Patient with Advanced, Inoperable Pancreatic Cancer

How Will I Treat This Patient? – Case Series
Patient with Advanced, Inoperable Pancreatic Cancer

Susan J. Littman, MD
Attending Physician
GI Oncology Clinic
Philadelphia, Pennsylvania

Case:

A 56-year-old female presents to her local hospital with a 2-month history of gradual weight loss, anorexia, vague abdominal pain, transient fever and recent dark urine. Her pain was described as epigastric in nature with occasional radiation to the back. On exam she was afebrile and vital signs stable, BSA 1.78 m², and she was visibly jaundiced. Abdomen was soft, nondistended with normal bowel sounds and without organomegaly. Patient is a nonsmoker and has no history of blood transfusion or IVDA, although does drink a glass of wine 2-5 times per week. Family history is negative for pancreatic or biliary disease, pancreas, breast or ovarian cancer. Her maternal grandmother died of metastatic CRC. She works as a fundraiser. Recent routine mammogram and colonoscopy were normal.

CT of the abdomen showed a mass in the head of the pancreas. MRI showed evidence of high-grade biliary obstruction, dilated biliary and pancreatic ducts in the region of the pancreatic head.

In this case we will review clinical problems associated with pancreatic cancer including how anatomy influences the clinical presentation of pancreatic cancer; the initial diagnostic workup and staging of pancreatic cancer, indications for surgical resection and factors determining resectability, caveats to elevations in Ca19.9, and therapeutic options for metastatic disease.

Question 1:  What are the initial treatment challenges with pancreatic cancer diagnosis and subsequent choice of treatment?

Early diagnosis and initial surgical management of pancreatic cancer play a key role in survival and potential cure of pancreatic cancer. The pancreas is a lobulated gland that lies transversely across the posterior abdomen extending from the duodenum, as it exits the stomach, to splenic hilum and is divided into a head, body, and tail. The head lies posterior to the distal stomach and anterior to the aorta, whereas the neck lies in close proximity to major blood vessels including the superior mesenteric artery and vein, inferior vena cava. The common bile duct passes through the head of the pancreas and typically joins with the main pancreatic duct at the major papilla, the Ampulla of Vater, allowing pancreatic enzymes and bile to empty into the duodenum.1

These anatomical features are key determinants in the clinical presentation of pancreatic cancer. Tumors arising in the head most often cause bile duct obstruction resulting in clinically evident jaundice. Cancers arising in the body and tail are insidious in their development and often are advanced when diagnosed. The diagnosis of pancreatic cancer can often be difficult since presenting signs and symptoms can be nonspecific, vague, and sometime absent. Pancreatic cancer is a disease of developed countries increasing throughout life with 85% occurring between ages 60-80 years and is slightly more common in males compared to females and the African American population compared to other races. The astute clinician must be aware of epidemiological factors associated with this cancer such as history of smoking, family history, pancreatitis, diabetes, and obesity. Certain occupational exposures and hereditary factors also increase risk. It is important to remember that the classic symptom triad of abdominal pain, weight loss, and jaundice may or may not be present.2

Information necessary to determine clinical staging is usually obtained from interpretation of triphasic contrast enhanced multi-slice CT imaging (“pancreatic protocol”) with 3D-imaging capabilities to enhance accurate visualization of tumor encasement of regional vasculature as well as physical examination and laboratory values.3 Preoperative staging of pancreatic cancer ultimately determines the initial therapeutic approach with a major initial decision point being whether tumor resection will be attempted or whether non-operative therapy is indicated. The TNM staging system criteria for pancreatic cancer is based on T or tumor size and extension, N, regional lymph node involvement, and M, the presence or absence of distant metastases at diagnosis, as in other cancers. Potentially resectable tumors are AJCC stage I or II or those lacking distant metastases, extensive local invasion, peritoneal involvement, malignant ascites or pleural effusions, regional lymphadenopathy or significant vessel encasement/occlusion.4 Additional techniques such as EUS or endoscopic ultrasound or ERCP or endoscopic retrograde cholangiopancreatography are often employed as diagnostic and staging tools for tumors in the head of the pancreas and can facilitate therapy including placement of biliary and pancreatic stents, celiac neurolysis, and/or tumor injection therapy.

Pancreatectomy includes the removal of the head of the pancreas, duodenum, gallbladder, bile duct, plus or minus a portion of the proximal stomach along with the tumor. The difficulty of the procedure is attributed to the careful analysis for extrapancreatic metastatic disease, followed by the separation of regional structures, and followed by reconstruction and prevention of iatrogenic injury during the operation.5 Distal pancreatectomy is the standard procedure for tumors of the body and tail of the pancreas.6 Unfortunately, less than 20% of individuals with pancreatic cancer present early enough to be eligible for surgical resection and potential cure.

