Presentation is loading. Please wait.

Presentation is loading. Please wait.

Colon Cancer CS and HIPEC 2011 David P. Ryan, M.D. Clinical Director, MGH Cancer Center Tucker Gosnell Gastrointestinal Cancer Center Associate Chief of.

Similar presentations


Presentation on theme: "Colon Cancer CS and HIPEC 2011 David P. Ryan, M.D. Clinical Director, MGH Cancer Center Tucker Gosnell Gastrointestinal Cancer Center Associate Chief of."— Presentation transcript:

1 Colon Cancer CS and HIPEC 2011 David P. Ryan, M.D. Clinical Director, MGH Cancer Center Tucker Gosnell Gastrointestinal Cancer Center Associate Chief of Hematology/Oncology

2 2

3 3

4 The Agenda The argument against CS HIPEC The argument for CS HIPEC An example of a surgical series Review the two randomized studies in the field Final thoughts 4

5 CS and HIPEC The Argument Against… Biologically flawed. Selection bias is inherent in all the surgical series. It’s toxic. The only way to answer the question is with a randomized controlled trial. 5

6 CS and HIPEC The Argument Against… Any medical intervention should help people 1. Be Cured More Often 2. Live Longer 3. Feel Better

7 CS and HIPEC The Argument For…

8 A. Peritoneal Carcinomatosis is associated with a terrible survival

9 CS and HIPEC The Argument For… A. Peritoneal Carcinomatosis is associated with a terrible survival B. Mechanical cytoreduction can cure or prolong survival

10 CS and HIPEC The Argument For… A. Peritoneal Carcinomatosis is associated with a terrible survival B. Mechanical cytoreduction can cure or prolong survival C. Heating chemotherapy makes it more lethal to cancer cells

11 CS and HIPEC The Argument For… A. Peritoneal Carcinomatosis is associated with a terrible survival B. Mechanical cytoreduction can cure or prolong survival C. Heating chemotherapy makes it more lethal to cancer cells D. Intraperitoneal delivery allows higher doses and is more lethal to cancer cells

12 CS and HIPEC The Argument For… A. Peritoneal Carcinomatosis is associated with a terrible survival B. Mechanical cytoreduction can cure or prolong survival C. Heating chemotherapy makes it more lethal to cancer cells D. Intraperitoneal delivery allows higher doses and is more lethal to cancer cells E. The Data: Surgical series suggest long term survival

13 A. Peritoneal Carcinomatosis from CRC is Terrible Median survival of patients with peritoneal carcinomatosis was 6-9 months in the 5FU era. (Chue DZ Cancer 1989) Only 1% of all metastatic patients regardless of peritoneal carcinomatosis patients lived for 5 years (Dye Clin Col Ca 2009)

14 A. Peritoneal Carcinomatosis from CRC is Terrible The Kohne model separates patients into low, intermediate, and poor risk based on presence of 4 characteristics: performance status, number of involved sites, alkaline phosphatase, and WBC count

15 A. Peritoneal Carcinomatosis from CRC is Terrible…Not Necessarily Lessons from N9741 Sanoff H K et al. JCO 2008;26:5721-5727

16 A. Peritoneal Carcinomatosis from CRC is Terrible…Not Necessarily Lessons from N9741 Kohne risk associated with OS PS associated with OS Sanoff H K et al. JCO 2008;26:5721-5727

17 A. Peritoneal Carcinomatosis from CRC is Terrible...Not Necessarily Lessons from N9741 Response to chemotherapy associated with 5 year survival 85/1682 patients survived for 5 years and 26% of them had a complete response to chemotherapy Sanoff H K et al. JCO 2008;26:5721-5727

18 A. Peritoneal Carcinomatosis from CRC is Terrible...Not Necessarily Lessons in the Modern Era Biology trumps everything else Patients with slow growing tumors do well Patients with tumors responsive to chemotherapy do well

