Background
Gastrointestinal (GI) cancers are a major cause of morbidity and mortality worldwide. In 2020, colorectal, pancreatic, and gastroesophageal cancers accounted for 27.1% of estimated global cancer-related deaths.1 Despite advances in therapeutics, 5-fluorouracil (5-FU) multidrug regimens (MDRs) remain cornerstones in the treatment of GI cancers. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) recommend the use of 5-FU MDRs (ie, FOLFOX, FOLFIRI, and FOLFIRINOX) as first-line treatment options for GI cancers.2–5 These regimens typically include a short intravenous injection (bolus) of 5-FU followed by a prolonged infusion over 46 to 48 hours.6
Pharmacokinetically, the rationale for using a bolus dose is to minimize the time required to reach a steady state therapeutic drug concentration.7,8 However, 5-FU has a half-life of 8 to 20 minutes, and therefore therapeutic levels occur quickly with infusional dosing.9,10 Mechanistically, the 5-FU bolus is thought to primarily affect RNA synthesis, whereas the continuous infusion is hypothesized to act through inhibition of thymidylate synthase.11,12 Whether both mechanisms are necessary for clinical efficacy is unclear.
To date, there are limited studies evaluating whether omitting the 5-FU bolus compromises the efficacy of 5-FU–based regimens. Capecitabine, an oral prodrug formulation of 5-FU, does not contain a comparable bolus component, yet studies show comparable efficacy when used in place of intravenous 5-FU.13–15 A recent survey suggested that 20% to 40% of practicing oncologists routinely remove the 5-FU bolus up-front, especially those who have been in practice longer and who specialize in GI oncology.16 Prior retrospective studies have suggested conflicting results in terms of outcomes, but those studies were limited by a small sample size and inability to adjust for baseline differences between treatment arms.17–20 The recent 5-FU shortage in the United States has also highlighted the relevance of reducing potentially unnecessary doses of 5-FU. Therefore, to address this common clinical question, we performed a large retrospective cohort study to determine the impact of omitting the 5-FU bolus on survival outcomes and toxicity.
Methods
Data Source
This study was approved by the Institutional Review Board at Yale School of Medicine. We used the Flatiron Health database, a nationwide electronic health record–derived, real-world longitudinal database comprising deidentified patient-level data curated via technology-enabled abstraction from approximately 280 cancer clinics (approximately 800 sites of care) in the United States.21,22 Our cohort included patients aged ≥18 years diagnosed with colorectal, pancreatic, or gastroesophageal malignancy between January 2011 and May 2022. For colorectal and pancreatic cancers, only patients with metastatic disease were included. For gastroesophageal cancers, patients with metastatic and/or unresectable disease were included. Patients were included only if they received FOLFOX, FOLFIRI, or FOLFIRINOX as recommended by NCCN Guidelines for the treatment of GI cancers in the first-line metastatic/advanced setting.2–5 We omitted regimens that do not routinely include a 5-FU bolus, such as 5-FU/cisplatin. Patients were also excluded if they received 5-FU MDRs at nonstandard doses (defined by NCCN Guidelines), started treatment >180 days after diagnosis, had baseline ECOG performance status (PS) ≥3, or had unknown or erroneous survival data (ie, treatment coded as starting after date of death).
Baseline Variables
Baseline demographic variables such as age, sex, race/ethnicity, and body mass index were derived from provided variables. Date of treatment was defined as the date when a first-line 5-FU MDR was initiated (ie, cycle 1, day 1). For ECOG PS, the value prior to and closest to the date of diagnosis within a 120-day window was used. Pretreatment laboratory variables were calculated based on laboratory measurements up to 60 days prior to date of treatment. The Charlson comorbidity index was derived from International Classification of Diseases (ICD) data based on a validated algorithm.23 Treatment facilities were categorized as either community or academic and also divided into 4 US geographic regions (Northeast, South, Midwest, and West) based on definitions from the Census Bureau.24 Starting doses of all 5-FU MDR components were extracted, including the doses of 5-FU, oxaliplatin, and irinotecan. In addition, starting doses of all NCCN-approved biologic treatments (eg, bevacizumab, cetuximab, trastuzumab) and immunotherapies were recorded.
Definition of Study Groups
Chemotherapy administration data were extracted and patients were categorized as receiving a “standard” dose of 5-FU bolus if they received a 400 mg/m2 ± 25% injection of 5-FU on the date of treatment in accordance with NCCN Guidelines at that time. Patients were categorized as not receiving the 5-FU bolus if they did not receive any 5-FU bolus on the date of treatment. Infusional dose of 5-FU was defined as 2,400 mg/m2 ± 25%. Patients who did not get both a bolus and infusion dose were omitted from the bolus group.
