Locally Advanced Pancreas Cancer, Is there a Role for Surgery?

Introduction

Pancreatic cancer (in this review, ductal adenocarcinoma) is the 10th most common cancer in the United States but trails only lung and colorectal cancers as the third leading cause of cancer deaths in the United States.^1-3 Surgical resection is the only required component of potentially curative multimodality treatment. Due to absence of effective screening, only approximately 20% of patients have resectable tumors at presentation.³ Locally advanced (LA) (30%-40%) or metastatic disease (50%-55%) are most commonly found at presentation and are associated with worse survival.^3-5 For initially unresectable or locally advanced pancreatic cancer (LAPC), five-year overall survival (OS) is <5%, motivating many patients and clinicians alike to pursue treatment courses aimed at downstaging toward resectability.^6,7

Over the past two decades, advances in cytotoxic chemotherapy regimens within multimodality treatment plans have improved the five-year overall survival (OS) to 12% from a long period of single-digit survival.^2,8-10 These advances have also helped convert some formerly unresectable patients, like those with de novo LAPC, into surgical candidates with a reasonable attempt at margin-negative (R0) resection.

Definitions

LAPC is defined according to the degree of tumor involvement with major vasculature (e.g., mesoportal venous encasement beyond standard reconstruction techniques and/or arterial encasement of the celiac trunk, hepatic artery, and/or superior mesenteric artery) (Table 1).^11-13

Table 1:

Anatomic Criteria for Borderline Resectable and Locally Advanced Pancreatic Cancer

Resectable	Borderline Resectable		Locally Advanced	Metastatic
	Segmental encasement or abutment of the common hepatic artery, possibly requiring resection and reconstruction	Celiac Axis or Common Hepatic Artery	Encased, with technical reconstruction precluded by extension to the celiac origin or confluence with splenic and left gastric arteries
	≤180° abutment; tumor-infiltrated tissue can be divested off SMA	SMA	>180° encasement
	Segmental encasement or occlusion with adequate proximal and distal landing zones for resection and reconstruction	SMV/PV	Occlusion location or distance precluding reconstruction

CT: computed tomography; SMA: superior mesenteric artery; SMV: superior mesenteric vein; PV: portal vein.

There are no formal guidelines regarding the “standard” approach to managing these patients, with many still subjected to attempts at upfront surgery. Perhaps the only agreement in more recent years is that upfront surgery for LAPC is ill-advised oncologically, due to local and distant disease considerations. Not only do initial staging scans underappreciate the true stage (micrometastatic disease is common in all clinical stages and likely more in LAPC), but an upfront operation (aborted or completed) may preclude timely initiation of systemic therapy. Additionally, without downsizing, the chance for margin-positive resection is quite high, making many of the arguments generally accepted for avoiding upfront surgery in borderline resectable pancreatic cancer (BRPC) even more apropos in LAPC. Consensus does not exist regarding the timing and role of surgery after an induction course of chemotherapy and/or (chemo)radiation therapy (RT), but many surgeons are biased toward surgical attempts when deemed safe.^9,10,13

Therapeutic Options

Utilization of multi-agent chemotherapy in LAPC is associated with higher rates of progression to surgery and resectability, with subsequent rates of R0 resection comparable to those of patients with initially resectable disease.⁴ FOLFIRINOX (fluorouracil [5-FU], leucovorin, irinotecan, oxaliplatin) and gemcitabine-based regimens are the primary systemic therapies, as of 2024. Historically, data for LAPC were extrapolated from studies conducted in the setting of BRPC or metastatic disease. Findings from the ACCORD trial performed in patients with metastatic disease demonstrated a clear survival benefit with use of FOLFIRINOX versus gemcitabine, leading to a preferential use of FOLFIRINOX, regardless of planned attempted resection.¹⁴ Recent trials evaluating the efficacy of these regimens in LAPC specifically have found that gemcitabine-based regimens such as gemcitabine-nab-paclitaxel (GNP) demonstrate both efficacy and acceptable toxicity.^15-18 A survival advantage with use of FOLFIRINOX may have been demonstrated in unresected patients with LAPC, but studies such as SWOG S1505 and others demonstrate similar OS outcomes between modified (reduced-dose) FOLFIRINOX (four cycles of 5-fluorouracil, 2400mg/m²; leucovorin calcium, 400 mg/m²; irinotecan hydrochloride, 180 mg/m²; and oxaliplatin, 85 mg/m²) and GNP among resectable patients, with GNP showing a higher pathological response rate.^19-21 Overall resection rates are higher for patients who receive FOLFIRINOX alone, however, rates of R0 resection and surgical conversion rates are comparable between those who receive FOLFIRINOX alone, GNP alone, and GNP with sequential FOLFIRINOX.^16,17,19 These findings reinforce the role of surgery rather than the chemotherapy regimen as the defining difference in OS after induction chemotherapy.

