Invasive cervical cancer: Patterns of recurrence and post-treatment surveillance

INTRODUCTION — Despite screening programs that have dramatically reduced the incidence of cervical cancer in the United States, cervical cancer is the fourth most common cancer in women worldwide [1]. Squamous cell carcinoma (SCC) accounts for approximately 80 percent of cervical cancers, while adenocarcinoma accounts for 15 percent, and adenosquamous carcinoma for 3 to 5 percent; neuroendocrine or small cell carcinomas are rare. (See "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis".)

Management and outcomes for women with invasive cervical cancer depend upon the stage of disease at diagnosis (table 1 and table 2). In general, primary treatment for cervical cancer (surgery or radiotherapy with or without chemotherapy) has a cure rate of approximately 80 to 95 percent in early-stage disease (stage I and nonbulky stage II disease) and approximately 40 to 60 percent for bulky stage II and stage III disease. A summary of survival rates by stage of disease according to International Federation of Gynecology and Obstetrics (FIGO) data is presented in the following table (table 3) [2].

Post-treatment surveillance after primary curative therapy for cervical cancer is uniformly recommended, although its effectiveness is not well studied. The main goal of surveillance is early detection of those recurrences that might be amenable to potentially curative salvage therapy. This is most likely with isolated central pelvic recurrences.

The timing and location of recurrent disease following potentially curative treatment for cervical cancer, the published data on the effectiveness of various surveillance strategies, and recommendations for post-treatment surveillance are reviewed here. Staging and primary management of invasive cervical cancer, as well as the approach to women treated for cervical cancer, are discussed separately. (See "Management of early-stage cervical cancer" and "Management of locally advanced cervical cancer" and "Invasive cervical cancer: Staging and evaluation of lymph nodes" and "Invasive cervical adenocarcinoma" and "Overview of approach to cervical cancer survivors".)

PATTERNS OF RECURRENCE — For women who underwent curative-intent therapy for cervical cancer, the predominant site of disease recurrence is local (ie, at the vaginal apex) or regional (ie, pelvic sidewall). The risk of persistent or recurrent pelvic disease increases with more advanced initial disease stage (table 1). As an example, one series reported pelvic failure rates of 10, 17, 23, 42, and 74 percent among 322 women undergoing radiation therapy (RT) alone for stage IB, IIA, IIB, III, and IVA disease, respectively [3].

Retrospective studies have reported the following distribution of anatomic sites of recurrence [4-7]:

●Central (ie, vaginal apex or pelvis without sidewall involvement) – 22 to 56 percent

●Pelvic sidewall – 28 to 37 percent

●Distant metastases or multiple recurrence sites – 15 to 61 percent

The risk of recurrence is associated with well-known prognostic indicators, including tumor size and nodal involvement [8]. In one series including 1211 women undergoing RT alone, the 10-year actuarial incidence rates of distant metastatic disease in women with stage IA, IB, IIA, IIB, III, and IVA disease were 3, 16, 31, 26, 39, and 75 percent, respectively [9].

Recurrence risk may also be associated with tumor histology, tumor grade, and lymphovascular space involvement (LVSI). In a retrospective study including 4343 women with cervical cancer, rates of recurrence were highest among those with the following [10]:

●Neuroendocrine tumors (hazard ratio [HR] 5.7, 95% CI 3.5-9.3)

●Tumors 2 to <4 cm (HR 3.1, 95% CI 1.9-4.9) and ≥4 cm (HR 4.7, 95% CI 2.9-7.6)

●≥3 positive pelvic lymph nodes (HR 2.6, 95% CI 1.9-3.4)

●LVSI (HR 1.7, 95% CI 1.4-2.1)

Effect of mode of treatment — The treatment approach to women with cervical cancer depends on whether their disease is early-stage or locally advanced. For women with early-stage disease, surgery is often the treatment of choice. However, the presence of intermediate or high-risk factors postoperatively may warrant additional treatment with RT. For patients with more locally advanced disease, treatment predominantly consists of chemoradiation (with or without a subsequent hysterectomy). These treatments may impact the risks and types of recurrence seen. (See "Management of early-stage cervical cancer" and "Management of locally advanced cervical cancer".)

Among patients treated for early-stage disease (table 1), there appears to be no difference in either the rate or anatomic distribution of recurrences in surgically treated patients and patients who underwent surgery followed by RT [4-7,11-14]. This was best illustrated in a randomized trial of radical surgery versus RT for stage IB to IIA cervical cancer (although patients with high-risk factors after surgery also were treated with adjuvant RT) [11]. This study reported that there was no significant difference in the five-year patterns of recurrence in patients who received pelvic RT versus surgery alone [11].

