HALAVEN( eribubilin) is indicated for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.

This was based on an open-label, randomized, multicenter trial of 762 patients with metastatic breast cancer who received at least two chemotherapeutic regimens for the treatment of metastatic disease and experienced disease progression within 6 months of their last chemotherapeutic regimen, EMBRACE study. A statistically significant improvement in overall survival was observed in patients randomized to the Halaven arm compared to the control. An updated, unplanned survival analysis, conducted when 77% of events had been observed, was consistent with the primary analysis. In patients randomized to Halaven, the objective response rate by the RECIST criteria was 11% (95% CI: 8.6%, 14.3%) and the median response duration was 4.2 months (95% CI: 3.8, 5.0 months). The difference between overall survival in the 2 treatment groups was statistically significant; median overall survival was 13.1 months with eribulin and 10.6 months with TPC (hazard ratio, 0.81; P = .041).

This was significant but not very pronounced. The magnitude of the improvement is similar to what has been reported for docetaxel vs mitomycin plus vinblastine (31%), and for capecitabine plus docetaxel vs docetaxel alone (26%). It does not mean that Havalen is better than all other chemo choices, which remains for subsequent studies to determine, only that it is somewhat better than “any single-agent treatment (chemotherapy, hormonal or biological) or radiotherapy or symptomatic therapy alone”. Many physicians chose to use vinorelbine, gemcitabine, or capecitabine in the control arm; none chose supportive care and none used combinations.There was a prior phase II study that included patient pre-treated with anthracyclines, taxanes or capecitibine.

Although approved after anthracycline therpay, a pattern of care study in 2014 showed that in practice the drug is used irrespective of prior anthracycline used. There was no significant difference detected for prior anthracycline use impacting the number of eribulin administrations or days of therapy.

There are also two studies supporting its use in first line, withouu prior treatment. At SABCS 2012, the results of a phase clinical trial (Study 206, NCT01268150) of eribulin monotherapy as first-line treatment for locally recurrent or metastatic HER2 negative breast cancer were presented. Efficacy and safety were evaluated. Of 56 enrolled patients, 54 had at least 1 post-baseline assessment. ORR was 31% [complete response (CR) 0%, partial response (PR) 31%, stable disease (SD) 48%], and CBR was 48%. The median time to response (TTR), duration of response (DOR), and PFS were 1.4, 5.8, and 6.1 months, respectively. Treatment-related serious adverse events occurred in 5 patients (9%): neutropenia (4%), and febrile neutropenia (5%). At SABCS 2012, the results of a phase clinical trial (Study 208, NCT01269346) of eribulin plus trastuzumab as first-line combined therapy for locally recurrent or metastatic HER2-positive breast cancer were presented. Efficacy and safety were evaluated. 37 of 52 planned patients have been treated. The ORR was 60% [CR 5%, PR 54%, SD 30%, progressive disease (PD%], and CBR was 70%. Treatment-related serious adverse events occurred in 4 patients (11%): neutropenia (8%), and febrile neutropenia (6%).

Xgeva(denosumab) is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. In the pivotal study, Denosumab was superior to zoledronic acid in delaying or preventing SREs in patients with breast cancer metastatic to bone and was generally well tolerated. With the convenience of a subcutaneous injection and no requirement for renal monitoring, denosumab represents a potential treatment option for patients with bone metastases. It is not approved for myeloma but there are studies supporting it for that diagnosis.

References

Halaven, Prescribing Information: http://www.eisai.com/pdf_files/Halaven_PI.pdf, 2013

35th Annual San Antonio Breast Cancer Symposium (SABCS): Abstract S6-6. Presented December 7, 2012

nccn, Breast Cancer 2013

Alison T. Stopeck, et al, Denosumab Compared With Zoledronic Acid for the Treatment of Bone Metastases in Patients With Advanced Breast Cancer: A Randomized, Double-Blind Study JCO November 8, 2010 JCO.2010.29.7101  

Monica N. Fornier Denosumab: Second Chapter in Controlling Bone Metastases or a New Book? JCO Dec 10, 2010:5127-5131

David H. Henry, Luis Costa, Francois Goldwasser, Vera Hirsh, Vania Hungria, Jana Prausova, Giorgio Vittorio Scagliotti, Harm Sleeboom, Andrew Spencer, Saroj Vadhan-Raj, Roger von Moos, Wolfgang Willenbacher, Penella J. Woll, Jianming Wang, Qi Jiang, Susie Jun, Roger Dansey and Howard Yeh, Randomized, Double-Blind Study of Denosumab Versus Zoledronic Acid in the Treatment of Bone Metastases in Patients With Advanced Cancer (Excluding Breast and Prostate Cancer) or Multiple Myeloma. JCO March 20, 2011 vol. 29 no. 9 1125-1132

Ali McBride, Claudio Faria, Xuan Li, Annette Powers; University of Arizona Cancer Center, Tucson, AZ; Eisai Inc., Woodcliff Lake, NJ
Eribulin treatment patterns in patients with and without prior anthracycline use. J Clin Oncol 32, 2014 (suppl 30; abstr 292)

Vahdat LT, Schwartzberg L, Gluck S, Rege J, OShaughnessy J. Results of a phase 2, multicenter, single-arm study of eribulin mesylate as first-line therapy for locally recurrent or metastatic HER2-negative breast cancer. Cancer Res 2012; (Suppl.): Abstr P1-12-02.

