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.

PURPOSE: To evaluate the efficacy and safety of the combination of ICE (ifosfamide 1.5 g m(-2), carboplatin 100 mg m(-2) and etoposide 150 mg m(-2), days 1-4, q 28 days, G-CSF 5 microg kg(-1) starting from day 6) alone and in combination with regional hyperthermia (RHT) in soft tissue sarcoma (STS) refractory to previous standard doxorubicin-ifosfamide-based chemotherapy. Patients and methods: Twenty patients with advanced STS of different histological sub-types were treated with the ICE regimen with 13 patients receiving additional RHT. A median of four courses of ICE were administered with RHT on days 1 and 3 (60 min, T(max) 42 degrees C). RESULTS: The objective response rate was 20%, with four partial responses (all treated with hyperthermia). In addition, two patients showed mixed responses and five patients stable disease. After a median follow-up time of 15 months, median time to progression was 6 months. Progression free rate estimates were 60% and 45% at 3 and 6 months, respectively. Median overall survival for all patients was 14.6 months. CONCLUSION: These results suggest that ICE alone or combined with RHT shows activity as second-line therapy in doxorubicin-ifosfamide-refractory STS.     

Gemcitabine and cisplatin combined with regional hyperthermia as second-line treatment in patients with gemcitabine-refractory advanced pancreatic cancer

Purpose: There is no standard second-line therapy for patients with advanced pancreatic cancer (APC) after gemcitabine (G) failure. Cisplatin (Cis)-based chemotherapy has shown activity in APC. It is proven that cytotoxicity of G and Cis is enhanced by heat exposure at 40° to 42°C. Therefore G plus Cis with regional hyperthermia (RHT) might be beneficial for patients with G-refractory APC.

Patients and methods: We retrospectively analysed 23 patients with advanced (n?=?2) or metastatic (n?=?21) pancreatic cancer with relapse after G mono first-line chemotherapy (n?=?23). Patients had received G (day 1, 1000?mg/m²) and Cis (day 2 and 4, 25?mg/m²) in combination with RHT (day 2 and 4, 1?h) biweekly for 4 months. We analysed feasibility, toxicity, time to second progression (TTP2), overall survival (OS) and clinical response.

Results: Between October 1999 and August 2008 23 patients were treated. Haematological toxicity was low with no grade 4 event. Hyperthermia-associated toxicity consisted of discomfort because of bolus pressure (3%), power-related pain (7%) or position-related pain (17%). Median TTP1 was 5.9 months (95% confidence interval (CI): 2.6–9.2), median TTP2 was 4.3 months (95%CI: 1.2–7.4) and OS 12.9 months (95%CI: 9.9–15.9). The disease control rate in 16 patients with available CT scans was 50%.

Conclusion: We show first clinical data of G plus Cis with RHT being clinically active in G-pretreated APC with low toxicity. A prospective controlled phase II second-line clinical trial (EudraCT: 2005-003855-11) and a randomised phase III adjuvant clinical trial offering this treatment (HEAT; EudraCT: 2008-004802-14) are currently open for recruitment.     

The synchronization of chemotherapy to circadian rhythms and irradiation in pre-operative chemoradiation therapy with hyperthermia for local advanced rectal cancer. Abbreviations: 5-FU 5-fluorouracil LV Leucovorin APR abdomino-perineal resection

Purpose: The therapeutic and adverse effects of pre-operative chrono-chemoradiation with local hyperthermia for patients with rectal adenocarcinoma were evaluated.

Materials and methods: Pre-operative radiation therapy of a total dose of 40?Gy (n?=?10) or 50?Gy (n?=?19) on the whole pelvis and hyperthermia once a week during the radiation therapy for 1?h were performed for patients with T2–T4 rectal adenocarcinoma. Chemotherapy consisted of 5-FU (250?mg?m^?2?per?day) and LV (25?mg?m^?2?per?day) administered by continuous infusion in the night for 5 days a week in the second and fourth weeks of radiation.

Results: Grade 3+ toxicities were seen only in two patients (6.9%). A significant down staging was seen in 41.4% of all cases and 52.6% of cases with a radiation dose of 50?Gy. Of the patients who had received surgical resection of a tumour, three (11.1%) had no residue pathologically in the specimen and eight (29.6%) had microscopic lesions.

