S. Oldenborg

Treatment and prognostic factors of radiation-associated angiosarcoma (RAAS) after primary breast cancer: A systematic review

BACKGROUND Radiation-associated angiosarcoma (RAAS) of the breast is a rare, aggressive disease. The incidence is increasing with the prolonged survival of women irradiated for primary breast cancer. Surgery is the current treatment of choice. Prognosis is poor. This review aims to evaluate all publications on primary treatment of RAAS to identify prognostic factors and evaluate treatment modalities. METHODS Databases were searched for articles with published individual patient data on prognostic factors, treatment and follow-up of patients with RAAS. A regression analysis was performed to test the prognostic values of age, interval between primary treatment and RAAS, tumour size and grade on the local recurrence-free interval (LRFI) and overall survival (OS). The effects of treatment modalities surgery, radiation (with or without hyperthermia) and chemotherapy or combinations were evaluated. RESULTS 74 articles were included, representing data on 222 patients. In these patients, the 5-year OS was 43% and 5-year LRFI was 32%. Tumour size and age were significant prognostic factors on LRFI and OS. Of all patients, 68% received surgery alone, 17% surgery and reirradiation and 6% surgery with chemotherapy. The remaining 9% received primary treatments without surgery. Surgery with radiotherapy had a better 5-year LRFI of 57% compared to 34% for surgery alone (p=0.008). The value of other treatment modalities could not be assessed. CONCLUSIONS This systematic review confirms the poor prognosis of RAAS. Tumour size and age were of prognostic value. The addition of reirradiation to surgery in the treatment of RAAS appears to enhance local control.

Reirradiation and hyperthermia for radiation-associated sarcoma†

The objective of this study was to evaluate the role of reirradiation and hyperthermia in the treatment of radiation‐associated sarcoma (RAS) in the thoracic region, which is an increasing, yet extremely rare condition with a poor prognosis.

Elective re-irradiation and hyperthermia following resection of persistent locoregional recurrent breast cancer: A retrospective study

Purpose: To analyse the therapeutic effect and toxicity of re-irradiation (re-RT) combined with hyperthermia (HT) following resection or clinically complete remission (CR) of persistent locoregional recurrent breast cancer in previously irradiated area. Methods and materials: Between 1988 and 2001, 78 patients with high risk recurrent breast cancer underwent elective re-RT and HT. All patients received extensive previous treatments, including surgery and high-dose irradiation (≥50Gy). Most had received one or more lines of systemic therapy; 44% had been treated for ≥ one previous locoregional recurrences. At start of re-RT + HT there was no macroscopically detectable tumour following surgery (96%) or chemotherapy (CT). Re-RT typically consisted of eight fractions of 4Gy, given twice weekly. Hyperthermia was added once a week. Results: After a median follow up of 64.2 months, three-year survival was 66%. Three- and five-year local control rates were 78% and 65%. Acute grade 3 toxicity occurred in 32% of patients. The risk of late ≥ grade 3 toxicity was 40% after three years. Time interval to the current recurrence was found to be most predictive for local control in univariate and multivariate analysis. The extensiveness of current surgery was the most relevant treatment related factor associated with toxicity. Conclusions: For patients experiencing local recurrence in a previously radiated area, re-irradiation plus hyperthermia following minimisation of tumour burden leads to a high rate of local control, albeit with significant toxicity. The latter might be reduced by a more fractionated re-RT schedule.

Preoperative chemoradiation combined with regional hyperthermia for patients with resectable esophageal cancer

Purpose: To analyse the treatment results of neo-adjuvant chemoradiation combined with regional hyperthermia in patients with resectable esophageal cancer. Patients and methods: Between August 2003 and December 2004, 28 patients entered a phase II study combining chemoradiation over a 4.5-week period with five sessions of regional hyperthermia. Chemotherapy consisted of carboplatin (AUC = 2) and paclitaxel (50 mg/m2) and radiotherapy of 41.4 Gy in 1.8 Gy daily fractions. Locoregional hyperthermia was applied using the AMC phased array of four 70 MHz antennas, aiming at a stable tumor temperature of 41°C for one hour. Carboplatin was infused during the hyperthermia session. Esophageal resection was planned at 6–8 weeks after the end of radiotherapy. The majority of the patients had a T3 tumor (86%) and were cN+ (64%). Median follow-up for survivors was 37 months (range 31–46). Results: Twenty-five patients (89%) completed the planned neo-adjuvant treatment and acute toxicity was generally mild. Twenty-six patients were operated on. A pathologically CR, PRmic, PR and SD were seen in 19%, 27%, 31% and 23% respectively. All patients had a R0 resection. In-field locoregional control during follow up for the operated patients was 100%. Quality of life was good for patients without disease progression. Survival rates at one, two and three years were 79%, 57% and 54% respectively. Conclusion: Neo-adjuvant chemoradiation combined with regional hyperthermia followed by esophageal resection for patients with esophageal cancer resulted in good locoregional control and overall survival.

