Martine Franckena

Hyperthermia dose-effect relationship in 420 patients with cervical cancer treated with combined radiotherapy and hyperthermia

Adding hyperthermia to standard radiotherapy (RT+HT) improves treatment outcome for patients with locally advanced cervical cancer (LACC). We investigated the effect of hyperthermia dose on treatment outcome for patients with LACC treated with RT+HT. We collected treatment and outcome data of 420 patients with LACC treated with hyperthermia at our institute from 1990 to 2005. Univariate and multivariate analyses were performed on response rate, local control, disease-specific survival and toxicity for these patients to search for a thermal dose response relationship. Besides commonly identified prognostic factors in LACC like tumour stage, performance status, radiotherapy dose and tumour size, thermal parameters involving both temperature and duration of heating emerged as significant predictors of the various end-points. The more commonly used CEM43T90 (cumulative equivalent minutes of T90 above 43 degrees C) was less influential than TRISE (based on the average T50 increase and the duration of heating, normalised to the scheduled duration of treatment). CEM43T90 and TRISE measured intraluminally correlate significantly and independently with tumour control and survival. These findings stimulate further technological development and improvement of deep hyperthermia, as they strongly suggest that it might be worthwhile to increase the thermal dose for LACC, either by treatment optimisation or by prolonging the treatment time. These results also confirm the beneficial effects from hyperthermia as demonstrated in our earlier randomised trial, and justify applying radiotherapy and hyperthermia as treatment of choice for patients with advanced cervical cancer.

Radiotherapy and Hyperthermia for Treatment of Primary Locally Advanced Cervix Cancer: Results in 378 Patients

PURPOSE To report response rate, pelvic tumor control, survival, and late toxicity after treatment with combined radiotherapy and hyperthermia (RHT) for patients with locally advanced cervical carcinoma (LACC) and compare the results with other published series. METHODS AND MATERIALS From 1996 to 2005, a total of 378 patients with LACC (International Federation of Gynecology and Obstetrics Stage IB2-IVA) were treated with RHT. External beam radiotherapy (RT) was applied to 46-50.4 Gy and combined with brachytherapy. The hyperthermia (HT) was prescribed once weekly. Primary end points were complete response (CR) and local control. Secondary end points were overall survival, disease-specific survival, and late toxicity. Patient, tumor, and treatment characteristics predictive for the end points were identified in univariate and multivariate analyses. RESULTS Overall, a CR was achieved in 77% of patients. At 5 years, local control, disease-specific survival, and incidence of late toxicity Common Terminology Criteria for Adverse Events Grade 3 or higher were 53%, 47%, and 12%, respectively. In multivariate analysis, number of HT treatments emerged as a predictor of outcome in addition to commonly identified prognostic factors. CONCLUSIONS The CR, local control, and survival rates are similar to previously observed results of RHT in the randomized Dutch Deep Hyperthermia Trial. Reported treatment results for currently applied combined treatment modalities (i.e., RT with chemotherapy and/or HT) do not permit definite conclusions about which combination is superior. The present results confirm previously shown beneficial effects from adding HT to RT and justify the application of RHT as first-line treatment in patients with LACC as an alternative to chemoradiation.

Clinical implementation of hyperthermia treatment planning guided steering: A cross over trial to assess its current contribution to treatment quality

Purpose: To assess the current feasibility of online hyperthermia treatment planning guided steering (HGS) and its current contribution to treatment quality in deep hyperthermia for locally advanced cervical cancer. Materials and methods: 36 patients were randomized to receive either their second and fourth (arm A) or their third and fifth (arm B) hyperthermia treatment of the series with the aid of HGS. The other treatments were conducted according to the Rotterdam Empirical Steering Guidelines (RESG). Results: During period I (second and third treatment of the series) similar results were found for HGS and RESG with a slight, non-significant difference found in favour of HGS. The average temperature T50 was 40.3°C for both (p = 0.409) and the dose parameter CEM43T90 was 0.64 for RESG and 0.63 for HGS (p = 0.154). However, during period II (fourth and fifth treatment of the series) HGS performed less well, with significant lower thermal dose parameters, minimum, mean and maximum intraluminal temperatures, tolerance measures and net integrated power. T50 was 40.4°C after RESG and 40°C after HGS (p = 0.001) and CEM43T90 0.57 and 0.38 (p = 0.01) respectively. Conclusion: We found that the procedure of online treatment planning guided steering is feasible. For maximal exploitation of its possibilities, however, better control and understanding of several patient, tumour and technical parameters is required. This study has been very helpful in identifying some of the challenges and flaws that warrant further investigation in the near future, such as patient positioning and the prevention of hotspot-related complaints.

