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Non-surgical Treatment of Diffuse Malignant Mesothelioma

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Non-surgical Treatment of Diffuse Malignant Mesothelioma Powered By Docstoc
					Non-surgical Treatment of Diffuse
   Malignant Mesothelioma
Conflict of interest statement

            None
                           Contents
• Chemotherapy
   – First-line chemotherapy
   – Second-line chemotherapy
   – Adjuvant and neo-adjuvant chemotherapy
• Radiotherapy
   –   Curative intent hemithoracic radiotherapy
   –   Radiotherapy after extrapleural pneumonectomy (EPP)
   –   Symptomatic radiotherapy
   –   Adjuvant radiotherapy to thoracic tracts
• Biotherapies
   – Immunomodulators
   – Targeted therapies
Every patient with malignant pleural mesothelioma
(MPM) should receive at least best supportive care.

                     Scherpereel A. Eur Respir J 2010; 35: 479.
Chemotherapy
First-line chemotherapy


 Single-agent chemotherapy:
 Platinum analogues, doxorubicin and some antimetabolites
 (methotrexate, raltitrexed, pemetrexed) have shown modest
 single-agent activity.
              Stahel RA. Ann Oncol 2010; 21 (Suppl 5): v126.
              Vorobiof DA, Mafafo K. Clin Lung Cancer 2009; 10: 112.
              Scherpereel A. Eur Respir J 2010; 35: 479.
    Chemotherapy
    First-line chemotherapy
Single-agent chemotherapy
Anthracyclines (doxorubicin, epirubicin, mitoxantrone, pirarubicin, detorubicin, liposomal encapsulated
doxorubicin)
Alkylating agents (cyclophosphamide, ifosfamide, mitomycin C)
Platinum compounds (cisplatin, carboplatin, oxaliplatin)
Vinka alkaloids (vincristine, vinorelbine, vindesine, vinflunine)
Taxanes (paclitaxel, docetaxel)
Antimetabolites (5-fluorouracil, methotrexate, gemcitabine, 5-azacytidine, edatrexate, pemetrexed,
trimetrexate)
Others (amsacrine, topotecan)
Biologics (BCG, interferon alfa, beta ve gamma, interleukin-2)

       Single agent chemotherapy:
       Response rate is 0 – 37%
                             Vorobiof DA, Mafafo K. Clin Lung Cancer 2009; 10: 112.
                             Scherpereel A. Eur Respir J 2010; 35: 479.
Chemotherapy
First-line chemotherapy


 Response rate and survival are:
 generally greater for combinations than for single agent
 regimens and also for platinum-containing regimens than for
 nonplatinum-containing combinations.
                           Ellis P. J Thorac Oncol 2006; 1: 591.
                           Tsao AS. J Clin Oncol 2009; 27: 2081.
Chemotherapy
First-line chemotherapy


 When a decision is made to treat with chemotherapy,
 patients in a good performance status should be treated
 with combination chemotherapy consisting of platinum –
 pemetrexed / raltitrexed.
                     Scherpereel A. Eur Respir J 2010; 35: 479.
                     Pinto C. Am J Clin Oncol 2011; 34: 99.
                     Stahel RA. Ann Oncol 2010; 21 (Suppl 5): v126.
Chemotherapy
First-line chemotherapy
 Phase III randomised trial:
 Pemetrexed-cisplatin X cisplatin (456 patients: 226 X 222)

 Response rates:
 Pemetrexed-cisplatin arm  41.3%
                                                             p=<.0001
 Cisplatin arm  16.7%

 Median survival time:
 Pemetrexed-cisplatin arm  12.1 mo                          p=.020
 Cisplatin arm  9.3 mo

 Median time to progression:
 Pemetrexed-cisplatin arm  5.7 mo
 Cisplatin arm  3.9 mo                                      p=.001


                           Vogelzang NJ. J Clin Oncol 2003; 21: 2636.
Chemotherapy
First-line chemotherapy
 Phase III randomised trial:
 Raltitrexed-cisplatin X cisplatin (250 patients)

