Treating late stage colorectal cancer   dr. saltz
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Treating late stage colorectal cancer dr. saltz



Dr Leonard Saltz presents the July 2012 Fight CRC Webinar - Despite great strides in cancer research, the fact remains that there is still no cure for stage IV (metastatic) disease. There are ...

Dr Leonard Saltz presents the July 2012 Fight CRC Webinar - Despite great strides in cancer research, the fact remains that there is still no cure for stage IV (metastatic) disease. There are promising treatment options for patients with late stage disease, but far too many patients will still hear their doctors say, "We are running out of options."



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Treating late stage colorectal cancer   dr. saltz Treating late stage colorectal cancer dr. saltz Presentation Transcript

  • Welcome! Treating Late Stage Colorectal Cancer Part of Fight Colorectal Cancer’s Monthly Patient Webinar Series Our webinar will begin shortlywww.FightColorectalCancer.org877-427-2111
  • Fight Colorectal Cancer1. Tonight’s speaker: Dr. Leonard Saltz2. Archived webinars: Follow up survey to come via email. Get a free Blue Star ofHope pin when you tell us how we did tonight.4. Ask a question in the panel on the right side of your screen5. Or call the Fight Colorectal Cancer Answer Line at 877-427-2111 877-427-2111
  • Fight Colorectal Cancer Upcoming Webinars Hospice vs Palliative Care Dr. Jim Meadows, Tennessee Oncology September 19, 2012 8 - 9:30 PM Eastern time Sex After Rectal Cancer Dr. Joel Tepper, UNC October 17, 2012 8 - 9:30 PM Eastern time Register at 1-877-427-2111
  • Fight Colorectal CancerDisclaimerThe information and services provided by Fight ColorectalCancer are for general informational purposes only.The information and services are not intended to be substitutesfor professional medical advice, diagnosis, or treatment.If you are ill, or suspect that you are ill, see a doctorimmediately. In an emergency, call 911 or go to the nearestemergency room.Fight Colorectal Cancer never recommends or endorses anyspecific physicians, products or treatments for any condition.www.FightColorectalCancer.org877-427-2111
  • Fight Colorectal Cancer Dr. Leonard Saltz Memorial Sloan Kettering Cancer Center Chief, Gastrointestinal Oncologywww.FightColorectalCancer.org877-427-2111
  • Understanding ColorectalCancer Treatment OptionsLeonard B. Saltz, MDChief, Gastrointestinal OncologyMemorial Sloan Kettering CancerCenter, New York, NY
  • Disclosures• I have consulted for and/or have research supported by: • Roche/Genentech • Bristol Myers Squibb • Imclone • Bayer • Merck • Biothera • Novartis • Sanofi • Immunomedex • Lorus • Morphotek
  • Overview• Understanding the language• Standard chemotherapy options• Toxicities and quality of life• New agents• Life after standard chemo
  • Terms Requiring Definitions• Cure• Overall Survival• Median Overall Survival• Progression-free Survival• Response• Stable Disease• Antitumor activity, Benefit• Progression of Disease
  • Other terms• “significantly better” – does not necessarily equal: “substantially better”• “statistically significantly better” – Does not necessarily equal: “clinically significantly better”
  • Anatomy of the Large Intestine
  • Staging of Colorectal Cancer (CRC)• Stage I: Not full thickness• Stage II: Full thickness• Stage III: Positive nodes• Stage IV: Distant mets
  • Colorectal Cancer Cure Rate• Stage I 95%• Stage II 80%• Stage III 65% +• Stage IV <10%
  • Intent of Therapy• Curative• Adjuvant• Neo-Adjuvant• Palliative
  • Chemotherapy for Metastatic Disease
  • 1996: Drugs Available for CRC• 5-FU (5-Fluorouracil)
  • 2012: Drugs Available for CRC• 5FU (5-Fluorouracil)• Camptosar (Irinotecan)• Eloxatin (Oxaliplatin)• Xeloda (Capecitabine)• Erbitux (Cetuximab)• Avastin (Bevacizumab)• Vectibix (Panitumumab) – Aflibercept (anticipated late 2012) – Regorafenib (anticipated late 2012)
  • Combination Chemotherapy for CRC Anatomy of the “FOLFs”• FOL = folinic acid (a.k.a. leucovorin)• F = 5FU (5-fluorouracil)• OX = oxaliplatin (Eloxatin) = FOLFOX• FOL = folinic acid (a.k.a. leucovorin)• F = 5FU (5-fluorouracil)• IRI = irinotecan (Camptosar) = FOLFIRI
  • FOLFIRI vs. FOLFOX Efficacy of First Line Regimen FOLFIRI FOLFOXRR 56% 54% p=0.68PFS 8.5 m 8.1 m p=0.65OS 20.4 m 21.5 m p=0.9 Tournigand et al, JCO 2004
