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Background: ER+, HER2- metastatic breast cancer (MBC) patients will receive sequential, endocrine based therapy, either as monotherapy or in combination with a targeted agent until endocrine resistance develops. OP-1250 is a small molecule Complete Estrogen Receptor Antagonist (CERAN) that completely inactivates ER by blocking the 2 activation functions of ER transcription (AF-1 & AF-2). While complete antagonism is believed to be the most critical mechanism of action, OP-1250 is also a strong degrader of the ER. OP-1250 demonstrates anti-cancer activity in preclinical models, including activity against brain metastases and in tumors with activating mutations in ESR1. OP-1250 is orally bioavailable with favorable pharmacokinetics (PK) yielding high and steady drug levels in multiple species. The characteristics of OP-1250 including PK, ability to cross the blood brain barrier, and complete antagonism of the ER suggest that OP-1250 may have superior efficacy over standard of care and experimental agents, both as a monotherapy and in combination with other targeted therapies. Methods: OP-1250-001 is a phase I/II first-in-human study to determine the Dose Limiting Toxicity (DLT), Maximum Tolerated Dose (MTD) and/or Recommended Phase II Dose (RP2D) and to characterize the safety, PK profile and preliminary efficacy in subjects with ER+, HER2- MBC. Eligible patients received prior endocrine therapy. OP-1250 was given orally, once a day continuously in 28-day cycles. Using a rolling 6 design, cohorts of 3 - 6 subjects were sequentially enrolled and monitored for DLTs. The study allows for expansion of 1 or 2 doses for further evaluation of safety and PK to best inform selection of the RP2D. The phase II portion will evaluate the preliminary activity of OP-1250 in 3 cohorts: 1) measurable disease; and 2 exploratory cohorts: 2) evaluable & non-measurable; and 3) central nervous system metastasis. Plasma is being collected for ctDNA sequencing to evaluate ESR1 and other relevant mutations. Results: Between August 5, 2020 and June 4, 2021, 28 subjects with a median age of 63 (range 37-82) have been enrolled. Of the 27 subjects for whom detailed data on prior therapy was reported, all subjects received > 1 prior endocrine therapy for MBC (74% received > 2 and 37% received > 3; range 1-6). All of the 27 subjects received a CDK4/6 inhibitor and 23 of 27 (85%) had received fulvestrant. 20 subjects of 28 (71%) subjects had visceral disease affecting the liver, lung, peritoneum, and/or pleura. OP-1250 was escalated through 5 dose cohorts (range 30 - 300 mg qd). 26 patients were evaluable for a DLT. As of the data cut-off date, no DLTs occurred. Most of the TEAE were grade 1 or 2. OP-1250 is orally bioavailable and extensively distributed with an effective half-life of approximately 2-3 days. Cmax and AUC show dose proportional increase. By cycle 2, exposure levels are at steady state with limited fluctuations and at all doses significantly higher than those seen with fulvestrant. Importantly, OP-1250 has now demonstrated clinical activity at doses that were well tolerated and within the predicted exposure windows where maximum efficacy was observed in preclinical models. Detailed response and safety data will be presented. Conclusion: OP-1250 is continuing evaluation in a phase I/II study. The population enrolled reflects the evolving standard of care in that all pts received prior CDK4/6 inhibitors and the majority also received fulvestrant. OP-1250 is well tolerated with a favorable PK across dose levels ensuring target coverage throughout the dosing interval. No MTD has been identified and selection of the RP2D will be based on consideration of long-term tolerability, efficacy, and the ability to combine with targeted agents. (NCT04505826) Citation Format: Manish Patel, Carlos Alemany, Zahi Mitri, Della Makower, Virginia Borges, Joseph Sparano, Trinh Le, Pamela Klein, Julia Lawrence, Peter Kushner, Demiana Faltaos, Cyrus Harmon, David Myles, JoAnne Zujewski, Erika Hamilton. Preliminary data from a phase I/II, multicenter, dose escalation study of OP-1250, an oral CERAN/SERD, in subjects with advanced and/or metastatic estrogen receptor (ER)-positive, HER2-negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-17-12.

Herein we report the use of Chaperonin-Containing TCP-1 (CCT or TRiC) as a marker to detect circulating tumor cells (CTCs) that are shed from tumors during oncogenesis. Most detection methods used in liquid biopsy approaches for enumeration of CTCs from blood, employ epithelial markers like cytokeratin (CK). However, such markers provide little information on the potential of these shed tumor cells, which are normally short-lived, to seed metastatic sites. To identify a marker that could go beyond enumeration and provide actionable data on CTCs, we evaluated CCT. CCT is a protein-folding complex composed of eight subunits. Previously, we found that expression of the second subunit (CCT2 or CCTβ) inversely correlated with cancer patient survival and was essential for tumorigenesis in mice, driving tumor-promoting processes like proliferation and anchorage-independent growth. In this study, we examined CCT2 expression in cancer compared to normal tissues and found statistically significant increases in tumors. Because not all blood samples from cancer patients contain detectable CTCs, we used the approach of spiking a known number of cancer cells into blood from healthy donors to test a liquid biopsy approach using CCT2 to distinguish rare cancer cells from the large number of non-cancer cells in blood. Using a clinically validated method for capturing CTCs, we evaluated detection of intracellular CCT2 staining for visualization of breast cancer and small cell lung (SCLC) cancer cells. We demonstrated that CCT2 staining could be incorporated into a CTC capture and staining protocol, providing biologically relevant information to improve detection of cancer cells shed in blood. These results were confirmed with a pilot study of blood from SCLC patients. Our studies demonstrate that detection of CCT2 could identify rare cancer cells in blood and has application in liquid biopsy approaches to enhance the use of minimally invasive methods for cancer diagnosis.

