advanced and metastatic pancreatic cancer

1. Dr. H. Navaneeth Reddy
First Year DNB Resident
Jupiter Hospital, Thane
Thane
Under the Guidance of Dr. Rajendra Bhalavat, Dr. Manish
Chandra, Dr. Ketan, Dr. Zaiba, Dr. Vibhay, Dr. Amrita
by

2. Introduction:
 Pancreatic cancer is the 9th most common cancer and 4th Most cause of cancer death in industralised countries
 Most common type is Pancreatic ductal adenocarcinoma (PDA)
Age and Gender:
 Around 70% of pancreatic cancers are diagnosed after the age of 65 yrs
 Male: Female ratio: 1.3:1
Predisposing factors:
 Cigarette smoking
 High calorie/Fat diet
 Genetic predisposition:
1. Associated with activation of K-Ras (oncogene)
2. Abnormalities of BRCA-2 (Familial breast, Ovarian and pancreatic cancer syndrome)
3. TP 16 (Familial Pancreas cancer syndrome)
4. LKB1/STK11 (Peutz-jeghers polyposis syndrome)
5. HNPCC syndrome
 Chemicals like 2-Naphthylamine, Benzidine, gasoline derivatives etc

3. staging

4.  T1, T2 and T3 are Resectable primary tumors
 T4 is unresectable primary tumor
Metastatic pancreatic cancer:
 Approx 50% of pts with Pancreatic Ductal Adenocarcinoma (PDA) will be
diagnosed with distant mets at the time of presentation
 Prognosis is very poor with over all median survival is less than 6 months
and an estimated 2 year survival is only 2%

6. Gemcitabine gold standard therapy for metastatic PDA
 5-FU is the principal treatment option for metastatic PDA in 1990s, Even
though the response rate were under 20% and median survival was just 6
months
 Burries et al conducted a study in 1997, which showed the superiority of
Gemcitabine over the 5-FU in advanced PDA and later it became the
most important standard pancreatic cancer therapy
 Gemcitabine (difluorodeoxycytidine-dFdC ) is a nucleoside analog of
deoxycytidine. After entering into the cell it phosphorylates to active
Monophosphate form and diphosphate form, Which gets incorporated in
DNA and inhibits chain elongation

7. Burris trial in 1997:
 It consisted of 126 advanced pancreatic cancer patients, which were randomized in two
arms
 First arm: Gemcitabine 1000 mg/m2 weekly for 7 weeks followed by 1 week rest, Then 3
doses per week every 4 weeks thereafter
 Second arm: Bolus of 5 FU 600mg/m2 once per week
 Clinical benefit based on pain score, Performance status and weight was noted in 28% of
Pts in first arm versus 4.8% of pts in 5 FU arm
 The overall survival rates in first arm was 5.65 months and in second arm it was 4.41
month; Survival at 12 months in first arm was 18% and in second arm was 2%
 Toxicities like Nausea, Thrombocytopenia and Neutropenia were more in first arm
compared to second arm
 Later FDA approved the Gemcitabine as a first line treatment for locally advanced
unresectable and metastatic pancreatic cancer

8.  Tempero et al made a study by modifying the dosing and infusion rates of
gemcitabine in order to increase the concentration of intracellular activated
Gemcitabine
 92 pts were randomized to either standard 30 min infusion at a dose of 2200
mg/m2 versus 1500 mg/m2 over 150 minutes at a fixed dose rate (FDR) of 10
mg/ m2
 Pts in standard arm had a overall median survival rate of 5 months where as
those in FDR arm had overall median survival rate of 8 months
 Toxicities were are also greater in FDR Gemcitabine

9.  Eastern Cooperative Oncology Group (ECOG) conducted three phase III study,
Comparing Gemcitabine (1000mg/m2) + Oxaliplatin (100mg/m2) every 2 weeks versus a
weekly 30 minute infusion of gemcitabine ( 1000 mg/m2) versus weekly FDR
Gemcitabine (1500 mg/m2)
 Total 832 patients were studied
 FDR Gemcitabine arm has greater Toxicity like Neutropenia and thrombocytopenia than
with other arms
Overall survival
Gemcitabine + Oxaliplatin No Survival advantage
30 min infusion of Gemcitabine 4.9 months
FDR Gemcitabine 6.2 months

10. Erlotinib (Oral Tyrosine kinase inhibitor of EGFR
):
 FDA approved this in 2005 for use in combination with gemcitabine for locally advanced
unresectable or metastatic pancreatic cancer
 National cancer institute of Canada clinical trails group (NCIC-CTG) conducted a large International
Phase III randomized trail of 569 patients of advanced/metastatic cancer
 Based on this study gemcitabine and Erlotinib combination became the first line treatment in
Metastatic cancer in good performance patients
Study Arm Median overall survival 1 yr overall survival
Gemcitabine (IV) (1000mg/m2 weekly
for 7 weeks followed by 1 week of rest,
then weekly X 3 every 4weeks) +
Erlotinib (100 mg or 150 mg per day
orally)
6.24 months 23%
Gemcitabine + Placebo 5.91 months 17%

11. Nab-Paclitaxel:
 Paclitaxel binds to microtubules there by stabilizing tubule polymerization and inhibits
cell mitosis
 Nab-paclitaxel bounds to albumin, results in increasing intra-tumoral drug level
 It was approved by FDA in September 2013 as a second line agent indicated for
combination therapy with gemcitabine

12. Gemcitabine and Nab-Paclitaxel
 Phase III trial was conducted in 861 patients
 Gemcitabine and Nab-Paclitaxel is best tolerated first line combimation; So preferred
for older patients >70 yrs
Study Arm Response Rate Rate of Disease
control
Nab-Paclitaxel 125 mg/m2 followed by
Gemcitabine 1000 mg/m2 weekly X 3
every 28 days
23% 48%
Gemcitabine 1000 mg/m2 weekly for 7
weeks followed by rest for 1 week,
Then on 1, 8 and 15 days every 4
7% 33%

13. FOLFIRINOX:
 Folfirinox ( Oxaliplatin 85 mg/m2, Irinotecan 180 mg/m2, Leucovorin 400 mg and 5FU
400 mg/m2)
Study Arm Response Rate Median overall survival
rate
Median progression
free survival
Folfirinox given as a
bolus followed by 2400
mg/m2 given as a
continuous 46 hr
intravenous infusion,
Every 2 weeks
31.6% 11.1 months 6.4 months
Gemcitabine
1000mg/m2 weekly for
7 weeks followed by 1
week rest then weekly
for 3 weeks for every 4
weeks
9.4% 3.3 months 3.3 months

14.  Due to Toxicity, Folfirinox is reserved for good performance status patients aged < 7o yrs
 In Practice, Omitting the bolus of 5 FU and Leucovorin can improve tolerability of the
patient

15. Based on these above trails:
These are the current standard of care for metastatic pancreatic cancer
1) Gemcitabine
2) Gemcitabine + Nab-Paclitaxel
3) Gemcitabine + Erlotinib and
4) FOLFIRINOX Regimens are applicable for good performance
patients
Can be Given in poor performance patients
also

16. Monitoring treatment response
 One has to moniter for signs of treatment toxicity
 CT and MRI for every 8 weeks
 Responses are assessed by Response Evaluation Criteria In Solid Tumors
(RECIST) Criteria
 CA 19-9 every 8 weeks (Decreased levels indicates good prognosis)

17. Overall survival(OS) according to treatment based
on results of prospective trails published after
2005