Definition of Outcomes
Real-world overall survival (OS) was calculated as the time between the date of treatment and date of either death or last known follow-up. This mortality data has been previously validated and found to have excellent agreement (>95%) within 15 days.25 Rates of neutropenia, anemia, and thrombocytopenia present within 14 days of first treatment (ie, day 1 of cycle 1) were graded based on CTCAE, version 5.0.26 Rate of granulocyte colony-stimulating factor (G-CSF) use within 30 days after treatment was obtained.
Statistical Analysis
Chi-square test for dichotomous variables and the Student’s t-test or Wilcoxon rank sum test were used for normal and nonnormal continuous variables, respectively. Hazard ratios (HRs) and 95% confidence intervals were calculated using the Cox proportional hazards method. Survival curves for time-to-event variables were estimated using the Kaplan-Meier method.
A propensity score was generated to account for any imbalances in baseline characteristics between the 2 study groups. All baseline covariates related to the exposure/treatment variables (P<.10) were included in a logistic regression model. Our final propensity score model included age, ECOG PS, Charlson comorbidity score, platelet counts, bilirubin levels, type of regimen, and type of cancer. We used inverse probability treatment weighting (IPTW) to reduce imbalances in measured confounders between treatment groups. Postweighting covariate balance was evaluated using standardized mean differences (SMDs), and imbalance was defined as SMD >0.1. Subsequent IPTW analyses were performed using IPTW-adjusted Cox proportional hazards models. Separate Cox proportional hazards models were applied to each individual subgroup during subgroup analysis.
All analyzed variables were >99% complete with the exception of geographic regions (missing 15%) and laboratory values, which were missing as follows: neutrophil count, 24%; hemoglobin value, 5%; platelet count, 5%; creatinine value, 10%; and bilirubin value, 10%. Missing measurements were treated as missing during subsequent analyses except baseline platelet and bilirubin levels, which were imputed. P≤.05 was considered statistically significant. Statistical analyses were performed using Stata, version 17.0 (StataCorp LLC).
Results
Of 18,821 patients with GI cancers treated with 5-FU MDRs, 11,765 were ultimately included (Figure 1). Median age was 63 years (range, 18–85 years), 59.6% were male, 64.2% were White, and 90.3% had ECOG PS 0 or 1. In our cohort, 8,670 (73.7%) patients had colorectal cancer, 1,481 (12.6%) had gastroesophageal cancer, and 1,614 (13.7%) had pancreatic cancer. Among the 5-FU regimens, 8,014 (68.1%) patients received FOLFOX, 2,137 (18.2%) received FOLFIRI, and 1,614 (13.7%) received FOLFIRINOX. In all, 10,148 (86.3%) patients received the standard-dose 5-FU bolus on the first day of their treatment, whereas 1,617 (13.7%) did not. The bolus was administered to 90.4% of patients who received FOLFOX, 89.2% of those who received FOLFIRI, and 61.6% of those who received FOLFIRINOX. Leucovorin (often given with 5-FU bolus) was given in 99% of the bolus group and 60% of the no bolus group.
Cohort description.
Abbreviations: 5-FU, 5-fluorouracil; GI, gastrointestinal; MDR, multidrug regimen (ie, FOLFOX, FOLFIRI, FOLFIRINOX); OS, overall survival; PS, performance status.
Citation: Journal of the National Comprehensive Cancer Network 22, 8; 10.6004/jnccn.2024.7029
There were strong temporal changes in prescribing behavior over the study period (see Figure S1 in the supplementary materials, available online with this article). Prior to 2014, 9% of patients received FOLFOX without the 5-FU bolus, compared with 12% after 2021 (P<.01). Prior to 2014, 10% of patients received FOLFIRI without the 5-FU bolus, compared with 13% after 2021 (P=.28). Prior to 2014, 9% of patients received FOLFIRINOX without the 5-FU bolus, compared with 61% after 2021 (P<.01).