Background: Endocrine therapy administered sequentially as monotherapy or in combination with targeted therapy is the primary treatment for HR+, and HER2- metastatic breast cancer (MBC). Most patients with HR+, HER2- MBC will develop resistance to available therapies. More effective therapies are needed for HR+, HER2- MBC and for the treatment of endocrine therapy-resistant disease. OP-1250 is a small molecule Complete Estrogen Receptor ANtagonist (CERAN) that completely inactivates ER, blocking the activity of both the AF1 and AF2 transcriptional activation functions, inhibits ER-driven breast cancer cell growth, and induces ER degradation. OP-1250 demonstrates anti-cancer activity in vitro and in vivo, including activity against mouse models of metastases in the brain and tumors with activating mutations in ESR1. OP-1250 is orally bioavailable with a favorable pharmacokinetic (PK) profile enabling once-daily dosing. OP-1250’s complete ER antagonism is hypothesized to result in superior efficacy compared to agents that only partially antagonize and/or degrade but do not completely antagonize ER. Trial design: Goals of this phase 1/2 are to determine the Dose Limiting Toxicity (DLT), Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D), to characterize the safety and PK profile, and to determine the preliminary activity of OP-1250 in subjects with HR+, HER2- MBC. Ph 1 (Dose Escalation) will evaluate escalating doses of orally administered OP-1250 to determine the safety, pharmacology, MTD (if any) and/or the RP2D. Cohorts of 3 to 6 subjects will be sequentially enrolled and monitored for DLTs during cycle 1. Eligibility criteria include males, and both pre- and post-menopausal females, age 18 or older, with ER+, HER2- advanced or MBC (pre-menopausal women must be on an LHRH antagonist); prior CDK4/6 and SERD and fulvestrant are permitted; ECOG of 0 or 1. The objectives of the phase 1 are: identification of the DLT, MTD and/or RP2D and assessment of the safety and tolerability and PK of OP-1250. Objectives of the phase 2 are to assess the objective response rate (ORR) of OP-1250 in 1) subjects with HR+, HER2- MBC who have progressed on endocrine therapy and have no evidence of central nervous system (CNS) metastases, 2) in patients with non-measurable disease, and 3) in patients with CNS disease. Correlative analyses include ER, PR, Ki67 in tumor biopsies and ctDNA pre- and post-therapy for activating mutations in ESR1. Summary: OP-1250, a complete estrogen receptor antagonist (CERAN), is currently being evaluated in a phase 1/2 study in ER+, HER2- MBC. For more information, please contact clinical@olema.com (NCT04505826) Citation Format: Carlos Alemany, Manish Patel, Zahi Mitri, Joseph Sparano, Virginia Borges, Della Makower, Pam Klein, Julia Lawrence, Trinh Le, Jo Anne Zujewski, Erika Harmilton. A phase 1/2 dose escalation and expansion study of OP-1250 in adults with advanced and/or metastatic hormone receptor-positive (HR+), HER2-negative (HER2−) breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P037.

