Treating Liver Metastases in Colorectal Cancer (Medscape)

[Guest guest]

http://www.medscape.com/viewarticle/506325

Expert Interview

Treating Liver Metastases in Colorectal Cancer: An Expert Interview

With Choti, MD

Medscape Hematology-Oncology. 2005; 8 (1): ©2005 Medscape

Editor's Note

In 2005, it is estimated that more than 104,000 cases of colon cancer

will be diagnosed in the United States alone[1] and that more than

56,000 patients will die of this disease.[1] The liver is the most

common site of colon cancer metastasis, and patients who undergo

resection of liver metastases can have prolonged survival. One

quarter to one third of patients who are able to undergo resection of

liver metastases will live 5 years or longer, and median survival

after resection is between 24 and 40 months.[2] Unfortunately, even

for patients with metastatic disease confined to the liver, not all

liver lesions are resectable, and even after successful resection,

microscopic disease elsewhere can lead to disease recurrence and

death. As novel systemic therapies that are proven to improve

survival in metastatic colorectal cancer emerge,[3] there is

increasing interest in treating patients who are potential candidates

for resection of metastases with preoperative and/or postoperative

chemotherapy.

Dr. Choti and colleagues discussed recent advances and

emerging strategies for the multidisciplinary management of liver

metastases from colorectal cancer in an education session at the 2005

annual meeting of the American Society of Clinical Oncology (ASCO).

[4] In an interview with Medscape, Dr. Choti explains the promise and

limitations of adding chemotherapy to liver surgery and how he

currently approaches patient management in this area.

Medscape: Dr. Choti, this morning you and your colleagues discussed

preoperative, or neoadjuvant, and postoperative, or adjuvant,

chemotherapy for patients with colorectal cancer and potentially

resectable hepatic metastases. If metastatic colorectal cancer is a

systemic disease, what is the rationale for treating metastases to

the liver with local therapy such as surgery?

Dr. Choti: That is an excellent question. We don't know why

necessarily by resecting metastases we improve outcomes and why some

patients can actually be cured, but it does happen. So, number one,

we need to base the rationale for resection on the empiric data

showing that some patients can be cured with surgery alone. Whether

in those selected patients these are the only sites of disease or you

are cytoreducing a tumor down to a volume of disease in which, for

some reason, microscopic residual disease does not progress, we don't

know. This, in particular, is why combining effective systemic

chemotherapy with resection is a theoretically good strategy.

Medscape: In terms of the scope of this problem, what percentage of

patients with metastatic colorectal cancer have liver-only disease

and are potential candidates for resection?

Dr. Choti: It depends on which series is looked at. Approximately two

thirds of patients have liver as their first site of metastatic

disease, but many of these patients also have extrahepatic disease.

Roughly one third of patients who develop metastatic disease appear

to have disease confined to their liver on imaging studies.

Medscape: What percentage of patients with liver-only disease can

undergo resection with current strategies?

Dr. Choti: That varies with the aggressiveness of the surgeon.

Somewhere in the range of one third to one half of patients with

liver-only metastatic disease may be candidates for resection.

Medscape: This morning, you and your colleagues were discussing the

use of preoperative, or neoadjuvant, chemotherapy as one means to

improve outcomes for patients with liver metastases. Can you explain

the rationale behind neoadjuvant chemotherapy?

Dr. Choti: There are a few issues. One is that even in patients with

resectable disease, although we are making dramatic improvements in

long-term outcomes with surgery, many of these patients without any

additional therapy still experience recurrence. The strategy is to

combine effective systemic chemotherapy with surgery to improve

outcomes. Then it becomes primarily a sequencing question. In a

patient with resectable disease, is it preferable to give

chemotherapy upfront and then perform the surgery after assessing

response? Or is it better to resect the disease and then give

chemotherapy postoperatively when there is no residual measurable

disease? We don't know the answer to this question.

As we have discussed at this conference, there are pros and cons to

giving chemotherapy first. In a patient who initially has resectable

disease, the goal is not to give long and extensive treatments with

chemotherapy but to give therapy of a relatively limited duration,

then get the tumor out, and perhaps give more chemotherapy after

surgery. In some patients who have marginally resectable or

unresectable disease, we would need to give chemotherapy first and

consider the option of operating on them if and when their disease

becomes resectable.

In our multidisciplinary conferences, we assess the individual

patient and discuss the best paradigm for any individual patient's

management. First, we think in terms of whether a patient may fit

into a curative intent paradigm or is the goal primarily palliative?

If the patient's disease is unresectable initially but may become

resectable, then we think about them in a curative intent mode and

tailor the strategy with that goal in mind. We attempt to maximize

the response through choice of initial chemotherapy regimen to

improve the chance of resection, at the same time trying to limit

hepatotoxicity, which may make liver surgery more difficult.

If resection is unlikely and we need to consider the overall

treatment as palliative, then we sometimes use the chemotherapy

differently and save regimens to maximize median survival and quality

of life. Occasionally, in patients in whom we have initially thought

treatment was palliative, we have been dramatically surprised by

response to therapy and are able shift the strategy to a curative

intent and consider liver resection or ablation. Similarly, when a

patient who we initially believe has resectable disease progresses

during preoperative chemotherapy and develops unresectable disease,

palliation is the primary goal.

