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Hyperthermic intracavitary chemotherapy in abdomen and chest

van Ruth, S.

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Citation for published version (APA):van Ruth, S. (2003). Hyperthermic intracavitary chemotherapy in abdomen and chest.

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Download date: 21 Oct 2020

CHAPTER ONE

Introduction and outline of the thesis

Introduction and outline of the thesis

Hyperthermic intracavitary chemotherapy has gained more attention recent years as thera­peutic approach for loco-regional disseminated cancers. Spratt et al' was the first who described this technique for a patient with pseudomyxoma peritonei. Nowadays, this multi-modality treatment is used in more than 30 centres worldwide.2 Hyperthermic intraperitoneal chemotherapy perfusion has been studied in patients with malignant mesothelioma, peri­toneal sarcomatosis and peritoneal carcinomatosis of gastric origin, but most efforts have been put on patients with pseudomyxoma peritonei and peritoneal carcinomatosis of col­orectal origin.' Intracavitary administration of chemotherapy has the potential to reach a high local dose with limited systemic side effects.4 Hyperthermia itself has a direct cytotoxic effect at a level ex­ceeding 42°C and is known to enhance the cytotoxicity of several cytostatic drugs, starting at a temperature of 39°C.5'7 Furthermore, the penetration depth of most cytostatic drugs is im­proved by hyperthermia/9 However, cytoreductive surgery is mandatory in order to leave as little residual tumour as possible because the penetration depth of cytostatic drugs is limited to at most a few millimetres."' Intra-operative chemotherapy allows distribution of drug and heat uniformly to all surfaces of the abdomen. For this reason, an operative setting under gen­eral anaesthesia is preferable over simple instillation of chemotherapeutics in addition to the fact that hyperthermia is not tolerated in awake patients. Since 1996, The Netherlands Cancer Institute/Antoni van Leeuwenhoek hospital has gained ample experience with cytoreductive surgery and Hyperthermic IntraPEritoneal Chemo­therapy (HIPEC). Both patients with pseudomyxoma peritonei and peritoneal carcinomatosis of colorectal origin have been treated." i: The cytostatic drug in our treatment regimen has been Mitomycin C (MMC) because of its known activity in colorectal cancer, its direct cyto­toxic effect and its thermal enhancement.5-13

Cytoreductive surgery and hyperthermic intracavitary chemotherapy perfusion in the tho­racic cavity was performed in our institute in 1998. This technique has been named Hyper­thermic IntraTHOracic Chemotherapy (HITHOC) perfusion. Both patients with limited malignant pleural mesothelioma and pleural thymoma were studied because these diseases can be seen as loco-regional disseminated cancers that might benefit from a loco-regional in­tensified therapeutic approach. Only minor experience with this multi-modality treatment exists world-wide; only case reports or small series of patients have been published.1419 The intrathoracic cytostatic agents that have been used, cisplatin and doxorubicin, are well known cytostatic drugs assessed as systemic therapy in both mesothelioma and thymoma patients. Witkamp has reported the initial data on cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy in his thesis from our institute.-" The present thesis deals with several aspects of both HIPEC and HITHOC procedures.

Chapter two gives a review on the surgical management so far of malignant pleural mesothe­lioma (MPM). Surgery has been considered the mainstay of treatment of MPM, unless the fact that surgery alone is never curative. Therefore, the emphasis has been on surgery com­bined with adjuvant therapies in recent years, but this approach did not lead to a clear survival benefit for MPM patients so far. Based on our favourable results with cytoreduction and

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Chapter 1

HIPEC in peritoneal disseminated colorectal cancer, we developed a feasibility study with cytoreduction and HITHOC for MPM and pleural thymoma patients. The initial results are described in chapter three. A larger series of patients with MPM treated by this multi-modality treatment with more extensive follow-up is given in chapter four. Part of succeed­ing this treatment is optimisation of the dosage of the cytostatic drugs that were used. Therefore pharmacokinetics of cisplatin and doxorubicin were studied. Chapter five de­scribes the possibility to achieve a high local dose in the thoracic cavity with limited systemic uptake. It is important to know whether the chemotherapy has the potential to kill residual tu­mour after cytoreduction. For this reason, the penetration characteristics of doxorubicin were analysed and reported in this chapter as well.

