Pancreatic Adenocarcinoma

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Pancreatic Adenocarcinoma Page 1 of 14 Disclaimer: This algorithm has been developed for MD Anderson using a multidisciplinary approach considering circumstances particular to MD Anderson’s specific patient population, services and structure, and clinical information. This is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient's care. This algorithm should not be used to treat pregnant women. Note: Consider Clinical Trials as treatment options for eligible patients CLINICAL DIAGNOSTIC WORK-UP AND TISSUE ACQUISITION PRESENTATION

CT scan or ultrasound-guided biopsy of Yes metastatic disease if accessible Clinical suspicion of pancreatic cancer (e.g., jaundice) or evidence of dilated pancreatic Metastases? duct and/or bile duct stricture ● Multidisciplinary planning presentation Yes ● EUS with FNA No ● Liver function tests, CA 19-9 ● CT chest (preferred) or chest x-ray 1,2 Mass in ● Pancreatic CT scan protocol For treatment based 3 pancreas on ● Obtain family history on tissue confirmation 4 imaging? ● Lifestyle risk assessment and clinical staging, see Pages 2-5

● Multidisciplinary planning presentation Yes ● Liver function tests, CA 19-9 Biopsy ● CT chest (preferred) or chest x-ray or brushings ● EUS with FNA if mass visualized in pancreas positive? ● ERCP with brushings as clinically indicated No Surgical consult EUS = endoscopic ultrasound FNA = fine needle aspiration ERCP = endoscopic retrograde cholangiopancreatography 1 Pancreatic CT scan protocol: multiphasic cross sectional imaging and thin slices; consider MRI, PET and/or EUS if CT results are equivocal 2 For patients who cannot undergo contrast enhanced CT (allergy, renal issues, etc.) consider MRI as an alternative 3 Consider referral for genetic counseling for patients with a family history of cancer. Universal gerrmline testing recommended for eligible patients. 4 See Physical Activity, Nutrition, and Tobacco Cessation algorithms; ongoing reassessment of lifestyle risks should be a part of routine clinical practice Department of Clinical Effectiveness V6 Approved by the Executive Committee of the Medical Staff on 09/17/2019 Pancreatic Adenocarcinoma Page 2 of 14 Disclaimer: This algorithm has been developed for MD Anderson using a multidisciplinary approach considering circumstances particular to MD Anderson’s specific patient population, services and structure, and clinical information. This is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient's care. This algorithm should not be used to treat pregnant women. Note: Consider Clinical Trials as treatment options for eligible patients PRESENTATION TREATMENT POST-OPERATIVE

● Individualized second line systemic therapy ● Consider best supportive care as indicated Yes ● Pre-operative clinical trial Evidence (preferred) or of locally 3 Post-treatment ● Systemic therapy advanced and/or 4 restaging Adequate and uneventful post-operative ● Consider chemoradiation in metastatic 5 No recovery within 12 weeks : select patients disease? 6 ● Consider adjuvant chemotherapy based on See Resection duration and response to neoadjuvant surveillance 1 Resectable chemotherapy on Page 8 4 pancreatic cancer ● Consider chemoradiation if not previously and low-risk2 given clinical features Adequate and uneventful post-operative recovery within 12 weeks5: 8,9 ● Restaging CT scan ● CA 19-9 Resection7 ● Adjuvant gemcitabine or fluorouracil-based chemotherapy6 4 ● Consider chemoradiation following chemotherapy

