Cervical cancer

Pathology

Squamous cell and adenosquamous carcinomas comprise approxi­mately 85% and adenocarcinoma approximately 15% of cervical cancers. Squamous carcinomas are large-cell keratinizing, large-cell non-keratinizing, and small-cell types.

Clinical management

Management of cervical cancer is to determine the stage of the dis­ease and to treat both the primary lesion and other extracervical disease. Cervical cancers spread by direct spread into the cervical stroma, parametrium, and beyond, and by lymphatic metastasis into parametrial, pelvic sidewall, and para-aortic nodes. Blood-borne spread is rare. Among the major factors that influence prognosis are (a) stage, (b) volume, (c) grade of tumour, (d) histological type, (e) lymphatic spread, and (f) vascular invasion. In a large study of patients with clinical disease confined to the cervix, the factors that predicted lymph node metastases and a decrease in disease-free survival were capillary-lymphatic space involvement by tumour, increasing tumour size, and increasing depth of stromal invasion (44, 45). A similar study of 626 patients with locally advanced dis­ease demonstrated that para-aortic and pelvic lymph node status, tumour size, clinical stage, patient age, and performance status were all significant prognostic factors for a reduction in progression-free interval and survival (46). The incidence of para-aortic and pelvic lymph node disease according to stage is illustrated in Table 62.4 (47-52).

Staging

Women should be fully staged using the International Federation of Gynecology and Obstetrics (FIGO) system (Box 62.2). FIGO staging is based largely on clinical assessment. Radiological staging, particu­larly by magnetic resonance imaging (MRI), allows more accurate determination of local disease spread (53), and also permits assess­ment of lymph node status. Routine use of imaging enhances the se­lection of women in whom surgery alone is likely to be curative. MRI has become so accurate at staging disease that formal examination under anaesthetic is no longer required in settings where imaging is routinely practised. In a limited number of pilot studies, positron emission tomography (PET) has demonstrated enhanced accuracy at diagnosing involved lymph nodes, but more robust studies are re­quired. If performed prior to pelvic exenteration a whole-body PET or PET/computed tomography (CT) scan may improve selection of patients and therefore improve survival and reduce morbidity.

Table 62.4 Rate of lymph node involvement according to stage of cervical cancer

Source data from references 47-52.

If performed prior to radiotherapy, a whole-body PET or PET/CT scan may change planned radiotherapy fields.

Treatment

Women with cervical cancer should be discussed in expert multidis­ciplinary forums with specialist surgeons, oncologists, pathologists, radiologists, and specialist nurses. This permits the best possible en­vironment for optimum decision-making. Both surgery and radio­therapy are effective in early-stage disease, whereas locally advanced disease relies on treatment by radiation or chemoradiation. Surgery does provide the advantage of conservation of ovarian function.

Factors that influence the mode of treatment include stage, age, and health status. Radiation can be used for all stages, whereas sur­gery should only be considered an option for early-disease, stage I and stage IIA. A large randomized trial reported identical 5-year overall and disease-free survival rates when comparing radiation therapy with radical hysterectomy, but women who had surgery and adjuvant radiotherapy suffered significantly higher morbidity than those who had either surgery or radiotherapy alone.

There are clear advantages to surgery in women at low operative risk. Surgery permits conservation of ovarian function in premeno­pausal women and also reduces the risk of chronic bladder, bowel, and sexual dysfunction associated with radiotherapy. Complications in the hands of skilled surgeons are uncommon. Surgery also per­mits the assessment of risk factors, such as lymph node status, that will ultimately influence prognosis. Complications of surgery in­clude fistulas (1%), lymphocyst, primary haemorrhage, and bladder injury. Chronic bowel and bladder problems that require medical or surgical intervention occur in up to 8-13% of women (54) due to parasympathetic denervation secondary to surgical clamping at the lateral excision margins. Surgery is commonly done by laparoscopy in modern practice, either by traditional techniques or robotically.

Stage IA disease

Microinvasive disease is one in which neoplastic cells invade from the epithelium to a maximum depth of 5 mm and a maximum hori­zontal spread of 7 mm.