Medscape: Are there factors that you can use to predict who is likely

to benefit from a curative approach? Do we have markers of

sensitivity that can help determine who is likely to respond to

neoadjuvant chemotherapy?

Dr. Choti: There are a variety of factors, some of which are related

to chemotherapy and chemosensitivity. Many are related to factors

such as the number and location of the metastatic disease within the

liver and elsewhere. Other factors, such as disease-free interval,

the histology of the primary tumor, and nodal status of the primary

tumor, also have prognostic implications. We consider a response to

chemotherapy as another favorable prognostic factor. Perhaps, in the

future, we will have methods such as tumor expression profiling,

proteomics, and molecular genetics to more accurately predict which

patients will derive the greatest benefit from aggressive liver

surgery and chemotherapy.

Medscape: You mentioned that chemotherapy can be administered before

surgery, after surgery, or both before and after surgery. Do we know

or are there studies planned to clarify whether the timing of therapy

affects survival or other end points in treating colorectal cancer

patients with liver metastases?

Dr. Choti: We do not currently have studies to answer this question.

In rectal cancer, we know that preoperative therapy can control local

disease and allow us to limit the extent of resection. In metastatic

colorectal cancer, we don't have information on how timing of

chemotherapy affects outcomes, but we are interested in these

questions. There is an EORTC [European Organization for Research

Treatment of Cancer] trial that I believe has completed accrual in

which they are looking at preoperative and postoperative chemotherapy

vs no chemotherapy, but this may only answer the question of whether

chemotherapy helps. It does not compare preoperative vs postoperative

chemotherapy.

In patients with resectable disease, we do not know whether

neoadjuvant chemotherapy is beneficial. There are trials under

development that will attempt to answer this question. We hope to

have a trial like this under way in the near future. Right now there

are theoretical reasons to consider chemotherapy before or after

resection. I believe that the strategy at present should be to

increase awareness of the potential role of systemic therapy and the

understanding that the optimal way to manage patients with liver

metastases may be the combination of surgery and chemotherapy,

however it is given.

Medscape: This suggests that good communication between medical

oncologists and surgical oncologists is an important factor in the

care of these patients. To what extent do you think adequate

communication is occurring today?

Dr. Choti: I think this is a very important point. Multidisciplinary

management is important when considering options. Medical oncologists

need to have an understanding of when disease is resectable and when

surgery should be offered. Similarly, the surgical oncologist or

liver surgeon needs to have a comprehensive understanding of the

various chemotherapeutic options available, including the benefit and

potential toxicities. I believe that sessions such as the discussion

of this topic this morning at ASCO are aimed at improving

communication and understanding. Providers need to appreciate that,

although we cannot cure many patients, there should no longer be an

automatic nihilistic approach to all patients with metastatic

disease. We need to integrate chemotherapy and surgery in

aggressively selected patients with advanced colorectal cancer.

I believe surgeons are developing a real understanding of the role of

chemotherapy, and this needs to be brought into the mainstream of

surgical education.

Medscape: Is neoadjuvant chemotherapy for patients with liver

metastases from colorectal cancer ready for the clinic?

Dr. Choti: There are several theoretical advantages to preoperative,

or neoadjuvant, chemotherapy.

One advantage of giving chemotherapy upfront is that we can determine

whether the tumor is responsive or not before resection, as opposed

to simply giving chemotherapy empirically after resection.

Additionally, in selected cases there may be progression if there is

a biologically aggressive tumor. Identification of this subset

preoperatively can spare a patient surgical resection, which is

unlikely to be beneficial.

Another reason is that giving systemic therapy earlier theoretically

may improve outcomes as the chemotherapy is started earlier. Finally,

a response from preoperative chemotherapy may reduce the size of

liver metastases, allowing for less extensive surgery.

The theoretical disadvantages include the possibility that a patient

who has initially resectable disease could progress to an

unresectable situation. Although this is uncommon, losing the window

of opportunity to attempt curative therapy is unfortunate. However,

as I mentioned in my discussion this morning, patients whose tumors

progress during chemotherapy are probably not those who are going to

do well even if they undergo resection.

In addition, chemotherapy can result in hepatotoxicity, particularly

when administered for prolonged duration. This liver steatosis, if

severe, can in fact decrease rather than increase resectability and

may actually make the liver resection riskier. What type of

chemotherapy -- and for what duration -- is associated with increased

hepatotoxicity is not clear. We have even less information on newer

biologic agents such as bevacizumab, which may also affect wound

healing or liver regeneration. I think we don't have enough

information regarding these issues at this time, but many of us are

trying to shed light on this subject. Let's wait and see.

There are currently no clinical trials open asking these questions,

so we manage our patients selectively. In some we offer preoperative

chemotherapy, and in some we go right to surgery first, depending on

various factors. In patients who are chemo-naive with multiple

metastases and stage 4 disease at presentation, we may be more

inclined to offer chemotherapy upfront. If a patient is marginally

resectable, in which case a response would improve the outcome of

resection, we may be aggressive about giving chemotherapy upfront as

well. If a patient has comorbidities or there is concern about

chemotherapy causing hepatotoxicity in a patient who will require a

large resection, I may be more inclined to go to surgery first.

The other factor we consider is whether a patient has been exposed to

chemotherapy or not, either in the metastatic setting or in the

adjuvant setting. If a patient has received adjuvant chemotherapy for

his or her primary disease and disease recurred early, then we may be

less inclined to use neoadjuvant or adjuvant chemotherapy with

resection of liver metastases.

