Summary of main results
No trials were identified that evaluated the benefits and harms of different follow-up protocols for women who have completed primary treatment for cervical cancer. Therefore the question of whether different protocols are associated with a survival benefit in terms of overall and recurrence-free survival cannot be answered by this review.
Overall survival and recurrence-free survival were specified as the primary outcomes of interest, but QoL should perhaps be the main focus if future trials are conducted, as cervical cancer is associated with recurrence and mortality rates, and any follow-up protocol needs to take into account both benefits and harms. The prognosis for women with cervical cancer is often poor, and in countries with worst survival, women probably will not receive any follow-up (American Cancer Society 2011).
Quality of the evidence
No studies met the inclusion criteria for this review, resulting in no evidence to assess.
Potential biases in the review process
A comprehensive search was performed, including a thorough search of the grey literature, and all references were sifted and data extracted by two review authors independently. We were restrictive in our inclusion criteria with regards to types of studies, as we planned to include only RCTs because we suspected that some of the NRS designs were of dubious quality and would have been prone to selection bias. No relevant NRSs appeared to use appropriate statistical adjustment or were of adequate quality. Therefore, we attempted to ensure (1) that we did not overlook any relevant evidence by searching a wide range of sources, and (2) that the review was not based on poor quality evidence by excluding case reports and poor quality retrospective studies. We believed it was better to highlight the need for RCTs or at the very least good quality NRSs, rather than report the results of low-quality studies, which are very likely to be misleading.
The greatest threat to the validity of the review is likely to be publication bias (i.e. studies that found follow-up regimens not effective and that may not have been published). We were unable to assess this possibility, as we did not find any studies that met the inclusion criteria.
Agreements and disagreements with other studies or reviews
We found no trials directly comparing different follow-up protocols after primary treatment for cervical cancer. As far as we are aware, no RCTs in this area are planned. The need for such studies to be designed and conducted is clear, as evidence derived from NRSs is inconsistent and unreliable.
Retrospective studies have been conducted to evaluate the effectiveness of routine follow-up in detecting recurrent disease (Bodurka Bevers 2000; Samlal 1998); to assess survival benefit in relation to early detection of recurrence (Duyn 2002; Kerbs 1982); and to establish which are the most sensitive follow-up surveillance methods for detection of recurrence (Soisson 1990).
The retrospective analysis of Bodurka Bevers 2000, which examines the efficacy of clinical surveillance for 993 women previously treated for stage IB and IIA cervical cancer, demonstrates that detection of asymptomatic recurrences is associated with prolonged OS and survival from time of initial detection of recurrence. In contrast, the retrospective analysis of Ansink 1996, which examines 674 sets of clinical records of women with stage IB cervical carcinoma treated by radical hysterectomy and lymph node dissection, concluded that routine follow-up is ineffective in detecting recurrent cervical cancer. Further conflict in results is evident between the findings of Bodurka Bevers 2000 and those of Morice 2004, which showed no survival benefit from detection of recurrence at an asymptomatic stage in women who had been treated for stage I and II carcinoma of the cervix. The results of Morice 2004 are supported by those of earlier studies by Duyn 2002.
Larson 1988 examined the records of 249 women with stage IB cervical cancer treated with radical hysterectomy to determine optimum surveillance strategies for detection of recurrence and concluded that combined clinical history and physical examination findings should serve as the mainstay of post-treatment surveillance. A decade later, Soisson 1990 focused on women who had undergone radical hysterectomy for FIGO stages IB and IIA cervical cancer for their evaluation of follow-up procedures. These results support the findings of Larson 1988. Of the 203 women in their study, 15% developed a recurrence, and 90% of these had had an abnormal physical examination or the presence of suspicious symptoms. A subsequent retrospective study by Sartori 2007 concluded that asymptomatic recurrence (i.e. 35% of recurrences in their study) can be diagnosed by pelvic examination, CT scan or both in 85% of cases. The limited evidence in cervical (as well as endometrial and vulval) cancer has, however, called into question the benefit of detecting recurrence at an asymptomatic stage because this did not appear to confer any survival benefit (Kew 2005). An additional problem in weighing the significance of studies is that it is difficult to compare results between them because the symptom status of the women successfully treated at the time of detection of recurrence is unclear.