 Response rates:
 Raltitrexed-cisplatin arm  23.6%
                                                              p=.056
 Cisplatin arm  13.6%

 Median survival:
 Raltitrexed-cisplatin arm  11.4 mo                          p=.048
 Cisplatin arm  8.8 mo

 1-year survival rate:
 Raltitrexed-cisplatin arm  46%
 Cisplatin arm  40%
                          Van Meerbeeck JP. J Clin Oncol 2005; 23: 6881.
     Chemotherapy
     First-line chemotherapy

Author         Year   Patient      Response         Median         Time to progression
                      number        rate, %       survival (mo)           (mo)
Ceresoli       2006    102            18.6             12.7                   6.5
Castagneto     2008     76             25              14                     8
Santoro        2008    861            21.7              -                     6.9
Li             2009     49             28              14                     4.6
Katirtzoglou   2010     62             29              14                     7




      The combination of pemetrexed / carboplatin is an
      alternative effective therapy.
                             Stahel RA. Ann Oncol 2010; 21 (Suppl 5): v126.
Chemotherapy
First-line chemotherapy
 Pemetrexed – cisplatin;
 Adverse events:
Hematologic       %          Others                             %
Hemoglobin       4.8         Nausea                            14.6
Leukocytes       17.7        Fatigue                           10.2
Neutrophils      27.9        Vomiting                          13.3
Platelets        5.8         Diarrhea                          4.4
                             Dehydration                       4.0
                             Stomatitis                        4.0
3 deaths;                    Anorexia                          2.2
before adding vitamin        Febrile neutropenia               1.8
supplementation              Infection                         1.3
                             Rash                              1.3
                        Vogelzang NJ. J Clin Oncol 2003; 21: 2636.
Chemotherapy
First-line chemotherapy
 Alternative agents:
 Gemcitabine – cisplatin
 Response rates: 12 – 48 %
 Median survival: 9.6 – 13 mo
                           Castagneto B. Am J Clin Oncol 2005; 28: 223.
                           Van Haarst JM. Br J Cancer 2002; 86: 342.
                           Byrne MJ. J Clin Oncol 1999; 17: 25.
                           Kalmadi SR. Lung Cancer 2008; 60: 259.
 Gemcitabine – carboplatin
 Response rates: 26%
 Median survival: 66 weeks
                           Favaretto AG. Cancer 2003; 97: 2791.
 Vinorelbine – cisplatin
 Response rates: 30%
 Median survival: 17 mo
                           Sorensen JB. Br J Cancer 2008; 99: 44.
Chemotherapy
First-line chemotherapy

 Elderly patients:
 Carboplatin – pemetrexed
 ≥ 70 years-old (n=48) vs < 70 years old (n=130)

 Grade 3 – 4 hematological toxicity, %
                         ≥ 70 years           < 70 years         p
 Neutropenia                25.0                 13.8           0.11
 Anemia                     20.8                  6.9           0.01
 Thrombocytopenia           14.6                  8.5           0.26
 Febrile neutropenia        2.1                   3.8

 Nonhematological toxicity was mild and similar in the two
 groups.
                       Ceresoli GL. Br J Cancer 2008; 99: 51.
Chemotherapy
First-line chemotherapy

 Timing of chemotherapy:
 A randomised trial;
 Early treatment vs delayed treatment
 43 patients: 21 vs 22
 Mitomycin – vinblastine – cisplatin (carboplatin)

 Median survival:
 14 months for early treatment group,
 10 months for delayed treatment group,

 Quality of life was better for early treatment group than
 delayed treatment group.
                     O’Brien MER. Ann Oncol 2006; 17: 270.
Chemotherapy
First-line chemotherapy

 Number of cycles:

 According to the protocols of phase III trials;
 Median 4 – 6 cycles of chemotherapy is given unless
 progression or severe toxicity occurs.
                 Vogelzang NJ. J Clin Oncol 2003; 21: 2636.
                 Van Meerbeeck JP. J Clin Oncol 2005; 23: 6881.


