INTRODUCTION — For patients with locally advanced unresectable or metastatic exocrine pancreatic cancer, palliative systemic chemotherapy can improve disease-related symptoms and prolong survival. Options for second-line systemic therapy after progression on a first-line regimen will be reviewed here. Initial palliative systemic chemotherapy, specific methods for symptom palliation, and management of patients with metastatic well-differentiated neuroendocrine (islet cell) tumors are discussed separately. (See "Initial systemic chemotherapy for metastatic exocrine pancreatic cancer" and "Supportive care of the patient with locally advanced or metastatic exocrine pancreatic cancer" and "Endoscopic ultrasound-guided celiac plexus interventions for pain related to pancreatic disease" and "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion".)
SECOND-LINE THERAPY VERSUS SUPPORTIVE CARE ALONE AND PATIENT SELECTION — A limited amount of data support a potential survival benefit for second-line chemotherapy compared with best supportive care alone. The only prospective data come from a trial in which 46 patients failing first-line gemcitabine monotherapy were randomly assigned to best supportive care with or without OFF chemotherapy as follows [1]:
●Oxaliplatin 85 mg/m2 on days 8 and 22
●Leucovorin (LV) 200 mg/m2 over 30 minutes followed by fluorouracil (FU) 2000 mg/m2 over 24 hours, with both drugs given on days 1, 8, 15, and 22
●Courses of chemotherapy repeated every six weeks
The trial was stopped prematurely because of insufficient accrual. However, the treated group had a significantly longer median survival from the start of second-line treatment (4.8 versus 2.3 months) and longer median survival from the start of gemcitabine (9 versus 7.9 months, p = 0.031).
There are no prospective data addressing the survival benefit of second-line therapy after initial therapy with more-intensive first-line regimens (eg, leucovorin plus oxaliplatin and irinotecan and short-term infusional FU [FOLFIRINOX] or gemcitabine-based combinations). (See "Initial systemic chemotherapy for metastatic exocrine pancreatic cancer".)
There is considerable heterogeneity in the survival of patients who receive second-line chemotherapy for advanced pancreatic cancer, and the best way to predict which patients will benefit is not established. Researchers have developed a nomogram to predict overall survival before administration of second-line chemotherapy, which may assist in clinical decision making [2]. In an analysis derived from 462 consecutive patients with advanced pancreatic cancer treated at a single French institution over a 10-year period, age, smoking status, liver metastases, performance status (PS), pain, jaundice, ascites, and duration of first-line and type of second-line chemotherapy regimen were identified as independent prognostic factors for overall survival after second-line chemotherapy. These variables were utilized to develop a prognostic model, the validity of which was confirmed in an external validation cohort. Scores determined three groups with median overall survivals of 11.3, 3.6, and 1.4 months, respectively. By applying the score in the population that was eligible but did not receive second-line chemotherapy, the magnitude of expected chemotherapy benefit was higher in better prognostic groups. The model was then used to develop a nomogram allowing the estimation of median and individual overall survival probabilities following first-line chemotherapy.
In our view, the decision to pursue second-line chemotherapy should be individualized and based on the patient's goals and preferences, and clinical prognostic characteristics such as those delineated in a prognostic nomogram. Factors influencing the choice of second-line therapy include the regimen used for first-line therapy, patient preference, and clinical characteristics, including PS (table 1) and comorbidity.
GENERAL PRINCIPLES — For patients being considered for second-line palliative systemic therapy, multiphasic computed tomography (CT) scan of the chest, abdomen, and pelvis should be performed to assess disease extent prior to initiating treatment [3]. Other staging studies should be performed only as dictated by symptoms. Serum levels of the tumor marker carbohydrate antigen 19-9 (CA 19-9; also called cancer antigen 19-9), if elevated, may be used to follow disease status during chemotherapy. (See "Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer", section on 'Abdominal CT' and "Initial systemic chemotherapy for metastatic exocrine pancreatic cancer", section on 'Response assessment'.)
All patients with metastatic pancreatic cancer should be offered aggressive treatment for pain and other symptoms related to the cancer. Referral for a palliative care consultation should be considered early in the treatment course, especially for patients with a high symptom burden. Early initiation of palliative care services improves clinical and quality of care outcomes and may prolong survival. (See "Supportive care of the patient with locally advanced or metastatic exocrine pancreatic cancer" and "Benefits, services, and models of subspecialty palliative care", section on 'Rationale for palliative care'.)
For patients with metastatic pancreatic cancer, genomic (ie, germline) testing (if not already known) and gene profiling of tumor tissue (ie, with next-generation sequencing) should be undertaken as quickly as possible after diagnosis because of the significant treatment implications both for first-line therapy and beyond [3]. (See "Initial systemic chemotherapy for metastatic exocrine pancreatic cancer", section on 'Germline and targeted tumor genomic testing' and 'Deficient mismatch repair or high tumor mutational burden' below.)
All patients should be offered information about clinical trials. Enrollment in clinical trials is preferred, if available. If protocol treatment is not available or participation is not feasible, chemotherapy is an option for patients with an adequate performance status (PS), controlled comorbidity, and a sufficient support system. Patients should understand that chemotherapy is palliative and not curative. Goals of care, patient preferences, treatment response, symptom burden, and psychosocial issues (including the patient's support system) should guide decisions for treatment [3]. (See "Discussing goals of care".)
