Julie Gralow

American Society of Clinical Oncology Technology Assessment on the Use of Aromatase Inhibitors As Adjuvant Therapy for Postmenopausal Women With Hormone Receptor–Positive Breast Cancer: Status Report 2004

PURPOSEnTo update the 2003 American Society of Clinical Oncology technology assessment on adjuvant use of aromatase inhibitors.nnnRECOMMENDATIONSnBased on results from multiple large randomized trials, adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer should include an aromatase inhibitor in order to lower the risk of tumor recurrence. Neither the optimal timing nor duration of aromatase inhibitor therapy is established. Aromatase inhibitors are appropriate as initial treatment for women with contraindications to tamoxifen. For all other postmenopausal women, treatment options include 5 years of aromatase inhibitors treatment or sequential therapy consisting of tamoxifen (for either 2 to 3 years or 5 years) followed by aromatase inhibitors for 2 to 3, or 5 years. Patients intolerant of aromatase inhibitors should receive tamoxifen. There are no data on the use of tamoxifen after an aromatase inhibitor in the adjuvant setting. Women with hormone receptor-negative tumors should not receive adjuvant endocrine therapy. The role of other biomarkers such as progesterone receptor and HER2 status in selecting optimal endocrine therapy remains controversial. Aromatase inhibitors are contraindicated in premenopausal women; there are limited data concerning their role in women with treatment-related amenorrhea. The side effect profiles of tamoxifen and aromatase inhibitors differ. The late consequences of aromatase inhibitor therapy, including osteoporosis, are not well characterized.nnnCONCLUSIONnThe Panel believes that optimal adjuvant hormonal therapy for a postmenopausal woman with receptor-positive breast cancer includes an aromatase inhibitor as initial therapy or after treatment with tamoxifen. Women with breast cancer and their physicians must weigh the risks and benefits of all therapeutic options.

American Society of Clinical Oncology 2003 Update on the Role of Bisphosphonates and Bone Health Issues in Women With Breast Cancer

PURPOSEnTo update the 2000 ASCO guidelines on the role of bisphosphonates in women with breast cancer and address the subject of bone health in these women.nnnRESULTSnFor patients with plain radiographic evidence of bone destruction, intravenous pamidronate 90 mg delivered over 2 hours or zoledronic acid 4 mg over 15 minutes every 3 to 4 weeks is recommended. There is insufficient evidence supporting the efficacy of one bisphosphonate over the other. Starting bisphosphonates in women who demonstrate bone destruction through imaging but who have normal plain radiographs is considered reasonable treatment. Starting bisphosphonates in women with only an abnormal bone scan but without evidence of bone destruction is not recommended. The presence or absence of bone pain should not be a factor in initiating bisphosphonates. In patients with a serum creatinine less than 3.0 mg/dL (265 mumol/L), no change in dosage, infusion time, or interval is required. Infusion times less than 2 hours with pamidronate or less than 15 minutes with zoledronic acid should be avoided. Creatinine should be monitored before each dose of either agent in accordance with US Food and Drug Administration (FDA) labeling. Oncology professionals, especially medical oncologists, need to take an expanded role in the routine and regular assessment of the osteoporosis risk in women with breast cancer. The panel recommends an algorithm for patient management to maintain bone health.nnnCONCLUSIONnBisphosphonates provide a supportive, albeit expensive and non-life-prolonging, benefit to many patients with bone metastases. Current research is focusing on bisphosphonates as adjuvant therapy. Although new data addressing when to stop therapy, alternative doses or schedules for administration, and how to best coordinate bisphosphonates with other palliative therapies are needed, they are not currently being investigated.

Randomized Phase II Trial of Denosumab in Patients With Bone Metastases From Prostate Cancer, Breast Cancer, or Other Neoplasms After Intravenous Bisphosphonates

