Folinic Acid, 5-fluorouracil, Irinotecan Research Articles

Evaluation of Stages, Treatment Protocols, and Outcomes of Colorectal Cancer among West Bank Patients.

Background: Colorectal cancer (CRC) is the second most widespread cancer among Palestinian patients. As cancer care improves in hospitals across the West Bank, services like palliative care, targeted therapy, bone marrow transplantation, and individualized therapy are still limited. This study aimed to assess the CRC stages, treatment protocols, and survival rates of patients in the West Bank. Methodology: This retrospective study collected data from the medical records of Al-Najah University Hospital (NUH), which specializes in the care of cancer patients. Patients with confirmed CRC (stages I-IV) undergoing surgical or medical treatment were included in the study. Data collection was standardized by using a data collection form to gather information from the medical records included in the study. All statistical analyses were performed using SPSS (version v27), and survival was assessed using a regression analysis of the number of days from the time of diagnosis to the most recent visit against the type of treatment (e.g., surgery, chemotherapy, radiotherapy). Results: A sample of 252 patients with CRC from NUH was collected, including 143 males and 109 females aged between 27 and 86 years, with the average age being 60.6 ± 11.4 years. The sample included 183 patients (72.6%) diagnosed with colon cancer only, 29 patients (11.5%) diagnosed with rectal cancer only, and 40 patients (15.9%) diagnosed with both. Diagnosis took place at CRC stage I for 3 patients (1.2%), stage II for 33 patients (13.1%), stage III for 57 patients (22.6%), and stage IV for 159 patients (63.1%). Surgery was the most prevailing mode of treatment for 230 patients (91.3%), while 227 patients (90.1%) received chemotherapy treatment, and 38 patients (15.1%) received radiotherapy. Of the 252 patients, 40 patients (15.8%) received FOLFOX (i.e., folinic acid, fluorouracil, oxaliplatin), and 25 patients (9.9%) received FOLFIRI (i.e., folinic acid, fluorouracil, irinotecan), while the 187 remaining patients (74.2%) were treated with capecitabine, oxaliplatin, bevacizumab, cetuximab, regorafenib, cisplatin, etoposide, gemcitabine, or a combination thereof. The sample was categorized into six outcomes: (1) death, (2) cure, (3) disease progression, (4) disease recurrence, (5) under-treatment, and (6) unknown. Mortality was high, with 104 patients (41.3%) dying within a short time after diagnosis, and may have been attributable to delayed diagnosis. Surgical treatment had a positive impact on increasing the survival years, and it was significant (p = 0.033). Conclusions: A high percentage of patients were diagnosed in advanced CRC stages. The treatment modes were adopted from general international guidelines; however, the cure rates were low, and mortality was high. More studies need to be undertaken to investigate the actual application of chemotherapy protocols, and survival would benefit from the involvement of clinical pharmacists in the chemotherapy protocol selection, dosing, frequency, and follow-up. The present study advocates for greater public awareness of CRC and attests to the merits of screening by primary care professionals, which can help to avoid this serious illness and to promote a better prognosis.

LM02 trial Perioperative treatment with panitumumab and FOLFIRI in patients with wild-type RAS, potentially resectable colorectal cancer liver metastases-a phase II study.

Twenty percent of colorectal cancer liver metastases (CLMs) are initially resectable with a 5-year survival rate of 25%-40%. Perioperative folinic acid, 5-fluorouracil, oxaliplatin (FOLFOX) increases progression-free survival (PFS). In advanced disease, the addition of targeting therapies results in an overall survival (OS) advantage. The aim of this study was to evaluate panitumumab and FOLFIRI as perioperative therapy in resectable CLM. Patients with previously untreated, wild-type Rat sarcoma virus (RAS), and resectable CLM were included. Preoperative four and postoperative eight cycles of panitumumab and folinic acid, 5-fluorouracil, irinotecan (FOLFIRI) were administered. Primary objectives were efficacy and safety. Secondary endpoints included PFS and OS. We enrolled 36 patients in seven centers in Austria (intention-to-treat analyses, 35 patients). There were 28 men and seven women, and the median age was 66 years. About 91.4% completed preoperative therapy and 82.9% underwent liver resection. The R0 resection rate was 82.7%. Twenty patients started and 12 patients completed postoperative chemotherapy. The objective radiological response rate after preoperative therapy was 65.7%. About 20% and 5.7% of patients had stable disease and progressive disease, respectively. The most common grade 3 adverse events were diarrhea, rash, and leukopenia during preoperative therapy. One patient died because of sepsis, and one had a pulmonary embolism grade 4. After surgery, two patients died because of hepatic failure. Most common grade 3 adverse events during postoperative therapy were skin toxicities/rash and leukopenia/neutropenia, and the two grade 4 adverse events were stroke and intestinal obstruction. Median PFS was 13.2 months. The OS rate at 12 and 24 months were 85.6% and 73.3%, respectively. Panitumumab and FOLFIRI as perioperative therapy for resectable CLM result in a radiological objective response rate in 65.7% of patients with a manageable grade 3 diarrhea rate of 14.3%. Median PFS was 13.2 months, and the 24-month OS rate was 73.3%. These data are insufficient to widen the indication of panitumumab from the unresectable setting to the setting of resectable CLM.

