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NEOPLASMS OF THE EXOCRINE PANCREASADJUVANT AND NEOADJUVANT APPROACHES FOR RESECTABLE PANCREATIC CANCER
BORDERLINE RESECTABLE
PANCREATIC CANCER
Douglas B. Evans
For the Multidisciplinary Pancreatic
Tumor Study Group
Departments of Surgical Oncology, The
University of Texas M. D. Anderson Cancer Center, Houston, Texas
The Importance of Pretreatment Staging
to define the extent of disease as a necessary component of the conduct
of clinical trials and outcome reporting
Evaluation
of the potential value of nonsurgical therapies (chemotherapy and radiation
therapy) in improving local disease control and survival of patients
with pancreatic cancer requires accurate pretreatment staging (to define
the study population) and a standardized system for the pathologic evaluation
of surgical specimens (to determine the completeness of resection).
This is routinely performed in most other solid tumors yet rarely completed
in an organized fashion in pancreatic cancer making the interpretation
of the published literature difficult or impossible. For example,
the definition of resectable pancreatic cancer used in most studies
is based upon whether or not the surgeon has removed the pancreatic
head, often with no system of margin analysis.
Multidetector
(multislice) computed tomography (CT) is used to objectively define
(anatomically) potentially resectable disease, borderline resectable
disease, locally advanced disease, and metastatic disease. Although
contrast-enhanced CT is widely available, accurate interpretation and
reporting of the tumor-related findings remains inconsistent.
For optimal pretreatment staging and assessment of operability, a CT
report in a patient with suspected periampullary or pancreatic cancer
should include the following information:
Commentary on the
presence or absence of a primary tumor in the pancreas;
Commentary on the
presence or absence of peritoneal and hepatic metastases;
Description of the
patency of the superior mesenteric vein-portal vein confluence and the
relationship of these veins to the tumor;
Description of the
relationship of the tumor to the superior mesenteric artery (SMA), celiac
axis, and hepatic artery.
Specific,
objective radiographic criteria can be used to create the following
definitions:
Potentially resectable disease:
1) no extrapancreatic disease,
2) a patent SMV-PV confluence (assuming the technical ability to resect
and reconstruct this venous confluence), and 3) a definable tissue plane
between the tumor and regional arterial structures including the celiac
axis, common hepatic artery and SMA.
Borderline resectable disease:
1) no extrapancreatic disease,
2) the following possible tumor-vessel relationships: an SMV-PV confluence
that can be reconstructed even is short segment venous occlusion is
present (ie, a suitable portal vein above, and a suitable SMV below
the area of occlusion); tumor abutment of the SMA of < 180o;
or short segment encasement of the hepatic artery amenable to resection
and reconstruction (this is usually at the origin of the gastroduodenal
artery and reconstruction may or may not require interposition grafting
with a short segment of reversed saphenous vein).
Locally advanced disease:
1) no extrapancreatic disease,
2) tumor encasement of the SMA or celiac axis defined as tumor involvement
of > 180o of the arterial circumference.
Metastatic disease:
Radiographic or clinical
evidence of distant organ or peritoneal metastases.
Despite
clear evidence that high-quality cross-sectional imaging predicts resectability
accurately, many patients undergo laparotomy for pancreatic cancer without
adequate preoperative assessment. Some patients are found to have
unresectable tumors intraoperatively when such a conclusion might have
been possible prior to surgery. Conversely, because of a lack
of adequate preoperative imaging and surgical expertise, many patients
who are resected with "curative intent" have been left with gross
residual disease not recognized by the surgeon intraoperatively, or
documented in the operative note.