After undergoing successful ERCP and stent placement, she was transferred to University-based high volume center and underwent pylorus-preserving pancreaticoduodenectomy. Surgical pathology showed a 2.0 cm moderately differentiated ductal adenocarcinoma, uncinate margin positive, 2 of 7 lymph nodes positive for metastatic cancer and perineural invasion (G2 pT3pN1, stage IIB).

Question 2:  Are you concerned about the possibility of recurrent disease?

Yes. Data from the American Cancer Society National Cancer Database shown below demonstrates the poor prognosis of pancreatic cancer even after “successful surgery.”

Stage

5-year observed survival rate (%)

IA

31.4

IB

27.2

IIA

15.7

IIB

7.7

III

6.8

IV

2.8

Adapted from AJCC Cancer Staging Handbook, 7th edition, Springer.

Recurrences in resected pancreatic cancer can be local, defined as within the resection bed, remnant pancreas or adjacent to the mesenteric or celiac arteries, or distal with most common sites being the liver, peritoneal cavity, intra-abdominal lymph nodes or distal sites including lung. Less common sites include bone, brain, muscle, skin, umbilicus, spermatic cord, and prostate. While biological features of the tumor are considered important in causing relapse, other than gross residual disease, the exact nature of these determinants are poorly defined. The presence of regional lymph node metastases, poorly differentiated histology, and increased size of the primary tumor are associated with decreased survival. Indicators of poor prognosis are perineural and/or lymphovascular invasion, elevated postoperative tumor markers, and incomplete resection.4

The patient received gemcitabine-based adjuvant chemotherapy and chemo-radiation to surgical bed on protocol. At the completion of all adjuvant therapy and at 1-year post surgery, CT of chest, abdomen, and pelvis showed no evidence of recurrence and Ca19.9 was normal.

Support for adjuvant gemcitabine monotherapy comes from CONKO-001 in which 398 patients in 88 German and Austrian centers were randomly assigned to gemcitabine versus observation following macroscopically complete resection. An intention-to-treat (ITT) analysis demonstrated increased DFS as well as a statistically significant improvement in overall survival with 6 months gemcitabine. Median disease-free survival for pancreatic cancer treated with gemcitabine-based chemotherapy was estimated at 13 to 16 months.7

Nine months later (about 19 months post-Whipple), patient presents with complaints of fatigue and weakness. Laboratory studies show a Ca19.9 value of 51 U/ml. Other laboratory findings include mild anemia and normal WBC, differential, and platelet counts. Chemistries including creatinine, BUN, glucose, electrolytes, albumin, protein, and bilirubin are normal. Alkaline phosphatase is 132 IU/L (25-120), AST is 65 IU/L (7-35), and ALT is 51 IU/L (1-30).

Question 3:  What are the implications of the elevated Ca19.9?

Of the many biomarkers that have been studied in pancreatic cancer, the most clinically useful serological marker is Ca-19.9. Ca19.9 is a sialylated protein related to the Lewis blood group antigen associated with the normal tissues of the pancreas, stomach, biliary tract, bronchial and salivary glands, and is elevated in a number of gastrointestinal malignancies. It is not tumor specific. In fact, it can be elevated in a number of benign diseases including inflammatory disorders, cirrhosis, cholestasis, and obstructive jaundice. In pancreatic cancer, it has been demonstrated to have a sensitivity and specificity of up to 90% and 98% respectively. Preoperatively, Ca19.9 correlates with AJCC staging. In resected disease, low Ca19.9 levels are prognostic for survival, whereas persistent elevation of Ca19.9 after surgery is indicative of residual tumor mass. The serum Ca19.9 level is also valuable in the evaluation of patients with pancreatic malignancy when measured after completion of a therapeutic intervention, as a secondary rise after initial postoperative decline is indicative of recurrence.8, 9

The patient undergoes a diagnostic workup including CT of chest, abdomen, and pelvis that shows multiple bilateral lung nodules without regional lymphadenopathy. Postsurgical changes related to the pylorus-preserving pancreaticoduodenectomy are described including atrophy of the pancreatic tail, pancreatic ductal dilatation, and stable postsurgical retroperitoneal fibrosis. No abdominal lymphadenopathy is noted. Liver, spleen, adrenals, kidneys, bowel, and bone are within normal limits. A small fat-containing umbilical hernia is noted.

She underwent CT-guided biopsy of a lung metastasis that confirms diagnosis of metastatic pancreatic cancer. Ca19.9 increased to 126 U/ml.

