Pancreatic cancer: New hopes after first line treatment

Aroldi, Francesca; Bertocchi, Paola; Savelli, Giordano; Rosso, Edoardo; Zaniboni, Alberto

doi:10.4251/wjgo.v8.i9.682

Cited by 23 publications

(20 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…nucleosides and nucleotides | click chemistry | superresolution microscopy | in vivo imaging | theranostics D rugs that interfere with DNA metabolism are currently used in the first-line therapies of leukemia (1), lymphoma (2), mesothelioma (3), pancreatic (4), and gastric (5) cancers, but they exhibit limited efficacies in certain subgroups of patients. Despite over 100 y of study (6), the cell/cancer type-selective toxicities exhibited by drugs that interfere with DNA metabolism remain poorly understood.…”

mentioning

confidence: 99%

Superresolution imaging of individual replication forks reveals unexpected prodrug resistance mechanism

Triemer

Messikommer

Glasauer

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Many drugs require extensive metabolism en route to their targets. High-resolution visualization of prodrug metabolism should therefore utilize analogs containing a small modification that does not interfere with its metabolism or mode of action. In addition to serving as mechanistic probes, such analogs provide candidates for theranostics when applied in both therapeutic and diagnostic modalities. Here a traceable mimic of the widely used anticancer prodrug cytarabine (ara-C) was generated by converting a single hydroxyl group to azide, giving "AzC." This compound exhibited the same biological profile as ara-C in cell cultures and zebrafish larvae. Using azide-alkyne "click" reactions, we uncovered an apparent contradiction: drug-resistant cells incorporated relatively large quantities of AzC into their genomes and entered S-phase arrest, whereas drug-sensitive cells incorporated only small quantities of AzC. Fluorescence microscopy was used to elucidate structural features associated with drug resistance by characterizing the architectures of stalled DNA replication foci containing AzC, EdU, γH2AX, and proliferating cell nuclear antigen (PCNA). Three-color superresolution imaging revealed replication foci containing one, two, or three partially resolved replication forks. Upon removing AzC from the media, resumption of DNA synthesis and completion of the cell cycle occurred before complete removal of AzC from genomes in vitro and in vivo. These results revealed an important mechanism for the low toxicity of ara-C toward normal tissues and drug-resistant cancer cells, where its efficient incorporation into DNA gives rise to highly stable, stalled replication forks that limit further incorporation of the drug, yet allow for the resumption of DNA synthesis and cellular division following treatment.

show abstract

mentioning

confidence: 99%

Superresolution imaging of individual replication forks reveals unexpected prodrug resistance mechanism

Triemer

Messikommer

Glasauer

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…proposed the following treatment algorithm for metastatic PAC: patients with a performance status score of 0-1, who are younger than 65 years and who have no comorbidities can receive FOLFIRINOX as a 1L treatment; patients with an ECOG score of 0-1 who are older than 65 years should receive gem + nab-P as a 1L therapy; and patients with an ECOG score > 1, who have serious comorbidities and are older than 65 years should receive gem monotherapy as a 1L treatment (18). After disease progression, Aroldi F et al proposed that the 2L treatment should depend on the 1L treatment.…”

Section: Discussionmentioning

confidence: 99%

“…After disease progression, Aroldi F et al proposed that the 2L treatment should depend on the 1L treatment. Patients who received 1L FOLFIRINOX should receive gem + nab-P or gem monotherapy, those who received 1L gem + nab-P should receive either platinum-based therapy (Xelox, Gemox or OFF), irinotecan-based therapy (FOLFIRI, Nal-Iri, Nal-Iri + 5-FU-leucovorin) or uoropyrimidine, and patients who received 1L gem monotherapy should receive irinotecan monotherapy or uoropyrimidine after consideration of the condition of the patient (18). Most studies recommend 2L therapy for patients who are able to tolerate it, with a few studies describing prognostic factors for receiving and bene ting from 2L therapy (23,25,26).…”

Section: Discussionmentioning

confidence: 99%

“…In cases in which neither FOLFIRINOX nor gem + nab-P can be used because the patient has a ECOG score of 2 or higher or because of the risk of grades 3-4 AEs, gem monotherapy is still the preferred treatment (16). To date, a few studies have developed treatment options following the progression of disease after 1L treatment (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27), but a reliable standard second-line (2L) or later-line…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Comparison of Pancreatic Cancer Treatment Outcomes: A Real-World Data Analysis

