PRIME EVENTS
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Malignant Ascites: A Novel Option for Management On February 19, 2009, Fresenius Biotech GmbH received a positive opinion from the European Medicines Agency’s (EMEA) Committee for Medicinal Products for Human Use for the marketing approval of catumaxomab (Removab®), indicated for the intraperitoneal treatment of malignant ascites in patients with epithelial cell adhesion molecule (EpCAM)–positive carcinomas where standard therapy is not available. Catumaxomab is a trifunctional monoclonal antibody with 2 antigen-recognition sites: one for human EpCAM, a cell surface antigen expressed by a variety of epithelial tumor cells, and one for human CD3, a T-cell surface antigen. In addition, another region of the antibody binds to receptors that are expressed on other cells of the immune system. The notion is that binding of catumaxomab to EpCAM-positive tumor cells, T lymphocytes, and other cells of the immune system may bring them close together and thus, may result in the reduction of tumor cells via multiple mechanisms. The advantage of catumaxomab is that it reduces the need for paracenteses in patients with malignant ascites. The most common side effects of this drug abdominal pain, tiredness, and a reduction in the number of lymphocytes.
A randomized, placebo-controlled trial investigating the use of tibolone (Livial®), a synthetic steroid, for the treatment of menopausal symptoms and prevention of osteoporosis was stopped 6 months prematurely because breast cancer survivors receiving tibolone had a significantly increased risk of disease recurrence. Results from this study were published in The Lancet Oncology. Tibolone is not approved in the US; however, it is approved in 90 countries for the treatment of menopausal symptoms and in 55 countries for the prevention of osteoporosis. In the randomized study, 3148 women who underwent surgery for breast cancer were randomized to tibolone (2.5 mg/day) or placebo. In the ITT population (n = 3098), after a median follow-up of 3.1 years, 15.2% of tibolone-treated patients had disease recurrence versus 10.7% of patients that received placebo (hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.14-1.70; P = .001). Additionally, most of the recurrences (72.6%) were distant metastases, which are usually fatal. Results from this study raise concern about the use of tibolone in patients with a history of breast cancer. The author of an accompanying editorial concluded that this study provide convincing data opposing the use of tibolone for treating menopausal symptoms, which can be managed with less risky therapies. Lancet Oncol. 2009;10:135-146.
TC Superior to AC in Early Breast Cancer Historically, most adjuvant regimens for node-negative breast cancer (BC) have included an anthracycline. Four cycles of doxorubicin and cyclophosphamide (AC) is commonly used adjuvant treatment, especially for patients with node-negative BC. However, long-term anthracycline-related cardiotoxicity is a concern and has become even more important recently with the introduction of cardiotoxic-targeted therapy for BC management. To evaluate the effect of an anthracycline-sparing regimen in early BC, a randomized phase III study was conducted to compare 4 cycles of docetaxel/cyclophosphamide (TC; 75/600 mg/m2; n = 506) versus four cycles of standard-dose AC (60/600 mg/m2; n = 510) in women with operable, stage I-III BC. The primary endpoint was disease-free survival (DFS). Previously reported 5-year follow-up results demonstrated a significant improvement in DFS with TC versus AC (86% vs 80%, respectively; P = .015). Recently published 7-year results showed that the superiority of TC over AC for DFS was sustained (81% vs 75%, respectively; P = .033). Additionally, TC showed a significant benefit for OS compared with AC (87% vs 82%, respectively; P = .032). Women ≥65 years of age (16% of patients in the trial) derived the same benefit from TC than younger patients. Overall, treatment was well tolerated; however, women ≥65 years of age experienced more febrile neutropenia with TC (8% vs 4%) and more anemia with AC (5% vs 1%) compared with younger patients. This study demonstrated the superiority of 4 cycles of TC over standard AC (DFS and OS) at 7 years in patients with early BC, regardless of age, HER2 status, or hormonal receptor status. A phase III study, comparing 6 cycles of TC vs TAC, is ongoing to determine whether anthracyclines are necessary for the adjuvant treatment of early breast cancer. J Clin Oncol. 2009 Feb 9. [Epub ahead of print]
