Management of early-stage cervical cancer

INTRODUCTION — Patients with cervical cancer limited to the cervix and uterus have early-stage disease. Primary treatment options for these patients include hysterectomy (ie, extrafascial, modified radical, radical), fertility-sparing surgery (ie, conization, trachelectomy), or radiation therapy with or without chemotherapy. The choice of therapy depends on tumor and patient factors, as well as available health system resources.

The approach to patients with early-stage cervical cancers is reviewed here. Diagnosis of cervical cancer, treatment of more advanced disease, and specific issues regarding the management of cervical adenocarcinomas and small cell cancers are reviewed elsewhere.

●(See "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis".)

●(See "Management of locally advanced cervical cancer".)

●(See "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis".)

●(See "Invasive cervical cancer: Staging and evaluation of lymph nodes".)

●(See "Small cell neuroendocrine carcinoma of the cervix".)

●(See "Invasive cervical adenocarcinoma".)

DEFINITION OF EARLY-STAGE CERVICAL CANCER — Staging of cervical cancer has changed significantly over time [1-3]; this topic will utilize the 2018 Federation of Gynecology and Obstetrics (FIGO) staging system (table 1) except when describing studies where other staging systems were used. The American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging system is shown in the table (table 2) [3].

The diagnosis of cervical cancer is made by histologic evaluation of a cervical biopsy. In resource-limited settings, staging is clinical and based on physical examination, a limited number of endoscopic diagnostic procedures (examination under anesthesia, proctoscopy, cystoscopy, hysteroscopy), and basic imaging studies (chest radiograph and intravenous pyelogram). In resource-abundant settings, staging may additionally be based on an expanded list of imaging studies (computed tomography, magnetic resonance imaging, and positron emission tomography) and pathologic findings. This is discussed in detail separately. (See "Invasive cervical cancer: Staging and evaluation of lymph nodes", section on 'Staging system'.)

Early-stage cervical cancer refers to FIGO stage IA, IB1, and IB2 disease (table 1).

●Stage IA – Invasive carcinoma that can be diagnosed only by microscopy, with maximum depth of invasion <5 mm. Stage IA is subdivided into the following categories:

•IA1 – Measured stromal invasion ≤3 mm in depth

•IA2 – Measured stromal invasion >3 mm and ≤5 mm in depth

●Stage IB1 – Invasive carcinoma with >5 mm depth of stromal invasion, and ≤2 cm in greatest dimension

●Stage IB2 – Invasive carcinoma >2 cm and ≤4 cm in greatest dimension

PRIMARY THERAPY

Surgery preferred over radiation — We suggest surgical management rather than primary radiation therapy (RT) for most patients with early-stage cervical cancer (see 'Rationale' below). The type of surgery (ie, cervical conization or extrafascial, modified radical, or radical hysterectomy) depends on the stage of disease. The Piver-Rutledge-Smith classification of hysterectomy is shown in the table (table 3); other classification systems have been published (eg, Querleu and Morrow (table 4)) [4,5]. (See "Radical hysterectomy", section on 'Types of radical hysterectomy' and 'Type of surgery' below.)

Rationale — For most patients with stage IA, IB1, and IB2 cervical cancer, we suggest surgery rather than primary RT; we reserve primary RT (with or without chemotherapy) for patients who are not candidates for primary surgery due to medical comorbidities, poor functional status, or limited health resources. This is based on the likely higher long-term morbidity with primary RT compared with surgery, including:

●Decreased quality of life – Quality of life (QOL) may be worse among patients who are treated with RT (with or without chemotherapy), but data are conflicting [6-8]. In a study of 98 patients treated for early-stage cervical cancer by surgery (42 percent) or primary chemoradiation (58 percent), chemoradiation resulted in a higher incidence of bowel dysfunction compared with primary surgery (42 versus 7 percent) during the 5 to 15 years after diagnosis [7]. There were also nonsignificant trends toward higher incidence of urinary incontinence (20 versus 9 percent), sexual dysfunction (35 versus 20 percent), and pelvic pain (30 versus 12 percent, respectively) with chemoradiation. By contrast, in an observational questionnaire survey study including 100 patients with early-stage cervical cancer, more patients treated with surgery (with or without RT) compared with RT alone experienced lower extremity edema (35 versus 6 percent; odds ratio [OR] 8.3, 95% CI 2.3-30.8) or difficulty emptying their bladder (44 versus 8.5 percent; OR 8.4, 95% CI 2.6-27.1 ); one limitation of this study is that the majority (58 percent) of patients undergoing surgery also received RT. QOL issues in cervical cancer survivors are discussed in more detail below. (See 'Decreased reported quality of life' below and 'Sexual dysfunction' below.)