Medscape: What are the next steps we need to take in this field in

terms of research?

Dr. Choti: There are several important issues. With rapidly changing

options for chemotherapy, including the combination of cytotoxic

agents and biologic therapies, we need to define the optimal regimens

in various clinical scenarios. We need to consider how we integrate

the biologics with chemotherapy, what cytotoxic regimens we use, and,

as we've discussed, the sequencing of therapy needs to be worked out.

In terms of the biologics, there are additional questions. For

example, bevacizumab presents potential issues regarding

administration around the time of extensive surgery. We don't know if

this will have an impact on wound healing, bleeding, or liver

regeneration. These questions will be emerging in the context of the

multimodality approach to patients with liver metastases.

An additional important issue regarding neoadjuvant chemotherapy is

how do we manage the type of resection, particularly in patients who

had unresectable disease and then responded. Do you need to resect

the volume of tissue in which the initial disease resided or can you

only take the nidus of residual disease? Does a tumor respond

circumferentially? We don't really understand how much one needs to

resect. Currently, we try to resect all sites within the liver that

contained disease, but this needs to be more clearly defined.

Response to initial therapy raises additional questions. If the

patient responds, we typically use the same regimen after surgery. If

the patient's cancer progressed or even if it is stable disease,

should we offer a different chemotherapy regimen in the postoperative

adjuvant setting, or should we not offer any chemotherapy? This is

completely unknown and requires further investigation.

What is the final word? Well, this is an exciting and evolving time

for patients with advanced colorectal cancer and physicians treating

them, but we have many unanswered questions. Stay tuned.

References

Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA Cancer

J Clin. 2005;55:10-30.

Choti MA, Sitzmann JV, Tiburi MF, et al. Trends in long-term survival

following liver resection for hepatic colorectal metastases. Ann

Surg. 2002;235:759-766.

Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus

irinotecan, fluorouracil, and leucovorin for metastatic colorectal

cancer. N Engl J Med. 2004;350:2335-2342.

Choti MA. Treatment of liver metastases: what are the limits? what

are the goals? Management of hepatic colorectal metastases. Proc Soc

Am Clin Oncol. 2005:302-306. Education Session.

Funding Information

Supported by an independent educational grant from Sanofi-Aventis.

Choti, MD , Associate Professor of Surgery and Oncology, The

Sidney Kimmel Comprehensive Cancer Center at s Hopkins,

Baltimore, land

Disclosure: Peppercorn, MD, MPH, has no disclosed no relevant

financial relationships.

Disclosure: Choti, MD, has disclosed no relevant financial

relationships.

[Guest guest]

Interesting article and timely in my case. Phil's hepatic pump may

have caused his ulcer however it also seems to have killed some of

the mets in the liver. Nice to see you here. How are you, Cindy and

your grand-daughter doing?

Narice

>

>

>

> http://www.medscape.com/viewarticle/506325

>

> Expert Interview

> Treating Liver Metastases in Colorectal Cancer: An Expert Interview

> With Choti, MD

>

>

>

> Medscape Hematology-Oncology. 2005; 8 (1): ©2005 Medscape

> Editor's Note

> In 2005, it is estimated that more than 104,000 cases of colon

cancer

> will be diagnosed in the United States alone[1] and that more than

> 56,000 patients will die of this disease.[1] The liver is the most

> common site of colon cancer metastasis, and patients who undergo

> resection of liver metastases can have prolonged survival. One

> quarter to one third of patients who are able to undergo resection

of

> liver metastases will live 5 years or longer, and median survival

> after resection is between 24 and 40 months.[2] Unfortunately, even

> for patients with metastatic disease confined to the liver, not all

> liver lesions are resectable, and even after successful resection,

> microscopic disease elsewhere can lead to disease recurrence and

> death. As novel systemic therapies that are proven to improve

> survival in metastatic colorectal cancer emerge,[3] there is

> increasing interest in treating patients who are potential

candidates

> for resection of metastases with preoperative and/or postoperative

> chemotherapy.

>

> Dr. Choti and colleagues discussed recent advances and

> emerging strategies for the multidisciplinary management of liver

> metastases from colorectal cancer in an education session at the

2005

> annual meeting of the American Society of Clinical Oncology (ASCO).

> [4] In an interview with Medscape, Dr. Choti explains the promise

and

> limitations of adding chemotherapy to liver surgery and how he

> currently approaches patient management in this area.

>

> Medscape: Dr. Choti, this morning you and your colleagues discussed

> preoperative, or neoadjuvant, and postoperative, or adjuvant,

> chemotherapy for patients with colorectal cancer and potentially

> resectable hepatic metastases. If metastatic colorectal cancer is a

> systemic disease, what is the rationale for treating metastases to

> the liver with local therapy such as surgery?

>

> Dr. Choti: That is an excellent question. We don't know why

> necessarily by resecting metastases we improve outcomes and why

some

> patients can actually be cured, but it does happen. So, number one,

> we need to base the rationale for resection on the empiric data

> showing that some patients can be cured with surgery alone. Whether

> in those selected patients these are the only sites of disease or

you

> are cytoreducing a tumor down to a volume of disease in which, for

> some reason, microscopic residual disease does not progress, we

don't

> know. This, in particular, is why combining effective systemic

> chemotherapy with resection is a theoretically good strategy.

