FOLFIRI Regimen Research Articles

Second line chemotherapy for advanced biliary cancer: FOLFOX versus FOLFIRI: Analysis of retrospective and prospective data

Aim. To evaluate the efficacy and toxicity of second-line polychemotherapy according to FOLFOX or FOLFIRI regimen in patients with biliary tract tumours after progression during first-line chemotherapy (CT). Materials and methods. The study is based on the analysis of retrospective and prospective data on the examination and treatment of 94 patients with biliary cancer of grades T1-4N0-2M0-1 followed-up and treated at the N.N. Blokhin National Medical Research Center of Oncology from 2015 to 2023. All patients were divided into 2 groups: Group 1 (FOLFOX, n=47) and Group 2 (FOLFIRI, n=47). In Group 1, patients received the recommended FOLFOX second-line CT regimen. Patients in Group 2 received FOLFIRI regimen. The endpoints were overall survival (OS) and incidence of grade 3-4 adverse events. Results. The study included 94 patients. In the FOLFOX group, the median OS was 13.0 months (1-year OS was 57.8±7.4%); for the FOLFIRI group, the median OS was 12.3 months (1-year OS was 54.4±7.3%). The toxicity profiles of FOLFOX and FOLFIRI were acceptable and consistent with those reported for the regimens. According to the grade 3–4 toxicity data, diarrhea was significantly more common in the FOLFIRI group (p=0.014), and neurotoxicity was more common in the FOLFOX group (p=0.006). During the second-line CT, the frequency of grade 1–4 toxicities in the groups did not differ: 18 (38.3%) events in the FOLFOX group and 19 (40.0%) events in the FOLFIRI group. Conclusion. Our results of evaluating the efficacy and toxicity of the second-line polychemotherapy regimens show that the FOLFOX and FOLFIRI CT regimens have equal efficacy in patients with advanced biliary tract cancer with a good performance according to the ECOG scale, who previously received the first-line therapy with a combination of gemcitabine with a platinum agent (cisplatin or oxaliplatin); also, our data demonstrate similar toxicity profiles of these regimens.

Chinese Medicine Combined with Adjuvant Chemotherapy for Improving Myelosuppression in Colorectal Cancer Patients: A Systematic Review and Network Meta-Analysis.

To assess the effectiveness of Chinese herbal medicine (CHM) combined with adjuvant chemotherapy on myelosuppression for colorectal cancer (CRC) patients using network meta-analysis (NMA). Literature searches in both international (PubMed, Embase, Web of Science, and Cochrane Library) and Chinese (China Science and Technology Journal Database, Wanfang Data, China National Knowledge Infrastructure) databases for relevant randomized controlled trials (RCTs) were conducted from inception until October 10, 2022. We included RCTs of patients who received CHM combined with chemotherapy, including FOLFOX, XELOX, FOLFIRI, and other relevant regimens in the CHM treatment group. The outcomes included the incidence of myelosuppression, leukopenia, hemoglobin reduction, and thrombocytopenia. Two reviewers independently screened the databases, extracted the data, and assessed the risk of bias and credibility of evidence. RevMan 5.4.1 software and STATA 14.0 were used to perform the NMA. A total of 31 RCTs were included, published from 2008 to 2021 in Chinese. Among these, 2,314 participants comparing the following 9 CHMs were identified: Shengbai Recipe (SBR), Bazhen Decoction (BZD), Jianpi Jiedu Recipe (JJR), Jianpi Recipe (JR), Compound Cantharis Capsule (CCC), Zaofan Pill (ZFP), Guilu Erxian Gel (GL), Buzhong Tiaogan Decoction (BZ), and Qiamagu Capsule (QM). The results of NMA found an indirect comparison. Based on the surface under the cumulative ranking curve (SUCRA), the ZFP+ chemotherapy group had the lowest incidence of myelosuppression, with an odds ratio (OR) of 0.08 [95% confidence interval (CI): 0.01, 0.76], whereas the GL+ chemotherapy group had the lowest incidence of leukopenia, hemoglobin reduction, and thrombocytopenia, with an OR of 5.25 (95% CI: 2.41, 11.43), 4.66 (95% CI: 2.23, 9.72), and 0.27 (95% CI: 0.13, 0.54), respectively. Moreover, BZD + chemotherapy could alleviate leukopenia, hemoglobin reduction, and thrombocytopenia (P<0.01). Pairwise comparison showed that there was no difference in the efficacy among the 8 CHMs+ chemotherapy group. The comparison and adjustment funnel plot indicated that small-study effect had no impact on these outcomes. This NMA provided evidence to support that patients with CRC benefit from receiving different combination of CHM chemotherapies. Among these, GL plus chemotherapy and BZD plus chemotherapy were the more effective for myelosuppression in patients; however, as the qualtiy of evidence is insufficient, further research is needed. (PROSPERO, No. CRD42022369025).

Abstract C167: An SN38 dendrimer nanoparticle, DEP irinotecan (SN38-SPL9111), demonstrates efficacy in mouse models of gastrointestinal cancer and augments anti-tumor effects of immune checkpoint blockade and PARP inhibition

