Continuous Infusion Of 5-fluorouracil Research Articles

Phase II study of the safety and efficacy of discontinuing pegfilgrastim for pancreatic adenocarcinoma treated with FOLFIRINOX.

663 Background: The original FOLFIRINOX regimen (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) for pancreatic ductal adenocarcinoma (PDAC) is associated with a high risk of febrile neutropenia (FN), and pegfilgrastim has been used to reduce the risk. However, it remains unclear how long pegfilgrastim needs to continue. This study evaluated the safety and efficacy of FOLFIRINOX after discontinuing pegfilgrastim in PDAC patients. Methods: This prospective phase II trial included patients with PDAC who received the first three courses of FOLFIRINOX, with primary pegfilgrastim prophylaxis for FN, and did not experience FN. The patients continued on FOLFIRINOX without pegfilgrastim from the fourth course. The primary endpoint was development of FN. The secondary endpoints included relative dose intensity (RDI), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The threshold and expected development of FN were 20% and 7%, respectively, at a one-sided significance level of 0.10 and statistical power of 80%. Based on this hypothesis, we calculated the number of patients needed to be 33. Results: In total, 34 patients (20 male, median age 66 years) were enrolled from August 2017 to September 2021. Twenty-three patients were unresectable, and 11 were borderline resectable. FN developed in one patient. Grade 4 neutropenia was observed in six patients, grade 3 neutropenia in 10 (29.4%), anemia in four (11.8%), diarrhea in two (5.9%), and malaise, lung infection, peripheral sensory neuropathy, colitis, and biliary tract infection in one (2.9%) each. Twenty-two patients required dose reduction, mainly because of neutropenia. Mean RDIs at the sixth course of oxaliplatin, irinotecan, leucovorin, acute infusion of fluorouracil, and continuous infusion of fluorouracil were 77.0%, 88.2%, 81.8%, 84.4%, and 87.6%, respectively. ORR, median PFS, and median OS were 44.1%, 15.8 months, and 25.8 months, respectively. Conclusions: FOLFIRINOX can be continued safely with a low incidence of FN after discontinuing pegfilgrastim in PDAC patients who did not experience FN during the first three courses of FOLFIRINOX, if the drug dose is reduced appropriately for neutropenia from the fourth course. Clinical trial information: UMIN000028055 .

Pegfilgrastim for the management of neutropenia during neoadjuvant chemotherapy with docetaxel, cisplatin, and 5-fluorouracil in esophageal cancer patients.

Neoadjuvant docetaxel, cisplatin, and 5-fluorouracil (DCF) therapy is a new standard for locally advanced esophageal squamous cell carcinoma. The optimal timing of pegfilgrastim with the DCF regimen to prevent febrile neutropenia (FN) remains controversial. The effectiveness of concomitant pegfilgrastim administration with continuous 5-fluorouracil (5-FU) infusion in the DCF regimen was therefore assessed. All patients who received neoadjuvant DCF for esophageal cancer were retrospectively assessed. Patients who had been scheduled to receive pegfilgrastim on days 3-5 (early group) or days 7-9 (regular group) of the DCF regimen were included. Uni- and multivariate analyses were used to assess risk factors for FN. Eighty-eight patients were included in the analysis. The 26 patients in the early group received pegfilgrastim as scheduled. In the 62 patients of the regular group, 51 received pegfilgrastim at a median of 7days after starting DCF chemotherapy. However, 11 patients in the regular group could not receive pegfilgrastim. Twenty-two patients of the regular group and 2 patients of the early group developed FN after the first session of DCF. Early administration of pegfilgrastim and grade 4 neutropenia were significantly associated with onset of FN, with multivariate analysis identifying early administration of pegfilgrastim as an independent preventive factor and grade 4 neutropenia as a risk factor, after adjusting for sex and age. Early pegfilgrastim administration is a safe approach that reduces the incidence of FN in DCF therapy. Using pegfilgrastim with continuous 5-FU infusion in the DCF regimen represents a reasonable option to prevent FN.

Perioperative or adjuvant mFOLFIRINOX for resectable pancreatic cancer (PREOPANC-3): study protocol for a multicenter randomized controlled trial

BackgroundSurgical resection followed by adjuvant mFOLFIRINOX (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) is currently the standard of care for patients with resectable pancreatic cancer. The main concern regarding adjuvant chemotherapy is that only half of patients actually receive adjuvant treatment. Neoadjuvant chemotherapy, on the other hand, guarantees early systemic treatment and may increase chemotherapy use and thereby improve overall survival. Furthermore, it may prevent futile surgery in patients with rapidly progressive disease. However, some argue that neoadjuvant therapy delays surgery, which could lead to progression towards unresectable disease and thus offset the potential benefits. Comparison of perioperative (i.e., neoadjuvant and adjuvant) with (only) adjuvant administration of mFOLFIRINOX in a randomized controlled trial (RCT) is needed to determine the optimal approach.MethodsThis multicenter, phase 3, RCT will include 378 patients with resectable pancreatic ductal adenocarcinoma with a WHO performance status of 0 or 1. Patients are recruited from 20 Dutch centers and three centers in Norway and Sweden. Resectable pancreatic cancer is defined as no arterial contact and ≤ 90 degrees venous contact. Patients in the intervention arm are scheduled for 8 cycles of neoadjuvant mFOLFIRINOX followed by surgery and 4 cycles of adjuvant mFOLFIRINOX (2-week cycle of oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 150 mg/m2 at day 1, followed by 46 h continuous infusion of 5-fluorouracil 2400 g/m2). Patients in the comparator arm start with surgery followed by 12 cycles of adjuvant mFOLFIRINOX. The primary outcome is overall survival by intention-to-treat. Secondary outcomes include progression-free survival, resection rate, quality of life, adverse events, and surgical complications. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after the inclusion of 378 patients in 36 months, with analysis planned 18 months after the last patient has been randomized.DiscussionThe multicenter PREOPANC-3 trial compares perioperative mFOLFIRINOX with adjuvant mFOLFIRINOX in patients with resectable pancreatic cancer.Trial registrationClinical Trials: NCT04927780. Registered June 16, 2021.