>

> Medscape: In terms of the scope of this problem, what percentage of

> patients with metastatic colorectal cancer have liver-only disease

> and are potential candidates for resection?

>

> Dr. Choti: It depends on which series is looked at. Approximately

two

> thirds of patients have liver as their first site of metastatic

> disease, but many of these patients also have extrahepatic disease.

> Roughly one third of patients who develop metastatic disease appear

> to have disease confined to their liver on imaging studies.

>

> Medscape: What percentage of patients with liver-only disease can

> undergo resection with current strategies?

>

> Dr. Choti: That varies with the aggressiveness of the surgeon.

> Somewhere in the range of one third to one half of patients with

> liver-only metastatic disease may be candidates for resection.

>

> Medscape: This morning, you and your colleagues were discussing the

> use of preoperative, or neoadjuvant, chemotherapy as one means to

> improve outcomes for patients with liver metastases. Can you

explain

> the rationale behind neoadjuvant chemotherapy?

>

> Dr. Choti: There are a few issues. One is that even in patients

with

> resectable disease, although we are making dramatic improvements in

> long-term outcomes with surgery, many of these patients without any

> additional therapy still experience recurrence. The strategy is to

> combine effective systemic chemotherapy with surgery to improve

> outcomes. Then it becomes primarily a sequencing question. In a

> patient with resectable disease, is it preferable to give

> chemotherapy upfront and then perform the surgery after assessing

> response? Or is it better to resect the disease and then give

> chemotherapy postoperatively when there is no residual measurable

> disease? We don't know the answer to this question.

>

> As we have discussed at this conference, there are pros and cons to

> giving chemotherapy first. In a patient who initially has

resectable

> disease, the goal is not to give long and extensive treatments with

> chemotherapy but to give therapy of a relatively limited duration,

> then get the tumor out, and perhaps give more chemotherapy after

> surgery. In some patients who have marginally resectable or

> unresectable disease, we would need to give chemotherapy first and

> consider the option of operating on them if and when their disease

> becomes resectable.

>

> In our multidisciplinary conferences, we assess the individual

> patient and discuss the best paradigm for any individual patient's

> management. First, we think in terms of whether a patient may fit

> into a curative intent paradigm or is the goal primarily

palliative?

> If the patient's disease is unresectable initially but may become

> resectable, then we think about them in a curative intent mode and

> tailor the strategy with that goal in mind. We attempt to maximize

> the response through choice of initial chemotherapy regimen to

> improve the chance of resection, at the same time trying to limit

> hepatotoxicity, which may make liver surgery more difficult.

>

> If resection is unlikely and we need to consider the overall

> treatment as palliative, then we sometimes use the chemotherapy

> differently and save regimens to maximize median survival and

quality

> of life. Occasionally, in patients in whom we have initially

thought

> treatment was palliative, we have been dramatically surprised by

> response to therapy and are able shift the strategy to a curative

> intent and consider liver resection or ablation. Similarly, when a

> patient who we initially believe has resectable disease progresses

> during preoperative chemotherapy and develops unresectable disease,

> palliation is the primary goal.

>

> Medscape: Are there factors that you can use to predict who is

likely

> to benefit from a curative approach? Do we have markers of

> sensitivity that can help determine who is likely to respond to

> neoadjuvant chemotherapy?

>

> Dr. Choti: There are a variety of factors, some of which are

related

> to chemotherapy and chemosensitivity. Many are related to factors

> such as the number and location of the metastatic disease within

the

> liver and elsewhere. Other factors, such as disease-free interval,

> the histology of the primary tumor, and nodal status of the primary

> tumor, also have prognostic implications. We consider a response to

> chemotherapy as another favorable prognostic factor. Perhaps, in

the

> future, we will have methods such as tumor expression profiling,

> proteomics, and molecular genetics to more accurately predict which

> patients will derive the greatest benefit from aggressive liver

> surgery and chemotherapy.

>

> Medscape: You mentioned that chemotherapy can be administered

before

> surgery, after surgery, or both before and after surgery. Do we

know

> or are there studies planned to clarify whether the timing of

therapy

> affects survival or other end points in treating colorectal cancer

> patients with liver metastases?

>

> Dr. Choti: We do not currently have studies to answer this

question.

> In rectal cancer, we know that preoperative therapy can control

local

> disease and allow us to limit the extent of resection. In

metastatic

> colorectal cancer, we don't have information on how timing of

> chemotherapy affects outcomes, but we are interested in these

> questions. There is an EORTC [European Organization for Research

> Treatment of Cancer] trial that I believe has completed accrual in

> which they are looking at preoperative and postoperative

chemotherapy

> vs no chemotherapy, but this may only answer the question of

whether

> chemotherapy helps. It does not compare preoperative vs

postoperative

> chemotherapy.

>

> In patients with resectable disease, we do not know whether

> neoadjuvant chemotherapy is beneficial. There are trials under

> development that will attempt to answer this question. We hope to

> have a trial like this under way in the near future. Right now

there

> are theoretical reasons to consider chemotherapy before or after

> resection. I believe that the strategy at present should be to

> increase awareness of the potential role of systemic therapy and

the

> understanding that the optimal way to manage patients with liver

> metastases may be the combination of surgery and chemotherapy,

> however it is given.

