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Mesothelioma:Mesothelioma:Basics and BeyondBasics and Beyond

Sue Gardner, MSN, AOCNPSue Gardner, MSN, AOCNPOncology Nurse PractitionerOncology Nurse PractitionerLehigh Valley Hospital and Health NetworkLehigh Valley Hospital and Health NetworkAllentown, PAAllentown, PA

Marianne Davies, MSN, APRNMarianne Davies, MSN, APRNDirector of Nursing Director of Nursing Medical Oncology and Clinical ResearchMedical Oncology and Clinical ResearchYale Cancer CenterYale Cancer Center

Acknowledgements:Acknowledgements:

Lloyd E. Barron II, MDLloyd E. Barron II, MDDennis Cornfield, MDDennis Cornfield, MDEliot L. Friedman, MDEliot L. Friedman, MDLehigh Valley Hospital and Health Lehigh Valley Hospital and Health NetworkNetworkONS Thoracic Focus GroupONS Thoracic Focus Group

IntroductionIntroduction

Mesothelioma: an insidious, aggressive Mesothelioma: an insidious, aggressive tumor arising from mesothelial tumor arising from mesothelial surfaces (tissues that line body surfaces (tissues that line body cavities).cavities).

Pleural cavity (Approx. 85% of cases)Pleural cavity (Approx. 85% of cases)Peritoneal cavity (Approx. 5Peritoneal cavity (Approx. 5--10%)10%)Tunica vaginalisTunica vaginalisPericardiumPericardium

EpidemiologyEpidemiology

Incidence of mesothelioma in the U.S. Incidence of mesothelioma in the U.S. is approximately 2000is approximately 2000--3000 cases/yr. 3000 cases/yr. 80% of pts. with pleural mesothelioma 80% of pts. with pleural mesothelioma are male.are male.Worldwide incidence increasing. Worldwide incidence increasing. Third world incidence increasing Third world incidence increasing dramatically.dramatically.U.S. may have increase in cases due U.S. may have increase in cases due to effects of 9/11.to effects of 9/11.

Risk Factors for Risk Factors for MesotheliomaMesothelioma

Occupational exposure to asbestosOccupational exposure to asbestosPrimary: mining of asbestosPrimary: mining of asbestosSecondary: carpentry, brake linings, Secondary: carpentry, brake linings,

boilers, plumbers, defense industry.boilers, plumbers, defense industry.

Indirect exposure : contamination in Indirect exposure : contamination in homes, industrial pollutionhomes, industrial pollution

SecondSecond--hand exposure: clothing of hand exposure: clothing of workers workers

How asbestos affects the pleuraHow asbestos affects the pleura

Fibers irritate the pleura by Fibers irritate the pleura by penetrating tissue and causing penetrating tissue and causing scarring.scarring.Fibers cause breakage of mitotic Fibers cause breakage of mitotic spindles, disrupting mitosis, and spindles, disrupting mitosis, and causing chromosomal damage.causing chromosomal damage.Induces DNA damageInduces DNA damagePhosphorylationPhosphorylation of MAP of MAP kinaseskinases

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Asbestos: Asbestos: (Greek root: “indestructible”)(Greek root: “indestructible”)

70% of pleural mesothelioma is 70% of pleural mesothelioma is associated with asbestos exposure.associated with asbestos exposure.Asbestos is commercial name for a Asbestos is commercial name for a group of hydrated magnesium silicate group of hydrated magnesium silicate fibrous materials.fibrous materials.Asbestos is resistant to heat and Asbestos is resistant to heat and combustion.combustion.Asbestos is used in cement, ceiling Asbestos is used in cement, ceiling and pool tiles, brake linings, and pool tiles, brake linings, shipbuilding.shipbuilding.

Asbestos riskAsbestos risk

Lifetime risk of asbestos workers developing Lifetime risk of asbestos workers developing mesothelioma 8mesothelioma 8--13%.13%.Synergism with cigarette smoking; risk of Synergism with cigarette smoking; risk of developing lung cancer 60 times higherdeveloping lung cancer 60 times higherthan nonthan non--smoker, nonsmoker, non--asbestos exposure.asbestos exposure.Asbestos workers have a higher rate of nonAsbestos workers have a higher rate of non--mesothelioma GI malignancies.mesothelioma GI malignancies.SecondSecond--hand exposure affects family hand exposure affects family members.members.

Other causesOther causes

High levels of High levels of tremolitetremolite asbestos fibers in asbestos fibers in soil (Greece, Turkey, Bulgaria).soil (Greece, Turkey, Bulgaria).Viral oncogenes: Simian virusViral oncogenes: Simian virus--40 (SV40 (SV--40)40)has has oncogeniconcogenic potential in humans. Its potential in humans. Its action results from inactivation of tumor action results from inactivation of tumor suppressor genes.suppressor genes.Rare cases of therapeutic radiation.Rare cases of therapeutic radiation.Inhalation of other fibrous silicates.Inhalation of other fibrous silicates.Interleukin VIII has growth Interleukin VIII has growth potentiatingpotentiatingactivity in mesothelioma cell lines.activity in mesothelioma cell lines.