Tumor Vascular Microenvironment of Colorectal Hepatic Metastasis and Chemotherapy Response.

The tumor vascular microenvironment has an important role in tumor progression and metastasis. The objective of this study was to assess the significance of metastatic hepatic tumor vascular microenvironment in relation to the response to systemic fluorouracil-based chemotherapy [folinic acid/fluorouracil/oxaliplatin (FOLFOX) or folinic acid/fluorouracil/irinotecan (FOLFIRI)]. A total of 48 consecutive patients with colorectal cancer (CRC) with hepatic metastasis were retrospectively reviewed, and factors such as metastatic tumor vascular microenvironment, chemotherapy response and hepatic resection, were analyzed. Tumor angiogenesis was microscopically evaluated by microvessel density (MVD) in sections stained immunochemically with antibody to CD34 in patients with hepatic resection. Angiogenesis in the tumor microenvironment in association with ring enhancement (RE) on computed tomography (CT) was also examined. Microscopic examination revealed that peripheral RE on CT of the metastatic tumor was associated with tumor angiogenesis by MVD. The overall response rate after six courses of first-line chemotherapy for liver metastasis with RE on CT was 64% (23/36), whereas the response rate for those without RE was 25% (3/12), which was significantly lower, although the survival of patients with RE-positive and RE-negative tumors did not differ significantly. Peripheral RE of metastatic hepatic tumor on CT was associated with angiogenesis in the tumor microenvironment and higher chemotherapy response.

Primary colon adenocarcinoma with choriocarcinoma differentiation: a case report and review of the literature

BackgroundChoriocarcinoma is an aggressive malignancy of trophoblastic tissue, typically of gestational etiology. Sporadic, nongestational cases are rarely found outside of the gonads. There are only 31 cases of primary choriocarcinoma of the colon reported in the literature. As a consequence of their rarity and aggressive nature, timely diagnosis and effective treatment have proved challenging, and prognosis is very poor. For that reason, we present a rare case with prolonged survival in the youngest reported patient .Case presentationA 26-year-old Caucasian woman presented with abdominal cramping and rectal and vaginal bleeding. Elevated serum human chorionic gonadotropin and an 8-cm right-sided mass seen on ultrasound suggested ectopic pregnancy. The patient was treated with methotrexate; however, her symptoms persisted, and her human chorionic gonadotropin levels continued to rise. Further workup showed a large mass of the sigmoid colon with multiple hepatic lesions suggestive of metastases. Preliminary pathology showed adenocarcinoma. Despite surgical resection and initiation of FOLFOX chemotherapy (folinic acid, fluorouracil, oxaliplatin), the patient had significant clinical deterioration, and her human chorionic gonadotropin increased exponentially. Further pathological review showed two distinct phenotypes: adenocarcinoma merging with choriocarcinoma. The result of evaluation of the metastatic lesions was also positive for choriocarcinoma. Treatment was promptly changed to a choriocarcinoma-targeting chemotherapy regimen of EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine), resulting in rapid and dramatic response. The patient had mild progression after 1 year and was switched back to FOLFOX with bevacizumab. After five cycles, scans showed further progression, and the patient was started on third-line therapy with FOLFIRI (folinic acid, fluorouracil, irinotecan) and bevacizumab. Eighteen months after her diagnosis, the patient was alive and maintaining an overall response.ConclusionsOur patient achieved a marked response and prolonged survival. Although a comprehensive review of the literature showed that survival with these tumors has improved over the past 10 years, prognosis remains poor. Currently, there is no established algorithm for the management of these rare tumors, but both the literature and our patient’s case indicate that a choriocarcinoma-targeted regimen is critical for survival. Further evaluation of these rare tumors is warranted in order to identify pathological patterns that may help in the diagnosis, management, and survival of these malignancies.

Adjuvant Therapy for High-Risk Stage II or III Colon Adenocarcinoma: A Propensity Score-Matched, Nationwide, Population-Based Cohort Study.

Purpose: To determine the optimal adjuvant chemotherapy regimen for patients with high-risk stage II or III colon adenocarcinoma, we conducted this propensity score-matched, nationwide, population-based cohort study to estimate the effects of adjuvant treatments in high-risk stage II or III colon adenocarcinoma. Patients and Methods: Using propensity score matching, we minimized the confounding effects of sex, age, pathologic stage, tumor location, total chemotherapy cycles, and Charlson comorbidity index scores on adjuvant treatment outcomes in patients with high-risk stage II or III resectable colon adenocarcinoma. We selected the patients from the Taiwan Cancer Registry database and divided them into four groups: Group 1, comprising patients who received surgery alone; group 2, comprising those who received adjuvant fluoropyrimidine alone; group 3, comprising those who received adjuvant oxaliplatin-fluoropyrimidine-leucovorin (FOLFOX); and group 4, comprising those who received adjuvant folinic acid-fluorouracil-irinotecan (FOLFIRI). Results: In both univariate and multivariate Cox regression analyses, the adjusted hazard ratios (aHRs, as well as the 95% confidence intervals (Cis)) for mortality observed for groups 1, 2, and 4 relative to group 3 were 1.55 (1.32 to 1.82), 1.22 (1.05 to 1.43), and 2.97 (2.43 to 3.63), respectively. After a stratified subgroup analysis for high-risk stage II colon adenocarcinoma, we noted that the aHR (95% CI) for mortality for group 2 relative to group 3 was 0.52 (0.30 to 0.89). Conclusions: Adjuvant fluoropyrimidine alone is the most optimal regimen for patients with high-risk stage II colon adenocarcinoma compared with the other adjuvant chemotherapy regimens. Adjuvant FOLFOX can serve as an optimal regimen for patients with pathologic stage III colon adenocarcinoma, regardless of age, sex, or tumor location.