Background: Endocrine therapy has been the primary treatment modality for HR+, HER2- metastatic breast cancer (MBC). Endocrine agents are administered sequentially, either in combination with targeted therapy or as monotherapy. The majority of patients with HR+, HER2- MBC will develop endocrine resistant disease. More effective and less toxic therapies are needed for the treatment of endocrine resistant disease. OP-1250 is a small molecule Complete Estrogen Receptor ANtagonist (CERAN) that completely inactivates Estrogen Receptor (ER), blocks ER-driven transcriptional activity, inhibits ER-driven breast cancer cell growth, and induces degradation of ER. OP-1250 demonstrates anti-cancer activity in vitro and in vivo, including activity against metastases in the brain and in tumors with activating mutations in ESR1. OP-1250 is orally bioavailable with a favorable pharmacokinetic profile supportive of once-daily dosing. OP-1250 is hypothesized to completely antagonize ER resulting in superior efficacy compared to agents that only have partial antagonism of ER. Its favorable pharmacologic profile makes it an attractive agent for chronic use in patients with MBC. Trial design: This is a Phase I/II open-label, first-in-human study to determine the Dose Limiting Toxicity (DLT), Maximum Tolerated Dose (MTD) and/or Recommended Phase II Dose (RP2D), to characterize the safety and pharmacokinetic (PK) profile, and to determine the preliminary efficacy of OP-1250 in adult subjects with HR+, HER2- MBC. Treatment will consist of oral, once a day dosing and subject evaluation will be performed in 28-day cycles. This study comprises 2 parts. Part 1 (Dose Escalation) will evaluate the safety and pharmacology of a range of doses of OP-1250 administered orally to subjects and to determine the maximum tolerated dose (if any) and/or the RP2D. Cohorts of 3 to 6 subjects will be sequentially enrolled and monitored for DLTs during the first cycle of study treatment. Part 2 (Dose Expansion) will evaluate the preliminary activity of OP-1250. Patients with and without central nervous system (CNS) disease will be enrolled at the RP2D. This is designed using a Simon 2 Stage Design. Total accrual will be determined by the number of dose levels needed to identify the RP2D. Eligibility criteria:Males and females, age 18 or older, with ER+, HER2− advanced or MBCPrior treatment with endocrine therapyECOG performance status of 0 or 1For dose expansion the subject must have measurable disease according to Response Evaluation Criteria in Solid Tumors Criteria (RECIST) 1.1 ObjectivesPart 1 (Dose Escalation)To identify the DLT, MTD and/or RP2D of OP-1250To assess the safety and tolerability of OP-1250To assess the pharmacokinetics of OP-1250 Part 2 (Phase II: Monotherapy Expansion)Objective response rate (ORR) of OP-1250 in subjects with HR+, HER2- MBC who have progressed on endocrine therapy and have no evidence of central nervous system (CNS) metastases.To conduct a preliminary assessment of the antitumor activity (ORR) of OP-1250 in subjects with HR+, HER2- MBC who have progressed on endocrine therapy and have CNS disease. Assessment of response will be determined according to RECIST 1.1 and Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria Correlative ScienceTo determine biomarker expression, such as, ER, PR, Ki67 and others in the most recently obtained archival tumor tissue sampleTo evaluate whether ESR1 in circulating tumor DNA (ctDNA) can be correlated with response and/or activity of OP-1250To examine ctDNA pre- and post-therapy for mutESR1 and PIK3CA variants, and other relevant markers For more information, please contact clinical@olemapharma.com Citation Format: Erika Hamilton, Carlos Alemany, Nancy U Lin, Pamela M Klein, Trinh Le, Peter J Kushner, Cyrus Harmon, Jo Anne Zujewski, Manish Patel. A phase I/II open-label, first-in-human, multicenter, dose escalation and dose expansion study of OP-1250 monotherapy in adult subjects with advanced and/or metastatic hormone receptor (HR)-positive, HER2-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-09-10.

For patients with resected non-small-cell lung cancer, national guidelines recommend cisplatin-based doublet chemotherapy as the preferred treatment. However, many patients receive a carboplatin-based regimen instead. We aimed to identify factors associated with use of a cisplatin-based regimen and explore its association with other quality-of-care measures.This analysis was part of the Florida Initiative for Quality Cancer Care, an audit and feedback project among 11 medical oncology practices. Feedback-sharing sessions based on findings of year 2006 took place in 2008. Eligible patients were random samples of those with resected stage I to III non-small-cell lung cancer treated in 2006 and 2009.In both years combined, 81 patients received adjuvant platinum-based doublets: 33 patients (41%) received cisplatin, and 48 patients (59%) received carboplatin. Use of a cisplatin-based doublet significantly increased in 2009 compared with 2006, from 24% to 56% (P = .006). Multivariable analysis determined that academic practices used cisplatin more frequently than nonacademic practices (odds ratios, 3.26; 95% CI, 1.19 to 8.91; P = .02). Moreover, patients treated in 2009 were more likely to receive cisplatin than those treated in 2006 (odds ratio, 4.89; 95% CI, 1.75 to 13.67; P = .002). No significant association between use of cisplatin and other quality-of-care measures was found.In this study, academic practice status and treatment year predicted use of adjuvant cisplatin-based chemotherapy. The increase in use of cisplatin in 2009, as compared with 2006, suggests that audit and feedback may be effective ways to promote such use.

Background In the Mammary Oncology Assessment of LEE011’s (Ribociclib's) Efficacy and Safety (MONALEESA-2) study, combination treatment with the selective inhibitor of cyclin-dependent kinases 4/6 ribociclib with letrozole significantly improved progression-free survival (PFS) versus letrozole alone in postmenopausal women with hormone receptor-positive HR+/HER2− advanced breast cancer (ABC). Herein we present results from the subset of US patients enrolled in MONALEESA-2. Patients and Methods Postmenopausal women with HR+/HER2− ABC without previous treatment for advanced disease were randomized (1:1) to ribociclib 600 mg/d (3 weeks on/1 week off) with letrozole 2.5 mg/d (continuous) or placebo with letrozole. The primary end point was locally assessed PFS. Results Overall, 213 US patients were enrolled in MONALEESA-2 (ribociclib, n = 100; placebo, n = 113). Baseline characteristics were similar between treatment groups and consistent with the global population. With a median follow-up of 27 months, 38 (38%) and 29 (26%) patients in the ribociclib and placebo groups, respectively, had continued to receive treatment. Median PFS was 27.6 months with ribociclib and 15.0 months with placebo (hazard ratio, 0.53). The most common all-cause adverse events were neutropenia (ribociclib, 72.0% [n = 72]; placebo, 4.6% [n = 5]), nausea (ribociclib, 69.0% [n = 69]; placebo, 44.0% [n = 48]), and fatigue (ribociclib, 60.0% [n = 60]; placebo, 50.5% [n = 55]). Two patients (ribociclib, 2.0%; placebo, 0%) experienced febrile neutropenia. Conclusion In the US subset of MONALEESA-2, ribociclib with letrozole showed superior efficacy versus letrozole alone. These findings are consistent with the global population and support first-line use of ribociclib with letrozole in patients with HR+/HER2− ABC.

