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Neoadjuvant and Adjuvant Chemotherapy for Liver Limited Metastases from Colorectal Cancer

Neoadjuvant and Adjuvant Chemotherapy for Liver Limited Metastases from Colorectal Cancer. Heinz-Josef Lenz , MD FACP Professor of Medici ne USC Norris Comprehensive Cancer Center. Questions. When to treat with chemotherapy What is the right chemotherapy prior surgery

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Neoadjuvant and Adjuvant Chemotherapy for Liver Limited Metastases from Colorectal Cancer

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  1. Neoadjuvant and Adjuvant Chemotherapy for Liver Limited Metastases from Colorectal Cancer Heinz-Josef Lenz, MD FACP Professor of Medicine USC Norris Comprehensive Cancer Center

  2. Questions • When to treat with chemotherapy • What is the right chemotherapy prior surgery • When to do the surgery for primary and liver metastases • What is the right chemotherapy after surgery

  3. Outline of Presentation • Overview • Therapy for Initially Resectable Liver Metastases • Therapy for Initially Unresectable Liver Metastases • Summary

  4. Hepatic Metastases from Colorectal Cancer • Approximately 30 to 40% of patients will have liver-only metastases at time of recurrence • Approximately 20 to 30% will have liver-only metastases at the time initial evaluation 25-30,000 patients with Liver-only metastases

  5. LIVER METASTASES location RESECTABLE 20-25% NON RESECTABLE 75-80% number size Downsizing RESECTABLE 10-20% SURVIVAL BENEFIT 30-40% AT 5 YEARS 15% AT 10 YEARS

  6. Therapy for Initially Resectable Liver Metastases

  7. Results of liver surgeryfor metastatic CRC (N > 100) N. of patients Operative mort 5-yr survival Adson, 1984 (1) 141 2.8% 23% Hughes, 1988 (2) 859 - 33% Doci, 1991 (3) 100 5% 30% Scheele, 1991 (4) 219 6% 39% Rosen, 1992 (5) 280 4% 25% Nordlinger, 1992 (6) 1818 2.4% 26% Gayowski, 1994 (7) 204 0% 32% Rees, 1997 (8) 114 1% 37% 1 - MA. Adson et al., Arch. Surg., 1984; 119: 647-51 5 - CB. Rosen et al., Ann. Surg., 1992; 216: 493-5052 - KS. Hugues, Surgery, 1988; 103: 278-88 6 - B. Nordlinger et coll., Ed. Paris Springer-Verlag, 1992; 141-593 - R. Doci et al., Br. J. Surg., 1991; 78: 797-801 7 - TJ. Gayowski et al., Surgery, 1994; 116: 703-11 4 - J. Scheele et al., Surgery, 1991; 110: 13-29 8 - M. Rees et al., Br. J. Surg., 1997; 84: 1136-40

  8. NCCN GUIDELINES 2007 “Patients who have completely resected liver metastases should be offered 4 to 6 months of adjuvant chemotherapy… observation or a shortened course of chemotherapy is considered for patients who have completed neoadjuvant chemotherapy.”

  9. Adjuvant Chemotherapy May reduce the risk of recurrence • Focus of completed and current trials • Systemic chemotherapy • Hepatic artery infusion (HAI)

  10. Adjuvant ChemotherapyMemorial Sloan-Kettering Randomized Study HAI + systemic CT Systemic CT #Pts 2-yr survival#Pts 2-yr survivalp-value Survival 74 86% 82 72% 0.03 Hepatic DFS 74 90% 82 60% <0.001 Any DFS 74 57% 82 42% 0.07 1 Liver Met 27 72% 33 79% 0.55 2-4 Liver Mets 33 97% 34 60% 0.0003 >4 Liver Mets 14 84% 15 64% 0.24 Positive Margins 10 90% 11 44% 0.02 NEJM 341:2039, 1999

