Results of concurrent chemotherapy and hyperthermia in patients with recurrent cervical cancer after previous chemoradiation.

BACKGROUND: Concomitant hyperthermia has been shown to improve response rate after cisplatin in recurrent cervical cancer in previously irradiated patients. It is unclear whether similar response rates can be obtained in patients with a recurrence after previous platinum-containing chemoradiation. OBJECTIVE: This study aimed to evaluate the outcome of cisplatin-based chemotherapy with concurrent hyperthermia in patients with recurrent cervical cancer after radiotherapy and cisplatin. METHODS: Patients with recurrent cervical cancer after cisplatin-based chemoradiation or neoadjuvant chemotherapy followed by surgery and radiotherapy who were treated with concurrent platinum-based chemotherapy and hyperthermia were eligible for this retrospective analysis. All patients received six or eight weekly platinum-based chemotherapy cycles in combination with six or eight weekly hyperthermia sessions. The time-to-event variables were estimated using Kaplan-Meier analysis. P-values less than 0.05 were considered significant. RESULTS: All 38 evaluable patients were selected from the hyperthermia database in the Academic Medical Centre (Amsterdam) and the Erasmus Medical Centre (Rotterdam). Mean age at relapse was 45.7 years (range 27-74). Median time to recurrence after first-line treatment was 15 months. A total of 27 patients had a local and/or regional recurrence; 11 had disease beyond the pelvis. All planned courses of cisplatin chemotherapy and hyperthermia were administered in 17/38 patients. Median follow-up was 6.5 months. One patient died during treatment; response rate was 4/37 (14%), with one complete response. Overall survival was 23% at 12 months and 4% at 24 months. The incidence of grade 3-4 haematological complications did not exceed 10%. CONCLUSION: In this retrospective study, concurrent cisplatin and hyperthermia after first-line cisplatin-containing chemoradiation showed poor response and survival. We do not recommend this treatment for recurrence of locally advanced cervical cancer.

Neoadjuvant chemotherapy followed by radiotherapy and concurrent hyperthermia in patients with advanced-stage cervical cancer: a retrospective study.

OBJECTIVE: To evaluate the efficacy of neoadjuvant chemotherapy, followed by radiotherapy and concurrent hyperthermia (triple therapy) in patients with advanced-stage cervical cancer. METHODS: We selected 43 patients from our hyperthermia database, who were treated from 1996 to 2010 with triple therapy for large primary tumours (>6 cm) or para-aortic lymph node metastases. All patients received platinum-based chemotherapy followed by full-dose radiotherapy, brachytherapy and five hyperthermia treatments. The response was evaluated by gynaecological examination and a CT-scan. Time-to-event variables were estimated using the Kaplan Meier method and the Cox regression method. RESULTS: The mean age of the patients was 50.4 years (range 29-80). The median tumour size was 5.6 cm at diagnosis (range 2.6-8.2), positive lymph nodes were present in 90.7%. A total of 67% of the patients completed all six planned courses of chemotherapy. After completion of neoadjuvant chemotherapy, 83.7% of patients achieved a complete or partial response. At the end of treatment, the complete response rate was 81.4% (95%CI 69.2-93.5). Grade 2, 3 and 4 acute vascular toxicity occurred in 17 patients. The incidence of grade 3-4 haematological toxicity did not exceed 10% and no neutropenic fever occurred. For grade 1-2 renal toxicity, a switch to carboplatin was made (n = 6). No acute grade 3-4 renal toxicity was observed. No treatment-related deaths were recorded. The median follow-up time was 29.8 months (range 4.1-124.8). Overall survival rate at 12 months was 79% (95%CI 57.4-92.3). CONCLUSION: The triple therapy seems feasible and effective in the treatment of advanced-stage, high-risk cervical cancer. However, chemotherapy-induced vascular toxicity occurred frequently, which may warrant the use of prophylactic anticoagulants. We recommend a phase II trial for prospective confirmation for comparison with standard chemoradiation and the use of anticoagulants.

Patient-reported acute GI symptoms in locally advanced cervical cancer patients correlate with rectal dose.