On physical exam she was afebrile, VSS, alert and oriented x 3, in no distress. ECOG PS: 0. Sclera are anicteric, no abnormal findings noted on HEENT, lymph node, cardiovascular, and lung exams. Abdomen was soft, non-tender, non-distended, bowel sounds present, without organomegaly. Surgical scars were well healed, and a small reducible umbilical hernia is present within the scar. Musculoskeletal and neurological exams were normal.

Question 4:  What are your therapeutic options?

Options for the treatment of stage IV pancreatic cancer include:

  1. Palliative therapy including pain-relieving procedures such as celiac nerve block, biliary obstruction relieving procedures including percutaneous or endoscopically placed biliary prostheses, palliative surgical bypass, and supportive care.
  2. Systemic chemotherapy.8

As this patient had an excellent performance status and was without need for palliative procedures, the treatment option best suited for her at this time was chemotherapy. The goal of treatment being to limit progression of metastatic disease, treat symptoms caused by the cancer, and prolong survival. Goals of therapy should always be discussed with patients prior to their initiation. An important component of this discussion, especially when therapeutic options are available, is a full discussion of the benefits and risks associated with each treatment. Patient’s values and preferences should be incorporated into treatment decisions. Shared decision-making facilitates patient autonomy, and appears to improve patient engagement and knowledge of their disease. While patient-centered oncology care may increase the demand on physician time and make clinical encounters more challenging, interactive deliberation of treatment options is associated with higher patient satisfaction and improved psychosocial outcomes.10

The multicenter Phase II/III PROTIGE trial included 342 ECOG 0 to 1 patients with metastatic pancreatic cancer without prior treatment randomly assigned to receive either FOLFIRINOX or gemcitabine alone. Duration of therapy goal was 6 months. Primary endpoint was overall survival. The multidrug combination was found to be significantly more efficacious than gemcitabine as summarized below:

 

Objective Response Rate

Median PFS

Median OS

1-year OS

FOLFIRINOX

31.6%

6.4 mo

11.1 mo

48.4 %

Gemcitabine

9.4%

3.3 mo

6.8 mo

20.6 %

P value

<0.001

<0.0001

<0.0001

<0.0001

However, FOLFIRINOX was significantly more toxic than gemcitabine, as shown.

 

Grade 3/4 neutropenia

Febrile neutropenia

Diarrhea

Neuropathy

FOLFIRINOX

45.7%

5.4%

12.8%

9%

Gemcitabine

21%

1.2%

1.8%

0%

P value

<0.001

0.03

<0.001

<0.001

 Adapted from Conroy T, Desseigne F, Ychou M, et al. N Engl J Med.11

After discussion, of the risks and benefits of FOLFIRINOX vs. gemcitabine-based chemotherapy, the decision was made to proceed with FOLFIRINOX. Therapy was reasonably well tolerated in that she had neutropenia and required pegfilgrastim support but did not develop febrile neutropenia or require hospital admission. Other adverse events included anemia, thrombocytopenia, diarrhea, elevation of AST, ALT and alkaline phosphatase levels, fatigue, nausea, and diarrhea.

After 12 cycles, she had excellent biochemical response with normalization of the Ca19.9 level to 25 U/ml. CT scans showed stable disease in the lungs and no new findings of metastatic disease.

Three months later, during a routine follow-up appointment off chemotherapy, the patient indicates that she is generally doing well but describes mild fatigue and weight loss of 3 pounds. She denied pain, nausea, vomiting, diarrhea, or other problems. CT chest abdomen and pelvis obtained just prior to the visit showed increasing multiple parenchymal nodules and infiltrates, new nodules in all segments and lobes consistent with disease progression. No recurrence within the abdomen. Ca19.9 has increased to 306 U/ml. She is not anxious to receive additional chemotherapy at this time because she is relatively asymptomatic. Together you elect to have her return in one month for close follow up.

The patient returns to see you one month later and is clinically unchanged. Ca19.9 has increased further to 1455 U/ml. You repeat her CT and it shows numerous bilateral lung nodules more confluent compared to the prior study keeping with progression of metastatic disease. No additional metastatic disease is identified.

Question 5:  What therapeutic options could be considered at this time?

The multicenter international trial phase III clinical trial MPACT or Metastatic Pancreatic Adenocarcinoma Clinical Trial was the second positive trial for patients with untreated metastatic pancreatic cancer. In this study, 861 subjects having a Karnofsky performance status of 70 or more were randomized to either nab(albumin bound)-paclitaxel plus gemcitabine or gemcitabine monotherapy until disease progression. Primary endpoint was overall survival. Patients who received the combination had improved survival as shown.

 

Objective Response Rate

Median PFS

Median OS

1-year OS

Nab-Paclitaxel/ gemcitabine

23%

5.5 mo

8.5 mo

35%

Gemcitabine

7%

3.7 mo

6.7 mo

22%

P value

<0.001

<0.001

<0.001

<0.001

Similarly the combination chemotherapy was more toxic than gemcitabine alone. Side effects are summarized below.

