Malignant Pleural Mesothelioma

Transcription

1 Malignant Pleural Mesothelioma Joseph Friedberg, MD Hedy Lee Kindler, MD Lee Krug, MD Kenneth Rosenzweig, MD

2 Epidemiology of Mesothelioma Incidence: 2,500 3,000 cases year in the US 5,000 cases per year in Western Europe An emerging gproblem in the developing world Onset 20 to 60 years following asbestos exposure Incidence peaked in US in 2000, will peak in 2018 in Europe Male: Female ratio 4:1 In the US, a disease of the elderly Median age is 74; 72% are > 65 Less common in African Americans

3 Case Presentation 69 yo carpenter, otherwise healthy Presented September 2010 with shortness of breath CT scan of the chest: Large right pleural effusion, multiple smallright pleural nodules, largest 1.6cm adjacent to right atrium, no enlarged mediastinal LNs Thoracentesis: Cytology suspicious cells October 2010 VATS / pleural l biopsy Epithelioid mesothelioma PFTs normal PET scan: Right pleural thickening with uptake just above background

4 Nov 2010: Pretreatment

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6 What are the treatment options for this patient? A) Treatment of his effusion and palliative systemic chemotherapy B) Surgery alone C) Surgery followed by chemotherapy +/ radiation therapy D) Induction chemotherapy followed by surgery E) Induction chemotherapy followed by surgery and post operative radiation

7 Rusch, Proc IASLC 2009

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9 The patient isn t sure if he wants surgery, and decides to start with chemotherapy. Which regimen would you offer him? A) Single agent pemetrexed B) Pemetrexed/carboplatin C) Pemetrexed/cisplatin D) Gemcitabine/cisplatin E) Vinorelbine

10 The trial that changed our outlook on the role of chemotherapy for MM Pemetrexed 500 mg/m 2 q 21D Cisplatin 75 mg/m 2 q 21D 456 patients Primary objective: OS (HR=.67) Placebo q 21D Cisplatin 75 mg/m 2 q 21D Stratification: Performance status, histology, gender, WBC, disease measurability, baseline homocysteine Vogelzang, JCO 2003

11 Pemetrexed + cisplatin: The benchmark regimen for mesothelioma PC C p Pts RR 41% 17% <0.001 MST M 93M TTP 5.7 M 3.9 M Vogelzang, JCO 2003

12 Phase II trials of pemetrexed + carboplatin Author Ceresoli 1 Castagneto 2 Patients Response 19% 25% Survival 12.7 mo 14 mo TTP 65mo mo Ceresoli, JCO Castagneto, Ann Oncol Ceresoli, Br J Ca 2008

13 An International EAP demonstrated similar outcomes when pemetrexed was combined with either cisplatin or carboplatin Pem- Pem- Pem Cisplatin carboplatin N=745 N=752 N=64 Response 26.3% 21.7% 5.5% TTP 7.0 mo mo 4.7 mo 1 year 63% 64% 48% survival Scagliotti, JCO 2003; Santoro, JTO 2008

14 What is the optimal duration of pemetrexed treatment? In the pivotal randomized study, pts received no more than 6 cycles of Pem Cis In MM pts who progress after a non pemetrexed regimen, 2 nd line pemetrexed 1 : improves PFS over BSC (no OS improvement) Small non randomized Dutch study in MM: maintenance pemetrexed is feasible 2 responses can occur after 6 cycles InNSCLC NSCLC, after a platinum regimen, maintenance pemetrexed is a standard tx option 2 1 Jassem JCO van de Bogaert JTO Ciuleanu Proc ASCO 2008

15 CALGB 30901: A study of pemetrexed maintenance 90 pts Pemetrexed + Cisplatin or Carboplatin x 4 cycles SD PR CR R A N D O M I ZE Pemetrexed until progression Stratification: Cis vs. carboplatin Epithelial vs. other Observation until progression Primary endpoint: PFS

16 The MS01 Trial: A randomized phase III trial of active symptom control with or without chemotherapy Newly diagnosed MPM Randomization Active Symptom Control (ASC) ASC + 4 cycles of MVP Mitomycin Vinblastine Cisplatin ASC + 12 weekly cycles of Vinorelbine

17 MS01 trial: Non significant OS benefit for vinorelbine likely due to reduced sample size Initial design: 840 pts in 4 yrs, 3 arms, 90% power. Accrual poor. Revised design: 2 arms, 420 pts, chemo arms pooled, 76% power ASC MVP Vin Pts Median 7.6 m 7.8 m 9.5 m 1 yr 29% 31% 42% HR: % CI p value Conclusion: Vinorelbine may improve MST by ~2 months (p=0.11; NS) Time (months) ASC alone ASC + N ASC + MVP