  11. Overall Survival among Patients Treated with Hepatic Arterial Infusion plus Systemic Chemotherapy (Combined Therapy) or with Systemic Chemotherapy Alone (Monotherapy) Median: 68.4 months Median: 55.2 months Kemeny, N. E. et al. N Engl J Med 2005;352:734-735

  12. Adjuvant ChemotherapyMemorial Sloan-Kettering Randomized Study Site of recurrence HAI group Systemic group Lung 15 (50%) 17 (38.6%) Liver 7 (23.3%) 30 (68.2%) Ovaries 4 (13.3%) 1 (2.3%) Bone 3 (10%) 3 (6.8%) Pelvis 4 (13.3%) 7 (15.9%) Lymph nodes 3 (10%) 10 (22.7%) Other 6 (20%) 6 (13.6%)

  13. N9945 - Preliminary Results • 54 of 70 patients initiate HAI FUDR + SYS • 52% had a solitary metastases and 24% presented with bilobar metastases • No post-operative or treatment related deaths were reported • Primary endpoint: 2-yr survival (2YS), with 80% of patients surviving 2 yrs as evidence of promising efficacy • 78% (42/54) of evaluable patients are alive with a minimum 28 months of follow-up • 6 deaths occurred in less than 2 yrs • 48% (26/54) have recurred, with 42% having liver involvement • Median time-to-progression is 30 months with an estimated 2YS rate of 88% (95% CI 76-97%)

  14. Adjuvant Chemotherapy - Current and Future StudiesC-09: Metastasectomy followed by with Oxaliplatin and Capecitabine +/- FUDR Open – Planned Accrual 400 Capecitabine + Oxaliplatin Resection of liver metastases (1-6) Randomize Capecitabine + Oxaliplatin alternating with HAI FUDR

  15. ALMCAO AGITG g Peri-operative FOLFOX4 chemotherapy and surgery for resectable liver metastases from colorectal cancerFinal efficacy results of the EORTC Intergroup phase III study 40983. B. Nordlinger, H. Sorbye, B. Glimelius, G.J. Poston, P.M. Schlag, P. Rougier, W.O. Bechstein, J. Primrose, E.T. Walpole, T. Gruenberger Statistical analysis L. Collette For the EORTC GI Group, CR UK, ALMCAO, AGITG and FFCD

  16. Trial Design and Objectives FOLFOX4 x 6 cycles FOLFOX4 x 6 cycles Surgery R • 364 patients • Potentially resectable (1-4) liver metastases • Goal: Improve progression-free survivalto demonstrate a 40% increase in median PFS (HR=0.71) with 80% power and 2-sided significance level 5% Surgery

  17. Pre-Operative Assessment • Outcome in chemotherapy arm • CR: 3.3% • PR: 35.2% • Stable: 33.5% • Progression 7.7% • Not evaluable: 20.3%

  18. Surgery

  19. Results

  20. Progression-free survival in eligible patients HR= 0.77; CI:0.60-1.00, p=0.041 100 90 +8.1%At 3 years Periop CT 80 70 60 50 36.2% 40 Surgery only 30 28.1% 20 10 0 (years) 0 1 2 3 4 5 6 O N Number of patients at risk : 125 171 83 57 37 22 8 115 171 115 74 43 21 5

  21. SURGERY FOLFOX6 modified + cetuximab + bevacizumab 6 cycles (no bevacizumab in cycle #6) FOLFOX6 modified + cetuximab + bevacizumab 6 cycles Resectable Liver Metastases from Colorectal Cancer no extrahepatic disease WHO PS 0,1 No previous chemo for mets follow up RANDOMIZATION SURGERY FOLFOX6 modified + cetuximab 6 cycles FOLFOX6 modified + cetuximab 6 cycles follow up Trial 40051 (BOS)

  22. Resectable Liver Metastases Summary • Studies support role for adjuvant therapy • Value of HAI-based therapy to be assessed

  23. Therapy for Initially Unresectable Liver Disease

  24. LIVER METASTASES location RESECTABLE 20-25% NON RESECTABLE 75-80% number size Downsizing RESECTABLE 10-20% SURVIVAL BENEFIT 30-40% AT 5 YEARS

  25. DEFINITIONS: ASCO 2006 LIVER THINK TANK • Neoadjuvant Therapy - Preoperativesystemic therapy for resectable hepatic metastases followed by post resection therapy. • Adjuvant Therapy - Systemic/regional therapy post hepatic resection. • Conversion Therapy – Systemic/regional therapy utilized for patients with unresectablehepatic metastases in an attempt to make the metastases resectable .