First-line systemic treatment strategies in patients with initially unresectable colorectal cancer liver metastases (CAIRO5): an open-label, multicentre, randomised, controlled, phase 3 study from the Dutch Colorectal Cancer Group

Patients with initially unresectable colorectal cancer liver metastases might qualify for local treatment with curative intent after reducing the tumour size by induction systemic treatment. We aimed to compare the currently most active induction regimens. In this open-label, multicentre, randomised, phase 3 study (CAIRO5), patients aged 18 years or older with histologically confirmed colorectal cancer, known RAS/BRAFV600E mutation status, WHO performance status of 0-1, and initially unresectable colorectal cancer liver metastases were enrolled at 46 Dutch and one Belgian secondary and tertiary centres. Resectability or unresectability of colorectal cancer liver metastases was assessed centrally by an expert panel of liver surgeons and radiologists, at baseline and every 2 months thereafter by predefined criteria. Randomisation was done centrally with the minimisation technique via a masked web-based allocation procedure. Patients with right-sided primary tumour site or RAS or BRAFV600E mutated tumours were randomly assigned (1:1) to receive FOLFOX or FOLFIRI plus bevacizumab (group A) or FOLFOXIRI plus bevacizumab (group B). Patients with left-sided and RAS and BRAFV600E wild-type tumours were randomly assigned (1:1) to receive FOLFOX or FOLFIRI plus bevacizumab (group C) or FOLFOX or FOLFIRI plus panitumumab (group D), every 14 days for up to 12 cycles. Patients were stratified by resectability of colorectal cancer liver metastases, serum lactate dehydrogenase concentration, choice of irinotecan versus oxaliplatin, and BRAFV600E mutation status (for groups A and B). Bevacizumab was administered intravenously at 5 mg/kg. Panitumumab was administered intravenously at 6 mg/kg. FOLFIRI consisted of intravenous infusion of irinotecan at 180 mg/m2 with folinic acid at 400 mg/m2, followed by bolus fluorouracil at 400 mg/m2 intravenously, followed by continuous infusion of fluorouracil at 2400 mg/m2. FOLFOX consisted of oxaliplatin at 85 mg/m2 intravenously together with the same schedule of folinic acid and fluorouracil as in FOLFIRI. FOLFOXIRI consisted of irinotecan at 165 mg/m2 intravenously, followed by intravenous infusion of oxaliplatin at 85 mg/m2 with folinic acid at 400 mg/m2, followed by continuous infusion of fluorouracil at 3200 mg/m2. Patients and investigators were not masked to treatment allocation. The primary outcome was progression-free survival, analysed on a modified intention-to-treat basis, excluding patients who withdrew consent before starting study treatment or violated major entry criteria (no metastatic colorectal cancer, or previous liver surgery for colorectal cancer liver metastases). The study is registered with ClinicalTrials.gov, NCT02162563, and accrual is complete. Between Nov 13, 2014, and Jan 31, 2022, 530 patients (327 [62%] male and 203 [38%] female; median age 62 years [IQR 54-69]) were randomly assigned: 148 (28%) patients to group A, 146 (28%) patients to group B, 118 (22%) patients to group C, and 118 (22%) patients to group D. Groups C and D were prematurely closed for futility. 521 patients were included in the modified intention-to-treat population (147 in group A, 144 in group B, 114 in group C, and 116 in group D). The median follow-up at the time of this analysis was 51·1 months (95% CI 47·7-53·1) in groups A and B and 49·9 months (44·5-52·5) in in groups C and D. Median progression-free survival was 9·0 months (95% CI 7·7-10·5) in group A versus 10·6 months (9·9-12·1) in group B (stratified hazard ratio [HR] 0·76 [95% CI 0·60-0·98]; p=0·032), and 10·8 months (95% CI 9·9-12·6) in group C versus 10·4 months (9·8-13·0) in group D (stratified HR 1·11 [95% CI 0·84-1·48]; p=0·46). The most frequent grade 3-4 events in groups A and B were neutropenia (19 [13%] patients in group A vs 57 [40%] in group B; p<0·0001), hypertension (21 [14%] vs 20 [14%]; p=1·00), and diarrhoea (five [3%] vs 28 [19%]; p<0·0001), and in groups C and D were neutropenia (29 [25%] vs 24 [21%]; p=0·44), skin toxicity (one [1%] vs 29 [25%]; p<0·0001), hypertension (20 [18%] vs eight [7%]; p=0·016), and diarrhoea (five [4%] vs 18 [16%]; p=0·0072). Serious adverse events occurred in 46 (31%) patients in group A, 75 (52%) patients in group B, 41 (36%) patients in group C, and 49 (42%) patients in group D. Seven treatment-related deaths were reported in group B (two due to multiorgan failure, and one each due to sepsis, pneumonia, portal vein thrombosis, septic shock and liver failure, and sudden death), one in group C (multiorgan failure), and three in group D (cardiac arrest, pulmonary embolism, and abdominal sepsis). In patients with initially unresectable colorectal cancer liver metastases, FOLFOXIRI-bevacizumab was the preferred treatment in patients with a right-sided or RAS or BRAFV600E mutated primary tumour. In patients with a left-sided and RAS and BRAFV600E wild-type tumour, the addition of panitumumab to FOLFOX or FOLFIRI showed no clinical benefit over bevacizumab, but was associated with more toxicity. Roche and Amgen.

