Defining the Optimal Duration of Neoadjuvant Therapy for Pancreatic Ductal Adenocarcinoma

Abstract

Despite recent advances, pancreatic ductal adenocarcinoma (PDAC) continues to be associated with dismal outcomes, with a cure evading most patients. While historic treatment for PDAC has been surgical resection followed by 6 months of adjuvant therapy, there has been a recent shift toward neoadjuvant treatment (NAT). Several considerations support this approach, including the characteristic early systemic spread of PDAC, and the morbidity often surrounding pancreatic resection, which can delay recovery and preclude patients from starting adjuvant treatment. The addition of NAT has been suggested to improve margin-negative resection rates, decrease lymph node positivity, and potentially translate to improved survival. Conversely, complications and disease progression can occur during preoperative treatment, potentially eliminating the chance of curative resection. As NAT utilization has increased, treatment durations have been found to vary widely between institutions with an optimal duration remaining undefined. In this review, we assess the existing literature on NAT for PDAC, reviewing treatment durations reported across retrospective case series and prospective clinical trials to establish currently used approaches and seek the optimal duration. We also analyze markers of treatment response and review the potential for personalized approaches that may help clarify this important treatment question and move NAT toward a more standardized approach.

While many other cancers have had significant advances leading to improvement in survival outcomes over the past few decades, pancreatic ductal adenocarcinoma (PDAC) is holding onto its legacy of poor outcomes. While currently ranked as the fourth leading cause of oncologic mortality in the United States and Europe, it is expected by the year 2030 to be second only to lung cancer.¹ Pancreatic ductal adenocarcinoma is associated with a grim 5-year survival rate of approximately 10% for all patients and ranging from 3% to 39% depending on disease stage and treatment.^2,3

The cornerstone curative treatment for PDAC is surgical resection, and standard of care dictates adjuvant chemotherapy postoperatively.^2,4 However, because of the advanced stage at presentation, up to 80% of patients are not candidates for upfront surgical resection due to the relationship between the tumor and major mesenteric vasculature or synchronous metastatic disease.⁵ For those with isolated local disease, patients are categorized as resectable, borderline resectable (BR), or locally advanced (LA) based on tumor vascular involvement. Precise definitions between these cohorts vary between individual guidelines.^6–9 In most cases, resectable and BR cases are considered to have a reasonable potential for surgical resection. Locally advanced cases have traditionally been considered unresectable; however, with the development of more effective systemic therapy, surgeons are becoming more willing to take these patients to the operating room in attempts to successfully resect their tumors.¹⁰ While neoadjuvant therapy is being increasingly used in resectable PDAC, there remains debate about its utility. For BR and LA cases, preoperative therapy has now become standard of care. However, the duration of preoperative treatment that should be given before attempting surgical resection has not been established and is the focus of this review.

RATIONALE FOR NEOADJUVANT TREATMENT APPROACH IN PDAC

Over the last decade, there has been a shift toward implementing preoperative treatment for PDAC, including resectable, BR, and LA cases.¹¹ The overarching goal of preoperative therapy is to downstage the cancer, control occult metastatic disease in an effort to improve resection outcomes, and enhance the chances of long-term survival. Similar preoperative approaches have become increasingly more common in the treatment of other types of gastrointestinal cancer with data supporting improved outcomes.¹²

This shift toward preoperative therapy in PDAC is largely driven by the systemic nature of the disease and high propensity for early metastatic spread. A quantitative analysis of the genetic evolution of PDAC indicated that an entire decade passes between the initial genetic mutation and formation of the first oncologic cell.¹³ An additional 5 years is required before metastatic ability is obtained, with death occurring at an average of 2 years later. While this may indicate a lengthy period before systemic spread of the disease, it does raise concern of the systemic nature of the cancer by the time a diagnosis is established. Even relatively small tumors are commonly found to already have perineural and lympho-vascular invasion.¹⁴ In a remarkable in vivo murine study, Rhim et al¹⁵ used tracking of pancreatic epithelial cells to show their invasion into the bloodstream and liver before cancer cells in the pancreas being evident on histology. These findings support the dissemination of cancer cells very early in the disease course and often before a tumor being discovered. Furthermore, in the event a primary tumor is discovered earlier in the disease course, computed tomography (CT) imaging is limited in its ability to visualize occult micrometastatic spread. The early use of preoperative therapy could potentially ensure treatment of these distant cells and treat occult disease not recognized on imaging before surgery.

