Diffuse Malignant Peritoneal Mesothelioma by shade1314

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									Diffuse Malignant Peritoneal Mesothelioma :
     Cytoreductive Surgery and HIPEC




            Giorgos C. Karakousis, M.D.
   Division of Endocrine and Oncologic Surgery
               Department of Surgery
   University of Pennsylvania School of Medicine
Diffuse Malignant Peritoneal Mesothelioma
Background


• Approximately 300-400 cases of Diffuse Malignant
  Peritoneal Mesothelioma (DMPM) in the U.S. annually
  (10-15% of mesothelioma cases)
• Mean age: 50 years
• Slight male predominance
• More and more being recognized as a distinct disease
• Recognized histologic variants: epitheloid, sarcomatoid
Diffuse Malignant Peritoneal Mesothelioma
Schematic of Peritoneum




                                            Adapted from asbestoshub.com
Diffuse Malignant Peritoneal Mesothelioma
Clinical Presentation


 •Weight loss—loss of muscle mass
 •Abdominal distension
 •Abdominal pain
 •Intestinal obstruction
 •Clinical symptoms related to regional progression
 of disease—rarely present with distant metastases
Diffuse Malignant Peritoneal Mesothelioma
Diagnosis


•CT
•Serum biomarkers (Ca-125, mesothelin)
•No work-up findings to suggest GI source for intra-
abdominal findings
•Immunohistochemistry (+ calretinin, cytokeratins,
mesothelin; - CEA)
Diffuse Malignant Peritoneal Mesothelioma
Treatment Approach


Systemic Therapy

Chemotherapy: Pemetrexed with cisplatin or gemcitabine
(modest clinical responses)



Regional Therapy
Diffuse Malignant Peritoneal Mesothelioma




           CT scan images of mesothelioma
Diffuse Malignant Peritoneal Mesothelioma
CT characteristics of MPM
            Regional Approach               Systemic Approach




                                             Feldman et al. JCO 2003; 21: 4560-67.
                                            Courtesy of Dr. H. Rich Alexander
Diffuse Malignant Peritoneal Mesothelioma
Regional Therapy



        Cytoreductive Surgery (Removing gross tumor)

        HIPEC (Hyperthermic intraperitoneal chemotherapy)
Diffuse Malignant Peritoneal Mesothelioma
Peritoneal Cancer Index Score (PCI)




     Total possible score: 39


                                Harmon et al. Int Sem in Surgical Oncology 2005; 2:1-10.
Diffuse Malignant Peritoneal Mesothelioma
Surgical Approach: Cytoreductive Surgery

•Peritonectomy
•Tumor nodule removal
•Organ resection (small or large
bowel, spleen, omentum)
                                            CC: Completeness of cytoreduction
                                            0 No visible evidence of disease
                                            1 Residual tumors <2.5 mm
                                            2 Residual tumors 2.5mm-2.5 cm
                                            3 Residual tumors > 2.5 cm or
                                            confluent nodules
Diffuse Malignant Peritoneal Mesothelioma
HIPEC: how it works




                                    40-420C

            Chemotherapy
            Mitomycin
            Cisplatin




                                        Adapted from Website operated by HipecTreatment.com LLC
Diffuse Malignant Peritoneal Mesothelioma
Rationale for HIPEC
      •Allows for use of high dose chemotherapy
      regionally which may give more benefit than
      systemic chemotherapy

      •Can treat all serosal surfaces more effectively and
      at a time when the disease burden is the lowest

      •Hyperthermia can have direct lethal effects on the
      tumor

      •Hyperthermia can potentiate the chemotherapy
Diffuse Malignant Peritoneal Mesothelioma
Rationale for HIPEC: Hyperthermia

                       Tumor microvasculature




                        Tumor microenvironment

                        O2                     pH

                           Fukumara, Jain et al. Microcirculation 2010; 17: 206-225.
Diffuse Malignant Peritoneal Mesothelioma
Phase II trials of CRS and HIPEC for DMPM




                              Sugarbaker et al. Ann of Surg Onc 2010; 17: 1710-12.
Diffuse Malignant Peritoneal Mesothelioma
CRS and HIPEC for DMPM: NCI Experience


•   N=49 patients
•   51% had prior surgery
•   71% went an additional
    treatment with intraperitoneal
    chemo 7-10 days post –surgery
    with 5-FU and paclitaxel




                                            Feldman et al. JCO 2003; 21: 4560-67.
Diffuse Malignant Peritoneal Mesothelioma




           CT scan images of mesothelioma
Diffuse Malignant Peritoneal Mesothelioma
CRS and HIPEC for DMPM: NCI Experience




                                            Feldman et al. JCO 2003; 21: 4560-67.
Diffuse Malignant Peritoneal Mesothelioma
CRS and HIPEC for DMPM: Multi-Institutional Experience




 •   N=405 patients
 •   Multi-Institutional




                                            Yan et al. JCO 2009; 27: 6237-6242.
Diffuse Malignant Peritoneal Mesothelioma
Prognostic Factors after CRS and HIPEC (Univariate)


 Clinicopathologic variables:

       Age ≤ 50 Years
       Female Gender
       Epithelial histologic subtype
       Absent Lymph node metastases
       Absent extra-abdominal metastases
       Peritoneal Cancer Index ≤ 20
       Completeness of cytoreduction score (lower)



                                            Yan et al. JCO 2009; 27: 6237-6242.
Diffuse Malignant Peritoneal Mesothelioma
Prognostic Factors after CRS and HIPEC (Multivariate)




 • Epithelial histologic subtype
 • Absence of lymph node
   metastases
 • CC-0 CC-1 (Completeness of
   cytoreduction)
 • HIPEC therapy




                                            Yan et al. JCO 2009; 27: 6237-6242.
Diffuse Malignant Peritoneal Mesothelioma
Surgery


     • Can be lengthy
     • Hospital stays can be long
     • Can be done safely
Diffuse Malignant Peritoneal Mesothelioma
 Unraveling the genetics




                                            Varghese, Alexander et al. Cancer 2010.
Diffuse Malignant Peritoneal Mesothelioma
 Unraveling the genetics: towards new therapies




                 *BEZ235 is a dual-class PI3K and mTOR inhibitor


                                            Varghese, Alexander et al. Cancer 2010.
Diffuse Malignant Peritoneal Mesothelioma
 Other novel therapies


 HN1




                                            Ho, Pastan et al. Int J Cancer 2010.
Diffuse Malignant Peritoneal Mesothelioma
 Summary
     • DMPM is relatively uncommon compared to pleural
     mesothelioma; symptoms generally correspond to
     regional progression

     • Regional therapy combining cytoreductive surgery
     and HIPEC has been associated with long term
     survival in selected patients

     • Disease burden, histologic subtypes, presence of
     lymph node metastases, and therapy approach are
     prognostic factors

     • New research is revealing genetic markers that can
     serve as prognostic factors and help to direct novel
     and targeted therapies

								
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