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.

From Localized Mild Hyperthermia to Improved Tumor Oxygenation: Physiological Mechanisms Critically Involved in Oncologic Thermo-Radio-Immunotherapy.

(1) Background: Mild hyperthermia (mHT, 39-42 °C) is a potent cancer treatment modality when delivered in conjunction with radiotherapy. mHT triggers a series of therapeutically relevant biological mechanisms, e.g., it can act as a radiosensitizer by improving tumor oxygenation, the latter generally believed to be the commensurate result of increased blood flow, and it can positively modulate protective anticancer immune responses. However, the extent and kinetics of tumor blood flow (TBF) changes and tumor oxygenation are variable during and after the application of mHT. The interpretation of these spatiotemporal heterogeneities is currently not yet fully clarified. (2) Aim and methods: We have undertaken a systematic literature review and herein provide a comprehensive insight into the potential impact of mHT on the clinical benefits of therapeutic modalities such as radio- and immuno-therapy. (3) Results: mHT-induced increases in TBF are multifactorial and differ both spatially and with time. In the short term, changes are preferentially caused by vasodilation of co-opted vessels and of upstream normal tissue vessels as well as by improved hemorheology. Sustained TBF increases are thought to result from a drastic reduction of interstitial pressure, thus restoring adequate perfusion pressures and/or HIF-1α- and VEGF-mediated activation of angiogenesis. The enhanced oxygenation is not only the result of mHT-increased TBF and, thus, oxygen availability but also of heat-induced higher O2 diffusivities, acidosis- and heat-related enhanced O2 unloading from red blood cells. (4) Conclusions: Enhancement of tumor oxygenation achieved by mHT cannot be fully explained by TBF changes alone. Instead, a series of additional, complexly linked physiological mechanisms are crucial for enhancing tumor oxygenation, almost doubling the initial O2 tensions in tumors.

A patterns of care analysis of hyperthermia in combination with radio(chemo)therapy or chemotherapy in European clinical centers.

PURPOSE: The combination of hyperthermia (HT) with radio(chemo)therapy or chemotherapy (CT) is an established treatment strategy for specific indications. Its application in routine clinical practice in Europe depends on regulatory and local conditions. We conducted a survey among European clinical centers to determine current practice of HT. METHODS: A questionnaire with 22 questions was sent to 24 European HT centers. The questions were divided into two main categories. The first category assessed how many patients are treated with HT in combination with radio(chemo)therapy or CT for specific indications per year. The second category addressed which hyperthermia parameters are recorded. Analysis was performed using descriptive methods. RESULTS: The response rate was 71% (17/24) and 16 centers were included in this evaluation. Annually, these 16 centers treat approximately 637 patients using HT in combination with radio(chemo)therapy or CT. On average, 34% (range: 3-100%) of patients are treated in clinical study protocols. Temperature readings and the time interval between HT and radio(chemo)therapy or CT are recorded in 13 (81%) and 9 (56%) centers, respectively. The thermal dose quality parameter "cumulative equivalent minutes at 43 °C" (CEM43°C) is only evaluated in five (31%) centers for each HT session. With regard to treatment sequence, 8 (50%) centers administer HT before radio(chemo)therapy and the other 8 in the reverse order. CONCLUSION: There is a significant heterogeneity among European HT centers as to the indications treated and the recording of thermometric parameters. More evidence from clinical studies is necessary to achieve standardization of HT practice.

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.

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. [...].

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.

Combined wIRA-Hyperthermia and Hypofractionated Re-Irradiation in the Treatment of Locally Recurrent Breast Cancer: Evaluation of Therapeutic Outcome Based on a Novel Size Classification.

Effective tumor control in patients suffering from unresectable locally recurrent breast cancer (LRBC) in pre-irradiated areas can be achieved by re-irradiation combined with superficial hyperthermia. Using this combined modality, total re-irradiation dose and toxicity can be significantly reduced compared to conventionally fractionated treatment schedules with total doses of 60-66 Gy. Applying contact-free, thermography-controlled water-filtered infrared-A superficial hyperthermia, immediately followed by hypofractionated re-irradiation, consisting of 4 Gy once per week up to a total dose of 20 Gy, resulted in high overall response rates even in large-sized tumors. Comparability of clinical data between different combined Hyperthermia (HT)/Radiotherapy (RT) treatment schedules is impeded by the highly individual characteristics of this disease. Tumor size, ranging from microscopic disease and small lesions to large-sized cancer en cuirasse, is described as one of the most important prognostic factors. However, in clinical studies and analyses of LRBC, tumor size has so far been reported in a very heterogeneous way. Therefore, we suggest a novel, simple and feasible size classification (rClasses 0-IV). Applying this classification for the evaluation of 201 patients with pre-irradiated LRBC allowed for a stratification into distinct prognostic groups.