Patient positioning in deep hyperthermia: influences of inaccuracies, signal correction possibilities and optimization potential

In this deep hyperthermia study, the robustness of SAR (specific absorption rate) patterns to patient-position variations is assessed, as well as the possibilities to correct for improper positioning and the benefits of non-standard positions. With a finite element model, the SAR distributions were predicted for ten patients at 33 positions. Position sensitivity is assessed for both SAR-focus steering, i.e. settings based on a calculated focus in a cylindrical patient representation, and HTP (hyperthermia treatment planning)-guided steering, i.e. model-based optimization of the SAR distribution. Position inaccuracies of less than 1 cm do not significantly affect SAR patterns. For SAR-focus steering, the SAR maximum is not always at the desired focus location, especially in the Y (anterior/posterior)- and Z (axial)-directions. For a maximum shift of 5 cm in all directions, both SAR-focus steering and HTP-guided steering are suitable to correct for improper positioning up to the level that none of the investigated positions appears preferable. Current positioning precision is sufficient in the X (right-left)-direction, but precision measurements are needed to reach the desired accuracy in the Y-direction. In the Z-direction, a cranial shift of the applicator is predicted to be beneficial. If the position is known accurately, correction of the treatment setting is possible without loss of heating efficiency. Additionally, no preferable positions exist.

Complaint-adaptive power density optimization as a tool for HTP-guided steering in deep hyperthermia treatment of pelvic tumors

For an efficient clinical use of HTP (hyperthermia treatment planning), optimization methods are needed. In this study, a complaint-adaptive PD (power density) optimization as a tool for HTP-guided steering in deep hyperthermia of pelvic tumors is developed and tested. PD distribution in patients is predicted using FE-models. Two goal functions, Opt1 and Opt2, are applied to optimize PD distributions. Optimization consists of three steps: initial optimization, adaptive optimization after a first complaint and increasing the weight of a region after recurring complaints. Opt1 initially considers only target PD whereas Opt2 also takes into account hot spots. After patient complaints though, both limit PD in a region. Opt1 and Opt2 are evaluated in a phantom test, using patient models and during hyperthermia treatment. The phantom test and a sensitivity study in ten patient models, show that HTP-guided steering is most effective in peripheral complaint regions. Clinical evaluation in two groups of five patients shows that time between complaints is longer using Opt2 (p = 0.007). However, this does not lead to significantly different temperatures (T50s of 40.3 (Opt1) versus 40.1 degrees C (Opt2) (p = 0.898)). HTP-guided steering is feasible in terms of PD reduction in complaint regions and in time consumption. Opt2 is preferable in future use, because of better complaint reduction and control.

Steering in locoregional deep hyperthermia: Evaluation of common practice with 3D-planning

Purpose: In Rotterdam, fifteen years of clinical experience with deep hyperthermia has sublimated in empirical treatment guidelines. In this paper, a hyperthermia treatment planning system (HTPS) is employed to investigate the effect of these guidelines on global power distribution, their effectiveness and the rationale behind each guideline. Materials and methods: Four guidelines were investigated. The first two prescribe steering actions for balancing intraluminal temperatures and alleviating complaints of deep-seated pain or pressure. The third guideline handles superficial complaints of pain or heat sensation. The last guideline states that frequency should be increased from 77 MHz upwards in case of multiple, opposite, painful regions uncontrollable by the previous steering actions. For all steering actions it is assumed that input power is increased until complaints occur. Sigma Hyperplan was used to calculate specific absorption rate (SAR) distributions for five patient models with locally advanced cervical cancer. Absorbed power ratios of different regions of interest were evaluated to illustrate steering efficacy and complaint reduction. Results and conclusions: Phase steering is effective in shifting the central power distribution to the periphery, and is an appropriate method to balance temperatures or to handle deep-seated complaints. Reduction of amplitude is the proper action to alleviate superficial complaints of heat or pressure. Compression of the SAR distribution, mainly in the lateral direction, is predicted with increasing frequency. Hence, for complaints in the lower back or on the sides, a frequency increase should be considered. We conclude that the results of the HTPS are in close agreement with the empirical steering guidelines.

