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New Drugs for Gastrointestinal, Ovarian, and Lung Cancer: Open Issues in Oncology

This conference in Rome on 20-21 May 2016 will discuss innovative strategies for gastrointestinal cancer, with a focus on a clinical case presentation of an intensive treatment strategy in a fit RAS mutant long-surviving metastatic colorectal cancer patient. Topics will include diagnosis, treatment strategies, and prognostic biomarkers.

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New Drugs for Gastrointestinal, Ovarian, and Lung Cancer: Open Issues in Oncology

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  1. Open issues in Oncology: new drugs for gastrointestinal, ovarian and lung cancer Rome, 20-21 May 2016 Innovative strategies for gastrointestinal cancer Clinical case presentation Intensive treatment strategy in fit RAS mutant long-surviving metastatic colorectal cancer patient Gemma Bruera, Enrico Ricevuto Oncology Territorial Care S. Salvatore Hospital Oncology Network ASL1 Abruzzo Dpt of Biotechnological and Applied Clinical Sciences University of L’Aquila

  2. Oncologic Hystory • C.M., M, 72 years • Comorbidities: None, primary Cumulative Illness Rating Scale (CIRS) • Familial history: C2 • 06/08/2013 Right emicolectomy pT3 pN0 (0/12) KRAS mutant c.35 G > A, MLH1, MSH2, MSH6 + • DFS 9 months • Evidence of liver and lung metastases (Other/Multiple metastatic sites) Bruera G et al, BMC Medicine 2012; 10(1):135 Bruera G et al, BioMed Res Int 2013:143273 Bruera G et al, BMC Medicine, 2013; 11 (1):59 2 2

  3. Questions: Diagnosis • Clinical correlation between RAS genotype and risk of metachronous metastases • Specific clinical management/follow-up of early RAS mutant CRC • Prognostic and predictive relevance of MMR protein loss (and/or MI) in clinical management of early CRC • Innovative prognostic and predictive biomarkers (CDX2) in clinical management of early CRC 3 3

  4. Diagnosis of metastatic disease • 20/09/2011 CT: “...submantellar lung node at right inferior lobe.. liver subcapsular node (12 mm)…”, confirmed by PET. • Tumor markers negative 4 4

  5. Questions: Treatment strategy • First line treatment strategy in • Young-elderly MCRC patient • Liver and lung metastases • KRAS mutant 5 5

  6. I line treatment • 10/11/2011 – 12/03/2012: 5-fluorouracile 900 mg/m2/die d1-2, 8-9, 15-16, 22-23 - irinotecan 160 mg/m2 d1,15 – bevacizumab 5 mg/kg d1,15 - oxaliplatin 80 mg/m2 d8,22, every 28 days, for 4 cycles (FIr-B/FOx schedule) • Received dose-intensity: 100% • Safety: G1 nausea, G1 asthenia, G1 neurotoxicity, G1 hypertension, G1 gengivorragia, G1 epistaxis, G1 leucopenia, G2 neutropenia. Ficorella C et al, Oncol Rep 2006; 15(5):1345-1350 Morelli MF et al, Oncol Rep 2010; 23(6):1635-40 Bruera G et al, BMC Cancer 2010, 10:567 Bruera G et al, BioMed Res Int 2013:143273 Ficorella C, Bruera G, et al. Clin Colorectal Cancer, 2012;11(4):229-237 6 6

  7. Limiting toxicity syndromes (LTS): FIr-B/FOx Bruera G et al, BMC Cancer 2010, 10:567 Bruera G et al, BioMed Res Int 2013, 2013:143273 7

  8. I line treatment • Evaluation of response: • 11/01/2012 CT (after 2 cycles): severe reduction of secondary lung and liver nodes • 19/03/2012 CT (after 4 cycles): complete response of lung metastasis, severe reduction of secondary liver nodes. 8 8

  9. Secondary liver surgery • 20/04/2012 Left hepatectomy and resection of VII segment Histology: pathologic complete response. Liver damage: fibrosis (F1-F2) with lymphoplasmacellular infiltrate (peacemeal-necrosis), steatosis (10-15% hepatocytes), hepatitis. • 21/05/2012 CT scan: negative • 06/06/2012 – 12/09/2012: FIr-B/FOxfor 3 cycles • Follow-up negative • PFS 35 months, PFS surgery 30 months, off-treatment 25 months • 08/10/2014 CT scan: evidence of lung, lymph nodes, and liver metastases Bruera G et al, Clin Colorectal Cancer 2012; 11(2):119-126 Bruera G et al, BMC Medicine 2012; 10(1):135 Bruera G et al, BioMed Res Int 2013:143273 9 9

  10. PFS OS 12 months 31 months Patient Fitness MCRC Fit (44%) I Line I Line FIr-B/FOx + Liver Surgery 10 Bruera G et al, BMC Cancer 2010;10:567

  11. OS Other/Multiple Mets (56%) Liver-Limited (44%) 21 months Metastatic extension MCRC Fit (44%) Unfit (56%) I Line FIr-B/FOx + Liver Surgery PFS 12 months 17 months 47 months Bruera G et al, Clin Colorectal Cancer 2012; 11(2):119-126 Bruera G et al, BMC Medicine 2012; 10(1):135

