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C. Manegold



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    MS14 - Interface Between Disease Modifying Treatment and Palliation (ID 31)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Supportive Care
    • Presentations: 1
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      MS14.2 - Decision Making; When to Stop Disease Modifying Treatment (ID 522)

      14:25 - 14:45  |  Author(s): C. Manegold

      • Abstract
      • Presentation
      • Slides

      Abstract
      Decision making in advanced NSCLC undoubtedly should primarily consider evidence based treatment standards recommended by international guidelines (1, 2) According to international guidelines, decision making in 2013 is characterized by customizing therapy in advanced non-small cell lung cancer, by selecting a specific therapeutic regimen based on tumor histology and molecular biology. This refers to first-line therapy in patients with good performance status, but also to subsequent lines of therapy since antineoplastic drugs and regimens used in induction therapy directly influence the selection of agents/regimens considered for second/third-line treatment. The availability of antineoplastic monoclonal antibodies, small molecules and newer cytotoxic such as pemetrexed, the antiangiogenic bevacizumab as well as the tyrosine kinase inhibitors erlotinib, gefitinib and crizotinib has recently changed the treatment algorithm of advanced NSCLC. Therapy optimization by modern medical therapy is characterized by treatment individualization based on predictive factors. This process seems to continue since other products holding considerable promise for the near future such as tumor vaccines and other immunotherapeutic approaches, anti-angeniogenic agents, and newer EGFR-targeting monoclonal antibodies have already reached the level of phase III-testing or the registration process. Today’s recommendation can be summarized as follows: First-line therapy: In patients with good performance status with non-squamous tumors haboring an activating EGFR-mutation, an EGFR tyrosine kinase inhibitor may be the leading option, not only because of being active but also because of its feasibility and improved toxicity profile (3-5). In patients with non-squamous cell tumors not expressing EGFR-mutations, combination therapy remains standard with pemetrexed as the preferred partner of cisplatin (6). Furthermore, it has been demonstrated that in non-squamous NSCLC the addition of bevacizumab to standard doublet therapy improves survival (7, 8). With regard to patients with squamous cell tumors gemcitabine, vinorelbine or taxanes in combination with platinum-based agents remain the chemotherapeutic standards. Bevacizumab and pemetrexed are not recommended in squamous cell tumors either because of the agents toxicity profile (bevacizumab) or because of being less effective in this particular histological subtype (pemetrexed). For elderly patients not being fit for standard doublet chemotherapy medical treatment requires modification. Here single agent therapy is widely considered to be the preferred option for maintaining quality of life, reducing tumor association symptoms and improving survival (9). Fit elderly patients benefit from combination chemotherapy as much as younger patients and platinum-based chemotherapy is recommended as well (10, 11). Combination therapy remains investigational in patients with poor performance status (≥ PS 2), and single agent chemotherapy is the preferred option (12). Second-line therapy: In patients with disease progression during or after completion of induction (first-line) chemotherapy second-line therapy is indicated if the patient remains in good clinical condition. Selection of drugs for second-line therapy is based on whether the drug has been used earlier, the toxicity profile or the patients wish. The approved options for second-line therapy are docetaxel and pemetrexed (in case of non-squamous histology), erlotinib and gefitinib (in tumors expressing activating EGFR-mutations) (13-16). Crizotinib has recently been registered for second-line therapy in ALK-positive tumors (17). Maintenance therapy: The prolongation of induction therapy represents an evidence based new option to improve outcome in advanced NSCLC, in general and with strong implications for second line therapy, in particular. Three randomized studies investigated pemetrexed and erlotinib as maintenance therapy following 4 cycles of chemotherapy (18-21). In these trials switch-early second-line- (pemetrexed, erlotinib) or continuation-true- (pemetrexed) maintenance therapy has significantly increased PFS and OS. Based on this given evidence these two compounds have been registered for maintenance therapy in patients with advanced NSCLC, not progressing following 4 cycles of first-line standard platinum-based therapy. According to the European Medicines Agency (EMA) pemetrexed is indicated as monotherapy for maintenance treatment of locally advanced or metastatic NSCLC other than predominantly squamous cell histology in patients who’s disease has not progressed immediately following platinum-based chemotherapy, including platinum-pemetrexed combinations, and erlotinib is indicated as monotherapy for maintenance treatment in patients with locally advanced or metastatic NSCLC with stable disease after 4 cycles of standard platinum-based first-line therapy. When prescribing erlotinib, clinical factors associate with prolonged survival should be taken into account. There is clearly more which