Cancer

May 04, 2021

In retrospective studies of treatment for patients with pancreatic cancer involving critical blood vessels, Mark J. Truty, M.D., M.S., a hepatobiliary and pancreas surgeon at Mayo Clinic in Rochester, Minnesota, and fellow researchers describe Mayo Clinic's experience and surgical outcomes in patients with traditionally inoperable tumors.

En bloc celiac axis resection for pancreatic cancer: Classification of anatomical variants based on tumor extent

Although surgical resection is the only known cure for pancreatic cancer, only a fraction of patients have tumors that are eligible for standardized surgical procedures. Tumors that involve or encase critical vascular structures (arteries) are rarely considered for surgery due to the technical complexity, high risk of positive margins, increased associated complications and historical poor outcomes. However, with the advent of modern effective chemotherapeutics and advancements in surgical techniques and postoperative care developed at Mayo Clinic, more patients are now potentially eligible for such curative-intent operations than ever before.

In this first study, the researchers reviewed Mayo Clinic's experience over a 25-year period with pancreatic cancer surgery that included resection of tumors that involved the celiac axis artery alone or in combination with other critical vessels (hepatic artery, superior mesenteric artery or both). This was the largest single-institution series of such advanced cases ever published. Results included the following:

• Among 90 celiac axis resections for pancreatic cancer, there was a significant increase in cases during the modern chemotherapy era (2011 to the present), with the majority (89%) receiving preoperative chemotherapy.
• Although the surgeries were associated with higher risks, there was a significant decrease in the 90-day mortality (4%) over time, with formal arterial revascularization being protective.
• In the majority of cases, surgeons were able to achieve a negative margin (88%) and this was associated with the use of concurrent preoperative chemoradiation (p = 0.004).
• Median overall survival was superior with the use of neoadjuvant chemotherapy (43.5 vs. 8.0 months). Major predictors of survival after neoadjuvant chemotherapy included chemotherapy duration, carbohydrate antigen 19-9 (CA 19-9) response and pathological response.

"Our data suggest that such complex resections are technically feasible; however, they carry significantly higher risk than standard pancreatic operations. Given these risks, upfront resection has no role whatsoever," says Dr. Truty. "In this series, neither the extent of resection nor the need for formal arterial revascularization had any detrimental influence on short-term morbidity, mortality or long-term oncologic survival, suggesting that such aggressive resections, if coupled with an effective upfront neoadjuvant strategy and management of associated complications, can have substantial benefit for a highly select subset of patients and might be oncologically sound."

The researchers also proposed a three-tier anatomical classification system for pancreatectomy with celiac axis resection based on tumor location that subsequently dictates extent of arterial structures requiring en bloc resection, type of pancreatectomy required, need for arterial revascularization and risk of associated need for elective gastrectomy due to surgically induced ischemia. Classes include the following:

• Class 1 tumors involve the celiac axis proper and its proximal branches without extension to the proper hepatic artery and gastroduodenal artery bifurcation.
• Class 2 tumors involve the celiac axis with extension laterally along the common hepatic artery to involve the proper hepatic artery and gastroduodenal artery bifurcation.
• Class 3 tumors involve the celiac axis with extension inferiorly and posteriorly to encase the proximal superior mesenteric artery with or without extension to the proper hepatic artery and gastroduodenal artery bifurcation.

Each class includes subclassifications. "This current proposed descriptive system allows for simple yet highly predictive terminology in most patients that dictates the procedure that would need to be performed," says Dr. Truty. "Such a new system is likely critically needed, as we anticipate there will be an increased demand and frequency of such advanced resections over time at specialized centers with the increased use of modern neoadjuvant therapies."

Study results were published in Journal of the American College of Surgeons in 2020.

Factors predicting response, perioperative outcomes and survival following total neoadjuvant therapy for borderline-locally advanced pancreatic cancer

"Pancreatic ductal adenocarcinoma is a lethal malignancy with increasing incidence," says Dr. Truty. "Most patients with anatomically resectable tumors develop metastatic disease postoperatively, which has discouraged surgery for tumors that involve critical blood vessels and for borderline resectable or locally advanced cancers."

Combined neoadjuvant chemotherapy and chemoradiation — otherwise known as total neoadjuvant therapy — addresses two key concerns in borderline resectable or locally advanced pancreatic ductal adenocarcinoma:

• Occult micrometastases with early systemic recurrence despite curative-intent resection
• Positive margin risk with known established detriment to surgical survival

"Despite no consensus on the optimal preoperative sequencing for these anatomically advanced tumors or specific response endpoints, most treatment guidelines for borderline resectable or locally advanced pancreatic ductal adenocarcinoma include total neoadjuvant therapy as a strategy targeting these concerns," says Dr. Truty.

Dr. Truty and fellow researchers reviewed Mayo Clinic's experience in patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma who underwent resection following this total neoadjuvant therapy strategy. Results included the following:

• Among the 194 patients studied, radiologic anatomical downstaging was not only uncommon (28%) but also not necessary in order to undergo successful surgery.
• En bloc venous or arterial resection or both was required in 125 (65%) patients, with 94% of patients achieving successful negative surgical margins.
• The median, one-year, two-year and three-year overall survival (recurrence-free survival) rates were 58.8 (23.5) months, 96% (65%), 78% (48%), and 62% (32%), respectively.
• Only three factors were independently associated with prolonged survival: extended-duration (six or more cycles) chemotherapy, optimal post-chemotherapy CA 19-9 response and major pathological response. Patients achieving all three factors had superior survival outcomes with a survival detriment for each failing factor.

"Total neoadjuvant therapy for borderline resectable or locally advanced pancreatic ductal adenocarcinoma is based on consideration of tumor biology and cancer dissemination. It is likely an optimal sequencing strategy for these patients," says Dr. Truty. "It allows initial treatment of occult metastases, locoregional tumor control and improved margin rates for the larger patient proportion eligible for resection. It also spares patients who demonstrate overt chemoresistance from potentially futile, higher risk operations.

"Surgical outcomes after total neoadjuvant therapy are favorable, with survival dependent on both chemotherapy duration and objective responses to chemotherapy, which are potentially modifiable before proceeding to resection by alterations in chemotherapeutic administration. If we postulate that neoadjuvant therapy ultimately prolongs survival, we must demonstrate chemotherapeutic response preoperatively, otherwise suboptimal outcomes are anticipated. Future prospective studies should focus on defining response endpoints; the critical question is not whether we should consider neoadjuvant therapy, but how it is best accomplished."

Study results were published in Annals of Surgery in 2021.

For more information

Truty MJ, et al. En bloc celiac axis resection for pancreatic cancer: Classification of anatomical variants based on tumor extent. Journal of the American College of Surgeons. 2020;231:8.

Truty MJ, et al. Factors predicting response, perioperative outcomes, and survival following total neoadjuvant therapy for borderline/locally advanced pancreatic cancer. Annals of Surgery. 2021;273:341.