Management of pancreatic cancer continues to be challenging. Dr. Margaret Tempero, an internationally renowned expert in pancreatic cancer and a former president of the American Society of Clinical Oncology, here elegantly discusses her approach to a patient with recently diagnosed pancreatic ductal adenocarcinoma, addressing diagnosis, evaluation, and management. In addition she wisely counsels us to keep heritable syndromes in mind when evaluating a patient with pancreatic cancer and gives us some practical advice on the serial follow-up of patients with advanced pancreatic cancer. I am sure you will agree with me that is short piece is full of practical and useful information.
--Ramaswamy Govindan, MD, OT Clinical Advisory Editor for Oncology
BY MARGARET TEMPERO, MD
Although statistics might lead you to think otherwise, pancreatic ductal adenocarcinoma (PDAC) is treatable and manageable, at least for a while. My practice covers the spectrum of presentations of this disease, including entities that can masquerade as PDAC.
In my initial consultation, I always try to make sure we have the right diagnosis. Tissue review is paramount, especially if the clinical presentation is atypical. Most advanced stage patients have weight loss, nonspecific pain, and hyperglycemia. If these are not present, I always investigate further.
Heritable syndromes are uncommon but it is important to recognize these. Pancreatic cancer can occur in excess in many syndromes such as BRCA-1, BRCA-2, FAMM, HNPCC, and unique families exist which are characteristic for familial pancreatic cancer. These latter families are defined by patients with two or more affected first-degree relatives.
Understanding family history and selected genetic syndromes has obvious implications for other family members. Screening programs using EUS and ERCP or MRCP for early diagnosis can be tailored to the syndrome and/or pattern in the family. This can also have implications for treatment, since patients in many of these syndromes respond well to cisplatin-containing regimens and PARP inhibitors may soon be approved for patients with BRCA mutations.
Extent of Disease
The second issue I address is extent of disease. Patients with metastatic disease can often be culled out with routine chest and abdominal CT scans. However, a dynamic phase CT scan is required to identify the extent of local vascular involvement or encasement. Thus, good communication with a competent abdominal imaging team is essential.
The new category of “borderline” resectable (see NCCN guidelines) presents a clinical conundrum, since neoadjuvant chemotherapy is often requested by our surgical colleagues.
No one knows the “best” neoadjuvant chemotherapy regimen or the true value of preoperative chemoradiation in this setting. So if a clinical trial is not available, I generally offer a combination chemotherapy regimen and make a decision about chemoradiation after we have achieved a plateau in declining tumor measurements or CA19-9 levels. If chemotherapy alone achieves the goal, we do not proceed with chemoradiation.
The selection of postoperative adjuvant therapy is an easier decision. Although gemcitabine has become the gold standard, I often treat with promising chemotherapy combinations. I realize this puts me “ahead of the data,” but these patients can’t wait for results of ongoing trials, and it will be years before trials of new combinations are conducted and completed. It’s important to remember that without adjuvant therapy the risk of relapse is 90%, so the risk of combination therapy seems warranted until we know more.
A tissue diagnosis is not required prior to surgical resection but is necessary prior to other forms of treatment. Neuroendocrine and acinar tumors, metastases from other primary sites, lymphoma, and benign tumors all can masquerade as PDAC.
If metastatic disease is present, biopsy of the metastatic site is preferable. If not, endoscopic ultrasound (EUS)-directed biopsy of the primary site is preferred over a CT-guided biopsy.
Many patients present with biliary ductal obstruction and biliary patency must be assured before starting treatment. I prefer an expandable metal stent unless surgery is imminent. If a preoperative stent is required because of cholangitis or delay in scheduling, a plastic stent is usually placed.
We manage patients with locally advanced disease as we manage those with borderline resectable disease. Eligible patients who do not demonstrate early systemic progression are offered chemoradiation with either capecitabine or gemcitabine. Again, a clinical trial is always favored.
Patients with systemic disease need systemic therapy. We always have first-line trials open for this group, but many patients opt out or are not eligible. Active combinations include; FOLFIRINOX, fixed-dose rate gemcitabine and alternate-week capecitabine, gemcitabine, docetaxel, and capecitabine (GTX); gemcitabine and nab-paclitaxel, gemcitabine and erlotinib, FOLFOX, and CAPOX.
Monotherapy with gemcitabine is offered to very frail patients with a poor performance status. Obviously the right treatment is ultimately the one that works and we are very quick to change regimens if the patient is not improving clinically or if their CA19-9 is rising.
Following patients on treatment can be a bit tricky. Pseudo-progression in liver and bone has been observed. If the patient’s CA19-9 is declining and the patient is improving clinically, I always continue treatment even in the presence of “new” lesions. These will often stabilize or even remit. CA19-9 is not a precise test, and different labs use different assays with different normal ranges. It’s important to be sure tests are repeated using the same assay and to look for serial trends.
It is not unusual to have aberrant values or to have false-positive interference from other events such as a partially occluded biliary stent. We consider a CA19-9 value of greater than 75 units to be “evaluable” for response.
Symptom management is an important part of care. Adequate nutritional intake is difficult for most patients who have little or no appetite, early satiety, and some degree of pancreatic insufficiency.
We recommend small frequent meals with liquid nutritional supplements and pancreatic enzyme replacement. Most patients require narcotic pain medication. These need to be given “round the clock” with long-acting narcotics, and short-acting narcotics should be offered for breakthrough pain.
Patients with pancreatic ductal adenocarcinoma have many challenging issues across the spectrum of management. Research emphasizing early detection and highly effective therapies will have the most impact on improving survival in this difficult disease.
MARGARET TEMPERO, MD, is Director of Research Programs and Deputy Director of the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco.