Pancreatic%20cancer Treatment

• Systemic therapy is utilized in all stages of PC
  • Includes neoadjuvant therapy, adjuvant therapy and 1st-line or subsequent therapy for locally advanced, metastatic and recurrent PC
• Patients previously given neoadjuvant therapy may receive adjuvant therapy after surgery for additional chemotherapy
  • Choice for adjuvant therapy should be based on the response to neoadjuvant therapy
  • Patients may be eligible for adjuvant therapy after neoadjuvant therapy given that adequate recovery is seen and without evidence of metastatic or recurrent disease
• Patients with locally advanced or metastatic pancreatic adenocarcinoma as confirmed on biopsy are recommended to undergo tumor molecular profiling, MSI and/or MMR testing on available tumor tissue prior to treatment
• Patients with BRCA1/2 mutations have improved responses to platinum-based therapies
• Before starting adjuvant chemotherapy, perform a full restaging scan which includes postoperative CT of the chest, abdomen and pelvis with contrast and CA 19-9 level to exclude metastatic disease
  • Restaging with imaging is also recommended after systemic therapy if chemoradiation is planned

Neoadjuvant Therapy

• Recommended for pancreatic cancer patients with borderline resectable tumors
• Recommended for patients with biopsy-confirmed resectable PC with poor prognostic or high-risk features
  • Has the advantage of sterilizing the field before resection potentially reducing spread during surgery and increase rates of R0 resection
• Improves overall survival of patients
  • Studies show decrease in tumor size prior to surgery
  • Improves tumor condition from borderline resectable to resectable status
  • Studies have shown a decrease in fistula-related morbidity rates after neoadjuvant treatment

• May be done with chemotherapy alone or with radiation therapy
• Helps categorize patients who are responsive to therapy
• Has shown potential for treatment of early stages of micrometastases
• Confirmation with biopsy is necessary before initiating neoadjuvant therapy
  • Repeat biopsy is recommended if initial results do not confirm cancer
  • Staging laparoscopy may be performed to evaluate for metastatic disease before neoadjuvant therapy
• Patients should be assessed for jaundice before initiating neoadjuvant therapy
  • Stent placement is recommended in patients with jaundice prior to initiation of neoadjuvant therapy
• Imaging such as pancreatic protocol CT or MRI of the abdomen, and chest/pelvic CT is recommended after neoadjuvant therapy to determine adequate staging and resectability status

Recommended Chemotherapeutic Regimens

• FOLFIRINOX^1,2 or modified FOLFIRINOX^1,2 with or without subsequent chemoradiation
  • Recommended also for patients with known BRCA1/2 or PALB2 mutations
• Gemcitabine + Cisplatin with or without subsequent chemoradiation for patients with known BRCA1/2 or PALB2 mutations
• Gemcitabine + albumin-bound Paclitaxel¹ with or without subsequent chemoradiation

Gemcitabine + Albumin-bound Paclitaxel

• Recommended as an option for neoadjuvant treatment of resectable or borderline resectable tumors 
• Administration of neoadjuvant treatment with Gemcitabine may help reduce the size and margin of the tumor in patients with resectable PC

FOLFIRINOX

• Treatment option as neoadjuvant therapy in patients with resectable or borderline resectable tumors
• Also recommended for patients with known BRCA1/2 or PALB2 mutations
• Limited to patients with ECOG 0-1

Adjuvant Therapy

• Must be initiated within 12 weeks after adequate recovery from surgery
  • 80% of patients experience disease recurrence at a distant site after resection
• Adjuvant treatment options for patients without previous neoadjuvant therapy and with no evidence of metastatic or recurrent disease include:
  • Clinical trial (preferred) or
  • Chemotherapy or
  • Induction chemotherapy followed by chemoradiation with or without subsequent chemotherapy
• Adjuvant treatment options for patients with previous neoadjuvant therapy and without evidence of metastatic or recurrent disease include additional chemotherapy and/or chemoradiation if with positive margin R1 resection 
• Chemoradiotherapy is preferred as compared to R1 surgical resection for tumors with high possibility for locoregional recurrence and metastasis
• Gemcitabine monotherapy have shown to significantly improve median overall survival
  • Has shown significant improvements in disease-free survival and overall survival based on the CONKO 001trial
• There is no significant difference in overall survival between 5-FU/Leucovorin and Gemcitabine based on the ESPAC-3 study
• There is no significant difference between pre- and post-chemoradiation with 5-FU and pre- and post-chemoradiation with Gemcitabine for adjuvant treatment

