Optimal management of resectable pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a disease that mostly presents at an advanced stage, with visible metastasis to other organs on imaging, for which options are mostly limited to systemic chemotherapy (1,2). While systemic chemotherapy can prolong life in such settings, it rarely provides cure (1,2). In a minority of PDAC patients (10–20%), the disease is diagnosed at a stage that is seemingly limited to the pancreas on imaging without arterial involvement and with limited venous involvement not necessitating reconstruction (2). At this early “resectable” stage, surgery could provide cure. Even for such early stage, however, surgery alone provides cure only in a minority of patients [5-year overall survival (OS) with surgery alone remains <10%] (3). This reflects the systemic nature of PDAC, even when imaging such as computed tomography (CT) scan suggests that the disease is limited to the pancreas. It is with this knowledge that systemic antineoplastic chemotherapy is utilized in the setting of resectable disease to help eradicate the invisible “micro-metastatic” disease.

Chemotherapy can be administered before surgery (neoadjuvant) or after surgery (adjuvant). There are potential benefits to neoadjuvant chemotherapy (NAC): (I) the odds of chemotherapy initiation and completion are significantly higher in the pre-surgical setting, and therefore theoretically the odds of eradication of micro-metastatic disease are higher; (II) with presence of imageable disease, it is possible to monitor treatment response by imaging, rather than delivering months of chemotherapy blindly in the post-surgical setting; and (III) it is possible to evaluate disease biology to prevent futile surgery, as if a patient has chemo-resistant micro-metastatic disease at presentation, localized treatment with the surgery first approach would only leave the patient at risk of complications without providing the desired cure. On the other hand, there may be theoretical downsides to the neoadjuvant therapy: (I) cancer progression while on chemotherapy could prohibit a potentially curative surgery; and (II) chemotherapy side effects could lead to physiologic decline and medical inoperability. Which of these approaches is superior in resectable PDAC is an area of debate.

Schwarz et al. recently reported the results of the PANACHE01-PRODIGE48 clinical trial (4). In this phase 2 trial, between February 2017 and July 2020, 153 patients with resectable PDAC were randomly assigned (2:2:1) to modified FOLFIRINOX (leucovorin, fluorouracil, irinotecan, oxaliplatin) [mFFX; modified by omission of fluorouracil (5-FU) bolus, and after April 2019 protocol amendment, by decrease of irinotecan from 180 to 150 mg/m²], FOLFOX (leucovorin, fluorouracil, oxaliplatin) (included 5-FU bolus), or up-front surgery. In the 2 NAC arms, chemotherapy was planned as 2-week cycles, for 4 cycles (2 months), followed by surgery in 3–5 weeks. In the up-front surgery arm, patients were planned to receive 6 months of adjuvant chemotherapy, within 12 weeks of surgery. Patients in the NAC arms were intended to receive adjuvant chemotherapy (4 months). Choice of adjuvant chemotherapy in all 3 arms was per French guidelines and per the treating physicians’ choice. This study was neither designed nor powered for comparison of the arms. The primary objective of the study was to evaluate the feasibility and efficacy of the 2 NAC regimens. The binary endpoints of the study included 12-month OS post-randomization, as well as the rate of completion of the full therapeutic sequence (defined as ≥2 cycles of NAC followed by surgery). An interim futility analysis was performed after the first 27 randomized patients reached the binary endpoints in each arm, which led to cessation of recruitment to the FOLFOX arm.

After completion of the study, mFFX was deemed “feasible” and “promising”, after meeting pre-defined efficacy boundaries (4). In the intention to treat population, 70.8% of patients in the mFFX arm completed the therapeutic sequence. One-year OS in the mFFX, FOLFOX, and up-front surgery arm was 84.3%, 71.4%, and 82.1%, respectively. The rate of surgical resection was similar between the mFFX (74%) and up-front surgery (72%). In the mFFX arm 61/69 (88%) finished the intended 4 cycles of NAC. In the up-front surgery arm, 11/25 [44%; 11/18 (61%) of resected patients] finished the intended 6 months of adjuvant chemotherapy, highlighting the challenges of chemotherapy in the post-surgical setting. One-year event-free survival (failure defined as progression before surgery, metastatic or unresectable disease at surgery, recurrence post-surgery, or death) was 51.4% in the mFFX arm and 38.7% in the up-front surgery arm. Considering that all patients in the study had “resectable” disease, the fact that over 50% of them experienced disease recurrence within a year of surgery in either arm underscores the current treatment modalities’ inability to eradicate micro-metastases in the majority of cases.

The results of this study contradicted a previously published randomized phase 2 trial (NORPACT-1) comparing two arms: 2 months of standard FFX followed by surgery and 4 months of adjuvant chemotherapy, versus up-front surgery followed by intended 6 months of chemotherapy; there was worse survival in the NAC arm (5). The 18-month OS (primary endpoint of this study) was lower in the NAC arm (60%), compared to the up-front surgery arm (73%; P=0.03). There could be many reasons for the unanticipated result of the NORPACT-1 trial. To prevent delays in up-front surgery, patients were randomized before tissue diagnosis or management of any existing biliary obstruction, which led to 13/77 (17%) of patients in the NAC arm not receiving even 1 cycle of NAC. Furthermore, other than the 12 academic hospitals with expertise in management of PDAC, 26 local hospitals were included for chemotherapy delivery. Patients with PDAC can encounter numerous challenges during the NAC, including but not limited to biliary complications. Consequently, treating patients at local hospitals can be challenging, as not all centers have a well-established infrastructure to manage such complexities in a timely manner. Lastly, FFX was given at standard dose, without clear guidance for real world dose reductions. Compared to NORPACT-1, PANACHE01-PRODIGE48 administered mFFX, which is overall considered to be better tolerated and as efficient as classical FFX (6). This may explain the inability to complete the intended 4 cycles of NAC in 40% of the patients in the NORPACT-1 study initiating NAC, compared to 8% for PANACHE01-PRODIGE48 patients (47% of the intention to treat population in NORPACT-1 vs. 12% in PANACE01-PRODIGE48).

