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Purpose: Hyperthermic intrathoracic chemotherapy (HITOC) is an additive, intraoperative treatment for selected malignant pleural tumors. To improve local tumor control, the thoracic cavity is perfused with a cisplatin-containing solution after surgical cytoreduction. Since cisplatin is probably carcinogenic to humans, potential contamination of surfaces and pathways of exposure should be systematically investigated to enable risk assessments for medical staff and thus derive specific recommendations for occupational safety., Methods: Wipe sampling was performed at pre-selected locations during and after ten HITOC procedures, including on the surgeon's gloves, for the quantitation of surface contaminations with cisplatin. After extraction of the samples with hydrochloric acid, platinum was determined as a marker for cisplatin by voltammetry., Results: High median concentrations of cytostatic drugs were detected on the surgeons' (1.73 pg Cis-Pt/cm 2 , IQR: 9.36 pg Cis-Pt/cm 2 ) and perfusionists' (0.69 pg Cis-Pt/cm 2 , IQR: 1.73 pg Cis-Pt/cm 2 ) gloves. The display of the perfusion device showed partially elevated levels of cisplatin up to 4.92 pg Cis-Pt/cm 2 and thus could represent an origin of cross-contamination. In contrast, cisplatin levels on the floor surfaces in the area of the surgeon and the perfusion device or in the endobronchial tube were relatively low., Conclusion: With a correct use of personal protective equipment and careful handling, intraoperative HITOC appears to be safe to perform with a low risk of occupational exposure to cisplatin., (© 2021. The Author(s).)

Background: Objective of this study was to assess postoperative morbidity and mortality as well as recurrence-free and overall survival in patients with thymic malignancies and pleural dissemination undergoing surgical cytoreduction and hyperthermic intrathoracic chemotherapy (HITOC)., Methods: Retrospective study between September 2008 and December 2017 with follow-up analysis in May 2018., Results: A total of 29 patients (male: n  = 17) with thymic malignancies and pleural spread (primary stage IVa: n  = 11; pleural recurrence: n  = 18) were included. Surgical cytoreduction was performed via pleurectomy/decortication (P/D; n  = 11), extended P/D ( n  = 15), and extrapleural pneumonectomy (EPP; n  = 3). These procedures resulted in 25 (86%) patients with macroscopically complete (R0/R1) resection. Intraoperative HITOC was performed for 60 minutes at 42°C either with cisplatin (100 mg/m 2 body surface area [BSA] n  = 8; 150 mg/m 2 BSA n  = 6; 175 mg/m 2 BSA n  = 1) or with a combination of cisplatin (175 mg/m 2 BSA)/doxorubicin (65 mg; n  = 14). Postoperative complications occurred in nine patients (31%). Cytoprotective therapy resulted in lower postoperative creatinine levels ( p  = 0.036), and there was no need for temporary dialysis in these patients. The 90-day mortality rate was 3.4%, as one patient developed multiple organ failure. While recurrence-free 5-year survival was 54%, an overall 5-year survival rate of 80.1% was observed. Survival depended on histological subtype ( p  = 0.01)., Conclusion: Surgical cytoreduction with HITOC is feasible in selected patients and offers encouraging survival rates. The application of cytoprotective agents appears to be effective for the prevention of postoperative renal insufficiency., Competing Interests: None declared., (Thieme. All rights reserved.)

