Pancreatic%20cancer Treatment

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

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

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 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

¹Preferred agent as recommended by NCCN clinical practice guidelines on pancreatic adenocarcinoma. Version 1.2022
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

Relationship between tumour response to systemic therapy and overall survival in unresectable hepatocellular carcinoma

Dr Raghav Sundar, 09 Sep 2019

Overall survival (OS) is currently the primary criteria in assessing the efficacy of a cancer treatment. Dr Raghav Sundar, a consultant medical oncologist at the National University Hospital, Singapore, details the crucial role played by tumour response in evaluating treatment efficacy, with a focus on the multiple kinase inhibitor lenvatinib in the treatment of hepatocellular carcinoma (HCC).

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