Management ofMetastatic Colorectal Cancer Dr Sujay Susikar Post Graduate Student Department of Surgical Oncology Government Royapettah Hospital
The challenges of metastatic CRC • A significant number of patients present with ~40% metastatic disease ~50% • Many newly diagnosed patients eventually develop metastatic disease5-year survival rate — 2% (if unresectable) to 50% (if resectable)
Management of synchronous metastasis Non Systemic Synchronous obstructing therapy addominal/ peritoneal Colon resection/ mets Obstructing or diverting Systemic imminent colostomy/ therapy obstruction bypass/ stentingSynchronous Metastatic colorectal carcinoma Colectomy with synchronous or staged resection OR neoadjuvant Resectable chemo OR colectolmy Adjuvant therapy F/B chemo and staged resection Synchronous liver and /or lung only mets Converted to resectable – synchronous or staged resection Unresectable Systemic therapy Remains unresectable – continuum of care
Management of potentially resectable colorectal cancer liver metastasesRegional treatments for hepatic metastases from CRC Surgical resection Local tumor ablation Percutaneous injection Cryotherapy, Radiofrequency ablation Regional hepatic intraarterial chemotherapy Chemoembolization, Radiation therapy (RT). Only surgery is associated with a survival advantage
Management of potentially resectable colorectal cancer liver metastases Resection offers the greatest likelihood of cure for patients with liver-isolated CRC. Five -year survival rates after resection range from 24 to 58 percent, averaging 40 percent Surgical mortality rates are generally <5 %
Patient selection for resectionCriteria for absolute unresectability Nontreatable extrahepatic disease, Unfit for surgery Involvement of more than 70 percent of the liver or six segments Radiographic evidence of involvement of the hepatic artery, major bile ducts, main portal vein, or celiac/paraaortic lymph nodesModern multidisciplinary consensus defines resectable CRC liver metastases simply as tumors that can be resected completely, leaving an adequate liver remnant
CRITERIA FOR RESECTABILITY General criteria for fitness1. Good performance status2. Absence of extra hepatic disease Specific Criteria that decides the outcome1. Risk of recurrence- Clinical Risk Score for CRC Anatomical criteria for resectability1. Number of metastases2. Precise location3. Relationship with the portal pedicle and the hepatic veins
Clinical Risk Score5 clinical criteria each assigned 1 point:1) Node-positive primary2)<12 month disease-free interval3) >1 liver tumors4) Largest tumor >5 cm5) CEA >200 ng/mL.
Principles of Resection in Colorectal Liver Metastases An R0 resection of both the intra- and extrahepatic disease sites must be feasible. At least two adjacent liver segments need to be spared. Vascular inflow and outflow, as well as biliary drainage to the remaining segments, must be preserved. The volume of the liver remaining after resection (i.e., the future liver remnant) must be adequate
Preoperative Patient Evaluation Colonoscopy Chest / abdominal/ pelvic CT CBC, Platelets, Chemistry CEA Determination of tumor K- RAS status Needle biopsy – if clinically indicated PET – CT only if potentially surgically curable M1 disease
Conversion therapy for initially unresectable metastases Induction chemotherapy in patients withisolated but initially unresectable CRC livermetastases
Selecting patients for neoadjuvant therapy Resection was always preferred, if possible, over local ablation strategies (cryosurgery, radiofrequency ablation [RFA], laser techniques). Immediate resection appropriate if adequate margins could be radiographically defined, there was no portal lymph node involvement, and four or fewer lesions. Resection could be considered for more than four lesions if they were localized to a single lobe. For patients with more than four metastases or bilobar involvement, resection considered appropriate only after tumor shrinkage using neoadjuvant chemotherapy.