Evaluation of the efficacy and toxicity of neo-adjuvant short course radiation therapy concurrently with continuous infusion 5-fluorouracil in the management of locally advanced rectal cancer patients.

Evaluation of the efficacy and toxicity of neo-adjuvant short course radiation therapy concurrently with continuous infusion 5-fluorouracil in the management of locally advanced rectal cancer patients.

First-line serplulimab or placebo plus chemotherapy in PD-L1-positive esophageal squamous cell carcinoma: a randomized, double-blind phase 3 trial

First-line systemic therapeutic options for advanced esophageal squamous cell carcinoma (ESCC) are limited. In this multicenter, double-blind phase 3 trial, a total of 551 patients with previously untreated, locally advanced or metastatic ESCC and PD-L1 combined positive score of ≥1 were randomized (2:1) to receive serplulimab (an anti-PD-1 antibody; 3 mg/kg) or placebo (on day 1), plus cisplatin (50 mg/m2) (on day 1) and continuous infusion of 5-fluorouracil (1,200 mg/m2) (on days 1 and 2), once every 2 weeks. The study met the primary endpoints. At the prespecified final analysis of progression-free survival (PFS) assessed by the blinded independent radiological review committee, serplulimab plus chemotherapy significantly improved PFS compared with placebo plus chemotherapy (median PFS of 5.8 months and 5.3 months, respectively; hazard ratio, 0.60; 95% confidence interval, 0.48–0.75; P < 0.0001). At the prespecified interim analysis of overall survival (OS), serplulimab plus chemotherapy also significantly prolonged OS compared with placebo plus chemotherapy (median OS of 15.3 months and 11.8 months, respectively; hazard ratio, 0.68; 95% confidence interval, 0.53–0.87; P = 0.0020). Grade 3 or higher treatment-related adverse events occurred in 201 (53%) and 81 (48%) patients in the serplulimab plus chemotherapy group and the placebo plus chemotherapy group, respectively. Serplulimab plus chemotherapy administered every 2 weeks significantly improved PFS and OS in patients with previously untreated, PD-L1-positive advanced ESCC, with a manageable safety profile. This study is registered with ClinicalTrials.gov (NCT03958890).

A Phase II Trial of TGFβ Type I Receptor Inhibitor, Galunisertib, plus Neoadjuvant Chemoradiation in Patients with Locally Advanced Rectal Cancer

<h3>Purpose/Objective(s)</h3> Transforming growth factor beta (TGFβ) is an immunosuppressive cytokine upregulated in colorectal cancer. Preclinical data demonstrated improved response to chemoradiation with TGFβ blockade in colorectal adenocarcinoma. Here we report the results of our single arm Phase II study combining the TGFβ type I receptor kinase inhibitor, galunisertib, with neoadjuvant chemoradiation in patients with locally advanced rectal adenocarcinoma. <h3>Materials/Methods</h3> Eligible patients had T3+ or N+ rectal adenocarcinoma planned for surgical resection. Enrolled patients completed a 14-day course of galunisertib, followed by chemoradiation with continuous infusion 5-fluorouracil or capecitabine with radiation to 50.4-54Gy in 28-30 fractions. On day 30, patients underwent another 14-day course of galunisertib concurrent with ongoing chemoradiation. Five to nine weeks after completing neoadjuvant therapy, patients underwent response assessment. Those with complete response by physical exam, proctoscopy, and MRI, could opt for non-operative management and proceed to mFOLFOX6. Those with less than a complete response underwent surgical resection. The primary endpoint was complete response (CR) rate, which was a composite of pathologic complete responses in those patients who proceeded to surgery, and clinical complete responses maintained at 1 year after completion of therapy for those who chose non-operative management. Using a Simon Two-Stage approach with 90% power and α=0.05, to detect a 20% improvement in complete response rate compared to historical control (15% vs 35%); we reject the null hypothesis if ≥10/38 patients have a CR. 38 patients were enrolled with 35 patients evaluable. <h3>Results</h3> Median age was 51y, 68% of patients were male, 87% of patients were Stage III, 97% of patients were node-positive, and 97% were proficient in mismatch repair. 95% of patients completed study therapy. Toxicity attributed to galunisertib was Grade 1-2. 28 patients went to surgery, with a mean neoadjuvant rectal (NAR) score (NAR = 5pN-3(cT-pT)+12]²/9.61) of 11.29, and pathologic complete response (pCR) in 7 patients. 7 patients underwent non-operative management, with 5 achieving clinical complete response (cCR) at 1 year. Therefore, complete responses were observed in 12 patients. Peripheral immune monitoring revealed percent change in CD3+CD4-CXCR3+ T cells and activated effector memory CD8 T cells correlated with response to therapy. Decreased phospho-Smad2 in day 15 biopsies correlated with treatment response. 2y PFS and OS were 81.5% and 97%. <h3>Conclusion</h3> The addition of TGFβ inhibition to neoadjuvant chemoradiation in locally advanced rectal cancer markedly improved response to therapy, was well tolerated, and warrants further investigation. Clinical Trial Information: NCT02688712.

