Pancreatic and Periampullary Adenocarcinoma
BACKGROUND
Approximately how many pancreatic adenocarcinoma (PCA) pts are diagnosed per yr in the U.S.?
As of 2013, the incidence of PCA is ~45,000 cases/yr in the U.S., with ∼35,000 deaths. Its incidence is higher in developed countries.
Where does PCA rank in cancer incidence in the U.S.? Cancer mortality?
As of 2009, PCA is the 10th most common cancer Dx but the 4th most common cause of cancer death in the U.S.
Is there a racial or sex predilection for PCA?
Yes. Blacks are more commonly affected than whites; however, the incidence is similar among males and females.
In what decades of life does PCA incidence peak?
The peak age of PCA is in the 6th–7th decades of life.
What are 3 environmental exposures associated with PCA?
Most common environmental risk factors for PCA:
1. Tobacco smoking
2. 2-naphthylamine
3. Benzidine
What % of PCA is familial?
~5% of PCA is familial.
What 2 genetic mutations have most frequently been associated with familial PCA?
p16 and BRCA2 are the 2 most common familial associated genetic changes found in PCA.
Is chronic pancreatitis associated with increased risk of PCA?
No. Chronic pancreatitis is not associated with risk of PCA. Historically, there appeared to be an association, but this can be explained by confounding factors.
Approximately at what vertebral bodies are the pancreas, celiac axis, and superior mesenteric artery (SMA) located?
Pancreas: L1-2
Celiac axis: T12
SMA: L1
What % of PCA arise in the head, body, and tail of the pancreas?
Common PCA sites are 75% in the head, 15% in the body, and 10% in the tail.
What is the distribution of local, regional, and metastatic disease at Dx?
∼10% of PCA pts have local disease at diagnosis
∼25% of PCA pts have regional node+ disease at diagnosis
∼50% of PCA pts have DM at diagnosis
For PCA, what are the 3 most common sites of DM?
Common sites of DM for PCA include the liver, peritoneum, and lungs.
Is there a role for screening in PCA?
No. There is no current role for PCA screening. There are studies evaluating the role of screening 1st-degree relatives of PCA with EUS, but this is still experimental.
What % of pancreatic tumors are from the exocrine pancreas?
~95% of PCA are from the exocrine pancreas.
What are the 4 most common pathologic subtypes of exocrine pancreatic tumors?
Most common subtypes of exocrine pancreatic tumors:
1. Ductal adenocarcinoma (80%)
2. Mucinous cystadenocarcinoma
3. Acinar cell carcinoma
4. Adenosquamous carcinoma
What are the most common oncogenes in PCA?
K-ras oncogene is present in ∼95% of PCA.
p16 mutations are seen in ∼90% of PCA.
p53 mutations occur in 55%–75% of PCA.
DPC4 mutations occur in ∼50% of PCA.
What are the most common presenting Sx of PCA?
Common presenting Sx of PCA are pancreatic/biliary duct obstruction, jaundice, and abdominal pain.
What Dz is commonly diagnosed 1–2 yrs prior to a PCA Dx?
60%–80% of PCA pts are diagnosed with diabetes 1–2 yrs prior to Dx. However, only a small proportion of diabetic pts develop PCA.
Periampullary cancers refer to tumors arising from what 4 structures?
Periampullary tumors are those arising from the ampulla of Vater, distal common bile duct (CBD), head of the pancreas, and adjacent duodenum.
WORKUP/STAGING
What is the DDx of a pancreatic mass?
The DDx of a pancreatic mass includes exocrine cancer, islet cell/neuroendocrine cancer, cystic adenomas, papillary cystic neoplasms (e.g., intraductal papillary mucinous tumor), lymphoma, acinar cell carcinoma, and metastatic cancer.
What is the initial workup for suspected PCA?
Suspected PCA workup includes a focused H&P, labs including CBC, CMP, and CA19-9, and abdominal CT scan.
In what circumstance will a PCA pt not excrete any CA19-9?
If a pt is red cell Lewis antigen A–B negative, then the pt cannot excrete CA19-9. The Lewis antigen– phenotype is present in 5%–10% of the population.