The use of RT in LAPC remains somewhat controversial.²² Variable outcomes regarding the addition of RT have been demonstrated in clinical trials. The Alliance A021501 trial, which compared OS after neoadjuvant modified FOLFIRINOX versus modified FOLFIRINOX plus CXRT in patients with BRPC, did not demonstrate improved survival among those who received RT. Complete pathologic response, however, was observed in two patients who received RT, leading to the overall recommendation that RT may be an effective treatment option in conjunction with modified FOLFIRINOX.²³

There are data to suggest improved locoregional control and OS with RT after multiagent induction chemotherapy.^24-27 Improved OS and R0 resection rates were observed in the PREOPANC-1 trial comparing gemcitabine-based CXRT to upfront surgery in localized pancreatic cancer, though this regimen did not include induction chemotherapy in either arm.²⁸ A French trial comparing outcomes of FOLFIRINOX versus FOLFIRINOX and CXRT in patients with BRPC or LAPC demonstrated increased tumor downstaging, increased R0 resection margins, and increased OS in the CXRT group. Of note, patients receiving CXRT also underwent a >3 month longer period of induction therapy than those who received FOLFIRNOX alone.²⁹ Other studies have demonstrated improved R0 resection rates in patients who receive induction chemotherapy and RT, particularly when the duration of chemoradiation was tailored to the degree of radiographic vascular involvement.^30,31 Clinical trials to identify optimal treatment strategies for localized pancreatic cancer, such as the PIONEER-Panc and PREOPANC-4 trials, are ongoing.^32,33

Treatment Sequencing

At present, patients with LAPC are usually treated with 4-6 months of multi-agent chemotherapy, often followed by a course of RT depending on findings at restaging. Use of induction therapy in place of de novo surgery decreases the risk of positive resection margins and early treatment failure.^22,34 Due to the opportunity to elicit a treatment response improving the potential for resectability following induction therapy in LAPC, immediate condemnation to a palliative-only approach should also be avoided.^22,34-36

Chemotherapy

Use of (modified) FOLFIRINOX and gemcitabine-based chemotherapy regimens have demonstrated great efficacy with acceptable toxicities when used for induction therapy in patients with LAPC.^18-20,35,36 Studies have demonstrated a 91% completion rate of these regimens when used preoperatively, compared to less than 60% in the adjuvant setting.^20,35,37 Even among patients who require chemotherapy switch, whether due to disease progression, insufficient tumor response, or chemotherapy-related toxicity, upwards of 70% undergo resection with similar perioperative outcomes.^37,38 Given the extensive benefits of induction chemotherapy without compromising OS or margin-negative resectability, induction chemotherapy should be administered to all patients with LAPC, toward a goal of eventual attempted resection.

Radiation Therapy

Despite controversy regarding utility of RT, current data favors its role preoperatively as opposed to the adjuvant setting and following induction therapy versus in place of systemic therapy.^28,39-42 Extended duration chemotherapy prior to RT is necessary to ensure truly localized disease and to fully characterize disease response.^38,42,43 Following completion of systemic therapy, administration of conventionally fractionated RT, multifractionated stereotactic body radiation therapy (SBRT), or dose-escalation CXRT has exhibited improved locoregional control, though no clearly defined OS benefit exists.^24-27,40 Proposed technological advances in delivery of SBRT using MR-based and cone beam CT show promise in maintaining or increasing potency while mitigating dose-limiting gastrointestinal toxicity ⁴⁴