Box 62.2 FIGO staging of carcinoma of the cervix uteri (2019)

Stage I

The carcinoma is strictly confined to the cervix uteri (extension to the corpus should be disregarded)

• IA: invasive carcinoma that can be diagnosed only by microscopy, with maximum depth of invasion <5 mm:^a

- IA1: measured stromal invasion <3 mm in depth.

- IA2: measured stromal invasion ≥3 mm and <5 mm in depth.

• IB: invasive carcinoma with measured deepest invasion ≥5 mm (greater than stage IA), lesion limited to the cervix uteri:^b

- IB1: invasive carcinoma ≥5 mm depth of stromal invasion and <2 cm in greatest dimension.

- IB2: invasive carcinoma ≥2 cm and <4 cm in greatest dimension.

- IB3: invasive carcinoma ≥4 cm in greatest dimension.

Stage II

The carcinoma invades beyond the uterus, but has not extended onto the lower third of the vagina or to the pelvic wall

• IIA: involvement limited to the upper two-thirds of the vagina without parametrial involvement:

- IIA1: invasive carcinoma <4 cm in greatest dimension.

- IIA2: invasive carcinoma ≥4 cm in greatest dimension

• IIB: with parametrial involvement but not up to the pelvic wall.

Stage III

The carcinoma involves the lower third of the vagina and/or extends to the pelvic wall and/or causes hydronephrosis or non-functioning kidney and/or involves pelvic and/or para-aortic lymph nodes.^c

• IIIA: carcinoma involves the lower third of the vagina, with no exten­sion to the pelvic wall.

• IIIB: extension to the pelvic wall and/or hydronephrosis or non­functioning kidney (unless known to be due to another cause).

• IIIC: involvement of pelvic and/or para-aortic lymph nodes, irre­spective of tumour size and extent (with r and p notations):¹²

- IIIC1: pelvic lymph node metastasis only.

- IIIC2: para-aortic lymph node metastasis.

Stage IV

The carcinoma has extended beyond the true pelvis or has involved (bi­opsy proven) the mucosa of the bladder or rectum. A bullous oedema, as such, does not permit a case to be allotted to stage IV.

• IVA: spread of the growth to adjacent organs.

• IVB: spread to distant organs.

^a Imaging and pathology can be used, when available, to supplement clinical findings with respect to tumour size and extent, in all stages.

^b The involvement of vascular/lymphatic spaces does not change the staging. The lateral extent of the lesion is no longer considered.

^c Adding notation of r (imaging) and p (pathology) to indicate the findings that are used to allocate the case to stage IIIC. For example, if imaging indicates pelvic lymph node metastasis, the stage allocation would be stage IIIC1r and, if confirmed by pathological findings, it would be stage IIIc1p. The type of imaging modality or path­ology technique used should always be documented. When in doubt, the lower sta­ging should be assigned.

Source data from Bhatla N, Berek JS, Cuello Fredes M, et al. Revised FIGO staging for carcinoma of the cervix uteri. IntJ Gynaecol Obstet 2019;145:129-35.

Microinvasive disease comprises 20% of invasive cancers. Stage IA1 disease (invasion <3 mm) is rarely associated with lymph node metastases (Table 62.4). This disease should be formally diagnosed by cone biopsy or diathermy excision. Knife cone biopsy does not cause any thermal damage, and the extent of disease may be more accurately assessed than on a loop excision specimen. If the disease and any associated intraepithelial neoplasia are removed with clear margins, no further treatment is necessary. If disease is present at the margins, further excision or hysterectomy is required.

Stage IB disease

Stage IB is divided into IB1 (≤4 cm diameter) and IB2 (≥4 cm diameter); stage IIA means upper vaginal, but not parametrial involvement.