Introduction: Objective of the 'German hyperthermic intrathoracic chemotherapy (HITOC) study' is to evaluate the HITOC as additional treatment after surgical cytoreduction for malignant pleural tumours. Even though HITOC is applied with increasing frequency, there is no standardised therapy protocol concerning the technique of HITOC, the selection as well as dosage of chemotherapeutic agents and perioperative management in order to provide a safe and comparable, standardised treatment regime., Methods and Analysis: This trial is a retrospective, multicentre observational study, which is funded by the German Research Foundation. Approximately 300 patients will be included. Four departments of thoracic surgery, which are performing the most HITOC procedures in Germany, are contributing to this study: Center for Thoracic Surgery at the University Hospital Regensburg, Thoracic Clinic Heidelberg of the University of Heidelberg, Center for Thoracic Surgery of the Hospital University of Munich and the Department of Thoracic Surgery at the University Hospital Freiburg. All patients who underwent surgical cytoreduction and subsequent HITOC at one of the four centres between starting the HITOC programme in 2008 and December 2019 will be included. Information on the performed HITOC will be obtained, focusing on the technique as well as the applied perfusion solution including the chemotherapeutic agent. Furthermore, parameters of the patient's postoperative recovery will be analysed to determine 30-day morbidity and mortality., Ethics and Dissemination: The approvals by the local ethics committee of the respective clinic and the three participating clinics have been obtained. The results will be presented in conferences and published in a peer-reviewed journal., Trial Registration Number: German Clinical Trials Registry (DRKS00015012; Pre-results)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: Hyperthermic intrathoracic chemotherapy (HITOC) is used for the treatment of malignant pleural tumors. Although HITOC proved to be safe, postoperative renal failure due to nephrotoxicity of intrapleural cisplatin remains a concern., Methods: This single-center study was performed retrospectively in patients who underwent pleural tumor resection and HITOC between September 2008 and December 2018., Results: A total of 84 patients (female n = 33; 39.3%) with malignant pleural tumors underwent surgical cytoreduction with subsequent HITOC (60 minutes; 42°C). During the study period, we gradually increased the dosage of cisplatin (100-150 mg/m 2 BSA n = 36; 175 mg/m 2 BSA n = 2) and finally added doxorubicin (cisplatin 175 mg/m 2 BSA/doxorubicin 65 mg; n = 46). All patients had perioperative fluid balancing. The last 54 (64.3%) patients also received perioperative cytoprotection. Overall 29 patients (34.5%) experienced renal insufficiency. Despite higher cisplatin concentrations, patients with cytoprotection showed significantly lower postoperative serum creatinine levels after 1 week (P = .006) and at discharge (P = .020). Also, they showed less intermediate and severe renal insufficiencies (5.6% vs 13.3%)., Conclusions: Adequate perioperative fluid management and cytoprotection seem to be effective in protecting renal function. This allows the administration of higher intracavitary cisplatin doses without raising the rate of renal insufficiencies., (© 2019 Wiley Periodicals, Inc.)

In regional chemotherapy of the pleural space a differentiation is made between intrapleural hyperthermic perfusion (IHP) and hyperthermic intrathoracic chemotherapy (HITOC). The HITOC in particular is carried out as an additive procedure after surgical cytoreduction of the pleural tumor manifestation. The main indications are for malignant pleural mesothelioma and thymoma with pleural spread (stage IVa), whereas treatment of secondary pleural carcinomatosis is indicated only in selected patients suitable for resection followed by HITOC. Cisplatin is the standard chemotherapeutic agent and a concentration of 150-175 mg/m 2 body surface area is recommended. Postoperative, HITOC-related complications (e.g. renal insufficiency) can be minimized by an adapted perioperative management. Safety measures should be accomplished adhered to for the protection of personnel. The aim of HITOC is to achieve a better local tumor control with a corresponding longer recurrence-free and overall survival.

The multimodal treatment of limited peritoneal metastases may improve prognosis in selected patients (pseudomyxoma peritonei, malignant peritoneal mesothelioma, colorectal, gastric and ovarian cancer) provided complete cytoreduction can be performed. Additive intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) is often performed. If the treatment is undertaken in experienced (and certified) centres, associated mortality is low. Intrapleural hyperthermic chemoperfusion (HITOC) can be performed in patients with pleural malignancies, mainly for malignant pleural mesothelioma or metastases from a thymoma. In single patients, pleural metastases from gastrointestinal malignancies might be an indication. Both therapies (HIPEC and HITOC) are complex and their exact role has to be defined within further prospective randomised trials., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (Georg Thieme Verlag KG Stuttgart · New York.)

Introduction: For several years, hyperthermic intrathoracic chemotherapy (HITHOC) has been performed in a few departments for thoracic surgery in a multimodality treatment regime in addition to surgical cytoreduction. Specific data about HITHOC in Germany are still lacking., Methods: Survey in written form to all departments of thoracic surgery in Germany. The objective is the evaluation of HITHOC with respect to number, indications, technique, perioperative protection measure and complications., Results: A total of 116 departments of thoracic surgery were contacted, with a return rate of 43% (n = 50). HITHOC was not performed in 33 departments, due to lack of resources or experience (n = 17), missing efficacy of the procedure (n = 8) and fear of excessive complication rates (n = 3). Since 2008, a total of 343 HITHOC procedures have been performed in 17 departments. Eight departments have their own perfusion machine, whereas the remaining departments borrow the perfusion machine. Indications were malignant pleural mesothelioma in all departments (n = 17), thymoma with pleural spread (n = 11) and secondary pleural carcinosis (n = 7). The HITHOC was performed in nearly all departments after closing the chest (n = 16), with a temperature of 42 °C (n = 12) and for 60 minutes (n = 15). Cisplatin was always used, either alone (n = 9) or in combination (n = 8). In all the participating departments, the aims of the HITHOC were improvement in local tumor control and prolonged recurrence-free and overall survival. Relevant HITHOC-associated complications were low., Conclusions: HITHOC is performed in at least 17 departments of thoracic surgery in Germany, and is widely standardised with protective measures and a low rate of complications. The aims of the HITHOC are improvement in local tumor control in pleural malignancies combined with prolonged overall survival and better quality of life., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (Georg Thieme Verlag KG Stuttgart · New York.)

