16. Follow-up care – Cervical Carcinoma
Major changes in the chapter on follow-up care
The chapter has been completely revised editorially and new literature references on the subject have been added. Overall, the value of PET-CT in symptomatic patients during follow-up has been emphasized in special situations for treatment planning. No new recommendations or statements have been added.
M.C. Koch, P. Hillemanns, F.A. Stübs, V. Küppers, M.W. Beckmann
Follow-up in patients with cervical carcinoma starts when the primary treatment has been completed. It consists of a patient history, physical examination, medical counseling, nursing care, and support. When there are abnormal findings during the follow-up, or if there is any clinical suspicion, imaging diagnosis should be carried out on a symptom-oriented basis in order to detect any locoregional or distant recurrences [611], [612], [613], [614], [615], [616], [617].
In a systematic literature review on follow-up strategies in patients with cervical carcinoma, including 17 retrospective studies, Elit et al. found that a follow-up interval of 3–4 months for the first 2–3 years, followed by a 6-monthly interval for a further 2 years, can be regarded as an international standard [618]. After that, check-ups were annual. The mean interval to recurrence is 7–36 months after completion of the primary therapy. The recurrence rates were 8–26%, with 14–57% of these being local pelvic recurrences and 15–61% distant metastases. Among the 8–26% of the patients who suffered a recurrence, the recurrence mainly (89–99%) developed within 5 years. The mean survival after recurrent disease was 7–17 months [618].
Asymptomatic recurrences were detected in 29–71% of cases through the clinical bimanual examination, with a chest X-ray in 20–47% of cases, with CT in 0–34% of cases, and with cytology in 0–17% of cases [618].
A study published in 2017 including 358 patients, 64 of whom (17.8%) had had recurrences, reported that 34 (53.1%) were symptomatic and 30 (46.9%) were asymptomatic. In most patients, the recurrence was detected by gynecological examination, both in symptomatic patients (50%) and asymptomatic ones (66.7%; P = 0.27). Cytological examination was able to detect only one recurrence in each of the two groups. This represents 2.9% in the symptomatic patients and 3.3 % in the asymptomatic ones (P = 0.99). Imaging techniques confirmed 10 recurrences (29.4%) in the symptomatic patients and eight recurrences in the asymptomatic ones (P = 0.77). There were no statistically significant differences between the two groups or between the different methods of detecting recurrences. Even after adjustment for potential confounders such as age or type of primary treatment, no association was detected [619]. The authors concluded that the gynecological examination was able to detect most recurrences in both symptomatic and asymptomatic patients and that all other examinations were able to detect recurrences effectively. In the authors’ view, therefore, prospective studies are needed particularly for the follow-up, analyzing the follow-up intervals and follow-up examinations in relation to survival improvement, quality of life, and costs.
During the follow-up, the patient requires intensive interdisciplinary and interprofessional care and support. Depending on need, specialist physicians with oncological expertise and also other professional groups — e.g., psycho-oncologists, physiotherapists, and specialist oncology nurses — should be included. Depending on individual need, the patient should be given information about options for further treatment and care [620], [621].
The following points should be mentioned in discussions with the patient during the follow-up:
- Temporary and long-term effects of the disease and treatment
- Assistance available (self-help groups, psychosocial cancer advice services)
- Psycho-oncological / psychotherapeutic treatment options
- Sexuality and partnership
- Quality of life
- Consensus
- Strong consensus
The present section of this guideline is intended as a consensus section on the best possible ways of providing counseling, care, and support. The authors and the guideline group are aware that the state of the evidence on the benefits of follow-up is very meagre and must be regarded extremely critically. The 2013 Cochrane analysis on follow-up in cervical carcinoma was unable to identify any RCTs for inclusion. The aim was to evaluate potential benefits, potential impairments, and the costs of follow-up, as well as the best possible follow-up protocol. The authors concluded that no evidence is available [622].
Imaging in particular should be used with due consideration, since according to the current data earlier detection of a recurrence is not associated with improved survival, but is associated with a deterioration in quality of life [620]. Cytological diagnosis [623] also only has very limited validity.
