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The economic burden of noncervical human papillomavirus disease in the United States

  • Delphine Hu
    Affiliations
    Program in Health Decision Science, Department of Health Policy and Management, Harvard School of Public Health, Boston, MA.
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  • Sue Goldie
    Correspondence
    Reprints: Sue J. Goldie, MD, MPH, Director of the Program in Health Decision Science, Department of Health Policy and Management, Harvard School of Public Health, 718 Huntington Ave, 2nd Floor, Boston, MA 02115.
    Affiliations
    Program in Health Decision Science, Department of Health Policy and Management, Harvard School of Public Health, Boston, MA.
    Search for articles by this author

      Objective

      The purpose of this study was (1) to estimate the direct medical costs of 7 major noncervical human papillomavirus (HPV)–related conditions that include genital cancers, mouth and oropharyngeal cancers, anogenital warts, and juvenile-onset recurrent respiratory papillomatosis, and (2) to approximate the economic burden of noncervical HPV disease.

      Study Design

      For each condition, we synthesized the best available secondary data to produce lifetime cost per case estimates, which were expressed in present value. Using an incidence-based approach, we then applied these costs to develop an aggregate measure of economic burden.

      Results

      The economic burden that was associated with noncervical HPV-6–, -11–, -16–, and -18–related conditions in the US population in the year 2003 approximates $418 million (range, $160 million to $1.6 billion).

      Conclusion

      The economic burden of noncervical HPV disease is substantial. Analyses that assess the value of investments in HPV prevention and control programs should take into account the costs and morbidity and mortality rates that are associated with these conditions.

      Key words

      Genital human papillomavirus (HPV) infection is the most common sexually transmitted disease in the United States.
      Centers for Disease Control and Prevention
      Prevention of genital HPV infection and sequelae: report of an external consultants' meeting: Department of Health and Human Services.
      Although the majority of infections are asymptomatic or self-limited, acquisition of specific types of HPV can result in clinically significant disease. Most notable among the oncogenic types (ie, high-risk types) of HPV are types 16 and 18, which are responsible for approximately 70% of all cervical cancer
      • Wiley D.A.
      • Mansongsong E.
      Human papillomavirus: the burden of infection.
      • Parkin D.M.
      • Bray F.
      Chapter 2: the burden of HPV-related cancers.
      and a lower proportion of cancer of the vagina, vulva, penis, anus, mouth, and oropharynx
      • Parkin D.M.
      • Bray F.
      Chapter 2: the burden of HPV-related cancers.
      ; and HPV-6 and -11, which are responsible for up to 90% of anogenital warts and virtually all cases of juvenile-onset recurrent respiratory papillomatosis (JORRP).
      • Wiley D.A.
      • Mansongsong E.
      Human papillomavirus: the burden of infection.
      • Lacey C.J.
      • Lowndes C.M.
      • Shah K.V.
      Chapter 4: burden and management of non-cancerous HPV-related conditions: HPV-6/11 disease.
      Collectively, HPV-6, -11, -16, and -18 impose a substantial disease burden and affect both quantity and quality of life.
      For Editors' Commentary, see Table of Contents
      See related editorial, page 487
      This past year, the US Food and Drug Administration approved a quadrivalent HPV vaccine (Gardasil) that protects against HPV-6, -11, -16, and -18 and has been highly effective in the prevention of anogenital warts and precancerous lesions of the cervix, vagina, and vulva in women who were not infected previously with these types.
      • Koutsky L.A.
      • Harper D.M.
      Chapter 13: current findings from prophylactic HPV vaccine trials.
      With the emergence of new technologies for the prevention and treatment of HPV-related disease (eg, HPV vaccines and HPV diagnostic tests) information about the clinical and economic burden that is associated with HPV-related disease can inform cost-effectiveness analyses and budget impact analyses.
      Economic studies to date of HPV-related conditions have focused primarily on cervical cancer and its precursor lesions.
      • Chesson H.W.
      • Blandford J.M.
      • Gift T.L.
      • Tao G.
      • Irwin K.L.
      The estimated direct medical cost of sexually transmitted diseases among American youth, 2000.
      • Insinga R.P.
      • Dasbach E.J.
      • Elbasha E.H.
      Assessing the annual economic burden of preventing and treating anogenital human papillomavirus-related disease in the US: analytic framework and review of the literature.
      • Fleurence R.L.
      • Dixon J.M.
      • Milanova T.F.
      • Beusterien K.M.
      Review of the economic and quality-of-life burden of cervical human papillomavirus disease.
      There are substantially fewer cost studies of noncervical HPV–associated sequelae.
      • Bishai D.
      • Kashima H.
      • Shah K.
      The cost of juvenile-onset recurrent respiratory papillomatosis.
      • Insinga R.P.
      • Dasbach E.J.
      • Myers E.R.
      The health and economic burden of genital warts in a set of private health plans in the United States.
      • Alam M.
      • Stiller M.
      Direct medical costs for surgical and medical treatment of condylomata acuminata.
      • Langley P.C.
      • Tyring S.K.
      • Smith M.H.
      The cost effectiveness of patient-applied versus provider-administered intervention strategies for the treatment of external genital warts.
      In fact, a recent literature review concluded there are no studies that have examined the direct medical costs attributable to noncervical HPV–related cancers or that have assessed the economic burden of noncervical HPV disease.
      • Insinga R.P.
      • Dasbach E.J.
      • Elbasha E.H.
      Assessing the annual economic burden of preventing and treating anogenital human papillomavirus-related disease in the US: analytic framework and review of the literature.
      The main objective of this study was (1) to estimate the direct medical costs that are associated with 7 major noncervical HPV–related diseases, which included genital cancers, mouth and oropharyngeal cancers, anogenital warts, and JORRP; and (2) to provide an aggregated measure of the economic burden of noncervical HPV–related disease.

      Materials and Methods

      We focused on 7 HPV-related conditions: HPV-6– and -11–associated anogenital warts, HPV-6– and -11–associated JORRP, and HPV-16– and -18–associated noncervical genital cancers (including anus, penis, vagina, vulva) and cancers of the mouth and oropharynx.

