Advances in systemic therapy and supportive care, as well as ongoing improvements in surgical techniques, have led to improved survival for many patients with pancreatic ductal adenocarcinoma. We have observed increased survival with FOLFIRINOX (leucovorin, fluorouracil, irinotecan, oxaliplatin)–based chemotherapy in both metastatic and adjuvant settings.1,2 For patients with resected disease, the median overall survival for patients receiving adjuvant modified FOLFIRINOX was 54.4 months, compared with 35.0 months with gemcitabine.2
Bradley N. Reames, MD, MS
Locally advanced pancreatic cancer accounts for roughly one-third of new pancreatic ductal adenocarcinoma diagnoses and is challenging to treat because vascular involvement jeopardizes curative-intent surgery. Current guidelines advise upfront chemotherapy and/or radiation for patients with locally advanced pancreatic cancer, and consideration of surgery if feasible, for patients with a good performance status who do not experience disease progression.3
Recent advances in systemic therapy for pancreatic ductal adenocarcinoma have likely expanded the pool of patients with locally advanced pancreatic cancer potentially eligible for curative-intent surgery. Despite more advanced disease at presentation, the median overall survival in highly selected patients with locally advanced pancreatic cancer receiving multimodality preoperative treatment and successful resection has ranged from 35 to 58 months in recent reports from high-volume centers,4-6 with survival not yet reached (> 60 months and ongoing) in patients who achieve a pathologic complete response.7
Although these data are encouraging, their generalizability is unclear and must be interpreted with caution. Treatment advances for pancreatic ductal adenocarcinoma have outpaced the completion of phase III trials to inform locally advanced pancreatic cancer management decisions, and it is likely that the interpretation and application of available literature are inconsistent between providers and institutions. Recent studies from Europe have demonstrated frequent disagreement on locally advanced pancreatic cancer management strategies in multidisciplinary team meetings.8,9 In particular, factors contributing to the decision to offer surgical exploration, a critical branch point in locally advanced pancreatic cancer management, remain opaque and poorly understood.
International Survey on Management of Locally Advanced Pancreatic Cancer
Work from our group, recently published by the Annals of Surgery, strongly confirms these findings and further explores how surgeons’ attitudes contribute to variation in management of locally advanced pancreatic cancer.10 We surveyed an international cohort of pancreatic cancer surgeons to investigate preferences for the evaluation and management of locally advanced pancreatic cancer, attitudes regarding exploration, and contraindications to surgery. The survey also included five real-life (de-identified) detailed clinical vignettes of patients with locally advanced pancreatic cancer treated with neoadjuvant therapy, each accompanied by two videos of post-neoadjuvant arterial and venous imaging. Surgeons were asked whether they would consider exploration or other management strategies for each vignette, and we explored the rationales behind the respondents’ decisions. Respondents were unaware that each patient had actually received a margin-negative resection.
We received more than 150 responses from high-volume pancreatic surgeons practicing on 4 continents. Within this highly specialized cohort, we found wide variations in management preferences and the propensity to offer exploration. For example, 39% of surgeons preferred 2 months of neoadjuvant therapy, 43% preferred 4 months, and 11% preferred 6 months or more. Despite significant vascular involvement on imaging, 41% of surgeons “always” or “often” would recommend neoadjuvant radiotherapy, whereas 48% “sometimes” and 11% “never” would recommend neoadjuvant radiotherapy.
Attitudes regarding the utility of CA19-9 to assess treatment responses also varied widely: 36% “never” or “rarely” considered CA19-9 a contraindication to exploration. However, 19% considered any abnormal (> 37 U/mL) or rising value a contraindication, and 29% considered values of 500 U/mL or 1,000 U/mL to be critical thresholds for decision-making.
Of particular interest was the variation in surgeons’ willingness to explore patients with locally advanced pancreatic cancer. In a highly specialized cohort of pancreatic surgeons, between 14% and 53% would offer exploration across the five clinical vignettes in which a successful R0 resection was achieved. Perhaps not surprisingly, the reasons behind recommendations against exploration and alternative treatment recommendations also varied widely. Most surgeons advised additional chemotherapy and/or clinical trial options for patients they deemed inoperable. Between 2% and 4% of surgeons in those scenarios suggested referral for an additional surgical opinion.