Pathologic Assessment of
the Surgical Specimen
The
modifications to the TNM staging system in the 6th edition
of the AJCC Cancer Staging Manual allow the accurate staging of patients
even if they do not undergo pancreatic resection. The T4 (and
Stage III) designation is reserved for locally advanced unresectable
primary tumors in the absence of distant metastases. In addition
to TNM staging, when the pancreaticoduodenectomy specimen is evaluated
pathologically, the retroperitoneal margin (the soft tissue margin directly
adjacent to the proximal 3-4 cm of the SMA) must be evaluated on permanent
sections by inking the margin and sectioning the tumor perpendicular
to the margin. It is critical that the surgeon identify this margin
at the time of resection because it cannot be assessed retrospectively
and many pathologists cannot accurately identify the retroperitoneal
margin on a pancreaticoduodenectomy specimen. The surgeon and pathologist
should classify the retroperitoneal margin after integrating the operative
findings and the histologic assessment of this margin. All pancreatic
resections should be classified according to residual disease status
(termed "R" factor): R0, no gross or microscopic residual disease;
R1, microscopic residual disease (microscopically positive surgical
margins with no gross residual disease); and R2, grossly evident residual
disease. The pathologist cannot usually differentiate an R1 (microscopically
positive) from an R2 (grossly positive) retroperitoneal margin in the
absence of information regarding the retroperitoneal dissection, which
should be included in the operative note. The R designation should
appear in the final pathology report if possible and should always be
listed in the dictated operative note (we do not sign off on the operative
note until the pathology report is available for review). For
example, if the surgeon states that gross tumor was encountered when
completing the retroperitoneal dissection, a positive histologic margin
should result in the R2 designation in the operative note and the medical
record. In the absence of this information being included in the
operative report, the proper R designation cannot be determined.
The difficulty in differentiating R1 from R2 resections has significant
implications for the conduct of clinical trials examining the potential
advantage of nonsurgical therapies, especially in patients with borderline
resectable tumors.
Preoperative Therapy for Borderline
Resectable Pancreatic Cancer
There
are many obvious advantages to preoperative treatment of patients with
borderline resectable pancreatic cancer.
The ability to provide
immediate systemic therapy for a disease that is systemic at diagnosis
in most patients.
Improved patient
selection for surgery; pancreaticoduodenectomy is associated with significant
patient morbidity even when performed in experienced hands. This
improved patient selection arises because patients with progressive
systemic or local disease are identified as part of the restaging evaluation
performed periodically during neoadjuvant treatment prior to planned
surgery.
Chemoradiation
may lessen the risk of a positive margin resection, analogous to the
data on the value of preoperative therapy for patients with rectal cancer.
In fact, the mesorectum and the radial margin of resection following
a low anterior resection is quite similar to the retroperitoneal margin
following pancreaticoduodenectomy.
Unfortunately,
many reports of neoadjuvant therapy for pancreatic cancer have included
heterogeneous patient populations, enrolling patients with locally advanced
and borderline resectable (also termed marginally resectable) pancreatic
cancer often with unclear anatomic definitions of the local extent of
disease. Few investigators report clear anatomic definitions of
locally advanced disease and many studies incorporate intraoperative
assessment of the extent of local tumor growth, data which is subjective
and not reproducible. In general, patients with locally advanced
pancreatic cancer (as defined above) should not be included in studies
of preoperative therapy because their inclusion confounds reports of
resection rates, and complicates comparisons to other studies.
Our
current approach to the patient with borderline resectable pancreatic
cancer involves either protocol or off-protocol therapy. Off protocol
therapy involves initial treatment with systemic therapy (gemcitabine
alone or in combination for 2 to 6 months) followed by standard-fractionation
(50.4 Gy) chemoradiation (gemcitabine or capecitabine as a radiation
sensitizer).
SELECTED REFERENCES
Breslin TM, Hess
KR, Harbison DB, et al. Neoadjuvant chemoradiotherapy for adenocarcinoma
of the pancreas: treatment variables and survival duration. Ann
Surg Oncol, 2001;8:123-132.
Crane CH, Wolff
RA, Abbruzzese JL, et al. Combining gemcitabine with radiation in pancreatic
cancer: understanding important variables influencing the therapeutic
index. Semin Oncol, 2001;28(suppl 10)1025-1033.
Raut CP, Evans DB,
Crane CH, Pisters PWT, Wolff RA. Neoadjuvant therapy for resectable
pancreatic cancer. Surg Oncol Clin N Am. 2004;4:639-61.
Wolff RA, Abbruzzese
JL, Evans DB. Neoplasms of the exocrine pancreas. In Holland
JF, Frei E, Bast RC, Kufe DW, Pollock RE, Weichelbaum RR, eds.
Cancer Medicine, Sixth Edition. Ontario: B.C. Decker, Inc. 2003, 1585-1614.
Wolff RA, Evans
DB, Gravel DM, et al. Phase I trial of gemcitabine combined with
radiation for the treatment of locally advanced pancreatic adenocarcinoma.
Clin Cancer Res, 2001;7:2246-2253.
