Treatment/Prognosis

Question 1

What is the 5-yr OS for all stages of PCA?

Answer 1

5-yr OS is 7% for all stages of Dz combined.

Question 2

What surgical procedure is required to resect a pancreatic head lesion?

Answer 2

Sg utilized for pancreatic head resection includes pylorus-preserving pancreaticoduodenectomy (PPPD) or classic pancreaticoduodenectomy (Whipple procedure).

Question 3

What anastomoses are performed in the classic pancreaticoduodenectomy (Whipple)?

Answer 3

There are 3 anastomoses performed for the Whipple procedure:

1. Pancreaticojejunostomy
2. Choledochojejunostomy (hepaticojejunostomy)
3. Gastrojejunostomy

Question 4

What are the 4 most favorable prognostic factors after resection?

Answer 4

Most favorable prognostic factors after resection of PCA:

1. Negative margins (R0)
2. Low grade (G1)
3. Small tumor size (<2 cm)
4. N0 status

Question 5

What is the modern MS for unresectable, margin– resected, and margin+ resected PCA pts?

Answer 5

The MS for PCA pts with the following surgeries in the era of adj and definitive CRT is:

1. Unresectable ∼13 mos
2. Margin+ resection ∼16–18 mos
3. Margin− resection ∼25 mos

Question 6

What is the current mortality rate for pancreaticoduodenectomy?

Answer 6

At tertiary care centers with high throughput (min 15–20/yr), the mortality rate for pancreaticoduodenectomy is <4%.

Question 7

What is the most feared complication for pancreaticoduodenectomy?

Answer 7

Anastamotic leaks are the most important complications after pancreaticoduodenectomy and can lead to peritonitis, abscess, autodigestion, hemorrhage, and delayed gastric emptying.

Question 8

Is there a benefit to R1 or R2 resection over definitive CRT for PCA?

Answer 8

No. Retrospective evidence suggests that survival is similar b/t 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 Sg does not improve outcome over definitive CRT.

Question 9

Should pts with resectable PCA undergo extended retroperitoneal lymphadenectomy?

Answer 9

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)

Question 10

Can definitive CRT replace surgical resection for resectable PCA?

Answer 10

No. Sg alone is sup to CRT alone for pts with resectable PCA per the Japanese PCA Study Group in an RCT of Sg alone vs. definitive CRT (50.4 Gy with continuous infusion (CI) 5-FU). The trial was stopped early d/t the benefit of Sg: MS was 12 mos vs. 9 mos, and 5-yr OS was 10% vs. 0%. (Doi R et al., Surg Today 2008)

Question 11

What are the adj Tx options for a PCA pt s/p resection?

Answer 11

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

Question 12

What is the standard postop RT Tx volume, dose, and fractionation for PCA?

Answer 12

Standard adj RT volume includes tumor bed, anastomoses (pancreaticojejunostomy and choledochojejunostomy), and LN basin (peripancreatic, celiac, sup mesenteric artery, porta hepatis, and aortocaval). The initial volume is treated to 45 Gy in 1.8 Gy/fx with a cone down to 50.4–54 Gy to the surgical bed depending on extent of resection. Keep max small bowel dose <51 Gy.

Question 13

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?

Answer 13

Based on RTOG 9704, LF was site of 1st failure in 28% of PCA and distant failure was 1st site in 73%.

Question 14

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.

Answer 14

The GITSG 91–73 trial 1st 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)

Question 15

Did the EORTC 40891 study on PCA support or contest the benefit of adj CRT?

Answer 15

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)

Question 16

Did the ESPAC-1 study on PCA support or contest the benefit of adj CRT?

Answer 16

Contest. ESPAC-1 included pts with grossly resected adenocarcinoma of the pancreas. The study used a 2 × 2 factorial design; Sg +/− 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).

Question 17

How does the presence of a +margin after resection for PCA influence the decision for adj CRT?

Answer 17

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) This is being examined in RTOG 0848, which randomizes postop pts, stratified by margin status, to either chemo alone or CRT after 5 cycles of induction chemo.

Question 18

Which study supports the role for adj gemcitabine for resected PCA over best supportive care? What subset of pts were excluded from this trial?

Answer 18

CONKO-001 included T1–T4, N0–N1 pts in an 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 CA 19-9 >90 (2.5 × upper limit of normal [ULN]) were excluded from this trial.

Question 19

What study compared adj 5-FU to gemcitabine following surgical resection?

Answer 19

ESPAC-3 showed an 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)

Question 20

Did the study RTOG 9704 on PCA support or contest a benefit of gemcitabine-based adj CRT?

Answer 20

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 CA 19-9 >90 U/mL, positive nodes, & RT quality assurance protocol deviations. (Regine W et al., JAMA 2008; Berger AC et al., IJROBP 2012)

Question 21

What is the Tx paradigm for borderline resectable PCA?

Answer 21

Borderline resectable PCA Tx paradigm: consider staging laparoscopy, stent placement if jaundice, and neoadj chemo +/− CRT → resection.

Question 22

What neoadj regimen should be used for borderline resectable PCA?

Answer 22

There is no standard neoadj Tx for PCA. Use similar paradigms as for locally advanced cases: multi-agent chemo for at least 4 cycles f/b consideration of fluoropyrimidine-based CRT, e.g., (1) gemcitabine/Abraxane or FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) +/− fluoropyrimidine-based chemo/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)

Question 23

What is the Tx paradigm for locally advanced PCA?

