The Diagnosis, Treatment, and Aftercare of Cervical Carcinoma

Background: Approximately 4380 cases of cervical carcinoma were diagnosed in Germany in 2016. In women who had not participated in early detection programs, cervical carcinoma was usually already in an advanced stage at the time of diagnosis. Certified structures for care in conformity with the existing guidelines are available.

Methods: The new German clinical practice guideline was revised with the participation of 50 medical societies under the expert guidance of the Guideline Program in Oncology, which includes the German Association of the Scientific Medical Societies (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF). A systematic literature review was conducted. Systematic reviews, meta-analyses, and randomized controlled trials (RCTs) were considered.

Results: The histologic tumor stage and lymph-node stage are essential determinants of the treatment strategy. The main innovation regarding surgical treatment is the revival of open hysterectomy (overall survival [minimally invasive vs open hysterectomy]: 94.04% vs 99.4%; hazard ratio [HR]: 6.00; 95% confidence interval [1.77; 20.30]). In addition, for tumors measuring 2 cm or less, sentinel node biopsy is recommended rather than radical pelvic lymphadenectomy. MRI-guided brachytherapy is an obligatory component of radiochemotherapy (overall survival [radiochemotherapy with vs without brachytherapy]: 58.2% vs 46.2%, p<0.001). The standard palliative treatment consists of bevacizumab combined with a platinum-containing agent (overall survival: HR: 0.77 [0.62; 0.95]; p = 0.007).

Conclusion: Despite the introduction of new treatments, the outcome of patients with advanced cervical carcinoma has not much improved. In the surgical treatment of cervical carcinoma, the open approach is now favored. The sentinel node biopsy technique has become well established for the surgical staging of small tumors. Controlled trials are needed so that the outcome of women with cervical carcinoma, particularly in its advanced and metastatic stages, can be improved.

Globally, cervical carcinoma is one of the most common cancers in women. In 2012, more than half a million women were newly diagnosed with cervical carcinoma worldwide. In Germany, 4380 women were diagnosed with cervical carcinoma in 2016 and 1562 women died of the disease. In almost 50% of cases, the cancer is diagnosed in an early stage (stage 1, Union internationale contre le cancer, UICC).

Immunization with the human papilloma virus (HPV) vaccine, which was approved in Germany in 2006, has currently no impact on the incidence of invasive cervical carcinoma (1). Squamous cell carcinoma accounts for the largest group of cases of cervical carcinoma (approx. 80%), followed by adenocarcinoma (5–20%) (2).

As the result of early detection programs, cervical carcinoma declined in Germany and other industrialized nations over the last years, but recently the incidence rates have stabilized. Here, the creation of evidence-based guidelines for the diagnosis, treatment and aftercare of malignant diseases plays a key role. In 2020, a reorganized cervical cancer screening program was introduced. Women aged 20 years and older continue to be eligible for annual cytology. Women aged 35 years and older receive a combination test, comprising human papilloma virus (HPV) testing and cervical cytology. HPV tests are typically rely on polymerase chain reaction (PCR) testing. The broad topic of prevention is the subject of the separate S3-level clinical practice guideline “Prevention of Cervical Cancer“ (register number 015/027O of the Association of the Scientific Medical Societies in Germany [AWMF, Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften]).

The aim of circulating the clinical guidelines presented in this article nationwide is to optimize cross-sector supply chains as well as stage-specific therapies for the primary disease and disease recurrence or metastatic spread. This approach is intended to reduce the mortality of patients with cervical carcinoma in the medium and long term and to improve the patient quality of life (3). Together with the patient, the most suitable diagnosis and treatment strategy should be established by way of participatory decision-making. The patient version of the guideline which is specifically designed to inform cervical cancer patients facilitates decision-making, as even laypersons find its content easy to understand.

Methods

Methods were chosen according to the AWMF guideline rules for S3-level clinical practice guidelines (www.awmf.org/leitlinien/awmf-regelwerk.html).

A legitimate group of 50 medical societies and institutions involved in the provision of care for these patients, including patient representatives, contributed to the creation of this S3-level clinical practice guideline (eTable 1). The literature search was conducted in the PubMed and Cochrane databases, separately for diagnosis and management, using a pre-defined search algorithm. Different search algorithms were used for randomized controlled trials (RCTs), systematic reviews and meta-analyses. From the 9578 primary hits, pertinent studies were selected, using pre-defined inclusion and exclusion criteria, first on the level of titles and abstracts, then on the full-text level (Figure 1). The following areas were identified for which new evidence was compiled:

Figure 1

PRISMA flowchart for the systematic review of the literature on the diagnosis/treatment of cervical carcinoma in the PubMed and Cochrane databases

Table

Evidence of treatment options

eTable 1

Working groups, medical societies, organizations, and patient representative groups, as well as delegated mandate holders involved in the creation of this clinical practice guideline

• Pelvic lymphadenectomy ± sentinel lymphadenectomy versus sentinel lymphadenectomy
• Laparoscopic radical hysterectomy versus open radical hysterectomy
• Neoadjuvant chemotherapy for cervical carcinoma
• Positron emission tomography (PET) scan for diagnosis, treatment decision and aftercare
• Preoperative imaging versus surgical staging for cervical carcinoma
• Palliative chemotherapy
• Neuroendocrine cervical carcinoma (NECC).

