Ifosfamide, carboplatin and etoposide (ICE) as second-line regimen alone and in combination with regional hyperthermia is active in chemo-pre-treated advanced soft tissue sarcoma of adults

Patients with high-risk soft tissue sarcomas (STS)-FNCLCC grade 2-3, size >5 cm, deep to the fascia-are at risk for developing local recurrence and distant metastasis despite surgical tumor resection. Therefore, the management of high-risk STS requires a multidisciplinary approach. Besides surgery, radiotherapy, and chemotherapy, regional hyperthermia (RHT) has the potential to become the fourth standard treatment modality for the treatment of these patients. RHT means non-invasive selective heating of the tumor area to temperatures within the range of 40-43°C for 60 min by the use of an electromagnetic heating device. Thereby RHT is always applied in addition to radiotherapy or chemotherapy or both but is not effective as a single treatment. Beside direct cytotoxicity, RHT in combination with chemotherapy enhances the drug cytotoxicity mainly by increased chemical reaction and intratumoral drug accumulation. For the neoadjuvant setting, RHT in combination with a doxorubicin- and ifosfamide-based chemotherapy has been shown to dramatically improve the tumor response rate but also prevents from early disease progression as compared to chemotherapy alone. The addition of RHT to a multimodal treatment of high-risk STS consisting of surgery, radiotherapy, and chemotherapy either in the neoadjuvant setting but also after incomplete or marginal tumor resection has been shown to significantly improve local recurrence- and disease-free survival. Based on these results and in conjunction with the low RHT-related toxicity, RHT combined with preoperative or postoperative chemotherapy should be considered as an additional standard treatment option for the multidisciplinary treatment of locally advanced high-grade STS.

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“…Additional 51% of patients showed stable disease [28]. This was in accordance with previous findings [29].…”

Section: Regional Deep Hyperthermiasupporting

confidence: 93%

Hyperthermia in soft tissue sarcoma

Lindner

Issels

2011

Curr. Treat. Options in Oncol.

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“…It is also unlikely that the remarkable systemic response of the patient was due to low-dose chemotherapy alone, since such a rapid onset of the response as observed in this patient was not seen previously, neither in cases receiving high-dose ICE alone in chemo-sensitive patients, nor in chemo-pretreated patients receiving ICE combined with regional hyperthermia as salvage treatment [8,14]. In the case presented here, much lower doses and dose intensity of the ICE regimen were used because of the poor clinical condition of the patient (ECOG 3).…”

Section: Discussionmentioning

confidence: 51%

“…The clinical situation required immediate therapeutic intervention. At the end of January 2011, the first cycle of regional hyperthermia was started in combination with low-dose three-drug chemotherapy based on the original full-dose regimen (ICE) as previously published [8]. Regional hyperthermia was performed by the use of an annular phased array applicator with eight pairs of microwave antennas surrounding the patient's abdomen to focus the heating field to the abdominal tumor (Pyrexar Company, Salt Lake City, Utah) without increase of systemic temperature as controlled routinely during treatment.…”

Section: Case Presentationmentioning

confidence: 99%

Systemic antitumor effect by regional hyperthermia combined with low-dose chemotherapy and immunologic correlates in an adolescent patient with rhabdomyosarcoma – a case report

Issels¹,

Линднер²,

Bergwelt‐Baildon³

et al. 2020

International Journal of Hyperthermia

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Introduction: An abscopal effect is a clinical observation whereby a local treatment is associated with regression of metastatic cancer at a site distant from the primary location of treatment. Here, we describe the clinical systemic effect induced by regional hyperthermia combined with low-dose chemotherapy and provide immunologic correlates. Case presentation: A 15-year-old patient had been diagnosed with alveolar rhabdomyosarcoma (ARMS). All previous treatment options failed in the patient including haploidentical stem cell transplantation and donor lymphocyte infusion. The patient presented with local and metastatic disease, and upon admission, underwent regional hyperthermia combined with low-dose chemotherapy. Immediately following therapy severe skin reactions were observed. Skin biopsies revealed an intraepithelial lymphocytic infiltration dominated by CD3 þ /CD8 þ T cells with a regular network of dendritic cells. Clinical images compared before and during sequential treatment cycles showed complete metabolic response of the local tumor for more than 10 months of therapy. In addition, metastases completely regressed although they were not direct targets of regional hyperthermia. The systemic effect was associated with enhanced frequency of NK cells and T cells expressing the lectin-like natural-killer group 2 D activating receptor (NKG2D), an increase of the CD56 bright subset of NK cells, as well as an increase of effector/memory and effector CD8 þ and CD4 þ T cells in the blood while the percentage of CD25 þ FOXP3 þ regulatory T cells declined. Conclusions: Regional hyperthermia combined with low-dose chemotherapy had the potential to create a systemic effect which was associated with activation of NK cells and T cells.

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“…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. To our knowledge, our analysis is the first to report results of an intensified perioperative chemotherapy approach in the context of relapsed or refractory STS.…”

Section: Discussionmentioning

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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Ifosfamide, carboplatin and etoposide (ICE) as second-line regimen alone and in combination with regional hyperthermia is active in chemo-pre-treated advanced soft tissue sarcoma of adults

Abstract: These results suggest that ICE alone or combined with RHT shows activity as second-line therapy in doxorubicin-ifosfamide-refractory STS.

Cited by 19 publications

References 30 publications

Hyperthermia in soft tissue sarcoma

Hyperthermia in soft tissue sarcoma

Systemic antitumor effect by regional hyperthermia combined with low-dose chemotherapy and immunologic correlates in an adolescent patient with rhabdomyosarcoma – a case report

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

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