Primary tumor resection is linked to growth of CRC liver metastases

PHOENIX – The standard sequential approach to treatment of patients with isolated synchronous liver metastases of colorectal cancer, entailing up-front removal of the primary tumor, is associated with growth of the metastases, according to results from a retrospective cohort study.

A team led by Dr. Alistair Slesser, a surgical registrar at the Royal Marsden Hospital in London, studied 114 patients with colorectal cancer who had synchronous liver metastases, meaning ones identified within a year of the cancer diagnosis, and no other metastases.

Results showed that patients whose initial treatment was resection of the colorectal primary tumor had ninefold higher odds of progression of their liver metastases at 3 months, compared with patients whose initial treatment was chemotherapy, he reported at the annual meeting of the American Society of Colon and Rectal Surgeons.

Although liver metastases showed regression during 3-6 months of treatment in both groups, the rate was somewhat slower in the primary tumor resection group.

"Our findings suggest that an up-front primary tumor resection is actually an adverse prognostic factor. Indeed, our results have demonstrated that up-front primary tumor resection seemed to negate the effects of the adjuvant therapy on the treatment of the liver metastasis," Dr. Slesser commented.

"How does this apply clinically? We would recommend that patients who have limited metastatic disease, instead of having an up-front primary tumor resection perhaps [they should] be treated with neoadjuvant chemotherapy first. Or perhaps another surgical approach, like a simultaneous resection, should be considered to negate the adverse effects of a primary tumor resection on the metastatic disease," he said.

"When patients have lesions which are suspicious for liver metastases, we would recommend that these patients [be] thoroughly investigated, and if metastatic disease is confirmed, then again, we would recommend that they have chemotherapy prior to any subsequent intervention," he added.

The mechanism leading to growth of liver metastases after primary tumor resection is unknown, according to Dr. Slesser. "There is possibly an association for ... biological reasons. The other reason is that perhaps when a patient has an up-front primary tumor resection, there is a delay in getting chemotherapy, and that can cause the progression that we see."

Session attendee Dr. Gary Dunn, of the University of Oklahoma, Oklahoma City, asked how much time elapsed between up-front resection and receipt of adjuvant chemotherapy in that group, and the variance in this measure, noting, "That will significantly affect your outcome, if some patients started at 6 weeks and some patients started at 12 weeks postop."

"Usually, patients waited 6 weeks before they started chemotherapy postoperatively," Dr. Slesser explained. "The majority of patients who had primary tumor resection had the adjuvant chemotherapy after the postoperative scan; the 3-month scan tends to be the postoperative scan."

Dr. Dunn further wondered about the comparability between groups of the chemotherapy received, asking what agents were used.

"At the Royal Marsden, the chemotherapy regimes tend to be quite uniform," Dr. Slesser replied. "Generally, all patients are on capecitabine [Xeloda] and oxaliplatin, with a monoclonal agent such as bevacizumab [Avastin]. They tend to get that when they have neoadjuvant chemotherapy."

Another attendee said, "Excellent paper, very well presented data, particularly considering there are a lot of retrospective series out there that are showing the up-front resection as a favorable prognostic indicator, which I don’t believe. ... But I would like to see a little more information about how the patients were treated subsequently. Were these patients who they were planning to get to surgery for resection, or were these patients who were treated for palliative intent? Did they have symptomatic primaries?"

"In the majority of these patients, the intent was curative surgery," Dr. Slesser replied. "We tried to exclude patients who were clearly referred for palliative treatment because we really wanted to assess patients who were referred for curative treatment."

Attendee Dr. David Shibata, of the Moffitt Cancer Center in Tampa, commented, "I think a critical question is that you have done a primary tumor resection and the liver tumor has tended to grow, which is not entirely surprising, but then in those cases, how many became unresectable from a liver standpoint?"

