Cervical Cancer Vaccines

1. Two prophylactic HPV vaccines, Cervarix™ (GlaxoSmithKline) and Gardasil™ (Merck) have been licensed for use. Both have been tested in large trials involving thousands of women from different countries across the world.
2. Impressive protection against persistent vaccine-specific HPV infection has been demonstrated over short- to medium-term follow-up periods. Long-term follow-up data are still required to answer the question of longevity of immune protection and whether booster vaccination(s) will be necessary, and at what time interval.
3. Because of ethical and consent issues, effectiveness cannot be determined among pre-adolescent girls, but is assumed by comparing data from the young women involved in the original vaccination trials. These suggest better cover if vaccination is given to young girls than to young adults.
4. It is difficult to assess the impact of an immunisation strategy when many factors are still unknown. 
5. The coverage for the third dose is critical as the vaccine is locally painful and girls may be reluctant to complete the course.
6. The vaccines remain prohibitively expensive - universal HPV vaccination is unlikely in resource-poor countries where they are most needed. 
7. Merck was the first of two pharmaceutical companies to license its vaccine in October 2006, giving it a commercial head start. This quadrivalent vaccine confers immunity against the two oncogenic strains of HPV responsible for 70% of cervical cancers (HPV 16 and 18), as well as two strains that together cause 90% of genital warts (HPV 6 and 11). To many, a vaccine that protects against four strains has appeared to be inherently ‘better’ than one protecting against two strains.15 The bivalent vaccine Cervarix did not become available until almost a year later, in September 2007. Cervarix protects against HPV types 16 and 18, but does not prevent genital warts.
8. Insofar as Cervarix does not prevent genital warts, its use may amount to a ‘missed opportunity’. Genital warts are a very common sexually transmitted viral infection responsible for unsightly lesions that are both difficult and costly to treat. Women with genital warts also risk spread of the infection to the respiratory tract of their newborn infant during childbirth. Recurrent respiratory papillomatosis is a rare, but chronic, debilitating disease characterised by hoarseness, stridor and respiratory distress in the newborn, and requires lifelong repeated surgical intervention and prolonged hospital stays, even causing death in a minority of cases.
9. Published data do not distinguish either vaccine as superior in terms of clinical effectiveness or toxicity. 
10. Future cervical screening - vaccinated women are still clearly at risk of contracting other oncogenic HPV types that can cause cervical cancer, and cervical screening will still be necessary, even for vaccinated women.
11. Safety scares. In general, both Cervarix and Gardasil appear to be safe and well tolerated. Injection site adverse events, including pain, swelling and redness, have been reported  Cervarix is recognised to be a more painful inoculation than Gardasil, but even so, most side effects disappear within the first day or two.
12. There have been no deaths attributable to either vaccine in any of the clinical trials to date. Pregnancy and congenital anomaly data have been reported for Gardasil, but not for Cervarix. Higher rates of congenital anomalies unrelated to type have been observed.
13. Maintaining high vaccine coverage. Interim results for the uptake of the third dose has shown a drop in coverage from 83% at the first dose to 74% for dose 3. Whether girls who receive only the first two doses of the vaccine will show sufficient immunity against HPV to prevent subsequent infection remains unclear.
14. The effect of mistimed doses is not fully understood. Data from hepatitis B vaccination studies suggest that longer intervals between second and third doses of the HPV vaccine may not be detrimental to the strength of the immunity generated, presumably as long as HPV exposure does not occur during the delay.

Excepts from Crosbie EL, Brabin L. BJOG Volume 117, Issue 2, pages 137–142, January 2010

FDA approves novel folate OCP

The US Food and Drug Administration (FDA) on 25 September 2010 approved a novel oral contraceptive that is formulated to provide both contraception and reduce the risk for neural tube defects in their offspring if and when they give birth. The new contraceptive, Beyaz (Bayer HealthCare Pharmaceuticals), contains levomefolate calcium, a metabolite of folic acid. Prepregnancy folate supplementation has been associated with a decreased risk of fetal neural tube defects. Thus arises the recommendation that women of childbearing age supplement their diet with folate. This is a logical step since women may become pregnant during oral contraceptive use or shortly after discontinuation. The approval is based on the already-approved oral contraceptive drospirenone/ethinyl estradiol (Yaz, Bayer HealthCare Pharmaceuticals), which contains the same doses of estrogen and progestin.