Efficacy and safety of laparoscopic radical resection following neoadjuvant therapy for pancreatic ductal adenocarcinoma: A retrospective study.

BACKGROUNDMultiple studies have demonstrated that neoadjuvant chemotherapy (NACT) can prolong the overall survival of pancreatic ductal adenocarcinoma (PDAC) patients. However, most studies have focused on open surgery following NACT.AIMTo investigate the efficacy and safety of laparoscopic radical resection following NACT for PDAC.METHODSWe retrospectively analyzed the clinical data of 15 patients with pathologically confirmed PDAC who received NACT followed by laparoscopic radical surgery in our hospital from December 2019 to April 2022. All patients underwent abdominal contrast-enhanced computed tomography (CT) and positron emission tomography-CT before surgery to accurately assess tumor stage and exclude distant metastasis.RESULTSAll 15 patients with pancreatic cancer were successfully converted to surgical resection after NACT, including 8 patients with pancreatic head cancer and 7 patients with pancreatic body and tail cancer. Among them, 13 patients received the nab-paclitaxel plus gemcitabine regimen (gemcitabine 1000 mg/m2 plus nab-paclitaxel 125 mg/m2 on days 1, 8, and 15 every 4 wk) and 2 patients received the modified FOLFIRINOX regimen (intravenous oxaliplatin 68 mg/m2, irinotecan 135 mg/m2, and leucovorin 400 mg/m2 on day 1 and fluorouracil 400 mg/m2 on day 1, followed by 46-h continuous infusion of fluorouracil 2400 mg/m2). After each treatment cycle, abdominal CT, tumor markers, and circulating tumor cell counts were reviewed to evaluate the treatment efficacy. All 15 patients achieved partial remission. The surgical procedures included laparoscopic pancreaticoduodenectomy (LPD, n = 8) and laparoscopic radical antegrade modular pancreatosplenectomy (L-RAMPS, n = 7). None of them were converted to a laparotomy. One patient with pancreatic head carcinoma was found to have portal vein involvement during the operation, and LPD combined with vascular resection and reconstruction was performed. The amount of blood loss and operation times of L-RAMPS vs LPD were 435.71 ± 32.37 mL vs 343.75 ± 145.01 mL and 272.52 ± 49.14 min vs 444.38 ± 68.63 min, respectively. The number of dissected lymph nodes was 16.87 ± 4.10, and 3 patients had positive lymph nodes. One patient developed grade B postoperative pancreatic fistula (POPF) after L-RAMPS, and one patient experienced jaundice after LPD. None of the patients died after surgery. As of April 2022, progressive disease was noted in 4 patients, 2 patients had liver metastasis, and one had both liver metastasis and lymph node metastasis and died during the follow-up period.CONCLUSIONLaparoscopic radical resection of PDAC after NACT is safe and effective if it is performed by a surgeon with rich experience in LPD and in a large center of pancreatic surgery.

433P Pre-treatment and post-treatment MRI extramural venous invasion, predicts disease-free survival and overall survival, in locally advanced rectal cancer

Presence of extramural venous invasion (EMVI) by magnetic resonance imaging (MRI) is an independent poor prognostic factor in locally advanced rectal cancer (LARC). Nevertheless, the efficacy of both pre-neoadjuvant therapy (NAT) and post-NAT MRI EMVI assessment to predict pathological response and long-term benefit (in terms of disease-free survival (DFS) and overall survival (OS) has not been clearly established. We analyzed 239 patients with LARC receiving NAT with continuous infusion fluorouracil (n=229) or capecitabine (n=10) diagnosed between 2009 and 2019. Baseline and post-NAT MRI EMVI status was assessed in 214 and 173 patients respectively by two radiologists with more than 20-year and 5-year experience. When discrepancies, EMVI status was decided by consensus. Post-surgical pathologic assessment detached good-responders (ypT0N0 and ypT1-2N0) from poor-responders (ypT3Nx or ypTxN1/2). Three-year DFS and 5-year OS were estimated using Kaplan-Meier product-limit method. Baseline EMVI positive (91/214; 42%) was significantly associated with poor pathological response (74/91; 81%) vs. EMVI negative (52/123; 43%), p=0.0001. In the subset of patients evaluated with pre and post MRI, 69/173 (40%) presented positive EMVI at baseline. 21/69 (30%) patients with positive baseline EMVI became negative after therapy (EMVI (+/-)). Three-year DFS was 80.9% in EMVI (-/-), 66.7% in EMVI (+/-), and 45.2% in EMVI (+/+), HR 1.84 (95% CI 1.38-2.44), p=0.000026. Five-year OS was 82.6%, 73.9% and 57.3%, respectively, with HR 1.67 (95% CI 1.26-2.23), p=0.0004. Baseline EMVI accurately predicted pathological efficacy after conventional NAT. Patients that negativized EMVI (+/-) showed significantly better DFS and OS compared to patients that remained positive EMVI (+/+).

5-Fluorouracil combined with cisplatin via arterial induction for advanced T-stage nasopharyngeal carcinoma: A 10-year outcome of a phase I/II study.