TIMING OF HEPATECTOMY IN PATIENTS PRESENTING WITH SYNCHRONOUS METASTASES Staged – Allows biological behavior of the metastatic disease become evident, improving the selection of patients Simultaneous resection of the primary and metastatic disease - preferable from the patients perspective No proof of inferior survival or greater morbidity for a one-stage procedure as compared to delayed (staged) hepatic resection
SURVEILLANCE AFTER METASTASECTOMYSurveillance strategy for patients with stage IV disease who are rendered surgically NED (no evidence of disease) CEA every three months for two years, then every six months for three to five years CT of the chest/abdomen and pelvis every three to six months for two years, then every 6 to 12 months up to a total of five years Colonoscopy in one year; if no advanced adenoma repeat in three years, then every five years; if advanced adenoma is found, repeat in one year
ABLATIONIndications Patients who do not meet the criteria for resectability Presence of liver-only disease. A complete margin-negative ablation can be achieved
ABLATION1. Cryotherapy Destruction of tumor cells by freeze thaw cycle. Probe positioned inside tumor Liquid nitrogen is circulated through tip of probe Temp lowered to -100° C 1-3 cycles of freezing for 15 mins with spontaneous periods of thaw Lethal temp -20° C Intracellular or extra cellular ice forms Ice ball of ~3-6cm Complications - biliary, abscess, myoglobinuria, haemorrhage, coagulopathy, cryoshock
ABLATION2. Radiofrequency ablation Radiofrequency waves (high frequency alternating current - 460khz) are converted into thermal energy Friction from rapidly moving ions results in heat Temp of ~60°C Coagulative necrosis Open/laparoscopic or percutaneous technique Effective with tumors upto 5 cm Complications – bilioma, biliary fistula, stricture, abscess
ABLATION 3. Laser interstitial thermal therapy (LITT) Placement of laser fiber or fibers directly into the tissue to be treated. Infrared laser producing lethal thermal injury to tumor cells LITT utilizes diode laser or more frequently Nd-YAG laser Coagulative necrosis Procedure is usually performed under MRI guidance
ABLATION4. Microwave coagulation therapy Uses microwave of frequency 2450 Mhz Produces heat by stimulation of water molecule Produces rapid frictional heating and coagulative necrosis5. Intratumoral alcohol injection Causes denaturation of protein leading to cell death Can be used for tumors <3cm
RADIOTHERAPYStereo tactic body radiation Tolerance of liver to radiation is poor. Conformational radiation therapy using multiple field & beam angles is used to deliver large doses to a target sparing surrounding normal tissues.
Selective Interstitial Radiation Therapy Injecting micro spheres containing yttrium 90 via hepatic artery Percutaneous cannulation of hepatic artery Spheres selectively lodge into tumor cells 200-300 Gy to tumor ,15-50 Gy to liver Emits Beta radiation with a penetrance of 2-3 mm Half life of 64 hours.
Chemotherapy for Metastatic Colorectal CancerTargeted therapies Bevacizumab ( Avastin)—binds the vascular endothelial growth factor ( VEGF). Cetuximab ( Erbitux)– targets the epidermal growth factor receptor ( EGFR). Pantumumab ( Vectibix)– targets the EGFR, in a different way than Cetuximab.
First- line chemotherapy FOLFOX( Oxaliplatin plus 5-FU and leucovorin Q2W) FOLFIRI( Irinotecan plus 5-FU and leucovorin Q2W) Patients should have a central line and a portable IV pump. In the U.S.A, most patients are offered first- line FOLFOX, and FOLFIRI is reserved for second- line therapy. CAPOX (capecitabine plus oxaliplatin) Benefit of adding Bevacizumab A significant higher response, it prolongs survival. Patients who can’t tolerate Irinotecan or Oxaliplatin Less toxic alternative: 5-FU+ leucovorin( +Bevacizumab)
Multiple Active Agents Associated With Increased Survival Combinations of multiple active agents associated with better outcome 5-FU, irinotecan, oxaliplatin Compared with 5-FU/LV, use of all 3 active therapies associated with improved survival Median survival with triple-drug regimens: ~ 20 months First-line doublet chemotherapy Associated with increased exposure to all 3 active agents during therapeutic course
Metastatic CRC: Which Chemotherapy First? FOLFOX = FOLFIRI CapeOx = FOLFOX Sequencing = combinations FOLFOX FOLFIRI FOLFIRI FOLFOX (1st line 2nd line) (1st line 2nd line) N pts (229) 111 69 109 81 RR 54% 4% 56% 15% Liver 21% 9% resection PFS (mos) 8.1 2.5 8.5 4.2 OS (mos) 20.6 21.5 GERCOR study
Second- line chemotherapy If FOLFOX( or Capecitabine+ Oxaliplatin) plus Bevacizumab was the first line regimen, the patient is usually switched to FOLFIRI with or without Bevacizumab. FOLFIRI+ Bevacizumab → FOLFOX( or Capecitabine+ Oxaliplatin) with or without Bevacizumab. Adding Cetuximab to Irinotecan can shrink tumors in patients who stop responding FOLFIRI regimen. Cetuximab plus Irinotecan is used for third- line therapy after failure of both FOLFOX and FOLFIRI. It is also used as second– line therapy if there is progression on FOLFIRI plus Cetuximab.