If protocol treatment is not available or is declined, we base our treatment choice for second-line therapy on clinical characteristics, including PS and comorbidity, the presence or absence of germline or tumoral (somatic) alterations in genes associated with homologous recombination repair deficiency such as breast cancer-associated gene (BRCA) and partner and localizer of BRCA2 (PALB2), histology, which regimen was used for first-line therapy, and patient preference, as outlined in the following sections.
ADEQUATE PERFORMANCE STATUS AND COMORBIDITY
Molecularly-targeted therapy
BRCA or PALB2 mutation carriers and other homologous recombination repair deficiency alterations — Pancreatic cancers that arise in the setting of an inherited mutation in breast cancer-associated (BRCA1, BRCA2) or partner and localizer of BRCA2 (PALB2) genes, and those with tumoral (somatic) mutations in these genes are associated with a defective DNA damage response, which increases sensitivity to DNA damaging agents such as platinum agents, and to drugs targeting the DNA damage response pathway, including poly(ADP-ribose) polymerase (PARP) inhibitors [4]. (See "Initial systemic chemotherapy for metastatic exocrine pancreatic cancer", section on 'Germline and targeted tumor genomic testing' and "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Inherited cancer susceptibility syndromes'.)
Most patients who have germline or somatic mutations in BRCA or PALB2 or other pathogenic or likely pathogenic variants in genes associated with homologous recombination repair deficiency (eg, ATM, BAP1, BARD1, BLM, BRIP1, CHEK2, FAM175A, FANCA, FANCC, NBN, RAD50, RAD51, RAD51C, and RTEL1) will have received a platinum-containing regimen for first-line therapy (eg, gemcitabine plus cisplatin, leucovorin [LV] plus oxaliplatin and short-term infusional fluorouracil [FU; FOLFOX], or FOLFIRINOX). For individuals with germline BRCA or PALB2 mutations without disease progression after at least 16 weeks of platinum-based chemotherapy, maintenance therapy with the PARP inhibitor olaparib may have been initiated. (See "Initial systemic chemotherapy for metastatic exocrine pancreatic cancer", section on 'Patients with homologous recombination repair deficiency'.)
At the time of disease progression, options include retreatment with the initial platinum-based regimen (if the patient was being maintained on a PARP inhibitor) or administration of a different platinum-containing regimen than what was administered first line (eg, FOLFOX for patients who previously received gemcitabine plus cisplatin, or vice versa). (See "Initial systemic chemotherapy for metastatic exocrine pancreatic cancer".)
For patients who did not receive initial platinum-based chemotherapy, we suggest treatment with a platinum-based chemotherapy regimen for second-line therapy (eg, gemcitabine plus cisplatin, FOLFOX (table 2), FOLFIRINOX (table 3), or modified FOLFIRINOX (table 4). (See "Initial systemic chemotherapy for metastatic exocrine pancreatic cancer", section on 'Platinum-based chemotherapy'.)
Another option, for patients who did not receive maintenance olaparib, is a PARP inhibitor. The available data on second-line PARP inhibitors after platinum-based chemotherapy are limited, but expanding [5-7]. As an example, in a preliminary report of a Targeted Agent and Profiling Utilization Registry (TAPUR) study cohort of 30 patients with advanced pancreatic cancer, germline or somatic BRCA1/2 inactivating mutations, and no standard treatment options (53 percent had received three or more prior lines of therapy) who received olaparib monotherapy (300 or 400 mg daily), there was one objective response and seven patients with stable disease (disease control rate 31 percent, objective response rate 4 percent) [7]. The median progression-free survival (PFS) was 8.1 weeks, but 47 percent were still alive at one year.
Whether outcomes are as favorable in patients who have pathogenic or likely pathogenic variants in genes other than BRCA that are associated with homologous recombination repair deficiency (eg, ATM, BAP1, BARD1, BLM, BRIP1, CHEK2, FAM175A, FANCA, FANCC, NBN, PALB2, RAD50, RAD51, RAD51C, and RTEL1) is unclear [8]. Experience is limited and further study of this population is warranted.
Notably, treatment with a PARP inhibitor in patients with advanced pancreatic cancer and a homologous recombination repair deficiency is not US Food and Drug Administration (FDA) approved and has not yet been considered a standard approach after failure of initial cytotoxic chemotherapy. Several trials examining this strategy are underway, and eligible patients should be encouraged to enroll. Outside of a protocol setting, in our view, for patients who do not undergo maintenance therapy with olaparib after first-line platinum-containing chemotherapy, the use of a PARP inhibitor is reasonable off label, especially in patients with a BRCA1 or 2 pathogenic or likely pathogenic variant.
Deficient mismatch repair or high tumor mutational burden — Immunotherapeutic approaches to cancer therapy are based on the premise that the immune system plays a key role in surveillance and eradication of malignancy and that tumors evolve ways to elude the immune system. (See "Principles of cancer immunotherapy".)
Some cancers with deficient mismatch repair (dMMR; the biologic footprint of which is high levels of microsatellite instability [MSI-H]) are particularly sensitive to immune-based therapies. These tumors, which have high levels of tumor mutational burden (TMB), are thought to be more immunogenic and responsive to immune checkpoint inhibitor immunotherapy. Objective, in some instances complete, and durable responses to immune checkpoint inhibitors targeting the programmed cell death receptor 1 (PD-1; eg, pembrolizumab) have been reported in a variety of patients with MSI-H cancers, including pancreatic cancers [9-11]. As an example, in the phase II KEYNOTE-158 study, which enrolled 22 patients with pancreatic cancer [11], there were four objective responses (18 percent), one of which was complete, and the median duration of response was 13.4 months.
