Radiotherapy of Cervical Cancer

Developments in External-Beam Radiotherapy

Although computed tomography (CT)-planned 3-dimensional (3D)-conformal external-beam radiotherapy of cervix cancer, including 3D contouring of target volumes and adjacent normal structures (‘organs at risk') has been implemented internationally since the 1990s, such techniques were not mandatory in most randomized trials on which current evidence-based recommendations are founded. In particular, simple opposing (anterior-posterior) techniques or 4-field techniques without CT-based contouring or dose calculation were permitted, leading to potentially compromised dose coverage of target volumes and limitations in protecting adjacent organs (e.g. small bowel, rectum, bladder). Therefore, accurate planning and delivery of external-beam radiotherapy have the potential to contribute to improved tumor control and less toxicity compared to previously published data.

Intensity-modulated radiotherapy (IMRT) and volume-modulated arc therapy (VMAT) represent such advanced techniques allowing precise dose delivery and maximum dose reduction in normal tissues. The benefits of IMRT in toxicity reduction have been shown in a small randomized trial in 44 patients with cervical cancer stages II B-IIIB [9]: In a concept with high-dose rate (HDR) brachytherapy of 3 × 7 Gy and weekly cisplatin 40 mg/m² for all patients, the external-beam radiotherapy of the pelvis to 50.4 Gy was given via conventional planning (4-field box techniques using boney landmarks for field definition, no blocks or shielding) versus via IMRT using defined CT-based target volume concepts. While oncologic outcomes appeared similar for both approaches, acute gastrointestinal toxicity grade ≥ 3 (5% vs. 27%) and chronic gastrointestinal toxicity (14% vs. 50%) were drastically reduced by the use of IMRT. In addition to the protection of tumor-adjacent organs, IMRT has also been used to selectively increase the dose of radiotherapy in defined tumor volumes. For tomotherapy, a modality of IMRT, the delivery of a total radiotherapy dose of 50.4 Gy in fractions of 1.8 Gy, with a simultaneous integrated boost (SIB) to the bilaterial clip-marked parametria (single dose 2.12 Gy, total dose 59.36 Gy) has been described as feasible and associated with low toxicity [10]. Consensus guidelines for contouring of the tumor target volumes for IMRT have been published [11].

The role of surgical staging of cervix cancer and the consequences for radiotherapy, e. g. the need to include the paraaortic region in the treated volume, are a matter of continuing debate. A Cochrane review of pre-treatment surgical lymph node involvement in women with advanced cervical cancer (stages IB2-IVA) found only insufficient evidence that surgical staging is beneficial and recommended individual patient counseling [12]. The German S3 Guideline for Diagnostics, Treatment and Follow-up of Cervical Cancer advocates surgical staging to enable treatment recommendations based on the true histopathologic extent of disease. Most recently, Marnitz et al. [13] reported first acute toxicity and treatment quality data of a trial in which 255 patients with stage IIB-IVA cervix cancer were randomized to clinical staging (CT abdomen, biopsy of suspicious paraaortic nodes) or to surgical staging including pelvic and paraaortic lymphadenectomy before concomitant chemoradiation including HDR brachytherapy and weekly cisplatin. Inclusion of the paraaortic region in the radiotherapy target volume (‘extended-field radiotherapy') was based on the results of the respective staging method. As a consequence, 23% of surgically staged patients and 12% of clinically staged patients received extended-field radiotherapy. There was a trend to more frequent higher-grade anemia in the surgically staged patients (54% grade 2, 10% grade 3) compared to clinically staged patients (45% grade 2, 6% grade 3). Oncologic outcome results are expected in 2019.

Developments in Brachytherapy

Intracavitary brachytherapy is a key element of the treatment concept for radical radiotherapy or chemoradiation of cervix cancer. It has been shown in large patient series that omission of brachytherapy results in a severe reduction in the curative potential of the treatment [14]. Traditionally, the brachytherapy dose has been prescribed to a defined point according to the ‘Manchester System', not taking into account individual patient anatomy or tumor extent. Typical brachytherapy dose concepts (in combination with external beam radiotherapy doses of 45 to 50 Gy) contained 3-5 fractions with doses of 5-7 Gy each. In recent years, individualized planning of brachytherapy of cervix cancer has been broadly introduced.

In Europe, this process was predominantly advanced by the GYN GEC-ESTRO Working Group (Gynaecological Groupe Européen de Curiethérapie, European Society for Radiotherapy and Oncology), which in a number of published recommendations defined the procedures of image-based 3D treatment planning of brachytherapy: This included the definition of a common terminology for the delineation of tumor and target volumes [15], the correct application of dose-volume histograms to report dose distributions in target volumes and adjacent organs [16], the methods of brachytherapy applicator commissioning and reconstruction in the planning process [17,] and the principles of magnetic resonance imaging (MRI) for the purpose of brachytherapy planning [18].