Surgical therapy for stage IB and IIA tumours 4 cm or less in diameter usually involves radical hysterectomy and pelvic lymphadenectomy. Radical hysterectomy involves removing the tu­mour with adequate disease-free margins, by means of excising the parametrial tissue around the cervix and upper vagina, with removal of part or all of the cardinal and uterosacral ligaments, depending on the extent of the dissection. More radical dissections are associ­ated with a higher incidence of perioperative morbidity and chronic bladder and bowel dysfunction with no survival advantage (55). Radical hysterectomy can be achieved laparoscopically, reducing the length of in-patient stay, blood loss, and perioperative morbidity and improving patient-reported outcomes.

The lymph node dissection should include obturator, internal, ex­ternal, and common iliac nodes. The presence of suspicious lymph nodes on preoperative MRI in early-stage disease should dictate chemoradiation as a sole treatment modality. If there is any doubt of the nature of enlarged nodes, laparoscopic biopsy or PET imaging should be considered before the treatment plan is finally decided.

Lymphadenectomy may result in lymphocyst formation. Lymphoedema following pelvic lymphadenectomy can occur, and its incidence increases if adjuvant radiotherapy is given.

In cases in which positive nodes are encountered, there are differing views. Some would advocate abandoning surgery in favour of radical chemoradiation. Others would argue that, if possible, rad­ical surgery should be completed to achieve an adjuvant setting for radiotherapy. If suspicious nodes are identified and confirmed to be diseased at frozen section, it is probably best to remove resect­able nodes and treat with chemoradiation, including brachytherapy, which requires the uterus to be in situ. Radical surgery followed by radical radiotherapy is associated with increased morbidity.

Adjuvant radiotherapy is normally recommended for women with resected positive pelvic nodes to reduce the risk of recurrence. Patients with ‘close’ vaginal margins (≤0.5 cm) may also benefit from pelvic irradiation (56).

Indirect evidence from non-randomized studies suggests that radiotherapy can improve pelvic control, but there is no firm evi­dence of increased survival (55, 57). Careful preoperative radio­logical imaging reduces the risk of encountering unexpected lymphadenopathy or unexpectedly large tumours, with parametrial invasion.

Because bulky IB2 tumours have a higher risk of positive nodes and close surgical margins, these are now regarded by many as being better treated with chemoradiation as opposed to surgery or radiotherapy alone. Some women with small-volume stage IB disease who wish to conserve their fertility might be suitable for trachelectomy (radical excision of the cervix) combined with ei­ther laparoscopic or open lymphadenectomy. The most common approach is a vaginal trachelectomy; however, more recently some surgeons are favouring an abdominal approach facilitating greater excision of the parametrium with this technique. Meta-analyses and large United Kingdom case series based on the vaginal approach have demonstrated recurrence rates of around 4%, and a 70% term delivery rate (58, 59). Some surgeons recommend the insertion of an abdominal isthmic cervical cerclage to reduce the risk of late mis­carriage. Indeed, in selected cases of IB1 disease that are just greater than 7 mm in horizontal spread, a large excisional biopsy may be ad­equate for central control, even though it may need to be combined with lymphadenectomy.

Stage IIB and above

It is not feasible to perform surgery with curative intent in these ad­vanced stages of disease. Radical radiotherapy and chemoradiation are the only modalities of treatment that offer the potential for cure. One randomized trial has suggested that preoperative chemotherapy to shrink disease followed by radical surgery may be superior to rad­ical radiotherapy, but this has not been confirmed (60). It is inevit­able that preoperative chemotherapy followed by surgery will still require some women to undergo adjuvant or non-adjuvant radio­therapy that is more likely to result in unacceptable toxicity.

Radical radiotherapy

Radical radiotherapy is indicated for women unfit for surgery, or with bulky stage IB2 disease and more advanced disease. The goals of such treatment are to treat primary disease and to control meta­static pelvic lymph nodes. The radical dose is delivered by external beam and intracavitary treatment (brachytherapy). The standard technique now is of remote after-loading (e.g. using the Selectron). Intracavitary treatment is designed to give high doses locally to the primary site. External beam radiotherapy is designed to treat any pelvic spread. The challenge in administering radiotherapy is in achieving an optimal dose throughout the primary tumour and pelvic sidewall without causing high morbidity. The peripheral field of treatment of intracavitary radiotherapy delivers an insufficient dose to treat the pelvic sidewalls. The dose-limiting normal tissues within the pelvis are the rectum posteriorly, the bladder anteriorly, and any loops of small bowel within the pelvic radiation fields.