>

> Medscape: This suggests that good communication between medical

> oncologists and surgical oncologists is an important factor in the

> care of these patients. To what extent do you think adequate

> communication is occurring today?

>

> Dr. Choti: I think this is a very important point.

Multidisciplinary

> management is important when considering options. Medical

oncologists

> need to have an understanding of when disease is resectable and

when

> surgery should be offered. Similarly, the surgical oncologist or

> liver surgeon needs to have a comprehensive understanding of the

> various chemotherapeutic options available, including the benefit

and

> potential toxicities. I believe that sessions such as the

discussion

> of this topic this morning at ASCO are aimed at improving

> communication and understanding. Providers need to appreciate that,

> although we cannot cure many patients, there should no longer be an

> automatic nihilistic approach to all patients with metastatic

> disease. We need to integrate chemotherapy and surgery in

> aggressively selected patients with advanced colorectal cancer.

>

> I believe surgeons are developing a real understanding of the role

of

> chemotherapy, and this needs to be brought into the mainstream of

> surgical education.

>

> Medscape: Is neoadjuvant chemotherapy for patients with liver

> metastases from colorectal cancer ready for the clinic?

>

> Dr. Choti: There are several theoretical advantages to

preoperative,

> or neoadjuvant, chemotherapy.

>

> One advantage of giving chemotherapy upfront is that we can

determine

> whether the tumor is responsive or not before resection, as opposed

> to simply giving chemotherapy empirically after resection.

>

> Additionally, in selected cases there may be progression if there

is

> a biologically aggressive tumor. Identification of this subset

> preoperatively can spare a patient surgical resection, which is

> unlikely to be beneficial.

>

> Another reason is that giving systemic therapy earlier

theoretically

> may improve outcomes as the chemotherapy is started earlier.

Finally,

> a response from preoperative chemotherapy may reduce the size of

> liver metastases, allowing for less extensive surgery.

>

> The theoretical disadvantages include the possibility that a

patient

> who has initially resectable disease could progress to an

> unresectable situation. Although this is uncommon, losing the

window

> of opportunity to attempt curative therapy is unfortunate. However,

> as I mentioned in my discussion this morning, patients whose tumors

> progress during chemotherapy are probably not those who are going

to

> do well even if they undergo resection.

>

> In addition, chemotherapy can result in hepatotoxicity,

particularly

> when administered for prolonged duration. This liver steatosis, if

> severe, can in fact decrease rather than increase resectability and

> may actually make the liver resection riskier. What type of

> chemotherapy -- and for what duration -- is associated with

increased

> hepatotoxicity is not clear. We have even less information on newer

> biologic agents such as bevacizumab, which may also affect wound

> healing or liver regeneration. I think we don't have enough

> information regarding these issues at this time, but many of us are

> trying to shed light on this subject. Let's wait and see.

>

> There are currently no clinical trials open asking these questions,

> so we manage our patients selectively. In some we offer

preoperative

> chemotherapy, and in some we go right to surgery first, depending

on

> various factors. In patients who are chemo-naive with multiple

> metastases and stage 4 disease at presentation, we may be more

> inclined to offer chemotherapy upfront. If a patient is marginally

> resectable, in which case a response would improve the outcome of

> resection, we may be aggressive about giving chemotherapy upfront

as

> well. If a patient has comorbidities or there is concern about

> chemotherapy causing hepatotoxicity in a patient who will require a

> large resection, I may be more inclined to go to surgery first.

>

> The other factor we consider is whether a patient has been exposed

to

> chemotherapy or not, either in the metastatic setting or in the

> adjuvant setting. If a patient has received adjuvant chemotherapy

for

> his or her primary disease and disease recurred early, then we may

be

> less inclined to use neoadjuvant or adjuvant chemotherapy with

> resection of liver metastases.

>

> Medscape: What are the next steps we need to take in this field in

> terms of research?

>

> Dr. Choti: There are several important issues. With rapidly

changing

> options for chemotherapy, including the combination of cytotoxic

> agents and biologic therapies, we need to define the optimal

regimens

> in various clinical scenarios. We need to consider how we integrate

> the biologics with chemotherapy, what cytotoxic regimens we use,

and,

> as we've discussed, the sequencing of therapy needs to be worked

out.

>

> In terms of the biologics, there are additional questions. For

> example, bevacizumab presents potential issues regarding

> administration around the time of extensive surgery. We don't know

if

> this will have an impact on wound healing, bleeding, or liver

> regeneration. These questions will be emerging in the context of

the

> multimodality approach to patients with liver metastases.

>

> An additional important issue regarding neoadjuvant chemotherapy is

> how do we manage the type of resection, particularly in patients

who

> had unresectable disease and then responded. Do you need to resect

> the volume of tissue in which the initial disease resided or can

you

> only take the nidus of residual disease? Does a tumor respond

> circumferentially? We don't really understand how much one needs to

> resect. Currently, we try to resect all sites within the liver that

> contained disease, but this needs to be more clearly defined.

>

> Response to initial therapy raises additional questions. If the

> patient responds, we typically use the same regimen after surgery.

If

> the patient's cancer progressed or even if it is stable disease,

> should we offer a different chemotherapy regimen in the

postoperative

> adjuvant setting, or should we not offer any chemotherapy? This is

> completely unknown and requires further investigation.

