Strategy for the treatment of metastatic CRC through the lines I Congresso de Oncologia D Or 2013: Satellite Symposium, ROCHE David Cosgrove, MD Johns Hopkins University
Disclosures No relevant financial disclosures
Objectives Review metastatic CRC epidemiology Review treatment options for liver only metastases Surgery Liver-directed therapy Review treatment options for widespread metastases Standard chemotherapy Rational combinations Future directions
CRC epidemiology Worldwide incidence 1.2 million annually 2 nd most common cancer diagnosis in women 3 rd most common cancer diagnosis in men US incidence decreasing Approx. 150,000 cases per year Over 90% of cases occur over 50 years of age 20-25% of patients with documented metastatic disease at presentation Over 50% of the remainder will develop metastatic disease
CRC risk factors Genetic/ Inherited FAP Lynch syndrome Environmental Obesity, high-fat diet Smoking Predisposition DM IBD h/o adenomatous polyps
CRC staging (TNM preferred)
5 year survival for stage 4 CRC is approximately 5%. Data collected up to the year 2005, so impact of modern chemotherapy not yet apparent.
CRC oligometastatic disease Liver only metastases Common scenario Liver tends to be the primary site of metastatic deposits from CRC Growing body of literature suggesting long-term DFS/ cure with liver resection Also role for intra-arterial therapy, ablative techniques etc. Isolated lung metastases Rarer scenario Potential role for surgical resection in select cases
Liver resection results in an average 5 yr OS of about 40% in select cases. This has held up over time, and with changing resection criteria. This obviously represents a marked improvement over expected survival with chemotherapy alone, even in patients with low burden disease.
Liver metastases in CRC Which patient? Basic principles No extrahepatic metastases Medically fit Less than 70% liver involvement/ less than 6 segments involved Criteria evolving complete resection of all known disease, with adequate liver remnant function
Liver Metastases: Determining options
Liver metastases: perioperative therapy Benefits Test of disease biology: identify those patients with previously occult extrahepatic disease and poor outcomes Downstaging/ converting previously unresectable or borderline lesions to resectability Typical regimens mirror those for mcrc Oxaliplatin/ Irinotecan-based Risks Chemotherapy-induced liver damage Systemic toxicity
Liver metastases: perioperative therapy Recommendations: Resectable tumor, fit patient: up front surgery Borderline/ unresectable tumor, fit patient: pre-operative chemotherapy and surgery if disease stable or improving and patient remains fit Post-operative chemotherapy: generally given, although data is lacking (FFCD 9002 and EORTC/NCI study assessing this both closed with poor accrual)
Liver metastases: multidisciplinary input MDC input can facilitate appropriate case-by-case decision-making. Adequate imaging to make determination Timing of surgery Adjuncts to surgery (RFA, PVE etc.) Perioperative treatments
Unresectable CRC metastases Chemotherapy-based treatment Generally delivered systemically Palliative in nature By definition, although OS measured in years Widely accepted initial therapy options Combination chemotherapy Growing list of potential agents Novel targeted therapies coming on stream Continuum of care model in development
Case report 42yo male, reports vague epigastric pain, weight loss over 3 months. No PMH, generally healthy CT scan: mulitfocal hepatic lesions, peri-portal LAD, sigmoid thickening, LAD. Liver lesion bx: moderately differentiated adenoca Dx: metastatic CRC Chemo plan?