In addition, follow-up is used to ensure the quality of the primary therapy. It should be noted here as well, from the point of view of health policy, that the 5-year prevalence of patients with cervical carcinoma is approximately 17,400 women (representing the number of patients in follow-up). By comparison, the 5-year prevalence of patients with breast carcinoma is 313,500 [624].
The 2017 European Society for Medical Oncology (ESMO) guideline states that there is no universally applicable follow-up regimen for patients with cervical cancer. The minimum should be a medical history and a gynecological examination (including rectal examination) carried out by a physician with experience in the follow-up of gynecological malignancies. In addition, the guideline refers to potential improvement in the early detection of recurrences with the addition of a cytological examination. Routine imaging or tumor markers in asymptomatic patients are not recommended, as the state of research is insufficient here. CT or PET-CT should only be carried out if clinically indicated. Check-ups every 3–6 months in the first 2 years and every 6–12 months in years 3–5 are recommended as a reasonable follow-up interval. After that, a return to annual screening with a gynecologic examination should be possible [625], [626].
16.1 Follow-up with no suspected recurrence
The following scheme for follow-up examinations was developed by the guideline group for the first 5 years after diagnosis and treatment, both for patients who have received organ-preserving therapy (independent of tumor stage) and also for those who have undergone hysterectomy.
Obligatory examinations should be carried out every 3 months for 3 years, and then every 6 months for a further 2 years. These include patient history, rectovaginal examination, speculum examination, and cytology.
- Consensus
- Consent
Optional examinations can be carried out if there are clinically unremarkable findings (in asymptomatic patients). These include colposcopy, HPV testing, vaginal ultrasonography of the lesser pelvis, and ultrasonography of the urinary tract.
- Consensus
- Strong consensus
Follow-up is carried out in the chain of care. With higher tumor stages, in fertility-preserving surgery with a higher risk profile, and with unclear findings or results, the established practice is that follow-up is carried out alternately between the physician who carried out the primary treatment and the specialist in charge of the patient’s care. A follow-up card or tumor-specific documentation is issued by the primary physician and optimally kept up to date by all of the physicians participating in follow-up care (the gynecologist, radiotherapist, and family physician) in order to ensure case-related communication.
The following three tables present details of the examinations and indications on which the recommendations are based. Further data collection or altered appointment intervals and additional examinations should be noted for patients who are taking part in research studies.
Obsolete measures include regular imaging procedures (CT, MRI, PET-CT) in asymptomatic patients and short-term tumor marker check-ups.
For explanations of the recommendations, see also sections 16.2, 16.3, 16.4, and 16.5.
From the sixth year onward, the regulations for regular check-ups in the framework of the Statutory Cancer Early Recognition Program (GKFP) apply.
Table 11: Obligatory locoregional follow-up examinations and intervals (checked 2021)
|
Examination |
Years 1-3 |
Years 4 and 5 |
|
|
Patient history¹ |
3-monthly check-ups |
6-monthly check-ups |
|
|
Clinical examination² |
3-monthly check-ups |
6-monthly check-ups |
|
|
Speculum examination and cytology (Pap)³ |
3-monthly check-ups |
6-monthly check-ups |
|
|
¹ History: general (prior and ancillary diagnoses, drug intake) and tumor-specific and treatment-specific history. In particular: itching, bleeding, pain, urination problems (incontinence, urinary retention), defecation problems (incontinence, constipation), respiratory symptoms, weight loss, unilateral or bilateral leg edema, lymphedema, vaginal dryness, dyspareunia, symptoms of hormonal failure, sensory disturbances, documentation of Eastern Cooperative Oncology Group (ECOG) status and the Karnofsky index. |
|||
|
EC |
Strong consensus |
||
Table 12: Optional locoregional follow-up examinations and intervals (checked 2021)
|
Investigation |
Years 1-3 |
Years 4 and 5 |
|
|
HPV⁴ |
In special situations |
In special situations |
|
|
Colposcopy/Vaginoscopy⁵ |
3-monthly check-ups |
