8. Foundations of treatment – Cervical Carcinoma

The imaging procedures CT, MRI, and FDG-PET-CT are not sufficiently sensitive and specific for certain detection of lymph-node metastases [308], [309], [310], [311]. As an example, mention may be made of a meta-analysis including 72 studies and 5042 patients, which compared the sentinel method in cervical carcinoma with the various imaging methods (CT, MRI, PET-CT) in relation to the detection of a lymph-node metastases [311]. The study reported a sensitivity of 91.4% in comparison with 74.7% (for PET-CT), 55.5% (for MRI), and 57.5% (for CT) and a specificity of 100% in comparison with 97.6% (for PET-CT), 93.2 % (for MRI), and 92.3 % (for CT). This indicates the superiority of the sentinel method over the imaging techniques.

Small metastases in particular often remain undetected on conventional imaging (see Chapter 6). On the other hand, systematic lymphadenectomy is associated with a substantial rate of intraoperative and postoperative complications (paresthesias, lymphoceles, lymphedema, etc.). The approach using sentinel lymph-node detection in specific conditions in primary cervical carcinoma therefore appears reasonable and recommendable in specific conditions (see recommendation 8.3.). However, the SENTICOL I study showed that after 6 months at the latest, no differences in lymphedema symptoms were detectable between the groups compared (radical lymphadenectomy vs. sentinel-node lymphadenectomy) [312].

In this context, with cervical carcinoma as a “midline tumor,” the sentinel method appears to have sufficient safety only in the case of a primary tumor < 2 cm in size, with combined imaging using patent blue and radioactive tracer, and bilateral imaging of sentinel lymph nodes [310]. However, the more recent Senticol studies include patients with tumors up to 4 cm. Full publications with the results have not yet appeared, however [312]. In the meantime, intraoperative imaging of sentinel lymph nodes using ICG is at least equivalent to combined imaging using radioactive tracer and patent blue [305].

The sentinel-node approach in women with cervical carcinoma has now been under evaluation for more than 15 years. However, the great majority of the available publications only report single-center and retrospective experience, so that their validity is limited. In the largest prospective, multicenter study to date (AGO Uterus 3), including a total of 590 patients, the rate of detection was 94% when technetium and patent blue were used in combination for marking. In addition, subsequent stratification between tumors > 2 cm and < 2 cm showed that the decisive negative predictive value only reached acceptable values (< 99%) with small tumors [309].

The superiority of the combined use of technetium and patent blue in relation to detection rates (94–97%; cf. Tax et al. 2015 and Wang et al. 2014) has in the meantime been confirmed by various meta-analyses and systematic reviews.

The same applies to dependence on tumor size. As an example, a 2014 meta-analysis by Kadkhodayan et al. may be mentioned here. In the study, the pooled analysis showed a detection rate of 94% and a sensitivity of 95% for tumors  2 cm, for which the detection rate was only 74% and the sensitivity 82%.

The need for bilateral imaging was described by Cibula et al. in a publication including 645 patients. In this study, the authors detected a significantly higher rate of lymph-node metastases in comparison with unilateral detection alone [313].

The certainty provided by bilateral detection is also confirmed by data from the prospective SENTICOL I study [312], in which not a single false-negative sentinel lymph node finding was noted in 104 patients in whom bilateral imaging was successful.

Previously, lymph-node marking using patent blue and a radioactive tracer was regarded as the standard sentinel method for cervical carcinoma [314], [315]. The combination of the two methods provided the highest rates of detected lymph nodes and highest sensitivity levels for positive lymph nodes (sensitivity 91.3%; 95% CI, 87.5 to 94.2) [316].

In recent years, the use of indocyanine green (ICG), visualized with “near-infrared” fluorescence filters, has increasingly become established as a valid alternative (however, this use is off-label). The advantage is that radioactive substances and patent blue (with an allergenic potential in pregnancy) can be completely avoided [306].

