Debra A. Patt

Pooled Analysis of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma

PURPOSE To provide a more precise estimate of long-term survival observed for ipilimumab-treated patients with advanced melanoma, we performed a pooled analysis of overall survival (OS) data from multiple studies. METHODS The primary analysis pooled OS data for 1,861 patients from 10 prospective and two retrospective studies of ipilimumab, including two phase III trials. Patients were previously treated (n = 1,257) or treatment naive (n = 604), and the majority of patients received ipilimumab 3 mg/kg (n = 965) or 10 mg/kg (n = 706). We also conducted a secondary analysis of OS data (n = 4,846) with an additional 2,985 patients from an expanded access program. OS rates were estimated using the Kaplan-Meier method. RESULTS Among 1,861 patients, median OS was 11.4 months (95% CI, 10.7 to 12.1 months), which included 254 patients with at least 3 years of survival follow-up. The survival curve began to plateau around year 3, with follow-up of up to 10 years. Three-year survival rates were 22%, 26%, and 20% for all patients, treatment-naive patients, and previously treated patients, respectively. Including data from the expanded access program, median OS was 9.5 months (95% CI, 9.0 to 10.0 months), with a plateau at 21% in the survival curve beginning around year 3. CONCLUSION To our knowledge, this is the largest analysis of OS to date for ipilimumab-treated patients with advanced melanoma. We observed a plateau in the survival curve, beginning at approximately 3 years, which was independent of prior therapy or ipilimumab dose. These data add to the evidence supporting the durability of long-term survival in ipilimumab-treated patients with advanced melanoma.

Cardiac Morbidity of Adjuvant Radiotherapy for Breast Cancer

PURPOSE Adjuvant breast irradiation has been associated with an increase in cardiac mortality, because left-sided breast radiation can produce cardiac damage. The purpose of this study was to determine whether modern adjuvant radiotherapy is associated with increased risk of cardiac morbidity. PATIENTS AND METHODS Data from the Surveillance, Epidemiology, and End Results-Medicare database were used for women who were diagnosed with nonmetastatic breast cancer from 1986 to 1993, had known disease laterality, underwent breast surgery, and received adjuvant radiotherapy. The Cox proportional-hazards model was used to compare patients with left- versus right-sided breast cancer for the end points of hospitalization with the following discharge diagnoses (International Classification of Diseases, 9th Revision codes): ischemic heart disease (410-414, 36.0, and 36.1), valvular heart disease (394-397, 424, 35), congestive heart failure (428, 402.01, 402.11, 402.91, and 425), and conduction abnormalities (426, 427, 37.7-37.8, and 37.94-37.99). RESULTS Eight thousand three hundred sixty-three patients had left-sided breast cancer, and 7,907 had right-sided breast cancer. Mean follow-up was 9.5 years (range, 0 to 15 years). There were no significant differences in patients with left- versus right-sided cancers for hospitalization for ischemic heart disease (9.9% v 9.7%), valvular heart disease (2.9% v 2.8%), conduction abnormalities (9.7% v 9.6%), or heart failure (9.7% v 9.7%). The adjusted hazard ratio for left- versus right-sided breast cancer was 1.05 (95% CI, 0.94 to 1.16) for ischemic heart disease, 1.07 (95% CI, 0.89 to 1.30) for valvular heart disease, 1.07 (95% CI, 0.96 to 1.19) for conduction abnormalities, and 1.05 (95% CI, 0.95 to 1.17) for heart failure. CONCLUSION With up to 15 years of follow-up there were no significant differences in cardiac morbidity after radiation for left- versus right-sided breast cancer.