Conclusions: These results yielded a high response rate with minimal toxicities for advanced low-rectal adenocarcinoma. The administration of 5-FU during the sleeping time before irradiation might have an advantage not only as a chronotherapy but also as a radiation sensitizer.     

Hyperthermia combined with intra-thoracic chemotherapy and radiotherapy for malignant pleural mesothelioma

Background: Prognosis for patients with malignant pleural mesothelioma (MPM) remains poor and such patients require intensive treatment. Few studies have examined hyperthermia for MPM. The present study investigated the feasibility of hyperthermia combined with weekly chemo-radiotherapy for patients with MPM and estimated the efficacy of this regimen.

Methods: A total of 11 patients (median patient age was 67 and all had pleural effusion) with MPM were enrolled in this study. The treatment regimen comprised of weekly thermo-radiotherapy with intra-thoracic chemotherapy 2–5 times at initiation of treatment. Hyperthermia was performed once per week for ～60?min. Hemithorax external radiotherapy was administered once weekly on the same day as hyperthermia and just before thermochemotherapy. Median total radiation dose was 6?Gy (range, 2–10?Gy). Chemotherapy was administered into the thoracic cavity through a tube. Chemotherapeutic agents administered were CDDP for seven patients, carboplatinum (CBDCA) for three patients and both CDDP and CBDCA for one patient. Dose of CDDP was 50?mg/body and dose of CBDCA was 200–300?mg?m^?2. Response rate and median survival time (MST) and palliative effect were investigated.

Results: Complete response was not achieved in any of the 11 patients. Partial response was achieved in three of 11 patients (27.3%), SD in six patients (54.5%) and PD in two patients (18.2%). There was no correlational relationship between thermal parameters and response. MST was 27.1 months. Pleural fluid decreased in all patients after therapy, while all patients displayed improved performance status and could be discharged from hospital. Patients with partial response had a relatively longer survival time than SD or PD. All patients underwent the complete course of treatment and only one of 11 patients developed grade 4 thrombocytopenia.

Conclusion: It was therefore concluded that hyperthermia combined with intra-thoracic chemotherapy using cisplatinum or carboplatinum may be tolerable. This approach appears effective and more acceptable for patients with MPM with pleural effusion than other multi-modality therapy.     

Phase I/II trial of intravenous Doxil® and whole abdomen hyperthermia in patients with refractory ovarian cancer

Objective: A phase I/II study of Doxil® combined with whole abdomen hyperthermia was conducted in patients with refractory ovarian cancer. Liposomal doxorubicin combined with hyperthermia has been shown to increase both liposomal delivery and drug extravasation into tumour xenografts resulting in enhanced cytotoxic effects.

Patients and methods: Thirty patients with either recurrent or persistent epithelial ovarian cancer were enrolled. All patients had either measurable or assessable disease. Patients received intravenous (IV) Doxil® at a dose of 40?mg?m^?2 as a 1-h infusion followed by whole abdomen hyperthermia. The phase I portion of the study was performed to determine the maximal tolerated dose (MTD) of hyperthermia. Quality of life (QoL) was performed at baseline, prior to each cycle and every 3 months. Plasma pharmacokinetic studies were performed with the first cycle.

Results: Ten patients participated in the phase I portion of the study which demonstrated that the MTD of hyperthermia was 60?min after either average vaginal and rectal temperatures of 40°C had been achieved or after 30?min of power application, whichever was shorter. All 30 patients were either paclitaxel and/or platinum resistant initially or developed resistant disease. The median number of prior chemotherapeutic regimens was three (range 2–8) and six patients had been previously treated with Doxil®. There were three partial responses for a response rate of 10% (95% CI: [2%, 27%]) and eight patients (27%; 95% CI: [12%, 46%]) had disease stabilization. The median time to progression or death was 3.4 months (95% CI: [2.6, 5.2]) and the median survival was 10.8 months (95% CI: [8.8, 17.4]). Twelve patients (40%) experienced palmar-plantar erythrodysesthesia (PPE), but only four (13%) experienced grade 3–4 PPE toxicity. Doxil® systemic exposure was higher in those with grade 3–4 PPE compared to those with no PPE. None of the patients had grade 3–4 thermal toxicity due to hyperthermia. QoL was not decreased in patients responding to therapy.

