Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy

JHOP - March 2011, Vol 1, No 1
Robert J. Ignoffo, PharmD, FASHP, FCSHP, FHOPA
Clinical Professor Emeritus
University of California, San Francisco
Professor of Pharmacy
College of Pharmacy, Touro University–California
Mare Island, Vallejo, CA
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Bevacizumab-based Therapy Improves Outcomes in Elderly Patients with NSCLC
Background: Efficacy and safety data of bevacizu mab plus cisplatin/gemcitabine for elderly patients with non–small-cell lung cancer (NSCLC) could be extracted through subgroup analysis of patients in the AVAiL trial.
Design: Using retrospective analysis of data from the placebo-controlled, phase 3 AVAiL trial, researchers evaluated data of the 304 study participants (aged ≥65 years). Most patients (83%) had adenocarcinoma. Patients in the AVAiL trial had received cisplatin 80 mg/m and gemcitabine 1250 mg/m for up to six cycles plus 7.5 mg/kg bevacizumab, 15 mg/kg bevacizumab, or placebo every 3 weeks until disease progression.
Summary: Combining the patients in the two bevacizumab arms, 79% completed more than four cycles. In addition, patients in these two arms had improvement in progression-free survival (PFS) compared with those in the placebo arm (7.5 mg/kg bevacizumab: hazard ratio [HR], 0.71; P = .023; 15 mg/kg bevacizumab: HR, 0.84; P = .25). Objective response rates were 40% in the 7.5- mg/kg bevacizumab group, 29% in the 15-mg/kg bevacizumab group, and 30% in the placebo group. Overall survival (OS) was similar for each bevacizumab arm versus placebo (7.5 mg/kg bevacizumab: HR, 0.84; P = .31; 15 mg/kg bevacizumab: HR, 0.88; P = .44).
Takeaway: Several cytotoxic combination regimens are effective in patients with metastatic NSCLC. Because resistance is a common problem in NSCLC and mediated via both epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), treatment may include VEGF or EGFR inhibitors. Bevacizumab combined with cisplatin was studied in the AVAiL trial and showed that when combined with cisplatin and gemcitabine, tumor response and OS were both improved using a bevacizumab dose of 7.5 mg/kg, but not the higher dose of 15 mg/kg. Based on this study, bevacizumab may be added to chemotherapy for initial therapy of advanced or recurrent NSCLC. Leighl NB, et al. J Thorac Oncol. 2010;5:1970-1976.

Adding Sorafenib to Doxorubicin May Prolong Survival in Advanced Liver Cancer
Sorafenib combined with doxorubicin in patients with advanced hepatocellular carcinoma (HCC) had not yet been evaluated in a phase 2 or 3 trial. Previous trials found that sorafenib prolonged OS in patients with HCC and Child-Pugh A disease and that, in combination with doxorubicin, it was well tolerated by patients with solid tumors.
Design: For this phase 2 study, researchers randomized patients with advanced HCC, Eastern Cooperative Oncology Group performance status 0 to 2, and Child- Pugh A status who had not received prior systemic therapy. Patients were assigned to treatment with 60 mg/m2 of doxorubicin intravenously every 21 days plus either sorafenib 400 mg or placebo orally twice daily. The primary outcome measure was time to progression (TTP).
Summary: The trial was halted early, based on analysis for efficacy. Of the 96 patients, 63 died: 25 in the doxorubicin-sorafenib group and 38 in the doxorubicin- placebo group. Median TTP was 6.4 months in the doxorubicin-sorafenib group compared with 2.8 months in the doxorubicin-placebo group (P = .02). The HR was 0.5 (95% confidence interval [CI], 0.3- 0.9), representing a 50% reduction in the risk of progression in patients treated with doxorubicin plus sorafenib compared with reduction of risk progression in those treated with doxorubicin plus placebo (P = .02). Median OS was 13.7 months versus 6.5 months, respectively (P = .006), and PFS was 6.0 months and 2.7 months, respectively (P = .006). Adverse effects of the two agents were additive and similar to what would be expected with each agent alone.
Takeaway: There is currently no standard treatment for patients with advanced HCC. Doxorubicin has been studied extensively in this disease, and has been shown to produce a small survival advantage compared with best supportive care alone (median survival, 10.6 vs 7.5 weeks). Other phase 2 studies have demonstrated a mean OS of 3 to 6 months. The disparity in results is probably related to patient selection. The current study produced promising results in TTP, median OS, and PFS for the combination of doxorubicin plus sorafenib. Furthermore, the addition of sorafenib to doxorubicin did not significantly increase toxicity over doxorubicin alone. Based on these results, a phase 3 trial of sorafenib plus doxorubicin versus sorafenib alone is being conducted. Abou-Alfa GK, et al. JAMA. 2010;304:2154-2160