Biophysical and photobiological basics of water-filtered infrared-A hyperthermia of superficial tumors.

Thermography-controlled, water-filtered infrared-A (wIRA) is a novel, effective and approved heating technique listed in the ESHO quality assurance guidelines for superficial hyperthermia clinical trials (2017). In order to assess the special features and the potential of wIRA-hyperthermia (wIRA-HT), detailed and updated information about its physical and photobiological background is presented. wIRA allows for (a) application of high irradiances without skin pain and acute grade 2-4 skin toxicities, (b) prolonged, therapeutically relevant exposure times using high irradiances (150-200 mW/cm2) and (c) faster and deeper heat extension within tissues. The deeper radiative penetration depth is mainly caused by forward Mie-scattering. At skin surface temperatures of 42-43 °C, the effective heating depth is 15 mm (T ≥ 40 °C) and 20 mm (T ≥ 39.5 °C). Advantages of wIRA include its contact-free energy input, easy power steering by a feed-back loop, extendable treatment fields, real-time and noninvasive surface temperature monitoring with observation of dynamic changes during HT, and - if necessary - rapid protection of temperature-sensitive structures. wIRA makes the compliant heating of ulcerated and/or bleeding tumors possible, allows for HT of irregularly shaped and diffusely spreading tumors, is independent of individual body contours, allows for very short 'transits' between HT and RT (1-4 min) or continuous heating between both therapeutic interventions. New treatment options for wIRA-HT may include malignant melanoma, vulvar carcinoma, skin metastases of different primary tumors, cutaneous T-and B-cell lymphoma, large-area hemangiomatosis, inoperable squamous cell, basal cell and eccrine carcinoma of the skin with depth extensions ≤20 mm.

Hypofractionated re-irradiation of large-sized recurrent breast cancer with thermography-controlled, contact-free water-filtered infra-red-A hyperthermia: a retrospective study of 73 patients.

PURPOSE: Evaluation of the efficacy and toxicity of a new setup of thermographically controlled water-filtered infra-red-A (wIRA) superficial hyperthermia (HT) combined with hypofractionated re-irradiation (re-RT) to treat large-sized breast cancer recurrences. METHODS: Records of 73 heavily pre-irradiated patients with 103 treatment regions, treated from September 2009 to July 2015 were retrospectively analysed. Sixty-four patients with macroscopic disease were treated with 94 regions including 46 patients with lymphangiosis carcinomatosa. Hypofractionated RT consisted of 4 Gy once per week up to a total dose of 20 Gy delivered within 1-4 min after wIRA-HT. Heating of tumour nodules and diffusely spreading cancer lesions was performed under real-time thermographic temperature monitoring, maintaining the maximum skin temperature in the ROI between 42 °C and 43 °C, achieving intratumoural temperatures up to a depth of 2 cm between 39.5 °C and 42 °C. Seventeen patients received re-re-irradiation (re-re-RT) using the same HT/RT-treatment schedule. RESULTS: Response rates in patients with macroscopic disease: 61% CR, 33% PR, 5% NC and 1% PD. Local control throughout life time after CR of macroscopic disease: 59%. All nine patients with microscopic disease had CR and local control throughout lifetime. Only grade 1 toxicities were observed. CONCLUSIONS: Application of thermographically controlled wIRA-HT combined with extremely low-dose re-irradiation provides good local control throughout lifetime of heavily pre-treated breast cancer recurrences. The twin wIRA radiator provides a sufficiently homogeneous heat deposition for the treatment of larger areas. The time lag between HT and re-RT is substantially reduced. The possibility of re-re-RT opens new therapeutic options for the future.

Long-term results of radiotherapy in patients with chronic palmo-plantar eczema or psoriasis.

BACKGROUND AND PURPOSE: Radiotherapy (RT) is well accepted for therapy-refractory palmo-plantar eczema or psoriasis, despite of lacking evidence regarding beneficial long term effects. Furthermore, the optimal irradiation dose is unknown. We evaluated the outcome of RT with two different RT single/total dose (SD/TD) treatment policies. PATIENTS AND METHODS: 28 consecutive patients with therapy-refractory eczema (n = 22) or psoriasis (n = 6) of palms and/or soles were irradiated twice a week either with a D(max) SD of 1 Gy (6/98-5/03; median TD: 12 Gy) or 0.5 Gy (6/03-7/04; median TD: 5 Gy). Median age was 52 years (27-71), median follow-up 20 months (4-76). Totally 88 regions were treated, 49 with 1 Gy, 39 with 0.5 Gy SD. Eight different symptoms were scored from 0 (absent) -3 (severe), giving a possible sum score of 0-24. Patients' rating of RT result was also documented (worse/stable/better/complete remission). RESULTS: The sum score was 15 (6-23) before RT, 2 (0-16) at the end of RT, and 1 (0-21) at last follow-up, respectively. The improvement was highly significant in both treatment regimens. Better or complete remission by the patients were reported in 44 and 39 (= 83 out of 88) localisations, that was often stable during the follow-up. 5 (6%) regions in 3 (11%) patients didn't benefit from RT. CONCLUSION: RT reveals excellent results in palmo-plantar eczema or psoriasis. We recommend a SD of 0.5 Gy twice a week up to a TD of 4-5 Gy.

