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Cervical Cancer: The Next Generation of Prevention, Detection, and Treatment

      Cervical cancer remains an important problem in the United States and, more significantly, the world, despite the US Food and Drug Administration’s approval of the first in-human papillomavirus (HPV) vaccine in 2006. In the United States in 2016, even with mature screening programs, an estimated 12,990 women will be diagnosed with cervical cancer and 4120 will die from the disease.
      • Siegel R.L.
      • Miller K.D.
      • Jemal A.
      Cancer statistics, 2016.
      Worldwide, these numbers are more staggering: Cervical cancer is the fourth most frequent cancer in women, with an estimated 530,000 new cases and 270,000 deaths in 2012.

      World Health Organization. Human papillomavirus (HPV) and cervical cancer. http://www.who.int/mediacentre/factsheets/fs380/en/. Accessed February 7, 2016.

      The treatment of cervical cancer in almost all cases will result in a loss of future fertility, as well as other significant treatment sequelae leading to a decreased quality of life.
      Unfortunately, cervical cancer continues to be a cancer of young women; in fact, as noted by Pelkofski et al
      • Pelkofski E.
      Cervical Cancer in Women Aged 35 Years and Younger.
      in this issue of Clinical Therapeutics, cervical cancer is the most common gynecologic malignancy in women <35 years of age. Those young women who develop cervical cancer, by virtue of their young age and the trend in the United States to delay childbearing, are at particular risk for loss of fertility, with 22% in the report from Pelkofski et al
      • Pelkofski E.
      Cervical Cancer in Women Aged 35 Years and Younger.
      having never been pregnant.
      In the series from Pelkofski et al, the “very young” patients (25 years or younger) were compared to the so-called "young" patients (26–35 years). While there was no difference in progression-free or overall survival between these two groups, the investigators did make some interesting observations. First, 5 of the 17 “very young” women with cervical cancer were aged 20 years or younger. It is of interest that all 5 of these women were diagnosed by Pap smear (author, personal communication), a screening procedure for which they would not be eligible under the current guideline.
      • Saslow D.
      • Solomon D.
      • Lawson H.W.
      • et al.
      American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer.
      While concerning, this finding must be placed into perspective: This is a very small-scale experience in a rural and underserved population from two mid-Atlantic universitybased practices, and the findings contradict those from a larger-scale population-based study that suggests the that rate of cervical cancer in women under age 21 years is “vanishingly small.”
      • Dinkelspiel H.
      • Kinney W.
      State of the science: cervical cancer screening in transition.
      There are no data to suggest that screening in women <21 years of age affects future rates of pre-invasive disease, and screening this population may result in unnecessary procedures because younger women are more likely to clear pre-invasive disease.
      • Moscicki A.B.
      • Cox J.T.
      Practice improvement in cervical screening and management (PICSM): symposium on management of cervical abnormalities in adolescents and young women.
      Nonetheless, the relatively large number of young women in this series merits further consideration in future, larger-scale studies. Second, the rate of small cell carcinoma, a subtype associated with a very poor prognosis, was 4.4%, which is greater than expected in the overall cervical cancer group (expected, <3%).
      • Cohen J.G.
      • Kapp D.S.
      • Shin J.Y.
      • et al.
      Small cell carcinoma of the cervix: treatment and survival outcomes of 188 patients.
      Third, and perhaps most important, the 5-year survival rate in the entire patient group (women aged 35 years or under) in the study by Pelkofski et al
      • Pelkofski E.
      Cervical Cancer in Women Aged 35 Years and Younger.
      was surprisingly low. Despite the fact that over 80% of women had early stage disease, the 5-year survival rate in the entire cohort was 42.1%, with a 5-year survival of 46% in patients with localized disease (expected, 68% for all stages combined, 92% for localized disease).

      American Cancer Society, Cancer Statistics Center. Cervix: At a Glance. https://cancerstatisticscenter.cancer.org/?_ga=1.165781501.293109391.1397432431#/cancer-site/Cervix. Accessed February 7, 2016.