      Lifetime cost per case of noncervical HPV–related conditions

      For each of the 7 conditions, we used the best available secondary data to estimate the lifetime cost per case. Because these costs are intended for use in economic evaluations, we sought to develop cost per case estimates that represent the stream of direct medical costs, which are expressed in present value, from the time of diagnosis to cure or death (henceforth referred to as “discounted lifetime cost per case”). Cost data that are used to inform estimates were identified from a literature review (Appendix). Whenever possible, we sought published discounted lifetime cost per case estimates (anogenital warts, JORRP, anal cancer).
      • Bishai D.
      • Kashima H.
      • Shah K.
      The cost of juvenile-onset recurrent respiratory papillomatosis.
      • Insinga R.P.
      • Dasbach E.J.
      • Myers E.R.
      The health and economic burden of genital warts in a set of private health plans in the United States.
      • Maroun J.
      • Ng E.
      • Berthelot J.M.
      • et al.
      Lifetime costs of colon and rectal cancer management in Canada.
      However, because of the paucity of available studies, especially regarding noncervical HPV-related cancers, we approximated the discounted lifetime cost per case by using the best available data and simple modeling exercises to reflect the lifetime cost stream (mouth/oropharyngeal cancer, penile cancer, vaginal cancer, and vulvar cancer).
      • Fields A.I.
      • Rosenblatt A.
      • Pollack M.M.
      • Kaufman J.
      Home care cost-effectiveness for respiratory-technology dependent children.
      • Lang K.
      • Menzin J.
      • Earle C.C.
      • Jacobson J.
      • Hsu M.A.
      The economic cost of squamous cell cancer of the head and neck: findings from linked SEER-Medicare data.
      Vaccine candidates: HPV.
      • Fetters M.D.
      • Lieberman R.W.
      • Abrahams P.H.
      • Sanghvi R.V.
      • Sonnad S.S.
      Cost-effectiveness of Pap smear screening for vaginal cancer after total hysterectomy for benign disease.
      American Medical Association
      Medicare fee calculator 2004 CD-ROM.
      Agency for Healthcare Quality and Research
      Healthcare Cost and Utilization Project nationwide inpatient sample, national statistics 2003.
      Further details of the estimation approach are provided in the disease-specific sections later in this article.
      To the extent possible, data sources from the United States were used,
      • Bishai D.
      • Kashima H.
      • Shah K.
      The cost of juvenile-onset recurrent respiratory papillomatosis.
      • Insinga R.P.
      • Dasbach E.J.
      • Myers E.R.
      The health and economic burden of genital warts in a set of private health plans in the United States.
      • Fields A.I.
      • Rosenblatt A.
      • Pollack M.M.
      • Kaufman J.
      Home care cost-effectiveness for respiratory-technology dependent children.
      • Lang K.
      • Menzin J.
      • Earle C.C.
      • Jacobson J.
      • Hsu M.A.
      The economic cost of squamous cell cancer of the head and neck: findings from linked SEER-Medicare data.
      Vaccine candidates: HPV.
      • Fetters M.D.
      • Lieberman R.W.
      • Abrahams P.H.
      • Sanghvi R.V.
      • Sonnad S.S.
      Cost-effectiveness of Pap smear screening for vaginal cancer after total hysterectomy for benign disease.
      American Medical Association
      Medicare fee calculator 2004 CD-ROM.
      Agency for Healthcare Quality and Research
      Healthcare Cost and Utilization Project nationwide inpatient sample, national statistics 2003.
      although we supplemented these data with studies from Canada and Europe.
      • Maroun J.
      • Ng E.
      • Berthelot J.M.
      • et al.
      Lifetime costs of colon and rectal cancer management in Canada.
      • Speight P.M.
      • Palmer S.
      • Moles D.R.
      • et al.
      The cost-effectiveness of screening for oral cancer in primary care.
      • van Agthoven M.
      • van Ineveld B.M.
      • de Boer M.F.
      • et al.
      The costs of head and neck oncology: primary tumours, recurrent tumours and long-term follow-up.
      Costs were adjusted for inflation and expressed in 2003 US dollars.
      US Department of Labor, Bureau of Labor Statistics
      Consumer price index: all urban consumers.
      Future costs associated with individual cases of HPV-related conditions were discounted 3% annually to reflect their present value.

      Economic burden of noncervical HPV disease

      To develop an aggregate measure of the economic burden of noncervical HPV-related conditions, we adopted an incidence-based approach whereby the discounted lifetime cost per case associated with each condition was applied to the total number of HPV-6–, -11–, -16–, and -18–attributable incident cases that occurred among men and women over a representative 1-year period (2003).
      Centers for Disease Control and Prevention
      Prevention of genital HPV infection and sequelae: report of an external consultants' meeting: Department of Health and Human Services.
      • Wiley D.A.
      • Mansongsong E.
      Human papillomavirus: the burden of infection.
      • Parkin D.M.
      • Bray F.
      Chapter 2: the burden of HPV-related cancers.
      • Lacey C.J.
      • Lowndes C.M.
      • Shah K.V.
      Chapter 4: burden and management of non-cancerous HPV-related conditions: HPV-6/11 disease.
      • Chesson H.W.
      • Blandford J.M.
      • Gift T.L.
      • Tao G.
      • Irwin K.L.
      The estimated direct medical cost of sexually transmitted diseases among American youth, 2000.
      US Cancer Statistics Working Group
      United States cancer statistics: 2003 incidence and mortality.
      American Cancer Society
      Cancer: facts and figures 2003.
      • Derkay C.S.
      Task force on recurrent respiratory papillomas: a preliminary report.
      • Armstrong L.R.
      • Preston E.J.
      • Reichert M.
      • et al.
      Incidence and prevalence of recurrent respiratory papillomatosis among children in Atlanta and Seattle.
      • Rubin M.A.
      • Kleter B.
      • Zhou M.
      • et al.
      Detection and typing of human papillomavirus DNA in penile carcinoma: evidence for multiple independent pathways of penile carcinogenesis.
      • Trimble C.L.
      • Hildesheim A.
      • Brinton L.A.
      • Shah K.V.
      • Kurman R.J.
      Heterogeneous etiology of squamous carcinoma of the vulva.
      • Iwasawa A.
      • Nieminen P.
      • Lehtinen M.
      • Paavonen J.
      Human papillomavirus in squamous cell carcinoma of the vulva by polymerase chain reaction.
      • Daling J.R.
      • Madeleine M.M.
      • Schwartz S.M.
      • et al.
      A population-based study of squamous cell vaginal cancer: HPV and cofactors.
      • Daling J.R.
      • Madeleine M.M.
      • Johnson L.G.
      • et al.
      Human papillomavirus, smoking, and sexual practices in the etiology of anal cancer.
      • Frisch M.
      • Fenger C.
      • van den Brule A.J.
      • et al.
      Variants of squamous cell carcinoma of the anal canal and perianal skin and their relation to human papillomaviruses.
      • Kreimer A.R.
      • Clifford G.M.
      • Boyle P.
      • Franceschi S.
      Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review.
      The resulting estimates were then added for the 7 conditions to approximate the total economic burden of noncervical HPV-related disease.

