Regional hyperthermia for soft tissue sarcoma - a survey on current practice, controversies and consensus among 12 European centers.

PURPOSE: To analyze the current practice of regional hyperthermia (RHT) for soft tissue sarcoma (STS) at 12 European centers to provide an overview, find consensuses and identify controversies necessary for future guidelines and clinical trials. METHODS: In this cross-sectional survey study, a 27-item questionnaire assessing clinical subjects and procedural details on RHT for STS was distributed to 12 European cancer centers for RHT. RESULTS: We have identified seven controversies and five consensus points. Of 12 centers, 6 offer both, RHT with chemotherapy (CTX) or with radiotherapy (RT). Two centers only offer RHT with CTX and four centers only offer RHT with RT. All 12 centers apply RHT for localized, high-risk STS of the extremities, trunk wall and retroperitoneum. However, eight centers also use RHT in metastatic STS, five in palliative STS, eight for superficial STS and six for low-grade STS. Pretherapeutic imaging for RHT treatment planning is used by 10 centers, 9 centers set 40-43 °C as the intratumoral target temperature, and all centers use skin detectors or probes in body orifices for thermometry. DISCUSSION: There is disagreement regarding the integration of RHT in contemporary interdisciplinary care of STS patients. Many clinical controversies exist that require a standardized consensus guideline and innovative study ideas. At the same time, our data has shown that existing guidelines and decades of experience with the technique of RHT have mostly standardized procedural aspects. CONCLUSIONS: The provided results may serve as a basis for future guidelines and inform future clinical trials for RHT in STS patients.

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.

Is it safe to irradiate the newest generation of ventricular assist devices? A case report and systematic literature review.

An increasing number of mechanical assist devices, especially left ventricular assist devices (VADs), are being implanted for prolonged periods and as destination therapy. Some VAD patients require radiotherapy due to concomitant oncologic morbidities, including thoracic malignancies. This raises the potential of VAD malfunction via radiation-induced damage. So far, only case reports and small case series on radiotherapy have been published, most of them on HeartMate II (HMII, Abbott, North Chicago, IL, USA). Significantly, the effects of irradiation on the HeartMate 3 (HM3, Abbott) remain undefined, despite the presence of controller components engineered within the pump itself. We report the first case of a patient with a HM3 who successfully underwent stereotactic hypofractionated radiotherapy due to an early-stage non-small-cell lung cancer. The patient did not suffer from any complications, including toxicity or VAD malfunction. Based on this case report and on published literature, we think that performing radiotherapy after VAD implantation with the aid of a multidisciplinary team could be performed, but more in vitro studies and cases series are needed to reinforce this statement.

Clinical estimation of α/ß values for prostate cancer from isoeffective phase III randomized trials with moderately hypofractionated radiotherapy.

BACKGROUND: The α/ß values for prostate cancer (PCa) are usually assumed to be low (1.0-1.8 Gy). This study estimated the α/ß values of PCa from phase III randomized trials of conventional (CRT) versus hypofractionated (HRT) external beam radiotherapy (RT), reported as isoeffective in terms of their 5-year biochemical (BF) or biochemical and/or clinical failure (BCF) rates. MATERIAL AND METHODS: The α/ß for each trial was estimated from the equivalent biological effective doses using the linear-quadratic model for each of their HRT and CRT schedules. The cumulative outcomes of these trials were evaluated by meta-analysis for odds ratio (OR), risk ratio (RR) and risk difference (RD). RESULTS: Eight trials from seven studies, randomized 6993 patients between CRT (n = 2941) and HRT (n = 4052). RT treatment varied between the two treatment groups in terms of dose/fraction, total dose, overall treatment time and %patients on androgen deprivation therapy (ADT). Differences in OR, RR, and RD for both BF and BCF were nonsignificant. The computed α/ß ranged from 1.3 to 11.1 Gy (4.9 ± 3.9 Gy; 95% CI: 1.6-8.2). On multivariate regression, %ADT was the sole determinant of computed α/ß (model R2: 0.98, p < .001). CONCLUSIONS: Clinically estimated α/ß for PCa from isoeffective randomized trials using known variables in the linear-quadratic expression ranged between 1.3 and 11.1 Gy. The estimated α/ß values were inversely related to %ADT usage, which should be considered when planning future RT dose-fractionation schedules.

Concurrent chemoradiotherapy vs. radiotherapy alone in locally advanced cervix cancer: A systematic review and meta-analysis.

