Van der Speeten K, Stuart OA, Mahteme H, Sugarbaker PH.

Department of Surgical Oncology, Ziekenhuis Oost-Limburg, Schiepse Bos 6, 3600, Genk, Belgium, kurt.vanderspeeten@zol.be.

Abstract

Purpose: A pharmacologic analysis of intracavitary doxorubicin in the treatment of patients with intracavitary cancer dissemination was performed to further evaluate the possible benefits of this treatment modality.

Methods: Twenty appendiceal malignancy patients with peritoneal carcinomatosis (PC), three appendiceal malignancy patients with direct extension into the pleural cavity, 20 patients with peritoneal mesothelioma and one patient with pleural mesothelioma were available for pharmacologic monitoring. After intraperitoneal or intrapleural administration of doxorubicin, plasma and peritoneal fluid samples were obtained at 15, 30, 45, 60 and 90 min in all patients. After intrapleural administration, plasma and pleural fluid samples were collected at similar intervals. Tumor and normal tissues were obtained when available. Doxorubicin concentrations were determined by high-performance liquid chromatography (HPLC).

Results: Intraperitoneal doxorubicin showed a prolonged retention in the peritoneal cavity. Doxorubicin concentrations in tumor tissue were consistently elevated above intraperitoneal concentrations from 30 through 90 min. For appendiceal malignancy, the concentrations of doxorubicin were significantly higher in minimally aggressive mucinous tumors. Pleural chemotherapy solutions retained doxorubicin to a greater extent than peritoneal fluid.

Conclusions: Doxorubicin shows characteristics favorable for intracavitary administration with sequestration of doxorubicin in cancer nodules.

Keywords: Intraperitoneal chemotherapy – Intrapleural chemotherapy – Doxorubicin – Pharmacokinetics – Pharmacodynamics – Appendiceal cancer – Peritoneal mesothelioma – Pleural mesothelioma

Spugnini EP, Crispi S, Scarabello A, Caruso G, Citro G, Baldi A.

S,A,F,U, Department, Regina Elena Cancer Institute -, Rome -, Italy. info@enricospugnini.net.

Abstract

Malignant Mesothelioma is an uncommon and very aggressive tumor that accounts for 1% of all the deaths secondary to malignancy in humans. Interestingly, this neoplasm has been occasionally described in companion animals as well. Aim of this study was the preclinical evaluation of the combination of piroxicam with platinum-based intracavitary chemotherapy in pets. Three companion animals have been treated in a three years period with this combination. Diagnosis was obtained by ultrasonographic exam of the body cavities that evidenced thickening of the mesothelium. A surgical biopsy further substantiated the diagnosis. After drainage of the malignant effusion from the affected cavity, the patients received four cycles of intracavitary CDDP at the dose of 50 mg/m² every three weeks if dogs or four cycles of intracavitary carboplatin at the dose of 180 mg/m² (every 3 weeks) if cats, coupled with daily administration of piroxicam at the dose of 0.3 mg/kg. The therapy was able to arrest the effusion in all patients for variable remission times: one dog is still in remission after 3 years, one dog died of progressive disease after 8 months and one cat died due to progressive neoplastic growth after six months, when the patient developed a mesothelial cuirass. The combination showed remarkable efficacy at controlling the malignant effusion secondary to MM in our patients and warrants further investigations.

Matsuzaki Y, Tomita M, Shimizu T, Hara M, Ayabe T, Onitsuka T.

Department of Surgery, Cardiovascular, Thoracic and General Surgery, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.

Abstract

Purpose: Despite extensive clinical research, no effective therapy for advanced malignant pleural mesothelioma has been established. In this study, we induced apoptosis in patients with this disease, using intrapleural perfusion hyperthermo-chemotherapy, a new procedure developed in our surgical department. We then measured the tumorcidal effect.