"About 60% ended up having hepatectomies," Dr. Slesser said, noting that the data reported looked only at the short-term time frame. "We do have further results, which will be in the paper, pertaining to survival. But the real aim of this study was to look at initial radiological progression of disease, because we thought that the primary tumor resection may be associated with a sudden increase in the size of metastasis."

The finding of a better liver outcome with initial chemotherapy "makes sense," session comoderator Dr. Marylise Boutros, of McGill University in Montreal, said in an interview. "That’s something that we would expect, that you can treat the largest burden of the disease, which is the metastasis – it’s a systemic disease – with chemotherapy up-front."

"But it’s definitely a smaller study, and this needs to be looked at in a larger subset and in a prospective fashion," she added.

Giving some background to the research, Dr. Slesser noted that "the mainstay of surgical treatment for these patients with limited metastatic disease is a sequential resection. Patients tend to have an up-front primary tumor resection, followed by adjuvant chemotherapy, followed by hepatic resection if feasible. On the other hand, patients who have extensive metastatic disease tend to have neoadjuvant chemotherapy prior to a surgical intervention."

He and his coinvestigators studied patients with isolated synchronous colorectal liver metastases who were referred to the Royal Marsden Hospital for treatment between 2005 and 2010 and had imaging done at baseline, 3 months, and 6 months.

The mean age of the cohort was 64 years, and the ratio of men to women was about 2:1. In terms of treatment, 51% of the patients underwent primary tumor resection, while the other 49% received neoadjuvant chemotherapy.

In univariate analysis, the factor most strongly associated with progression of liver metastases – defined as an increase in their cumulative diameter of at least 20% – at 3 months was a primary tumor resection, according to Dr. Slesser.

In a multivariate analysis, relative to their counterparts in the neoadjuvant chemotherapy group, patients undergoing primary tumor resection had dramatically elevated odds of progression of liver metastases (odds ratio, 9.0; P = .001).

Additionally, metastatic burden showed an upward trend between baseline and 6 months in the group undergoing primary tumor resection (from 40 to 51 mm; P = .19), whereas it decreased significantly in the neoadjuvant chemotherapy group (from 96 to 52 mm; P = .001).

Overall, 93% of patients having a primary tumor resection went on to receive adjuvant chemotherapy, according to Dr. Slesser.

Comparing baseline to 3 months versus 3 months to 6 months, liver metastases began regressing in the primary tumor resection group, with the growth rate changing from 4.0 to –3.0 mm/month (P less than .001), reflecting the effect of the adjuvant chemotherapy, he said. Liver metastases in the neoadjuvant chemotherapy group continued to regress, albeit also at a slower pace, with the growth rate changing from –5.6 to –4.0 mm/month (P = .003).

Dr. Slesser disclosed no relevant conflicts of interest.

PHOENIX – The standard sequential approach to treatment of patients with isolated synchronous liver metastases of colorectal cancer, entailing up-front removal of the primary tumor, is associated with growth of the metastases, according to results from a retrospective cohort study.

A team led by Dr. Alistair Slesser, a surgical registrar at the Royal Marsden Hospital in London, studied 114 patients with colorectal cancer who had synchronous liver metastases, meaning ones identified within a year of the cancer diagnosis, and no other metastases.

Results showed that patients whose initial treatment was resection of the colorectal primary tumor had ninefold higher odds of progression of their liver metastases at 3 months, compared with patients whose initial treatment was chemotherapy, he reported at the annual meeting of the American Society of Colon and Rectal Surgeons.

Although liver metastases showed regression during 3-6 months of treatment in both groups, the rate was somewhat slower in the primary tumor resection group.

"Our findings suggest that an up-front primary tumor resection is actually an adverse prognostic factor. Indeed, our results have demonstrated that up-front primary tumor resection seemed to negate the effects of the adjuvant therapy on the treatment of the liver metastasis," Dr. Slesser commented.