The efficacy of concurrent chemoradiotherapy (CTRT) in locally advanced cervix cancer (LACC, stages IIB-IVA) is contentious. This is due to the variable extent of therapeutic benefit reported in different randomized clinical trials and meta-analyses that usually include all stages of cervix cancer. A systematic review and meta-analysis was therefore conducted to evaluate the efficacy of concurrent CTRT over radiotherapy (RT) alone, predominantly in LACC for the key endpoints; complete response (CR), long-term loco-regional control (LRC), overall survival (OS), grade III/IV acute and late toxicities. Six databases namely - PubMed, EMBASE, SCOPUS, Web of Science, Google Scholar and Cochrane library were explored and supplemented by hand-searching. Only prospective randomized trials conducted in LACC between concurrent CTRT and RT alone with no surgical interventions were included. Fourteen English language articles from 1788 citations were shortlisted for the final analysis. Of the 2445 patients evaluated (CTRT: n=1217; RT: n=1228), 95.7% had LACC and 96% had a squamous cell histology. Eight studies used cisplatin alone, 4 had cisplatin-based combination chemotherapy (CT) while 2 used mitomycin-C, either alone or in combination. CTRT improved the CR (+10.2%, p=0.027), LRC (+8.4%, p<0.001) and OS (+7.5%, p<0.001) over RT alone. However a 10.4% higher incidence of grade III/IV acute toxicities (p<0.001) was also evident with CTRT. Late toxicities in both groups were equivalent. Subgroup analysis and meta-regression did not reveal any significant advantage in outcomes between the 3 CTRT regimens. Thus, although concurrent CTRT provides conclusive therapeutic benefit over RT alone in LACC, the choice of CT agents should be based on their cost-effectiveness and the anticipated expenses for the management of any associated acute toxicities. This assumes importance particularly in resource-constrained low-middle-income countries with the highest burden of LACC, where majority of the patients meet the treatment costs as out-of-pocket expenses.

Crizotinib inhibits migration and expression of ID1 in MET-positive lung cancer cells: implications for MET targeting in oncology.

AIMS: ID1 is an important component of the MET-SRC signaling pathway, which is a regulator of cell migration and invasion. We hypothesized that the ALK/MET inhibitor crizotinib inhibits migration via MET-SRC-ID1, rather than ALK. MATERIALS & METHODS: We used ALK fusion-positive and -negative lung cancer cell lines; crizotinib, PHA-665752, and saracatinib, and stable transfection with shMET. We performed western blotting for p-ALK, ALK, p-MET, MET, p-SRC, SRC and ID1, and quantitative real-time PCR for ID1. RESULTS: Crizotinib decreased p-MET, p-SRC and ID1 levels in ALK- and or MET-positive cell lines and inhibited cell migration. Knockdown of MET was comparable with the effect of crizotinib. CONCLUSION: The effects of crizotinib on ID1 expression and cancer cell migration were associated with the presence of activated MET, rather than ALK fusion.

Present Practice of Radiative Deep Hyperthermia in Combination with Radiotherapy in Switzerland.

BACKGROUND: Moderate hyperthermia is a potent and evidence-based radiosensitizer. Several indications are reimbursed for the combination of deep hyperthermia with radiotherapy (dHT+RT). We evaluated the current practice of dHT+RT in Switzerland. METHODS: All indications presented to the national hyperthermia tumor board for dHT between January 2017 and June 2021 were evaluated and treatment schedules were analyzed using descriptive statistics. RESULTS: Of 183 patients presented at the hyperthermia tumor board, 71.6% were accepted and 54.1% (99/183) finally received dHT. The most commonly reimbursed dHT indications were "local recurrence and compression" (20%), rectal (14.7%) and bladder (13.7%) cancer, respectively. For 25.3% of patients, an individual request for insurance cover was necessary. 47.4% of patients were treated with curative intent; 36.8% were in-house patients and 63.2% were referred from other hospitals. CONCLUSIONS: Approximately two thirds of patients were referred for dHT+RT from external hospitals, indicating a general demand for dHT in Switzerland. The patterns of care were diverse with respect to treatment indication. To the best of our knowledge, this study shows for the first time the pattern of care in a national cohort treated with dHT+RT. This insight will serve as the basis for a national strategy to evaluate and expand the evidence for dHT.

Radiation-Associated Angiosarcoma of the Breast and Chest Wall Treated with Thermography-Controlled, Contactless wIRA-Hyperthermia and Hypofractionated Re-Irradiation.