Effect of timing of surgery on survival after preoperative hyperfractionated accelerated radiotherapy (HART) for locally advanced rectal cancer (LARC): is it a matter of days?

We intend to analyse retrospectively whether the time interval ("gap duration" = GD) between preoperative radiotherapy and surgery in locally advanced rectal cancer (LARC) has an impact on overall survival (OS), cancer specific survival (CSS), disease free survival (DFS) and local control (LC). Two hundred seventy nine patients with LARC were entered in Trial 93-01 (hyperfractionated accelerated radiotherapy 41.6 Gy/26 Fx BID) shortly followed by surgery. From these 250 patients are fully assessable. The median GD of 5 days was used as a discriminator. The median follow-up for all patients was 39 months. GD > 5 days was a significant discriminator for actuarial 5-years OS (69% vs 47%, p = 0.002), CSS (82% vs 57%, p = 0.0007), DFS (62% vs 41%, p = 0.0003) but not for LC (93% vs 90%, p = non-significant). In multivariate analysis, the following factors independently predict outcome; for OS: age, GD, circumferential margin (CM) and nodal stage (ypN); for CSS: GD, ypN and vascular invasion (VI); for DFS: CEA, distance to anal verge, GD, ypN and VI; for LC: CM only. Gap duration predicts survival outcome but not local control. The patients submitted to surgery after a median delay of more than 5 days had a significantly better outcome.

Preoperative hyper-fractionated accelerated radiotherapy (HART) in locally advanced rectal cancer (LARC) immediately followed by surgery. A prospective phase II trial.

BACKGROUND AND PURPOSE: We aim to report on local control in a phase II trial on preoperative hyper-fractionated and accelerated radiotherapy schedule (HART) in locally advanced resectable rectal cancer (LARC). This fractionation schedule was designed to keep the overall treatment time (OTT) as short as possible. PATIENTS AND METHODS: This is a prospective trial on patients with UICC stages II and III rectal cancer. The patients were submitted to a total dose of 41.6 Gy, delivered in 2.5 weeks at 1.6 Gy per fraction twice a day with a 6-h interfraction interval. Surgery was performed within 1 week after the end of irradiation. Adjuvant chemotherapy was delivered in a subset of patients. RESULTS: Two hundred and seventy nine patients were entered and 250 are fully assessable, with a median follow-up of 39 months. The 5-years actuarial local control (LC) rate is 91.7%. The overall survival (OS) is 59.6%. The freedom from disease relapse (FDR) is 71.5%. Downstaging was observed in 38% of the tumors. CONCLUSION: The actuarial LC at 5 years is 91.7%, although we are dealing with stages II-III LARC, mainly located in the lower rectum (median distance = 5 cm). The pattern of failure is dominated by distant metastases and treatment intensification will obviously require a systemic approach.

Concomitant cisplatin significantly improves locoregional control in advanced head and neck cancers treated with hyperfractionated radiotherapy.

PURPOSE: To determine whether the application of two courses of cisplatin simultaneously with hyperfractionated radiotherapy improves the outcome in locally advanced and/or node-positive nonmetastatic carcinomas of the head and neck, compared with hyperfractionated radiotherapy alone. PATIENTS AND METHODS: From July 1994 to July 2000, 224 patients with squamous cell carcinomas of the head and neck (excluding nasopharynx and paranasal sinus) were randomly assigned to hyperfractionated radiotherapy (median dose, 74.4 Gy; 1.2 Gy twice daily) or the same radiotherapy combined with two cycles of concomitant cisplatin (20 mg/m2 on 5 days of weeks 1 and 5). The primary end point was time to any treatment failure; secondary end points were locoregional failure, metastatic relapse, overall survival, and late toxicity. RESULTS: There was no difference in radiotherapy between both treatment arms (74.4 Gy in 44 days). The full cisplatin dose was applied in 93% and 71% of patients during the first and second treatment cycles, respectively. Acute toxicity was similar in both arms. Median time to any treatment failure was not significantly different between treatment arms (19 months for combined treatment and 16 months for radiotherapy only, respectively) and the failure-free rate at 2.5 years was 45% and 33%, respectively. Locoregional control and distant disease-free survival were significantly improved with cisplatin (log-rank test, P = .039 and .011, respectively). The difference in overall survival did not reach significance (log-rank test, P = .147). Late toxicity was comparable in both treatment groups. CONCLUSION: The therapeutic index of hyperfractionated radiotherapy is improved by concomitant cisplatin.