All in all, the evidence of 52 studies, which met the evidence criteria, was summarized and shown in evidence tables.

In the following section, we will review the key innovations in the diagnosis and treatment of cervical carcinoma. Particular focus will be given to those topics which are supported by new evidence.

Results

The data presented here are based on a systematic literature search in the Pubmed und Cochrane databases. Only systematic reviews, meta-analyses and RCTs were considered (Table). The various studies included in this review will be discussed in the respective sections. If no or only insufficient evidence was available, the corresponding statements and recommendations were drawn up as a consensus of the guideline group.

The Quality Indicator Working Group reviewed and adjusted the content of nine quality indicators (QIs). The quality indicator “R0 resection in case of exenteration“ was not included again. Depending on the extent of the disease, the surgical technique of exenteration involves the resection of the bladder, uterus with adnexa and/or rectum. Since exenteration does no longer represent the surgical standard in Germany, it was removed from the list of QIs. The quality indicator “complete report of conization findings“ from the primary treatment was added as a QI; thus, the QI set continues to comprise nine QIs (eBox). The results of the evaluation of the evidence related to the identified topics are presented in eTable 2.

eBox

List of quality indicators

eTable 2

Evidence of treatment options

Surgical treatment

Various surgical principles are available (Figure 2). Minimally invasive surgery was considered the gold standard for (radical) hysterectomy to reduce morbidity. Since 2018, data of a randomized controlled trial (phase III study), including 631 patients with FIGO IA1 to FIGO IB1 cervical carcinoma (classification of the Fédération Internationale de Gynécologie et d‘Obstétrique, FIGO), have been published. Patients were randomized to undergo either laparoscopic radical hysterectomy (including “robotic surgery“) or open abdominal radical hysterectomy. Non-inferiority of minimally invasive versus open surgery with regard to disease-free survival after 4.5 years could not be demonstrated: 96.5% versus 86.0% (95% confidence interval: [−-16.4; −-4.7]; p = 0.87 for non-inferiority).With regard to overall survival after three years, open hysterectomy was also significantly superior to laparoscopic hysterectomy: 99.0% versus 93.8% (hazard ratio [HR] 6.00; [1.77; 20.30]). The rates of intra-operative and post-operative adverse events were similar in both treatment arms. No statement could be made with regard to the low-risk tumor (<2  cm) subgroups without lymphovascular invasion, with depth of invasion <10  mm and without lymph-node involvement (4)..

Figure 2

Types of treatment and their combinations for women with primary cervical carcinoma

Central to the treatment strategy for patients with cervical carcinoma is the determination of the histological tumor stage, including the lymph node stage. Various studies have shown that imaging techniques do not offer adequate sensitivity and specificity to reliably detect the presence of lymph node metastases (5, 6, 7, e1).

A meta-analysis of 72 included studies (N = 5042) compared the sentinel node biopsy method – marking with radiotracer and patent blue dye versus marking with indocyanine green dye (Figure) – with computed tomography (CT) imaging, magnetic resonance imaging (MRI) and PET-CT scan in respect to the detection of lymph node metastases in patients with cervical carcinoma. The meta-analysis showed the superiority of the surgical technique of sentinel node biopsy compared to imaging techniques: sensitivity of 91.4% versus 74.7% (PET-CT), 55.5% (MRI), and 57.5% (CT); specificity of 100% versus 97.6% (PET-CT), 93.2% (MRI) and 92.3% (CT). Especially small metastases (<5  mm) are often not detected by conventional imaging techniques (8); however, these small lesions are highly relevant for prognosis.

Figure 3

Sentinel lymph node stained with indocyanine green

Since cervical carcinoma is a “midline tumor”, bilateral sentinel lymph-node detection is required. In the available studies, conclusive values were achieved in patients with primary tumor sizes ≤ 2  cm for the decisive negative predictive value (negative predictive value: 99.1% [96.6; 100]). For larger carcinomas, however, the currently available evidence is still inconclusive (6).

