Clinical results of cytoreduction and HIPEC for malignant peritoneal mesothelioma.

Department of Surgery, University of Maryland Medical Center, Baltimore, MD 21201, USA.
Cancer treatment and research 02/2007; 134:343-55.
Source: PubMed


Taken together, these reports provide very provocative and encouraging data that have prompted some to conclude that cytoreduction and HIPEC represents a "new standard of care" for patients with MPM [26]. Certainly, for selected patients who have good performance status (low operative risk) and in whom complete or near complete cytoreduction can be achieved, this form of therapy is associated with a very notable overall survival ranging from 67 to 92 months in 2 larger series. Patient selection remains the central criteria for successful outcome. Patients should be carefully evaluated for co-morbid illnesses that would make them an unacceptable operative risk. Subsequently, CT scan and possibly laparoscopy should be performed to assess resectability with the appreciation that patients with suboptimal resection do very poorly. Pre-operative assessment of disease resectability is difficult to ascertain but some useful information can be obtained from a careful review of the CT scan; some investigators have advocated routine laparoscopy. Technically, details of HIPEC vary from center to center to some degree with respect to type of chemotherapy, dose of chemotherapy, duration of HIPEC, degree of hyperthermia, and method of recirculating the chemotherapy using either the open or closed technique. The use of the HIPEC technique, however, is considered the optimal method of ensuring complete distribution of therapeutic agents to the peritoneal cavity. Hyperthermia is routinely used for its synergistic actions with chemotherapy and its direct tumoricidal activity in experimental models. However, the therapeutic contribution of HIPEC above the effects of successful cytoreduction cannot be determined with available data although palliation of ascites is observed with HIPEC even without cytoreduction. There are no data indicating that one intra-operative chemotherapy regimen is superior to any other. The centers that report use of prolonged induction or post-operative intraperitoneal chemotherapy do not appear to have superior outcomes to those centers that use a more simple treatment regimen. Finally, although the intensity of therapy is considerable, once recovered, the patients appear to enjoy a good HRQOL. Although not specific for patients with MPM, 2 reports have convincingly demonstrated that HRQOL is significantly improved after HIPEC.