●Ovarian failure – Ovarian failure is common after pelvic RT; this is an important consideration given that over 40 percent of patients diagnosed with cervical cancer are under the age of 45. Pelvic RT (with or without concomitant chemotherapy) uniformly results in ovarian failure due to the doses required for curative-intent therapy; if ovarian preservation is felt to be important (eg, avoiding premature menopause, allowing future fertility options), transposition of the ovaries out of the radiation field should be considered. (See "Ovarian transposition before pelvic radiation".)

By contrast, the ovaries are generally left intact at the time of surgery; however, patients may still be at risk for premature ovarian failure possibly due to impairment of ovarian perfusion. (See 'Type of surgery' below and "Hysterectomy (benign indications): Patient-important issues and surgical complications", section on 'Decreased ovarian function or earlier menopause'.)

In addition, limited data suggest that surgery is at least as effective as RT:

●The only randomized trial was conducted in 1997 in 343 patients with stage IB and IIA cervical cancer and found that radical surgery compared with RT had equivalent rates of five-year survival (83 percent for both) and disease-free survival (DFS; 74 percent for both), and comparable recurrence rates (surgery: 25 percent; RT: 26 percent) [9]. Although severe morbidity was higher in the surgery group, it is not clear that these findings apply to current practice, given that contemporary surgical practices and more modern RT techniques likely result in fewer complications compared with procedures performed over twenty years ago.

●The largest observational study to address this issue was a retrospective study of 4885 patients with stage IB1 to IIA cervical cancer with data from the United States Surveillance, Epidemiology, and End Results registry. Surgery was associated with a survival benefit compared with RT alone (hazard ratio [HR] 0.41, 95% CI 0.35-0.50) [10]. A limitation of this study was that one-half of the patients in the hysterectomy group received adjuvant RT and comparisons were not made between patients treated solely with surgery versus RT.

Type of surgery — Conization is often performed as part of the diagnostic evaluation and staging procedure for early-stage cervical cancer and used as treatment for patients who wish to preserve fertility. (See "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis", section on 'Diagnosis' and 'Patients who wish to preserve fertility' below.)

●Stage IA1

•For patients with stage IA1 cervical cancer and no evidence of lymphovascular space invasion (LVSI) on the conization specimen, management depends on margin status (algorithm 1).

-For patients in whom margins are negative, no further treatment is necessary; however, simple hysterectomy may be an acceptable alternative.

-For patients in whom conization margins are positive, we suggest repeat cone biopsy or extrafascial (ie, simple) hysterectomy rather than modified radical hysterectomy [11].

Repeat conization is performed in patients who wish to preserve fertility (see 'Patients who wish to preserve fertility' below). By contrast, for patients who desire definitive treatment and have completed childbearing, we perform extrafascial hysterectomy, which involves removal of the uterus and cervix, but not the parametria or more than the upper margin of the vagina (table 3). Vaginal hysterectomy is the preferred approach, but laparoscopic, robotic-assisted laparoscopic, or abdominal approaches may be performed. (See "Hysterectomy (benign indications): Selection of surgical route".)

Given that patients who are candidates for these procedures are at low risk for lymph node involvement, pelvic lymphadenectomy is not typically indicated, but may be performed in some cases.

•Patients with stage IA1 disease and evidence of LVSI on conization are treated similarly to patients with stage IA2 disease (algorithm 1), and is described in detail below.

Patients with stage IA1 disease have an extremely low risk of recurrence. In a literature review including patients with squamous cervical cancer, among patients with stromal invasion <1 mm and 1 to 3 mm, lymph node metastases were present in 0.1 percent (3 of 2274) and 0.4 percent (5 of 1324) of patients, respectively [12,13]. The rate of recurrence was also low (0.4 and 1.7 percent, respectively). An important limitation of this study was that it reported only depth of invasion, but not horizontal spread, so stage could not be confirmed.

●Stage IA2 – The standard treatment for stage IA2 cervical cancers is a modified radical hysterectomy (class II hysterectomy) [4,14], but extrafascial (ie, simple) hysterectomy may be an acceptable alternative for some patients (algorithm 1).

Modified radical hysterectomy includes removal of the uterus, cervix, upper one-fourth of the vagina, and parametria. Pelvic lymphadenectomy is performed at the time of modified radical hysterectomy; para-aortic lymphadenectomy is performed if the pelvic nodes are suspicious for metastatic disease. Although data are limited, some centers have replaced lymphadenectomy with sentinel lymph node evaluation. This is discussed in more detail separately. (See "Invasive cervical cancer: Staging and evaluation of lymph nodes", section on 'Surgical evaluation of lymph nodes'.)

Ovarian metastases are less common with squamous cell histology than adenocarcinoma (0.8 versus 5 percent in one series [15]); thus, ovaries are typically preserved in patients with squamous histology and more commonly removed in those with adenocarcinoma.

Modified radical hysterectomy is an effective treatment for patients with low-risk, early-stage cervical cancer [4,14,15]; however, this has not been formally studied and its use is extrapolated from studies on radical hysterectomy. In a retrospective series including over 1250 patients with cervical cancer treated with radical hysterectomy and pelvic lymphadenectomy, the rate of recurrence for patients with stage IA disease at 12-year follow-up was 1 percent (1 of 104 patients) [16].

Less extensive surgery in the form of extrafascial (ie, simple) hysterectomy may be a reasonable alternative in patients with stage IA2 disease but is not recommended for patients with stage IB disease. In one systematic review including three randomized trials and 18 cohort studies, 2583 patients with either stage IA2 (36 percent) or IB1 (61 percent) cervical cancer were treated with simple hysterectomy [17]. While the overall mortality rate was higher for patients who underwent simple compared with radical hysterectomy (143 of 2613 patients [5.8 percent] versus 174 of 3863 patients [4.5 percent], 18 studies), this was only significant in patients with stage IB1 disease (HR 1.55, 95% CI 1.18-2.03, one study).

●Stage IB1 and IB2 – Patients with stage IB1 and IB2 cervical cancers will typically undergo a radical hysterectomy (class III hysterectomy) that includes removal of more vaginal tissue (up to the upper one-half) and parametrial tissue, in addition to a lymph node assessment (algorithm 1).

The additional resection of tissue, as compared with a modified radical hysterectomy, is performed in these patients given the trend towards poorer prognosis with stage IB disease. In the retrospective series above, the risk of recurrence at 12-year follow-up was: stage IB (40 of 762 patients; 5 percent) and IB2 (11 of 78 patients; 14 percent); stage IB2 was an independent risk factor for poor prognosis (relative risk 2.4, 95% CI 1.4-4.1) [16]. (See "Radical hysterectomy" and "Invasive cervical adenocarcinoma", section on 'Prognostic factors and differences in outcome compared with SCC'.)

Mode of surgery — For patients with IA2 and higher tumors undergoing modified radical or radical hysterectomy for cervical cancer, we recommend laparotomy rather than minimally invasive surgery (MIS; conventional laparoscopy or robotic-assisted laparoscopy). For patients with smaller tumors (ie, stage IA1), however, we suggest MIS, after appropriate counseling of the risks and benefits associated with this technique; some patients with smaller tumors, however, may elect for laparotomy.

MIS was employed for cervical cancer procedures starting in the early 2000s based on decreased operative morbidity with minimally invasive techniques. However, use of these minimally invasive approaches decreased after subsequent studies reported mixed oncologic outcomes, with some demonstrating that MIS is inferior compared with laparotomy for cervical cancer [18-22]; representative studies include:

●A randomized trial included 631 patients with stage IA1 (with lymphovascular invasion), IA2, and IB1 cervical cancer who were assigned to radical hysterectomy using MIS or laparotomy; most patients (92 percent) had stage IB1 disease. Patients in the MIS compared with laparotomy group had similar rates of postoperative adjuvant therapy (29 versus 28 percent, respectively) [18]. The MIS group had a lower rate of DFS at 4.5 years (86 versus 96.5 percent) and lower DFS (91.2 versus 97.1 percent), overall survival (93.8 versus 99 percent), and a higher rate of death from cervical cancer (4.4 versus 0.6 percent) at three years. Approximately 42 percent of trial participants had tumors on final pathology that measured ≥2 cm; however, the authors noted that the trial was underpowered to evaluate outcomes for tumor size <2 cm or other low-risk features (no LVSI, <10 mm depth, no lymph node involvement).

●Similarly, in a meta-analysis of 15 observational studies including almost 9500 patients undergoing radical hysterectomy for stage IA1 to IIA cervical cancer, MIS compared with open surgery was associated with a higher risk of recurrence or death (pooled HR 1.71, 95% CI 1.36-2.15) [23]. Outcomes after robotic versus traditional MIS were similar in the pooled analysis. Although this study supports open surgery over MIS, it included those with stage IIA disease; it is unclear how the results would be affected if this population had been excluded.