In his thesis, Witkamp reported on some of the pharmacokinetics of MMC during HIPEC procedures.2" Chapter six gives a review of the pharmacokinetics of MMC after intra-opera-tive intraperitoneal administration as reported in literature so far. Several aspects such as dose method, accompanied hematotoxicity and uptake with regard to the peritoneal-plasma barri­er provide more insight into this complex matter. To gain better insight into the pharmacoki­netics of MMC, like distribution volume and elimination kinetics, we developed a population pharmacokinetic and pharmacodynamic model (chapter seven) based on a large series of pharmacokinetic data. Knowledge of the relationships between pharmacokinetics and phar­macodynamics can contribute to rationalise the dosing and may lead to a more accurate dose advice. An estimated ideal dose of MMC is provided at the end of this chapter. Another im­portant part of HIPEC is the application of hyperthermia. The effect of hyperthermia used during HIPEC was further investigated and the results are reported in chapter eight. Special attention was given to the possible relation between core temperature and temperature gradi­ent because it was anticipated that core temperature could influence the heat penetration. The earlier thesis on HIPEC from our institute showed that cytoreductive surgery and HIPEC seems an attractive approach not only for patients with colorectal cancer but also for patients with pseudomyxoma peritonei (PMP).:"The diverse problem clinical appearance of PMP and its variable clinical course after cytoreduction and HIPEC was a challenging feature we were confronted with. Based on studies of Ronnett et al21", a better classification of PMP in three pathologic entities could be made. We also studied the pathology of PMP in order to come to a better selection of candidates for our therapeutic approach (chapter nine). Until now, no general accepted protocol for follow-up of PMP patients after cytoreduction and HIPEC has been described. Physical examination and Computed Tomography are mostly used. Tumour marker studies in PMP patients are scarce. Chapter ten provides new data on the tumour marker Carbohydrate Antigen 19.9 (CA19.9) in PMP patients, treated by cytoreduction and HIPEC. The usefulness of this marker during follow-up as an alternative for performing rou­tine CT scans is shown. In chapter eleven a general discussion and conclusions of the pre­sented data are given.

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Introduction and outline of the thesis

References

1 Spratt JS, Adcock RA, Muskovin M, Shcrrill W, McKeown J. Clinical delivery system for in­traperitoneal hyperthermic chemotherapy. Cancer Res 1980; 40: 256-260.

2 Ceelen WP, Hesse U, de Hemptinne B, Pattyn P. Hyperthermic intraperitoneal chemoperfusion in the treatment of locally advanced intra-abdominal cancer. Br J Surg 2000; 87: 1006-1015.

3 de Bree E. Witkamp AJ, Zoetmulder FA. Intraperitoneal chemotherapy for colorectal cancer. J Surg Oncol 2002; 79: 46-61.

4 Markman M. Intraperitoneal chemotherapy. Semin Oncol 1991; 18: 248-254. 5 Storm FK. Clinical hyperthermia and chemotherapy. Radiol Clin N America 1989; 27: 621-627.

6 Barlogie B, Corry PM, Drewinko B. In vitro thermochemotherapy of human colon cancer cells with cis-dichlorodiammineplatinum(II) and mitomycin C. Cancer Res 1980; 40: 1165-1168.

7 Teicher BA, Kowal CD, Kennedy KA, Sartorelli AC. Enhancement by hyperthermia of the in vitro cyotoxicity ov mitomycin C toward hypoxic tumor cells. Cancer Res 1981; 41: 1096-1099.

8 van de Vaart PJM, van der Vange N, Zoetmulder FAN, van Goethem AR, van Tellingen O, ten Bokkel Huinink WW et al. Intraperitoneal cisplatin with regional hyperthermia in advanced ovari­an cancer: pharmacokinetics and cisplatin-DNA adduct formation in patients and ovarian cancer cell lines. Eur J Cancer 1998: 34: 148-154.