Two recently published reviews of follow-up for women after treatment for cervical cancer have been identified. Elit 2009a aimed to determine the optimal recommended programme for the follow-up of women who are disease free after completing primary therapy for cervical cancer. Their review included 17 retrospective trials of follow-up in cervical cancer involving women at different stages and after completion of a range of different treatments. Recurrence was detected by a variety of surveillance tests, including physical examination, imaging or vaginal vault cytology. The authors reported a recurrence rate of 10% to 18%, with most cases detected within two years of treatment. Crucially, 26% of women were asymptomatic at the time of recurrence. With a significantly higher median survival for recurrent cervical cancer seen in asymptomatic versus symptomatic women with recurrent disease (Bodurka Bevers 2000; Zola 2007), available evidence suggests that women would benefit from having an earlier diagnosis of recurrent disease. Elit 2009a recommended that follow-up consultations should involve full physical examinations, although they presented little hard evidence to support their recommendation. They also noted that vaginal vault smears added little to the detection of early disease recurrence. Zanagnolo 2009 examined surveillance programmes for women who experience recurrence. They considered a range of surveillance procedures, including non-invasive surveillance by physical examination, cervical cytology, tumour markers and various imaging techniques of chest radiography, CT and MRI scans, PET and fluoro-2-deoxy-glucose PET (FDG-PET). Most of the 42 studies that they reviewed were retrospective analyses of follow-up data with one prospective cost analysis (Hricak 1996), a healthcare professional survey (Kew 2005), a prospective feasibility study (Kew 2006) and a handful of prospective studies examining the complementary roles of imaging techniques (Amit 2006; Chung 2007). Despite shortcomings of studies available for review by both Zanagnolo 2009 and Elit 2009a, recommendations were made for the use of MRI above CT scan in the follow-up of cervical cancer because of its increased specificity in the detection of recurrent disease. Brookes 2009 subsequently evaluated surveillance with PET or CT scans and found significantly higher survival in the asymptomatic recurrences of cervical cancer. These results call for prompt evaluation of the role of routine radiological surveillance post treatment—a conclusion also reached by authors of a survey report of UK gynaecological oncologists’ surgical management and follow-up of women with cervical cancer (Nobbenhuis 2012).
Three sets of national or international guidelines were identified:
This guideline, formed at a consensus meeting, acknowledged that the most appropriate follow-up strategy in cervical cancer has not been clearly stated. However, the guideline recommends that clinical follow-up with gynaecological examination with PAP smear should be performed every three months for the first two years, every six months for the next three years and yearly thereafter.
Recommendations state that squamous cell carcinoma antigen in squamous cell carcinoma may be useful in women’s follow-up if initially increased. They also acknowledge that PET or CT might have a role in early local recurrence and detection of metastasis.
This guideline acknowledges that no systematic reviews have examined clinical outcomes of randomised controlled trials or individual randomised controlled trials comparing one follow-up strategy versus another or comparing different time intervals of follow-up. Based on the Gynecology Cancer Disease Site Group expert consensus opinion informed by evidence from retrospective studies, the following recommendations have been made.
Women need to be informed about symptoms of recurrence because most women have signs or symptoms of recurrence that occur outside of scheduled follow-up visits.
Follow-up care after primary treatment should be conducted and coordinated by a physician experienced in the surveillance of women with gynaecological malignancy.
Continuity of care and dialogue between the healthcare professional and the patient may well enhance and facilitate early detection of cancer recurrence and may help avoid duplication of surveillance testing and effort.
A reasonable follow-up strategy involves follow-up visits every three to four months within the first two years and every six to 12 months from years three to five.
After five years of recurrence-free follow-up, the patient should return to annual assessment with a history, a general physical and pelvic examination with cervical/vaginal cytology performed by the primary care physician.
At a minimum, follow-up visits should include a patient history and a complete physical examination.
Symptoms elicited during the patient history should include general performance status, lower back pain, especially if it radiates down one leg, vaginal bleeding or unexplained weight loss.
A physical examination should attempt to identify abnormal findings related to general health and/or those that suggest vaginal, pelvic sidewall or distant recurrence. As central pelvic recurrences are potentially curable, the physical examination should include a speculum examination with bimanual and pelvic/rectal examination.
The routine use of other investigations in asymptomatic women is not advocated, as their role has yet to be evaluated in a definitive manner.
Little evidence suggests that vaginal vault cytology adds significantly to the clinical examination in detecting early disease recurrence. If cytology is performed as part of routine follow-up after surgery for cervical cancer, its role would be to detect new precancerous conditions of the vagina, and it should be done no more frequently than once a year. An abnormal cytology result that suggests the possibility of neoplasia warrants colposcopic evaluation and directed biopsy for histological confirmation.
The role of abdominal or pelvic computed tomography, magnetic resonance imaging scans, positron emission tomography or ultrasound as part of routine follow-up has not been fully evaluated in prospective studies.
Use of serum markers such as squamous cell carcinoma antigen or cancer antigen 125 has shown promise in predicting surgical findings or in monitoring the post-radiotherapy course when disease is present; however, their role in following women post-treatment has yet to be determined.
Annual cytology/vaginal cytology tests can be considered as indicated to detect lower genital tract dysplasia; however, the detection rate of recurrent cervical cancer is low using cervical and vaginal cytology alone.
Patient education regarding symptoms suggestive of recurrence should be provided.
Imaging is not routinely recommended but may be indicated in women with symptoms or examination findings suspicious for recurrence.
In women at high risk for loco-regional (central or para-aortic) failure, a combined PET-CT scan (e.g. three to six months after treatment) or other radiological imaging may be useful in detecting asymptomatic disease that is potentially curable.
Laboratory assessment (e.g. complete blood count (CBC), blood urea nitrogen (BUN), creatinine) remains optional based on clinical indications.
Women with persistent or recurrent disease need to be evaluated through the use of additional imaging studies as clinically indicated and surgical exploration in selected cases.
Vaginal dilator use is recommended after radiotherapy. Women treated with radiotherapy are prone to vaginal stenosis.
Adapted with permission from Koh W-J, et. al., NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Cervical Cancer V.3.2013. © 2013 National Comprehensive Cancer Network, Inc. Available at NCCN.org (accessed 23 September 2013).