Abstract Background: Irinotecan is a topoisomerase 1 inhibitor pro-drug used to treat gastrointestinal (GI) cancers including as first line for colorectal cancer (CRC) as part of the FOLFIRI plus monoclonal antibody (mAb) regimen, and for pancreatic cancer in the FOLFIRINOX regimen. However, irinotecan causes severe and dose-limiting side effects, including diarrhea and neutropenia. Starpharma has developed a highly optimized polylysine dendrimer enhanced (DEP) nanoparticle conjugate of the irinotecan active metabolite, SN38 (DEP SN38 or DEP irinotecan). DEP SN38 avoids the need for liver conversion of irinotecan to SN38 and achieves preferential tumor targeting. DEP SN38 is in phase 2 clinical investigation as monotherapy or combination therapy in patients with solid tumors (EudraCT no: 2019-001318-40). SN38 is known to enhance the efficacy of immune checkpoint blockade (ICB) via effects on immune cells in the tumor microenvironment. Here, we evaluated the anti-tumor effects of DEP SN38 alone or in combination with either ICB (anti- programmed cell death-1 [PD1] mAb) or poly adenosine diphosphate (ADP) ribose polymerase (PARP) inhibition (olaparib) in mouse models of GI cancer. Methods: HT29 (human CRC) and CAPAN-1 (human pancreatic cancer) cell line xenografts were established subcutaneously in BALB/c nude or NOD-scid-Gamma immunodeficient mice, respectively. Three doses of DEP SN38 (at 5-10mg/kg SN38) or irinotecan (35-80 mg/kg) were administered intravenously (IV) on days 1, 8, 15. Olaparib (50 mg/kg) was delivered by daily IV injection for 5 days/week over 3 weeks. DEP SN38 (IV on days 1, 8, 15 at 18-35 mg/kg SN38) or irinotecan (75 mg/kg) plus rat anti-PD1 mAb therapy or control mAb (intraperitoneally, 100 mg/kg then 50 mg/kg on days 5, 8, 12) was evaluated in both MC38 (C57BL/6) and CT26 (BALB/c) allograft models of CRC. Toleration of drug was bodyweight loss ≤15%. Results: DEP SN38 treatment of HT29 or CAPAN-1 xenografts led to tumor regressions, prolonged control of tumor growth and improved survival. In contrast, conventional irinotecan had minimal effect on tumor growth versus vehicle control. DEP SN38 was well tolerated by mice with minimal bodyweight loss. Administration of anti-PD1 mAb alone confirmed the known modest sensitivity of MC38, and resistance of CT26 syngeneic tumors, to ICB. DEP SN38 plus anti-PD1 mAb, enhanced anti-tumor responses in the MC38 model beyond those seen for each agent alone and also resulted in tumor eradication and prolonged survival. In the CT26 model, anti-PD1 mAb was also augmented by addition of DEP SN38 but not irinotecan alone, despite resistance of CT26 tumors to anti-PD1 mAb alone. The HT29 CRC model was resistant to Olaparib alone. In contrast, anti-tumor effects and prolonged survival were observed with olaparib plus DEP SN38. Conclusions: DEP SN38 demonstrated superior efficacy compared to irinotecan when used in models of GI cancer. The anti-tumor efficacy of both ICB and PARP inhibition was augmented by DEP SN38 in models of CRC, and these combinations should be investigated clinically. Citation Format: Benjamin J Blyth, Brian D Kelly, Michael Giannis, Anne Cargill, Aynaz Seta, Graham P Heery, Anthony Eglezos, Cameron N Johnstone, Jeremy R A Paull. An SN38 dendrimer nanoparticle, DEP irinotecan (SN38-SPL9111), demonstrates efficacy in mouse models of gastrointestinal cancer and augments anti-tumor effects of immune checkpoint blockade and PARP inhibition [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C167.

Cost-Utility and Budget Impact Analyses of Oral Chemotherapy for Stage III Colorectal Cancer: Real-World Evidence after Policy Implementation in Thailand.

This study conducted a cost-utility analysis and a budget impact analysis (BIA) of outpatient oral chemotherapy versus inpatient intravenous chemotherapy for stage III colorectal cancer (CRC) in Thailand. A Markov model was constructed to estimate the lifetime cost and health outcomes based on a societal perspective. Eight chemotherapy strategies were compared. Clinical and cost data on adjuvant chemotherapy were collected from the medical records of 1747 patients at Siriraj Hospital, Thailand. The cost-effectiveness results were interpreted against a Thai willingness-to-pay threshold of USD 5003/quality-adjusted life year (QALY) gained. A 5-year BIA was performed. Of the eight strategies, CAPOX then FOLFIRI yielded the highest life-year and QALY gains. Its total lifetime cost was also the highest. An incremental cost-effectiveness ratio of CAPOX then FOLFIRI compared to 5FU/LV then FOLFOX, a commonly used regimen USD was 4258 per QALY gained.The BIA showed that when generic drug prices were applied, 5-FU/LV then FOLFOX had the smallest budgetary impact (USD 9.1 million). CAPOX then FOLFIRI required an approximately three times higher budgetary level (USD 25.1 million). CAPOX then FOLFIRI is the best option. It is cost-effective compared with 5-FU/LV then FOLFOX. However, policymakers should consider the relatively high budgetary burden of the CAPOX then FOLFIRI regimen.

Comparison of the Efficacy of FOLFIRI and Paclitaxel Chemotherapy Regimens in the Second Line Treatment of Metastatic Gastric Cancer

Introduction: Although the incidence of gastric cancer has shown a significant decrease over the years, it remains the fourth leading cause of cancer-related deaths, resulting in more than 700,000 annual deaths worldwide. The main goal of metastatic gastric cancer treatment is to alleviate symptoms and, if feasible, improve survival. The purpose of our study was to compare the effectiveness of two chemotherapy regimens, FOLFIRI and paclitaxel, which are commonly used in the second-line treatment of metastatic gastric cancer.&#x0D; Material and Method: Patients over the age of 18 with a diagnosis of metastatic gastric carcinoma who were treated with either FOLFIRI or paclitaxel as second-line therapy were enrolled in our study. These two treatment groups were compared in terms of overall and progression-free survival. &#x0D; Results: A total of 99 patients were included. 56 (56.6%) patients had received FOLFIRI and 43 (43.3%) had received paclitaxel. The median overall survival for the entire cohort was 9 months: 10 months for FOLFIRI and 8 months for paclitaxel, with no statistically significant difference between them. In multivariate analysis, Eastern Cooperative Oncology Group (ECOG) performance status, body mass index, and number of chemotherapy cycles were identified as independent prognostic factors.&#x0D; Conclusion: We compared two commonly used regimens in the second-line treatment of metastatic gastric cancer, FOLFIRI and paclitaxel, in terms of overall and progression-free survival. There was no statistically significant difference between the two regimens. Both regimens can be considered as reasonable second-line treatment options. According to the results of our study, the choice of chemotherapy for second-line treatment should be made on an individual basis, considering factors such as the treatment received in the first-line, side effects, medication cost, and accessibility.