Apart from the primary indication of contraception, Beyaz is also approved for the treatment of symptoms of premenstrual dysphoric disorder (PMDD), acne vulgaris and the prevention of fetal neural tube defects in women who choose an oral contraceptive as their method of contraception.

According to the FDA (www.fda.gov), the primary efficacy study for Beyaz was a multicenter, double-blind, randomized, controlled U.S. trial in 379 healthy women aged 18 to 40 who were treated with Beyaz or YAZ alone for up to 24 weeks. Beyaz was found to increase folate levels in women. In a German study of Beyaz, folate levels remained elevated for several weeks following discontinuation of Beyaz.  Safety and efficacy data for contraception, PMDD, and acne indications were obtained from previous YAZ clinical trials.

The clinical trials of Beyaz did not yield any findings that would suggest it differs from Yaz in terms of its overall safety profile. It is expected that the most common adverse events for Beyaz will be the same as those for Yaz. Adverse effects most frequently reported by users of combined oral contraceptives are irregular uterine bleeding, nausea, breast tenderness, and headaches.

Link Between Endometriosis and Cancer

         Women with endometriosis appear to be more likely to develop certain types of cancer. What scientists know about the link - and why it might occur - were the focus of a session at the inaugural symposium of the Endometriosis Foundation of America. Chief of the Hormonal and Reproductive Epidemiology branch at the National Cancer Institute, Louise Brinton’s interest in the long-term effects of endometriosis led her to Sweden about 20 years ago. Using the country's national inpatient register, she identified more than 20,000 women who had been hospitalized for endometriosis.[1] After an average follow-up of more than 11 years, the risk for cancer among these women was elevated by 90% for ovarian cancer, 40% for hematopoietic cancer (primarily non-Hodgkin's lymphoma), and 30% for breast cancer. Having a longer history of endometriosis and being diagnosed at a young age were both associated with increased ovarian cancer risk.

An increased risk for tumors with increasing years of follow-up was found. This made it unlikely that the ovarian cancer diagnoses were related to increased surveillance during endometriosis treatment. Also of special interest was the finding that women whose site of origin of endometriosis was the ovary had a particularly high risk for ovarian cancer. Dr. Brinton and colleagues published their research in 1997. A larger, more recent examination of the Swedish register, published in 2006 by Anna-Sofia Melin and colleagues, produced similar results.[2]

These 2 studies indicate a high risk related to follow-up time and site of origin of endometriosis, which suggests a biologic effect between the 2 diseases. On the other hand, confounding factors could be at work. For example, women being treated for endometriosis are more likely to be experiencing infertility, which affects risk because childbearing offers some protection against ovarian cancer. A 2002 pooled case-control study by Roberta B. Ness and colleagues found that the odds of developing ovarian cancer were 50% higher among women diagnosed with endometriosis, even after adjusting for factors such as duration of oral contraception use and number of births.[3] The risk was even higher -- a 3.5-fold increase -- for women with endometrioid or clear cell tumors, 2 subtypes of ovarian cancer. A 2005 case-control study by Brinton and colleagues also found a 2.5- to 3.5-fold increase in endometrioid and clear cell tumors among women with endometriosis.[4]

The overall lifetime risk for ovarian cancer is 1.4%, according to the American Cancer Society.[5] Endometriosis affects as many as 7% to 15% of women of reproductive age. Regarding the link between epithelial ovarian cancer and endometriosis, according to a 2000 study of women with ovarian cancer by Hiroyuki Yoshikawa and colleagues, endometriosis was present in 39% of the women with clear cell tumors and 21% of those with endometrioid tumors, vs just 3% of those with serous or mucinous tumors.[6] Nezhat and colleagues also identified a link between endometriosis and ovarian cancer.[7] A pathology review of samples from 76 patients with stage 1 ovarian cancer revealed that most were associated with endometriosis or endometrioma. Most patients presented with pelvic pain or adnexal mass, supporting the idea that healthcare providers should be alert to the possibility of ovarian cancer in women with a history of endometriosis.

