How To Treat A Cancer With A Radical

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1 Management of mesothelioma Amsterdam, March 6,

2 management Palliation Symptomatic care Pain Breathlessness Radiotherapy Chemotherapy Surgery Radical (intention to cure) Surgery Radiotherapy Multimodality including chemotherapy costopleural syndrome Typical pain for mesothelioma Nociceptive by chest wall involvement: R/ opioids, rapidly escalating according to WHO analgesic ladder Inflammatory: R/ + NSAID Neuropathic: R/ + tricyclic AD s /anticonvulsants Consider percutaneous cervical cordotomy for refractory pain/ unmanageable opioid toxicity (Jackson 1999, Kanpolat 2002) Highly skilled procedure Significant results in highly selected pts 2

3 breathlessness Cause: Comorbidity (COPD) Pleural fluid Trapped lung Mechanism: the presence of a pleural effusion leads to a decreased (afferent) mechanoreceptor input for a given (efferent) motor output Symptomatic treatment Strategies for pleural fluid Observation/medical treatment Thoracentesis Pleurodesis Chest drain Medical/surgical thoracoscopy Pleurectomy Chronic drainage 3

4 chemical pleurodesis CALGB (Dresler, 2005) Selected pts, 4 mesothelioma 4-5 g talc Thoracoscopy + poudrage (N= 242) vs. thoracostomy + slurry (N= 240): 78% vs. 71% (NS, unless in subgroups) Grade 3 fever, dyspnea & pain in up to 30% of pts 6% toxic deaths! Dose related? Talc most effective sclerosant Use low talc doses! recommendation In the presence of equipoise, both procedures can be used depending on institutional expertise Patient selection is important 4

5 Most physicians Patient selection Consider an expected survival beyond 2-3 m necessary to justify cost, risks and discomfort of pleurodesis Are unable to predict survival for pts with MPE PS<2 ph pleural fluid <7.3? Heffner, 2003: >50% of pts with low PF ph had improvement Pleural surfaces have to be approximated chronic drainage Pleuroperitoneal shunting (Denver) No RCT, high failure rate Chronic indwelling tunnelled pleural catheter (PleuRx ) Large institutional series, not mesothelioma specific (Tremblay, 2006) Median survival of 29 mesothelioma pts: 203 d 1 RCT vs. doxycycline pleurodesis (Putnam,1999) 144 pts, PS 0-2, no mesothelioma cases; 30% on chemotherapy PleuRx somewhat more effective shorter hospitalisation, 13% complications vs. 0 median survival 3 m Recommendation: To be considered in patients not candidate for pleurodesis Not compatible with systemic chemotherapy 5

6 palliative radiotherapy No RCT; 1 systematic review (Ung, 2006) Retrospective and uncontrolled series Palliative radiotherapy provides pain relief in about half of all patients for a median duration of 2-3 m Small volumes, short schedules preferable More effective if bone erosion or subcutaneous masses; less effective for diffuse pain and for retreatment Rarely effective for breathlessness and superior vena caval obstruction No data on QOL ERS-ESTS-recommendations (1) Palliative radiotherapy aimed at pain relief may be considered in cases of painful chest wall infiltration or nodules (2C) 6

7 Prophylactic irradiation of tracks % 10% Relative Risk: 0.47, 95% CI , p = 0.72) Ung,2006 7

8 discussion Trials not entirely comparable Underpowered Large UK RCT planned/ongoing European NW-SE gradient Enthusiasm for PIT partly explainable from an era of therapeutic nihilism Prophylactic vs. palliative track irradiation ERS-ESTS-recommendations (2) The value of prophylactic radiotherapy of tracks is questionable 8

9 Chemotherapy Currently, the only regular intervention with proven impact on outcome in MPM Presently, no role for any biological agent ERS-ESTS-recommendations (3) When a decision is made to treat patients with chemotherapy alone, patients in a good performance status should be treated with first line combination chemotherapy consisting of platinum and pemetrexed or raltitrexed (1B) 9