What is the appropriate imaging for suspected PCA?
Triphasic thin-sliced CT abdomen. The 3 phases include arterial, portal venous, and parenchymal phases of enhancement.
Name 4 appropriate procedures for obtaining tissue from a suspicious pancreatic mass.
Procedures to obtain tissue from a suspicious pancreatic mass:
1. EUS-guided FNA
2. CT-guided FNA
3. Endoscopic retrograde cholangiopancreatography (ERCP)
4. Pancreatic resection (i.e., histologic Dx is not required before surgery)
When is it appropriate to obtain tissue prior to surgery for lesions suspicious on imaging?
Tissue diagnosis prior to surgery is not routinely necessary, except for: (1) clinical trial enrollment, (2) prior to neoadjuvant therapy, or (3) prior to chemo/CRT in unresectable patients.
What is the major advantage of EUS-guided FNA over CT-guided FNA of a pancreatic mass?
EUS-guided FNA is associated with lower risk of peritoneal seeding (2% vs. 16%).
When is ERCP indicated instead of EUS?
ERCP carries a higher risk of iatrogenic pancreatitis, so it is reserved for cases where PCA is causing biliary obstruction and cholangitis requiring stenting.
What is the NCCN 2014 classification scheme for PCA?
PCA are classified into 4 categories (and per AJCC 7th edition [2011] staging):
1. Resectable (T1-3N0 or N+) (stages I–II)
2. Borderline resectable (T4NX) (stage III)
3. Locally advanced (T4NX) (stage III)
4. Metastatic (TXNXM1) (stage IV)
What 3 criteria are necessary for a primary pancreatic tumor to be resectable (per NCCN)?
NCCN resectability for PCA is defined as:
1. No distortion of SMV or portal vein
2. Clear fat plane around celiac artery, SMA, and hepatic artery
3. No distant mets or mets to nodes beyond field of resection
What characteristics make a primary pancreatic tumor unresectable (per NCCN)?
Unresectable characteristics include:
1. >180-degree encasement of SMA
2. Any celiac abutment for head lesions; >180-degree encasement for body/tail lesions
3. Unreconstructable SMV/PV occlusion
4. Aortic invasion/encasement
What are the characteristics of borderline resectable pancreatic head/body tumors (per NCCN)?
The definitions vary, but NCCN definition of borderline resectability for PCA are:
1. SMV/PV involvement (distortion, narrowing or occlusion) that can be resected and reconstructed using nearby vessels.
2. Tumor abutment on SMA ≥180-degrees
3. Gastroduodenal artery encasement up to the hepatic artery, including up to short segment encasement or direct abutment of the hepatic artery, without celiac axis involvement.
What pancreatic tail lesions are considered “borderline resectable”?
Invasion into the adrenal gland, colon, mesocolon, or kidney are considered borderline resectable for PCA tail lesions.
What location of PCA is associated with higher rates of resectability: head, body, or tail?
PCA head tumors are more resectable b/c they cause Sx early (and therefore present with earlier-stage Dz).
At presentation, what % of PCA pts is resectable?
10%–20% of PCA pts are potentially resectable at presentation.
What % of pts with resectable PCA tumors by CT imaging will be resectable at the time of surgery?
~65%–80% of PCA pts deemed resectable by CT are resectable at the time of surgery.
What is the role of staging laparoscopy?
Staging laparoscopy at the time of surgery is not routinely warranted. Select pts with tumors >3 cm, tumors in the body/tail, equivocal CT findings of metastasis, or CA19-9 >100 U/mL may benefit.
What imaging is indicated to assess for metastatic disease?
CT chest is routinely performed for mets workup of PCA. PET-CT may be more sensitive for systemic disease, but is not yet standard.
What is the significance of a postresection CA19-9 >90 U/mL?
In RTOG 9704, 53 pts (14%) had CA19-9 >90 U/mL, and only 2 of these pts survived up to 3 yrs.
What is the AJCC 7th edition (2011) T and N staging for PCA?