Mortality/MorbidityMortality/Morbidity

Age: Peak incidence 35Age: Peak incidence 35--45 years after 45 years after asbestos exposure. Commonly develops asbestos exposure. Commonly develops between 5between 5thth and 7and 7thth decade of life. decade of life. Race: not a factor in mesothelioma Race: not a factor in mesothelioma development.development.Sex: More common in men Sex: More common in men –– 3:1 3:1 male/female ratio. Can occur in children, male/female ratio. Can occur in children, but not related to asbestos exposure.but not related to asbestos exposure.Median survival is 11 months.Median survival is 11 months.

Tumor developmentTumor development

Pleural mesothelioma begins as Pleural mesothelioma begins as plaques or nodules of malignant tissue plaques or nodules of malignant tissue that coalesce to form sheets of tumor.that coalesce to form sheets of tumor.Tumor usually begins growth in the Tumor usually begins growth in the lower chest and spreads upwards. lower chest and spreads upwards. May invade diaphragm, and encase May invade diaphragm, and encase the surface of lung tissue with a rind the surface of lung tissue with a rind of tumor that can be as thick as 5 cm.of tumor that can be as thick as 5 cm.

Tumor spreadTumor spread

Tumor can grow along drainage or Tumor can grow along drainage or thoracotomythoracotomy tracts.tracts.Pleural tumor can invade the lung Pleural tumor can invade the lung parenchyma, chest wall, parenchyma, chest wall, mediastinummediastinum, , esophagus, ribs, vertebra, brachial esophagus, ribs, vertebra, brachial plexus, and superior vena cava. plexus, and superior vena cava. Metastases can occur to liver, bone Metastases can occur to liver, bone and adrenal glands.and adrenal glands.

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Initial signs/symptoms ofInitial signs/symptoms ofpleural mesothelioma:pleural mesothelioma:

DyspneaDyspneaPleuriticPleuritic chest painchest painFeverFeverSweatsSweatsFatigueFatigueWeight lossWeight lossPleural effusionPleural effusion

Peritoneal mesothelioma Peritoneal mesothelioma symptomssymptoms

Weight lossWeight lossAbdominal painAbdominal painBloating ( Bloating ( ascitesascites))Bowel obstructionBowel obstructionBlood clotting abnormalitiesBlood clotting abnormalitiesFeverFeverAnemia Anemia

DiagnosisDiagnosis

Medical history, including work history, Medical history, including work history, exposure to asbestos.exposure to asbestos.Complete physical examinationComplete physical examinationChest Chest xrayxrayCT scan of chest/abdomenCT scan of chest/abdomenMRIMRIPET scanPET scanBiopsyBiopsy

Radiographic findingsRadiographic findings

Usually unilateral pleural abnormality, with Usually unilateral pleural abnormality, with unilateral pleural effusionunilateral pleural effusion60% of patients present with right60% of patients present with right--sided sided disease. 5% have bilateral disease.disease. 5% have bilateral disease.Mesothelioma can present as a lung mass, Mesothelioma can present as a lung mass, or with diffuse pleural thickening that can or with diffuse pleural thickening that can cause cause mediastinalmediastinal shift.shift.Usually significant unilateral loss of lung Usually significant unilateral loss of lung volume.volume.

Copyright UpToDate 2005 ( permission to use for medical education only).

CT scan / MRI of chestCT scan / MRI of chest

CT scan helpful in determining CT scan helpful in determining whether there is tumor invasion into whether there is tumor invasion into the chest wall, the chest wall, mediastinummediastinum, or ribs., or ribs.

MRI better at determining whether MRI better at determining whether there is tumor extension into the there is tumor extension into the diaphragm, or through the diaphragm diaphragm, or through the diaphragm into the peritoneal cavity. MRI is the into the peritoneal cavity. MRI is the more sensitive test if the tumor is more sensitive test if the tumor is thought to be thought to be resectableresectable..

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Figure 1a. Pleural effusion in a 70-year-old man with a history of asbestos exposure and known left-sided MPM. Axial contrast material-enhanced CT scans obtained at different levels show unilateral pleural effusion (P) with extensive calcified pleural plaques (arrows).

Used with permission of Gautham Reddy, UCSF, and Radiological Society of North America

PET scanPET scan

PET appears more sensitive than CT PET appears more sensitive than CT scan for finding scan for finding extrathoracicextrathoracic disease.disease.Studies showed PET to be better at Studies showed PET to be better at differentiating between benign and differentiating between benign and malignant lung disease.malignant lung disease.PET not as accurate in detecting PET not as accurate in detecting malignant nodal disease.malignant nodal disease.

