprints evolve, the current guidelines need to be revisited. Finally, the use of IORT can help rural, socioeconomically, and infrastructure-deprived populations and geographic regions as the convenience of single-fraction RT and the possibility of breast preservation are likely to encourage more women to choose BCT than mastectomy. This option can also likely lead to more women choosing to get screened for breast cancer, thus enabling the diagnosis of breast cancer at an earlier stage and improving the survival outcomes.

A Model Hospice Inpatient Unit Specializing in Patients Living with Advanced Dementia.

Objective: This report describes a pilot hospice inpatient unit dedicated to individuals experiencing distressing behaviors from dementia. Background: Patients with dementia who experience distressing symptoms cannot be well managed on typical inpatient units. Hospice of the Valley selected one unit to dedicate to dementia care. Methods: Data were analyzed from 237 patients admitted to the unit between May 2019 and April 2020. Behaviors were identified and rated for severity on admission, discharge, and postdischarge. Rates of inpatient death and associated behaviors were calculated. Results: Fifty percent of patients had their behaviors sufficiently managed to allow discharge. The most common behavior exhibited was agitation; the most common symptom leading to death was pain. Discussion: An inpatient hospice unit dedicated to patients with dementia can be successful. The hospice agency gains admissions that would otherwise be diverted to behavioral care settings. This successful pilot may be a model for other hospices.

Impact of a Hospital Community Based Palliative Care Partnership: Continuum from Hospital to Home.

Objectives: To discuss the outcomes of a formalized care transition process for palliative care patients from the hospital to the community. Background: Patients who received inpatient palliative care services from the specialist palliative care team in the hospital or who were identified as needing community palliative care services have inadequate support on discharge. Methods: A retrospective review of the medical records of patients admitted to the community based palliative care (CBPC) program, Arizona Palliative Home Care (AZPHC) over a 12-month period (June 2018 to May 2019) was undertaken with a focus on the frequency and pattern of hospital events pre- and postadmission to the program. Patient/family satisfaction data obtained from telephone surveys were evaluated. The medical records from patients (n = 294) with advanced complex illnesses who were admitted to AZPHC from the five Honor Health Network hospitals were included in this study. Results: Of the 294 patients' records reviewed, 80% were in the 65 and older age group and had a mean length of stay on AZPHC of ∼40 days. Comparing acute care utilization pre and post AZPHC admission, there was a reduction of 68.95% at 60 days and 68.22% at 90 days. In addition, 128 avoided hospital events were recorded, and 86% of patients were very likely to recommend AZPHC to family or friends. Discussion: Collaboration between a hospital palliative care team and a CBPC program resulted in high quality transitions across care settings and reduction in acute care utilization.

Avoided Hospitalization Criteria: Validating the Impact of a Community-Based Palliative Care Program.

Objective: This report describes the experiences of a community-based palliative care (CBPC) program's efforts to understand the patterns of hospital utilization, specifically utilization reduction experienced by admitted patients. Efforts to quantify and describe an avoided hospitalization and opportunities to use these data to strengthen partnerships with local insurance payers to assure sustainability of the CBPC will be discussed. Background: Patients with serious chronic illness experience emergency room care and hospitalizations with increasing frequency as their health deteriorates. CBPC programs are well positioned to decrease hospital utilization by early involvement and improved care management. Methods: Arizona Palliative Home Care (AZPHC) program is a free standing CBPC in Maricopa County, Arizona, serving 3300 patients annually. An interdisciplinary team was formed within the CBPC to facilitate the identification of avoided hospital events and communicate these data to community partners in an effective and consistent manner. The processes developed by this team are described. Results: AZPHC has enhanced its hospitalization avoidance strategies by communicating the rate of hospitalization avoidance events in a consistent and strategic manner. Providing instances of avoided hospitalizations with accompanying patient narratives to payers has enabled AZPHC to demonstrate the impact the CBPC has on improving quality of care and reducing overall costs. Discussion: CBPC programs require payment for sustainability; therefore, partnerships with local insurance payers are essential. Presenting data that validate the impact of a program from a clinical and financial perspective will advance the growth of payer-CBPC provider relationships and secure a future for funded CBPC programs.

Outcome evaluation of a randomized trial of the PhoenixCare intervention: program of case management and coordinated care for the seriously chronically ill.