BACKGROUND AND PURPOSE: To investigate relationships between patient-reported acute gastro-intestinal symptoms in a locally advanced cervical cancer (LACC) prospective cohort and clinical and dosimetric parameters, while also taking spatial dose into account. MATERIAL AND METHODS: A total of 103 patients was included, receiving radiotherapy based on a plan-library-based plan-of-the-day protocol, combined either with concurrent chemotherapy or with neo-adjuvant chemotherapy and concomitant hyperthermia. Toxicity endpoints were extracted from questionnaires sent out weekly during treatment and regularly in the acute phase after treatment. Endpoints were defined for symptoms concerning obstipation, diarrhea, fecal leakage, bowel cramps and rectal bleeding. Dose surface maps were constructed for the rectum. Clinical parameters and dosimetric parameters of the bowel bag and rectum were collected for all patients. RESULTS: The use of concomitant chemotherapy and an increase in Planning Target Volume (PTV) resulted in a significant increase in reported diarrhea. The dose-volume parameters V5Gy-V25Gy of the rectum were found to be significant, unlike dose-volume parameters of the bowel bag. Additionally, a significantly higher dose to the inferior part of the rectum was found for patients reporting diarrhea. No significance was reached for fecal leakage and bowel cramps. CONCLUSION: The significance of results for patients reporting diarrhea symptoms found for PTV volume indicates a potential benefit for a plan-of-the-day protocol. Additionally, the results suggest that a reduction of inferior rectum dose could decrease patient-reported diarrhea symptoms, while the administration of concomitant chemotherapy appears to lead to radiosensitizing effects that increase these symptoms.

Optimal Patient Positioning (Prone Versus Supine) for VMAT in Gynecologic Cancer: A Dosimetric Study on the Effect of Different Margins.

PURPOSE/OBJECTIVE: It is unknown whether the historically found dosimetric advantages of treating gynecologic cancer with the patient in a prone position with use of a small-bowel displacement device (belly-board) remain when volumetric arc therapy (VMAT) is used and whether these advantages depend on the necessary margin between clinical target volume (CTV) and planning target volume (PTV). The aim of this study is to determine the best patient position (prone or supine) in terms of sparing organs at risk (OAR) for various CTV-to-PTV margins and VMAT dose delivery. METHODS AND MATERIALS: In an institutional review board-approved study, 26 patients with gynecologic cancer scheduled for primary (9) or postoperative (17) radiation therapy were scanned in a prone position on a belly-board and in a supine position on the same day. The primary tumor CTV, nodal CTV, bladder, bowel, and rectum were delineated on both scans. The PTVs were created each with a different margin for the primary tumor and nodal CTV. The VMAT plans were generated with our in-house system for automated treatment planning. For all margin combinations, the supine and prone plans were compared with consideration of all OAR dose-volume parameters but with highest priority given to bowel cavity V45Gy (cm(3)). RESULTS: For both groups, the prone position reduced the bowel cavity V45Gy, in particular for nodal margins ≥10 mm (ΔV45Gy = 23.9 ± 10.6 cm(3)). However, for smaller margins, the advantage was much less pronounced (ΔV45Gy = 6.5 ± 3.0 cm(3)) and did not reach statistical significance. The rectum mean dose (Dmean) was significantly lower (ΔDmean = 2.5 ± 0.3 Gy) in the prone position for both patient groups and for all margins, and the bladder Dmean was significantly lower in the supine position (ΔDmean = 2.6 ± 0.4 Gy) only for the postoperative group. The advantage of the prone position was not present if it needed a larger margin than the supine position. CONCLUSION: For patients with gynecologic cancer, the historically found dosimetric advantages for the prone position remain for modern dose delivery techniques if large margins are needed. However, the advantage is lost for small margins and if the prone position needs a larger margin than the supine position.

Validation of Fully Automated VMAT Plan Generation for Library-Based Plan-of-the-Day Cervical Cancer Radiotherapy.

PURPOSE: To develop and validate fully automated generation of VMAT plan-libraries for plan-of-the-day adaptive radiotherapy in locally-advanced cervical cancer. MATERIAL AND METHODS: Our framework for fully automated treatment plan generation (Erasmus-iCycle) was adapted to create dual-arc VMAT treatment plan libraries for cervical cancer patients. For each of 34 patients, automatically generated VMAT plans (autoVMAT) were compared to manually generated, clinically delivered 9-beam IMRT plans (CLINICAL), and to dual-arc VMAT plans generated manually by an expert planner (manVMAT). Furthermore, all plans were benchmarked against 20-beam equi-angular IMRT plans (autoIMRT). For all plans, a PTV coverage of 99.5% by at least 95% of the prescribed dose (46 Gy) had the highest planning priority, followed by minimization of V45Gy for small bowel (SB). Other OARs considered were bladder, rectum, and sigmoid. RESULTS: All plans had a highly similar PTV coverage, within the clinical constraints (above). After plan normalizations for exactly equal median PTV doses in corresponding plans, all evaluated OAR parameters in autoVMAT plans were on average lower than in the CLINICAL plans with an average reduction in SB V45Gy of 34.6% (p<0.001). For 41/44 autoVMAT plans, SB V45Gy was lower than for manVMAT (p<0.001, average reduction 30.3%), while SB V15Gy increased by 2.3% (p = 0.011). AutoIMRT reduced SB V45Gy by another 2.7% compared to autoVMAT, while also resulting in a 9.0% reduction in SB V15Gy (p<0.001), but with a prolonged delivery time. Differences between manVMAT and autoVMAT in bladder, rectal and sigmoid doses were ≤ 1%. Improvements in SB dose delivery with autoVMAT instead of manVMAT were higher for empty bladder PTVs compared to full bladder PTVs, due to differences in concavity of the PTVs. CONCLUSIONS: Quality of automatically generated VMAT plans was superior to manually generated plans. Automatic VMAT plan generation for cervical cancer has been implemented in our clinical routine. Due to the achieved workload reduction, extension of plan libraries has become feasible.