 

Grade 3/4 neutropenia

Febrile neutropenia

Fatigue

Neuropathy

Diarrhea

Nab-Paclitaxel/
gemcitabine

38%

3%

17%

17%

6%

Gemcitabine

27%

1%

1%

1%

1%

P value

Not reported

Not reported

Not reported

Not reported

Not reported

Adapted from Von Hoff, DD. N Engl J Med.12

You discuss the MPACT data, the risks and benefits of chemotherapy with gemcitabine and nab-paclitaxel and decide to proceed with second-line treatment for metastatic pancreatic cancer. In additional to the efficacy data and AEs reported, it is important to remember that taxanes cause total alopecia as well as joint and muscle pain, side effects best discussed with patients in advance.

There are no guidelines regarding the order of chemotherapy combinations for pancreatic cancer patients with good performance status. Other chemotherapy combinations including gemcitabine plus erlotinib, gemcitabine and 5-FU monotherapy or combinations may be considered depending on patient preference, performance status, or other factors.

Pancreatic cancer clinical trials can be found on the NCI website (www.cancer.gov). In addition to providing general information, the site includes a searchable database, allowing one to search by cancer type, trial location, trial type, phase, type of treatment, trial status, trial sponsor, and also by specific drugs. The site provides a 10-step guide for assisting patients with identifying a cancer clinical trial. The American Cancer Society website (www.cancer.org) has additional information primarily aimed at guiding patients through the process of decision-making regarding clinical trials. Overall, identification of an appropriate clinical trial requires assessment of the individual patient’s eligibility, referral or discussion with the PI and/or research team, evaluation of potential risks and benefits to the patient associated with the treatment, adequately communicating study procedures including the informed consent process, significance of the clinical research, and any additional costs incurred by trial participation.

Patient-oriented websites such as Pancreatic Cancer Action Network (www.pancan.org) and ASCO (www.cancer.net) are good resources for patient education.

References

  1. Longnecker DS. 2014. Anatomy and Histology of the Pancreas. The Pancreapedia: Exocrine Pancreas Knowledge Base. DOI: 10.3998/panc.2014.3
  2. Picozzi VJ. Pancreatic Cancer: Clinical Presentation. In: Von Hoff, DD, Evans, DB, Hruhan, RH, eds. Pancreatic Cancer. Sudbury, MA. Jones and Bartlett Publishers. 2005;155-164.
  3. Ojeda-Fournier H, Choe KA. In: Lowy, AM, Leach SD and Philip PA, eds. Pancreatic Cancer. New York, New York. Springer. 2008; 255-270.
  4. Exocrine and Endocrine Pancreas. In: Edge SB, Fritz AG, Byrd DR, Greene FL, Compton CC, Trotti A, eds. AJCC Cancer Staging Handbook, seventh edition, American Joint Committee on Cancer. Chicago, IL. Springer. 2010;285296.
  5. Yen TWF, Abdalla EK, Pisters PWT, and Evans, DB. Pancreaticoduodenectomy. In: Von Hoff DD, Evans DB, Hruhan RH, eds. Pancreatic Cancer. Sudbury, MA. Jones and Bartlett Publishers. 2005;265-285.
  6. Gallagher SF, Zervos EE, Murr MM. Distal Pancreatectomy. In: Von Hoff DD, Evans DB, Hruhan RH, eds. Pancreatic Cancer. Sudbury, MA. Jones and Bartlett Publishers. 2005;299-311.
  7. Oettle H, Neuhaus P, et al. Adjuvant Chemotherapy With Gemcitabine and Long-term Outcomes Among Patients With Resected Pancreatic Cancer, The CONKO-001 Randomized Trial. JAMA. 2013;310:1473-1481.
  8. Tempero MA (chair), et al. NCCN clinical practice guidelines in oncology, Version 2.2014. Pancreatic Adenocarcinoma. www.nccn.org.
  9. Katz MH, Moosa AR, Bouvet M. Serological Diagnosis of Pancreatic Cancer. In: Von Hoff DD, Evans DB, Hruhan RH, eds. Pancreatic Cancer. Sudbury, MA. Jones and Bartlett Publishers. 2005;235-249.
  10. Katz SJ, Belkora J, Elwyn G. Shared decision making for the treatment of cancer: challenges and opportunities. Journal of Oncology Practice. 2014;10:205-208.
  11. Conroy, T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817-1825.
  12. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691-703.

 

Partners in Pancreatic Cancer would like to recognize and thank Celgene Corporation
for their educational support of PartnersinPancreaticCancer.com.

©2017 MediCom Worldwide, Inc. All rights reserved