This year, the American Society of Clinical Oncology (ASCO) celebrates the 50th anniversary of its founding. ASCO’s 2014 annual meeting acknowledged the society’s role in the advances made against cancer and presented the latest research and educational information about prevention, detection, and treatment of cancer. This year’s meeting was well attended and provided a wealth of learning opportunities. Below are some highlights of the many ASCO presentations. These highlights touch upon the potentially practice-changing use of exemestane to treat breast cancer patients, preservation of fertility in premenopausal breast cancer survivors, and a study that shows that loratadine is not effective in treating pegfilgrastim-induced bone pain.
Exemestane Plus Ovarian Suppression a Valid Option in Premenopausal Early Breast Cancer
The aromatase inhibitor exemestane was superior to tamoxifen when combined with ovarian function suppression (OFS) in preventing recurrence in premenopausal women with hormone-sensitive breast cancers. These were the findings of a joint analysis of 2 important phase 3 clinical trials, TEXT (Tamoxifen and Exemestane Trial) and SOFT (Suppression on Ovarian Function Trial), that were presented at the American Society of Clinical Oncology 2014 annual meeting and published simultaneously in the New England Journal of Medicine.1,2
Lead author, Olivia Pagani, MD, explained that up until now exemestane has been used only in postmenopausal women. “This analysis demonstrates that an aromatase inhibitor is effective adjuvant therapy for premenopausal women when combined with ovarian suppression. Exemestane [plus OFS] is a valid alternative to tamoxifen [plus OFS] in young women with hormone-sensitive disease. It is a new adjuvant treatment option that reduces recurrence in this setting,” she stated. Pagani is clinical director of the Breast Unit at the Oncology Institute of Southern Switzerland in Bellinzona.
OFS is used more frequently in Europe than in the United States to achieve low estrogen levels in patients with hormone-sensitive breast cancer. Tamoxifen is considered the standard of care in this setting, and adjuvant chemotherapy is sometimes used depending on the judgment of the oncologist and patient preference.
Both SOFT and TEXT compared 5 years of tamoxifen plus OFS versus 5 years of exemestane plus OFS. SOFT was a 3-arm trial comparing both of those treatment approaches versus tamoxifen alone; results of the tamoxifen-alone arm have not yet been analyzed, so it is currently not possible to determine if tamoxifen alone is superior, equal, or inferior to hormonal therapy plus OFS.
The joint analysis of SOFT and TEXT included 4690 patients from both trials enrolled in the OFS-containing arms.
Chemotherapy was given at the discretion of the treating physician, and 42.6% did not receive chemotherapy. About 28% of the women who did not get chemotherapy had tumors larger than 2 cm and some positive nodes. In a separate interview, Pagani said that the study suggests that exemestane plus OFS could replace chemotherapy in some patients.
“Our study suggests that for hormone-sensitive tumors, go for exemestane and OFS and you can avoid chemotherapy,” Pagani stated.
At a median follow-up of 68 months, 5-year disease-free survival was 91.1% with exemestane plus OFS versus 87.3% in the tamoxifen plus OFS group (P < .001). The 5-year rate of freedom from breast cancer was 92.8% in the exemestane-treated patients compared with 88% in those who received tamoxifen (P < .001). Among patients who did not receive chemotherapy and were treated with exemestane plus OFS, 97.6% of those in the TEXT population and 97.5% of those in the SOFT population were free of breast cancer at 5 years.
The 5-year rate of freedom from recurrence at a distant site was 93.8% in the exemestane plus OFS group compared with 92% in the tamoxifen plus OFS group. At 5 years, overall survival was 95.9% in the exemestane group and 96.9% in the tamoxifen group. However, it is premature to determine survival, Pagani said.
Side effects of both drugs were as expected. Adverse events that were more frequent with exemestane included fractures, musculoskeletal symptoms, vaginal dryness, decreased libido, and dyspareunia; those more frequently reported with tamoxifen included thromboembolic events, hot flushes, night sweats, and urinary incontinence. Gynecologic cancers were reported in 7 exemestane-treated patients and in 9 patients in the tamoxifen group; endometrial cancers occurred in 2 and 5 patients, respectively. About 30% of patients in both arms experienced grade 3 or 4 adverse events.
Experts said that they were awaiting results of the tamoxifen-alone arm of the TEXT trial to see whether these findings would be practice changing.
1. Pagani O, Regan MM, Walley B, et al. Randomized comparison of adjuvant aromatase inhibitor (AI) with exemestane (E) plus ovarian function suppression (OFS) vs tamoxifen (T) plus OFS in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC): joint analysis of IBCSG TEXT and SOFT trials. Presented at: 50th Annual Meeting of the American Society of Clinical Oncology; May 30-June 3, 2014; Chicago, IL. Abstract LBA1.
2. Pagani O, Regan MM, Walley BA, et al; the TEXT and SOFT Investigators and the International Breast Cancer Study Group. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014;371(2):107-118.
Loratadine and Bone Pain
Pegfilgrastim, which mobilizes white blood cells that fight infection, is indicated by the US Food and Drug Administration for the treatment of cancer patients with nonmyeloid malignancies who are receiving anticancer drugs that are associated with clinically significant febrile neutropenia.1 Although pegfilgrastim is a highly effective drug, about half of the patients who receive it experience moderate to severe bone pain that can interfere with quality of life and compromise adherence to treatment.2
“The mechanism of this bone pain is unclear,” said Joanna Schwartz, PharmD, BCOP, of Albany College of Pharmacy and Health Sciences in Colchester, Vermont, one of the authors of a phase 2 pilot study of loratadine for the prevention of pegfilgrastim-induced bone pain (PIP). Lead author was Julia Moukharskaya, MD, of the University of Vermont College of Medicine in Burlington.