"How does this apply clinically? We would recommend that patients who have limited metastatic disease, instead of having an up-front primary tumor resection perhaps [they should] be treated with neoadjuvant chemotherapy first. Or perhaps another surgical approach, like a simultaneous resection, should be considered to negate the adverse effects of a primary tumor resection on the metastatic disease," he said.

"When patients have lesions which are suspicious for liver metastases, we would recommend that these patients [be] thoroughly investigated, and if metastatic disease is confirmed, then again, we would recommend that they have chemotherapy prior to any subsequent intervention," he added.

The mechanism leading to growth of liver metastases after primary tumor resection is unknown, according to Dr. Slesser. "There is possibly an association for ... biological reasons. The other reason is that perhaps when a patient has an up-front primary tumor resection, there is a delay in getting chemotherapy, and that can cause the progression that we see."

Session attendee Dr. Gary Dunn, of the University of Oklahoma, Oklahoma City, asked how much time elapsed between up-front resection and receipt of adjuvant chemotherapy in that group, and the variance in this measure, noting, "That will significantly affect your outcome, if some patients started at 6 weeks and some patients started at 12 weeks postop."

"Usually, patients waited 6 weeks before they started chemotherapy postoperatively," Dr. Slesser explained. "The majority of patients who had primary tumor resection had the adjuvant chemotherapy after the postoperative scan; the 3-month scan tends to be the postoperative scan."

Dr. Dunn further wondered about the comparability between groups of the chemotherapy received, asking what agents were used.

"At the Royal Marsden, the chemotherapy regimes tend to be quite uniform," Dr. Slesser replied. "Generally, all patients are on capecitabine [Xeloda] and oxaliplatin, with a monoclonal agent such as bevacizumab [Avastin]. They tend to get that when they have neoadjuvant chemotherapy."

Another attendee said, "Excellent paper, very well presented data, particularly considering there are a lot of retrospective series out there that are showing the up-front resection as a favorable prognostic indicator, which I don’t believe. ... But I would like to see a little more information about how the patients were treated subsequently. Were these patients who they were planning to get to surgery for resection, or were these patients who were treated for palliative intent? Did they have symptomatic primaries?"

"In the majority of these patients, the intent was curative surgery," Dr. Slesser replied. "We tried to exclude patients who were clearly referred for palliative treatment because we really wanted to assess patients who were referred for curative treatment."

Attendee Dr. David Shibata, of the Moffitt Cancer Center in Tampa, commented, "I think a critical question is that you have done a primary tumor resection and the liver tumor has tended to grow, which is not entirely surprising, but then in those cases, how many became unresectable from a liver standpoint?"

"About 60% ended up having hepatectomies," Dr. Slesser said, noting that the data reported looked only at the short-term time frame. "We do have further results, which will be in the paper, pertaining to survival. But the real aim of this study was to look at initial radiological progression of disease, because we thought that the primary tumor resection may be associated with a sudden increase in the size of metastasis."

The finding of a better liver outcome with initial chemotherapy "makes sense," session comoderator Dr. Marylise Boutros, of McGill University in Montreal, said in an interview. "That’s something that we would expect, that you can treat the largest burden of the disease, which is the metastasis – it’s a systemic disease – with chemotherapy up-front."

"But it’s definitely a smaller study, and this needs to be looked at in a larger subset and in a prospective fashion," she added.

Giving some background to the research, Dr. Slesser noted that "the mainstay of surgical treatment for these patients with limited metastatic disease is a sequential resection. Patients tend to have an up-front primary tumor resection, followed by adjuvant chemotherapy, followed by hepatic resection if feasible. On the other hand, patients who have extensive metastatic disease tend to have neoadjuvant chemotherapy prior to a surgical intervention."

He and his coinvestigators studied patients with isolated synchronous colorectal liver metastases who were referred to the Royal Marsden Hospital for treatment between 2005 and 2010 and had imaging done at baseline, 3 months, and 6 months.

The mean age of the cohort was 64 years, and the ratio of men to women was about 2:1. In terms of treatment, 51% of the patients underwent primary tumor resection, while the other 49% received neoadjuvant chemotherapy.