Tumor-associated Macrophages and Neuroendocrine Differentiation Decrease the Efficacy of Bevacizumab Plus Chemotherapy in Patients With Advanced Colorectal Cancer

BackgroundIn the present study, we investigated the prognostic and predictive role of neuroendocrine differentiation (NED) and tumor-associated macrophage (TAM) infiltration in tumor tissue from patients with advanced colorectal cancer who had received bevacizumab plus chemotherapy. Patients and MethodsA total of 123 consecutive patients with advanced colorectal cancer who had received bevacizumab plus irinotecan/oxaliplatin-based combination chemotherapy were included in the present study. In addition to the clinicopathologic parameters, the presence of NED and the level of TAM infiltration were studied as covariates for survival analysis. ResultsThe median patient age was 57 years (range, 30-76 years). The chemotherapy backbone was FOLFIRI (folinic acid, 5-fluorouracil, irinotecan) for 75% of the patients. Univariate analysis showed that only NED and TAM infiltration were significant predictive factors for progression-free survival. Left-sided tumors and low TAM infiltration were favorable factors for overall survival on univariate analysis. However, the TAM level was the only independent prognostic factor for overall survival (hazard ratio, 0.301; 95% confidence interval, 0.102-0.892). ConclusionOur results suggest that increased TAM infiltration in tumor tissue and NED could decrease the efficacy of bevacizumab plus combination chemotherapy in patients with advanced colorectal cancer. TAM infiltration in the tumor tissue could be used as a biomarker in patients with advanced colorectal cancer receiving bevacizumab plus chemotherapy.

Aflibercept Plus FOLFIRI in the Real-life Setting: Safety and Quality of Life Data From the Italian Patient Cohort of the Aflibercept Safety and Quality-of-Life Program Study

BackgroundAflibercept combined with FOLFIRI (folinic acid, 5-fluorouracil, irinotecan) as second-line treatment of metastatic colorectal cancer (mCRC) significantly improved survival compared with FOLFIRI alone in the pivotal VELOUR (aflibercept vs. placebo in combination with irinotecan and 5-fluorouracil in the treatment of patients with metastatic colorectal cancer after failure of an oxaliplatin-based regimen) trial. No quality-of-life assessment was performed in VELOUR; therefore, the ASQoP (Aflibercept Safety and Quality-of-Life Program) trial was designed to capture the safety and health-related quality of life (HRQL). Patients and MethodsASQoP was an international, open-label, single-arm trial evaluating the safety and HRQL of aflibercept combined with FOLFIRI administered in a real-life setting to 781 patients with mCRC, pretreated with an oxaliplatin-based regimen with or without bevacizumab. The Italian subset of ASQoP enrolled 200 patients from 28 institutions. The primary endpoint was safety; HRQL was a secondary endpoint, assessed by validated questionnaires (European quality of life 5-dimension instrument 3-level; European Organization for Research and Treatment for Cancer Quality of Life Questionnaire Core 30, version 3; and EORTC-CR29) at baseline, during treatment, and at the end of treatment. ResultsThe median age of the Italian ASQoP population was 63 years; the median number of aflibercept and FOLFIRI cycles was 7. Treatment-emergent adverse events were reported in 97.5% of patients. Hypertension (28.5%), neutropenia (27.5%; from laboratory data), asthenic conditions (20.0%), diarrhea (17.0%), and stomatitis (13.0%) were the most frequent (incidence, ≥ 5%) grade 3/4 toxicities. One toxic death occurred during the study period due to sepsis, without neutropenic complications. No significant worsening of HRQL was shown during treatment. ConclusionAflibercept combined with FOLFIRI was well tolerated when administered as second-line treatment for patients with mCRC in a real-life setting. It did not affect HRQL and showed similar rates of treatment-emergent adverse events as those observed in the VELOUR trial. No new safety signals were identified.

Network meta-analysis of the efficacy of first-line chemotherapy regimens in patients with advanced colorectal cancer.

