Residency · Residency · Radiation Oncology

Pancreatic Cancer: Role of Radiation in Borderline Resectable and Locally Advanced Disease

Overview

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers, with a five-year overall survival (OS) rate of approximately 10-12% across all stages. Surgical resection remains the only potentially curative option, yet only 15-20% of patients present with disease amenable to surgery. PDAC is classified into four categories based on resectability: resectable, borderline resectable (BR), locally advanced (LA), and metastatic. The role of radiation therapy in PDAC is highly debated within gastrointestinal oncology due to conflicting results from clinical trials and differing opinions among specialties. Stereotactic body radiation therapy (SBRT) has gained popularity as an alternative to conventional chemoradiation, offering shorter treatment durations and potentially improved local tumor control.

Disease Categories

Resectable

Resectable pancreatic cancer is defined by the absence of arterial involvement, specifically no contact with the celiac axis, superior mesenteric artery (SMA), or common hepatic artery. Venous involvement is either absent or limited to 180 degrees or less contact with the superior mesenteric vein (SMV) or portal vein without any contour irregularity. Radiation therapy generally does not play a role in resectable disease. The standard approach involves neoadjuvant chemotherapy—commonly FOLFIRINOX or gemcitabine with nab-paclitaxel—followed by surgical resection.

Borderline Resectable

Borderline resectable disease involves limited arterial contact, defined as 180 degrees or less with the SMA or celiac axis, or contact with the common hepatic artery that does not extend to the proper hepatic artery or celiac axis. Venous involvement is more extensive, including greater than 180 degrees contact with the SMV or portal vein, contour irregularity, or thrombosis that remains amenable to vascular reconstruction. In this setting, radiation therapy has its strongest indication. Neoadjuvant radiation—either chemoradiation (CRT) or SBRT—is combined with chemotherapy to improve the chances of achieving a margin-negative (R0) resection.

Locally Advanced (Unresectable)

Locally advanced pancreatic cancer is characterized by extensive arterial involvement, such as more than 180 degrees contact with the SMA or celiac axis, or invasion of the aorta. Venous involvement includes unreconstructable occlusion of the SMV or portal vein. Radiation therapy is typically employed after induction chemotherapy as consolidation or for local control in patients who do not develop distant metastases. Although conversion to resectability is possible, it is uncommon.

Clinical Trial Evidence

LAP07 (Hammel et al., 2016)

The LAP07 trial was a phase III study involving patients with locally advanced pancreatic cancer. After four months of gemcitabine with or without erlotinib, patients were randomized to continue chemotherapy or receive chemoradiation therapy (CRT) consisting of 54 Gy with concurrent capecitabine. The trial found no significant difference in overall survival between the two arms (15.2 months vs. 16.5 months). However, CRT improved local tumor control and reduced local progression rates (32% vs. 46%). The lack of OS benefit was attributed to the predominance of distant metastases as the cause of death. This trial suggests that while radiation improves local control, it does not overcome the systemic nature of pancreatic cancer.

Alliance A021501 (Katz et al., 2022)

Alliance A021501 was a phase II trial comparing neoadjuvant modified FOLFIRINOX (mFOLFIRINOX) alone for eight cycles versus mFOLFIRINOX for seven cycles followed by hypofractionated radiation therapy (either 25 Gy in 5 fractions or 33.5 Gy in 5 fractions via SBRT) in borderline resectable PDAC. The radiation arm was closed early due to a lower R0 resection rate and worse 18-month OS (66.7% in the CRT arm vs. 93.1% in the chemotherapy-alone arm). These controversial results have been criticized for heterogeneous radiation techniques, a short induction chemotherapy period before radiation, and a small sample size. Some interpret this as evidence against radiation in borderline resectable pancreatic cancer (BRPC), while others argue that the trial design was flawed and inconclusive.

PREOPANC (Versteijne et al., 2022)

The PREOPANC trial was a phase III study comparing neoadjuvant gemcitabine-based chemoradiotherapy (36 Gy in 15 fractions with concurrent gemcitabine) to upfront surgery in patients with resectable and borderline resectable PDAC. The trial demonstrated a significant improvement in 5-year overall survival with neoadjuvant CRT (20.5%) compared to upfront surgery (6.5%), with a hazard ratio of 0.73 (p=0.025). The R0 resection rate was also higher in the neoadjuvant CRT group (71% vs. 40%). This represents the strongest randomized evidence supporting neoadjuvant CRT in (borderline) resectable PDAC. The subsequent PREOPANC-2 trial compared neoadjuvant CRT to neoadjuvant FOLFIRINOX and found no difference in overall survival between these approaches.