      Results

      Juvenile-onset Recurrent Respiratory Papillomatosis

      Cost estimates for juvenile-onset recurrent respiratory papillomatosis were obtained from a published study.
      • Bishai D.
      • Kashima H.
      • Shah K.
      The cost of juvenile-onset recurrent respiratory papillomatosis.
      In this study, the discounted lifetime cost per case was estimated at $131,910, with a wide plausible range of $54,800-$276,170. Base case assumptions included an average duration of illness of 4.2 years during which each patient underwent 4.4 surgical procedures per year, a ratio of follow-up office visits to surgery of 3:1, and a tracheotomy rate of 11%.
      • Bishai D.
      • Kashima H.
      • Shah K.
      The cost of juvenile-onset recurrent respiratory papillomatosis.
      Costs that were considered focused on those related to the primary treatment of JORRP, which consisted of surgery (ie, physician fees and hospitalization) and follow-up visits (ie, physician fees), and to tracheotomy (ie, physician fees, hospitalization, and maintenance). In the absence of published data, the authors assumed the yearly cost of tracheotomy maintenance to be $94,980 (range, $75,980-$113,980). However, this figure has considerable uncertainty because the majority of JORRP patients with tracheotomy do not require mechanical ventilation, which comprises the bulk of tracheotomy-associated costs. As a result, we elected to use this study's lower bound estimate of $54,800 as our base case value for the average lifetime cost per case of JORRP.
      Estimates of the annual incidence of JORRP vary widely, from 80-1500 and 1448-3260 new cases.
      • Derkay C.S.
      Task force on recurrent respiratory papillomas: a preliminary report.
      • Armstrong L.R.
      • Preston E.J.
      • Reichert M.
      • et al.
      Incidence and prevalence of recurrent respiratory papillomatosis among children in Atlanta and Seattle.
      Assuming a midpoint yearly incidence of 1500 and that all cases of JORRP are attributable to HPV-6 or -11, the estimated total lifetime direct medical cost that is associated with new cases of JORRP over a representative 1-year period is $82.2 million. When upper and lower bound values for JORRP incidence and lifetime cost per case are used, this cost ranges from $4.4-$900 million.

      Anogenital warts

      Because a single episode of anogenital warts often is associated with the use of a combination of different therapies and there is wide variation in cost among the different treatment options, we sought published estimates of the cost per episode of newly diagnosed genital warts. We used the average cost per case of $505 from 2 available estimates from the Centers for Disease Control and Prevention ($510) and a published study ($500; range, $420 -$580).
      • Chesson H.W.
      • Blandford J.M.
      • Gift T.L.
      • Tao G.
      • Irwin K.L.
      The estimated direct medical cost of sexually transmitted diseases among American youth, 2000.
      • Insinga R.P.
      • Dasbach E.J.
      • Myers E.R.
      The health and economic burden of genital warts in a set of private health plans in the United States.
      In the latter study, cost per episode estimates were derived from the Marketscan database by summing all payments on the basis of diagnosis code for a single episode of anogenital warts (defined as a 12-month interval free of anogenital wart care preceding and after the current episode).
      • Insinga R.P.
      • Dasbach E.J.
      • Myers E.R.
      The health and economic burden of genital warts in a set of private health plans in the United States.
      Costs reflect health plan payments to physicians for office visits that were related to diagnosis, treatment, and/or follow-up and to pharmacies for self-applied medications or analgesics.
      • Insinga R.P.
      • Dasbach E.J.
      • Myers E.R.
      The health and economic burden of genital warts in a set of private health plans in the United States.
      To estimate the discounted lifetime cost per case of anogenital warts, we sought estimates for the average cost per episode of care and applied this cost to 75% of all new wart cases, assuming a spontaneous cure rate of 25%
      • Chesson H.W.
      • Blandford J.M.
      • Gift T.L.
      • Tao G.
      • Irwin K.L.
      The estimated direct medical cost of sexually transmitted diseases among American youth, 2000.
      and an average duration per episode of care of 3 months.
      • Insinga R.P.
      • Dasbach E.J.
      • Myers E.R.
      The health and economic burden of genital warts in a set of private health plans in the United States.
      These assumptions yielded a lifetime direct medical cost per case of anogenital warts of $379. Estimates of the annual incidence of anogenital warts are imprecise and range from 250,000-1,000,000.
      • Chesson H.W.
      • Blandford J.M.
      • Gift T.L.
      • Tao G.
      • Irwin K.L.
      The estimated direct medical cost of sexually transmitted diseases among American youth, 2000.
      Using the midpoint estimate of 500,000 new cases per year and assuming 90% of all anogenital warts are caused by HPV-6 or -11,
      • Insinga R.P.
      • Dasbach E.J.
      • Elbasha E.H.
      Assessing the annual economic burden of preventing and treating anogenital human papillomavirus-related disease in the US: analytic framework and review of the literature.
      we estimated the total lifetime cost that is associated with all new cases of anogenital warts that occur within a given year to be $171 million. This estimate closely approximates the figure of $190 million that was reported by Chesson et al.
      • Chesson H.W.
      • Blandford J.M.
      • Gift T.L.
      • Tao G.
      • Irwin K.L.
      The estimated direct medical cost of sexually transmitted diseases among American youth, 2000.
      The range for our estimate is $71-$392 million, with the upper and lower bound estimates of incidence and lifetime cost per case.

      Anal cancer

      Because published US cost estimates for anal cancer were unavailable, the discounted lifetime cost per case of anal cancer was approximated from a Canadian cost study of rectal cancer.
      • Maroun J.
      • Ng E.
      • Berthelot J.M.
      • et al.
      Lifetime costs of colon and rectal cancer management in Canada.
      Cost estimates included diagnostic assessment, staging work-up, initial treatment, surveillance, treatment of recurrent disease, management of metastatic disease, and terminal care. The estimated discounted lifetime cost per case of $27,660 was consistent with the estimate of $26,850 (range, $13,420-$53,700) reported by Goldie et al,
      • Goldie S.J.
      • Kuntz K.M.
      • Weinstein M.C.
      • Freedberg K.A.
      • Palefsky J.M.
      Cost-effectiveness of screening for anal squamous intraepithelial lesions and anal cancer in human immunodeficiency virus-negative homosexual and bisexual men.
      who used data from a US study of colorectal cancer to approximate anal cancer costs.
      In 2003, the American Cancer Society projected that there were 4000 new cases of anal cancer in the United States.
      American Cancer Society
      Cancer: facts and figures 2003.
      Assuming that 82.8% of all anal cancer is attributable to HPV types 16 and 18,
      • Parkin D.M.
      • Bray F.
      Chapter 2: the burden of HPV-related cancers.
      • Daling J.R.
      • Madeleine M.M.
      • Johnson L.G.
      • et al.
      Human papillomavirus, smoking, and sexual practices in the etiology of anal cancer.
      • Frisch M.
      • Fenger C.
      • van den Brule A.J.
      • et al.
      Variants of squamous cell carcinoma of the anal canal and perianal skin and their relation to human papillomaviruses.
      we estimated the total lifetime cost of all HPV-attributable incident cases of anal cancer that occurred in 2003 to be $92 million (range, $44-$178 million).