TPS1110 Background: There are currently no curative treatments for patients with metastatic triple-negative breast cancer (mTNBC), and prognosis for this disease is very poor. Emerging treatment combinations of anti-programmed death ligand 1 (PD-L1) agents with chemotherapy have shown promise in mTNBC. SGN-LIV1A, or ladiratuzumab vedotin (LV), is a novel investigational humanized IgG1 antibody-drug conjugate (ADC) directed against LIV-1, which is highly expressed in breast cancer cells. LV mediates delivery of monomethyl auristatin E (MMAE), which drives antitumor activity through cytotoxic cell killing and induces immunogenic cell death (ICD). Preliminary results from an ongoing phase 1 study of LV monotherapy has shown LV to be well tolerated and to have encouraging antitumor activity in patients with mTNBC. Combining LV and pembrolizumab may result in complementary, as well as synergistic, activity through LV-induced ICD that creates a microenvironment favorable for enhanced anti-PD-L1 activity. Methods: This single-arm, open-label, phase 1b/2 study evaluates the safety and antitumor activity of LV in combination with pembrolizumab as first-line therapy for patients with unresectable locally advanced or mTNBC (NCT03310957, 2017-002289-35). Patients must have measureable disease per RECIST v1.1, an ECOG score of 0 or 1, and no prior cytotoxic or anti-PD-L1 treatment for advanced disease. This study has 2 parts that are enrolling sequentially: a dose-finding phase that starts at LV 2.5 mg/kg + pembrolizumab 200 mg intravenously every three weeks, and a dose expansion phase. The primary objectives are to evaluate the safety/tolerability and objective response rate of LV + pembrolizumab, and identify the recommended phase 2 dose of LV. The secondary objectives are to assess duration of response, disease control rate, progression-free survival, and overall survival. Additional objectives include assessing PD-L1 and LIV-1 expression-response relationship. Study enrollment is ongoing in the US and EU. Clinical trial information: NCT03310957.

Purpose: This study was designed to establish the maximum tolerated dose (MTD) and to evaluate tolerability, pharmacokinetics, and antitumor activity of etirinotecan pegol. Experimental Design: Patients with refractory solid malignancies were enrolled and assigned to escalating-dose cohorts. Patients received 1 infusion of etirinotecan pegol weekly 3 times every 4 weeks (w × 3q4w), or every 14 days (q14d), or every 21 days (q21d), with MTD as the primary end point using a standard 3 + 3 design. Results: Seventy-six patients were entered onto 3 dosing schedules (58–245 mg/m2). The MTD was 115 mg/m2 for the w × 3q4w schedule and 145 mg/m2 for both the q14d and q21d schedules. Most adverse events related to study drug were gastrointestinal disorders and were more frequent at higher doses of etirinotecan pegol. Late onset diarrhea was observed in some patients, the frequency of which generally correlated with dose density. Cholinergic diarrhea commonly seen with irinotecan treatment did not occur in patients treated with etirinotecan pegol. Etirinotecan pegol administration resulted in sustained and controlled systemic exposure to SN-38, which had a mean half-life of approximately 50 days. Overall, the pharmacokinetics of etirinotecan pegol are predictable and do not require complex dosing adjustments. Confirmed partial responses were observed in 8 patients with breast, colon, lung (small and squamous cell), bladder, cervical, and neuroendocrine cancer. Conclusion: Etirinotecan pegol showed substantial antitumor activity in patients with various solid tumors and a somewhat different safety profile compared with the irinotecan historical profile. The MTD recommended for phase II clinical trials is 145 mg/m2 q14d or q21d. Clin Cancer Res; 19(1); 268–78. ©2012 AACR.

The author presents a psychobiography of Eugene Gendlin, one of the pioneers in the field of the Experiential Therapy, and the creator of Focusing, its main therapeutic tool. After unfolding this historic and personal profile he shareshis experiences in practicing and teaching Focusing: in his own experience, in the clients’ experience, and in the learners’ experience. By doing this, the author explains and exemplifies the main concepts of Focusing, and the key steps of the experiential change process. El autor presenta una psicobiografía de Eugene Gendlin, uno de los pioneros en el campo de la Terapia Experiencial, y el creador del Focusing, su principal herramienta terapéutica. Después de desplegar este perfil histórico y personal, comparte sus experiencias en la práctica y en la enseñanza del Focusing: en su propia experiencia, en la experiencia de los clientes, y en la experiencia de los formandos. Haciendo esto, el autor explica y ejemplifica los conceptos principales del Focusing, y los pasos clave del proceso de cambio experiencial.