The combination of patent blue dye and radiotracer was the standard staining method used with sentinel node biopsies in patients with cervical carcinoma (9, 10). The use of indocyanine green (ICG), visualized with the help of near-infrared fluorescence filters, is a newly established, valid alternative method. The avoidance of radioactive substances and patent blue dye is of advantage. Both methods are contraindicated in pregnancy (11). Various studies have shown that ICG matches the sensitivity and specificity achieved with the combination of patent blue dye and radiotracer.

So far, sentinel lymphadenectomy has not yet emerged as a standard procedure for all stages; its use in tumors ≤ 2  cm is considered safe in terms of complication rate and with regard to sensitivity and specificity. Histopathological processing of the sentinel lymph node should always include ultrastaging. Ultrastaging is an immunohistochemical examination which uses one or more pan-cytokeratin antibodies if no tumor cells can be detected with standard H&E staining.

Radiation therapy

The three key elements of radiochemotherapy are external radiation therapy, concurrent cisplatin-based chemotherapy (HR of 0.69 in comparison to radiotherapy alone; [0.61; 0.77], p<0.00001) and brachytherapy. The recommendations for the use of intensity-modulated radiotherapy (IMRT) and of MRI-guided brachytherapy planning were given greater strength.

Brachytherapy at the site of the macroscopic tumor is an obligatory component of radiochemotherapy for cervical carcinoma (12). It should preferably be administered as image-guided adaptive brachytherapy (IGABT). The use of IMRT was evaluated in a meta-analysis (13). These radiotherapy techniques help to spare high-risk organs, such as bladder, rectum, small intestine, and ovaries (gastrointestinal toxicity grade 2: odds ratio [OR] 0.5; [0.28; 0.89], p = 0.02; grade >3: OR 0.55; [0.32; 0.95], p = 0.03; urogenital toxicity grade 2: OR 0.41; [0.2; 0.84], p = 0.01; grade >3: OR 0.31; [0.14; 0.67], p = 0.003). Treatment-related acute and late reactions can be reduced by the use of IMRT (13, 14, 15, 16).

Neoadjuvant chemotherapy

Neoadjuvant chemotherapy (NACT) is not standard in the treatment of patients with cervical carcinoma. A meta-analysis found no improvement in overall survival for the stages Ib1 to III (OR 1.17; [0.85; 1.61], p = 0.35) (17). Various studies showed a significant reduction of lymph node metastases (OR 0.45; [0.29; 0.7], p = 0.0005) and parametrial infiltration (OR 0.48; [0.25; 0.92], p = 0.03). However, this reduction had no effect on overall survival (17). The reduced rate of adjuvant radiotherapy (58% versus 80%) after NACT has no impact on overall survival (18). NACT can be used in selected high-risk patients to increase the rate of resectable tumors. Especially in women wishing to have children, this is important as it may enable a uterus-sparing management strategy (17). After NACT and fertility-sparing surgery, 50% of the women became pregnant and 40% gave birth to a living child (19). In a meta-analysis including 88 pregnant women, 80% of the children showed no perinatal morbidity and no developmental abnormalities later in life (20). In comparison, infant morbidity was less than 4% for all newborns in 2016 (21).

Positron emission tomography for diagnosis, treatment decision and aftercare

PET-CT plays no role in routine radiological diagnosis, because it does not allow to differentiate between superinfection and infiltrating tumor of the cervix (22, 23, 24). Based on new study data, PET-CT can be used in individual cases, for example, if no histological confirmation of the involvement of para-aortic lymph nodes is obtainable or to select patients for histological confirmation (25, 26). Possible reasons for not obtaining histological confirmation include reduced general condition of the patient, her condition after para-aortic nodal irradiation or status post multiple previous surgical procedures. In all other cases, histological confirmation should obtained first. With 94%, PET-CT offers superior specificity in the detection of lymph node metastasis compared to MRI, whereas MRI offers with 88% superior sensitivity in the detection of lymph node metastasis (27). In the recurrence situation, PET-CT may be performed to rule out lymph node and distant metastases in patients in whom a further local treatment (radio(chemo)therapy [R(CH)T], exenteration) is considered.

Palliative chemotherapy

Patients with established distant metastasis are treated with palliative pharmacotherapy. The standard so far has been cisplatin-based combination therapy. Cisplatin can be replaced by carboplatin with the same efficacy, especially in patients with impaired renal function. An RCT showed that platinum-naïve patients benefit from cisplatin in comparison to carboplatin in terms of overall survival (median survival 13 months versus 23 months, HR 1.57; [1.06; 2.23]) (28).

In the first-line treatment of metastatic cervical carcinoma, the addition of bevacizumab improved overall survival in the randomized, controlled, phase 3 GOG240 trial (13.3 months versus 16.8 months; HR 0.77; [0.062; 0.95]); p = 0.007) (29).Bevacizumab increased the rate of adverse events, such as arterial hypertension, thromboembolic events, neutropenia, or gastrointestinal fistula.