19 B. Mechanical Cytoreduction Can Cure or Prolong Survival Approximately 20-30% of patients with isolated liver and lung metastases will be cured The leap… – Therefore, resection of isolated extrahepatic disease can also be curable – Therefore, mechanical cytoreduction can prolong survival in a noncurative setting

20 B. Mechanical Cytoreduction Can Cure or Prolong Survival If someone has liver metastases do we use this paradigm? Standard chemotherapy Stage 4 colon cancer Standard chemotherapy + mechanical cytoreduction

21 C. Heating Chemotherapy Makes it More Lethal

22 Klaver et al Ann Surg 2011

23 D. IP Chemo Allows Higher Doses and Is More Lethal Armstrong DK et al. N Engl J Med 2006;354:34-43. Ovarian Cancer

24 D. IP Chemo Allows Higher Doses and Is More Lethal Armstrong DK et al. N Engl J Med 2006;354:34-43. Assumes either a dose response problem or a dose delivery problem Mitomycin and cisplatin have no activity when delivered IV against colon ca No other use in metastatic colorectal cancer Ovarian Cancer

25 E. CS + HIPEC The Data: 5y Survival 12-75% Yan et al Ann Surg Onc 2009

26 E. CS + HIPEC The Data: Mortality 0-17% Chua et al Ann Surg 2009

27 E. CS and HIPEC The Netherlands Cancer Institute From 1995-2003, 117 patients with carcinomatosis from CRC were treated at one center with CS and HIPEC Synchronous and metachronous patients less than age 71 and no liver/lung mets were eligible Complete macroscopic cytoreduction was attempted in each patient HIPEC with mitomycin was used All patients received 5FU/LV or Irinotecan post CS and HIPEC Verwaal et al Ann Surg Onc 2005

28 E. CS and HIPEC The Netherlands Cancer Institute 117 patients (97 colon, 15 appendix, 5 rectum) – 59 had complete cytoreduction – 44 had minimal tumor left behind (<2.5mm deposits) – 14 had gross disease left behind 7 (6%) died of treatment related causes The median survival was 21.8 months – 1year 75% – 3year 28% – 5year 19% 28 Verwaal et al Ann Surg Onc 2005

29 E. CS and HIPEC The Netherlands Cancer Institute 29 Extent of resection was the strongest predictor of survival Verwaal et al Ann Surg Onc 2005

30 E. CS and HIPEC The Netherlands Cancer Institute 30 Criticisms – Highly selected group of patients. – Was there an ongoing selection bias? – Which biology did better? Appendix? – Which chemotherapy was administered? – How many had chemotherapy prior to resection? – How many had a response to chemotherapy? Verwaal et al Ann Surg Onc 2005

31 E. CS and HIPEC The Netherlands Cancer Institute Authors conclusions In other words…many are called but few are chosen! Verwaal et al Ann Surg Onc 2005

32 E. CS and HIPEC The Surgical Series Very few are controlled phase II studies. Patients come in all shapes and sizes…synchronous, metachronous, different chemotherapy A strong trend over the years to only include those patients in whom the surgeon feels that a complete cytoreduction is possible In my own personal experience, recently the surgeons say “come back in 6 months after FOLFOX/Bev” What we need is a randomized controlled trial! 32

33 CS HIPEC vs Standard Therapy The one randomized study Verwaal V J et al. JCO 2003;21:3737-3743

34 CS HIPEC vs Standard Therapy Eligibility – <72 – No evidence of metastatic disease on abd CT and cxray – Normal liver and renal fxn – First presentation of metastatic disease and no 5FU within last 12 months Verwaal V J et al. JCO 2003;21:3737-3743

35 . CS HIPEC vs Standard Therapy

36 . Verwaal V J et al. JCO 2003;21:3737-3743 ©2003 by American Society of Clinical Oncology CS HIPEC vs Standard Therapy Toxicity 7 (15%) developed a GI fistula 14 patients never started postop 5FU 4 patients (8%) died of surgery complications