Material and Methods: Our study included 6 consecutive patients with malignant pleural mesothelioma (stage III: 5; stage IV: 1). Because of the advanced stage of the disease, none of the patients underwent tumor resection or pleurectomy. All patients, however, received perfusion treatment. Tumor cells collected from pleural effusions pre-and at 0, 24, and 48 h postperfusion were examined using an immunocytochemical stain to determine apoptosis. The percentage of positively stained cells was expressed as the apoptotic index.

Results: Preperfusion, the apoptotic index was 3.8% +/- 2.0%, indicating spontaneous apoptosis of untreated
tumor cells. Postperfusion, the apoptotic index at 0, 24, and 48 h was 22.8% +/- 5.15%, 63.8% +/- 8.2%, and 47.8% +/- 6.9%, respectively. The patients had a median survival time of 30 months. No patient morbidity was associated with the perfusion treatment.

Conclusion: In patients with malignant pleural mesothelioma, intrapleural perfusion hyperthermo-chemotherapy induced potent apoptosis of tumor cells, increasing immediately postperfusion and peaking at 24 h.

van Sandick JW, Kappers I, Baas P, Haas RL, Klomp HM.

Department of Surgical Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. j.v.sandick@nki.nl

Abstract

Background: A minority of patients with malignant pleural mesothelioma (MPM) are considered for surgery. To achieve a microscopically radical resection, combination with other treatment modalities is mandatory. The most effective combination is unknown. In our institute we have retrospectively analyzed the results of two combined modality regimens containing surgery.

Patients: Between January 2002 and September 2005, 15 MPM patients were treated with extrapleural pneumonectomy (EPP) and postoperative hemithoracic radiation (RT; 54 Gy). Previously, between January 1999 and December 2001, 20 patients underwent a combination of cytoreductive surgery – pleurectomy or EPP – and intraoperative hyperthermic intrathoracic chemotherapy (HITHOC), followed by radiotherapy to the thoracotomy scar and drainage tracts (24 Gy).

Results: The median operating time for EPP/RT was shorter (5.3 versus 6.9 h; P < 0.0001). Postoperative complications occurred in 8 EPP/RT patients (53%) and in 14 HITHOC patients (70%). Two HITHOC patients died postoperatively. Median overall survival was 29 months for EPP/RT patients and 11 months for HITHOC patients (P = ns). The median time to local recurrence was not reached for EPP/RT patients, and was 9 months for HITHOC patients (P = 0.003). Local control was achieved in ten EPP/RT patients (67%) with a follow-up of 5–59 months compared to four HITHOC patients (20%) with a follow-up of 4–27 months.

Conclusions: In highly selected patients local control can be achieved with combination therapy but is accompanied by a high rate of (surgical) complications. Distant failure rates warrant further studies exploring the role of systemic chemotherapy while the use of cytoreductive surgery with intraoperative chemoperfusion for MPM is not supported.

Keywords: Malignant pleural mesothelioma – Extrapleural pneumonectomy – Intraoperative hyperthermic intrathoracic chemotherapy – Adjuvant radiotherapy – Combined modality treatment

Ng JM, Hartigan PM.

Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, USA; Harvard Medical School, Boston, Massachusetts, USA.

Abstract

Purpose of review: Extrapleural pneumonectomy is a radical and aggressive surgery that presents a great challenge to the thoracic anesthesiologist. This surgery is performed routinely by only a few centers in the world and this review represents our institution’s experience in anesthetic care.

Recent findings: Prominent among the developing multimodal treatment options is the combination of extrapleural pneumonectomy with intraoperative intracavitary hyperthermic chemotherapy. Outcome survival benefits have recently been demonstrated for the less completely cytoreductive pleurectomy procedure when combined with intraoperative intracavitary hyperthermic chemotherapy and trials are well under way for extrapleural pneumonectomy plus intraoperative intracavitary hyperthermic chemotherapy. Anesthetic management of extrapleural pneumonectomy is further impacted by these developments.