Defining Response

As complete pathologic response in the setting of PDAC is extremely rare (approximately 4% of resected tumors), the goal of induction therapy is to convert these patients to resectability by tumor downstaging or adequate tumor response.³³ Reported rates of tumor downstaging in LAPC are 22%-32%, thus most clinicians assess for a tumor response predictive of an R0 resection prior to recommending surgery.^22,33,45,46

The definition of an adequate response in LAPC varies, in part due to historical reliance on absence of disease progression rather than response in deciding to proceed with surgery.²² Consequently, a fluid adaptation of treatment regimen and duration has arisen, presenting an opportunity to improve selection of surgical candidates by incorporating evaluation of tumor response.

Response may be classified according to tumor biology, tumor anatomy, or both. Several tumor response scoring (TRS) systems exist, though these are largely based on histopathological findings and are often used to define indications for adjuvant treatment after tumor resection.^47,48 The Response Evaluation Criteria In Solid Tumors, or “RECIST,” criteria, characterizes tumor response according to tumor shrinkage or disease progression. Originally developed to standardize definitions of response used in reporting outcomes of anticancer drug trials, many oncologists use these guidelines in clinical decision-making as well. By RECIST criteria (version 1.1), measurable, “target” lesions may demonstrate any of four responses: complete response, partial response, progressive disease, or stable disease.^49,50 In surgical decision-making for LAPC, progressive disease precludes curative intent surgery, as local progression often occurs concurrently with distant progression. The remaining three responses suggest more favorable, or at least stable, tumor biology,

Using pre- and post-treatment comparisons, tumor anatomical response may be assessed radiographically in several ways: by tumor volume, tumor attenuation, or the tumor vessel interface (TVI). Radiographic tumor volume may be calculated by inputting measurements of the tumor’s longest (L) and shortest (W) axial diameters and craniocaudal (H) axes into the formula for ellipsoid volume (π/6 × L × W × H) (Figure 1). The post-treatment change in volume may be calculated as a percentage of the baseline volume.^51-53

Figure 1.

Pre-treatment imaging demonstrates tumor measuring (A) 2.2 mm (l) x 2.1 mm (w) in axial dimensions and (B) 1.7 mm (h) in craniocaudal dimensions on coronal view. Post-treatment imaging demonstrates slight decrease in tumor volume, with tumor measuring (C) 1.8 mm (l) x 1.7 mm (w) in axial dimensions and (D) 1.6 mm (h) in craniocaudal dimensions on coronal view.

Tumor attenuation may also be used to characterize response. While a correlation between tumor volume and margin status in patients with LAPC has not been demonstrated, increased tumor attenuation on CT following induction therapy has been shown to positively correlate with R0 resection.⁵⁴

Other radiographic findings previously proposed as indicators of tumor response include the tumor/parenchyma interface and regression of tumor-vessel contact, however, treatment-related changes may create some difficulty distinguishing viable tumor from the surrounding tissue, leading to overestimation of tumor size and vascular contact.^55-57

In addition to radiographic measures of response, trends in serum cancer antigen (CA) 19-9 (when available) should be used to biologically assess treatment response.^41,58Normalization of CA 19-9 (≤37.0 U/mL) in patients with elevated pre-treatment levels and maintained normalcy in those with a normal pretreatment CA 19-9 pretreatment are associated with major pathologic response.⁵³ Serum CA 19-9 values <91.8 kU/L following induction therapy predict both successful resection and OS.⁵⁹ Likewise, a post-treatment reduction in serum CA 19-9 to <50% of the baseline value is also associated with increased likelihood of successful resection.^15,59 Thus, there are a number of CA19-9 cutoffs, but the downward response is what portends a favorable postoperative oncologic outcome.

In patients with a normal or undetectable baseline serum CA 19-9, trends in serum carcinoembryonic antigen (CEA) have demonstrated promise in predicting clinical and survival outcomes in patients after induction therapy.^60,61 Elevated baseline CEA levels (≥5 ng/mL) have been associated with higher incidence of disease progression at restaging and lower rates of surgical resection. Post-treatment CEA normalization has also been associated with improved OS.⁶⁰ When evaluated in combination with CA 19-9, CEA has the potential to better characterize treatment response and prognosis.^60,62,63

Discussion

Following an adequate response to induction therapy and favorable tumor anatomy, patients with LAPC should be considered for curative intent surgery with special considerations.