18 The gemcitabine cisplatin regimen, though quite active, shows significant heterogeneity between trials Author # Gemcitabine Cisplatin RR MS Byrne D1,8, D1 q28d 48% 9.5 Nowak D1,8, D1 q28d 33% 11.2 Castagneto D1,8 75 D1 q21d 26% 12 vanhaarst D1,8 80 D1 q21d 16% 9.6 SWOG D1,8,15 30D1,8,15 q28d 12% 10 1 Byrne, JCO Nowak, Br J Ca Castagneto, Proc ASCO van Haarst, Br J Ca Kalmadi, Lung Ca 2007

19 Retrospective Canadian series: No difference in overall survival between gemcitabine or pemetrexed platinum doublets h h b These regimens have not been compared prospectively in MM

20 From Nov 2010 Jan 2011 he received pemetrexed/cisplatin x 4 cycles. He now agrees to undergo surgery January 2011 Post Chemo

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22 What surgery should be performed? A) Extrapleural pneumonectomy B) Lung sparing surgery (i.e., pleurectomy/decortication) C) VATS/pleurodesis D) No surgery

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24 Which of the following is true with respect to lung sparing (radicalpleurectomy pleurectomy, RP) versus lung sacrificing (extrapleural pneumonectomy, EPP) surgery for mesothelioma... A) EPP results in longer survival than RP, but unfortunately is only an option for the most fit patients B) RP tends to have the same mortality rate as EPP, but a significantly lower complication rate C) Local recurrence is more frequent with EPP than RP D) EPP achieves a more complete macroscopic complete resection than RP E) RP is only an option for patients with early disease not involving the pulmonary fissures

25 The patient went on to have: Pleurectomy/decortication Extensive but non confluent tumor studding all pleural surfaces Pathology confirmed epithelioid subtype 1/2 right level 4 and 1/4 level 7 LNs positive Pathologically staged as T2N2M0

26 Surgery for malignant pleural mesothelioma Rusch, Proc

27 Surgery for malignant pleural mesothelioma Rusch, Proc

28 Surgery for malignant pleural mesothelioma Rusch, Proc

29 Surgery for malignant pleural mesothelioma Teamwork approaches for surgery based treatments Chemotherapy, pre and/or postop Radiation, postop (or preop) Intraoperative adjuvants Heated chemotherapy Heated Betadine Photodynamic therapy (PDT) Rusch, Proc

30 The goal of surgery is to achieve a macroscopic complete resection Extrapleural pneumonectomy Advantages standardized, di d least residual microscopic i cancer, empty chest facilitates IMRT Disadvantage leaves the patient t with one lung Lung sparing surgery Disadvantages not standardized, more residual microscopic disease, more challenging for adjuvant XRT, surgically more technically challenging (at least for me) Advantage leaves the patient with two lungs

31 Extrapleural Pneumonectomy

32 Neoadjuvant multimodality trials chemotherapy EPP +/ RT Weder 2004 Chemo N # RR PFS MST EPP (mo) (mo) Gem % Cis X 3 Gem % 19 Cis x 4 Gem NR Cis x 3 Krug Pem % Cis x 4 Van Pem Cis x 3 Flores 2006 Weder 2007 Schil 2010 OPERATIVE MORTALITY FOR THESE SERIES: 0 5%

33 MARS Trial Treasure, Lancet Oncol pts Fit for surgery (BTS guidelines) Staged with PET, mediastinoscopy 3 cycles platinumbased chemotx restaged R A N D O M I Z E EPP + RT Best oncological management ~6,000 cases in UK; ~300 screened; 57 consented for randomisation; 24 EPP Median survival: EPP 14.4 mo, no EPP 19.5 mo

34 The MARS Trial MARS Trial These data, although limited, suggest that radical surgery in the form of EPP within trimodal therapy offers no benefit and possibly harms patients Correspondence from several international leaders titled: The MARS feasibility trial: conclusions not supported by data Study to assess ability to randomize 50 pts in a year took three years (failed) and not designed to test outcomes Over half of the patients not randomized no data on them Protocol violations 3 nonsurg had EPP, 3 had non EPP surgery 18% mortality for the 17 protocol EPP pts We believe the interpretation of the study is inappropriate, could move clinical research for mesothelioma in the wrong direction and might be harmful to patients seeking advice.