The Florida Initiative for Quality Cancer Care (FIQCC) was established to evaluate the quality of cancer care at the regional level across the state of Florida. This study assessed adherence to validated quality indicators in colorectal cancer (CRC) and the variability in adherence by practice site, volume, and patient age.The FIQCC is a consortium of 11 medical oncology practices in Florida. Medical record reviews were conducted for 507 patients diagnosed with CRC and seen as new medical oncology patients in 2006. Thirty-five indicators were evaluated individually and categorized across clinical domains and components of care.The mean adherence for 19 of 35 individual indicators was85%. Pathology reports were compliant on reporting depth of tumor invasion (96%; range, 86% to 100%), grade (93%; range, 72% to 100%), and status of proximal and distal surgical resection margins (97%; range. 86% to 100%); however, documentation of lymphovascular and perineural invasion did not meet adherence standards (76%; range, 53% to 100% and 39%; range, 5% to 83%, respectively). Among patients with nonmetastatic rectal cancer, documentation of the status of surgical radial margins was consistently low across sites (42%; range, 0% to 100%; P = .19). Documentation of planned treatment regimens for adjuvant chemotherapy was noted in only 58% of eligible patients.In this large regional initiative, we found high levels of adherence to more than half of the established quality indicators. Although the quality of care delivered within FIQCC practices seems to be high, several components of care were identified that warrant further scrutiny on both a systemic level and at individual centers.

Objective: An American Psychosocial Oncology Society workgroup has developed indicators of the quality of psychosocial care that can be measured through review of medical records. The present report describes the first large-scale use of these indicators to evaluate psychosocial care in outpatient medical oncology settings. Methods: Medical records of 1660 colorectal, breast and non-small cell cancer patients first seen by a medical oncologist in 2006 at 11 practice sites in Florida were reviewed for performance on indicators of the quality of psychosocial care. Results: Assessment of emotional well-being was significantly less likely to be documented than assessment of pain (52 vs 87%, po0.001). A problem with emotional well-being was documented in 13% of records and evidence of action taken was documented in 58% of these records. Ten of eleven practice sites performed below an 85% threshold on each indicator of psychosocial care. Variability in assessment of emotional-well being was associated (po0.02) with practice site and patient gender and age while variability in assessment of pain was associated (po0.001) with practice site and cancer type. Conclusions: Findings illustrate how use of the psychosocial care indicators permits identification of specific practice sites and processes of care that should be targeted for quality improvement efforts. Additionally, findings demonstrate the extent to which routine assessment of emotional well-being lags behind routine assessment of pain in cancer patients. Copyright r 2010 John Wiley & Sons, Ltd.

1041Background: First-line ribociclib + letrozole significantly prolongs progression-free survival vs letrozole alone in patients aged ≥65 y with hormone receptor–positive (HR+), HER2− advanced bre...

Purpose Amrubicin is a synthetic anthracycline with potent topoisomerase II inhibition. This phase II study was conducted to confirm safety and activity of amrubicin in the treatment of refractory small-cell lung cancer (SCLC). Patients and Methods Patients with refractory SCLC (either with progressive disease as best response or progression within 90 days of first-line therapy) received amrubicin (40 mg/m2/d for 3 every 21 days). The primary end point was overall response rate (ORR); secondary end points included progression-free survival (PFS), overall survival (OS), and change in left ventricular ejection fraction (LVEF). Results Seventy-five patients with a median progression-free interval after first-line therapy of 38 days were enrolled; 69 patients received a median of four amrubicin cycles (range, one to 12 cycles). The ORR was 21.3% (95% CI, 12.7% to 32.3%), with one complete response (1.3%) and 15 partial responses (20%). Median PFS and OS were 3.2 months (95% CI, 2.4 to 4.0 months) and 6.0 months (95% CI, 4.8 to 7.1 months), respectively. The ORR in 43 patients who never responded to first-line therapy was 16.3% (95% CI, 6.8% to 30.7%). Most commonly reported grade 3 or 4 adverse events included neutropenia (67%), thrombocytopenia (41%), and anemia (30%), with febrile neutropenia in 12%. There was no decrease in mean LVEF with cumulative amrubicin doses exceeding 750 mg/m2. Conclusion Single-agent amrubicin showed promising activity with a 21.3% ORR and an acceptable safety profile when used as second-line therapy patients with platinum-refractory SCLC. Amrubicin did not induce early cardiotoxicity, but its long-term effects are unknown.

Background: The American Psychosocial Oncology Society has developed the first indicators of the quality of psychosocial care for cancer patients. This report describes the initial evaluation of these indicators. Methods: Medical records of 388 colorectal cancer patients first seen by a medical oncologist in 2006 at seven practice sites were reviewed by trained abstractors whose accuracy was documented by periodic checks. Results: Rates of assessment of emotional well-being within 1 month of a patient’s first visit with a medical oncologist ranged from 6% to 84% (mean = 60%; P < .001). Among the 45 patients identified as having a problem with emotional well-being, rates of evidence of action taken (or explanation for no action) ranged from 0% to 100% (mean = 51%; P = .85). A direct comparison showed that pain was assessed more often than emotional well-being in these patients (87% vs 60%, P < .001). Conclusions: Findings show these indicators can be measured easily and reliably, demonstrate variability across practices that suggests potential for improvement, and yield information that can be used to take actions to improve quality. Additional findings suggest that, to date, efforts to promote routine symptom assessment have been more successful for pain than for emotional well-being.