NEOPLASMS OF THE EXOCRINE PANCREASADJUVANT AND NEOADJUVANT APPROACHES FOR RESECTABLE PANCREATIC CANCER
BORDERLINE RESECTABLE
PANCREATIC CANCER
Douglas B. Evans
For the Multidisciplinary Pancreatic
Tumor Study Group
Departments of Surgical Oncology, The
University of Texas M. D. Anderson Cancer Center, Houston, Texas
The Importance of Pretreatment Staging
to define the extent of disease as a necessary component of the conduct
of clinical trials and outcome reporting
Evaluation
of the potential value of nonsurgical therapies (chemotherapy and radiation
therapy) in improving local disease control and survival of patients
with pancreatic cancer requires accurate pretreatment staging (to define
the study population) and a standardized system for the pathologic evaluation
of surgical specimens (to determine the completeness of resection).
This is routinely performed in most other solid tumors yet rarely completed
in an organized fashion in pancreatic cancer making the interpretation
of the published literature difficult or impossible. For example,
the definition of resectable pancreatic cancer used in most studies
is based upon whether or not the surgeon has removed the pancreatic
head, often with no system of margin analysis.
Multidetector
(multislice) computed tomography (CT) is used to objectively define
(anatomically) potentially resectable disease, borderline resectable
disease, locally advanced disease, and metastatic disease. Although
contrast-enhanced CT is widely available, accurate interpretation and
reporting of the tumor-related findings remains inconsistent.
For optimal pretreatment staging and assessment of operability, a CT
report in a patient with suspected periampullary or pancreatic cancer
should include the following information:
Commentary on the
presence or absence of a primary tumor in the pancreas;
Commentary on the
presence or absence of peritoneal and hepatic metastases;
Description of the
patency of the superior mesenteric vein-portal vein confluence and the
relationship of these veins to the tumor;
Description of the
relationship of the tumor to the superior mesenteric artery (SMA), celiac
axis, and hepatic artery.
Specific,
objective radiographic criteria can be used to create the following
definitions:
Potentially resectable disease:
1) no extrapancreatic disease,
2) a patent SMV-PV confluence (assuming the technical ability to resect
and reconstruct this venous confluence), and 3) a definable tissue plane
between the tumor and regional arterial structures including the celiac
axis, common hepatic artery and SMA.
Borderline resectable disease:
1) no extrapancreatic disease,
2) the following possible tumor-vessel relationships: an SMV-PV confluence
that can be reconstructed even is short segment venous occlusion is
present (ie, a suitable portal vein above, and a suitable SMV below
the area of occlusion); tumor abutment of the SMA of < 180o;
or short segment encasement of the hepatic artery amenable to resection
and reconstruction (this is usually at the origin of the gastroduodenal
artery and reconstruction may or may not require interposition grafting
with a short segment of reversed saphenous vein).
Locally advanced disease:
1) no extrapancreatic disease,
2) tumor encasement of the SMA or celiac axis defined as tumor involvement
of > 180o of the arterial circumference.
Metastatic disease:
Radiographic or clinical
evidence of distant organ or peritoneal metastases.
Despite
clear evidence that high-quality cross-sectional imaging predicts resectability
accurately, many patients undergo laparotomy for pancreatic cancer without
adequate preoperative assessment. Some patients are found to have
unresectable tumors intraoperatively when such a conclusion might have
been possible prior to surgery. Conversely, because of a lack
of adequate preoperative imaging and surgical expertise, many patients
who are resected with "curative intent" have been left with gross
residual disease not recognized by the surgeon intraoperatively, or
documented in the operative note.
