Primecuts – This Week In the Journals

December 12, 2011

By Sunnie Kim, MD

Faculty Peer Review

In an effort to steer clear of financial collapse, European leaders announced last week that they signed an intergovernmental treaty to enforce stricter budgetary discipline. The treaty, a result of nearly ten hours of talks, will hopefully begin the process of stabilizing the Eurozone. The bigger news may be that Britain finds itself the lone man out after refusing to sign the treaty after being denied some exemptions to the fiscal regulations. Although the rest of the world can breathe a small sigh of relief (for now) at progress, the saga will no doubt continue to unfold.

Moving onto the world of health news, in another contentious and emotion-ridden battle, cancer patients found both uplifting and discouraging news in the arena of breast cancer research. As many of us heard, last month the FDA revoked the use of Avastin (bevacizumab) for the treatment of metastatic HER 2 negative breast cancer [1]. At the heels of this disappointing news, this week the New York Times reported that the New England Journal of Medicine published a study showing that pertuzumab, an anti-HER 2 humanized monoclonal antibody, in conjunction with trastuzumab (also known as Herceptin) and docetaxel, significantly prolonged progression free survival in patients with metastatic HER 2 positive breast cancer [2]. Pertuzumab, another brainchild of Genentech (the same makers of Avastin), is a humanized monoclonal antibody that binds HER2 at a different epitope of the HER 2 extracellular domain than that of trastuzumab. The hope is that the synergistic activity of both agents may induce a more comprehensive block of the HER2 signaling, thereby resulting in greater antitumor activity.

The randomized, double-blind, placebo controlled study assigned HER 2-positive metastatic breast cancer patients to receive either placebo, trastuzumab and docetaxel or pertuzumab, trastuzumab and docetaxel. Those in the pertuzumab group showed a progression-free survival prolonged by 6.1 months; from 12.4 months in the placebo group compared to 18.5 months (P<0.001). The side effect profile was overall balanced between the two groups, namely that the group receiving pertuzumab did not have increased rates of symptomatic or asymptomatic cardiac dysfunction. Although the subset of patients to potentially benefit from this study is smaller than those hoping to gain some benefit from Avastin, the news of a drug that both increases progression free survival with a comparable side effect profile to the current standard regimen should be a source of encouragement for the breast cancer community.

In further oncological news, two other reviews tackled the efficacy of cancer screenings, in particular mammography and PSAs. The British Medical Journal published an updated modeling of the Forrest report, the seminal publication in 1986 that introduced mammographic breast screening to the UK [3,4]. The publication was in response to a 2009 Cochrane review that questioned whether screening was leading to more overdiagnosis and overtreatment with minimal mortality benefit. Gotzsche and Nielsen, in their 2009 Cochrane review, estimated that screening led to a 15% reduction in breast cancer mortality and to 30% overdiagnosis and overtreatment. The authors concluded that for every 200 women screened throughout 10 years, only one will see a mortality benefit while 10 healthy women will be diagnosed with breast cancer and be treated unnecessarily. In addition, more than 200 women may undergo significant psychological distress due to false positive findings. The newest reworking of the Forrest report includes the harms from false positives and unnecessary surgery, which the original report does not take into account. The Forrest report’s main outcome measure was the Quality adjusted life year (QALY), which combined life years gained from screening with losses of quality of life from false positive diagnoses and surgery. The analysis shows that inclusion of the harms from false positive results reduced the benefits of screening by about half (3301 to 1536 QALYs after 20 years) and resulted in negative QALYs after 7 years of screening, 70 QALYs after 10 years, and 834 QALYs after 20 years. With the breast screening age progressively becoming younger in the United States, the issues of overdiagnosis and risks associated with working up false positives will undoubtedly become an increasingly concerning issue. The result of negative QALYs after 7 years also brings up the issue of limiting mammography in patients whose life expectancy is short.