Conclusions: Therapy with intravenous Doxil® and whole abdomen hyperthermia for patients with platinum/paclitaxel resistant ovarian cancer is feasible and does not negatively impact quality of life.     

Avascular osteonecrosis after hyperthermia in children and adolescents with pelvic malignancies: A retrospective analysis of potential risk factors

Purpose: In children with locally advanced or recurrent malignant tumours, prognosis can be improved by regional deep hyperthermia (RHT) in combination with platin-based chemotherapy. However, because of the increasing number of patients that achieve long-time remission with this therapy, it is necessary to evaluate long-term sequelae of thermochemotherapy. During the years 1993–2004 one has observed avascular osteonecrosis (AON) of the femoral head after RHT in seven children with pelvic germ cell tumours or rhabdomyosarcomas.

Methods: Although AON may develop in patients with malignancies treated with chemo- or radiotherapy alone, RHT might nevertheless contribute to the occurrence of AON. In order to determine potential risk factors for AON after RHT, this study analysed the relationship of AON to the patient's age, medical history and treatment parameters such as thermal dose equivalent and power output.

Results and conclusions: In the present study AON was associated with young age as well as intensity of hyperthermia indicated by high power levels that exceed 20?W per kg body weight and/or application of eight or more heat sessions as well as additional radiotherapy. Based on this observation, it was assumed that an optimized three dimensional thermal field modelling may be helpful to avoid hazardous temperatures in the femoral heads during RHT treatment and to reduce AON of the femoral heads.     

Two phase I dose-escalation/pharmacokinetics studies of low temperature liposomal doxorubicin (LTLD) and mild local hyperthermia in heavily pretreated patients with local regionally recurrent breast cancer

Purpose: Unresectable chest wall recurrences of breast cancer (CWR) in heavily pretreated patients are especially difficult to treat. We hypothesised that thermally enhanced drug delivery using low temperature liposomal doxorubicin (LTLD), given with mild local hyperthermia (MLHT), will be safe and effective in this population.

Patients and methods: This paper combines the results of two similarly designed phase I trials. Eligible CWR patients had progressed on the chest wall after prior hormone therapy, chemotherapy, and radiotherapy. Patients were to get six cycles of LTLD every 21–35 days, followed immediately by chest wall MLHT for 1 hour at 40–42?°C. In the first trial 18 subjects received LTLD at 20, 30, or 40?mg/m²; in the second trial, 11 subjects received LTLD at 40 or 50?mg/m².

Results: The median age of all 29 patients enrolled was 57 years. Thirteen patients (45%) had distant metastases on enrolment. Patients had received a median dose of 256?mg/m² of prior anthracyclines and a median dose of 61?Gy of prior radiation. The median number of study treatments that subjects completed was four. The maximum tolerated dose was 50?mg/m², with seven subjects (24%) developing reversible grade 3–4 neutropenia and four (14%) reversible grade 3–4 leucopenia. The rate of overall local response was 48% (14/29, 95% CI: 30–66%), with. five patients (17%) achieving complete local responses and nine patients (31%) having partial local responses.

Conclusion: LTLD at 50?mg/m² and MLHT is safe. This combined therapy produces objective responses in heavily pretreated CWR patients. Future work should test thermally enhanced LTLD delivery in a less advanced patient population.     

Short-course preoperative radiotherapy combined with chemotherapy,delayed surgery and local hyperthermia for rectal cancer: a phase II study

Purpose: The aim of this study was to investigate the feasibility of short-course radiotherapy with oral capecitabine, hyperthermia and delayed surgery for neoadjuvant treatment of rectal cancer.

Methods: Patients with clinically staged T2-3N0-2M0 primary rectal cancer were included. All patients received short-course 25?Gy in 5?Gy fractions radiotherapy with capecitabine, local hyperthermia and metronidazole. Capecitabine 1000?mg/m² twice a day was given on days 1–14. Local hyperthermia, 41–45?°C for 60?min, was performed on days 3–5. Metronidazole 10?g/m² was administered per rectum on days 3 and 5. The time interval to surgery was not less than four weeks after neoadjuvant treatment. The primary end-point was pathological complete response (pCR). Secondary end-points included neoadjuvant treatment toxicity, tumour regression, surgical and oncological outcomes.

