Tetramodal therapy with transurethral resection followed by chemoradiation in combination with hyperthermia for muscle-invasive bladder cancer: early results of a multicenter phase IIB study.

BACKGROUND: Transurethral resection of bladder tumor (TUR-BT) followed by chemoradiation (CRT) is a valid treatment option for patients with muscle-invasive bladder cancer (MIBC). This study aimed to investigate the efficacy of a tetramodal approach with additional regional hyperthermia (RHT). METHODS: Patients with stages T2-4 MIBC were recruited at two institutions. Treatment consisted of TUR-BT followed by radiotherapy at doses of 57-58.2 Gy with concurrent weekly platinum-based chemotherapy and weekly deep RHT (41-43 °C, 60 min) within two hours of radiotherapy. The primary endpoint was a complete response six weeks after the end of treatment. Further endpoints were cystectomy-free rate, progression-free survival (PFS), local recurrence-free survival (LRFS), overall survival (OS) and toxicity. Quality of life (QoL) was assessed at follow-up using the EORTC-QLQ-C30 and QLQ-BM30 questionnaires. Due to slow accrual, an interim analysis was performed after the first stage of the two-stage design. RESULTS: Altogether 27 patients were included in the first stage, of these 21 patients with a median age of 73 years were assessable. The complete response rate of evaluable patients six weeks after therapy was 93%. The 2-year cystectomy-free rate, PFS, LRFS and OS rates were 95%, 76%, 81% and 86%, respectively. Tetramodal treatment was well tolerated with acute and late G3-4 toxicities of 10% and 13%, respectively, and a tendency to improve symptom-related quality of life (QoL) one year after therapy. CONCLUSION: Tetramodal therapy of T2-T4 MIBC is promising with excellent local response, moderate toxicity and good QoL. This study deserves continuation into the second stage.

Quantification of thermal dose in moderate clinical hyperthermia with radiotherapy: a relook using temperature-time area under the curve (AUC).

BACKGROUND: Thermal dose in clinical hyperthermia reported as cumulative equivalent minutes (CEM) at 43 °C (CEM43) and its variants are based on direct thermal cytotoxicity assuming Arrhenius 'break' at 43 °C. An alternative method centered on the actual time-temperature plot during each hyperthermia session and its prognostic feasibility is explored. METHODS AND MATERIALS: Patients with bladder cancer treated with weekly deep hyperthermia followed by radiotherapy were evaluated. From intravesical temperature (T) recordings obtained every 10 secs, the area under the curve (AUC) was computed for each session for T > 37 °C (AUC > 37 °C) and T ≥ 39 °C (AUC ≥ 39 °C). These along with CEM43, CEM43(>37 °C), CEM43(≥39 °C), Tmean, Tmin and Tmax were evaluated for bladder tumor control. RESULTS: Seventy-four hyperthermia sessions were delivered in 18 patients (median: 4 sessions/patient). Two patients failed in the bladder. For both individual and summated hyperthermia sessions, the Tmean, CEM43, CEM43(>37 °C), CEM43(≥39 °C), AUC > 37 °C and AUC ≥ 39 °C were significantly lower in patients who had a local relapse. Individual AUC ≥ 39 °C for patients with/without local bladder failure were 105.9 ± 58.3 °C-min and 177.9 ± 58.0 °C-min, respectively (p = 0.01). Corresponding summated AUC ≥ 39 °C were 423.7 ± 27.8 °C-min vs. 734.1 ± 194.6 °C-min (p < 0.001), respectively. The median AUC ≥ 39 °C for each hyperthermia session in patients with bladder tumor control was 190 °C-min. CONCLUSION: AUC ≥ 39 °C for each hyperthermia session represents the cumulative time-temperature distribution at clinically defined moderate hyperthermia in the range of 39 °C to 45 °C. It is a simple, mathematically computable parameter without any prior assumptions and appears to predict treatment outcome as evident from this study. However, its predictive ability as a thermal dose parameter merits further evaluation in a larger patient cohort.

Prospective Evaluation of Changes in Pain Levels, Quality of Life and Functionality After Low Dose Radiotherapy for Epicondylitis, Plantar Fasciitis, and Finger Osteoarthritis.

Background: The objective benefits of low dose radiotherapy (LDRT) for non-malignant joint disorders are controversial. This study evaluated changes in pain, quality of life (QoL) and function after LDRT for epicondylitis, plantar fasciitis, and finger osteoarthritis. Materials and Methods: Patients over 40 years old with epicondylitis, plantar fasciitis, and finger osteoarthritis were had pain following at least 6 months of conservative therapy. Patients received 0.5 Gy LDRT twice weekly for 4 weeks repeated once after 8 weeks in patients who failed to achieve complete pain relief. Patients assessed their pain according to the visual analog scale. Handgrip strength was measured with an isometric dynamometer and the fast self-paced walking test was used in patients with plantar fasciitis. QoL was evaluated according to the EQ-5D and HAQ-DI questionnaires. Results: Outcomes for 157 patients (204 sites) were documented at 2, 6, and 12 months after last LDRT. Pain reduction at rest (p < 0.001), during activity (p < 0.001) and increase in handgrip strength (extension p < 0.001, flexion p = 0.002) were highly significant for patients with lateral epicondylitis. Patients with medial epicondylitis reported pain relief at rest (p = 0.041) and during activity (p = 0.041) and significant increase in handgrip strength (p = 0.022). Patients with plantar fasciitis reported pain reduction at rest (p < 0.001), during activity (p < 0.001) and faster walking times (p < 0.001). A trend toward improved QoL was observed. Patients with finger osteoarthritis reported significant pain relief during activity (p < 0.001) and a gain in handgrip strength (p = 0.004), with a trend to both pain relief at rest (p = 0.056) and stronger pinch grip (p = 0.099). Conclusions: LDRT achieved significant pain relief at rest and during activity and a corresponding objective improvement in handgrip strength in patients with epicondylitis. Pain relief at rest, during activity and improvement in walking time were demonstrated in patients with plantar fasciitis. LDRT achieved pain relief during activity, and handgrip strength was improved in patients with finger osteoarthritis. No significant effect was seen on quality of life measures for these conditions. The observed benefits were maintained 12 months after LDRT for all 3 indications and we recommend this low cost, safe intervention for patients over 40 who have failed prior conservative therapy.

A Pilot Study of Radiotherapy and Local Hyperthermia in Elderly Patients With Muscle-Invasive Bladder Cancers Unfit for Definitive Surgery or Chemoradiotherapy.

Purpose: To present the outcomes of a pilot study with hyperthermia (HT) and radiotherapy (RT) in elderly patients of muscle-invasive bladder cancers (MIBC) unfit for surgery or chemoradiotherapy (CTRT). Methods: Sixteen elderly patients with unifocal or multifocal MIBCs received a total dose of 48 Gy/16 fractions/4 weeks or 50 Gy/20 fractions/4 weeks, respectively. HT with a radiofrequency HT unit was delivered once weekly for 60 min before RT and a mean temperature of 41.3°C was attained (maximum temperature 41.1-43.5°C). Local control was assessed using RECIST criteria at 3-monthly intervals by cystoscopy with or without biopsy. Results: The median age, KPS and age-adjusted Charlson comorbidity index were 81 years, 70 and 5, respectively. At median follow-up of 18.5 months (range: 4-65), bladder preservation was 100% with satisfactory function. 11/16 patients (68.7%) had no local and/or distant failure, while isolated local, distant and combined local and distant failures were evident in 2, 2, and 1 patient, respectively. Two local failures were salvaged by TUR-BT resulting in a local control rate of 93.7%. The 5-year cause-specific (CS) local disease free survival (LDFS), disease free survival (DFS), and overall survival (OS) were 64.3, 51.6, and 67.5%, respectively while 5-year non-cause-specific (NCS)-LDFS, NCS-DFS, and NCS-OS were 26.5, 23.2, and 38%, respectively. None of the patients had acute or late grade 3/4 gastrointestinal or genitourinary toxicities. Conclusions: The outcomes from this pilot study indicate that thermoradiotherapy is a feasible therapeutic modality in elderly MIBC patients unfit for surgery or CTRT. HTRT is well-tolerated, allows bladder preservation and function, achieves long-term satisfactory locoregional control and is devoid of significant treatment-related morbidity. This therapeutic approach deserves further evaluation in randomized studies.

Radiotherapy for Melanoma: More than DNA Damage.