Although the high probability of chemotherapy producing negative effects on a patient's quality of life is undeniable, there is evidence indicating patients are more tolerant of systemic treatment preoperatively compared with postoperatively.^16,17 Perioperative mortality related to pancreatectomy has consistently been improving in recent decades; however, procedure-related morbidity remains a significant risk. The most common surgical complications after pancreatic resection are pancreatic fistula formation, delayed gastric emptying, bleeding, infection, and development of intra-abdominal abscess.^18,19 Patients who develop a pancreatic fistula postoperatively are more likely to have a delay in adjuvant treatment or abandon it altogether—resulting in diminished overall survival (OS).²⁰ If traditional treatment with surgery followed by adjuvant therapy is pursued, up to one third of patients may have delayed recovery or develop significant complications postoperatively that preclude additional treatment.^21,22 Neoadjuvant treatment (NAT) ensures patients receive at least a portion of their systemic therapy, which has proven benefit for this disease.²³ Patients who are able to receive adjuvant chemotherapy may require several weeks of recovery postoperatively. In a study of patients with resectable PDAC by Tzeng et al,²⁴ patients receiving multimodality therapy had a significantly higher chance of completing all prescribed therapy if it was done in a neoadjuvant setting (83%) compared with an adjuvant approach (58%).

Another proposed benefit of using preoperative therapy for nonmetastatic cases of PDAC is to microscopically analyze the effect of chemotherapy on an individual's cancer and the visible histopathologic response. Importantly, the histopathologic response correlates to survival and can be used as a tool to consider alternative chemotherapy in the adjuvant setting if minimal response is seen at time of resection.^4,25 This has the potential to improve OS outcomes in PDAC. Furthermore, administration of novel therapies in the neoadjuvant setting allows for analysis of histopathologic response as surrogate end point, which facilitates a more rapid assessment of the efficacy of new therapies and helps determine their potential benefit in a timely fashion.

From a surgical standpoint, preoperative has not been shown to compromise operative planning, approach, or perioperative outcomes.^17,22 An analysis of 30 prospective phase II trials compared postoperative morbidity and mortality in patients receiving preoperative therapy versus surgery alone. For initially resectable and BR disease, patients receiving preoperative treatment had no significant increase in surgical complications in comparison with those undergoing a surgery-first approach. There was a slight increase in complications for tumors initially labeled as unresectable; however, this was thought to be because of the higher tumor burden and the more aggressive surgical resections necessary for advanced disease.²⁶

While NAT algorithms for nonmetastatic PDAC are increasingly used, there have been no studies focusing on determining the most effective preoperative treatment duration. As a result, surgeons and medical oncologists must decide when to stop preoperative treatment and pursue surgical resection, balancing the risk of toxicity from chemotherapy that may preclude curative surgery while still achieving an adequate duration of preoperative therapy to recognize its benefits. In an endeavor to better understand the use of NAT for patients older than 75 years, Miura et al²⁷ examined a large group of individuals who received preoperative treatment and their associated outcomes. Although age was not found to be a cause for a significant difference in survival, failure to complete prescribed therapy due to toxicities or complications stemming from other comorbidities did lead to worsened OS. Although limited data are available to guide this clinical decision on the usage of NAT, there is great importance for clinicians to have the aptitude to balance the potential benefits and detriments of using this treatment method for each individual patient. The purpose of this review is to analyze different preoperative therapy approaches in an effort to determine whether an optimal duration before attempting surgical resection exists.