CRC chemotherapy through history Drug, year 5-Fluorouracil/ LV (1970s) Oxaliplatin (2002) Irinotecan (2001) Cetuximab/ Panitumumab Bevacizumab (2005) Aflibercept (2012) Regorafenib (2012) Median OS (average) 10-11 mo 20 mo+ 20 mo+ 22 mo+ 24 mo+ 24 mo 27 mo
First line chemotherapy, CRC 5-FU established as a useful cytotoxic over 40 years ago; best results when given with LV in CRC Limited duration of response Oxaliplatin: Synergizes with 5-FU Initial signal as single agent, but not pursued in subsequent studies Shown to be beneficial in conjunction with 5-FU in a randomized, Phase 3 study of 420 patients in 2000 De Gramont et al, J Clin Oncol 2000;18(16):2938
First line chemotherapy, CRC FOLFOX regimens widely assessed for appropriate RR and toxicity profile. Optimal regimen FOLFOX6 or modified FOLFOX6 Median OS in most updated studies approx. 20 months Toxicity Acute sensory neuropathy (cold sensitivity) Cumulative peripheral neuropathy (likely no benefit from calcium/magnesium supplementation) Acute infusion reactions Goldberg RM et al, J Clin Oncol 2004;22(1):23
Oxaliplatin vs. Irinotecan Irinotecan Activity as single agent post 5-FU Better activity when combined with 5-FU: 387 patients, randomly assigned to 5-FU/LV vs. Irinotecan with 5- FU/LV as first line therapy. Better RR, DFS and OS with Irinotecan (17.4 vs. 14.1 mo) 2 other trials revealed similar improvements. Appropriate first line option for metastatic CRC Douillard JY et al. Lancet 2000;355(9209):1041
Oxaliplatin vs. Irinotecan Irinotecan toxicity Diarrhea, myelosuppression, cholinergic reactions UGT1A1 polymorphisms Which is best to give in the first line vs. second line? Aggregate data suggest that both Oxaliplatin-containing regimens and Irinotecan-containing regimens have similar efficacy in the first line (RR, DFS and OS) One US Intergroup study originally suggested superiority of Oxaliplatin, but this was not recapitulated in other trials. Overall, either regimen is appropriate
Oxaliplatin plus Irinotecan? Combining both active agents in the first line has been assessed IROX or FOLFOXIRI regimens can be delivered safely (minimally increased toxicity over doublet therapies) One study claimed improved rates of conversion to resectability of liver metastases with 30-drug regimen Conflicting data on overall survival benefit Overall, not recommended at this time
Standard of care, first line mcrc FOLFOX6 (or modified FOLFOX6) is generally prescribed first in the US Dose limited by neuropathy in most cases (6 months) FOLFIRI used as a second line option after FOLFOX failure or intolerance Less risk of late failure due to toxicity Capecitabine can be substituted into either regimen with no impact on efficacy (although different toxicity profile) Median OS between 20-24 months through this strategy
VEGF targeted therapy Bevacizumab Monoclonal AB against VEGF Documented anti-tumor response in CRC, and other malignancies Should be combined with cytotoxic regimen Aflibercept VEGF-trap Documented response in mcrc second line therapy in combination with Irinotecan only Not tested with other cytotoxics
Bevacizumab Initial approval in CRC granted after documented improved RR, DFS and OS with IFL regimen 813 pts, previously untreated, randomized to IFL vs. IFL with Bevacizumab RR 45 vs. 35%, DFS 10 vs. 6mo, OS 20 vs. 15 mo all in favor of Bevacizumab Subsequently tested with other Irinotecan-based as well as Oxaliplatin-based combinations Also approved for use in second line regimens even if disease progressed on a prior Bevacizumab combination
Aflibercept VELOUR trial assessed Aflibercept with FOLFIRI in patients with progression through FOLFOX 1226 patients, randomly assigned Median OS 13.5 vs. 12.1 mo, improved DFS, independent of prior VEGF-targeted therapy Has caused some controversy since approval last year related to significance of clinical impact and overall cost, especially in comparison with Bevacizumab
VEGF-targeted agent toxicity Class effects of targeting vascular growth factors: HTN, proteinuria, renal damage Bleeding/clots Wound issues, including GI perforation around the time of surgery At least 4 weeks advised between surgical intervention and VEGF-targeted agent prescription
Standard of Care, first/second line mcrc FOLFOX6 (or modified) with Bevacizumab (as long as not contraindications) as first line option Continue until disease progression or toxicity FOLFIRI with Bevacizumab (or Aflibercept) as second line Continue until disease progression or toxicity Maintenance therapy discussion?