>

> What is the final word? Well, this is an exciting and evolving time

> for patients with advanced colorectal cancer and physicians

treating

> them, but we have many unanswered questions. Stay tuned.

>

> References

> Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA

Cancer

> J Clin. 2005;55:10-30.

> Choti MA, Sitzmann JV, Tiburi MF, et al. Trends in long-term

survival

> following liver resection for hepatic colorectal metastases. Ann

> Surg. 2002;235:759-766.

> Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus

> irinotecan, fluorouracil, and leucovorin for metastatic colorectal

> cancer. N Engl J Med. 2004;350:2335-2342.

> Choti MA. Treatment of liver metastases: what are the limits? what

> are the goals? Management of hepatic colorectal metastases. Proc

Soc

> Am Clin Oncol. 2005:302-306. Education Session.

>

>

> Funding Information

>

> Supported by an independent educational grant from Sanofi-Aventis.

>

>

>

> Choti, MD , Associate Professor of Surgery and Oncology,

The

> Sidney Kimmel Comprehensive Cancer Center at s Hopkins,

> Baltimore, land

>

>

> Disclosure: Peppercorn, MD, MPH, has no disclosed no

relevant

> financial relationships.

>

> Disclosure: Choti, MD, has disclosed no relevant financial

> relationships.

[Guest guest]

Great stuff. For those with metastatic disease to the liver, I

think it is one of the most informative pieces I've ever seen,

laying out the surgical prognosis pretty well. Liver surgery still,

to this day, is one of the options that I think most people do not

understand (insofar as when it is appropriate), and this goes a good

ways towards laying it out.

Thanks again for posting.

Joe

>

>

>

> http://www.medscape.com/viewarticle/506325

>

> Expert Interview

> Treating Liver Metastases in Colorectal Cancer: An Expert

Interview

> With Choti, MD

>

>

>

> Medscape Hematology-Oncology. 2005; 8 (1): ©2005 Medscape

> Editor's Note

> In 2005, it is estimated that more than 104,000 cases of colon

cancer

> will be diagnosed in the United States alone[1] and that more than

> 56,000 patients will die of this disease.[1] The liver is the most

> common site of colon cancer metastasis, and patients who undergo

> resection of liver metastases can have prolonged survival. One

> quarter to one third of patients who are able to undergo resection

of

> liver metastases will live 5 years or longer, and median survival

> after resection is between 24 and 40 months.[2] Unfortunately,

even

> for patients with metastatic disease confined to the liver, not

all

> liver lesions are resectable, and even after successful resection,

> microscopic disease elsewhere can lead to disease recurrence and

> death. As novel systemic therapies that are proven to improve

> survival in metastatic colorectal cancer emerge,[3] there is

> increasing interest in treating patients who are potential

candidates

> for resection of metastases with preoperative and/or postoperative

> chemotherapy.

>

> Dr. Choti and colleagues discussed recent advances and

> emerging strategies for the multidisciplinary management of liver

> metastases from colorectal cancer in an education session at the

2005

> annual meeting of the American Society of Clinical Oncology (ASCO).

> [4] In an interview with Medscape, Dr. Choti explains the promise

and

> limitations of adding chemotherapy to liver surgery and how he

> currently approaches patient management in this area.

>

> Medscape: Dr. Choti, this morning you and your colleagues

discussed

> preoperative, or neoadjuvant, and postoperative, or adjuvant,

> chemotherapy for patients with colorectal cancer and potentially

> resectable hepatic metastases. If metastatic colorectal cancer is

a

> systemic disease, what is the rationale for treating metastases to

> the liver with local therapy such as surgery?

>

> Dr. Choti: That is an excellent question. We don't know why

> necessarily by resecting metastases we improve outcomes and why

some

> patients can actually be cured, but it does happen. So, number

one,

> we need to base the rationale for resection on the empiric data

> showing that some patients can be cured with surgery alone.

Whether

> in those selected patients these are the only sites of disease or

you

> are cytoreducing a tumor down to a volume of disease in which, for

> some reason, microscopic residual disease does not progress, we

don't

> know. This, in particular, is why combining effective systemic

> chemotherapy with resection is a theoretically good strategy.

>

> Medscape: In terms of the scope of this problem, what percentage

of

> patients with metastatic colorectal cancer have liver-only disease

> and are potential candidates for resection?

>

> Dr. Choti: It depends on which series is looked at. Approximately

two

> thirds of patients have liver as their first site of metastatic

> disease, but many of these patients also have extrahepatic

disease.

> Roughly one third of patients who develop metastatic disease

appear

> to have disease confined to their liver on imaging studies.

>

> Medscape: What percentage of patients with liver-only disease can

> undergo resection with current strategies?

>

> Dr. Choti: That varies with the aggressiveness of the surgeon.

> Somewhere in the range of one third to one half of patients with

> liver-only metastatic disease may be candidates for resection.

>

> Medscape: This morning, you and your colleagues were discussing

the

> use of preoperative, or neoadjuvant, chemotherapy as one means to

> improve outcomes for patients with liver metastases. Can you

explain

> the rationale behind neoadjuvant chemotherapy?

