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 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
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 + 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
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 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)]
- 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 Paclitaxel1,3
- 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)
- 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
- 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
2Limited to patients with ECOG 0-1
3Reasonable in patients with ECOG 0-2
Management of Recurrence
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