This network meta-analysis compared the short-term and long-term efficacies of first-line chemotherapy regimens in patients with advanced colorectal cancer (CRC). The 10 regimens included folinic acid + 5-fluorouracil + oxaliplatin (FOLFOX), folinic acid + 5-fluorouracil + irinotecan (FOLFIRI), folinic acid + 5-fluorouracil + gemcitabine (FFG), folinic acid + 5-fluorouracil + trimetrexate (FFT), folinic acid + 5-fluorouracil (FF), irinotecan + oxaliplatin (IROX), raltitrexed + oxaliplatin (TOMOX), folinic acid + tegafur-uracil (FTU), raltitrexed, and capecitabine. Electronic searches were performed in the Cochrane Library, PubMed and Embase databases from inception to June 2017. Network meta-analysis combined direct and indirect evidence to obtain odds ratios (ORs) and surface under the cumulative ranking curves (SUCRA) of different chemotherapy regimens for advanced CRC. Fourteen randomized controlled trails (RCTs) covering 4,383 patients with advanced CRC were included. The results revealed that FOLFOX, FOLFIRI, IROX, and TOMOX all showed higher overall response rates (ORRs) than FF or raltitrexed. Compared with raltitrexed, the aforementioned four regimens also had higher 1-year progression-free survival (PFS) rates. In addition, FOLFOX and FOLFIRI exhibited higher disease control rates (DCRs) and 1-year PFS rates than FF or raltitrexed. Cluster analysis revealed that FOLFOX, FOLFIRI, and TOMOX had better short-term and long-term efficacies. These findings suggest FOLFOX, FOLFIRI, and TOMOX are superior to other regimens for advanced CRC. These three regimens are therefore recommended for clinical treatment of advanced CRC.

Randomized phase II study of 2nd-line FOLFIRI versus modified FOLFIRI with PARP inhibitor ABT-888 (veliparib) (NSC-737664) in metastatic pancreatic cancer (mPC): SWOG S1513.

TPS4147 Background: PC is characterized by multiple DNA repair defects, including in BRCA1/ 2, and other homologous recombination (HR) genes such as FANC, ATM, ATR (Waddell N, Nature 2015). Folinic acid/5-fluorouracil/ irinotecan (FOLFIRI) is a 2nd line therapy option in mPC, but overall survival (OS) averages only 6 mos (Yoo C, Br J Cancer 2009). It is known that PARP facilitates repair from topoisomerase 1-associated DNA damage, and that preclinically PARP inhibitors (PARPi) increase DNA breaks from camptothecins, resulting in synergistic antitumor effects (Smith LM, Clin Cancer Res 2005, Davidson D, Invest New Drugs 2013). PARPi are active in mPC harboring BRCA1/2 mutations. Given the preclinical synergism between ABT-888 with irinotecan, and the safety and preliminary efficacy noted in a phase I trial (Berlin J, J Clin Oncol 2014; abstr 2574), we designed a randomized phase II study of mFOLFIRI /ABT-888 vs FOLFIRI alone for 2nd line mPC patients (pts). Blood and tumor samples are collected at baseline to retrospectively analyze biomarkers related to DNA repair capacity, including the HRD assay and BROCA-HR, a targeted multi-gene sequencing to detect alterations within the Fanconi Anemia-BRCA (HR), non-homologous end joining (NHEJ), and DNA mismatch repair pathways, and correlate with efficacy. Methods: Phase II study in 143 pts randomized (1:1) to mFOLFIRI/ABT-888 or FOLFIRI. For optimal PARP inhibition, ABT-888 is dosed Days (D) 1-7 and mFOLFIRI (no 5-FU bolus) D3-5 in 14D-cycles. In the control arm, FOLFIRI is dosed D1-3 in 14D-cycles. Primary endpoint: compare OS between treatment arms; secondary endpoints: safety, progression-free survival, response rates; translational: correlate germline/somatic BRCA1/2 mutations, and other DNA repair biomarkers with efficacy in each arm. Standard eligibility criteria apply. Assuming that the addition of ABT-888 will increase OS from 6 to 9 mos, 128 eligible pts (143 pts total) are required, based on a one-sided type 1 error of 10%, and 80% power. Kaplan-Meier methodology will be used to estimate median OS for each treatment arm. This study is open to accrual (NCT02890355). Clinical trial information: NCT02890355.

Posterior Reversible Encephalopathy Syndrome (PRES) in a Patient with Metastatic Gastric Cancer While Receiving FOLFIRI Chemotherapy: A Case Report