In the United States, pembrolizumab is now approved for treatment of a variety of advanced solid tumors, including pancreatic cancers, that are MSI-H or dMMR, that have progressed following prior treatment, and for which there are no satisfactory alternative treatment options, the first such approval of a tissue-agnostic anticancer treatment. Updated year 2020 guidelines from the American Society of Clinical Oncology (ASCO) endorse use of pembrolizumab as second-line therapy for individuals with MSI-H/dMMR tumors [3]. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors".)
Unfortunately, ≤2 percent of advanced pancreatic cancers have dMMR [10,12]. In other, unselected patients with advanced pancreatic cancer, the benefits of immunotherapy have not been established, and such treatment remains investigational [13].
An important point is that MSI-H or dMMR may indicate the presence of Lynch syndrome, an inherited condition that predisposes to several cancers, including pancreatic cancer. All patients with an MSI-H/dMMR pancreatic cancer should undergo germline genetic assessment for Lynch syndrome, regardless of age or family history [14]. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis", section on 'Microsatellite instability testing'.)
While the vast majority of dMMR tumors have high TMB, not all TMB-high tumors have dMMR. There is increasing evidence of the benefit of immune checkpoint inhibitors in this population, and pembrolizumab is now also approved for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that are tissue TMB high (≥10 mut/Mb) by an FDA-approved assay. Unfortunately, very few pancreatic cancers are proficient mismatch repair (pMMR)/TMB high, and it is not clear that they respond to immune checkpoint inhibitor immunotherapy [15]. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Frequency of high TMB across tumor types' and "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors", section on 'Tumors with high mutational burden'.)
Next generation sequencing and targeted therapy — Several ongoing trials (eg, the National Cancer Institute Molecular Analysis for Therapy Choice [NCI-MATCH] and ASCO TAPUR trials) are using next-generation sequencing of multiple genes (gene panel tests) to identify molecular abnormalities in the tumors of patients with refractory cancers that may potentially match molecularly targeted therapies that are either in clinical trials or approved for treatment of other cancer types. Two such gene panel tests (the Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets [MSK-IMPACT] and the FoundationOne CDx [F1CDx]) are FDA approved in the United States. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications", section on 'Cancer screening and management'.)
In the setting of advanced pancreatic cancer, genomic (germline) or somatic tumor testing may identify potentially actionable alterations for which a clinical trial is available evaluating a targeted therapy that is approved for another type of cancer. It is estimated that approximately 25 percent of pancreatic cancers harbor potentially actionable molecular alterations, and that the adoption of precision medicine using molecularly guided treatments targeting oncogenic drivers and the DNA damage response and repair pathway can have a substantial impact on survival in patients with advanced pancreatic cancer [16].
We prefer that these patients be enrolled in clinical trials, given that simply having a potentially targetable mutation does not guarantee that the patient will benefit from a therapy that presumably targets that mutation [17]. However, targeted testing may also reveal other molecular abnormalities for which an approved treatment is available, as described in the sections below.
RET fusion-positive tumors — Selpercatinib is an option for advanced pancreatic cancer with a rearranged during transfection (RET) gene fusion and disease progression on or following prior systemic treatment. Efficacy in 45 patients with a variety of solid tumors containing a RET fusion gene was addressed on the LIBRETTO-001 basket trial [18]. In the entire cohort, the objective response rate was 44 percent, and median duration of response was 24.5 months; six of the 11 patients with advanced pancreatic cancer had a partial response (54 percent), and the median duration of response had not been reached with a median 14.9 months of follow-up. The most common grade ≥3 treatment-emergent adverse effects were hypertension and transaminase elevation.
In September 2022, the US FDA granted a tissue-agnostic, accelerated approval to selpercatinib for adult patients with locally advanced or metastatic solid tumors with a RET gene fusion and disease progression on or following prior systemic treatment who have no satisfactory alternative treatment options. Unfortunately few patients with advanced pancreatic cancer (0.6 percent in one review of 160 patients [19]) harbor a RET gene fusion.
TRK fusion-positive cancers — The tropomyosin receptor kinase (TRK) inhibitors larotrectinib and entrectinib are approved broadly for cancers of any histology or origin that have a chromosomal rearrangement in one of the neurotrophic tyrosine receptor kinase (NTRK) genes that are responsible for encoding the TRK proteins, resulting in a constitutively activated TRK fusion protein. Although one of these chromosomal rearrangements is rarely found in pancreatic ductal adenocarcinomas (detected in 0.34 and 0.56 percent of cases in two separate series [20,21]), responses to TRK inhibition are reported in such cases [22,23]. Updated year 2020 guidelines from ASCO endorse use of larotrectinib or entrectinib for second-line therapy for individuals with TRK fusion-positive pancreatic cancer [3]. (See "TRK fusion-positive cancers and TRK inhibitor therapy", section on 'Treatment with TRK inhibitors'.)
Testing algorithms to identify TRK fusions are discussed in detail elsewhere. (See "TRK fusion-positive cancers and TRK inhibitor therapy", section on 'Testing algorithms'.)
RAS G12C-mutated tumors — For patients with a RAS G12C mutation who have progressed on initial chemotherapy, we suggest sotorasib rather than cytotoxic chemotherapy.