Baseline Characteristics Associated With 5-FU Bolus Administration
Baseline characteristics appeared to influence prescribing patterns (Table 1). Patients who received the 5-FU bolus were younger (P<.01) and healthier, with a lower ECOG PS (P<.01) and Charlson comorbidity score (P<.01). Those who received the 5-FU bolus were also more likely to receive a higher starting dose of oxaliplatin (83.0 vs 80.2 mg/m2; P<.01) and irinotecan (170.2 vs 150.0 mg/m2; P<.01) compared with those who did not (Table 1). Community practitioners were more likely to give the bolus compared with academic practitioners (P<.01). This difference persisted even after adjusting for differences in the ratios of GI cancer types treated at academic versus community practices (P<.01).
Baseline Patient and Treatment Characteristics
In our unadjusted analysis, there were no statistically significant differences in survival among the subgroups of patients with colorectal (OS, 23.6 vs 24.5 months; P=.13), gastroesophageal (OS, 10.4 vs 10.2 months; P=.84), and pancreatic cancer (OS, 8.9 vs 9.5 months; P=.33) (Table 2). However, among the full cohort, patients who received the 5-FU bolus had a higher OS (OS, 20.3 vs 14.0 months; HR, 0.74; 95% CI, 0.69–0.79; P<.01) (Supplementary Figure S2). Patients who received the 5-FU bolus were more likely to have colorectal cancer (P<.01) and less likely to have pancreatic cancer (P<.01).
Primary and Secondary Outcomes
IPTW Analyses
A propensity score was generated for 11,745 patients and IPTW was used with excellent balancing of covariates (Supplementary Table S1). After the 2 arms were balanced by the IPTW analysis, administration of the 5-FU bolus was not associated with an improvement in OS (HR, 0.99; 95% CI, 0.91–1.07; P=.74) (Figure 2, Supplementary Table S2). We also found no significant difference in OS among our preplanned subgroups, including subgroups by age, sex, ECOG PS, cancer type, regimen, and practice setting (Figure 3, Supplementary Table S2).
Kaplan-Meier estimates of overall survival with IPTW analysis.
Abbreviations: 5-FU, 5-fluorouracil; HR, hazard ratio; IPTW, inverse probability of treatment weighted.
Citation: Journal of the National Comprehensive Cancer Network 22, 8; 10.6004/jnccn.2024.7029
Subgroup analysis after IPTW analysis.
Abbreviations: HR, hazard ratio; IPTW, inverse probability of treatment weighted; PS, performance status.
Citation: Journal of the National Comprehensive Cancer Network 22, 8; 10.6004/jnccn.2024.7029
Given the potential impact of noted temporal trends, we stratified our analysis by year of treatment but found no difference in OS (HR, 0.98; 95% CI, 0.91–1.06; P=.62). Likewise, no difference in OS was found when stratified based on the regimen used (FOLFOX vs FOLFIRI vs FOLFIRINOX) (HR, 0.97; 95% CI, 0.90–1.05; P=.51) (Supplementary Figure S3) or cancer type (HR, 0.98; 95% CI, 0.91–1.06; P=.62). Because the doses of other chemotherapy drugs in regimens could impact survival, we further adjusted for oxaliplatin and irinotecan doses and again found no difference in OS (HR, 0.98; 95% CI, 0.86–1.11; P=.78). This was also true when we examined the use of adjunctive monoclonal antibodies and immunotherapies (HR, 1.00; 95% CI, 0.93–1.09; P=.83) (Supplementary Table S3).
Adverse Events
In the unadjusted analysis, patients who received 5-FU bolus were more likely to experience neutropenia within 14 days of treatment (22.3% vs 14.6%; P<.01), including more grade 3/4 neutropenia (8.2% vs 6.0%; P<.01) (Table 2). There were no differences in the rates of anemia (80.0% vs 81.7%; P=.33) or thrombocytopenia (14.9% vs 16.4%; P=.07) in the bolus versus no bolus groups, respectively. After IPTW analysis, patients who received the 5-FU bolus were still more likely to experience neutropenia than those who did not (22.7% vs 10.7%; P<.01). However, patients who received the 5-FU bolus were also now more likely to experience thrombocytopenia within 14 days after treatment (16.1% vs 11.2%; P<.01). There remained no difference in the rates of anemia (80.2% vs 81.4%; P=.47). Given the concomitant impact of oxaliplatin and irinotecan on myelosuppression, we performed another analysis adjusting for doses of oxaliplatin and irinotecan. The 5-FU bolus was still associated with increased risks for neutropenia (P=.02) and thrombocytopenia (P<.01). Finally, we examined G-CSF use and found that patients who received the 5-FU bolus required G-CSF at significantly higher rates within 30 days after treatment (29.1% vs 19.6%; P<.01).
