Neoadjuvant Therapy for Borderline Resectable Pancreatic Head Adenocarcinoma: Problem-Solving Exam Question
Clinical Vignette
A 62-year-old man presents with progressive jaundice, 15-pound weight loss over 2 months, and dark urine. His past medical history includes well-controlled hypertension on lisinopril. He remains active, working full-time as an accountant (ECOG performance status 1).
Laboratory findings:
- Total bilirubin: 8.2 mg/dL
- CA 19-9: 850 U/mL
- Normal creatinine and liver transaminases (2× upper limit of normal)
Imaging (pancreatic protocol CT):
- 3.2 cm hypodense mass in the pancreatic head
- Superior mesenteric artery (SMA) encasement >180° for approximately 2 cm
- Superior mesenteric vein (SMV) abutment <180°
- No distant metastases on chest/abdomen/pelvis CT
- No ascites or peritoneal nodules
EUS-FNA confirms: Pancreatic ductal adenocarcinoma
Question 1: Resectability Classification (10 points)
Based on NCCN criteria, classify this patient's tumor and justify your answer. What is the primary determinant of this classification?
Model Answer
This tumor is borderline resectable based on >180° encasement of the SMA 1. The NCCN defines borderline resectable disease as having a higher likelihood of incomplete (R1) resection if taken directly to surgery, making patients poor candidates for upfront resection 1. The >180° arterial involvement is the critical factor—any SMA encasement >180° automatically classifies the tumor as borderline resectable regardless of venous involvement 1. The SMV abutment alone would not preclude resectability, but the extensive SMA involvement does 1.
Question 2: Immediate Management (15 points)
What two procedures must be performed before initiating neoadjuvant therapy? Explain the rationale and timing for each.
Model Answer
1. Biliary stenting (required immediately): Placement of a short self-expanding metal stent is mandatory before administering neoadjuvant therapy in patients with jaundice 1. The bilirubin of 8.2 mg/dL contraindicates chemotherapy until biliary decompression is achieved 1. Metal stents are preferred over plastic stents for preoperative drainage 1.
2. Staging laparoscopy (strongly recommended): Should be performed before starting neoadjuvant treatment to exclude occult peritoneal metastases 1, 2. This is particularly important in borderline resectable disease with elevated CA 19-9 (>850 U/mL), as approximately 10-15% of patients will have radiographically occult metastatic disease that would preclude benefit from neoadjuvant therapy 1, 2.
Question 3: Neoadjuvant Regimen Selection (20 points)
This patient meets criteria for intensive chemotherapy. Compare FOLFIRINOX versus gemcitabine/nab-paclitaxel as neoadjuvant options. Which regimen do you recommend and why? What would change your recommendation?
Model Answer
Recommend FOLFIRINOX as first-line neoadjuvant therapy for this patient 1.
Rationale for FOLFIRINOX:
- ECOG 1 with good functional status qualifies him for intensive therapy 1
- FOLFIRINOX demonstrates higher rates of R0 resection in borderline resectable disease (approaching 100% in some series) 3
- Produces complete pathological responses in select cases of borderline resectable disease 4
- Age 62 is well within the acceptable range (FOLFIRINOX should be limited to ECOG 0-1 patients, typically <75 years) 1
Gemcitabine/nab-paclitaxel is the appropriate alternative if:
- Patient develops grade 3-4 toxicity on FOLFIRINOX requiring early switch 5
- Patient has borderline performance status (KPS 70-80 rather than ECOG 0-1) 1
- Patient preference after informed discussion of toxicity profiles 6
Key point: If FOLFIRINOX fails (progression or intolerance within first 2-4 months), early switch to gemcitabine/nab-paclitaxel can salvage approximately 52% of patients to resection 5. The sequence does not significantly impact overall survival (13.7 vs 13.8 months), so either can serve as rescue therapy 6.
Question 4: Treatment Duration and Restaging Criteria (25 points)
Design the complete neoadjuvant treatment algorithm including:
- Duration of chemotherapy
- Role of radiation therapy
- Restaging schedule and criteria for proceeding to surgery
- Criteria that would abort the surgical plan
Model Answer
Neoadjuvant Treatment Algorithm:
Phase 1: Induction Chemotherapy (4-6 months preferred)
- Administer FOLFIRINOX for 4-6 months (preferably closer to 6 months) 1
- Typical dosing: 8-12 cycles (every 2 weeks) 4, 3
- Monitor CA 19-9 every 2 cycles 2
Phase 2: Consolidation Radiation (selective)
- Add chemoradiation or SBRT only after completing 4-6 months of systemic chemotherapy if no metastatic progression occurs 1
- Chemoradiation should be fluoropyrimidine-based (capecitabine or continuous-infusion 5-FU) at 45-54 Gy 1, 7
- Radiation is reserved for patients who remain locally advanced without developing distant metastases during chemotherapy 1
Restaging Protocol:
- Repeat pancreatic protocol CT after every 2-3 months of chemotherapy 1
- Measure CA 19-9 with each restaging 2
- Final restaging CT/MRI within 4 weeks before planned surgery 2
Criteria to Proceed to Surgery:
- No new metastatic disease on restaging imaging 1
- Stable or decreasing CA 19-9 (significant decrease suggests good response) 3, 5
- Tumor downsizing or stable disease (even without complete radiographic resolution of vascular involvement) 8, 3
- Maintained performance status (ECOG 0-2) 1
Criteria to Abort Surgical Plan:
- Development of distant metastases (automatic exclusion) 1, 2
- CA 19-9 progression during treatment (>25% rise from nadir suggests occult progression) 1
- Local tumor progression (increasing size or new vascular involvement) 1, 5
- Decline in performance status to ECOG ≥3 1
Critical caveat: Post-neoadjuvant CT has reduced accuracy (58% vs 83% for upfront surgery) due to treatment-related fibrosis mimicking persistent vascular invasion 2. Therefore, surgical exploration should still be offered if all other criteria are met, even if imaging suggests persistent borderline features 2, 3.