Sotorasib, a specific inhibitor of RAS G12C, is approved by the FDA for patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer, who have received at least one prior systemic therapy. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'RAS mutations'.)
The G12C substitution is relatively uncommon in pancreatic ductal adenocarcinoma, comprising only 1 to 2 percent of all RAS mutations [24,25]. The activity of sotorasib in pancreatic cancer was first noted in the CodeBreak100 phase I/II study of 129 previously heavily treated patients; of the 12 who had pancreatic ductal adenocarcinoma, one had a confirmed objective response across several doses, and 8 others had stable disease (disease control rate 75 percent) [26].
Activity in an expanded cohort of 38 patients with metastatic pancreatic ductal adenocarcinoma from this phase I/II study was reported in a February 2022 ASCO virtual plenary session [27]. The median treatment duration was 4.1 months, and eight had a confirmed partial response (21 percent objective response rate), and the disease control rate was 84 percent. Grade 3 or higher treatment-related adverse events occurred in six patients: diarrhea and fatigue in two each, and abdominal pain, ALT increase, AST increase, pleural effusion, and pulmonary embolism (one each).
Sotorasib has several drug interactions and should typically not be coadministered with proton pump inhibitors, H2-receptor antagonists, strong cytochrome P450 3A4 (CYP3A4) inducers, and certain CYP3A4 substrates and P-gp substrates.
Non-targeted therapy for adenocarcinomas — There are few randomized trials of second-line therapy for patients without potentially targetable molecular abnormalities who have failed initial gemcitabine-containing chemotherapy, and there is no universally accepted standard of care. There are even fewer data on second-line therapy for patients receiving a FU plus oxaliplatin regimen for first-line therapy. We prefer that eligible patients be enrolled on clinical trials testing new strategies. If protocol treatment is not available or is declined, we base our treatment choice on which regimen was used for first-line therapy and the patient's performance status (PS) and biliary function; our approach is consistent with updated Clinical Practice Guidelines from ASCO [28] and consensus-based recommendations from the NCCN [29]:
●For patients who are refractory to or intolerant of first-line FOLFIRINOX who retain an Eastern Cooperative Oncology Group (ECOG) PS of 0 to 1 (table 1), normal biliary function, and continued favorable comorbidity (table 5), we prefer gemcitabine plus nabpaclitaxel (table 6). For others, we suggest gemcitabine monotherapy (table 7), gemcitabine plus capecitabine (table 8), or a fluoropyrimidine alone. (See 'After first-line FOLFIRINOX' below.)
●For patients initially treated with FOLFOX because of an elevated total bilirubin level who continue to have an elevated serum bilirubin level, second-line therapy should be undertaken only cautiously as nanoliposomal irinotecan, irinotecan, and gemcitabine have increased rates of toxicity at standard doses. (See 'Patients with an elevated bilirubin level despite stenting' below.)
●For patients treated initially with a gemcitabine-containing regimen who retain a PS of 0 to 1 and a favorable comorbidity profile (table 5), combination chemotherapy using a regimen that contains FU and oxaliplatin, or FU and irinotecan is a reasonable approach. Liposomal irinotecan in combination with FU is also acceptable as long as liver function is adequate. For patients with an ECOG PS of 2 who have relatively favorable comorbidity (table 5), monotherapy may be appropriate. If single-agent therapy is chosen, options include FU plus LV, capecitabine alone, S-1 where available, or taxane monotherapy. (See 'After first-line gemcitabine' below.)
After first-line gemcitabine — There are few randomized trials examining the benefit of second-line therapy after failure of a gemcitabine-containing regimen. For patients who retain an ECOG PS of 0 or 1 (table 1), have a relatively favorable comorbidity profile, a preference and support system for aggressive medical therapy, and access to chemotherapy port and infusion pump management services, combination chemotherapy using a regimen that contains FU plus liposomal irinotecan (as long as liver function is appropriate) or FU and unencapsulated irinotecan is a reasonable approach. We also consider that oxaliplatin combined with FU is also acceptable, although the phase III PANCREOX trial comparing modified FOLFOX6 with FU plus LV demonstrated a higher rate of grade 3 or 4 adverse effects and significantly reduced overall survival in the oxaliplatin group. FOLFIRINOX may be offered to patients with limited neuropathy and an excellent PS. (See 'Oxaliplatin-based regimens' below.)
Options for single-agent therapy include FU/LV, capecitabine, and where available, S-1.
Liposomal irinotecan — Liposomal irinotecan (MM-398) is a liposomal encapsulated preparation that allows irinotecan to remain in circulation for a longer duration compared with standard irinotecan; this allows for higher drug uptake within tumor cells and conversion of irinotecan to its active form, SN38 [30]. The efficacy of liposomal irinotecan in combination with FU and LV was assessed in the international phase III NAPOLI-1 trial, in which 417 patients with gemcitabine-refractory locally advanced or metastatic pancreatic cancer were randomly assigned to weekly administration of FU with LV for four of every six weeks (the control arm), liposomal irinotecan alone every three weeks, or liposomal irinotecan prior to FU and LV every two weeks [31]. Dexamethasone and a serotonin receptor antagonist could be administered in the combination arm per standard irinotecan protocols.