Results: A total of 81 patients were included in the analysis. Ten (12.3%) patients had grade 3 toxicity and one (1.2%) patient had grade 4 toxicity. Sphincter-sparing surgery was performed for 78 (96.3%) patients. There was no postoperative mortality. Postoperative complications occurred in 11 (13.8%) patients. Sixteen (20%) patients had a pCR. The median follow-up was 40.9 months. There were no local recurrences. Nine (11.1%) patients developed distant metastases. Three-year overall survival was 97% and the three-year disease-free survival was 85%.

Conclusions: Short-course radiotherapy with chemotherapy, radiosensitizers and delayed surgery is a feasible treatment for rectal cancer and may lead to tumour regression rate comparable with long-course chemoradiation.     

Magnetic nanoparticle hyperthermia enhancement of cisplatin chemotherapy cancer treatment

Abstract

Purpose: The purpose of this study was to examine the therapeutic effect of magnetic nanoparticle hyperthermia (mNPH) combined with systemic cisplatin chemotherapy in a murine mammary adenocarcinoma model (MTGB).

Materials and methods: An alternating magnetic field (35.8?kA/m at 165?kHz) was used to activate 110?nm hydroxyethyl starch-coated magnetic nanoparticles (mNP) to a thermal dose of 60?min at 43?°C. Intratumoral mNP were delivered at 7.5?mg of Fe/cm³ of tumour (four equal tumour quadrants). Intraperitoneal cisplatin at 5?mg/kg body weight was administered 1?h prior to mNPH. Tumour regrowth delay time was used to assess the treatment efficacy.

Results: mNP hyperthermia, combined with cisplatin, was 1.7 times more effective than mNP hyperthermia alone and 1.4 times more effective than cisplatin alone (p?<?0.05).

Conclusions: Our results demonstrate that mNP hyperthermia can result in a safe and significant therapeutic enhancement for cisplatin cancer therapy.     

Phase II trial of combined regional hyperthermia and gemcitabine for locally advanced or metastatic pancreatic cancer

Purpose: Despite advances in cancer therapy, treating pancreatic cancer remains one of the major challenges in the field of medical oncology. We conducted this phase II study to evaluate the efficacy and safety of regional hyperthermia combined with gemcitabine for the treatment of unresectable advanced pancreatic cancer.

Methods: Eligibility criteria included histologically proven, locally advanced or metastatic pancreatic cancer. Gemcitabine was administered intravenously at a dose of 1000?mg/m² on days 1, 8, and 15 every 4 weeks. Regional hyperthermia was performed once weekly, 1 day preceding or following gemcitabine administration. The primary end point was the 1-year survival rate. Secondary objectives were determination of tumour response and safety.

Results: We enrolled 18 patients with advanced pancreatic cancer between November 2008 and May 2010. The major grade 3–4 adverse events were neutropenia and anaemia; however, there were no episodes of infection. The objective response rate (ORR) and disease control rate (ORR + stable disease) were 11.1% and 61.1%, respectively. Median overall survival (OS) was 8 months, and the 1-year survival rate was 33.3%. Median OS of patients with locally advanced pancreatic cancer was 17.7 months.

Conclusions: Regional hyperthermia combined with gemcitabine is well tolerated and active in patients with locally advanced pancreatic cancer.     