Role of staging laparoscopy

To evaluate for occult metastatic disease in this high-risk population, staging laparoscopy should be considered. An estimated 18%-19% of patients with LAPC have occult metastases identified on staging laparoscopy prior to systemic therapy.^64,65 As one of the goals of systemic therapy is elimination of micrometastases and reduction in overall tumor burden, staging laparoscopy following completion of induction therapy is more useful for determining surgical candidacy or need for ongoing treatment. While laparoscopy may be performed at the time of intended curative resection or as a separate, staged procedure in the preoperative period between induction therapy and attempted resection, the potential need for additional therapy if occult metastases or positive cytology are identified, along with the time and financial costs of an aborted procedure, should be considered.

Decision for surgery

Exploration in carefully selected patients is not associated with worse OS when resection cannot be completed.^60,61 Proper patient selection after induction chemotherapy, however, is key to optimizing the A-B-C clinical staging factors (Table 2), thus increasing the probability of a successful resection.^66-69 In ideal surgical candidates, optimization would manifest in the following ways:

Table 2:

Anatomic and Patient-Specific Factors for Resectability in Pancreatic Cancer

	A (Anatomy)	B (Biology)	C (Condition)
Potentially Resectable	No radiographic evidence of tumor interface with CA, SMA, or CHA Between 0°-180° tumor interface of PV or SMV, without venous contour irregularity	Normal or mildly elevated CA19-9 No clear evidence of regional lymphadenopathy or distant metastatic disease	ECOG performance status 0-1 Absence of major comorbidities
Borderline Resectable	<180° tumor interface with CA or SMA Short-segment interface with CHA, amenable to reconstruction >180° tumor interface with PV or SMV +/− reconstructable occlusion	Moderately elevated CA19-9        OR Confirmed regional lymphadenopathy        OR Radiographic evidence suggestive (but not diagnostic) of metastatic disease	ECOG performance status 2-3 Multiple comorbidities amenable to optimization and prehabilitation
Unresectable	>180° tumor interface with CA or SMA Tumor involvement or occlusion precluding PV or SMV reconstruction	Confirmed extra-regional lymphadenopathy	ECOG performance status ≥3 Multiple comorbidities without capacity for optimization

CA: celiac axis; SMA: superior mesenteric artery; CHA: common hepatic artery; SMV: superior mesenteric vein; PV: portal vein; CA 19-9: carcinoembryonic antigen 19-9; ECOG: Eastern Cooperative Oncology Group

• maximized anatomic downsizing to reduce or even eliminate one or both venous and/or arterial resections (A-anatomy),

• proving to the greatest possible extent the absence of metastatic disease that could manifest shortly after resection (B-biology),

• and optimization of comorbidities during the period of induction chemotherapy with prehabilitation and partnering services, such as Geriatric Oncology (C-condition).

In such patients who meet these criteria, it is reasonable to attempt surgical resection.

Venous resection and reconstruction

More than one-third of cases require vascular reconstruction.⁷⁰ Venous resections and reconstructions are often performed ubiquitously in pancreatic surgeries.^13,71,72 Characterization of the relationship between the tumor and mesoportal veins on preoperative imaging predicts the need for venous resection and histologic evidence of vessel invasion. Using a cutoff value of 180°, a greater TVI is associated with a higher positive predictive value for venous resection and with decreased progression-free and OS.⁷³ The need for venous resection should be anticipated during preoperative surgical planning, with extensive consideration to the feasibility and availability of reconstruction.

Arterial resection and revascularization

Significant perioperative morbidity and mortality often prohibits arterial resection and revascularization. In meta-analyses, median perioperative morbidity is 53% in patients who undergo arterial resection, of which 38% is directly attributable to the resection.^43,74A five-times increased risk of perioperative mortality has also been demonstrated in patients who undergo arterial resection.⁷⁴ In many cases, arterial resections require high complexity combination resections, including resection of the superior mesenteric artery and/or the common or proper hepatic arteries (Figure 2). They may also require multiple organ resections (e.g., colon, stomach, etc.) and concomitant venous resections, further compounding the perioperative morbidity and mortality risks.^42,43

Figure 2.

