The unacceptable case fatality risk observed worldwide
James Fleck, MD, PhD: Anticancerweb 31 (03), 2021
Cervical cancer is a malignant tumor that appears in the epithelial cells of the lower segment of the uterus (cervix) and is associated with the human papilloma virus (HPV). Worldwide, more than 600,000 cases are diagnosed annually. It is the fourth malignant tumor in incidence (ASR = 13.7) and mortality (ASR = 7.3). In Africa, cervical cancer reaches the second position in the ranking of malignant diseases, assuming an even higher incidence (ASR = 25.6) and mortality rate (ASR=17.7). Data published by the International Agency for Research on Cancer (IARC), a Division of World Health Organization (WHO) gives us a comprehensive idea of the magnitude of the problem. Table 1 shows the most important cervical cancer epidemiological data in five continents.
Table 1: Female cancer epidemiological data
A preliminary analysis of Table 1 gives us the impression that cervical cancer is a major health problem only in Africa, Asia and Latin America, as its incidence and mortality rates barely reach the tenth position in Europe and Northern America. However, it is necessary to look beyond these numbers to really understand the global magnitude of the problem. Both incidence and mortality rates indicate the number of cases per 100,000 inhabitants. Table 2 describes the incidence and mortality rates of cervical cancer in five continents. Data are expressed in Age-Standardized Rate (ASR), allowing populations to be compared, since age distribution is quite different in the five continents, which definitively influences the crude incidence and mortality rates. Both are very important epidemiological parameters, but insufficient to clearly express the impact of medical interventions that favor early diagnosis, as well as advances in adjuvant treatment.
Table 2: Incidence and mortality of cervical cancer expressed in ASR in five continents
Let's look at the case fatality risk (CFR), which means the proportion (%) of women who die from cervical cancer among the total number of women diagnosed with the disease in one year. Table 3 shows the CFR for all cancer, female cancer and cervical cancer in five continents. The magnitude of differences can be seen in figure 1. The figure shows that the magnitude of the differences in CFRs are smaller in cervical cancer than those observed for all types of cancer or for female cancer across the five continents.
Table 3: CFR for all cancer, female cancer and cervical cancer in five continents
Figure 1: Magnitude of the CFR in five continents
The high CFR for cervical cancer observed in both Europe (CFR = 44.68) and Northern America (CFR = 42.37) indicates cervical cancer diagnosed in more advanced stages and/or not subjected to the best curative approach. In fact, the USA cancer statistics published by the American Cancer Society in 2019 showed that 51% of women were diagnosed with advanced or metastatic cervical cancer. Figure 2 illustrates the comparison between the three epidemiologic parameters in the five continents. Lower cervical cancer incidence and mortality rates in Europe and North America are not accompanied by an expected lower CFR.
Figure 2: Cervical cancer incidence, mortality and case fatality rate (CFR) in five continents
Cervical cancer is a malignant disease that should have been overcome in the world. The Pap smears or Pap test was introduced in the book Diagnosis of Uterine Cancer by the Vaginal Smear published in 1943, authored by Georgios Nikolaou Papanikolaou and Herbert Frederick Traut, describing a simple and reproducible technique that allowed the early diagnosis of cervical cancer. Since 1950, all American cancer societies joined efforts in the strong recommendation of exfoliative cytology (Pap test) all over the world. Later on, by the turn of XXI century, HPV next-generation hybridization has been used in the histologic diagnosis of cervical intraepithelial neoplasia grade 2+ (CIN2+) providing an even earlier diagnosis. The sensitivity of Pap smears and HPV test are 55.4% and 94.6%, respectively. Conversely, Pap smears has a specificity of 96.8% compared to 94.1% for the HPV test. The negative predictive value of both tests is 99%, which leads to a very precise and very early diagnosis. Recently, researchers from the Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA identified artificial intelligence as a simple, universal and reliable ally for an accurate cervical cancer screening. Published in January 2019 in the Journal of National Cancer Institute, a population-based longitudinal study validated the use of digitalized uterine cervix images in the identification of premalignant lesions (CIN2 and CIN3) as well as carcinoma in situ (CIS). Tested in Costa Rica high risk women population, the new method revealed a higher accuracy (AUC = 0.91) when compared to conventional cytology of the uterine cervix (AUC = 0.71). All of these screening methods are now available, allowing early diagnosis of cervical cancer and subsequent appropriate interventions, leading to a cure rate that is close to 100%. A globally observed CFR of more than 40% is unacceptable. Failure to provide effective educational programs and social inequality are the main causes for this universal health disaster.
