11. Drug treatment – Cervical Carcinoma

The standard in the treatment of patients with cervical carcinoma in stages ≤ FIGO stage II is either surgery or radio(chemo)therapy (see Chapter 8, Foundations of treatment). Randomized controlled studies comparing radiotherapy with or without simultaneous chemotherapy were carried out in the mid-1990s (see section 10.1.4, Indication for primary radiotherapy or radio(chemo)therapy).

The agent used for drug treatment was usually cisplatin monotherapy. Combination drug therapies did not show any significant improvement in the progression-free or overall survival, although they had increased toxicity [391], [392], [393], [463], [464], [465], [466], [467], [468] (see section 10.1.4). In the primary and adjuvant situations, none of the studies showed any benefit from using additional targeted therapy alongside chemotherapy. The standard treatment protocols in the primary situation are therefore currently protocols without targeted therapy.

Systemic chemotherapy, as an integral component of combined radio(chemo)therapy, is one of the standards in the primary treatment of patients with cervical carcinoma [391], [392], [393], [468]. Targeted therapies have a potential benefit only on the basis of the data from the GOG-240 study in the primary metastatic, persistent, or recurrent situation, with an increased range of side effects (see section 18.3.5.1, Targeted therapy). The individual treatment goals must be discussed with the patient here (see recommendation 8.6).

The same principle also applies to adjuvant radio(chemo)therapy, in which research studies have also shown an advantage for radio(chemo)therapy in comparison with radiotherapy alone [107], [272], [394], [469] (see also section 10.1.5, Adjuvant radio(chemo)therapy). Due to the increased morbidity resulting from the combination of several procedures, the unimodal principle applies: surgery alone or radio(chemo)therapy alone after histological definition of the irradiation field [470] (see Chapter 8, Foundations of treatment).

Two option in primary treatment are currently the subjects of critical debate: neoadjuvant chemotherapy and extended adjuvant chemotherapy after the completion of surgical treatment or radio(chemo)therapy.

Administration of neoadjuvant chemotherapy (NACT) has been shown to have advantages in relation to several organ cancers, particularly with regard to local operability (e.g., Level 3 guideline on “Diagnosis, Treatment, and Follow-up of Breast Cancer,” AWMF register no. 032/045OL, version 4.3) [471]). This treatment principle has therefore also been included in studies on patients with cervical carcinoma. A 2012 Cochrane analysis showed that neoadjuvant chemotherapy — planned before subsequent surgery — at a dosage of cisplatin > 25 mg/m² per week and with an interval for total administration of less than 14 days leads to a longer progression-free survival (HR 0.75; 95% CI, 0.61 to 0.93; P = 0.008) and overall survival (HR 0.75; 95% CI, 0.62 to 0.96; P = 0.02) [324] When the random effect model was used, the effect was no longer significant (OR 0.60; 95% CI, 0.32 to 1.12; P = 0.11). Due to the small numbers of patients in the six studies on which the analysis was based (n = 1078), the authors continue to recommend that this should not be used outside of research studies.

A 2016 meta-analysis did not show any improvement in the progression-free survival, overall survival (overall survival: OR 1.17; 95% CI, 0.85 to 1.61; P = 0.35) or disease-free survival (OR 1.09; 95% CI, 0.77 to 1.56; P = 0.62) with neoadjuvant chemotherapy [326]. This meta-analysis included 739 patients from five RCTs. A significant reduction in lymph-node metastases (OR 0.45; 95% CI, 0.29 to 0.7; P = 0.0005) and parametrial infiltration (OR 0.48; 95% CI, 0.25 to 0.92; P = 0.03) was observed, but with no effect on the overall or disease-free survival. In a phase III study, patients with cervical carcinoma FIGO IB2–IIB were randomly assigned to receive either NACT (bleomycin 7 mg on days 1–5, vincristine 0.7 mg/m2 on day 5, mitomycin 7 mg/m² on day 5, cisplatin 14 mg/m² on days 1–5) along with radical hysterectomy, or radical hysterectomy directly. A total of 134 patients were randomized equally to the two arms. The study was terminated early after the first interim analysis 4 years after study entry due to inferiority of patients in the NACT arm (HR 2.11; 99% CI, 0.34 to 13.2). The rate of adjuvant radiotherapy was significantly reduced in the NACT arm (58% vs. 80%) [472]. chemotherapy. The recurrence rate was significantly higher in the intervention arm than in the control arm (10 vs. six recurrences) [473]. In a meta-analysis of 1302 patients with cervical cancer (FIGO IB–IIB), no significant differences in the overall survival were observed between patients who received neoadjuvant chemotherapy and those who received direct surgery (OR 1.07; 95% CI, 0.48 to 2.41; P = 0.86). However, the rate of positive lymph-node metastases was significantly reduced by neoadjuvant chemotherapy in this meta-analysis (OR 0.57; 95% CI, 0.41 to 0.79; P = 0.0008) [474].