6-monthly check-ups |
|
|
4 HPV testing: for specific issues (e.g., status post cervicectomy, suspected dysplasia with “level change,” status post primary R(CH)T, as Pap is difficult to assess). 5 Colposcopy (reflective light microscopy of the vaginal part of the cervix and vagina): recommended at expert consensus level; carried out without staining and after acetic acid and iodine testing with a biopsy of the suspicious area. Particularly indicated if there is any suspicion of pathological findings and for early recognition of preinvasive and central invasive lesions, also after primary radio(chemo)therapy and status post organ-preserving therapy. |
|||
|
EC |
Strong consensus |
||
Table 13: Optional extended follow-up examinations and intervals (checked 2021)
|
Investigation |
Years 1-3 |
Years 4 and 5 |
|
|
Vaginal and renal ultrasound⁶ |
6-monthly |
6-monthly |
|
|
Ultrasound of the liver⁷ |
On clinical suspicion |
On clinical suspicion |
|
|
Port rinsing⁸ |
6-monthly |
6-monthly |
|
|
Breast diagnosis⁹ |
At baseline, then GKFP |
At baseline, then GKFP |
|
|
Tumor markers¹⁰ |
Not routinely |
Not routinely |
|
|
Other imaging procedures¹¹ |
On clinical suspicion |
On clinical suspicion |
|
|
6 Vaginal and renal ultrasound: possible at intervals of approx. 6 months for early recognition of ureteral obstructions (status post radio(chemo)therapy, pelvic wall recurrence). 7 Ultrasound (upper abdomen, scalene): only in case of clinical suspicion. 8 Port: inspection of the port if present and rinsing of it at 6-monthly intervals (also if follow-up interval is > 6 months). 9 Breast diagnosis: mammography, breast ultrasonography at baseline, then in accordance with GKFP guidelines. 10 Tumor markers: SCC in serum in patients with squamous cell carcinoma, CEA and CA-125 in patients with adenocarcinoma only if levels were raised at the primary diagnosis, not in routine practice. 11 Other imaging examinations: CT of the chest/abdomen, MRI of the pelvis, cystoscopy and rectoscopy only in case of clinical suspicion and/or in symptomatic patients. For PET examinations and PET-CT/MRI, there are no data showing a positive effect on locoregional control or overall survival. |
|||
|
EC |
Strong consensus |
||
16.2 History, physical examination, and cytology
Taking a detailed history makes it possible to identify sequelae of the disease or treatment in patients with cervical carcinoma. Information can then be provided about specific assistance and treatment services (see Chapters 15, Rehabilitation and 12, Supportive therapy). The genital examination not only allows rapid and easy diagnosis of atrophic phenomena (status post radio(chemo)therapy, hormonal failure), ulcerations, and recurrences, but also of lymphedema in the legs. The physical examination with palpation allows assessment of the pelvic wall and lymph-node stations (scalene, inguinal). Inflammations can be diagnosed using a pH examination and an unstained specimen and can be treated. Another important point in the patient history is sexuality (see section 15.12, Sexuality).
In contrast to the diagnosis of primary CIN and primary cervical carcinoma, it must be remembered that a benefit from cytology can only be expected in recurrent cervical carcinoma if the recurrence is central and the vaginal mucosa is infiltrated. In addition, technical analysis of the Pap smear following radio(chemo)therapy is difficult due to marked atrophic and radiogenic changes, and it often provides only little diagnostic information.
In 2011, Rimel et al. showed, in a retrospective multicenter study including 929 patients and 4167 cytological examinations, that abnormal Pap findings occur during the follow-up (particularly after radiotherapy) in one-third of patients who have had cervical carcinoma [623]. There were 147 recurrences, only 12 of which (8.1%) were detected using cytology. Cytology is a possible diagnostic method during the follow-up. However, in the absence of a further symptom-oriented clinical examination, it is by no means sufficient [627].
16.3 Colposcopy, HPV, and ultrasound
Similarly, it must also be borne in mind that a benefit of colposcopy can only be expected in cases of central recurrence with vaginal infiltration or in residual tumors following primary radio(chemo)therapy. For preinvasive recurrent lesions (CIN, VAIN), earlier recognition may be possible in some cases using colposcopy. There are no published data on this. Colposcopic findings are documented in accordance with the 2011 Rio Classification (http://www.ifcpc.org/images/docs/nomenclature7-11.pdf) [628].
