Locally Advanced Pancreatic Cancer
Because very few studies directly comparing FOLFIRINOX with gemcitabine-based combination regimens have been completed, there is no clear consensus on the preferred treatment regimen, in both borderline and unresectable LAPC. Decisions to treat are influenced predominantly by comorbidities, adverse effect profiles, and performance status of patients, as FOLFIRINOX is the more toxic of the 2 treatment backbones. Therefore, FOLFIRINOX has mostly been utilized in patients with relatively good functional status (Eastern Cooperative Oncology Group [ECOG] performance status 0 to 1).89 In elderly patients and those with poor functional status, ECOG 2 to 4, gemcitabine as a single agent is a reasonable alternative in the neoadjuvant setting of borderline resectable disease.
The exact role of radiation therapy in addition to induction chemotherapy in borderline resectable pancreatic cancer has not been clearly established because of the lack of prospective studies in this area. Multiple large retrospective series have identified high rates of conversion to margin-negative resection with neoadjuvant chemoradiation alone.90 Based on available data, it is reasonable for patients with borderline resectable disease to proceed with any of the following treatment options: chemotherapy, chemoradiation, or induction chemotherapy followed by chemoradiation (Figure). Chemotherapy and chemoradiation are generally more appropriate with patients with high CA 19-9 levels or those at an elevated risk of having positive margins or occult metastatic disease.91 Obtaining negative margin resections is the predominant goal of neoadjuvant radiotherapy.89 Many studies have identified margin status to be one of the most significant prognostic factors in PDA.57,59,92,93 Additionally, several studies have highlighted that radiotherapy in the neoadjuvant setting could improve negative margin resection rates, local control, and clinical outcomes in patients with borderline resectable locally advanced disease.94–97 A common multimodal regimen utilized in the neoadjuvant setting combines capecitabine, an oral prodrug that is converted to fluorouracil, with radiation therapy. This combination has also been shown to improve resectability rates and long-term clinical outcomes in patients with borderline resectable disease.98 Additionally, neoadjuvant radiation therapy can potentially downstage patients with unresectable disease at the time of diagnosis to become surgical candidates.99 Despite the paucity of data, interval scans utilizing CT following neoadjuvant therapy should be obtained 2 to 4 months after completion of therapy to determine therapeutic response, evaluate for disease progression, and, most important, reassess surgical stage/resectability. It is clinically acceptable to proceed to resection with radiographically stable disease post-neoadjuvant therapy.
Many patients classified as borderline resectable are able to proceed with surgery following neoadjuvant therapy. Unfortunately, specific data on adjuvant therapy following neoadjuvant chemotherapy or chemoradiotherapy and surgical resection in borderline resectable patients is scarce. Clinical practice guidelines are extrapolated from studies where upfront resection in clearly resectable patients was followed by adjuvant therapy. Based on these data, approximately 6 months of perioperative chemotherapy with or without chemoradiotherapy is a reasonable consideration. Nevertheless, about 80% of patients at the time of diagnosis are deemed to be unresectable, and a smaller number do not proceed to surgery despite an initial classification as borderline resectable. Of the 80% of patients with advanced disease, about half are metastatic at presentation and the remaining 30% to 40% are defined as having unresectable LAPC.100
CASE CONTINUED
The patient is deemed borderline resectable. He receives neoadjuvant therapy with gemcitabine and nab-paclitaxel. Two months after therapy, interval imaging with abdominal CT does not show improvement in tumor size and there is now evidence that the tumor has invaded the celiac axis and is abutting more than 180° of the SMA. The patient presents to the oncologist to discuss further management. He has lost about 15 lb since his last evaluation, is capable of self-care, but is unable to carry on with any work activities.
What is the appropriate management of unresectable nonmetastatic LAPC?
UNRESECTABLE LOCALLY ADVANCED CANCER
As in the case of borderline resectable disease, there are many treatment options for patients with unresectable LAPC. Timing, optimal chemotherapy regimen, and the addition of regularly and hypofractionated radiotherapy are issues currently under investigation. However, there are some general considerations and principles that are followed as reflected in the NCCN guidelines and recent studies. The primary therapeutic aims in patients with unresectable locally advanced disease are to increase survival and improve palliation.
The elderly comprise a large percentage of the patients diagnosed with unresectable locally advanced disease. Pharmacokinetics and toxicity profiles are altered in the elderly population.101,102 Therefore, it is important to assess functional status and comorbidities as these are critical factors in determining treatment regimens, similar to patients with borderline resectable disease. Currently, the most common first-line therapies in advanced pancreatic cancer are gemcitabine alone, gemcitabine and nab-paclitaxel, FOLFIRINOX, gemcitabine/capecitabine, and gemcitabine/oxaliplatin.103 The overall treatment approach to unresectable locally advanced pancreatic adenocarcinoma closely mirrors that of patients with borderline resectable disease and metastatic disease. Much of the data supporting treatment regimens in unresectable LAPC is extrapolated from clinical trials looking at advanced or metastatic pancreatic cancer.
Consensus opinions domestically and from Europe recommend that patients with locally advanced unresectable disease undergo upfront chemotherapy (Figure).104 This is based on the premise that initial chemotherapy may destroy occult metastatic cells and increase the efficacy of consolidative chemotherapy, particularly with radiation in the future. Upfront chemoradiotherapy has only been investigated in a small series of trials in which no clear survival benefit was observed and has the added consequence of treatment-related toxicity.105 However, data is limited in this regard, with variations in treatment protocols and cohort compositions contributing to the inconclusive findings.