In addition, retrospective reports of patients receiving RT alone or in conjunction with surgery show similar distributions of site of recurrence as reports of patients treated with surgery alone. For example, one single-institution review included 334 patients, 41 (13.4 percent) of whom had gross nodal disease identified at the time of radical hysterectomy. Of these 41 patients:

●Fifteen did not proceed with the hysterectomy and underwent lymphadenectomy alone. All patients were treated postoperatively with whole pelvic RT and vaginal brachytherapy (VBT).

●Twenty-six patients underwent both radical hysterectomy and lymphadenectomy. Based on pathologic findings, 11 underwent whole pelvic RT, while eight proceeded with whole pelvic RT and VBT.

Compared with no radical hysterectomy, radical hysterectomy was not associated with significant differences in:

●The rate of local (11.5 versus 26.7 percent) or distant recurrence (19.2 versus 33.3 percent), respectively

●Progression-free survival (PFS, median, 74.9 versus 46.8 months)

●Overall survival (OS, 91.8 versus 69.4 months, p = 0.886)

For women with locally advanced disease, chemoradiation results in a lower risk of locoregional relapse. For example, in one trial the rate of relapse with RT alone was 34 percent, which was significantly higher than the rate of relapse after chemoradiation (18 percent) [15]. (See "Management of locally advanced cervical cancer", section on 'Primary chemoradiation' and "Management of early-stage cervical cancer", section on 'Alternatives in select populations'.)

Symptomatology and timing — The majority of locoregional and distant recurrences (75 percent in one review [16]) are symptomatic [16], and the median time to recurrence ranges from 7 to 36 months after primary treatment [6-8,12,17-22]. In a systematic review of the literature, 62 to 89 percent of cervical cancer recurrences were detected within two years of primary treatment, while by year 5, 89 to 99 percent of recurrent disease had been detected [16].

Prognosis in recurrent disease — Prognosis in recurrent disease depends upon the site of recurrence and the ability to pursue potentially curative therapy, in addition to other factors. Favorable prognostic factors include a localized, central pelvic recurrence with no sidewall fixation, a disease-free interval greater than six months, and size of the recurrence less than 3 cm in diameter. (See "Management of recurrent or metastatic cervical cancer".)

Despite improvements in the management of metastatic cervical cancer, more than 90 percent of patients who develop a distant recurrence will die of their disease within five years [23]. However, a subset of patients with isolated pulmonary metastases might be eligible for a potentially curative resection. (See "Management of recurrent or metastatic cervical cancer" and "Surgical resection of pulmonary metastases: Outcomes by histology".)

SURVEILLANCE STRATEGIES — Surveillance after primary curative therapy for cervical cancer is uniformly recommended, although its effectiveness is not well studied [16,24,25]. The concept of long-term surveillance for patients treated with curative intent is based on the premise that early detection of recurrence may lead to treatments that have lower morbidity and increase survival. Early detection of recurrence is aimed at treating patients with potentially curative salvage therapy. This is most likely in women who develop a central recurrence (ie, vaginal apex or pelvis without sidewall involvement), although cure of patients with isolated pulmonary metastases is also possible. (See "Surgical resection of pulmonary metastases: Outcomes by histology" and "Management of recurrent or metastatic cervical cancer", section on 'Limited metastatic disease'.)

Benefit of surveillance — No prospective comparative studies have specifically addressed the efficacy of routine surveillance for asymptomatic women compared with symptom-based reassessment. Retrospective series suggest that early detection of a localized disease recurrence in asymptomatic women may provide a survival benefit, but the best way to identify these women is unclear [12,13,17,26].

One of these retrospective reports was an outcomes analysis of 1096 women with stage 1B cervical cancer; approximately half of the women were treated with primary surgery and the other women with primary radiation therapy (RT) alone [17]. The post-treatment surveillance strategy included physical and pelvic examination with cervicovaginal cytology every three months for one year, every four months during years 2 and 3, and every six months during years 4 and 5. A chest radiograph was performed at the end of year 1. Major findings were:

●Only 19 of 133 women who relapsed were asymptomatic at diagnosis.

●All pelvic recurrences (n = 37) were detected by pelvic exam; none were detected using cytology.

●Prognostic factors associated with longer survival included asymptomatic disease, central pelvic, and/or pulmonary recurrences.

Although retrospective in nature, these data provide support for routine surveillance to detect recurrences at a time when they are still asymptomatic. The available modalities for post-treatment surveillance include history and physical examination, including pelvic examination, vaginal vault cytology (Pap smear), chest radiograph, computed tomography (CT) scans, pelvic ultrasound, intravenous pyelography (IVP), magnetic resonance imaging (MRI), and positron emission tomography (PET) scans.

Approach — Multiple groups have issued guidelines for the follow-up after cervical cancer, including Cancer Care Ontario [16], the National Comprehensive Cancer Network [24], the American College of Obstetrics and Gynecology [25], and the Society of Gynecologic Oncology [27]. What follows below reflects our approach to surveillance as well as evidence to support various components of follow-up, which were also supported by a 2009 systematic review conducted by Cancer Care Ontario [16].