Background and PurposeCurrently, there is no optimal dose recommendation for a 120-h continuous infusion of 5-fluorouracil via arterial cannulation for advanced T-stage nasopharyngeal carcinoma (NPC). Thus, the aim of this study was to determine the maximum tolerated dose (MDT), along with the efficacy, late adverse events, and 10-year survival outcome of 5-fluorouracil administered continuously for 120 h combined with cisplatin via the superficial temporal artery in patients with advanced T-stage NPC.Materials and MethodsFifty-one patients with histologically confirmed advanced T-stage NPC were eligible for inclusion in this clinical trial. The patients received induction chemotherapy consisting of cisplatin (20 mg/m2/d for 1–5 d) and 5-fluorouracil, administered continuously for 120 h at different dose gradients via a superficial temporal artery. To identify the MTD of 5-fluorouracil infused arterially, we employed a 3 + 3 design during study phase I. The initial dose administered was 200 mg/m2/d, which then was gradually escalated by 50 mg/m2/d until the MTD was reached. Following two cycles of induction chemotherapy, current radical chemoradiotherapy commenced. We assessed the efficacy, survival, toxicity, and quality of life of patients following treatment.ResultsThe overall response (complete response + partial response) rates following induction chemotherapy in the primary mass and lymph nodes were 100% and 100%, respectively. All 51 (100%) patients achieved T-category down-staging after intra-arterial chemotherapy. The MTD was 450 mg/m2/d for 120 h. No late neurological toxicities, such as brain stem injury, temporal lobe necrosis, and spinal cord injury, were observed. The 5- and 10-year overall survival (OS) rates were 78.0% and 71.7%, respectively, with a median OS of 131 months.ConclusionContinuous infusion of 5-fluorouracil combined with cisplatin via the superficial temporal artery showed promising survival benefits and few toxicities in patients with advanced T-stage NPC.

Effect of concomitant use of G-CSF and myelosuppressive chemotherapy on bone marrow and peripheral granulocytes in a mouse model.

Granulocyte-colony stimulating factor (G-CSF) stimulates bone marrow progenitor cell proliferation and enhances neutrophil production. Exogenous G-CSF administration is indicated for chemotherapy-induced neutropenia management. However, there is a paucity of basic research examining the effects of the concomitant use of G-CSF and chemotherapy on myeloid cells in vivo. Whether concomitant G-CSF and chemotherapy adversely affect myeloid cell proliferation have not been determined. Herein, we examined the effects of the concomitant use of pegfilgrastim and 5-fluorouracil on myeloid cells and peripheral blood cells in mouse models. Balb/c mice were treated intraperitoneally with 5-fluorouracil (20μg/g b.w.) or a vehicle as a control for 5days, and pegfilgrastim was administered subcutaneously at 1μg/g b.w. on day 3. As a result, we demonstrated that the concomitant use of pegfilgrastim suppressed the 5-fluorouracil-induced decrease of granulocytic cells in both bone marrow and peripheral blood in mice. To assess the clinical efficacy of early administration of pegfilgrastim during docetaxel, cisplatin, and 5-fluorouracil therapy in patients with esophageal cancer, we retrospectively identified 42 consecutive patients treated with this regimen. The incidence of both febrile neutropenia and grade 4 neutropenia was significantly lower in patients who received pegfilgrastim than in those who did not receive it (P = 0.002 and P = 0.002, respectively). These results suggest that the concomitant use of pegfilgrastim and chemotherapy, consisting of continuous infusions of 5-fluorouracil, improved chemotherapy-induced neutropenia without detrimental effects on proliferating myeloid granulocytic cells.

A phase II trial of TGFβ type I receptor inhibitor, galunisertib, plus neoadjuvant chemoradiation in patients with locally advanced rectal cancer.

3617 Background: Transforming growth factor beta (TGFβ) is an immunosuppressive cytokine upregulated in colorectal cancer. Preclinical data demonstrated improved response to chemoradiation with TGFβ blockade in colorectal adenocarcinoma. Here we report the results of our single arm Phase II study combining the TGFβ type I receptor kinase inhibitor, galunisertib, with neoadjuvant chemoradiation in patients with locally advanced rectal adenocarcinoma. Methods: Eligible patients had T3+ or N+ rectal adenocarcinoma planned for surgical resection. Enrolled patients completed a 14-day course of galunisertib, followed by chemoradiation with continuous infusion 5-fluorouracil or capecitabine with radiation to 50.4-54Gy in 28-30 fractions. On day 30, patients underwent another 14-day course of galunisertib concurrent with ongoing chemoradiation. Five to nine weeks after completing neoadjuvant therapy, patients underwent response assessment. Those with complete response by physical exam, proctoscopy, and MRI, could opt for non-operative management and proceed to mFOLFOX6. Those with less than a complete response underwent surgical resection. The primary endpoint was complete response rate (CR), which was a composite of pathologic complete responses in those patients who proceeded to surgery, and clinical complete responses maintained at 1 year after completion of therapy for those who chose non-operative management. Using a Simon Two-Stage approach with 90% power and α = 0.05, to detect a 20% improvement in complete response rate compared to historical control (15% vs 35%); we reject the null hypothesis if ≥10/38 patients have a CR. 38 patients were enrolled with 35 patients evaluable. Results: Median age was 51y, 68% of patients were male, 87% of patients were Stage III, 97% of patients were node-positive, and 97% were proficient in mismatch repair. 95% of patients completed study therapy. Toxicity attributed to galunisertib was Grade 1-2. 28 patients went to surgery, with a mean neoadjuvant rectal (NAR) score (NAR = 5pN-3(cT-pT)+12]2/9.61) of 11.29, and pCR in 7 patients. 7 patients underwent non-operative management, with 5 achieving cCR at 1 year. Therefore, complete responses were observed in 12 patients. Peripheral immune monitoring revealed percent change in CD3+CD4-CXCR3+ T cells and activated CD8EM T cells correlated with response to therapy. 2y PFS and OS were 81.5% and 97%. Conclusions: The addition of TGFβ inhibition to neoadjuvant chemoradiation in locally advanced rectal cancer markedly improved response to therapy, was well tolerated, and warrants further investigation. Clinical trial information: NCT02688712.