Arsenic Immediately after Induction Improves Survival in APL
Background: Although arsenic trioxide (As2O3) is used as an effective treatment for relapsed acute promyelocytic leukemia (APL), its benefit as consolidation treatment for patients in first remission has not been confirmed.
Design: The North American Leukemia Intergroup Study Group randomized 481 patients to an induction regimen of tretinoin/cytarabine/daunorubicin, followed by two courses of the consolidation regimen of tretinoin/ daunorubicin, or to the same induction and consolidation regimen plus two 25-day courses of As2O3 consolidation immediately after induction. After consolidation, patients were randomly assigned to 1 year of maintenance therapy with either tretinoin alone or in combination with methotrexate/mercaptopurine.
Summary: Of the 90% of patients on each arm who achieved remission, event-free survival was significantly improved for patients assigned to the As2O3 arm (80% vs 63% at 3 years; P <.0001). Survival was also better in the As2O3 arm (86% vs 81% at 3 years; P = .059), as was disease- free survival (90% vs 70% at 3 years; P <.0001).
Takeaway: Standard consolidation has consisted of two cycles of an anthracycline (daunorubicin or idarubicin) plus all-trans retinoic acid (ATRA). Recent studies, however, have suggested an important role for As2O3. This study aimed to provide further data that consolidation with As2O3 is a reasonable approach for patients who have achieved complete remission. All end points of survival were improved with As2O3 when combined with ATRA and daunorubicin. Based on this data, As2O3 combination–based regimens have been added to the National Comprehensive Cancer Network guidelines as a standard consolidation regimen for APL. Powell BL, et al. Blood. 2010;116:3751-3757. 

Adjuvant Docetaxel, Doxorubicin, Cyclophosphamide for Node-negative Breast Cancer
Among others, the Breast Cancer International Research Group (BCIRG) 001 trial showed that an adjuvant regimen of docetaxel, doxorubicin, and cyclophosphamide (TAC) reduced the risk for recurrence of breast cancer and for death over fluorouracil, doxorubicin, and cyclophosphamide (FAC). These results, however, have been in node-positive patients. Outcome data for patients with node-negative breast cancer have not yet been defined.
Design: In this phase 3 open-label study, researchers randomized 1060 women with high-risk, node-negative breast cancer to receive TAC (75 mg/m2, 50 mg/m2, 500 mg/m2; n = 539) or FAC (500 mg/m2, 50 mg/m2, 500 mg/m2; n = 521) every 3 weeks for six cycles beginning within 60 days of surgery. The primary end point, disease- free survival (DFS), was assessed at ≥5 years of follow- up. The secondary end point was OS.
Summary: Of 1051 evaluable patients, 87.8% in the TAC group and 81.8% in the FAC group achieved DFS—a 32% reduction in the risk of disease recurrence (HR, 0.68; 95% CI, 0.49-0.93; P = .01) for the TAC group. OS was achieved by 95.2% of patients in the TAC group and 93.5% in the FAC group—a 24% reduction in the risk of death (HR, 0.76; 95% CI, 0.45-1.26; P = .29) for the TAC group. Sub group analyses found no significant difference in DFS by hormone-receptor status, menopausal status, or number of high-risk factors. There was also no significant treatment interaction with HER2 status or hormone-receptor status. Grade 3 and 4 adverse events occurred in 28.2% of patients in the TAC group and 17.0% in the FAC group (P <.001). Most adverse events with TAC were remedied with granulocyte colony-stimulating factor.
Takeaway: It is noteworthy that in this study, the rate of drug adherence was 94.5% and 97.7% for the TAC and FAC groups, respectively. The OS after 77 months of follow-up was not significantly different between treatment groups; however, the number of events was too small for analysis and will require longer follow-up. It is impressive that the risk of recurrence was significantly reduced by 32% with TAC therapy, which compares favorably with the BCIRG 001 trial’s use of the TAC and FAC regimens in node-positive patients (ie, a higher stage of disease) that produced a 28% risk reduction in the TAC group. Both the BCIRG study and this present study show that adjuvant TAC is effective in patients with node-positive and with node-negative, early-stage, high-risk breast cancer. Martin M, et al; for the GEICAM 9805 Investigators. N Engl J Med. 2010;363:2200-2210.