Schwartz noted that granulocyte colony-stimulating factor (G-CSF)–induced bone marrow expansion of white blood cell precursors has been associated with histamine release and possibly pain. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as naproxen have not been highly effective in studies of treatment of PIP.
Based on anecdotal evidence, the investigators postulated that the antihistamine loratadine could be an effective treatment for PIP. Disappointingly, loratadine failed to have an impact in this phase 2 pilot study.
The prospective, randomized, placebo-controlled trial enrolled 227 patients undergoing pegfilgrastim treatment who were observed for the development of clinically significant PIP, which was defined as a score of 5 or higher on the Brief Pain Inventory instrument, with a 2-point or greater increase from baseline after an initial dose of pegfilgrastim. Of these, 65 patients developed PIP and were eligible for randomization, with 45 of them going on to be randomized to loratadine 10 mg or placebo daily for 7 days, initiated on day 1 of pegfilgrastim administration.
Twenty patients dropped out of the study because they did not receive further pegfilgrastim, leaving 25 for evaluation (13 in the loratadine group and 12 in the placebo group). Patients randomized to loratadine achieved 59% improvement in PIP from baseline compared with 54.5% for placebo, which was not significantly different.
Results remained the same after data were adjusted for use of rescue analgesics, including NSAIDs and non-NSAIDS.
“This proves the value of confirming pilot studies. Based on this study, loratadine should not be used to treat PIP. However, a prophylactic study with loratadine versus naproxen use starting the day prior to pegfilgrastim is ongoing, and may guide a future role for this agent in the treatment of PIP,” Schwartz said.
1. Neulasta [package insert]. Thousand Oaks, CA: Amgen Inc; February 2014.
2. Moukharskaya J, Abrams DM, Khan FB, et al. Randomized phase II pilot study of loratadine for the prevention of bone pain caused by pegfilgrastim. Presented at: 50th Annual Meeting of the American Society of Clinical Oncology; May 30-June 3, 2014; Chicago, IL. Abstract 9628.
Goserelin Preserves Ovarian Function in Premenopausal Women With Breast Cancer
The addition of goserelin to chemotherapy was shown to preserve ovarian function, fertility, and the ability to have a successful pregnancy in premenopausal women with hormone receptor–negative (HR–) early breast cancer, according to results of the Prevention of Early Menopause Study (POEMS), an international Intergroup trial coordinated by the Southwest Oncology Group. The study was presented as a late-breaking oral abstract during the American Society of Clinical Oncology 2014 annual meeting.
“This is the first demonstration of fertility prospects and more successful pregnancies in women with breast cancer. Premenopausal women with HR– breast cancer should be offered this option,” stated lead author Halle Moore, MD, of the Cleveland Clinic in Ohio.
Goserelin and other luteinizing hormone-releasing hormone (LHRH) analogs shut down ovarian function and put patients in a postmenopausal state. The goal of using this drug is to protect the ovaries during chemotherapy.
Ovarian failure was the primary end point of the study and was defined as amenorrhea for the prior 6 months and postmenopausal levels of follicle-stimulating hormone (FSH). The investigators also assessed disease-free survival (DFS) and overall survival (OS).
The study, which was conducted from February 2004 to May 2011, randomized 257 premenopausal women (median age, 38 years) with stage I-IIIA HR– breast cancer to treatment with cyclophosphamide-containing chemotherapy (standard arm) or the same chemotherapy plus goserelin given as monthly injections starting 1 week before chemotherapy.
More than 90% got anthracycline-containing chemotherapy, and cancer stage distribution was similar in the 2 arms. Endocrine toxicity was twice as high in the goserelin arm compared with chemotherapy and included hot flashes, mood swings, dry vagina, and headache.
At 2 years, ovarian failure occurred in 22% of the chemotherapy arm versus 8% of the goserelin arm (P = .04). Regardless of stratification factors, goserelin achieved a lower rate of ovarian failure. The 2-year rate of ovarian dysfunction was also significantly lower in the goserelin arm: 33% with standard chemotherapy versus 14% with goserelin (P = .03). Goserelin did not increase the risk of any complications or terminations of pregnancy compared with chemotherapy alone.
Eighteen patients in the standard chemotherapy arm and 25 in the goserelin arm tried to become pregnant. Women in the goserelin arm were about 2.5 times more likely to conceive. Successful pregnancies were reported in 12 patients (11%) in the standard chemotherapy arm and 22 (21%) in the goserelin arm. Live births were reported in 8 patients in the standard chemotherapy arm (7%, 12 babies) and 15 patients in the goserelin arm (15%, 18 babies; P = .03). Goserelin did not increase the risk of any complications or terminations of pregnancy compared with chemotherapy alone.
Unexpectedly, goserelin also improved DFS and OS. The 4-year DFS rate was 78% in the standard chemotherapy arm and 89% in the goserelin arm (P = .04), and 4-year OS was 82% versus 92%, respectively (P = .06).
The study had some limitations, however, including missing data for 38% of patients, but Moore said this is the largest randomized study of LHRH agonist use for ovarian protection in HR– breast cancer, and it is the most informative study reporting pregnancy outcomes with an LHRH analog during chemotherapy.
Moore HCF, Unger JM, Phillips K-A, et al. Phase III trial (Prevention of Early Menopause Study [POEMS]-SWOG S0230) of LHRH analog during chemotherapy (CT) to reduce ovarian failure in early-stage, hormone receptor-negative breast cancer: an international Intergroup trial of SWOG, IBCSG, ECOG, and CALGB (Alliance). Presented at: 50th Annual Meeting of the American Society of Clinical Oncology; May 30-June 3, 2014; Chicago, IL. Abstract LBA505.