In meta-analyses on follow-up in women who had undergone conization due to CIN 2/3, a significantly better pooled sensitivity of 93% (95% CI, 85–97%) was observed in the HPV test in comparison with cytology at 72% (95% CI, 66–78%), with similar specificity [629]. For preinvasive recurrent lesions after invasive cervical carcinoma, it can be assumed that earlier detection is possible with the HPV test, but there are no published data on this. Pap smears following cervicectomy are of limited diagnostic value [630]. Depending on the patient’s HPV high-risk status, continuing check-ups at 6-monthly intervals may be considered even after the 5-year follow-up if there have been positive findings.
An ultrasound examination (vaginal, renal ultrasound) makes it possible to diagnose urinary disturbances, new ureteral stenoses, or increasing tissue in the lesser pelvis, as well as newly appearing free fluid in the pouch of Douglas.
16.4 Tumor markers
Routine controls of tumor markers to diagnose recurrences shall not be carried out.
- Consensus
- Strong consensus
The SCC level after primary therapy shows a strong correlation with the clinical course of disease in women with squamous cell carcinoma. There is no evidence to date that an earlier diagnosis of recurrences or metastases improves the overall survival in patients with cervical carcinoma [631], [632]. Regular checking of the SCC level is therefore not recommended [632]. The guideline group also had no data available regarding the value of regular check-ups on the markers carcinoembryonic antigen (CEA) and cancer antigen 125 (CA-125) in adenocarcinomas, or neuron-specific enolase (NSE) in neuroendocrine carcinomas.
16.5 Imaging procedures
Imaging procedures are of no value in asymptomatic patients. Curative approaches are possible with central recurrences, which are usually diagnosed at the vaginal examination, or on vaginal ultrasound or cytology. In symptomatic patients, diagnostic procedures with which those treating the patient have the greatest personal experience should be carried out in such a way as to allow the appropriate treatment planning and monitoring of therapies. The standard procedures are CT or MRI, both with contrast administration. Cervical carcinoma is not included in the assessment of the value of PET-CT in oncology conducted by the Institute for Quality and Cost-Effectiveness in the Health-Care System (IQWiG).
No clear statements can be made regarding the value and benefit of PET-CT during the follow-up after cervical carcinoma, due to limited data (few studies, poor methodology). There are some indications that PET-CT may have a certain value in the recurrent situation, especially before exenterative treatment options or radio(chemo)therapy, and that it can influence treatment planning (see Chapter 6, Diagnosis).
An FDG-PET study including 42 patients showed a sensitivity of 82%, a specificity of 97%, and an accuracy of 92% for local recurrence of cervical carcinoma. For distant recurrences, the sensitivity was 100%, the specificity 90%, and the accuracy 94% in comparison with the final histological findings [633].
A meta-analysis published in 2018 including 707 patients from 17 studies investigated the clinical value of PET and PET-CT in patients with suspected cervical cancer recurrences. The diagnostic quality was evaluated both in relation to individuals and in relation to regions. The pooled sensitivity for PET and PET-CT was 0.97 (0.95–0.99). If the tumor marker SCC was elevated, the pooled sensitivity was 0.99 (0.93–1.00). Comparably high values were seen here in the lung, mediastinum, liver, spleen, inguinal, para-aortic and supraclavicular lymph nodes. In addition, it was shown that there was a change in treatment plan in 57% of cases. The authors concluded that PET-CT is a reliable diagnostic tool in suspected cervical cancer recurrence and can influence the subsequent treatment management [634].
A Brazilian meta-analysis published in 2019 examined the use of PET and PET-CT for staging and re-staging in patients with cervical cancer in comparison with the use of CT or MRI. It included six studies with 233 patients that investigated the detection rate for local recurrence. FDG-PET showed significantly better results (AUC 0.9882 PET vs. AUC 0.606 control; P [Mohandas, H. et al. 2017].
Another 2018 publication sums up the literature on the use of PET and PET-CT in cervical cancer. It also concludes that PET-CT is routinely used internationally in the primary setting, for evaluation of treatment response, and also during the follow-up [636].