Prostate-Specific Antigen based screenings continued to take a hit this week as the Annals of Internal Medicine published a review showing that prostate cancer screenings with PSA resulted in small or no reduction in mortality after about 10 years along with associated harms in the evaluation and treatment of elevated PSAs [5]. The 2 largest and highest quality trials included in the review found conflicting results. The ERSPC trial found PSA screening every 2 to 7 years to be associated with a 20% relative reduction in mortality from prostate cancer whereas the PLCO trial found no effect [7,8]. Although the diagnosis of prostate cancer increased, the mortality benefit is small as the detection of low risk cancers does not cause morbidity or mortality. The effect of screening was shown to be associated with potential harms including infections and urinary retention in 1 of 200 men who undergo prostate biopsy. As a caveat though, there appeared to be a mortality benefit in a subset of younger men who were treated with prostatectomy [6]. If we can detail guidelines that target populations that may benefit from the diagnosis (i.e. younger men) despite the risks associated with work-ups, PSA-based screenings may still have an important role in prostate cancer associated mortality.

On the flip side, prostate cancer patients have some encouraging news coming their way this week as JAMA published a review shedding some more light on the controversial association between androgen deprivation therapy and its alleged cardiovascular risk [9]. Over the past 5 years, the cardiac risk associated with androgen deprivation therapy has gained momentum namely through two retrospective studies. In 2006, Keating et al found that GnRH agonist was associated with 44% increased risk of diabetes, 16% increase in coronary artery disease, 11% in myocardial infarction, and 16% increase in sudden cardiac death. Following that study, in 2007, Tsai et al found that androgen deprivation therapy was associated with a 2.6 time increase in cardiovascular death in men receiving radical prostatectomy. As a result of these and other studies, the FDA issued a safety warning in 2010 that GnRH agonists increased risk of diabetes and certain cardiovascular disease in men receiving these medications for treatment of prostate cancer. The current review included only randomized, multicenter phase 3 trials and found that in a meta-analysis of more than 4000 patients that ADT did not increase the risk of cardiovascular death among men with unfavorable-risk, nonmetastatic prostate cancer. Specifically, cardiovascular death in patients receiving ADT vs control were comparable (225 /2200 v 252/1941; RR, 0.93) and ADT was also not associated with excess cardiovascular death in trials of at least 3 years or in trials of 6 months or less (RR, 0.91 and 1 respectively). However the authors point out that none of the trials included were stratified by preexisting cardiovascular comorbidity, so it is still possible that men who have predisposing cardiovascular conditions could be more prone to adverse effects from ADT. It may be assuring for prostate cancer patients without pre-existing cardiovascular risk factors to pursue ADT; however in those who are at higher risk, a thoughtful conversation weighing the risks and benefits with both an oncologist and cardiologist is prudent.

And finally in my reading this week, I came across a particularly interesting piece that addresses the cancer risk in a seldom mentioned population: the nuns! The Lancet reports that there may be a role for contraceptives in those women who have committed themselves to celibacy [12]. Nulliparity has been shown to increase a woman’s risk for breast, ovarian, and uterine cancer. The piece references a study by Fraumeni and colleagues, who compiled data for cancer mortality rates in over 30,000 Catholic nuns in the US between 1900 and 1954 [13]. It showed that nuns have an increased risk of dying from the aforementioned cancers compared to the general population. Although the Catholic Church strictly condemns all forms of contraception except abstinence, OCPs may have found a loophole in one of the Church’s faithful followers. In Pope Paul VI’s Humanae Vitae, it states that “the Church does not consider at all illicit the use of those therapeutic means necessary to cure bodily disease, even if a foreseeable impediment to procreation should result therefrom – provided such impediment is not directly intended. [14]

The use of OCPs as a means to decrease the risk of such cancers has been documented in two large epidemiological studies [15,16]. The two studies showed that the adjusted relative risks (RR) of ovarian and endometrial cancers were reduced by 50-60% compared with never users. The protective effects persisted for 20 years, displaying its long term benefit. The data for breast cancer, however, was not as potent: the RR of breast cancer was not reduced. In its ongoing battle between science and faith, the Church may have found a permissible solution in alleviating the cancer burden of its nuns without compromising its tenets. Don’t the nuns deserve at least some kind of earthly recompense for their spiritual conviction? Medical therapy may very well be the much appreciated, if unorthodox, gift during this revered season.