In univariate analysis, the factor most strongly associated with progression of liver metastases – defined as an increase in their cumulative diameter of at least 20% – at 3 months was a primary tumor resection, according to Dr. Slesser.

In a multivariate analysis, relative to their counterparts in the neoadjuvant chemotherapy group, patients undergoing primary tumor resection had dramatically elevated odds of progression of liver metastases (odds ratio, 9.0; P = .001).

Additionally, metastatic burden showed an upward trend between baseline and 6 months in the group undergoing primary tumor resection (from 40 to 51 mm; P = .19), whereas it decreased significantly in the neoadjuvant chemotherapy group (from 96 to 52 mm; P = .001).

Overall, 93% of patients having a primary tumor resection went on to receive adjuvant chemotherapy, according to Dr. Slesser.

Comparing baseline to 3 months versus 3 months to 6 months, liver metastases began regressing in the primary tumor resection group, with the growth rate changing from 4.0 to –3.0 mm/month (P less than .001), reflecting the effect of the adjuvant chemotherapy, he said. Liver metastases in the neoadjuvant chemotherapy group continued to regress, albeit also at a slower pace, with the growth rate changing from –5.6 to –4.0 mm/month (P = .003).

Dr. Slesser disclosed no relevant conflicts of interest.

PHOENIX – The standard sequential approach to treatment of patients with isolated synchronous liver metastases of colorectal cancer, entailing up-front removal of the primary tumor, is associated with growth of the metastases, according to results from a retrospective cohort study.

A team led by Dr. Alistair Slesser, a surgical registrar at the Royal Marsden Hospital in London, studied 114 patients with colorectal cancer who had synchronous liver metastases, meaning ones identified within a year of the cancer diagnosis, and no other metastases.

Results showed that patients whose initial treatment was resection of the colorectal primary tumor had ninefold higher odds of progression of their liver metastases at 3 months, compared with patients whose initial treatment was chemotherapy, he reported at the annual meeting of the American Society of Colon and Rectal Surgeons.

Although liver metastases showed regression during 3-6 months of treatment in both groups, the rate was somewhat slower in the primary tumor resection group.

"Our findings suggest that an up-front primary tumor resection is actually an adverse prognostic factor. Indeed, our results have demonstrated that up-front primary tumor resection seemed to negate the effects of the adjuvant therapy on the treatment of the liver metastasis," Dr. Slesser commented.

"How does this apply clinically? We would recommend that patients who have limited metastatic disease, instead of having an up-front primary tumor resection perhaps [they should] be treated with neoadjuvant chemotherapy first. Or perhaps another surgical approach, like a simultaneous resection, should be considered to negate the adverse effects of a primary tumor resection on the metastatic disease," he said.

"When patients have lesions which are suspicious for liver metastases, we would recommend that these patients [be] thoroughly investigated, and if metastatic disease is confirmed, then again, we would recommend that they have chemotherapy prior to any subsequent intervention," he added.

The mechanism leading to growth of liver metastases after primary tumor resection is unknown, according to Dr. Slesser. "There is possibly an association for ... biological reasons. The other reason is that perhaps when a patient has an up-front primary tumor resection, there is a delay in getting chemotherapy, and that can cause the progression that we see."

Session attendee Dr. Gary Dunn, of the University of Oklahoma, Oklahoma City, asked how much time elapsed between up-front resection and receipt of adjuvant chemotherapy in that group, and the variance in this measure, noting, "That will significantly affect your outcome, if some patients started at 6 weeks and some patients started at 12 weeks postop."

"Usually, patients waited 6 weeks before they started chemotherapy postoperatively," Dr. Slesser explained. "The majority of patients who had primary tumor resection had the adjuvant chemotherapy after the postoperative scan; the 3-month scan tends to be the postoperative scan."

Dr. Dunn further wondered about the comparability between groups of the chemotherapy received, asking what agents were used.