Vikström¹,

Shangin²,

Viitanen³

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Since the ground-breaking phase III MPACT trial showed clear benefit of gemcitabine-nab-paclitaxel, this regimen has emerged as the standard of care for advanced pancreatic adenocarcinoma (PAC). Prior to this study, few studies have shown how results from randomized controlled trial translate to the real world. This study investigated how patients fared in the real world. Methods This single-centre, retrospective study was conducted in the Vaasa Central Hospital, Finland. 148 patients with PAC (ICD-10 C25) between 1/2011-12/2016 were identified with resectable, locally advanced or metastatic disease. Information about the basic characteristics, treatment regimens and adverse effects (AEs) were extracted from patient files and analysed. Results The median overall survival (OS) was 10.4 months for treated and 2.8 months for untreated patients. For metastatic disease OS was 4.9 months, for locally advanced 9.1 months. Patients who received 3 or more treatment lines had OS 19.1 months, while those who received 2 or 1 line had 11.3 and 6.2 months, respectively. The following grade 2–4 haematologic toxicities occurred: anaemia (n = 19), leukopenia (n = 49), neutropenia (n = 55) and thrombocytopenia (n = 9). Febrile neutropenia occurred 7 times. A total of 12 grade 5 AEs were recorded in 7 patients, and 3 other patients died of unknown complications. Conclusion This study shows that active treatment is worth pursuing in most PAC patients and study results from this real-world data study differ from randomized controlled trials. Special caution should be applied when continuing chemotherapy in patients with ECOG 2 and who are older than 70 years.

show abstract

“…Many factors influence the decision to select between FOLFIRINOX and GA including age, performance status, associated comorbidities and potential toxicity (7). FOLFIRINOX is often chosen for patients with good performance status, age ≤75 years and lack of or controlled comorbidities (7,8). Usually in this scenario, GA is the preferred second-line treatment after progression on FOLFIRINOX in the absence of prospective data.…”

mentioning

confidence: 99%

Impact of Nab–Paclitaxel-based Second-line Chemotherapy in Metastatic Pancreatic Cancer

Dadi

Stanley

Shahda

et al. 2017

View full text Add to dashboard Cite

OS (7.5 vs. 4.7 months; HR=0.67, p=0.05). Multivariate analyses adjusted for age showed a significantly improved PFS (adjusted HR=0.60, p=0.04) and a suggestion of improved OS (adjusted HR=0.67, p=0.05) Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer and is the fourth leading cause of cancer-related mortality in the United States (US) (1). In 2017 alone, 53,670 cases of PDAC are expected, resulting in approximately 43,090 deaths in the US (2). The median overall survival (OS) of patients with PDAC is 20% at 1 year and 8% at 5 years (3). Despite recent progress, there is a clear need to improve systemic treatments for PDAC. Recently, nab-paclitaxel (NP) in combination with gemcitabine (GA) was shown to lead to a clinically meaningful and significant improvement in the median OS and median progression-free survival (PFS) when compared with gemcitabine alone (4). This has led to the approval of GA as a first-line treatment for PDAC similar to FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan and oxaliplatin), the only other first-line treatment for patients with metastatic PDAC (5).In clinical practice, many patients may receive FOLFIRINOX as first-line treatment and GA as the secondline treatment especially in the US (6). Many factors influence the decision to select between FOLFIRINOX and GA including age, performance status, associated comorbidities and potential toxicity (7). FOLFIRINOX is often chosen for patients with good performance status, age ≤75 years and lack of or controlled comorbidities (7,8). Usually in this scenario, GA is the preferred second-line treatment after progression on FOLFIRINOX in the absence of prospective data. Alternatively, 5-fluorouracil-based second-line therapy in combination with nanoparticle liposomal irinotecan (9) or oxaliplatin (10, 11) has shown OS benefit in second-line treatment. Interestingly, up to 50% of patients with PDAC may be eligible for second-line chemotherapy (12, 13). 5533

show abstract

Pancreatic cancer: New hopes after first line treatment

Cited by 23 publications

References 44 publications

Superresolution imaging of individual replication forks reveals unexpected prodrug resistance mechanism

Superresolution imaging of individual replication forks reveals unexpected prodrug resistance mechanism

Comparison of Pancreatic Cancer Treatment Outcomes: A Real-World Data Analysis

Impact of Nab–Paclitaxel-based Second-line Chemotherapy in Metastatic Pancreatic Cancer

Contact Info

Product

Resources

About