Chemotherapy-induced broadly reactive autoantibodies in the treatment of malignancies

The aim of the study was to evaluate the relationship between chemotherapy and autoimmune reactions in patients with metastatic colorectal cancer. Cancer and autoimmunity are known to be interrelated, but until now it has been unclear to what extent chemotherapy specifically contributes to autoimmune reactions. We studied immunoglobulin M (IgM) levels in response to the administration of various human tissues before and during adjuvant chemotherapy. Patients received seven cycles of chemotherapy with the FOLFIRI plus cetuximab regimen. IgM levels against the tested tissues increased already after the first cycle of chemotherapy and continued to increase during the second and third cycles. Autoimmune responses then began to decrease from the fourth to seventh cycles, but remained elevated from baseline for most of the study tissues. Our results suggest that chemotherapy can induce a wide range of autoimmune reactions. Monitoring self-reactive IgM responses during treatment may help prevent or alleviate side effects associated with autoimmunity.

Variation in FOLFOX, FOLFIRI, and FOLFOXIRI effects on CD8+ T cell and PDL1 levels in MSS CRC patients.

3526 Background: Colorectal cancer (CRC) is a heterogenous disease treated with FOLFOX, FOLFIRI, and FOLFOXIRI chemotherapy regimens. About 85% of CRC patients have microsatellite stable (MSS) tumors that resist immune checkpoint blockade (ICB). Some studies suggest that chemotherapy modulates the MSS CRC tumor microenvironment (TME) to enhance CD8+ T cell infiltration, but ICB remains ineffective. We evaluated the TME of MSS CRC patients to investigate chemotherapy impact on immune markers. Methods: CRC patient samples (n = 16,827) underwent DNA (592-gene or whole exome)/RNA (whole transcriptome) sequencing at Caris Life Sciences. Immune cell fractions within TMEs were estimated from RNA deconvolution (quanTIseq; Finotello, 2019; n = 11,109). PDL1 expression was assessed by IHC (SP142; ≥2+/5%). Patients who received FOLFOX (n = 425), FOLFIRI (n = 88), or FOLFOXIRI (n = 19) &lt; 1 year prior to tumor collection or who didn’t receive these treatments &gt; 4000 days before tumor collection (untreated, n = 6,608) were analyzed. Statistical significance was determined using chi-square, Fisher’s exact, and Mann-Whitney U tests, where appropriate. Results: FOLFOX-treated CRC (n = 213) had a higher CD8+ T cell fraction vs untreated (n = 3,449, FC = 1.9, p &lt; 0.01) CRC and there was no difference among FOLFIRI-treated (n = 37, FC = 1.1, p = 0.13) or FOLFOXIRI-treated (n = 9, FC = 2.2, p = 0.49) CRC. Survival outcomes were similar in FOLFOX-treated CD8+ T cell-high (n = 82) vs low (n = 161, HR = 1.3, p = 0.12) and in FOLFOX-treated PDL1+ (n = 13) vs PDL1- (n = 338) CRC (HR = 1.6, p = 0.14). The CD8+ T cell fraction was similar in untreated KRAS wild-type (WT, n = 1714) vs untreated KRAS-mutated (mut, n = 1718) CRC (FC = 1.3, p &lt; 0.01). FOLFOX-treated KRAS-mut CRC had a higher CD8+ T cell fraction (n = 1718 untreated, 96 treated, FC = 2.3, p &lt; 0.01) and CD69 expression (n = 1724 untreated, 97 treated, FC = 1.7, p &lt; 0.01) vs untreated KRAS-mut CRC. This FOLFOX-dependent effect on CD8+ T cells was lower in WT KRAS CRC (n = 114 FOLFOX-treated, n = 1714 untreated, FC = 1.6, p &lt; 0.01) but survival outcomes were similar in FOLFOX-treated WT (n = 210) vs KRAS-mut (n = 210) CRC (HR = 1.0, p = 0.82). The CD8+ T cell fraction was similar in untreated right- (R; n = 803) vs left-sided CRC (L; n = 927, FC = 1.3, p &lt; 0.01) but PDL1+ IHC rates were significantly higher in R-CRC (n = 1340 L, 1124 R, FC = 2.2, p &lt; 0.01). The CD8+ T cell fraction was similar in untreated WT (n = 3144) vs BRAF-mut CRC (n = 248, FC = 0.8, p &lt; 0.01), but BRAF-mut were more frequently PDL1+ (n = 4622 WT, 340 mut, FC = 4.2, p &lt; 0.01). PDL1+ rates were similar in untreated (n = 1124) vs FOLFIRI-treated R-CRC (n = 12, FC = 2.0, p = 0.46) but were higher in FOLFIRI-treated (n = 9) vs untreated (n = 1340) L-CRC (n = 9, FC = 6.0, p = 0.04). Conclusions: We describe an association between FOLFOX and subsequent infiltration by CD8+ T-cells and high PDL1+ rates in R-CRC, BRAF-mut CRC, and FOLFIRI-treated L-CRC. The findings provide insights for future therapeutic strategies.