We follow the surveillance guidelines of the Society of Gynecologic Oncology [27]. These include:

History and physical examination — We perform history and physical exams every six months for two years, every 6 to 12 months for up to five years, and then annually as the primary surveillance modality. Patients with high-risk disease can be followed more frequently (every three months) than patients with low-risk disease (six months). This is supported by the Cancer Care Ontario systematic review, which reported that physical examination (including pelvic, chest, and abdominal examination and careful lymph node survey) detected a median of 52 percent (range, 0 to 71 percent) of asymptomatic recurrences [16]. Symptoms that raise concern for a cervical cancer recurrence include: vaginal bleeding or discharge, abdominopelvic pain, urinary symptoms, and/or change in bowel habits.

Physical examination findings suspicious for recurrence include: enlarged lymph nodes, in particular groin or supraclavicular nodes; a vaginal lesion that is friable, raised, or nodular; nodularity in the rectovaginal septum; or a palpable mass at any location, most commonly in the pelvis.

Cervicovaginal cytology — For women who have undergone RT, we do not perform cervicovaginal cytology routinely as part of surveillance because it is rarely helpful. However, for those patients who did not undergo RT (eg, those treated with primary hysterectomy for very early disease), annual cervical cytology should be performed [27].

In the Cancer Care Ontario systematic review, a median of 6 percent (range, 0 to 16 percent) of asymptomatic recurrences were diagnosed based upon vaginal vault cytology [16]. It is possible that in patients who received RT, the accuracy of cervicovaginal cytology may be compromised by anatomic and tissue changes from RT, which lends more rationale not to obtain it.

Chest radiograph — We do not perform chest radiographs in patients in the absence of symptoms. For the small number of women who develop an isolated pulmonary recurrence, early detection might increase the proportion who are considered candidates for potentially curative metastasectomy. However, data on this subset of women were not reported in the individual studies, and there are no data to address whether early detection and treatment of these patients increased their cure rate. (See "Surgical resection of pulmonary metastases: Outcomes by histology".)

CT scan — We do not routinely perform computed tomography (CT) scans for surveillance. The utility of CT as a method to detect asymptomatic recurrences has not been established, and there is no consensus on this. In the systematic review, between 0 and 34 percent of asymptomatic recurrences were diagnosed by CT [16].

PET/CT scan — Positron emission tomography (PET) in combination with computed tomography (CT; PET/CT) scans are often performed in the initial work-up and staging of cervical cancer and are used in surveillance after treatment. In patients at high risk for locoregional failure, we perform a PET/CT three to six months after therapy to detect early or asymptomatic recurrence, which may be curable. Additional radiologic studies can be performed to assess for recurrence when clinically indicated but not performed as routine surveillance.

Initial staging of cervical cancer is a United States Medicare-reimbursable indication for PET/CT scanning. PET/CT is a sensitive and specific method of detecting lymph node metastases in newly diagnosed cervical cancer, and most institutions perform a PET/CT scan during initial staging as an adjunct to conventional imaging. While a PET scan can be performed as a single modality, we only order it as part of a combined study with CT for better delineation of potential disease. However, we acknowledge that the diagnostic characteristics of PET versus PET/CT have not been formally evaluated and that much of the data evaluating this treatment modality are historically specific to PET alone [28-32].

Other tests — In the systematic review, all other studies, including ultrasound, MRI, and IVP were not of clinical benefit in detecting recurrent disease [16].

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".)

SUMMARY AND RECOMMENDATIONS

●Surveillance after primary curative therapy for cervical cancer is uniformly recommended, although its effectiveness is not well studied. The main goal of surveillance is early detection of those recurrences that might be amenable to potentially curative salvage therapy. This is most likely in patients who have an isolated central pelvic recurrence. (See 'Introduction' above.)

●The optimal surveillance strategy has not been established. There is consensus on the need to perform clinical evaluation (a review of systems and physical examination). (See 'Approach' above.)

●Careful clinical evaluation is the most important component of the follow-up for patients with cervical cancer (a review of systems and physical examination with particular attention to the supraclavicular and inguinal lymph nodes, as well as rectovaginal and abdominal examinations). (See 'History and physical examination' above.)

●For women who have undergone radiation therapy (RT), we do not perform cervicovaginal cytology routinely as part of surveillance because it is rarely helpful. However, for those patients who did not undergo RT (eg, those treated with primary hysterectomy for very early disease), annual cervical cytology should be performed. (See 'Cervicovaginal cytology' above.)

●Imaging should not be routinely performed as part of surveillance in asymptomatic patients. (See 'CT scan' above and 'PET/CT scan' above.)

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