Median overall survival, the primary endpoint, was longer with combination therapy (median 6.1 versus 4.2 months, hazard ratio [HR] 0.67, 95% CI 0.49-0.92), as was PFS (3.1 versus 1.5 months with control). At 12 weeks, 57 percent of patients treated with the combination were alive and progression free compared with only 26 percent of the control group. The objective response rate was 16 versus 1 percent. The most commonly reported grade 3 or worse adverse events with combination therapy were neutropenia (27 percent), fatigue (14 percent), diarrhea (13 percent), vomiting (11 percent), nausea (8 percent), asthenia (8 percent), and abdominal pain (7 percent). Liposomal irinotecan monotherapy did not demonstrate superior efficacy over the control arm, and it was associated with more severe toxicity than with combination therapy, suggesting that the drug should only be used in combination.
Based on these results, liposomal irinotecan has been approved, in combination with FU and LV, for patients with metastatic pancreatic cancer following prior administration of a gemcitabine-based regimen. The recommended dose and schedule of liposomal irinotecan is 70 mg/m2 administered by IV infusion over 90 minutes, prior to LV and FU, every two weeks. For patients who are known to be homozygous for the UGT1A1 *28 or *6 allele (eg, those with Gilbert's syndrome), the recommended starting dose of liposomal irinotecan is lower, 50 mg/m2 every two weeks. This subject is discussed in detail elsewhere. (See "Dosing of anticancer agents in adults", section on 'UGT1A1 polymorphisms and irinotecan'.)
Unencapsulated irinotecan — Others have shown modest activity for irinotecan in combination with FOLFIRI [32-34]. In two phase II studies totaling 90 patients with gemcitabine-refractory advanced pancreatic adenocarcinoma, the partial response rates were 8 and 14 percent, respectively, with disease control rates (objective response plus stable disease) of approximately 35 percent.
Similar results have been demonstrated with second-line irinotecan plus S-1 [35].
Oxaliplatin-based regimens — Several oxaliplatin-based regimens are active in patients who have failed single-agent gemcitabine, including oxaliplatin plus FU and LV [1,34,36-38], and oxaliplatin in combination with capecitabine [38,39], S-1 [40], gemcitabine [41,42], irinotecan [43,44], or docetaxel [45].
●Regimens combining oxaliplatin plus FU and LV [36,46,47] or oxaliplatin plus capecitabine [36] may be superior to best supportive care alone or a fluoropyrimidine alone, although the data are disparate, as illustrated by the following observations:
•As noted above, the superiority of oxaliplatin (85 mg/m2 on days 8 and 22) plus short-term infusional FU (2000 mg/m2 over 24 hours) and LV (200 mg/m2 over 30 minutes, both given on days 1, 8, 15, and 22; this regimen is referred to as OFF) compared with best supportive care alone was shown in a randomized phase III CONKO-003 trial [1]. Each cycle was 42 days in length. The trial was stopped prematurely after the enrollment of only 46 patients because of low recruitment (best supportive care was not accepted by patients). Despite no confirmed responses better than stable disease, OFF was associated with a significantly longer median overall survival (4.8 versus 2.3 months). Patients receiving oxaliplatin had significantly more neurotoxicity (48 versus 10 percent), but it was mostly grade 1 or 2; otherwise, the regimen was well tolerated.
The contribution of oxaliplatin was addressed in a later trial in which the same schedule of FU and LV was tested with and without oxaliplatin in 168 patients with gemcitabine-refractory advanced pancreatic cancer; the majority (86 to 89 percent) had metastatic disease [48]. The oxaliplatin group had significantly better overall survival (the primary endpoint; median 5.9 versus 3.3 months) and a significantly greater time to tumor progression (2.9 versus 2 months). There was no significant difference in the rates of grade 3 or 4 hematologic toxicities, although as expected, neurologic side effects were more prominent with OFF.
On the other hand, a benefit for adding oxaliplatin to short-term infusional FU plus LV could not be shown in the phase III PANCREOX trial, in which 108 patients with advanced pancreatic cancer previously treated with gemcitabine were randomly assigned to modified FOLFOX6 or short-term infusional FU/LV alone [49]. PFS was similar, and median overall survival was actually inferior with FOLFOX (6.1 versus 9.9 months).
Despite these disparate findings, a 2018 focused update of the ASCO guidelines for therapy of metastatic pancreatic cancer continued to support an FU plus oxaliplatin regimen after failure of first-line gemcitabine plus nabpaclitaxel, although FU plus nanoliposomal irinotecan was preferred [28].
•Combinations of oxaliplatin with capecitabine and S-1 are also active [36,39,40]. In a phase II trial, 41 patients who failed one prior chemotherapy regimen received oxaliplatin (130 mg/m2 every three weeks, decreased to 110 mg/m2 for patients older than the age of 65 and those with a PS of 2 (table 1)) plus capecitabine (1000 mg/m2 twice daily for 14 of every 21 days, decreased to 750 mg/m2 for patients older than 65 and those with a PS of 2) [39]. There was one partial response but a 22 percent clinical benefit rate; median PFS was 10 weeks. The 6- and 12-month survival rates were 44 and 21 percent, respectively.
●There are no prospective trials of FOLFIRINOX (table 3) in patients treated with first-line gemcitabine. In a retrospective analysis of 27 patients treated with second-line FOLFIRINOX at a single institution over a six-year period, the objective response rate was 19 percent, 12 others had stable disease (44 percent), and the median time to tumor progression was 5.4 months [50]. Grade 3 or 4 neutropenia developed in 56 percent of patients, but there was only one case of febrile neutropenia.