RETROSPECTIVE STUDIES OF PREOPERATIVE CHEMOTHERAPY IN PDAC

A search of PubMed and clinicaltrials.gov was performed to review larger retrospective case series and prospective clinical trials of NAT for PDAC (defined by >20 patients). We identified 16 retrospective single-institution studies evaluating neoadjuvant folinic acid, fluorouracil, irinotecan hydrochloride, and oxaliplatin (FOLFIRINOX) (Fig. 1A^28–43) and 8 studies examining gemcitabine-based chemotherapy (Fig. 1B^38,42–48). Depending on the type of chemotherapy used, the length of each chemotherapy cycle will vary; thus, we recorded therapy durations in separate graphs based on chosen treatment. The durations used in these uncontrolled studies were analyzed to identify any trends that may be evident. In their span from 2009 to 2019, they demonstrate a large range in preoperative treatment duration (as seen in the graphs hereinafter). Each study reports positive findings associated with preoperative therapy compared with historical controls, with suggestions of prolonged progression-free survival, OS, and resection rates—particularly when used for resectable and BR cases. However, these findings demonstrate a dramatic variability in treatment patterns for NAT, with an overall median treatment duration of 12 weeks and a range from 2 to 58 weeks before attempted surgical resection. Interestingly, OS for resectable cases seen in both retrospective and prospective clinical studies did not vary based on treatment duration, as seen in Figure 1C.

FIGURE 1.

Retrospective case series evaluating preoperative FOLFIRINOX (A)^28–43 and gemcitabine based therapies (B)^38,42–48 for pancreatic adenocarcinoma. The graphs hereinafter demonstrate the median and range of durations shown in each retrospective review with an overall median treatment of 12 weeks and a range from 2 to 58 weeks. Median duration is identified in the bar graph with range of duration demonstrated by the solid line. Survival by treatment duration is shown in (C), demonstrating no improvement in survival across different treatment durations.

PROSPECTIVE CLINICAL TRIALS OF PREOPERATIVE CHEMOTHERAPY IN PDAC

Resectable PDAC

Twenty-seven prospectively controlled clinical trials targeting resectable PDAC were examined for comparison of NAT durations and associated outcomes. Given the variation in cycle length depending on the type of treatment used, the duration of therapy was assessed in weeks. The median duration of the combined trials was 8 weeks with a range of 2 to 17 weeks. With the exception of 3 studies,^49–51 the remaining 24 trials supported the use of NAT for resectable disease.^22,49–75 Although each study focused on different primary outcomes, significant improvements in resection rates, margin negative resection rates (R0), and OS were commonly reported despite the variation in treatment methods and durations. The variation in the length of therapy over the past 20 years is depicted in Figure 2A. A recent increase in sample size and number of studies can be seen in the last several years, which corresponds with an increasing prevalence of NAT studies in PDAC. Several landmark studies included in this analysis have served as foundations for both future clinical trials and clinical decision making by physicians, many of which are discussed in further detail in the upcoming sections.

FIGURE 2.

Prospective clinical trials of neoadjuvant therapy for resectable (A),^22,49–74 borderline resectable (B),^68–89 and locally advanced (C)^83–100 PDAC from 2000 to 2020, demonstrating high variability of treatment duration even in the controlled setting of a predefined clinical trial protocol. Chemotherapy regimen is identified by the color of the circle. Sample size is represented by the size of the circle.

In 2018, Reni et al⁶² performed the PACT-15—a phase 2/3 randomized clinical trial, which collected data on 88 patients with resectable PDAC who were randomly assigned to receive either surgery with 24 weeks of adjuvant gemcitabine, surgery followed by 24 weeks of adjuvant PEXG (cisplatin, epirubicin, gemcitabine, and capecitabine), or 12 weeks of neoadjuvant PEXG followed by resection and 12 more weeks of adjuvant PEXG therapy. The primary end point for the study, event-free survival at 1 year, was 23%, 50%, and 66% in the 3 arms, respectively, suggesting efficacy of NAT. As the trial was ongoing, evidence regarding benefits of using modified FOLFIRINOX as a systemic therapy was gaining traction, instigating the decision to not proceed with the phase III portion of the trial.⁶²

The 2019 Prep-02/JSAP study conducted by Motoi et al⁵¹ was a randomized control trial comparing neoadjuvant gemcitabine and tegafur, gimeracil, oteracil (S-1) chemotherapy to a surgery-first approach. Of 364 patients enrolled in the study, 182 patients received NAT and 180 underwent surgery followed by systemic therapy. The NAT arm consisted of 6 weeks of chemotherapy before resection followed by 12 weeks of adjuvant treatment with S-1 alone. Although their final results did not show a significant difference in resection rate or the rate of R0 resection, there was a significant increase in OS in the neoadjuvant arm compared with the surgery-first arm, demonstrating an encouraging outcome.