  • Oral Chemotherapy Cautionary Notes• Just as likely to have side effects as i.v. chemo• No convenience benefit unless all drugs taken are oral• Requires a highly motivated patient capable of assuming substantial responsibility• Difficult if nausea, vomiting, or diarrhea are present or expected
  • Anti-Angiogenesis The Angiogenic Switch Angiogenic Switch 1-2 mmSmall tumor Larger tumor• Nonvascular • Vascular• “Dormant” • Metastatic potential
  • Normal and Tumor Blood Vessels Normal Blood Vessels Tumor Blood Vessels Growth and survival ... ........ ...Maturation factors present .. ... ....... factors (eg, VEGF) Less dependent on cell .. ... present survival factors ... ....... ... . .... ... ..... .. . ..... ......... . .. . Leaky .. .. . ........ ..... . Less permeable .. .. Fewer pericytes Supporting pericytes ... ....... present . .... . Preferential Reduced integrin expression of expression v 3 v 5 & 5 1 integrins
  • Phase III IFL +/- Avastin in Metastatic Colorectal Cancer IFL + Placebo IFL + Avastin (n = 412) (n=403) P ValueMedian overallsurvival 15.6 m 20.3 m 0.00003MedianProgression-Free 6.2 m 10.6 m <0.00001SurvivalResponse Rate 35% 45% 0.003Hurwitz et al.. NEJM 2004
  • Bevacizumab: Safety concerns• Gastrointestinal perforation• Arterial thrombotic events
  • EGF Receptor Signaling Transduction R R RAS RAF K K SOS PI3-K pY pY GRB2 pY MEK STAT PTEN AKT MAPK Gene Transcription Cell Cycle Progression G2 M S G1Proliferation / Survival / Angiogenesis MetastasisMaturation Apoptosis
  • Cetuximab + Irinotecan) Independent Radiology Review Irinotecan-Refractory Patients, n=120 (Saltz et al: ASCO 2001)PR 27 (22.5%) (95% C.I. 15%-31%)SD 9 ( 7%) (minimum 12 weeks)• Median Dur. of response (n=27): 186 days• Investigator-reported PR= 23 (19%)
  • Single Agent Cetuximab: Investigator-Reported Response Rate (n=57) (Saltz et al, JCO 2004)• PR = 6 (10.5%, 95% CI 4%-22%)• SD = 21 (37%) – Minimum 12 weeks required for stable disease.• Independent review confirmed 5 PR’s, for response rate of 8.8%.
  • “BOND” Trial• Randomized Phase II trial in Irinotecan- refractory CRC• Cetux + Irinotecan versus Cetux• 2:1 randomization, 300 pts• 1o endpoint: response rate
  • Bond Trial: Results (Cunningham et al, NEJM 2004) Cetux + Irino CetuxRR 22.9% 10.8%PFS 4m 1.6 m
  • Cetux Trials in Refractory CRC Response Rate Cetux + CPT-11 22.5% (Saltz, ASCO 2001) Cetux + CPT-11 22.9% (Cunningham, NEJM 2004) Cetux 10.5% (Saltz, JCO 2004) Cetux 10.8 % (Cunningham, NEJM 2004)
  • CRYSTAL Trial van Cutsem et al: NEJM 2009• Randomized phase III trial of first line FOLFIRI +/- weekly cetuximab.• Measurable metastatic colorectal cancer• 1217 patients randomized
  • CRYSTAL TRIAL: Efficacy Van Cutsem: ASCO 2007 FOLFIRI- FOLFIRI P value Cetux (n=599) (n=599)PFS 8.9 m 8.0 m 0.0481 yr PFS 34% 23%RR 47% 39% 0.0038SD 37% 47%DCR 84% 86%
  • Understanding KRAS• Protein in the cell involved in transmitting signal from receptor on cell surface to the nucleus• If the gene for KRAS is mutated, then the KRAS protein sends a signal regardless of whether there is a signal from the surface receptor or not
  • EGF Receptor Signaling Transduction R R RAS RAF K K SOS PI3-K pY pY GRB2 pY MEK STAT PTEN AKT MAPK Gene Transcription Cell Cycle Progression G2 M S G1Proliferation / Survival / Angiogenesis MetastasisMaturation Apoptosis
  • Understanding KRAS• If KRAS is mutated, Erbitux and Vectibix won’t work, and therefore are not used• If KRAS is wild-type (non-mutated) then Erbitux or Vectibix might work• Median overall survival benefit in trials with KRAS wild-type tumors is in range of 3-4 months
  • CRYSTAL Trial: PFS time by skin reactions: cetuximab + FOLFIRIGrade of Skin 0-1 2 3Rash (none or mild) (moderate) (severe)Progression-freesurvival 5.4 m 9.4 m 11.3 m
  • Some Other Toxicities• Nausea / Vomiting• Diarrhea• Fatigue• Neurotoxicity
  • MOSAIC: FOLFOX for Stage II – III ColonCancer: Peripheral Sensory Neuropathy Andre et al: JCO 2009 Grade 1 60 Grade 2 Grade 3 50 48.1 % of treated patients 40 30 31.4 30.9 27.6 17.4 14.2 11.4 22.2 20 14 12.5 12 8.8 10 7.2 4.2 2.9 1.4 1.2 1.7 0.5 2.1 0.5 0.5 0 During Tx 6 months 1 year 2 years 3 years 4 years
  • Neurotoxicity from Oxaliplatin• Cold sensitivity• Numbness and tingling• Loss of position sense• Loss of fine motor skill• Pain
  • What’s new?
