Results of the preplanned interim analysis of the ALSYMPCA (Alpharadin in Symptomatic Prostate Cancer) trial were presented in September at the European Multidisciplinary Cancer Congress in Stockholm, Sweden (Abstract 1LBA). The trial was an international, randomized, double-blind, placebo-controlled, phase III study of radium-223 chloride (Alpharadin, Bayer HealthCare Pharmaceuticals) plus best standard of care compared with a placebo plus best standard of care in men with metastatic, castration-resistant prostate cancer (mCRPC). A total of 922 enrolled patients who had either failed prior docetaxel-based chemotherapy or were not eligible to be treated with docetaxel-based chemotherapy received up to 6 intravenous treatments with radium-223 chloride or placebo, with a 4-week period between each treatment. Results of the preplanned interim analysis were strong enough to prematurely stop the trial. The study met its primary endpoint of overall survival; radium-223 improved overall survival by 44% compared to placebo (median of 14 months vs 11.2 months, respectively; HR, 0.695; P=.00185). The time to first skeletal-related event significantly improved from 8.4 months with placebo to 13.6 months with radium-223 (HR, 0.61; P=.00046). Levels of total alkaline phosphatase (ALP) were normalized in 33% of men treated with radium-223 versus 1% of men who received a placebo. Treatment with radium-223 improved time to prostate-specific antigen (PSA) progression by 49% compared to placebo (HR, 0.671; P=.00015). Radium-223 chloride is not yet approved in the United States or Europe, but it was granted fast track designation by the US Food and Drug Administration (FDA) in August 2011.
Mutations of the SF3B1 gene were found in a significant proportion of patients with myelodysplastic syndromes (MDS), according to a presentation by Papaemmanuil and associates at the 2011 European Multidisciplinary Cancer Congress. There was also a relationship between the gene mutation and ring sideroblasts in bone marrow, which makes SF3B1 the first gene to be closely associated with a particular feature of MDS. Targeted sequencing of SF3B1 was conducted in 2,087 samples (from blood, bone marrow, or primary tumor cells) from patients with a variety of myeloid and other common cancers. Somatic mutations of SF3B1 were present in 20.3% of MDS patients, 5.3% of patients with AML, and 2.9% of patients with myeloproliferative neoplasms. In patients with MDS whose disease was defined by the presence of ring sideroblasts, 64.6% of them had the SF3B1 mutation. Researchers also found that the gene mutation was present in 1–5% of patients with other common cancers, such as breast cancer, multiple myeloma, and kidney cancer. Available data for 123 patients with MDS showed that 34 of them had the SF3B1 mutation. Compared to those without the mutation, these patients had a milder form of MDS and significantly better overall survival, and they were less likely to survive without their MDS developing into leukemia. Due to the fact that mutations in the SF3B1 gene tended to be correlated with a better prognosis, the findings suggest the possibility of screening patients for the mutation and then adjusting treatment strategies accordingly.
Chances of survival increased to 88% in rectal cancer patients who were treated with capecitabine in combination with 5 weeks of radiation before surgery, according to 3-year follow-up data from the ACCORD (Action Clinique Coordonnées en Cancérologie Digestive) 12/0405-PRODIGE 2 trial. Gerard and colleagues presented the 3-year follow-up data on October 3 at the annual meeting of the American Society for Radiation Oncology (ASTRO). A total of 598 patients with locally advanced rectal cancer were randomly assigned to receive either Cap45 (capecitabine and radiation at 45 Gy) or Capox50 (capecitabine and oxaliplatin plus radiation at 50 Gy). Compared to the Cap45 treatment regimen, patients who were treated with the Capox50 regimen did not have significantly increased chances of the cancer returning, nor did they have a significant increase in the chance of survival at 3 years after treatment. Adverse events were greatly increased in the Capox50 arm due to oxaliplatin, which also failed to increase the likelihood of local tumor sterilization. When the radiation dose was increased from 45 Gy to 50 Gy in 5 weeks, it was effective, well tolerated, and did not extend the duration of treatment. The study investigators found that preoperative treatment with capecitabine and 5 weeks of radiation at 50 Gy (Cap50 regimen) was safe and reduced the chances of cancer returning to 5% or less.
A prospective, multicenter, observational study conducted by the Australian Colonic Endoscopic Resection study group investigated whether endoscopic criteria can predict invasive disease in patients referred for endoscopic mucosal resection (EMR) and whether these criteria can help to direct the optimal treatment strategy. Data regarding lesion characteristics and procedural, clinical, and histologic outcomes were collected from 479 patients with a mean sessile colorectal polyp size of 35.6 mm. The investigators identified Paris classification 0–IIa+c morphology, nongranular surface, and Kudo pit pattern type V as risk factors for submucosal invasion. The most commonly observed lesion (O–IIa granular) had a low rate of submucosal invasion (1.4%). EMR achieved complete removal of the polyp in 89.2% of patients. Significant risk factors for failure of EMR included a prior attempt at EMR (odds ratio [OR], 3.8%; 95% confidence interval [CI], 1.77–7.94; P=.001) and ileocecal valve involvement (OR, 3.4; 95% CI, 1.20–9.52; P=.021). Lesion size greater than 40 mm and use of argon plasma coagulation were significant independent predictors of recurrence after effective EMR (OR, 4.37 and 3.51, respectively). No deaths were caused by EMR, and 83.7% of patients were able to avoid surgery. The study findings were published in the June issue of Gastroenterology.