Summary: Anesthetic management importantly contributes to containment of the perioperative complications of extrapleural pneumonectomy. An appreciation of the technical aspects and physiologic disruptions associated with extrapleural pneumonectomy is critical to effective management. While data on this relatively uncommon surgical procedure are scarce, some referral centers have accumulated extensive experience. This review summarizes relevant surgical aspects and anesthetic insights from the Brigham and Women’s Hospital experience. Included are the anesthetic implications of intraoperative intracavitary hyperthermic chemotherapy in combination with extrapleural pneumonectomy – an emerging therapeutic option in the treatment of malignant pleural mesothelioma.

Sugarbaker PH.

Washington Cancer Institute, Washington, DC 20010, USA. paul.sugarbaker@medstar.net

Abstract

Intraoperative chemotherapy with heat has been identified as a treatment option for patients with cancer spread to peritoneal surfaces. This treatment modality is viewed as a supplement to several other treatments for this group of patients including cytoreductive surgery, systemic chemotherapy, early postoperative intraperitoneal chemotherapy, and long-term bidirectional chemotherapy. The pharmacologic basis for using heat to supplement chemotherapy effects are related to the increased penetration of chemotherapy into tumor with hyperthermia, the delayed clearance of chemotherapy from the peritoneal cavity after direct instillation, and an increased cytotoxicity that has been documented with selected chemotherapy agents. Data to support the use of perioperative hyperthermic intraperitoneal chemotherapy with mucinous appendiceal carcinomatosis comes from a large number of single institution phase II studies. Also, peritoneal and pleural mesothelioma are benefited. In colon cancer carcinomatosis, large phase II multi-institutional trials and a single phase III trial documented an increased median survival of these patients from approximately 1 year to over 2 years. Prophylaxis against peritoneal carcinomatosis in gastric cancer has been demonstrated in phase III trials. In ovarian cancer the rationale for this treatment remains large but its current application is limited. Much work needs to be done to identify a proper clinical perspective on hyperthermia used with chemotherapy in patients with peritoneal surface malignancy.

Keywords: Colorectal cancer; gastric cancer; ovarian cancer; appendiceal cancer; peritoneal mesothelioma
]]> http://www.mesothelioma-line.com/articles/2007/08/19/laboratory-and-clinical-basis-for-hyperthermia-as-a-component-of-intracavitary-chemotherapy/feed/ 0 http://www.mesothelioma-line.com/articles/2007/07/20/limited-cardiotoxicity-after-extensive-thoracic-surgery-and-intraoperative-hyperthermic-intrathoracic-chemotherapy-with-doxorubicin-and-cisplatin/ http://www.mesothelioma-line.com/articles/2007/07/20/limited-cardiotoxicity-after-extensive-thoracic-surgery-and-intraoperative-hyperthermic-intrathoracic-chemotherapy-with-doxorubicin-and-cisplatin/#comments Fri, 20 Jul 2007 15:25:01 +0000 Administrator http://www.mesothelioma-line.com/articles/2007/07/20/limited-cardiotoxicity-after-extensive-thoracic-surgery-and-intraoperative-hyperthermic-intrathoracic-chemotherapy-with-doxorubicin-and-cisplatin/ Annals of Surgical Oncology. 2007 Oct;14(10):3019-26. Epub 2007 Jul 20. [Link]

Eelco de Bree¹, Serge van Ruth¹, Carl E. Schotborgh², Paul Baas³ and Frans A. N. Zoetmulder¹

• (1) Department of Surgical Oncology, Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands
• (2)Department of Cardiology, Slotervaart Hospital, Amsterdam, The Netherlands
• (3) Department of Thoracic Oncology, Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands

Abstract

Background: Recently, pleural mesothelioma has been treated by cytoreductive surgery and intraoperative hyperthermic intrathoracic chemotherapy with doxorubicin and cisplatin. The well-established cardiotoxicity of doxorubicin and distressing data from an animal study raised concern about its impact on cardiac function. In the present study, early cardiotoxicity of this treatment modality was prospectively analyzed.