1 Resectable is defined as: 4 See Appendix B – Chemoradiation and Stereotactic Body Radiation Therapy Regimens ● Patent superior mesenteric vein-portal vein (SMV-PV) confluence 5 If post-operative recovery is greater than 12 weeks, adjuvant therapy will be at the discretion of the treating provider ● No interface between tumor and superior mesenteric artery (SMA) or celiac 6 Typically FOLFIRINOX or GemCape or single agent gemcitabine (see Appendix A – Chemotherapy Regimens) ● No metastases 7 If patient exhibits all low-risk features and all other factors are favorable, primary resection can be considered 2 Low-risk features: 8 For patients who cannot undergo contrast enhanced CT (allergy, renal issues, etc.) consider MRI as an alternative ● No suspicion of metastatic disease 9 Pancreatic CT scan protocol: multiphasic cross sectional imaging and thin slices; consider MRI, PET and/or EUS ● CA 19-9 less than or equal to 500 units/mL with normal bilirubin if CT results are equivocal ● Manageable and optimized comorbidities 3 Typically gemcitabine plus paclitaxel or FOLFIRINOX (see Appendix A – Chemotherapy Regimens) Department of Clinical Effectiveness V6 Approved by the Executive Committee of the Medical Staff on 09/17/2019 Pancreatic Adenocarcinoma Page 3 of 14 Disclaimer: This algorithm has been developed for MD Anderson using a multidisciplinary approach considering circumstances particular to MD Anderson’s specific patient population, services and structure, and clinical information. This is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient's care. This algorithm should not be used to treat pregnant women. Note: Consider Clinical Trials as treatment options for eligible patients

PRESENTATION TREATMENT Follow metastatic section Staging Yes of this algorithm on Page 7 laparoscopy Yes positive for metastatic Elevated CA 19-9 Yes Is staging disease? and/or other clinical No laparoscopy indications of appropriate? metastatic disease 1 ● Pre-operative clinical trial preferred Resectable 3 4 ● Systemic chemotherapy with chemoradiation pancreatic No 4 Metastases? cancer and or SBRT in select patients 2 ● Restage after each treatment modality high-risk No clinical features Adequate and uneventful postoperative recovery within 12 weeks5: Resection Consider adjuvant chemotherapy6 Characterize/optimize based on duration and response to Comorbidities comorbidities; diet and neoadjuvant chemotherapy3 exercise recommended

SBRT = stereotactic body radiation therapy 1 Resectable is defined as: 3 Typically gemcitabine plus paclitaxel or FOLFIRINOX (see Appendix A – Chemotherapy Regimens) See surveillance ● Patent superior mesenteric vein-portal vein (SMV-PV) confluence 4 See Appendix B – Chemoradiation and Stereotactic Body Radiation Therapy Regimens on Page 8 ● No interface between tumor and superior mesenteric artery (SMA) or celiac 5 If post-operative recovery is greater than 12 weeks, adjuvant therapy will be at the discretion of the treating provider ● No metastases 6 Typically FOLFIRINOX or GemCape or single agent gemcitabine (see Appendix A – Chemotherapy Regimens) 2 High-risk features: ● Suspicion of metastatic disease ● CA 19-9 greater than 500 units/mL with a normal bilirubin ● Reversible and optimizable comorbidities

Department of Clinical Effectiveness V6 Approved by the Executive Committee of the Medical Staff on 09/17/2019 Pancreatic Adenocarcinoma Page 4 of 14 Disclaimer: This algorithm has been developed for MD Anderson using a multidisciplinary approach considering circumstances particular to MD Anderson’s specific patient population, services and structure, and clinical information. This is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient's care. This algorithm should not be used to treat pregnant women. Note: Consider Clinical Trials as treatment options for eligible patients PRESENTATION TREATMENT

Borderline resectable pancreatic cancer1

For management of progressed/metastatic Clinical trial preferred disease for second line options, see Page 7 Yes ● Clinical trial (preferred) 2 Radiographic, ● Systemic therapy followed by 3 3 and/or biochemical, chemoradiation or SBRT (in Post-treatment and/or clinical select patients) if no evidence of restaging After resection, consider adjuvant evidence of disease 4 progression and/or metastatic progression? chemotherapy based on duration and disease on interval scanning Yes response to neoadjuvant therapy No Multidisciplinary planning presentation and consider Resection? surgical resection No For management of progressed/metastatic disease for second line options, see Page 7

