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Non-surgical Treatment of Diffuse Malignant M esothelioma

Non-surgical Treatment of Diffuse Malignant M esothelioma. G u nt u l u Ak , MD Eski s ehir Osmangazi University Medical Faculty Department of Pulmonary Medicine. Conflict of interest statement. None. Contents. Chemotherapy First-line chemotherapy Second-line chemotherapy

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Non-surgical Treatment of Diffuse Malignant M esothelioma

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  1. Non-surgical Treatment of Diffuse Malignant Mesothelioma GuntuluAk, MD EskisehirOsmangazi University Medical Faculty Department of Pulmonary Medicine

  2. Conflict of interest statement None

  3. Contents • Chemotherapy • First-line chemotherapy • Second-line chemotherapy • Adjuvant and neo-adjuvant chemotherapy • Radiotherapy • Curative intent hemithoracic radiotherapy • Radiotherapy after extrapleuralpneumonectomy (EPP) • Symptomatic radiotherapy • Adjuvant radiotherapy to thoracic tracts • Biotherapies • Immunomodulators • Targeted therapies

  4. Every patient with malignant pleural mesothelioma (MPM) should receive at least best supportive care. Scherpereel A. Eur Respir J 2010; 35: 479.

  5. ChemotherapyFirst-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.

  6. 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.

  7. ChemotherapyFirst-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.

  8. ChemotherapyFirst-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.

  9. ChemotherapyFirst-line chemotherapy 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 mo Cisplatin arm  9.3 mo Median time to progression: Pemetrexed-cisplatin arm  5.7 mo Cisplatin arm  3.9 mo p=<.0001 p=.020 p=.001 Vogelzang NJ. J Clin Oncol 2003; 21: 2636.

  10. ChemotherapyFirst-line chemotherapy 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 mo Cisplatin arm  8.8 mo 1-year survival rate: Raltitrexed-cisplatin arm  46% Cisplatin arm  40% p=.056 p=.048 Van Meerbeeck JP. J Clin Oncol 2005; 23: 6881.

  11. ChemotherapyFirst-line chemotherapy The combination of pemetrexed / carboplatin is an alternative effective therapy. Stahel RA. Ann Oncol 2010; 21 (Suppl 5): v126.

  12. ChemotherapyFirst-line chemotherapy Pemetrexed – cisplatin; Adverse events: 3 deaths; before adding vitamin supplementation Vogelzang NJ. J Clin Oncol 2003; 21: 2636.

  13. ChemotherapyFirst-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.

  14. ChemotherapyFirst-line chemotherapy Elderly patients: Carboplatin – pemetrexed ≥ 70 years-old (n=48) vs < 70 years old (n=130) Grade 3 – 4 hematological toxicity, % Nonhematological toxicity was mild and similar in the two groups. Ceresoli GL. Br J Cancer 2008; 99: 51.

  15. ChemotherapyFirst-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.

  16. ChemotherapyFirst-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.

  17. ChemotherapyFirst-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.

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

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

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

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

  22. ChemotherapySecond-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.

  23. 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 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.

  24. ChemotherapySecond-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.

  25. ChemotherapySecond-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.

  26. ChemotherapySecond-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.

  27. ChemotherapySecond-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.

  28. ChemotherapyAdjuvant 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.

  29. ChemotherapyAdjuvant 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.

  30. ChemotherapyNeo-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.

  31. ChemotherapyAdjuvant and neo-adjuvant chemotherapy

  32. 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.

  33. RadiotherapyRadiotherapy 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.

  34. 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 toxicity Allen AM. Int J Radiat Oncol Biol Phys 2006; 65: 640. Kristensen CA. Rad Oncol 2009; 92: 96.

  35. RadiotherapyRadiotherapy after EPP

  36. 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.

  37. RadiotherapyAdjuvant 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.

  38. RadiotherapyAdjuvant 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 10% for control arm p=0.53 Bydder S. Br J Cancer 2004; 91: 9.

  39. RadiotherapyAdjuvant 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 10% for best supportive care arm p=0.748 O’Rourke N. Radiother Oncol 2007; 84: 18.

  40. RadiotherapyAdjuvant 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 *p=0.384 **p=0.3729 Metintas M, Ak G. Lung Cancer 2008; 61: 255.

  41. RadiotherapyAdjuvant radiotherapy to thoracic tracts *p=0.275 **p=0.0183 ***p=0.002 *p=0.105 **p=0.008 ***p=0.000 Metintas M, Ak G. Lung Cancer 2008; 61: 255.

  42. RadiotherapyAdjuvant radiotherapy to thoracic tracts Median survival: 9 mo for patients with local dissemination, 10 mo for patients without local dissemination p=0.6385 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.

  43. BiotherapiesImmunomodulators İnterferon interleukin (IL-2) Ranpirnase, ribonuclease inhibitor Monotherapy is not effective

  44. BiotherapiesTargeted therapies Thalidomide (anti-angiogenic drug) Bevacizumab Gefitinib İmatinib Erlotinib ... ... ...

  45. BiotherapiesTargeted 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.

  46. BiotherapiesTargeted therapies Bevacizumab: Phase II study; cisplatin – gemcitabine cisplatin – gemcitabine – bevacizumab Response rate: 25% vs 22% Median survival: 15.6 mo vs 14.7 mo p=0.91 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.

  47. BiotherapiesTargeted 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 responseswereobserved Mathy A. Lung Cancer 2005; 50: 83.

  48. BiotherapiesTargeted 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.

  49. BiotherapiesTargeted 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

  50. 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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