 The role of maintenance chemotherapy in MPM is not well
 known.
Chemotherapy
First-line chemotherapy
 Best supportive care = chemotherapy

 Randomised phase III trial;
  Aktive symptom control (n=136)
  Aktive symptom control – mitomycin, vinblastine,
 cisplatin (n=137)
 Aktive symptom control – weekly vinorelbine (n=136)

 No survival and quality of life differences were observed
 between both arms.
 Median survival was 9.5 months for aktive symptom control
 – weekly vinorelbine (p=0.08).
                             Muers MF. Lancet 2008; 371: 1685.
  Chemotherapy
  First-line chemotherapy

                     Chemotherapy           BSC               Total            P
Number of patients       109                52                 161
Cell type; n (%)
  Epithelial           72 (66.0)          34 (65.4)         106 (65.8)       0.632
  Mixed                18 (16.5)          7 (13.4)           25 (15.5)
  Sarcomatous           9 (08.3)          3 (05.8)           12 (07.5)
  Undefined            10 (09.2)          8 (15.4)           18 (11.2)
Stage; n (%)
  I                    29 (26.6)          17 (32.7)         46 (28.6)        0.420
  II                   25 (13.8)          11 (21.2)         26 (16.1)
  III                  47 (43.1)          17 (32.7)         64 (39.8)
  IV                   18 (16.5)           7 (13.4)         25 (15.5)
Mean Karnofsky         79.3±7.8           77.1±8.7          78.6±8.1         0.117
Median Survival        11.3±0.9            8.0±0.9        Log-rank=3.8       0.0508
                                    Metintas M, Ak G. Lung Cancer 2007; 55: 379.
Chemotherapy
First-line chemotherapy

 Response to therapy                   Response rate        MS (Months)

 Objective response                      28 (25.7%)           17.0±4.6

     Complete                              4 (03.7%)          36.0±13.7

     Partial + Regression                24 (22.0%)           16.0±2.7

 Stable disease                          39 (35.8%)           16.0±0.9

 Progressive disease                     42 (38.5%)            6.0±0.3


                            Metintas M, Ak G. Lung Cancer 2007; 55: 379.
Chemotherapy
First-line chemotherapy

Survival   Chemotherapy (%)      Best supportive (%)                P

  12           52 (47.7)                18 (34.6)              p=0.0052

  24           12 (11.0)                  5 (9.6)               p=0.47

  36            8 (7.3)                   2 (3.8)              p=0.0381

  60            2 (3.8)                      -
                           Metintas M, Ak G. Lung Cancer 2007; 55: 379.
Chemotherapy
First-line chemotherapy

Characteristics   Chemotherapy         Best supportive care            p

                  n        MS            n            MS

Stage 1 - 2       44    14.0±1.3        28         11.0±3.9      0.4943

Stage 3 - 4       65    9.0±1.2         24         5.0±1.0        0.001

Epithelial

 Stage 1 - 2      28    14.3±2.5        18         11.0±7.9      0.9870

 Stage 3 - 4      44    12.0±1.7        16         4.0±1.1        0.001


                        Metintas M, Ak G. Lung Cancer 2007; 55: 379.
Chemotherapy
Second-line chemotherapy

 There is no widely approved second-line chemotherapy
 agent for MPM.


 İf pemetrexed is not given in the first line setting, it should
 be administered in the second-line setting, either alone or in
 combination with platinum.


