Tomas-Hendrik Knocke

Definitive radiotherapy based on HDR brachytherapy with iridium 192 in uterine cervix carcinoma: report on the Vienna University Hospital findings (1993–1997) compared to the preceding period in the context of ICRU 38 recommendations

UNLABELLED According to the reports described in the literature, fractionated HDR brachytherapy seems to represent one option for the primary treatment of cervical carcinoma. In order to render such treatment transparent and comparable for those interested in the field, we have attempted to report our recent experience obtained in Vienna from 1993-1997 using the terminology proposed by the ICRU report 38, focusing in particular on dose and volume reporting and a linear-quadratic model. Based on these parameters, a comparison with the preceding period in Vienna (LDR/HDR) has been made, with an attempt to correlate different methods and parameters with outcome. MATERIAL AND METHODS One hundred and eighty-nine patients (mean age 67 years) were treated with curative intent (stage Ia: 2, Ib: 11, IIa: 11, IIb: 79, IIIa: 19, IIIb: 59, IVa: 5, IVb: 3 patients) using a combination of intracervical high-dose rate (HDR) brachytherapy (ring-tandem applicator) and a box technique for external-beam therapy (EBT: 48.6-50 Gy, linac 25 MV). Small tumors were treated with 5-6 fractions of 7 Gy at point A and 50 Gy EBT (25 Gy in the brachytherapy reference volume) which is isoeffective to 76-86 Gy at point A. Large tumors received 3-4 fractions of 7 Gy after 50 Gy EBT with open fields, which is isoeffective to 82-92 Gy at point A. TRAK varied from mean 1.4 cGy (3 fractions) to 2.8 cGy (6 fractions) at one meter. 3-D treatment planning for brachytherapy was based on conventional X-rays and in 181/189 patients on computed tomography (CT) with the applicator in place. Computer-calculated volumes of the brachytherapy reference isodose (7 Gy/fraction) ranged from 46-155 ccm (mean 87 ccm); the respective mean hwt-volume (height x width x thickness) was 180 ccm. The 60 Gy HWT volumes (25 Gy from EBT) for the irradiation of small tumors ranged from 240 to 407 ccm (mean 337 ccm) and for larger tumors (50 Gy for EBT) from 452 to 785 ccm (mean 607 ccm). The mean dose for brachytherapy was 16.2 Gy (6.2-37.8 Gy) at the ICRU rectum reference point and 14.4 Gy (4.6-35.7 Gy) at the ICRU bladder point. Taking into account the dose for EBT, the mean isoeffective dose at the ICRU rectum reference point was 69.9 Gy (28.4-98.7 Gy). Overall treatment time was six weeks for small tumors and eight weeks for large tumors. RESULTS After a mean follow-up of 34 months, actuarial pelvic control and disease-specific survival rates at three years were 77.6/68.6% for all patients, 100/77.1% for stage Ib, 100/100% stage IIa, 87.0/78.0% stage IIb, 52.7/52.1% stage IIIa, 69.1/58.6% stage IIIb and 60/53.3% stage IVa. According to the LENT/SOMA score which had been prospectively introduced, the actuarial late complication rate for grades 3 and 4 was 2.9% for the bladder, 4.0% for the bowel, 6.1% for the rectum and 30.6% for the vagina (shortening and obliteration); in total for all grades 23.6, 18.4, 24.2, and 67.6%, respectively. CONCLUSION In our experience, HDR brachytherapy combined with EBT is an efficient method if sufficient radiation doses and volumes are applied, both with regard to tumor control and adverse side effects. In future, the therapeutic window will be increased by systematic integration of magnetic resonance imaging (MRI) into treatment planning, thus allowing for a highly individualized approach with further adaptation of radiation dose and volume both to the target and to the individual topography of organs at risk.

Impact of multiple HPV infection on response to treatment and survival in patients receiving radical radiotherapy for cervical cancer

To obtain information on the incidence and the clinical significance of infection with various types of the human papillomavirus (HPV) in cancer of the uterine cervix, we retrospectively examined the HPV status of 106 patients who had received radical radiotherapy for cervical cancer stages IB to IIIB. DNA was extracted from formalin‐fixed, paraffin‐embedded biopsies and PCR was carried out to identify HPV types 16, 18, 31, 35, 33 and 45. To detect additional HPV types, consensus PCR products were cloned and sequenced. A catalyzed signal‐amplified colorimetric in situ hybridization was carried out in 84 of 106 specimens as a positive control. Response to therapy, progression‐free survival (PFS) and cervical cancer‐specific survival (CCSS) were the statistical endpoints. Survival analysis was carried out using univariate and multivariate analysis (Cox regression). Ninety‐six patients (90.6%) were HPV‐positive and 42/96 (43.7%) were positive for multiple HPV types. Eight patients had persistent disease after radiotherapy. From these 8 patients, 7 were infected with multiple HPV types and only 1 patient had an infection with a single HPV type. After a median follow up period of 50 months, patients with multiple HPV infection had a significantly shorter PFS and CCSS compared to those with single HPV infection (24.8% and 34.9% vs. 64% and 60.8%, Log rank, p < 0.01 and 0.04). In multivariate analysis, the presence of multiple HPV types (RR 1.9), node status (RR 2.3), tumor size (RR 3.2) and histologic type (RR 4.8) were independent prognostic factors of CCSS. Our results demonstrate that the presence of multiple HPV types is associated with poor response and with reduced survival in cervical cancer patients who receive radiotherapy as the primary treatment.

Serum VEGF levels in patients undergoing primary radiotherapy for cervical cancer: impact on progression-free survival

Vascular endothelial growth factor (VEGF) plays an important role in the regulation of tumour growth and metastasis. It was the aim of this study to examine the impact of serum VEGF levels on the likelihood of response to radiotherapy and on the disease-free survival in patients with cervical cancer. Blood was taken before commencing treatment and serum VEGF was assessed by quantitative ELISA in 23 patients with cervical cancer stage IB-IVA undergoing primary radiotherapy. Serum VEGF levels were correlated with clinical and histopathologic factors as well as with response to radiotherapy and time to progression. Nineteen of the 23 patients had a complete response and four patients had persistent disease at 3 months. The median follow-up was 25 months (95% confidence interval: 23.5-26.5 months). At the time of analysis, eight patients were tumour-free and 15 patients had tumour progression; 12 of these 15 patients died of disease. Overall, the median serum VEGF level was 244 pg/ml (range 31.9-817.6 pg/ml). All four patients with local failure had VEGF levels >244 pg/ml, whereas 11 of the 19 patients with complete response had serum VEGF of < or =244 pg/ml (P=0.035). The median time to progression was 5 months in patients with VEGF of >244 pg/ml compared to 19 months in patients with VEGF of < or = 244 pg/ml (log rank, P=0.003). In multivariate analysis, serum VEGF, tumour size and histological type, but not the patients age, stage and grade of histological differentiation influenced the progression-free survival. Elevated pre-therapeutic serum VEGF levels are associated with poor response and a shorter time to progression in patients with cervical cancer undergoing primary radiotherapy.