>

> Dr. Choti: There are a few issues. One is that even in patients

with

> resectable disease, although we are making dramatic improvements

in

> long-term outcomes with surgery, many of these patients without

any

> additional therapy still experience recurrence. The strategy is to

> combine effective systemic chemotherapy with surgery to improve

> outcomes. Then it becomes primarily a sequencing question. In a

> patient with resectable disease, is it preferable to give

> chemotherapy upfront and then perform the surgery after assessing

> response? Or is it better to resect the disease and then give

> chemotherapy postoperatively when there is no residual measurable

> disease? We don't know the answer to this question.

>

> As we have discussed at this conference, there are pros and cons

to

> giving chemotherapy first. In a patient who initially has

resectable

> disease, the goal is not to give long and extensive treatments

with

> chemotherapy but to give therapy of a relatively limited duration,

> then get the tumor out, and perhaps give more chemotherapy after

> surgery. In some patients who have marginally resectable or

> unresectable disease, we would need to give chemotherapy first and

> consider the option of operating on them if and when their disease

> becomes resectable.

>

> In our multidisciplinary conferences, we assess the individual

> patient and discuss the best paradigm for any individual patient's

> management. First, we think in terms of whether a patient may fit

> into a curative intent paradigm or is the goal primarily

palliative?

> If the patient's disease is unresectable initially but may become

> resectable, then we think about them in a curative intent mode and

> tailor the strategy with that goal in mind. We attempt to maximize

> the response through choice of initial chemotherapy regimen to

> improve the chance of resection, at the same time trying to limit

> hepatotoxicity, which may make liver surgery more difficult.

>

> If resection is unlikely and we need to consider the overall

> treatment as palliative, then we sometimes use the chemotherapy

> differently and save regimens to maximize median survival and

quality

> of life. Occasionally, in patients in whom we have initially

thought

> treatment was palliative, we have been dramatically surprised by

> response to therapy and are able shift the strategy to a curative

> intent and consider liver resection or ablation. Similarly, when a

> patient who we initially believe has resectable disease progresses

> during preoperative chemotherapy and develops unresectable

disease,

> palliation is the primary goal.

>

> Medscape: Are there factors that you can use to predict who is

likely

> to benefit from a curative approach? Do we have markers of

> sensitivity that can help determine who is likely to respond to

> neoadjuvant chemotherapy?

>

> Dr. Choti: There are a variety of factors, some of which are

related

> to chemotherapy and chemosensitivity. Many are related to factors

> such as the number and location of the metastatic disease within

the

> liver and elsewhere. Other factors, such as disease-free interval,

> the histology of the primary tumor, and nodal status of the

primary

> tumor, also have prognostic implications. We consider a response

to

> chemotherapy as another favorable prognostic factor. Perhaps, in

the

> future, we will have methods such as tumor expression profiling,

> proteomics, and molecular genetics to more accurately predict

which

> patients will derive the greatest benefit from aggressive liver

> surgery and chemotherapy.

>

> Medscape: You mentioned that chemotherapy can be administered

before

> surgery, after surgery, or both before and after surgery. Do we

know

> or are there studies planned to clarify whether the timing of

therapy

> affects survival or other end points in treating colorectal cancer

> patients with liver metastases?

>

> Dr. Choti: We do not currently have studies to answer this

question.

> In rectal cancer, we know that preoperative therapy can control

local

> disease and allow us to limit the extent of resection. In

metastatic

> colorectal cancer, we don't have information on how timing of

> chemotherapy affects outcomes, but we are interested in these

> questions. There is an EORTC [European Organization for Research

> Treatment of Cancer] trial that I believe has completed accrual in

> which they are looking at preoperative and postoperative

chemotherapy

> vs no chemotherapy, but this may only answer the question of

whether

> chemotherapy helps. It does not compare preoperative vs

postoperative

> chemotherapy.

>

> In patients with resectable disease, we do not know whether

> neoadjuvant chemotherapy is beneficial. There are trials under

> development that will attempt to answer this question. We hope to

> have a trial like this under way in the near future. Right now

there

> are theoretical reasons to consider chemotherapy before or after

> resection. I believe that the strategy at present should be to

> increase awareness of the potential role of systemic therapy and

the

> understanding that the optimal way to manage patients with liver

> metastases may be the combination of surgery and chemotherapy,

> however it is given.

>

> Medscape: This suggests that good communication between medical

> oncologists and surgical oncologists is an important factor in the

> care of these patients. To what extent do you think adequate

> communication is occurring today?

>

> Dr. Choti: I think this is a very important point.

Multidisciplinary

> management is important when considering options. Medical

oncologists

> need to have an understanding of when disease is resectable and

when

> surgery should be offered. Similarly, the surgical oncologist or

> liver surgeon needs to have a comprehensive understanding of the

> various chemotherapeutic options available, including the benefit

and

> potential toxicities. I believe that sessions such as the

discussion

> of this topic this morning at ASCO are aimed at improving

> communication and understanding. Providers need to appreciate

that,

> although we cannot cure many patients, there should no longer be

an

> automatic nihilistic approach to all patients with metastatic

> disease. We need to integrate chemotherapy and surgery in

> aggressively selected patients with advanced colorectal cancer.

>

> I believe surgeons are developing a real understanding of the role

of

> chemotherapy, and this needs to be brought into the mainstream of

> surgical education.

>

> Medscape: Is neoadjuvant chemotherapy for patients with liver

> metastases from colorectal cancer ready for the clinic?

>

> Dr. Choti: There are several theoretical advantages to

preoperative,

> or neoadjuvant, chemotherapy.