      Penile cancer

      We identified 3 publications with cost estimates for penile cancer.
      Vaccine candidates: HPV.
      • Schoen E.J.
      • Colby C.J.
      • To T.T.
      Cost analysis of neonatal circumcision in a large health maintenance organization.
      • Van Howe R.S.
      A cost-utility analysis of neonatal circumcision.
      Our base case estimate was developed from an Institute of Medicine study of the costs and benefits of HPV vaccination.
      Vaccine candidates: HPV.
      In this study, an expert committee developed a stage-specific clinical scenario for penile cancer to characterize resource utilization and to estimate healthcare costs. For example, costs that were related to local penile cancer included a primary care physician visit, surgery, anesthesia, hospitalization, radiation (in 50% of patients), chemotherapy (in 50% patients), and a single physician visit with a specialist. With advanced penile cancer, the clinical scenario was almost identical, with the exception of an additional 6 specialist physician visits because of the increased morbidity that is associated with advanced cancer (ie, urinary and sexual dysfunction). Cost estimates include direct medical costs that were related to initial treatment (ie, physician fees, hospitalization, surgery, radiation, and/or chemotherapy), and short-term follow-up visits (ie, 1 year) but not those that were associated with diagnostic assessment, long-term surveillance, treatment of recurrent disease, management of metastatic disease, or terminal care. Assuming two-thirds of all penile cancers are local at the time of diagnosis and the remaining one-third of the cancers are advanced,
      Vaccine candidates: HPV.
      we determined that the discounted lifetime cost per case was $15,120. This estimate falls roughly midway between the 2 published estimates of $7,500 and $29,640, which we used as a plausible range.
      • Schoen E.J.
      • Colby C.J.
      • To T.T.
      Cost analysis of neonatal circumcision in a large health maintenance organization.
      • Van Howe R.S.
      A cost-utility analysis of neonatal circumcision.
      Using data from the American Cancer Society and National Cancer Institute, we estimated that 1145 new cases of penile cancer occurred in the United States in 2003.
      US Cancer Statistics Working Group
      United States cancer statistics: 2003 incidence and mortality.
      American Cancer Society
      Cancer: facts and figures 2003.
      Assuming 25.2% of all penile cancers are attributable to HPV-16 and -18,
      • Parkin D.M.
      • Bray F.
      Chapter 2: the burden of HPV-related cancers.
      • Rubin M.A.
      • Kleter B.
      • Zhou M.
      • et al.
      Detection and typing of human papillomavirus DNA in penile carcinoma: evidence for multiple independent pathways of penile carcinogenesis.
      the total lifetime cost of all HPV-16– and -18–associated penile cancers that occurred in 2003 was estimated at $4.4 million dollars (range, $2.2-$8.6 million).

      Vaginal cancer

      Estimates for the discounted lifetime cost per case of vaginal cancer were developed with data from a published cost-effectiveness study of Papanicolaou smear screening for vaginal cancer after total hysterectomy.
      • Fetters M.D.
      • Lieberman R.W.
      • Abrahams P.H.
      • Sanghvi R.V.
      • Sonnad S.S.
      Cost-effectiveness of Pap smear screening for vaginal cancer after total hysterectomy for benign disease.
      Available vaginal cancer-related cost data included the cost of diagnosis (ie, biopsy and colposcopy) and initial treatment (ie, surgery or radiation), which were drawn from actual reimbursement rates by third-party payers (base case), with Medicare reimbursement rates representing the lower bound of cost estimates. In accordance with the National Cancer Institute, we assumed standard therapy for stage I was radiation or surgery (with treatment equally divided between radiation and surgery) and radiation for stages II, III, and IV. In 2003 US dollars, this translated to a lifetime cost for stage I vaginal cancer of $22,726 (range, $17,044-$28,568) and for stages II, III and IV of $20,003 (range, $15,003-$25,263). Assuming a distribution by stage at diagnosis of 26% for stage I, 37.2% for stage II, 24.1% for stage III, and 12.7% for stage IV,
      • Berek J.S.
      • Hacker N.F.
      Practical gynecology oncology.
      we estimated the present value of the lifetime cost of a new case of vaginal cancer to be $20,710 (range, $15,530-$26,120).
      The American Cancer Society estimated that 2000 new cases of vaginal and other female genital tract cancers occurred in the year 2003.
      American Cancer Society
      Cancer: facts and figures 2003.
      Vaginal cancer represents approximately 53.8% or 1077 of all cancers in this category.
      US Cancer Statistics Working Group
      United States cancer statistics: 2003 incidence and mortality.
      When we assumed that 32% of all vaginal cancer is related to HPV-16 and -18,
      • Parkin D.M.
      • Bray F.
      Chapter 2: the burden of HPV-related cancers.
      • Daling J.R.
      • Madeleine M.M.
      • Schwartz S.M.
      • et al.
      A population-based study of squamous cell vaginal cancer: HPV and cofactors.
      the total lifetime cost of all HPV-16– and -18–associated vaginal cancers that occurred in 2003 was estimated at $7.1 million (range, $5.4-$9.0 million).

      Vulvar cancer

      Because published cost estimates for vulvar cancer were unavailable, we constructed a simple mathematical model to estimate the discounted lifetime cost per case of vulvar cancer. We developed stage-specific estimates that included the cost of diagnosis, initial treatment, and short-term surveillance (Appendix). Incorporating cost and clinical data from national databases and the published literature,
      American Medical Association
      Medicare fee calculator 2004 CD-ROM.
      Agency for Healthcare Quality and Research
      Healthcare Cost and Utilization Project nationwide inpatient sample, national statistics 2003.
      • Beller U.
      • Quinn M.A.
      • Benedet J.L.
      • et al.
      Carcinoma of the vulva: FIGO 6th annual report on the results of treatment in gynecological cancer.
      we estimated the discounted lifetime cost per case of vulvar cancer to be $18,050 (range, $11,860-$24,250).
      With the assumption that 4000 new cases of vulvar cancer occurred in the United States in 2003 and that 32% of all vulvar cancer is attributable to HPV-16 and -18,
      • Parkin D.M.
      • Bray F.
      Chapter 2: the burden of HPV-related cancers.
      American Cancer Society
      Cancer: facts and figures 2003.
      • Trimble C.L.
      • Hildesheim A.
      • Brinton L.A.
      • Shah K.V.
      • Kurman R.J.
      Heterogeneous etiology of squamous carcinoma of the vulva.
      • Iwasawa A.
      • Nieminen P.
      • Lehtinen M.
      • Paavonen J.
      Human papillomavirus in squamous cell carcinoma of the vulva by polymerase chain reaction.
      the total lifetime cost of all HPV-attributable cases of vulvar cancer that newly occurred in 2003 was $23.1 million (range, $15.2-31.0 million).