Figure 17a. Preoperative PET evaluation in a 78-year-old man with biopsy-proved MPM. (a) Axial contrast-enhanced CT scan shows circumferential nodular left-sided pleural thickening (arrows). (b, c) Axial (b) and coronal (c) PET scans show diffusely increased FDG uptake in the pleura of the left hemithorax (arrows), a finding that correlates well with the CT finding.

Used with permission of Gautham Reddy, MD, UCSF, and Radiologic Society of North America.

Differential diagnosisDifferential diagnosis(benign and malignant)(benign and malignant)

Inflammatory process; i.e. Inflammatory process; i.e. empyemaempyemaMetastatic Metastatic adenocarcinomaadenocarcinoma of the of the pleurapleuraSarcoma (Sarcoma (fibrosarcomafibrosarcoma and malignant and malignant fibrous fibrous histiocytomahistiocytoma) can present like ) can present like sarcomatoussarcomatous mesotheliomasmesotheliomas..Mixed cellular mesothelioma can have Mixed cellular mesothelioma can have appearance of appearance of synovialsynovial sarcoma.sarcoma.

Biopsy Biopsy -- continuedcontinued

Approximately 10% of patients who Approximately 10% of patients who have an invasive diagnostic procedure have an invasive diagnostic procedure will seed tumor cells along the biopsy will seed tumor cells along the biopsy site.site.

Risk of recurrence from seeding can Risk of recurrence from seeding can be reduced by giving prophylactic be reduced by giving prophylactic radiation to the radiation to the thoracentesisthoracentesis, chest , chest tube, or biopsy site.tube, or biopsy site.

3 Major 3 Major HistologicHistologic TypesTypes

Epithelial Epithelial –– most common, comprising most common, comprising 5050--60% of all 60% of all mesotheliomasmesotheliomas..SarcomatoidSarcomatoid –– composed of malignant composed of malignant spindle cells that mimic tumors such spindle cells that mimic tumors such as as fibrosarcomafibrosarcoma or or leiomyosarcomaleiomyosarcoma..Mixed ( or biphasic) Mixed ( or biphasic) –– have both have both epithelioidepithelioid and and sarcomatoidsarcomatoid features.features.

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PathologyPathology

Gross examination shows firm grey tumor Gross examination shows firm grey tumor that melds the visceral and parietal surfaces that melds the visceral and parietal surfaces into plaques. into plaques. The lung can be encased with thick bands of The lung can be encased with thick bands of tumor several centimeters thick, despite tumor several centimeters thick, despite minimal infiltration into the lung minimal infiltration into the lung parenchyma.parenchyma.Invasion of chest wall, diaphragm, Invasion of chest wall, diaphragm, pericardium and pericardium and mediastinalmediastinal lymph nodes lymph nodes can occur early.can occur early.

Pleural biopsy : at low magnification, there is infiltration of soft tissue by small

aggregates and islands of cells (A) that have a paler appearance than nearby

reactive lymphocytes (B).

Slide used with permission of Dennis Cornfield, MD, Health Network Lab, Allentown, PA

A

B

Higher magnification shows uniform, cuboidal mesothelioma cells present in glandular and papillary structures.

Slide used with permission of Dennis Cornfield, MD, Health Network Lab, Allentown, PA

Poor prognostic variablesPoor prognostic variables

SarcomatousSarcomatous histologyhistologyPleural ( as opposed to peritoneal) Pleural ( as opposed to peritoneal) primaryprimaryOlder ageOlder agePain at diagnosisPain at diagnosisMale genderMale genderPoor performance statusPoor performance statusHigh LDH, WBCs, platelet levelsHigh LDH, WBCs, platelet levels

ImmunohistochemistryImmunohistochemistry

IHC helps differentiate between IHC helps differentiate between epithelioidepithelioidmesothelioma, primary lung cancer, mesothelioma, primary lung cancer, metastatic metastatic adenocarcinomaadenocarcinoma..Panels of positive / negative markers help Panels of positive / negative markers help rule specific malignancies in or out. rule specific malignancies in or out. New monoclonal antibodyNew monoclonal antibody--based serum based serum assay for assay for mesothelinmesothelin, a 40 , a 40 kDakDa glycoprotein glycoprotein found on the surface of mesothelioma and found on the surface of mesothelioma and ovarian cancer cells, but not normal tissue.ovarian cancer cells, but not normal tissue.

Immunohistochemicalstain for calretinin is positive in tumor nuclei and cytoplasm.

The majority ofmesotheliomas are +for calretinin. Mostadenocarcinomas arenegative. This stainis performed to try todifferentiate betweenmesotheliomas and adenocarcinomas.

Slide used with permission of Dennis Cornfield, MD, Health Network Lab, Allentown, PA

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Mesothelioma cells show positivity for AE1/AE3,an antibody combination that reacts with benign or neoplastic cells of epithelial origin.