Ifosfamide,Cisplatin and Etoposide (ICE)Combined Chemotherapy with Recombinant Human Granulocyte Colony-Stimulating Factor Support in Small Cell Lung Cancer

Abstract

This study was aimed to evaluate the effect of ifosfamide, cisplatin and etoposide (ICE) combined chemotherapy in small cell lung cancer (SCLC), and to test the feasibility of adding recombinant human granulocyte colony-stimulating factor (rhG-CSF) to aggressive chemotherapy. Thirty consecutive, previously untreated, patients with SCLC (17 with limited disease and 13 with extensive disease) entered this study. The ICE regimen consisted of ifosfamide (I) 4 g/m² i.v. with same dose mesna i.v. on first day, cisplatin (C) 25 mg/m² i.v. on days 1 to 3 and etoposide (E) 100 mg/m² i.v. on days 1 to 3. A total of 30 MU rhG-CSF i.v. were given from day 7 to 14 if WBC were lower than 3000x10⁶/L, neutrophils were lower than 1000x10⁶/L. Overall response (OR) rate was 93% with a complete response (CR) rate of 23%. Median survival was 12 months [95% confidence interval (CI): 11-14] and median response duration was 10 months [95% CI: 8-10]. Thirty-seven percent of patients had grade 3 neu-tropenia, 40% had grade 3 anemia, and 1% had grade 2 thrombocytopenia. Nonhematologic toxicity was mild with nausea and vomiting being the most common. RhG-CSF, which reduced leukopenic nadirs and shortened the neutropenic period, was also well tolerated. This chemotherapy protocol seems to be active, well tolerated and is currently being compared with various conventional chemotherapies.     

Hyperthermia and irradiation of head and neck squamous cancer cells causes migratory profile changes of tumour infiltrating lymphocytes

Purpose: CD4⁺CD25⁺FoxP3⁺ regulatory T-cells (Treg) are responsible for immunoevasion mechanisms induced by cancer. Specific chemokines such as CCL22 are presumed to mediate active Treg trafficking into the tumour site. In this context, the effects of irradiation and hyperthermia of tumour cells on Treg migration and the CCL22 concentration in the tumour cell supernatants after treatment were studied. Moreover, the relationship between CCL22 concentration and Treg cell migration was also examined.

Materials and methods: Treg and CD4⁺CD25^? T-cells were isolated from human peripheral blood. Supernatants were obtained from primary cell cultures derived from head and neck carcinoma patients. Tumour cell cultures were treated with a dose of 2 Gy and hyperthermia (41.5°C) or with hyperthermia or irradiation alone. Cancer cell culture supernatants were then used for a transmigration assay.

Results: Treg and CD4⁺CD25^? T-cells showed an increased transmigration towards supernatants of hyperthermia-treated tumour cells. After combined application of hyperthermia and irradiation, Treg migration was similar to control levels, but CD4⁺CD25^? migration was still enhanced. Irradiation caused a significantly decreased Treg influx, whereas the CD4⁺CD25^? T-cell migration was not altered after the same treatment. Changes of Treg chemotaxis could be attributed to a treatment-associated escalation of the CCL22 in the tumour cell supernatants.

Conclusion: The combination of irradiation and hyperthermia is able to modify transmigration of tumour infiltrating lymphocytes beneficially and individually. In this in vitro system hyperthermia alone negatively impacts the immune response by selectively recruiting Treg, whereas hyperthermia with the addition of irradiation negates this effect.     

The clinical benefit of hyperthermia in pancreatic cancer: a systematic review

Objective: In pancreatic cancer, which is therapy resistant due to its hypoxic microenvironment, hyperthermia may enhance the effect of radio(chemo)therapy. The aim of this systematic review is to investigate the validity of the hypothesis that hyperthermia added to radiotherapy and/or chemotherapy improves treatment outcome for pancreatic cancer patients.

Methods and materials: We searched MEDLINE and Embase, supplemented by handsearching, for clinical studies involving hyperthermia in pancreatic cancer patients. The quality of studies was evaluated using the Oxford Centre for Evidence-Based Medicine levels of evidence. Primary outcome was treatment efficacy; we calculated overall response rate and the weighted estimate of the population median overall survival (m_p) and compared these between hyperthermia and control cohorts.

Results: Overall, 14 studies were included, with 395 patients with locally advanced and/or metastatic pancreatic cancer of whom 248 received hyperthermia. Patients were treated with regional (n?=?189), intraoperative (n?=?39) or whole-body hyperthermia (n?=?20), combined with chemotherapy, radiotherapy or both. Quality of the studies was low, with level of evidence 3 (five studies) and 4. The six studies including a control group showed a longer m_p in the hyperthermia groups than in the control groups (11.7 vs. 5.6?months). Overall response rate, reported in three studies with a control group, was also better for the hyperthermia groups (43.9% vs. 35.3%).