RF-power and temperature data analysis of 444 patients with primary cervical cancer: Deep hyperthermia using the Sigma-60 applicator is reproducible

Treatment reproducibility is important to guarantee reproducible treatment-outcome, a low-complication rate and efficient treatment procedures. This study evaluated the performance of loco-regional deep hyperthermia with four BSD-2000 configurations during 1990–2005 using the direct available parameters, i.e., temperature and power. Primary cervical cancer patients (n = 444) were all treated within the Sigma-60. Patients were grouped in three weight-groups: <61 kg, 61–70 kg, >70 kg. Different temperature and power indices were extensively analyzed per BSD configuration, per weight-group, and over the time-period. No substantial variations were found for temperature/power indices over the four BSD configurations or for the temperature doses in similar weight-groups. The ‘bare’ power indices were increased with weight; however, the derivative power-related (W/kg, W/cm2) and temperature indices decreased. Large variations were found in the power-related parameters during 1991–1996 (1st time-period), whereas they were much smaller during 1997–2005 (2nd time-period). The most relevant change noted was the adaptation of the treatment strategy with respect to power modulation. The average frequency of switched-off was 3.4 and 8.9 times/treatment session for the 1st and 2nd time-period, respectively, while the average duration of each switched-off time was 78.2 vs. 38.3 s. The yearly average of vagina T50 was in the range of 39.3–40.2°C (1st time-period) and 40.0–40.5°C (2nd time-period). In 40% of the patients, a positive correlation was found between normalized net integrated power per pelvic area and vagina T50. Good reproducible heating is achieved with the BSD-2000 Sigma-60 irrespective of the regular technological upgrades of the system and variation of trained staff-members.

Review of radiotherapy and hyperthermia in primary cervical cancer

This review focuses on combined radiotherapy and hyperthermia for the primary treatment of cervical cancer compared to the current international standard of chemoradiation. Practical considerations, biological effects and clinical results are discussed.

Use of combined radiation and hyperthermia for gynecological cancer.

Purpose of review We reviewed all literature on the clinical use of combined radiation and hyperthermia for gynecologic malignancies. Recent findings Combined radiation and hyperthermia should be considered an alternative to chemoradiation for patients with locally advanced cervix cancer and be the first treatment of choice for these patients when radiation cannot be combined with chemotherapy. Several randomized trials have shown an improvement by adding hyperthermia to radiation that is comparable to the improvement found with the addition of chemotherapy to radiation. Hyperthermia does not seem to add to treatment-induced toxicity and the results of hyperthermia are consistent even at 12 years follow-up and could be reproduced in a large, unselected group of cervix cancer patients. A novel indication for combined radiotherapy and hyperthermia is vaginal cancer. Recently, a cohort study showed that the addition of hyperthermia to radiation seems to improve overall survival for patients with vaginal cancer International Federation of Gynecology and Obstetrics stage III. Summary Combined radiation and hyperthermia should be considered for patients with locally advanced cervix cancer (International Federation of Gynecology and Obstetrics stage IIb and upwards) as an alternative to chemoradiation for patients with a contraindication for chemotherapy. For other patients, the optimal treatment combination is the subject of randomized trials. For vaginal cancer, a prospective registration study is currently ongoing.

Implementation of treatment planning in the routine clinical procedure of regional hyperthermia treatment of cervical cancer: An overview and the Rotterdam experience

Purpose: This manuscript provides an overview in the field of hyperthermia treatment planning (HTP) in cervical cancer. Treatment planning techniques: The workflow of an HTP assisted treatment generally consists of patient imaging, tissue segmentation, model generation, electromagnetic (EM) and thermal calculations, optimisation, and clinical implementation. A main role in HTP is played by numerical simulations, for which currently a number of software packages are available in hyperthermia. To implement these simulations, accurate applicator models and accurate knowledge of dielectric and thermal parameters is mandatory. Model validation is necessary to check if this is implemented well. In the translation from HTP models to the clinic, the main aspect is accurate representation of the actual treatment situation in the HTP models. Accurate patient positioning and organ-specific segmentation can be helpful in minimising the differences between model and clinic. Steering strategies: In the clinic, different approaches are possible: simple, i.e. target centre point (TCP) steering, often called ‘target steering’, or only pretreatment planning versus advanced, i.e. active HTP guided steering or image guided hyperthermia by non-invasive thermometry (NIT). The Rotterdam experience: To illustrate the implementation of HTP guided steering, the Rotterdam approach of complaint adaptive steering is elaborated, in which optimisation is adapted with increased constraints on tissues with heat-induced discomfort. Conclusions: Many publications on HTP show that HTP can be considered a feasible method to optimise and control a hyperthermia treatment, with the objective to enhance treatment quality and documentation. Ultimately, after overcoming the various uncertainties, this may lead to dose prescription.