Implications for Current Practice and a Call for Action
We and others have highlighted the variation in different surgeons’ approaches to this clinical challenge and the subjectivity inherent in critical locally advanced pancreatic cancer management decisions, namely determinations of operability. It is easy to appreciate how difficult these decisions can be. Numerous observational studies have questioned the ability of cross-sectional imaging to determine treatment response or resectability after neoadjuvant therapy.11-14
“Every patient with locally advanced pancreatic cancer ought to receive a robust and nuanced multidisciplinary discussion to determine the best management approach.…”— Bradley N. Reames, MD, MS
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For example, rates of R0 resection as high as 92% to 94% have been reported in selected patients with locally advanced pancreatic cancer after neoadjuvant therapy,6,14 despite infrequent evidence of radiologic downstaging.6 Although CA19-9, circulating tumor cells, metabolic imaging, and other biomarkers have been proposed as potentially useful objective markers for locally advanced pancreatic cancer treatment response, the ideal measurement strategy remains unknown.
This work has several implications. First, high-quality randomized trials are desperately needed for patients with locally advanced pancreatic cancer. Thankfully, such trials are underway. ALLIANCE A021501 is evaluating neoadjuvant FOLFIRINOX with or without stereotactic body radiation therapy, followed by resection for borderline resectable pancreatic ductal adenocarcinoma, and has successfully finished recruitment.15 “Precision Promise,” a novel adaptive clinical trial platform designed by the Pancreatic Cancer Action Network, is another example, scheduled to be launched in 2019. Though large multi-institutional randomized trials of multimodality therapy are difficult to develop, coordinate, and accrue, it is our responsibility to patients, both as clinicians and scientists, to tackle these challenges.
Second, this work suggests that every patient with locally advanced pancreatic cancer ought to receive a robust and nuanced multidisciplinary discussion to determine the best management approach, preferably among providers experienced in the complex care required of locally advanced pancreatic cancer. Such discussions must include consideration of the surgeons’ and hospitals’ ability to care for these patients. The technical complexity of a pancreatectomy for locally advanced pancreatic cancer, possibly with vascular resection and/or reconstruction, requires substantial technical skill and institutional resources for a successful surgical outcome. As a result, although recommendations against exploration at a particular hospital or by a particular surgeon are no doubt appropriate, consideration of a second surgical opinion may add value for select patients.
Most important, the aggressive nature and poor prognosis of pancreatic ductal adenocarcinoma overall require that surgeons and oncologists distinguish the ability to resect from the benefit of resection. To inform this discussion, more research is needed to better understand which patients with locally advanced pancreatic cancer may potentially benefit from exploration. However, until new research is available, the previously mentioned studies suggest that variation in locally advanced pancreatic cancer management may be improved by a clinical guideline or consensus statement on the preferred management approach.
To that end, The Pancreas Club, generously supported by the Nikki Mitchell Foundation, will be hosting medical, radiation, and surgical oncologists from around the world for a consensus conference on the multidisciplinary management of locally advanced pancreatic cancer, in conjunction with its 54th Annual Meeting on March 1–2, 2020, in Chicago. I am hopeful that the statement produced at this conference will take one small step toward improving the care of all patients with locally advanced pancreatic cancer.
Dr. Reames is Assistant Professor of Surgery, Department of Surgery and Division of Surgical Oncology at the University of Nebraska Medical Center, Omaha.
Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO or The ASCO Post.
DISCLOSURE: Dr. Reames reported no conflicts of interest.
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3. National Comprehensive Cancer Network (NCCN): NCCN Clinical Practice Guidelines in Oncology: Pancreatic Adenocarcinoma, Version 3.2019. Available at https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Accessed October 3, 2019.
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15. Katz MHG, Ou FS, Herman JM, et al: Alliance for clinical trials in oncology (ALLIANCE) trial A021501: Preoperative extended chemotherapy vs chemotherapy plus hypofractionated radiation therapy for borderline resectable adenocarcinoma of the head of the pancreas. BMC Cancer 17:505, 2017.