1 MD Anderson Cancer Center’s definition for borderline resectable pancreatic cancer with or without high risk features: Based on anatomic considerations; a tumor abutment of less than or equal to 180° of circumference of superior mesenteric artery (SMA); short-segment encasement abutment of the common hepatic artery or gastroduodenal artery; short-segment occlusion of superior mesenteric vein (SMV) or superior mesenteric vein-portal vein (SMV-PV) and patent vessel above and below. High-risk features: ● Suspicion of metastatic disease ● CA 19-9 greater than 500 units/mL with a normal bilirubin ● Reversible and optimizable comorbidities 2 Typically gemcitabine plus paclitaxel or FOLFIRINOX (see Appendix A – Chemotherapy Regimens) 3 See Appendix B – Chemoradiation and Stereotactic Body Radiation Therapy Regimens 4 Typically FOLFIRINOX or GemCape or single agent gemcitabine (see Appendix A – Chemotherapy Regimens) Department of Clinical Effectiveness V6 Approved by the Executive Committee of the Medical Staff on 09/17/2019 Pancreatic Adenocarcinoma Page 5 of 14 Disclaimer: This algorithm has been developed for MD Anderson using a multidisciplinary approach considering circumstances particular to MD Anderson’s specific patient population, services and structure, and clinical information. This is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient's care. This algorithm should not be used to treat pregnant women. Note: Consider Clinical Trials as treatment options for eligible patients PRESENTATION TREATMENT

Consider: 3 ● No metastasis and ● Systemic therapy or 4 4 ● No further local progression ● Chemoradiation or SBRT in select patients or ● Observation

Serial post-

● Clinical trial treatment 4 4 ● Chemoradiation or SBRT (if not previously Individualized Locally advanced1 (preferred) restaging for delivered) or surveillance or additional pancreatic cancer ● First line 4-6 months or Local progression only 3 ● Systemic therapy or treatment as clinically systemic therapy2 as indicated ● Best supportive care indicated, see Page 6-8 per protocol

3 ● Second line systemic therapy or Metastasis ● Best supportive care

1 Locally advanced defined as: ● Interface between tumor and SMA or celiac greater than 180° ● Interface with aorta ● Unresectable venous occlusion 2 Typically gemcitabine plus paclitaxel or FOLFIRINOX (see Appendix A – Chemotherapy Regimens) 3 See Appendix A – Chemotherapy Regimens 4 See Appendix B – Chemoradiation and Stereotactic Body Radiation Therapy Regimens

Department of Clinical Effectiveness V 6 Approved by the Executive Committee of the Medical Staff on 09/17/2019 Pancreatic Adenocarcinoma Page 6 of 14 Disclaimer: This algorithm has been developed for MD Anderson using a multidisciplinary approach considering circumstances particular to MD Anderson’s specific patient population, services and structure, and clinical information. This is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient's care. This algorithm should not be used to treat pregnant women. Note: Consider Clinical Trials as treatment options for eligible patients

RECURRENCE TREATMENT

Systemic chemotherapy1 Yes

Previous Local disease only at radiation time of recurrence Individualized therapy? Consider chemoradiation2 or SBRT2 surveillance Yes No Symptoms associated to recurrence?

No 1 Systemic chemotherapy and subsequent chemoradiation2 or SBRT2 as clinically indicated

1 See Appendix A – Chemotherapy Regimens 2 See Appendix B – Chemoradiation and Stereotactic Body Radiation Therapy Regimens

Department of Clinical Effectiveness V6 Approved by the Executive Committee of the Medical Staff on 09/17/2019 Pancreatic Adenocarcinoma Page 7 of 14 Disclaimer: This algorithm has been developed for MD Anderson using a multidisciplinary approach considering circumstances particular to MD Anderson’s specific patient population, services and structure, and clinical information. This is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient's care. This algorithm should not be used to treat pregnant women. Note: Consider Clinical Trials as treatment options for eligible patients PRESENTATION TREATMENT