It is now accepted that breast cancer (BC) can no longer be viewed as one biologic entity. Emerging data demonstrate that tumor stratification by gene expression profiles and other techniques divides breast cancer into 5 discrete molecular subtypes according to hormone receptor expression (positive or negative), epithelial cellular origin (basal or luminal), and HER2 overexpression. Moreover, there is increasing evidence that these molecular subtypes differ in their response to therapeutic agents. A retrospective subset analysis of a randomized phase III Breast Cancer International Research Group (BCIRG) 001 trial was conducted to investigate the prognostic significance and response to adjuvant chemotherapy of immunohistochemically-defined subsets of patients with BC treated with a docetaxel-containing regimen (docetaxel, doxorubicin, and cyclophosphamide [TAC] or fluorouracil, doxorubicin, and cyclophosphamide [FAC]). A total of 1350 patients with node-positive early BC were included in this analysis and subdivided based on tumor characteristics as 1) triple negative (ER-, PR-, HER2-), 15%; 2) HER2 (HER2+, PR-, ER-), 9%; 3) luminal B (ER+ and/or PR+ and either HER2+ and/or Ki67high), 61%; and 4) luminal A (ER+ and/or PR+ and not HER2+ or Ki67high), 16%. The multivariate Cox regression analysis included as primary prognostic variables biologic subtypes and chemoendocrine therapy (TAC, FAC, and tamoxifen). The biologic subtypes were prognostically significant for disease-free survival (DFS) and overall survival (OS). Three-year DFS rates (P values versus luminal B) were 67% (P<.0001) for triple negative, 68% (P = .0008) for HER2, 82% (P = NA) for luminal B, and 91% (P = .0027) for luminal A subtype. Compared with FAC, TAC showed a significant 3-year DFS benefit in the luminal B (P = .025) and a combined ER+/HER2- group treated with tamoxifen (P = .041), with a marginal trend in the triple-negative (P = .051) and HER2 (P = .068) subtypes. However, the luminal A subset showed no DFS benefit with TAC when added to tamoxifen. This analysis showed that breast tumors can be divided into immunohistochemically defined subsets with strong prognostic implications. The authors concluded that TAC significantly compliments endocrine therapy in tamoxifen-treated patients in the luminal B group and that it is effective in the triple-negative subset in the absence of specific targeted therapy. However, given the retrospective nature of this study, the authors emphasized that these findings should be considered “hypothesis generating.” J Clin Oncol. 2009 Feb 9. [Epub ahead of print]
Gene-expression profiling has revolutionized the way breast cancer (BC) is viewed. A recently published review article discussed the findings from gene-expression studies that have contributed significantly in this regard and limitations for clinical practice. Highlights from this review are presented.
The gene-expression profiling research is promising and will lead to molecularly tailored treatment and identification of markers and biologic pathways that might be involved in determining prognosis, response, and resistance to therapy in different molecular subgroups of BC. N Engl J Med. 2009;360:790-800.
Salpingo-oophorectomy is a cancer prevention approach that is used in many women who carry germline mutations in the BRCA1 and/or BRCA2 genes. Previous studies have reported a notably reduced risk of breast and other gynecologic cancers in BRCA1/2 mutation carriers who had undergone risk-reducing salpingo-oophorectomy (RRSO); however, the extent of this benefit is unclear. Therefore, to estimate the magnitude of the risk reductions, a meta-analysis was conducted of the pooled results from 10 published studies that investigated breast or gynecologic cancer outcomes in BRCA1/2 mutation carriers following RRSO. Results from this meta-analysis showed a statistically significant reduction of 79% in the risk of fallopian tube and ovarian cancer (hazard ratio [HR], 0.21; 95% confidence interval [CI], 0.12-0.39) and a 51% reduction in breast cancer risk in BRCA1/2 mutation carriers who had undergone RRSO (HR, 0.49; 95% CI, 0.37-0.65). Furthermore, when the effect of RRSO was determined separately for BRCA1 and BRCA2 mutation carriers, a similar reduction of 53% in breast cancer risk was shown for each of the 2 groups. For the gynecologic cancers, the BRCA1 and BRCA2 groups were too small to be analyzed individually. Overall, risk-reduction estimates obtained from this analysis revealed a substantially reduced risk of breast and ovarian cancer in BRCA1/2 mutation carriers who had undergone RRSO. Given that a residual cancer risk remains following surgery, supplementary risk reduction and screening tests are required to decrease cancer incidence and death as much as possible in the high-risk subset. J Natl Cancer Inst. 2009;101:80-87.
