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

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

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.

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

7. CS and HIPEC The Argument For…

8. CS and HIPEC The Argument For…
Peritoneal Carcinomatosis is associated with a terrible survival

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

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

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

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

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:

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:

17. A. Peritoneal Carcinomatosis from CRC is Terrible
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:

18. A. Peritoneal Carcinomatosis from CRC is Terrible
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. C. Heating Chemotherapy Makes it More Lethal
Klaver et al Ann Surg 2011

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

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

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 , 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%
Verwaal et al Ann Surg Onc 2005

29. E. CS and HIPEC The Netherlands Cancer Institute
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
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!

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

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:

35. CS HIPEC vs Standard Therapy.
Verwaal V J et al. JCO 2003;21:

36. 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
Verwaal V J et al. JCO 2003;21:
©2003 by American Society of Clinical Oncology

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

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

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

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

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
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

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
Evaluating the role of cytoreductive surgery
Evaluating the role of HIPEC in those patients who receive cytoreductive surgery