Effect of Neoadjuvant Chemotherapy Plus Regional Hyperthermia on Long-term Outcomes Among Patients With Localized High-Risk Soft Tissue Sarcoma

Issels, Rolf D.; Линднер, Ларс; Verweij, Jaap; Wessalowski, Rüdiger; Reichardt, Peter; Wust, Peter; Ghadjar, Pirus; Hohenberger, Peter; Angele, Martin K.; Salat, Christoph; Vujašković, Željko; Daugaard, Soeren; Mella, Olav; Mansmann, Ulrich; Dürr, Hans Roland; Knösel, Thomas; Abdel-Rahman, S.; Schmidt, Michael; Hiddemann, Wolfgang; Jauch, Karl‐Walter; Belka, Claus; Gronchi, Alessandro

doi:10.1001/jamaoncol.2017.4996

Cited by 259 publications

(180 citation statements)

References 32 publications

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“…A therapeutic paradigm shift is required. Back‐to‐basic, simpler approaches (eg, regional hyperthermia) will increase the therapeutic index of ICIs and convert non‐responders into responders. Harnessing of the immense forces liberated by the ICI blockade by an off‐label, low‐dose ipilimumab and nivolumab therapy, supplemented with IL‐2 treatment and hyperthermia, could induce a safe and effective GVM.…”

Section: Discussionmentioning

confidence: 99%

Exploiting autoimmunity unleashed by low‐dose immune checkpoint blockade to treat advanced cancer

Bakács¹,

Moss²,

Kleef³

et al. 2019

Scand J Immunol

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As a result of the cancer immunotherapy revolution, more than 2000 immuno‐oncology agents are currently being tested or are in use to improve responses. Not unexpectedly, the 2018 Nobel Prize in Physiology or Medicine was awarded to James P. Allison and Tasuku Honjo for their development of cancer therapy by the blockade of co‐inhibitory signals. Unfortunately, manipulation of the co‐inhibitory receptors has also resulted in a safety issue: widespread iatrogenic immune‐related adverse events (irAEs). Autoimmunity is emerging as the nemesis of immunotherapy. Originally, it was assumed that CTLA‐4 blockade selectively targets T cells relevant to the antitumour immune response. However, an uncontrolled pan T cell activation was induced compromising tolerance to healthy self‐tissues. The irAEs are very similar to that of a chronic graft‐versus‐host‐disease (GVHD) reaction following allogeneic bone marrow transplantation (BMT). We hypothesized that ipilimumab induced a graft‐versus‐malignancy (GVM) effect, which eradicated metastatic melanoma in a minority of patients, but also involved an auto‐GVHD reaction that resulted in widespread autoimmunity in the majority. Therefore, we argued for a profound theoretical point against the consensus of experts. The task is not to desperately put the genie back in the bottle by immune‐suppressive treatments, but instead to harness the autoimmune forces. In this way, the same goal could be achieved by an antibody as by the adoptive transfer of alloreactive donor lymphocytes, but without severe GVHD. The proof‐of‐principle of a low‐dose‐combination immune checkpoint therapy, consisting only of approved drugs and treatments, was demonstrated in 111 stage IV cancer patients.

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Section: Discussionmentioning

confidence: 99%

Exploiting autoimmunity unleashed by low‐dose immune checkpoint blockade to treat advanced cancer

Bakács¹,

Moss²,

Kleef³

et al. 2019

Scand J Immunol

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“…e multimodal approach included RHT to maximize the local efficacy of chemotherapy. RHT, when applied in parallel, improves response rates of chemotherapy in high-risk STS, compared with chemotherapy alone [10], and might therefore facilitate resection in otherwise nonresectable STS. ICE, a polychemotherapy regimen reportedly active in smaller series of STS patients [23,24], was used.…”

Section: Discussionmentioning

confidence: 99%

“…Multimodal treatment including (neo)adjuvant anthracycline/ifosfamide-based chemotherapy in combination with regional hyperthermia (RHT) can improve progression-free and overall survival of STS patients with localized disease when compared with (neo)adjuvant chemotherapy alone [10]. Furthermore, response rates are doubled by the addition of RHT [7] and are higher than agents approved for use in the second-line treatment of STS (such as trabectedin, eribulin, or pazopanib) [11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Ifosfamide, Carboplatin, and Etoposide (ICE) in Combination with Regional Hyperthermia as Salvage Therapy in Patients with Locally Advanced Nonmetastatic and Metastatic Soft-Tissue Sarcoma