Recommended Chemotherapeutic Regimens

• Preferred regimens include modified FOLFIRINOX or Gemcitabine + Capecitabine
  • Modified FOLFIRINOX yielded superior outcomes in terms of median disease-free survival and overall survival compared to Gemcitabine monotherapy based on the PRODIGE-24 study
  • Gemcitabine + Capecitabine is found to be more superior as adjuvant therapy compared to Gemcitabine monotherapy based on the ESPAC study
• Other recommended regimens include:
  • Continuous infusion 5-FU
  • Induction therapy with continuous infusion 5-FU followed by chemoradiation with or without subsequent continuous infusion 5-FU
  • 5-FU + Leucovorin
  • Induction chemotherapy with bolus 5-FU + Leucovorin followed by chemoradiation with or without subsequent bolus 5-FU + Leucovorin
  • Capecitabine
  • Gemcitabine
  • Induction chemotherapy with Gemcitabine followed by chemoradiation with or without subsequent Gemcitabine
  • S-1 (Tegafur, Gimeracil, Oteracil) is used in Asia as an alternative to Gemcitabine-based therapies

• Treatment depends on performance status of the patient
  • Patients with good performance status and Eastern Cooperative Oncology Group (ECOG) score of 0-2 may undergo chemotherapy and CRT
  • Patients with good performance: ECOG 0-1, good biliary drainage and adequate nutritional intake or ECOG 0-2 (if considering Gemcitabine + albumin-bound Paclitaxel)
• Patients with good performance status
  • If available, clinical trial participation is recommended
  • Other treatment options include systemic therapy, induction chemotherapy followed by chemoradiation or stereotactic body radiotherapy (SBRT), or chemoradiation or SBRT in select patients who are not suitable for combination treatment
  • Recommended 1st-line chemotherapeutic regimens include:
    • Continuous infusion 5-FU
    • Capecitabine
    • Fluoropyrimidine + Oxaliplatin [eg Capecitabine + Oxaliplatin (CapeOx), 5-FU + Leucovorin + Oxaliplatin (OFF)]
    • FOLFIRINOX^1,2 or modified FOLFIRINOX^1,2 and also recommended for BRCA1/2 or PALB2 mutations
    • Gemcitabine
    • Gemcitabine + Capecitabine
    • Gemcitabine + Cisplatin¹ (for BRCA1/2 or PALB2 mutations)
    • Gemcitabine, Docetaxel, Capecitabine (GTX) (fixed-dose-rate)
    • Gemcitabine + Erlotinib
    • Gemcitabine + albumin-bound Paclitaxel^1,3
    • Gemcitabine + albumin-bound Paclitaxel + Cisplatin
    • S-1
• Patients with poor performance status
  • Treatment options include palliative and supportive care and monotherapy or palliative RT
  • Recommended 1st-line chemotherapeutic regimens of unresectable/locally advanced tumors include:
    • Capecitabine¹
    • Continuous infusion 5-FU¹
    • Gemcitabine¹