Quantification of intra-fraction changes during radiotherapy of cervical cancer assessed with pre- and post-fraction Cone Beam CT scans.

BACKGROUND AND PURPOSE: With the introduction of Intensity Modulated Radiotherapy (IMRT) and image-guided plan-of-the-day strategies, the treatment of cervical cancer has become more sensitive to intra-fraction uncertainties. In this study we quantified intra-fraction changes in cervix-uterus shape, bladder and rectum filling, and patient setup using pre- and post-fraction CBCT scans. MATERIALS AND METHODS: A total of 632 CBCT scans were analyzed for 16 patients with large tip-of-uterus displacement (>2.5 cm) measured in an empty and full bladder CT scan. In all scans, the bladder, cervix-uterus, and rectum were delineated. For rectum and bladder, intra-fraction volume changes were assessed. Systematic cervix-uterus intra-fraction displacements were obtained by non-rigidly aligning the pre-fraction cervix-uterus to that in the post-fraction CBCT. Intra-fraction patient setup changes were obtained by rigidly aligning pre- and post-CBCTs using the bony anatomy. RESULTS: The mean time between pre- and post-fraction CBCT scan was 20.8 min. The group-mean intra-fraction displacements averaged over the cervix-uterus were 0.1±1.4/1.8±1.5/-2.8±1.8 (LR/CC/AP) mm. The group-mean 5th and 95th percentile intra-fraction displacements were -2.3,2.1/-0.8,4.9/-5.8,0.5 (LR/CC/AP) mm. There was a significant correlation between bladder inflow rate and cervix-uterus motion (r=0.6 and p<0.01). Intra-fraction changes in patient setup were 1.3/0.4/0.6 and 1.4/1.0/1.1 mm (LR/CC/AP), for systematic and random changes, respectively. CONCLUSION: Intra-fraction cervix-uterus motion can be considerable and should be taken into account using appropriate PTV margins.

Clinical implementation of an online adaptive plan-of-the-day protocol for nonrigid motion management in locally advanced cervical cancer IMRT.

PURPOSE: To evaluate the clinical implementation of an online adaptive plan-of-the-day protocol for nonrigid target motion management in locally advanced cervical cancer intensity modulated radiation therapy (IMRT). METHODS AND MATERIALS: Each of the 64 patients had four markers implanted in the vaginal fornix to verify the position of the cervix during treatment. Full and empty bladder computed tomography (CT) scans were acquired prior to treatment to build a bladder volume-dependent cervix-uterus motion model for establishment of the plan library. In the first phase of clinical implementation, the library consisted of one IMRT plan based on a single model-predicted internal target volume (mpITV), covering the target for the whole pretreatment observed bladder volume range, and a 3D conformal radiation therapy (3DCRT) motion-robust backup plan based on the same mpITV. The planning target volume (PTV) combined the ITV and nodal clinical target volume (CTV), expanded with a 1-cm margin. In the second phase, for patients showing >2.5-cm bladder-induced cervix-uterus motion during planning, two IMRT plans were constructed, based on mpITVs for empty-to-half-full and half-full-to-full bladder. In both phases, a daily cone beam CT (CBCT) scan was acquired to first position the patient based on bony anatomy and nodal targets and then select the appropriate plan. Daily post-treatment CBCT was used to verify plan selection. RESULTS: Twenty-four and 40 patients were included in the first and second phase, respectively. In the second phase, 11 patients had two IMRT plans. Overall, an IMRT plan was used in 82.4% of fractions. The main reasons for selecting the motion-robust backup plan were uterus outside the PTV (27.5%) and markers outside their margin (21.3%). In patients with two IMRT plans, the half-full-to-full bladder plan was selected on average in 45% of the first 12 fractions, which was reduced to 35% in the last treatment fractions. CONCLUSIONS: The implemented online adaptive plan-of-the-day protocol for locally advanced cervical cancer enables (almost) daily tissue-sparing IMRT.