Slide used with permission of Dennis Cornfield, MD, Health Network Lab, Allentown, PA

Biomarkers that may preBiomarkers that may pre--date symptomsdate symptomsin a highin a high--risk population:risk population:

Tissue polypeptide antigenTissue polypeptide antigenCarcinoembryonicCarcinoembryonic antigen ( CEA)antigen ( CEA)HyaluronicHyaluronic acid and acid and ferritinferritinHyaluronicHyaluronic acid aloneacid aloneCytokeratinCytokeratin--19 fragment19 fragmentCACA--125125Soluble Soluble mesothelinmesothelin--related proteinrelated protein

Promising Biomarker: Promising Biomarker: OsteopontinOsteopontin

Glycoprotein that is Glycoprotein that is overexpressedoverexpressed in in lung, breast, colorectal, gastric, lung, breast, colorectal, gastric, ovarian cancer and melanoma.ovarian cancer and melanoma.OsteopontinOsteopontin mediates cellmediates cell--signaling signaling pathways that are associated with pathways that are associated with asbestosasbestos--induced carcinogenesis.induced carcinogenesis.OsteopontinOsteopontin may be a marker for may be a marker for transformed transformed mesothelielmesotheliel cells.cells.

Serum markersSerum markers

SMRP SMRP –– serum serum mesothelinmesothelin--related related protein elevated in 84% mesothelioma protein elevated in 84% mesothelioma patients, and in less than 2% with patients, and in less than 2% with other pleural diseases.other pleural diseases.Serum markers are best used in Serum markers are best used in combination with combination with cytopathologycytopathology and and histopathology.histopathology.

Six features common to cancer Six features common to cancer cells: (all present in malignant cells: (all present in malignant mesothelioma)mesothelioma)

1. Growth advantage – cells respond to epidermal growth factors and platelet-derived growth factors

2. Action of telomerase – allows continued cell division

3. Absence of tumor suppressor genes4. Induction of anti-apoptotic processes5. Increased angiogenesis ( vegf ) 6. Matrix interactions

StagingStaging

ButchartButchart SystemSystem–– based on tumor based on tumor locationlocationTumor confined, invading, Tumor confined, invading, penetrating, penetrating, metastatismetastatisDoes not detail lymph node Does not detail lymph node involvement or level of chest wall involvement or level of chest wall infiltration of tumorinfiltration of tumor

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StagingStaging

International Mesothelioma Interest Group: International Mesothelioma Interest Group: modified TNM system used to predict modified TNM system used to predict prognosisprognosis2002 TNM system adopted by American 2002 TNM system adopted by American Joint Committee on Cancer (AJCC) and Joint Committee on Cancer (AJCC) and IUCC.IUCC.Brigham staging system: based on Brigham staging system: based on resectabilityresectability of tumor and nodal involvementof tumor and nodal involvement

Oncology Nursing Society Institutes of LearningOncology Nursing Society Institutes of Learning

MesotheliomaMesothelioma

Treatment OptionsTreatment OptionsPast, Present, FuturePast, Present, Future

Marianne Davies RN, MSN, APRNMarianne Davies RN, MSN, APRNDirector of Nursing Director of Nursing Medical Oncology & Clinical ResearchMedical Oncology & Clinical ResearchYale Cancer CenterYale Cancer Center

November 2005November 2005

Management StrategiesManagement Strategies

SurgicalSurgicalRadiation TherapyRadiation TherapyChemotherapyChemotherapy-- systemic or systemic or intracavitaryintracavitaryPhotodynamic TherapyPhotodynamic TherapyMultimodality TherapyMultimodality TherapyClinical TrialsClinical Trials

Surgical ManagementSurgical Management

Thoracoscopic pleurodesisThoracoscopic pleurodesis

PleurectomyPleurectomy

Extrapleural pneumonectomyExtrapleural pneumonectomy

Presurgical EvaluationPresurgical Evaluation

Pulmonary evaluationPulmonary evaluation–– Complete history of exposuresComplete history of exposures–– Pulmonary function testsPulmonary function tests

Cardiac evaluationCardiac evaluation–– EKGEKG–– MUGAMUGA

Renal evaluation (for post op Renal evaluation (for post op chemotherapy)chemotherapy)

PleurectomyPleurectomy

Resection of the visceral and parietal Resection of the visceral and parietal pleura. Pericardial and diaphragmatic pleura. Pericardial and diaphragmatic resection and lung nodule resection.resection and lung nodule resection.Complications: bronchopleural fistula, Complications: bronchopleural fistula, prolonged air leak, hemorrhage, prolonged air leak, hemorrhage, pneumonia, subcutaneous pneumonia, subcutaneous emphysema, incomplete resection, emphysema, incomplete resection, empyema & vocal cord paralysisempyema & vocal cord paralysis2% mortality2% mortality

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Extra pleural Extra pleural PneumonectomyPneumonectomy