The surgical procedure for radical hysterectomy is discussed separately. (See "Radical hysterectomy".)

Alternatives in select populations

Patients who wish to preserve fertility — Patients with early-stage disease at low risk of cancer recurrence (ie, lesion size ≤2 cm; no lymph node metastases) are considered potential candidates for fertility-sparing surgery [11]. The surgical options include conization and trachelectomy. Fertility-sparing surgery for cervical cancer is discussed in detail separately. (See "Fertility-sparing surgery for cervical cancer".)

Patients who are not surgical candidates — Patients who are not surgical candidates for treatment due to medical comorbidities or poor functional status should receive primary RT. Although some experts prefer chemoradiation, there are no data demonstrating that the benefits of chemoradiation outweigh the increased morbidity of treatment in patients with early-stage cervical cancer. (See "Management of locally advanced cervical cancer", section on 'Primary chemoradiation'.)

Typically, the whole pelvis is treated to 45 Gy in 25 once-daily fractions of 1.8 Gy. Magnetic resonance imaging and positron emission tomography are useful for radiation treatment planning to evaluate the size and extent of the primary tumor and the presence and extent of parametrial involvement, bladder or rectal invasion, and nodal disease. These regions are boosted with external beam radiation to 50.4 to 63 Gy. Brachytherapy is used to give the final dose to the cervical primary, to a total of 80 (small-volume cervical tumors) to 87 Gy or higher (larger-volume cervical tumors) (image 1).

When indicated, computed tomography-based planning should be used to adequately visualize the cervix, rectum, bladder, small bowel, and nodal areas. The inferior border should give a minimum margin of 3 to 4 cm from the tumor, which can be aided by the placement of a marker at the time of simulation (image 2). A marker can also be placed clinically in the cervix or if there is vaginal extent, at the most distal edge of the tumor. This will help ensure adequate coverage.

The presence of distal vaginal disease into the lower one-third of the vagina places the inguinal lymph nodes at risk and they should be included in the treatment field.

Patients may be treated in prone or supine positions. For the prone position, a "belly board" is used to displace small bowel superiorly from the pelvis and reduce toxicity.

ADJUVANT THERAPY

Indications — For patients with early-stage cervical cancer treated with a primary surgical approach, adjuvant therapy should be administered if final pathologic findings suggest they are at risk for disease recurrence. These criteria and our recommendations for treatment are discussed below and in the algorithm (algorithm 1).

Intermediate-risk disease — In the absence of patient comorbidities, we suggest chemoradiation as adjuvant therapy for patients with intermediate-risk disease, rather than radiation therapy (RT) or chemotherapy alone.

Final pathologic criteria (sometimes referred to as Sedlis criteria) used to define patients at intermediate risk include the following [24]:

●Presence of lymphovascular space invasion (LVSI) plus deep one-third cervical stromal invasion and tumor of any size

●Presence of LVSI plus middle one-third stromal invasion and tumor size >2 cm

●Presence of LVSI plus superficial one-third stromal invasion and tumor size >5 cm

●No LVSI but deep or middle one-third stromal invasion and tumor size >4 cm

The risks of recurrence and death in the presence of these factors are up to 30 percent following surgery alone [24,25]. (See 'Prognosis' below.)

In a retrospective analysis including almost 130 patients with intermediate-risk disease treated over a 13-year period, those treated with platinum-based chemoradiation compared with RT alone resulted in a lower recurrence rate (9 versus 23 percent) and a trend towards improved progression-free survival (PFS) at five years (90 versus 78 percent; hazard ratio [HR] 2.82, 95% CI 0.99-8.02) [26]. However, there was no difference in overall survival (OS) between the treatment groups (though the OS rate at five years was not reported).

The importance of adjuvant RT as a component of adjuvant therapy was shown in a 2012 meta-analysis that compared adjuvant RT with no further treatment after hysterectomy in 397 patients with early-stage cervical cancer (stage IB to IIA) [27]. Adjuvant RT resulted in:

●A reduction in the risk of disease progression (relative risk [RR] 0.58, 95% CI 0.37-0.91).

●No difference in the risk of death at five years (RR 0.84, 95% CI 0.3-2.36), although the wide confidence interval suggests the study was underpowered to assess survival.

●More toxicity, including serious (ie, grade 3/4) hematologic toxicity (RR 2.38) and gastrointestinal toxicity (RR 7.32), although this was in an era where intensity-modulated radiation (IMRT) was not performed. IMRT has been shown to decrease hematologic and gastrointestinal side effects. (See 'High-risk disease' below.)

