Non-surgical Treatment of Diffuse Malignant M esothelioma

Non-surgical Treatment of Diffuse Malignant Mesothelioma

Guntulu Ak, MDEskisehir Osmangazi University Medical Faculty

Department of Pulmonary Medicine

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.

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.

ChemotherapyFirst-line chemotherapy

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.

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)


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.


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.


Phase III randomised trial: Pemetrexed-cisplatin X cisplatin (456 patients: 226 X 222)

Response rates:Pemetrexed-cisplatin arm 41.3%Cisplatin arm 16.7% Median survival time:Pemetrexed-cisplatin arm 12.1 moCisplatin arm 9.3 mo Median time to progression:Pemetrexed-cisplatin arm 5.7 moCisplatin arm 3.9 mo

Vogelzang NJ. J Clin Oncol 2003; 21: 2636.

p=.020

p=.001

p=<.0001


Phase III randomised trial: Raltitrexed-cisplatin X cisplatin (250 patients)

Response rates:Raltitrexed-cisplatin arm 23.6%Cisplatin arm 13.6% Median survival:Raltitrexed-cisplatin arm 11.4 moCisplatin arm 8.8 mo 1-year survival rate:Raltitrexed-cisplatin arm 46%Cisplatin arm 40%

Van Meerbeeck JP. J Clin Oncol 2005; 23: 6881.

p=.048

p=.056


The combination of pemetrexed / carboplatin is an alternative effective therapy.

Stahel RA. Ann Oncol 2010; 21 (Suppl 5): v126.

Author Year Patient number

Response rate, %

Median survival (mo)

Time to progression (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


Pemetrexed – cisplatin; Adverse events:

Vogelzang NJ. J Clin Oncol 2003; 21: 2636.

Hematologic %

Hemoglobin 4.8

Leukocytes 17.7

Neutrophils 27.9

Platelets 5.8

Others %

Nausea 14.6

Fatigue 10.2

Vomiting 13.3

Diarrhea 4.4

Dehydration 4.0

Stomatitis 4.0

Anorexia 2.2

Febrile neutropenia 1.8

Infection 1.3

Rash 1.3

3 deaths; before adding vitamin supplementation


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.


Alternative agents:

Vinorelbine – cisplatin Response rates: 30%Median survival: 17 mo

Sorensen JB. Br J Cancer 2008; 99: 44.

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

≥ 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

Grade 3 – 4 hematological toxicity, %

Nonhematological toxicity was mild and similar in the two groups.

Ceresoli GL. Br J Cancer 2008; 99: 51.


Timing of chemotherapy:A randomised trial;Early treatment vs delayed treatment 43 patients: 21 vs 22Mitomycin – 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.


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.

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 BSC Total PNumber of patients 109 52 161Cell type; n (%) Epithelial Mixed Sarcomatous Undefined

72 (66.0)18 (16.5) 9 (08.3)10 (09.2)

34 (65.4)7 (13.4)3 (05.8)8 (15.4)

106 (65.8) 25 (15.5) 12 (07.5) 18 (11.2)

0.632

Stage; n (%) I II III IV

29 (26.6)25 (13.8)47 (43.1)18 (16.5)

17 (32.7)11 (21.2)17 (32.7) 7 (13.4)

46 (28.6)26 (16.1)64 (39.8)25 (15.5)

0.420

Mean Karnofsky 79.3±7.8 77.1±8.7 78.6±8.1 0.117Median Survival 11.3±0.9 8.0±0.9 Log-rank=3.8 0.0508


Metintas M, Ak G. Lung Cancer 2007; 55: 379.

Response to therapy Response rate MS (Months)

Objective response

Complete

Partial + Regression

Stable disease

Progressive disease

28 (25.7%)

4 (03.7%)

24 (22.0%)

39 (35.8%)

42 (38.5%)

17.0±4.6

36.0±13.7

16.0±2.7

16.0±0.9

6.0±0.3





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) -

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

Stage 3 - 4

28

44

14.3±2.5

12.0±1.7

18

16

11.0±7.9

4.0±1.1

0.9870

0.001



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.

ChemotherapySecond-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 arm9.7 mo for best supportive care arm

Response rate: 18.7% for pemetrexed plus best supportive care arm1.7 % 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.


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.


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.


Phase II study: weekly vinorelbine63 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.


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 moMean 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.


If EPP is planned, platinum-based neoadjuvant or adjuvant combination chemotherapy should be considered.