  • Continuing Avastin• TML trial shows that continuation of Avastin with 2nd line therapy improves median overall survival by 1.4 months
  • Aflibercept• Adding aflibercept to second line FOLFIRI improves median overal survival by 1.5 months.• Not clear that this offers any advantage over second line Avastin• No evidence that Aflibercept by itself, or with chemo that has failed, has any benefit
  • Regorafenib vs Placebo Regorafenib Placebo N=505 N=255Median Overall Survival 6.4 months 5.0 months Partial Response 1% 0.4% Stable Disease 43% 15% DCR* 41.0 15% *DCR = PR+SD (≥6 weeks after randomization) Van Cutsem et al: Proc ASCO 2012
  • What can we do when we’veused up the standard drugs?
  • Treatment options after standard care• Clinical trials• Supportive care / hospice care
  • Clinical Trials• Phase I What is the highest tolerable dose and what are the side effects?• Phase II Is it safe and active in a defined population?• Phase III Is it better that standard care?• Phase IV Post-marketing studies; variations on a theme.
  • Clinical Trials: Important Concepts:• Informed consent• Right to refuse/withdraw• No hidden agendas• No hidden placebos
  • Supportive care• Important in ALL aspects of cancer care – Pain control – Emotional Support – Nutrition – Exercise – Discussions of end of life care preferences
  • Seductive Traps• The internet• Alternative care• Unproven drugs and procedures – (Beware the rhetorical “what harm could it do?”
  • COST of CAREA. Venook (Discussant) ASCO 2012 The Elephant in the Room
  • Average Selling Price (ASP) + 6% (about 5 yr old data) (Patient assumption: 75 kg, 1.8 m2 patient, two weeks Rx)• 5FU 500 mg/m2 $ 7• Leucovorin 500 mg/m2 $ 47• Xeloda 2000 mg/m2/d $ 1065• Camptosar 180 mg/m2 $ 2135• Eloxatin 85 mg/m2 $ 3296• Avastin 5 mg/kg $ 2283• Erbitux 250 mg/m2 $ 4964
  • Impact on Cost of Care: back of the envelope• Bevacizumab – $2864 per 400 mg vial* – Average weekly dose = 175 mg• Regorafenib $$$ unknown – Sorafenib $8377 / month• Aflibercept $$ per UCSF pharmacy – $$$ unknown
  • Cost of Bev beyond progression (Cost of only the bev; no MD, nursing, or pharmacy fees, no other meds)• $2864 per 400 mg vial -> $7.16 per mg – 175 mg/week x 4.33 weeks/month = 758 mg/month – If vials are shared: 758 mg/month x $7.16/mg = $5427.28 per month, x 5.7 months = $30,935.50 per patient treated for 1.4 months OS benefit -> $30,935.50 x 8.57 = $265,117 per year of life saved – If vials not shared, then $2864 every 2 weeks for 24.7 weeks (5.7 months) -> $35,370.40 per patient treated $35,935.40 x 8.57 = $303,124 per year of life saved – (note: these are not Quality-adjusted)
  • Colorectal cancer in 2012: my reality check• These are modest advances• A minority of patients appear to benefit• And the costs are unsustainableTHE CHALLENGE• Actually deliver on promise of personalized medicine• To do so, we need better tools to predict outcomes• And it must be affordable A. Venook, ASCO Discussant 2012
  • Challenges• Maintain optimism tempered by, and grounded in, reality• Select therapies rationally• Assure availability of appropriate therapies to all patients
  • Conclusions• Treatment options for colon cancer patients are better than they were, but not as good as they need to be.• Please consider participation in clinical trials when they are appropriate. Without your help, we can’t make the progress that we all so desperately need.
  • Fight Colorectal Cancerwww.FightColorectalCancer.org877-427-2111
  • Fight Colorectal Cancer Funding Research Directly Lisa Dubow Fund
  • Fight Colorectal Cancer CONTACT US Fight Colorectal Cancer 1414 Prince Street, Suite 204 Alexandria, VA 22314 (703) 548-1225 Toll-Free Answer Line: 1-877-427-2111 www.FightColorectalCancer.orgEmail us: