Jacoba van der Zee

Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: a prospective, randomised, multicentre trial

Summary Background Local-control rates after radiotherapy for locally advanced tumours of the bladder, cervix, and rectum are disappointing. We investigated the effect of adding hyperthermia to standard radiotherapy. Methods The study was a prospective, randomised, multicentre trial. 358 patients were enrolled from 1990 to 1996, in cancer centres in the Netherlands, who had bladder cancer stages T2, T3, or T4, N0, M0, cervical cancer stages IIB, IIIB, or IV, or rectal cancer stage M0–1 were assessed. Patients were randomly assigned radiotherapy (median total dose 65 Gy) alone (n=176) or radiotherapy plus hyperthermia (n=182). Our primary endpoints were complete response and duration of local control. We did the analysis by intention to treat. Findings Complete-response rates were 39% after radiotherapy and 55% after radiotherapy plus hyperthermia (p Interpretation Hyperthermia in addition to standard radiotherapy may be especially useful in locally advanced cervical tumours. Studies of larger numbers of patients are needed for other pelvic tumour sites before practical recommendations can be made.

Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: Results from five randomized controlled trials

PURPOSE Claims for the value of hyperthermia as an adjunct to radiotherapy in the treatment of cancer have mostly been based on small Phase I or II trials. To test the benefit of this form of treatment, randomized Phase III trials were needed. METHODS AND MATERIALS Five randomized trials addressing this question were started between 1988 and 1991. In these trials, patients were eligible if they had advanced primary or recurrent breast cancer, and local radiotherapy was indicated in preference to surgery. In addition, heating of the lesions and treatment with a prescribed (re)irradiation schedule had to be feasible and informed consent was obtained. The primary endpoint of all trials was local complete response. Slow recruitment led to a decision to collaborate and combine the trial results in one analysis, and report them simultaneously in one publication. Interim analyses were carried out and the trials were closed to recruitment when a previously agreed statistically significant difference in complete response rate was observed in the two larger trials. RESULTS We report on pretreatment characteristics, the treatments received, the local response observed, duration of response, time to local failure, distant progression and survival, and treatment toxicity of the 306 patients randomized. The overall CR rate for RT alone was 41% and for the combined treatment arm was 59%, giving, after stratification by trial, an odds ratio of 2.3. Not all trials demonstrated an advantage for the combined treatment, although the 95% confidence intervals of the different trials all contain the pooled odds ratio. The greatest effect was observed in patients with recurrent lesions in previously irradiated areas, where further irradiation was limited to low doses. CONCLUSION The combined result of the five trials has demonstrated the efficacy of hyperthermia as an adjunct to radiotherapy for treatment of recurrent breast cancer. The implication of these encouraging results is that hyperthermia appears to have an important role in the clinical management of this disease, and there should be no doubt that further studies of the use of hyperthermia are warranted.

Relationship between thermal dose and outcome in thermoradiotherapy treatments for superficial recurrences of breast cancer: Data from a phase III trial

PURPOSE The objective of this study was to determine whether the thermal dose delivered during hyperthermia treatments and other thermal factors correlate with outcome after combined radiation and hyperthermia of breast carcinoma recurrences. Data were from the combined hyperthermia and radiation treatment arms of four Phase III trials, which when pooled together, demonstrated a positive effect of hyperthermia. METHODS AND MATERIALS Four Phase III trials addressing the question of whether hyperthermia could improve the local response of superficial recurrent breast cancer to radiation therapy were combined into a single analysis. Thermal dosimetry data were collected from 120 of the 148 breast cancer recurrence patients who received hyperthermia. The data were analyzed for correlations between thermal parameters as well as important clinical parameters and outcome (complete response rate, local disease free survival, time to local failure, and overall survival). RESULTS Five thermal parameters were tested, all associated with the low regions of the measured temperature distributions. Max(TDmin) and Sum(TDmin) were associated with complete response where TDmin is the minimum thermal dose measured by any of the tumor temperature sensors during a treatment: Max(TDmin) is the maximum of TDmin over a series of treatments. Using a categorical relationship with a cutoff of 10 min for Sum(TDmin), the complete response rate was 77% for Sum(TDmin) > 10 min and 43% for Sum(TDmin) < or = 10 min (p = 0.022, adjusted for study center and significant clinical factors). The overall complete response rate for hyperthermia and radiation was 61% compared to 41% for radiation alone. Either Max(TDmin) or Sum(TDmin) were also associated with local disease free survival, time to local failure and overall survival. CONCLUSIONS An earlier report of this trial demonstrated a significant benefit when hyperthermia was added to radiation in the treatment of breast cancer recurrences. The analysis of thermal factors demonstrates that parameters representative of the low end of the measured temperature distributions are associated with initial complete response rate, local disease-free survival, time to local failure and overall survival.