A systematic review including 538 patients showed that ICG achieves equivalent detection rates in comparison with the combination of technetium and patent blue (OR 0.96; 95%: CI, 0.45 to 2.02; P = 0.91). For detection of bilateral lymph nodes, ICG tended to be superior to the combination of patent blue and radioactive tracer, but without reaching statistical significance (OR 0.37; 95% CI, 0.07 to 2.12; P = 0.27) [305].

With regard to histological processing of the tissue, what is known as ultra-staging should be used in analogy with breast carcinoma in order to achieve a sufficiently high rate of detection of any metastases that are present. This technique is discussed in detail in Chapter 7, Pathology.

Sentinel lymphadenectomy alone is therefore still not a standard procedure for all stages. The great majority of studies to date only refer to the sentinel technique in conjunction with systematic lymphadenectomy and do not have any data regarding survival. Only limited conclusions can therefore be drawn regarding the safety of sentinel lymphadenectomy alone. In addition, the maximum tumor size of 2 cm [309] for achieving adequate safety with the method is based on retrospective analyses.

The primary goals in the planned prospective randomized phase III study (Senticol III; ClinicalTrials.gov identifier: NCT03386734) are the 3-year disease-free survival rate and quality of life in patients with early cervical carcinoma. For this purpose, patients are to be randomized 1 : 1 into the following two groups: sentinel lymph-node extirpation vs. pelvic systematic lymphadenectomy. A total of 950 patients are to be included. The study will hopefully provide a conclusive answer to the question of the safety of this technique, with the highest level of evidence. The study also includes higher-stage tumors (FIGO IA1 to IIa1) [312].

The publication of a comparable prospective and randomized study by the AGO/ARO, including 1200 patients, for evaluation of the sentinel approach is also pending at the time of the revision of the guideline (NCT01157962). However, the authors of the guideline consider that the data are sufficient for the method to be recommended in the conditions mentioned, particularly in view of the low rate of lymph-node metastases in early stages (TIA1 + L1, IA2, IB1 < 2 cm).

In the context a lymphadenectomy for cervical carcinoma, a distinction is made on the one hand between the different anatomical lymph drainage areas (pelvic and para-aortic) that drain the uterus.

Different terms are also used in the literature in relation to the radicality of a lymphadenectomy. These are explained below to allow better understanding of the recommendations.

In general, assessment of the parametrial, vesicouterine, and peritoneal spread is possible or useful in the context of a histological lymph-node evaluation.

Radical lymphonodectomy

The aim in radical systematic lymphadenectomy is to remove all lymph nodes along the lymphatic tracts in the corresponding lymphatic drainage area. It is used for diagnosis (supplemented by quick-section examinations) and treatment. Validated data on the number of lymph nodes that need to be removed per lymphatic drainage area in order to achieve sufficient safety are not available to the guideline group. At least 15–20 pelvic lymph nodes and 8–10 para-aortic lymph nodes can be used as an indication.

Systematic pelvic lymphadenectomy includes the removal of all lymph nodes and adipose tissue in the area of the pelvic vessels. The lymphatic vessels and lymph nodes medial and lateral to the external and internal iliac artery, around the common iliac artery, and in the area of the obturator artery and vein are removed as far as the pelvic floor.

If there is pelvic lymph-node involvement, para-aortic lymphadenectomy is carried out along the aorta and vena cava as far as the end of the renal vessels.

Selective lymph node staging

Selective lymph-node staging is used for histological diagnosis. An attempt is made to remove a representative number of lymph nodes from the corresponding lymphatic drainage areas in order to define the stage.

In principle, this procedure is not recommended by the guideline group, as no valid data are available regarding the benefit of the technique.

Lymph node debulking

Lymph-node debulking is an attempt in the advanced setting (≥ FIGO stage IIB) to remove at least the macroscopically affected lymph nodes in order to reduce the tumor size before primary radio(chemo)therapy.

Therapeutic lymphonodectomy

Therapeutic lymphadenectomy is a term that can only be viewed in connection with total mesometrial resection (TMMR). In this procedure, systematic radical lymphadenectomy is carried out along the anatomic and embryonic developmental borders in order to avoid adjuvant radio(chemo)therapy despite lymph-node involvement. As only single-center data are available, this approach cannot currently be regarded as a standard procedure [317], [318].

