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From OncoLog, October 2013, Vol. 58, No. 10

Graphic: Compass: Quarterly discussion of cancer types for which there is no standard treatment or more than one standard treatment

Resectable or Borderline Resectable Pancreatic Adenocarcinoma: Initial Treatment Options
Neoadjuvant chemoradiation may benefit patients with resectable or borderline resectable disease

By Sunni Hosemann  

Introduction

Adenocarcinoma of the exocrine pancreas accounts for 95% of pancreatic cancers. Neuroendocrine pancreatic cancers, which account for the remaining 5%, differ in their natural history, biology, and treatment and are not considered here.

Pancreatic adenocarcinomas are initially classified as resectable, borderline resectable, locally advanced/nonresectable, or metastatic/disseminated. This discussion centers on resectable and borderline resectable pancreatic adenocarcinomas, for which decisions about initial treatment—surgery or neoadjuvant therapy—are the most unsettled among experts. At The University of Texas MD Anderson Cancer Center, the preferred treatment sequence is neoadjuvant therapy for both resectable and borderline resectable pancreatic adenocarcinomas. However, this sequence differs from the standard treatment at many institutions.

A deadly disease

Pancreatic adenocarcinoma has a well-deserved reputation as a deadly disease. The survival rates of patients with pancreatic adenocarcinoma are not improving, and the incidence of this complex disease appears to be rising.

Because pancreatic adenocarcinomas rarely cause early symptoms that would prompt investigation, most patients present with advanced disease. “It is possible that these tumors have been present for several years before diagnosis,” said Jason Fleming, M.D., a professor in the Department of Surgical Oncology.

Pancreatic adenocarcinoma is generally considered to be a biologically aggressive disease. The high rate of local or distant recurrence (80%–90%) in patients whose disease appeared to be localized and was surgically removed suggests that micrometastatic disease is often present but unrecognized at diagnosis. This possibility has prompted many experts to consider pancreatic adenocarcinoma a systemic disease in most patients at presentation and is the strongest rationale for using chemotherapy or chemoradiation before rather than after surgery.

Assessment and staging

Initial treatment decisions for patients with pancreatic adenocarcinomas are based on clinical staging because some of the information needed for pathological staging is available only after surgically removed specimens have been analyzed. The initial classification of pancreatic adenocarcinomas as resectable, borderline resectable, locally advanced/ nonresectable, or metastatic/disseminated is based on clinical information and imaging studies.

Because surgery for pancreatic adenocarcinomas is complex and has a high potential for morbidity and because resection must be complete (all surgical margins are negative for tumor cells; R0) to be effective, accurate pretreatment staging is essential. Advanced diagnostic imaging techniques have made clinical staging possible without exploratory laparotomy. These techniques include computed tomography with a special pancreatic protocol, which employs multiphasic helical scans to capture images during the arterial and venous filling phases after contrast agent injection. Also, endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography make it possible to perform fine-needle biopsy, assess critical vessel involvement, and place stents for biliary decompression without open surgery.

Pancreatic adenocarcinomas are classified as resectable if they are separated from critical vessels—the superior mesenteric and portal veins, superior mesenteric artery, celiac axis, and hepatic artery—by a clearly defined tissue plane. Borderline resectable tumors abut, distort, or encase one or more of these vessels; this decreases the likelihood that an R0 resection can be achieved. Tumors that encase more than half the circumference of the celiac axis or the superior mesenteric artery are considered locally advanced and unresectable.

Treatment considerations

According to Gauri Varadhachary, M.D., a professor in the Department of Gastrointestinal Medical Oncology, multidisciplinary cooperation prior to the initiation of any therapy for localized pancreatic adenocarcinoma is critical. If neo adjuvant therapy will be the initial treatment, certain interventions must precede it: biopsy confirmation of disease must be obtained, and for patients who have biliary obstruction, stents must be placed.

“Before any treatment begins, it’s necessary to determine whether surgery is a possibility,” Dr. Fleming said. “This is very important in terms of patient and family expectations.” He stressed that in addition to tumor resectability, patient factors such as performance status, which may be compromised by comorbidities, frailty, or the disease itself, also influence surgical potential. “Many patients who present with this cancer are quite weak, and some are malnourished, but these conditions can improve after the obstructed biliary tree is drained and the tumor treated preoperatively.” Dr. Fleming said.

At many institutions, the standard approach for patients whose pancreatic adenocarcinoma is considered resectable is to perform surgery first—a laparotomy in which the diagnosis is confirmed, staging is completed, and the tumor is resected unless found to be unresectable. Studies have shown that postoperative adjuvant therapy offers a modest survival benefit; however, a substantial number of patients do not receive postoperative therapy owing to a number of factors, including disease progression, comorbid illnesses, surgery-related morbidity, and delayed recovery from surgery.