T1: limited to pancreas and ≤2 cm
T2: limited to pancreas and >2 cm
T3: extends beyond pancreas but without celiac axis or SMA involvement
T4: celiac axis or SMA involvement
N1: regional node involvement
What are the AJCC 7th edition (2011) stage groupings for PCA?
Stage 0: Tis
Stage IA: T1N0M0
Stage IB: T2N0M0
Stage IIA: T3N0M0
Stage IIB: T1-3N1M0
Stage III: T4NXM0
Stage IV: TXNXM1
What is the stage of a PCA pt with positive cytology at time of laparoscopy?
Positive cytology is stage IV (M1).
Does the AJCC 7th edition (2011) TNM staging for ampullary, bile duct, and duodenal cancer differ from PCA?
Yes.
TREATMENT/PROGNOSIS
What is the 5-yr OS for all stages of PCA?
5-yr OS is 5% for all stages of disease.
What surgical procedure is required to resect a pancreatic head lesion?
Surgery utilized for pancreatic head resection includes pylorus-preserving pancreaticoduodenectomy (PPPD) or classic pancreaticoduodenectomy (Whipple procedure).
What anastomoses are performed in the classic pancreaticoduodenectomy (Whipple)?
There are 3 anastomoses performed for the Whipple procedure:
1. Pancreaticojejunostomy
2. Choledochojejunostomy (hepaticojejunostomy)
3. Gastrojejunostomy
What are the 4 most favorable prognostic factors after resection?
Most favorable prognostic factors after resection of PCA:
1. Negative margins (R0)
2. Low grade (G1)
3. Small tumor size (<3 cm)
4. N0 status
What is the modern MS for unresectable, margin-negative resected, and margin-positive resected PCA pts?
The MS for PCA patients with the following surgeries in the era of adjuvant and definitive CRT is:
1. Unresectable ∼11 mos
2. Margin+ resection ∼16–18 mos
3. Margin– resection ∼25 mos
What is the current mortality rate for pancreaticoduodenectomy?
At tertiary care centers with high throughput, the mortality rate for pancreaticoduodenectomy is <4%.
What is the most feared complication for pancreaticoduodenectomy?
Anastamotic leaks are the most important complications after pancreaticoduodenectomy and can lead to peritonitis, abscess, autodigestion, hemorrhage, and delayed gastric emptying.
Is there a benefit to R1 or R2 resection over definitive CRT for PCA?
No. Retrospective evidence suggests that survival is similar between PCA pts who had R1 or R2 resection and definitive CRT. Therefore, planned resections should be done in pts where R0 resections are likely. Debulking surgery does not improve outcome over definitive CRT.
Should pts with resectable PCA undergo extended retroperitoneal lymphadenectomy?
No. Resectable PCA pts should not undergo an extended retroperitoneal lymphadenectomy. There is no survival benefit to extended lymphadenectomy by an RCT (5-yr 25% vs. 31%, NSS). (Riall TS et al., J Gastrointest Surg 2005)
Can definitive CRT replace surgical resection for resectable PCA?
No. Surgery alone is superior to CRT alone for pts with resectable PCA per the Japanese PCA Study Group in an RCT of surgery alone vs. definitive CRT (50.4 Gy with continuous infusion [CI] 5-FU). The trial was stopped early due to the benefit of surgery: MS was 12 mos vs. 9 mos, and 5-yr OS was 10% vs. 0%. (Doi R et al., Surg Today 2008)
What are the adj Tx options for a PCA pt s/p resection?
Adj Tx options after a pancreaticoduodenectomy:
1. Adj gemcitabine (CONKO-001)
2. Adj gemcitabine alone → 5-FU/RT→ gemcitabine alone (RTOG 9704)
3. Adj 5-FU/RT (GITSG 91-73); consider maintenance gemcitabine afterward
4. Adj 5-FU → 5-FU/RT → 5-FU (RTOG 9704)
5. Observation alone
What is the standard postop radiation Tx volume, dose, and fractionation for PCA?