Resection of the parietal and visceral Resection of the parietal and visceral pleural, contained lung, pericardium and pleural, contained lung, pericardium and ipsilateral diaphragm.ipsilateral diaphragm.Diaphragm and pericardium reconstructedDiaphragm and pericardium reconstructedComplications: supraventricular Complications: supraventricular arrhythmias, respiratory failure, empyema, arrhythmias, respiratory failure, empyema, bronchopleural fistula, vocal cord paralysis, bronchopleural fistula, vocal cord paralysis, myocardial infarction & CHF.myocardial infarction & CHF.High mortality rateHigh mortality rate

Post Surgical CarePost Surgical Care

Monitoring fluid balanceMonitoring fluid balanceMonitoring for arrhythmiasMonitoring for arrhythmiasOxygen supplementationOxygen supplementationPain ManagementPain ManagementAggressive pulmonary careAggressive pulmonary careDVT prophylaxisDVT prophylaxis

Surgical TrialsSurgical Trials

Mesothelioma and Radical Surgery Mesothelioma and Radical Surgery (MARS)(MARS)–– Randomized controlled trial evaluating Randomized controlled trial evaluating

role of role of extrapleuralextrapleural pneumonectorypneumonectory (EPP), (EPP), as part of as part of trimodalitytrimodality treatment)treatment)

–– 670 patients670 patients–– EndEnd--points: points: periperi--operative mortality, operative mortality,

effect on QOLeffect on QOL

Chang (2004) Thoracic Surgery Clinics 14 (4)Chang (2004) Thoracic Surgery Clinics 14 (4)

Intracavitary Intracavitary ChemotherapyChemotherapy

Chest tube administrationChest tube administration–– Liposomal cisplatinLiposomal cisplatin–– MitomycinMitomycin

IntraIntra--operative chemotherapyoperative chemotherapy–– After aggressive tumor resection a lavage After aggressive tumor resection a lavage

with chemotherapeutic drugs under with chemotherapeutic drugs under hyperthermic conditions performed in hyperthermic conditions performed in order to kill remaining microscopic cell.order to kill remaining microscopic cell.

Baldini (2004), Thoracic Surgery Clinics 14 (4): Baldini (2004), Thoracic Surgery Clinics 14 (4): 543543--88

Radiation TherapyRadiation Therapy

Palliative Palliative –– Pain relief in 50Pain relief in 50--70% of patients70% of patients

Following Following extrapleuralextrapleuralpneumonectomypneumonectomyLimited use with unLimited use with un--resectableresectable diseasedisease–– No survival benefitNo survival benefit–– No improvement in side effect No improvement in side effect

Radiation TherapyRadiation Therapy

Limited role as malignant Limited role as malignant mesothelioma is overall radioresistantmesothelioma is overall radioresistantDose limiting thoracic structures Dose limiting thoracic structures (heart, esophagus, liver, lung)(heart, esophagus, liver, lung)Trials exploring use of pemetrexed as Trials exploring use of pemetrexed as radiosensitizerradiosensitizer

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Conventional Conventional ChemotherapyChemotherapy

Cisplatin, mitomycin, cyclophosphamide and Cisplatin, mitomycin, cyclophosphamide and ifosfamide: responses of 10ifosfamide: responses of 10--20%20%Doxorubicin: responses of 0Doxorubicin: responses of 0--40%40%Methotrexate: 35Methotrexate: 35--45%45%Doxil: 27%Doxil: 27%PaclitaxelPaclitaxelGemcitabine: responses 31%Gemcitabine: responses 31%MitoxantroneMitoxantroneEdatrexate: response 27%Edatrexate: response 27%

Combination Combination ChemotherapyChemotherapy

CisplatinCisplatin–– Cisplatin, mitomycin C, vinblastineCisplatin, mitomycin C, vinblastine–– Cisplatin & gemcitabineCisplatin & gemcitabine

CarboplatinCarboplatinIfosfamideIfosfamide & Interferon alpha2A& Interferon alpha2AVinorelbine and oxaliplatinVinorelbine and oxaliplatin

Andreopoulou et al (2004) Annals of Oncology Andreopoulou et al (2004) Annals of Oncology 15 (9)15 (9)

MitomycinMitomycin C, C, vinblastinevinblastineand and CisplatinCisplatin

MVPMVP–– MitomycinMitomycin C 8 mg/mC 8 mg/m22 q 6 wksq 6 wks–– VinblastineVinblastine 6 mg/m6 mg/m22 q 3 wksq 3 wks–– CisplatinCisplatin 50 mg/m50 mg/m22 q 3 wksq 3 wks

150 patients (43% PS 150 patients (43% PS >> 2)2)Response rateResponse rate-- 15.3%15.3%Median survival 7 mMedian survival 7 m–– 10 m with PS 0/110 m with PS 0/1–– 6 m with PS 2/36 m with PS 2/3