Modified FOLFIRINOX (mFOLFIRINOX) and gemcitabine + nab-paclitaxel are the 2 most active regimens in PDAC, and it was not until recently that these regimens were compared head-to-head in the neoadjuvant resectable PDAC setting. The study SWOG S1505 compared 12 weeks of neoadjuvant mFOLFIRINOX to gemcitabine with nab/paclitaxel.²² The primary end point was the 2-year OS, where patients had a median survival of 22.4 and 23.6 months respectively, showing no significant improvement in one treatment regimen over another. However, the reported overall resectability rate of 72% and complete or major pathologic response of 33% supported the efficacy and benefits of receiving systemic treatment before proceeding to the operating room.

An ongoing, randomized phase III trial, A021806, compares perioperative chemotherapy with adjuvant chemotherapy for resectable pancreatic cancer.¹⁰¹ Patients are randomized into an interventional arm, receiving 16 weeks of mFOLFIRINOX followed by surgery and 8 more weeks of mFOLFIRINOX. The control group will undergo surgery followed by 24 weeks of chemotherapy with mFOLFIRINOX. The primary objective of the trial is to compare OS between the 2 arms and, once resulted, may prove beneficial to further determine benefit of preoperative therapy.

Borderline Resectable PDAC

Preoperative therapy has been more frequently used for BR PDAC. Twenty-two clinical trials were examined, showing a median duration of treatment of 11 weeks (range, 2–17 weeks) (Fig. 2B^68–88,102). Similar to the results of the resectable PDAC trials, consensus from these studies was in favor of preoperative treatment for BR cases on the basis of increased resection rates, rates of R0 resection, progression-free survival, and OS. A subtle trend toward increasing treatment durations can be observed; however, in the last 2 to 4 years, there has remained a wide variety of lengths used with promising results throughout.

In 2016, the Alliance for Clinical Trials in Surgical Oncology Trial A021101 primarily focused on determining the feasibility of a prospective multicenter multimodality therapy for BR PDAC.⁸⁰ Twenty-two patients received mFOLFIRINOX every 2 weeks for a total of 8 weeks followed by 5.5 weeks of external-beam radiation therapy (RT) with capecitabine before resection. Preoperative therapy led to a substantial R0 resection rate with 46% of resected patients having a major or complete pathologic response and median OS of 21.7 months. This study demonstrated the feasibility of a systemic therapy first approach for BR PDAC.

Two years later in 2018, the PREP-01 study enrolled patients with both resectable and BR disease. In this single-arm phase II trial, patients received 6 weeks of preoperative therapy with gemcitabine and S-1 followed by resection and adjuvant gemcitabine. The primary end point of 2-year survival was significantly prolonged to 55.9% for patients who completed preoperative treatment and increased to 74.6% if adjuvant treatment was also completed. In comparison with trials with only gemcitabine-based adjuvant treatment, the survival rates of those completing preoperative treatment were comparable. Furthermore, 88% of patients were able to receive the entire regimen of preoperative treatment while only 68% had the capacity to complete adjuvant chemotherapy.⁶⁹ This observation does point to the difficulty faced by patients in completing postoperative systemic therapy as previously discussed.

In a randomized, multicenter phase II/III study performed by Jang et al⁷⁸ reported in 2018, patients were assigned to receive either 6 weeks of preoperative chemoradiotherapy with gemcitabine or surgery followed by chemoradiation. The trial closed early after preliminary review showed definitive evidence of improved survival outcomes in the preoperative treatment arm.⁷⁸

Also published in 2018 was a study performed by Tsai et al⁷³ focusing on molecular profiling via endoscopic ultrasound fine needle aspiration to help guide the selection of NAT. Of the 130 enrolled patients with resectable and BR disease, 95 of them had molecular profiling and were assigned to receive 8 weeks of either fluoropyrimidine-based or gemcitabine-based therapy as their preoperative treatment. Patients unable to be profiled were prescribed the same duration of treatment with either FOLFIRINOX or gemcitabine. Of the enrolled resectable cases, 92% completed all prescribed treatment and underwent successful resection alongside 74% of the BR cases. Accompanying these high resectability rates, the reported OS also proved encouraging with a median of 45 months after completion of treatment.⁷³

