In the Literature - September 2015

September 2015, Vol 6, No 8

In This Article


Docetaxel-Based Chemotherapy Improves Relapse-Free Survival in Patients with High-Risk Localized Prostate Cancer

The current treatment landscape for patients with high-risk localized prostate cancer is predominantly confined to a combination of androgen-­deprivation therapy (ADT) plus radiotherapy, which has been shown to improve survival over radiotherapy alone. Although risk-based chemotherapy is a standard approach to treatment in solid cancers, few trials assessed the use of chemotherapy for patients with high-risk localized prostate cancer. Now a new study evaluated the use of docetaxel-based chemotherapy for patients with high-risk localized prostate cancer (Fizazi K, et al. Lancet Oncol. 2015;16:787-794).

Previous studies have demonstrated that docetaxel, with or without estramustine, results in improved outcomes, including survival, in patients with metastatic castration-resistant prostate cancer. These findings have led Fizazi and colleagues to conduct the phase 3, randomized, controlled clinical trial known as GETUG 12, which evaluated the efficacy of docetaxel plus estramustine and ADT versus ADT alone in patients with high-risk localized prostate cancer. The preliminary results showed improved prostate-specific antigen (PSA) response and no negative effect on the patient’s quality of life with the combination therapy compared with ADT alone.

This latest report from GETUG 12 was focused on relapse-free survival—which is defined as biochemical failure, onset of metastases, proven local relapse, use of salvage treatment, and death—in patients with high-risk localized prostate cancer. The trial was conducted at 26 hospitals in France, and enrolled patients with treatment-naïve prostate cancer and ?1 risk factors, including T3 to T4 disease, a Gleason score of ?8, PSA >20 ng/mL, or pathologic node-positive disease. Overall, 207 patients received the docetaxel plus estramustine and ADT combination and 206 patients received ADT alone, with a median follow-up of 8.8 years.

Overall, the rate of disease relapse or death was 43% among patients receiving the chemotherapy-based combination therapy compared with 54% among patients who received ADT alone. In addition, the 8-year relapse-free survival was 62% in the chemotherapy group versus 50% in the ADT-alone group, and biochemical failure was the most common relapse event.

The chemotherapy was well-tolerated, and grade ?2 adverse events were comparable between the 2 groups. Furthermore, there was no excess of secondary cancers, and no leukemia was reported in the chemotherapy group. According to Fizazi and colleagues, testosterone recovery after stopping ADT is not likely to be the reason for the benefits of chemotherapy on relapse-free survival, because analysis of serum testosterone showed no difference between the 2 groups; further analysis will help to elucidate the patterns of relapse.

The use of docetaxel-based chemotherapy is a viable treatment option for patients without castration-resistant disease; however, additional studies and longer follow-up are needed to confirm that relapse-free survival results in improved metastasis-free survival and overall survival in patients with high-risk localized prostate cancer.

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Second-Line Treatment with Ramucirumab After First-Line Sorafenib for Advanced Hepatocellular Carcinoma

Hepatocellular carcinoma is the second most common cause of cancer-related death and occurs most often in patients with cirrhosis. Vascular endothelial growth factor (VEGF) plays an important role in tumor growth and angiogenesis, and is overexpressed in patients with ­hepatocellular carcinoma. The treatment options for this patient population are limited; sorafenib is the only drug that has shown improved median overall survival (OS). However, sorafenib is associated with significant toxicities. Previous studies with ramucirumab, a VEGF inhibitor, demonstrated antitumor activity in patients with hepatocellular carcinoma and in those with renal-cell carcinoma after sorafenib therapy. A REACH study assessed the safety and efficacy of ramucirumab in patients with advanced hepatocellular carcinoma after first-line therapy with sorafenib (Zhu AX, et al. Lancet Oncol. 2015;16:859-870).

REACH was a randomized, double-blind, multicenter, phase 3 clinical trial of 565 patients with hepatocellular carcinoma who had received sorafenib and were randomized in a 1:1 ratio to receive ramucirumab 8 mg/kg or placebo every 2 weeks. The primary end point was OS; the secondary end points included the median progression-free survival (PFS), time to tumor progression, and objective response.

Treatment with ramucirumab did not significantly improve OS compared with placebo; the median OS was 9.2 months with ramucirumab versus 7.6 months with placebo. Nevertheless, Zhu and colleagues reported improvements in the secondary end points. The median PFS was 2.8 months with ramucirumab compared with 2.1 months with placebo; the median time to tumor progression was 3.5 months with ramucirumab versus 2.6 months with placebo, and an objective response was reported in 7% of patients receiving ramucirumab compared with <1% of patients receiving placebo. The safety profile of ramucirumab was consistent with previous studies.

