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Case

Mariumu is a 37-year-old female, parity 4. She is from rural Tanzania and visited rural health clinics several times with vaginal discharge. According to the STI guidelines, she was treated for sexually transmitted disease several times. Because discharge came back after each treatment very soon, she was referred to the regional hospital. On speculum examination, cervical cancer was suspected. She had an examination under anesthesia and was diagnosed with cervical cancer stage 2B (infiltration in the parametria). She was referred to the national cancer hospital and was prescribed chemoradiation. Radiation therapy was free of charge, but unfortunately the national cancer hospital did not have chemotherapy in stock. She went to the local pharmacy to find out that chemotherapy cost 200 USD, which she could not afford. She received only radiotherapy and was sent home. Six months later, she developed severe abdominal pain radiating to her left leg. Her left leg was edematous. She consulted the rural health center and was prescribed paracetamol for 3 days. She had agonizing pains for months and appalling vaginal discharge. After 6 months, she stopped urinating and went subconscious. She died 4 days later.

Cervical cancer accounts for 0.5 million cases and 260,000 deaths annually, of which 85% in low- and middle-income countries (LMIC)(¹). The burden of cervical cancer is high in LMIC since the disease is more prevalent, quality of care often poor, and women are diagnosed in a later stage. Cervical cancer is caused by a persistent human papilloma virus (HPV) infec-tion. It takes 10-15 years after infection to develop into cervi-cal precursor lesions of cervical cancer and cervical cancer itself: ample time to screen and treat. Cervical cancer is highly preventable by HPV vaccinations and treatment of pre-cancerous lesions. Early-stage cervical cancer is treatable with surgery, and locally advanced stage cervical cancer with (chemo) radiation. Unfortunately, most women in LMIC are diagnosed in the stage of disseminated cervical cancer and only palliative care can diminish some of the symptoms.
In this article, we will focus on available evidence on pre-vention and treatment of cervical cancer in LMIC settings. Awareness, education, access to reproductive health care, and integration of cervical cancer prevention in exist-ing health services are issues that need urgent attention, in order to make prevention of cervical cancer efficient. Major global stakeholders are the Global Alliance for Vac-cines and Immunization (GAVI), Cervical Cancer Action (CCA) and the World Health Organization (WHO).

Primary prevention

HPV vaccination is effective and requires two injections in girls between the age of 9-14 years (for women 15 years or older a three-dose schedule is recommended). The efficacy of the HPV vaccine in preventing Cervical Intraepithelial Neoplasia (CIN) 2 or worse by any HPV type is about 62% (2). Although HPV vaccination could prevent cervical cancer, it does not replace screening. Vaccination reduces abnormal screening tests and subsequent therapy for precursors of cervical cancer.

Secondary prevention

Secondary prevention consists of elimination of Cervical Intraepithelial Neoplasia (CIN). CIN, the precursor le-sion of cervical cancer, is categorized into CIN1, -2, and -3. If left untreated, CIN2 or -3 (collectively referred to as CIN2+) can progress to cervical cancer in a period ranging from 10-15 years. Suitable screening methods for detecting CIN in LMIC are HPV testing and Visual Inspection with Acetic Acid (VIA). Most efficient is a single-visit screen-and-treat approach to prevent multiple visits to a health facility. Cytology-based screening programs are not suitable in LMIC since they require sophisticated infrastructure.

In HIV-positive women, rates of incidence of CIN2+ le-sions are higher (Hazard Ratio 2.55 (95% CI 1.69-3.86)), depending on their CD4+ count (3). The rate of persistence or recurrence of CIN2+ after treatment is also higher. Therefore, we recommend that cervical cancer screen-ing should be integrated in HIV treatment services (4).

  • HPV testing: sensitivity of a single High Risk HPV (hr-HPV) test exceeds 90-95%, allowing only a few screening visits in a lifetime. WHO advises intervals of 10 years, starting from the age of 30 years in LMIC (5). Specific-ity of HPV tests is lower than cytology based testing. Hr-HPV testing does not need skilled laboratory techni-cians(6). Women with a positive hr-HPV may be referred for VIA and cryotherapy or loop electrosurgical excision procedure (LEEP) in the same visit (one visit approach).
  • VIA: after the application of the acetic-acid (vinegar) to the cervix, acetowhite positive lesions will appear in case of cervical dysplasia. Although sensitivity nearly reaches sensitivity of cytology, specificity is usually lower (49-86%), which might lead to overtreatment. False positive acetowhite lesions are usually seen in case of infection (cervicitis) or chronic inflammation.

There are three primary treatments for CIN suit-able for LMIC: cryotherapy, LEEP, and cold knife con-ization (CKC), which will be explained below:

  • Cryotherapy: Cryotherapy is affordable in LMIC and in a meta-analysis of 28,827 cases it achieved cure rates of 85% (CIN3), 92% (CIN2) and 94% (CIN1)(5). The tip of the cryo should cover the entire lesion. Double freezing is recom-mended (3 minutes each, interrupted with a period of 5 minutes of thaw). A relatively novel means of treating pre-malignant cervical lesions is the thermo-coagulator which uses heating (100 -110 degree Celsius) instead of freezing. A meta-analysis shows same performances compared with cryotherapy with less side effects (7, 8). Lesions larger than 75% of the cervix need excisional therapy (LEEP or CKC)(9).
  • LEEP: The benefits of LEEP are greater compared to cryotherapy, and the downsides were fewer or similar. However, there are greater resource-related implications for LEEP than for cryotherapy, which is why LEEP is not available in all settings. LEEP is recommended in large lesions (>75% of the cervix) and for intra-cervical lesions(9).
  • CKC: Cold knife conization is defined as excision of a cone-shaped or cylindrical wedge from the cervix uteri that includes the transformation zone and all or a portion of the endocervical canal. It is utilized for the definitive diagnosis of intraepithelial lesions, for exclud-ing microinvasive carcinomas, and for conservative treatment of cervical intraepithelial neoplasia (CIN).

Treatment of cervical cancer in general

Each country or region has treatment and referral plans in place for women diagnosed with invasive cervical cancer to be referred to tertiary-level institutions. Diagnosis is often made clinically and confirmed with pathology.

Treatment of early stage cervical cancer

Early stage cervical cancer is defined as FIGO stages 1A1, 1A2 (micro-invasive carcinomas) and 1B1 (less than 4 cm). In most LMIC, staging is done clinically during pelvic examination. The size of the tumour is measured, the relation of the tumour with the vaginal vault, involvement of parametrial tissue and sacro-uterine ligaments as well as involvement of rectum. Chest x-ray and ultrasound are recommended to rule out pulmonary metastasis and hydronephrosis, respectively. CT-scan or MRI is advised in case of stage 1B2 or more. In Table 1, the treatment modalities available in most LMIC are depicted.

Palliative care

Cervical cancer is very distressing for the patient and her relatives, and women in LMIC in particular can have a very painful journey when they are diagnosed with the disease. They should not be left alone during this journey, and in many countries it is therefore possible to deliver home based care to these patients. Women with cervical cancer in advanced stages or women with recurrence of cervical cancer need palliative care to relieve symptoms. Symptoms and palliative care of cervical cancer patients are (10, 11):

  • Pain: medication for all women should be available according to the WHO Pain Relief guidelines: start with paracetamol and add NSAID, codeine, amitrip-tyline and opioids when necessary. Pain medication should be administered to suppress pain.
  • Vaginal discharge: can be treated with metronidazole orally or applying local solution.
  • Vaginal bleeding: if available palliative radiotherapy can decrease the bleeding
  • Nausea: anti-emetics
  • Constipation: laxatives
  • Rectovaginal fistula: colostomy if surgeon and colostomy bags are available
  • Psychological distress: counselling and support

Conclusion

Cervical cancer is common in LMIC. However, it can be prevented by vaccination and screening. In many LMIC, vac-cination of girls against HPV virus is or will soon be included in their national immunization programs. Screening pro-grams are based on HPV tests or Visual Inspection with acetic acid. For women who are diagnosed positive at screen-ing for precursors, affordable treatment is available to prevent cervical cancer. When cervical cancer is diagnosed in early stages, surgery is the treatment of choice. However, most patients will be diagnosed in advanced stages. Pal-liative care should be available for all women with advanced cervical cancer.

Healthcare providers in first and second level institutions have an important role in the prevention of cervical cancer, and need to refer patients in time in case of (suspicion of) cervical cancer. Health workers should also provide care and support to women who have been discharged home from the hospital for palliative care. Patients with advanced stage cervical cancer in LMIC need treat-ment in tertiary hospitals since treat-ment is often multimodal and complex.

Effective immunization and screen-ing and treatment programs may prevent suffering and pre-mature deaths in the future.

References

  1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality world-wide: sources, methods and major patterns in GLOBO-CAN 2012. Int J Cancer. 2015 Mar 01;136(5): E359-86.
  2. Harper DM, DeMars LR. HPV vaccines – A review of the first decade. Gynecologic Oncology.
  3. Whitham HK, Hawes SE, Chu H, Oakes JM, Lifson AR, Kiviat NB, et al. A Comparison of the Natural History of HPV Infection and Cervical Abnormalities among HIV-Positive and HIV-Neg-ative Women in Senegal, Africa. Cancer Epidemiol Biomarkers Prev. 2017 Jun;26(6):886-94.
  4. Denslow SA, Rositch AF, Firnhaber C, Ting J, Smith JS. Incidence and progression of cervical lesions in women with HIV: a systematic global review. Int J STD AIDS. 2014 Mar;25(3):163-77.
  5. Sauvaget C, Muwonge R, Sankaranarayanan R. Meta-analysis of the effectiveness of cryotherapy in the treatment of cervical intraepithelial neoplasia. Int J Gynaecol Obstet. 2013 Mar;120(3):218-23.
  6. Kuhn L, Denny L. The time is now to implement HPV testing for primary screening in low re-source settings. Prev Med. 2017 May;98:42-4.
  7. Dolman L, Sauvaget C, Muwonge R, Sankaranarayanan R. Meta-analysis of the efficacy of cold coagulation as a treatment method for cervical intraepithelial neoplasia: a systematic review. BJOG. 2014 Jul;121(8):929-42.
  8. Campbell C, Kafwafwa S, Brown H, Walker G, Madetsa B, Deeny M, et al. Use of thermo-coagulation as an alternative treatment modality in a ‘screen-and-treat’ programme of cervical screening in rural Malawi. Int J Cancer. 2016 Aug 15;139(4):908-15.
  9. Santesso N, Schunemann H, Blumenthal P, De Vuyst H, Gage J, Garcia F, et al. World Health Organization Guidelines: Use of cryotherapy for cervical intraepithelial neoplasia. Int J Gyn-aecol Obstet. 2012 Aug;118(2):97-102.
  10. Merriman A, Kiwanuka R. Palliative Care. A Textbook of Gynecology for Less-Resourced Locations [serial on the Internet]. 2012: Available from: http://www.glowm.com/resource_type/resource/textbook/title/a-textbook-of-gy-necology-for-less-resourced-locations/resource_doc/35.
  11. Engender Health, Path. Palliative Care for Women With Cervical Cancer: A FIELD MAN-UAL2003: Available from: http://screening.iarc.fr/doc/RH_palliative_care_guide.pdf.