Management of Metastatic Colorectal Cancer

Popeskou Sotirios Georgios

Contents

• Introduction
• Management of primary tumor
• Management of synchronous hepatic metastases
• Management of extra-hepatic metastases
• Discussion
Epidemiology

• 20% Distant metastatic disease at the time of diagnosis 1

• Liver : 20-30% (Overall-Synchronous)2 (3/4 Liver alone, 1/4 other visceral metastases)
Stage I: 3.7%
Stage II: 13.3%
Stage III: 30.4%

• Lung : 10-12% (Overall-Synchronous)3

2/3 associated with liver metastasis 1/3 Lung alone
Higher incidence in Rectal CA

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015; 65:5
2. Manfredi S. Epidemiology and Management of Liver Metastases From Colorectal Cancer Ann Surg 2006 Aug; 244 (2): 254-259
3. Mitry E. Epidemiology, management and prognosis of colorectal cancer with lung metastases: a 30-year population-based study. Gut. 2010 Oct;59(10):1383-8. doi: 10.1136/gut.2010.211557
Introduction

CRC
Spread

• Regional Lymph nodes

• Liver
• Lungs
Lymphatic Hematogenous Contiguous Transperitoneal • Peritoneum-Adjacent organs
• Other

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015; 65:5
2. Manfredi S. Epidemiology and Management of Liver Metastases From Colorectal Cancer Ann Surg 2006 Aug; 244 (2): 254-259
3. Mitry E. Epidemiology, management and prognosis of colorectal cancer with lung metastases: a 30-year population-based study. Gut. 2010 Oct;59(10):1383-8. doi: 10.1136/gut.2010.211557
Symptoms and signs

• Right upper quadrant pain

• Abdominal distention
• Early satiety
• Supraclavicular adenopathy
• Periumbilical nodules
• Hemoptysis, Thoracic pain, pneumothorax

Symptomatic patients in higher risk for : 3

• more invasive tumor

• higher death rates
• poorer prognosis

3. Amri R, Bordeianou LG, Sylla P, Berger DL. Impact of screening colonoscopy on outcomes in colon cancer surgery. JAMA Surg 2013; 148:747.
Pre-op Workup
• CT Scan (Chest/Abdomen)
High sensitivity for distant metastases
Low reliability for small size peritoneal implants 4
• Liver MRI
Better detection of small lesions
Better evaluation in the presence of fatty liver changes 5
• PET CT
Controversial literature. 6,7
Higher specificity and sensitivity for extra-hepatic disease than CT
Chemotherapy/Rx therapy may false results 8

Recommended for potentially curable metastatic CRC

• Pelvic MRI (extra-mesorectal metastases)

• Diagnostic Laparoscopy
• Intraoperatory U/S
• Pulmonary function tests, Brain IRM, mediastinoscopy, EBUS
4. Evaluation of preoperative computed tomography in estimating peritoneal cancer index in colorectal peritoneal carcinomatosis Ann Surg Oncol 2009 Feb;16(2):327-33
5. Sahani . Current status of imaging and emerging techniques to evaluate liver metastases from colorectal carcinoma Ann. Surg. 2014 May;259(5):861-72
6. Ruers TJ.Improved selection of patients for hepatic surgery of colorectal liver metastases with (18)F-FDG PET: a randomized study. J Nucl Med. 2009 Jul;50(7):1036-41
7. Moulton CA. Effect of PET before liver resection on surgical management for colorectal adenocarcinoma metastases: a randomized clinical trial. JAMA. 2014 May 14;311(18):1863-9
8. Galzer ES. Effectiveness of positron emission tomography for predicting chemotherapy response in colorectal cancer liver metastases. Arch Surg. 2010 Apr;145(4):340-5
 Primary Tumor management in stage IV

• No Data from RCT to guide treatment.

• Asymptomatic or not?
- Obstruction
- Bleeding
- Perforation

• Resectable metastatic disease?

• Goal:
Complete removal: Tumor with adequate margins.
Complete mesocolic/mesorectal excision
En bloc resection of contiguous structures (if possible)

Nelson H. Guidelines 2000 for colon and rectal cancer surgery J Natl Cancer Inst. 2001;93(8):583
 Primary Tumor management in stage IV

• Symptomatic Primary – Potentially resectable metastatic disease:

- Free Perforation  Emergency Surgery with oncologic resection

- Covered perforation Drainage possible (risk of tumor track spreading)

- Obstruction  Proximal Ostomy with mucous fistula

 Emergency Surgery with oncologic resection

Nelson H. Guidelines 2000 for colon and rectal cancer surgery J Natl Cancer Inst. 2001;93(8):583
Intention to Cure or Palliative Strategy
or or