Efficacy of vemurafenib based regimens in colorectal cancer: A systematic review of clinical trials.

e15566 Background: Colorectal cancer (CRC) is the 3rd most common cancer worldwide, and BRAF gene mutation is present in almost 10% of these cancers. It results in constitutive activation of the mitogen-activated protein kinase pathway (MAPKP). Abnormal activation of MAPKP leads to uncontrolled mitotic activity and inhibition of apoptosis. In this systematic review, we will assess the efficacy of vemurafenib (BRAF inhibitor) based regimens in CRC. Methods: We followed PRISMA guidelines to conduct this systematic review. A literature search was performed on PubMed, Clinicaltirals.gov, and Embase with mesh terms, ‘’Colorectal Neoplasms’’ and “Proto-Oncogene Proteins B-raf” from the inception of data till 01/05/2023. We screened 4572 articles and included 1 randomized clinical trial (RCT, N = 100), and 4 non-randomized trials (nRCTs, N = 85), measuring the efficacy of vemurafenib (V) based regimens in BRAF V600E-mutated CRC. Results: In 5 clinical trials (N = 185), 90 patients were treated with triple therapy, 45 with dual therapy, and 50 were in the control arm. In triple therapy, 69 patients were treated with V plus irinotecan (I) and cetuximab (C), overall response rate (ORR) was 17% and 35%, and progression-free survival (PFS) was 4.2 and 7.7 months in the randomized and the non-randomized study, respectively. PFS was improved significantly with a hazard ratio (HR) of 0.50 (95% CI, 0.32 to 0.76, P = .001) in favor of V+I+C compared to C+I. Among combinations of V+C, adding 5-fluorouracil/leucovorin/irinotecan (FOLFIRI) as third combination showed the highest ORR of 81% and overall survival (OS) and PFS of 15.4 and 9.7 months, respectively. In two drug regimens, V was combined with Cobimetinib (Co) and Panitumumab (P) in two non-randomized studies, and partial response (PR) was 26% and 13%, respectively. (Table 1). Conclusions: BRAF + EGFR inhibitor combination is showing promising antitumor effects, and the addition of the FOLFIRI regimen was more effective than adding irinotecan alone while comparing treatment regimens in BRAF V600E-mutated CRC patients with metastasis. V+Co showed antitumor effects in CRC BRAF mutated patients who were heavily pre-treated. More randomized trials needed. [Table: see text]

Drug monitoring detects under- and overdosing in patients receiving 5-fluorouracil-containing chemotherapy—results of a prospective, multicenter German observational study

Body surface area (BSA)-based dosing of 5-fluorouracil (5-FU) results in marked inter-individual variability in drug levels, whereas determination of plasma 5-FU concentration and area under the curve (AUC) is a more precise dosing method but has not been integrated into clinical routine. We conducted a multicenter, prospective study to study 5-FU AUC distributions and assess clinical factors predicting therapeutic dosing in patients receiving BSA-dosed 5-FU. Between June 2017 and January 2018, a total of 434 patients receiving continuous, infusional BSA-dosed 5-FU from 37 sites in Germany were included. Plasma 5-FU concentration and AUC were measured in venous blood samples at steady state. The primary objective was to determine 5-FU AUC distributions in relation to the target range, which is defined as 20-30 mg× h/l. The second objective was to explore clinical parameters that correlate with achievement of 5-FU AUC target range. The primary tumor was mainly located in the gastrointestinal tract (96.3%), with colorectal cancer being the most common (71.2%) tumor entity. 5-FU was administered as monotherapy (8.1%) or as part of FOLFOX (33.2%), FOLFIRI (26.3%), or other regimens (12.4%). Treatment setting was adjuvant (31.3%) or metastatic (64.5%). The median AUC was 16 mg× h/l. Only 20.3% of patients received 5-FU treatment within the target range, whereas the majority of patients (60.6%) were underdosed and 19.1% of patients were overdosed. In the univariate logistic regression, treatment setting was the only clinical parameter that significantly correlated with achievement of the target range. Patients treated in the metastatic setting had a 2.1 (95% confidence interval 1.186-3.776, P= 0.011) higher odds to reach the target range compared with patients treated in the adjuvant setting. The majority of patients received suboptimal doses of 5-FU using BSA dosing. Therapeutic drug monitoring of 5-FU is an option for optimized individualized cancer therapy and should be integrated into the clinical practice.

Using a combination of fruquintinib, raltitrexed, and S-1 as a third-line treatment for metastatic colorectal cancer with co-existence of Hodgkin lymphoma: a case report.

Patients with metastatic colorectal cancer (mCRC) beyond second line treatment have a poor prognosis. Fruquintinib, regorafenib, trifluridine/tipiracil (TAS-102), panitumumab and cetuximab combined with single-agent chemotherapy regimens are currently recommended as third-line therapies for patients exhibiting disease progression. Effective late-line therapies for mCRC are urgently needed. The FRESCO randomized clinical trial (RCT) prompts fruquintinib as a third-line treatment in advanced colorectal cancer (CRC). A phase II study in our center reported the efficacy and safety of S-1 plus raltitrexed for the treatment of chemo-refractory mCRC. The combination of the fruquintinib, raltitrexed, and S-1 has not been reported in mCRC. This case report presents a patient with mCRC who received third-line treatment with fruquintinib, raltitrexed, and S-1. A 54-year-old male presenting with hematochezia was admitted to West China Hospital of Sichuan University in June 2017 and underwent surgery for a tumor between the rectum and sigmoid colon. Postoperative pathology identified adenocarcinoma (wild-type RAS/RAF, no PIK3CA mutation), and the patient was diagnosed with mCRC (pathological stage, pT3pN1apM0). The mFOLFOX6 regimen was administered. The patient was subsequently diagnosed with Hodgkin lymphoma in May 2018 and treated with the ABVD regimen after multidisciplinary discussions. Liver metastases (intestinal-type adenocarcinoma) were detected in November 2018, and second-line therapy with the FOLFIRI regimen was initiated in January 2019. Lung metastases were identified in September 2019, so the patient was treated with a combination of raltitrexed, S-1, and fruquintinib. A partial response (PR) was detected in November 2019, and the patient underwent resection of the hepatic lesion on November5, 2020. Computed tomography (CT) images in November 2021 revealed a stable disease; thus, raltitrexed was discontinued, and S-1 and fruquintinib were maintained. The treatment is still responding until the last follow-up (December 2022). The case was characterized by the simultaneous existence of mCRC and Hodgkin lymphoma, which required management by a multidisciplinary team. Third-line therapy with fruquintinib, raltitrexed, and S-1 achieved a PR that permitted surgical resection and enabled a relatively long progression-free survival. The findings suggest that the three agents regimen might be clinically effective as late-line therapy for mCRC.