Dr. Sunnie Kim is a 3rd year resident at NYU Langone Medical Center

Peer reviewed by Cara Litvin, MD, Section Editor, Clinical Correlations

References:

1. Margaret A. Hamburg. FDA Commissioner announces Avastin decision. US Food and Drug Administration. 11/18/11. Internet. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm280536.htm

2. Baselga, Jose et al. Pertuzumab plus Traztuzumab plus Docetaxel for Metastatic Breast Cancer. NEJM. 2011 10.1056. 12/7/11. Available at http://www.nejm.org/doi/full/10.1056/NEJMoa1113216

3. Raftery, James. Possible net harms of breast cancer screening: updated modeling of Forrest report. BMJ 2011;343:d7627. 12/8/11. Available at http://www.bmj.com/content/343/bmj.d7627

4. Gotzsche PC, Nielsen M. Screening for breast cancer with mammography. Cochrane Database Syst Rev 2009;4:CD001877. Available at http://summaries.cochrane.org/CD001877/screening-for-breast-cancer-with-mammography

5. Chou R, Croswell JM, Dana T, Bougatsos C, Blazina I, Fu R, Gleitsmann K, Koenig HC, Lam C, Maltz A, Rugge JB, Lin K. Ann Intern Med. 2011 Dec 6;155(11):762-71. Available at http://www.annals.org/content/early/2011/10/07/0003-4819-155-11-201112060-00375.full

6. Bill-Axelson A, Holmsberg L, Ruutu M, Garmo H, Stark JR, Busch C, et al; SPCG-4 Investigators. Radical prostatectomy versus watchful waiting in early prostate cancer. NEJM. 2011;364:1708-17. Available at http://www.nejm.org/doi/full/10.1056/NEJMoa1011967

7. Schroder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, Nelen V, et al; ERSPC Investigators. Screening and prostate-cancer mortality in a randomized European study. NEJM. 2009;360:1320-8. Available at http://www.nejm.org/doi/full/10.1056/NEJMoa0810084

8. Andriole GL, Crawford ED, Grubb RL 3rd, Buys SS, Chia D, Church TR, et al; PLCO Project Team. Mortality results from a randomized prostate-cancer screening trial. NEJM. 2009;360:1310-9. Available at: http://www.nejm.org/doi/full/10.1056/NEJMoa0810696

9. Nguyen, Paul et al. Association of Androgen Deprivation Therapy With Cardiovascular Death in Patients with Prostate Cancer: A meta-analysis of Randomized Trials. JAMA. Available at: http://jama.ama-assn.org/content/306/21/2359

10. Keating NL, O’Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol. 2006;24(27):4448-4456. Available at: http://jco.ascopubs.org/content/24/27/4448.abstract

11. Tsai HK, D’Amico AV, Sadetsky N, Chen MH, Carroll PR. Androgen deprivation therapy for localizedprostate cancer and the risk of cardiovascularmortality. J Natl Cancer Inst. 2007;99(20):1516-1524. Available at: http://jnci.oxfordjournals.org/content/99/20/1516

12. Britt K, Short R. The plight of nuns: hazards of nulliparity. The Lancet. 10.1016/S0140-6736(08)61345-8. Available at: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61746-7/fulltext?_eventId=login

13. Fraumeni JF Jr, Lloyd JW, Smith EM, Wagoner JK. Cancer mortality among nuns: role of marital status in etiology of neoplastic disease in women. J Natl Cancer Inst. 1969:42:455-68.

14. Pope Paul VI. Humanae Vitae. July 25 1968. Available at: http://www.vatican.va/holy_father/paul_vi/encyclicals/documents/hf_p-vi_enc_25071968_humanae-vitae_en.html

15. Hannaford PC, Iversen L, Macfarlane TV. Mortality among contraceptive pill users: cohort evidence from Royal College of General Practitioners’ Oral Contraception Study. BMJ 2010; 340:927-35. Available at: http://www.bmj.com/content/340/bmj.c927.full

16. Vessey M, yeates D, Flynn S. Factors affecting mortality in a large cohort study with special reference to oral contraceptive use. Contraception 2010; 82:221-29. Available at: http://www.contraceptionjournal.org/article/S0010-7824(10)00143-5/abstract

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