The 2020 NCCN guideline clearly recommends PET-CT as the primary diagnostic imaging modality for patients with suspected cervical cancer recurrence — with the known methodological weaknesses of this clinical guideline [637].
In women with a clinical or imaging suspicion of recurrence, PET-CT may support the search for distant metastases [638]. However, it can only be helpful in cases in which there is a manageable disease situation in the pelvis or in the locoregional lymph nodes, and the clinical benefit of PET-CT in this situation is unclear [639].
16.6 Extended diagnostic procedures for suspected recurrence
If a locoregional recurrence is suspected, histological confirmation shall be obtained.
- Consensus
- Consent
Imaging diagnosis in symptomatic patients with suspected locoregional recurrences or metastases is discussed in sections 17.2, Diagnosis of local recurrence, and 18.2, Imaging. If a locoregional recurrence is suspected, then histological confirmation must be obtained in addition to the exclusion of distant metastases; prior treatments that have already been carried out must be ascertained; and the feasibility of locoregional treatment must be checked. The necessary diagnostic procedures correspond to the preliminary preoperative investigations (see also recommendations 17.1 and 17.2).
For assessment of the local findings, a gynecological examination (vaginal and rectal palpation and speculum examination), vaginal ultrasonography, renal ultrasonography, and pelvic MRI (to assess the tumor’s relationship to other organs) are appropriate, as well as cystoscopy and rectoscopy if there is suspected extension of the tumor into neighboring organs. Biopsy confirmation of the recurrence should also be obtained.
To exclude distant metastases, CT of the chest and abdomen and PET-CT in special situations (for organ metastases and lymph-node metastases) and scalene ultrasound (for lymph-node metastases) can be carried out additionally, but this is increasingly being abandoned in initial re-staging in favor of whole-body imaging.
16.7 HPV vaccination after high-grade dysplasia or cervical carcinoma
Vaccination of girls aged 12–17 years before first sexual intercourse is currently recommended by the STIKO, and the costs are met by the statutory health insurance companies [640]. Two vaccines starting from age 9 are approved throughout Europe for both sexes, with no upper age limit. Many health insurance companies continue to reimburse HPV vaccinations on an individual case basis even beyond the interval set by the STIKO. There is evidence that HPV vaccination can still be useful even after age 18 [641], [642], [643], [490] and after a previous HPV infection in order to reduce the reinfection rate [644], [645], [646], [647], [648], [649]. The limitations of the existing data need to be taken into account and are mentioned in the studies cited. The Level 3 guideline on “Vaccine Prevention of HPV-associated Neoplasias” (AWMF register no. 082/002) and the Level 3 guideline “Prevention of Cervical Carcinoma” (AWMF register no. 015/027OL) include statements on vaccination outside of the age group recommended by the STIKO, or after prior HPV infection.
16.7.1 HPV vaccination after conization
The significance of prophylactic HPV vaccination after the completion of treatment for cervical carcinoma is unclear.
- Consensus
- Strong consensus
No data are available to the guideline group regarding vaccination following invasive cervical carcinoma. Positive data have in the meantime become available on the benefit of HPV vaccination after conization with dysplasias (CIN 2+) to reduce the likelihood of recurrence.
Analyses of study populations from the phase III approval studies for both HPV vaccines show that there is protection against recurrent disease in women who were vaccinated during their HPV infection but before the development of CIN. There is no effect on the course of the active infection, but after treatment (conization), there was a 46% reduction in the rate of recurrent genital dysplasia/condylomas and a 64.9% lower rate of CIN 2+ [649]. One reason for this might be the patients’ lack of immunocompetence. Following surgical treatment for dysplasia, there is a 5% risk of recurrence. However, this risk can be reduced by more than 50% through vaccine-induced immunity [649]. Similar results were seen when the HPV vaccination was administered 1 week after conization, with a reduction in the risk of recurrence from 7.2% (with the placebo) to 2.5% (in the vaccination group) [650]. All patients with recurrent CIN had positive HR-HPV findings after conization [650].
Against this background, vaccination following dysplasia or after treatment for dysplasia appears to be a possible option, although it has markedly lower success rates [641], [642], [649], [650], [651], [652], [653], [654].
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