Introduction: Gastric cancer is one of the most common cancers worldwide. Approximately 50 percent of patients have a metastatic disease at presentation. In these situations, the goals of therapy include palliation of symptoms and prolongation of survival with either local methods or systemic therapies. FOLFIRI (Folinic acid, Fluorouracil, Irinotecan) is a chemotherapy protocol that has been used in gastrointestinal malignancies. Neurological symptoms are not unexpected in patients with cancers receiving chemotherapy, however the development posterior reversible encephalopathy syndrome (PRES) in such patients without significant elevation of blood pressure is extremely rare and only documented in few cases. Case report: A 28-years-old female, known to have benign essential hypertension, and metastatic gastric cancer to the peritoneum. She was admitted with abdominal pain associated with vomiting for one week. CT scan of the abdomen was suggestive of partial intestinal obstruction presumed to be due to her cancer. The decision was to continue bowel rest and IV hydration, and then to start palliative chemotherapy (FOLFIRI). The patient received the first cycle, followed by the second cycle after 2 weeks. During that time, her nausea and vomiting had worsened after a transient improvement, requiring multiple antiemetics. On day 2 of her second cycle, she had 3 generalized tonic seizures with up rolling of the eyes and stool incontinence. Brain MRI with contrast showed multiple bilateral cortical and subcortical T-2 hyper intense lesions in the parietal and occipital lobes, as well as the cerebellar hemisphere. The image was negative for ischemic changes, surrounding edema, intracranial hemorrhage, space occupying lesion, or midline shift. These finding were consistent with posterior reversible encephalopathy syndrome. No significant elevation of blood pressure was noted. Subsequently, the patient developed acute respiratory failure associated with cardiogenic and septic shock. She was transferred to the intensive care unit and died after few days of her transfer. Conclusion: Here, we describe a rare case of PRES developed in a patient with gastric cancer while receiving FOLFIRI chemotherapy. PRES is a clinical radiographic syndrome of heterogeneous etiologies that have similar findings on neuroimaging studies. Whether it's related only to chemotherapy or combined effect of gastric cancer and chemotherapy is unknown. It requires further studies.Figure 1

Liver toxicity in colorectal cancer patients treated with first-line FOLFIRI-containing regimen: a single institution experience

Background: Chemotherapy-induced toxic liver injury is a relevant issue in the clinical management of patients affected with metastatic colorectal cancer (mCRC). This retrospective study evaluated patterns of liver toxicity in patients treated with FOLinic acid, Fluorouracil, IRInotecan (FOLFIRI)-based regimens. Methods: One hundred and fifty-six mCRC patients treated at the University Campus Bio-Medico between January 2003 and January 2013 were included in this retrospective analysis. All patients received a FOLFIRI backbone-based chemotherapy. Basal liver enzymes levels were assessed before starting the treatment and before every therapy course. R ratio and the aspartate aminotransferase/alanine aminotransferase ratio were calculated. Results: Ninety-one patients were male versus 55 female, and the median age of the population was 62 years (range: 38–83). Most patients had liver involvement at the beginning of first-line regimen (101 patients, 64.74%) and 59 patients had received a previous 5-FU based therapy in the adjuvant setting (37.82%). Aspartate aminotransferase level (167.87 vs 41.05 U/l; p < 0.001), Alanine aminotransferase level (94.48 vs 39.80 U/l; p = 0.004) and alkaline phosphatase (289.0 vs 172.44 U/l; p = 0.02) were significantly increased during the first 3 months of treatment. In the entire population, the calculated R ratio was 3.96 (95% CI: 3.25–4.51). In all three regimens, the calculated R ratio was between 2 and 5, without any statistical differences. Conclusions: FOLFIRI-based hepatotoxicity has been indirectly defined as a mixed pattern injury in all three regimens evaluated.

Spontaneous rectovaginal fistula during bevacizumab therapy for colon cancer

Dear Editor: In October 2011, a 61-year-old female presented with a painless rectovaginal fistula. Nine years ago she underwent a right colectomy due to ascending colon cancer. Follow-up revealed hepatic metastasis treated initially with chemotherapy folinic acid–fluorouracil–irinotecan (FOLFIRI)/FOLFOX within a clinical assay followed by metastasectomy in June 2003. In September 2004 and due to a lung metastasis, treatment of FOLFIRI and cetuximab was started with partial response and being resected in March 2006. In July 2007, another lung lesion was diagnosed and again resected. In February 2008, she presented an unresectable systemic disease (lung and liver) starting bevacizumab plus FOLFIRI due to persistence of residual neurotoxicity. Partial disease control was gained after six courses and withdrew after 12 courses of chemotherapy. In March 2009, the disease again progressed and the same treatment was reintroduced with a partial disease control after other six courses. These courses were intermittently administered until October 2011. The reasons for this intermittent regime were twofold: due to drug-toxicity and on patient demand. After the last six courses of FOLFIRI and bevacizumab, she complained in October of 2011 of foulsmelling discharge from her vagina without other symptoms. At exploration she presented a low rectovaginal fistula with no evidence of local tumor in rectum and vagina. No history of trauma was related. A full thickness endoanal repair was performed in November after withdrawal of bevacizumab 4 weeks before. She denied a colostomy. Bevacizumab is the most common antiangiogenic agent used for treatment of metastatic colorectal cancer. Gastrointestinal or spontaneous bowel perforations and postoperative fistulae have been related to this drug. Rectovaginal fistulas have been associated with prior rectal cancer surgery. The double-stapling technique for rectal anastomosis and a partial vaginectomy increases the incidence of the disease. Radiation in rectal cancer is another source of rectovaginal fistula with a 0.3 to 6 % incidence. Gynecologic surgery in ovarian cancer treated with bevacizumab, especially if there is rectovaginal nodularity, seems to increase the risk of perforation or fistula formation and have been lately reported. A very recent study identified nine patients (4.1 %) out of 222, having six patients with rectal cancer, one with synchronous colorectal cancer, and two with colon cancer. Two thirds had anal fistulas and one third colovesicular fistulas. Cessation of bevacizumab led to fistula healing in six cases, but three required fecal diversion. In this paper, development of fistula appeared soon after initiation of bevacizumab. Spontaneous healing after bevacizumab withdrawal has been reported in other papers too. Therefore, the particular aspects of this case are: surgery of a right colon cancer 9 years ago and no radiotherapy; long history of systemic disease with intermittent courses of bevacizumab since 2008 until presentation of a spontaneous rectovaginal fistula. Timing of fistula development is more likely secondary to bevacizumab therapy although the appearance of a rectovaginal fistula is late. J. C. Bernal-Sprekelsen (*) : F. J. Landete : J. Lopez Hospital General de Requena, Requena, Valencia, Spain e-mail: jcbs94@gmail.com