  12. Other/Multiple Mets (52%) Liver-Limited (48%) KRAS mutant genotype MCRC Fit (47%) Unfit (42%) I Line FIr-B/FOx + Liver Surgery PFS OS Bruera G et al, BMC Medicine 2012; 10(1):135 Bruera G et al, Crit Rev Oncol Hematol 2015; 93(3):190-202 12

  13. c.35 G>A mutant (25%) Wild-type (53%) PFS c.35 G>A KRAS mutant genotype MCRC Fit (44%) Unfit (56%) I Line FIr-B/FOx + Liver Surgery Conventional Treatments OS Bruera G et al, BMC Medicine 2013; 11(1):59 Bruera G et al, Crit Rev Oncol Hematol 2015; 93(3):190-202 13

  14. c.35 G>A mutant (25%) Other mutant (22%) c.35 G>A KRAS mutant genotype MCRC Fit (44%) Unfit (56%) I Line FIr-B/FOx + Liver Surgery Conventional Treatments PFS OS Bruera G et al, BMC Medicine 2013; 11(1):59 Bruera G et al, Crit Rev Oncol Hematol 2015; 93(3):190-202 14

  15. Disease progression • 08/10/2014 CT: “...lung nodes at medium lobe and right laterobasal segment…multiple confluent lymph nodes at right ilum (2 cm)... subcapsular node (17 mm) VII liver segment…”, confirmed by PET, with evidence of pathologic thickening of rectum-sigma. • 13/11/2014 Colonscopy: “…perianastomotic thickening of mucosa..” Histology “…infiltrating adenocarcinoma..” • Tumor markers negative 15 15

  16. II line treatment • 17/11/2014 – 16/02/2015: 5-fluorouracile 800 mg/m2/die d1-2, 8-9, 15-16, 22-23 - irinotecan 140 mg/m2 d1,15 – bevacizumab 5 mg/kg d1,15 – oxaliplatin 70 mg/m2 d8,22, every 28 days, for 3 cycles (FIr-B/FOx re-challenge) • Received dose-intensity: 100% • Safety: G1 nausea, G1 anorexia, G1 asthenia, G1 neurotoxicity, G1 hypertension, G1 gengivorragia, G1 epistaxis, G1 leucopenia, G2 neutropenia. Bruera G et al, Int J Oncol 2014; 44: 17-26 16 16

  17. II line treatment • Evaluation of response: • 25/02/2015 CT: partialresponse of lungnodes (30%) • 25/03/2015– 17/06/2015: other 3 cycles of FIr-B/FOx re-challenge • Ongoingmaintenancetherapy: bevacizumab/capecitabine (PFS 16 months+) OS: 4 years, 6 months+

  18. Triplet CT/targeted agent (18.5%) Other treatments (81.5%) II Line Re-challenge MCRC Fit (44%) Unfit (56%) I Line FIr-B/FOx + Liver Surgery Conventional Treatments Triplet or Re-challenge (80%) PFS OS Bruera G et al, Int J Oncol 2014; 44: 17-26 18

  19. Triplet CT/targeted agent (18.5%) Triplet regimens (35.2%) II Line Re-challenge MCRC Fit (44%) Unfit (56%) I Line FIr-B/FOx + Liver Surgery Conventional Treatments Triplet or Re-challenge (80%) PFS OS Bruera G et al, Int J Oncol 2014; 44: 17-26 19

  20. c.35 G>A mutant (20%) Wild-type (55%) II Line c.35 G>A KRAS mutant MCRC Fit (44%) Unfit (56%) I Line FIr-B/FOx + Liver Surgery Conventional Treatments Triplet or Re-challenge (80%) PFS OS Bruera G et al, Int J Oncol 2014; 44: 17-26 Bruera G et al, Crit Rev Oncol Hematol 2015; 93(3):190-202 20

  21. c.35 G>A mutant (20%) Other mutant (25%) II Line c.35 G>A KRAS mutant MCRC Fit (44%) Unfit (56%) I Line FIr-B/FOx + Liver Surgery Conventional Treatments Triplet or Re-challenge (80%) PFS OS Bruera G et al, Int J Oncol 2014; 44: 17-26 Bruera G et al, Crit Rev Oncol Hematol 2015; 93(3):190-202 21

  22. QuestionsMedical Oncologist • First line medical treatment (intensive versus conventional) • Modulation of first line treatment strategy in elderly patients • Prognostic relevance of metastatic extension and treatment choice • Medical treatment strategy after radical resection of metastases: wait & see, n. of cycles, biologic agents, same treatment? • Second line treatment strategies: also including re-challenge? 22 22

  23. QuestionsSurgeon • Timing of evaluation of response: n. of cycles • Double resection of liver and lung metastases • Surgery after clinical complete response • Liver metastasectomy after clinical complete response of extra-hepatic metastases • Liver damage after chemotherapy (morbidity/mortality) • Imaging and intra-operative detection of liver metastases (i.o. US) 23 23

  24. QuestionsPathologist • Liver damage after chemotherapy • Definition of pathologic complete response • Molecular discrepancy between primary tumor and metastases, pre- and post-treatment • Multi-genes characterization (RAS, BRAF, and…?) • Conventional molecular diagnostics versus NGS in clinical practice: validation, clinical implications, cost-effectiveness 24 24

  25. QuestionsRadiotherapist • Role of loco-regional therapies in metastatic disease • Stereo-tactic approach in single lung/liver metastases 25 25

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