● Clinical trial (preferred) 1 ● FOLFIRINOX if ECOG performance status 0-1 Good performance status 1 2 ● Gemcitabine plus paclitaxel protein-bound if ECOG performance status 0-2 (ECOG 0-1) 1 ● Other gemcitabine doublet if ECOG performance status 0-1 3 ● Olaparib Metastatic disease at presentation Individualized Poor performance status  Best supportive care if ECOG performance status greater than 2 or surveillance or 1 (ECOG ≥ 2)  Gemcitabine alone with or without erlotinib if ECOG performance status 2 additional treatment as clinically Second line therapy: indicated ● Clinical trial (preferred) 1 ● After gemcitabine-based therapy : 1 ○ Liposomal irinotecan plus fluorouracil or 1 Good performance status ○ FOLFIRINOX or 1 1 (ECOG 0-1) ○ mFOLFOX6 or XELOX or 3 ○ Olaparib 1 ● After FOLFIRINOX-based therapy : Metastatic disease 1 ○ Gemcitabine plus paclitaxel protein-bound or after primary 1 other gemcitabine doublet except gemcitabine plus fluorouracil treatment

Poor performance status Best supportive care (ECOG ≥ 2)

ECOG = Eastern Cooperative Oncology Group 1 See Appendix A – Chemotherapy Regimens 2 For patient with ECOG performance status 2, modify dose as appropriate (refer to dosing for average performance status in Appendix A) 3 Olaparib may be used as maintenance treatment in the setting of platinum sensitive tumors with BRCA family mutations and no disease progression during > 16 weeks of first-line, platinum-based chemotherapy Department of Clinical Effectiveness V 6 Approved by the Executive Committee of the Medical Staff on 09/17/2019 Pancreatic Adenocarcinoma Page 8 of 14 Disclaimer: This algorithm has been developed for MD Anderson using a multidisciplinary approach considering circumstances particular to MD Anderson’s specific patient population, services and structure, and clinical information. This is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient's care. This algorithm should not be used to treat pregnant women.

SURVEILLANCE (For patients who had surgery as primary treatment)

Physical Examination Every 6 months for a total of 5 years, then annually for a total of 5 years

1,2 First 3 years: ● Surveillance (portal venous phase) CT abdomen Perform every 6 months ● Chest x-ray ● CA 19-9

1,2 Years 4-5: ● Surveillance (portal venous phase) CT abdomen Perform every 6 months ● CT chest ● CA 19-9

1,2 Years 6-10: ● Surveillance (portal venous phase) CT abdomen Perform annually ● CA 19-9

1 Consider dedicated pancreatic CT protocol, MRI, PET and/or EUS if surveillance CT results are equivocal, e.g., suspicion of recurrence within pancreatic remnant, extrapancreatic local recurrence, question of liver metastases, etc. 2 For patients who cannot undergo contrast enhanced CT (allergy, renal issues, etc.) consider MRI as an alternative

Department of Clinical Effectiveness V6 Approved by the Executive Committee of the Medical Staff on 09/17/2019 Pancreatic Adenocarcinoma Page 9 of 14 Disclaimer: This algorithm has been developed for MD Anderson using a multidisciplinary approach considering circumstances particular to MD Anderson’s specific patient population, services and structure, and clinical information. This is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient's care. This algorithm should not be used to treat pregnant women. Note: Consider Clinical Trials as treatment options for eligible patients

BILIARY OBSTRUCTION 2 ERCP with insertion of a biliary stent(s) if Yes biliary system can be drained

Yes Metastases?

No or Uncertain ERCP with insertion of a plastic or metal biliary stent Pancreatic CT1 Biopsy confirmed Biliary obstruction scan protocol adenocarcinoma?

