This article presents an overview of current detection and treatment options, written by a certified gynaecological oncologist practising in Queensland.

Australia has the lowest mortality (1.7 per 100 000 women) and second-lowest incidence (6.9 per 100 000 women) of cervical cancer in the developed world; largely because of its National Cervical Screening Program, which costs $138m annually. This involves two million women per year undergoing screening, of whom 100 000 will have an abnormal Papanicolaou (Pap) smear report. Of this group with Pap smear abnormalities, around 30 per cent will have a histological abnormality, half of which are high grade. In the last decade, both incidence and mortality for cervical cancer have declined by over 50 per cent. Compared to the incidence of squamous cell carcinoma, the incidence of adenocarcinoma of the cervix has remained unchanged, mostly due to its relative inaccessibility to detection techniques.

The two age groups that account for the majority of cervical cancers are women 30–39 years old, and women 60–69 years old. There are some differences geographically within Australia in incidence and mortality, but these differences are narrowing. However, Indigenous women are still six-times more likely to die from cervical cancer than non-Indigenous women. The introduction, in 2006, of a vaccine against the human papilloma virus (HPV) may represent our best chance of changing this statistic.

HPV

Over 99.7 per cent of cervical cancers have detectable HPV DNA, and this sexually acquired infection, if persistent, appears to be a necessary step in developing cervical cancer. This progression is slow and the overwhelming majority of women clear the infection spontaneously in eight to 14 months. Almost 25 per cent of young, sexually active women at any given time will have active HPV infection. Lifetime risk of exposure to genital strains of HPV is up to 85 per cent.

There are over 150 types of HPV, some of which cause warts on the skin of the vulva, vagina, cervix, inside the urethra, on the penis and anal region. Of these HPV strains, 15 cause cervical cancer. The HPV types that cause common skin warts and visible genital warts do not cause cervical cancer.

Vaccination

High-risk strains, including HPV 16 and 18, are involved in 60–80 per cent of cancers, and these are the strains targeted in recently released vaccines. It is important to remember that vaccination against HPV does not replace regular Pap smears, which are still necessary, though ultimately there should be a reduction in the number of abnormal smears reported. HPV vaccines are now available to females aged nine to 26 years old and males aged nine to 15 years old. These vaccines prevent 70 per cent of HPV strains that cause cervical cancer and 90 per cent of those that cause anogenital warts. Women up to the age of 45 can also be vaccinated as they have up to a 14 per cent incident infection with HPV.

Detection

The detection of HPV is facilitated by recent advances in molecular biology, although none of these detection methods is in general use currently for diagnosis in an individual patient. HPV detection is used commonly as a ‘test of cure’ in patients treated for high-grade lesions, in other words cervical intraepithelial neoplasia (CIN) 2 to 3. This is currently recommended to be tested at 12 months post-treatment and again annually, along with cytology, until both are negative on two consecutive occasions, at which time the patient can return to a normal two-year screening interval.

Screening

Cervical cytology screening programs can detect pre-invasive, as well as invasive, cellular changes of the cervix. Cervical cancer typically has a long pre-invasive state (often a decade or more) and the treatment for pre-invasive disease is effective; therefore, screening programs can potentially prevent the occurrence of invasive cervical cancer.

Pap smear test

The Pap smear is the current standard screening test for lower genital tract neoplasia. Sensitivity ranges from 55 to 80 per cent for high-grade lesions and specificity is generally over 90 per cent. Up to 50 per cent of Pap smears taken in a setting of invasive carcinoma will be negative. Therefore, a clinically abnormal macroscopic cervical appearance, abnormal bimanual examination and feel of the cervix and/or symptoms of persistent abnormal bleeding or discharge should mean referral to a gynaecologist regardless of smear result.

Liquid-based cytology

Newer liquid-based cytologies, such as the ThinPrep Pap Test, will increase the yield of adequate Pap smear readings and may reduce the false negative rate in patients with chronic cervicitis, blood or inflammation, which may obscure a reading, repetitive possible low-grade Pap smear reports and HIV infection. These liquid-based technologies also enable HPV testing to be done on the same sample. New technologies and combinations of HPV testing and cytology do not have significant additional benefits on life expectancy compared to conventional cytology when used as an annual screening tool, but are more costly. However, they may be cost effective when incorporated into less frequent screening programs (for example, every three years). This may become an option for vaccinated patients in the future. Liquid-based cytology appears to detect glandular lesions better than conventional Pap smears, which have not been effective for lowering the incidence of, or death rate owing to, endocervical adenocarcinoma in screened versus unscreened populations, and may be useful in this group.

Screening guidelines

Current screening guidelines in Australia are that all women who have ever been sexually active should commence having Pap smears between the ages of 18 and 20 years and then continue doing so until age 70. Regrettably, around 35 per cent of eligible women fail to comply with these recommendations and over 90 per cent of invasive cancers come from this group.