Metastatic Tumors

• Treatment depends on performance status of the patient
• Patients with response or stable disease after 4-6 months of chemotherapy may undergo maintenance therapy
• Patients with good performance status
  • Participation in a clinical trial is the preferred treatment option
  • Other treatment option is systemic therapy
  • Recommended 1st-line chemotherapeutic regimens include:
    • Fluoropyrimidine + Oxaliplatin (eg CapeOx, OFF)
    • FOLFIRINOX^1,2 or modified FOLFIRINOX^1,2 and also recommended for BRCA1/2 or PALB2 mutations
    • Gemcitabine
    • Gemcitabine + Capecitabine
    • Gemcitabine + Cisplatin¹ for BRCA1/2 or PALB2 mutations
    • GTX (fixed-dose-rate)
    • Gemcitabine + Erlotinib
    • Gemcitabine + albumin-bound Paclitaxel¹
    • Gemcitabine + albumin-bound Paclitaxel + Cisplatin
    • S-1
    • Pembrolizumab for MSI-H, dMMR or high tumor mutational burden [TMB-H (≥10 mutations/Mb)] tumors
  • Recommended maintenance therapeutic regimens include:
    • 5-FU ± Irinotecan (option for patients with Oxaliplatin allergy or Oxalipatin-related progressive neuropathy) or continuous infusion 5-FU + Leucovorin + Oxaliplatin (FOLFOX) or Capecitabine in patients who received FOLFIRINOX as 1st-line therapy
    • Gemcitabine monotherapy or Gemcitabine + albumin-bound Paclitaxel modified in patients who received Gemcitabine + albumin-bound Paclitaxel as 1st-line therapy
    • Olaparib¹ in patients with BRCA1/2 mutations and with previous platinum-based chemotherapy
    • Rucaparib in patients with BRCA1/2 or PALB2 mutations and without disease progression after previous platinum-based chemotherapy
• Patients with poor performance status
  • Treatment options include palliative and supportive care and monotherapy or targeted therapy considering molecular profile or palliative RT
  • Recommended 1st-line chemotherapeutic regimens include:
    • Capecitabine¹
    • Entrectinib [for neurotropin receptor kinase (NTRK) gene fusion-positive patients]
    • Continuous infusion 5-FU¹
    • Gemcitabine¹
    • Larotrectinib (for NTRK gene fusion-positive patients)
    • Pembrolizumab (for MSI-high [MSI-H], dMMR or TMB-H tumors)

Subsequent Therapy for Patients with Locally Advanced, Metastatic or Recurrent Tumors

• Choice of regimen is dependent on previous chemotherapy and performance status of the patient
• Patients with good performance status
  • Participation in clinical trial is preferred in patients with disease progression
  • Other treatment options for patients with disease progression include systemic therapy or targeted therapy based on molecular profile or RT for severe pain unresponsive to analgesic therapy
  • Preferred regimens include:
    • Entrectinib or Larotrectinib in patients with NTRK gene fusion-positive tumors
    • Pembrolizumab in patients with MSI-H, dMMR or TMB-H tumors
  • Recommended chemotherapeutic regimens for patients if with previous Gemcitabine-based therapy include:
    • Continuous infusion 5-FU
    • 5-FU + Leucovorin + liposomal Irinotecan
    • Capecitabine
    • CapeOx
    • FOLFIRI (5-FU + Leucovorin + Irinotecan)
    • FOLFIRINOX² or modified FOLFIRINOX²
    • FOLFOX
    • OFF
  • Recommended chemotherapeutic regimens for patients if with previous Fluoropyrimidine-based therapy include:
    • 5-FU + Leucovorin + liposomal Irinotecan (if without previous Irinotecan therapy)
    • Gemcitabine
    • Gemcitabine + Cisplatin for known BRCA1/2 or PALB2 mutations
    • Gemcitabine + Erlotinib
    • Gemcitabine + albumin-bound Paclitaxel³
    • Gemcitabine + albumin-bound Paclitaxel + Cisplatin
• Patients with poor performance status
  • Treatment options for patients with disease progression include palliative and supportive care and monotherapy or targeted therapy based on molecular profile or palliative RT
  • Preferred regimens include:
    
    • Entrectinib or Larotrectinib in patients with NTRK gene fusion-positive tumors
    • Pembrolizumab in patients with MSI-H or dMMR tumors
  • Recommended chemotherapeutic regimens include continuous infusion 5-FU or Capecitabine or Gemcitabine

5-FU

• Recommended as 1st-line and subsequent treatment option for patients with locally advanced pancreatic caner and patients with poor performance with metastatic pancreatic cancer
• With or without Irinotecan as maintenance treatment option in patients with metastatic disease who did not progress during 1st-line treatment with FOLFIRINOX
  • Option for patients with Oxaliplatin-related progressive neuropathy or allergy