The PANACHE01-PRODIGE48 and NORPACT-1 studies therefore, highlight the importance of having an established infrastructure for the delivery and completion of NAC. Medical oncology team should have expertise in administration, dose adjustment, supportive measures, and toxicity management of any NAC such as FFX. A team, consisting of surgical oncology, gastroenterology, and/or interventional radiology, should be available at all times to ensure timely management of biliary complications to prevent delays in treatment. Furthermore, considering challenges with nutrition, diabetes, physical deconditioning, mental exhaustion, a PDAC dedicated team consisting of a dietician, endocrinologist, physical therapist, and psychologist would be needed to ensure optimization of patient status throughout the long journey of patients through the NAC. If and when a patient’s condition prohibits treatment with a protracted course of NAC, goals and sequencing of care would need to be reconsidered, ideally under the direction of a PDAC-oriented multidisciplinary team (7).

As PANACHE01-PRODIGE48 was a feasibility study, it was not designed or powered to compare the mFFX to the up-front surgery arm. Therefore, while PANACHE01 shows the feasibility and preliminary efficacy of NAC with mFFX, it does not establish the optimal choice of therapy in the resectable setting. PREOPANC-3 (NCT04927780) and ALLIANCE A021806 (NCT04340141) phase 3 randomized clinical trials aim to compare perioperative mFFX (4 months neoadjuvant and 2 months of adjuvant) to 6 months of adjuvant mFFX (8,9). NeoFOL-R (NCT05529940) is evaluating the efficacy of 3 months of neoadjuvant followed by 3 months of adjuvant mFFX versus surgery followed by 6 months of adjuvant mFFX for PDAC patients in Korea.

There are still many unanswered questions in the setting of resectable PDAC management.

What is the ideal choice of chemotherapy regimen in this setting? SWOG1505 and NEONAX showed feasibility and efficacy of peri-operative gemcitabine plus nab-paclitaxel, and PREP‑02/JSAP‑05 neoadjuvant gemcitabine plus S-1 in this setting (10-12). An ongoing study (PANCREAS, NCT03322995) is evaluating the role of transcriptomic-based classification (basal-like and classical) in prospective assignment of treatment to patients in this setting, given that basal-like PDAC likely responds better to gemcitabine plus nab-paclitaxel (13).

What is the optimal duration of NAC? Is 2 months of therapy adequate to achieve the benefits of neoadjuvant therapy, or are more protracted courses needed?

If more than 2 months of chemotherapy is planned, what would one do if optimal response (based on imaging, tumor marker response and/or circulating tumor DNA) to NAC is not achieved after 2 months of therapy? Would one switch chemotherapy, switch to chemoradiation, or transition to surgery? An ongoing clinical trial (PANC, NCT03322995) is evaluating the role of algorithmic-based adaptation of treatment plan to patients’ condition and tumor response [per imaging and carbohydrate antigen 19-9 (CA19-9)] (14).

What is the role of radiation in this setting? The phase 3 PREOPANC-2 study showed similar efficacy for gemcitabine-based neoadjuvant chemoradiation (3 cycles of gemcitabine, with hypo-fractionated radiation of 36 Gy in 15 fractions) followed by surgery and 4 cycles of adjuvant gemcitabine, compared to 4 months of neoadjuvant FFX (without adjuvant chemotherapy) for patients with resectable or borderline resectable PDAC in the neoadjuvant setting (15).

How can we incorporate therapies matched to the molecular features of the tumor (precision oncology) in this setting? What would be the role for Kirsten rat sarcoma virus (KRAS) inhibitors and immunotherapies, including cellular therapies, in management of these patients, particularly in the window-of-opportunity setting?

In summary, PANACHE01-PRODIGE48 trial showed feasibility and preliminary efficacy of neoadjuvant mFFX for treatment of patients with resectable PDAC. NORPACT-1 showed that if NAC is not administered under the care of institutions with adequate infrastructure and expertise to carry the patients safely through their neoadjuvant journey with minimal treatment interruptions, outcomes of NAC could be suboptimal. Both studies overall showed suboptimal outcomes, with the majority of patients experiencing eventual recurrence of the cancer. Incorporation of tumor molecular-based matched therapies, and adjustment of treatment plan per patients’ clinical condition and tumors’ response to therapy could further improve outcomes in this setting. Truly personalized oncology, incorporating prospective biological predictors of chemotherapy response as well as molecular targets based on next-generation sequencing and dynamic monitoring of response using circulating tumor DNA, could improve the outcomes significantly for patients with localized and resectable PDAC.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Pancreatic Cancer. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://apc.amegroups.com/article/view/10.21037/apc-25-33/coif). The authors have no conflicts of interest to declare.

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