37 . Verwaal V J et al. JCO 2003;21:3737-3743 ©2003 by American Society of Clinical Oncology CS HIPEC vs Standard Therapy

38 . ©2003 by American Society of Clinical Oncology CS HIPEC vs Standard Therapy

39 . ©2003 by American Society of Clinical Oncology CS HIPEC vs Standard Therapy Less burden of disease = better outcome

40 CS HIPEC vs Standard Therapy Criticisms Prior to the era of multiagent chemotherapy…or was it? What happens if we exclude the appendiceal patients? Do we know that patients were randomized on the ability of the most important stratification factor? – Is the ability to cytoreduce prognostic, predictive, or both?

41 Adam R, et al., Ann Surgery. 2004 Oct;240(4):644-57. But we never proved it with liver metastases???

42 CS and HIPEC Criticisms Let’s assume that complete resection of disease if possible is a good thing. We can’t tease out the independent effects of CS and HIPEC Has anyone ever attempted to separate the two components?

43 The other randomized trial Following CS, randomized patients to IP Chemo + Standard 5FU/LV Chemo or Standard 5FU/LV Chemo

44 Elias et al

45 IP Chemo versus Standard Chemo following CS

46 Randomized Controlled Trials Represent the “gold standard” for evaluating new therapies – Eliminate biases of both patients and doctors – Allow for accurate assessment of magnitude of effect in patients meeting the eligibility requirements – Law of Unintended Consequences

47 Randomized Controlled Trials Fat comes back but not where you expect it!

48 Randomized Controlled Trials The Breast Cancer Experience Very good complete responses and even “cures” for HDT and ASCT 5% mortality No need for randomized trials

49 Randomized Controlled Trials The Breast Cancer Experience Welch and Mogielnicki. BMJ 2002

50 Randomized Controlled Trials The Breast Cancer Experience Welch and Mogielnicki. BMJ 2002

51 Randomized Controlled Trials The Breast Cancer Experience “We conclude that initial conditions matter; that conflicting values are ubiquitous, pervade all stages of the process, and permeate the judgment of all parties to the discussion; and that an institutional deficit exists in the evaluation of procedures. Unlike the evaluation of new drugs, which occurs within a statutory framework, administered by a federal agency, governed by explicit rules, and embedded in a culture and tradition, the evaluation of procedures for which there is no commercial sponsor is much less organized.”

52 The Great Divide Surgeons and Medical Oncologists Surgeons – History of innovating – Trained in the art of surgical series – Veni Vidi Vici Med Onc – History of drug development – Trained to trust only in phase III studies – Nihilists 52

53 CS and HIPEC My Conclusions Many are called but few are chosen – All the surgical series are flawed by tremendous selection bias

54 CS and HIPEC My Conclusions Many are called but few are chosen Toxicity is not trivial – In an era when response to chemotherapy really matters, do we really want to risk severe toxicity and even death? – For something with a 3-5% mortality, isn’t it incumbent on us to prove its worth?

55 CS and HIPEC My Conclusions Many are called but few are chosen Toxicity is not trivial Complete surgical resection of metastatic colorectal cancer may improve long term survival and even cure the rare patient

56 CS and HIPEC My Conclusions Many are called but few are chosen Toxicity is not trivial Complete surgical resection of metastatic colorectal cancer may improve long term survival and even cure the rare patient I highly doubt that HIPEC does anything of positive consequence

57 CS and HIPEC My Conclusions We need 2 randomized trials for patients with peritoneal carcinomatosis from colorectal cancer 1. Evaluating the role of cytoreductive surgery 2. Evaluating the role of HIPEC in those patients who receive cytoreductive surgery


Download ppt "Colon Cancer CS and HIPEC 2011 David P. Ryan, M.D. Clinical Director, MGH Cancer Center Tucker Gosnell Gastrointestinal Cancer Center Associate Chief of."

Similar presentations


Ads by Google