Purpose Although most classical Hodgkin's lymphoma (CHL) patients are cured, a significant minority fails primary therapy and may die as a result of their disease. Age, stage, and other basic clinical and laboratory parameters, which comprise the International Prognostic Score (IPS), are used at diagnosis to predict outcome. To date, there is no consensus on biologic markers that add value to these parameters. Patients and Methods We evaluated 107 CHL patients for bcl-2, p53, and p21 expression by immunohistochemistry using tissue microarrays and correlated the results with outcome. The median follow-up of the 79 surviving patients was 6.8 years. Results Univariate analysis showed that age ≥ 45 years, stage III or IV, and IPS ≥ 3 were associated with a poor failure-free survival (FFS) and overall survival (OS). bcl-2 was expressed in 26% of patients and was associated with poor FFS and a trend for OS. p53 expression in combination with lack of p21 expression was not associated with outcome. Multivariate analysis showed that three factors were independently associated with both FFS and OS: age ≥ 45 years, stage III or IV, and bcl-2 expression. Using these three parameters, a scoring system was devised that stratified patients into three risk groups (with zero, one, or two to three of these risk factors) and a progressively worse FFS and OS (P < .001). Conclusion Expression of bcl-2 in CHL is a useful, independent prognostic marker and can be used in association with clinical parameters to identify newly diagnosed patients with a good, intermediate, or poor prognosis.

Background Estrogens play a pivotal role in the development of breast cancer. Endocrine therapy based on estrogen blockade is a well-established treatment in hormone-dependent breast cancer. Tamoxifen citrate has long been considered the "gold standard" due to its relative safety and efficacy. Aromatase inhibitors are anti-estrogen agents that target specifically the aromatase enzyme, which is the final step in the estrogen production. The first use of aromatase inhibitors in breast cancer was associated with adverse effects such as rash, drowsiness, and adrenal-gland suppression. Newer third-generation agents are emerging as potential alternatives to tamoxifen, associating clinical efficacy with a more favorable safety profile. Objectives The aim of this article is to review the mechanisms of actions pharmacology, adverse effects, and clinical applications of the aromatase inhibitors available in the United States. Methods The terms breast cancer or neoplasia, aromatase, aromatase inhibitors, third-generation, endocrine therapy , and antiestrogens were used to search MEDLINE for English-language studies published between 1966 and April 2004. A parallel search was performed at the corresponding Web site of each of the aromatase inhibitors available in the United States. Identified publications relevant to the article objectives were selected. Results Anastrozole, letrozole, and exemestane are the 3 commercially available aromatase inhibitors approved by the US Food and Drug Administration for the treatment of hormone receptor-positive breast cancer in postmenopausal women. They have been used in several clinical scenarios, including advanced and early disease and chemoprevention, and in the neoadjuvant setting. There is evidence that aromatase inhibitors are more effective and tolerable than tamoxifen in advanced breast cancer and in the neoadjuvant setting. Based on the results of a large, randomized trial, their use in early disease and in chemoprevention is also promising. Aromatase inhibitors appear safe; however, the long-term safety profile is still unknown, especially concerning bone metabolism. Conclusion Third-generation aromatase inhibitors are a new treatment modality in estrogen and/or progesterone-receptor positive breast cancer. Although they are replacing the "classic" antiestrogen agents used in metastatic breast cancer, their benefit in early disease and as chemopreventive agents is not completely clear. Ongoing clinical studies should become available within the next few years and will provide additional recommendations for their use in patients with breast cancer.

BACKGROUND To the authors' knowledge, the prevalence of vitamin B12 deficiency among patients with plasma cell dyscrasias (PCD) is largely unknown. Identifying this vitamin deficiency in such patients could help improve their anemia and increase their tolerance to potentially neurotoxic agents. METHODS The authors retrospectively reviewed the charts and laboratory results of 664 consecutive patients diagnosed with PCD who had their vitamin B12 and folate status evaluated between 1997 and 2001 at the Cleveland Clinic Multiple Myeloma Research Program. The patients were screened for vitamin B12 deficiency using serum vitamin B12 and methylmalonic acid. RESULTS Of the 664 patients whose medical charts were reviewed, information on vitamin B12 status was available for 522 patients (78%). Among these 522 patients, 71 (13.6%) had laboratory-defined vitamin B12 deficiency and the remaining 451 patients (86.4%) did not. On univariate analysis, vitamin B12 deficiency correlated with immunoglobulin A (IgA) PCD (P = 0.04), higher mean corpuscular volume (P = 0.008), and longer follow-up (P = 0.048). In a covariate adjusted model, only the presence of IgA PCD was associated with an increased prevalence of vitamin B12 deficiency (P = 0.003). CONCLUSIONS Vitamin B12 deficiency was prevalent in patients with PCD, especially in patients with the IgA subtype. Serum vitamin B12 measurements should be part of the initial evaluation and subsequent workups for anemia in patients with PCD. Cancer 2004. © 2004 American Cancer Society.