A small, exploratory study by Foster and colleagues evaluated the antiviral activity of telaprevir (Incivek, Vertex) in treatment-naïve adults with genotype 2 or 3 chronic hepatitis C virus (HCV) infection. Forty-nine patients (23 with genotype 2 HCV infection and 26 with genotype 3 HCV infection) were randomized to receive 1 of 3 regimens for 2 weeks: monotherapy (telaprevir 750 mg every 8 hours); triple therapy (telaprevir plus peginterferon α-2a [180 μg weekly] plus ribavirin [400 mg twice daily]); or placebo plus peginterferon and ribavirin. All treatment arms then received peginterferon and ribavirin for 22 or 24 weeks. Rates of sustained virologic response (SVR) among patients with genotype 2 HCV infection were 56% with telaprevir monotherapy, 100% with telaprevir-based triple therapy, and 89% with peginterferon plus ribavirin. Patients with genotype 3 HCV infection had SVR rates of 50%, 67%, and 44%, respectively. Published online on June 1 in Gastroenterology, this study concluded that telaprevir monotherapy reduces levels of HCV RNA in patients with chronic genotype 2 HCV infection, but telaprevir has limited activity in patients with genotype 3 HCV infection.
In order to determine whether consuming larger amounts of coffee can improve response to treatment in patients with HCV infection, Freedman and associates examined coffee intake and response to treatment using data from the lead-in phase of the HALT-C trial. Enrolled patients (n=885) had HCV infection and fibrosis or cirrhosis at baseline, exhibited no signs of hepatic decompensation or hepatocellular carcinoma, and had failed to respond to interferon therapy. Patients recorded coffee intake be-fore re-treatment with peginterferon α-2a (180 μg/wk) and ribavirin (1,000–1,200 mg/day). The investigators assessed patients for early virologic response (2 log10 reduction in HCV RNA level at Week 12; n=466) and undetectable levels of HCV RNA at Week 20 (n=320), Week 48 (end of treatment; n=284), and Week 72 (SVR; n=157). Patients who consumed more than 3 cups of coffee per day had twice as great a decline in HCV RNA viral load from baseline compared to nondrinkers (median 4.0 vs 2.0 log, respectively). After adjusting for sex, age, race/ethnicity, alcohol use, presence of cirrhosis, ratio of aspartate aminotransferase to alanine aminotransferase, interleukin-28B genotype, interferon dose reduction, and other factors affecting response, patients who drank the most coffee remained approximately twice as likely to respond to treatment. Response rates were significantly higher in heavy coffee consumers compared to nondrinkers at all time points (early virologic response: 76% vs 46%, respectively; Week 20 response: 52% vs 26%, respectively; SVR: 26% vs 11%, respectively). These findings, which were published in the June issue of Gastroenterology, suggest that heavy coffee consumption is an independent predictor of improved virologic response to peginterferon and ribavirin treatment in patients with HCV infection.
On August 26, the US Food and Drug Administration (FDA) announced its approval of crizotinib (Xalkori, Pfizer), a kinase inhibitor, for the treatment of locally advanced and metastatic non–small-cell lung cancers (NSCLC) that express an abnormal anaplastic lymphoma kinase (ALK) gene. A diagnostic test for the ALK gene abnormality, the Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular Inc.), was approved concurrently. Approval of crizotinib was based on combined results from 2 single-arm trials: PROFILE 1005 (Phase II, Open-Label Single Arm Study of the Efficacy and Safety of PF-02341066 in Patients With Non-Small Cell Lung Cancer Harboring a Translocation or Inversion Event Involving the Anaplastic Lymphoma Kinase Gene; 136 patients) and a part 2 expansion cohort of a phase I study, known as Study 1001 (119 patients). The primary endpoint was objective response rate (ORR). A total of 255 patients with locally advanced or metastatic ALK-positive NSCLC received 250 mg of crizotinib twice daily. The ORR was 50% in PROFILE 1005 and 61% in Study 1001. The median response duration for PROFILE 1005 and Study 1001 was 42 weeks and 48 weeks, respectively. Common adverse events included vision disorders, nausea, diarrhea, vomiting, edema, and constipation. Grade 3/4 events that occurred in at least 4% of patients were increased alanine transaminase and neutropenia. Severe, life-threatening, or fatal treatment-related pneumonitis has been reported with a frequency of 1.6% in crizotinib clinical trials.