The PREOPANC trial published in 2020 was a multicenter phase III clinical trial where patients with resectable and BR PDAC were randomized to receive either 12 weeks of gemcitabine-based chemoradiotherapy before resection and adjuvant therapy with gemcitabine or a surgery-first approach, followed by adjuvant treatment with gemcitabine.⁷⁴ While the primary end point of OS showed no significant difference between the 2 arms, there was a significant improvement in R0 resection rates for those receiving preoperative treatment: 71% versus 40% in the surgery-first arm. In addition, disease-free survival and compliance with therapy completion also improved with neoadjuvant therapy.

Most recently, results from the Alliance A021501 phase II trial that evaluated preoperative mFOLFIRINOX with or without RT in BR PDAC were presented.⁸⁹ The primary end point of the study was the 18-month OS with the OS of each being compared with a historical control (50%). A total of 16 weeks of chemotherapy was administered in the chemotherapy-only arm, whereas 14 weeks of chemotherapy followed by stereotactic body RT or hypofractionated image-guided RT both in 5 fractions was administered in the chemoradiotherapy arm. Eligible patients underwent surgical resection followed by 8 weeks of systemic therapy with modified folinic acid, fluorouracil, oxaliplatin. While neoadjuvant chemotherapy improved the 18-month OS rate (68%) and median OS (31 months), preoperative chemoradiotherapy did not improve OS (47%) compared with historical data.

Locally Advanced PDAC

Given some of the success with systemic therapy in the preoperative setting for resectable and BR disease, this treatment approach is more recently being explored in LA cases traditionally deemed to be unresectable. Eighteen clinical trials were assessed.^{82–88,90–99,103} As would be expected because of a more advanced disease process, these trials did not show as significant of an increase in resection rates as compared with trials with resectable and BR cases. Despite this, a majority of the analyzed studies suggested an improvement in OS in addition to adequate disease control. Figure 2C indicates a slight increase in treatment duration over the past several years while still maintaining a substantial variation.

MARKERS OF TREATMENT RESPONSE TO NAT IN PDAC

A growing body of literature supports the use of NAT for nonmetastatic PDAC. However, many patients still develop early recurrence after preoperative therapy followed by surgery, and the optimal duration of preoperative treatment has yet to be determined. The question for clinicians is how to best use preoperative therapy strategies for each patient. Ideally, measures of treatment response would be incorporated to determine timing of surgery for patients receiving NAT. Unfortunately, there is no ideal measure of treatment response for PDAC. Computed tomography imaging is the most commonly used for staging and assessment of treatment response in pancreatic cancer.¹⁰⁰ Unfortunately, CT imaging is unable to clearly differentiate between tumor invasion and the inflammation and fibrosis present after use of chemotherapy.^104–106 Therefore, CT imaging cannot be relied upon to determine whether a patient has responded adequately or if they have minimal treatment response. Katz et al¹⁰⁷ showed that it is very rare to observe radiographic evidence of downstaging after NAT. Instead of relying on CT to determine the response of the primary tumor, the decision to proceed with operative management should be based on whether metastases have presented themselves. Ferrone et al³⁹ continued to support this line of thinking with a retrospective series that concluded imaging after completion of NAT was no longer able to predict the inability to achieve R0 resection. If a patient did not show signs of metastatic spread, then they should proceed with an attempt at resection.³⁹ However, these studies do not define the period to treat patients preoperatively before embarking on surgical management. For those who do have evidence of progression while receiving preoperative treatment, it is likely that their oncologic process will lead to a poor outcome. A series of trials by Evans et al¹⁰⁸ showed a median survival of 7 to 9 months for patients who had progression during NAT. For those patients, it is suggested to refrain from surgical intervention, thus sparing them the long recovery after a resection.

