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Cervical Cancer Update 2016

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Over the past few decades, there has been a significant reduction in the incidence of cervical squamous cell carcinoma (SCC) in the U.S., Canada, Australia (New South Wales) and in nearly all European countries, due primarily to the development of the Papanicolaou (Pap) test and its widespread use. There are two main types of cervical cancers: squamous cell cancer (SCC) and adenocarcinoma (ADC). More than two-thirds are SCCs while 15% are ADC. One uncommon type, small cell neuroendocrine carcinoma (SNEC), has a much poorer survival rate than either SCC or ADC9. Three-quarters of all cervical cancers are known to be caused by two types of human papillomavirus – HPV 16 and 183. The two vaccines that provide the most effective protection against the most common types of HPV are Gardasil and Cervarix, approved by the U.S. Food and Drug Administration (FDA) in 2006 and 2009, respectively.

Histological staging is the most important predictor of cervical cancer survival. Recurrence rates vary from 8% to 26% of all patients, with a median time to recurrence of between seven months and three years following initial treatment5. This article will look at assessment factors that need to be considered in product development, underwriting and claims adjudication.

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About Cervical Cancer and its Risk

The main causative agent for cervical cancers is human papillomavirus (HPV) infection. Such infections rarely have physically obvious symptoms. They can usually only be diagnosed via direct visual examination of the cervix itself and administration of a Pap test, during which surface cells are removed and then assessed under a microscope for abnormalities.

The World Cancer Research Fund and American Institute for Cancer Research have found 12 high-risk varieties of HPV (specifically HPV 16 and 18, which are responsible for three-quarters of all cervical cancers, as well as HPV 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59) that increase the risk of an infection progressing to cervical cancer. Other factors that increase cervical cancer risk include estrogen-progesterone oral ontraceptive pill (OCP), presence of the human immunodeficiency virus (HIV), and smoking3.

HPV infection frequently resolves without treatment, but women experiencing persistent HPV infections are at risk of developing precancerous cervical conditions.
Abnormal Pap test results are termed either low-grade squamous intraepithelial lesions (LSIL) or high-grade squamous intraepithelial lesions (HSIL)12, terms that describe the type of cells viewed. Cervical intraepithelial neoplasia (CIN) 2 and 3 biopsy results denote a precancerous condition with potential to develop into cancer: 1/3 to 1/2 of HSIL and CIN 2 or 3 lesions might develop into invasive cervical cancer, 10% to 15% of CIN 1 and LSIL lesions progress further14.

Incidence Trends

As of 2012, cervical cancer was the fourth most common cancer among women and the seventh most common overall worldwide3. More than half a million new cases were diagnosed globally that year, with 80% occurring in developing countries. Squamous cell carcinoma (SCC) is responsible for 75% to 90% of all cervical cancer malignancies.

Poverty has long been a driver of high cervical cancer incidence rates. A U.S. study in the 1990s found that women in high-poverty counties had at least a 1/3 higher incidence rate than those in low-poverty counties10. It is the most common cancer among black women in the Southern African countries of Swaziland, South Africa, Botswana, Lesotho, and Namibia.

In Australia, although general incidence rates are low, the incidence rate for Aboriginal women is six to eight times higher than for non-Aboriginal women. Lack of screening and subsequent delays in diagnosis are considered to be the primary contributing factors to this higher rate13.

Poverty is, however, not the only driver: health factors also play a role. Cervical cancer risk is higher for women who have experienced one full-term pregnancy versus those who have never been pregnant. In addition, it is 77% higher for girls aged 17 or under who have experienced a full-term pregnancy, compared to women older than age 253.

A sizable health factor in cervical cancer is smoking. An estimated 7% of cases are linked to the habit. Cervical SCC risk is found to be 1.5 times higher for current smokers than for current non-smokers, and is 73% higher for those exposed to tobacco smoke than for those who have never been exposed.

The risk of cervical SCC risk in those with one first-degree relative (parent or sibling) diagnosed with cervical cancer can be as much as 80% higher than for the general population3.

Pap smear tests, which sample cells from the ectocervix and not from the glandular epithelium (where ADC arises), has substantially reduced cervical SCC incidence. A study in Sweden of 12,527 women between the ages of 32 and 38 found that those screened for HPV and by Pap tests had a 40% reduction in their risk of CIN 2 or 3 or full-blown cervical cancer, compared to those who only had Pap tests12. Additionally, a study in India of 131,746 women age 30 to 57 found that having had a single HPV test and subsequent treatment significantly reduced the numbers of advanced cervical cancer cases as well as mortality from the disease15.