      Put together, these findings are hypothesis generating. It would appear, based on this small series, that cervical cancer is more aggressive in the younger age group, although the reasons for this concept are not elucidated by the findings from the study and could be related to viral factors, individual patient characteristics, noncompliance with treatment, or other, yet-unidentified features of this particular population of women.
      Fortunately, new treatment paradigms are currently being researched, albeit primarily in the advanced and recurrent disease setting. In a previous issue of Clinical Therapeutics, we presented two updates on cervical cancer treatment, focusing on angiogenesis and immunotherapy.
      • Eskander R.N.
      • Tewari K.S.
      Immunotherapy: an evolving paradigm in the treatment of advanced cervical cancer.
      • Krill L.S.
      • Tewari K.S.
      Exploring the therapeutic rationale for angiogenesis blockade in cervical cancer.
      In the current issue, Craften and Salani
      • Crafton
      Beyond Chemotherapy: An Overview and Review of Targeted Therapy in Cervical Cancer.
      provide us with an update of the advances in cervical cancer treatment, including the clinical development of poly-(ADP-ribose) polymerase inhibitors in cervical cancer, both recently published and ongoing. Bevacizumab, a vascular endothelial growth factor inhibitor, is an excellent example of a recent advance in cervical cancer treatment that resulted in improved progression-free survival without negatively affecting overall quality of life. Other antiangiogenic treatment options under study are described by the investigators. Immunotherapy offers promise and makes rational sense in the setting of a virally induced disease. Cervical cancer treatment vaccines (as opposed to preventive vaccines) have been studied for years, but recent advances suggest greater success rates, and clinical trials continue. Rather than preventing disease, treatment vaccines are utilized to treat already established disease by stimulating a patient’s immune system to recognize viral-related antigens. Checkpoint inhibitors such as programmed T-cell death (PD)-1 inhibitors also offer a logical immunologic treatment paradigm. As the investigators note, up-regulation of PD-1 and PD ligand 1 has been observed in HPV-positive cervical cells, suggesting that impaired local immunity contributes to the progression of HPV-related cervical disease; this observation suggests that PD-1 and PD ligand 1 inhibitors may be effective in women with cervical cancer. Finally, PARP inhibitors offer new treatment options, as up-regulation of PARP has been demonstrated in cervical cancer cells. While most data are preliminary, the treatment modalities discussed in this review offer new strategies for the management of not only advanced and recurrent disease but also potentially primary disease.
      Even after the diagnosis and successful treatment of cervical cancer, survivorship is a long and difficult road. The extensive sequelae of both radical surgery and chemoradiation, including lifelong gastrointestinal, bladder, and sexual side effects, have been well-documented.
      • Pfaendler K.S.
      • Wenzel L.
      • Mechanic MB
      • Penner K.R.
      Cervical cancer survivorship: long-term quality of life and social support.
      Health-related behaviors, including smoking, lack of physical activity, and increased alcohol consumption, also contribute to decreased overall survival and quality of life in cervical cancer survivors. As noted by Osann et al,
      • Iyer N.S.
      Health Behaviors in Cervical Cancer Survivors and Associations with Quality of Life.
      prospective studies have shown that cervical cancer survivors who are smokers have more recurrences than do nonsmokers with significantly shorter overall survival.
      Iyer et al
      • Iyer N.S.
      Health Behaviors in Cervical Cancer Survivors and Associations with Quality of Life.
      undertook their study to describe the prevalence of health behaviors, specifically, physical activity, smoking, and alcohol consumption, among cervical cancer survivors, with the ultimate goal of examining the associations between health behaviors and quality of life. Cervical cancer survivors were recruited to participate in a randomized psychosocial by-telephone counseling trial. Notably, 15% of survivors continued to smoke, 4% reported high alcohol consumption, and 62.8% were not physically active. The majority of the women reported having at least one health behavior practice below the recommended standard. Participants who improved their health behaviors after the study intervention and during the 4-month follow-up period experienced a greater improvement in quality of life than did those women who did not improve their health behaviors. The results of this study suggest that it is important to focus not only on the treatment of cervical cancer but also on survivorship. Even minimal changes in health behaviors can have a significant effect on quality of life. Interventions such as the one described in the article by Osann et al
      • Iyer N.S.
      Health Behaviors in Cervical Cancer Survivors and Associations with Quality of Life.
      can be crucial in improving health behaviors and potentially not only quality of life but also overall survival in cervical cancer patients.
      Ultimately, we as a society have the power to completely annihilate cervical cancer by being more proactive about vaccinating our children. The HPV vaccines have been shown to be effective and well tolerated in multiple studies.
      • Castle P.E.
      • Maza M.
      Prophylactic HPV vaccination: past, present, and future.
      The new generation of vaccines covers more HPV types and therefore is anticipated to be even more effective in preventing cervical cancer. The experience in Australia suggests that increasing compliance with vaccination can result in a decrease in HPV-related genital disease.
      • Brotherton J.M.
      • Saville A.M.
      • May C.L.
      • et al.
      Human papillomavirus vaccination is changing the epidemiology of high-grade cervical lesions in Australia.
      • Saville A.M.
      Cervical cancer prevention in Australia: Planning for the future.
      • Garland S.M.
      The Australian experience with the human papillomavirus vaccine.
      In the United States, however, we have not done as well as our Australian counterparts, with vaccination rates remaining unacceptably low.
      • Berenson A.B.
      An update on barriers to adolescent human papillomavirus vaccination in the USA.
      Cervical cancer is a disease that is devastating at multiple levels. It is particularly aggressive in the youngest patients and is associated with poor health behaviors even in survivorship. New treatments, while exciting, have not yet been shown to improve overall survival. We must continue to develop treatments and behavioral approaches for survivors as these efforts are crucial, but just as importantly we must increase our efforts of prevention by advocating for vaccination and educating children, parents, and providers about the efficacy and tolerability of HPV vaccines.

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