Palliative Chemotherapy
treatment for
advanced
metastatic disease

National Comprehensive Cancer Network Guidelines for CRC Lung metastasis 18.6.2015
 Neo-adjuvant Chemotherapy for resectable metastatic disease

• Optimal criteria, regiment, timing related to surgery not clearly defined

• Potential to convert non-resectable to resectable
• Shown to decrease non-therapeutic laparotomies-reveals bad prognosis cases
• Can increase post-op morbidity/mortality

• Choice of chemotherapy regiment (National Comprehencive Cancer network)

FOLFOX or XELOX or FOLFIRI with or without bevacizumab
FOLFOX or FOLFIRI with or without panitumumab or FOLFIRI with or without cetuximab (wild-type KRAS only)
FOLFOXIRI with or without bevacizumab

Reddy SK. Timing of multimodality therapy for resectable synchronous colorectal liver metastases: a retrospective multi-institutional analysis. Ann Surg Oncol 2009; 16:1809.
Vauthey JN. Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol 2006; 24:2065.
Nordlinger B,. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled
trial. Lancet 2008; 371:1007.
 KRAS

• KRAS gene:- KRAS wild-type (normal)

- KRAS mutant-type

40% of CRC patients present mutant KRAS

• Clinical significance:
- No response to EGFR-inhibitor medication
- Worse Prognosis

Malapelle. AS Mutant Allele-Specific Imbalance (MASI) Assessment in Routine Samples of Patients With Metastatic Colorectal CancerJ Clin Pathol. 2015;68(4):265-269.
Valtorta. KRAS gene amplification in colorectal cancer and impact on response to EGFR-targeted therapy. 2013; Int. J. Cancer 133 (5): 1259–65
Hartman DJ.Mutant allele-specific imbalance modulates prognostic impact of KRAS mutations in colorectal adenocarcinoma and is associated with worse overall
survival. Int J Cancer 2012;131:1810–17.
 Hepatic Metastases
• Regional treatment options:
- Surgical Resection
- Radio Frequency Ablation

- Hepatic Intra-arterial Chemotherapy

- Local tumor ablation (instillation of acetic acid)
- Radiation therapy

• Surgical resection
Treatment of choice when feasible
5-year survival rates 24-58%
Surgical mortality <5%

Fernandez FG. Five-year survival after resection of hepatic metastases from colorectal cancer in patients screened by positron emission tomography with (FDG-PET). Ann Surg 2004; 240:438
Fong Y. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999; 230:309.
Abdalla EK. Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Ann Surg 2004; 239:818.
Wei AC. Survival after hepatic resection for colorectal metastases: a 10-year experience. Ann Surg Oncol 2006; 13:668.
Hepatic Metastases-Resectability

• “Old Rules”
- max 3 lesions in one lobe
- 1cm margins
- no portal lymph node involvement

• Resectable CRC Liver Metastases:

- Tumors that can be resected completely
- No hepatic artery, main portal vein involvement
- No celiac/para-aortic lymph node involvement
- Adequate post resection hepatic functional reserve
- No unresectable extra-hepatic disease
- Primary tumor resected for cure

Berri RN. Curable metastatic colorectal cancer: recommended paradigms. Curr Oncol Rep 2009; 11:200.
Adam R. Is hepatic resection justified after chemotherapy in patients with colorectal liver metastases and lymph node involvement? J Clin Oncol 2008; 26:3672.
National Comprehensive Cancer Network (NCCN). NCCN Clinical practice guidelines in oncology. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp (Accessed on April 01, 2014).
Hepatic Metastases - Chemotherapy

• Initially resectable disease:

- Neo-adjuvant chemotherapy and reevaluation
If Response or stable Resection of Primary tumor and metastases

• Initially unresectable disease:

- 5-15% conversion to permit R0 resection
- 4-9% complete response

Estimated 5-year overall survival 30-50%

Reddy SK. Timing of multimodality therapy for resectable synchronous colorectal liver metastases: a retrospective multi-institutional analysis. Ann Surg Oncol 2009; 16:1809.
Nordlinger B,. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): RCT. Lancet 2008; 371:1007.
Alberts SR, Oxaliplatin, fluorouracil, and leucovorin for patients with unresectable liver-only metastases from colorectal cancer: a North Central Cancer Treatment Group phase II study. J Clin Oncol 2005; 23:9243
Ychou M Tritherapy with fluorouracil/leucovorin, irinotecan and oxaliplatin (FOLFIRINOX): a phase II study in colorectal cancer patients with non-resectable liver metastases. Cancer Chem Pharm 2008; 62:195.
Falcone. Phase III trial of infusional FOLFOXIRI compared with infusional FOLFIRI as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol 2007; 25:1670
 Pulmonary metastases
• No standard indications- No RCT