Neoadjuvant chemotherapy followed by surgery versus primary radiochemotherapy was compared in an RCT including 633 patients. Patients with cervical carcinoma FIGO IB2–IIB were included. Three cycles of carboplatin AUC5 or AUC6 d1, q21d and paclitaxel 175 mg d1, q21d were administered. The primary end point was disease-free survival. Primary radiochemotherapy was superior to the combination of neoadjuvant chemotherapy and radical hysterectomy in relation to disease-free survival (HR 1.38; 95% CI, 1.02 to 1.87; P = 0.038). A clinically nonsignificant advantage in terms of overall survival was observed for neoadjuvant chemotherapy in combination with radical hysterectomy (75.4% vs. 74.7%; HR 1.025; 95% CI, 0.752 to 1.398; P = 0.87). Hematologic side effects markedly predominated in the group of patients receiving neoadjuvant chemotherapy [406].

The decisive aspect for the effectiveness of neoadjuvant chemotherapy is the response rate during therapy. Several meta-analyses have shown an improvement in overall survival, progression-free survival, and disease-free survival between responders and nonresponders [475], [476], [477], [478]. In a meta-analysis including 4727 patients with cervical cancer (FIGO IB2–IVa), Zhu et al. noted an improvement in overall survival among clinical responders (HR 3.36; 95% CI, 2.41 to 4.69). The hazard ratio was even higher in patients who had a pathological response (HR 5.45; 95% CI, 3.42 to 8.70). Effects were also evident for disease-free survival [475]. In another meta-analysis, the odds ratio for 5-year survival was 5.785 (95% CI, 4.124 to 8.115) [476].
A major, although experimental, indication for neoadjuvant chemotherapy in cervical cancer is the desire to preserve fertility in women of childbearing age. The guideline group had two systematic reviews on this topic available to it. Laios et al. included a total of seven trials including 86 patients with cervical carcinoma who were of childbearing age. Most of the chemotherapy protocols were cisplatin-based. After neoadjuvant chemotherapy and fertility-preserving surgery, five of ten women became pregnant (0.49; 95% CI, 0.32 to 0.66) and four of ten women had live births (0.42; 95% CI, 0.32 to 0.53) [479]. In another meta-analysis including 88 pregnant women who received neoadjuvant chemotherapy for cervical cancer, 80.7% of the infants were healthy at birth. After a median follow-up period of 17 months, all of the infants were healthy. The mean weight of the neonates was 2163.2 g. Long-term data were available for 81 women. Among them, 16 (19.8%) had recurrences and 11 (90%) died of cervical cancer [325].

Neoadjuvant drug treatment may be offered to patients if risk factors have already been found during the preoperative diagnostic work-up that establish a need for postoperative radiochemotherapy (see recommendation 8.6). This is the case in the following clinical situations:

• Bulky disease, with a tumor size of more than 4 cm documented on imaging
• Imaging suspicion of positive lymph nodes
• Presence of several histopathologically defined risk factors such as G3, L1, V1

When the indication for carrying out neoadjuvant chemotherapy is being established, the benefits and risks need to be weighed up against each other. According to the available literature, the intention in neoadjuvant drug therapy is to improve operability, as it reduces the incidence of positive lymph nodes and parametrial infiltration [480], [324]. Neoadjuvant drug chemotherapy also reduces the need for adjuvant radiochemotherapy (OR 0.57; 95% CI, 0.33 to 0.98) [480]. These potential benefits have to be compared with the risks and side effects of dose-intensified platinum-containing chemotherapy (e.g., nephrotoxicity, ototoxicity, and hematological side effects).

Successful treatment with neoadjuvant chemotherapy can be documented using vaginal ultrasonography or magnetic resonance imaging of the pelvis. The decisive aspect here is that the same procedure should always be chosen that was used as the primary diagnostic procedure (see Chapter 6, Diagnosis). If surgery is carried out after neoadjuvant chemotherapy, it is currently unclear what effect tumor-involved lymph nodes after neoadjuvant chemotherapy have on the further treatment. It is also unclear what the surgical resection margins should be. Adequate assessment of the previous tumor spread is not possible intraoperatively. Surgery should therefore be carried out in the form that was previously planned.

With regard to adjuvant chemotherapy alone after surgery or after radiotherapy or radio(chemo)therapy, no conclusions can be reached due to the considerable heterogeneity of the studies and sometimes small numbers of patients. An indication for adjuvant chemotherapy has been established in high-risk patients with several risk factors — L1, V1, deep stromal infiltration, R1 resection or advanced tumors (≥ FIGO stage IIB). According to the published studies, consolidating chemotherapy after surgery or after the completion of radio(chemo)therapy does not lead to any certain improvement in overall survival, but involves increased toxicity [481] (see also section 10.1.7, Adjuvant chemotherapy after completed radio(chemo)therapy).