PURPOSEnPatients with bone metastases and elevated urinary N-telopeptide (uNTx), representing excessive bone resorption, are at increased risk for skeletal-related events (SREs), cancer progression, and death. Osteoclast-mediated bone resorption is regulated by RANKL. We evaluated the effect of denosumab, a fully human monoclonal antibody against RANKL, in patients with bone metastases and elevated uNTx levels despite ongoing intravenous (IV) bisphosphonate (BP) therapy.nnnPATIENTS AND METHODSnEligible patients had histologically confirmed malignancy, > or = 1 bone metastases, and uNTx levels higher than 50 nmol/L bone collagen equivalents (BCE)/mM creatinine despite IV BPs. They were stratified by tumor type and screening uNTx levels (50 to 100 or > 100 nmol/L BCE/mM creatinine), and randomly assigned to continue IV BPs every 4 weeks or receive subcutaneous denosumab 180 mg every 4 weeks or every 12 weeks.nnnRESULTSnAmong 111 patients accrued, the primary end point of uNTx levels lower than 50 nmol/L BCE/mM creatinine (uNTx < 50) at week 13 was achieved by 49 (71%) of 69 patients in the denosumab arms, compared with 10 (29%) of 35 patients in the IV BP arm (P < .001). The proportion of patients with uNTx lower than 50 was maintained at week 25 (64% denosumab arms; 37% IV BP arm; P = .01). The incidence of SREs was six (8%) of 73 and six (17%) of 35 in the denosumab group and IV BP group, respectively. Rates of adverse events were similar between treatment groups.nnnCONCLUSIONnAmong patients with elevated uNTx despite ongoing IV BP therapy, denosumab normalized uNTx levels more frequently than the continuation of IV BP. Fewer patients receiving denosumab experienced on-study SREs than those receiving IV BPs.

18Fluorodeoxyglucose Positron Emission Tomography to Detect Mediastinal or Internal Mammary Metastases in Breast Cancer

PURPOSEnTo determine the prevalence of suspected disease in the mediastinum and internal mammary (IM) node chain by 18fluorodeoxyglucose (FDG) positron emission tomography (PET), compared with conventional staging by computed tomography (CT) in patients with recurrent or metastatic breast cancer.nnnPATIENTS AND METHODSnWe retrospectively evaluated intrathoracic lymph nodes using FDG PET and CT data in 73 consecutive patients with recurrent or metastatic breast cancer who had both CT and FDG PET within 30 days of each other. In reviews of CT scans, mediastinal nodes measuring 1 cm or greater in the short axis were considered positive. PET was considered positive when there were one or more mediastinal foci of FDG uptake greater than the mediastinal blood pool.nnnRESULTSnOverall, 40% of patients had abnormal mediastinal or IM FDG uptake consistent with metastases, compared with 23% of patients who had suspiciously enlarged mediastinal or IM nodes by CT. Both FDG PET and CT were positive in 22%. In the subset of 33 patients with assessable follow-up by CT or biopsy, the sensitivity, specificity, and accuracy for nodal disease was 85%, 90%, and 88%, respectively, by FDG PET; 54%, 85%, and 73%, respectively, by prospective interpretation of CT; and 50%, 83%, and 70%, respectively, by blinded observer interpretation of CT. Among patients suspected of having only locoregional disease recurrence (n = 33), 10 had unsuspected mediastinal or IM disease by FDG PET.nnnCONCLUSIONnFDG PET may uncover disease in these nodal regions not recognized by conventional staging methods. Future prospective studies using histopathology for confirmation are needed to validate the preliminary findings of this retrospective study.

Use of Serial FDG PET to Measure the Response of Bone-Dominant Breast Cancer to Therapy

RATIONALE AND OBJECTIVESnThe authors performed this study to determine the feasibility of using quantitative 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) to monitor the response of breast cancer bone metastases to therapy.nnnMATERIALS AND METHODSnTwenty-four women with stage IV bone-dominant breast carcinoma were included in this study. Whole-body FDG PET imaging was performed at serial time points during the course of therapy. FDG PET scans were interpreted quantitatively by using the maximum standard uptake value (SUV) of the most conspicuous bone lesion at baseline FDG PET. PET results were compared to the overall assessment of response (response, stable disease, progressive disease) with a combination of conventional imaging, change in tumor marker values, and subjective symptom changes by experienced medical oncologists blinded to the findings at FDG PET. Changes in FDG SUV were also correlated quantitatively to the changes in a particular tumor marker (CA 27.29).nnnRESULTSnThe changes in FDG SUV with therapy showed correlation with the overall clinical assessment of response (P < .01). The percentage change in FDG uptake with therapy showed strong correlation with the percentage change in tumor marker value (P < .01).nnnCONCLUSIONnPreliminary results indicate that serial whole-body FDG PET can help quantitatively assess the response of breast cancer bone metastases to therapy. Prospective trials are needed to further investigate its accuracy.