• Often manifestation of widespread dissemination

• Metastasectomy can substantially prolong survival

• Recurrent metastasis resection offers better survival than palliative treatment

• Overall Survival affected negatively by: Rectal cancer

Elevated CEA pre-op
Multiple LM’s
Positive Hilar/mediastinal LNs

• Previously treated liver metastasis-No effect on survival

• High Reccurence Rates
Risk factors for survival after lung metastasectomy in colorectal cancer patients: a systematic review and meta-analysis.Ann Surg Oncol 2013 Feb;10(2):572-9
Salah.Pulmonary metastasectomy in CRC patients with previously resected liver metastasis. Ann Surg Onc 2015, vol 22;6; 1844-1850
Suzuki. Long-term Outcomes after surgical resection of pulmonary metastases from coloretal cancer. Ann Thor Surg 2015 vol 99;2 435-440
Pulmonary metastases
Criteria

• Complete tumor resection with adequate pulmonary function

• Extra-pulmonary metastatic disease absent or present but controlled

• Patients with resectable synchronous metastases can be resected

synchronously or using a staged approach.

• Re-resection can be considered in selected patients.

• Preoperative chemotherapy for potentially convertible disease.

National Comprehensive Caner Network Guidelines for CRC Lung metastasis 18.6.2015
 Peritoneal Carcinomatosis

• Peritoneal carcinomatosis present at 8% of CRC patients at

initial diagnosis
• Believed to be terminal condition

• CRS, Laparotomy with splenectomy, great and lesser omentectomy,

left & right subphrenic peritonectomy,stripping of Glisson’s capsule,
cholecystectomy, complete pelvic peritonectomy and resection of
the female internal genitalia using a ball electrosurgical tip.
• Removal of ALL implants >2.5mm

• HIPEC, 4 drainage tubes and 1 inflow catheter are placed intra-abdominally.

Infusion with continuous pumping of heated chemotherapy at 48 C

Esquivel.The American Society of Peritoneal Surface Malignancies (ASPSM) Multiinstitution Evaluation of the Peritoneal Surface Disease Severity Score (PSDSS) in 1,013 Patients with Colorectal Cancer with
Peritoneal Carcinomatosis Ann Surg Oncol (2014) 21:4195–4201
Sugarbaker. Surgical Management of Carcinomatosis from Colorectal CancerClinics in Colon and Rectal Surgery, volume 18, number 3, 2005
Peritoneal Carcinomatosis

Selection Criteria

• Good response to systemic therapy

• no evidence of extra-abdominal disease;
• up to three small, resectable parenchymal hepatic metastases
• no evidence of biliary obstruction;
• no evidence of ureteral obstruction;
• no evidence of intestinal obstruction at more than one site
• small bowel involvement: no evidence of gross disease in the
mesentery with several segmental sites of partial obstruction;
• small volume disease in the gastro-hepatic ligament

Esquivel. Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy in the Management of Peritoneal Surface Malignancies of Colonic Origin: A
Consensus StatementAnnals of Surgical Oncology 14(1):128–133
 Peritoneal Carcinomatosis

Retrospective Review n=1.013 70%CRS+HIPEC vs. 30% Chemotherapy alone

Median survival : CRS+HIPEC 41months vs. Chemotherapy alone 10 months
3-year survival : 66% vs. 25%
5-year survival : 58% vs. 19%

• Improved survival, optimization of quality of life

• Acceptance of CRS and HIPEC as approach 5-year survival rates of hepatic metastatic resections

• 25% of patients do NOT have a benefit (incomplete cytoreduction)

• Peritoneal Surface Disease Severity Score (PSDSS) . No need for intra-operative staging
1. Symptoms
2. Extent of dissemination determined by a CT scan
3. Primary tumor histology

Esquivel.The American Society of Peritoneal Surface Malignancies (ASPSM) Multiinstitution Evaluation of the Peritoneal Surface Disease Severity Score (PSDSS) in 1,013 Patients with Colorectal Cancer with
Peritoneal Carcinomatosis Ann Surg Oncol (2014) 21:4195–4201
Sugarbaker. Surgical Management of Carcinomatosis from Colorectal CancerClinics in Colon and Rectal Surgery, volume 18, number 3, 2005
Retroperitoneal lymph node involvement

• Isolated Retroperitoneal Lymph node metastasis <2% of CRC patients

• Salvage surgery used to be avoided due to poor prognosis
• 5-year Overall survival 0-12%
• High recurrence rates >60%

• Few Low volume Retrospective paperssmall benefit in overall survival

Choi. Extensive lymphadenectomy in colorectal cancer with isolated para-aortic lymph node metastasis below the level of renal vessels J Surg Oncol. 2010;101(1):66
Shibata D Surgical management of isolated retroperitoneal recurrences of colorectal carcinoma Dis Colon Rectum. 2002;45(6):795.
Ho. Operative salvage for retroperitoneal nodal recurrence in colorectal cancer: a systematic review Ann Surg Oncol. 2011;18(3):697.
Conclusions