G-CSF-induced carotid inflammation.

A 58-year-old woman with newly diagnosed metastatic duodenal adenocarcinoma presented at the emergency department of Brigham and Women's Hospital (Boston, MA, USA) in June, 2021, with worsening right-sided neck and jaw pain and difficulty swallowing. 9 days beforehand, the patient had started chemotherapy with FOLFOXIRI (fluorouracil continuous infusion 1600 mg/m2/day for 46 h, folinic acid 200 mg/m2, irinotecan 165 mg/m2, and oxaliplatin 85 mg/m2) and bevacizumab (5 mg/kg). 7 days prior to presentation, the patient was given pegfilgrastim (pegylated granulocyte colony-stimulating factor [G-CSF], 6 mg) for primary prevention of chemotherapy-induced neutropenia.

Evaluation of the Effect of Combination Chemotherapy with Five-day Infusion of Fluorouracil Plus Vinorelbine in Pretreated Metastatic Breast Cancer Patients

Abstract Background continuous infusion (CI) of 5-fluorouracil (5-FU) has proven in several studies to be an active and well tolerated treatment for advanced pretreated breast cancer. Navelbine has also shown activity in this setting. Aim This is retrospective study to evaluate the clinical activity and side effects of a combination chemotherapy consisting of a five-day continuous infusion of fluorouracil and i.v. vinorelbine in metastatic previously treated breast cancer patients. Patients and Methods Fifty-four patients received 5FU 600 mg/m2/d for 5 consecutive days as a continuous infusion and vinorelbine 25 mg/m2 on days 1 and 5 as a short intravenous (I/V) infusion every 3 weeks. Results Eleven (20.4%) complete responses, 20 (37%) partial responses and 14 (25.9%) stationary disease were documented, accounting for a clinical benefit rate of 83.3%. The median progression free survival was 6.8 months. The median overall survival was 25.8 months. Treatment was well tolerated, with Grade 3 anemia, febrile neutrobenia and stomatitis in 9.3%, 5.6% and 1.9% respectively as the main toxic reactions. Conclusions: This drug combination is active in metastatic previously treated breast cancer patients with acceptable toxicity profile.

The "Chinese Expert Consensus on the Clinical Application of the Chinese Modified Triplet Combination with Irinotecan (CPT-11), Oxaliplatin (LOHP), Continuous Infusion 5-Fluorouracil, and Leucovorin for Colorectal Cancer".

Colorectal cancer is the second most common malignant tumor in China. The FOLFOXIRI regimen, which combines 5-fluorouracil/leucovorin, oxaliplatin, and irinotecan, is a high-intensity and highly effective chemotherapy regimen. However, the original regimen is poorly tolerated in Chinese patients. In order to promote the standardization and rational application of FOLFOXIRI regimen by clinicians in China, the “Chinese Expert Consensus on the Clinical Application of the Chinese Modified Triplet Combination with Irinotecan (CPT-11), Oxaliplatin (LOHP), Continuous Infusion 5-Fluorouracil, and Leucovorin for Colorectal Cancer” was formulated by the Committee of Colorectal Cancer in Chinese Southwest Oncology Group. Based on the mechanism underlying the combined three drugs and toxicity profile, the dosage of Chinese modified FOLFOXIRI (cmFOLFOXIRI) regimen and the management of adverse reactions are proposed. This consensus recommended that the FOLFOXIRI regimen be used in neoadjuvant, conversion, and palliative therapy for colorectal cancer under specific conditions. This consensus aimed to drive the application of cmFOLFOXIRI in the field of colorectal cancer in order to bring benefits to colorectal cancer patients.

Usefulness of a novel transarterial chemoinfusion plus external-beam radiation therapy for advanced hepatocellular carcinoma with tumor thrombi in the inferior vena cava and right atrium: Case study.

BackgroundInvasion beyond inferior vena cava (IVC) to right atrium (RA) is a rare complication in patients with advanced hepatocellular carcinoma (HCC), and results in fatal oncologic emergencies, including pulmonary embolism and right heart failure.AimAs there is no gold standard treatment for unresectable HCC with tumor thrombi involving IVC and RA, we considered it valuable to assess safety and efficacy of a combination of hepatic arterial infusion chemoembolization (HAIC) therapy and external‐beam radiation therapy (EBRT).Methods and resultsThe “New FP” was chosen as the HAIC therapy, in which the enhanced permeation and retention effect was achieved using a cisplatin‐Lipiodol suspension combined with continuous infusion of 5‐fluorouracil (5‐FU). Sixteen patients with HCC with tumor thrombi in IVC, RA, and pulmonary arteries were enrolled. modified response evaluation criteria in solid tumors‐based evaluation of response to the combination treatment was as follows: complete response, 6.2% (1 patient); partial response, 81.3% (13 patients); stable disease, 12.5% (2 patients); progressive disease, 0%. The median overall survival time (MST) was 19.0 months. Notably, MST of patients receiving sequential sorafenib monotherapy (39.0 months) was significantly longer than that of the rest (15.3 months).ConclusionThe combination of New FP and EBRT is an efficacious treatment option for unresectable HCC involving IVC and RA, complicated with pulmonary embolism. Sequential administration of molecular‐targeted drugs may prolong survival in such patients.