In our view, it is reasonable to offer FOLFIRINOX as an option to patients with limited neuropathy and a good PS.
●Combinations of oxaliplatin with gemcitabine are also active [41,42]. As an example, in a study of 33 patients receiving second-line gemcitabine plus oxaliplatin, seven had a partial response, while 52 percent had clinical benefit [41].
●In a series of 30 patients treated with oxaliplatin plus irinotecan, three had a partial response (two of whom subsequently underwent resection), and six had clinical benefit; 23 percent were still alive at one year [43].
Meta-analysis — There are no randomized trials directly comparing an oxaliplatin versus an irinotecan-based regimen in this setting. A meta-analysis of five trials examining the effectiveness of adding oxaliplatin or various irinotecan formulations to a fluoropyrimidine after progression on a first-line gemcitabine-based regimen [31,35,40,48,49] concluded that the combination of a fluoropyrimidine plus irinotecan significantly improved both PFS and overall survival (hazard ratio 0.7, 95% CI 0.55-0.89), while oxaliplatin-based combinations modestly improved PFS but not overall survival [51].
Other regimens
Fluoropyrimidine monotherapy
●S-1, an orally active fluoropyrimidine, is modestly active in gemcitabine-refractory disease [52,53]. It is not available in the United States.
●Modest utility for capecitabine (1000 mg/m2 twice daily for 14 days of every 21-day cycle) plus erlotinib (150 mg once daily) was suggested in a phase II trial of 32 patients with gemcitabine-refractory advanced pancreatic cancer [54]. Although only three patients (10 percent) achieved a radiologic response, five others had a ≥50 percent decrease in carbohydrate antigen 19-9 (CA 19-9; also called cancer antigen 19-9) level, and median survival was 6.5 months. Grade 3 or 4 toxicities included diarrhea (17 percent), rash (13 percent), hand-foot syndrome (13 percent), and stomatitis (10 percent).
Raltitrexed combinations — Raltitrexed (Tomudex), a folate analog, is a pure thymidylate synthase inhibitor that is available in Canada and elsewhere, but not in the United States. Activity for raltitrexed in combination with irinotecan was shown in a randomized phase II trial that compared 21-day cycles of raltitrexed (3 mg/m2 on day 1) with 21-day cycles of irinotecan (200 mg/m2 on day 1) plus raltitrexed (3 mg/m2 day 2) in 38 patients who failed gemcitabine [55]. Combined therapy was superior in terms of objective response rate (16 versus 0 percent), clinical benefit rate (29 versus 8 percent), PFS (4 versus 2.5 months), and overall survival (6.5 versus 4.3 months).
Comparable results were also seen in a single-arm trial of 21-day cycles of raltitrexed (3 mg/m2 on day 1) plus oxaliplatin (130 mg/m2 on day 1) after failure of first-line gemcitabine [56]. Ten of 41 patients (24 percent) had a partial response, and the median survival was 5.2 months.
Taxane monotherapy
●Second-line weekly paclitaxel was studied in 30 patients who failed gemcitabine [57]. The objective response rate was 10 percent, and the overall disease control rate was 47 percent (14 of 30 patients); median survival from the start of paclitaxel was 6.7 months.
●Nabpaclitaxel (Abraxane) is also modestly active as a second-line agent after first-line gemcitabine monotherapy. In a phase II trial in which 19 patients with gemcitabine-refractory advanced pancreatic cancer received single-agent nabpaclitaxel (100 mg/m2 on days 1, 8, and 15 of each 28-day cycle), one had a partial response, and six had stable disease as the best response [58]. The estimated median overall survival was 7.3 months.
After first-line FOLFIRINOX — For individuals previously treated with first-line FOLFIRINOX who retain an ECOG PS of 0 to 1 (table 1), normal biliary function, continued favorable comorbidity (table 5), and a preference and support system for aggressive medical therapy we suggest gemcitabine plus nabpaclitaxel (table 6). For others, gemcitabine monotherapy (table 7), gemcitabine plus capecitabine (table 8), or a fluoropyrimidine alone are all reasonable options.
There are few data on second-line chemotherapy in patients failing first-line LV plus short-term infusional FU plus oxaliplatin and irinotecan (FOLFIRINOX) and no randomized trials. (See "Initial systemic chemotherapy for metastatic exocrine pancreatic cancer", section on 'FOLFOX and FOLFIRINOX'.)
Potential options in this setting include gemcitabine plus nabpaclitaxel, gemcitabine monotherapy, or a single-agent taxane. Updated year 2020 guidelines for treatment of metastatic pancreatic cancer from ASCO endorse gemcitabine plus nabpaclitaxel for those patients who retain an ECOG PS 0 to 1, have a relatively favorable comorbidity profile, a preference and support system for aggressive medical therapy, and access to chemotherapy port and infusion pump management services [3].
The efficacy and tolerability of gemcitabine plus nabpaclitaxel (table 6) in this setting has been addressed in the following reports:
●In a prospective multicenter cohort study of 57 consecutive patients progressing while receiving FOLFIRINOX, the objective response rate was 18 percent, the overall disease control rate was 58 percent, median overall survival was 8.8 months, and the median PFS was 5.1 months [59]. Grade 3 or 4 toxicities were experienced by 40 percent of treated patients and included neutropenia (13 percent), neurotoxicity (13 percent), asthenia (9 percent), and thrombocytopenia (7 percent).