"At the Royal Marsden, the chemotherapy regimes tend to be quite uniform," Dr. Slesser replied. "Generally, all patients are on capecitabine [Xeloda] and oxaliplatin, with a monoclonal agent such as bevacizumab [Avastin]. They tend to get that when they have neoadjuvant chemotherapy."

Another attendee said, "Excellent paper, very well presented data, particularly considering there are a lot of retrospective series out there that are showing the up-front resection as a favorable prognostic indicator, which I don’t believe. ... But I would like to see a little more information about how the patients were treated subsequently. Were these patients who they were planning to get to surgery for resection, or were these patients who were treated for palliative intent? Did they have symptomatic primaries?"

"In the majority of these patients, the intent was curative surgery," Dr. Slesser replied. "We tried to exclude patients who were clearly referred for palliative treatment because we really wanted to assess patients who were referred for curative treatment."

Attendee Dr. David Shibata, of the Moffitt Cancer Center in Tampa, commented, "I think a critical question is that you have done a primary tumor resection and the liver tumor has tended to grow, which is not entirely surprising, but then in those cases, how many became unresectable from a liver standpoint?"

"About 60% ended up having hepatectomies," Dr. Slesser said, noting that the data reported looked only at the short-term time frame. "We do have further results, which will be in the paper, pertaining to survival. But the real aim of this study was to look at initial radiological progression of disease, because we thought that the primary tumor resection may be associated with a sudden increase in the size of metastasis."

The finding of a better liver outcome with initial chemotherapy "makes sense," session comoderator Dr. Marylise Boutros, of McGill University in Montreal, said in an interview. "That’s something that we would expect, that you can treat the largest burden of the disease, which is the metastasis – it’s a systemic disease – with chemotherapy up-front."

"But it’s definitely a smaller study, and this needs to be looked at in a larger subset and in a prospective fashion," she added.

Giving some background to the research, Dr. Slesser noted that "the mainstay of surgical treatment for these patients with limited metastatic disease is a sequential resection. Patients tend to have an up-front primary tumor resection, followed by adjuvant chemotherapy, followed by hepatic resection if feasible. On the other hand, patients who have extensive metastatic disease tend to have neoadjuvant chemotherapy prior to a surgical intervention."

He and his coinvestigators studied patients with isolated synchronous colorectal liver metastases who were referred to the Royal Marsden Hospital for treatment between 2005 and 2010 and had imaging done at baseline, 3 months, and 6 months.

The mean age of the cohort was 64 years, and the ratio of men to women was about 2:1. In terms of treatment, 51% of the patients underwent primary tumor resection, while the other 49% received neoadjuvant chemotherapy.

In univariate analysis, the factor most strongly associated with progression of liver metastases – defined as an increase in their cumulative diameter of at least 20% – at 3 months was a primary tumor resection, according to Dr. Slesser.

In a multivariate analysis, relative to their counterparts in the neoadjuvant chemotherapy group, patients undergoing primary tumor resection had dramatically elevated odds of progression of liver metastases (odds ratio, 9.0; P = .001).

Additionally, metastatic burden showed an upward trend between baseline and 6 months in the group undergoing primary tumor resection (from 40 to 51 mm; P = .19), whereas it decreased significantly in the neoadjuvant chemotherapy group (from 96 to 52 mm; P = .001).

Overall, 93% of patients having a primary tumor resection went on to receive adjuvant chemotherapy, according to Dr. Slesser.

Comparing baseline to 3 months versus 3 months to 6 months, liver metastases began regressing in the primary tumor resection group, with the growth rate changing from 4.0 to –3.0 mm/month (P less than .001), reflecting the effect of the adjuvant chemotherapy, he said. Liver metastases in the neoadjuvant chemotherapy group continued to regress, albeit also at a slower pace, with the growth rate changing from –5.6 to –4.0 mm/month (P = .003).

Dr. Slesser disclosed no relevant conflicts of interest.