HTA and Gastric Cancer: Evaluating Alternatives in Third- and Fourth-Line Patients.

Metastatic gastric cancer (mGC) represents an economic and societal burden worldwide. The present study has two aims. Firstly, it evaluates the benefits and the added value of the introduction of trifluridine/tipiracil (FTD/TPI) in the Italian clinical practice, defining the comparative efficacy and safety profiles with respect to the other available treatment options (represented by the best supportive care (BSC) and FOLFIRI (5-FU, irinotecan, and leucovorin) regimens). Secondly, it assesses the potential economic and organizational advantages for hospitals and patients, focusing on third- and fourth-line treatments. For the achievement of the above objective, a health technology assessment study was conducted in 2021, assuming the NHS perspective within a 3-month time horizon. The literature reported a better efficacy of FTD/TPI with respect to both BSC and FOLFIRI regimens. From an economic perspective, despite the additional economic resources that would be required, the investment could positively impact the overall survival rate for the patients treated with the FTD/TPI strategy. However, the innovative molecule would lead to a decrease in hospital accesses devoted to chemotherapy infusion, ranging from a minimum of 34% to a maximum of 44%, strictly dependent on FTD/TPI penetration rate, with a consequent opportunity to take on a greater number of oncological patients requiring drug administration for the treatment of any other cancer diseases. According to experts' opinions, lower perceptions of FTD/TPI emerged concerning equity aspects, whereas it would improve both individuals' and caregivers' quality of life. In conclusion, the results have demonstrated the strategic relevance related to the introduction of FTD/TPI regarding the coverage of an important unmet medical need of patients with metastatic gastric cancer who were refractory to at least two prior therapies, with important advantages for patients and hospitals, thus optimizing the clinical pathway of such frail patients.

A Cost-effectiveness Analysis of Adding Cetuximab to the First-line Treatment of Metastatic Colorectal Carcinoma in Iran; Considering Genetic Screening for Precision Medicine.

This study aimed to evaluate the cost-effectiveness of cetuximab in different genetic populations of metastatic colorectal carcinoma patients, including KRAS and RAS wild types and mutants, when added to FOLFIRI treatment regimens for evidence-based disease management in Iran. A Markov decision model was designed in TreeAge software with the three states of stable, progress, and death. Clinical outcomes were extracted from published clinical studies, and costs were extracted from the Iranian local data. The primary outcome was an incremental cost-effectiveness ratio (ICER) in the simulated population. The cost-utility model from the perspective of the health system indicated that the average direct medical costs of a patient that has not been genetically screened are $56,985.27 and $20,767.74 in FOLFIRI + cetuximab and FOLFIRI regimens, respectively. However, costs per patient in the KRAS wild-type population were $21,845.52 in FOLFIRI and $78,321.22 in FOLFIRI + cetuximab. In RAS wild-type patients, FOLFIRI and FOLFIRI + cetuximab costs per patient were $23,111.62 and $84,976.39, respectively. Incremental QALYs for the above scenarios were 0.069, 0.193, and 0.285, respectively. Therefore, the ICER of add-on cetuximab in Iran compared to the treatment alternatives in the scenarios with and without KRAS screening was $520,771.55/QALY, $292,768.16/QALY, and $217,460.51/QALY. Although genetic screening in precision medicine reduces costs per outcome, according to the willingness-to-pay threshold of $4349.50 in the Iranian health system, add-on cetuximab to the FOLFIRI regimen is not a cost-effective strategy even with genetic screening and a 20% price reduction.

Pathologic complete response after laparoscopic surgery following treatment with nivolumab and ipilimumab for anticancer drug-resistant MSI-high descending colon cancer: a case report and literature review

BackgroundPreoperative treatment is performed for locally advanced colon cancer with extensive tumor proximity or suspected invasion of skeletal muscles, major organs, and blood vessels. Oxaliplatin-based regimens are often used in preoperative chemotherapy. However, microsatellite instability (MSI)-high colorectal cancer is often resistant to cytotoxic anticancer agents. Herein, we describe a case of treatment of anticancer drug-resistant MSI-high locally advanced colon cancer and review cases of complete response to immune checkpoint inhibitor therapy for colorectal cancer.Case presentationA 57-year-old woman was referred to our hospital with a large tumor in the descending colon and extensive thoracic and abdominal wall involvement, including the ribs and diaphragm. No distant metastasis was observed. The tumor had perforated the abdominal wall and formed an abscess. Upon visiting our hospital, emergency surgery was performed. An abdominal wall incision was made to drain the abscess and laparoscopic colostomy was performed. Histopathological examination of biopsy specimens revealed an adenocarcinoma with positive immunohistochemical expressions of both CDX2 and CK20. The patient was diagnosed with a descending colon cancer. Genetic examination found MSI-high, Kras mutation (F12G), and wild-type BRAF. After the inflammation improved, chemotherapy with the FOLFIRI regimen was initiated, but the tumor grew rapidly. As a second-line treatment, nivolumab and ipilimumab combination therapy was initiated. After four cycles of these therapies, the patient was administered nivolumab alone for five cycles. Tumor shrinkage was observed and radical surgery was performed. The patient underwent laparoscopic descending colon and partial thoracic and abdominal wall resection. The abdominal wall muscle was dissected from the abdominal cavity, and subcutaneous tissues, diaphragm, ribs were dissected from the body surface. Pathological examination revealed mucus components, fibrous tissues, and no malignant cells, indicating a complete pathological response (pCR). The patient had a good postoperative course and returned to work after being discharged. No recurrence was observed six months postoperatively.ConclusionsHerein, we report a case of anticancer drug-resistant MSI-high colon cancer that was resected after treatment with immune checkpoint inhibitors, and a pCR was achieved. This new treatment strategy can be used for the treatment of cases that are not responsive to conventional therapies.