Patients and Methods: In 13 pleural mesothelioma patients, cardiotoxicity was monitored by clinical examination, electrocardiography, Troponin levels, cardiac ultrasonography, and estimation of left ventricular ejection fraction (LVEF) by radionuclide ventriculography before and during the first 6 months after cytoreductive surgery and intraoperative hyperthermic intrathoracic chemotherapy with doxorubicin (25–54 mg/m2) and cisplatin (65–120 mg/m2).

Results: No clinical cardiac failure or treatment-related death was observed. In two patients transient atrial fibrillation was noted; one associated with pulmonary emboli. Early posttreatment Troponin release was not of predictive value. Ultrasonography did not reveal significant alterations. LVEF decreased significantly (mean 0.07 or 11%, P = .001) during the first 3 months and remained stable thereafter. In univariate analysis, the degree of LVEF reduction was statistically related to maximal intrathoracic doxorubicin concentration (P = .031) and total cisplatin dose (P = .029). Direct exposure of the heart to the drugs as a result of partial pericardectomy was not associated with greater LVEF decrease. On the contrary, partial pericardectomy seemed to be associated with a smaller LVEF decline than when the pericardium remained intact (P = .045). In this small series, no statistically significant correlation between other treatment or pharmacokinetic parameters and LVEF decline was found. Notably, higher doxorubicin plasma concentrations and exposure were not associated with increased LVEF reduction.

Conclusions: Early cardiotoxicity is limited after this treatment modality using substantial doses of doxorubicin and cisplatin. Hence, this study suggests that intrathoracic chemotherapy with doxorubicin and/or cisplatin may be used for primary and secondary pleural malignancies, even immediately after extensive thoracic surgery, without concern of severe early cardiotoxicity.

Keywords: Intrathoracic chemotherapy – Intrapleural chemotherapy – Cardiotoxicity – Doxorubicin – Cisplatin – Mesothelioma

Opitz I, Lardinois D, Arni S, Hillinger S, Vogt P, Odermatt B, Rousson V, Weder W.

Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.

Abstract

Objective: Local recurrence remains a major problem in the treatment of malignant pleural mesothelioma. The aim of the underlying study was to establish a standardised local recurrence model in rats which enables to study different intrapleural therapies.

Materials and methods: Fifty microlitre containing 1 × 10⁶ cells of a syngeneic rat malignant mesothelioma cell line (II-45), established from mesothelioma in Fischer 344 rats exposed to asbestos, were inoculated subpleurally via a left-sided thoracotomy. Tumour size was assessed 6 days later and the tumour nodule completely resected. Evaluation of recurrence at the resection site was performed after 10 days (n = 6) and 6 days (n = 6). The recurrent nodule was histopathologically confirmed. In a second experiment, this new recurrence model was evaluated for the effect of intrapleural therapy with different agents: 4 ml of cisplatin-solution (100 mg²/kg BW), cisplatin combined with the fibrin-based sealant Vivostat^®, 4 ml taurolidine 2%, repeated injection of 1 μg of the chemokine CCL-19 at the tumour site and 4 ml povidone-iodine in a dilution 1:10. In a control group, the chest cavity was filled with 4 ml 0.9% NaCl. The primary endpoint was the extent of tumour recurrence.

Results: Six days after inoculation, all animals presented a standardised tumour nodule at the injection site of a mean diameter of 5.1 (±0.8) mm. Evaluation of the recurrence after 10 days showed a relapse directly at the resection site, but additional tumour nodules on the ipsi- and contralateral chest wall were found and histologically confirmed. The animals that were sacrificed 6 days after resection of the tumour nodule showed a recurrence only at the resection site with no macroscopic or microscopic evidence of other tumour. Resection of the tumour nodule combined with intrapleural application of the different agents lead to clear reduction of recurrence. The strongest effect was observed
after intrapleural application of cisplatin-Vivostat^® with significant decrease of the longest, widest and thickest diameter of the recurrence.

Conclusions: With this new recurrence model for investigation of malignant pleural mesothelioma in rats, we were able to investigate new intrapleural therapies after pneumonectomy. The intrapleural application of cisplatin-Vivostat^® significantly reduced the extent of local recurrence.

