Highly conformal combined radiotherapy with cisplatin and gemcitabine for treatment of loco-regionally advanced cervical cancer – a retrospective study

Patients with histologically confirmed cervical cancer, FIGO stage IBI to IVA, treated with IMRT and concomitant combined chemotherapy with cisplatin and gemcitabine at the Bern University Hospital Department of Radiation Oncology were included in this retrospective study according to the institutional ethical standards.

We evaluated all medical and radiotherapy records, pretreatment and follow-up data as well as radiographic images of 17 patients treated between May 2011 and December 2015. Patient characteristics are summarized in Table 1.

All patients underwent a pretreatment staging workup as defined by institutional standards (medical history, general physical and gynecological examination under anesthesia, digital rectal examination, tumor biopsy, comprehensive laboratory blood analysis, rectoscopy and cystoscopy). Tumor staging was defined according to the International Federation of Obstetrics and Gynecology (FIGO) and the TNM-UICC system (7th edition). Further staging and radiotherapy as well as surgical treatment details are described in detail in our previously published work [9, 10].

Contouring: Image sets acquired by CT, diagnostic ¹⁸FDG-PET/CT and MRI were imported into the Eclipse Planning System (Varian Medical System, Palo Alto, CA). The gross tumor volume of the cervix (GTVc) was defined as the visible macroscopic tumor based on all of the available clinical and imaging data. Clinical target volume for primary tumor area (CTVc) encompassed GTVc, uterus, parametria and the upper third of the vagina. In cases of vaginal involvement, CTVc was expanded 2 cm into the vagina caudally of the tumor. The planning target volume of the primary tumor (PTVc) was created using anisotropic expansion, taking cervical and surrounding structure movements into consideration. The PTVc was expanded to 15 mm in the antero-dorsal direction and 10 mm in the lateral direction. PTVc was manually corrected when needed. In the dorsal direction PTVc margin extended maximally to the posterior rectal wall and maximally 1.5 cm anteriorly into the bladder [11].

Dose Prescription: In the first phase PTVc was irradiated with a total dose of 50.4 Gy. After 45 Gy a control MRI was performed to evaluate tumor response and measure tumor size. In cases where the remaining tumor was larger than 4 cm in diameter, an additional EBRT boost of 9 Gy was administered to the PTVc. Otherwise, for tumors smaller than 4 cm in diameter, the PTVc was irradiated with an EBRT boost of 5.4 Gy. The single dose used was always 1.8 Gy.

Dose Constraints: Dose constraints for organs at risk were standardized as follows: 60% of rectal volume should receive no more than 50 Gy, 35% of bowel volume should receive no more than 35Gy, 50% of bladder volume should receive no more than 50 Gy and 10% of the femoral heads volume should receive no more than 50 Gy.

Brachytherapy: EBRT was followed by a HDR boost to the primary tumor. We used a microSelectron® HDRB Unit and a Vienna Ring CT-MRI Applicator Set. MRI images were evaluated together with our radiology department to define the high and intermediate risk areas. Afterwards, we reconstructed the high risk and intermediate risk areas detected in the MRI images on our planning CT images [12, 13]. Brachytherapy consisted of a total dose of 18 Gy delivered in 4 weekly fractions, with a single dose of 6 Gy.

All patients were scheduled to receive cisplatin 40 mg/m² by intravenous infusion over 60 min followed by gemcitabine 125 mg/m² administered by intravenous infusion over 30 min once a week for 6 weeks, combined with radiation treatment on days 1–5 over 6 weeks respectively. Immediately after completion of the chemo-radiotherapy schedule, patients underwent brachytherapy (BCT) in week 7, followed by two weeks of rest. Thereafter patients underwent two consecutive 21-day cycles of adjuvant chemotherapy with cisplatin 50 mg/m² on day 1 and gemcitabine 1000 mg/m² on days 1 and 8. The treatment schema was based on rules defined by Dueñas-González et al. [8].

According to the internal standards of the University Hospital of Bern, multiple variables were controlled and were required to be met to fulfill the necessary safety requirements prior to each chemotherapy cycle: ECOG 0–2, thrombocytes >100 G/l, leucocytes >3 G/L or neutrophils >1.0 G/l, neurotoxicity less than grade 3 according to CTCAE v4 and calculated creatinine clearance of at least 60 ml/min (by Cockcroft-Gault). These factors were evaluated weekly by the responsible oncologists.

In cases of hematological toxicity, or reduced general condition, gemcitabine was reduced or omitted, in cases of neurotoxicity, or renal insufficiency cisplatin was reduced or omitted. Erythrocyte transfusion limit was Hb ≤ 80 g/l. In cases of fever and infection, chemotherapy dose was delayed.

Concomitant treatment for the prevention of nausea were aprepitant (125 mg on the first day of chemotherapy and 80 mg on the second and third day), methylprednisone (125 mg on the first day) and dexamethasone (4 mg from the second to the fourth day).

In order to prevent kidney damage, hydration treatment was provided by intravenous infusion of 1000 ml fluid before and after cisplatin application (0.9% NaCl before and Glucosaline 2:1 after cisplatin +10 mm KCl and 8 mm MgCl2). Sodium Chloride and Glucose Solution for Infusion 0.18% and 4%.

Erythrocyte transfusions were given for symptomatic anemia or hemoglobin levels ≤80 g/l. Platelet transfusions were given for Tc < 20 G/l with bleeding or fever, otherwise if <10G/l. Filgrastim was used to prevent severe neutropenia.

Statistical methodology: Results are presented as count (percent) or median (minimum-maximum). The Kaplan-Meier curve was used for disease-free survival (DFS) analysis. DFS was measured from the first day of therapy to the first, clinical or radiological or metabolic sign of disease.

There were no significant pauses or omissions of radiotherapy. The number of omitted chemotherapy applications during the concomitant part is presented in Fig. 1. Adjuvant combined gemcitabine / cisplatin chemotherapy was given in 10 (58.8%) and 9 (52.9%) patients in the first and second adjuvant cycle respectively.

Diarrhea was recorded in 9 (52.9%) patients, of those 4 (23.5%) were grade 1, 4 (23.5%) were grade 2 and 1 (5.9%) was grade 3. Nausea was noted in 5 (29.4%) patients, of those grade 1 in 2 (11.8%), grade 2 in 1 (5.9%) and grade 3 in 2 (11.8%) patients. Acute cystitis was noted in 4 (23.5%) patients, of those 3 (17.6%) grade 1 and 1 (5.9%) grade 2. Vaginitis emerged in 4 (23.5%) patients during treatment, of those 3 (17.6%) patients had grade 1 and 1 (5.9%) grade 2. No other gastrointestinal or genitourinary toxicities were reported.

Acute hematological toxicities during concomitant radio-chemotherapy are presented in Fig. 2 in the form of cumulative incidence.

Chronic gastrointestinal or urogenital toxicity was reported or diagnosed in 10 (58.8%) patients. Five (29.4%) reported upper gastrointestinal toxicities grade 1, 4(23.5%) reported cystitis grade 1, and one patient (5.9%) grade 2. Two (11.8%) patients reported vaginal dryness grade 1, one (5.9%) shortening of vagina grade 1, and two (11.8%) patients reported grade 3 toxicities in the form of a vaginal stenosis.