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.

First results of triple-modality treatment combining radiotherapy, chemotherapy, and hyperthermia for the treatment of patients with Stage IIB, III, and IVA cervical carcinoma

Patients with advanced cervical carcinoma are treated routinely with radiotherapy and cisplatin‐containing chemotherapy. It has been shown that hyperthermia can improve the results of both radiotherapy and cisplatin. In the current study, the feasibility and efficacy of the combination of all three modalities was studied in previously untreated patients with cervical carcinoma.

Factors influencing the outcome of radiotherapy in malignant mesothelioma of the pleura - A single-institution experience with 189 patients

PURPOSE To determine the factors influencing the response to palliative radiotherapy (RT) in malignant mesothelioma of the pleura (MM). METHODS AND MATERIALS A retrospective review was conducted of the records of all patients with mesothelioma who were referred to our institution between 1979 and 1996. A total of 227 RT series were administered to 189 patients with MM. Of these, 21 patients with chest wall nodules also received concomitant local hyperthermia. RESULTS The median survival was 5 months from the start of RT and only 17% of patients were alive at 1 year after treatment. Chest pain and painful chest wall metastases were the main indications for RT. A higher local response rate was seen for patients treated with a 4-Gy per fraction scheme, vs. those receiving fractions of less than 4 Gy (50% vs. 39%). Pain recurrence occurred predominantly within the previous RT field, and pain recurred after a median of 69 days (range 32-363) in the group treated using 4-Gy fractions. When compared with a matched group, patients treated with combined RT and hyperthermia had higher response rates and fewer in-field recurrences. CONCLUSIONS RT provides local palliation in at least 50% of patients with MM who were treated using a 4-Gy/fraction scheme to a median dose of 36 Gy. The low response rates with RT alone suggest that combined RT and local hyperthermia should be further evaluated in MM.

Human tumour pH and its variation

The variation in human tumour pH values is large. The aim of this study was to analyse the reasons for these large variations and to determine whether tumour pH can be predicted on the basis of any easily measured parameter. One hundred and five determinations of tumour pH were performed in various human tumours, using the Philips C 902S tissue pH electrode. No correlations were found between the tumour pH and the tumour histology, degree of differentiation, tumour size, patient age or treatment history, and whether or not the tumour was ulcerated. However, tumour pH was significantly lower in primary tumours than in lymph node metastases. Tumours at their primary site (primary, recurrent or residual) were also more acid than distant metastases. The vascular disruption caused by the measuring technique was found to be acceptable.

Practical limitations of interstitial thermometry during deep hyperthermia

PURPOSE Intratumor thermometry during hyperthermia treatment is considered important for several reasons. The morbidity that we experienced from interstitially placed catheters in deep-seated tumors gave reason to weigh the advantages and disadvantages against each other. METHODS AND MATERIALS The available thermometry in 215 patients treated with hyperthermia for deep-seated tumors was analyzed with the aim to evaluate practically feasible intratumor measurements. The influence of intratumor measurements on the treatment procedure was assessed. RESULTS Total 120 catheters were placed interstitially in 78 patients. Over the years, the percentage of patients with interstitial thermometry decreased considerably. Forty-nine catheters could remain in place during the whole hyperthermia treatment series. The remaining catheters had to be removed for more or less severe complications, including one fatal event. In fact, the interstitial catheters caused the most severe treatment-related morbidity. During 188 of the total 859 treatments, at least one interstitial catheter was available for thermometry. Per treatment with catheter(s) in situ, the average number of intratumor measurement sites was 6.9. The value of interstitial thermometry for power steering during treatment, to both optimize intratumor temperature distribution and prevent toxicity, appeared limited. The mean volume of the tumors with interstitial thermometry was 314 cm3, SD 325. In relation to the large tumor volumes, the thermal dose parameters calculated from the available data is considered to be of limited value. CONCLUSION In view of the possible severe complications and the limited clinical value of the information achieved by interstitially placed thermometry catheters, interstitial thermometry was not found to routinely benefit the individual patient.

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.