Studies have been inconsistent on whether endometriosis is linked to breast cancer or non-Hodgkin's lymphoma. Anecdotal evidence has linked endometriosis to melanoma, brain and endocrine cancers, and thyroid cancer. Large epidemiologic studies are required to examine these associations.

The Pathogenesis of Endometriosis and Cancer

Both endometriosis and ovarian cancer are progressive diseases and depend on estrogen for their growth. Studies have shown that endometrial tissue shows elevated activity of aromatase, an enzyme used for a key step in the biosynthesis of estrogens.

Another factor that appears to play a role in both diseases is inflammation. Inflammation can cause cancer, as seen in hepatitis of the liver and asbestosis of the lung. Endometriosis is characterized by a chronic inflammatory state, which leads to the release of cytokine. These cytokines may promote the growth of tumours by causing unregulated mitotic division, growth, and differentiation. The combination of inflammation with estrogen can be a vicious circle.

The 2 diseases share numerous other characteristics. For example, both are related to early menarche and late menopause, infertility, and nulliparity. Factors that relieve or offer protection against both conditions include tubal ligation, oral contraceptives, hysterectomy, and progesterone exposure.

Mutations in genes that are known to suppress tumors, such as PTEN, p53, and bcl, have been found in both ovarian tumors and adjacent endometriotic lesions.

Of course, links between the 2 diseases don't prove that one causes the other. But there's reason to believe that endometriosis contributes to ovarian cancer, as evidenced by Dr. Brinton's finding that cancer risk increases with duration of endometriosis. If endometriosis does increase the risk for ovarian cancer, then treating it might reduce the risk

Advice to Surgeons and Patients

Surgeons who operate on women with endometriosis, which includes fertility specialists performing in vitro fertilization (IVF), need to be alert to the possibility of ovarian cancer. Ultrasound scanning should be carried out during the preoperative evaluation and the follow-up. Surgeons are also cautioned to biopsy any ovarian cysts instead of just draining them. Every adnexal mass has to be thoroughly evaluated.

Although the elevated risk for ovarian cancer appears to be real, women with endometriosis should not become too anxious about it. Even though a 2- to 3-fold increase in the risk for ovarian cancer is noted, it's still a very rare condition with the absolute risk being low.

References

1.      Brinton LA, Gridley G, Persson I, Baron J, Bergqvist A. Cancer risk after a hospital discharge diagnosis of endometriosis. Am J Obstet Gynecol. 1997;176:572-529. Abstract
2.      Melin A, Sparén P, Persson I, Bergqvist A. Endometriosis and the risk of cancer with special emphasis on ovarian cancer. Hum Reprod. 2006;21:1237-1242. Abstract
3.      Ness RB, Cramer DW, Goodman MT, et al. Infertility, fertility drugs, and ovarian cancer: a pooled analysis of case-control studies. Am J Epidemiol. 2002;155:217-224. Abstract
4.      Brinton LA, Sakoda LC, Sherman ME, et al. Relationship of benign gynecologic diseases to subsequent risk of ovarian and uterine tumors. Cancer Epidemiol Biomarkers Prev. 2005;14:2929-2935. Abstract
5.      US National Institutes of Health. National Cancer Institute Fact Sheet. BRCA1 and BRCA2: cancer risk and genetic testing. Available at: http://www.cancer.gov/cancertopics/factsheet/Risk/BRCA Accessed May 24, 2010.
6.      Yoshikawa H, Jimbo H, Okada S, et al. Prevalence of endometriosis in ovarian cancer. Gynecol Obstet Invest. 2000;50(suppl 1):11-17. Abstract

7.      DeLigdisch L, Pénault-Llorca F, Schlosshauer P, Altchek A, Peiretti M, Nezhat F. Stage I ovarian carcinoma: different clinical pathologic patterns. Fertil Steril. 2007;88:906-910. Abstract

 Edited from an article by Devon Schuyler on  Medscape Ob/Gyn & Women's Health