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

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

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.

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

CS and HIPEC The Argument For…

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

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

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

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

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

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)

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

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

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

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;26:5721-5727

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

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

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

C. Heating Chemotherapy Makes it More Lethal

C. Heating Chemotherapy Makes it More Lethal Klaver et al Ann Surg 2011

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

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.

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

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

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

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

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

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

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

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!

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

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

CS HIPEC vs Standard Therapy . Verwaal V J et al. JCO 2003;21:3737-3743

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;21:3737-3743 ©2003 by American Society of Clinical Oncology

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

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

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

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?

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

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?

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

Elias et al

IP Chemo versus Standard Chemo following CS

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

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

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

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

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

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.”

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

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

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?

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

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

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