Pre-invasive disease

As for all screening tests, results of the Pap smear cannot be used to make a definitive diagnosis or initiate treatment. The function of the Pap smear is solely to screen for cellular abnormalities that are associated with an increased risk for the development of cervical cancer. Thus, it selects those women who should have further evaluation, such as colposcopy and/or biopsy. Treatment decisions are then made based on diagnostic results from histological examination, usually from colposcopically directed biopsies.

Low-grade cytological abnormalities

Low-grade cytological abnormalities are now accepted as representing acute HPV infection. Up to 80 per cent of low-grade lesions regress by 12 months, and less then four per cent progress to high-grade lesions in the same time period. The National Health and Medical Research Council (NHMRC) guidelines – Screening to prevent cervical cancer: guidelines for the management of asymptomatic women with screen-detected abnormalities (2006) reflect this finding. The NHMRC recommends initial conservative follow up of low-grade squamous intraepithelial lesions on Pap smear with a repeat smear in 12 months, unless the patient is over 30 years old with no preceding negative smear history. If the patient is over 30 years old with no preceding negative Pap smear history, or the repeat Pap smear is again low grade, referral for colposcopy is required. If a low-grade lesion (CIN1 or less) is confirmed on colposcopy, conservative follow up is now the norm and should result in a around 30 per cent fewer excisional procedures (wire loop excision) taking place in the younger age group, which has obvious benefits for future fertility needs.

High-grade pre-invasive changes

High-grade pre-invasive changes (CIN2 to 3) are treated via diathermy (wire loop excision), laser or cryotherapy. Single treatment is usually extremely effective. A cone biopsy involves a larger excision of cervical tissue and is generally reserved for adenocarcinoma in situ (the glandular ‘equivalent’ of CIN3), disease going up the cervical canal that cannot be fully visualised at colposcopy, or if invasive disease is suspected.

Follow up

Treatment of pre-invasive disease is highly effective, and follow up is important to ensure no recurrence of disease. Follow up usually takes the form of a repeat colposcopy and Pap smear at six months, then repeat Pap smear and HPV testing at 12 months. Providing this is normal, it is repeated annually until both HPV and cytology are normal. When this occurs for two consecutive years, cytology can then be reduced to every two years, as for the general population. Patients treated for adenocarcinoma in situ, despite clear margins on cone biopsy, are at ongoing risk for developing further pre-invasive or invasive disease long term, and are therefore advised to have a completion hysterectomy (with ovarian conservation) once childbearing is completed.

Cervical cancer

Risk factors

Risk factors for cervical cancer include: smoking, early coitus, multiple partners, multiple pregnancies, poor general health, poor nutrition and a genetic predisposition to cervical cancer. Lifestyle factors predisposing women to cervical cancer include prolonged stress, eating disorders, poor diet, excessive exercise and inadequate rest. Illnesses that increase a woman’s risk include diabetes and immune disorders. Immunosuppressent agents also increase a woman’s risk.

Presenting symptoms

The most common presenting symptom is abnormal vaginal bleeding or bloodstained discharge, which may smell offensive in the presence of secondary infection. Symptoms may be precipitated by contact, for instance coitus. All persistent postcoital bleeding should be investigated. Pain (particularly sciatic type pain), pressure symptoms and sometimes vaginal passage of urine or faeces are usually signs consistent with advanced disease.

Pre-treatment work up

Staging

Cervical cancer is staged clinically, apart from intravenous pyelogram (IVP) and X-ray examination of the lung and skeletal systems. This is because, worldwide, most patients are treated in areas that do not have access to high-level imaging techniques and most are treated with radiation only. Therefore, computerised tomography (CT) and magnetic resonance imaging (MRI) of the abdomen and pelvis cannot alter the clinical stage assigned at the time of initial evaluation, but are very useful in determining the extent of the disease and, therefore, treatment planning. The initial evaluation to determine stage and treatment plan usually consists of an examination under anaesthetic, cystoscopy, proctoscopy, cervical biopsy or cone biopsy, and curettage with both a gynaecological oncologist and radiation oncologist present.

Imaging

MRI scans are becoming the preferred imaging technique to define the extent of a tumour, because of their high resolution of pelvic anatomy. They are also useful in pregnancy, as MRI poses no risk to the fetus. Positron emission tomography (PET) scans, which use a radionuclide-labelled sugar to detect sites of malignancy (which are avid users of glucose), are increasingly used in helping to define the extent of disease and therefore the most appropriate therapy, particularly in more advanced disease. Ultimately, if other distant sites of potential tumour are discovered on imaging, fine needle aspiration cytology is then required to confirm this, in order to make any therapeutic decisions.