Despite its reputation as a radioresistant tumour, there is evidence to support a role for radiotherapy in patients with melanoma and we summarise current clinical practice. Melanoma is a highly immunogenic tumour and in this era of immunotherapy, there is renewed interest in the potential of irradiation, not only as an adjuvant and palliative treatment, but also as an immune stimulant. It has long been known that radiation causes not only DNA strand breaks, apoptosis, and necrosis, but also immunogenic modulation and cell death through the induction of dendritic cells, cell adhesion molecules, death receptors, and tumour-associated antigens, effectively transforming the tumour into an individualised vaccine. This immune response can be enhanced by the application of clinical hyperthermia as evidenced by randomised trial data in patients with melanoma. The large fraction sizes used in cranial radiosurgery and stereotactic body radiotherapy are more immunogenic than conventional fractionation, which provides additional radiobiological justification for these techniques in this disease entity. Given the immune priming effect of radiotherapy, there is a strong but complex biological rationale and an increasing body of evidence for synergy in combination with immune checkpoint inhibitors, which are now first-line therapy in patients with recurrent or metastatic melanoma. There is great potential to increase local control and abscopal effects by combining radiotherapy with both immunotherapy and hyperthermia, and a combination of all three modalities is suggested as the next important trial in this refractory disease.

Is hyperthermia combined with radiotherapy adequate in elderly patients with muscle-invasive bladder cancers? Thermo-radiobiological implications from an audit of initial results.

PURPOSE: The aim of this study was to evaluate the outcomes of loco-regional hyperthermia (HT) with radiotherapy (RT) and/or chemotherapy (CT) in elderly patients with muscle-invasive bladder cancers (MIBC). MATERIAL AND METHODS: Twenty consecutive MIBC patients were treated with HTRT (n = 8) or HTCTRT (n = 12) following transurethral resection of their bladder tumours. Weekly HT was administered prior to RT to a mean temperature of 40.6-42.7 °C for 60 min. A mean RT dose of 54.6 Gy (SD ± 4.2) was delivered. Single-agent cisplatin (n = 2) or carboplatin (n = 10) was used in HTCTRT patients. RESULTS: The median age was 81 years. HTRT patients received a mean RT dose of 51.0 Gy compared to 57.1 Gy with HTCTRT (p < 0.001) in a shorter overall treatment time (OTT) (30.8 ± 6.9 versus 43.9 ± 4.0 days, p < 0.001). All HTRT patients had long-term local disease control, while 41.6% of HTCTRT recurred during follow-up. None of the HTRT patients experienced grade III/IV acute and late toxicities, while these were evident in two and one HTCTRT patients respectively. Taken together, the 3-year bladder preservation, local disease-free survival, cause-specific survival and overall survival were 86.6%, 60.7%, 55% and 39.5% respectively. Even though the mean biological effective dose (BED) for both groups was similar (57.8 Gy15), the thermo-radiobiological BED estimated from HT-induced reduction of α/ß was significantly higher for HTRT patients (91 ± 4.4 versus 85.8 ± 4.3 Gy3, p = 0.018). CONCLUSIONS: Thermal radiosensitisation with consequent reduction in α/ß results in a higher thermo-radiobiological BED with a relatively higher RT dose/fraction and shorter OTT. This translates into a favourable outcome in elderly MIBC patients. Any benefit of CT in these patients needs further investigation.

Anisotropic phantom measurements for quality assured use of diffusion tensor imaging in clinical practice.

BACKGROUND: Diffusion-weighted magnetic resonance imaging (MRI) is being increasingly applied in clinical practice, for example in neuronavigation and in modern radiation treatment planning. Quality assurance (QA) is therefore important to avoid clinical errors. PURPOSE: To compare four analytical programs and a neuronavigation tool to evaluate our in-house diffusion-weighted imaging protocol in order to be able to implement diffusion tensor imaging (DTI) into clinical practice. MATERIAL AND METHODS: A phantom containing crossing fibers was used for the QA. Fiber tracking and fractional anisotropy (FA) analyses were performed, and the geometrical resolution was verified using the phantom. RESULTS: FA results were reproducible within each program and no significant differences between programs were observed. Also, no significant differences in FA values were found when comparing the results between the four software programs. Geometrical resolution of the anatomical data-set was satisfactory; however the crossing of the fibers was not accurately represented by three of the four programs. CONCLUSION: Phantom QA is necessary before using DTI for novel procedures to identify the uncertainties associated with DTI data. It is important to remember that the results are software-dependent and that representation of the tracts may vary between software products. We therefore recommend caution with regard to the application of fiber tracking results intraoperatively when dealing with abnormal fiber tract anatomy.