Key messages
• FOLFIRINOX and gemcitabine plus a taxane extend the lives of people with advanced pancreatic cancer compared to gemcitabine alone.
• Our findings suggest that fluoropyrimidine-based combination chemotherapy extends the lives of people with advanced pancreatic cancer compared to gemcitabine plus a taxane.
What is pancreatic cancer?
Pancreatic cancer is a highly aggressive cancer, often diagnosed at late stages where surgery cannot be offered. Symptoms are often absent at early stages, but at late stages, they can include abdominal pain, weight loss, nausea, anorexia, and yellow skin and eyes. When diagnosed at a late stage, treatments can include chemotherapy (drugs that kill cancer cells or slow their growth), radiotherapy (X-ray treatment), or other medications. These treatments are aimed at controlling cancer-related symptoms and extending people's lives, but are not curative. More people are being diagnosed with pancreatic cancer worldwide and hence this review is important to understand the best way to treat advanced pancreatic cancer.
What did we want to find out?
This review aimed to find out which treatments were most effective for advanced, incurable pancreatic cancer. We also wanted to identify the side effects of these treatments.
What did we do?
We looked for all studies in people with pancreatic cancer that was (1) locally advanced, where cancer has spread from the pancreas to nearby tissues; or (2) metastatic, where cancer has spread to other parts of the body. We collected data on people's overall survival time (time until death from any cause), side effects, and quality of life. We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.
What did we find?
We included 75 studies, involving 11,333 participants, in the review. They compared one therapy against either best supportive care (symptom management only) or another type of therapy. Only one study investigated radiotherapy. The rest investigated a wide variety of chemotherapy regimens (treatment plans that specify the dose, schedule, and treatment duration). Because of this variety, we were able to combine the results from multiple studies for only some comparisons.
Main comparisons and key results
Four studies compared chemotherapy regimes – which are now considered outdated – to best supportive care. Chemotherapy likely results in little to no difference in survival times. We were uncertain about the side effects of chemotherapy and the impact on people's quality of life.
Eight studies compared various chemotherapy regimens to gemcitabine. Compared to gemcitabine, 5-fluorouracil likely reduces survival time and has fewer side effects. Giving gemcitabine at a fixed dose rate likely improves survival and increases side effects. Compared to gemcitabine, FOLFIRINOX improves survival and quality of life but increases side effects.
Twenty-eight studies compared gemcitabine-based combination chemotherapy regimens to gemcitabine alone. Compared to gemcitabine alone:
• gemcitabine plus platinum makes little to no difference in survival, may increase side effects, and may worsen quality of life.
• gemcitabine plus fluoropyrimidine likely improves survival, increases side effects, and may improve quality of life.
• gemcitabine plus topoisomerase inhibitors make little to no difference in survival and quality of life, and increase side effects.
• gemcitabine plus a taxane improves survival time and quality of life, but increases side effects.
Nine studies compared various chemotherapy combinations to gemcitabine plus nab-paclitaxel. Compared to gemcitabine plus nab-paclitaxel, fluoropyrimidine-based chemotherapy combinations may improve survival, cause a distinct set of side effects, and likely do not affect quality of life. Compared to standard administration, alternative ways of administering gemcitabine plus nab-paclitaxel showed little to no difference in survival, side effects, or quality of life.
Four studies compared fluoropyrimidine-based combinations to fluoropyrimidines alone. The combination regimens have little to no impact on survival, side effects, or quality of life compared to fluoropyrimidines alone.
We were uncertain about the effects of radiotherapy on pancreatic cancer as we included only one, poor-quality radiotherapy study.
In summary, this review has shown that in advanced disease, combination chemotherapy with FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, oxaliplatin combination) and gemcitabine plus a taxane extend the lives of people with advanced pancreatic cancer compared to gemcitabine alone. These combinations do increase side effects compared to giving just one chemotherapy. Furthermore, the evidence suggests that fluoropyrimidine-based combination chemotherapies extend people's lives compared to gemcitabine plus nab-paclitaxel.
What are the limitations of the evidence?
We are confident that, compared to gemcitabine alone, (1) FOLFIRINOX and (2) gemcitabine plus a taxane extend people's lives. We are moderately confident that fluoropyrimidine-based combination chemotherapies extend survival time compared to gemcitabine plus nab-paclitaxel. The multiple different fluoropyrimidine combinations studied in this comparison reduced our confidence in the evidence. In general, other limitations of the evidence included having too few studies, small studies, or both, for some comparisons we were interested in.
How current is this evidence?
The evidence is current to March 2023.
Combination chemotherapy remains standard of care for metastatic pancreatic cancer. Both FOLFIRINOX and gemcitabine plus a taxane improve OS compared to gemcitabine alone. Furthermore, the evidence suggests that fluoropyrimidine-based combination chemotherapy regimens improve OS compared to gemcitabine plus nab-paclitaxel. The effects of radiotherapy were uncertain as only one low-quality trial was included. Selection of the most appropriate chemotherapy for individuals still remains unpersonalised, with clinicopathological stratification remaining elusive. Biomarker development is essential to assist in rationalising treatment selection for patients.
Pancreatic cancer (PC) is a lethal disease with few effective treatment options. Many anti-cancer therapies have been tested in the locally advanced and metastatic setting, with mixed results. This review synthesises all the randomised data available to help better inform patient and clinician decision-making. It updates the previous version of the review, published in 2018.