Sequencing of Tamoxifen and Radiotherapy After Breast-Conserving Surgery in Early-Stage Breast Cancer

PURPOSEnTamoxifen (TAM) is thought to exert a cytostatic effect on hormone-sensitive breast cancer cells. Some preclinical studies show reduced radiosensitivity in irradiated malignant mammary epithelial cells when pretreated with TAM; other studies refute these results. Recent randomized clinical trials suggest an antagonistic effect of TAM on cytotoxic therapy, with improved disease-free survival (DFS) with sequential versus concurrent TAM. An exploratory analysis was undertaken to evaluate the optimal sequencing of TAM and radiotherapy (RT) after breast-conserving surgery.nnnPATIENTS AND METHODSnSouthwest Oncology Group trial 8897 (Intergroup 0102) randomly assigned node-negative women with T1-3 breast cancers to cyclophosphamide, doxorubicin, fluorouracil (CAF); CAF --> TAM; cyclophosphamide, methotrexate, fluorouracil (CMF); and CMF --> TAM. For this analysis, data are reported only in the TAM groups. RT was allowed either before adjuvant therapy (sequential [SEQ] RT; 107 patients) or after chemotherapy but concurrent with TAM (concurrent [CONC] RT; 202 patients). Survival data were adjusted for receptor status, age, and tumor size.nnnRESULTSnWith a median follow-up of 10.3 years, 10-year DFS values were 83% and 83% for CONC versus SEQ RT groups (log-rank P = .73; P = .76 adjusted for patient characteristics), and 10-year overall survivals were 88% and 90%, respectively (log-rank P = .59; adjusted P = .65). Patterns of failure showed no increase in in-breast recurrence rates between CONC RT and SEQ RT groups, with 10-year local recurrence rates of 7% for CONC RT and 5% for SEQ RT (hazard ratio, 0.73; 95% CI, 0.26 to 2.04; P = .54).nnnCONCLUSIONnThe current analysis does not suggest an adverse effect on local or systemic control with CONC versus SEQ TAM and RT in node-negative breast cancer. A randomized trial is encouraged to validate these results.

Clinical cancer advances 2007

A MESSAGE FROM ASCOS PRESIDENT: For the third year, the American Society of Clinical Oncology (ASCO) is publishing Clinical Cancer Advances: Major Research Advances in Cancer Treatment, Prevention, and Screening, an annual review of the most significant cancer research presented or published over the past year. ASCO publishes this report to demonstrate the important progress being made on the front lines of clinical cancer research today. The report is intended to give all those with an interest in cancer care-the general public, cancer patients and organizations, policymakers, oncologists, and other medical professionals-an accessible summary of the years most important cancer research advances. These pages report on the use of magnetic resonance imaging for breast cancer screening, the association between hormone replacement therapy and breast cancer incidence, the link between human papillomavirus and head and neck cancers, and the use of radiation therapy to prevent lung cancer from spreading. They also report on effective new targeted therapies for cancers that have been historically difficult to treat, such as liver cancer and kidney cancer, among many others. A total of 24 advances are featured in this years report. These advances and many more over the past several years show that the nations long-term investment in cancer research is paying off. But there are disturbing signs that progress could slow. We are now in the midst of the longest sustained period of flat government funding for cancer research in history. The budgets for the National Institutes of Health and the National Cancer Institute (NCI) have been unchanged for four years. When adjusted for inflation, cancer research funding has actually declined 12% since 2004. These budget constraints limit the NCIs ability to fund promising cancer research. In the past several years the number of grants that the NCI has been able to fund has significantly decreased; this year, in response to just the threat of a 10% budget cut, the nations Clinical Trials Cooperative Groups reduced the number of patients participating in clinical trials by almost 2,000 and senior researchers report that many of the brightest young minds no longer see the promise of a career in science, choosing other careers instead. Its time to renew the nations commitment to cancer research. Without additional support, the opportunity to build on the extraordinary progress to date will be lost or delayed. This report demonstrates the essential role that clinical cancer research plays in finding new and better ways to care for the more than 1.4 million people expected to be diagnosed with cancer this year. I want to thank the Editorial Board members, the Specialty Editors, and the ASCO Cancer Communications Committee for their dedicated work to develop this report. I hope you find it useful. Sincerely, Nancy E. Davidson, MD President American Society of Clinical Oncology.