●Similar results were reported in a small multicenter phase II trial of 30 patients receiving second-line gemcitabine/nabpaclitaxel after failure of first-line FOLFIRINOX [60]. The objective response rate was 13 percent, disease control rate was 47 percent, and median overall survival and PFS were 7.6 and 3.8 months, respectively. Grade 3 or 4 adverse events included neutropenia (50 percent), febrile neutropenia (6.7 percent), thrombocytopenia (20 percent), anemia (27 percent), peripheral sensory neuropathy and anorexia (13 percent each).
Whether these results are better than could be expected with gemcitabine monotherapy is not clear, given that there are no randomized trials, and the only data on gemcitabine alone are from uncontrolled series (response rates average 8 to 11 percent, disease control rate 26 to 40 percent, median overall survival 3.6 to 5.7 months, and median PFS values of 1.5 to 2.5 months [61-65]).
Additional information is available from a retrospective multicenter comparator study of 427 patients with advanced pancreatic cancer previously treated with FOLFIRINOX and then received gemcitabine plus nabpaclitaxel (n = 219) or gemcitabine alone (n = 208) at the discretion of their clinician [65]. Despite imbalances in the groups that might have favored better outcomes with gemcitabine alone (eg, the group receiving combined therapy had more patients presenting with metastatic disease, more than two metastatic sites, and more peritoneal metastases) combination therapy was associated with a better disease control rate (56 versus 32 percent), modestly better median PFS (3.5 versus 2.3 months), and longer overall survival (7.1 versus 4.7 months). These benefits came at the cost of significantly more treatment-related toxicity (grade ≥3 in 44 versus 29 percent), especially hematologic and neuropathy. These data are obviously limited by their retrospective nature.
Patients with an elevated bilirubin level despite stenting — For patients initially treated with FOLFOX because of an elevated total bilirubin level who continue to have an elevated serum bilirubin level, second-line therapy should be undertaken only cautiously as nanoliposomal irinotecan, irinotecan, and gemcitabine have increased rates of toxicity at standard doses.
Acinar cell cancers — There is no established second-line approach to systemic chemotherapy after failure of initial therapy with an oxaliplatin-based regimen such as FOLFOX or FOLFIRINOX. (See "Initial systemic chemotherapy for metastatic exocrine pancreatic cancer", section on 'Acinar cell carcinomas'.)
Options that have been reported as active in case reports or small series include a gemcitabine-based regimen such as GEMOX [66-68], gemcitabine plus cisplatin [68] or gemcitabine plus docetaxel and capecitabine [68], S-1 [69] (where available), and an irinotecan-based regimen such as FOLFIRI [70], or cisplatin plus irinotecan [68].
Germline testing might reveal mutations in BRCA2 for which a PARP inhibitor might be beneficial [71], but the frequency with which germline mutations in DNA damage repair pathways or other potentially actionable genetic alterations are found in acinar cell pancreatic carcinomas is unknown [72,73].
Response assessment — As with initial systemic chemotherapy, response assessment during treatment typically relies on periodic cross-sectional radiographic imaging with computed tomography (CT) or magnetic resonance imaging (MRI) (typically every two to three months after treatment initiation) [3]. If they were initially elevated, serum levels of the tumor marker carbohydrate antigen 19-9 (CA 19-9) may be measured at the start of treatment and then every one to three months during therapy. Suspected disease progression based on rising CA 19-9 levels should be confirmed radiographically. (See "Initial systemic chemotherapy for metastatic exocrine pancreatic cancer", section on 'Response assessment'.)
ECOG PS 2 OR A COMORBIDITY PROFILE THAT PRECLUDES AGGRESSIVE THERAPY — For patients with a borderline Eastern Cooperative Oncology Group (ECOG) performance status (PS) or comorbidity profile that precludes aggressive combination chemotherapy, options for those who wish to pursue cancer-directed therapy include gemcitabine monotherapy or a fluoropyrimidine or taxane monotherapy. The addition of nabpaclitaxel to gemcitabine or irinotecan to fluorouracil may be offered in this setting, with proactive dose and schedule adjustments to minimize toxicities [3].
ECOG PS 3 OR POORLY CONTROLLED COMORBIDITY — Regardless of histology or breast cancer-associated gene/partner and localizer of BRCA2 (BRCA/PALB2) mutation status, patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥3 or poorly controlled comorbid conditions should only be offered systemic chemotherapy on an individualized, case-by-case basis; supportive care should be emphasized [3].
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The COVID-19 pandemic has increased the complexity of cancer care. Important issues include balancing the risk from delaying cancer treatment versus harm from COVID-19, minimizing the number of clinic and hospital visits to reduce exposure whenever possible, mitigating the negative impacts of social distancing on delivery of care, and appropriately and fairly allocating limited health care resources. Specific guidance for decision-making in advanced pancreatic cancer is available from several groups, including the European Society of Medical Oncology. These and other recommendations for cancer care during active phases of the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pancreatic cancer".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Pancreatic cancer (The Basics)")
●Beyond the Basics topic (see "Patient education: Pancreatic cancer (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●General principles
•All patients with metastatic pancreatic cancer should be offered aggressive treatment of pain and other symptoms related to the cancer. Early initiation of palliative care services improves clinical and quality-of-care outcomes and may prolong survival. (See 'General principles' above.)
