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pancreatic%20cancer
PANCREATIC CANCER
Pancreatic cancer is malignancy arising from the pancreas.
It is the 13th most common cancer in the world, 10th most common in the United States, and 4th leading cause of cancer-related deaths in the United Stated and Europe.
Exocrine tumors account for 95% of malignant pancreatic disease.
It is more common in women.
The median age of occurrence is at 71 years old.

Pancreatic%20cancer Treatment

Principles of Therapy

  • 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 gene 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

Pharmacotherapy

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

  • FOLFIRINOX1,2 or modified FOLFIRINOX1,2 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 + Nab-Paclitaxel1 with or without subsequent chemoradiation

Gemcitabine + Nab-Paclitaxel

  • Recommended as an option for neoadjuvant treatment of 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 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
  • 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
Systemic Therapy
Locally Advanced Tumors
  • 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 SBRT, or chemoradiation or SBRT in select patients who are 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])
      • FOLFIRINOX1,2 or modified FOLFIRINOX1,2 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 Paclitaxel1
      • 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 who will receive combination regimens must have an ECOG score of 0-2 and ECOG score of 0-3 for patients who will receive monotherapy
  • 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)
      • FOLFIRINOX1,2 or modified FOLFIRINOX1,2 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
      • S-1
    • Recommended maintenance therapeutic regimens include:
      • FOLFIRI1 or FOLFOX or Capecitabine in patients who received FOLFIRINOX as 1st-line therapy
      • Gemcitabine monotherapy or Gemcitabine + nab-Paclitaxel modified in patients who received Gemcitabine + nab-Paclitaxel as 1st-line therapy
      • Olaparib in patients with BRCA1/2 mutations and with previous platinum-based chemotherapy
  • Patients with poor performance status
    • Treatment option include palliative and supportive care and monotherapy or targeted therapy considering MSI/MMR status and/or gene profile or palliative RT
    • Recommended 1st-line chemotherapeutic regimens include:
      • Capecitabine1
      •  Entrectinib (for NTRK gene fusion-positive patients)
      • Continuous infusion 5-FU1
      • Gemcitabine1
      • Larotrectinib (for NTRK gene fusion-positive patients)
      • Pembrolizumab (for MSI-high [MSI-H] or dMMR tumors)

Second-Line 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 MSI/MMR status and/or gene profile or RT for severe pain unresponsive to analgesic therapy
    • 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 Paclitaxel
      • Entrectinib or Larotrectinib in patients with NTRK gene fusion-positive tumors
      • Pembrolizumab in patients with MSI-H or dMMR tumors
  • Patients with poor performance status
    • Treatment options for patients with disease progression include palliative and supportive care and monotherapy or targeted therapy based on MSI/MMR status and/or gene profile or palliative RT
    • Recommended chemotherapeutic regimens include continuous infusion 5-FU or Capecitabine or Gemcitabine
    • Entrectinib or Larotrectinib in patients with NTRK gene fusion-positive tumors
    • Pembrolizumab in patients with MSI-H or dMMR tumors

5-FU

  • Recommended as 1st- and 2nd-line treatment option for patients with locally advanced pancreatic caner and patients with poor performance with metastatic pancreatic cancer

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 
    • 2nd-line treatment option for patients with locally advanced unresectable and metastatic pancreatic cancer after Gemcitabine-based 1st-line treatment
  • Showed significant improvement in overall survival in patients with advanced pancreatic cancer

Capecitabine + Oxaliplatin (CapeOx)

  • 2nd-line treatment option for patients with locally advanced pancreatic cancer after Gemcitabine-based 1st-line treatment

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

  • Includes CapeOx (Capecitabine + Oxaliplatin) and modified FOLFOX
  • Treatment option as 1st-line therapy for patients with locally advanced or metastatic PC 
  • 2nd-line 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 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

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- and 2nd-line therapy of symptomatic patients with locally advanced and metastatic unresectable pancreatic cancer with poor performance status
  • Studies show that there was an increase in the median survival rate with fixed-dose rate regimen compared with standard therapy
  • 2nd-line 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 + Nab-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 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

FOLFOX

  • 2nd-line treatment option for patients with locally advanced unresectable and metastatic pancreatic cancer after Gemcitabine-based first-line treatment

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 2nd-line treatment of metastatic disease in patients with known MSI-H or dMMR tumors

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
1Preferred agent as recommended by NCCN clinical practice guidelines on pancreatic adenocarcinoma. Version 1.2020
2Limited to patients with ECOG 0-1

Management of Recurrence

Recurrence After Resection

  • Confirmatory biopsy is recommended prior to treatment
  • Germline testing and gene profiling if not done previously as well as MSI and/or MMR testing on available tumor tissue 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
  • 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:
    • Induction chemotherapy followed by chemoradiation or SBRT if not previously done
    • SBRT in patients with isolated local recurrence
  • Recommended dose in chemoradiation is 45-54 Gy in 1.8-2.0 Gy fractions 
  • 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
    • 2nd-line therapy
      • Gemcitabine-based regimen (eg Gemcitabine + nab-Paclitaxel, Gemcitabine + Erlotinib, 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 2nd-line therapy
      • Gemcitabine-based regimen if previously given Fluoropyrimidine-based therapy
      • Fluoropyrimidine-based regimen if previously given Gemcitabine-based therapy
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