Stahel R.A. Ann Oncol 2010; 21 (Suppl 5): v126.

ChemotherapyAdjuvant and neo-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 %15Median survival was 19 months

ChemotherapyAdjuvant chemotherapy

Sugarbaker DJ. J Thorac Cardiovasc Surg 1999; 117: 54.

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 EPP37 (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.

ChemotherapyNeo-adjuvant chemotherapy

Author Year Patient num Treatment MS (mo)

Sugarbaker 1999 183 EPP + RT + ChT 19Weder 2004 19 ChT + EPP + RT 23Flores 2006 21 ChT + EPP + RT 19Weder 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

ChemotherapyAdjuvant and neo-adjuvant chemotherapy

RadiotherapyCurative 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 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.

RadiotherapyRadiotherapy 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 toxicityAllen AM. Int J Radiat Oncol Biol Phys 2006; 65: 640.Kristensen CA. Rad Oncol 2009; 92: 96.


Author Year Patient number

Treatment Median survival (mo)

Rusch 2001 62 EPP + HDRT 10

dePerrot 2007 50 EPP + RT 11

Rice 2007 100 EPP + IMRT 10

RadiotherapySymptomatic 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.

RadiotherapyAdjuvant radiotherapy to thoracic tracts

Randomised study:40 patients:20 patients, who didn’t receive radiotherapy20 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 radiotherapy0% for patients received radiotherapy

Boutin C. Chest 1995; 108: 754.

Randomised study:43 patients, 58 intervention sites:28 radiotherapy arm, single 10 Gy30 control arm

Metastasis rate:7% for radiotherapy arm10% for control arm

Bydder S. Br J Cancer 2004; 91: 9.

p=0.53


Randomised study:61 patients:31 radiotherapy arm, 21 Gy in 3 fractions30 best supportive care arm,

Metastasis rate:13% for radiotherapy arm10% for best supportive care arm

O’Rourke N. Radiother Oncol 2007; 84: 18.

p=0.748


212 patients, Local dissemination rate: 13.2%

Local dissemination:10.4% for CT+/-CPNB13.0% for thoracoscopy25.8% for thoracotomy p=0.025



*Local dissemination , % **Median local dissemination time (mo)

Epithelial 10.8 7

Mixed 12.9 2

Sarcomatous 23.8 2

Undefined 16.8 5*p=0.384**p=0.3729


*Local dissemination, %

**Median local dissemination

time (mo)

***Median survival (mo)

Supportive care 10.3 2 8

Chemotherapy 12.1 6 10

Multimodal treatment 23.1 12 16

*Local dissemination , %

**Median local dissemination

time (mo)

***Median survival (mo)

Objective respose 4.9 17 13

Stable disease 10 7 13

Progressive disease 18.2 5 6

*p=0.105**p=0.008***p=0.000

*p=0.275**p=0.0183***p=0.002


Median survival:9 mo for patients with local dissemination,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,


p=0.6385


BiotherapiesImmunomodulators

İnterferon interleukin (IL-2)

Ranpirnase, ribonuclease inhibitor

Monotherapy is not effective

BiotherapiesTargeted therapies

Thalidomide (anti-angiogenic drug)BevacizumabGefitinibİmatinibErlotinib .........

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.


Bevacizumab:Phase II study;cisplatin – gemcitabinecisplatin – gemcitabine – bevacizumabResponse rate: 25% vs 22%Median survival: 15.6 mo vs 14.7 mo

Karrison TKH. J Clin Oncol 2007; 25: 18S.

p=0.91

Erlotinib – bevacizumab:Phase II, multicenter study, 24 patiens:No complete or partial responses12 patients had stable disease Time to progression was 2.2 months, median survival 5.8 months

Jackman DM. Cancer 2008; 113: 808.


Gefitinib (500 mg, P.O.)Phase II study; 43 patients who didn’t receive therapy before studyOnly 2 patients had objective responsesİt’s not effective for MPM.

Golindan R. Clin Cancer Res 2005; 11: 2300.


İmatinib (400 mg P.O., max 800 mg)Phase II study25 patients No responses were observed

Mathy A. Lung Cancer 2005; 50: 83.

Erlotinib (150 mg)Phase II study;63 patients who didn’t receive chemotherapy before 33 of them had measurable diseaseThere were no objective responsesMedian survival was 10 months1 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.

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 monthsMedian 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


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.

Biotherapies

Non-surgical Treatment of Diffuse Malignant M esothelioma

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