69% improvement in symptoms69% improvement in symptoms

Favaretto et al (2003) Cancer 97 (11)Favaretto et al (2003) Cancer 97 (11)

GemcitabineGemcitabine & Carboplatin& Carboplatin

Phase II Phase II MulticenterMulticenter study in Italystudy in Italy50 patients50 patientsCarboplatin AUC 5 & Carboplatin AUC 5 & GemcitabineGemcitabine1000mg/m1000mg/m22 day 1,8,15day 1,8,15Partial response: 26%Partial response: 26%Median response duration: 55 weeksMedian response duration: 55 weeksMedian survival: 66 weeksMedian survival: 66 weeksClinical benefitClinical benefit

Altinbas (2004), Medical Oncology 21 (4)Altinbas (2004), Medical Oncology 21 (4)

IfosfamideIfosfamide & interferon& interferon--alpha2Aalpha2A

42 patients (39 42 patients (39 evaluableevaluable))ScheduleSchedule–– IfosfamideIfosfamide 3000mg/m3000mg/m22 11--3d (+3d (+mesnamesna))–– Interferon alpha2A 4.5 MU sc 3d/wkInterferon alpha2A 4.5 MU sc 3d/wkResponsesResponses–– 21% PR, 33% SD, 48% PD21% PR, 33% SD, 48% PDSurvivalSurvival–– 10 m overall, 21 m for PR’s10 m overall, 21 m for PR’s

Fennell et al (2005) Lung Cancer 47 (2)Fennell et al (2005) Lung Cancer 47 (2)

VinorelbineVinorelbine & Oxaliplatin& Oxaliplatin

Phase II trial as first line therapyPhase II trial as first line therapyVinerelbineVinerelbine 30 mg/m30 mg/m22 day 1, 8 and day 1, 8 and Oxaliplatin 130 mg/mOxaliplatin 130 mg/m22 q 21 daysq 21 daysResponse rate 23%Response rate 23%Progression free survival 4.7 mProgression free survival 4.7 mOne year survival 27%One year survival 27%Significant grade 3Significant grade 3--4 toxicity4 toxicity

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New AdvancesNew Advances

–– PemetrexedPemetrexedPemetrexed: Novel Multitargeted antifolatePemetrexed: Novel Multitargeted antifolateImproves survival, reduces diseaseImproves survival, reduces disease--related related symptoms, and produces objective responsessymptoms, and produces objective responsesActivity dependent on cellular folate levelsActivity dependent on cellular folate levelsResponse rate 14%Response rate 14%

ChemotherapyChemotherapy

Pemetrexed (AlimtaPemetrexed (Alimta®®))–– Dosing: 500 mg/mDosing: 500 mg/m22 IV over 10 min, IV over 10 min,

q3wksq3wks–– Folic Acid:350Folic Acid:350--1000mg mcg po, 2 weeks 1000mg mcg po, 2 weeks

before then dailybefore then daily–– BB1212: 1,000 mcg IM 2 weeks before & : 1,000 mcg IM 2 weeks before &

q9wksq9wks–– Dexamethasone 4 mg twice daily before, Dexamethasone 4 mg twice daily before,

day of and day after therapyday of and day after therapy

Pemetrexed MonitoringPemetrexed Monitoring

Predose homocystine and methylmalonic Predose homocystine and methylmalonic acid levelsacid levelsCBC, platelets, renal and hepatic function CBC, platelets, renal and hepatic function prior to each cycleprior to each cycleCreatinine Clearance >45 ml/minCreatinine Clearance >45 ml/minDose reductions if nadirDose reductions if nadir–– ANC <500/mmANC <500/mm33 and Platelets >50,000/mmand Platelets >50,000/mm33

dose at 75%dose at 75%–– Platelets <50,000/mmPlatelets <50,000/mm3 3 dose at 50%dose at 50%

Pemetrexed ToxicityPemetrexed Toxicity

–– Side effectsSide effectsNeutropenia (grade 3 & 4)Neutropenia (grade 3 & 4)InfectionInfectionDiarrheaDiarrheaMucositisMucositisSkin rashSkin rashFatigueFatigue

ChemotherapyChemotherapy

Combination therapy: additive or Combination therapy: additive or synergistic effectssynergistic effects–– Pemetrexed 500 mg/mPemetrexed 500 mg/m22 & cisplatin 75 & cisplatin 75

mg/mmg/m22

–– Pemetrexed & carboplatin AUC 5 Pemetrexed & carboplatin AUC 5 –– Pemetrexed & gemcitabinePemetrexed & gemcitabine–– Improved response rates to 45%Improved response rates to 45%

Vogelzang et al (2003) J Clin Oncology 21Vogelzang et al (2003) J Clin Oncology 21

