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Cervical Cancer 2015 and Beyond: A Focus on Innovative Treatments and Attention to Survivorship

      Cervical cancer is primarily a disease of less-developed countries.
      • Sankaranarayanan R.
      Overview of cervical cancer in the developing world. FIGO 26th annual report on the results of treatment in gynecological cancer.
      In contrast, for countries with established screening programs and access to medical care, the number of cases of cervical cancer has declined significantly over the past few decades. With the introduction of human papillomavirus (HPV) testing/typing and increasing uptake of the HPV vaccine, it is anticipated that HPV-related cervical disease (both preinvasive and invasive) will ultimately become obsolete in developed countries. The robust vaccination program in Australia illustrates this point, as it has nearly eradiated genital warts after 5 years.
      • Ali H.
      • Donovan B.
      • Wand H.
      • et al.
      Genital warts in young Australians five years into national human papillomavirus vaccination programme: national surveillance data.
      • Chow E.P.
      • Read T.R.
      • Wigan R.
      • et al.
      Ongoing decline in genital warts among young heterosexuals 7 years after the Australian human papillomavirus (HPV) vaccination programme.
      Unfortunately, cervical cancer continues to be a cause of significant morbidity and mortality around the world, primarily for women in countries where there are no screening and vaccination programs. With 528,000 new cases every year, cervical cancer is the fourth most common cancer affecting women worldwide, after breast, colorectal, and lung cancers.
      Latest world cancer statistics
      Global cancer burden rises to 14.1 million new cases in 2012: marked increase in breast cancers must be addressed.
      It is also the fourth most common cause of cancer death (266,000 deaths in 2012) in women worldwide. Moreover, even in the United States, 12,360 cases of cervical cancer were anticipated in 2014 and 4020 deaths from the disease.
      • Siegel R.
      • Ma J.
      • Zou Z.
      • Jemal A.
      Cancer statistics, 2014.
      These cases of cervical cancer are primarily due to screening failures as a result of lack of access to care. Despite the ability to entirely prevent this disease, there are still women in the United States who die of cervical cancer each year.
      Although the cure rates for early disease (stage I) are excellent, at ~80% depending on tumor size, the cure rates for locally advanced cervical cancer are far lower, at ~50%.
      • Monk B.J.
      • Tian C.
      • Rose P.G.
      • Lanciano R.
      Which clinical/pathologic factors matter in the era of chemoradiation as treatment for locally advanced cervical carcinoma? Analysis of two Gynecologic Oncology Group (GOG) trials.
      Bevacizumab was recently approved by the US Food and Drug Administration as an addition to the armamentarium of drugs available to treat advanced and recurrent cervical cancer; the cure rates, however, for advanced and recurrent disease remain dismally low.
      • Tewari K.S.
      • Sill M.W.
      • Long 3rd, H.J.
      • et al.
      Improved survival with bevacizumab in advanced cervical cancer.
      Perhaps equally important, the adverse effects of the treatment for all stages of cervical cancer are substantial and often lifelong, particularly for those women who require treatment with radiation therapy.
      • Mirabeau-Beale K.L.
      • Viswanathan A.N.
      Quality of life (QOL) in women treated for gynecologic malignancies with radiation therapy: a literature review of patient-reported outcomes.
      Even young women with early-stage disease who are likely to be cured will face long-term adverse effects from radical surgery, including loss of their fertility.
      For the focused edition of Clinical Therapeutics on cervical cancer that was published in January 2014, we chose to emphasize prevention via vaccination, arguably the most important instrument in our toolbox for managing this potentially preventable disease. Unfortunately, the decrease in incidence of cervical cancer as a result of HPV vaccination will be decades in the future, and, more importantly, the uptake of the vaccine in the United States continues to be unacceptably low.
      • Laz T.H.
      • Rahman M.
      • Berenson A.B.
      An update on human papillomavirus vaccine uptake among 11-17 year old girls in the United States: National Health Interview Survey, 2010.
      As a result, in this issue of Clinical Therapeutics, we chose to focus instead on 2 main topics: (1) the development of new treatment options for current and future women facing this disease; and (2) the management of treatment sequelae.