Sentinel lymphonodectomy

Sentinel lymphadenectomy is carried out similarly to the already established procedure in breast carcinoma. The aim is to achieve sufficient diagnostic/oncological certainty with maximum tissue-sparing. The sentinel lymph nodes are initially detected bilaterally and then removed. The sentinel procedure is also used in parallel with radical lymphadenectomy. In addition to its low morbidity, this technique can potentially detect unusual lymphatic drainage pathways [10] or increase the detection rate of micrometastases through the use of histologic ultrastaging [8]  [15]. The role of detection of intrauterine nodes (Lucas-Championnière lymph nodes) and/or parametrial lymph nodes is unclear. These lymph nodes are difficult to detect with the sentinel technique using technetium, due to their proximity to the primary tumor [319].

Stage pT1a1 is associated with lymphatic infiltration (L1) in approximately 4.4% of cases (invasion depth < 1 mm) to 16.4% of cases (invasion depth 1–3 mm). In the absence of this risk factor, positive lymph nodes are found in fewer than 1% of the patients; in L1, the rate rises to more than 8% [329]. Lymphadenectomy is therefore not indicated in stage pT1a1 with the presence of up to one risk factor [330]. In patients with pT1A1 cervical carcinoma and lymphatic infiltration (L1), the guideline group recommends bilateral sentinel lymphadenectomy (SNB) (see recommendation 8.11.).

With the surgical procedures, the patient must have the advantages and disadvantages of the various treatment procedures explained (e.g., conization vs. cervicectomy vs. simple hysterectomy). Data on conization are mainly available for preinvasive lesions. The guideline group accepts the argument by analogy here for microinvasive cervical carcinoma. Conization is preferably carried out in the form of high-frequency loop excision (loop electrosurgical excision procedure, LEEP / large loop excision of the transformation zone, LLETZ), or as laser conization. The two procedures are oncologically comparable and can be used depending on the local circumstances and the operator’s level of experience [331][332][333][334]. Earlier guidelines already rejected scalpel conization and in particular the Sturmdorf suture [1]. The Sturmdorf suture is rejected because of the markedly altered postoperative anatomy, which makes adequate follow-up care difficult or almost impossible [332][334]. The recurrence rate is also low after conization alone (with negative resection margins) [335].

In simple hysterectomy in patients who are not wishing to have children, the various access routes (vaginal, abdominal, laparoscopic) can be regarded as equivalent. The choice can be based on the patient’s preferences and general surgical principles.

The stage-dependent risk factors as the basis for treatment are presented in section 7.3, Table 13 (Microinvasive carcinoma) and Table 14 (Macroinvasive carcinoma).

If there are histologically negative sentinel lymph nodes bilaterally, the sentinel methods alone can be carried out in patients with microinvasive tumors (IA1–IA2) and a maximum of two risk factors (see chapter 8.1.1.2).

The stage-dependent risk factors as the basis for treatment are presented in section 7.3, Table 13 (microinvasive carcinoma) and Table 14 (macroinvasive carcinoma).

In the present guideline, R(CH)T means simultaneous radiochemotherapy with cisplatin as a radiosensitizer (for details, see section 8.6.2.4).

In stage pT1a2 (depth of invasion 3.1–5.0 mm), affected lymph nodes are already found in 8.3% of cases even without infiltration of the lymphatic vessels, so that pelvic lymphadenectomy or pelvic lymph-node staging (bilateral sentinel lymphadenectomy) should be carried out [329]. It is unclear whether radical cervicectomy offers greater safety in comparison with conization (with free resection margins) in stage pT1a2 without infiltration of the lymphatics. Parametrial involvement is unlikely at this stage, so that the benefit of radical cervicectomy in comparison with conization (or simple cervicectomy) in these early stages cannot be clearly assessed. Radical cervicectomy is associated with a higher morbidity rate [336] [337] [338] [339]. 