Systemic Therapy for Patients With Advanced Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline

PURPOSE To provide evidence-based recommendations to practicing oncologists and others on systemic therapy for patients with human epidermal growth factor receptor 2 (HER2) -positive advanced breast cancer. METHODS The American Society of Clinical Oncology convened a panel of medical oncology, radiation oncology, guideline implementation, and advocacy experts and conducted a systematic literature review from January 2009 to October 2012. Outcomes of interest included overall survival, progression-free survival (PFS), and adverse events. RESULTS A total of 16 trials met the systematic review criteria. The CLEOPATRA trial found survival and PFS benefits for docetaxel, trastuzumab, and pertuzumab in first-line treatment, and the EMILIA trial found survival and PFS benefits for trastuzumab emtansine (T-DM1) in second-line treatment. T-DM1 also showed a third-line PFS benefit. One trial reported on duration of HER2-targeted therapy, and three others reported on endocrine therapy for patients with HER-positive advanced breast cancer. RECOMMENDATIONS HER2-targeted therapy is recommended for patients with HER2-positive advanced breast cancer, except for those with clinical congestive heart failure or significantly compromised left ventricular ejection fraction, who should be evaluated on a case-by-case basis. Trastuzumab, pertuzumab, and taxane for first-line treatment and T-DM1 for second-line treatment are recommended. In the third-line setting, clinicians should offer other HER2-targeted therapy combinations or T-DM1 (if not previously administered) and may offer pertuzumab, if the patient has not previously received it. Optimal duration of chemotherapy is at least 4 to 6 months or until maximum response, depending on toxicity and in the absence of progression. HER2-targeted therapy can continue until time of progression or unacceptable toxicities. For patients with HER2-positive and estrogen receptor-positive/progesterone receptor-positive breast cancer, clinicians may recommend either standard first-line therapy or, for selected patients, endocrine therapy plus HER2-targeted therapy or endocrine therapy alone.

Acute Myeloid Leukemia After Adjuvant Breast Cancer Therapy in Older Women: Understanding Risk

PURPOSE The purpose of this study was to determine the risk of developing acute myeloid leukemia (AML) after adjuvant chemotherapy for breast cancer in older women. PATIENTS AND METHODS Data from the Surveillance, Epidemiology, and End Results-Medicare linked database were used for women diagnosed with nonmetastatic breast cancer from 1992 to 2002. The primary end point was a claim with an inpatient or outpatient diagnosis of AML (International Classification of Diseases ninth revision, codes 205 to 208), comparing patients treated with and without adjuvant chemotherapy, and by differing chemotherapy regimens. The cumulative hazard of AML was estimated using the Kaplan-Meier method. Cox proportional hazards models were used to determine factors independently associated with the development of AML. RESULTS In this observational study, there were 64,715 patients: 10,130 received adjuvant chemotherapy and 54,585 did not. The median patient age was 75.6 years (range, 66 to 104 years). The mean follow-up was 54.8 months (range, 13 to 144 months). The absolute risk of developing AML at 10 years after any adjuvant chemotherapy for breast cancer was 1.8% versus 1.2% for women who had not received chemotherapy. The adjusted hazard ratio for AML with adjuvant chemotherapy versus none was 1.53 (95% CI, 1.14 to 2.06). Granulocyte colony-stimulating factor (G-CSF) within the first year of diagnosis did not convey a significantly increased risk of AML (hazard ratio, 1.14; 95% CI, 0.67 to 1.92). CONCLUSION There is a small but real increase in AML after adjuvant chemotherapy for breast cancer in older women. This study may underestimate the true incidence because myelodysplastic syndrome cannot be identified through claims. G-CSF use within the first year of diagnosis does not convey an increased risk of AML in older women.