EGFR targeted therapy Cetuximab Mouse/human chimeric monoclonal Ab against EGFR Activity as single agent (in the third line) or in combination with Irinotecan (second or third line) even with prior Irinotecan failure Panitumumab Fully humanized monoclonal Ab against EGFR Also single agent activity in CRC, never fully assessed in combination with cytotoxics Not compared head-to-head with Cetuximab
EGFR biomarkers: kras, BRAF
Kras, BRAF impact on treatment If there is an activating mutation downstream of EGFR, then EGFR inhibition will not impact this pathway. Cetuximab/ panitumumab ineffective in kras/braf mutated tumors Some variation in effectiveness likely, but no clinical impact in this situation BRAF also likely a negative prognostic marker, independent of its predictive ability
EGFR-targeted agent toxicity Infusion reaction Common with Cetuximab, very rare with Panitumumab due to fully humanized state Rash Acneiform rash, often requires treatment (topical/ systemic) Nausea Weakness/ malaise Hypomagnesemia, hypokalemia
Standard of care, third line mcrc After Oxaliplatin-based and Irinotecan-based disease progression: Single agent Cetuximab Cetuximab with Irinotecan Single agent Panitumumab ONLY in kras/braf wild type tumors If mutated tumors, then consider most recently approved agent vs. clinical trial
Fourth/ last line of therapy, mcrc Regorafenib Angiogenesis inhibitor, targeting multiple kinases Similar in structure to sorafenib CORRECT trial 760 patients, BSC vs. Regorafenib, after failure of all prior therapies Modest benefit in PFS (0.2mo) and OS (1.4mo) led to approval HFSR, hypertension, nausea, rash, fatigue, liver dysfunction are commonly reported side effects.\
Case report Case discussed at MDC Given youth and prior good health, patient was being considered for heroic surgical intervention IF reasonable chemotherapy response No indication to treat the primary tumor at this point FOLFOX6 with Bevacizumab x 6 months of therapy: Limited disease response, but not robust enough to consider surgery Factors influencing this decision?
Case report Maintenance chemotherapy with 5- FU/LV/Bevacizumab x 3 months Progressive disease (liver) on new scan, so FOLFOX6 with Bevacizumab resumed Oxaliplatin reaction (severe) after 2 doses, treatment postponed Switch to FOLFIRI with Bevacizumab x 4 cycles Developed DVT, so Bevacizumab discontinued Continues FOLFIRI x 2 more cycles
Case report Updated scan reveals stable liver disease, but new lung nodularity, bilateral. Switched to third line therapy: Irinotecan and Cetuximab Tolerated for almost a year, with minimal interruption Developed rash, reflux symptoms, but disease stable Liver remains dominant disease site, and patient anxious to consider directed therapy to treat the bulk of this tumor Advised against, given lack of data and lack of focus on larger cancer picture
Case report Second opinion suggests radioembolization x 2 to cover all areas of disease in liver Stable disease on follow up scans Significant gastritis due to radiation damage Chemo break Mostly necessitated by the mucositis/gastritis Progressive lung lesions Starts Regorafenib 2/13 Stable disease after 2 months
Liver directed therapy Commonly employed in primary liver cancers (HCC, cholangioca, NET) Assessed in mcrc Y90 results in 9mo median OS in heavily pre-treated patients, liver only metastases Compares favorably to systemic agent impact in similar cases Studies ongoing DEBIRI vs. FOLFIRI in second line therapy, liver only disease
Future directions Improved biomarker discovery/ validation and associated treatments Ongoing assessment for molecularly targeted agents Deployment of epigenetic therapies in CRC 5-aza currently being assessed Combination locoregional and systemic therapies earlier in the course of treatment Further refinement of surgical techniques
Future directions Plethora of new agents for the treatment of CRC in the last decade, but not massive impacts on median OS with each additional approval Have we reached a plateau of systemic therapy impact? Median OS now stands at about 24-27 months for nonresectable patients Can we do better?
Continuum of care model Proposal to move away from the stringent lines of therapy model Personalized approach based on all information available from the tumor and patient Utilize the various effective therapies in a continual manner, with rational combinations and accurate response assessments Requires flexibility, real time biomarker or tumor assessment
2012 by American Association for Cancer Research Richardson A L, and Iglehart J D Clin Cancer Res 2012;18:3209-3211
Future biomarker assessment BEAMing Requires some knowledge (or presumed knowledge) of tumor DNA, methylation etc Quantification of overall tumor burden (estimate) Useful after definitive therapy to ensure eradication of disease (surgery prognostic marker; chemotherapy predictive marker) Myriad of potential applications in initial and ongoing assessment s within this continuum of care model
Conclusion Lines of therapy our current practice 1 st line: FOLFOX, Bev 2 nd line: FOLFIRI, Bev (or Aflibercept) 3 rd line: EGFR-targeted (if WT tumor) w/wo Irinotecan 4 th line: Regorafenib vs. clinical trial Goal should be more personalized, continuum of care model, with more rational combination of this above and newer agents.