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    ABSTRACT: Patienten mit lokal fortgeschrittenem oder metastasiertem Pankreaskarzinom haben nach einem Progress auf die First-line-Chemotherapie mit Gemcitabin oder der Kombination aus Gemcitabin mit einem Platinanalogon bzw. Erlotinib keine wirklichen Optionen in der Second-line-Therapie. Die Prognose dieser Krebsform ist zudem mit einer 5-Jahresüberlebensrate von unter 5% extrem schlecht. In vivo und in vitro Studien belegten die Verstärkung der Zytotoxizität sowohl von Gemcitabin als auch von Cisplatin durch Hyperthermie und mit dem Verfahren der Hyperthermie wurden in der Therapie der Weichteilsarkome in der Vergangenheit große Erfolge erzielt. Auf Grund dieser Erkenntnisse wurden an fünf Kliniken im Raum München Patienten mit lokal fortgeschrittenem oder metastasiertem Pankreaskarzinom mit Gemcitabin (G) und Cisplatin (P) in Kombination mit Regionaler Hyperthermie (RHT) behandelt. Die Daten waren nicht-interventionell erfasst worden. In der hier vorliegenden Arbeit wurden die Daten von 64 Patienten, die zwischen Dezember 1997 und September 2007 eine GP+RHT-Behandlung begonnen hatten, retrospektiv ausgewertet. Der primäre Endpunkt war die Zeit bis zur Tumorprogression (TTP). Der sekundäre Endpunkt war die Analyse der objektiven Ansprechrate und die Erfassung des medianen Gesamtüberlebens und der Toxizität. Es wurden pro Zyklus 1000 mg/m2 Gemcitabin an Tag 1 und 25 mg/m2 Cisplatin zusammen mit Hyperthermie an den Tagen 2 und 4 verabreicht. Die Patienten wurden je nach Vortherapie in vier unterschiedlichen Gruppen ausgewertet. Die besten Ergebnisse wurden mit der Gruppe B1 (6 Patienten progredient auf eine adjuvante Gemcitabin-Vortherapie) erreicht, im Vergleich mit der Gruppe A (11 chemonaive Patienten mit nicht-resektablen Tumoren), der Gruppe B2 (32 Patienten progredient auf Gemcitabin-Mono oder eine Gemcitabin-basierte Erstlinientherapie) und der Gruppe C (15 Patienten, die bereits mindestens zwei Vortherapien erhalten hatten, wovon mindestens eine Gemcitabin-basiert war). Das Gesamtüberleben ab Erstdiagnose der Gruppe B1 war 23,7 Monate und entsprach dem erwarteten Überleben für kurativ operierte und adjuvant therapierte Patienten. Die TTP dieser Gruppe war mit 8,2 Monaten länger als eine Platin-basierte First-line- oder Second-line-Therapie erwarten ließe. Die Gruppe A zeigte ebenfalls eine längere TTP als publizierte Platin-basierte First-line-Studien. Sie zeigte ein vergleichbares Gesamtüberleben ab dem Therapiebeginn wie die anderen Gruppen. Dieses entsprach mit 7,2 Monaten ebenfalls den Ergebnissen veröffentlichter Platin-basierte First-line-Therapien. Die Gruppe A hatte allerdings mit 8,4 Monaten das kürzeste Gesamtüberleben berechnet ab der Erstdiagnose. Dies wurde unter anderem darauf zurückgeführt, dass mehrere Patienten keine Second-line-Therapie erhalten hatten. Beim Vergleich der Gruppe B2 mit anderen Second-line-Studien zeigte sich, dass die TTP kürzer war und das mediane Überleben im gleichen Bereich lag wie bei publizierten Platin-haltigen Second-line-Studien. Bei der Analyse dieser Second-line-Studien wurde gezeigt, dass Platin-haltige Regime in der Second-line-Therapie im Median die besten Ergebnisse bezogen auf die TTP, das mediane Überleben, die Ansprechrate und die Tumorkontrollrate zeigten. Die Gruppe C erbrachte bessere Ergebnisse als die Gruppe B2. In dieser Gruppe wurde allerdings eine geringe Zunahme der milden bis moderaten Anämien und Leukopenien im Vergleich mit den anderen Gruppen festgestellt. Ob die Toxizität von Gemcitabin und Cisplatin durch die Hyperthermie verstärkt wurde, lies sich in dieser Arbeit nicht klären. Es fiel in allen Gruppen eine Häufung von Harnwegsinfektionen auf, was durch das für die Hyperthermiebehandlung notwendige Katheterisieren verursacht sein konnte. Die Hyperthermie-spezifische Toxizität war gering.
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    ABSTRACT: Cytoreductive surgery and continuous hyperthermic peritoneal perfusion (CHPP) involve the conduct of a complex surgical procedure and delivery of high-dose hyperthermic chemotherapy to the peritoneum. This therapeutic modality has been shown to benefit patients with peritoneal carcinomatosis resulting from gastrointestinal and ovarian tumors and mesothelioma. However, it is unknown whether the primary disease (mesothelioma versus peritoneal carcinomatosis) affects hemodynamic and metabolic perturbations during the course of CHPP with cisplatin. We examined the perioperative course of patients undergoing CHPP with cisplatin and evaluated the effect of primary diagnosis (mesothelioma versus peritoneal carcinomatosis) on hemodynamic and metabolic parameters in response to peritoneal perfusion. Sixty-nine mesothelioma and 100 peritoneal carcinomatosis patients underwent 169 consecutive cytoreduction and CHPP procedures with general anesthesia. During CHPP, patients from both groups developed significant increases in central venous pressure, and heart rate, decreases in mean arterial pressure (all P < 0.0001), metabolic acidosis with significant decreases in pH and bicarbonate (P < 0.0001), deterioration of gas exchange with significant increases in PaCO(2) and oxygen alveolar-arterial gradient (P < 0.0001), and significant increases in activated partial thromboplastin time (aPTT) and prothrombin time (PT) and decreases in hematocrit and platelet counts (all P < 0.0001). However, patients with mesothelioma had lesser increases in temperature (P < 0.01) and heart rate (P < 0.0001) and lesser decreases in hematocrit (P = 0.0013) during CHPP and greater decreases in sodium bicarbonate (P = 0.0082) after completion of CHPP compared with patients with peritoneal carcinomatosis. We conclude that the transient hemodynamic and metabolic perturbations associated with cytoreductive surgery and CHPP with cisplatin can vary according to the primary diagnosis (mesothelioma versus peritoneal carcinomatosis) warranting this therapy.
    Annals of Surgical Oncology 02/2009; 16(2):334-44. DOI:10.1245/s10434-008-0253-z · 3.93 Impact Factor
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    ABSTRACT: Malignant peritoneal mesothelioma (MPM) is a rare malignancy that arises from the serosal membranes of the abdominal cavity. In 1972, Moertel published a paper characterizing the clinical course of patients afflicted with MPM and the now recognized clinical features associated with tumor progression within the abdominal cavity. 1 Borow first reported the association between asbestos exposure and mesothelioma that same year. 2 Despite the current recognition that MPM is a distinct entity from its pleural variant, progress in the treatment of patients afflicted with MPM has been hampered by several factors. First, it is an extraordinarily rare condition: only 10‐15% of all patients with mesothelioma present with the peritoneal form of the disease, and this translates into approximately 300‐400 cases in the USA annually. As a consequence, throughout the last two decades many clinical trials testing systemic agents for patients with malignant mesothelioma did not distinguish between those with the pleural versus the peritoneal form of disease. 3‐5 Many of these trials included a small number of patients with MPM and for whom no confident conclusions regarding efficacy of the experimental regimen could be made. It is now becoming increasingly recognized that patients with MPM have a distinct disease for which specific therapies should be developed. Another significant feature of MPM that has challenged our ability to understand the contribution of various therapeutic interventions to patient outcome is the remarkable variability in the biology of this condition. In 1973, Rogoff and colleagues reported outcomes in four patients treated at Memorial Sloan‐Kettering Cancer Center in New York using surgical cytoreduction and whole-abdominal radiotherapy. 6 Two of the four patients survived longer than 5 years. Antman and colleagues reported outcomes of 37 patients with MPM treated at the Dana Farber Cancer Institute and the Brigham and Women’s Hospital between 1965 and 1984 and also noted that, while some patients progressed and succumbed rapidly, others survived for many years after treatment. 7 In their series, patients treated after 1982 underwent cytoreduction, placement of an intraperitoneal (IP) catheter, and received between 8‐10 cycles of IP doxorubicin and cisplatin. Subsequent to that 30 Gy of whole-abdominal radiation was administered. In their analysis, patients with smaller tumor burden and female gender had prolonged survival; those with epithelioid tumors did poorly compared with those with other histopathological types. Since that initial description, the use of multimodal therapy using cytoreduction with some form of high-dose regional chemotherapy has become increasingly
    Annals of Surgical Oncology 11/2009; 17(1):21-2. DOI:10.1245/s10434-009-0763-3 · 3.93 Impact Factor
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