                            Sorensen J. Lung Cancer 2006; 54: S46.
                            Janne PA. J Thorac Oncol 2006; 1: 506.
                            Jassem J. J Clin Oncol 2008; 26: 1698.
Chemotherapy
Second-line chemotherapy
 Multicenter, phase III study: 243 patients
  pemetrexed plus best supportive care (n=123)
  best supportive care (n=120)
 Median survival:
 8.4 mo for pemetrexed plus best supportive care arm
 9.7 mo for best supportive care arm

 Response rate:
 18.7% for pemetrexed plus best supportive care arm
 1.7 % for best supportive care arm

 Time to progression was longer for pemetrexed plus best
 supportive care arm than best supportive care arm
                               Jassem J. J Clin Oncol 2008; 26: 1698.
Chemotherapy
Second-line chemotherapy
 Retreatment with pemetrexed-based chemotherapy (PBC):
 31 patients:
 15 pemetrexed or 16 pemetrexed plus platinum


 Response rate: 19%
 Median survival after retreatment: 10.5 mo

 Progression free survival and overall survival after re-
 treatment with PBC were correlated with progression free
 survival achieved after first-line PBC.
                           Ceresoli GL. Lung Cancer 2011; 72: 73.
Chemotherapy
Second-line chemotherapy
 Gemcitabine – vinorelbine:
 30 patients who were pretreated with pemetrexed with or
 without a platinum


 Response rate: 10%
 Median survival: 10.9 mo

 The gemcitabine-vinorelbine combination was found
 moderately active with acceptable toxicity profile.
                               Zucali PA. Cancer 2008; 112: 1555.
Chemotherapy
Second-line chemotherapy

 Phase II study: weekly vinorelbine
 63 patients who had not received previous vinorelbine


 Response rate: 16%
 Median survival: 9.6 mo

 Vinorelbine had reasonable response rate with acceptable
 toxicity profile.
                            Stebbing J. Lung Cancer 2009; 63: 94.
Chemotherapy
Second-line chemotherapy
 Phase II study:
 Gemcitabine – docetaxel: on day 1 and 14 of a 28-day cycle.
 37 patients

 Response rate: 18.9%
 Time to progression: 7 mo
 Mean survival: 16.2 mo (13 – 19.3 mo)

 The biweekly administration of docetaxel and gemcitabine,
 along with granulocyte colony-stimulating factor support, is
 safe and may be a viable option for second line setting.

                        Tourkantonis I. Am J Clin Oncol 2011; 34: 38.
Chemotherapy
Adjuvant and neo-adjuvant chemotherapy



 If EPP is planned, platinum-based neoadjuvant or
 adjuvant combination chemotherapy should be
 considered.
                  Stahel R.A. Ann Oncol 2010; 21 (Suppl 5): v126.
Chemotherapy
Adjuvant chemotherapy
 183 patients with Malignant pleural mesothelioma (MPM):

  EPP
  2 cycles carboplatin – paclitaxel
  thoracic radiationtherapy (50 Gy) with concurrent
 paclitaxel weekly
  2 cycles carboplatin – paclitaxel

 2-year-survival rate was 38%, 5-year-survival rate %15
 Median survival was 19 months

              Sugarbaker DJ. J Thorac Cardiovasc Surg 1999; 117: 54.
Chemotherapy
Neo-adjuvant chemotherapy
59 MPM patients with stage cT3N1M0 or less:

 3 cycles cisplatin – pemetrexed
 EPP
 postoperative radiotherapy (54 Gy)

55 (93%) patients received 3 cycles of chemotherapy
42 (74%) patients EPP
37 (65%) patients postoperative radiotherapy

Median survival was 18.4 months
Median survival for the 37 patients was 33 months
                          Van Schil. Eur Respir J 2010; 36: 1362.
Chemotherapy
Adjuvant and neo-adjuvant chemotherapy
        Author   Year   Patient num      Treatment       MS (mo)
 Sugarbaker      1999      183         EPP + RT + ChT      19
 Weder           2004      19          ChT + EPP + RT      23
 Flores          2006      21          ChT + EPP + RT      19
 Weder           2007      61          ChT + EPP + RT     19.8

 Rea             2007      21         ChT + EPP + HDRT    25.5

 Batirel         2008      16         EPP + HDRT + ChT     19
 Krug            2009      77         ChT + EPP + HDRT    16.6
 Hasani          2009      36          EPP + RT + ChT     20.4
 Buduhan         2009      46          ChT + EPP + RT      24
 Van Schil       2010      57          ChT + EPP + RT     18.4
Radiotherapy
Curative intent hemithoracic radiotherapy


  The use of curative intent hemithoracic radiotherapy has
  been limited because of toxicity in MPM, especially the
  (homolateral) lung.
                       Pinto C. Am J Clin Oncol 2011; 34: 99.
                       Stahel RA. Ann Oncol 2010: 21 (Suppl5): v126.
Radiotherapy
Radiotherapy after EPP

 Radiotherapy should not be performed after pleurectomy or
 decortication.


