1. Borderline Resectable Pancreatic Cancer
Fung Man Him Matrix
QMH
Joint Hospital Surgical Grand Round

2. Content Epidemiology Definitions Evaluation Surgical Considerations
Neoadjuvant chemotherapy

3. Cancer of the Pancreas Rank 6th in cancer mortality in Hong Kong
Rank 4th in the US
Overall 5 year survival: 5%
80% Unresectable
50-55% metastatic
20-25% locally advanced
20% resectable at presentation
Post resection and adjuvant treatment 5 year survival: 20%
Stathis A et al. Nat Rev Clin Oncol. 2010

4. Unresectable Metastatic Locally Advanced
R2 resection: no improvement in survival
R1 resection: reduced survival
J Gastrointest Surg. 2000
Median survival < 1 year
Loehrer et al. J Clin Oncol 2011

5. Borderline resectable
Surgery is the only cure for CA pancreas
R0 resection is crucial to long term survival
Historically, vascular involvement renders resection with negative margin problematic and increases morbidities
Increasing evidence to show vascular resection in selected cases does not compromise margin and hence the term “Borderline resectable pancreatic cancer”

6. Borderline resectable pancreatic cancer
Involvement by tumor that exceeds one-half circumference of the vessel is highly specific for unresectable tumor
Lu et al. AJR Am J Roentgenol. 1997
Abutment:
Contact ≤ 180 degrees of circumference of blood vessel
Encasement:
Contact >180 degree of circumference of blood vessel

7. Borderline resectable pancreatic cancer
Mahipal et al. World J Gastrointest Oncol. 2015
Borderline resectable pancreatic cancer
NCCN
AHPBA/SSAT/SSO
MD Anderson
Intergroup (Alliance)
Celiac artery
No abutment for pancreatic head cancer. For body/tail, ≤ 180° contact
No abutment or encasement
Abutment
Tumor-vessel interface < 180° of vessel wall circumference
CHA
Solid tumor contact ≤ 180° allowing for reconstruction
Abutment or short segment encasement
Abutment or short-segment encasement
Reconstructable short-segment interface of any degree
SMA
Solid tumor contact ≤ 180°
Tumor-vessel wall interface < 180° of vessel wall circumference
SMV/PV
Solid tumor contact > 180° or contact of ≤ 180° with contour irregularity or thrombosis allowing for safe reconstruction
Occlusion
Tumor-vessel interface ≥ 180° of vessel wall circumference and/or reconstructible occlusion
More conservative in the AHPBA/SSO/SSAT criteria
NCCN require the presence of SMV distortion rather than just contact
Patient may be resectable based on the NCCN guideline
CHA: Common hepatic artery; SMA: Superior mesenteric artery; SMV: Superior mesenteric vein; PV: Portal vein; NCCN: National Comprehensive Cancer Network; AHPBA/SSAT/SSO: Americas Hepato-Pancreato-Biliary Association/Society for Surgery of the Alimentary Tract/Society of Surgical Oncology

8. MD Anderson Type B borderline resectable tumors
Suspicion of metastatic disease
Radiologically indeterminate liver lesions
Suspicious distant lymph node
Biopsy proven regional lymph node
Ca 19-9 greater than 1000 u/mL with a normal bilirubin
High risk of early treatment failure with surgery alone
suspicious but not diagnostic for metastatic disease; these may include radiographically
indeterminate liver lesions, suspicious but not biopsy-proven distant lymph nodes, a biopsy-proven
regional lymph node, or cancer antigen (CA) 19-9 levels greater than 1,000 units/mL (in the presence
of normal levels of bilirubin)
Katz MH et al. J Am Coll Surg 2008
Schwarz L et al. Br J Surg 2014
Schwarz L et al. Hematol Oncol Clin North Am 2015

9. MD Anderson Type C borderline resectable tumors
marginal performance status
severe pre-existing comorbidity profile (including advanced age) that put patient at high risk for a major surgical procedure

10. Schwarz et al. Hematology/Oncology Clinics of North America 2015

11. Evaluation CT scan MRI PET CT
Good spatial resolution, most widely used, recommended
Less sensitive for small hepatic and peritoneal metastases
Wong et al. Clin Gastroenterol Hepatol. 2008 
MRI
More sensitive for subcentimeter liver and peritoneal metastases
PET CT
Helps to detect metastases
More sensitive than CT scan for distant disease
Need more data to support routine use
Farma et al. Ann Surg Oncol. 2008

12. Evaluation EUS Able to detect focal lesions as small as 2-3mm in size
sensitivities and accuracy approaching 100% and specificity >95% even for lesions <2 cm
Complementary to CT scan for vascular staging
Glazer et al. Pancreatology 2017
62 patients with BRPC (NCCN)
97% R0 resection
34 patients required venous resection
88% identified by EUS; 67% identified by CT
EUS detected 11 (29%) patients that are not detected by CT
CT detected 4 patients that are not detected by EUS
Operator dependent