      Oropharyngeal and mouth cancer

      The discounted lifetime cost per case of oropharyngeal and mouth cancer was estimated from an existing study in which patients with newly diagnosed head and neck cancer from the Surveillance, Epidemiology, and End Results (SEER) registry were matched by age and gender to control subjects, and direct medical care costs over a 5-year period were compared between the 2 groups on the basis of Medicare payments.
      • Lang K.
      • Menzin J.
      • Earle C.C.
      • Jacobson J.
      • Hsu M.A.
      The economic cost of squamous cell cancer of the head and neck: findings from linked SEER-Medicare data.
      To estimate the lifetime cost per case, we assumed that the cost difference between patients with head and neck cancer and control subjects was attributable to cancer care and discounted the cost difference in years 2-5 with a rate of 3%. This approach yielded an average cost per case of head and neck cancer of $33,020.
      To construct a plausible range for our estimate, we relied on cost data from 2 European studies. For the lower bound estimate, we used cost data from a British study of the cost-effectiveness of screening for oral cancer.
      • Speight P.M.
      • Palmer S.
      • Moles D.R.
      • et al.
      The cost-effectiveness of screening for oral cancer in primary care.
      This study reported annual direct medical costs by stage for a 3-year period after the initial diagnosis. Using the stage distribution that was observed in patients in this same study, we estimated the average discounted lifetime costs to be $15,340. For the upper bound estimate, we used cost data from a retrospective Netherlands study that estimated the cost of treatment, potential recurrence, and follow-up over a 10-year period for oral cavity, laryngeal, and oropharyngeal cancers that were treated in 2 university hospitals.
      • van Agthoven M.
      • van Ineveld B.M.
      • de Boer M.F.
      • et al.
      The costs of head and neck oncology: primary tumours, recurrent tumours and long-term follow-up.
      With a 4% discount rate, the study estimated an average lifetime cost per case of $46,800.
      In 2003, the American Cancer Society projected that there were 9200 new cases of mouth cancer and 8300 new cases of oropharyngeal cancer in the United States.
      American Cancer Society
      Cancer: facts and figures 2003.
      Assuming 2.9% of all mouth cancers and 10.7% of all oropharyngeal cancers are caused by HPV-16 and -18,
      • Parkin D.M.
      • Bray F.
      Chapter 2: the burden of HPV-related cancers.
      • Kreimer A.R.
      • Clifford G.M.
      • Boyle P.
      • Franceschi S.
      Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review.
      we estimated the total lifetime costs for all new cases of mouth and oropharyngeal cancer that occurred in 2003 to be $38.1 million (range, $17.7-$54.1 million).

      Economic burden of noncervical HPV-6–, -11–, -16–, and -18–related disease

      For the 7 HPV-6–, -11–, -16–, and -18–related conditions that were considered, the total economic burden (expressed in 2003 US dollars) associated with the new cases that occurred in 2003 was $418 million, with a plausible range of $160 million to $1.6 billion (Table). Under base case assumptions, HPV-6– and -11–related conditions accounted for >60% of the total burden. This was due to the high incidence and large HPV-attributable fraction of JORRP and anogenital warts and the considerable discounted lifetime cost per case that was associated with JORRP. Three conditions (JORRP, anogenital warts, and anal cancer) were responsible for >80% of the costs that were attributable to noncervical HPV-related conditions.
      TABLENumber of new cases of disease, percent HPV-attributable fraction, estimated lifetime cost per case, and total direct medical costs of 7 major noncervical HPV-attributable conditions, United States, 2003
      VariableIncidence: new cases in 2003 (n)HPV-6/11 or -16/18 attributable fraction (%)
      Estimated by multiplying the HPV-attributable fraction of disease by the proportion specifically attributed to HPV-6/11 or -16/18.
      Average discounted lifetime cost per new case ($)
      Estimates in 2003 US dollars.
      Total lifetime cost of new cases occurring in 2003 (million $)
      Estimates in 2003 US dollars.
      ,
      Estimated by multiplying the average total lifetime cost per new case, the annual incidence of disease, and the HPV-type–specific attributable fraction.
      References
      JORRP1,50010054,800 (54,800-276,170)82.2
      • Bishai D.
      • Kashima H.
      • Shah K.
      The cost of juvenile-onset recurrent respiratory papillomatosis.
      ,
      • Fields A.I.
      • Rosenblatt A.
      • Pollack M.M.
      • Kaufman J.
      Home care cost-effectiveness for respiratory-technology dependent children.
      ,
      American Medical Association
      Medicare fee calculator 2004 CD-ROM.
      ,
      Agency for Healthcare Quality and Research
      Healthcare Cost and Utilization Project nationwide inpatient sample, national statistics 2003.
      ,
      • Derkay C.S.
      Task force on recurrent respiratory papillomas: a preliminary report.
      ,
      • Armstrong L.R.
      • Preston E.J.
      • Reichert M.
      • et al.
      Incidence and prevalence of recurrent respiratory papillomatosis among children in Atlanta and Seattle.
      Anogenital warts500,00090379 (315-435)
      Assumes 25% of all anogenital warts clear spontaneously without treatment.6
      171
      • Chesson H.W.
      • Blandford J.M.
      • Gift T.L.
      • Tao G.
      • Irwin K.L.
      The estimated direct medical cost of sexually transmitted diseases among American youth, 2000.
      ,
      • Insinga R.P.
      • Dasbach E.J.
      • Elbasha E.H.
      Assessing the annual economic burden of preventing and treating anogenital human papillomavirus-related disease in the US: analytic framework and review of the literature.
      ,
      • Insinga R.P.
      • Dasbach E.J.
      • Myers E.R.
      The health and economic burden of genital warts in a set of private health plans in the United States.
      Anal cancer4,00082.827,660 (13,420-53,700)92
      • Parkin D.M.
      • Bray F.
      Chapter 2: the burden of HPV-related cancers.
      ,
      • Maroun J.
      • Ng E.
      • Berthelot J.M.
      • et al.
      Lifetime costs of colon and rectal cancer management in Canada.
      ,
      American Cancer Society
      Cancer: facts and figures 2003.
      ,
      • Daling J.R.
      • Madeleine M.M.
      • Johnson L.G.
      • et al.
      Human papillomavirus, smoking, and sexual practices in the etiology of anal cancer.
      ,
      • Frisch M.
      • Fenger C.
      • van den Brule A.J.
      • et al.
      Variants of squamous cell carcinoma of the anal canal and perianal skin and their relation to human papillomaviruses.
      ,
      • Goldie S.J.
      • Kuntz K.M.
      • Weinstein M.C.
      • Freedberg K.A.
      • Palefsky J.M.
      Cost-effectiveness of screening for anal squamous intraepithelial lesions and anal cancer in human immunodeficiency virus-negative homosexual and bisexual men.
      Penile cancer1,14525.215,120 (7,500-29,640)4.4
      • Parkin D.M.
      • Bray F.
      Chapter 2: the burden of HPV-related cancers.
      ,
      Vaccine candidates: HPV.
      ,
      US Cancer Statistics Working Group
      United States cancer statistics: 2003 incidence and mortality.
      ,
      American Cancer Society
      Cancer: facts and figures 2003.
      ,
      • Rubin M.A.
      • Kleter B.
      • Zhou M.
      • et al.
      Detection and typing of human papillomavirus DNA in penile carcinoma: evidence for multiple independent pathways of penile carcinogenesis.
      Vaginal cancer1,0773220,710 (15,530-26,120)7.1
      • Parkin D.M.
      • Bray F.
      Chapter 2: the burden of HPV-related cancers.
      ,
      • Fetters M.D.
      • Lieberman R.W.
      • Abrahams P.H.
      • Sanghvi R.V.
      • Sonnad S.S.
      Cost-effectiveness of Pap smear screening for vaginal cancer after total hysterectomy for benign disease.
      ,
      US Cancer Statistics Working Group
      United States cancer statistics: 2003 incidence and mortality.
      ,
      American Cancer Society
      Cancer: facts and figures 2003.
      ,
      • Daling J.R.
      • Madeleine M.M.
      • Schwartz S.M.
      • et al.
      A population-based study of squamous cell vaginal cancer: HPV and cofactors.
      , ,
      • Berek J.S.
      • Hacker N.F.
      Practical gynecology oncology.
      Vulvar cancer4,0003218,050 (11,860-24,250)23.1
      • Parkin D.M.
      • Bray F.
      Chapter 2: the burden of HPV-related cancers.
      , ,
      American Medical Association
      Medicare fee calculator 2004 CD-ROM.
      ,
      Agency for Healthcare Quality and Research
      Healthcare Cost and Utilization Project nationwide inpatient sample, national statistics 2003.
      ,
      American Cancer Society
      Cancer: facts and figures 2003.
      ,
      • Trimble C.L.
      • Hildesheim A.
      • Brinton L.A.
      • Shah K.V.
      • Kurman R.J.
      Heterogeneous etiology of squamous carcinoma of the vulva.
      ,
      • Iwasawa A.
      • Nieminen P.
      • Lehtinen M.
      • Paavonen J.
      Human papillomavirus in squamous cell carcinoma of the vulva by polymerase chain reaction.
      ,
      • Beller U.
      • Quinn M.A.
      • Benedet J.L.
      • et al.
      Carcinoma of the vulva: FIGO 6th annual report on the results of treatment in gynecological cancer.
      Mouth and oropharyngeal cancer17,5006.6
      Represents a weighted average of the percentage of mouth and oropharyngeal cancer that is attributable to HPV-16/18.3,25,34
      33,020 (15,340-46,800)38.1
      • Parkin D.M.
      • Bray F.
      Chapter 2: the burden of HPV-related cancers.
      ,
      • Lang K.
      • Menzin J.
      • Earle C.C.
      • Jacobson J.
      • Hsu M.A.
      The economic cost of squamous cell cancer of the head and neck: findings from linked SEER-Medicare data.
      ,
      • Speight P.M.
      • Palmer S.
      • Moles D.R.
      • et al.
      The cost-effectiveness of screening for oral cancer in primary care.
      ,
      • van Agthoven M.
      • van Ineveld B.M.
      • de Boer M.F.
      • et al.
      The costs of head and neck oncology: primary tumours, recurrent tumours and long-term follow-up.
      ,
      American Cancer Society
      Cancer: facts and figures 2003.
      ,
      • Kreimer A.R.
      • Clifford G.M.
      • Boyle P.
      • Franceschi S.
      Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review.
      All conditions418
      Hu. The economic burden of noncervical human papillomavirus disease in the United States. Am J Obstet Gynecol 2008.
      a Estimated by multiplying the HPV-attributable fraction of disease by the proportion specifically attributed to HPV-6/11 or -16/18.
      b Estimates in 2003 US dollars.
      c Estimated by multiplying the average total lifetime cost per new case, the annual incidence of disease, and the HPV-type–specific attributable fraction.
      d Assumes 25% of all anogenital warts clear spontaneously without treatment.
      • Chesson H.W.
      • Blandford J.M.
      • Gift T.L.
      • Tao G.
      • Irwin K.L.
      The estimated direct medical cost of sexually transmitted diseases among American youth, 2000.
      e Represents a weighted average of the percentage of mouth and oropharyngeal cancer that is attributable to HPV-16/18.
      • Parkin D.M.
      • Bray F.
      Chapter 2: the burden of HPV-related cancers.
      American Cancer Society
      Cancer: facts and figures 2003.
      • Kreimer A.R.
      • Clifford G.M.
      • Boyle P.
      • Franceschi S.
      Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review.

