Shari Goldfarb

Adverse Symptom Event Reporting by Patients vs Clinicians: Relationships With Clinical Outcomes

BACKGROUND In cancer treatment trials, the standard source of adverse symptom data is clinician reporting by use of items from the National Cancer Institutes Common Terminology Criteria for Adverse Events (CTCAE). Patient self-reporting has been proposed as an additional data source, but the implications of such a shift are not understood. METHODS Patients with lung cancer receiving chemotherapy and their clinicians independently reported six CTCAE symptoms and Karnofsky Performance Status longitudinally at sequential office visits. To compare how patients vs clinicians reports relate to sentinel clinical events, a time-dependent Cox regression model was used to measure associations between reaching particular CTCAE grade severity thresholds with the risk of death and emergency room visits. To measure concordance of CTCAE reports with indices of daily health status, Kendall tau rank correlation coefficients were calculated for each symptom with EuroQoL EQ-5D questionnaire and global question scores. Statistical tests were two-sided. RESULTS A total of 163 patients were enrolled for an average of 12 months (range = 1-28 months), with a mean of 11 visits and 67 (41%) deaths. CTCAE reports were submitted by clinicians at 95% of visits and by patients at 80% of visits. Patients generally reported symptoms earlier and more frequently than clinicians. Statistically significant associations with death and emergency room admissions were seen for clinician reports of fatigue (P < .001), nausea (P = .01), constipation (P = .038), and Karnofsky Performance Status (P < .001) but not for patient reports of these items. Higher concordance with EuroQoL EQ-5D questionnaire and global question scores was observed for patient-reported symptoms than for clinician-reported symptoms. CONCLUSIONS Longitudinally collected clinician CTCAE assessments better predict unfavorable clinical events, whereas patient reports better reflect daily health status. These perspectives are complementary, each providing clinically meaningful information. Inclusion of both types of data in treatment trial results and drug labels appears to be warranted.

Effect of Aromatase Inhibitors on Background Parenchymal Enhancement and Amount of Fibroglandular Tissue at Breast MR Imaging

PURPOSE To evaluate whether treatment with an aromatase inhibitor (AI) influences background parenchymal enhancement (BPE) or amount of fibroglandular tissue (FGT) at breast magnetic resonance (MR) imaging in postmenopausal women with prior history of breast cancer. MATERIALS AND METHODS A waiver of authorization and patient consent was granted by the institutional review board for this HIPAA-compliant retrospective study. Postmenopausal women with breast cancer and MR imaging findings of the contralateral unaffected breast, before and during 6-12 months of AI treatment (anastrozole, letrozole, or exemestane), between August 1999 and June 2010 were retrospectively identified (n = 149). Two readers performed blinded side-by-side comparison of BPE and MR imaging-depicted FGT before and during treatment. BPE and FGT were classified as the same or greater on one of the two MR studies and by using categorical scales: minimal, mild, moderate, or marked for BPE and fatty, scattered, heterogeneously dense, or dense for FGT. Consensus was reached in cases of disagreement. The sign test was used to conduct a side-by-side comparison of BPE and FGT before and during AI treatment. RESULTS A decrease in BPE occurred in 33.9% (37 of 109) of women during anastrozole treatment, while an increase occurred in only one (P < .0001); 28 of 37 decreases resulted in a category change of BPE. A decrease in MR imaging-depicted FGT occurred in 5.5% (six of 109) of women, while no increases occurred (P = .031). During letrozole treatment, a decrease in BPE occurred in 46% (15 of 33), while an increase occurred in one woman (P = .0003); a decrease in FGT occurred in only one woman, and no increases occurred. Similar results were seen when women also undergoing chemotherapy were excluded. Only seven women were treated with exemestane. CONCLUSION Treatment with 6-12 months of anastrozole or letrozole was associated with decreases in BPE, which occurred in a greater proportion of women than decreases in FGT.

Phase II Study of Paclitaxel Given Once per Week Along With Trastuzumab and Pertuzumab in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer

PURPOSE The CLEOPATRA (Clinical Evaluation of Trastuzumab and Pertuzumab) study demonstrated superior progression-free survival (PFS) and overall survival when pertuzumab was added to trastuzumab and docetaxel. Paclitaxel given once per week is effective and less toxic than docetaxel. We performed a phase II study to evaluate the efficacy and safety of pertuzumab and trastuzumab with paclitaxel given once per week. PATIENTS AND METHODS Patients with metastatic human epidermal growth factor receptor 2-positive breast cancer with zero to one prior therapy were enrolled. Treatment consisted of paclitaxel 80 mg/m(2) once per week plus trastuzumab (8 mg/kg loading dose → 6 mg/kg) once every 3 weeks plus pertuzumab (840 mg loading dose → 420 mg) once every 3 weeks, all given intravenously. The primary end point was 6-month PFS assessed by Kaplan-Meier methods. RESULTS From January 2011 to December 2013, we enrolled 69 patients: 51 (74%) and 18 (26%) treated in first- and second-line metastatic settings, respectively. At a median follow-up of 21 months (range, 3 to 38 months), 6-month PFS was 86% (95% CI, 75% to 92%). The median PFS was 19.5 months (95% CI, 14 to 26 months) overall. PFS was 24.2 months (95% CI, 14 months to not reached [NR]) and 16.4 months (95% CI, 8.5 months to NR) for those without and with prior treatment, respectively. At 1 year, Kaplan-Meier PFS was 70% (95% CI, 56% to 79%) overall, 71% (95% CI, 55% to 82%) for those without prior therapy, and 66% (95% CI, 40% to 83%) for those with prior therapy. Treatment was well-tolerated; there was no febrile neutropenia or symptomatic left ventricular systolic dysfunction. CONCLUSION Paclitaxel given once per week with trastuzumab and pertuzumab is highly active and well tolerated and seems to be an effective alternative to docetaxel-based combination therapy.

Sexual and Reproductive Health in Cancer Survivors

As patients live longer after cancer diagnosis and treatment, attention to symptoms and quality of life (QoL) are of increasing importance both during treatment and throughout survivorship. Two complications of multi-modal cancer treatment that can profoundly affect both men and women are sexual dysfunction and infertility. Survivors at highest risk for treatment-related sexual dysfunction are those with tumors that involve the sexual or pelvic organs and those whose treatment affects the hormonal systems mediating sexual function. Sexual dysfunction may not abate without appropriate intervention. Therefore, early identification and treatment strategies are essential. Likewise, multiple factors contribute to the risk of infertility from cancer treatment and many cancer patients of reproductive age would prefer to maintain their fertility, if possible. Fortunately, advances in reproductive technology have created options for young newly diagnosed patients to preserve their ability to have a biologic child. This paper will focus on the sexual and reproductive problems encountered by cancer survivors and discuss some treatment options.

Detection of HER2-Positive Metastases in Patients with HER2-Negative Primary Breast Cancer Using 89Zr-Trastuzumab PET/CT

Our objective was to determine whether imaging with a human epidermal growth factor receptor 2 (HER2)–targeted PET tracer can detect HER2-positive metastases in patients with HER2-negative primary breast cancer. Methods: Patients with HER2-negative primary breast cancer and evidence of distant metastases were enrolled in an Institutional Review Board–approved prospective clinical trial. Archived pathologic samples from the patient’s primary breast cancer were retested to confirm HER2-negative disease. Patients with confirmed HER2-negative primary breast cancer underwent 89Zr-trastuzumab PET/CT to screen for 89Zr-trastuzumab metastases. Metastases avid for 89Zr-trastuzumab by PET/CT were biopsied and pathologically examined to define HER2 status. Patients with pathologically proven HER2-positive metastases subsequently received off-protocol HER2-targeted therapy to evaluate treatment response. Results: Nine patients were enrolled, all of whom had pathologic retesting that confirmed HER2-negative primary breast cancer. Five demonstrated suggestive foci on 89Zr-trastuzumab PET/CT. Of these 5 patients, 2 had biopsy-proven HER2-positive metastases and went on to benefit from HER2-targeted therapy. In the other 3 patients, biopsy showed no evidence of HER2-positive disease, and their foci on 89Zr-trastuzumab PET were considered false-positive. Conclusion: In this proof-of-concept study, we demonstrated that 89Zr-trastuzmab PET/CT detects unsuspected HER2-positive metastases in patients with HER2-negative primary breast cancer. Although these are only initial results in a small sample, they are a proof of the concept that HER2-targeted imaging can identify additional candidates for HER2-targeted therapy. More specific HER2-targeted agents will be needed for clinical use.

Sexual Functioning Among Endometrial Cancer Patients Treated With Adjuvant High-Dose-Rate Intra-Vaginal Radiation Therapy