Effects of sequential chemotherapy of FOLFIRI/FOLFOX on the endocrine axes of ACTH–cortisol and renin–angiotensin–aldosterone

The chemotherapies of FOLFOX (leucovorin+5-fluorouracil+oxaliplatin) and FOLFIRI (folinic acid+5-fluorouracil+irinotecan) are effective for a variety of malignant tumors. In particular, the sequential chemotherapy of FOLFOX/FOLFIRI has become the preferred post-operational treatment approach for gastrointestinal cancer and an important palliative care program for advanced cancer. However, the sequential chemotherapy of FOLFOX/FOLFIRI showed severe side effects due to the fact that the toxicity of the drugs can be enhanced by each other. Here, we report the dynamic changes in the activities of serum ACTH, cortisol, renin, angiotensin, and aldosterone in patients following multiple cycles of FOLFOX/FOLFIRI sequential chemotherapy. We found that the sequential chemotherapy might cause damage to the activities of the endocrine cells and/or the sympathetic nerve, and alter endocrine function, specifically the ACTH-cortisol and renin-angiotensin-aldosterone axes.

Randomised phase-II trial of CAPIRI (capecitabine, irinotecan) plus bevacizumab vs FOLFIRI (folinic acid, 5-fluorouracil, irinotecan) plus bevacizumab as first-line treatment of patients with unresectable/metastatic colorectal cancer (mCRC)

Background:To compare the efficacy and safety of CAPIRI+bevacizumab (Bev) in comparison with FOLFIRI+Bev as first-line treatment for patients with metastatic colorectal cancer (mCRC).Methods:Patients were randomised to receive either FOLFIRI plus Bev 5 mg kg−1 every 2 weeks (Arm-A) or CAPIRI plus Bev 7.5 mg kg−1 every 3 weeks (Arm-B).Results:Three hundred thirty-three patients (Arm-A=167; Arm-B=166) were enrolled into the study. No difference was observed in median progression-free survival (PFS) (10.0 and 8.9 months; P=0.64), overall survival (25.7 and 27.5 months; P=0.55) or response rates (45.5 and 39.8.7% P=0.32) for FOLFIRI-Bev and CAPIRI-Bev, respectively. Patients treated with CAPIRI-Bev presented significantly higher incidence of diarrhoea (P=0.005), febrile neutropenia (P=0.003) and hand–foot skin reactions (P=0.02) compared with patients treated with FOLFIRI-Bev. Treatment delays (P=0.05), dose reduction (P<0.001) and treatment discontinuation owing to toxicity (P=0.01) occurred more frequently in the CAPIRI-Bev arm.Conclusion:The PFS of FOLFIRI-BEV is not superior to that observed with the CAPIRI-Bev regimen. CAPIRI-Bev has a less favourable toxicity profile, requiring dose reductions, in order to be considered as an option in first-line treatment of patients with mCRC.

Incidence of delayed nausea and vomiting in patients with colorectal cancer receiving irinotecan-based chemotherapy

This study sought to prospectively determine the frequency of delayed nausea and vomiting with irinotecan-based chemotherapy following day 1 prophylaxis with a 5-HT3 receptor antagonist and dexamethasone. Patients with colorectal cancer aged ≥ 18 years with ECOG performance status ≤ 2 receiving irinotecan alone, combined with cetuximab or as part of a standard folinic acid, 5- fluorouracil, irinotecan (FOLFIRI) regimen for the first time were eligible. All patients received a 5-HT3 receptor antagonist and dexamethasone 8 mg on day 1 prior to irinotecan. No routine prophylaxis for delayed emesis was given. Antiemetic outcome was recorded in patient-completed diaries for the 120-h study period after irinotecan administration. Primary endpoint was frequency of delayed (24-120 h) emesis. Forty-four patients were enrolled, and all are evaluable. The median age was 61 (39-79) years; the male-female ratio was 37:7. Four patients (9%) experienced vomiting or retching during the delayed period. Three patients (7%) vomited during the first 24 h after irinotecan. The overall no emesis rate was 89% (39/44). Fifteen patients (34%) experienced delayed nausea (mildin 11 patients, moderate in four patients). Six patients (14%) took rescue antiemetics during the delayed period. Delayed and overall complete response (no emesis or use of rescue antiemetics) rates were 82% and 77% respectively. The use of a 5-HT3 antagonist and dexamethasone prior to irinotecan results in excellent control of nausea and vomiting (CR 86%) during the 24 h after chemotherapy. Without further antiemetic treatment, most patients (82%) will not experience delayed emesis or require rescue antiemetics. Routine prophylaxis for delayed emesis following irinotecan does not appear to be warranted.