BACKGROUND: Radiation-associated angiosarcoma of the breast (RAASB) is a rare, challenging disease, with surgery being the accepted basic therapeutic approach. In contrast, the role of adjuvant and systemic therapies is a subject of some controversy. Local recurrence rates reported in the literature are mostly heterogeneous and are highly dependent on the extent of surgery. In cases of locally recurrent or unresectable RAASB, prognosis is very poor. METHODS: We retrospectively report on 10 consecutive RAASB patients, most of them presenting with locally recurrent or unresectable RAASB, which were treated with thermography-controlled water-filtered infrared-A (wIRA) superficial hyperthermia (HT) immediately followed by re-irradiation (re-RT). Patients with RAASB were graded based on their tumor extent before onset of radiotherapy (RT). RESULTS: We recorded a local control (LC) rate dependent on tumor extent ranging from a high LC rate of 100% (two of two patients) in the adjuvant setting with an R0 or R2 resection to a limited LC rate of 33% (one of three patients) in patients with inoperable, macroscopic tumor lesions. CONCLUSION: Combined HT and re-RT should be considered as an option (a) for adjuvant treatment of RAASB, especially in cases with positive resection margins and after surgery of local recurrence (LR), and (b) for definitive treatment of unresectable RAASB.

Comment on Kronenfeld et al. Clinical Outcomes for Primary and Radiation-Associated Angiosarcoma of the Breast with Multimodal Treatment: Long-Term Survival Is Achievable. Cancers 2021, 13, 3814.

On 2 July 2021, Kronenfeld et al. [...].

Immune infiltrates in patients with localised high-risk soft tissue sarcoma treated with neoadjuvant chemotherapy without or with regional hyperthermia: A translational research program of the EORTC 62961-ESHO 95 randomised clinical trial.

BACKGROUND: The EORTC 62961-ESHO 95 randomised trial showed improved long-term survival of patients with high-risk soft-tissue sarcoma by adding regional hyperthermia to neoadjuvant chemotherapy. We hypothesised that immune infiltrate of patients treated with neoadjuvant therapy associate with clinical outcome. METHODS: Tumour infiltrating lymphocytes (TILs) and CD8, FOXP3, PD-1, and PD-L1 were evaluated in sequential biopsies of patients after four cycles of therapy. RESULTS: From a subgroup of 109 patients who had been randomised between July 1997 and November 2006 to neoadjuvant chemotherapy (53 patients) or neoadjuvant chemotherapy with regional hyperthermia (56 patients), 137 biopsies were obtained. TILs increased in paired second biopsies independent of treatment allocation (p < 0.001). FOXP3 regulatory T cells decreased (p = 0.002), and PD-L1 expression of tumours became undetectable. In the multivariate analysis, post-treatment high TILs correlated to LPFS (HR: 0.34; 95% CI 0.15-0.75; p = 0.008) and DFS (HR: 0.38; 95% CI 0.17-0.82; p = 0.015). In comparing post-treatment immune infiltrate between treatment arms, tumour response was associated with neoadjuvant chemotherapy with regional hyperthermia (p = 0.013) and high TILs (p = 0.064). High CD8 cell infiltration was associated with improved LPFS (HR: 0.27; 95% CI 0.09-0.79; Log-rank p = 0.011) and DFS (HR: 0.25; 95% CI 0.09-0.73; Log-rank p = 0.006). Improved survival at 10 years was associated with immune infiltrate after neoadjuvant chemotherapy with regional hyperthermia. CONCLUSION: Preoperative therapy re-programs a non-inflamed tumour at baseline into an inflamed tumour. The post-treatment immune infiltrate became predictive for clinical outcomes. The combination with regional hyperthermia primes the tumour microenvironment, enabling enhanced anti-tumour immune activity in high-risk soft tissue sarcomas. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00003052.

Efficacy and Safety Evaluation of the Various Therapeutic Options in Locally Advanced Cervix Cancer: A Systematic Review and Network Meta-Analysis of Randomized Clinical Trials.