>

> One advantage of giving chemotherapy upfront is that we can

determine

> whether the tumor is responsive or not before resection, as

opposed

> to simply giving chemotherapy empirically after resection.

>

> Additionally, in selected cases there may be progression if there

is

> a biologically aggressive tumor. Identification of this subset

> preoperatively can spare a patient surgical resection, which is

> unlikely to be beneficial.

>

> Another reason is that giving systemic therapy earlier

theoretically

> may improve outcomes as the chemotherapy is started earlier.

Finally,

> a response from preoperative chemotherapy may reduce the size of

> liver metastases, allowing for less extensive surgery.

>

> The theoretical disadvantages include the possibility that a

patient

> who has initially resectable disease could progress to an

> unresectable situation. Although this is uncommon, losing the

window

> of opportunity to attempt curative therapy is unfortunate.

However,

> as I mentioned in my discussion this morning, patients whose

tumors

> progress during chemotherapy are probably not those who are going

to

> do well even if they undergo resection.

>

> In addition, chemotherapy can result in hepatotoxicity,

particularly

> when administered for prolonged duration. This liver steatosis, if

> severe, can in fact decrease rather than increase resectability

and

> may actually make the liver resection riskier. What type of

> chemotherapy -- and for what duration -- is associated with

increased

> hepatotoxicity is not clear. We have even less information on

newer

> biologic agents such as bevacizumab, which may also affect wound

> healing or liver regeneration. I think we don't have enough

> information regarding these issues at this time, but many of us

are

> trying to shed light on this subject. Let's wait and see.

>

> There are currently no clinical trials open asking these

questions,

> so we manage our patients selectively. In some we offer

preoperative

> chemotherapy, and in some we go right to surgery first, depending

on

> various factors. In patients who are chemo-naive with multiple

> metastases and stage 4 disease at presentation, we may be more

> inclined to offer chemotherapy upfront. If a patient is marginally

> resectable, in which case a response would improve the outcome of

> resection, we may be aggressive about giving chemotherapy upfront

as

> well. If a patient has comorbidities or there is concern about

> chemotherapy causing hepatotoxicity in a patient who will require

a

> large resection, I may be more inclined to go to surgery first.

>

> The other factor we consider is whether a patient has been exposed

to

> chemotherapy or not, either in the metastatic setting or in the

> adjuvant setting. If a patient has received adjuvant chemotherapy

for

> his or her primary disease and disease recurred early, then we may

be

> less inclined to use neoadjuvant or adjuvant chemotherapy with

> resection of liver metastases.

>

> Medscape: What are the next steps we need to take in this field in

> terms of research?

>

> Dr. Choti: There are several important issues. With rapidly

changing

> options for chemotherapy, including the combination of cytotoxic

> agents and biologic therapies, we need to define the optimal

regimens

> in various clinical scenarios. We need to consider how we

integrate

> the biologics with chemotherapy, what cytotoxic regimens we use,

and,

> as we've discussed, the sequencing of therapy needs to be worked

out.

>

> In terms of the biologics, there are additional questions. For

> example, bevacizumab presents potential issues regarding

> administration around the time of extensive surgery. We don't know

if

> this will have an impact on wound healing, bleeding, or liver

> regeneration. These questions will be emerging in the context of

the

> multimodality approach to patients with liver metastases.

>

> An additional important issue regarding neoadjuvant chemotherapy

is

> how do we manage the type of resection, particularly in patients

who

> had unresectable disease and then responded. Do you need to resect

> the volume of tissue in which the initial disease resided or can

you

> only take the nidus of residual disease? Does a tumor respond

> circumferentially? We don't really understand how much one needs

to

> resect. Currently, we try to resect all sites within the liver

that

> contained disease, but this needs to be more clearly defined.

>

> Response to initial therapy raises additional questions. If the

> patient responds, we typically use the same regimen after surgery.

If

> the patient's cancer progressed or even if it is stable disease,

> should we offer a different chemotherapy regimen in the

postoperative

> adjuvant setting, or should we not offer any chemotherapy? This is

> completely unknown and requires further investigation.

>

> What is the final word? Well, this is an exciting and evolving

time

> for patients with advanced colorectal cancer and physicians

treating

> them, but we have many unanswered questions. Stay tuned.

>

> References

> Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA

Cancer

> J Clin. 2005;55:10-30.

> Choti MA, Sitzmann JV, Tiburi MF, et al. Trends in long-term

survival

> following liver resection for hepatic colorectal metastases. Ann

> Surg. 2002;235:759-766.

> Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus

> irinotecan, fluorouracil, and leucovorin for metastatic colorectal

> cancer. N Engl J Med. 2004;350:2335-2342.

> Choti MA. Treatment of liver metastases: what are the limits? what

> are the goals? Management of hepatic colorectal metastases. Proc

Soc

> Am Clin Oncol. 2005:302-306. Education Session.

>

>

> Funding Information

>

> Supported by an independent educational grant from Sanofi-Aventis.

>

>

>

> Choti, MD , Associate Professor of Surgery and Oncology,

The

> Sidney Kimmel Comprehensive Cancer Center at s Hopkins,

> Baltimore, land

>

>

> Disclosure: Peppercorn, MD, MPH, has no disclosed no

relevant

> financial relationships.

>

> Disclosure: Choti, MD, has disclosed no relevant financial

> relationships.