 Post-operative irradiation after EPP should only be proposed
 in clinical trials, in specialised centers, as a part of
 multimodal treatment.
                          Scherpereel A. Eur Respir j 2010; 35: 479.
Radiotherapy
Radiotherapy after EPP


 In an attempt to improve local control after EPP, it has been
 shown feasible to deliver radiotherapy doses of >45 Gy with
 both 3D conformal (3D-CRT) and intensity-modulated
 radiotherapy (IMRT).
                     Stahel RA. Ann Oncol 2010; 21 (Suppl 5): v126.

 IMRT and pulmonary toxicity
                 Allen AM. Int J Radiat Oncol Biol Phys 2006; 65: 640.
                 Kristensen CA. Rad Oncol 2009; 92: 96.
Radiotherapy
Radiotherapy after EPP

Author     Year   Patient   Treatment      Median
                  number                 survival (mo)

Rusch      2001     62      EPP + HDRT        10

dePerrot   2007     50       EPP + RT         11

Rice       2007    100      EPP + IMRT        10
Radiotherapy
Symptomatic radiotherapy


 The presence of subcutaneous nodules or chest wall
 infiltration causing pain is the most frequent indication for
 palliative radiotherapy in MPM.
                           Pinto C. Am J Clin Oncol 2011; 34: 99.
                           Scherpereel A. Eur Respir J 2010: 35: 479.

 Hypofractionated schedules are used (3 5 Gy / fraction) and
 the total doses range from 30 through 36 Gy.
Radiotherapy
Adjuvant radiotherapy to thoracic tracts
 Randomised study:
 40 patients:
 20 patients, who didn’t receive radiotherapy
 20 patients, who received 3x7 Gy radiotherapy for 3
 consecutive days in the 4 weeks following invasive
 diagnostic procedure.

 Metastasis rate:
 40% for patients who didn’t receive radiotherapy
 0% for patients received radiotherapy
                                  Boutin C. Chest 1995; 108: 754.
Radiotherapy
Adjuvant radiotherapy to thoracic tracts
 Randomised study:
 43 patients, 58 intervention sites:
 28 radiotherapy arm, single 10 Gy
 30 control arm


 Metastasis rate:
 7% for radiotherapy arm
                                                   p=0.53
 10% for control arm
                                Bydder S. Br J Cancer 2004; 91: 9.
Radiotherapy
Adjuvant radiotherapy to thoracic tracts
 Randomised study:
 61 patients:
 31 radiotherapy arm, 21 Gy in 3 fractions
 30 best supportive care arm,


 Metastasis rate:
 13% for radiotherapy arm
                                                    p=0.748
 10% for best supportive care arm
                         O’Rourke N. Radiother Oncol 2007; 84: 18.
Radiotherapy
Adjuvant radiotherapy to thoracic tracts
 212 patients,
 Local dissemination rate: 13.2%
 Local dissemination:
 10.4% for CT+/-CPNB
 13.0% for thoracoscopy
 25.8% for thoracotomy                               p=0.025

                *Local dissemination , %           **Median local
                                              dissemination time (mo)
 Epithelial               10.8                            7
 Mixed                    12.9                            2
 Sarcomatous              23.8                            2       *p=0.384
 Undefined                16.8                            5       **p=0.3729
                        Metintas M, Ak G. Lung Cancer 2008; 61: 255.
Radiotherapy
Adjuvant radiotherapy to thoracic tracts
                            *Local         **Median local      ***Median
                       dissemination, %     dissemination     survival (mo)
                                              time (mo)
Supportive care              10.3                 2                8  *p=0.275
                                                                      **p=0.0183
Chemotherapy                 12.1                 6                10 ***p=0.002
Multimodal treatment         23.1                12                16