Although REACH did not meet its primary end point of OS, the study yielded a particularly noteworthy finding. A subgroup analysis showed that ramucirumab was especially effective at improving OS in patients with a baseline ?-fetoprotein concentration of ?400 ng/mL, where the median OS was 7.8 months with ramucirumab versus 4.2 months in the placebo group. Elevated ?-fetoprotein concentration is associated with poor prognosis in hepatocellular carcinoma, and the conferred benefit with ramucirumab in patients with an elevated ?-fetoprotein concentration bolsters support for targeting angiogenesis in advanced hepatocellular cancer.

In addition, Zhu and colleagues postulated that elevated ?-fetoprotein concentrations may help to identify patients who would benefit most from ramucirumab therapy; further studies are needed to confirm this hypothesis.

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Modified Tool Helps Treatment Decisions for Breast Cancer Associated with Brain Metastases

The current prognostic tools for patients with breast cancer and brain metastases use several variables to predict overall survival (OS), including age, tumor subtype, and Karnofsky performance score. Brain metastases are associated with significant morbidity and mortality and have been reported in all stages of breast cancer. A new study investigated the use of a modified breast graded prognostic assessment (breast-GPA) tool that incorporates the number of brain metastases to predict OS in patients with breast cancer and brain metastases (Subbiah IM, et al. J Clin Oncol. 2015;33:2239-2245).

Subbiah and colleagues identified 1552 patients from a medical oncology database who had breast cancer and received treatment for newly diagnosed brain metastases between 1996 and 2013. Medical records were used to identify prognostic factors, and magnetic resonance imaging was analyzed to quantify the number of brain lesions. After confirming that breast-GPA and the number of brain metastases are independent predictors of OS, Subbiah and colleagues modified the breast-GPA to integrate the number of brain metastases with the existing prognostic factors of age, tumor subtype, and Karnofsky performance score.

Using the modified breast-GPA, the data showed that the unadjusted median survival time was significantly higher in patients with 1 to 3 brain lesions than in patients who had >3 brain lesions (13.2 months vs 6.3 months, respectively; P <.001); the results were similar for OS.

The modified breast-GPA can help in 2 ways. First, it can help providers to guide treatment decisions for patients with breast cancer who have brain metastases. For example, patients with good prognosis can receive more aggressive treatment.

In addition, the modified breast-GPA can help providers and researchers to select patients for clinical trials in breast cancer. In fact, the modified breast-GPA is currently being validated in an independent cohort, as well as in a multi-­institutional collaboration, for its use as a patient selection tool for clinical trials.

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Everolimus Improves Outcomes When Added to Trastuzumab and Paclitaxel as First-Line Therapy in HR-Negative, HER2-Positive Advanced Breast Cancer

Resistance to trastuzumab is a common problem for patients with HER2 breast cancer. Previous studies have shown that adding mTOR inhibition with everolimus to trastuzumab-based therapy provided clinical benefits in heavily pretreated patients with HER2-positive advanced breast cancer who had disease progression. This led to the launch of 2 phase 3 clinical trials, BOLERO-1 and BOLERO-3. BOLERO-3 showed a significant improvement in progression-free survival (PFS) with the addition of everolimus in patients whose disease had progressed with trastuzumab-based therapy. The benefits of everolimus were especially pronounced in patients with hormone receptor (HR)-negative tumors. BOLERO-1 compared the use of everolimus as first-line treatment in the full patient population and in the HR-negative subpopulation (Hurvitz SA, et al. Lancet Oncol. 2015;16:816-829).

In the BOLERO-1 phase 3, randomized, double-blind, multicenter clinical trial, 719 patients with HER2-positive advanced breast cancer who had not received therapy with trastuzumab or chemotherapy for advanced breast cancer were randomized in a 2:1 ratio to receive everolimus 10 mg or placebo once daily plus trastuzumab and paclitaxel, with a median follow-up of 41.3 months.

PFS in the full patient population was 14.95 months with everolimus versus 14.49 months with placebo, indicating no significant differences between the 2 groups. However, the difference in PFS, although also not significant, was markedly evident in the HR-negative subpopulation at 20.27 months with everolimus versus 13.08 months with placebo. Hurvitz and colleagues noted that the threshold for statistical significance in the HR-negative subpopulation was stringent. The toxicity profile of everolimus-­based therapy was consistent with that of previous studies. Because the 3-drug combination is associated with a high incidence of adverse events, monitoring and managing these events are essential.

The findings from BOLERO-1 support the data from BOLERO-3, suggesting that adding everolimus to trastuzumab and paclitaxel may be a first-line therapy option for patients with HR-negative, HER2-positive advanced breast cancer. Ongoing studies are evaluating the benefits of adding PI3K/mTOR inhibitors to endocrine therapy and HER2-targeted therapy for patients with HR-positive, HER2-positive advanced breast cancer.

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