In general, eligible patients should be encouraged to participate in clinical trials.

High-risk disease — We recommend adjuvant chemoradiation for patients at high risk of recurrence. Patients are considered to be at high risk if any of the following features (sometimes referred to as Peters criteria) are present at final pathologic review [28,29]:

●Positive surgical margins

●Pathologically confirmed involvement of the pelvic lymph nodes

●Microscopic involvement of the parametrium

Although trials supporting chemoradiation in high-risk, early-stage cervical cancer utilized concurrent cisplatin and fluorouracil (FU) in combination with RT, we generally use single-agent cisplatin with RT instead, because it is used most frequently as primary treatment of locally advanced cervical cancer and is associated with less morbidity than cisplatin plus FU. (See "Management of locally advanced cervical cancer", section on 'Primary chemoradiation'.)

For patients with high-risk factors, the recurrence risk is approximately 40 percent and the risk of death is up to 50 percent following surgery alone [28-30]. (See 'Prognosis' below.)

The benefits of adjuvant chemoradiation were shown in GOG 109, in which 268 patients underwent a hysterectomy for early cervical cancer and were found to have high-risk disease [28,29]. These patients were randomly assigned treatment with RT (49.3 Gy in 29 fractions to a standard pelvic field) with or without concurrent chemotherapy (four cycles of cisplatin 70 mg/m² on day 1, plus FU 1000 mg/m² per day by continuous infusion for four days, every three weeks). With a median follow-up of 42 months, compared with chemoradiation with cisplatin and FU, RT alone resulted in [28]:

●Lower PFS at four years (63 versus 80 percent, respectively; HR 2.01)

●Lower OS at four years (71 versus 81 percent, respectively; HR 1.96)

●Less serious (ie, grade 3/4) toxicity, including neutropenia (3 versus 35 events), leukopenia (1 versus 40), nausea (2 versus 17), and vomiting (2 versus 15)

While in general patients in GOG 109 meeting any of Peters criteria (ie, node-positive disease, positive margins, involvement of the parametrium) had improved survival with the addition of chemotherapy to radiation, there were insufficient numbers of patients in any single subgroup to demonstrate a benefit.

RT technique — Adjuvant pelvic radiation therapy (RT) targets the at-risk tissues in the pelvis to eradicate potential occult sites of disease. Traditionally, treatment has been delivered using a four-field technique, which employs equally weighted anteroposterior-posteroanterior (AP-PA) and opposed lateral beams. With conventional two-dimensional (2D) RT, radiation field borders and design were described relative to skeletal anatomy. With the use of three-dimensional (3D) imaging, 3D conformal RT plans should be designed to adequately cover soft tissue regions at risk, including nearby parametrial and vaginal tissue and the pelvic lymph nodes. It is important to consider variations in patient anatomy and postsurgical changes.

It is necessary to adequately cover all locoregionally draining lymphatics, which include obturator, internal iliac, presacral, external iliac, and common iliac lymph nodes (and para-aortics if at sufficient risk for disease) through the vessel coalescence at the inferior vena cava, which roughly corresponds to a superior field border at the L4 to L5 disk space. Inferiorly, the field edge should extend 3 to 4 cm below the lowest extent of disease or to the bottom of the obturator foramen. The lateral margin should be set 1.5 to 2 cm lateral to the pelvic brim or at the lateral edge of the planned target volume contours and is designed to give a margin on the pelvic vessels and lymphatics (image 3).

Evidence suggests that more contemporary RT techniques administered postoperatively, such as IMRT, may achieve similar survival outcomes with an improved toxicity profile [31-33]. As an example, in the phase III PARCER trial, among 300 patients with cervical cancer undergoing postoperative radiation, disease-free survival was similar with image-guided IMRT versus 3D conformal RT (77 versus 81 percent; HR 1.03, 95% CI 0.62-1.71), but three-year cumulative incidence of late toxicity was reduced (28 versus 49 percent; HR 0.50, 95% CI 0.33-0.76) [34]. Similarly, in a phase III trial of IMRT versus standard therapy for the postoperative treatment of cervical or endometrial carcinoma (TIME-C trial), among 278 patients randomly assigned to either traditional four-field pelvic irradiation or IMRT, IMRT decreased gastrointestinal and urinary toxicity, with a trend for an improvement in quality-of-life scores [33,35]. (See "Radiation therapy techniques in cancer treatment", section on 'Intensity-modulated radiation therapy'.)

Timing of chemotherapy and radiation — Although we suggest concurrent rather than sequential chemoradiation, one randomized trial has shown promising results with sequential therapy.