PemetrexedPemetrexed TrialsTrials

Phase III study of Phase III study of pemetrexedpemetrexed in in combination with combination with cisplatincisplatin versus versus cisplatincisplatin alone in patients with MPMalone in patients with MPM456 patients PS 0/1456 patients PS 0/1Median survival 9.3 m Median survival 9.3 m ↑↑to 12.1 mto 12.1 mResponse rateResponse rate–– 17% 17% cisplatincisplatin–– 41% 41% pemetrexedpemetrexed and and cisplatincisplatin

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Vogelzang et al (2000), Proc Am Soc Clin OncolVogelzang et al (2000), Proc Am Soc Clin Oncol

PemetrexedPemetrexed TrialsTrials

RanpirnaseRanpirnase ((OnconaseOnconase) plus ) plus doxorubicin versus doxorubicin alone doxorubicin versus doxorubicin alone in patients with MPMin patients with MPM–– Doxorubicin 60 mg/mDoxorubicin 60 mg/m22 q 21 dq 21 d–– Doxorubicin 60 mg/mDoxorubicin 60 mg/m22 day 1 plus day 1 plus

onconaseonconase 240 240 µµg/mg/m22 day 1, 8, 15 with a day 1, 8, 15 with a possible dose escalation up to 480 possible dose escalation up to 480 µµg/mg/m22

Additional TherapyAdditional Therapy

ImmunotherapyImmunotherapyPhotodynamic therapyPhotodynamic therapyPleural PerfusionPleural PerfusionImmunomodulatory gene therapyImmunomodulatory gene therapyTargeted TherapyTargeted Therapy

Photodynamic TherapyPhotodynamic Therapy

Targeted for superficially growing Targeted for superficially growing tumors on surfaces and cavities, tumors on surfaces and cavities, sparing surrounding tissuesparing surrounding tissueIntraoperative PDTIntraoperative PDT–– IV sensitizing agent is administered IV sensitizing agent is administered

preoperatively and after local resection, a preoperatively and after local resection, a light source is placed in the surgical light source is placed in the surgical cavitycavity

–– Success dependent on drug dose, total Success dependent on drug dose, total light and oxygen to allow reactionlight and oxygen to allow reaction

ImmunotherapyImmunotherapy

InterferonInterferon--alpha in combination with alpha in combination with ifosfamide/mesna: 4ifosfamide/mesna: 4--30% response30% responseInterferonInterferon--beta: 10beta: 10--40%40%ILIL--2: 52: 5--40%40%

Targeted TherapyTargeted Therapy

Angiogenesis inhibitionAngiogenesis inhibition–– Ranpirnase (Onconase)Ranpirnase (Onconase)–– VEGF inhibitors: SU5416, bevacizumab VEGF inhibitors: SU5416, bevacizumab

and thalidomideand thalidomide–– IressaIressa-- inhibitor of EGFR tyrosine kinaseinhibitor of EGFR tyrosine kinase–– GleevecGleevec-- PDGF inhibitorsPDGF inhibitors–– GefitinibGefitinib

GefitinibGefitinib

Phase II trial in previously untreated Phase II trial in previously untreated patients with pleural or peritoneal patients with pleural or peritoneal mesotheliomamesotheliomaGefitinibGefitinib: inhibitor of the epidermal growth : inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinasefactor receptor (EGFR) tyrosine kinaseDose: 500 mg Dose: 500 mg popo daily q 21 daysdaily q 21 days43 patients enrolled43 patients enrolled49% stable disease lasting 249% stable disease lasting 2--8 cycles8 cycles

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Favaretto (2005) Lung Cancer 49 S1, S117Favaretto (2005) Lung Cancer 49 S1, S117--121121

Clinical TrialsClinical Trials

Phase III: Phase III: hemithoracichemithoracic radiotherapy radiotherapy after primary treatment with after primary treatment with cisplatincisplatin//pemetrexedpemetrexed followed by followed by surgerysurgeryPhase II: Phase II: neoadjuvantneoadjuvant chemotherapy chemotherapy with with cisplatincisplatin or carboplatin/ or carboplatin/ pemetrexedpemetrexed followed by radiotherapy followed by radiotherapy and surgery.and surgery.

Muers et all (2004) Thorax 59Muers et all (2004) Thorax 59

Clinical TrialsClinical Trials

Phase III Randomized controlled trial Phase III Randomized controlled trial comparing active symptom control (ASC) comparing active symptom control (ASC) with or without chemotherapy (MSwith or without chemotherapy (MS--01)01)Anticipated Anticipated accruralaccrural: 840: 840Three armsThree arms–– ASCASC–– ASC plus MVP ( ASC plus MVP ( mitomito, , vinblastinevinblastine, , cisplatincisplatin))–– ASC plus ASC plus vinorelbinevinorelbine