      Patients with advanced or recurrent cervical cancer have a bleak prognosis, and innovative noncytotoxic treatment regimens are urgently needed. There is extensive evidence that cisplatin-based combination chemotherapy is the best treatment option for these women; the most recent data support the addition of bevacizumab.
      • Tewari K.S.
      • Sill M.W.
      • Long 3rd, H.J.
      • et al.
      Improved survival with bevacizumab in advanced cervical cancer.
      • Monk B.J.
      • Sill M.W.
      • McMeekin D.S.
      • et al.
      Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study.
      Although the addition of bevacizumab produced a statistically significant improvement in overall survival (leading to FDA approval in 2014 of this drug for cervical cancer), the median overall improvement in survival was only 3.7 months.
      • Tewari K.S.
      • Sill M.W.
      • Long 3rd, H.J.
      • et al.
      Improved survival with bevacizumab in advanced cervical cancer.
      The articles by Krill and Tewari
      • Krill L.S.
      • Tewari K.
      Exploring the therapeutic rationale for angiogenesis blockade in cervical cancer.
      and Eskander and Tewari
      • Eskander R.N.
      • Tewari K.
      Immunotherapy: an evolving paradigm in the treatment of advanced cervical cancer.
      focus on the development of novel noncytotoxic treatments for advanced and recurrent disease. Krill and Tewari explore the role of angiogenesis in the development of cervical neoplasia, building on the success with bevacizumab already demonstrated by the Gynecology Oncology Group. Translational research suggests that proangiogenic pathways are important in the development and metastasis of cervical cancer, indicating that other antiangiogenic agents may be successful in treating this disease. In addition to the proangiogenic signaling cascades, it is logical that this HPV-related disease would respond to treatments that augment natural immunity. In fact, current research in cancer in general is focusing on improving the immune response to the disease. Along these lines, Eskander and Tewari outline the development of immunotherapies for the management of cervical cancer.
      • Schlosser H.A.
      • Theurich S.
      • Shimabukuro-Vornhagen A.
      • et al.
      Overcoming tumor-mediated immunosuppression.
      The authors discuss therapeutic (rather than prophylactic) vaccines for women with cervical cancer, as well as the use of immune checkpoint inhibitors that are also being studied in other cancers, most notably melanoma.
      While we investigate new treatments, we must also keep in mind the cervical cancer survivors, who even when cured of disease experience significant impacts on their quality of life. There are currently 245,022 cervical cancer survivors living in the United States, many of whom are young women with many decades of life in front of them.
      • de Moor J.S.
      • Mariotto A.B.
      • Parry C.
      • et al.
      Cancer survivors in the United States: prevalence across the survivorship trajectory and implications for care.
      Radiation therapy is an effective treatment for locally advanced and bulky cervical cancer, but it also has adverse effects that may persist and progress over time, particularly with respect to bowel, bladder, and sexual function. Pfaendler et al
      • Pfaendler K.S.
      • Wenzel L.
      • Mechanic M.B.
      • Penner K.R.
      Cervical cancer survivorship: long-term quality of life and social support.
      review the literature with respect to quality of life for cervical cancer survivors, paying particular attention to these adverse effects, as well as the effects of radical surgery on women with cervix-confined disease. New radiation dosing regimens offer hope for improved treatment outcomes with decreased doses delivered to normal tissues. Despite improvement in radiation techniques, including intensity-modulated radiation therapy, significant life-threatening toxicity (particularly to the gastrointestinal tract and bladder) persist. As presented by Trifiletti et al,
      • Trifiletti D.M.
      • Watkins W.T.
      • Duska L.
      • et al.
      Severe gastrointestinal complications in the era of image-guided high dose-rate intracavitary brachytherapy for cervical cancer.
      clinical suspicion must be high when caring for women with gastrointestinal complaints after curative combination chemoradiotherapy for locally advanced disease.
      Until we are able to eradicate cervical cancer via improved screening with HPV testing/typing and increased uptake of the HPV vaccines, we must continue to seek and develop new, less toxic treatments for the hundreds of thousands of women diagnosed with cervical cancer each year. In addition, the Patient Protection and Affordable Care Act encourages us as a care community to focus on cancer survivorship, improving the lives of women who may be cured of disease but who still experience significant treatment-related toxicity.

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