In some of the clinical trials analyzed hereinabove, CT imaging was used as a method to determine whether NAT was successful in downstaging the disease.^{82,83,87,91,99,102,103} Two studies had designated times throughout NAT where CT imaging would be assessed to determine whether the patient was ready for resection, causing a variation in the studies' treatment durations.^82,99 While this method may at first seem beneficial to ensure a patient is a surgical candidate before operation, the concern of imaging misinterpretation following NAT is necessary to consider. Therefore, while reimaging is needed to rule out metastatic spread, we believe that it should be reserved for that reason and not relied upon to determine the primary tumor's response to systemic therapy or ability to achieve R0 resection.

Positron emission tomography scans are commonly used in the staging process of a tumor; however, they are more costly and lack the evidence to become standard of care.¹⁰⁹ Recently, endoscopic ultrasound has gained attention for its potential for increased sensitivity—particularly as it relates to early disease with small tumor burden.¹¹⁰ However, this invasive procedure is not typically repeated after obtaining a diagnosis and is not frequently used for restaging after preoperative treatment.

With imaging being inconclusive in PDAC, there is great need for alternative methods to assess an individual patient's therapeutic response and make clinical decisions. This knowledge could not only aid in surgical planning but also help predict if a drug treatment and its duration are adequate. The most common biomarker associated with pancreatic cancer is carbohydrate antigen 19-9 (CA 19-9). Because of its high false-positive rate, CA 19-9 is not labeled a diagnostic marker.⁴ Rather, it is typically used as a prognostic tool in early stages of the disease and has been tracked as a marker of prognosis and treatment response.^2,25 While not all clinical trials focused on NAT of PDAC report the fluctuation in this biomarker, those who do most often report a decrease throughout therapy.¹¹¹ A decrease in CA 19-9 greater than 50% correlates to an improved OS rate, an improvement in resection rates, and histopathologic responses.²⁵ Other studies have indicated that a normalization of CA 19-9 is the strongest prognostic marker for long-term survival and can be a reliable correlate of response to NAT.^111,112 In an effort to combine information gained via imaging and biomarkers, Akita et al¹¹³ examined the relationship between CA 19-9, fluorodeoxyglucose–positron emission tomography (FDG-PET), and patients' responses to therapy. A statistically significant improvement in OS was found if the patient had a favorable response in both CA 19-9 and FDG-PET. Elevations in CA 19-9 were associated with a metastatic recurrence, whereas lack of a response seen via FDG-PET was associated with local recurrence. An unfavorable response to either method resulted in a poor OS rate.¹¹³ A recent study by Thalji et al¹¹⁴ examined the association between NAT duration, CA 19-9 response, and OS. A positive response, and especially a normalization, of this biomarker has been statistically associated with improved OS. Furthermore, patients receiving NAT greater than 4 months were statistically more likely to have a greater than 50% response in CA 19-9 compared with patients treated for a shorter period. Although further confirmatory studies are required, this information could prove key in determining optimal preoperative treatment durations for PDAC.¹¹⁴ Unfortunately, prognostic significance of CA 19-9 in PDAC has its limitations. While it has been shown to have strong prognostic value and association with OS, CA 19-9 is not elevated in up to 20% of patients and thus cannot be used to guide treatment decisions for all patients.^2,115

The microenvironment of PDAC is known to be heavily influenced by inflammatory mediators.¹¹⁶ When this relationship to NAT has been examined, an upregulation of inflammatory markers is associated with a poor response to preoperative treatment.¹¹⁷ Systemic immune inflammatory index (SII Index) is a biomarker previously used in the prognosis of other gastrointestinal malignancies and is currently emerging as a predictor of survival for PDAC when assessed at time of diagnosis. A patient's SII Index is calculated using their absolute platelet, neutrophil, and lymphocyte counts—laboratories frequently used in routine clinical care. Two separate studies conducted by Aziz et al¹¹⁸ and Jomrich et al¹¹⁹ concluded that an elevated preoperative SII Index was statistically associated with a decrease in OS for patients with resectable PDAC. A study focusing on the prognostic significance of SII Index after NAT performed by Murthy et al¹¹⁵ resulted in no significant correlation between pretherapy levels and clinical outcomes. However, an increased posttreatment index greater than 900 was found to be a negative prognostic marker of OS. Furthermore, they found a posttreatment reduction of at least 80% correlated with CA 19-9 response.¹¹⁵ With the inability to use CA 19-9 as a prognostic tool in some cases, these findings raise the possibility that these 2 markers together could prove to be prognostic for a greater percentage of patients with PDAC.