Objectives: The effects of cisplatin on the lung parenchyma during hyperthermic intrathoracic chemotherapy perfusion have not been analysed in detail. The objective of this study was to evaluate both the concentration and depth of the penetration of cisplatin in human lung tissue after hyperthermic exposure under ex vivo conditions., Methods: This experimental study was approved by the local ethics committee. Twelve patients underwent pulmonary wedge resections after elective thoracic lobectomies were performed (resected lobe), and the lung tissue (approximately 1-2 cm(3)) was incubated (in vitro) with cisplatin (0.05 mg/ml; 60 min, 42°C). Subsequent tissue beds (depth, 0.5 mm; median weight, 70-92 mg) were prepared from the outside to the middle, and the amount of cisplatin per tissue weight was analysed using atomic absorption spectrometry. Afterwards, the penetration of cisplatin depth was calculated and related to the different concentrations per tissue., Results: Cisplatin penetrated into the human lung tissue after ex vivo hyperthermic exposure. The median amount of platinum [nmol cisplatin/g lung tissue] decreased significantly (P ≤ 0.05) depending on the penetration depth: 32 nmol/g (1 mm), 20 nmol/g (2 mm) and 6.8 nmol/g (4 mm). The calculated median concentrations of cisplatin (µg/ml) were 2.4 µg/ml (1 mm), 1.4 µg/ml (2 mm) and 0.5 µg/ml (4 mm), respectively., Conclusions: Under ex vivo hyperthermic conditions, cisplatin diffused into human lung tissue. The median penetration depth of the cisplatin was approximately 3-4 mm. The penetration of cisplatin into lung tissue may affect the local therapy of residual tumour cells on the lung surface using hyperthermic intrathoracic chemotherapy perfusion in patients with malignant pleural tumours., (© The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Introduction: Patients with pleural thymoma spread (Masaoka stage IV a) should be treated within a multimodal treatment regime. However, the extent of local surgical resection to achieve optimal tumour control remains controversial., Patients and Methods: Prospective analysis between September 2008 and April 2013 of all patients with a Masaoka stage IV a thymoma, who underwent radical pleurectomy/decortication (P/D) followed by hyperthermic intrathoracic chemotherapy (HITHOC)., Results: A total of 11 patients (male n = 7; mean age 46.5 ± 11.4 years) with a primary stage IV a thymoma (n = 3) or thymoma with pleural relapse (n = 8) were included after successful transsternal thymoma resection. WHO histological classification was: B1 n = 1, B2 n = 6, B3 n = 3 and C n = 1. A radical P/D (5/11; 45 %) was extended with resection of the pericardium and diaphragm in 6/11 (55 %) patients. After surgical resection (91 % complete macroscopic R0/R1-resection) the HITHOC with cisplatin (100 mg/m2 body surface area (BSA) n = 7; 150 mg/m2 BSA n = 4) was performed for one hour at 42 °C. Operative revision was necessary in two patients (chylo- and hematothorax) with one patient also requiring temporary renal replacement therapy due acute renal failure (cisplatin 150 mg/m2 BSA). 30-day mortality was 0 %. Local recurrence (pulmonary n = 1, paravertebral n = 2) was documented in 3/10 (30 %) patients after R0/R1 resection. After a mean follow-up of 23 months the overall median survival was 27 months and 82 % (9/11) patients are still alive at the end of the study period., Conclusions: Masaoka stage IV a thymoma could be safely treated with lung-sparing radical P/D and HITHOC with cisplatin in a multimodality treatment regime. Early results with respect to recurrence and survival are encouraging, but further studies are warranted and we have to await long-term results., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Assessing the pharmacokinetics of intrapleurally administered cisplatin during hyperthermic intrathoracic chemotherapy perfusion (HITHOC) following pleurectomy/decortication in patients with malignant pleural mesothelioma or advanced thymoma with pleural spread., Methods: Pharmacokinetic analysis (ICP-MS) of intrapleural cisplatin with a dosage of 100 mg/m(2) (n = 5) or 150 mg/m(2) (n = 5) at 42°C perfusate temperature. Simultaneous pleural perfusion fluid and serum samples were collected at the beginning and every 15 min. Serum samples were collected at the end of the operation, 6, 12, and 24 hr postoperative., Results: Mean cisplatin levels in the perfusate slightly decreased during the HITHOC. The mean area under the curve ratios (AUC perfusate :AUC serum ) of cisplatin were nearly similar. The mean AUCs of cisplatin in the perfusate were approximately 58 and 55 times greater than detected in the serum. The mean peak of cisplatin in the serum was reached after 1 hr of HITHOC. The AUC of cisplatin in the serum did not significantly differ (P = 0.18) between both groups up to 24 hr after perfusion., Conclusions: HITHOC with cisplatin provides a pharmacological advantage of high local intrapleural cisplatin concentrations. Elevation of the cisplatin dosage to 150 mg/m(2) did not lead to a significant increase of the systemic cisplatin concentration., (Copyright © 2013 Wiley Periodicals, Inc.)