When surgery is employed first, a recovery period of at least 8 weeks is required before adjuvant chemotherapy can begin. During this time, the potential for metastasis is heightened, as the surgery itself can impair immune function and possibly even accelerate the growth of small metastases.

The MD Anderson approach

Noting the high percentage of patients whose disease recurred after surgery, many physicians began to view pancreatic adenocarcinoma as a disease with a high potential for clinically undetectable metastases at presentation. These observations led MD Anderson physicians to begin treating patients whose disease was considered resectable or borderline resectable with neoadjuvant therapy rather than upfront surgery.

Neoadjuvant therapy


The goal of neoadjuvant therapy is to increase the probability of a successful (R0) surgery and reduce the probability of local or distant recurrence. At MD Anderson, neoadjuvant therapy consists of chemotherapy, chemoradiation, or—for select patients considered to be at high risk of developing metastatic disease on the basis of imaging studies and serum markers—induction chemotherapy followed by chemoradiation. Dr. Varadhachary said she encourages patients to receive neoadjuvant therapy as part of a clinical study when available.

When given concurrently with radiation, some chemotherapy drugs act as radiosensitizers. According to Dr. Varadhachary, the currently used radiosensitizing chemotherapy regimens may include 5-fluorouracil, capecitabine, or gemcitabine. Induction chemotherapy regimens often are gemcitabine “doublets” (gemcitabine plus another drug). In addition, the FOLFIRINOX regimen (oxaliplatin, irinotecan, 5-fluorouracil, and leucovorin), which is used to treat advanced pancreatic adenocarcinoma, is being evaluated as an induction chemotherapy (followed by chemoradiation and surgery) in a clinical trial that began enrolling patients with borderline resectable pancreatic adenocarcinoma earlier this year.

Dr. Fleming noted that the neoadjuvant use of radiation in pancreatic adenocarcinoma patients has not been validated in large trials and is thus another area lacking widespread consensus. However, Dr. Fleming said, “Our experience suggests that neoadjuvant radiation improves our ability to achieve margin-negative surgery.” Dr. Fleming and his colleagues postulate that radiation kills the outermost layer of tumor cells to create a nonviable rim around the tumor, and this rim is very often the margin needed to achieve a complete resection.

Christopher Crane, M.D., a professor in the Department of Radiation Oncology, concurred. “We found that in borderline resectable tumors where there was arterial invasion, the use of chemoradiation led to margin-negative resection in 95% of patients, and these were cases where we would have expected all of them to have positive margins.” Dr. Crane added that radiation therapy delivered preoperatively also prevents exocrine output at the pancreaticojejunal anastomoses, thereby helping to prevent anastomotic leaking, one of the major complications of surgery.

Graphic: Treatment options for pancreatic adenocarcinoma

According to Dr. Crane, the standard neoadjuvant radiation therapy for pancreatic adenocarcinoma patients at MD Anderson is three-dimensional conformal radiation, usually delivered over 5 1⁄2 weeks. This technique is effective and well tolerated; more advanced techniques would only increase the cost to the patient.

Dr. Crane stressed the importance of using a well-tolerated chemoradiation regimen and paying sufficient attention to supportive care during treatment to maximize the patient’s potential to proceed to surgery.

“Under the old paradigm, surgery selected patients for adjuvant therapy,” said Robert Wolff, M.D., a professor in the Department of Gastrointestinal Medical Oncology. “It should be the other way around.”

Dr. Crane added that it is important that all members of the multidisciplinary team, including the surgeon, have the opportunity to observe the patient’s health during chemoradiation so that the patient’s tolerance for surgery can be assessed. “Patients with this disease tend to be quite ill, and often their performance status is reduced,” he said, “so vigilance is required.”

Surgery

The only potentially curative treatment for pancreatic adenocarcinoma is surgery—complete resection of the tumor and surrounding tissue with negative margins (R0), meaning that postsurgical pathological analysis finds no gross or microscopic residual disease in an acceptable margin of removed tissue. Studies have shown that anything less than an R0 resection diminishes the value of the surgery: The survival outcomes in patients with even microscopic disease in the surgical margins (R1) are similar to those of patients who received palliative treatment and no surgery.

Surgery for pancreatic adenocarcinoma typically involves exploratory laparoscopy, during which staging is completed, immediately followed by definitive resection unless the disease is found to be unresectable.