Capecitabine

• Recommended option for patients with locally advanced and metastatic pancreatic cancer
  • 1st-line treatment option for patients with locally advanced disease or metastatic disease with poor performance status 
  • Subsequent treatment option for patients with locally advanced unresectable and metastatic pancreatic cancer after Gemcitabine-based 1st-line treatment
  • Maintenance treatment option in patients with metastatic disease who did not progress during 1st-line treatment with FOLFIRINOX

• Showed significant improvement in overall survival in patients with advanced pancreatic cancer

Capecitabine + Oxaliplatin (CapeOx)

• Subsequent treatment option for patients with locally advanced and metastatic pancreatic cancer with good performance status after Gemcitabine-based 1st-line treatment

Entrectinib

• NTRK inhibitor
• Recommended in the 1st-line treatment of metastatic disease with poor performance and subsequent treatment of locally advanced or metastatic disease in patients with known NTRK gene fusion-positive tumors

Fluoropyrimidine (5-FU + Leucovorin or Capecitabine) + Oxaliplatin

• Includes CapeOx, OFF and modified FOLFOX
• Treatment option as 1st-line therapy for patients with locally advanced or metastatic PC 
• Subsequent treatment option for patients with locally advanced and metastatic pancreatic cancer after Gemcitabine-based 1st-line treatment
• Modified FOLFOX may extend the overall survival in patients with advanced Gemcitabine-refractory pancreatic cancer

FOLFIRINOX

• Recommended as 1st-line therapy for patients with locally advanced and metastatic pancreatic cancer with good performance status
• May be considered in patients with ECOG performance status 0-1 with bilirubin level <1.5 x  upper limit of normal (ULN)
• May be used in patients with PALB2 and BRCA1/BRCA2-related pancreatic cancer and pancreatic acinar cell carcinoma
• Several studies show that this combination has anti-tumor activity and promising response rates in patients with locally advanced unresectable disease, anti-tumor activity, >30% response rate, and dramatic improvements in median progression-free survival and objective response rates in patients with metastatic pancreatic cancer
• Modified FOLFIRINOX wherein the initial doses of bolus 5-FU and Irinotecan are reduced by 25% resulted insignificantly decreased toxicity rates
  

FOLFOX

• Subsequent treatment option for patients with locally advanced unresectable and metastatic pancreatic cancer after Gemcitabine-based first-line treatment
• Maintenance treatment option in patients with metastatic disease who did not progress during 1st-line treatment with FOLFIRINOX
  • Option for patients with Irinotecan-related gastrointestinal toxicity

Gemcitabine

• Monotherapy is recommended in the following:
  • Option for front-line treatment in patients with locally advanced or metastatic disease with good performance status 
  • Option for 1st-line and subsequent therapy of symptomatic patients with locally advanced and metastatic unresectable pancreatic cancer with poor performance status
  • Maintenance treatment option in patients with metastatic disease who did not progress during 1st-line treatment with Gemcitabine + albumin-bound Paclitaxel
• Studies show that there was an increase in the median survival rate with fixed-dose rate regimen compared with standard therapy
• Subsequent treatment option for patients with locally advanced and metastatic pancreatic cancer after 5-FU-based 1st-line treatment
• May be considered in patients with ECOG performance status 2 and/or bilirubin level >1.5 x ULN

Gemcitabine + Albumin-bound Paclitaxel

• Recommended for the treatment of pancreatic cancer patients with locally advanced and metastatic disease and good performance status
• May be considered in patients with ECOG performance status 2 due to heavy tumor load and in patients with ECOG performance status 0-1 with bilirubin level <1.5 x ULN
• Studies have shown that addition of albumin-bound Paclitaxel to Gemcitabine significantly improved overall survival, response rate, and progression-free survival rates, with up to 42 months long-term overall survival reported

Gemcitabine + Erlotinib

• Recommended option for patients with locally advanced or metastatic pancreatic cancer with good performance status
• Significant improvement in overall survival and progression-free survival were seen in patients with advanced pancreatic cancer who received this combination

Gemcitabine + Capecitabine

• Considered as a treatment option for pancreatic cancer patients with locally advanced metastatic disease with good performance status who are willing to undergo more aggressive treatment regimens

Gemcitabine + Cisplatin

• Recommended option for patients with locally advanced or metastatic disease with known BRCA1/2 or PALB2 mutations