  26. Hepatic Artery Infusion (HAI)for Unresectable Liver Metastases

  27. CALGB 9481: HAI FUDR versus Systemic 5FU and Leucovorin Eligibility • Liver-only, unresectable metastases from CRC • No prior therapy for metastatic CRC HAI FUDR 0.18 mg/kg + DEX 25 mg over 14 days Every 28 days (N = 68) R 5-FU 425 mg/m2 + LV 20 mg/m2 Daily x 5 every 4 weeks (N = 67) Kemeny NE et al. J Clin Oncol 24:1395-1403, 2006

  28. CALGB 9481: Overall Survival HAI5FU/LV Med OS (months) 24.4 20.0 (p=0.034) THP (months) 9.8 7.3 (p=0.034) TEP (months) 7.7 14.8 (p=0.029) RR 47% 24% HAI 5FU/LV

  29. 1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 0 0 0 0 1 1 2 2 3 3 CALGB 9481: Hepatic vs Nonhepatic Disease Progression Hepatic Nonhepatic HAI HAI Systemic, P=0.034 Systemic, P=0.029 Proportion hepatic progression–free Proportion nonhepatic progression–free Years from trial entry Years from trial entry Kemeny et al. J Clin Oncol. 2006;24:1395.

  30. HAI as Neoadjuvant Therapy for Initially Unresectable Disease Potential Limitations • Invasive • Percutaneously placed catheters have a high rate of complications • Surgical placement may delay systemic therapy • Lack of treatment for potential extrahepatic disease • Limited studies

  31. Role of Neoadjuvant Systemic Chemotherapy for Liver-only Metastases

  32. Resection of non-resectable liver metastases after systemic chemotherapy Published series No Resect 18 (19%) 11 53 (16%) 77 (20%) 95 (14%) 6 (11%) 57 (43%) Authors Levi Fowler Bismuth Giachetti Adam Wein Rivoire Year 1992 1992 1996 1999 2001 2001 2002 No Pts 98 - 330 389 701 53 131 Type Chemo Fu-Fol-Oxali Fu-Fol Fu-Fol-Oxali Fu-Fol-Oxali* Fu-Fol-Oxali Fu-Fol Fu-Fol-Oxali 5-yr Surv - - 40% 50% 39% - - * Fu-Fol-Oxali : Chronomodulated Liver only metastases

  33. 100 80 60 Survival (%) 40 20 0 1 2 3 4 5 6 7 8 9 10 Years Survival after Liver Resection of Colorectal Metastases Paul Brousse Hospital - 473 patients (Apr. 88 - Jul. 99) 91% Resectable : 335 Initially non resectable : 138 66% P= 0.01 48% 30% 52% 33% 23% No Surgery Adam R et al. Ann Surg 2004

  34. Collaboration : Oncologists - Surgeons For Non Resectable Metastases 1- Current chemotherapy allows at least 20% of patients to be rescued by liver surgery 2- The survival benefit of these patients is substantial (30% and 20% rate at 5 and 10 years) 3- Resectability: a new end point for treatment strategy

  35. Neoadjuvant Oxaliplatin Paul Brousse Hospital Study Initially non-resectable Non-resectable Resectable Chemo: 701 (80%) 872 patients 1988 - 1996 900 Chemotherapy 14% 800 700 14% of 701 CT-treated patients achieved a response permitting resection 600 500 86% 400 Resection: 266 (31%) 300 95 36% 200 171 100 171 64% 0 Adam R. et al., Ann. Surg. Oncol., 2001; 8: 347-353