Comparison of irinotecan and oxaliplatin as the first-line therapies for metastatic colorectal cancer: a meta-analysis

BackgroundIrinotecan (IRI) and oxaliplatin (Ox) are standard therapeutic agents of the first-line treatments for metastatic colorectal cancer (mCRC). Previous meta-analyses of randomized controlled trials (RCTs) showed that treatment with Ox-based compared with IRI-based regimens was associated with better overall survival (OS). However, these reports did not include trials of molecular targeting agents and did not take methods for the administration of concomitant drugs, such as bolus or continuous infusion of 5-fluorouracil, into account. A systematic literature review was performed to compare the efficacy and toxicity profiles between IRI- and Ox-based regimens as the first-line treatments for mCRC.MethodsThis meta-analysis used data from the Cochrane Central Register of Controlled Trials, PubMed, and SCOPUS. The primary endpoint was OS, and the secondary endpoints were progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs).ResultsNineteen trials involving 4571 patients were included in the analysis. No statistically significant difference was observed between the two groups in terms of OS, PFS, and ORR. There was no significant heterogeneity. Regarding ≥ grade 3 AEs, IRI-based regimens were associated with a high incidence of leukopenia, febrile neutropenia, and diarrhea. Moreover, there was a high incidence of thrombocytopenia and peripheral sensory neuropathy in patients who received Ox-based regimens. In a subgroup analysis, IRI combined with bevacizumab was correlated with a better PFS (HR = 0.90, 95% CI = 0.82–0.98, P = 0.02), but not with OS (pooled HR = 0.91, 95% CI = 0.80–1.03, P = 0.15).ConclusionAlthough the safety profiles of IRI- and Ox-based regimens varied, their efficacy did not significantly differ. The combination of anti-VEGF antibody and IRI was associated with better PFS compared with anti-VEGF antibody and Ox. Both regimens could be used as the first-line treatments for mCRC with consideration of the patients’ condition or toxicity profiles.

Pembrolizumab plus chemotherapy for previously untreated, HER2-negative unresectable or metastatic advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: KEYNOTE-859.

TPS263 Background: For patients with unresectable, locally advanced recurrent or metastatic G/GEJ cancer, the standard of care includes a fluoropyrimidine plus a platinum-based agent as first-line therapy. The PD-1 inhibitor pembrolizumab has demonstrated durable antitumor activity in this patient population across lines of therapy. Herein, we describe the randomized, double-blind, phase 3 KEYNOTE-859 trial (NCT03675737) of first-line pembrolizumab plus chemotherapy in patients with advanced G/GEJ adenocarcinoma. Methods: Patients with histologically or cytologically confirmed, locally advanced unresectable or metastatic G/GEJ adenocarcinoma with known PD-L1 expression status, HER2-negative disease, measurable disease per RECIST v1.1, and ECOG performance status of 0 or 1 will be randomly assigned 1:1 to receive pembrolizumab plus chemotherapy or placebo plus chemotherapy. Randomization will be stratified by geographic region (Europe/Israel/North America/Australia vs Asia vs rest of world), PD-L1 tumor expression status (combined positive score &lt; 1 vs ≥1), and combination chemotherapy (FP vs CAPOX). Pembrolizumab or placebo will be administered at 200 mg IV every 3 weeks (Q3W). The chemotherapy regimen will be investigator’s choice of FP (continuous infusion of 5-fluorouracil [800 mg/m2/day on days 1-5 of each cycle] plus IV cisplatin [80 mg/m2] Q3W) or CAPOX (oral capecitabine [1000 mg/m2 twice daily on days 1-14 of each cycle] plus IV oxaliplatin [130 mg/m2 on day 1 of each cycle] Q3W). Duration of cisplatin or oxaliplatin may be capped at 6 cycles per local country guidelines; treatment with 5-fluorouracil or capecitabine may continue per protocol. Treatment with pembrolizumab or placebo will continue for ≤35 administrations (~2 years) or until disease progression, unacceptable toxicity, intercurrent illness that prevents further administration of treatment, investigator decision, or noncompliance. Imaging will be performed at screening and subsequently every 6 weeks until disease progression, start of new anticancer treatment, withdrawal of consent, or death. Adverse events will be monitored throughout the study from the time of randomization to 30 days after the last dose of study treatment (90 days for serious adverse events). The dual primary end points are OS and PFS per RECIST v1.1 as assessed by blinded independent central review (BICR). Secondary end points include ORR and DOR per RECIST v1.1 as assessed by BICR, safety, and tolerability. Enrollment is ongoing. Clinical trial information: NCT03675737.

Efficacy and safety of modified FOLFIRINOX as salvage therapy for patients with refractory advanced biliary tract cancer: a retrospective study.