GTX Regimen

• Recommended option for patients with locally advanced or metastatic pancreatic cancer and good performance status
• May improve overall response rate
• Adverse effects include grade 3/4 leukopenia, grade 3/4 anemia and grade 3/4 thrombocytopenia

Larotrectinib

• NTRK inhibitor
• Recommended in the 1st-line treatment of metastatic disease with poor performance and subsequent treatment of locally advanced or metastatic disease in patients with known NTRK gene fusion-positive tumors

Olaparib

• An oral poly (ADP-ribose) polymerase (PARP) inhibitor recommended for maintenance therapy in patients with metastatic disease with known BRCA1/2 mutations who did not progress during 1st-line treatment with platinum-based therapies

Pembrolizumab

• An anti-PD-1 receptor antibody which improves antitumor immunity by blocking interaction with PD-L1 and PD-L2 and releasing PD-1-mediated inhibition of the immune response
• Recommended in the 1st-line treatment of metastatic disease with poor performance and subsequent treatment of metastatic disease in patients with known MSI-H or dMMR tumors

Rucaparib

• An oral poly (ADP-ribose) polymerase (PARP) inhibitor recommended for maintenance therapy in patients with metastatic disease with known BRCA1/2 mutations who did not progress during 1st-line treatment with platinum-based therapies

S-1 (Tegafur-Gimeracil-Oteracil)

• A reasonable alternative following postsurgical resection for metastatic pancreatic adenocarcinoma
• A combination that reduced the GI adverse effects of 5-FU

Sotorasib

• A specific RAS G12C inhibitor which may be used for patients with RAS G12C mutation and have progressed on initial chemotherapy

Recurrence After Resection

• Confirmatory biopsy is recommended prior to treatment
• Genetic testing for inherited mutations and molecular profiling of tumor tissue if not done previously are also recommended prior to treatment

Local Recurrence

• No specific recommendations for locally recurrent PC
• Surgery is an option for select patients such as patients with good performance status or location of recurrenceis in the pancreas only
• Clinical trial is preferred
• Additional options include palliative and supportive care without additional therapy
  • Option for patients with poor performance status 
• Treatment option for patients with recurrent, unresectable disease include:
  • Systemic therapy followed by chemoradiation or SBRT if not previously done
  • Chemoradiation or SBRT in patients who are not candidates for induction chemotherapy
• Recommended dose in chemoradiation is 45-54 Gy in 1.8-2.0 Gy fractions 
• Reported doses in SBRT include doses of 3 fractions for a total dose of 30-45 Gy or 5 fractions for a total dose of 25-50 Gy
• Chemoradiation is suggested with biopsy-confirmed local recurrence if not previously given
• Chemotherapy is preferred for patients previously given radiation therapy

Metastatic Disease With or Without Local Recurrence

• Indicators for patients at high-risk for metastasis include:
  • Markedly elevated CA 19-9
  • Large primary tumors
  • Large regional lymph nodes
  • Highly symptomatic
  • With borderline resectable tumors 
• Treatment depends on interval after previous therapy
• Supportive care is recommended if alternative chemotherapy and clinical trials are unsuccessful and if patient has a poor performance status
• Recommended therapy for patients with completed therapy ≥6 months prior to diagnosis of recurrence:
  • Clinical trial is preferred 
  • Previous therapeutic regimen
  • Subsequent therapy
    • Gemcitabine-based regimen (eg Gemcitabine + albumin-bound Paclitaxel with or without Cisplatin, Gemcitabine + Erlotinib, Gemcitabine + Cisplatin (for patients with known BRCA1/2 or PALB2 mutations), 5-FU + Leucovorin + liposomal Irinotecan) if previously given Fluoropyrimidine-based therapy
    • Fluoropyrimidine-based regimen (eg CapeOx, FOLFOX, FOLFIRI) if previously given Gemcitabine-based therapy

• For patients with completed therapy <6 months prior to diagnosis of recurrence:
  • Clinical trial is preferred
  • Switching to recommended subsequent therapy
    • Gemcitabine-based regimen if previously given Fluoropyrimidine-based therapy
    • Fluoropyrimidine-based regimen if previously given Gemcitabine-based therapy