New paradigm: continuum of care Exposure to all active agents and modalities Maximal Overall Survival and Quality Of Life by minimizing toxicity and unnecessary treatment No more distinct “lines of therapy”
Achievements in the first-line treatment of mCRC BSC (1980s) 5-FU/FA (1990s) FOLFOX, FOLFIRICT combination + MAbs CT combination + Tailored MAb therapy 0 6 12 18 24 30 Time (months)
CRC: Adenoma-Carcinoma Sequence Normal Hyperproliferative Adenoma Carcinoma Colon Epithelium APC Methylation APC KRAS 18q p53 Further hMSH2 abnormalities hMSH2 mutation deletion deletion accumulation hMLH1 hMLH1 of geneticabnormalities inactivation abnormalities (hereditary) 32% to 57% KRAS mutant
Toward Personalized Therapy of CRC Ligand: AREG/EREG Target for EGFR-ERBITUXTarget for EGFT-TK inhibitor EGFR-TK pY GRB2 pY SOS P13K pY RAS RAF STAT MEK AKT PTEN MAPK Gene transcription P Cell-cycle progression P MYC Cyclin D1 JUN FOS MYC Cyclin D1Proliferation/ maturation Chemotherapy/ Survival Invasion and radiotherapy resistance Angiogenesis (anti-apoptosis) metastasis
Toward Personalized Therapy of CRC EGFR antibodies KRAS and BRAF mutations correlate with lack of response to treatment with monoclonal antibodies targeting EGFR VEGF antibodies Patients who do not have a contraindication may benefit from bevacizumab, although no predictive marker has been identified Combining EGFR and VEGF antibodies Data do not demonstrate benefit
NCCN: KRAS Mutation Testing Recommended to guide treatment plan KRAS codons 12 and 13 Testing considerations Qualified laboratories Formalin-fixed paraffin-embedded tissue Primary tumor and/or the metastasis
NCCN: BRAF Mutation Testing Not yet recommended, but noted in the guidelines Testing considerations Formalin-fixed paraffin-embedded tissues Typically PCR and direct DNA sequence analysis Qualified laboratories
Chemotherapy side effects Drug Side effects5-FU and Leucovorin Diarrhea, mucositis, temporary low blood counts Xeloda Hand- foot syndrome diarrhea and mucositis Irinotecan Diarrhea, low blood counts, fatigue, hair loss
Chemotherapy side effects Drug Side effectsOxaliplatin Sensory neuropathy, acute paresthesias and dysesthesias of the hands, feet and perioral region, jaw tightness, and pseudolaryngospasm Avastin Increase BP, impair wound healing, bleeding, bowel perforation(1.4~2%) and fistula formation, proteinuria, thromboembolic events(4.5%): stroke, heart attack Erbitux Allergic reactions, skin rash, headache, nausea, low blood magnesium
Duration of therapy Traditional practice – continue till Unacceptable toxicity Clinical deterioration or Disease progression Newer approach – discontinuation of treatment after fixed time period
Treatment-Free Intervals Rationale Decrease intensity of therapy Reduce toxicity Prevent discontinuation of therapy Increase QOL Types of treatment breaks Treatment break with maintenance regimen Complete Chemotherapy-free intervals (CFI)
Assessment during therapy CT scan, PET ( every 2~3 cycles) CEA ( every 1~3months) Persistently rising CEA levels should prompt restaging, but suggest disease progression and the need for an alternative treatment strategy. Caution should be used when interpreting a rising CEA level during the first 4 to 6 weeks of a new therapy, since spurious early elevation in serum CEA may occur, especially after Oxaliplatin.
Management of metastatic colorectal cancerGeneral Principles Patients with mCRC, particularly those with liver or lung only metastases, should be carefully evaluated upfront to determine the feasibility of curative resection The current approach to the treatment of mCRC is to use various agents (5- fluorouracil/leucovorin [5-FU/LV], capecitabine, irinotecan, oxaliplatin, bevacizumab, cetuximab, and patitumumab) in combination or as single agents FOLFIRI (infusional 5-FU, leucovorin, plus irinotecan) and FOLFOX (infusional 5-FU, leucovorin, plus oxaliplatin) exhibit similar efficacy in mCRC. 5-FU/LV in patients who cannot tolerate intensive therapy , either may be combined with bevacizumab
Carcinoid tumors Neuroendocrine tumors More common in appendix and rectum Half are functional – MC produce seratonin Appendicial carcinoids < 1 cm – no risk of metastasis and managed with appendectomy Tumors 1 – 2 cm – controversial > 2 cm – managed with formal right hemicolectomy Rectal carcinoids – typically not functional < 1 cm never metastasize – managed with local excision or fulguration 1 – 2 cm controversial > 2cm – more radical surgery
High grade neuroendocrine carcinoma Extrapulmonary small cell carcinoma Chest imaging always performed to rule out mets from lung Nonspecific presentation and clinical features similar to adenocarcinoma Distant spread common Recommendations extrapolated from small cell lung cancer Combined modality treatment with chemo and surgery
Lymphoma Majority non Hodgkins type Maybe low, intermediate or high grade histology B cell diffuse large cell histology most common Majority affect cecum or rectum Usually present with non specific abdominal pain, rectal bleeding, obstruction or a mass Diagnosis made n histology Work up – bone marrow biopsy, full body scanning Treatment – combined modality with chemotherapy and surgery Role of radiation therapy unclear
Conclusion Patients with mCRC, particularly those with liver or lung only metastases, should be carefully evaluated upfront to determine the feasibility of curative resection The availability of multiple therapies and the judicious use of surgery have improved outcomes for metastatic CRC Use of these agents may soon be individualized as data about predictive factors evolves