Mortality/Survival Trends

In 2012, 265,000 deaths were reported from cervical cancer globally11. Socioeconomic factors and ethnicity also play a large part in cervical cancer mortality. In the U.S., high-poverty counties have a 70% higher mortality than low-poverty counties10. Globally, a wide  variance in survival rates has been found: the five-year age-standardized relative survival rate in Uganda is 19%, but 76% in South Korea and 77% in Hong Kong. Additionally, in Singapore, 81% of cases are diagnosed at localized stage but only 7% of those diagnosed in Chennai, India occur at the same stage17.

  • In the EUROCARE 4 study (those diagnosed between 2000 and 2002), one-, five- and ten-year relative survival rates for cervical cancer were 84.3%, 65.2% and 59%, respectively6.
  • Farley et al. investigated 273 women in the U.S. between 1988 and 1999 and found no difference in survival between Stage I ADC and Stage I adenosquamous carcinoma (ASC), but there was a significant decrease in survival at FIGO Stage II to IV for ASC2. (FIGO = International Federation of Gynecology and Obstetrics)
  • Intaraphet et al.’s study of over 2,000 Thai patients during the period 1995 to 2011 showed the following survival by histological type9:

Diagnosis and Treatment

The most common sign of cervical cancer is abnormal bleeding between menstrual
periods or following intercourse, douching or after a pelvic exam, or heavier or longer
bleeding than usual. Increased vaginal discharge may also be a sign1. If cervical cancer is present, tumor stage is determined at the time of primary diagnosis and is not altered, even upon recurrence.

Cervical intraepithelial neoplasias and carcinoma in situ

Cryotherapy can cure between 91% and 100% of CIN 1, 75% to 96% of CIN 2 and
70% to 92% of CIN 3 lesions. Large loop excision of the transformation zone (called
LLETZ in the U.K. and LEEP in the U.S.) can also be used; however, up to 20% of post-LLETZ biopsies have shown disease at the margins, and these women are at high risk of recurrence and of developing invasive cervical cancer14.

Invasive cervical cancer

Stage IA1 cervical cancers are usually treated with a simple hysterectomy, which generally clears affected women of the disease. Those with Stage IA2 and IB cervical cancers are generally treated with radical hysterectomy and bilateral pelvic lymphadenectomy.

For women being treated by conization (cone biopsy) and/or radiotherapy, no significant difference in outcome has been found between treating Stage IB1 and IIA cervical cancers by radiotherapy only or by radical hysterectomy. Post-operative radiotherapy is used in patients with lymph node involvement.

Stage IB2 patients are not suitable candidates for surgery as there is usually pelvic and para-aortic lymph node metastasis. These patients are treated with chemoradiotherapy (cisplatin or cisplatin/5-fluorouracil [5FU]). Stage IIB and Stage III cervical cancers are treated concurrently with chemoradiotherapy (cisplatin plus 5FU).

Patients with Stage III or IVA cervical cancers who are treated with radiation, 5FU andcisplatin show a five-year survival rate of 63% compared to 57% for those treated only by radiotherapy, and a recurrence rate of 42% for those with combined therapy compared to 62% in those treated by radiotherapy alone8.

Advanced cervical cancer is frequently treated with palliative chemotherapy, but some patients with metastatic disease can be treated with extended-field irradiation, which has been shown to have a 27% five-year survival rate. Use of the chemotherapy drug Epirubicin has also been found to be effective in the treatment of Stage III cervical cancer as well as in adjuvant therapy in preventing distant relapse (recurrence of cancer elsewhere in the body). Serum tumor marker CA-125 may be elevated in those with advanced or recurrent disease but should not be used as a marker for cervical cancer8, 14.

Recurrence Rates

Recurrence rates vary from 8% to 26%, with a median time to recurrence of between seven months and three years5. Patients with Stage IB or IIA cancers have a 10% to 20% relapse rate while up to 75% of patients who have nodal metastasis or locally advanced disease will relapse. Even with combined chemoradiation therapy, 20% to 40% of all Stage II patients will relapse. Prognosis is better where the tumor recurrence is less than 3 cm, with no side wall attachment and where recurrence is more than six months following treatment7, 8.