Answer 23

Locally advanced unresectable PCA Tx paradigm: biliary stent (if jaundice) can be done 1st then based on KPS→ (1) induction chemo → restage → CRT, (2) definitive CRT if not candidate for multi-agent chemo, or (3) chemo alone. CRT regimens typically involve 5-FU or gemcitabine. Chemo alone or induction chemo involves gemcitabine (poor KPS or unable to tolerate multiple agents), gemcitabine + Abraxane, FOLFIRINOX, or other combination in clinical study. Multi-agent chemo is preferred, and 4–6 cycles for induction chemo.

Question 24

What is the role of regional LN RT with neoadj or definitive CRT for borderline resectable or locally advanced PCA?

Answer 24

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), while others have continued to treat LN in the definitive setting (Ben-Josef E et al., IJROBP 2004). Recent Alliance (A021501) & NRG (RTOG 1201) cooperative group clinical trial designs have not involved elective LN RTin the neoadj or definitive setting, respectively.

Question 25

What is the evidence to support induction chemo prior to CRT in locally advanced PCA?

Answer 25

In a retrospective study of locally advanced PCA pts from MDACC, pts who rcvd induction gemcitabine f/b 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)

Question 26

What definitive CRT regimen should be used for locally advanced PCA?

Answer 26

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.

Question 27

What study established the role of definitive CRT vs. RT alone in locally advanced PCA? What were the study arms and survival outcomes?

Answer 27

The GITSG 9273 trial (pts enrolled in the 1970s). 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 b/t the CRT arms. (Moertel CG et al., Cancer 1981)

Question 28

What study suggests that gemcitabine alone may be sup to 5-FU–based CRT in locally advanced PCA? What were the study arms and survival outcomes?

Answer 28

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)

Question 29

What study suggests that concurrent gemcitabine-based CRT is sup to gemcitabine alone for locally advanced PCA?

Answer 29

ECOG 4201, which closed early d/t slow accrual. 74 pts (71 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)

Question 30

What were the trial design, findings, and criticisms of the recent trial, LAP-07, regarding Tx for locally advanced PCA?

Answer 30

442 pts underwent 4 cycles of induction chemo w/ gemcitabine +/– erlotinib f/b continued gem or RT+cape 800 mg bid. RT involved 54 Gy/30 fx w/o prophylactic nodal irradiation. Erlotinib had trend to poorer survival (HR 1.19, p = 0.09). Only ∼1/2 of pts underwent 2nd randomization. MS did not differ b/t the CRT (15.2 mos) vs. chemo (16.5 mos) groups (NSS). CRT associated with decreased with LRF (32% vs. 46%, p = 0.03) but increased DM (60% vs. 44%, p = 0.04). Toxicities were similar (except worse nausea with CRT), and there was increased time off therapy for the CRT group (6.1 vs. 3.7 mos, p = 0.02) (Hammel P et al., JAMA 2016). Criticism: use of single-agent chemo in the induction arm. Of note, QA revealed 68% RT plans had minor or major deviations, and 9% of pts randomized to CRT never rcvd RT.

Question 31

What 2 regimens may have greater activity than gemcitabine alone in metastatic PCA?

Answer 31

FOLFIRINOX and gemcitabine + Abraxane both were sup 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 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)

Question 32

Estimate the MS and 1-yr OS for pts with locally advanced PCA at Dx, based on LAP-07.

Answer 32

Outcomes for locally advanced PCA: MS was ∼13 mos and 1-yr OS was ∼50% based on LAP-07.

Question 33

In PCA pts, what are 3 Tx options for tumor-associated biliary obstruction?

Answer 33

Tx options for tumor-associated biliary obstruction:

1. Endoscopic biliary stent
2. Percutaneous biliary drainage with subsequent internalization
3. Open biliary-enteric bypass

Question 34

In PCA pts, what are 3 Tx options for tumor-associated gastric outlet obstruction?

Answer 34

Tx options for tumor-associated outlet obstruction:

1. Gastrojejunostomy
2. Enteral stent
3. PEG tube

Question 35

In PCA pts, what Tx should be considered for tumor-associated severe abdominal pain refractory to analgesic med?

Answer 35

Celiac plexus neurolysis is an effective option for Tx-refractory pain.

Radiation

Question 36

Are there any data on stereotactic body radiotherapy (SBRT) for pancreatic cancer?

Answer 36

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).

John Hopkins, MSKCC, Stanford (Herman J et al., Cancer 2014) 49 pts, rcvd 1 cycle gemcitabine, then 33 Gy in 5 fx, with 1-yr freedom from local progression (FFLP) 78%, MS 13.9 mos, with 11% grade 2 or more toxicity, 1 G5 GI bleed, 1 G3 bleed, 1 G3 ulcer.

Question 37

Is there a potential for dose escalation with the use of IMRT in pancreatic cancer?

Answer 37

Yes. A phase I–II trial of IMRT dose-escalation (50–60 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). Single institution data from MDACC (Krishnan S et al., IJROBP 2016) found improved survival (MS 17.8 vs. 15 mos, p = 0.03) in pts with BED >70 Gy10 compared to biological effective dose (BED) ≤70 Gy10. No increased toxicity was seen in the higher-dose group. An example of BED 70 Gy10 would be 57.27 Gy in 25 fx.

Question 38

Do Tx paradigms differ b/t pancreatic and periampullary adenocarcinoma?

Answer 38

Yes. Tx paradigms can differ b/t 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)