must be considered and which would lead to stop or even not to initiate a modern medical therapy. Even if national and international treatment recommendations undoubtedly represent the backbone of the decision making process, the management of patients with advanced non-small cell lung cancer often clinically requires modification for a number of reasons not necessarily considered by guidelines.This refers to first and subsequent-line treatment as well. The majority of lung cancer patients are older patients and often express specific age related treatment expectations. Other relevant factors for decision making in a non-curative setting are patient social environment and patient psychological status, regulations of national health care providers and reimbursement systems, drug availability, diagnostic and health care infrastructure. These circumstances modify decision making and lead to the use of older agents and regimens, to changes in dosing and scheduling of newer agents and regimens, to single agent therapy, to a reduction of treatment cycles and to a more free indication of best supportive care measures. Our increased understanding of the molecular biology of lung cancer and the change of its epidemiology has opened up venues for more rational treatment strategies and at the same time has challenged the additional diagnostic algorithms, the established health care financing and the complex process of drug development. Customized therapy and therapeutic targeting were made possible through the identification of new treatment predictors and the development of a number of antineoplastic agents which have shown clinical evidence for being more beneficial then the treatment standard in selected patients. Consequently, therapy individualization by histology and molecular markers has significantly influence the work of pathologists around the globe and the process of obtaining a therapeutically relevant tumor diagnosis. Not only histological sub-typing becomes clinical relevant but molecular information is also of increasing importance for treatment selection. Routine molecular testing in certified laboratories must be established, and this diagnostic process should ideally performed under the guidance of evidence based recommendation such as the recently published guidelines from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology for the molecular testing to select patients for EGFR-ALK-thyrosine kinase inhibitors (22). This process requires advanced diagnostic techniques and expertise. Investigating and implementing medical targeting in lung cancer because of its large dimension is costly and characterize by the limitation of financial and clinical resources, and currently not every where available. Since the majority of large randomized phase III trials during the last decade turned out negative in their primary endpoints, the time of conducting trials on large unselected patient population seems definitely over and the classical investigational strategy must probably be replaced by smaller trials in selected patients, and trials using study endpoints which can function as substitutes for the traditional overall survival endpoints (23). This inevitable change in the altitude of conducting clinical trials will increase the need for patients treated in clinical trials and, therefore, has a significant impact in decision making in advanced NSCLC. Another hurdle for making promising therapies difficult to be generally prescribed are that clinical evidence of being beneficial and the scientific rational do not necessarily equal clinical practicability and reimbursement in a given cultural and economic system. For Europe and specifically Germany it is important that an agent has reached a positive vote by the registration agency EMA and that it find acceptance by the national health care providers responsible for reimbursement. For this reasons the clinical evidence of being beneficial must be well documented and strong. Information about treatment selection by predictive factors and treatment restriction to patients who benefit the most is very welcome. In addition, if the treatment selection requires advanced diagnostic testing generally accepted and validated methods should easy to be reached and should provide reliable and reproducible results by at the same time being cost effective. References: 1. Azzoli et al, J Clin Oncol 29, 3825-3831, 2011 2. Peters et al, Ann Oncol 23 (suppl. 7), 56-64, 2012 3. Mok et al et al, N Engl J Med 361, 947-957, 2009 4. Zhou et al, Lancet Oncol 12, 735-742, 2011 5. Rosell et al, Lancet Oncol 13, 329-346, 2012 6. Scagliotti et al, J Clin Oncol 26, 3543-3551, 2008 7. Sandler et al, N Engl J Med 355, 2542-2550, 2006 8. Reck et al, J Clin Oncol 27, 1227-1235, 2009 9. Gridell et al, J Natl Cancer Inst 95, 362-372, 2003 10. Langer et al, J Clin Oncol 22 (suppl), 639 (abstr. 2571), 2003 11. Quoix et al, Lancet 378, 1079-1088, 2011 12. Gridelli et al, Ann Oncol 15, 419-426, 2004 13. Shepherd et al, J Clin Oncol 18, 2095-2103, 2000 14. Hanna et al, J Clin Oncol 22, 1589-1597, 2004 15. Thatcher et al, Lancet 366, 1527-1537, 2005 16. Douillard et al, J Clin Oncol 28, 744-752, 2010 17. Shaw et al, N Engl J Med 368, 2385-2394, 2013 18. Capuzzo et al, Lancet Oncol 11, 521-529, 2010 19. Ciuleanu et al, Lancet 374, 1432-1400, 2009 20. Paz-Ares et al, Lancet Oncol 13, 247-255, 2012 21. Paz-Ares et al, J Clin Oncol 31, 2895-2902, 2013 22. Lindeman et al, J Thoracic Oncol 8, 823-859, 2013 23. Pilz and Manegold, Memo 6, 92-97, 2013

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