  • A study by Perez et al. found the ten-year actuarial incidence of distant metastasis was 3% in Stage IA, 16% in Stage IB, 31% in Stage IIA, 26% in Stage IIB, 39% in Stage III and 75% in Stage IVA7.
  • A study of 106 patients in Beijing, China between 1999 and 2013 with Stage IA-IIB cervical cancers recorded a median period to recurrence of 13 months16.
  • A study of 120 patients in Bangladesh with Stage IB-IIA cervical cancer found that at year four 42% had relapsed. The median time to recurrence was 19 months for local recurrence and 33 months for distant recurrence. Eighty percent of patients who relapsed did so within three years of diagnosis18. Table 4 (below) shows the association of recurrence with prognostic factors.

HPV Prevention

Vaccinations against the two most common types of HPV, which can cause between
40% and 60% of LSIL and HSIL cancers, are recommended for both males and females of ages 11 and 12, although it can be given to children as young as age nine. Gardasil may also be given to males and females between ages 13 and 26, which can protect against HPV 6, 11, 16 and 18, while Cervarix can protect against HPV 16 and 181.

It will take many years for the full benefit of vaccination to be achieved and before a potential discount can be offered to those vaccinated. The earliest effects will be seen in women ages 20 to 29. With 80% vaccination coverage in women aged 12 and 13, a study in the U.K. projects an eventual 63% reduction in invasive cancer, a 51% reduction in CIN 3 and a 27% reduction in cytological abnormalities before age 304.

Summary

HPV 16 and 18 are responsible for up to three-quarters of cervical cancers globally, with squamous cell carcinoma responsible for 75% to 90% of all cases. It will be several years before the full benefit of vaccination is first seen in women between the ages of 20 to 29 and before a potential discount could be offered to those who received the vaccine.

Nearly all patients with Stage IA1 cervical cancers and patients with Stage IB1 or IIA cervical cancer can be cleared of the disease with a simple hysterectomy. No significant difference in outcome has been found between treating the disease by radiotherapy only or by radical hysterectomy.

Patients with Stage III or IVA cervical cancer who are treated by radiation plus 5FU and cisplatin have a recurrence rate of 42%, compared to 62% of those treated by radiotherapy alone. Up to 75% of patients who have nodal metastasis or locally advanced disease will relapse, and even among those treated with combined chemoradiation therapy, 20% to 40% of Stage II patients will also relapse.

The American Joint Committee on Cancer (AJCC) advises that the results of the pathologic evaluation should not be allowed to change the clinical stage but be recorded separately; hence, it is the clinical stage upon which the risk evaluation should be made as well as pricing assumptions for product development.