Rituximab with chemotherapy is the current gold standard therapy for aggressive B-cell non-Hodgkin lymphoma (NHL), and positron emission tomography (PET) is a routine modality in the early diagnosis and follow-up of these patients. In patients with aggressive NHL, PET has shown to be a powerful predictor of relapse and survival in the pre-rituximab era. However, little is known about the effect of rituximab on PET scan interpretation. This is important to identify since rituximab’s mechanism of action may involve recruitment of immune cells to the tumor, which may lead to false-positive PET results. A retrospective analysis was conducted to evaluate the usefulness of PET for mid-therapy and post-therapy response determination in patients with aggressive B-cell NHL treated with rituximab-containing chemotherapy regimens (N = 51). A PET scan was considered positive if higher than mediastinal activity or if background activity was observed. The accuracy of mid-therapy and post-therapy PET for predicting relapse was determined based on the positive predictive value (PPV), negative predictive value (NPV), sensitivity, and specificity. Mid-therapy PET scans were positive in 32.5% and post-therapy PET scans were positive in 18.7% of patients. The PPV, NPV, sensitivity, and specificity of mid-therapy PET for predicting relapse were 33%, 68%, 33%, and 68%, respectively. For post-therapy PET, these values were 19%, 81%, 13%, and 80%, respectively. Of these values, PPV and sensitivity of mid-therapy and post-therapy PET were lower than that previously reported in non-rituximab–treated patients with aggressive NHL. However, similar to the pre-rituximab era, negative mid-therapy and post-therapy PET scans were associated with prolonged progression-free survival in rituximab-treated patients. Overall, results from this analysis suggest that positive mid-therapy and post-therapy PET scans may have limited prognostic value in patients with aggressive B-cell NHL treated with rituximab-containing regimens. Furthermore, due to the low PPV, rituximab-treated patients with aggressive B-cell NHL who have positive PET imaging in residual masses should obtain histologic confirmation of lymphoma persistence prior to a change in therapy and initiation of salvage treatment. Ann Oncol. 2009;20:309-318.
A majority of patients with follicular lymphoma (FL) respond to initial treatment, but they often experience disease progression. Rituximab added to chemotherapy has been shown to improve overall survival (OS) in patients with FL compared to treatment with chemotherapy alone. However, limited data are available from randomized clinical trials to guide the use of rituximab as maintenance therapy in this patient population. A meta-analysis of randomized, controlled trials was conducted to evaluate the effects of rituximab maintenance therapy on OS in patients with FL. A total of 1143 adult patients from 5 trials were included; OS data were available for 985 patients. Rituximab maintenance therapy was associated with a significant improvement in OS compared with observation or rituximab treatment at relapse (hazard ratio [HR] of death, 0.60; 95% confidence interval [CI], 0.45-0.79); however, it was associated with more infection-related adverse events (HR, 1.99; 95% CI, 1.21-3.27). Patients with relapsed or refractory FL had a survival benefit with maintenance rituximab therapy compared to patients who underwent observation (HR for death, 0.58; 95% CI, 0.42-0.79). However, among previously untreated patients, the benefit was not statistically significant (HR for death, 0.68; 95% CI, 0.37-1.25). Based on these results, the authors suggested patients with previously treated FL should receive maintenance rituximab for up to 2 years (4 weekly infusions every 6 months or single infusion every 2-3 months) in addition to standard therapy following successful induction therapy. However, they emphasized the higher infection rates with rituximab therapy should be taken into account when making a treatment decision. J Natl Cancer Inst. 2009;101:248-255.
BRIEF REPORTS Benefit of Adjuvant Zoledronic Acid in Premenopausal Patients with Breast Cancer A large randomized phase III clinical study ABCSG-12 was conducted to determine the efficacy of adjuvant endocrine therapy (3 years of goserelin plus anastrozole or tamoxifen) with or without zoledronic acid in premenopausal women with endocrine-responsive early breast cancer. After a median follow-up of 47.8 months, the addition of zoledronic acid to endocrine therapy in comparison to endocrine therapy alone resulted in a relative reduction of 36% in the risk of disease progression (hazard ratio, 0.64; 95% confidence interval, 0.46-0.91; P = .01). For more information on this study, please visit PRIME Oncology’s Virtual Journal Club with Michael Gnant, MD. N Engl J Med. 2009;360:679-691. We welcome your comments and suggestions regarding content and format at primelines@primeoncology.org. |
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