PURPOSE We used the Female Sexual Function Index (FSFI) to investigate the prevalence of sexual dysfunction (SD) and factors associated with diminished sexual functioning in early stage endometrial cancer (EC) patients treated with simple hysterectomy and adjuvant brachytherapy. METHODS AND MATERIALS A cohort of 104 patients followed in a radiation oncology clinic completed questionnaires to quantify current levels of sexual functioning. The time interval between hysterectomy and questionnaire completion ranged from <6 months to >5 years. Multivariate regression was performed using the FSFI as a continuous variable (score range, 1.2-35.4). SD was defined as an FSFI score of <26, based on the published validation study. RESULTS SD was reported by 81% of respondents. The mean (± standard deviation) domain scores in order of highest-to-lowest functioning were: satisfaction, 2.9 (± 2.0); orgasm, 2.5 (± 2.4); desire, 2.4 (± 1.3); arousal, 2.2 (± 2.0); dryness, 2.1 (± 2.1); and pain, 1.9 (± 2.3). Compared to the index population in which the FSFI cut-score was validated (healthy women ages 18-74), all scores were low. Compared to published scores of a postmenopausal population, scores were not statistically different. Multivariate analysis isolated factors associated with lower FSFI scores, including having laparotomy as opposed to minimally invasive surgery (effect size, -7.1 points; 95% CI, -11.2 to -3.1; P<.001), lack of vaginal lubricant use (effect size, -4.4 points; 95% CI, -8.7 to -0.2, P=.040), and short time interval (<6 months) from hysterectomy to questionnaire completion (effect size, -4.6 points; 95% CI, -9.3-0.2; P=.059). CONCLUSIONS The rate of SD, as defined by an FSFI score <26, was prevalent. The postmenopausal status of EC patients alone is a known risk factor for SD. Additional factors associated with poor sexual functioning following treatment for EC included receipt of laparotomy and lack of vaginal lubricant use.

Cancer and Fertility Program Improves Patient Satisfaction With Information Received

PURPOSE A cancer and fertility program was established at a large cancer center to support clinicians in discussing treatment-related fertility risks and fertility preservation (FP) options with patients and in referring patients to reproductive specialists. The program provides resources, clinician education, and fertility clinical nurse specialist consultation. This study evaluated the programs impact on patient satisfaction with information received. PATIENTS AND METHODS Retrospective cross-sectional surveys assessed satisfaction before (cohort 1 [C1]) and after (cohort 2 [C2]) program initiation. Questionnaires were investigator-designed, gender-specific, and anonymous. RESULTS Most C1 (150 males, 271 females) and C2 (120 males, 320 females) respondents were 2 years postdiagnosis; the most frequently reported cancers were testicular, breast, and lymphoma. A significant difference in satisfaction with the amount of information received was seen between C1 and C2. For males, satisfaction with information on fertility risks was high in both cohorts but significantly greater in C2 for information on sperm banking (χ(2) = 9.3, P = .01) and finding a sperm bank (χ(2) = 13.3, P = .001). For females, satisfaction with information was significantly greater in C2 for information on fertility risks (χ(2) = 62.1, P < .001), FP options (χ(2) = 71.9, P < .001), help with decision making (χ(2) = 80.2, P < .001), and finding a reproductive endocrinologist (χ(2) = 60.5, P < .001). Among patients who received and read information materials, 96% of males and 99% of females found them helpful. Among C2 females, fertility clinical nurse specialist consultation was associated with significantly greater satisfaction with information on FP options (χ(2) = 11.2, P = .004), help with decision making (χ(2) = 10.4, P = .006), and finding a reproductive endocrinologist (χ(2) = 22.6, P < .001), with 10% reporting lack of knowledge as a reason for not pursuing FP. CONCLUSION Improvements in patient satisfaction with information received demonstrate the potential for fertility programs in cancer care settings to improve the quality of clinician-patient discussions about fertility.

A National Network to Advance the Field of Cancer and Female Sexuality

INTRODUCTION Understanding sexual health issues in cancer patients is integral to care for the continuously growing cancer survivor population. AIM To create a national network of active clinicians and researchers focusing on the prevention and treatment of sexual problems in women and girls with cancer. METHODS Interdisciplinary teams from the University of Chicago and Memorial Sloan-Kettering Cancer Center jointly developed the mission for a national conference to convene clinicians and researchers in the field of cancer and female sexuality. The invitee list was developed by both institutions and further iterated through suggestions from invitees. The conference agenda focused on three high-priority topics under the guidance of a professional facilitator. Breakout groups were led by attendees recognized by collaborators as experts in those topics. Conference costs were shared by both institutions. MAIN OUTCOME MEASURE Development of Scientific Working Groups (SWGs). RESULTS One hundred two clinicians and researchers were invited to attend the 1st National Conference on Cancer and Female Sexuality. Forty-three individuals from 20 different institutions across 14 states attended, including representation from eight National Cancer Institute (NCI)-funded cancer centers. Attendees included PhD researchers (N = 19), physicians (N = 16), and other healthcare professionals (N = 8). Breakout groups included (i) Defining key life course sexuality issues; (ii) Building a registry; and (iii) Implementing sexual health assessment. Breakout group summaries incorporated group consensus on key points and priorities. These generated six SWGs with volunteer leaders to accelerate future research and discovery: (i) Technology-based interventions; (ii) Basic science; (iii) Clinical trials; (iv) Registries; (v) Measurement; and (vi) Secondary data analysis. Most attendees volunteered for at least one SWG (N = 35), and many volunteered for two (N = 21). CONCLUSION This 1st National Conference demonstrated high motivation and broad participation to address research on cancer and female sexuality. Areas of need were identified, and SWGs established to help promote research in this field.