      Comment

      Despite formidable data gaps, our review of secondary data and estimation of the direct medical costs that are associated with 7 HPV-related conditions demonstrate a substantial economic burden imposed by HPV-attributable noncervical disease in the United States. With the use of an incidence-based approach, the economic burden associated with noncervical HPV-related conditions that occurred in the United States in the year 2003 approximates $418 million. This figure has a considerably wide plausible range of $160 million to $1.6 billion, which is driven predominantly by the substantial uncertainty in the cost of JORRP and the incidence of JORRP and anogenital warts.
      Two vaccines against HPV-16 and -18 have been found to be highly efficacious against same type incidence and precancerous lesions of the cervix, vagina, and vulva among women without indication of previous infection with these types; the quadrivalent vaccine currently licensed in the United States also prevents infection with HPV-6 and -11, which are responsible for most genital warts and JORRP.
      • Koutsky L.A.
      • Harper D.M.
      Chapter 13: current findings from prophylactic HPV vaccine trials.
      Given these options for primary prevention of HPV-related disease, along with enhanced screening approaches for secondary prevention of HPV-related cervical cancer, there is considerable interest in comparative assessments of the health and economic consequences that are associated with alternative strategies to reduce the burden of HPV-related disease. Accordingly, we provide a comprehensive estimate of the economic burden of noncervical HPV-related disease in the United States. Although we consider this figure to be an approximate estimate at best, nonetheless, our results highlight the significant cost dimensions of this health problem and the importance of preventing these conditions to reduce both the health and economic burden of HPV infection. The estimated costs that are associated with each HPV-related condition can be used in future economic evaluations of HPV vaccination, and the lower and upper bound estimates as the plausible range for sensitivity analyses.
      Our study has several limitations that merit acknowledgement. First, sources of cost data were limited, and the quality of available information was variable. For example, much of the data that were used to derive lifetime cost per case estimates were not comprehensive. Many estimates included only selected aspects of care, such as diagnosis and treatment, and omitted costs that were related to staging, surveillance, or recurrence. In these instances, cost per case figures likely underestimate the actual lifetime cost of the disease. In addition, sources of cost information ranged from private health insurance to Medicare claims, each of which is associated with its own inherent flaws and biases.
      • Insinga R.P.
      • Dasbach E.J.
      • Elbasha E.H.
      Assessing the annual economic burden of preventing and treating anogenital human papillomavirus-related disease in the US: analytic framework and review of the literature.
      • Lave J.R.
      • Pashos C.L.
      • Anderson G.F.
      • et al.
      Costing medical care: using Medicare administrative data.
      Second, we did not consider nonmedical direct or indirect costs, such as transportation costs to healthcare facilities or the value of work time lost receiving healthcare. Studies that address these types of costs are unavailable for noncervical HPV-related conditions.
      • Insinga R.P.
      • Dasbach E.J.
      • Elbasha E.H.
      Assessing the annual economic burden of preventing and treating anogenital human papillomavirus-related disease in the US: analytic framework and review of the literature.
      Incorporation of these costs would make the economic burden of noncervical HPV–attributable disease even higher. Third, other HPV-attributable conditions such as vulvar, vaginal, penile, and anal intraepithelial neoplasia were not included in our burden analysis. However, because there are no screening recommendations for these conditions and the fraction of cases that can be attributed to HPV is unknown, the contribution of these conditions to the total HPV cost burden is also unknown. Fourth, the population-attributable fraction of noncervical cancers to HPV is uncertain. Because HPV is highly prevalent in healthy subjects, this method may overestimate the fraction of cancers to attributable HPV infection.
      • Parkin D.M.
      • Bray F.
      Chapter 2: the burden of HPV-related cancers.
      Finally, there was considerable uncertainty surrounding the cost of JORRP and the incidence of JORRP and anogenital warts. Because these 2 conditions may account for >60% of the economic burden of noncervical HPV disease, we believe refinement of these estimates to be a particularly high priority for future research studies.
      Directly comparable estimates of the total economic burden of noncervical HPV-related disease associated with incident cases over a 1-year period were not available. Previous studies have focused primarily on individual facets of this health problem, such as anogenital warts or JORRP.
      • Chesson H.W.
      • Blandford J.M.
      • Gift T.L.
      • Tao G.
      • Irwin K.L.
      The estimated direct medical cost of sexually transmitted diseases among American youth, 2000.
      • Insinga R.P.
      • Dasbach E.J.
      • Elbasha E.H.
      Assessing the annual economic burden of preventing and treating anogenital human papillomavirus-related disease in the US: analytic framework and review of the literature.
      • Bishai D.
      • Kashima H.
      • Shah K.
      The cost of juvenile-onset recurrent respiratory papillomatosis.
      • Insinga R.P.
      • Dasbach E.J.
      • Myers E.R.
      The health and economic burden of genital warts in a set of private health plans in the United States.
      • Derkay C.S.
      Task force on recurrent respiratory papillomas: a preliminary report.
      We were unable to identify any published estimates of the total lifetime direct medical cost of anal, penile, vaginal, or vulvar cancer. This may be due to the fact that these cancers are relatively uncommon. As a result, economic burden data for HPV have been confined largely to cervical disease
      • Chesson H.W.
      • Blandford J.M.
      • Gift T.L.
      • Tao G.
      • Irwin K.L.
      The estimated direct medical cost of sexually transmitted diseases among American youth, 2000.
      • Insinga R.P.
      • Dasbach E.J.
      • Elbasha E.H.