To assess the effects of chemotherapy, radiotherapy, or both on overall survival, severe or life-threatening adverse events, and quality of life in people undergoing first-line treatment of advanced pancreatic cancer.
We searched for published and unpublished studies in CENTRAL, MEDLINE, Embase, and CANCERLIT, and handsearched various sources for additional studies. The latest search dates were in March and July 2023.
We included randomised controlled trials comparing chemotherapy, radiotherapy, or both with another intervention or best supportive care. Participants were required to have locally advanced, unresectable pancreatic cancer or metastatic pancreatic cancer not amenable to curative intent treatment. Histological confirmation was required. Trials were required to report overall survival.
We used standard methodological procedures expected by Cochrane.
We included 75 studies in the review and 51 in the meta-analysis (11,333 participants). We divided the studies into seven categories: any anti-cancer treatment versus best supportive care; various chemotherapy types versus gemcitabine; gemcitabine-based combinations versus gemcitabine alone; various chemotherapy combinations versus gemcitabine plus nab-paclitaxel; fluoropyrimidine-based studies; miscellaneous studies; and radiotherapy studies. In general, the included studies were at low risk for random sequence generation, detection bias, attrition bias, and reporting bias, at unclear risk for allocation concealment, and high risk for performance bias.
Compared to best supportive care, chemotherapy likely results in little to no difference in overall survival (OS) (hazard ratio (HR) 1.08, 95% confidence interval (CI) 0.88 to 1.33; absolute risk of death at 12 months of 971 per 1000 versus 962 per 1000; 4 studies, 298 participants; moderate-certainty evidence). The adverse effects of chemotherapy and impacts on quality of life (QoL) were uncertain. Many of the chemotherapy regimens were outdated.
Eight studies compared non-gemcitabine-based chemotherapy regimens to gemcitabine. These showed that 5-fluorouracil (5FU) likely reduces OS (HR 1.69, 95% CI 1.26 to 2.27; risk of death at 12 months of 914 per 1000 versus 767 per 1000; 1 study, 126 participants; moderate certainty), and grade 3/4 adverse events (QoL not reported). Fixed dose rate gemcitabine likely improves OS (HR 0.79, 95% CI 0.66 to 0.94; risk of death at 12 months of 683 per 1000 versus 767 per 1000; 2 studies, 644 participants; moderate certainty), and likely increase grade 3/4 adverse events (QoL not reported). FOLFIRINOX improves OS (HR 0.51, 95% CI 0.43 to 0.60; risk of death at 12 months of 524 per 1000 versus 767 per 1000; P < 0.001; 2 studies, 652 participants; high certainty), and delays deterioration in QoL, but increases grade 3/4 adverse events.
Twenty-eight studies compared gemcitabine-based combinations to gemcitabine. Gemcitabine plus platinum may result in little to no difference in OS (HR 0.94, 95% CI 0.81 to 1.08; risk of death at 12 months of 745 per 1000 versus 767 per 1000; 6 studies, 1140 participants; low certainty), may increase grade 3/4 adverse events, and likely worsens QoL. Gemcitabine plus fluoropyrimidine improves OS (HR 0.88, 95% CI 0.81 to 0.95; risk of death at 12 months of 722 per 1000 versus 767 per 1000; 10 studies, 2718 participants; high certainty), likely increases grade 3/4 adverse events, and likely improves QoL. Gemcitabine plus topoisomerase inhibitors result in little to no difference in OS (HR 1.01, 95% CI 0.87 to 1.16; risk of death at 12 months of 770 per 1000 versus 767 per 1000; 3 studies, 839 participants; high certainty), likely increases grade 3/4 adverse events, and likely does not alter QoL. Gemcitabine plus taxane result in a large improvement in OS (HR 0.71, 95% CI 0.62 to 0.81; risk of death at 12 months of 644 per 1000 versus 767 per 1000; 2 studies, 986 participants; high certainty), and likely increases grade 3/4 adverse events and improves QoL.
Nine studies compared chemotherapy combinations to gemcitabine plus nab-paclitaxel. Fluoropyrimidine-based combination regimens improve OS (HR 0.79, 95% CI 0.70 to 0.89; risk of death at 12 months of 542 per 1000 versus 628 per 1000; 6 studies, 1285 participants; high certainty). The treatment arms had distinct toxicity profiles, and there was little to no difference in QoL. Alternative schedules of gemcitabine plus nab-paclitaxel likely result in little to no difference in OS (HR 1.10, 95% CI 0.82 to 1.47; risk of death at 12 months of 663 per 1000 versus 628 per 1000; 2 studies, 367 participants; moderate certainty) or QoL, but may increase grade 3/4 adverse events.
Four studies compared fluoropyrimidine-based combinations to fluoropyrimidines alone, with poor quality evidence. Fluoropyrimidine-based combinations are likely to result in little to no impact on OS (HR 0.84, 95% CI 0.61 to 1.15; risk of death at 12 months of 765 per 1000 versus 704 per 1000; P = 0.27; 4 studies, 491 participants; moderate certainty) versus fluoropyrimidines alone. The evidence suggests that there was little to no difference in grade 3/4 adverse events or QoL between the two groups.
We included only one radiotherapy (iodine-125 brachytherapy) study with 165 participants. The evidence is very uncertain about the effect of radiotherapy on outcomes.