An Open-label, Single-arm, Phase 2 Trial of Panitumumab Plus FOLFIRI as Second-line Therapy in Patients with Metastatic Colorectal Cancer

This prospective analysis evaluated the effect of tumor KRAS status on efficacy of second-line panitumumab plus folinic acid/5-fluorouracil/irinotecan (FOLFIRI). This phase 2, open-label, single-arm study enrolled patients with unresectable, measurable metastatic colorectal cancer (mCRC) after failure of first-line treatment with oxaliplatin-based chemotherapy plus bevacizumab. Patients received panitumumab 6 mg/kg plus FOLFIRI every 2 weeks until disease progression or intolerability. Tumor assessments per Response Evaluation Criteria in Solid Tumors (RECIST) were performed by the investigators every 8 weeks from weeks 8-32 and every 12 weeks thereafter. KRAS status was determined by real-time polymerase chain reaction (PCR) on DNA extracted from fixed tumor sections. Efficacy endpoints included objective response rate, progression-free survival (PFS), and overall survival (OS). Safety endpoints included incidence of adverse events (AEs). Endpoints were evaluated by tumor KRAS status. Of 116 patients enrolled, 109 patients with known tumor KRAS status received treatment; 59% had wild-type KRAS, and 41% had mutant KRAS. Fifteen patients (23%) with wild-type KRAS and 7 patients (16%) with mutant KRAS had a complete or partial response to treatment. Median PFS was 26 weeks (95% CI, 19-33 weeks) and 19 weeks (95% CI, 12-25 weeks) in the wild-type KRAS and mutant KRAS strata, respectively. Median OS was 50 weeks (95% CI, 39-76 weeks) and 31 weeks (95% CI, 23-47 weeks) in wild-type KRAS and mutant KRAS strata, respectively. Skin-related toxicities (86% of all patients) and diarrhea (74%) were the most common AEs. Panitumumab plus FOLFIRI numerically improved objective response rate, PFS, and OS in favor of patients with wild-type KRAS tumors. The safety profile was consistent with panitumumab plus FOLFIRI trials in similar patient populations.

Folinic acid, 5-fluorouracil, irinotecan (FOLFIRI) plus chemoradiation (CRT) with 5-fluorouracil (5FU) as adjuvant treatment for patients with operable gastric cancer (OGC): A feasibility study with pharmacogenetic analysis.

44 Background: To evaluate the efficacy and safety of FOLFIRI plus CRT with 5FU as adjuvant treatment for patients with OGC. Methods: Patients received treatment with FOLFIRI (irinotrecan 150 mg/m2, d1, LV 200 mg/m2, d1+2 and 5FU [400 mg/m2/d bolus and 600 mg/m2/d, 22 h infusion, d1+2]) for 2 15-day cycles followed by RT (45Gy) with 5FU continuous infusion (325 mg/m2/d in the 1st and 5th week) administration. Eight additional cycles of FOLFIRI were administered after the completion of CRT. BRCA1, ERCC1, XPD, TOPO-I, TOPO-IIA and B and TS mRNA expression was determined in the primary tumor where available. Results: The median age of the 171 enrolled patients was 62 years, 114 (66%) were males, 136 (79%) had R0 resections and 152 (89%) had at least a D1 resection. Treatment was completed as per protocol in 107 (63%) of the patients. CRT was completed in all but 5 (3%) patients. The median rate of drug exposure was 93% for irinotecan, 87% for 5FU and 91% for LV. The most common grade 3/4 adverse events were neutropenia (32%), febrile neutropenia (3.5%) and diarrhea (7%). After a median follow-up of 45.7 months 84 had relapsed and 70 were deceased. The median disease-free survival (DFS) was 30 months (95% CI: 18-41 months), while the projected median overall survival (mOS) was 53.7 months (95% CI: 30-77 months). The recurrence free probability at 5 years was 44% while the probability of survival at 5 years was 46%. From the studied pharmacogenetic markers only TS low expression was correlated with a trend towards improved DFS and OS in patients with R0 resections. Conclusions: These results show that the administration of FOLFIRI plus CRT with 5FU as adjuvant treatment in OGC is a feasible approach with acceptable toxicity and challenging efficacy which merits further evaluation in a randomized trial. No significant financial relationships to disclose.