The definitive surgical treatment for adenocarcinoma of the pancreatic head is pancreaticoduodenectomy (also known as a Whipple procedure). This is a technically challenging surgery because the pancreas is connected to numerous blood vessels and ducts that must be reconstructed. Many anastomoses are required, and each represents a potential site of leaks, which are among the many possible complications of the surgery. The surgery is historically associated with high perioperative mortality rates.

Patient outcomes from pancreaticoduodenectomy are greatly affected by the experience of the surgical team. According to the American Cancer Society, the surgical mortality rate of patients undergoing pancreaticoduodenectomy is 15% at centers that perform few such surgeries each year but less than 5% at centers that perform many. At MD Anderson, the surgical mortality rate of patients who undergo the procedure is less than 1%.

Toward wider adoption of neoadjuvant therapy


A number of studies have provided evidence of the effectiveness of the MD Anderson approach to treating resectable or borderline resectable pancreatic adenocarcinoma. For example, one retrospective analysis showed that patients who underwent neoadjuvant therapy were more likely to receive all planned therapy: Of those who had upfront surgery, fewer than 60% were able to receive adjuvant therapy; in contrast, about 70% of patients who received neoadjuvant therapy were able to undergo subsequent surgery. The most common reason patients did not proceed to surgery was that their disease progressed during neoadjuvant therapy. The researchers believed these patients had aggressive or already advanced disease and would have experienced recurrence shortly after surgery if surgery had been performed first.

Even with these results, the neoadjuvant therapy approach has not been widely used. However, Dr. Wolff believes that recent developments may spur wider adoption of the approach. “First is the growing recognition that surgery-first has not changed outcomes for 25 years,” he said. “And second, with advances in imaging, a new clinical subcategory—borderline resectable disease—has emerged.” He believes that identifying this subset of patients has been pivotal because it suggested the possibility that these patients might have better surgical outcomes if they receive neoadjuvant therapy. In one MD Anderson study, of 150 patients with borderline resectable disease who were treated with neoadjuvant therapy, 60 (40%) ultimately went on to have surgery. The median overall survival duration for the patients who underwent surgery was more than 40 months, and fewer than 10% had positive surgical margins.

Dr. Wolff said that practitioners are overcoming their reluctance to move away from the standard surgery-first approach and use neoadjuvant treatment for a subset of patients considered to be at higher risk of developing metastatic disease. Dr. Wolff hopes that as more results become available for patients with borderline resectable disease, the neoadjuvant therapy paradigm will be easier to adopt for patients with resectable disease. Additionally, Dr. Varadhachary is optimistic that as better systemic approaches and novel agents are found to be effective against advanced pancreatic cancer, they can be moved to the neoadjuvant therapy setting with better results.

Dr. Fleming added that a key advantage of neoadjuvant therapy is that it allows physicians to identify patients who have risk factors that can be modified. He said, “We can use that time before surgery to bolster nutritional factors, build up the person’s general strength and condition, and even address other medical issues that might have precluded surgery or placed the person at high risk for complications.”

References

American Cancer Society. Cancer Facts & Figures 2013 [PDF].

Evans DB, for the Multidisciplinary Pancreatic Cancer Study Group. Resectable pancreatic cancer: the role for neoadjuvant/preoperative therapy. HPB (Oxford). 2006;8:365–368.

Katz MH, Pisters PW, Evans DB, et al. Borderline resectable pancreatic cancer: the importance of this emerging stage of disease. J Am Coll Surg. 2008;206:833–846.

Katz MH, Wang H, Fleming JB, et al. Long-term survival after multidisciplinary management of resected pancreatic adenocarcinoma. Ann Surg Oncol. 2009;16:836–847.

National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Pancreatic Adenocarcinoma, V1.2013 [subscription only].

Tempero MA, Arnoietti JP, Behrman S, et al. Pancreatic adenocarcinoma. J Natl Compr Canc Netw. 2010;8:972–1017.

Contributing Faculty
The University of Texas MD Anderson Cancer Center

Photo: Dr. Christopher Crane

Christopher Crane, M.D.
Professor, Radiation Oncology

Photo: Jason B. Fleming

Jason B. Fleming, M.D.
Professor, Surgical Oncology

Photo: Dr. Gauri R. Varadhachary Gauri R. Varadhachary, M.D.
Professor, Gastrointestinal Medical Oncology
Photo: Robert A. Wolff Robert A. Wolff, M.D.
Professor, Gastrointestinal Medical Oncology

For more information, talk to your physician, visit www.mdanderson.org, or call askMDAnderson at 877-632-6789.

Other articles in OncoLog, October 2013 issue:

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