Standard adj RT volume includes tumor bed, anastomoses (pancreaticojejunostomy and choledochojejunostomy), and LN basin (peripancreatic, celiac, superior mesenteric artery, porta hepatis, and aortocaval). The initial volume is treated to 45 Gy in 1.8 Gy/fx with a cone down to 50.4–59.4 Gy to the surgical bed depending on extent of resection. Small bowel should be excluded after 50.4 Gy.
For pts with resected PCA, LF is the site of 1st failure for what % of pts treated with adj CRT? Distant failure as the 1st site?
Based on RTOG 9704, LF was site of 1st failure in 23%–28% of PCA and distant failure was 1st site in 71%–77%.
What U.S. study 1st reported a benefit of adj CRT vs. no additional Tx for resected PCA? Describe the arms of this study and the major results.
The Gastrointestinal Tumor Study Group (GITSG 91-73) trial 1 st reported benefit to adj CRT for PCA in 1985. All pts had R0 resections.
Standard arm: postop observation
Experimental arm: adj CRT using split-course RT to 40 Gy (2-wk break after 20 Gy) with intermittent bolus 5-FU → 2 full yrs of adj 5-FU alone
Improved MS (20 mos vs. 11 mos) and 2-yr OS (42% vs. 15%) in the adj CRT arm (Kalser MH et al., Arch Surg 1985)
Did the EORTC 40891 study on PCA support or contest the benefit of adj CRT?
Support. The EORTC 40891 trial used the same randomization as GITSG 91-73, except the Tx arm did not rcv maintenance adj 5-FU for 2 yrs. Median PFS was 17 mos (CRT) vs. 16 mos (observation), NSS; MS was 24 mos (CRT) vs. 19 mos (observation), NSS. For the subset of PCA pts, 5-yr OS was 20% (CRT) vs. 10% (observation) (p = 0.09). (Klinkenbijl JH et al., Ann Surg 1999) Of note, in addition to T1-2N0-1 PCA, 45% of pts had periampullary adenocarcinoma, which were excluded in GITSG 91-73, and generally have better prognosis. Authors concluded that routine adj CRT was not warranted, although statistical reanalysis of this study found a significant survival benefit with adj therapy. (Garofalo MC et al., Ann Surg 2006)
Did the European Study Group for Pancreatic Cancer-1 (ESPAC-1) study on PCA support or contest the benefit of adj CRT?
Contest. ESPAC-1 included pts with grossly resected adenocarcinoma of the pancreas. The study used a 2 × 2 factorial design; surgery +/– CRT and +/– adj chemo. Adj CRT was similar to GITSG. Adj chemo was 6 mos of 5-FU. MS was 15 mos (CRT) vs. 16 mos (no CRT), NSS; OS was 20 mos (chemo) vs. 14 mos (no chemo) (p = 0.0005).
Criticisms: Physicians could randomize pts into 2 × 2 or directly into 1 of the 2 randomizations. “Background Tx” was allowed (i.e., observed pts may have rcvd chemo +/– RT). There was no central RT QA. (Neoptolemos JP et al., Lancet 2001) Note: Analysis of 2 × 2 subset suggests that CRT had a deleterious effect; 5-yr OS was 10% (CRT) vs. 20% (no CRT) (p = 0.05).
How does the presence of a +margin after resection for PCA influence the decision for adj CRT?
UK Clinical Trials Unit meta-analysis of 5 RCTs, including individual data from 4 RCTs, found that the benefit of adj CRT was greater in R1 pts compared to R0 pts, although the difference was not SS. Also, the benefit of adj chemo alone decreased in R1 pts compared to R0 pts, suggesting that CRT may have a more important role in R1 pts. (Butturini G et al., Arch Surg 2008)
Which study supports the role for adj gemcitabine for resected PCA over best supportive care? What subset of pts were excluded from this trial?
CONKO-001 included T1-T4, N0-N1 pts in a RCT of observation vs. adj gemcitabine. Outcomes favored adj Tx: median DFS was 13 mos vs. 7 mos (SS). MS was 23 mos vs. 20 mos (SS), and 5-yr OS was 21% vs. 10% (SS), 10-yr OS was 12.2% vs. 7.7%. (Oettle H et al., JAMA 2013) Note: Pts with CA19-9 >90 were excluded from this trial.
