National comprehensive cancer network recommendations for drugs without US food and drug administration approval in metastatic breast cancer: A cross-sectional study.

BACKGROUND: National Comprehensive Cancer Network (NCCN) guidelines can include recommendations for off-label use of anti-cancer drugs. Here, we evaluate NCCN recommendations not supported by US Food and Drug Administration (FDA) approval and explore associations with such recommendations. METHODS: All NCCN recommendations for MBC and their supporting data were identified. Drug labels were reviewed to determine whether recommendations are FDA approved. Logistic regression was used to compare FDA approved and off-label recommendations for pre-specified categories, including drug type, tumor subtype, level of recommendation and line of therapy. RESULTS: Of 124 recommendations identified, 68 (55%) were off-label. Chemotherapy and human epidermal growth factor receptor 2 (HER2) targeted drugs were associated with lower odds of FDA approval (OR = 0.28, p = 0.001 and OR = 0.29, 95% p = 0.005, respectively). Recommendations for endocrine therapy (OR = 3.44, p = 0.009) and non-HER2 targeted treatment (OR = 10.0, p < 0.001) were more commonly FDA approved indications. Compared to combination therapies, monotherapies were more likely to be FDA approved (OR = 3.45, p = 0.001) as were category 1 (OR = 7.63, p = 0.001) and preferred NCCN recommendations (OR = 4.07, p < 0.001). Compared to off-label recommendations, NCCN recommendations of approved drugs were based on significantly higher sample size (mean 477 vs. 342 patients, p = 0.02) and were non-significantly associated with availability of randomized data (OR = 2.0, 95% CI 0.89-4.49, p = 0.09). CONCLUSION: More than half of all NCCN recommendations for MBC are off-label, mostly involving chemotherapy containing regimes for HER2 negative disease and combinations which include HER2-targeted drugs. Improved transparency of NCCN guidelines may result from reporting of the strength of the evidence supporting recommendations for MBC.

Role of Bisphosphonates in Breast Cancer Therapy.

Opinion statement Bisphosphonates are utilized routinely in breast cancer. In metastatic disease with bone involvement, bisphosphonates prevent or delay skeletal-related events and can improve pain control. Different agents have shown benefit compared with placebo or no treatment. While in unselected patients, comparison between zoledronic acid and pamidronate did not show a significant difference, exploratory analyses showed that in patients with osteolytic lesions or hypercalcemia, zoledronic acid is superior to pamidronate. De-escalating treatment with zoledronic acid from every 4 to every 12 weeks has been shown to provide similar control of skeletal morbidity and may result in less toxicity and reduced cost. While available data support bisphosphonate treatment for 2 years in metastatic disease, typical treatment duration is influenced by performance status with treatment discontinued only once patients are not well enough to continue receiving systemic therapy or developed treatment-related adverse events. In early-stage breast cancer, individual trials of adjuvant bisphosphonates have reported inconsistent results. However, the Early Breast Cancer Trialists' Collaborative Group showed that bisphosphonates significantly reduce distant recurrence, bone recurrence, and breast cancer mortality, an effect observed in postmenopausal women only. The relative benefit of bisphosphonates was not influenced by receptor status, tumor grade, nodal involvement, or administration of adjuvant chemotherapy. Current guidelines support consideration of adjuvant zoledronic acid or oral clodronate for 3-5 years in postmenopausal women with early-stage disease. Although bisphosphonates are tolerated well, serious adverse events, including osteonecrosis of the jaw and renal impairment, can occur, especially for higher dose density schedules utilized in metastatic disease. Decision to include bisphosphonates in the treatment plan should be based on the anticipated absolute benefit and potential for adverse effects. In some patients with both early-stage and metastatic disease, omission of bisphosphonates is reasonable as the potential benefit from this treatment is not likely to outweigh its risks.