ESPAC-1 and ESPAC-3 (Adjuvant Setting)

In the adjuvant setting, the ESPAC-1 trial found that adjuvant chemoradiotherapy (using a split-course 40 Gy in 20 fractions) was detrimental compared to adjuvant chemotherapy alone. However, this trial has been criticized for outdated radiation techniques, including split-course radiation and lack of quality assurance, which do not reflect modern radiation delivery. ESPAC-3 compared adjuvant gemcitabine to 5-fluorouracil/leucovorin without a radiation arm and found no difference in outcomes between the chemotherapy regimens.

SBRT for Pancreatic Cancer

Rationale

SBRT offers several advantages over conventional chemoradiation. It delivers treatment over a shorter period, typically 1 to 5 fractions instead of 25 to 28 fractions. SBRT allows for a higher biologically effective dose (BED) to the tumor with steep dose gradients that spare adjacent organs at risk (OARs). This approach minimizes treatment breaks from systemic therapy, which is critical in a disease with high systemic relapse rates.

Dose-Fractionation

The most common SBRT regimen for pancreatic cancer is 33 to 40 Gy delivered in 5 fractions. For tumors abutting sensitive structures such as the duodenum or stomach, a lower dose of 25 Gy in 5 fractions is used to reduce toxicity. Single-fraction 25 Gy SBRT remains investigational. Ablative doses with a BED10 greater than 70 Gy have been associated with improved local control.

GI Toxicity Concerns

The duodenum is the dose-limiting organ at risk due to risks of ulceration, perforation, and hemorrhage. The stomach must be similarly spared. Key dose constraints include a maximum duodenal or gastric dose below 35 Gy in 5 fractions and a volume receiving 33 Gy (V33) of less than 1 cc. Fiducial markers or endoscopic clips are used for precise image guidance and tumor localization. Motion management strategies such as abdominal compression, breath hold, or real-time tracking are essential to minimize dose to adjacent organs.

Institutional Data

Johns Hopkins reports using SBRT at 33 Gy in 5 fractions following induction chemotherapy for locally advanced pancreatic cancer, achieving a median overall survival of 18.4 months and one-year local control of 78%. Stanford has explored single-fraction 25 Gy SBRT, which showed high local control but raised concerns about gastrointestinal toxicity. MD Anderson has pioneered adaptive SBRT with online plan adaptation to account for daily anatomic changes, enhancing precision and safety.

Radiation Therapy Technique

Conventional CRT

Conventional chemoradiation typically involves a dose of 50.4 Gy delivered in 28 fractions of 1.8 Gy each, with concurrent capecitabine or 5-fluorouracil. The target volume includes the gross tumor volume (GTV), encompassing the pancreatic mass and involved lymph nodes, plus a clinical target volume (CTV) margin of 1 to 1.5 cm, carefully respecting the stomach and duodenum. Intensity-modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT) is preferred to reduce gastrointestinal toxicity. Four-dimensional computed tomography (4D-CT) is used to assess tumor motion, with either an internal target volume (ITV)-based approach or abdominal compression employed for motion management.

SBRT

SBRT requires mandatory 4D-CT imaging. The GTV is defined by the pancreatic mass on contrast-enhanced CT or MRI, correlated with PET-CT when available. The ITV encompasses the GTV across all respiratory phases. The planning target volume (PTV) is generated by adding a 2 to 5 mm margin to the ITV, depending on motion management and image-guided radiation therapy (IGRT) capabilities. Daily cone-beam CT (CBCT) or CT-guided radiation therapy (CTGRT) is used for image guidance. Fiducial markers, typically gold seeds placed endoscopically, enable real-time tumor tracking. Emerging MR-linac technology allows for real-time visualization and gating on the tumor, facilitating dose escalation and improved sparing of gastrointestinal structures.