Conclusions: Hyperthermia, when added to chemotherapy and/or radiotherapy, may positively affect treatment outcome for patients with pancreatic cancer. However, the quality of the reviewed studies was limited and future randomised controlled trials are needed to establish efficacy.     

Three Conventional-Drug Combination (Ifosfamide,Carboplatin, Etoposide - ICE Regimen) in Advanced Non-Small Cell Lung Cancer (NSCLC)

Abstract

Fifty consecutive patients with stage IIIB-IV non-small cell lung cancer (NSCLC) received the ICE regimen at intermediate doses (ifosfamide 1 g/m², carboplatin 120 mg/m², etoposide 80 mg/m², day 1 to 3, q.4 weeks, for a maximum of 6 cycles). Overall 2 complete response (CR) and 10 partial response (PR) (overall response, OR: 24%, 95% C.I. 14-37%) were observed. An additional 7 patients had stable disease (SD) lasting more than 6 months, therefore a clinical benefit (CR+PR+SD >6 mos) was achieved in 19 patients (38%). Median time-to-progression (TTP) was 7 months and median overall survival (OS) was 11 months; 1- and 2-year survival rates were 36% and 10%. The ICE regimen was well tolerated and devoid of any cardiac, hepatic or neurologic toxicity. Moderate nausea and vomiting were easily manageable, grade 2 alopecia was universal, while hematological toxicity was mild (grade 2 leuko-and thrombocytopenia). Due to its efficacy and safety profile, this 3-drug regimen can be considered for routine community use.     

A method to convert MRI images of temperature change into images of absolute temperature in solid tumours

Abstract

Purpose: During hyperthermia (HT), the therapeutic response of tumours varies substantially within the target temperature range (39–43?°C). Current thermometry methods are either invasive or measure only temperature change, which limits the ability to study tissue responses to HT. This study combines manganese-containing low temperature sensitive liposomes (Mn-LTSL) with proton resonance frequency shift (PRFS) thermometry to measure absolute temperature in tumours with high spatial and temporal resolution using MRI.

Methods: Liposomes were loaded with 300?mM MnSO₄. The phase transition temperature (T_m) of Mn-LTSL samples was measured by differential scanning calorimetry (DSC). The release of manganese from Mn-LTSL in saline was characterised with inductively coupled plasma atomic emission spectroscopy. A 2T GE small animal scanner was used to acquire dynamic T₁-weighted images and temperature change images of Mn-LTSL in saline phantoms and fibrosarcoma-bearing Fisher-344 rats receiving hyperthermia after Mn-LTSL injection.

Results: The T_m of Mn-LTSL in rat blood was 42.9?±?0.2?°C (DSC). For Mn-LTSL samples (0.06?mM–0.5?mM Mn²⁺ in saline) heated monotonically from 30?°C to 50?°C, a peak in the rate of MRI signal enhancement occurred at 43.1°?±?0.3?°C. The same peak in signal enhancement rate was observed during heating of fibrosarcoma tumours (N?=?3) after injection of Mn-LTSL, and the peak was used to convert temperature change images into absolute temperature. Accuracies of calibrated temperature measurements were in the range 0.9–1.8?°C.

Conclusion: The release of Mn²⁺ from Mn-LTSL affects the rate of MR signal enhancement which enables conversion of MRI-based temperature change images to absolute temperature.     

Phase II study of continuous-infusion high-dose ifosfamide in advanced and/or metastatic pretreated soft tissue sarcomas