Restaging imaging for LAPC after multiple cycles of FOLFIRINOX and chemotherapy switch to GNP. Tumor encasement of the celiac artery (CA), origin of the splenic artery (SA), and the common hepatic artery (CHA) is shown. Common bile duct (CBD) and portal vein (PV) stents are in place. Tumor delineated by dotted white line and measures 46.7 mm (l) x 29.6 mm (w).

In some patients, reasonable attempt at arterial resection and reconstruction is required due to anatomic variation, acquired conditions (e.g., stenoses, aneurysm, atherosclerotic disease), or extent of arterial involvement.⁴³ In these patients, differences in morbidity rates between operation types and resected artery should be noted. In a recent study evaluating outcomes after celiac artery resection during distal or total pancreatectomy, no worsened morbidity and mortality was observed in patients who underwent celiac artery resection following appropriate induction therapy.⁴² Arterial resection during pancreatoduodenectomy, however, is associated with much higher risks due to risk of anastomotic leaks, and, for this reason, is performed more infrequently.^43,75,76

Despite these outcomes, if potential morbidity and mortality has been thoroughly weighed against oncologic benefit, rigorous patient selection should occur with optimization prior to planned resection. Regardless of pancreatectomy type, anticipated arterial resection should be preceded by extended induction chemotherapy and potentially CXRT, with no evidence of disease progression (or, ideally, downsizing) on restaging.^38,42,43 In ideal patients, normalization of CA 19-9 after induction therapy is also observed. ⁴⁶ In recent series describing arterial resection for LAPC, patients were relatively young in their 50’s, and, although not explicitly reported, presumably with adequate performance status to undergo several cycles of induction chemotherapy and CXRT.^42,43,74,75

Summary

With careful patient selection, medical optimization to reduce surgical risk, diligent attention to tumor response after induction chemotherapy, and extensive preparation for planned vascular reconstruction, there is a clear role for surgery in improving oncologic outcomes for patients with LAPC.

Key Points:

• Commonly grouped together, borderline resectable and locally advanced pancreatic cancer should be categorized and treated as distinct clinical stages.

• While radiation therapy is associated with local control, additional studies are needed to clearly define guidelines for its use in locally advanced pancreatic cancer.

• Radiographic and clinical response to induction therapy should be carefully assessed prior to attempted resection.

• If resection is attempted, margin-negative resection should be the goal.

• In carefully selected patients, exploration with nontherapeutic laparotomy is not associated with worse overall survival.

Synopsis:

Locally advanced pancreatic cancer (LAPC) represents a unique clinical scenario in which the tumor is considered localized but unresectable due to anatomical factors. Despite a consensus against upfront surgery, no standard approach to induction therapy exists for patients with LAPC. Extended systemic therapy has shown promise in establishing tumor response and remains standard of care. While associated with improved local control, the timing and role of radiation therapy remains in question. Following adequate response to induction chemotherapy, a safe attempt at margin-negative resection can be considered. Special attention should be given to required vascular skeletonization and/or resection with reconstruction.

Clinics Care Points.

• While there is no role for upfront surgery in locally advanced pancreatic cancer, a palliative-only approach to treatment should be avoided at diagnosis

• Additional studies are needed to define the role of radiation therapy as it relates to induction therapy in LAPC.

• Attempted margin-negative resection is safe and reasonable in carefully selected patients with a demonstrated radiographic and clinical response to induction therapy.

• Prior to attempted resection, staging laparoscopy after completion of induction therapy is a useful tool to assess for occult metastases in this high-risk population.

• The likely need for vascular resection and reconstruction during attempted resection should be thoroughly considered in all patients with LAPC.

Abbreviation/Glossary list:

LAPC

locally advanced pancreatic cancer

BRPC

borderline resectable pancreatic cancer

RECIST

Response Evaluation Criteria in Solid Tumors

OS

overall survival

RT

radiation therapy

CXRT

chemoradiation

SBRT

stereotactic body radiation therapy

SMA

superior mesenteric artery