Cancer Treatment Today » Hormonal Treatment

Tamoxifen and endometrial cancer – pro

M Levin, MD — Sun, 13 Oct 2013 12:44:48 +0000

Tamoxifen is a venerable drug that revolutionized breast cancer care when it was first introduced. More recently, it has been largely supplanted by aromatase inhibitors(AI), but tamoxifen is still useful in pre-menopausal women, in whom AIs do not work.

Tamoxifen has a variety of bothersome side effects, related mostly to forced early menopause.
In addition, a rare complication of tamoxifen is uterine lining overgrowth, which can proceed to endometrial bleeding. Abnormal uterine bleeding occurs in more than 50% of premenopausal women taking tamoxife and in this group of women, up to 23% will have an underlying endometrial abnormality such as polyps, hyperplasia, or EC. However, the incidence of endometrial disease is not markedly different compared with that in premenopausal women with breast cancer and AUB who are not taking tamoxifen. However, two meta-analyses found the risk of uterine/endometrial cancer nearly doubled with tamoxifen use. In the great majority of the cases, these are early stage cancers that are curable with hysterectomy. Unfortunately, there are no effective or generally accepted ways to monitor endometrial overgrowth. Given the higher rate of endometrial disease in premenopausal women taking tamoxifen who have development of uterine bleeding, further evaluation is warranted via endometrial sampling with an office biopsy or with operative curettage (with or without hysteroscopy). There are no guidelines that recommend preventative hysterectomy or cystoscopy.

Recently, USPTF recommended ten years of adjuvant tamoxifen instead of five. This greatly increases concern for the development of endometrial caner over this longer period. The ASCO guideline* (Visvanathan et al) has this to say: “Follow-up should include a baseline gynecologic examination before initiation of treatment and annually thereafter, with a timely work-up for abnormal vaginal bleeding.”
H.F. Kennecke,New guidelines for treatment of early hormone-positive breast cancer with tamoxifen and aromatase inhibitors, BCMJ, Vol. 48, No. 3, April 2006, 121-126

Kala Visvanathanet al, American Society of Clinical Oncology Clinical Practice Guideline Update on the Use of Pharmacologic Interventions Including Tamoxifen, Raloxifene, and Aromatase Inhibition for Breast Cancer Risk Reduction, JCO July 1, 2009 vol. 27 no. 19 3235-3258

Bushnell CD wt al, (2004) Risk of ischemic stroke with tamoxifen treatment for breast cancer: A meta-analysis. Neurology 63:12301233.

Jamie N. Bakkum-Gamez et al, Challenges in the Gynecologic Care of Premenopausal Women With Breast Cancer, Mayo Clin Proc. 2011 March; 86(3): 229–240.

For the Lay version see here

Faslodex for breast cancer – pro

M Levin, MD — Sun, 03 Feb 2013 17:34:43 +0000

(Faslodex)Fulvestrant is a selective estrogen receptor down-regulator (SERD). It acts not by competing with estrogen at the estrogen receptors, but by selectively down modulating it and causing it to be degraded and disappear. Fulvestrant is indicated for the treatment of hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following anti-estrogen therapy. It used to be thought that this unique mechanism of action gives fulvestrant greater efficacy than other hormonal treatments but that does not appear to be the case. Four comparative clinical trials showed similar efficacy to the other hormonal agents (aromatase inhibitors and tamoxifen) with good tolerability profile. Nevertheless, Fulvestrant provided effective second-line therapy in this setting for postmenopausal women who had relapsed or progressed after previous endocrine therapy.

One might wonder then if fulvestrant has anything to recommend it in first line, especially since it is very often used in that line. For this reason,creating quite a stir, the U.K. National Institute for Health and Clinical Excellence (NICE) said in 2011 that it found no evidence Faslodex was significantly better than existing treatments, and it did not recommend its routine use in the country’s National Health Service. It is a more convenient drug in some situations, since it is an injectable drug that is administered once monthly. There are patients, especially in institutional setting for whom once monthly fulvestrant is more realistic than either IV or daily oral drugs.

Fulvestrant and Xeloda were recently reported by Carreca et al to be tolerable and effective combination in the elderly patients.

In women with hormone-receptor-positive metastatic breast cancer, combining anastrozole and fulvestrant extends progression-free and overall survival, according to a paper released online today in the New England Journal of Medicine. Median progression-free survival – the primary outcome measure – was 13.5 months among the 345 women getting 1 mg of oral anastrozole per day, vs 15.0 months among the 350 who concurrently received 500 mg of fulvestrant followed by 250 mg at 14 days, 28 days and then at one month intervals (p=0.007).

Overall survival, a secondary outcome, rose to 47.7 months with combination therapy from 41.3 months in the anastrozole group (p=0.005), where patients were encouraged to switch to fulvestrant if their cancer progressed. The median follow-up time was 35 months. This combination is not recommended by NCCN(BINV-N, 2014).

Croxtall, J. D.; McKeage, K. (2011). “Fulvestrant”. Drugs 71 (3): 363–380.

Rita S. Mehta, M.D., William E. Barlow, Ph.D., Kathy S. Albain, M.D., Ted A. Vandenberg, M.D., Shaker R. Dakhil, M.D., Nagendra R. Tirumali, M.D., Danika L. Lew, M.A., Daniel F. Hayes, M.D., Julie R. Gralow, M.D., Robert B. Livingston, M.D., and Gabriel N. Hortobagyi, M.D. Combination Anastrozole and Fulvestrant in Metastatic Breast CanceR, N Engl J Med 2012; 367:435-444.

Mauri D, Polyzos NP, Mavroudis D, Georgoulias V, Casazza G. Fulvestrant in the treatment of advanced breast cancer: a systematic review and meta-analysis of randomized controlled trials. Valachis A, Crit Rev Oncol Hematol. 2010 Mar;73(3):220-7.