● ERCP with insertion of plastic stent until biopsy confirmation of malignancy No ● If insertion not technically possible, percutaneous biliary drain with attempt to subsequently insert indwelling plastic or expandable metal stent MECHANICAL GASTRIC OUTLET OBSTRUCTION High3 Duodenal stent with or without radiation therapy

Yes Surgical Life expectancy risk Mechanical gastric > 3 months or Low Surgical bypass outlet obstruction non-extensive metastases? ● Duodenal stent with or without radiation therapy No ● Duodenal stent and/or venting gastrostomy tube

ERCP = endoscopic retrograde cholangiopancreatography 1 For patients who cannot undergo contrast enhanced CT (allergy, renal issues, etc.) consider MRI as an alternative 2 Biliary stent(s) may be metal or plastic 3 Presence of comorbidities and malnutrition Department of Clinical Effectiveness V6 Approved by the Executive Committee of the Medical Staff on 09/17/2019 Pancreatic Adenocarcinoma Page 10 of 14 Disclaimer: This algorithm has been developed for MD Anderson using a multidisciplinary approach considering circumstances particular to MD Anderson’s specific patient population, services and structure, and clinical information. This is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient's care. This algorithm should not be used to treat pregnant women. APPENDIX A: Chemotherapy Regimens

Gemcitabine-based regimens1,2,3: Fluoropyrimidine-based regimens1,2: Gemcitabine4 Gemcitabine plus paclitaxel protein bound (Abraxane®)6 mFOLFOX 6 2 2 ● Gemcitabine 600-750 mg/m IV on Days 1, 8, 15 Good performance status: ● Oxaliplatin 85 mg/m IV over 2 hours on Day 1 2 2 2 7 (fixed dose infusion rate of 10 mg/m /minute preferred) ● Paclitaxel protein-bound 100-125 mg/m IV on Days 1, 8, 15 ● Leucovorin 400 mg/m IV over 2 hours on Day 1 2 2 7 ● With or without erlotinib 100 mg PO daily ● Gemcitabine 600-750 mg/m IV on Days 1, 8, 15 ● Fluorouracil 400 mg/m IV bolus on Day 1 , then 2 2 ● Repeat every 28 days (fixed dose infusion rate of 10 mg/m /min preferred) fluorouracil 2,400 mg/m IV continuous infusion over 46 hours GemCis - gemcitabine and cisplatin ● Repeat every 28 days ● Repeat every 14 days 2 ● Gemcitabine 600-750 mg/m IV on Day 1 (fixed dose Average performance status: XELOX or CapeOx 2 2 2 infusion rate of 10 mg/m /min preferred) ● Paclitaxel protein-bound 125-175 mg/m IV on Day 1 ● Capecitabine 1,500-1,800 mg/m PO divided twice daily on 2 2 ● Cisplatin 30 mg/m IV over 60 minutes on Day 1 ● Gemcitabine 600-750 mg/m IV on Day 1 Days 1-14, then 2 2 ● Repeat every 14 days (fixed dose infusion rate of 10 mg/m /min preferred) ● Oxaliplatin 85-100 mg/m IV over 2 hours on Day 1 ● Repeat every 14 days GemCape - gemcitabine and capecitabine4 ● Repeat every 21 days 2 ● Gemcitabine 600-750 mg/m IV on Days 1 and 8 GTX FOLFIRINOX4,6 2 2 2 (fixed dose infusion rate of 10 mg/m /minute preferred) ● Gemcitabine 300-400 mg/m IV on Days 4 and 11 ● Oxaliplatin 75-85 mg/m IV over 2 hours on Day 1 2 2 2 ● Capecitabine 1,500-1,800 mg/m /day PO divided twice (fixed dose infusion rate of 10 mg/m /minute preferred) ● Irinotecan 125-180 mg/m IV over 90 minutes on Day 1 2 2 7 daily on Days 1-14 ● Docetaxel 30-40 mg/m IV on Days 4 and 11 ● Leucovorin 400 mg/m IV over 2 hours on Day 1 2 2 7 ● Repeat every 21 days ● Capecitabine 1,000 mg/m /day PO divided twice daily on Fluorouracil 400 mg/m IV bolus on Day 1 , then GemCape - gemcitabine and capecitabine4 Days 1-14 fluorouracil 2,400 mg/m2 IV continuous infusion over 46 hours (dosing from ESPAC 4 in the adjuvant setting) ● Repeat every 21 days ● Repeat every 14 days 2 ● Gemcitabine 1,000 mg/m IV over 30 minutes weekly on Liposomal irinotecan (Onivyde®) plus 5-fluorouracil8 5 2 Days 1, 8, and 15 (fixed dose infusion rate of GemOx - gemcitabine and oxaliplatin ● Liposomal irinotecan 70 mg/m IV over 90 minutes on Day 1 2 2 2 7 10 mg/m /minute preferred) ● Gemcitabine 600-750 mg/m IV on Day 1 ● Leucovorin 400 mg/m IV over 2 hours on Day 1 2 2 2 7 ● Capecitabine 1,660 mg/m /day PO in divided doses on (fixed dose infusion rate of 10 mg/m /minute preferred) ● Fluorouracil 400 mg/m IV bolus on Day 1 , then 2 2 Days 1-21 ● Oxaliplatin 85 mg/m IV over 2 hours on Day 1 ● Fluorouracil 2,400 mg/m IV continuous infusion over 46 hours ● Repeat every 28 days ● Repeat every 14 days ● Repeat every 14 days