Discussion
The optimal modality of 5-FU administration has been extensively studied in clinical trials since its discovery as an antineoplastic agent in 1957.27 Bolus regimens were the subject of initial trials in colorectal cancer.28,29 In the 1980s, the increasing availability of outpatient infusion pumps led to the adoption of continuous 5-FU infusions, which had higher response rates.28,30–32 However, the bolus dose remained in 5-FU MDRs without clear pharmacologic or clinical rationale. In this large retrospective multicenter study, we found that omitting bolus 5-FU did not impact clinical efficacy but did reduce the risk of toxicity.
Historically, the benefit of including the 5-FU bolus component has not been studied as a primary endpoint in clinical trials, but several studies suggest that the bolus may not be needed. The phase III OPTIMOX1 trial in colorectal cancer comparing FOLFOX4 (using both bolus and infusional 5-FU) versus FOLFOX7 (infusional 5-FU only) suggests that there is no additional benefit to bolus 5-FU, although this was not the primary endpoint.33 Retrospective studies in pancreatic cancer comparing FOLFIRINOX versus modified FOLFIRINOX (which does not contain 5-FU bolus) have also not demonstrated survival differences.20,34
In our study, we observed no differences in survival, regardless of the specific 5-FU MDR used or the cancer subtype. The inclusion of more patients with pancreatic cancer in the group that did not receive the 5-FU bolus likely contributed to the decreased OS found in the pre-IPTW analysis only. Our findings are also consistent with prior findings of increased neutropenia and thrombocytopenia associated with the bolus. Moreover, we found an increase in G-CSF use associated with the bolus, suggesting that omitting the bolus may be associated with a reduction in both direct and indirect health care costs.
Of interest, we also observed temporal trends in 5-FU bolus use over time in our dataset. Most notable is the increase in 5-FU bolus omission for FOLFIRINOX after 2017. This trend tracked with updates in the NCCN Guidelines for Pancreatic Adenocarcinoma from 2017 to 2019, which suggested omitting the 5-FU bolus due to toxicity, and with the publication of the PRODIGE-24 trial in 2018 using modified FOLFIRINOX (although this was in the adjuvant setting).35–37 We also observed an increase in 5-FU omission for the FOLFOX regimen. We hypothesize that this trend may be explained by the increasing subspecialization of oncologists in the past decade and the fact that bolus omission is more prevalent among experienced GI oncologists.16,38,39 However, irrespective of these trends, the vast majority of patients in the United States still received the 5-FU bolus (86.2%), suggesting that this research question has broad significance in the management of GI cancers.
The advantages of our study include a large cohort size, data elements derived from a high-quality database, the incorporation of multiple GI cancer types, and the application of advanced causal inference methodology. Our large sample size allowed us to adequately assess for relevant outcomes, including survival and adverse effects. Our data span a large number of centers, including both academic and community practices, which enhances our real-world validity. We were able to include patients who are normally excluded from clinical trials due to ECOG PS >1. Finally, using real-world data, we evaluated a clinically relevant question that has not been studied in the context of a randomized clinical trial. Although many oncology trials are currently focused on novel drug development, our study highlights the value of pragmatic trials that incorporate real-world data, which can improve tolerability and toxicity of treatments for patients.40,41 Such trials can offer an added advantage over real-world analyses alone if they are done prospectively, because the resulting quality of evidence can have greater impact on guideline changes and downstream practice patterns.
Our study was impacted by limitations common to retrospective studies, namely the effect of unmeasured confounders. Additionally, we only evaluated 5-FU bolus use in the metastatic/advanced setting, because adjuvant data were not available in our database. It is unknown whether the conclusions could be extrapolated to the adjuvant setting, and future studies in this setting should be considered. Our study was also limited by lack of knowledge regarding anatomic sites of disease and oligometastatic disease, which can have improved survival, especially in colorectal cancer.42 Lastly, our data were gathered from centers in the United States, which may limit conclusions at the global level.
Conclusions
In a large multicenter cohort of >11,000 patients, we did not detect a difference in OS when the 5-FU bolus component was omitted from first-line 5-FU MDRs in the metastatic/advanced setting. Our data suggest that omitting the 5-FU bolus may lead to reduced treatment toxicity without compromising efficacy. Future prospective studies are needed to confirm these findings, especially applicability to the adjuvant setting.
References
- 1.↑
Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209–249.