Question 5: Alternative Strategy for Medically Unfit Patients (15 points)
If this same patient had ECOG performance status 3 (symptomatic, in bed >50% of the day) due to severe COPD exacerbation at presentation, outline your treatment approach. What defines "medically unfit" for intensive chemotherapy?
Model Answer
For ECOG 3 or medically unfit patients, the treatment paradigm shifts entirely:
Definition of "Medically Unfit":
- ECOG performance status ≥2 1
- Age >75-80 years with significant comorbidities 1, 2
- Bilirubin >1.5× upper limit of normal despite stenting 1
- Severe malnutrition despite optimal supportive care 1
Modified Treatment Algorithm:
Biliary decompression (still required) 1
Single-agent chemotherapy rather than combination regimens 1:
Consider upfront chemoradiation or SBRT if patient presents with severe local symptoms (intractable pain, duodenal obstruction) 1
Palliative radiation therapy for pain control if chemotherapy is not tolerated 1
Best supportive care alone if performance status does not improve with biliary drainage and nutritional support 1
Key principle: FOLFIRINOX and gemcitabine/nab-paclitaxel should be limited to ECOG 0-1 patients 1. Attempting intensive regimens in unfit patients increases toxicity without survival benefit and may preclude any subsequent therapy 1.
Question 6: Surgical Planning After Successful Neoadjuvant Therapy (15 points)
After 6 months of FOLFIRINOX, restaging shows stable disease with persistent SMA abutment (now <180°), normalized CA 19-9 (45 U/mL), and no metastases. At exploration, what are the key technical objectives? What defines a successful oncologic resection?
Model Answer
Key Surgical Objectives:
1. Achieve R0 (margin-negative) resection 1, 2:
- R0 is defined as no cancer cells within 1 mm of all resection margins 1
- This is the sole independent prognostic factor for survival and the primary surgical goal 1, 2
- Likelihood of R0 resection is the key criterion determining surgical candidacy 1
2. Meticulous perivascular dissection 1:
- Complete mobilization of portal vein and SMV from uncinate process 1
- Skeletonization of SMA down to the level of adventitia to maximize uncinate yield and radial margin clearance 1
- Use ultrasonic or thermal dissectors (Harmonic scalpel/LigaSure) rather than stapler for SMA dissection 1
3. Liberal use of vascular resection when indicated 1, 8:
- If tumor tethering to portal vein/SMV is encountered, perform lateral venorrhaphy or segmental resection with reconstruction 1
- Even after neoadjuvant therapy, vascular resection may be required in 50-60% of borderline resectable cases 8, 3
- Vascular resection does not worsen outcomes if R0 resection is achieved 1
4. Standard lymphadenectomy 1, 2:
- Remove ≥16 lymph nodes (hepatoduodenal ligament, common hepatic artery, portal vein, right celiac axis, right half of SMA distribution) 1, 2
- Extended lymphadenectomy offers no survival advantage and should not be performed 1
- Document lymph node ratio (LNR ≥0.2 is a negative prognostic factor) 2
Definition of Successful Oncologic Resection:
- R0 resection achieved (margins ≥1 mm) 1, 2
- ≥16 lymph nodes examined 1, 2
- Complete macroscopic tumor removal 1
Critical reality check: Even with meticulous technique, microscopic margin involvement (R1) occurs in >75% of pancreatic resections 7, 2. However, patients still benefit from adjuvant chemotherapy even after R1 resection 7, so surgery should not be aborted intraoperatively solely due to close margins if macroscopic clearance is achieved 1.
Scoring Rubric
- Question 1: 10 points (5 for correct classification, 5 for identifying SMA involvement as determinant)
- Question 2: 15 points (7 for biliary stenting with rationale, 8 for staging laparoscopy with rationale)
- Question 3: 20 points (10 for recommending FOLFIRINOX with justification, 10 for alternative scenarios)
- Question 4: 25 points (8 for duration/sequencing, 7 for restaging protocol, 10 for proceed/abort criteria)
- Question 5: 15 points (5 for defining unfit, 10 for modified treatment algorithm)
- Question 6: 15 points (10 for surgical objectives, 5 for defining successful resection)
Total: 100 points