The STARS trial suggested improved disease-free survival (DFS) and OS results with sequential chemoradiation (cisplatin 60 to 75 mg/m² plus paclitaxel 135 to 175 mg/m² in a 21-day cycle, given two cycles before and two cycles after radiotherapy), over RT alone (total dose, 45 to 50 Gy), and over concurrent chemoradiation (weekly cisplatin, 30 to 40 mg/m²), in patients with at least one adverse risk factor [36]. In this trial, among 1048 patients with stage IB to IIA cervical cancer with adverse pathologic factors followed for a median of 56 months, the DFS for sequential chemoradiation versus RT alone was 90 versus 82 percent (HR 0.65, 95% CI 0.44-0.96), and the five-year risk of cancer death was 92 versus 88 percent, respectively (HR 0.58, 95% CI 0.35-0.95), after adjustment for lymph node involvement. Sequential RT also improved three-year DFS compared with concurrent chemoradiation (95 versus 85 percent; HR 0.65, 95% CI 0.44-0.96). Improvements in DFS and cancer death risk observed with concurrent chemoradiation versus RT were not statistically significant.

Although these results are promising, we await confirmatory clinical trials prior to recommending sequential chemoradiation, and instead suggest concurrent chemoradiation, given previous evidence of benefit in early-stage cervical cancer.

PROGNOSIS — The major prognostic factors affecting survival among patients with cervical squamous cell carcinoma are stage, nodal status, tumor volume, depth of cervical stromal invasion, and lymphovascular space invasion (LVSI).

Disease stage (table 1) is the most important prognostic factor (table 5), followed by lymph node status [30,37-41]. After radical hysterectomy and lymphadenectomy, patients with stage IB1 and IB2 disease have a five-year survival of 91.6 and 83.3 percent, respectively, compared with 60.8 percent for those with pelvic nodal involvement [42]. Outcomes are worse for patients with involved para-aortic nodes (five-year survival, 37.5 percent).

Among patients who have undergone surgical staging or lymphadenectomy, the number of involved lymph nodes also influences prognosis. In one report, five-year survival rates for patients with one, two, three to four, and five or more positive lymph nodes were 62, 36, 20, and 0 percent, respectively [43]. The prognostic significance of pelvic node micrometastases in patients with early-stage disease is unclear [44-48].

The importance of LVSI as an independent risk factor is controversial. A literature review reported that only 3 of 25 studies found that LVSI was an independent risk factor affecting survival in patients with early cervical cancer and concluded the prognostic significance of LVSI was questionable [49].

Human papillomavirus (HPV) status may also affect prognosis. Almost all cervical cancers are HPV related, which may confer a better prognosis than HPV-negative cancers [50,51]. In one prospective study including 2845 patients with invasive cervical cancer (almost 90 percent of whom had HPV-positive disease), HPV-positive compared with HPV-negative cancer was associated with a relative 43 percent decrease in mortality (excess hazard ratio 0.57, 95% CI 0.48-0.69) [51].

POST-TREATMENT SURVEILLANCE — Patients treated for cervical cancer of any stage typically receive post-treatment surveillance, although its effectiveness has not been well-studied. The main goal of surveillance is early detection of those recurrences that might be amenable to potentially curative therapy. The type (eg, physical examination, cervicovaginal cytology, imaging) and interval of surveillance is discussed in detail separately. (See "Invasive cervical cancer: Patterns of recurrence and post-treatment surveillance", section on 'Surveillance strategies'.)

LONG-TERM QUALITY OF LIFE

Adverse effects

Decreased reported quality of life — Cervical cancer treatment is associated with a negative impact on quality of life (QOL), which can persist for years following treatment.

●QOL may be worse among patients who are treated with radiation therapy (RT) or chemotherapy [6,52,53]. (See 'Rationale' above.)

In one study, 121 cervical cancer survivors (majority with early-stage cervical cancer) who underwent surgery with or without adjuvant treatment (RT or chemotherapy) participated in a QOL survey [52]. All patients were at least seven years out from their initial diagnosis. The main findings of this study were:

•Patients treated with surgery followed by adjuvant RT had the poorest QOL scores compared with patients treated with either surgery alone or surgery followed by adjuvant chemotherapy. They also reported significantly higher levels of symptom severity for nausea, vomiting, pain, and appetite loss.

•Patients treated with surgery alone and those treated with surgery followed by adjuvant chemotherapy reported similar QOL scores to patients without a history of cervical cancer. However, those treated with adjuvant RT had significantly lower scores compared with the normative sample.