Reirradiation and hyperthermia for irresectable locoregional recurrent breast cancer in previously irradiated area: Size matters

BACKGROUND/PURPOSE Treatment options for irresectable locoregional recurrent breast cancer in previously irradiated area are limited. Hyperthermia, elevating tumor temperature to 40-45°C, sensitizes radio-and-chemotherapy. Four hundred and fourteen patients treated with reirradiation+hyperthermia (reRT+HT) in the AMC(n=301) and the BVI(n=113), from 1982 to 2005 were retrospectively analyzed for treatment response, locoregional control (LC) and prognostic factors for LC and toxicity. PATIENTS/METHODS All patients received previous irradiation (median 50 Gy). reRT consisted of 8 × 4 Gy-2/week (AMC) or 12 × 3 Gy-4/week (BVI). Hyperthermia was added once (AMC)/twice (BVI) a week. RESULTS Overall clinical response rate was 86%. The 3-year LC rate was 25%. The number of recurrence episodes, distant metastases (DM), tumor site, tumor size, time to recurrence and treatment year were significant for LC. Acute ⩾ grade 3 toxicity occurred in 24% of patients. Actuarial late ⩾ grade 3 toxicity was 23% at 3-years. In multivariable analysis reRT fraction dose was significantly related to late ⩾ grade 3 toxicity. CONCLUSION reRT+HT is an effective curative and palliative treatment option for patients with irresectable locoregional recurrent breast cancer in previously irradiated area. Early referral, treatment of chest wall recurrences ⩽ 5 cm in the absence of distant metastases, provided the highest local control rates. The cumulative effects of past and present treatments should be accounted for by adjusting treatment protocol to minimize toxicity.

On verification of hyperthermia treatment planning for cervical carcinoma patients.

Purpose: The aim of this study was to verify hyperthermia treatment planning calculations by means of measurements performed during hyperthermia treatments. The calculated specific absorption rate (SARcalc) was compared with clinically measured SAR values, during 11 treatments in seven cervical carcinoma patients. Methods: Hyperthermia treatments were performed using the 70 MHz AMC-4 waveguide system. Temperatures were measured using multisensor thermocouple probes. One invasive thermometry catheter in the cervical tumour and two non-invasive catheters in the vagina were used. For optimal tissue contact and fixation of the catheters, a gynaecological tampon was inserted, moisturized with distilled water (4 treatments), or saline (6 treatments) for better thermal contact. During one treatment no tampon was used. At the start of treatment the temperature rise (ΔTmeas) after a short power pulse was measured, which is proportional to SARmeas. The SARcalc along the catheter tracks was extracted from the calculated SAR distribution and compared with the ΔTmeas-profiles. Results: The correlation between ΔTmeas and SARcalc was on average R = 0.56 ± 0.28, but appeared highly dependent on the wetness of the tampon (preferably with saline) and the tissue contact of the catheters. Correlations were strong (R ∼ 0.85–0.93) when thermal contact was good, but much weaker (R ∼ 0.14–0.48) for cases with poor thermal contact. Conclusion: Good correlations between measurements and calculations were found when tissue contact of the catheters was good. The main difficulties for accurate verification were of clinical nature, arising from improper use of the gynaecological tampon. Poor thermal contact between thermocouples and tissue caused measurement artefacts that were difficult to correlate with calculations.