9 Panteix G, Guillaumont M, Cherpin L. Cuichard J, Gilly FN, Carry PY et al. Study of the pharma­cokinetics of mitomycin C in humans during intraperitoneal chemothermia with special mention of the concentration in local tissues. Oncology 1993; 50: 366-370.

10 Witkamp AJ, de Bree E. Van Goethem R, Zoetmulder FA. Rationale and techniques of intra-opera-tive hyperthermic intraperitoneal chemotherapy. Cancer Treat Rev 2001; 27: 365-374.

11 Witkamp AJ, de Bree E. Kaag MM. Boot H, Beijnen JH. van Slooten GW et al. Extensive cytore-ductive surgery followed by intra-operative hyperthermic intraperitoneal chemotherapy with mito-mycin-C in patients with peritoneal carcinomatosis of colorectal origin. Eur J Cancer 2001; 37: 979-984.

12 Witkamp AJ, de Bree E, Kaag MM, van Slooten GW, van Coevorden F, Zoetmulder FA. Extensive surgical cytoreduction and intraoperative hyperthermic intraperitoneal chemotherapy in patients with pseudomyxoma peritonei. Br J Surg 2001; 88: 458-463.

13 Haller DG. Chemotherapy in gastrointestinal malignancies. Sem Oncol 1988; 15: 50-64. 14 Yellin A, Simansky DA, Paley M. Refaely Y. Hyperthermic pleural perfusion with cisplatin. Cancer

2001:92:2197-2203.

15 Iyoda A, Yusa T, Hiroshima K, Fujisawa T. Surgical resection Combined with Intrathoracic Hyper­thermic Perfusion for Thymic Carcinoma with an Intrathoracic Disseminated Lesion: A Case Re­port. Anticancer Research 1999; 19: 699-702.

16 Carry PY, Brachet A, Gilly FN, Sayag AC, Petit PY, Rochette C et al. A new device for the treatment of pleural malignancies: intrapleural chemohyperthermia preliminary report. Oncology 1993; 50: 348-352.

17 Ratto GB, Civalleri D, Esposito M, Spessa E, Alloisio A, De Cian F et al. Pleural space perfusion with cisplatin in the multimodality treatment of malignant mesothelioma: a feasibility and pharmo-cakinetic study. J Thorac Cardiovasc Surg 1999; 117: 759-765.

18 Rice TW. Adelstein DJ, Kirby TJ, Saltarelli MG, Murthy SR, Van Kirk MA et al. Aggressive multi-modality therapy for malignant pleural mesothelioma. Ann Thorac Surg 1994; 58: 24-29.

19 Refaely Y, Simansky DA. Paley M, Gottfried M, Yellin A. Resection and perfusion ther­mochemotherapy: a new approach for the treatment of thymic malignancies with pleural spread. Ann Thorac Surg 2001; 72: 366-370.

20 Witkamp AJ. Hyerthermic intraperitoneal chemotherapy in peritoneal surface malignancy [Disser­tation]. University of Amsterdam, 2003.

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Chapter I

21 Ronnett BM, Yan H, Kurman RJ, Shmookler BM, Wu L, Sugarbaker PH. Patients with pseudomyx­oma peritonei associated with disseminated peritoneal adenomucinosis have a significantly more favorable prognosis than patients with peritoneal mucinous carcinomatosis. Cancer 2001; 92:85-91.

22 Ronnett BM, Zahn CM, Kurman RJ, Kass ME, Sugarbaker PH, Shmookler BM. Disseminated peri­toneal adenomucinosis and peritoneal mucinous carcinomatosis. A clinicopathologic analysis of 109 cases with ephasis on distinguishing pathologic features, site of origin, prognosis, and relation­ship to 'pseudomyxoma peritonei'. Am J Surg Pathol 1995; 19: 1390-1408.

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