OBJECTIVE: To document outcomes of a randomized trial of the PhoenixCare demonstration program of palliative care and coordinated care/case management for seriously chronically ill individuals who simultaneously received active treatment from managed care organizations (MCOs). DESIGN: Patients, continuously enrolled between July 1999, and March 2001, were randomly assigned to the PhoenixCare program or a control group receiving usual MCO care. SETTING: Hospice of the Valley, Phoenix, Arizona. PARTICIPANTS: Participants were 192 patients with chronic obstructive pulmonary disease (COPD) or chronic heart failure (CHF), who had an estimated 2-year life expectancy. INTERVENTION: Intensive home-based case management provided by registered nurse casemanagers, in coordination with patients' existing source of medical care, comprised the intervention. Program foci included disease and symptom management, patient self-management of illness and knowledge of illness-related resources, preparation for end-of life, physical and mental functioning, and utilization of medical services. OUTCOME MEASURES: Outcomes, assessed every 3 months by telephone interview, included measures related to all program foci; the SF-36 was used to evaluate physical and mental functioning; emergency department visits exemplified medical service utilization. RESULTS: Compared to controls, PhoenixCare patients exhibited significantly better outcomes on self-management of illness, awareness of illness-related resources, and legal preparation for end of life. They reported lower symptom distress, greater vitality, better physical functioning and higher self-rated health than randomized controls. Emergency department utilization was equivalent across groups. Patients with COPD showed stronger responsiveness to the intervention. CONCLUSION: A novel model of patient care that combined greatly enhanced palliative carefocused case management with ongoing MCO-based treatment was associated with improved functioning of chronically severely ill patients in the last years of life.

The PhoenixCare Program.

In response to a perceived need for patient access to palliative care and supportive services prior to hospice eligibility, Phoenix-based Hospice of the Valley (HOV) applied for and received a 3-year demonstration grant (1999-2001) from The Robert Wood Johnson (RWJ) Promoting Excellence in End-Of-Life Care Project. HOV established the PhoenixCare project as a demonstration of palliative and coordinated care (case management) services for seriously chronically ill individuals still undergoing active treatment of their disease within a managed care setting. The model emphasized patient/family self-empowerment and prevention. The goal was to demonstrate that it was possible to expand the scope of care for the seriously chronically ill, add palliative care, and improve patient quality of life at less (or no more) cost than that for a comparable group of managed care patients not receiving PhoenixCare services. The model proved most useful to patients willing and able to assume a degree of control over their own care. Physicians referred fewer than 5% of the patients enrolled while managed care plan case managers and hospital discharge planners referred 83%, suggesting that in organized systems of care physicians are not a primary source for patient referrals. The structure and content of the PhoenixCare model, its general acceptability to patients, physicians and managed care plans, and its applicability to other sites are discussed in this article. Outcomes from the study will be published in a subsequent paper.

Surveillance and monitoring of adult cancer survivors.

Advances in early detection and treatment have improved survival in common adult cancers. Surveillance for late recurrence and secondary primary malignancies is recommended for most patients. Initial treatment with surgery, radiation, chemotherapy, or hormonal therapy can result in both local and systemic sequelae, including treatment-related new cancers. Patients with head and neck, lung, breast, colorectal, and prostate cancers constitute the largest groups requiring long-term monitoring and follow-up care.

The changing face of phase 1 cancer clinical trials: new challenges in study requirements.

Phase 1 studies in cancer have changed in recent years. Now, with the advent of new, less toxic, targeted agents, more patients may be candidates for new drug studies earlier in the course of their disease. It is to the advantage of the members of the oncology community to know more regarding the details and requirements for participation in early-phase clinical trials so they can advocate for their patients and help them decide when such trials may be an appropriate choice. To examine the work intensity of early phase cancer clinical trials, the authors of this report compared the study requirements of phase 1 and 2 protocols. Five parameters were studied as a surrogate of study complexity-the number of physical examinations, vital sign determinations, electrocardiograms (ECGs), nonpharmacokinetic laboratory tests, and pharmacokinetic (PK) sampling-in the first 4 weeks of protocol in 90 studies (49 phase 1 studies and 41 phase 2 studies). From July 2004 through March 2007, there were 49 phase 1 trials in the phase 1 Program, 9 phase 2 studies that were conducted by physicians appointed in that program, and 32 phase 2 trials with accessible data in the Department of Thoracic/Head & Neck Medical Oncology. In the phase 1 trials versus the phase 2 trials, there were significantly more (P < .05) physical examinations (mean +/- standard error, 3.16 +/- 0.24 vs 2.22 +/- 0.13), vital sign determinations (5.63 +/- 0.61 vs 2.80 +/- 0.26), ECGs (4.36 +/- 1.16 vs 0.80 +/- 0.17), nonpharmacokinetic laboratory tests (18.08 +/- 1.31 vs 10.12 +/- 0.65), and PK sampling (15.14 +/- 1.79 vs 1.02 +/- 0.53). These values also differed significantly (P < .005 for each) when the median values were compared in nonparametric tests. Although both phase 1 and phase 2 trials had substantial study requirements, those for the phase 1 studies were significantly higher. The successful conduct of early-phase clinical trials requires significant research infrastructure.

Adjuvant biologic therapy for breast cancer.

Breast cancer continues to be a major health problem despite a decrease in mortality rates over the past 2 decades. Although many advances have been made in the treatment of breast cancer, drug therapy for the disease continues to evolve as more is learned about cell biology and cellular signaling pathways. The development of targeted agents offers the hope of new therapies with better efficacy and tolerability. Biologic therapy has been a cornerstone of targeted therapy for the treatment of advanced breast cancer and is now entering the adjuvant arena. This review summarizes the results of several adjuvant studies and discusses future directions for breast cancer biotherapy.