Assessing the Short-term and Long-term Burden of Illness in Cervical Cancer

June 15, 2008
Robert J. Lipsy, PharmD, BCPS

Supplements and Featured Publications, Cervical Cancer: Burden of Illness, Volume 14, Issue 6 Suppl

Human papillomavirus (HPV) infection is associated with significant clinical, social, and financial burdens. Infection is often asymptomatic, which increases the risk of unwitting transmission. Up to 29 million American women between the ages of 14 and 59 years are currently infected, and 80% of women will contract the infection by 50 years of age.

Persistent oncogenic HPV infection is the leading cause of cervical dysplasia and neoplasia, and evidence shows that oncogenic HPV is present in 99.7% of cervical cancer specimens. Cervical cancer and cervical dysplasias are responsible for the vast majority of morbidities and deaths associated with HPV-related illness. The direct annual healthcare costs for screening, treating, and managing abnormalities related to cervical cancer and cervical dysplasias in the United States are estimated to be as high as $4.6 billion.

Although the direct costs of cervical cancer are substantial, only 10% of all expenditures derive from invasive disease; more than two thirds of the total cost is attributable to screening and testing. Annual indirect costs resulting from lost productivity and loss of earnings due to premature death are also significant and are estimated to be higher than direct costs.

(Am J Manag Care. 2008;14:S177-S184)

When assessing the burden of illness for cervical disease, it is often assumed that invasive cervical cancer accounts for the majority of costs. In reality, the effects of cervical cancer and cervical dysplasias are diverse and encompass direct and indirect costs that result from frequently overlooked factors related to secondary prevention methods and quality-of-life (QOL) issues.1 The importance and impact of these direct and indirect costs vary by audience in the managed care setting. Direct costs may be more relevant to payers such as managed care plans because increasing medical expenditures affect them immediately. Payers must also remain cognizant of indirect costs and QOL issues. These may influence patients’ compliance with screening and follow-up care for cervical abnormalities, further affecting outcomes and costs. Purchasers such as employers maintain a relatively uniform interest in direct and indirect cost data and QOL burden because all of these components—particularly productivity issues and absenteeism—can profoundly impact their bottom line.

Human Papillomavirus Infection

The National Cancer Institute estimates that more than 6 million new genital HPV infections occur annually.2 Almost 24.9 million women aged 14 to 59 years in the United States are actively infected, and 80% of sexually active women will contract genital HPV by 50 years of age.2 It is estimated that between 64% and 82% of sexually active adolescent girls will test positive for HPV, and it is believed that sexually active males in the same age group are similarly infected.2 More than 50% of these infections are caused by oncogenic virus types.2

HPV is responsible for 5.2% of all cancers worldwide.2 Whereas HPV types 6 and 11 are associated with 10% of cases of low-grade or low-risk lesions and 90% of cases of genital warts, oncogenic HPV types 16 and 18 account for ~76% of all cases of high-grade CIN or dysplasias and invasive cervical cancer in the United States.5 Cervical cancer represents 9.8% of all cancers in women.2

Secondary prevention methods, such as Papanicolaou’s cervical smear (Pap test), have dramatically reduced the incidence of cervical cancer and its associated mortality, yet cervical cancer continues to be diagnosed in more than 11,000 women annually in the United States, and 4000 die each year from the disease (1 woman every 2.5 hours).6 A greater proportion of younger women die from cervical cancer than from other gynecologic cancers, with a reported 26 years of life lost per woman because of death from cervical cancer in the United States as compared with 19 for breast cancer and 18 for ovarian cancer.7 The prevalence of cervical cancer in a younger population is of significant concern to healthcare plans and employers, particularly as it relates to increased medical costs and lost workdays for younger employees.

When cervical cancer is diagnosed at the dysplasia stage, it has a nearly 100% cure rate, making early detection very important to those involved in managed care.8 Secondary prevention efforts, such as routine screening programs, have significantly reduced the incidence of cervical cancer and subsequent mortality. At one time, cervical cancer was the leading cause of cancer death for women, but the cervical cancer mortality rate declined 74% between 1955 and 1992 and it now ranks fifteenth, presumably as a result of the implementation of secondary prevention initiatives and related improvements.8 Although improvements to secondary prevention methods are ongoing, their impact appears to have plateaued. There has been no noticeable improvement in screening adherence rates in the past 6 years, and among participants in commercial health plans, it has remained at ~80% since 2001.9 Screening efforts have presumably led to the decline in cases of cervical squamous cell carcinoma, but the incidence of cervical adenocarcinoma has been increasing.10 This increase may result from the Pap test’s inefficiency in detecting adenocarcinoma or a greater number of oncogenic HPV infections in younger women.10 Without expanded employment of preventive measures such as vaccination, the rates of cervical cancer and cervical dysplasia may rise in response to these screening inefficiencies and a growing number of HPV infections.2,8,9