Relation between body size and temperatures during locoregional hyperthermia of oesophageal cancer patients

Purpose. To analyse the relation between patients’ body size and temperatures during locoregional hyperthermia for oesophageal cancer. Methods. Patients were treated with neo-adjuvant chemoradiotherapy plus hyperthermia, given with the AMC-4 waveguide system. Temperatures were measured at tumour location in the oesophageal lumen using multisensor thermocouple probes. Systemic temperature rise (ΔTsyst) was monitored rectally. Steady-state tumour temperatures were expressed in terms of T90, T50 and T10, averaged over the five hyperthermia sessions, and correlated with patients’ body mass, dorsoventral and lateral diameter and fat layer thickness, measured at tumour level using a CT scan made in treatment position. Fat percentage (Fat%) was estimated using diameters and fat layer thickness. Effective tumour perfusion (Wb) was estimated from the temperature decay during the cool-down period. Results. Temperatures were inversely related to body mass, diameters, fat layer thickness, and fat percentage. The strongest univariate correlations were found with lateral fat layer thickness, lateral diameter, and body mass. An increase in lateral diameter (28→42 cm), or in lateral fat layer thickness (0→40 mm) or in body mass (50→120 kg) all yielded a ∼1.5°C decrease in tumour temperature rise. Multivariate correlation analysis proved that the combination of Fat%, ΔTsyst and Wb was most predictive for the achieved tumour temperatures, accounting for 81 ± 12% of the variance in temperatures. Conclusions. Intra-oesophageal temperatures during locoregional hyperthermia are inversely related to patients’ body size parameters, of which fat percentage is the most significant prognostic factor. These findings could be used to define inclusion criteria of new studies on intrathoracic hyperthermia.

Characteristics and performance evaluation of the capacitive Contact Flexible Microstrip Applicator operating at 70 MHz for external hyperthermia

Purpose: To characterise and evaluate the capacitive Contact Flexible Microstrip Applicator operating at 70 MHz, CFMA-70. This applicator is introduced for the treatment of superficial tumours with extension in depth beyond the range of regular superficial applicators. Methods: E-field measurements were performed in an elliptical phantom filled with a saline solution using an E-field vector probe. E-field distributions and SAR patterns are compared to those of the CFMA-434 and of 70 MHz waveguides. The applicator has been used for the treatment of 6 patients with breast cancer with a tumour depth exceeding 4 cm. Results: The effective heating depth of the CFMA-70 is 50% larger than for the CFMA-434. Its effective field size is 26 × 20 cm (aperture 29 × 20 cm), larger than for an equally sized CFMA-434. In contrast to the CFMA-434 the SAR pattern of this applicator is insensitive to the bolus thickness. Comparison to 70 MHz waveguides shows that the E-field component normal to the applicator is 100% larger for the CFMA-70. During clinical applications acceptable temperatures were realised for individual sessions (also at depth), but in many cases treatment limiting hot spots occurred close to superficial bony structures near the applicator edge. Both surface irregularities and the normal field component may be responsible. Conclusions: The CFMA-70 has adequate penetration depth for the treatment of superficial tumours exceeding a depth of 4 cm. However, the relatively large normal E-field component may induce treatment-limiting hot spots at tissue interfaces in the direction normal to the applicators surface.

Re-irradiation and Hyperthermia in Breast Cancer

Half of locoregional recurrences after breast cancer treatment are isolated events. Restaging should be carried out to select patients for curative salvage treatment. The approach depends on the characteristics of the primary and recurrent cancer, previous locoregional and systemic treatments, site of recurrence, comorbidities and the patients wishes. A multidisciplinary discussion should be associated with the shared decision-making process. In view of the potential long-term disease-free survival, meticulous target volume delineation and selection of the most appropriate techniques should be used to decrease the risk of toxicity. This overview aims to provide clinicians with tools to manage the different scenarios of breast cancer patients with locoregional recurrences in the context of re-irradiation.

Development of a 70 MHz unit for hyperthermia treatment of deep-seated breast tumors

Hyperthermia of tumors in intact breast extending beyond the heating depth of our superficial 434 MHz CFMA antennas requires an alternative approach. A dedicated system was designed for this purpose, consisting of a treatment bed fitted with a 50×40×16cm temperature controlled open water bolus. The patient lies in prone position with the breast immersed in the water positioned in front of a 34×20cm 70 MHz waveguide placed in the bottom of the bolus. Hyperthermia was applied once a week for the whole breast with the 70 MHz applicator for 6 patients treated with thermoradiotherapy for deep lesions of recurrent breast cancer or melanoma. Two 14-sensor thermocouple thermometry probes were placed in catheters to monitor the invasive temperature. Results: The combination of 300–900W antenna power and a water temperature of 42°C was well tolerated for the entire session of one hour and resulted in good tumor temperatures with T10 = 42.2°C, T50 = 41.1°C, T90 = 39.8°C. No toxicity or complaints were associated with the heating. A water mattress and other measures were needed to assure a comfortable position throughout the treatment. Conclusion: the 70 MHz breast applicator system performed well and tumor temperatures were good.