Pathologic Assessment of
the Surgical Specimen
The
modifications to the TNM staging system in the 6th edition
of the AJCC Cancer Staging Manual allow the accurate staging of patients
even if they do not undergo pancreatic resection. The T4 (and
Stage III) designation is reserved for locally advanced unresectable
primary tumors in the absence of distant metastases. In addition
to TNM staging, when the pancreaticoduodenectomy specimen is evaluated
pathologically, the retroperitoneal margin (the soft tissue margin directly
adjacent to the proximal 3-4 cm of the SMA) must be evaluated on permanent
sections by inking the margin and sectioning the tumor perpendicular
to the margin. It is critical that the surgeon identify this margin
at the time of resection because it cannot be assessed retrospectively
and many pathologists cannot accurately identify the retroperitoneal
margin on a pancreaticoduodenectomy specimen. The surgeon and pathologist
should classify the retroperitoneal margin after integrating the operative
findings and the histologic assessment of this margin. All pancreatic
resections should be classified according to residual disease status
(termed "R" factor): R0, no gross or microscopic residual disease;
R1, microscopic residual disease (microscopically positive surgical
margins with no gross residual disease); and R2, grossly evident residual
disease. The pathologist cannot usually differentiate an R1 (microscopically
positive) from an R2 (grossly positive) retroperitoneal margin in the
absence of information regarding the retroperitoneal dissection, which
should be included in the operative note. The R designation should
appear in the final pathology report if possible and should always be
listed in the dictated operative note (we do not sign off on the operative
note until the pathology report is available for review). For
example, if the surgeon states that gross tumor was encountered when
completing the retroperitoneal dissection, a positive histologic margin
should result in the R2 designation in the operative note and the medical
record. In the absence of this information being included in the
operative report, the proper R designation cannot be determined.
The difficulty in differentiating R1 from R2 resections has significant
implications for the conduct of clinical trials examining the potential
advantage of nonsurgical therapies, especially in patients with borderline
resectable tumors.
Preoperative Therapy for Borderline
Resectable Pancreatic Cancer
There
are many obvious advantages to preoperative treatment of patients with
borderline resectable pancreatic cancer.
The ability to provide
immediate systemic therapy for a disease that is systemic at diagnosis
in most patients.
Improved patient
selection for surgery; pancreaticoduodenectomy is associated with significant
patient morbidity even when performed in experienced hands. This
improved patient selection arises because patients with progressive
systemic or local disease are identified as part of the restaging evaluation
performed periodically during neoadjuvant treatment prior to planned
surgery.
Chemoradiation
may lessen the risk of a positive margin resection, analogous to the
data on the value of preoperative therapy for patients with rectal cancer.
In fact, the mesorectum and the radial margin of resection following
a low anterior resection is quite similar to the retroperitoneal margin
following pancreaticoduodenectomy.
Unfortunately,
many reports of neoadjuvant therapy for pancreatic cancer have included
heterogeneous patient populations, enrolling patients with locally advanced
and borderline resectable (also termed marginally resectable) pancreatic
cancer often with unclear anatomic definitions of the local extent of
disease. Few investigators report clear anatomic definitions of
locally advanced disease and many studies incorporate intraoperative
assessment of the extent of local tumor growth, data which is subjective
and not reproducible. In general, patients with locally advanced
pancreatic cancer (as defined above) should not be included in studies
of preoperative therapy because their inclusion confounds reports of
resection rates, and complicates comparisons to other studies.
Our
current approach to the patient with borderline resectable pancreatic
cancer involves either protocol or off-protocol therapy. Off protocol
therapy involves initial treatment with systemic therapy (gemcitabine
alone or in combination for 2 to 6 months) followed by standard-fractionation
(50.4 Gy) chemoradiation (gemcitabine or capecitabine as a radiation
sensitizer).
SELECTED REFERENCES
Breslin TM, Hess
KR, Harbison DB, et al. Neoadjuvant chemoradiotherapy for adenocarcinoma
of the pancreas: treatment variables and survival duration. Ann
Surg Oncol, 2001;8:123-132.
Crane CH, Wolff
RA, Abbruzzese JL, et al. Combining gemcitabine with radiation in pancreatic
cancer: understanding important variables influencing the therapeutic
index. Semin Oncol, 2001;28(suppl 10)1025-1033.
Raut CP, Evans DB,
Crane CH, Pisters PWT, Wolff RA. Neoadjuvant therapy for resectable
pancreatic cancer. Surg Oncol Clin N Am. 2004;4:639-61.
Wolff RA, Abbruzzese
JL, Evans DB. Neoplasms of the exocrine pancreas. In Holland
JF, Frei E, Bast RC, Kufe DW, Pollock RE, Weichelbaum RR, eds.
Cancer Medicine, Sixth Edition. Ontario: B.C. Decker, Inc. 2003, 1585-1614.
Wolff RA, Evans
DB, Gravel DM, et al. Phase I trial of gemcitabine combined with
radiation for the treatment of locally advanced pancreatic adenocarcinoma.
Clin Cancer Res, 2001;7:2246-2253.