35 Retrospective US analysis of 663 consecutive patients ( ) EPP N=385 P/D N=278 Operative mortality 7% 4% Local recurrence 33% 65% Distant recurrence 66% 35% Overall Survival 14 months 5 year survival 12% Stage I 22 months 46 months Stage II Stage III Stage IV 19 months 18 months 10 months 13 months 4 months 9 months Flores, J Thor Cardiovasc Surg 2008

36 Lung sparing surgery for MPM Non standardized technique or even nomenclature: decortication, pleurectomy, pleurectomy/decortication, radical pleurectomy Traditional indications/applications curative intent for very minimal disease palliative debulking for very advanced disease Reserved for patients who can t tolerate pneumonectomy Even by advocates typically considered an intraoperative decision, especially with respect to involvement with the pulmonary fissures Recent trend in some centers to become much more aggressive with lung sparing surgery

37 Recent single institution studies comparing EPP to lung sparing surgery Nakas, Eur J CT Surg, Lazdunski, J Thor Friedberg, Ann Thor 2012 Onc, 2012 Surg, 2011 #of RP/EPP patients 67/98 54/22 14/14 % Stage III or IV (RP/EPP) 100%/100% 63%/86.5% 86%/86% % epithelial (RP/EPP) 70% (not broken 67%/64% 79%/43% down) Same surgeon? Not specified yes yes Intraoperative ti Rx none Heated diodine PDT Operative mortality (RP/EPP) 3%/7% 0%/4.5% 0%/14% Median survival (RP/EPP) 13.4/14.7 months 23/12.8 months Not reached at 25 months/8.4 months

38 28 patients (14/14) having modified EPP or RP and PDT (86% stage III/IV) Friedberg, Ann Thor, 2011

39 Chest Wall Tumor and lung Mobilization of Tumor off Chest Wall, Diaphragm and Pericardium Denuded lung Tumor and diaphragmatic pleura Tumor and outer layer of pericardium Diaphragm musculature Inner layer of pericardium

40 Separating the Tumor from the Lung tumor Tumor extending into fissure Liberated lung

41 The Appearance of the Right Major Fissure After a Radical Pleurectomyy Azygus vein Superior segmental artery t Basilar arterial trunk Posterior segmental artery t Middle lobe arterial trunk

42 2200 cc tumor removed as part of a lung-sparing macroscopic complete resection

43 The cast of the fissure from a lung-sparing g macroscopic complete resection

44 Radical Pleurectomy and Intraoperative Photodynamic Therapy f Mli Pl l M h li for Malignant Pleural Mesothelioma Friedberg, Ann Thor, patients, 97% Stage III/IV Median f/u months OS all pts 31.7 months and 41.2 months for 31 epithelial pts Epithelial N2 (20 pts) 31.7 months, Epithelial N0 1 (7pts) 57.1 months

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46 Which of the following is true with respect to lung sparing (radicalpleurectomy pleurectomy, RP) versus lung sacrificing (extrapleural pneumonectomy, EPP) surgery for mesothelioma... A) EPP results in longer survival than RP, but unfortunately is only an option for the most fit patients B) RP tends to have the same mortality rate as EPP, but a significantly lower complication rate C) Local recurrence is more frequent with EPP than RP D) EPP achieves a more complete macroscopic complete resection than RP E) RP is only an option for patients with early disease not involving the pulmonary fissures

47 Radiation for mesothelioma Conventional RT requires pneumonectomy Newer techniques (IMRT) may expand the role of radiation with applicability in the setting of lung preservation Aft l t /d ti ti tbl After pleurectomy/decortication or unresectable disease

48 Radiation Therapy Technique Photon/Electron Port film Isodose Distribution

49 Intensity Modulated Radiation Therapy (IMRT) A way to deliver more conformal doses of RT than photon/electron Main organ at risk is lung Contralateral (remaining) lung in EPP Both hlungs in P/D Other organs at risk include heart, liver, kidney

50 IMRT Toxicity after EPP: BWH/DFCI and MDACC Series / BWH/DFCI 1 13 pts S/P EPP, all received some form of chemotherapy (heated intraoperative, neoadjuvant, adjuvant) Treated to 5400 cgy with IMRT 12/04 9/05 6 toxic deaths (pneumonitis) Probably too much radiation to remaining lung MDACC 2 63 consecutive MM pts who underwent EPP and IMRT (median dose 45 Gy) 6 (10%) had pulmonary death not from disease after IMRT within 6 months Recommended pulmonary V20 < 5% 1. Allen, et al, IJROBP, Rice, et al. IJROBP 2007

51 IMRT with Intact Lungs MSKCCExperience (IJROBP, 2012) 36 patients, median dose 4680 cgy 1 year survival = 75%, 2 year survival = 53% 20% grade 3 or 4 pneumonitis Update at this meeting and imig (Rimner, et al.) 64 patients Most local failures occur in sites of previously resected local disease