Prescribing rules have been devised for determining the pre­cise dose of radiotherapy within the pelvis, and improved plan­ning by CT has enabled more accurate targeting of external beam radiation in particular. An example is the Manchester system. This uses a number of predetermined source sizes and radioactive load­ings such that a constant dose rate is delivered to a point A. Point A is defined as a point 2 cm lateral to the central axis of the uterus and 2 cm from the lateral fornix. A second point (B) lying in the same plane 3 cm lateral to point A is used to determine the dose to parametrial tissues. Following the insertion of the sources for each patient, a dose distribution is calculated. The total dose is a product of the dose rate and treatment time. The usual doses delivered are 70-80 Gy to point A and 60 Gy to point B, limiting the bladder and rectal dose to 60 Gy. To achieve this, it is necessary to have adequate packing to keep the bladder and bowel away from the intracavitary source. External beam radiation is usually given 2-3 weeks after intracavitary treatment to allow for involution of the primary dis­ease. External beam radiotherapy is fractionated over 20-30 days' treatment, as this technique allows a cancericidal effect while ena­bling normal tissue recovery between fractions.

Routine extended field radiotherapy designed to include para­aortic nodes has not been proven to improve survival compared with pelvic radiotherapy alone, and it is associated with significantly more gastrointestinal complications (61). While there does not ap­pear to be significant benefit from extended field irradiation for all cases, para-aortic node irradiation is appropriate in cases of proven para-aortic node involvement as indicated by diagnostic imaging or surgical staging.

Chemoradiation

Five randomized trials from the United States (62-66) have shown an overall survival advantage for cisplatin-based therapy given con­currently with radiation therapy. The patient populations in these studies included women with FIGO stages IB2-IVA cervical cancer treated with primary radiation therapy and women with FIGO stages I-IIA disease found to have poor prognostic factors (metastatic dis­ease in pelvic lymph nodes, parametrial disease, or positive surgical margins) at the time of primary surgery. Although the trials vary somewhat in terms of stage of disease, dose of radiation, and schedule of cisplatin and radiation, they all demonstrate significant survival benefit for this combined approach, the risk of death from cervical cancer being decreased by 30%. These trials reported higher rates of short- and medium-term complications with chemoradiation, and although longer follow-up is required to examine the true morbidity of this treatment regimen, there is now international acceptance that chemoradiation is superior to radiation alone.

Recurrent cancer

Treatment for recurrent cervical cancer depends on the mode of primary therapy and the site of recurrence. Women who have had initial treatment by surgery should be considered for radiotherapy, and those who have had radiotherapy should be considered for exenterative surgery, provided the recurrence is central and there is no evidence of distant recurrence. These women require very careful preoperative assessment and counselling in order to under­stand the consequences of defunctioning surgery. Exenterative sur­gery in carefully selected cases can result in 5-year survival rates of 50%. Positive nodes at the time of attempted salvage surgery and positive resection margins are associated with a poor prognosis. Anterior exenteration requires excision of the bladder and most of the vagina en bloc with the recurrence, and posterior exenteration requires excision of the sigmoid rectum with formation of a colos­tomy. Sometimes a combination of the two is required. This type of surgery should only be undertaken by teams of highly skilled pelvic surgeons. Relapse within 2 years of primary treatment, the presence of hydronephrosis, and symptoms of pain are all associated with poorer outcomes in terms of exenterative surgery.

Palliation of progressive cervical cancer

Chemotherapy is palliative and should be reserved for patients who are not considered curable by the other two treatment modalities. Urinary tract symptoms are particularly common in advanced cervical disease. Ureteric obstruction with subsequent pain, infec­tion, and ultimately impaired renal function are common features.

In progressive late-s tage disease, there is usually ureteric ob­struction, which heralds a terminal phase. Pain can be particularly distressing due to infiltration of the lumbosacral nerve plexuses. Meticulous attention to pain control and psychological and emo­tional support are essential.