Trimodality treatment including induction and/or adjuvant chemotherapy, surgical resection and in some cases radiotherapy offers a curative intention in selected patients with pleural malignancies (malignant pleural mesothelioma, thymoma with pleural spread). Nevertheless, locoregional tumor recurrence mainly limits the outcome and the quality of life. A few years ago an additional intraoperative chemotherapy perfusion was developed in order to improve local tumor control and prognosis after surgical resection in a multimodality treatment setting. Cytoreductive surgery with the purpose of a macroscopic complete resection could be achieved by radical pleurectomy or extrapleural pneumonectomy. The concept, techniques and perioperative management of this additional treatment option are presented along with a detailed review of the recent literature.

Objectives: A combination of cytoreductive surgery and hyperthermic intrathoracic chemotherapy perfusion (HITHOC) was performed for the treatment of primary and secondary pleural malignancies. We describe the perioperative management and our clinical experience., Methods: Between September 2008 and August 2011, eight patients with pleural manifestation of thymoma (Masaoka stage IVa) and eight patients with malignant pleural mesothelioma (MPM) were prospectively enrolled. Postoperative morbidity, recurrence and survival rates were analysed., Results: All the patients received multimodality therapy, including chemotherapy, radiation and surgical resection (pleurectomy/decortication) followed by the HITHOC procedure. Chemotherapy perfusion was performed with cisplatin (100-150 mg/m(2)) at 42°C for 1 h. Severe chemotherapy-related complications were not observed. Reoperation was necessary in two patients. There was no 30-day mortality. The median stay on the intensive care unit was 1 day, and the median duration of hospitalization was 15 days. Pleural recurrence of thymoma was evident in one thymoma patient 6 months after HITHOC. At mean follow-up of 22 months, seven thymoma patients (7/8; 88%) are alive without recurrence. Tumour progression was present in six mesothelioma patients (6/8; 75%). Four patients (50%) with MPM are alive, including two with no evidence of mesothelioma, and the median survival is 18 months., Conclusions: Cytoreductive surgery in combination with HITHOC can be performed with acceptable morbidity and mortality rates in selected patients. Patients should be evaluated by an interdisciplinary team to determine their eligibility for this therapeutic alternative. Early clinical results may encourage the use of this surgical option to provide better local tumour control in a multimodality treatment setting.

Recently cytoreductive surgery of primary and secondary pleural tumors has been combined with hyperthermic intrathoracic chemotherapy perfusion (HITHOC) for better local tumor control. In comparison to simple instillation of chemotherapeutic agents into the pleural cavity, the combination of surgical resection of pleural tumors and simultaneous HITHOC seems to be a more effective treatment. Intra-operative perfusion allows an improved distribution of the drug in the pleural space and a higher local concentration of the chemotherapeutic agents in contrast to systemic chemotherapy. Additional advantages of HITHOC are a better response to chemotherapeutic agents and synergistic antineoplastic effects. A prerequisite for safe application of HITHOC is compliance with safety regulations. Due to the reduction in morbidity and mortality this new concept is a valuable alternative for selected patients who do not undergo radical resection (e.g. extrapleural pneumonectomy). HITHOC is an additional therapeutic option in the multimodal treatment of patients with primary or secondary tumors of the pleura.