•The decision to pursue second-line chemotherapy should be individualized and based on the patient's goals and preferences, and clinical prognostic characteristics such as those delineated in a prognostic nomogram. (See 'Second-line therapy versus supportive care alone and patient selection' above.)
•Next generation sequencing should be routinely obtained given the emerging roles of therapies that target specific populations such as those with KRAS G12C mutations, TRK fusions, and deficient mismatch repair. (See 'Molecularly-targeted therapy' above.)
•Enrollment in clinical trials is preferred, if available. If protocol treatment is not available or participation is not feasible, we base our treatment choice on clinical characteristics, including performance status (PS) and comorbidity, the results of genomic testing and next generation sequencing of tumor tissue, histology, the first-line regimen, and patient preference.
●Patients with adequate performance status and comorbidity
•Homologous recombination repair deficiency
-For patients with a germline mutation in BRCA or PALB2 who received maintenance therapy with a poly(ADP-ribose) polymerase (PARP) inhibitor after at least 16 weeks of a platinum containing regimen for first-line therapy, options at the time of disease progression include retreatment with the initial platinum-based regimen or administration of a different platinum-containing regimen than what was administered first-line (eg, FOLFOX for a patient who previously received gemcitabine plus cisplatin, or vice versa). (See 'BRCA or PALB2 mutation carriers and other homologous recombination repair deficiency alterations' above and "Initial systemic chemotherapy for metastatic exocrine pancreatic cancer", section on 'Patients with homologous recombination repair deficiency'.)
-For patients with any germline or somatic homologous recombination repair (HRR) deficiency-associated pathogenic variant who did not undergo maintenance therapy with olaparib after first-line platinum-containing chemotherapy, a PARP inhibitor could be used off-label for second-line therapy, especially for those with a pathogenic or likely pathogenic variant in BRCA 1 or 2.
For patients who did not receive initial platinum-based chemotherapy, we suggest a platinum-based chemotherapy regimen (eg, gemcitabine plus cisplatin, FOLFOX (table 2), FOLFIRINOX (table 3), or modified FOLFIRINOX (table 4)) (Grade 2C).
•Deficient mismatch repair or high tumor mutational burden – For second-line therapy of individuals with deficient mismatch repair or a high tumor mutational burden, we suggest pembrolizumab monotherapy (table 9) rather than cytotoxic chemotherapy (Grade 2C). (See 'Deficient mismatch repair or high tumor mutational burden' above.)
•TRK fusion-positive cancers – For patients with tropomyosin receptor kinase (TRK) fusion-positive cancers, we suggest a TRK inhibitor (larotrectinib or entrectinib) rather than cytotoxic chemotherapy (Grade 2C). (See 'TRK fusion-positive cancers' above.)
•RAS G12C-mutated tumors – For patients with a RAS G12C mutation who have progressed on initial chemotherapy, we suggest sotorasib rather than cytotoxic chemotherapy (Grade 2C). (See 'RAS G12C-mutated tumors' above.)
•Non-targeted therapies for adenocarcinoma
-For individuals previously treated with first-line FOLFIRINOX who retain an ECOG PS of 0 to 1 (table 1), normal biliary function, continued favorable comorbidity (table 5), a preference and support system for aggressive medical therapy, we suggest gemcitabine plus nabpaclitaxel (table 6) (Grade 2C). For others, gemcitabine monotherapy (table 7), gemcitabine plus capecitabine (table 8), or a fluoropyrimidine alone are all reasonable options. (See 'After first-line FOLFIRINOX' above.)
-For patients treated initially with a gemcitabine-containing regimen who retain an ECOG PS of 0 to 1 (table 1), a favorable comorbidity profile (table 5), a preference and support system for aggressive medical therapy, options include FOLFIRI, liposomal irinotecan in combination with FU (as long as liver function is adequate) (table 10), or FU plus oxaliplatin (table 2). FOLFIRINOX (table 3) or modified FOLFIRINOX (table 4) may be offered to patients with limited neuropathy and an excellent PS. (See 'After first-line gemcitabine' above and "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'Irinotecan' and "Treatment protocols for pancreatic cancer".)
-For patients previously treated with a gemcitabine-containing regimen who have an ECOG PS of 2 but relatively favorable comorbidity (table 5), we suggest monotherapy with a fluoropyrimidine, S-1 (where available) or a taxane (Grade 2C). (See 'ECOG PS 2 or a comorbidity profile that precludes aggressive therapy' above.)
-For patients initially treated with FOLFOX who have a persistently elevated serum bilirubin, second-line therapy should be undertaken only cautiously; liposomal irinotecan (table 10), irinotecan (table 11), gemcitabine alone (table 7), and capecitabine are all more toxic at standard doses. (See 'Patients with an elevated bilirubin level despite stenting' above.)
•Acinar cell carcinoma – There is no established second-line approach to systemic chemotherapy after failure of initial therapy with an oxaliplatin-based regimen such as FOLFOX or FOLFIRINOX. Options include GEMOX (table 12), gemcitabine plus cisplatin (table 13), gemcitabine plus docetaxel and capecitabine, S-1 (where available), or an irinotecan-based regimen such as FOLFIRI, or cisplatin plus irinotecan.
●ECOG performance status 3 or poor comorbidity – Patients with an ECOG PS ≥3 or poorly controlled comorbid conditions should only be offered systemic chemotherapy on an individualized, case-by-case basis; supportive care should be emphasized. (See 'ECOG PS 3 or poorly controlled comorbidity' above.)