13. Evaluation
CA 19-9
preoperative CA 19-9 correlate with pancreatic cancer staging
Karachristos A et al. J Gastrointest Surg. 2005
post-resection CA 19-9 levels prior to initiation of adjuvant chemotherapy have independent prognostic value, can be followed to indicate response to therapy
Hess V Lancet Oncol. 2008
Should be checked
Before surgery
After surgery before adjuvant
During surveillance

14. Surgical considerations
Mesenterico-portal venous resection
Arterial resection

15. Comparable survival Yekebas et al. Ann Surg 2008
482 pancreatic resections for ductal adenocarcinoma in Germany
100 vascular resections vs 382 no vascular resection
77 true histological vascular invasion; 23 no histological vascular invasion
No neoadjuvant
No difference in T, N staging and margin negative rate (90% vs 82%)
No difference in hospital morbidity (39.7 % vs 40.3%)
No difference in hospital mortality (4% vs 3.7%)
No difference in median survival: 15 months vs 16 months, p=0.9
Nodal staging and histological grading were the only factors to predict survival
Pitfalls: combined PV/SMV resection with arterial resection to discuss together
No mentioning of neoadjuvant / adjuvant chemotherapy was given
Most are venous resections

16. Comparable survival Cheung TT et al. World J Gastroenterol. 2014
78 patients with pancreaticoduodenectomy for cancer of pancreas from to 2012
32 vascular resections vs 46 standard PD; No neoadjuvant
No difference in overall survival or disease free survival
one-year, three-year and five-year overall survival rates –
70.6%, 33.3% and 22.2% (vascular resection) vs
71.1%, 23.6% and 13.5%, (standard) P = 0.815
No difference in pancreatic fistula rates (15.6% vs 21.7%)
No difference in hospital mortality (3.1% vs 4.3%)
Most are venous resections

17. Mesenterico-portal venous resection
Kelly et al. Journal of Gastrointestinal Surgery July 2013
492 patients from 6 tertiary centres from 2000 to 2007
70 had vein resections (14%), 422 did not (86%)
No difference in R0 resection (66 vs 75%)
No difference in median disease-free survival (8.6 months vs 13.9 months)
No difference in median overall survival (12.4 months vs 19.3 months)
Higher perioperative morbidity (51 vs. 33 %; p < 0.01)
More blood loss (1,032 ± 956 vs. 602 ± 507 mL; p < 0.01)

18. Arterial resections Limited data
Mollberg et al. Annals of Surgery 2011
Meta-analyses of 26 retrospective studies of resection of pancreatic cancer from to 2010
366 arterial resections vs 2243 no arterial resections
Significantly greater perioperative morbidity (median 53.6%)
Significantly greater perioperative mortality (median 11.8%)

19. Morbidity and mortality
Worni et al JAMA Surg. 2013
10206 patients with pancreatic resection for malignant disease from 2000 to in the US
412 patients (4%) with VR, increasing from 0.7%(2000) to 6% (2009)
VR is associated with higher risk for intraoperative (8.7% vs 5.8%, p=0.001) and postoperative (49% vs 43.4%, p=0.008) complications
Also higher mortality (6% vs 1.9%, p<0.001)
Bleeding / vascular complications / liver ischemia / venous congestion
Improved survival to those with no surgery
But no added benefit to venous resection alone

20. Guideline and Consensus
Clear evidence supporting straightforward operative exploration and resection of mesenterico-portal axis
No good evidence that arterial resections during right-sided pancreatic resections are of benefit. Such resections may be harmful with increased morbidity and mortality and should not be recommended on a routine basis
International Study Group of Pancreatic Surgery (ISGPS) Surgery, 2014

21. Neoadjuvant chemo-radiotherapy
Theoretical benefits
Early treatment of micrometastases
Select patients with more favourable tumour biology for surgery
Achieve downstaging and/or increase the likelihood of R0 resection
Ensures the use of chemotherapy
Evans DB et al. Ann Surg oncol 2010
Katz MH et al. Arch Surg 2012
FOLFIRINOX / mFOLFIRNOX / Gemcitabine / combinations
Emerging evidence
Debatable especially for isolated, resectable venous involvement
ISGPS. Surgery 2014
FOL – folinic acid (leucovorin), a vitamin B derivative that modulates/potentiates/reduces the side effects of fluorouracil;
F – fluorouracil (5-FU), a pyrimidine analog and antimetabolite which incorporates into the DNA molecule and stops DNA synthesis;
IRIN – irinotecan (Camptosar), a topoisomerase inhibitor, which prevents DNA from uncoiling and duplicating; and
OX – oxaliplatin (Eloxatin), a platinum-based antineoplastic agent, which inhibits DNA repair and/or DNA synthesis.
Problems: disease progression during neoadjuvant chemo; low response on imaging,

22. Summary Definitions of borderline resectable cancer of pancreas
Venous resection should be considered if R0 resection and reconstruction is possible in selected patients, noting possibly higher morbidity
Complementary role of EUS in the evaluation of vascular involvement to CT
Evidence on neoadjuvant chemo/chemo-irradiation emerging