• Multidisciplinary approach
• Individualized treatment according to each patient
• Evolution of Chemiotherapeutic agents
• More aggressive surgery
• New evolving techniques
References
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015; 65:5
2. Manfredi S. Epidemiology and Management of Liver Metastases From Colorectal Cancer Ann Surg 2006 Aug; 244 (2): 254-259
3. Mitry E. Epidemiology, management and prognosis of colorectal cancer with lung metastases: a 30-year population-based study. Gut. 2010 Oct;59(10):1383-8. doi: 10.1136/gut.2010.211557
4. Esquivel. Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy in the Management of Peritoneal Surface Malignancies of Colonic Origin: A Consensus StatementAnnals of Surgical
5. Oncology 14(1):128–133
6. National Comprehensive Caner Network Guidelines for CRC Lung metastasis 18.6.2015
7. Risk factors for survival after lung metastasectomy in colorectal cancer patients: a systematic review and meta-analysis.Ann Surg Oncol 2013 Feb;10(2):572-9
8. Salah.Pulmonary metastasectomy in CRC patients with previously resected liver metastasis. Ann Surg Onc 2015, vol 22;6; 1844-1850
9. Suzuki. Long-term Outcomes after surgical resection of pulmonary metastases from coloretal cancer. Ann Thor Surg 2015 vol 99;2 435-440
10. Reddy SK. Timing of multimodality therapy for resectable synchronous colorectal liver metastases: a retrospective multi-institutional analysis. Ann Surg Oncol 2009; 16:1809.
11. Nordlinger B,. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): RCT. Lancet
2008; 371:1007.
12. Alberts SR, Oxaliplatin, fluorouracil, and leucovorin for patients with unresectable liver-only metastases from colorectal cancer: a North Central Cancer Treatment Group phase II study. J Clin Oncol
2005; 23:9243
13. Ychou M Tritherapy with fluorouracil/leucovorin, irinotecan and oxaliplatin (FOLFIRINOX): a phase II study in colorectal cancer patients with non-resectable liver metastases. Cancer Chem Pharm
2008; 62:195.
14. Falcone. Phase III trial of infusional FOLFOXIRI compared with infusional FOLFIRI as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol 2007;
25:1670
15. Berri RN. Curable metastatic colorectal cancer: recommended paradigms. Curr Oncol Rep 2009; 11:200.
16. Adam R. Is hepatic resection justified after chemotherapy in patients with colorectal liver metastases and lymph node involvement? J Clin Oncol 2008; 26:3672.
17. Choi. Extensive lymphadenectomy in colorectal cancer with isolated para-aortic lymph node metastasis below the level of renal vessels J Surg Oncol. 2010;101(1):66
18. Shibata D Surgical management of isolated retroperitoneal recurrences of colorectal carcinoma Dis Colon Rectum. 2002;45(6):795.
19. Ho. Operative salvage for retroperitoneal nodal recurrence in colorectal cancer: a systematic review Ann Surg Oncol. 2011;18(3):697.
20. Fernandez FG. Five-year survival after resection of hepatic metastases from colorectal cancer in patients screened by positron emission tomography with (FDG-PET). Ann Surg 2004; 240:438
21. Fong Y. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999; 230:309.
22. Abdalla EK. Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Ann Surg 2004; 239:818.
23. Wei AC. Survival after hepatic resection for colorectal metastases: a 10-year experience. Ann Surg Oncol 2006; 13:668.
24. Evaluation of preoperative computed tomography in estimating peritoneal cancer index in colorectal peritoneal carcinomatosis Ann Surg Oncol 2009 Feb;16(2):327-33
25. Sahani . Current status of imaging and emerging techniques to evaluate liver metastases from colorectal carcinoma Ann. Surg. 2014 May;259(5):861-72
26. Ruers TJ.Improved selection of patients for hepatic surgery of colorectal liver metastases with (18)F-FDG PET: a randomized study. J Nucl Med. 2009 Jul;50(7):1036-41
27. Moulton CA. Effect of PET before liver resection on surgical management for colorectal adenocarcinoma metastases: a randomized clinical trial. JAMA. 2014 May 14;311(18):1863-9
28. .Galzer ES. Effectiveness of positron emission tomography for predicting chemotherapy response in colorectal cancer liver metastases. Arch Surg. 2010 Apr;145(4):340-5
29. . Amri R, Bordeianou LG, Sylla P, Berger DL. Impact of screening colonoscopy on outcomes in colon cancer surgery. JAMA Surg 2013; 148:747.