Vahdat LT, Schwartzberg L, Wilks S, Rege J, Liao J, Cox D, OShaughnessy J. Eribulin mesylate + trastuzumab as first-line therapy for locally recurrent or metastatic HER2-positive breast cancer. results from a phase 2, multicenter, single-arm study. Cancer Res 2012; (Suppl.): Abstr P5-20-04.

Xgeva, Prescribing Information

Read the Layperson version here.

A recent review(Hickey et al, 2008) concluded: “Ultimately, the decision to take estrogen for severe menopausal symptoms should rest with the patient who is fully informed regarding the potential adverse effects on disease prognosis. A benefit of multidisciplinary care is the ability to calculate individual patient recurrence risks and to use this information in decision making about treatment choices. In addition, if endocrine therapies are producing severe menopausal symptoms with relatively small benefits in terms of recurrence or survival, the multidisciplinary (MD) team may advise that these can reasonably be stopped or adjusted. For women with advanced breast cancer, the issues of quality of life(QOL) are paramount and Hormonal Therapy may be considered following discussion with the patient”.

Tamoxifen treatment is a complicating factor. In postmenopausal women, tamoxifen acts as a weak estrogen in the ovaries, uterus, and vaginal epithelium. On the other hand, Tajima et al reported on the anti-estrogenic effects seen in the vaginal epithelium of premenopausal women being treated with tamoxifen for infertility. Tamoxifen may block systemic effects on topical estrogenic preparations. Leyden in 2008 writes: “In some cases, local estrogen can be an alternative option, although patients must be carefully monitored, and many may not be comfortable with this approach.” Cochrane Systemic Review in 2004 said: “In women with a history of breast cancer, systemic estrogen or progesterone therapy is contraindicated because of the increased risk of breast cancer recurrence. Vaginal estrogen preparations often are used to treat symptoms of vaginal atrophy in these patients because of the low levels of systemic absorption.”

Therefore, use of estrogen preparation, albeit cautiously, is a reasonable option in this situation. Using androgens is, on the other hand, is problematic. Androgel is an androgen containing cream that can be sued vaginally. AndroGel, an androgen, is indicated for replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone, such as:

•Primary Hypogonadism (Congenital or Acquired) – testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter’s syndrome, chemotherapy, or toxic damage from alcohol or heavy metals. These men usually have low serum testosterone levels and gonadotropins (FSH, LH) above the normal range.
•Hypogonadotropic Hypogonadism (Congenital or Acquired) – idiopathic gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation. These men have low testosterone serum levels but have gonadotropins in the normal or low range. Using it for vaginal dryness is an off-label use.

Using androgens for vaginal dryness is subject to a clinical trial: Vaginal Testosterone Cream For Atrophic Vaginitis in Women Taking Aromatase Inhibitors for Breast Cancer, NCT01122342. Results are not yet available, and I was not able to find published literature to support the safety of androgen gels for breast cancer patients.

AugDyVa.pdf

Mateya Trinkaus, Sheray Chin, Wendy Wolfman, Christine Simmons and Mark Clemons Should Urogenital Atrophy in Breast Cancer Survivors Be Treated with Topical Estrogens? The Oncologist March 2008 vol. 13 no. 3 222-231

Tajima C, Takeda B, Tamaki Y. Effect of tamoxifen on cervical mucus, vaginal smear and endometrial findings. Fertil Steril. 1979;24:23–26.

Suckling J, Lethaby A, Kennedy R. Local oestrogen for vaginal atrophy in postmenopausal women (review). In: The Cochrane Library—Collaboration TC, ed. 4 Wiley, 2007

Ponzone R, Biglia N, Jacomuzzi ME, et al. Vaginal oestrogen therapy after breast cancer: is it safe? Eur J Cancer (2005) 41(17):2673-2681.

Dew JE, Wren BG, Eden JA. A cohort study of topical vaginal estrogen therapy in women previously treated for breast cancer. Climacteric (2003) 6(1):45-52.

M. Hickey; C. Saunders; A. Partridge; N. Santoro; H. Joffe; V. Stearns Practical Clinical Guidelines for Assessing and Managing Menopausal Symptoms After Breast Cancer
Annals of Oncology. 2008;19(10):1669-1680.

Read the Layperson version here.