Background: Ifosfamide has important activity in pretreated soft tissue sarcomas (STS), and recent data support a clinically significant dose-response relationship for this agent. Administration by continuous infusion and hematopoietic support have rendered dose intensification regimens possible by reducing both hematologic and non-hematologic toxicities. The optimal dose and schedule of ifosfamide when given at high doses remain to be defined. In a previous phase I study, we demonstrated the feasibility of a continuous infusion (c.i.) high-dose ifosfamide (HDI) regimen in the ambulatory setting for patients with advanced solid tumors. The objective of the present phase II study was to assess the antitumor activity and toxicity of such a schedule in patients with advanced pretreated STS.Patients and methods: Thirty-eight patients with advanced and/or metastatic STS, all pretreated with an anthracycline with or without standard-dose ifosfamide, were treated. Ifosfamide was given by c.i. at a dose of 3.5 g/m²/day over four consecutive days, with equidose mesna uroprotection over five days. G-CSF was added at a dose of 200 µg/m²/day subcutaneously from day 6 to day 12. Cycles were repeated every three weeks in the outpatient setting.Results: A total of 159 cycles of therapy were given (median 4 per patient, range 3–6). Treatment compliance was generally satisfactory. The major toxicity was hematologic, with six febrile neutropenic episodes requiring hospitalisation and parenteral antibiotics. Acute renal failure occurred in one patient after three cycles of therapy; central nervous system toxicity was mild. An overall response rate of 39% was observed (95% confidence interval, 26% to 55%), with one complete and 14 partial remissions. All but one of the responder patients had previously received standard-dose ifosfamide. The median response duration was nine months (range 5–21+ months), and the overall median survival ranged from 6–30+ months (median 13 months).Conclusions: High-dose ifosfamide is an active regimen in anthracycline- pretreated STS. Future clinical trials should be aimed at evaluating the impact of different administration schedules on clinical response and outcome. The potential role of HDI as front-line chemotherapy as well as in the adjuvant treatment of STS needs to be investigated in randomized trials.     

Neoadjuvant chemotherapy combined with regional hyperthermia (RHT) for locally advanced primary or recurrent high-risk adult soft-tissue sarcomas (STS) of adults: long-term results of a phase II study

In this phase II study, activity and safety of neoadjuvant regional hyperthermia (RHT) combined with chemotherapy was investigated in 59 patients with primary advanced or recurrent high-risk soft-tissue sarcoma (STS). Patients received four EIA cycles consisting of etoposide, ifosfamide and doxorubicin combined with RHT followed by surgical resection and adjuvant treatment. The overall objective response (OR) rate was 17%, with one complete (2%) and eight partial (15%) responses. In addition, 13 minor responses (25%) were seen. At time of surgery, complete necrosis (pCR) occurred in 6 patients and >75% necrosis (favourable histological response (FHR)) in 12 patients. At the completion of protocol treatment, 36 patients were rendered disease-free which was significantly associated with the initial radiographic and/or pathological tumour response (P=0.004). Treatment-related toxicity was acceptable overall. At a medium follow-up of 82 months, local treatment failure occurred in 33 patients, median overall survival (OS) was 52 months, and the 5-year survival rate was 49% (95% confidence interval (CI): 36-61%). OS which did not differ for extremity versus non-extremity STS (P=0.21) was better for patients responding to EIA combined with RHT (P<0.01).     

Analysis of clinical data to determine the minimum number of sensors required for adequate skin temperature monitoring of superficial hyperthermia treatments

Purpose: Tumor response and treatment toxicity are related to minimum and maximum tissue temperatures during hyperthermia, respectively. Using a large set of clinical data, we analyzed the number of sensors required to adequately monitor skin temperature during superficial hyperthermia treatment of breast cancer patients.

Methods: Hyperthermia treatments monitored with >60 stationary temperature sensors were selected from a database of patients with recurrent breast cancer treated with re-irradiation (23?×?2?Gy) and hyperthermia using single 434?MHz applicators (effective field size 351–396?cm²). Reduced temperature monitoring schemes involved randomly selected subsets of stationary skin sensors, and another subset simulating continuous thermal mapping of the skin. Temperature differences (ΔT) between subsets and complete sets of sensors were evaluated in terms of overall minimum (T_min) and maximum (T_max) temperature, as well as T90 and T10.

Results: Eighty patients were included yielding a total of 400 hyperthermia sessions. Median ΔT was?<0.01?°C for T90, its 95% confidence interval (95%CI) decreased to ≤0.5?°C when?>50 sensors were used. Subsets of?<10 sensors result in underestimation of T_max up to ?2.1?°C (ΔT 95%CI), which decreased to ?0.5?°C when?>50 sensors were used. Thermal profiles (8–21 probes) yielded a median ΔT?T_max, with a 95%CI of ?0.2?°C and 0.4?°C, respectively. The detection rate of T_max?≥43?°C is?≥85% while using?>50 stationary sensors or thermal profiles.