In another effort to identify additional markers of treatment response, a recent study focused on correlating circulating tumor cells (CTCs) with NAT and disease recurrence. Patients receiving NAT had a significant reduction in the number of CTCs after administration, and their quantity continued to drop after resection.¹²⁰ This study concluded that the preoperative number of CTCs was the only predictor for recurrence of malignancy within 12 months of resection. In 2021, Hata et al¹²¹ studied circulating tumor DNA to observe its correlation with patterns of metastatic spread. They found not only a remarkably high prevalence of circulating tumor DNA in patients with evident radiographic metastases but also a significantly higher prevalence in patients with occult disease not initially seen on imaging.¹²¹ In 2020, Nicolle et al¹²² presented GemPred, a RNA-based whole transcriptome signature that was shown to act as a predictor of tumor sensitivity for patients receiving gemcitabine. They studied it in an adjuvant setting; however, there is potential for the discovered data to be assessed with a neoadjuvant setting in mind.¹²² Though not routinely measured markers of PDAC at this time, CTCs, their DNA, and tumor RNA may be critical components of determining treatment duration for patients, particularly seeing how this malignancy often has micrometastasized upon discovery and thus should be treated systemically as quickly as possible. Finally, a method to observe the effects of NAT that has perhaps the strongest link to OS is through analyses of histopathologic treatment response. However, this is obviously limited for clinical decision making, as the patient must proceed to surgery before knowing this information.

TOWARD A PERSONALIZED APPROACH TO TREATMENT DURATION

Through the retrospective studies and clinical trials analyzed, a dramatic variability in NAT durations exists. Multiple durations have led to encouraging resection rates, R0 resection rates, and OS with no single duration proving significantly superior. Importantly, a substantial number of patients progress on preoperative treatment or do not make it to surgery because of toxicity. Many published studies fail to report an intention to treat analysis, reporting only patients who proceed through surgical resection, missing a critical cohort of patients in their neoadjuvant outcomes. Patients who succumb to chemotherapy toxicity and failure to thrive during preoperative treatment have the potential to miss out on potentially curative surgery. As a result, defining the duration of neoadjuvant chemotherapy for PDAC is critically important and the need for continuing prospective studies is apparent. As seen in this review, no single duration of preoperative therapy has proven itself worthy of becoming the standard approach. Because of the wide variation in treatment lengths providing positive results, clinical decision making regarding preoperative treatment duration should be made on an individual basis with the help of imaging, biomarkers, and an individual's physical condition upon presentation (Fig. 3). The field needs to move toward a personalized-medicine approach within a multidisciplinary team, rather than a predetermined, one-duration-fits-all prescription of 2, or 4 or 6 months of preoperative chemotherapy before surgical resection. Success using such an approach requires the development of novel measures of treatment response which to date are limited. This is an essential area of research for future studies to more appropriately use preoperative therapy to selectively identify the cohort of patients most likely to benefit from surgical resection, avoid surgery in those who will succumb to early postoperative progression, and limit the number of patients who miss an opportunity for surgical resection because of toxicity from neoadjuvant chemotherapy.

FIGURE 3.

Modalities of measuring neoadjuvant treatment response to help guide a personalized approach to clinical decision making and preoperative treatment duration.

CONCLUSIONS

Neoadjuvant treatment for PDAC is gaining popularity both in literature and clinical practice. This trend is driven by several factors, including the potential for higher resectability rates and increased percentage of patients completing multimodality therapy, which has the potential to translate to improved OS. Limitations in treatment response and identification of the optimal treatment regimen and duration are critical to overcome in the near future to improve outcomes for this devastating disease. While recent research into biomarkers, newer imaging modalities, and novel therapies has given hope for an improvement in the prognosis of this disease, there is much work to be done to achieve a drastic decrease in its mortality.