- 2.↑
Ajani JA, D’Amico TA, Barzi A, et al. NCCN Clinical Practice Guidelines in Oncology: Gastric Cancer. Version 1.2024. Accessed March 15, 2024. To view the most recent version, visit https://www.nccn.org
- 3.↑
Ajani JA, D’Amico TA, Barzi A, et al. NCCN Clinical Practice Guidelines in Oncology: Esophageal and Esophagogastric Junction Cancers. Version 2.2024. Accessed March 15, 2024. To view the most recent version, visit https://www.nccn.org
- 4.↑
Benson AB III, Venook AP, Adam M, et al. NCCN Clinical Practice Guidelines in Oncology: Colon Cancer. Version 1.2024. Accessed March 15, 2024. To view the most recent version, visit https://www.nccn.org
- 5.↑
Tempero MA, Malafa MP, Benson AB III, et al. NCCN Clinical Practice Guidelines in Oncology: Pancreatic Adenocarcinoma. Version 1.2024. Accessed March 15, 2024. The view the most recent version, visit https://www.nccn.org
- 6.↑
Cheeseman SL, Joel SP, Chester JD, et al. A ‘modified de Gramont’ regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer 2002;87:393–399.
- 7.↑
Tarek TA. Pharmacokinetics of drugs following IV bolus, IV infusion, and oral administration. In: Ahmed TA, ed. Basic Pharmacokinetic Concepts and Some Clinical Applications. IntechOpen; 2015.
- 9.↑
Kerr DJ. Safe to omit bolus in 5-FU for colorectal cancer? Accessed December 1, 2022. Available at: https://www.medscape.com/viewarticle/957511
- 10.↑
Diasio RB, Harris BE. Clinical pharmacology of 5-fluorouracil. Clin Pharmacokinet 1989;16:215–237.
- 11.↑
Cancer Network. Experts debate bolus vs continuous infusion 5-FU. Accessed December 1, 2023. Available at: https://www.cancernetwork.com/view/experts-debate-bolus-vs-continuous-infusion-5-fu
- 12.↑
Amorim LC, Peixoto RD. Should we still be using bolus 5-FU prior to infusional regimens in gastrointestinal cancers? A practical review. Int Cancer Conf J 2021;11:2–5.
- 13.↑
Porschen R, Arkenau HT, Kubicka S, et al. Phase III study of capecitabine plus oxaliplatin compared with fluorouracil and leucovorin plus oxaliplatin in metastatic colorectal cancer: a final report of the AIO Colorectal Study Group. J Clin Oncol 2007;25:4217–4223.
- 14.↑
Souglakos J, Boukovinas I, Kakolyris S, et al. Three- versus six-month adjuvant FOLFOX or CAPOX for high-risk stage II and stage III colon cancer patients: the efficacy results of Hellenic Oncology Research Group (HORG) participation to the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) project. Ann Oncol 2019;30:1304–1310.
- 16.↑
Peixoto RD, Coutinho AK, Weschenfelder RF, et al. Fluorouracil bolus use in infusional regimens among oncologists-a survey by Brazilian group of gastrointestinal tumors. JCO Glob Oncol 2021;7:1270–1275.
- 17.↑
Basilio AJ, Shah AB, Sommerer KR, et al. Impact of empirically eliminating 5-fluorouracil bolus and leucovorin in patients with metastatic colorectal cancer receiving first-line treatment with mFOLFOX6. Br J Cancer Res 2021;4:463–468.
- 18.↑
Shaib WL, Draper A, Kalu K, et al.Survival analysis of colorectal cancer patients treated with first-line modified FOLFOX6 with or without bolus fluorouracil. J Clin Oncol 2021;39(Suppl):Abstract 35.
- 19.↑
Nakazawa J, Tsuruta N, Shimokawa M, et al. Multicenter retrospective analysis of original versus modified FOLFIRINOX in metastatic pancreatic cancer: results of the NAPOLEON study. Oncology 2023;101:22–31.
- 20.↑
de Jesus VHF, Camandaroba MPG, Donadio MDS, et al. Retrospective comparison of the efficacy and the toxicity of standard and modified FOLFIRINOX regimens in patients with metastatic pancreatic adenocarcinoma. J Gastrointest Oncol 2018;9:694–707.