Daily practices in chemotherapy for advanced gastric or gastroesophageal junction adenocarcinoma: METESTOMAC French prospective cohort.

Around 50% of gastric cancers are diagnosed at an advanced stage. Several chemotherapy regimens are now internationally validated. Few data are available on the routine daily management of advanced gastric or gastroesophageal junction cancers. We aimed to describe chemotherapy practices, tolerance, and efficacy overall survival (OS) and Progression free survival (PFS) in a prospective French cohort. Patients starting palliative chemotherapy were prospectively enrolled in 49 French centres. The primary objective was to report and describe patients' characteristics and treatment strategies. Secondary objectives were OS, PFS, objective response rate, adverse events rate, performance status deterioration during the chemotherapy. A total of 182 patients were included; 179 were analysed. Most patients received platinium-based chemotherapy as the first treatment and FOLFIRI as second; 62.0% of patients received a second line, and 32.4% a third line. More than two thirds of Her2-positive patients were first treated with trastuzumab. The FOLFIRI regimen was the most frequently used second-line therapy. Median OS was 13.3months, similar whatever the chemotherapy or combinations used in the first line. One- and 2-year OS increased with the number of chemotherapy lines received, from respectively 24.7% and 5.7% (1 line), to 46.9% and 12.4% (2 lines) and 88.1% and 29.9% (3 or more lines) (p < 0.0001). Our study showed that treatment strategies in France are based on a succession of doublets, making it possible to offer a second and third line of treatment more often. This treatment strategy must be taken into account for future trials with immunotherapy combinations.

The Efficacy and Safety of Hepatic Arterial Infusion Chemotherapy Based on FOLFIRI for Advanced Intrahepatic Cholangiocarcinoma as Second-Line and Successive Treatment: A Real-World Study

Objective Intrahepatic cholangiocarcinoma (iCCA) is a primary liver malignancy with a poor prognosis and limited treatment. Cisplatin with gemcitabine is used as the standard first-line chemotherapy regimen; however, there is still no robust evidence for second-line and successive treatments. Although preliminary evidence suggests a vital role of precision therapy or immunotherapy in a subset of patients, the gene alteration rate is relatively low. Herein, we explored the second-line and successive treatments using hepatic arterial infusion chemotherapy (HAIC) based on FOLFIRI after the failure of gemcitabine and platinum combined with target and immunotherapy in refractory CCAs. Methods Advanced patients with iCCAs confirmed by diagnostic pathology, who progressed at least on a gemcitabine/platinum doublet and/or other systemic chemotherapy combined with target therapy and immune checkpoint inhibitor, were included. All patients received infusional 5-fluorouracil/leucovorin with irinotecan (FOLFIRI) via HAIC until progression or unacceptable toxicity. The primary objective was the feasibility of treatment, with secondary objectives of disease control rate (DCR) and 6-month survival rate. Results A total of 9 iCCA patients treated between Dec 2020 and May 2021 were enrolled; 2 patients suffered from distant metastasis, while 7 had local lymph node metastasis and portal vein or hepatic vein invasion. HAIC was delivered as second-line therapy in 6/9 patients, while a third or successive therapy in 3/9 patients. The patients accepted an average of 2.90 ± 1.69 cycles of HAIC. The objective response rate was 22.2%; the disease control rate was 55.5% (5/9); median progression-free survival was 5 months; and 6-month survival rate was 66.7% (6/9). Conclusions Our results provide preliminary evidence that HAIC based on FOLFIRI regimen is efficient and safe in some patients progressing after previous treatment. Therefore, HAIC may be a promising and valuable complementary therapy for advanced CCAs as a second-line and successive therapy. Otherwise, the combination of HAIC with precision medicine may improve clinical benefits (clinical registration number: 2021BAT4857).

A post-marketing safety study of ramucirumab with FOLFIRI in patients with metastatic colorectal cancer.