      Assessing the annual economic burden of preventing and treating anogenital human papillomavirus-related disease in the US: analytic framework and review of the literature.
      • Fleurence R.L.
      • Dixon J.M.
      • Milanova T.F.
      • Beusterien K.M.
      Review of the economic and quality-of-life burden of cervical human papillomavirus disease.
      and likely represent an underestimate of the economic burden that is posed by HPV infection.
      Quantification of the cost dimensions of noncervical HPV–attributable disease is important because it offers insight into not only the overall economic magnitude but also the relative contribution of different HPV-related conditions. For example, although cervical disease is responsible for most of the cost burden that is associated with HPV-related disease, the contribution of noncervical disease is still considerable, with our base case estimate representing nearly 9% of the total economic burden when incidence-based estimates are used.
      • Chesson H.W.
      • Blandford J.M.
      • Gift T.L.
      • Tao G.
      • Irwin K.L.
      The estimated direct medical cost of sexually transmitted diseases among American youth, 2000.
      • Fleurence R.L.
      • Dixon J.M.
      • Milanova T.F.
      • Beusterien K.M.
      Review of the economic and quality-of-life burden of cervical human papillomavirus disease.
      Among the noncervical HPV–attributable conditions, anogenital warts contribute to the largest fraction of the total burden, followed by anal cancer and JORRP. In fact, noncancerous conditions due to HPV-6 and -11 (JORRP and anogenital cancer) are responsible for >60% of the total economic burden of noncervical HPV-related disease. Such information may be useful to policymakers and public health researchers for informed decisions about investments in potential HPV prevention programs.
      In summary, our results demonstrate the substantial economic burden that is imposed by HPV-attributable noncervical disease in the United States. Future research priorities should include the refinement of cost estimates for noncervical HPV-related conditions, the incidence of JORRP and anogenital warts, and the population HPV-attributable fraction of noncervical conditions.

      Appendix

      Literature review of the available costing studies for noncervical HPV-related conditions

      Published articles that have addressed the cost of each of the 7 noncervical HPV-related conditions that were considered in this study (ie, anogenital warts, JORRP, and cancer of the anus, penis, vagina, vulva, mouth, and oropharynx) were identified with a systematic computerized search of MEDLINE and the British National Health Service Economic Evaluation Database and by manual review of the bibliographies of selected articles. The MeSH key word cost or cost analysis was combined with the key words human papillomavirus, anogenital warts, juvenile-onset recurrent respiratory papillomatosis, anal cancer, penile cancer, vaginal cancer, vulvar cancer, oropharyngeal cancer, mouth cancer, and head and neck cancer. Whenever possible, we sought published discounted lifetime cost per case estimates (anogenital warts, JORRP).
      • Chesson H.W.
      • Blandford J.M.
      • Gift T.L.
      • Tao G.
      • Irwin K.L.
      The estimated direct medical cost of sexually transmitted diseases among American youth, 2000.
      • Bishai D.
      • Kashima H.
      • Shah K.
      The cost of juvenile-onset recurrent respiratory papillomatosis.
      • Insinga R.P.
      • Dasbach E.J.
      • Myers E.R.
      The health and economic burden of genital warts in a set of private health plans in the United States.
      However, because of the paucity of available studies, especially regarding noncervical HPV-related cancers, we approximated the discounted lifetime cost per case by using the best available data and simple modeling exercises to reflect the lifetime cost stream (mouth/oropharyngeal cancer, penile cancer, vaginal cancer, and vulvar cancer).
      • Fields A.I.
      • Rosenblatt A.
      • Pollack M.M.
      • Kaufman J.
      Home care cost-effectiveness for respiratory-technology dependent children.
      • Lang K.
      • Menzin J.
      • Earle C.C.
      • Jacobson J.
      • Hsu M.A.
      The economic cost of squamous cell cancer of the head and neck: findings from linked SEER-Medicare data.
      Vaccine candidates: HPV.
      • Fetters M.D.
      • Lieberman R.W.
      • Abrahams P.H.
      • Sanghvi R.V.
      • Sonnad S.S.
      Cost-effectiveness of Pap smear screening for vaginal cancer after total hysterectomy for benign disease.
      American Medical Association
      Medicare fee calculator 2004 CD-ROM.
      Agency for Healthcare Quality and Research
      Healthcare Cost and Utilization Project nationwide inpatient sample, national statistics 2003.
      We were unable to identify any published costing studies for anal cancer and used cost estimates for rectal cancer as a proxy. To the extent possible, data sources from the United States were used,
      • Bishai D.
      • Kashima H.
      • Shah K.
      The cost of juvenile-onset recurrent respiratory papillomatosis.
      • Insinga R.P.
      • Dasbach E.J.
      • Myers E.R.
      The health and economic burden of genital warts in a set of private health plans in the United States.
      • Fields A.I.
      • Rosenblatt A.
      • Pollack M.M.
      • Kaufman J.
      Home care cost-effectiveness for respiratory-technology dependent children.
      • Lang K.
      • Menzin J.
      • Earle C.C.
      • Jacobson J.
      • Hsu M.A.
      The economic cost of squamous cell cancer of the head and neck: findings from linked SEER-Medicare data.
      Vaccine candidates: HPV.
      • Fetters M.D.
      • Lieberman R.W.
      • Abrahams P.H.
      • Sanghvi R.V.
      • Sonnad S.S.
      Cost-effectiveness of Pap smear screening for vaginal cancer after total hysterectomy for benign disease.
      American Medical Association
      Medicare fee calculator 2004 CD-ROM.
      Agency for Healthcare Quality and Research
      Healthcare Cost and Utilization Project nationwide inpatient sample, national statistics 2003.
      although we supplemented these data with studies from Canada and Europe.
      • Maroun J.
      • Ng E.
      • Berthelot J.M.
      • et al.
      Lifetime costs of colon and rectal cancer management in Canada.
      • Speight P.M.
      • Palmer S.
      • Moles D.R.
      • et al.
      The cost-effectiveness of screening for oral cancer in primary care.
      • van Agthoven M.
      • van Ineveld B.M.
      • de Boer M.F.
      • et al.
      The costs of head and neck oncology: primary tumours, recurrent tumours and long-term follow-up.