Abstract P5-18-20: Phase II study of pertuzumab, trastuzumab, and weekly paclitaxel in patients with metastatic HER2-overexpressing metastatic breast cancer.

Background: Pertuzumab (P) is a monoclonal antibody which binds to extracellular domain II of HER2 distally from trastuzumab (H), disrupting HER2 dimerization and signaling. The CLEOPATRA phase III trial showed that HP + docetaxel in HER2+ metastatic breast cancer (MBC) prolonged progression-free survival (PFS) compared to placebo + H + docetaxel. We report preliminary results of a phase II study to evaluate the safety and efficacy of weekly paclitaxel with HP (THP). Methods: Patients (pts) with HER2+ MBC with 0–1 prior treatment (Rx) are eligible. Pts receive weekly (w) paclitaxel (80mg/m2), q3w trastuzumab (loading dose 8mg/kg → 6mg/kg), and q3w pertuzumab (flat loading dose 840mg → flat dose 420mg). The primary endpoint is PFS at 6 months (mo). Secondary endpoints include response, safety (including cardiac events), and tolerability. Evaluable pts are those who have started study Rx and are assessed at 6 mo for PFS. Left ventricular ejection fraction (LVEF) is monitored by echocardiogram every 3 mo. Cardiac events are defined as symptomatic LV systolic dysfunction (LVSD), non-LVSD cardiac death, or probable cardiac death. Results: As of 6–1-12, 38 of the planned 69 pts were enrolled and 20 pts were evaluable at 6 mo. Median age is 52 years (range 32 to 72). A total of 11 pts (55%) previously received trastuzumab in the adjuvant or metastatic setting, and 8 pts (40%) were being treated in the second-line metastatic setting. Of the 20 evaluable pts, G 3/4 toxicities were sepsis (1 pt, 5%), cholecystitis (1 pt, 5%), fatigue (1 pt, 5%), skin ulceration (1 pt, 5%) and cystic macular degeneration (1 pt with prior prolonged Rx with paclitaxel, 5%). Common G 1/2 toxicities included alopecia (20 pts, 100%), peripheral neuropathy (20 pts, 100%), fatigue (18 pts, 90%), ALT/AST elevation (17 pts, 85%), diarrhea (15 pts, 75%), rash (13 pts, 65%), nail changes (10 pts, 50%), mucositis (9 pts, 45%), dry skin (8 pts, 40%), and nausea (8 pts, 40%). Median LVEF was 64% at baseline (range 50% to 69%), 60% at 3mo (range 50% to 73%), and 60% at 6mo (range 49% to 67%). There were no cardiac events. At 6 mo, 15/20 pts (75%) were progression-free (2 CR, 8 PR and 5 SD); 5 pts had progressed. The 6 mo PFS results for all 38 enrolled patients will be updated. Conclusions: Our single-center phase II study continues to accrue, with no clinically significant diarrhea or signal of increased cardiac toxicity to date. Pertuzumab was recently FDA-approved in combination with trastuzumab and docetaxel. If the estimate of safety and activity is similar to results with docetaxel in CLEOPATRA, this study will provide support for weekly paclitaxel as an alternative option in combination with trastuzumab and pertuzumab in this setting. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-20.

How to ask and what to do: A guide for clinical inquiry and intervention regarding female sexual health after cancer

Purpose of reviewAs the number of female cancer survivors continues to grow, there is a growing need to bridge the gap between the high rate of womens cancer-related sexual dysfunction and the lack of attention and intervention available to the majority of survivors who suffer from sexual problems. Previously identified barriers that hinder communication for providers include limited time, lack of preparation, and a lack of patient resources and access to appropriate referral sources. Recent findingsThis study brings together a recently developed model for approaching clinical inquiry about sexual health with a brief problem checklist that has been adapted for use for female cancer survivors, as well as practical evidence-based strategies on how to address concerns identified on the checklist. Examples of patient education sheets are provided as well as strategies for building a referral network. SummaryBy providing access to a concise and efficient tool for clinical inquiry, as well as targeted material resources and practical health-promoting strategies based on recent evidence-based findings, we hope to begin eliminating the barriers that hamper oncology providers from addressing the topic of sexual/vaginal health after cancer.