10 Sorensen, 2008 ERS-ESTS-recommendations (4) Administration of chemotherapy should not be delayed and should not wait for the appearance of functional clinical signs (1C). Chemotherapy should be stopped in case of progressive disease, grade 3-4 toxicities, or cumulative toxic doses (1A), or following up to six cycles in patients who respond or are stable (2C) 10

11 Personal remarks Select your patient! Good PS (WHO 0-1); fit for combination chemotherapy No prior cancer or chemotherapy Few data on 75+ patients Non-epitheloid subtype: no evidence for being predictive for absence of benefit ERS-ESTS-recommendations (5) Patients demonstrating prolonged symptomatic and objective response with first line chemotherapy may be treated again with the same regimen in the event of recurrence (2C) In other cases, inclusion of the patients in clinical trials is encouraged (2C). 11

12 Debulking surgery Pleurectomy/decortication (P/D) Several uncontrolled surgical series using open or VATS (Waller 1995) Mortality 1-2%; prolonged air leakage in 10% R2 resection Can be considered in symptomatic patients with entrapped lung syndrome who cannot benefit from chemical pleurodesis (ERS/ESTS 2C) AND with an expected survival of >6 m Controversial effect on survival (Halstead, 2005) Radical treatment Treasure,

13 Radical treatment Radical surgery: extrapleural pneumonectomy (EPP) Is considered R1 resection = rationale for its use as part of combined modality strategy Should be performed only in clinical trials, in specialized centers Radical RT: no RCT (Chapman, 2006) no survival benefit (Ung,2006) impossible because of the pulmonary toxicity Surgery followed by radiotherapy PORT 1 retrospective single institutional series (N= 62) shows a reduction in local relapse rate compared to historical series with EPP only (Rusch, 2001) Ongoing studies with pleural IMRT (Rosenzweig, 2009) on intact lung 13

14 EPP followed by adjuvant chemotherapy ± radiotherapy Only retrospective uncontrolled evidence Denominator? Sugarbaker, pts, single institutional EPP + adjuvant chemo and radiotherapy Mst 19 m; 5y SR 15% Flores, pts, 3 institutions EPP + adjuvant chemo, radiotherapy or both Adjuvant treatment > no adjuvant Poor compliance, high toxicity Neoadjuvant chemotherapy followed by EPP SAKK, 2007 US, 2009 EORTC, 2009 N/n institutions 61/6 77/9 59/11 Induction regimen Cis-gem x 3 Cis-pem x 4 Cis-pem x 3 Compliance CT 95% 83% 93% EPP (% ITT) 45 (74%) 54 (70%) 42 (74%) Operative mortality 2.2% 7% 6.5% pcr (% EPP) 0 (0) 3 (5) 2 (5) PORT completed 36 (59%) 40 (52%) 37 (65%) Median OS (ITT) 19.8 m 16.8 m 18.4 m Median OS (PP) 23 m 29 m 33 m Local relapse (% PP) NS 11 (28%) 6 (16%) Median PFS (ITT) 13,5 m 10.1 m 13.9 m 14

15 ERS-ESTS-recommendations (6) PORT should not be performed after pleurectomy or decortication (1A) PORT after EPP should only be proposed in clinical trials, in specialized centers, as a part of multimodal treatment (1A) Patients who are considered candidates for a multimodal approach should be included in prospective randomised trials in experienced centers Clinical trial of pemetrexed/cisplatin followed by surgery and radiation (SAKK 17/04 trial) 15

16 Chemotherapy vs. surgery Hillerdal, 2008 Carbo-gemc-caelyx, EP, stage 1 2, PS 0 1, <70 y Take home messages PILC 2010 All patients should receive adequate palliation of dyspnea and pain before starting chemotherapy Fit patients should be considered for palliative chemotherapy with platinum/antifolate for 4-6 cycles or even more in case of good response Sensitive patients should at relapse be considered for retreatment with chemotherapy Attempts at radical treatment should only be considered in experienced institutions and preferably as part of a clinical trial 16

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