  36. 95 patients 39 alive (41%) 25 alive disease free (26%) 14 alive with disease (15%) Role of Neoadjuvant Treatment Patient status at a mean follow-up of 4.2 years 56 dead (59%)

  37. Survival after primary or secondaryresection of liver metastases

  38. N014A: Resection of Unresectable CRC Limited to the Liver Using FOLFOX6 + Cetuximab CR/PR resectable  O.R.  CT x 2 PR, unresectable  Rx to Prog/Tolerability Prog  Off Study, Rx per M.D. • Endpoints: Resectability, Response Rate, Survival Oxaliplatin+5-FU/LV (FOLFOX6) + C225 Evaluation

  39. Specific Chemotherapy Associated Hepatic Toxicity • Irinotecan – Steatohepatitis • Oxaliplatin – Sinusoidal/vascular injury • Acute & chronic clinical sequelae • Biologics - ???? • Bevacizumab – 6 to 8 wks before resection • Liver regeneration & hemorrhage • Morbidity is increased with prolonged course of chemotherapy (Aloia et al, J Clin Oncol, 2006)

  40. Liver Toxicity of Neoadjuvant Therapy • Patients with steatohepatitis had an increased 90-day mortality compared with patients who did not have steatohepatitis (P=0.001) *Comparison of each group vs no chemotherapy. Vauthey et al. J Clin Oncol. 2006;24:2065.

  41. Vascular Changes in Liver Post Systemic Chemotherapy Aloia et al, J Clin Oncol 24: 4983,2006 Peliosis: Vasodilation & Congestion Hepatic atrophy & sinusoidal congestion ▼ ▼ Hemorrhagic Centrilobular Necrosis Nodular Regenerative Hyperplasia

  42. Collaboration Oncologists - Surgeons for Timing of Surgery after Chemotherapy… • As soon as the metastases become resectable… • Not to miss the « good » therapeutic window: Tumoral progression: Surgery even potentially curative, has poor results • Not to « overtreat » the patient • Complete response: a major problem for the surgeon • with however a minority of pathology-proven necrosis • Hepatotoxicity: a clinical impact related to duration

  43. Studies including selected patients(liver metastases only, no extrahepatic disease) (r=0.96; p=0.002) Studies including nonselected patients with mCRC (solid line) (r=0.74; p<0.001) Phase III studies including nonselected patientswith mCRC (dashed line) (r=0.67; p=0.024) Impact of Increasing Response Rates 0.6 0.5 0.4 0.3 Resection rate 0.2 0.1 0 0.3 0.4 0.5 0.6 0.7 0.8 0.9 Response rate Folprecht G, et al. Ann Oncol 2005;16:1311–1319

  44. FOLFIRI alone ERBITUX + FOLFIRI CRYSTAL Trial: Surgery with Curative Intent ITT population Liver-limited disease population p=0.0034* odds ratio 3.0 [95% CI: 1.4 - 6.5] No residual tumor in patients with liver metastases n=599 / group n=599 / group n=134 / n=122 *CMH test Van Cutsem et al, ASCO 2007

  45. OncoSurgical strategies in liver metastasesfrom palliative to curative… Survival Curative Palliative Time

  46. Summary - Unresectable Liver Metastases • Patients with liver metastases benefit from chemotherapy followed by surgery • Oxaliplatin-containing regimens render an additional 10% or more patients resectable • Use of CPT-11 less well studied • Role of HAI remains uncertain • Response-enhancing agents needed • Potential for chemotherapy-induced liver disease

  47. Overall Summary • Options available for patients in the adjuvant, perioperative, and neoadjuvant settings • Patients amenable to surgery have a better outcome, even if recurrence • Variety of new studies open or in development

  48. Overall Summary • Management requires multidisciplinary approach • Medical Oncology • Surgery • Radiology • Development of practice guidelines

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