What study compared adj 5-FU to gemcitabine following surgical resection?
ESPAC-3 showed a MS of 23 mos for pts treated with 5-FU (and folinic acid) vs. 23.6 mos for pts treated with gemcitabine (NSS). (Neoptolemos JP et al., JAMA 2010)
Did the study RTOG 9704 on PCA support or contest a benefit of gemcitabine-based adj CRT?
This is controversial. RTOG 9704 randomized R0 and R1 PCA pts to CI 5-FU (250 mg/m2/d) CRT (50.4 Gy) and pre- and post-CRT with either additional 5-FU or gemcitabine. Among all eligible pts, there were no differences. In a preplanned subset analysis of pts with pancreatic head tumors, trends favored gemcitabine: MS was 20.5 mos vs. 16.7 mos, and 3-yr OS was 31% vs. 22%, but results were NSS (p = 0.09). The 3-yr LR was significantly better for the gemcitabine arm (23% vs. 28%). Updated 2012 results showed significantly worse survival in pts with CA19-9 >90 U/mL. (Regine W et al., JAMA 2008; Berger AC et al., IJROBP 2012)
What is the Picozzi regimen for pts with PCA?
The Picozzi regimen is adj CRT with interferon-alfa, 5-FU, cisplatin, and RT (45—54 Gy). 42% of pts were admitted during CRT and 95% of pts had ≥G3 toxicity; however, outcomes were very promising: 5-yr OS was 55%, and MS was 25.4 mos. (Picozzi VJ et al., Am J Surg 2003, Ann Oncol 2011)
What is the Tx paradigm for borderline resectable PCA?
Borderline resectable PCA Tx paradigm: consider staging laparoscopy, stent placement if jaundice, and neoadj CRT → resection.
What neoadj CRT regimen should be used for borderline resectable PCA?
There is no standard neoadj Tx for PCA. Use similar paradigms as for locally advanced cases: (1) 5-FU/RT, (2) gemcitabine/RT, (3) gemcitabine/Abraxane or FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) followed by 5-FU/RT or (4) induction gemcitabine/Taxotere/Xeloda (GTX) → 5-FU/RT, with RT to 45–50.4 Gy in 1.8–2 Gy/fx or 30 Gy in 3 Gy/fx per the MDACC paradigm. (Breslin TM et al., Ann Surg Oncol 2001)
What is the Tx paradigm for locally advanced PCA?
Locally advanced unresectable PCA Tx paradigm: biliary stent (if jaundice) can be done 1st → (1) definitive CRT, (2) induction chemo → restage → CRT, or (3) chemo alone. CRT regimens typically involve 5-FU or gemcitabine. Chemo alone or induction chemo involves gemcitabine, gemcitabine + Abraxane, FOLFIRINOX, or other combination in clinical study.
What is the role of regional LN radiation with neoadj or definitive CRT for borderline resectable or locally advanced PCA?
LN irradiation is controversial in the neoadj or definitive setting. In this setting, some institutions trend toward using smaller fields that treat gross tumor plus a small margin (McGinn CJ et al., JCO 2001), with others have continued to treat LN in the definitive setting. (Ben-Josef E et al., IJROBP 2004 )
What is the evidence to support induction chemo prior to CRT in locally advanced PCA?
In a retrospective study of locally advanced PCA pts from MDACC, pts who received induction gemcitabine followed by CRT had longer MS than pts that had initial CRT (12 mos vs. 8 mos). They hypothesize that induction chemo may select for pts that benefit from CRT. (Krishnan S et al., Cancer 2007)
What definitive CRT regimen should be used for locally advanced PCA?
Standard regimen for definitive CRT: 5-FU (CI 250 mg/m2/d) + RT, with RT to 50–60 Gy in 1.8 Gy/fx or 30 Gy in 3 Gy/fx.
What study established the role of definitive CRT vs. RT alone in locally advanced PCA? What were the study arms and survival outcomes?