1. Global Cancer Observatory: International Agency for Research on Cancer and World Health Organization, 2020
2. Siegel R L, Miller K D and Jemal A: Cancer Statistics 2019, American Cancer Society, CA Cancer J Clin69: 7-34, 2019
3. Papanicolaou GN, Traut HF. "The diagnostic value of vaginal smears in carcinoma of the uterus". American Journal of Obstetrics and Gynecology, 42:193, 1941
4. Mayrand M H , Duarte-Franco E, Rodrigues I: Human Papillomavirus DNA versus Papanicolaou Screening Tests for Cervical Cancer, N Engl J Med 357:1579-1588, 2007
5. Liming Hu, David Bell, Sameer Antani, Zhiyun Xue, et al: An Observational Study of Deep Learning and Automated Evaluation of Cervical Images for Cancer Screening, JNCI Jan, 2019
6. Photo by Jonathan Ford on Unsplash
Despite the great tools for screening and diagnosing cervical cancer – such as Pap smears and HPV test –, we still have to deal with frighting numbers when it comes to the epidemiology of this disease. Even in developed countries, the case fatality risk for cervical cancer is absurdly high. That being said, it is important to raise awareness about this reality. I believe education is key: women need to know about the existence of this disease and about the ways to screen and diagnose it. For that to become a reality, governmental action is required so more resources are available to fight this enemy.
The persistence of high incidence, mortality and lethality of cervical cancer, not only in underdeveloped countries, but also in developed centers, although efficient diagnostic tests such as Pap smears and HPV test, and even a vaccine for HPV are available, only reflects the inability of healthcare systems to deal with a disease that should be easily diagnosed but instead, continues to kill hundreds of women all over the globe.
Artificial intelligence keeps evolving year after year, showing us that machines can really be more precise than human specialists in disease predictions, as showed by the Nacional Cancer Institute's study. In this case, the main algorithm used was Deep Learning, which relies on a huge image database. After the DL model is trained, the diagnosis turns to be more precise. That occurs because all images are analyzed in a "pixel perspective", where the human eye cannot reach.
The emerge of the Pap test in the middle of the 20th century should be enough to early diagnose cervical cancer. However, data compiled from recent years shows the elevated incidence of this disease with high percentage of patients being diagnosed in an advanced stage. Death by a pelvic cancer is a horrible end and the fact it could be avoided is tearful. With HPV vaccine, there should be a decrease in incidence of cervical cancer in future years and also let´s hope the health system finds and corrects the gaps that prevent early diagnosis.
From 1943 onwards, techniques were described that allow the early diagnosis of cervical cancer. Even in the present day, with new tests and screening for HPV, with the vaccine and new therapeutic interventions that lead to a chance of cure close to 100%, we can see that the risk of fatality, even in developed countries, remains above 40%. Thus, the inefficiency of health programs in early diagnosis of cancer is visible, resulting in deaths that could have been prevented. Therefore, the importance of counseling and educating women about the need for preventive exams.
Cervical cancer is a disease that has been known for decades, and surprisingly remains very prevalent in our society today. What is most surprising in this case is that, since 1943, there has been a publication related to the early diagnosis of cervical cancer. Despite this, even after all these years, the fatality rates resulting from a late diagnosis remain high on all continents. Even though the emphasis on Africa, Asia and Latin America, the numbers are also quite significant in continents with predominantly developed countries. Haven't the benefits of early diagnosis of cervical cancer already been proven? What is still missing for preventive exams to be effectively inserted into the population's medical routine?
Despite the consolidation of very useful techniques in the fight against cervical cancer, such as the Pap smear and the HPV vaccine, we still face a very difficult reality in the prevention of this disease. Cervical cancer is still a disease with a high incidence and mortality. Such facts point us to an inefficiency of health programs in carrying out early diagnoses. In view of this, we need to focus on public strategies that educate women about the need for preventive exams.
Cervical cancer is indeed a universal shame. It is inconceivable that it is still a public health issue around the world, primarily affecting women in low and middle-income countries. Prevention and early diagnosis are essential to fight this disease and reduce mortality. It is necessary to expand access to screening tests and vaccines against HPV, in addition to investing in education and awareness about the importance of women's health.
Cervical cancer is indeed a worldwide shame. Figure 1 shows that the magnitude of differences in CFRs - Case Fatality Risk- are smaller in cervical cancer than those observed for all cancers or female cancer across five continents. This is a shame because we have tools to diagnose premalignant changes, which allows for appropriate intervention, and we have a vaccine for the main factor in the development of cervical cancer - the human papilloma virus. So, these frightening numbers that could be much smaller demonstrate the inability of the health system to guarantee the full health of women.
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