BackgroundRamucirumab [human vascular endothelial growth factor (VEGF) receptor-2 monoclonal antibody] + levofolinate, fluorouracil, and irinotecan (FOLFIRI) was approved for the treatment of metastatic colorectal cancer (CRC) in Japan based on the results from the phase 3 RAISE trial (NCT01183780). However, safety information of ramucirumab + FOLFIRI in the real-world setting is limited. Therefore, the present study was conducted to evaluate the safety of ramucirumab + FOLFIRI under routine clinical practice in patients with metastatic CRC (mCRC) after first-line chemotherapy.MethodsA single-arm, prospective, multicenter, non-interventional, observational study was conducted between August 2016 and May 2020. Patients with mCRC treated with ramucirumab + FOLFIRI for the first time were included. Patients were observed for 12 months from the start of ramucirumab. Data were recorded using the electronic data capture system.ResultsIn total, 362 patients with a mean age of 64.1 years were evaluated for safety, of whom 355 patients were evaluated for effectiveness. A higher proportion of the patients were males (n=200; 55.2%), had metastases and recurrent sites (n=362, 100.0%), and had received prior anti-cancer treatment (n=355; 98.1%). Approximately 83.7% (n=303) and 25.4% (n=92) of patients had medication history of bevacizumab and anti-epidermal growth factor receptor (EGFR) antibodies, respectively. Overall, 84.3% (n=305) of patients experienced any grade adverse events (AEs). Neutrophil count decreased (n=138; 38.1%), hypertension (n=58; 16.0%), and diarrhea (n=57; 15.7%) were observed frequently. The clinically relevant grade ≥3 AEs of special interest (AESIs) with >2% incidence included neutropenia (n=101; 27.9%), hypertension (n=35; 9.7%), proteinuria (n=23; 6.4%), hepatic dysfunction (n=15; 4.1%), febrile neutropenia (n=10; 2.8%), and leukopenia (n=9; 2.5%). The presence of renal disease at baseline increased the risk of proteinuria [risk ratio: 2.1; 95% confidence interval (CI): 1.1–4.2]. Three deaths were reported due to AEs, of which 1 was study treatment related. The 12-month survival rate of the ramucirumab + FOLFIRI regimen was 59%, mortality mainly (90%) occurring due to progressive disease.ConclusionsAlthough the current observational study enrolled patients with various medication history, the regimen of ramucirumab + FOLFIRI was manageable under clinical practice. No new safety concerns beyond the findings observed in previous clinical trials were reported.

The impact of second-line treatment after fist-line cisplatin plus gemcitabine in advanced biliary tract cancers: A mono-institutional retrospective study.

e16180 Background: The prognosis of advanced biliary tract cancers (ABTCs) is poor with a 5 year overall survival (OS) lower than 20%. The standard of care first-line chemotherapy is the combination of cisplatin plus gemcitabine. The efficacy of second-line treatment is supported by few evidence and only one randomized phase III clinical trial is reported. The ABC-06 trial showed a minimal improvement in overall survival with FOLFOX compared to active symptoms control (ASC). Herein, we provide a retrospective analysis of patients treated with second-line treatment at our Institution investigating the impact of treatment regimen and possible prognostic or predictive factors. Methods: ABTCs patients receiving second-line treatment following a first-line chemotherapy with cisplatin plus gemcitabine were included in the analysis. The following variables were collected: gender; age (&lt; 65 years vs ≥ 65 years); baseline ECOG PS (0-1 vs ≥2); second-line regimen (FOLFIRI vs FOLFOX); comorbidities (yes vs no); number of comorbidities (0-1 vs ≥ 2); number of metastatic sites (1 vs ≥2). Univariate and multivariate analysis for progression free survival (PFS) and OS were performed. Results: Fifty-one patients affected with ABTCs receiving second-line treatment between January 2016 and May 2021 were included in the analysis. The median age was 70 years (38-82), 39% (20) were males, 70% (36) were aged ≥ 65 years, ECOG PS was 0-1 in 86% (44) of patients; 39% (20) had ≥2 comorbidities; 60% (31) had ≥ 2 metastatic sites. Second-line regimen included FOLFIRI (28; 55%), FOLFOX (15; 29%), capecitabine (2; 4%) and experimental drugs (6; 12%). The overall population median PFS and OS at second-line were 3.5 months (median follow-up 11.4 months) and 8.8 months (median follow-up 22.6 months), respectively. Two patients (4%) achieved a partial response and the disease control rate was 39%. At the univariate and multivariate analysis, no variable was associated with PFS. At the univariate analysis, second-line regimen FOLFIRI (p = 0.03) and single metastatic site (p = 0.06) were associated with improved OS; at the multivariate analysis only the second-line regimen was confirmed associated with OS (p = 0.02). In particular, out of 43 evaluable patients, the median OS according to treatment (FOLFIRI vs FOLFOX) was 11.3 months versus 5.4 months (p = 0.019, HR 0.46, 95% CI: 0.18-0.88). Conclusions: Despite the retrospective analysis and the limited sample size, we confirm the importance of second-line chemotherapy in ABTCs patients, when feasible. Our results show that the second-line FOLFIRI regimen after a platinum-containing fist-line, was independently associated with improved OS. Given that the ABC-06 trial compared FOLFOX to ASC, a randomized trial of FOLFOX vs FOLFIRI as second-line would provide further information in this setting.

P-148 The impact of second-line treatment after fist-line cisplatin plus gemcitabine in advanced biliary tract cancers: A mono-institutional retrospective study

The prognosis of advanced biliary tract cancers (ABTCs) is poor with a 5 year overall survival (OS) lower than 20%. The standard of care first-line chemotherapy is the combination of cisplatin plus gemcitabine. The efficacy of second-line treatment is supported by few evidence and only one randomized phase III clinical trial is reported. The ABC-06 trial showed a minimal improvement in overall survival with FOLFOX compared to active symptoms control (ASC). Herein, we provide a retrospective analysis of patients treated with second-line treatment at our Institution investigating the impact of treatment regimen and possible prognostic or predictive factors. ABTCs patients receiving second-line treatment following a first-line chemotherapy with cisplatin plus gemcitabine were included in the analysis. The following variables were collected: gender; age (< 65 years vs ≥ 65 years); baseline ECOG PS (0-1 vs ≥2); second-line regimen (FOLFIRI vs FOLFOX); comorbidities (yes vs no); number of comorbidities (0-1 vs ≥ 2); number of metastatic sites (1 vs ≥2). Univariate and multivariate analysis for progression free survival (PFS) and OS were performed. Fifty-one patients affected with ABTCs receiving second-line treatment between January 2016 and May 2021 were included in the analysis. The median age was 70 years (38-82), 39% (20) were males, 70% (36) were aged ≥ 65 years, ECOG PS was 0-1 in 86% (44) of patients; 39% (20) had ≥2 comorbidities; 60% (31) had ≥ 2 metastatic sites. Second-line regimen included FOLFIRI (28; 55%), FOLFOX (15; 29%), capecitabine (2; 4%) and experimental drugs (6; 12%). The overall population median PFS and OS at second-line were 3.5 months (median follow-up 11.4 months) and 8.8 months (median follow-up 22.6 months), respectively. Two patients (4%) achieved a partial response and the disease control rate was 39%. At the univariate and multivariate analysis, no variable was associated with PFS. At the univariate analysis, second-line regimen FOLFIRI (p=0.03) and single metastatic site (p=0.06) were associated with improved OS; at the multivariate analysis only the second-line regimen was confirmed associated with OS (p=0.02). In particular, out of 43 evaluable patients, the median OS according to treatment (FOLFIRI vs FOLFOX) was 11.3 months versus 5.4 months (p=0.019, HR 0.46, 95% CI: 0.18-0.88). Despite the retrospective analysis and the limited sample size, we confirm the importance of second-line chemotherapy in ABTCs patients, when feasible. Our results show that the second-line FOLFIRI regimen after a platinum-containing fist-line, was independently associated with improved OS. Given that the ABC-06 trial compared FOLFOX to ASC, a randomized trial of FOLFOX vs FOLFIRI as second-line would provide further information in this setting.

