Metastatic Pancreatic cancer

Dr. H. Navaneeth Reddy

First Year DNB Resident

Jupiter Hospital, ThaneUnder the Guidance of Dr. Rajendra Bhalavat, Dr. Manish Chandra, Dr. Ketan, Dr. Zaiba, Dr. Vibhay, Dr. Amrita

by

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

staging

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%

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

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

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

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 advantage30 min infusion of Gemcitabine 4.9 monthsFDR Gemcitabine 6.2 months

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%

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

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 weeks

7% 33%

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 rateMedian 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

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

Based on these above trails:These are the current standard of care for metastatic pancreatic cancer

1) Gemcitabine2) Gemcitabine + Nab-Paclitaxel3) Gemcitabine + Erlotinib and4) FOLFIRINOX Regimens are applicable for good

performance patients

Can be Given in poor performance patients also

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)

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