Conclusions: Adequate coverage of the skin temperature distribution during superficial hyperthermia treatment requires the use of?>50 stationary sensors per 400?cm² applicator. Thermal mapping is a valid alternative.     

Hyperthermia worsens ischaemic brain injury through destruction of microvessels in an embolic model in rats

Purpose: Basal lamina is a major part of the microvascular wall and plays a critical role in the integrity of microvasculature. The aim of this study is to determine whether hyperthermia worsens the destruction of microvascular integrity in the ischaemic injured brain.

Materials and methods: Focal cerebral ischaemia was induced by embolising a pre-formed clot into the middle cerebral artery (MCA). Rats received either normothermic or hyperthermic treatment. Neurological score and infarct size were evaluated at 24?h after the MCA occlusion. Microvascular collagen type IV and laminin were measured with fluorescence microscopy. The activities of matrix metalloproteinases (MMP-2 and MMP-9) and plasminogen activators (tPA and uPA) were determined by zymography.

Results: Treatment with hyperthermia significantly increased infarct volume (p?<?0.01), cortex swelling (p?<?0.01), striatum swelling (p?<?0.05) and neurologic score (p?<?0.01) at 24?h after the MCA occlusion. Compared to the normothermic groups, hyperthermia significantly worsened the losses of microvascular basal lamina structure proteins, collagen type IV and laminin, at 6?h (p?<?0.001) and 24?h (p?<?0.01) after MCA occlusion. Hyperthermia increased the MMP-9 activity at 6 and 24?h after MCA occlusion compared with normothermia (p?<?0.05), whereas increased the MMP-2 activity at 6?h only (p?<?0.05). Hyperthermia also elevated uPA activity significantly at 6 and 24?h after MCA occlusion compared to normothermia (p?<?0.05).

Conclusions: These results demonstrate that hyperthermia exacerbates the destruction of microvascular integrity possibly by increasing the activities of MMP-2, MMP-9 and uPA in the ischaemic cerebral tissues.     

Regional abdominal hyperthermia combined with systemic chemotherapy for the treatment of patients with ovarian cancer relapse: Results of a pilot study

Purpose: Due to the poor prognosis of patients with ovarian cancer relapse (OCR), newer strategies are warranted to improve the therapeutic index. We performed a prospective phase I/II-study of regional abdominal hyperthermia (RHT) combined with systemic chemotherapy in OCR patients in order to evaluate outcome, efficacy and tolerance.

Materials and methods: OCR patients with an Eastern Cooperative Oncology Group status <2, without any thromboembolic disease or severe cardiovascular co-morbidities, and pre-treated with at least one systemic chemotherapy regimen due to epithelial ovarian cancer were enrolled into the present study. RHT was applied using a SIGMA 60 applicator and a Hybrid-System SIGMA-Eye/MRT composed of a 1.5T-MRT and a Sigma-Eye-applicator.

Results: Overall, 36 OCR patients were enrolled. The majority of the patients (>80%) were classified as platinum resistant. The most common chemotherapeutic agent applied was pegylated-liposomal-doxorubicin (47.2%) followed by carboplatin (16.6%) and topotecan (13.9%). One patient (2.8%) achieved a complete remission (CR), 12 patients (33.3%) yielded a partial remission (PR) and 16 patients (44.4%) developed a progressive disease (PD). In platinum-sensitive patients we observed higher response (57.1% versus 31%) and lower progression rates (28.6% versus 48.3%) than in platinum-resistant patients. Eleven patients (30.5%) discontinued treatment due to toxicity. The main toxicity was a haematological one with grade 3/4 anaemia, leucopenia and thrombocytopenia occurring in 13.9%, 5.6% and 8.3%, respectively. Median overall survival was 12 months (range: 1–48), while median progression-free survival was 5 months (range: 0.5–34).

Conclusions: Our results demonstrate the feasibility of RHT combined with systemic treatment. Prospective phase III trials are warranted to evaluate the benefit and efficacy in heavily pre-treated patients with OCR.