Real-world safety and supportive care use of second-line 5-fluorouracil-based regimens among patients with metastatic pancreatic ductal adenocarcinoma

Objective Chemotherapy-related adverse events (AEs) can negatively impact the care of patients. The prevention and management of AEs often require additional medications. This study evaluated the percentages of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) undergoing second-line therapy with 5-fluorouracil (5-FU)-based regimens that experienced AEs during treatment and received medication to manage those AEs. Methods We conducted a retrospective observational analysis utilizing the Flatiron Health database of adult patients with mPDAC who started second-line therapy between January 2016 and August 2020. The occurrence of diarrhea, fatigue, nausea and vomiting, neuropathy, and hematologic AEs including G3/G4 anemia, neutropenia, and thrombocytopenia was assessed. The use of concomitant medications including atropine and granulocyte colony stimulating factor (G-CSF) was assessed. Results Of the 825 eligible patients, 29.0% (n = 239) received FOLFIRINOX, 24.0% (n = 198) received FOLFOX, 6.8% (n = 56) received FOLFIRI, and 40.2% (n = 332) received liposomal irinotecan-based regimens. FOLFIRI and FOLFIRINOX regimens were associated with the highest rates of anemia (16.1% and 15.5%), neutropenia (19.6% and 22.6%), and thrombocytopenia (14.3% and 9.6%). The liposomal irinotecan and FOLFOX regimens were associated with lower rates of anemia (11.8% and 12.1%), neutropenia (12.4% and 14.7%), and thrombocytopenia (2.4% and 8.1%). G-CSF use was observed among 63.6%, 34.9%, 33.9%, and 44.9% of patients treated with FOLFIRINOX, FOLFOX, FOLFIRI, and liposomal irinotecan-based regimens, respectively. Diarrhea was observed among 12.5%, 4.5%, 12.5%, and 10.2% of patients who were treated with FOLFIRINOX, FOLFOX, FOLFIRI, and liposomal irinotecan-based regimens, respectively. Nausea and vomiting occurred in 14.9%, 12.6%, 10.5%, and 13.1% of patients treated with FOLFIRINOX, FOLFOX, FOLFIRI, and liposomal irinotecan-based regimens, respectively. Atropine use was higher in patients treated with FOLFIRINOX and FOLFIRI (90.8% and 94.6%, respectively) than in patients treated with liposomal irinotecan-based regimens (75.6%). Conclusions In patients with mPDAC who received second-line therapy, those who received liposomal irinotecan-based regimens had the lowest rates of anemia, neutropenia, and thrombocytopenia compared to FOLFIRI, FOLFIRINOX, and FOLFOX, while requiring a similar or lower level of medication to treat and manage those adverse events. Patients treated with FOLFIRI received the highest dose of pegfilgrastim to manage neutropenia. The results of this real-world analysis are consistent with prior evaluations of patients with mPDAC and highlight the importance of managing adverse events and associated cost implications.

The Efficacy and Tolerability of Xeliri-Aflibercept Combination in A Metastatic Colorectal Cancer Patient After 5-Fu- Induced Symptomatic Bradycardia: A Case Report and A Brief Review of Literature

5-Fluorouracil (5-FU) and oral fluoropyrimidines are the backbone of colorectal cancer (CRC) chemotherapy, but these have many traditional and cardiotoxic side effects. Rechallenge is usually not recommended due to high mortality rates after ischemic symptoms and other cardiac side effects, but replacing these drugs with another fluropyrimidine, or bolus 5-FU, can be considered for some patients. Aflibercept combined with a FOLFIRI regimen is an accepted second-line therapy for metastatic colorectal cancer (mCRC) patients. XELIRI is another effective and feasible irinotecan and fluoropyrimidine combination, which is more toxic than the FOLFIRI regimen and is not routinely recommended. However, modified doses of XELIRI (mXELIRI) were found to be non-inferior to FOLFIRI. The efficacy of the mXELIRI and aflibercept combination has not investigated yet. We present a patient with infusional 5-FU-induced sinus bradycardia that we could not continue FOLFIRI-aflibercept due to this cardiac side effect. We replaced infusional 5-FU with reduced dosages of capecitabine and irinotecan as in the mXELIRI regimen and combined those with aflibercept. The patient tolerated this regimen well without cardiac or severe gastrointestinal side effects, and had 12 months of progression-free survival. Replacing capecitabine with infusional 5-FU might be an option for some patients experiencing 5-FU-related sinus bradycardia. However, oncologists should arrange the treatment plan according to the risk/benefit ratio. Aflibercept combined with mXELIRI may be an alternative regimen for patients who refuse port catheter placement or who are not able to receive infusional-5-FU due to adverse side effects.