OAR Constraints (5-Fraction SBRT)

Dose constraints for organs at risk in a 5-fraction SBRT regimen include limiting the duodenum and stomach to a maximum dose below 35 to 38 Gy and a volume receiving 33 Gy (V33) of less than 1 cc. The small bowel volume receiving 25 Gy (V25) should be less than 20 cc. For kidneys, the volume receiving 12 Gy (V12) should be less than 25% bilaterally. The liver volume receiving 12 Gy (V12) should be less than 50%, and the spinal cord maximum dose should be below 25 Gy.

<image>An axial CT image showing SBRT dose distribution for a borderline resectable pancreatic head tumor. The GTV (red) abuts the superior mesenteric vein (labeled). The 33 Gy prescription isodose (green) tightly covers the PTV. The duodenum (orange contour) is in close proximity, with the 25 Gy isodose line (yellow) demonstrating the steep dose gradient protecting the duodenal wall. Dose-volume histogram inset shows duodenal V33 <1 cc and liver/kidney dose compliance.</image>

<image>A clinical decision algorithm for the role of radiation in pancreatic cancer. Starting with "Pancreatic cancer staging," branches into resectable (surgery-first or neoadjuvant chemo, RT rarely used), borderline resectable (neoadjuvant chemo then CRT or SBRT then surgery), locally advanced (induction chemo 4-6 months, reassess: if no progression, consider CRT/SBRT for local control; if progression, continue systemic therapy or BSC), and metastatic (systemic therapy only, palliative RT for pain). Key trial results (PREOPANC, LAP07, Alliance A021501) are annotated at relevant decision points.</image>

<image>A side-by-side comparison of conventional CRT (50.4 Gy/28 fx) versus SBRT (33 Gy/5 fx) for a locally advanced pancreatic body tumor. Both plans are shown in axial and coronal views. The CRT plan has a larger treatment volume but lower dose per fraction. The SBRT plan has a smaller PTV with steep dose gradients. Treatment duration (5.5 weeks vs. 1 week), BED10, and GI toxicity rates from published series are compared in a table below the images.</image>

Key Clinical Pearls

The role of radiation in pancreatic cancer remains highly debated. Radiation therapy provides effective local tumor control but has not consistently improved overall survival because pancreatic cancer is characterized by early systemic dissemination. The PREOPANC trial offers the strongest randomized evidence supporting neoadjuvant chemoradiation for borderline resectable pancreatic cancer, demonstrating a significant five-year overall survival benefit (20.5% vs. 6.5%). The Alliance A021501 trial should be interpreted with caution due to early closure of the radiation arm and heterogeneous radiation techniques, limiting its ability to definitively address radiation's role in borderline resectable PDAC. When employing SBRT, the duodenum is the critical dose-limiting structure; maintaining a V33 of less than 1 cc in a 5-fraction regimen is essential, and the use of fiducial markers with daily cone-beam CT is mandatory for safe delivery. Induction chemotherapy for four to six months with regimens such as FOLFIRINOX or gemcitabine/nab-paclitaxel is crucial for patient selection. Only patients who do not develop distant progression during induction should proceed to radiation, ensuring that the tumor biology is favorable enough to benefit from local therapy.

References

• Hammel P et al. "Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: the LAP07 randomized clinical trial." JAMA. 2016;315(17):1844-1853.
• Katz MHG et al. "Alliance A021501: preoperative mFOLFIRINOX or mFOLFIRINOX plus hypofractionated radiation therapy (RT) for borderline resectable (BR) adenocarcinoma of the pancreas." J Clin Oncol. 2022;40(suppl 17):LBA4.
• Versteijne E et al. "Neoadjuvant chemoradiotherapy versus upfront surgery for resectable and borderline resectable pancreatic cancer: long-term results of the Dutch randomized PREOPANC trial." J Clin Oncol. 2022;40(11):1220-1230.
• Rudra S et al. "Using adaptive magnetic resonance image-guided radiation therapy for treatment of inoperable pancreatic cancer." Cancer Med. 2019;8(5):2123-2132.
• Herman JM et al. "Phase 2 multi-institutional trial evaluating gemcitabine and stereotactic body radiotherapy for patients with locally advanced unresectable pancreatic adenocarcinoma." Cancer. 2015;121(7):1128-1137.

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