- 21.↑
Ma X, Long L, Moon S, et al. Comparison of population characteristics in real-world clinical oncology databases in the US: Flatiron Health, SEER, and NPCR. medRxiv. Preprint posted online June 7, 2023. doi:10.1101/2020.03.16.20037143
- 22.↑
Birnbaum B, Nussbaum N, Seidl-Rathkopf, et al.Model-assisted cohort selection with bias analysis for generating large-scale cohorts from the EHR for oncology research. ArXiv. Preprint posted online January 13, 2020. doi:10.48550/arXiv.2001.09765
- 23.↑
Quan H, Sundararajan V, Halfon P, et al. Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data. Med Care 2005;43:1130–1139.
- 24.↑
US Census Bureau. Census regions and divisions of the United States. Accessed January 1, 2024. Available at: https://www2.census.gov/geo/pdfs/maps-data/maps/reference/us_regdiv.pdf
- 25.↑
Zhang Q, Gossai A, Monroe S, et al. Validation analysis of a composite real-world mortality endpoint for patients with cancer in the United States. Health Serv Res 2021;56:1281–1287.
- 26.↑
Ludmir EB, Palta M, Willett CG, et al. Total neoadjuvant therapy for rectal cancer: an emerging option. Cancer 2017;123:1497–1506.
- 27.↑
Heidelberger C, Chaudhuri NK, Danneberg P, et al. Fluorinated pyrimidines, a new class of tumour-inhibitory compounds. Nature 1957;179:663–666.
- 28.↑
Haller DG, Catalano PJ, Macdonald JS, et al. Phase III study of fluorouracil, leucovorin, and levamisole in high-risk stage II and III colon cancer: final report of Intergroup 0089. J Clin Oncol 2005;23:8671–8678.
- 29.↑
Gustavsson B, Carlsson G, Machover D, et al. A review of the evolution of systemic chemotherapy in the management of colorectal cancer. Clin Colorectal Cancer 2015;14:1–10.
- 30.↑
Piedbois P, Rougier P, Buyse M, et al. Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 1998;16:301–308.
- 31.↑
Rougier P, Paillot B, LaPlanche A, et al. 5-Fluorouracil (5-FU) continuous intravenous infusion compared with bolus administration. Final results of a randomised trial in metastatic colorectal cancer. Eur J Cancer 1997;33:1789–1793.
- 32.↑
Leichman CG, Fleming TR, Muggia FM, et al. Phase II study of fluorouracil and its modulation in advanced colorectal cancer: a Southwest Oncology Group study. J Clin Oncol 1995;13:1303–1311.
- 33.↑
Tournigand C, Cervantes A, Figer A, et al. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer—a GERCOR study. J Clin Oncol 2006;24:394–400.
- 34.↑
Tong H, Fan Z, Liu B, et al. The benefits of modified FOLFIRINOX for advanced pancreatic cancer and its induced adverse events: a systematic review and meta-analysis. Sci Rep 2018;8:8666.
- 35.↑
Tempero MA, Malafa MP, Al-Hawary M, et al. NCCN Clinical Practice Guidelines in Oncology: Pancreatic Adenocarcinoma. Version 2.2017. To view the most recent version, visit https://www.nccn.org
- 36.↑
Tempero MA, Malafa MP, Chiorean EG, et al. NCCN Clinical Practice Guidelines in Oncology: Pancreatic Adenocarcinoma. Version 1.2019. To view the most recent version, visit https://www.nccn.org
- 37.↑
Conroy T, Hammel P, Hebbar M, et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med 2018;379:2395–2406.
- 38.↑
Pompilio N. Specialization trend is changing the oncology landscape. Accessed January 1, 2024. Available at: https://www.onclive.com/view/specialization-trend-is-changing-the-oncology-landscape
- 39.↑
Durkal V. Adaptation in oncology practice opens the door to specialization. Accessed January 1, 2024. Available at: https://www.targetedonc.com/view/adaptation-in-oncology-practice-opens-the-door-to-specialization
- 40.↑
Benbow JH, Rivera DR, Lund JL, et al. Increasing inclusiveness of patient-centric clinical evidence generation in oncology: real-world data and clinical trials. Am Soc Clin Oncol Educ Book 2022;42:1–11.
- 41.↑
Baumfeld Andre E, Reynolds R, Caubel P, et al. Trial designs using real-world data: the changing landscape of the regulatory approval process. Pharmacoepidemiol Drug Saf 2020;29:1201–1212.
- 42.↑
Moretto R, Rossini D, Zucchelli G, et al. Oligometastatic colorectal cancer: prognosis, role of locoregional treatments and impact of first-line chemotherapy—a pooled analysis of TRIBE and TRIBE2 studies by Gruppo Oncologico del Nord Ovest. Eur J Cancer 2020;139:81–89.