Concurrent radiation therapy and paclitaxel or docetaxel chemotherapy in high-risk breast cancer

PURPOSEnEvidence supports the inclusion of the taxanes in the treatment of breast cancer. A recent randomized trial has shown a survival advantage to the addition of paclitaxel in the adjuvant treatment of node-positive patients. Several studies have suggested diminished local control if adjuvant radiation is delayed, while in vitro and in vivo studies have demonstrated a benefit of concurrent administration of taxanes with radiation. For these reasons, we began in 1995 to administer radiation therapy concurrently with the taxanes in advanced breast cancer. This retrospective review examines the feasibility of such treatment.nnnMETHODS AND MATERIALSnForty-four patients were treated with concurrent radiation and either paclitaxel (29 patients) or docetaxel (15 patients). One patient received both paclitaxel and docetaxel. Eighteen patients were treated for recurrent disease, 9 had received prior radiation. Toxicity was assessed by the RTOG scale for acute and late effects.nnnRESULTSnConcurrent radiation and taxane chemotherapy was well tolerated. Nine patients (20%) experienced Grade 3 acute skin toxicity. This was more likely with docetaxel than paclitaxel (p = 0. 04). Among patients undergoing breast conservation, there were no Grade 3 toxicities. With a median follow-up of 11 months, 1 patient has developed breast fibrosis.nnnCONCLUSIONnConcurrent administration of both paclitaxel and docetaxel with radiation resulted in acceptable toxicity. Overall, the acute skin toxicity seen with docetaxel was more pronounced. However, among patients undergoing breast conservation the taxanes were both well tolerated. Further study is necessary to assess the impact of concurrent treatment on long-term outcome.

Phase I/II Study of Ixabepilone plus Capecitabine in Anthracycline–Pretreated/Resistant and Taxane-Resistant Metastatic Breast Cancer

PURPOSEnThe aim of this study was to determine the safety, maximum tolerated dose (MTD), recommended phase II dose, and efficacy of the epothilone B analogue ixabepilone plus capecitabine in anthracycline-pretreated/ resistant and taxane-resistant metastatic breast cancer (MBC).nnnPATIENTS AND METHODSnA total of 106 patients were enrolled. The study consisted of a dose-escalation phase (phase I) and a tumor response rate evaluation phase (phase II). Seventy-four patients were treated in phase I with schedule A (ixabepilone 40 mg/m2 intravenously on day 1 plus capecitabine 1650-2000 mg/m2 on days 1-14 of a 21-day cycle) or schedule B (ixabepilone 8-10 mg/m2 on days 1-3 plus capecitabine 1650 mg/m2 on days 1-14 of a 21- day cycle).nnnRESULTSnNo dose-limiting toxicities (DLTs) were observed in the 8/1650 mg/m2 and 10/1650 mg/m2 cohorts; 1 of 30 patients in the 40/1650 mg/m2 cohort and 2 of 30 patients in the 40/2000 mg/m2 cohort had a DLT consisting of grade 3 plantar-palmar erythrodysesthesia (PPE). The 40/2000 mg/m2 dose was defined as the MTD for schedule A, and a total of 62 patients were treated for the phase II portion of the trial, which examined tumor response. The objective response rate was 30%, median time-to-response was 6 weeks, median duration of response was 6.9 months, and median progression-free survival was 3.8 months. Grade 3/4 treatment-related events in phase II included fatigue (34%), PPE (34%), myalgia (23%), nausea (16%), peripheral neuropathy (19%), and diarrhea/vomiting (10%). Grades 3/4 neutropenia (69%) and leukopenia (55%) were managed primarily by dose reduction/treatment interruption.nnnCONCLUSIONnIxabepilone plus capecitabine demonstrated clinical activity and an acceptable safety profile in patients with anthracycline-pretreated/resistant and taxane-resistant MBC. Ixabepilone was recently approved in the United States for the treatment of resistant/refractory locally advanced or MBC.

Bone loss in patients with breast cancer receiving aromatase inhibitors and associated treatment strategies.

Hormone-receptor-positive breast cancer in postmenopausal women is treated increasingly with aromatase inhibitors because of increased efficacy and reduced incidence of endometrial cancer compared with tamoxifen. However, aromatase inhibitor therapy increases bone turnover as a result of nearly complete oestrogen depletion, leading to increases in bone loss and fragility fractures that erode patients functional independence and quality of life. Management of patients with aromatase inhibitor-associated bone loss (AIBL) is currently evolving and intervention strategies are under investigation. Although no treatments are specifically approved for AIBL, bisphosphonates are currently the intervention of choice for patients with low bone mineral density or evidence of rapid bone turnover, along with adequate calcium and vitamin D supplementation and a healthy lifestyle. In this setting, the majority of information available regarding bisphosphonate efficacy is from studies of intravenous zoledronic acid (4 mg) every 6 months. Data from four large international studies (three of identical design in postmenopausal women and one in premenopausal women) indicate that zoledronic acid is effective in the management of AIBL. Treatment algorithms based on risk factors and bone mineral density are under development, and the results of ongoing studies should help define optimal bone health management for patients undergoing aromatase inhibitor treatment for early breast cancer.