Ｉｎ ｖｉｔｒｏ実験系によるＦＯＬＦＩＲＩ療法およびｍＦＯＬＦＯＸ ６療法レジメンの有効性およびＥＧＦＲ発現変動の評価

Recently,the number of patients with colorectal cancer has been increasing.Many patients are not aware of any symptoms until the disease is advanced.It is important to select effective regimens for colorectal cancer therapy and combination therapy with a molecular-targeted agent has recently been used for this purpose.However,the effects of anticancer drugs on epidermal growth factor receptor (EGFR),a molecular-targeted protein,have not been clarified.We therefore evaluated the effects of folinic acid/5-fluorouracil/irinotecan (FOLFIRI) and folinic acid/5-fluorouracil/oxaliplatin (mFOLFOX citation=6)treatments,using the 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2 H-tetrazolium bromide (MTT) assay,as well as the effects of these treatments on EGFR expression in LoVo cells.The results suggested that 5-fluorouracil and irinotecan have a stronger antiproliferative effect than oxaliplatin.The reduction in viability for LoVo cells treated with FOLFIRI was greater than that for Lovo cells treated with mFOLFOX 6 on day 22.Moreover,EGFR mRNA and protein levels were increased more by mFOLFOX 6 than by FOLFIRI.These results suggest that FOLFIRI therapy may be more effective than mFOLFOX 6 therapy against LoVo cells in consideration of EGFR expression.

Cost-minimization analysis of sequence changes between FOLFIRI and FOLFOX6 therapy for advanced colorectal cancer in Japan

Background: Randomized, controlled trials (RCTs) in 220 patients with advanced colorectal cancer reported no significant differences in survival periods between folinic acid/5-fluorouracil/irinotecan (FOLFIRI) and folinic acid/5-fluorouracil/oxaliplatin (FOLFOX6) therapies, irrespective of the treatment sequence. Based on a literature search, an economic assessment of both treatments given in 1 of 2 sequences (FOLFIRI and FOLFOX6, or FOLFOX6 and FOLFIRI) has not been conducted in Japan. Objective: The present cost-minimization analysis used a mathematical Markov model to assess health care costs of these 2 treatment sequences from the perspective of National Health Insurance (NHI) in Japan. Methods: The analysis simulated the expected costs resulting from the influence of treatment sequence in a hypothetical cohort of 10,000 patients with nonresectable advanced colorectal cancer over a period of 100 months using a hypothetical Markov model. Clinical parameters were obtained from the RCTs. Cost parameters included those for physical examination, medication, and personnel. Medication and physical examination costs were based on 2008 NHI drug prices and medical service fees, respectively. Costs were discounted at a monthly rate of 0.4575% (equivalent to an annual rate of 3%). The influence of each parameter (clinical and cost parameters) was assessed using a probabilistic sensitivity analysis by the 10,000-time Monte Carlo simulation. Results: When FOLFIRI was used as the initial treatment in this analysis, costs to the NHI were reduced. On analysis of the influence of each parameter, the expected reduction in costs, compared with FOLFOX administered as the initial treatment, was significant (¥7,787,828 [95% CI, ¥6,098,517-¥9,499,952]). Conclusions: The findings of this cost-minimization analysis suggest that using FOLFIRI followed by FOLFOX versus the reverse strategy produced cost savings from the perspective of the NHI in Japan. However, differences in adverse-events profiles may warrant treatment adjustments in individual patients.

CAPIRI (capecitabine, irinotecan) + bevacizumab vs FOLFIRI (folinic acid, 5 fluorouracil, irinotecan) + bevacizumab for the treatment of patients with metastatic colorectal cancer (mCRC): Interim analysis for safety of a randomized phase III trial

15008 Background: CAPIRI has been reported to be associated with significant toxicity. Therefore, an unplanned interim analysis for safety of a randomized trial evaluating CAPIRI + Bevacizumab vs FOLFIRI + Bevacizumab regimens for the treatment of mCRC was performed. Methods: Assuming time to tumor progression (TTP) of 7.5 months for Arm B and 5.5 months for Arm B, 280 patients should be enrolled in the study (two-tailed log-rank test; a=0.05, b=0.8).Patients were randomized to receive either (Arm A) CPT-11 (250 mg/m2, d1) and Capecitabine (2,000 mg/m2, d1–14) every 3 weeks (Arm A) or CPT-11 (180 mg/m2, d1), LV (200 mg/m2, d1+2) and 5-FU (400 mg/m2/d bolus and 600 mg/m2/d, 22h infusion, d1+2) every 2 weeks (Arm B). Results: Among the 156 enrolled patients (Arm A = 74; Arm B = 82), were evaluable for toxicity (administered cycles: 1061). Treatment delays were observed in 4% and 2% Arm A and B patients, respectively (p=0.09). Dose reduction was required in 9.5% and 4.5% Arm A and B patients, respectively (p=0.002). Treatment discontinuation due to treatment related toxicity occurred in 13% and 4.5% Arm A and B patients, respectively. Sixty days mortality rate was low in both arms (Arm A: 1.5%, Arm B: 1.2%). There was no difference between the two regimens in terms of objective response rate, TTP and OS (n = 142 patients). Conclusions: These preliminary results show that CAPIRI + Bevacizumab regimen could safely administered in patients with mCRC. No significant financial relationships to disclose.