1 For gemcitabine-based and fluorouracil-based regimen, combination chemotherapy is preferred over monotherapy in the preoperative setting 6 Typical pre-operative neoadjuvant regimens: gemcitabine plus paclitaxel or FOLFIRINOX 2 Dosing should be started at the lower level and modified as patient tolerates 7 Many MD Anderson GI Oncologists omit the bolus of fluorouracil/leucovorin 3 If fixed dose infusion rate not utilized, administer gemcitabine 1,000 mg/m2 over 30 minutes 8 FDA approved for the treatment of metastatic adenocarcinoma of the pancreas in 4 Typical post-operative adjuvant regimens: FOLFIRINOX or GemCape or single-agent gemcitabine (depending on response and recovery) combination with fluorouracil and leucovorin 5 Many MD Anderson GI Oncologists omit Day 15 Department of Clinical Effectiveness V6 Approved by the Executive Committee of the Medical Staff on 09/17/2019 Pancreatic Adenocarcinoma Page 11 of 14 Disclaimer: This algorithm has been developed for MD Anderson using a multidisciplinary approach considering circumstances particular to MD Anderson’s specific patient population, services and structure, and clinical information. This is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient's care. This algorithm should not be used to treat pregnant women.

APPENDIX B: Chemoradiation and Stereotactic Body Radiation Therapy (SBRT)

Chemoradiation Regimens Long course chemoradiation ● Total dose 50 Gy in 25 fractions or 50.4 Gy in 28 fractions 1 2 ● Concurrent capecitabine 1,650 mg/m PO in two divided doses on each day of radiation or 2 2 ● Concurrent gemcitabine 300-400 mg/m IV given at fixed dose infusion once weekly

Short course chemoradiation ● Total dose 30 Gy in 10 fractions 1 2 ● Concurrent capecitabine 1,650 mg/m PO in two divided doses on each day of radiation or 2 2 ● Concurrent gemcitabine 300-400 mg/m IV given at fixed rate dose infusion once weekly

Hypofractionated chemoradiation ● Total dose 60-67.5 Gy in 15 fractions 1 2 ● Concurrent capecitabine 1,650 mg/m PO in two divided doses on each day of radiation ● Requires image guidance

SBRT

● Total dose 33 – 40 Gy in five fractions ● Usually requires fiducials ● Requires daily image guidance

1 Infusional fluorouracil may be used instead 2 If fixed dose infusion rate of 10 mg/m2/minute not utilized, administer gemcitabine over 30 minutes

Department of Clinical Effectiveness V6 Approved by the Executive Committee of the Medical Staff on 09/17/2019 Pancreatic Adenocarcinoma Page 12 of 14 Disclaimer: This algorithm has been developed for MD Anderson using a multidisciplinary approach considering circumstances particular to MD Anderson’s specific patient population, services and structure, and clinical information. This is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient's care. This algorithm should not be used to treat pregnant women.