J, Madarnas Y, Franek JAFulvestrant for systemic therapy of locally advanced or metastatic breast cancer in postmenopausal women: a systematic review. Flemming . Breast Cancer Res Treat. 2009 May;115(2):255-68.

I. U. Carreca, R. Amelio, F. Bellomo, A. Galvano, G. Pernice, D. Combined treatment with fulvestrant plus capecitabine in elderly advanced breast cancer (EABC): Three-year evaluation of efficacy and safety. ASCO 2010, Abstract No: 283

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Generic Versus Brand Name Aromasin – pro

M Levin, MD — Sun, 05 Aug 2012 14:58:07 +0000

Brand-name Aromasin is manufactured by Pfizer, Inc. However, the patent for this medicine has expired in early 2012, and it is now available in generic form. Aromasin is available in generic form in one strength: exemestane 25 mg tablets.

Generic Aromasin is made by Roxane Laboratories, Inc., and Greenstone LLC. The version made by Greenstone is an “authorized generic,” which means that it is actually made by Pfizer and is actually the real, brand-name tablet but is packaged and sold as a generic.

There is no literature to support that brand is better then generic. All generic medications must undergo testing for bio-eqivalence before the U.S. Food and Drug Administration (FDA) decides if the generics are equivalent to the brand-name medications and assigns a rating to each one.

An “AB” rating means that the FDA has determined that a generic medication is equivalent to a brand-name medication. The generic exemestane currently available has an “AB” rating, meaning it should be equivalent to Aromasin.

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Tamoxifen, Endometrium and Hysterectomy – pro

M Levin, MD — Fri, 03 Aug 2012 20:25:40 +0000

Tamoxifen has different effects on different tissues. Whereas it blocks estrogen in the breast, it has pro- estrogenic effects on bone and in the uterus. Working as an estrogen-like substance, it can cause dysfunctional uterine bleeding and endometrial thickening and very rarely, superficial, easily treatable, endometrial cancer and sarcoma. In a review of all NSABP breast cancer treatment trials, the rate of sarcoma in women treated with tamoxifen was 17 per 100,000 patient years versus none in the placebo group. Similarly, in a separate trial of high-risk women without breast cancer taking tamoxifen as part of a breast cancer prevention trial with a median follow-up of 6.9 years, there were four in the tamoxifen group versus none in the placebo group, translating into a very low riask. This is compared with the incidence of one to two per 100,000 patient years in the general population .

Some women develop endometrail thickening when take tamoxifen. The significance of endometrial thickening is not clear. At one time, women were regularly subjected to regular screening, ultrasound and even intra-uterine biopsies. Experience had not borne out such an approach. Beyond a routine gynecologic examination eliciting any history of abnormal bleeding, it has been recommended that screening studies and procedures for detecting endometrial pathology in women taking tamoxifen should be left to the discretion of the individual gynecologist. Routine ultrasound screening is not recommended because of significant incidents of false-positive endovaginal ultrasound screening tests. Of course , any abnormal uterine bleeding should be completely evaluated.

There are no guidelines to recommend hysterectomy routinely for patients of tamoxifen. One guideline that has taken up this issue is this Society of Gynecologic Oncology pf Canada and it recommends: “In asymptomatic women on tamoxifen, a routine ultrasound for endometrial thickening should not be performed.” It does not recommend routine hysterectomy.

ACOG Committee Opinion, Guidance, Number 336, June 2006

SGOC, Canada. Clinical Practice Guidelines 249, October 2010

ACOG Committee Opinion, Guidance, Number 336, June 2006

SGOC, Canada. I is Clinical Practice Guidelines 249, October 2010

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Herceptin and Arimidex for HER+, ER/PR+ Metastatic Breast Cancer – pro

M Levin, MD — Wed, 20 Jun 2012 17:44:05 +0000

Preclinical evidence suggests Herceptin can restore and amplify responsiveness to hormonal therapy. The combination of Tykerb and Femara is FDA approved and is thought to work through this mechanism. A randomized phase III TAnDEM studyinvestigated Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor in receptor 2-positive, hormone receptor-positive metastatic breast cancer. Patients who received trastuzumab and anastrozole had better PFS than patients that received anastrozole only. There was no difference in overall survival between the two treatments. The numbers of adverse events and severe adverse events were higher with the combination arm compared to anastrozole only arm. This was a crossover design, which may have interfered with finding a difference in survival between the two arms.

Much more research needs to be done and guidelines have not yet incorporated Herceptin and Arimidex as standard recommendation. The accompanying editorial suggested that the such evidence, “should be viewed as pioneering and hypothesis driven; they are likely to become obligatory references in the field of HER2 breast cancer.”

Bella Kaufman, John R. Mackey, Michael R. Clemens, Poonamalle P. Bapsy, Ashok Vaid, Andrew Wardley, Sergei Tjulandin, Michaela Jahn, Michaela Lehle, Andrea Feyereislova, Cédric Révil and Alison JonesTrastuzumab Plus Anastrozole Versus Anastrozole Alone for the Treatment of Postmenopausal Women With Human Epidermal Growth Factor Receptor 2–Positive, Hormone Receptor–Positive Metastatic Breast Cancer: Results From the Randomized Phase III TAnDEM Study JCO November 20, 2009 vol. 27 no. 33 5529-5537

Javier Cortes et al, How to Treat Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Amplified Breast Cancer
JCO November 20, 2009 vol. 27 no. 33 5492-5494

Howard M. Stern Improving Treatment of HER2-Positive Cancers: Opportunities and Challenges Sci Transl Med Mar 28, 2012:127rv2

Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

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