Bücklein

Limmroth

Kampmann

et al. 2020

Sarcoma

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Patients with localized relapse of soft-tissue sarcoma (STS) after anthracycline-based chemotherapy have a dismal prognosis, particularly when surgery is not possible. To facilitate resection and improve long-term tumor control, we applied an intensified perioperative treatment consisting of ICE (ifosfamide 6 g/m2, carboplatin 400 mg/m2, and etoposide 600 mg/m2) in combination with regional hyperthermia (RHT) to maximize local control. Here, we retrospectively evaluate the safety and efficacy of this strategy. Patients aged ≥18 years with locally advanced high-risk STS, either with or without metastasis, treated with ICE + RHT after the failure of first-line anthracycline-based chemotherapy were included in this analysis. Radiographic response, toxicity, progression-free survival (PFS), and overall survival (OS) were assessed. Between 1996 and 2018, 213 sarcoma patients received ICE at our centre. Of these, 110 patients met the selection criteria (progressive disease, suitable high-grade STS histology, anthracycline pretreatment, RHT treatment) for this analysis. Fifty-four patients had locally advanced disease without metastases (LA-STS), and 56 patients had additional metastatic disease (M-STS). Disease control was achieved in 59% of LA-STS patients and in 47% of M-STS patients. For LA-STS, 21% of the patients achieved radiographic response, facilitating resection in 4 patients (7%), compared with 11% of the M-STS patients, facilitating resection in 5 patients (9%). PFS was significantly longer in LA-STS than in M-STS (10 vs. 4 months, p<0.0001). Median OS was 26 months in LA-STS and 12 months in M-STS. Disease control was the only independent prognostic factor for improved OS in multivariate analysis. Toxicity was high with neutropenic fever occurring in 25% of the patients and three therapy-related deaths (3%). ICE + RHT demonstrated activity in high-risk STS and facilitated resection in selected patients after anthracycline failure. Disease control was associated with improved OS. Based on the observed toxicities, the dose should be reduced to 75%.

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“…Synergism between the beneficial effects of local or regional hyperthermia combined with chemotherapy and radiotherapy has been proven in numerous clinical studies (Datta et al, ; Issels, ; Peeken, Vaupel, & Combs, ) Recently, in a phase III study advantages of regional hyperthermia in combination with chemotherapy also on long‐term outcomes have been demonstrated in patients with high‐risk soft tissue sarcoma. The hazard ratio of prolonged survival rates for chemotherapy in combination with hyperthermia compared to chemotherapy alone was 0.73 (95% Confidence Interval (CI) 0.54–0.98, p = .04) with 10‐year overall survival of 52.6% (95% CI 44.7%–60.6%) versus 42.7% (95% CI 35.0%–50.4%) (Issels et al, ). Besides chemotherapy and radiotherapy sensitizing properties, hyperthermia has an intrinsic anticancer activity, of which several different pathophysiological mechanisms have been postulated.…”

Section: Introductionmentioning

confidence: 99%

Thermal distribution, physiological effects and toxicities of extracorporeally induced whole‐body hyperthermia in a pig model

Lassche¹,

Frenzel

Mignot³

et al. 2020

Physiol Rep

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Background Extracorporeally induced whole‐body hyperthermia (eWBH) might be a beneficial treatment in cancer patients. Objectives of this pig study were to assess thermal distribution, (patho‐)physiological effects, and safety of eWBH with a new WBH device. Methods Fourteen healthy adult pigs were anesthetized, mechanically ventilated, and cannulated; 12 were included in the analysis. Blood was heated in 11 pigs (one pig served as control) using a WBH device (Vithèr Hyperthermia B.V.) containing two separate fluidic circuits and a heat exchanger. Temperature was monitored on nine different sites, including the brain. Core temperature (average of 4 deep probes) was elevated to 42°C for 2 hr. Results Elevation of core body temperature to 42°C took on average (± standard deviation) 38 ± 8 min. Initially observed temperature spikes diminished after lowering maximal blood temperature to 45°C. Hereafter, brain temperature spikes never exceeded 42.5°C, mean brain temperature was at highest 41.9°C during maintenance. WBH resulted in increased heart rates and decreased mean arterial pressures. The vast amounts of fluids required to counter hypotension tended to be smaller after corticosteroid administration. Hemodialysis was started in three animals (potassium increase prevention in two and hyperkalemia treatment in one). Severe rhabdomyolysis was observed in all pigs (including the control). All animals survived the procedure until planned euthanasia 1, 6, or 24 hr post procedure. Conclusion Fast induction of eWBH with homogenous thermal distribution is feasible in pigs using the Vithèr WBH device. Severe hemodynamic disturbances, rhabdomyolysis, and hyperkalemia were observed.

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Effect of Neoadjuvant Chemotherapy Plus Regional Hyperthermia on Long-term Outcomes Among Patients With Localized High-Risk Soft Tissue Sarcoma

Abstract: clinicaltrials.gov Identifier: NCT00003052.

Cited by 259 publications

References 32 publications

Exploiting autoimmunity unleashed by low‐dose immune checkpoint blockade to treat advanced cancer

Exploiting autoimmunity unleashed by low‐dose immune checkpoint blockade to treat advanced cancer

Ifosfamide, Carboplatin, and Etoposide (ICE) in Combination with Regional Hyperthermia as Salvage Therapy in Patients with Locally Advanced Nonmetastatic and Metastatic Soft-Tissue Sarcoma

Thermal distribution, physiological effects and toxicities of extracorporeally induced whole‐body hyperthermia in a pig model

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