Combined Modality TherapyCombined Modality Therapy

Factors affecting limited success of Factors affecting limited success of chemotherapy, chemotherapy, extrapleuralextrapleuralpneumonectomypneumonectomy and and hemithoracichemithoracicradiotherapyradiotherapy–– Metastatic disease at presentationMetastatic disease at presentation–– UnresectableUnresectable disease disease –– Limited evaluation of patients with limited Limited evaluation of patients with limited

stage diseasestage disease

Peritoneal MesotheliomaPeritoneal Mesothelioma

Surgical DebulkingSurgical Debulking–– Greater & lesser omentectomyGreater & lesser omentectomy–– Right & left subphrenic peritonectomyRight & left subphrenic peritonectomy–– Complete pelvic peritonectomyComplete pelvic peritonectomy–– Visceral resections: colectomy, ileectomyVisceral resections: colectomy, ileectomy

Peritoneal MesotheliomaPeritoneal Mesothelioma

Intraoperative intraperitoneal Intraoperative intraperitoneal chemotherapychemotherapy–– Cisplatin 50 mg/m2 and Doxorubicin 15 Cisplatin 50 mg/m2 and Doxorubicin 15

mg/m2.mg/m2.–– Heated to 41Heated to 41°°CC–– Infused over 90 minutes while additional Infused over 90 minutes while additional

surgical debridement is donesurgical debridement is done

Peritoneal MesotheliomaPeritoneal Mesothelioma

PostPost--operative intraperitoneal operative intraperitoneal chemotherapychemotherapy–– Paclitaxel (20 mg/m2/d x 5)Paclitaxel (20 mg/m2/d x 5)–– May be infused via intraperitoneal portMay be infused via intraperitoneal port–– Monthly x 6 months after surgeryMonthly x 6 months after surgery

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Peritoneal MesotheliomaPeritoneal Mesothelioma

Combination TherapyCombination Therapy–– Cisplatin 50Cisplatin 50--60 mg/m60 mg/m2 2 IV or IP day oneIV or IP day one–– Irinotecan 50Irinotecan 50--60 mg/m60 mg/m22 IV day 1, 8 and IV day 1, 8 and

1515–– Courses repeated every 4 weeks x 6 Courses repeated every 4 weeks x 6

cyclescycles

Feldman et al (2003) J Clin Onc. 21 (24)Feldman et al (2003) J Clin Onc. 21 (24)

Combination Therapy: Combination Therapy: Prognostic FactorsPrognostic Factors

49 patients49 patientsLaparotomyLaparotomy, tumor resection, , tumor resection, continuous continuous hyperthermichyperthermic peritoneal peritoneal perfusion with perfusion with cisplatincisplatin (250 mg/m(250 mg/m22) ) and a single and a single postopertivepostopertiveintraperitonealintraperitoneal dwell of dwell of fluorouricilfluorouricil and and paclitaxelpaclitaxel

Disease ResponseDisease Response

Criteria for evaluationCriteria for evaluationDisease free progression vsDisease free progression vsPartial response vsPartial response vsStable diseaseStable diseaseFuture directions in measuring Future directions in measuring responseresponse

Management of Management of Paraneoplastic SyndromesParaneoplastic Syndromes

Pleural effusions: 95% of patients will Pleural effusions: 95% of patients will develop during disease coursedevelop during disease course–– Drainage and pleuradesisDrainage and pleuradesis–– Open pleurectomy & DecorticationOpen pleurectomy & Decortication–– Chest tubesChest tubes–– Small bore pleurex cathetersSmall bore pleurex catheters–– Pleuroperitoneal shuntPleuroperitoneal shunt

Symptom ManagementSymptom Management

DyspneaDyspneaChest/Abdominal PainChest/Abdominal PainCoughCoughFatigueFatigueDepressionDepression

DyspneaDyspnea

Assessment scalesAssessment scalesOxygen supplementationOxygen supplementationTherapeutic thoracentesisTherapeutic thoracentesisOpiods: to reduce sensation of Opiods: to reduce sensation of breathlessness: nebulized morphinebreathlessness: nebulized morphineBronchodilators and corticosteroidsBronchodilators and corticosteroidsAnxiolyticsAnxiolyticsPulmonary rehabilitationPulmonary rehabilitation

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PainPain

WHO analgesic ladderWHO analgesic ladderPercutaneous cervical cordotomyPercutaneous cervical cordotomyEpidural catheter for long term controlEpidural catheter for long term controlRadiation therapyRadiation therapy

CoughCough

Antitussives: Hydrocodone 5mg q 4Antitussives: Hydrocodone 5mg q 4--6 6 hrshrsOpiate tincturesOpiate tincturesOral steroidsOral steroidsNebulized local anaestheticsNebulized local anaestheticsAntibiotic therapy for underlying Antibiotic therapy for underlying infectioninfectionWarm, humidified airWarm, humidified air

AcknowledgementsAcknowledgements

Yale Comprehensive Cancer CenterYale Comprehensive Cancer CenterYale University School of MedicineYale University School of MedicineYale University School of NursingYale University School of NursingYaleYale--New Haven HospitalNew Haven HospitalNevada Cancer InstituteNevada Cancer Institute

Thank You