Background Gemcitabine plus cisplatin is regarded as the standard first-line therapy for patients with advanced biliary tract cancer (BTC); however, no standard chemotherapy has yet been recommended after treatment failure. Modified FOLFIRINOX (mFOLFIRINOX) appears to be a better-tolerated regimen, which leads to improved survival in metastatic pancreatic cancer that has histological and molecular similarities with BTC. We assessed the efficacy and safety of mFOLFIRINOX as salvage therapy in advanced BTC patients who were refractory to previous chemotherapy. Methods A total of 15 consecutive patients with documented unresectable locally advanced or metastatic BCT who received the mFOLFIRINOX regimen were included in the study. Patients were intravenously administrated with oxaliplatin (65mg/m2), leucovorin (400mg/m2), irinotecan (150mg/m2), and continuous infusion of fluorouracil (2400mg/m2) over 46h. The objective response rates (ORR), disease control rates (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were recorded. Results At least three cycles of mFOLFIRINOX regimen were delivered to 15 patients with a median number of 6.0cycles (IQR 5.5-11.0). The median duration of treatment was 3.8months (IQR 2.9-8.5). Four patients (26.7%) achieved an ORR, and 12 patients (80.0%) had a DCR. The median PFS and OS were 6.7months (95%CI 2.3-11.1) and 13.2months (95%CI 7.3-19.1), respectively. Five patients (33.3%) had treatment-related grade 3/4 AEs. The most common grade 3/4 AE was neutropenia (n = 3, 20.0%), while there was no occurrence of febrile neutropenia. Conclusion Treatment with mFOLFIRINOX has promising efficacy and favorable tolerance as salvage therapy in patients with refractory advanced BCT.

CORONARY VASOSPASM ASSOCIATED WITH 5-FLUOROURACIL CHEMOTHERAPY

SESSION TITLE: Medical Student/Resident Cardiovascular Disease Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: 5-Fluorouracil (5FU) is the third most commonly used chemotherapeutic agent in the treatment of solid malignancies, particularly colorectal and pancreatic neoplasms. (1,2) Coronary vasospasm associated with 5FU is a known complication. (3) Cardiotoxicity occurs in 1% to 18% of patients receiving 5FU, and the incidence of this complication is on the rise.(4) The objective of this report is to highlight the characteristics of this uncommon complication. CASE PRESENTATION: A 66-year-old male with a past medical history of coronary artery disease status-post 4-vessel coronary artery bypass graft surgery and stage 4 colon adenocarcinoma with metastasis to the liver, presented to the emergency department (ED) with complaints of sudden onset of burning deep sub-sternal chest pain with no radiation. The chest pain began approximately eight hours after his first round of 5FU, leuocorin and eloxatin (FOLFOX) chemotherapy. In the ED he was given aspirin and heparin. EKG was concerning for ST-segment elevation myocardial infarction in the inferior leads. Troponins were negative (<0.01). A subsequent left heart catheterization revealed patent grafts and normal coronary arteries. An echocardiogram showed no acute wall motion abnormalities and an ejection fraction of 65%. The 5FU was discontinued and the patient’s chest pain improved. He was discharged with sublingual nitroglycerin and diltiazem. Two weeks later, the patient returned with similar chest pain after his second cycle with 5FU, leuocorin and eloxatin (FOLFOX). The symptoms of his coronary artery vasospasm were believed to be due to 5FU chemotherapy. He was further instructed to go to the cardiovascular ICU to receive nitroglycerine infusions before each cycle of FOLFOX. Unfortunately, the patient expired two months after starting chemotherapy; from cardiopulmonary arrest secondary to sepsis. DISCUSSION: This is a case of a 66-year-old male with a past medical history of coronary artery disease and stage 4 colon adenocarcinoma on 5-Fluorouracil, leuocorin and eloxatin (FOLFOX) chemotherapy presenting for coronary vasospasm likely from 5-Fluorouracil. Cardiotoxicity related to 5FU is poorly understood. Leading theories of the mechanism of 5FU-induced coronary vasospasm seem to involve 5FU's modification of smooth muscle tone. (5,6) Patients on 5FU with coronary vasospasm may have ECG findings suggestive of occlusion, (3) similar to our patient. Treatment of affected patients is determined by confirmation of 5FU as the definitive cause of the coronary vasospasm, as well as the requirement of 5FU as the only suitable chemotherapeutic agent. If possible, care providers should consider switching to an acceptable chemotherapeutic substitute. CONCLUSIONS: In conclusion, consideration should be given for patients with coronary artery disease starting 5-Fluorouracil chemotherapy. Reference #1: 1. Grem JL. 5-Fluorouracil: forty-plus and still ticking. A review of its preclinical and clinical development. Invest New Drugs 2000; 18: 299-313. 2. Myers CE. The pharmacology of the fluoropyrimidines. Pharmacol Rev 1981; 33: 1-15. 3. de Forni M, Malet-Martino MC, Jailais P, et al. Cardiotoxicity of high-dose continuous infusion fluorouracil: a prospective clinical study. Clin Oncol 1992; 10: 1795-1801. 4. Lestuzzi C, Vaccher E, Talamini R, et al. Effort myocardial ischemia during chemotherapy with 5-fluorouracil: an underestimated risk. Ann Oncol 2014; 25: 1059-1064. 5. Bonetti PO, Lerman LO and Lerman A. Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler Throb Vasc Biol 2003, 23: 168-175. 6. Reddy KG, Nair RN, Sheehan HM, et al. Evidence that selective endothelial dysfunction may occur in the absence of angiographic or ultrasound atherosclerosis in patients with risk factors for artherosclerosis. I Am Coll Cardio! 1994; 23: 833-843. DISCLOSURES: No relevant relationships by Ahmad ababneh, source=Web Response No relevant relationships by HANAD BASHIR, source=Web Response No relevant relationships by Ahmad JABRI, source=Web Response No relevant relationships by Gauranga Mahalwar, source=Web Response