Keywords: Mesothelioma; Animal model; Recurrence; Extrapleural pneumonectomy; Intrapleural; Cisplatin

Katsuragi N, Shiraishi Y, Kita H, Toishi M, Miyasaka Y, Tanaka S.

Section of Chest Surgery, Fukujuji Hospital, Kiyose, Japan.

Abstract

Malignant pleural mesothelioma is an uncommon neoplasm that caused 647 deaths in Japan in 2004. The incidence of the disease is increasing and is estimated to reach its peak in 2025. We reviewed the clinical features in 11 consecutive patients with pathologically confirmed diffuse malignant pleural mesothelioma in our institution from January 1997 to December 2002. Of the 11 patients, 9 were male and 2 were female with a mean age of 66 (range, 55 to 90) years. Symptoms included dyspnea in 4 patients, chest pain in 3, dyspnea plus chest pain in 2, and cough in 2. Median period between symptom onset and presentation was 1 (range, 0 to 6) month. A history of asbestos exposure was identified in 3 patients and suspected in 5. A definitive diagnosis was made by closed pleural biopsy in 8 patients, pleural fluid cytology in 2, and autopsy in 1. Histological subtypes included epithelioid in 6 patients, sarcomatoid in 2, biphasic in 1, and unknown in 2. International Mesothelioma Interest Group (IMIG) staging included stage II in 6 patients, stage III in 3, and stage IV in 2. Median period between presentation and diagnosis was 1 (range, 0 to 22) month. Treatment included intrapleural chemotherapy in 4 patients, extrapleural pneumonectomy in 3, pleural drainage in 2, and best supportive care in 2. During the follow-up period, 9 patients died and 2 survived. Median survival time after diagnosis was 3 (range, 0 to 51) months. Of the 11 patients, 7 (64%) died within 6 months after the first presentation, and only 1 (9%) lived longer than 2 years after diagnosis.

Lucchi M, Chella A, Melfi F, Dini P, Ambrogi M, Fino L, Fontanini G, Mussi A.

Division of Thoracic Surgery, Cardiac and Thoracic Department, University of Pisa, Pisa, Italy.

Abstract

Objective: From therapeutic nihilism to extremely aggressive management, there is a wide range of possibilities in the treatment of malignant pleural mesothelioma (MPM). Unfortunately, there is little evidence as regards the best treatment to offer to the MPM patients. In 1999, we started a phase II study based on the multimodality treatment of stage II-III MPM, the results of which have been analysed and reported.

Methods: From 1999 to 2004, 49 patients with IMIG stage II-III MPM underwent a multimodality treatment including: intrapleural pre-operative interleukin 2 (IL-2, 18×10(6)UI/day per 3 days), pleurectomy/decortication, intrapleural post-operative epidoxorubicin (25mg/m(2) per 3 days), IL-2 (18×10(6)UI/day per 3 days), adjuvant radiotherapy (30Gy), systemic chemotherapy (cisplatin 80mg/m(2) day 1, gemcitabine 1250mg/m(2) day 1 and 8 up to 6 courses) and long-term sub-cutaneous IL-2 (3×10(6)UI/day 3 days per week).

Results: There were 41 males and 8 females with a median age of 61 years (range 41-77). All the patients had a diagnosis of MPM by thoracoscopy before inclusion. We did not experience any post-operative mortality. The histology was: 39 epitheliomorf, 6 bifasic and 4 sarcomatous. According to the IMIG the post-operative staging was III in 40 cases and II in 9 cases. With a median follow-up of 59 months (range 14-81) 13 patients are still alive and the median actuarial survival is 26 months (31 and 21 months for stage II and III, respectively). Only the Performance Status at the diagnosis affected survival significantly.

Conclusions: The multimodality treatment we adopted for stage II-III MPM was feasible, well tolerated by most of the patients and produced a favourable outcome. New targeted therapies are awaited for further improvements in the treatment of this disease.