References

1. American Cancer Society (2014), ”Cancer Facts and Figures 2014,” available from: http://www.cancer.org/
acs/groups/content/@research/documents/webcontent/acspc-042151.pdf
2. Berek J, Hacker N. “Berek and Hacker’s Gynecologic Oncology,” 2010, Ch. 9: 341-369, available from: https://books.google.ie/books?id=bA3ODcFV5oC&pg=PA369&lpg=PA369&dq=patient+care+and+evaluation+stud
y+Shingleton+et+al.&source=bl&ots=b6hgK92cqp&sig=YEeIYbNLO-rDeF68L-7G0ygZY_E&hl=en&sa=X&ei=A
c7cVOqDDoz5UPzHgNAP&ved=0CCcQ6AEwAA#v=onepage&q=patient%20care%20and%20evaluation%20
study%20Shingleton%20et%20al.&f=false
3. Cancer Research UK (2014), “Cervical Cancer Statistics,” available from: http://www.cancerresearchuk.
org/cancer-info/cancerstats/types/cervix/
4. Cuzick J, Castanon J, Sasieni P. “Predicted Impact of Vaccination Against Human Papillomavirus 16/18 on
Cancer Incidence and Cervical Abnormalities in Women Aged 20–29 in the UK”, British Journal of Cancer 2010, 102(5): 933–939, available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2833241/
5. Elit L, Fyles AW, Oliver TK, Devries-Aboud MC, FungKee-Fung M, and members of the Gynecology Cancer
Disease Site Group of Cancer Care Ontario’s Program in Evidence-Based Care, ”Follow-up for Women After 
Treatment for Cervical Cancer,” Current Oncology 2010, 17(3): 65-69, available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880906/pdf/conc17-3-65.pdf
6. EUROCARE (2009), “The EUROCARE-4 Database on Cancer Survival in Europe,” 
available from:  http://www.eurocare.it/Results/tabid/79/Default.aspx#longsurv00
7. Friedlander M, Grogan M. “Guidelines for the Treatment of Recurrent and Metastatic Cervical Cancer,” The
Oncologist 2002, 7(4): 342-347, available from:
http://theoncologist.alphamedpress.org/content/7/4/342.full
8. Gallup D. (2008) ”The Spread and Staging of Cervical Cancer,” Global Library of Women’s Medicine, available from: http://www.glowm.com/
section_view/heading/The%20Spread%20and%20Staging%20of%20Cervical%20Cancer/item/231
9. Intaraphet S, Kasatpibal N, Søgaard Khunamornpong S, Patumanond J, Chandacham A, Chitapanarux I, Siriaunkgul S. ”Histological Type-specific Prognostic
Factors of Cervical Small Cell Neuroendocrine Carcinoma, Adenocarcinoma, and Squamous Cell
Carcinoma,” OncoTargets and Therapy 2014:7 1205-14,
available from: https://www.dovepress.com/histologicaltype-specific-prognostic-factors-of-cervical-small-cell-npeer-reviewed-fulltext-article-OTT
10. Journal of the National Cancer Institute (2004), ”Cervical Cancer Mortality by Ethnicity and Socioeconomic Area, 1995-1999,” JNCI 96(1); 11, available from: http://jnci.oxfordjournals.org/content/96/1/11.full
11. Mathew A, George PS. “Trends in Incidence and Mortality Rates of Squamous Cell Carcinoma and Adenocarcinoma of Cervix - Worldwide’, Asian Pacific Journal of Cancer Prevention, 2009 Oct-Dec, 10(4): 645-50, available from: http://www.ncbi.nlm.nih.gov/pubmed/19827887#
12. Naucler P, Ryd W, Törnberg S, Strand A, Wadell G, Eifgren K, Rådberg T, Strander B, Johansson B, Forslund O, Hansson B, Rylander E, Dillner J. ”Human
Papillomavirus and Papanicolaou Tests to Screen for Cervical Cancer,” The New England Journal of Medicine 2007; 357: 1589-97, available from: http://www.nejm.org/doi/full/10.1056/NEJMoa073204
13. O’Brien ED, Bailie, RS. Jelfs, PL. ”Cervical Cancer Mortality in Australia: Contrasting Risk by Aboriginality,
Age and Rurality,” International Journal of Epidemiology 2000; 29(5):813-6, available from: http://ije.oxfordjournals.org/content/29/5/813.long
14. Sankaranarayanan R, Thara S, Esmy P, Basu P. ”Cervical Cancer: Screening and Therapeutic Perspectives,”Medical Principles and Practice 2008; 17:351-64, available from: http://www.karger.com/Article/
Pdf/141498
15. Sankaranarayanan R, Nene BM, Shastri SS, Jayant K, Muwonge R, Budukh AM, Hingmire S, Malvi SG, Thorat R, Kothari A, Chinoy R,. Kelkar R, Kane S, Desai S, Keskar VR, Rajeshwarkar R, Panse N, Dinshaw KA .“HPV Screening for Cervical Cancer in Rural India,” The New England Journal of Medicine 2009; 360(14):1385-1394, available from: http://www.nejm.org/doi/full/10.1056/NEJMoa0808516
16. Shu T, Bai P, Zhang R, Li S. “[Clinical Analysis and Prognostic Factors in 106 Patients with Stage Ia-IIb
Cervical Cancer with Pulmonary Metastasis],” Zhonghua Zhong Liu Za Zhi 2014 Sep; 36(9): 703-7, available from: http://www.ncbi.nlm.nih.gov/pubmed/25564063
17. Singh GK, Azuine RE, Siahpush M. “Global Inequalities in Cervical Cancer Incidence and Mortality are Linked to Deprivation, Low Socioeconomic Status, and Human Development,” International Journal of MCH and AIDS 2012; 1(1): 17-30, available from: http://mchandaids.org/pdf/3-Commenrary-Global.pdf
18. Sobhan F, Sobhan F, Sobhan A. “Recurrence of Cancer Cervix in Patients Treated by Radical Hysterectomy Followed by Adjuvant External Beam Radiotherapy,”Bangladesh Medical Research Council Bulletin 2010; 36: 52-6, available from: http://www.banglajol.info/index.php/BMRCB/article/viewFile/6987/5304

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RGA has made all reasonable efforts to ensure that the information provided in this publication is accurate at the time of inclusion and accepts no liability for any inaccuracies or omissions. None of the information or opinions contained in this publication should be construed as constituting medical advice.
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The Author

  • Hilary Henly
    Head of Underwriting (Ireland)
    Director of Divisional Underwriting Research
    RGA International Re
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Summary

Three-quarters of all cervical cancers are known to be caused by two types of human papillomavirus – HPV 16 and 183.  This article will look at assessment factors that need to be considered in product development, underwriting and claims adjudication.
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