Treatment options in locally advanced cervix cancer (LACC) have evolved around radiation therapy (RT) and/or chemotherapy (CT), hypoxic cell sensitizers, immunomodulators (Imm), and locoregional moderate hyperthermia (HT). A systematic review and network meta-analysis was conducted to synthesize the evidence for efficacy and safety in terms of long-term locoregional control (LRC), overall survival (OS), and grade ≥3 acute morbidity (AM) and late morbidity (LM). Five databases were searched, and 6285 articles (1974-2018) were screened per the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. Fifty-nine randomized trials in untreated LACC without surgical intervention were shortlisted. These used 13 different interventions: RT alone and/or neoadjuvant CT (NACT), adjuvant CT (ACT), concurrent chemoradiation therapy (CTRT) (weekly cisplatin [CDDP]/3-weekly CDDP/combination CT with CDDP/non-CDDP-based CT), hypoxic cell sensitizers, Imm, or HT. Odds ratios (ORs) using random effects network meta-analysis were estimated. Interventions for each endpoint were ranked according to their corresponding surface under cumulative ranking curve values. Of the 9894 patients evaluated, the total events reported for LRC, OS, AM, and LM were 5431 of 8197, 4482 of 7958, 1710 of 7183, and 441 of 6333, respectively. ORs and 95% credible intervals (CrIs) for the 2 best strategies were HT + RT versus CTRT + ACT (OR, 1.23; 95% CrI, 0.49-3.19) for LRC, CTRT (3-weekly CDDP) versus HTCTRT (OR, 1.14; 95% CrI, 0.35-3.65) for OS, RT + ACT versus RT (OR, 0.01; 95% CrI, 0.00-1.04) for AM, and NACT + RT + ACT versus RT + Imm (OR, 0.42; 95% CrI, 0.02-7.39) for LM. The 3 interventions with the highest cumulative surface under cumulative ranking curve values for all 4 endpoints were HTRT, HTCTRT, and CTRT (3-weekly CDDP). Articles with low risk of bias and those published during 2004 to 2018 also retained these interventions as the best. Two-step cluster analysis grouped these 3 modalities in a single distinctive cluster. HTRT, HTCTRT, and CTRT with 3-weekly CDDP were identified as therapeutic modalities with the best comprehensive impact on key clinical endpoints in LACC. This warrants a phase 3 randomized trial among these strategies for a head-to-head comparison and additional validation.

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.

Conventional Versus Hypofractionated Radiation Therapy for Localized or Locally Advanced Prostate Cancer: A Systematic Review and Meta-analysis along with Therapeutic Implications.

PURPOSE: A systematic review and meta-analysis were conducted to evaluate the therapeutic outcomes of conventional radiation therapy (CRT) and hypofractionated radiation therapy (HRT) for localized or locally advanced prostate cancer (LLPCa). METHODS AND MATERIALS: A total of 599 abstracts were extracted from 5 databases and screened in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Only phase III trials randomized between CRT and HRT in LLPCa with a minimum of 5 years of follow-up data were considered. The evaluated endpoints were biochemical failure, biochemical and/or clinical failure, overall mortality, prostate cancer-specific mortality, and both acute and late gastrointestinal (GI) and genitourinary (GU) (grade ≥2) toxicity. RESULTS: Ten trials from 9 studies, with a total of 8146 patients (CRT, 3520; HRT, 4626; 1 study compared 2 HRT schedules with a common CRT regimen), were included in the evaluation. No significant differences were found in the patient characteristics between the 2 arms. However, the RT parameters differed significantly between CRT and HRT (P<.001 for all). The use of androgen deprivation therapy varied from 0% to 100% in both groups (mean ± standard deviation 43.3% ± 43.6% for CRT vs HRT; P=NS). The odds ratio, risk ratio, and risk difference (RD) between CRT and HRT for biochemical failure, biochemical and/or clinical failure, overall mortality, prostate cancer-specific mortality, acute GU toxicity, and late GU and GI toxicities were all nonsignificant. Nevertheless, the incidence of acute GI toxicity was 9.1% less with CRT (RD 0.091; odds ratio 1.687; risk ratio 1.470; P<.001 for all). On subgroup analysis, the patient groups with ≤66.8% versus >66.8% androgen deprivation therapy (RD 0.052 vs 0.136; P=.008) and <76% versus ≥76% full seminal vesicles in the clinical target volume (RD 0.034 vs 0.108; P<.001) were found to significantly influence the incidence of acute GI toxicity with HRT. CONCLUSIONS: HRT provides similar therapeutic outcomes to CRT in LLPCa, except for a significantly greater risk of acute GI toxicity. HRT enables a reduction in the overall treatment time and offers patient convenience. However, the variables contributing to an increased risk of acute GI toxicity require careful consideration.