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Key Topics in the Management of Patients With Resectable and Advanced Pancreatic Cancer

Dan Laheru, MD

Professor of Oncology
Ian T. MacMillan Professorship in Clinical Pancreatic Cancer Research
Co-Director, Gastrointestinal Cancer Program
Co-Director, Skip Viragh Center for Pancreatic Cancer Research and Clinical Care
Member, Miller-Coulson Academy of Clinical Excellence
The Sidney Kimmel Comprehensive Cancer Center
The Johns Hopkins University School of Medicine
Baltimore, Maryland


Daniel Laheru, MD, has no relevant financial relationships to disclose.


View ClinicalThoughts from this Author

Released: February 5, 2021

Although pancreatic cancer remains a disease with poor prognosis, continuing advances have improved outcomes for many patients. In this commentary, I review some recent notable topics in pancreatic cancer treatment and discuss some of the strategies I employ in my clinic.

Neoadjuvant and Adjuvant Therapy
Approximately 15% to 20% of patients who present with pancreatic cancer with have resectable (stage I or II) disease. Numerous trials have now shown that neoadjuvant or adjuvant chemotherapy can improve outcomes for patients with resectable disease. Most patients with locally confined pancreatic cancer intuitively understand that their only chance for a cure is with surgery, so many would like to have their tumors resected before moving on to any chemotherapy. The conversation with the patient in choosing between neoadjuvant therapy and adjuvant therapy is a very important one. All patients with resectable pancreatic cancer should receive some form of chemotherapy; this is in contrast to patients with stage I or stage II colon cancer who can have their tumor resected and not need adjuvant therapy, as the chance for cure with surgery alone is very high.

The approach we take at my institution is to recommend neoadjuvant chemotherapy for resectable pancreatic cancer. Borderline resectable tumors are generally very risky to explore with surgery before chemotherapy, and we recommend neoadjuvant therapy for these patients as well.

If patients select to do neoadjuvant therapy, explaining the sequence of events is key. For example, a patient would receive 4 months of chemotherapy before surgery followed by 2 months of chemotherapy after surgery. I tell patients that chemotherapy is much better tolerated before surgery than after surgery, and so the more we can give them upfront the better.

The conversation then often evolves to address patient concerns about tumor growth during neoadjuvant therapy and the potential to miss an opportunity for surgery. I tell patients that, thankfully, there is a very small risk of this happening, as the majority of patients with potentially resectable disease do not see their tumors grow to the point where they are no longer resectable during neoadjuvant therapy.

Another clear advantage of a neoadjuvant approach is that this allows us to better understand the biology of their cancer. For example, if during neoadjuvant therapy, we identify a liver lesion in the patient that was not initially recognized, the patient does not go through an operation that will not be beneficial.

The discussion of which chemotherapy to give in the neoadjuvant setting was clarified recently by the phase II SWOG S1505 trial, which randomized patients to 12 weeks of chemotherapy with either FOLFIRINOX or gemcitabine plus nab-paclitaxel. Many expected that greater benefit would be observed with FOLFIRINOX, but the study demonstrated very nicely that gemcitabine plus nab-paclitaxel is also very reasonable as neoadjuvant chemotherapy. I think that FOLFIRINOX or gemcitabine plus nab-paclitaxel for patients with locally confined cancer receiving chemotherapy are equally good choices.

We also discuss stereotactic radiation, particularly for tumors that are involving either the superior mesenteric artery or the celiac artery. We know that for resected tumors, if the cancer returns, the chances for local recurrence can be up to 30%. Initially, there were concerns about competition between systemic vs local recurrence, and we wondered if we really have the luxury of delivering radiation over 5-6 weeks. However, with more contemporary radiation, particularly for tumors that are near the superior mesenteric artery or the celiac artery, a combination of chemotherapy and radiation therapy in a neoadjuvant approach offers the best chance at keeping cancers from coming back locally and systemically.

At the recent ASCO GI 2021 meeting, we saw results from the phase II Alliance A021501 study, which randomized patients with borderline resectable pancreatic cancer to neoadjuvant mFOLFIRINOX with or without stereotactic body radiation therapy (SBRT). Of the 40 patients in the SBRT arm who completed neoadjuvant mFOLFIRINOX and started SBRT, only 19 (48%) underwent resection and only 14 (35%) underwent margin negative resection. In contrast, of the 47 patients in the neoadjuvant mFOLFIRINOX only arm, 38 (68%) underwent resection and only 28 (60%) underwent margin negative resection. These data run somewhat contrary to our own institutional experience and have certainly generated a lot of discussion in the field. In speaking with a number of the investigators leading this study, it would appear that the SBRT arm underperformed largely unrelated to the radiation therapy itself, with additional patients in the SBRT arm developing progressive disease or being found to have metastases prior to getting to surgery in the SBRT arm. We eagerly await further results in this area.

Novel Approaches for Advanced Disease
At present, FOLFIRINOX and gemcitabine plus nab-paclitaxel should be initially considered as first-line chemotherapy options for patients with advanced, unresectable disease without actionable mutations, with nanoliposomal irinotecan plus 5-FU/LV recommended for patients who require second-line therapy after gemcitabine plus nab-paclitaxel (gemcitabine plus nab-paclitaxel can be considered for patients who have previously received FOLFIRINOX).

Up to 25% of patients with pancreatic cancer may be candidates for targeted therapy due to an actionable mutation. For patients who harbor a germline or somatic pathogenic BRCA mutation or alteration to other genes that encode a DDR protein, platinum-based chemotherapy (eg, FOLFIRINOX or gemcitabine plus cisplatin) has been shown to be of particular benefit. In addition, PARP inhibitors are now being investigated for treating patients with key alterations in DDR genes. Recently, we saw results from the phase III POLO study, which randomized patients with metastatic pancreatic cancer with a deleterious/suspected deleterious germline BRCA1/2 mutation who had received ≥ 4 months of first-line platinum-based therapy without progression to either maintenance therapy with olaparib, a PARP inhibitor, or placebo. This study demonstrated that PFS was significantly improved with olaparib maintenance, but the median OS was similar between arms. I think this was because the patients who were randomized to placebo had to have, by definition, at least stable disease while receiving platinum-based chemotherapy. If their cancer had grown subsequently, they could return to the platinum-based chemotherapy that was successful the first time around.

The ASCO pancreatic cancer guidelines were recently updated to include recommendations for  genetic testing for all patients, even though the mutations identified for pancreatic cancer are not as numerous as what is seen for other cancers. Aside from DDR mutations, NTRK fusions and  microsatellite instability high/mismatch repair deficiency can be actionable in pancreatic cancers. Even though the frequency of these is low for patients with metastatic pancreatic cancer, we do not want to miss any opportunities for beneficial treatment in these patients, so identifying mutations as early as possible is critical.

Your Thoughts
How do you manage your patients with resectable pancreatic cancer? How do you choose first-and second-line systemic therapy for your patients with advanced disease? Are you assessing molecular alterations in your patients, and have you employed targeted therapies? Answer the polling question and join the conversation by posting a comment in the discussion section.

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Supported by educational grants from
Bristol-Myers Squibb
Ipsen Biopharmaceuticals, Inc.

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