●At least one trial suggests that QOL is not affected by the mode of surgery [54].

•In a randomized trial evaluating QOL in patients with cervical cancer after surgery, those receiving open versus minimally invasive radical hysterectomy reported similar QOL scores at both six weeks and three months postoperatively, despite worsened disease-free survival among those assigned to minimally invasive surgery [54]. (See 'Mode of surgery' above.)

Ovarian failure — Ovarian failure is more common in patients receiving RT compared with surgery. This is discussed in detail above. (See 'Rationale' above.)

Sexual dysfunction — While RT is associated with more long-term sexual dysfunction [55-57], both hysterectomy and RT can lead to changes in the length or caliber of the vagina and decreased vaginal lubrication and elasticity. These changes can adversely affect sexual function, overall QOL, and psychosocial well-being following treatment [55,56,58-61]. The reported frequency with which these changes occur is quite variable, ranging from 4 to 100 percent for vaginal shortening, and 17 to 58 percent for reduced lubrication [55].

A 2012 systematic review of the literature included 20 studies that reported on the sexual well-being of cervical cancer survivors and came to the following conclusions [62]:

●Lack of lubrication is a frequent complaint among cervical cancer survivors, especially among patients who were treated with RT.

●Compared with patients without a history of cervical cancer, cancer survivors did not appear to have issues related to difficulty achieving orgasm. Two studies suggest that orgasmic difficulties do occur but resolve within six months or one year following surgical or RT treatment, respectively.

●Dyspareunia is more common among cervical cancer survivors compared with patients without cervical cancer. Dyspareunia resolves within three months after surgery for cervical cancer, but persists up to two years or longer in patients treated with RT.

Approaches to treatment of dyspareunia include the use of vaginal lubricants and moisturizers, vaginal estrogen therapy, and use of vaginal dilators. (See "Genitourinary syndrome of menopause (vulvovaginal atrophy): Treatment" and "Female sexual pain: Differential diagnosis".)

Treatment of other types of sexual dysfunction is discussed in detail separately. (See "Overview of sexual dysfunction in females: Management" and "Treatment of female orgasmic disorder".)

Hormone replacement therapy for menopausal symptoms — Given the available data, we suggest hormone replacement therapy rather than nonhormonal treatments for patients with cervical cancer who experience bothersome menopausal symptoms (eg, vasomotor symptoms, vaginal dryness, or dyspareunia) as a result of treatment. General principles of the risk and benefits of postmenopausal hormone therapy are discussed separately. (See "Menopausal hormone therapy: Benefits and risks" and "Genitourinary syndrome of menopause (vulvovaginal atrophy): Treatment".)

There are few data regarding the safety of hormone replacement therapy following cervical cancer treatment, but the available data suggest that hormone replacement therapy does not increase the replication of human papillomavirus [63] or the risk of recurrence [64,65]. For example, among 120 patients with stage I or II cervical cancer, there was no statistically significant difference in five-year survival among patients who did or did not use hormone replacement therapy (80 versus 65 percent, respectively), or in the incidence of cancer recurrence (20 versus 32 percent, respectively) [64].

SPECIAL CIRCUMSTANCES

Pregnancy — At the time of diagnosis, 1 to 3 percent of patients diagnosed with cervical cancer are pregnant or postpartum. About one-half of these cases are diagnosed prenatally. Decisions regarding timing of treatment of cervical cancer and delivery require careful consideration of the stage of disease, the trimester in which the diagnosis is made, and the preferences of the affected patient regarding the pregnancy. The approach to and treatment of cervical cancer in pregnancy is covered separately. (See "Cervical cancer in pregnancy".)

Incidentally diagnosed cancer — Most patients found to have early-stage disease after a simple hysterectomy do not require any additional therapy. However, if features that suggest more advanced disease are identified (ie, deep stromal invasion, positive surgical margins), further surgical or medical treatment may be required. (See 'High-risk disease' above and "Management of locally advanced cervical cancer", section on 'Incidentally diagnosed cancer'.)

Adenocarcinoma and small cell cancers — Unique issues specific to cervical adenocarcinoma and treatment of neuroendocrine (small cell) tumors are discussed separately. (See "Invasive cervical adenocarcinoma" and "Small cell neuroendocrine carcinoma of the cervix".)

Considerations during the COVID-19 pandemic — The COVID-19 pandemic has increased the complexity of cancer care. Important issues in areas where viral transmission rates are high include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These and recommendations for cancer care during active phases of the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Treatment of cervical cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Cervical cancer (The Basics)")

●Beyond the Basics topics (see "Patient education: Cervical cancer treatment; early-stage cancer (Beyond the Basics)" and "Patient education: Fertility preservation in early-stage cervical cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition of early-stage disease – Early-stage cervical cancer includes stages IA, IB1, and IB2 disease and is determined by the depth of stromal invasion and the overall tumor size (table 1). (See 'Definition of early-stage cervical cancer' above.)

●Primary therapy – Our approach is outlined in the algorithm (algorithm 1). We suggest surgical management rather than primary radiation therapy (RT) for most patients with early-stage cervical cancer (Grade 2C). However, RT, with or without chemotherapy, is an appropriate alternative for patients who are not candidates for primary surgery due to medical comorbidities or poor functional status. (See 'Surgery preferred over radiation' above.)

•Stage IA1 without LVSI – For most patients with microinvasive disease (stage IA1) who have no evidence of lymphovascular space invasion (LVSI) on conization specimen, management depends on margin status.

-For patients in whom margins are negative, no further treatment is necessary; however, simple hysterectomy may be an acceptable alternative for patients who desire definitive treatment and have completed childbearing.

-For patients with positive conization margins, we suggest treatment with repeat conization or extrafascial hysterectomy rather than radical hysterectomy (Grade 2C). Repeat conization is performed in patients who desire future fertility, while extrafascial hysterectomy is preferred for those who desire definitive treatment and have completed childbearing. (See 'Type of surgery' above.)

•Stages IA1 with LVSI, and IA2 to IB2

-For most patients with stage IA1 with LVSI and IA2 cervical cancer, we suggest modified radical hysterectomy with lymphadenectomy rather than radical or simple hysterectomy (Grade 2C). A fertility-sparing procedure (eg, conization, trachelectomy) is an appropriate alternative for patients who desire future fertility. (See 'Type of surgery' above and 'Patients who wish to preserve fertility' above.)

-For stage IB1 and IB2 disease, we suggest radical hysterectomy with lymphadenectomy rather than a modified radical hysterectomy (Grade 2C). There is a trend towards poorer prognosis in patients with higher-stage disease. (See 'Type of surgery' above.)

●Mode of surgery

•For patients with stage IA2 and larger tumors undergoing modified radical or radical hysterectomy, we recommend laparotomy rather than minimally invasive surgery (MIS) (Grade 1B). Laparotomy appears to have better oncologic outcomes than MIS in larger tumors. (See 'Mode of surgery' above.)

•For patients with stage IA1 disease undergoing extrafascial hysterectomy, we suggest MIS rather than laparotomy (Grade 2C). However, patients should be counseled regarding the risks and benefits associated with less invasive surgery, and some patients may alternatively elect for a laparotomy. (See 'Mode of surgery' above.)

●Adjuvant therapy – Indications for adjuvant therapy are as follows (algorithm 1):

•Intermediate-risk disease – For patients with early-stage cervical cancer with intermediate-risk features (ie, lymphovascular invasion, cervical stromal invasion, or tumor size >4 cm), we suggest adjuvant chemoradiation rather than RT alone (Grade 2C). (See 'Intermediate-risk disease' above.)

•High-risk disease

-For patients with early-stage cervical cancer with high-risk features (ie, positive surgical margins, pathologically involved pelvic nodes, or positive involvement of the parametria), we recommend adjuvant chemoradiation rather than RT alone (Grade 1B). (See 'High-risk disease' above.)

•Administration of chemoradiation

-We suggest adjuvant RT be administered with single-agent cisplatin rather than the combination of cisplatin plus fluorouracil (Grade 2C), extrapolating from the setting of locally advanced disease. (See 'High-risk disease' above.)

-Although we typically suggest concurrent chemoradiation rather than sequential treatment (Grade 2C), given more data with this approach, sequential treatment is a reasonable alternative. (See 'High-risk disease' above.)

-We suggest use of image-guided intensity-modulated RT (IG-IMRT) rather than three-dimensional conformal radiation therapy (3D-CRT) (Grade 2C), but 3D-CRT is a reasonable alternative when IG-IMRT is not available. (See 'RT technique' above.)

●Prognosis – Stage is the most important prognostic factor, followed by nodal status. Outcomes are worse for patients with involved pelvic or para-aortic nodes (table 5). (See 'Prognosis' above.)

●Management of menopausal symptoms following treatment – For patients with cervical cancer with menopausal symptoms following treatment, hormone replacement therapy appears to be a safe treatment option. (See 'Hormone replacement therapy for menopausal symptoms' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Jennifer F De Los Santos, MD, who contributed to an earlier version of this topic review.