In patients with PD-L1-positive cervical carcinoma (CPS score ≥= 1), the checkpoint inhibitor pembrolizumab (200  mg q3w) is a further option for second or higher lines of treatment. In the single-arm phase 1b Keynote-028 trial, the overall response rate with pembrolizumab was 17% [5%; 37%] in cervical carcinoma patients with PD-L1 expression who had received multiple previous treatments. The median duration of response was 5.4 months (4.1–7.5 months) (30). In a single-arm basket trial (Keynote-158, phase II), the overall response rate was 14.6% [7.8%; 24.2%]. An overall survival of 11 months [9.1; 14.1 months] was reported for women with PD-L1-positive cervical carcinoma.

The most common side effects were rash (21%), pyrexia (17%), hypothyroidism (11.2%), and hyperthyroidism (9.2%) (31). In the United States, pembrolizumab is already approved for the treatment of patients with metastatic cervical carcinoma. In Germany, the treatment is provided once the health insurance has agreed to cover the costs.

Neuroendocrine carcinoma

Neuroendocrine cervical carcinoma (NECC) is a rare high-risk form of cervical carcinoma (0.9%–1.5%) (32, 33). The WHO classification (2014) distinguishes between poorly differentiated NECC (small-cell or large-cell neuroendocrine cervical carcinoma) and well-differentiated NECC (typical and atypical carcinoid) (34, 35). Compared to adenocarcinoma or squamous cell carcinoma, NECC has a poor prognosis, in both types independent of treatment (36, 37, 38) and independent of whether neuroendocrine differentiation is present alone or in combination with a non-neuroendocrine component.

Five-year survival rates range from 34% to 37% with a mean overall survival of 40 months (39, 40). The mean recurrence-free survival is 16 months (40). In earlier stages (FIGO I–IIA), radical hysterectomy is the treatment of choice, optionally followed by adjuvant chemotherapy (HR 0.84; [0.64; 1.09]) or a primary neoadjuvant approach. Radical hysterectomy is the most common treatment and appears to show the best survival rates (39, 40). Patients with locally advanced NECC (IIB–IVB) or recurrence receive combined radiochemotherapy or chemotherapy (39, 40) (HR 0.42; [0.23; 0.76]).

Discussion

For most of the research questions, only few well-founded and sometimes heterogeneous data are available. The evidence of the available studies is low. There is a lack of large prospective randomized trials. Numerous single-center studies with usually small sample sizes have investigated various technical aspects, but no large prospective randomized trials have been developed on the basis of their findings. This applies to surgical and medical management as well as radiotherapy. Due to the very low total number of cases compared to other organ entities (in Germany less than 5000 primary cases per year), the economic and scientific incentive to provide the necessary basis for the methodologically sound revision of the current version of this guideline is often lacking.

For many women with advanced cervical carcinoma, the prognosis is still poor. Most affected are women who have not participated in the organized early detection programs and consequently present with already advanced stage disease at the time of first diagnosis. This may explain the pattern of persistently high mortality and decreasing incidence. Improvements for the affected women have been achieved in various areas of care, especially with regard to surgical and medical management as well as radiotherapy. These are also associated with significantly prolonged survival. However, there is still a great need for research, especially on the systemic treatment of advanced/metastatic cervical carcinoma.

Conflict of interest statement
Prof. Beckmann received funding for the preparation of the guideline from the German Cancer Aid (DKH, Deutsche Krebshilfe).

Dr. Koch received consulting and lecture fees from Roche. He holds shares in Roche and Bayer.

Mr. Horn received reimbursement of travel expenses related to the preparation of the guideline from the German Cancer Aid (DKH).

Prof. Fehm received honoraria for a membership in a data monitoring committee or advisory board from Merck Sharp & Dome (MSD).

The remaining authors declare that no conflict of interest exists.

Manuscript received on 16 August 2021; revised version accepted on 4 October 2021

Clinical guidelines are not peer-reviewed in the Deutsche Ärzteblatt, as well as in many other journals, because clinical (S3) guidelines are texts which have already been repeatedly evaluated, discussed and broadly consented by experts (peers).

Translated from the original German by Ralf Thoene, MD

Corresponding author
Prof. Dr. med. Matthias W. Beckmann
Frauenklinik des Universitätsklinikum Erlangen
Universitätsstraße 21–23
91054 Erlangen, Germany

Cite this as:
Beckmann MW, Stuebs FA, Vordermark D, Koch MC, Horn LC, Fehm T: Clinical practice guideline: The diagnosis, treatment, and aftercare of cervical carcinoma. Dtsch Arztebl Int 2021; 118: 806–12. DOI: 10.3238/arztebl.m2021.0352

►Supplementary material

eTables, eBox: www.aerzteblatt-international.de/m2021.0352

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