In all of the published retrospective studies, an organ-preserving procedure is equivalent to other procedures when there is an infiltration depth of < 5 mm and despite the additional presence of individual risk factors (L1, V1 G3 ?) [340] [341]. Even when the patient is not wishing to preserve her fertility, there is no indication from the oncological point of view for carrying out a hysterectomy [340] [341]. If the patient wishes maximum safety, a simple hysterectomy can be discussed with them.

Patients in stage pT1a1/pT1a2 with several risk factors and organ preservation must be informed preoperatively that adjuvant postoperative radio(chemo)therapy is recommended if there are three or more risk factors postoperatively. This is not compatible with fertility preservation, however.

The stage-dependent risk factors as the basis for treatment are presented in section 7.3, Table 13 (microinvasive carcinoma) and Table 14 (macroinvasive carcinoma).

In the present guideline, R(CH)T means simultaneous radiochemotherapy with cisplatin as a radiosensitizer (for details, see section 8.6.2.4).

Patients with cervical carcinoma up to FIGO IB1 should be offered open radical hysterectomy (see recommendation 8.14.). This recommendation is based on a randomized and controlled study by Ramirez et al. A total of 631 patients with FIGO IA1–IB1 cervical carcinoma were randomly assigned to undergo either laparoscopic radical hysterectomy (including robotic surgery) or abdominal open radical hysterectomy. The study does not allow conclusions to be drawn about stages IIA1 and IIA2. The exact data are presented in Chapter 9, Surgical treatment.

The stage-dependent risk factors as the basis for treatment are presented in section 7.3, Table 13 (microinvasive carcinoma) and Table 14 (macroinvasive carcinoma).

In the present guideline, R(CH)T means simultaneous radiochemotherapy with cisplatin as a radiosensitizer (for details, see section 8.6.2.4).

The guideline group’s recommendation is based at the expert level. The underlying data are presented in Chapters 9 and 10, section 8.3, and Chapters 11 and 18.

The stage-dependent risk factors as the basis for treatment are presented in section 7.3, Table 13 (microinvasive carcinoma) and Table 14 (macroinvasive carcinoma).

In the present guideline, R(CH)T means simultaneous radiochemotherapy with cisplatin as a radiosensitizer (for details, see section 8.6.2.4).

Despite a systematic search (see the Guideline Report), it was not possible to identify any studies that would allow a clear answer to the question of whether radical hysterectomy offers any benefits for the patient with pelvic and/or para-aortic lymph-node metastases, in relation to disease-free survival or overall survival. In view of the increased morbidity due to the combination of procedures (see also Chapter 9), the guideline group is of the opinion that no benefit for the patient can therefore be assumed. The patient should in any case be informed about the increased morbidity resulting from the standard operation and radio(chemo)therapy.

Chapter 17, Local recurrenceThe data on which this recommendation is based are presented in Chapter 17, Local recurrence. The specific situations in which exenteration is possible are also presented there. Overall, the state of the data is very limited here as well. A recent Cochrane review in 2014, for example, which examined the efficacy and safety of exenterative procedures in gynecological malignancies (not including ovarian carcinoma) in comparison with other treatment options was not able to identify any RCTs meeting the inclusion criteria [342].

In the present guideline, R(CH)T means simultaneous radiochemotherapy with cisplatin as a radiosensitizer (for details, see section 8.6.2.4).

In this Level 3 guideline, the term “palliative therapy” includes the complete treatment of patients with incurable disease. This is the case, for example, in the metastatic or locally advanced situation (≥ FIGO stage IIB). “Palliative therapy” thus means not exclusively the specialized palliative medicine administered after the completion of oncological therapy. Palliative therapy takes place with various stage-dependent and situation-dependent aims: (1) improving quality of life, (2) symptomatic control, and (3) prolonging life. The interdisciplinary conference is a good opportunity for establishing which of these goals is the priority for the patient in each situation. A treatment recommendation such as “further therapy with palliative considerations” is too unspecific in this context.