Long-term Benefit of Radiotherapy Confirmed, Tamoxifen for Ductal Carcinoma In Situ
Background: Enhanced screening efforts have increased the number of patients diagnosed with ductal carcinoma in situ (DCIS). Of the treatment options available (surgery, radiotherapy, and hormonal therapy), radiotherapy has previously been shown effective in reducing recurrences of in situ or invasive ipsilateral disease. These long-term results of the UK, Australia, and New Zealand DCIS trial highlight the role of tamoxifen in this patient population.
Design: Researchers randomized 1701 patients with locally excised DCIS into a 2 X 2 factorial trial of radiotherapy, tamoxifen, or both. Each patient and surgeon team decided whether to enter into the 4-way randomization, or one of two 2-way randomizations. Researchers recommended a radiotherapy dose of 50 Gy in 25 fractions over 5 weeks (2 Gy/day on weekdays) and a tamoxifen dose of 20 mg daily for 5 years. Intention-to-treat analysis was performed on the primary end points of invasive ipsilateral new breast events for radiotherapy and any new breast event, including contralateral disease and DCIS, for tamoxifen.
Summary: At a median follow-up of 12.7 (range, 10.9-14.7) years of 1694 patients eligible for analysis, 163 invasive (122 ipsilateral; 39 contralateral), 197 DCIS (174 ipsilateral; 17 contralateral), and 16 of un known invasiveness or laterality was diagnosed. Incidence of all new breast events was reduced with radiotherapy (HR, 0.41; 95% CI, 0.30-0.56; P <.0001), as well as with tamoxifen (HR, 0.71; 95% CI, 0.58-0.88; P = .002), with radiotherapy reducing the incidence of ipsilateral invasive disease (HR, 0.32; 95% CI, .19-0.56; P <.0001) and ipsilateral DCIS (HR, 0.38; 95% CI,0.22-0.63; P <.0001), but having no effect on contralateral breast cancer (HR, 0.84; 95% CI, 0.45-1.58; P = .6). Tamoxifen reduced recurrent ipsilateral DCIS (HR, 0.70; 95% CI, 0.51-0.86; P = .03) and contralateral tumors (HR, 0.44; 95% CI, 0.25-0.77; P = .005), but had no effect on ipsilateral invasive disease.
Takeaway: Several studies using adjuvant radiotherapy alone in DCIS have shown that it decreases local recurrence by 50% but not the occurrence of metastatic disease, and it does not reduce OS. This study confirms the results of previous studies that radiation therapy is the most effective treatment to prevent ipsilateral DCIS and all breast events. Tamoxifen has the added benefit of a systematic effect on reducing the risk of contralateral DCIS. Subgroup analysis showed that radiotherapy was most effective in women older than 50 years, whereas tamoxifen was most effective for women who had a low or an intermediate grade of disease. Therefore, both radiotherapy and tamoxifen should be used in the management of patients with DCIS. Cuzick J, et al. Lancet Oncol. 2011;12:21-29.

Systematic Review of Anti-EGFR Treatment and KRAS Mutation Status
KRAS, an oncogene that is frequently mutated in colorectal cancer (CRC), is a central signaling node that integrates signaling cascades in many EGFR pathways. It has been hypothesized, and many retrospective studies corroborate, that mutations in this gene could prevent benefit from anti-EGFR therapy. Taking it one step forward, researchers are conducting randomized controlled trials to evaluate the predictive ability of KRAS testing on survival outcomes with cetuximab or panitumumab treatment in patients with advanced CRC.

Design: The investigators searched MEDLINE, PubMed, and the Human Genome Epidemiology Literature Finder for studies reporting on at least one of the following: overall mortality; recurrence, relapse, or disease progression; and treatment failure, which included time-to-event outcomes. The search was limited to those reported up through March 24, 2010, and stratified patients with CRC who had received cetuximab or panitumumab by KRAS status. Using undirected graphs, the investigators identified overlapping populations and excluded them from the meta-analysis. To summarize survival outcomes, they performed random-effects metaanalysis of HRs, relative HRs, and odds ratios (ORs) using the DerSimonian-Laird model. To summarize accuracy for predicting outcomes, they performed bivariate random-effects meta-analysis of sensitivity and specificity and calculated summary positive and negative likelihood ratios using corresponding CIs.
Summary: The 45 publications that were eligible for analysis represent 24 nonoverlapping studies. Of these, 4 were re-analyses of randomized controlled trials of anti- EGFR therapy versus best supportive care or chemotherapy alone, from which the investigators found no significant benefit in OS or PFS in patients with KRAS mutations (HR, 1.0). Their analysis of 22 studies with nonoverlapping populations found a summary specificity of 0.49 (CI, 0.43-0.55) and a summary sensitivity of 0.93 (CI, 0.87-0.97), which corresponds to a summary positive likelihood ratio of 7.35 (CI, 3.72-14.50) and a summary negative likelihood ratio of 0.55 (CI, 0.49-0.61).
Takeaway: This meta-analysis study of KRAS mutation– positive or –negative CRC patients who were treated with anti-EGFR therapy shows that OS is almost 80% longer in those with wild-type KRAS. Furthermore, median PFS or TTP was shorter among patients with KRAS-positive tumors than with wild-type KRAS. The high positivity ratio suggests that KRAS mutations are a strong predictor of reduced survival, progression, and treatment failure. This study corroborates the warning on the US Food and Drug Admin istra tion–approved labeling that restricts the use of anti-EGFR antibody therapy to patients with CRC who test negative for KRAS mutations. Dahabreh IJ, et al. Ann Intern Med. 2011;154:37-49.

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