The GITSG 9273 trial (pts enrolled in the 1970 s). Arm 1: RT alone, split-course 60 Gy in 2 Gy/fx; arm 2: 5-FU + RT, split-course RT to 40 Gy in 2 Gy/fx; arm 3: 5-FU + RT, split-course RT to 60 Gy in 2 Gy/fx. All arms rcvd maintenance 5-FU × 2 yrs. MS favored the CRT arms: 5.3 mos (arm 1) vs. 9.7 mos (arm 2) vs. 9.3 mos (arm 3). 1-yr OS favored the CRT arms: 10% (arm 1) vs. 35% (arm 2) vs. 46% (arm 3). There were no statistical differences between the CRT arms. (Moertel CG et al., Cancer 1981)
What study suggests that gemcitabine alone may be superior to 5-FU–based CRT in locally advanced PCA? What were the study arms and survival outcomes?
FFCD/SFRO study (French). Arm 1: RT (60 Gy) + CI 5-FU + intermittent cisplatin → maintenance gemcitabine; arm 2: induction gemcitabine → maintenance gemcitabine. Upfront CRT was more toxic and had worse survival outcomes. MS was 8.6 mos vs. 13 mos, and 1-yr OS was 32% vs. 53%. Criticism: The upfront CRT was not standard and was very poorly tolerated. (Chauffert B et al., Ann Oncol 2008)
What study suggests that concurrent gemcitabine-based CRT is superior to gemcitabine alone for locally advanced PCA?
ECOG 4201, which closed early due to slow accrual. 71 pts (69 evaluable). Arm 1: gemcitabine alone; arm 2: gemcitabine + RT, then gemcitabine alone. MS and 2-yr OS were better with CRT (11.1 mos vs. 9.2 mos and 12% vs. 4%, respectively). There were higher G4/5 toxicities with arm 2, but G3/4 toxicities were similar. (Loehrer PJ et al., JCO 2011)
What 2 regimens may have greater activity than gemcitabine alone in metastatic PCA?
FOLFIRINOX and gemcitabine + Abraxane both were superior to gemcitabine alone in 2 separate phase III RCTs in metastatic PCA. In a French study of 342 pts, FOLFIRINOX had an MS of 11.1 mos vs. 6.8 mos for gemcitabine and increased QOL despite increased G3/4 toxicities. (Conroy T et al., NEJM 2011) The Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT) international study of 861 pts showed gemcitabine + Abraxane had MS of 8.5 mos vs. 6.7 mos for gemcitabine alone. (Von Hoff DD et al., NEJM 2013)
Estimate the MS and 3-yr OS for pts with resectable PCA at Dx, based on RTOG 9704.
Outcomes for resected PCA, if treated with adj CRT: MS was ~20 mos and 3-yr OS was ~30% based on RTOG 9704; if untreated, MS was 11–12 mos.
Estimate the MS and 1-yr OS for pts with locally advanced PCA at Dx, based on GITSG 9273.
Outcomes for locally advanced PCA: MS was ~9 mos and 1-yr OS was ~35% based on GITSG 9273.
Estimate the MS and 1-yr OS for pts with metastatic PCA at Dx.
Outcomes for metastatic PCA: MS was ~6 mos, and 1-yr OS was ~20% based on an NCIC study.
In PCA pts, what are 3 Tx options for tumor-associated biliary obstruction?
Tx options for tumor-associated biliary obstruction:
1. Endoscopic biliary stent
2. Percutaneous biliary drainage with subsequent internalization
3. Open biliary-enteric bypass
In PCA pts, what are 3 Tx options for tumor-associated gastric outlet obstruction?
Tx options for tumor-associated outlet obstruction:
1. Gastrojejunostomy
2. Enteral stent
3. PEG tube
In PCA pts, what Tx should be considered for tumor-associated severe abdominal pain refractory to analgesic medications?
Celiac plexus neurolysis is an effective option for Tx-refractory pain.
In the absence of 3D planning, what are the borders for the initial AP and lat RT fields for PCA of the head?
Classic pancreatic head fields rcvd 45 Gy in 1.8 Gy/fx.