Treatment

Surgery and chemoradiation are the mainstays of treatment for cervical carcinoma. Stage for stage, the success rates for the two treatment modalities are identical and the type of treatment is usually selected by stage, extent of disease, patient preferences and co-morbidities (for example, if a pelvic kidney is present, surgery is preferable, if possible). Surgical treatment (if suitable) is generally preferable for premenopausal women, as it enables preservation of ovarian function and also probably has less sexual dysfunction associated with it.

The extent of surgery varies depending on the stage and fertility wishes as described below.

Early stage disease

• Stage IA1: lesion is <3mm invasion and <7mm wide. Perform cone biopsy only if no extensive lymph vascular space invasion (LVSI) is present, endocervical curette is negative and future fertility is desired. If fertility is not required, perform a simple hysterectomy. No lymph node dissection is required.
• Stage IA2: lesion is between 3mm and 5mm invasion and <7mm wide. Perform radical hysterectomy (see below) and pelvic lymphadenectomy if fertility is not required. If fertility is desired, perform a radical trachelectomy and pelvic lymphadenectomy (see below).
• Stage IB1: tumour is >7mm wide or 5mm deep, or macroscopically evident with a diameter of up to 4cm. Perform a radical hysterectomy (or radical trachelectomy up to 2cm in those desiring fertility) with pelvic lymphadenectomy or chemoradiation.
• Stage IB2: tumour is >4cm diameter. The optimal management of women with primary tumours measuring 4cm or more in diameter is controversial. Proposed treatment strategies include: primary chemoradiation with the option of subsequent completion hysterectomy (currently the most used option); neoadjuvant chemotherapy, followed by radical hysterectomy and pelvic radiation, pending pathology findings; primary radical hysterectomy and lymphadenectomy followed by tailored chemoradiation.
• Stage IIA: tumour extends onto upper vagina. If cervical tumour is small, in other words <4cm, consider surgical option as above or chemoradiation.

Locally advanced disease

• Stage IIB: tumour extends into parametrial tissues, but not to sidewall (tissue lateral to cervix).
• Stage IIIA: tumour has spread to lower one-third of vagina, but nowhere else.
• Stage IIIB: tumour has spread to the pelvic side wall, or has blocked a ureter.
• Stage IVA: tumour has spread to the rectum or bladder. These patients may require surgical diversion of the bladder or bowel before definitive chemoradiation.
• Stage IVB: tumour has spread to distant organs, for instance lungs.

Women with locally advanced cervical squamous cell cancer are best treated with primary chemoradiation, as surgery alone will not provide adequate clearance and will still require adjuvant radiation. It is desirable to minimise side effects to avoid dual radical treatments if possible (in other words, surgery plus chemoradiation). Patients are still potentially curable up to stage IVA (up to 15 per cent five-year survival).

Definitions

• Radical hysterectomy: compared to a simple hysterectomy to achieve adequate clearance from the tumour, a vaginal and paracervical cuff of tissue is excised in continuity with the cervix. Much of the morbidity of this procedure comes from the additional dissection required to attain lateral clearance (bladder and bowel dysfunction) but this is usually temporary. In addition to a laparotomy, this procedure can also be completed entirely laparoscopically (with or without a robot) and an international randomised trial we are participating in is currently evaluating this against the conventional laparotomy route.
• Radical trachelectomy: in patients with no lymph vascular invasion (LVSI) and tumours <2cm who want ongoing fertility, this procedure involves radical excision of the cervix with a vaginal and paracervical cuff, with reanastamosis of the vagina to the isthmus of the uterus with or without cerclage. This procedure enables the patient to undergo future childbearing, can be performed vaginally, laparoscopically or abdominally, and is combined with a pelvic lymphadenectomy.
• Chemoradiation: definitive radiation with concomitant chemotherapy (weekly cisplatin 40mg/m2). Chemoradiation compared to radiation alone for the treatment of cervical cancer has been shown to provide a 30–50 per cent reduction in the risk of death, and is now the preferred option for the treatment of cervical cancer.

Follow up

Following therapy, patients should be monitored every three months for two years, every six months until five years, and then annually. The majority of recurrences occur in the first two years after treatment.

Recurrent disease

The incidence of failure is closely related to stage. The prognosis with recurrent disease largely depends on the site of recurrence and how well localised it is. Central recurrences without evidence of distal disease may be amenable to an anterior or posterior exenterative surgical procedure, or may necessitate a total exenterative surgical procedure, depending on distribution of recurrence. The anterior procedure involves removal of the bladder with ileal conduit formation, vagina with or without reconstruction, and possibly the uterus and cervix if still present and affected by tumour recurrence. The posterior procedure involves removal of bowel and tumour, and construction of a colostomy. If it is feasible to proceed with these ‘rescue’ procedures, there is approximately a 40–50 per cent five-year survival rate, but adequate preoperative counselling is essential for the enormous psychosexual challenge facing the patient. Definitive chemoradiation may also be used for recurrent disease when the patient has initially undergone surgical treatment alone.