Recommendations on Disease Management for Patients With Advanced Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer and Brain Metastases: American Society of Clinical Oncology Clinical Practice Guideline

PURPOSE To provide formal expert consensus-based recommendations to practicing oncologists and others on the management of brain metastases for patients with human epidermal growth factor receptor 2 (HER2) -positive advanced breast cancer. METHODS The American Society of Clinical Oncology (ASCO) convened a panel of medical oncology, radiation oncology, guideline implementation, and advocacy experts and conducted a systematic review of the literature. When that failed to yield sufficiently strong quality evidence, the Expert Panel undertook a formal expert consensus-based process to produce these recommendations. ASCO used a modified Delphi process. The panel members drafted recommendations, and a group of other experts joined them for two rounds of formal ratings of the recommendations. RESULTS No studies or existing guidelines met the systematic review criteria; therefore, ASCO conducted a formal expert consensus-based process. RECOMMENDATIONS Patients with brain metastases should receive appropriate local therapy and systemic therapy, if indicated. Local therapies include surgery, whole-brain radiotherapy, and stereotactic radiosurgery. Treatments depend on factors such as patient prognosis, presence of symptoms, resectability, number and size of metastases, prior therapy, and whether metastases are diffuse. Other options include systemic therapy, best supportive care, enrollment onto a clinical trial, and/or palliative care. Clinicians should not perform routine magnetic resonance imaging (MRI) to screen for brain metastases, but rather should have a low threshold for MRI of the brain because of the high incidence of brain metastases among patients with HER2-positive advanced breast cancer.

Pathways, Outcomes, and Costs in Colon Cancer: Retrospective Evaluations in Two Distinct Databases

PURPOSE The goal of this study was to use two separate databases to evaluate the clinical outcomes and the economic impact of adherence to Level I Pathways, an evidence-based oncology treatment program in the treatment of colon cancer. PATIENTS AND METHODS The first study used clinical records from an electronic health record (EHR) database to evaluate survival according to pathway status in patients with colon cancer. Disease-free survival in patients receiving adjuvant treatment and overall survival in patients receiving first-line therapy for metastatic disease was calculated. The second study used claims data from a national administrative claims database to examine direct medical costs and use, including the cost of chemotherapy and of chemotherapy-related hospitalizations according to pathway status. RESULTS Overall costs from the national claims database-including total cost per case and chemotherapy costs-were lower for patients treated according to Level I Pathways (on-Pathway) compared with patients not treated according to Level I Pathways. Use of pathways was also associated with a shorter duration of therapy and lower rate of chemotherapy-related hospital admissions. Survival for patients on-Pathway in the EHR database was comparable with those in the published literature. CONCLUSION Results from two distinct databases suggest that treatment of patients with colon cancer on-Pathway costs less; use of these pathways demonstrates clinical outcomes consistent with published evidence.

Final Results of a Randomized Phase II Study Demonstrating Efficacy and Safety of BSI-201, a Poly (ADP-Ribose) Polymerase (PARP) Inhibitor, in Combination with Gemcitabine/Carboplatin (G/C) in Metastatic Triple Negative Breast Cancer (TNBC).

Background: TNBC is an aggressive breast cancer subtype which shares molecular and pathologic features with BRCA1-related breast cancers. BRCA-deficient cells are sensitive to inhibition of PARP1, a critical enzyme of cell proliferation and DNA repair, and thus represent a rational target of PARP inhibitor-based cancer therapy. The objectives of this study were to evaluate BSI-201, a potent PARP1 inhibitor, in combination with G/C in subjects with metastatic TNBC. Methods: Eligible subjects had measurable disease and received ≤2 prior cytotoxic regimens for ER-, PR-, and HER2-negative metastatic breast cancer. Patients were randomized (1:1) to G/C alone or G/C + BSI-201. Gemcitabine (1000 mg/m2; IV) and carboplatin (AUC = 2; IV) were given on days 1 and 8, and BSI-201 (5.6 mg/kg; IV) on days 1, 4, 8, and 11 every 21 days. Endpoints were clinical benefit rate (CBR = CR + PR + SD ≥6 months), objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results: Preliminary analyses of all 116 dosed patients showed that, based on all patient visits through March 2009, BSI-201 + G/C improved CBR, ORR, median PFS, and median OS, compared with G/C alone. The frequency and nature of adverse events did not differ between arms.Conclusions: This analysis demonstrates that BSI-201 + G/C improved patient9s outcomes, as measured by CBR, ORR, PFS and OS, compared with G/C alone. BSI-201 + gemcitabine/carboplatin was well tolerated and did not potentiate chemotherapy-related toxicities. Final data on CBR and ORR, as well as updated analyses of PFS and OS for all 116 dosed patients will be presented based on all patient visits through September 2009. Exploratory correlative analyses of PARP expression and overall clinical response will also be presented, as well as initial correlative analyses between number of metastatic therapies and clinical response. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3122.