AP superior: T10-11 interspace
AP inferior: L3-4 interspace
AP left: 2 cm from left border of vertebral body
AP right: 2 cm to right of preop duodenum
Lateral superior-inferior: same as AP
Lateral posterior: 2 cm into vertebral body
Lateral anterior: 2 cm ant to preop gross Dz or duodenum
Are there any data on stereotactic body radiation therapy (SBRT) for pancreatic cancer?
Several studies have evaluated SBRT for unresectable PCA. Early reports suggest excellent LC; however, a significant proportion of pts experience duodenal toxicity.
Stanford (Chang DT et al., Cancer 2009): 77 pts with unresectable PCA rcvd 25 Gy × 1 with CyberKnife SBRT. The 6- and 12-mo isolated LR rate was 5% and 5%, respectively. The PFS at 6 and 12 mos were 26% and 9%, respectively. The 1-yr OS was 21%. At 12 mos, the ≥G2 late toxicity was 25%, including 1 small bowel perforation (G4), 1 duodenal stricture (G3), and 3 gastric ulcers (G3).
Beth Israel Deaconess (Mahadevan A et al., IJROBP 2010): 36 pts with unresectable PCA rcvd 24–36 Gy CyberKnife SBRT in 3 fx. Gemcitabine was given after SBRT. LC rate was 78%, and MS was 14.3 mos. 39% developed ≥G2 toxicity (25% G2, 14% G3), including 3 pts with vomiting and dehydration (G3) and 2 pts with GI bleed (G3).
Is there a potential for dose escalation with the use of IMRT in pancreatic cancer?
Yes. A phase I–II trial of IMRT dose-escalation (50 to 60 Gy) with concurrent gemcitabine in 50 pts with unresectable PCA found dose-limiting toxicities in 11 pts, including duodenal bleed (3 pts) and perforation (1 pt). The recommended dose was 55 Gy, with an estimated 24% rate of dose-limiting toxicity. (Ben-Josef E et al., IJROBP 2012)
Do Tx paradigms differ between pancreatic and periampullary adenocarcinoma?
Yes. Tx paradigms can differ between pancreatic vs. periampullary cancers. Consider observation for completely resected T1-T2, N0 ampulla of Vater carcinoma. Retrospective reviews suggest high OS (5-yr OS ∼80%) with observation alone. (Willett C et al., Surg Gynecol Obstet 1993) Otherwise, periampullary adenocarcinoma generally follows PCA paradigms, especially for T3-T4, poor histologic grade, LVSI/PNI, (Krishnan S et al., IJROBP 2008), or node+ pts. (Zhou J et al., Radiother Oncol 2009)
TOXICITY
What are the expected acute and late RT toxicities associated with Tx of resected and unresectable PCA?
Acute toxicities: nausea, diarrhea, small bowel obstruction, weight loss, anorexia, abdominal pain
Late toxicities: small bowel obstruction/stenosis/perforation, gastric/small bowel ulceration and/or bleeding, biliary stenosis obstruction, 2nd malignancies
What are the standard dose limitations for the liver, kidneys, spinal cord, and stomach and small bowel for pancreatic RT?
Standard dose limits for normal structures during pancreatic cancer RT:
Liver: mean <30 Gy
Kidneys: mean <15–18 Gy for each kidney
Spinal cord: ≤45–50 Gy
Stomach and small bowel: V15 <120 cc (if contouring individual loops); V45 <195 cc (if contouring peritoneal space)
What are duodenal toxicities related to fractionated RT or SBRT for PCA?
Radiation can induce duodenal injury: ulceration, bleeding, perforation, and fistula formation. These mostly occur in the 1st 12 mos after completing RT.
What are duodenal constraints for fractionated RT?
For fractionated RT, duodenum V55 Gy <1 cm3, and maximum point dose <60 Gy was associated with decreased G2 or higher toxicity. (Kelly P et al., IJROBP 2013)
What is the typical follow-up schedule after Tx of pancreatic cancer?
Pancreatic cancer follow-up schedule after Tx: surveillance every 3–6 mos × 2 yrs, then annually. At each visit, perform full H&P for Sx assessment, and consider CA19-9 levels, LFTs, and contrast CT scan chest/abdomen.
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