Purpose: Identifying and addressing psychosocial concerns is increasingly recognized as an important aspect of cancer care that needs to be improved. As part of the Florida Initiative for Quality Cancer Care, medical record reviews were conducted to evaluate cancer care, including psychosocial care, at oncology practices in Florida in 2006. Results were subsequently disseminated to the practices, and performance was reassessed at the same practices in 2009. Methods: Data were available for patients with colorectal, breast, and non–small-cell lung cancer first seen by a medical oncologist in 2006 (n 1,609) and 2009 (n 1,720) at the same 10 practice sites. Performance on each psychosocial indicator was evaluated for overall change over time and for variability in change based on practice site and cancer type. Results: The percentage of patients identified as having a problem in emotional well-being increased significantly over time, from 24% to 31% among those assessed (P .002) and from 13% to 16% overall (P .026). In contrast, there no significant changes over time in assessment of emotional well-being (53% to 51%, P .661) or in action taken to address problems (57% to 45%, P .098). Conclusion: Findings suggest more intensive efforts than audit and feedback will be required to improve the quality of psychosocial care and that greater recognition of problems with emotional well-being may tax the ability of practices to link patients with appropriate services. Systematic research is needed to identify and disseminate effective strategies for implementing routine assessment of well-being and addressing the increased demands for care this will generate.

Audit and feedback have been widely used to enhance the performance of various medical practices. Non-small-cell lung cancer (NSCLC) is one of the most common diseases encountered in medical oncology practice. We investigated the use of audit and feedback to improve the care of NSCLC.Medical records were reviewed for patients with NSCLC first seen by a medical oncologist in 2006 (n = 518) and 2009 (n = 573) at 10 oncology practices participating in the Florida Initiative for Quality Cancer Care. In 2008, feedback from 2006 audit results was provided to practices, which then independently undertook steps to improve their performance. Sixteen quality-of-care indicators (QCIs) were evaluated on both time points and were examined for changes in adherence over time.A statistically significant increase in adherence was observed for five of 16 QCIs. Adherence to brain staging using magnetic resonance imaging or computed tomography scan for stage III NSCLC (57.8% in 2006 v 82.8% in 2009; P = .001), availability of chemotherapy flow sheet (89.2% v 97.0%; P.001), documentation of performance status for stage III and IV disease (43.4% v 51.3%; P.001), availability of pathology report for patients undergoing surgery (95.2% v 99.2%; P = .02), and availability of signed chemotherapy consent (69.5% v 76.3%; P = .04). There were no statistically significant decreases in adherence on any QCIs.Audit with feedback was associated with a modest but important improvement in the treatment of NSCLC. Whether these changes are durable will require long-term follow-up.

Irinotecan is a very active chemotherapeutic agent used for the treatment of several malignancies, including colorectal cancer, gastroesophageal tumors, lung cancer, breast cancer, ovarian cancer, and primary brain tumors. Irinotecan exerts its antineoplastic effects through its active metabolite 7-ethyl-10-hydroxycamptothecin. This metabolite is also responsible for the classic side effects associated with irinotecan that include diarrhea and neutropenia. A pegylated form of this agent, etirinotecan pegol, is undergoing clinical development with the main goal of increasing its therapeutic efficacy and its safety. This agent decreases the maximal exposure to 7-ethyl-10-hydroxycamptothecin while providing continuous exposure to the treated tumor. The half-life of etirinotecan pegol is 50 days and it has been studied in different schedules: weekly, every other week, and once every 3 weeks. The maximum tolerated dose of etirinotecan pegol was found to be 145 mg/m(2). There have already been two phase II clinical trials published showing the efficacy of this novel agent in the treatment of metastatic ovarian and breast cancer. The side effect profile was acceptable for most patients, with a number of patients experiencing diarrhea and even neutropenia.

Background The quality of cancer care has become a national priority; however, there are few ongoing efforts to assist medical oncology practices in identifying areas for improvement. The Florida Initiative for Quality Cancer Care is a consortium of 11 medical oncology practices that evaluates the quality of cancer care across Florida. Within this practice-based system of self-assessment, we determined adherence to colorectal cancer quality of care indicators (QCIs) in 2006, disseminated results to each practice and reassessed adherence in 2009. The current report focuses on evaluating the direction and magnitude of change in adherence to QCIs for colorectal cancer patients between the 2 assessments. Study Design Medical records were reviewed for all colorectal cancer patients seen by a medical oncologist in 2006 (n = 489) and 2009 (n = 511) at 10 participating practices. Thirty-five indicators were evaluated individually and changes in QCI adherence over time and by site were examined. Results Significant improvements were noted from 2006 to 2009, with large gains in surgical/pathological QCIs (eg, documenting rectal radial margin status, lymphovascular invasion, and the review of ≥12 lymph nodes) and medical oncology QCIs (documenting planned treatment regimen and providing recommended neoadjuvant regimens). Documentation of perineural invasion and radial margins significantly improved; however, adherence remained low (47% and 71%, respectively). There was significant variability in adherence for some QCIs across institutions at follow-up. Conclusions The Florida Initiative for Quality Cancer Care practices conducted self-directed quality-improvement efforts during a 3-year interval and overall adherence to QCIs improved. However, adherence remained low for several indicators, suggesting that organized improvement efforts might be needed for QCIs that remained consistently low over time. Findings demonstrate how efforts such as the Florida Initiative for Quality Cancer Care are useful for evaluating and improving the quality of cancer care at a regional level.