52 Case Presentation: Contouring

53 Case Presentation: IMRT Isodose Curves

54 Case Presentation: IMRT Isodose Curves

55 IMRT in Mesothelioma Still controversial Need to be VERY VERY careful After EPP Probably has a dosimetric advantage of photon/electron in a subset of patients 10% of patients recur in areas that might be underdosed with photon/electron (Gupta, et al, JTO, 2008) After P/D or unresectable Feasible, but still need more experience

56 Case Presentation, continued Pleural IMRT to 4860 cgy completed June 2011 Complications After 7 fractions (1260 cgy) pericarditis After completion of treatment pneumonitis ii Both resolved with steroids

57 June 2011 post RT, pneumonitis

58 May 2012: Local Recurrence in Chest and Peritoneal Carcinomatosis

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60 How would you treat this patient? 1) Cisplatin and pemetrexed 2) Carboplatin and pemetrexed 3) Single agent pemetrexed 4) Single agent vinorelbine 5) Best supportive care

61 Second line therapy: Patients in thepivotal PemCis trial Do pts who receive 2 nd line treatment live longer? OR Do pts who live longer receive more 2 nd line tx? Manegold, Ann Oncol 2005 Manegold et al, Ann Oncol 2005, 16:923 7

62 The first 2 nd line randomized phase III trial in MPM: Pemetrexed vs. BSC in previously treated, pemetrexed naïve pts Pemetrexed + BSC (N=123) BSC (N=120) OS 8.4 mo 9.7 mo (p=0.74) PFS 3.6 mo 1.5 mo (p=0.015) DCR 59% 19% Time to initiation of next chemo % pts receiving chemo after 15.7 mo 4.3 mo 29% 52% Jassem et al, J Clin Oncol 26: , 2008

63 Second line Pemetrexed for MPM Italian Retrospective, Multicenter Survey Data on 181 patients from 8 institutions during received first line pemetrexed regimen 42 rechallenged with pemetrexed regimen Compared to non pemetrexed regimen, higher DCR (71% vs 52%), PFS (6 vs 3 mo) and OS (11 vs 7 mo) Benefit greater in good PS, TTP > 12 mo, younger age 31 rechallenged with pemetrexed / platinum DCR no different c/w single agent pemetrexed, but PFS and OS significantly longer Zucali et al, Lung Canc 75:360 7, 2012

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65 The patient is retreated with pemetrexed and carboplatin. After 2 cycles, the CT shows stable disease. After 4 cycles, he has disease progression. How would you treat this patient now? A) Single agent vinorelbine B) Gemcitabine and carboplatin C) Clinical trial D) Best supportive care

66 Vinorelbine in previously treated MPM Rationale from MRC first line study PhaseIIstudy study (n=63) RR 16%, median survival 9.6 mo Not all patients had received prior pemetrexed Mdi Median time since first line therapy was 6 mo All pts were classified as low risk according to EORTC prognostic score Rt Retrospective ti MSKCC cohort 45 pts treated as 2 nd or 3 rd line 80% prior pemetrexed regimen; 64% epithelioid RR 0% (excludes 8% RR), 44% SD Median survival 5 mo Stebbing et al, 2009, 63:94 7 Zauderer et al, IMIG 2012

67 The largest trial ever performed in MM: Phase III Trial of vorinostat vs. placebo in previously treated patients 125centers in 23countries participated 661 patients enrolled from July 2005 to February patients Vorinostat 300mg BID x 3 D Q7D Placebo 1 0 endpoint: Overall survival Stratification: histology, PS, # prior regimens (1 vs. 2) Statistics: 80% power to demonstrate 25% hazard difference (median OS 6 vs. 8 mo); HR target

68 Vorinostat vs. Placebo: Outcomes Vorinostat Placebo HR P OS 31 wk 27 wk PFS 6.3 wk 6.1 wk 0.75 <0.001 RR 0.6% 0.3% OS PFS Krug, ESMO 2011

69 Some of the agents in clinical trials for MM ADI-PEG20 CBP-501 CP-870, 893 ARQ-197 Tremelimumab GSK Target Arginine CDK CD-40 C-MET CTLA-4 FAK Ganetespib HSP-90 IMC-A12 MORAb009, SS1P, CRS-207, BAY RAD-001 GDC-0980 Bortezomib Dasatinib GC-1008 Axitinib, Bevacizumab, BNC105P, Cediranib, NGR-hTNF, Pazopanib, Vatalanib, Sorafenib, Sunitinib, Vandetanib IGF-1 Mesothelin mtor PI3K/mTor Proteasome Src TGF-B VEGF

70 Chemotherapy for MPM Conclusions Standard first line therapy is a platinum based doublet with pemetrexed Benefit of second line therapy not yet clearly established Rechallenge with pemetrexed if previous benefit Vinorelbine reasonable option, though response rate is poor Multiple targeted therapies in trials; enrollment to studies is paramount

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