Using such advanced brachytherapy concepts, excellent results have been presented from institutions with large experience. The Medical University of Vienna reported, for the treatment period 2001-2008, a 3-year overall survival in stages IB, IIB, and IIIB of 74%, 79%, and 45%, with a corresponding 3-year cause-specific survival of 83%, 84%, and 52% [19]. The introduction of MRI-guided brachytherapy has been evaluated in the international prospective observational study EMBRACE, which has recently completed accrual.

A novel concept is to emulate the dose distribution achieved by intracavitary brachytherapy by external-beam techniques such as stereotactic radiosurgery. Comparative planning studies showed good dose coverage of the target volumes by stereotactic techniques [20]. Low toxicity and favorable early tumor control has been reported for such an approach in patients who could not undergo brachytherapy [21].

Developments in Systemic Therapy as Part of Chemoradiation

Using concomitant chemoradiation with cisplatin alone as backbone, intensification of the systemic component has been pursued by intensifying concomitant chemotherapy, by adding sequential chemotherapy cycles, or both. In addition to classic chemotherapy agents, molecular targeting agents have also been evaluated.

In a randomized trial in 515 patients with stage IIB-IVA cervical cancer, external-beam radiotherapy with 50.4 Gy plus LDR brachytherapy plus concomitant 6 cycles of cisplatin weekly 40 mg/m² was compared to the same treatment with additional concomitant gemcitabine 125 mg/m² weekly plus 2 sequential cycles of cisplatin 50 mg/m² (day 1) and gemcitabine 1000 mg/m² (days 1 and 8) [22]. Adding gemcitabine in the concomitant phase plus adding the 2 sequential cycles did lead to a significant improvement in the primary endpoint of progression-free survival at 3 years (74.4% vs. 65%) and also in overall survival. However, the trial was criticized for the increase in hematologic toxicity in the intensified treatment arm (grade 3/4: 72% vs. 24%). The treatment approach has not been generally accepted, as the trial was performed in part in less developed countries and the radiotherapy per protocol was not optimal by current standards.

A smaller matched-pair analysis, however, also suggested a potential benefit of adding sequential chemotherapy, in this case 3 cycles of cisplatin 60 mg/m² (day 1) and 5-fluorouracil 1000 mg/m² (days 1-5) to concomitant cisplatin-based chemoradiation [23]. Here, improved overall survival (93% vs. 70%) was observed in the group with consolidation chemotherapy and this was explained predominantly by reduced distant metastases.

In an earlier 4-arm trial, adding 3 cycles of oral 5-fluorouracil to either radiotherapy alone or to radiotherapy with concurrent mitomycin C and oral 5-fluorouracil did not significantly improve survival [24].

Based on the positive survival effects of integrating vascular endothelial growth factor (VEGF) targeting by bevacizumab in recurrent or metastatic cervix cancer [25], bevacizumab has also been included in experimental protocols of radical, curative-intent chemoradiation for cervix cancer. In the phase II trial RTOG 0417, patients with cervical cancer stages FIGO IIB-IIIB (or IB-IIA with histologically proven pelvic nodal metastases or IIA > 5 cm) were treated with pelvic radiotherapy to 45 Gy HDR brachytherapy 5 × 6 Gy (or LDR brachytherapy), 6 cycles of weekly cisplatin (40 mg/m²) and bevacizumab 10 mg/m² (every 2 weeks, 6 cycles) [26]. Sequential systemic therapy was not given. The investigational treatment was safe and an intertrial comparison, with all inherent limitations, with the chemoradiation arm of the above-mentioned trial RTOG 90-01 [2] suggested a potentially favorable survival outcome for the addition of bevacizumab, with a 3-year overall survival of 80.2% compared to 76.8% in the reference arm.

The quality of chemoradiation in cervix cancer has recently been assessed in national and international surveys and patterns-of-care studies: in the US, 65% of randomly selected patients receiving radiotherapy for cervix cancer (period 2005-2007) began treatment in a facility which treated 3 or less patients with this indication per year. Small, non-academic facilities frequently provided protracted or incomplete treatment or failed to give concurrent chemotherapy [27]. In a separate analysis in the US, hospitals with a high case volume had higher rates and more consistent patterns of delivering concomitant chemotherapy; patients who received radiotherapy alone had a worse prognosis [28]. In a 2012 survey in Germany, 87% of institutions indicated that they treated 0-25 patients per year, concomitant cisplatin monotherapy was preferred by 90% of responders and HDR brachytherapy as boost technique in 84% [29].