The Florida Initiative for Quality Cancer Care (FIQCC) comprises 11 Florida practice sites that participate in comprehensive reviews of quality of care specific to patients with cancer. Here, we examined site adherence to performance indicators to assess quality of care for patients with breast cancer (BC).Quality indicators were scripted on the basis of accepted guidelines from the Quality Oncology Practice Initiative, National Comprehensive Cancer Network, American College of Surgeons, and site-specific expert panel consensus. Comprehensive chart reviews, including both medical and surgical oncology quality measures, were conducted for patients with BC first seen in 2006 by a medical oncologist at one of the sites. Statistical comparisons were made by the Pearson χ(2) exact test, using Monte Carlo estimation.Charts of 622 patients were reviewed. Of the 34 indicators, seven for medical oncology and four for surgical oncology fell below the 85% level of adherence. A statistically significant difference (P.001) in variation of performance across the sites was found for the following medical and surgical oncology indicators: documentation of menopausal status, family history, informed consent, planned chemotherapy regimen and flow sheet, American Joint Committee on Cancer staging, HER2/neu status, reporting of margin orientation and inking of the margins, histological grade, having a sentinel lymph node biopsy for invasive BC, and obtaining a mammogram within 14 months of definitive surgery.The FIQCC has identified how multiple aspects of BC care can be improved. Findings are being used at the participating institutions to guide quality improvement efforts.

Limited data on the quality of care in non-small- cell lung cancer (NSCLC) are available. This study aims to assess the quality of care in NSCLC among 11 medical oncology practices in Florida and to explore the impact of practice volume on care. Methods: Clinical guidelines and existing indicators were re- viewed, and an expert survey was conducted to identify a set of process-based quality of care indicators (QI). Medical records of new patients with NSCLC seen in 2006 were retrospectively reviewed for the adherence to these QIs. Results: We reviewed the compliance with a set of 11 QIs (four general and seven NSCLC specific) among 531 patients. The patient median age was 68 years; 51% were male, and 49% had advanced NSCLC. The median adherence rates to general QIs and NSCLC-specific QIs were 95% (range 69% to 99%) and 69% (range 29% to 91%), respectively. We identified three main areas of deficiencies: chemotherapy consenting (69%), brain staging for stage III NSCLC (59%), and performance status as- sessment for advanced stages (42%). Significant variation in the adherence rates across practice sites was observed in five of 11 QIs. Conclusion: On the basis of this data set of participating institutions in Florida, several areas in the care of patients with NSCLC were identified as targets for future quality improvement efforts.

Results are presented on magnetic viscosity measurements performed at room temperature on Ba-ferrite pressed powder samples of different particle sizes. Maximum values of viscosity coefficients ( S ) occur around coercive fields, except for a sample with an intrinsic coercive force of 4639 Oe, in which the maximum is at a much higher field (5706 Oe). Activation volumes are of the order of 10 −17 cm 3 and decrease along with particle size (except, again, for the high coercivity sample). Experimental values of coercive fields and viscosity parameters ( kT / q ), used in connection with Gaunt's theory, suggest that the viscosity mechanism in Ba-ferrite, for particle sizes from 7 to 0.7 > m is the strong pinning of domain walls.

Classic Hodgkin lymphoma (cHL) and mediastinal (thymic) large B-cell lymphoma (MLBL) have clinical, histopathologic, and molecular genetic similarities. MAL, a gene that encodes a protein associated with lipid rafts in T and epithelial cells, is overexpressed in a majority of MLBLs and has been reported in a minority of cHLs. To study the clinical significance of MAL in cHL, we immunostained 86 cases; 16 cHLs (19%) expressed MAL. Expression correlated with nodular sclerosis subtype, and within this subtype, with grade 2 histology. Univariable analysis revealed association of age of 45 years or older, MAL expression, and an International Prognostic Score of more than 2 with worse failure-free survival. Age of 45 years or older, MAL expression, and stage III or IV were associated with worse overall survival (OS). Cox proportional hazards modeling showed age (P = .04 and P = .03, respectively) and MAL expression (P = .03 and P = .01, respectively) as independent predictors of failure-free survival and OS. Stage was of borderline significance in OS (P = .08). MAL expression seems to identify a subset of cHL with an adverse outcome and provides additional evidence for a link between cHL and MLBL. In the vast majority of cases, Hodgkin lymphoma (HL) is a B-cell lymphoma that is derived from germinal center stage B cells that have defective immunoglobulin transcription. 1 Studies suggest a relationship between HL and mediastinal (thymic) large B-cell lymphoma (MLBL), a particular type of diffuse large B-cell lymphoma (DLBL). 2-4 HL and MLBL share many