                            *Local         **Median local      ***Median
                       dissemination , %    dissemination     survival (mo)
                                              time (mo)
Objective respose             4.9                17                13
                                                                      *p=0.105
Stable disease                10                  7                13 **p=0.008
Progressive disease          18.2                 5                 6 ***p=0.000

                            Metintas M, Ak G. Lung Cancer 2008; 61: 255.
Radiotherapy
Adjuvant radiotherapy to thoracic tracts

 Median survival:
 9 mo for patients with local dissemination,                p=0.6385
 10 mo for patients without local dissemination

 The most suitable patients for prophylactic radiotherapy;
 receiving supportive care,
 thoracotomy without multi-modal therapy,
 Sarcomatous and mixed cell type tumors,

                       Metintas M, Ak G. Lung Cancer 2008; 61: 255.
Biotherapies
Immunomodulators


 İnterferon                           Monotherapy is not effective
 interleukin (IL-2)

 Ranpirnase, ribonuclease inhibitor
Biotherapies
Targeted therapies

 Thalidomide (anti-angiogenic drug)
 Bevacizumab
 Gefitinib
 İmatinib
 Erlotinib
 ...
 ...
 ...
Biotherapies
Targeted therapies

 Thalidomide:
 Oral (200 mg, max 400 mg)

 40 patients:
 12 patients showed disease stabilization for > 6 months
 Median survival time was 230 days
                                Baas P. Lung cancer 2005; 48:291.
Biotherapies
Targeted therapies
 Bevacizumab:
 Phase II study;
 cisplatin – gemcitabine
 cisplatin – gemcitabine – bevacizumab
 Response rate: 25% vs 22%                                 p=0.91
 Median survival: 15.6 mo vs 14.7 mo
                         Karrison TKH. J Clin Oncol 2007; 25: 18S.

 Erlotinib – bevacizumab:
 Phase II, multicenter study, 24 patiens:
 No complete or partial responses
 12 patients had stable disease
 Time to progression was 2.2 months, median survival 5.8
 months
                         Jackman DM. Cancer 2008; 113: 808.
Biotherapies
Targeted therapies

 Gefitinib (500 mg, P.O.)
 Phase II study; 43 patients who didn’t receive therapy before
 study
 Only 2 patients had objective responses
 İt’s not effective for MPM.
                        Golindan R. Clin Cancer Res 2005; 11: 2300.

 İmatinib (400 mg P.O., max 800 mg)
 Phase II study
 25 patients
 No responses were observed
                                 Mathy A. Lung Cancer 2005; 50: 83.
Biotherapies
Targeted therapies

 Erlotinib (150 mg)
 Phase II study;
 63 patients who didn’t receive chemotherapy before
 33 of them had measurable disease
 There were no objective responses
 Median survival was 10 months
 1 year survival rate 43%
 Median progression free survival 2 months
  Single agent erlotinib was not effective in MPM
                          Garland LL. J Clin Oncol 2007; 25: 2406.
Biotherapies
Targeted therapies

 Sorafenib (400 mg, P.O.)
 Phase II study;
 50 patients who had received 0 to 1 chemotherapy
 regimens,
 Objective responses rate was 6%
 Median survival was 9.7 months
 Median progression free survival was 3.6 months
  Sorafenib has limited activity in MPM, additional studies
 of sorafenib in MPM are not warranted.
                            Dubey S. J thorac Oncol 2010; 5: 1655
Biotherapies

 İmmunomodulating agents, targeted biotherapies and
 vaccines should not be used in the treatment of MPM
 outside clinical trials.
                        Scherpereel A. Eur Respir J 2010; 35: 479.

				
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