      Stage-specific estimation of the cost of vulvar cancer diagnosis and treatment

      In developing stage-specific estimates of the average lifetime cost of vulvar cancer (Appendix Table 1), we limited our costs to those that were related to diagnosis, treatment, and surveillance. Treatment strategies were based on the recommendations of the National Cancer Institute, whereby stage I vulvar cancer was treated with surgery alone and stages II–IV were treated with a combination of surgery and radiation.
      APPENDIX TABLE 1Estimated average discounted lifetime cost of vulvar cancer by stage and overall
      StageBase case ($)
      Estimates in 2003 US dollars.
      Lower bound ($)
      Estimates in 2003 US dollars.
      Upper bound ($)
      Estimates in 2003 US dollars.
      All vulvar cancer
      • Beller U.
      • Quinn M.A.
      • Benedet J.L.
      • et al.
      Carcinoma of the vulva: FIGO 6th annual report on the results of treatment in gynecological cancer.
      (%)
      I10,103.036,713.0513,547.1133.1
      II20,992.3813,478.2728,506.4934.6
      III23,027.3615,397.9830,656.7423.8
      IV23,027.3615,397.9830,656.748.5
      Overall (weighted by stage)18,045.3011,859.0524,249.47
      Hu. The economic burden of noncervical human papillomavirus disease in the United States. Am J Obstet Gynecol 2008.
      a Estimates in 2003 US dollars.
      We developed stage-specific clinical scenarios to determine which unit costs should be included in our calculations (Appendix Table 2). For example, diagnosis of all stages consisted of an initial physician office visit, biopsy, examination of the biopsy specimen for pathology, and a follow-up visit to discuss the biopsy results. Treatment costs of stage I vulvar cancer consisted of costs that were related to vulvectomy, pathologic examination of an intraoperative frozen specimen and the entire surgical specimen, and hospitalization. Treatment costs of stages II-IV vulvar cancer included the cost of radiation therapy in addition to the cost of vulvectomy, pathology, and hospitalization. We assumed that all patients were seen by a physician on a semiannual basis for surveillance for 5 years after treatment. Sources of cost data included the 2004 Medicare Fee Schedule for physician fees that are related to the various components of care and the Healthcare Cost and Utilization project for hospitalization-related costs.
      American Medical Association
      Medicare fee calculator 2004 CD-ROM.
      Agency for Healthcare Quality and Research
      Healthcare Cost and Utilization Project nationwide inpatient sample, national statistics 2003.
      For physician-related costs, we used nonfacility fees as the upper bound estimate and facility fees for the lower bound estimate and averaged the 2 for the base case estimate. With regard to hospitalization-related costs, we used the mean cost and charge within the category “cancer of other female genital organs” as our plausible range and the average for the base case estimate.
      APPENDIX TABLE 2Current procedure terminology codes and costs that were used for estimation of the total lifetime cost of vulvar cancer
      VariableCurrent procedure terminology codeBase case ($)
      Estimates in 2003 US dollars.
      Lower bound estimate ($)
      Estimates in 2003 US dollars.
      Upper bound estimate ($)
      Estimates in 2003 US dollars.
      Diagnosis
      Initial physician visit99241, 99242, or 99243108.3046.22170.38
      Biopsy56605, 56606, 56820, or 56821148.4185.89210.92
      Pathological examination88305140.91140.91140.91
      Follow-up visit99241, 99242, 99243108.3046.22170.38
      Stage I treatment
      Surgical excision or simple vulvectomy11622, 56620, or 56625478.35190.83765.87
      Pathological examination88309 ± 88331367.82308.21427.42
      Hospitalization (applied to 50%)15,828.548,680.0822,977.01
      Stage II, III, and IV treatment
      Radical vulvectomy56630, 56631, or 566321,231.771,069.641,393.91
      Pathological examination88309 and 88331367.82308.21427.42
      Hospitalization15,828.548,680.0822,977.01
      Radiation therapy (applied to 50% of stage II, 100% of stage III/IV)77263, 77295, 77300, 77336, 77413, and 774274,069.963,839.434,300.49
      Surveillance
      Physician office visit99242111.7394.47128.98
      Hu. The economic burden of noncervical human papillomavirus disease in the United States. Am J Obstet Gynecol 2008.
      a Estimates in 2003 US dollars.

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      Linked Article

      • The economic impact of HPV vaccines: not just cervical cancer
        American Journal of Obstetrics & GynecologyVol. 198Issue 5
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          Cervical cancer is the leading cause of cancer death among women worldwide. Although regular screening dramatically reduces the incidence and death from cervical cancer, effective screening requires substantial investment of resources to ensure adequate population coverage, acceptable test performance, and appropriate management of abnormal results. The discovery that cervical cancer was caused by human papillomavirus (HPV) led rapidly to the development of vaccines targeted against HPV-16 and -18, which account for approximately 70% of cancer cases.
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