The impact of cervical cancer and cervical dysplasia on managed care can be characterized by the disease stage at the time of diagnosis. The rate of various abnormalities diagnosed through routine screening and false-positive test results can have a significant effect on the burden of illness. In one managed care population, ~5% of women undergoing routine screening had an abnormal Pap test in 1998.11 Of these women, the peak incidence of CIN 1 was 5.1 per 1000 women aged 20 to 24 years and the peak incidence of CIN 2/3 was 8.1 per 1000 women aged 25 to 29 years, indicating a slightly higher incidence of more serious lesions in the older age group.11 This notable rate of precancerous lesions in young women inevitably translates into significant costs for managed care organizations (MCOs). Follow-up of abnormal Pap tests found CIN 1/3 or cancer in only 19.4% of patients, demonstrating the test’s potential for producing false-positive results that may require unnecessary follow-up and lead to excessive expenditures.10 A total of 51% of abnormal Pap tests produced falsepositive results, and 29% of women underwent inadequate follow-up procedures according to accepted management guidelines. These factors indicate that some increased costs relate to screening methods rather than the disease itself.11

Quality-of-life Burden

Figure 1

In addition to psychological burdens, significant economic burdens are associated with HPV-related disease, including direct and indirect costs. The focus of MCOs is clearly on direct medical costs. The vast majority of these costs are related to routine screening, follow-up of abnormal Pap tests, and treatment of dysplasia.1 Estimates in 2005 US dollars of the direct healthcare costs of cervical cancer in the United States were as high as $4.6 billion annually.1,12 Although various studies’ estimates for direct costs related to sexually transmitted diseases differed somewhat according to the methodology used, even the lowest determination of HPV-related disease spending placed it second only to human immunodeficiency virus (HIV) spending. Direct costs in 2004 US dollars for HPV-related disease exceeded spending for genital herpes ($1.9 billion) and Chlamydia ($2 million-$3 billion) and came in fourth overall among direct costs for all infectious diseases, behind HIV, nosocomial infections, and food-borne bacterial infections.14 In addition to the $4.6 billion (in 2005 US dollars) in direct healthcare costs for cervical cancer and cervical dysplasias, the costs of anogenital warts and other cancers associated with oncogenic HPV contribute a small amount to the annual, direct expenditures of HPVrelated disease, raising the total economic burden to as high as $5 billion (in 2006 US dollars).1,12 The most conservative estimates of direct annual costs (in 2005 US dollars) for HPV-related cervical disease are $2.4 billion for routine screening, $339 million for false-positive Pap tests, $169.5 million for CIN 1, $508 million for CIN 2/3, and $395 million for invasive disease ().1 These cost estimates do not account for some of the newer secondary prevention technologies, such as liquid-based cytology and HPV DNA testing, in which specimens are collected at the physician’s office and subsequently analyzed by a pathologist.14

Additional interventions that offer primary prevention, such as HPV vaccination, may serve to overcome some of the vast costs allocated to secondary prevention methods and follow-up. Although effective screening programs have greatly reduced the number of cervical cancers diagnosed in the United States, no program is 100% effective. Despite the great economic burden of cervical cancer prevention and diagnosis through screening, it is estimated that 55% to 60% of cases of cervical cancer are diagnosed in women who have not undergone a Pap test in the previous 3 years.1 Primary prevention in the form of HPV vaccination may help minimize the shortcomings of current secondary prevention methods (screening) and, in turn, minimize costs.

Economic Burden: Indirect Costs

Indirect costs, including lost productivity and lost future earnings, account for a significant portion of the total costs for all cancers, particularly those in the later stages, which are associated with higher mortality rates. The National Institutes of Health estimated that the cost of all cancers in the United States totaled $206.3 billion in 2006, with direct medical costs contributing $78.2 billion, indirect morbidity costs (cost of lost productivity due to illness) contributing $17.9 billion, and indirect mortality costs (cost of lost productivity due to premature death) contributing $110.2 billion.16

Indirect costs are also significant in cervical cancer and are likely several times greater than direct costs.14 Insinga’s study of lost productivity due to premature death from cervical cancer determined that more than 130,000 women would likely have been alive in the year 2000 had they not died prematurely from cervical cancer.17 He found that more than 75% of women who received a diagnosis of cervical cancer died before 60 years of age and 25% died before 40 years of age.17 Using workforce participation data from 2000, Insinga estimated that 29% of the women would have been active in the workforce that year. Based on the projected annual earnings for these women, the study estimated a loss of $1.3 billion (in 2000 US dollars).17 This was significantly more than the estimated annual direct medical costs of $300 to $400 million (in 2004 US dollars) associated with cervical cancer. This study and others have estimated that the indirect costs of cervical cancer constitute more than three fourths of the overall economic burden of the disease.17,18

A study by Max et al used California hospital discharge information from 1997 to estimate direct and indirect costs for cervical and other gynecologic cancers that were either primary or secondary diagnoses.18 There were 452 cervical cancer deaths that year, and because cervical cancer often occurs in younger women, it was estimated that 28.7 lifeyears were lost per death, resulting in approximately 12,989 total life-years lost.18 The total estimated loss of future earnings (in 1998 US dollars) was determined to be $158 million discounted at 3%, or a loss of $350,839 per cervical cancer death. The study also found that indirect costs were twice the direct costs.18

Indirect costs, with a primary focus on lost productivity and future earnings, have not been studied and documented as extensively as direct costs. This may be partly because of the qualitative nature of indirect costs and the overall lower level of interest in these costs in managed care, except to employers and epidemiologists. Reported cost estimates are likely underestimated, because the existing data sets have not fully considered costs related to lost work or leisure time resulting from followup secondary prevention, disease-associated morbidity, and cancer treatment. Despite this apparent underestimation, the impact of indirect costs relative to cervical cancer remains significant to society and particularly to employers within the managed care process.

Conclusion

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