Benchmarks for Value in Cancer Care: An Analysis of a Large Commercial Population

PURPOSE Cancer costs are increasing at an unprecedented rate. Key cost drivers include chemotherapy, hospital admissions/emergency room visits, and aggressive end-of-life care. We sought to evaluate these costs in a commercial payer population in collaboration with consultants from Milliman. PATIENTS AND METHODS We used a retrospective analysis of Medstat 2007 to evaluate chemotherapy costs and use. Included patients had a cancer diagnosis; received chemotherapy during the evaluation period; had at least 1 day of coverage between January 1 and December 31, 2007 (medical and prescription coverage); was younger than age 70, and had active employment or was the spouse of an active employee. Costs are allowed amounts and are trended until 2009. Admission rates and emergency room visits are reported. Hospice use and chemotherapy during the last 14 and 30 days of life were also evaluated. RESULTS In this commercial population of 14 million patients, 0.68% had claims for a cancer diagnosis; approximately 22% of those received chemotherapy during the study time period. Patients with cancer receiving chemotherapy averaged

Evaluating Use Characteristics for the Oncotype Dx 21-Gene Recurrence Score and Concordance With Chemotherapy Use in Early-Stage Breast Cancer

111,000 per year in total medical and pharmacy costs. The average hospitalization rate for any reason was 1 admission/yr. Approximately 40% (or 0.4 admits/year) were identified as being chemotherapy related. Of the 3.5% of patients who died in the hospital, 51% received chemotherapy within 30 days of death. CONCLUSION Understanding the costs of cancer care offers opportunities to formulate a strategic plan to control cancer costs and maintain quality care. Comprehensive cancer solutions to address the full spectrum of care will facilitate improved quality and patient outcomes.

The Effectiveness of Tyrosine Kinase Inhibitors and Molecular Monitoring Patterns in Newly Diagnosed Patients With Chronic Myeloid Leukemia in the Community Setting

PURPOSE Oncotype Dx 21-gene assay recurrence score (RS) predicts recurrence of early-stage breast cancer (ESBC). We investigated whether patient, tumor, or practice characteristics drive its use and explored Oncotype DX RS and chemotherapy use in subgroups. METHODS Patients with ESBC with documented estrogen receptor-positive, lymph node-negative, human epidermal growth factor receptor 2-negative tumors registered within McKesson Specialty Healths iKnowMed electronic health record were included. Patient and practice characteristics by region and size were analyzed. The association between Oncotype DX RS value and use of chemotherapy were assessed. RESULTS The study included 6,229 patients. Of these, 1,822 (29%) had an Oncotype DX RS result. Test use was 36%, 38%, 34%, 25%, and 6%, respectively, in patients age ≤ 45, 46-55, 56-65, 66-75, and ≥ 76 years; 33%, 25%, and 9% in patients with Eastern Cooperative Oncology Group performance status of 0, 1, and ≥ 2; 7%, 9%, 25%, 38%, 27%, and 10% in T1mic, T1a, T1b, T1c, T2, and T3 tumors; and 26%, 32%, and 33% for grades 1, 2, and 3 tumors. Of the 1,822 patients with available Oncotype DX RS, adjuvant chemotherapy use was 6%, 42%, and 84% in the low-, intermediate-, and high-risk groups. CONCLUSION Patients who were younger, had better ECOG performance status, or had higher grade tumors were more likely to undergo RS testing. It appears that the RS test may have influenced the decision about whether to administer adjuvant chemotherapy: a low RS score was associated with lower chemotherapy use and a high RS score was associated with higher chemotherapy use.